The ZRT Laboratory Blog

New Frontiers in Neurotransmitter Lab Assessment: Everything You Need to Know About the Expanded NeuroAdvanced Profile

Fri, 23 Apr 2021 10:30:24 -0700

Mental health is on all our minds, now more than ever! The acuteness of stress in everyday life, even before the start of the pandemic, brought out the necessity to reshape how we understand and approach mental health. At the very core, the previously ingrained notion that mental health (or lack thereof) is solely a brain-only problem ought to be dispelled [1].

Don’t get me wrong, the brain is truly magnificent in its complexity, orchestrating the delicate interplay between the body and the mind. All the sensory information—anything the body senses, feels, hears, smells, touches, or ingests—this plethora of inputs engages the brain to interpret and stimulate our feelings, thoughts, reactions, and behavior. The brain is a powerful master controller, the seat of memory, intelligence, and a myriad of cognitive processes; it is the true source of all the things that define our humanness. However, viewing it separate from the rest of the body is inherently limiting, especially in the context of mental health, as this approach desensitizes us to the influences of our lifestyle, environment, genetics, and prior health history [2].

After all, the brain and the body are interconnected in the most marvelous and elaborate ways that rely on the rich bi-directional communication network to allow the individual to thrive. And when one of the system’s components falls out of sync with the other, that delicate balance is lost, supporting favorable conditions for disease to plant its roots. Conceptually, this interconnectedness is not a novel paradigm, but rather an attempt to rationalize and explain disorders pertaining to brain, and therefore mental health from the systems biology angle.

Urinary Neurotransmitter Testing

The neurotransmitter test provides a framework for understanding the connection of our body’s physical health to our brain’s well-being. In a nutshell, it is an effective advanced screening tool designed to gather information about the levels of specific neurotransmitters, amino acid precursors, and metabolites originating in various organs throughout the body. These molecules convey messages to the brain either directly by crossing the blood-brain barrier (BBB), indirectly via the nerves of the enteric nervous system, or the vagus nerve itself [3]. The levels of these molecules, determined by the neurotransmitter test (too low, too high, or just right, i.e., within range), are as individual as each individual patient, reflective of that person’s own ecosystem (genes + lifestyle + environment).

Discovering the detailed interplay between neurotransmitters and perhaps other endocrine signaling molecules, has helped fortify our understanding of how biological function in the body influences brain health. The results of the test provide a biochemical basis that helps explain mental health-related symptoms the patient is suffering from and enable the practitioner to move forward with creating a highly individualized therapeutic intervention, usually based on a combination of lifestyle and dietary changes that include personalized nutritional intervention strategies (e.g., methylation support, antioxidants, targeted amino acids, vitamins + minerals, adaptogens, etc.).

This test is a great example of how complementary medicine tackles the notion of “chemical imbalance” from something hypothetical, subjective, and rather elusive; to quantifiable, objective and, more importantly, therapeutically actionable.

Expanding the NeuroAdvanced Profile

During the past year, we have accelerated our efforts to combine our vast laboratory testing experience with current clinical literature findings to advance the current offerings in our Neurotransmitter test. The newly expanded profile now offers 11 additional analytes that complement the previous panel to offer an even more focused assessment of biological function of the brain and the body.

Taurine

One such new analyte that has prominently taken residence in ZRT’s Neurotransmitter test, is the sulfur-containing amino acid taurine. Taurine, simply put, is good for the brain and good for the heart [4, 5]. But it does so much more!

Think of taurine as a tiny superhero that does all kinds of cool things in the body:

promotes healthy gamma-aminobutyric acid (GABA) levels
increases nitric oxide
helps eliminate toxins
scavenges and neutralizes hypochlorous acid, a reactive species produced by neutrophils
prevents mitochondrial membrane permeability
protects neurons from excitotoxicity
restores fatty acid oxidation and therefore helps generate adenosine triphosphate, and more [6]!

This all means that taurine can help relieve anxiety, promote sleep, increase exercise performance, improve metabolism, and the list goes on. So exciting!

Although taurine can be synthesized in the body from cysteine, the de novo pathways may not always supply sufficient taurine for all its broad functions; therefore, taurine should be obtained from diet. Taurine is found in most meats and fish, and increasing intake of these foods may help restore normal taurine levels. Additionally, taurine supplementation is considered safe and can be tolerated up to 3 g taurine per day without adverse effects.

Tryptophan

Tryptophan, undeniably dubbed as the post-Thanksgiving dinner slumber-inducing molecule, serves as the precursor to serotonin and thus, melatonin—so it is important for mood, sleep, gut motility, and many other important processes in the body. Tryptophan originates in diet—high tryptophan foods include chocolate, meat, tofu, fish, beans, milk, nuts, seeds, oatmeal, and eggs. The recommended daily intake for tryptophan is 4 mg per kilogram of body weight or 1.8 mg per pound, and depending on diet, a person may or may not be getting enough tryptophan. It is important to get sufficient tryptophan specifically because tryptophan spills down two major biosynthetic pathways relevant to the inflammatory neuropsychiatric interface: the generation of the neurotransmitter serotonin as mentioned above, and the formation of kynurenine derivatives and therefore niacin (vitamin B3).

Tryptophan supplementation, however, comes with a caveat and must be approached with caution. In the presence of physiological events that trigger inflammation, high amounts of tryptophan can be directed down the kynurenine pathway and utilized to make excess of excitotoxic molecules (see the following section on kynurenines) [7].

Kynurenines

ZRT Laboratory is now offering testing for the family of tryptophan metabolites collectively termed kynurenines. While tryptophan is the precursor to serotonin and melatonin, upwards of 90% of all tryptophan is diverted down the kynurenine pathway, which is best recognized for its role in inflammatory and anti-inflammatory pathways associated with disease, neuroprotection and neurotoxicity [8]. Under normal physiological conditions, this pathway culminates in generating (niacin-derived) nicotinamide adenine dinucleotide (NAD), a molecule critical to providing the cell with a source of energy.

During inflammatory insults that increase with aging, however, the kynurenine pathway is upregulated—the enzymes tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) respond to immune activation by interferons, cytokines, and/or free radicals to generate higher levels of toxic kynurenine metabolites that are neurotoxic and related to brain diseases and mental health [9].

Neuroinflammation

Clinical science started to explore the relationship between inflammation and mental health fairly recently, and the results have been very compelling [10-13]! Sustained activation of the peripheral immune/inflammatory response (e.g., during chronic infections, autoimmune disease, or even cancer), bluntly speaking, is bad for the brain [14]. Vulnerable individuals, even without prior history of mental disorders, can develop mood pathologies as a consequence of being exposed to systemic inflammatory events [15]. Turns out, the brain is not so “immune-privileged” as previously regarded, and the immune-to-brain communication network ensures that. Prolonged inflammation events in the periphery can signal to the brain—either by having cytokines cross the BBB or circumvent the BBB all together—to eventually culminate in microglial activation in the brain, that then results in propagation of pro-inflammatory cytokines locally in the brain. So in a sense, the brain takes a “snapshot” of the peripheral immune response and replicates it with similar molecular components [16].

Connection to Kynurenines

The ins and outs of this mechanism for neuroinflammation-triggering-turbulent-changes-to-one’s-mood phenomenon remains largely uncharacterized, but several pathways have emerged as promising candidates for therapeutic intervention. One such pathway is the kynurenine pathway.

As mentioned above, increased kynurenine levels, in response to elevated TDO/IDO activity during systemic inflammation, lead to increased levels of downstream metabolites with neuroactive properties, both neuroprotective (kynurenic acid) and neurotoxic (3-Hydroxykynurenine or 3-OH Kynurenine). These compounds can inhibit (kynurenic acid) or activate (3-OH Kynurenine) N-methyl-d-aspartate (NMDA) glutamate receptors [17]. Neurotoxicity elicited by 3-OH Kynurenine appears to also be related to generation of oxidative stress produced by reactive radical species, formed as a result of autooxidation. 3-OH Kynurenine gives rise to neurotoxic metabolites, such as quinolinic acid, which also activate the NMDA receptor, induce lipid peroxidation, and promote oxidative stress [18]. 3-OH Kynurenine formed in the periphery and circulating in the bloodstream can easily cross the BBB to induce oxidative stress locally within the brain [19]. Moreover, concurrent serotonin biosynthesis is reduced due to less tryptophan availability—also a factor in compromising brain and consequently mental health [9].

Immune activation of the kynurenine pathway has been reported in anxiety [20], depressive [21], and other [22] brain disorders, including neurodegenerative diseases of aging [23-25].

Xanthurenic Acid

Xanthurenic acid is a metabolite of 3-Hydroxykynurenine that serves as an indirect marker of vitamin B6 status as vitamin B6 insufficiency leads to elevated levels of xanthurenic acid in urine [27]. This pathway is best tested as a loading test following tryptophan ingestion (2 g oral), which results in high xanthurenic acid under situations of vitamin B6 deficiency. If xanthurenic acid levels are elevated in the absence of tryptophan administration, vitamin B6 deficiency is considered to be significant.

Vitamin B6 deficiency that contributes to elevated xanthurenic acid levels can also increase oxidative stress in the body. The hydroxylated quinoline structure of xanthurenic acid can bind iron and increase DNA oxidative damage [28]. (It is fair to mention that other research studies report that when xanthurenic acid is complexed with iron, it can have antioxidant activity [29]. Therefore, it’s hard to say whether xanthurenic acid is definitively prooxidant or antioxidant, and probably depends on the redox state of the cell.) Nevertheless, elevated xanthurenic acid levels may suggest antioxidant insufficiency and ought to be addressed therapeutically.

Histidine & N-Methylhistamine

The original NeuroAdvanced profile offered testing for histamine, which proved to be useful in identifying patients with allergies. The newly expanded profile now includes histamine’s precursor, histidine, and metabolite, N-methylhistamine.

Histidine is a semi-essential amino acid that gives rise to the neurotransmitter histamine. Histidine protects neurons, assists with making new blood cells, reduces inflammation and oxidative stress, and helps with tissue repair and growth. Histidine also helps ameliorate fatigue, promotes clear thinking and concentration, reduces appetite, decreases anxiety, and improves sleep and glucose homeostasis. Dosages of histidine up to 4 g/day have shown no negative side effects and have been associated with general improvements. Meat, fish, eggs, soy, and beans are all high in histidine.

N-methylhistamine is a major metabolite of the neurotransmitter histamine, which prominently appears in studies involving gastrointestinal food allergies [30], irritable bowel disease [31], colitis, [32] and others.

Glutamine

Glutamine is an essential and the most abundant free amino acid in the human body. Glutamine provides fuel for rapidly dividing cells (lymphocytes, enterocytes, and epithelial cells of the intestines), helps balance ammonia levels in the body, improves immune system function, contributes to biosynthesis of proteins, amino acids, nucleic acids, and glutathione, and protects intestinal lining. Additionally, glutamine increases glutamate and GABA levels in the brain and in the body.

Although the body usually makes enough glutamine to meet all its needs, extreme stress (e.g., strenuous exercise, persistent stress, or injury) can increase the demand for glutamine beyond the amount naturally manufactured. Low glutamine levels are reported after intense exercise [33], in overtraining syndrome [34], diabetes [35], depression [36], autism spectrum disorder [37, 38], and are associated with high oxidative stress [39]. Research on high glutamine levels is scarce, however high-circulating have been reported to be associated with bipolar depression [40].

Tyrosine & Tyramine

Last, but not least, tyrosine and its metabolite tyramine are now nestled in the “excitatory neurotransmitter” section. Tyrosine is an amino acid obtained from diet (sesame seeds, cheese, soy, meat, nuts, and fish) or synthesized in the body from the amino acid phenylalanine.

Tyrosine gives rise to dopamine, norepinephrine and epinephrine—our favorite motivation/pleasure and stress molecules, thyroid hormones, and the trace amine tyramine. Tyramine is found naturally in food, specifically in aged, fermented, cured, or spoiled food where microbes with decarboxylase enzymes convert tyrosine to tyramine. These foods include aged cheeses, smoked fish, cured meats, some types of beer, red wine, and sherry. In sensitive individuals, high tyramine ingestion can trigger migraines [41]. If your face flushes and you get a splitting headache after ingesting these types of foods/drinks, it is probably your body’s reaction to tyramine. This is because tyramine has vasoactive properties and can increase blood pressure by hijacking sympathetic nerves and displacing norepinephrine.

Laboratory Testing for Neurotransmitters and Amino Acid Precursors

If your patients are suffering from mental health symptoms, and neurotransmitter/amino acid imbalances are suspect, you can get some insight into what might be causing the problems. Much of this information can be obtained from ZRT’s Urine Neurotransmitter Testing. Urine is by collected on a filter strip at home four times throughout the day from morning on awakening to just before bed. The neurotransmitter profile will tell you what neurotransmitters are “off” to help identify the root cause of dysfunction and help develop a suitable and personalized treatment plan that hopefully will help reinstate optimal health.

As your laboratory of choice, we are committed to cutting-edge, innovative, evidence-based testing! Discover a new way to approach mental health in your practice!

Related Sources

References

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An Individualized Plan for Managing ADHD: Laboratory Testing & Lifestyle Modifications to Provide Symptom Relief

Tue, 23 Feb 2021 09:05:47 -0800

Many children with Attention Deficit Hyperactivity Disorder (ADHD) struggle with fitting in and according to some experts, may receive as many as 20,000 negative messages by age 10 than their neurotypical peers. Little wonder then that many struggle with self-esteem and the belief that they are somehow broken. Being labeled as “different” – and this difference perceived as unacceptable to others – can impair an individual’s social development and actually exacerbate their struggles. One study found that children with ADHD whose families expressed high levels of criticism failed to experience the usual decline in symptoms with age, and maintained persistent, high levels of ADHD symptoms into their teenage years. Needless to say, ADHD is often discussed in the context of the problems it presents. It is time for a change that will allow the neurotypical world to make space for neurodiversity with the goal of creating greater well-being for individuals with ADHD and their families.

This blog will provide an overview of ADHD, referencing recent research studies published by experts on ADHD. For a much deeper dive into the etiology of the disorder, please refer to the recently published, World Federation of ADHD International Consensus Statement [1].

How Common is ADHD?

With a prevalence of 5.9%, ADHD is the most common neurodevelopmental disorder in children. Marked by inattention, hyperactivity and impulsivity, the neural mechanisms that underlie these hallmark symptoms vary dramatically from patient to patient, making ADHD a distinct challenge for parents, teachers and health care providers. Stimulant medications, used as first line of treatment, can provide valuable symptom relief for some patients; however, clinical response to specific therapeutic interventions in ADHD is highly individual. Some patients preferentially respond to either methylphenidate or amphetamine preparations, only tolerate non-stimulant therapy options, or achieve symptom remission only on a combination of stimulants and non-stimulants, patterns of which are currently not predictable [2 -8]. Some patients can also develop undesirable side effects during the course of treatment (e.g., sleep disturbances, appetite suppression, growth retardation, cardiovascular changes and/or exacerbation of existing tic disorders), which can compromise treatment adherence [1].

Heterogeneity of ADHD

Precisely what makes ADHD so difficult to understand is its heterogeneity, with various genetic and environmental factors likely contributing to the aberrant physiology of the disorder [1]. In other words, the reasons for why someone develops ADHD are as unique as each individual patient [9]. Moreover, to make matters even more complex, besides the classic symptoms described above, many children with ADHD suffer from emotional dysregulation symptoms, such as irritability, aggression, anger issues and negative emotions [10]. Often regarded as distracted, disorganized and disruptive, children with ADHD tend to have difficulty with self-regulation and delayed development of executive functioning skills, leaving many parents feeling lost as to how to create routine and a harmonious family life.

Furthermore, if the disorder persists into adulthood, which in many cases it does, if not well-managed, potential for negative consequences in academic achievement, employment performance and social relationships can present significant detriments to the quality of life for affected individuals.

ADHD Myths

There are many myths surrounding the disorder, many of which are dispelled in the World Federation of ADHD International Consensus Statement [1]. Some examples include:

Advantages of ADHD

ADHD can come with its own advantages. Yes, advantages! Of which there are many. The main one is the ability to “think outside the box.” Individuals with ADHD have a natural predisposition to creativity and innovation, refusing to be constrained by conformity. Pushing the boundaries of ordinary concepts in a non-linear fashion, people with ADHD may notice details that others disregard as distractions, and have an intermittent ability to be hyperfocused on their interests, paving the way to conceive cutting edge solutions to existing problems that stumped everyone else.

The Ultimate Goal is to Make Life Easier

The paradoxical nature of ADHD – the swings into super-focused mode during heart-pumping thrills of a quickly changing reality, and the paralyzing overwhelm over the mundane routine – can be very challenging in the day-to-day grind. When a child is easily under- and over-stimulated by the surrounding environment at the same time, parents often seek to ease hyperactivity, improve their child’s focus and balance emotional regulation. In other words, perhaps the ultimate goal in managing ADHD is to do it in such a way that life at home and at school becomes easier and more rewarding for children and their families, while at the same time working with the strengths and positive attributes that ADHD offers.

Diagnosis and Laboratory Testing for ADHD

The diagnostic standard for ADHD takes into account developmental history and symptom evaluation, based on behavior ratings provided by parents and teachers. Although there is no blood test for ADHD at this time, certain laboratory tests can help rule out other conditions that may closely resemble symptoms of ADHD, either mimicking the disorder or exacerbating it. Therefore, there is a real need to augment behavioral diagnostics with supplementary tools supporting a more thorough global clinical assessment.

Vitamin D, not surprisingly, is very important for brain health [11]. Lower maternal vitamin D levels during pregnancy were associated with an elevated risk for the child to develop ADHD [12]. Recent research demonstrates that adding vitamin D as adjunctive therapy to methylphenidate, can reduce ADHD symptoms without adverse effects [13].

The effect of vitamin D supplementation to improve inattentiveness, hyperactivity and behavior was significant but modest, probably because only one nutrient was supplemented. Optimal neurotransmission requires many different types of vitamins and minerals to serve as cofactors in the production of neurotransmitters, and various types of fatty acids to support neuronal membrane structure, with many other micronutrients working overtime in the background. Just keep in mind that even modest effects can all add up eventually to help improve the quality of life for a given individual.

Pushing the boundaries of ordinary concepts in a non-linear fashion, people with ADHD may notice details that others disregard as distractions, and have an intermittent ability to be hyperfocused on their interests, paving the way to conceive cutting-edge solutions to existing problems that stumped everyone else.

Ferritin - if iron is the readily available merchandise in the front of the store, ferritin is the warehouse in the back. Although no differences have been detected in children with and without ADHD in their iron levels, ferritin levels tend to run low in ADHD [14, 15].

Young bodies undergo tremendous amounts of growth. As the child grows, the body’s stores of iron are stretched to the limit, and unfortunately there is only so much it can absorb from food in one day. Preschoolers and adolescents often have low iron and/or ferritin stores, especially those with ADHD [16]. The last thing that the body will take iron from is blood cells, stealing iron from the liver and brain to make and maintain healthy red blood cells. So, with a low ferritin level, the brain is likely to be starving for this important metal [17].

Why is iron so important you may ask? Well, it is vital for a number of cellular processes including neurotransmitter synthesis (e.g., dopamine and serotonin), myelination of neurons and mitochondrial function [18]. So, does iron supplementation help with improving ADHD symptoms? You bet! After 12 weeks of supplementing ferrous sulfate (80 mg/day), the iron supplementation group showed enhanced attention and reduced hyperactivity and impulsivity [19, 20].

Thyroid hormones play a big role in brain development (hence mental health), even before the child is born. A large Danish cohort study showed that maternal hyperthyroidism during pregnancy (addressed after the birth of the child) was associated with increased risk of ADHD in the child [21]. Indeed, individuals with hyperthyroidism tend to have ADHD-like symptoms, such as anxiety, nervousness, irritability and physical hyperactivity [22].

Specific to thyroid dysfunction and its relationship to ADHD in a pediatric population, research shows that children with a diagnosis of hyperthyroidism have an ADHD prevalence ratio of 1.7 compared to children without hyperthyroidism. This means that if a child is diagnosed with hyperthyroidism, they may or may not simultaneously have ADHD, despite having symptoms that closely resemble ADHD. Without testing for thyroid function, it is impossible to tell whether the symptoms are attributed to innate ADHD or a dysfunctional thyroid system.

Even more notable, in 40% of cases, the mental health diagnosis preceded the diagnosis of hyperthyroidism by 90 days, with ADHD being diagnosed before hyperthyroidism in 68.3% of cases [23]. Let’s stop and think for a moment, because this is a really big deal! Treatments for hyperthyroidism and ADHD are very different. Treating hyperactivity due to hyperthyroidism with stimulant medications will not only not resolve the symptoms, but also may be harmful to the individual.

Nutritional elements like zinc have been reported to be low in urine [24] and in plasma [25] in children with ADHD. Low plasma zinc was reported to have a negative effect on information processing in children with ADHD [25]. Along these lines, some researchers also pay attention to copper levels, specifically presenting evidence that an elevated copper to zinc ratio may significantly contribute to the risk and severity of ADHD [26]. Magnesium was also reported to be low in children with ADHD compared to neurotypical controls [27, 28]. Magnesium deficiency has shown to be linked to fatigue, lack of concentration, nervousness, mood swings and aggression [29]. Some researchers argue that correcting magnesium homeostasis with supplementation may be key to reducing externalizing behaviors [30].

Heavy metals like lead and mercury are potent neurotoxins, meaning that they damage brain tissue, undoubtedly posing a significant threat to healthy brain development [31]. Newborns and young children are particularly vulnerable to the harmful effects of heavy metals with serious long-term ramifications. Even with mild exposure (there is no such thing as a safe level of exposure with heavy metals), children are at risk of developing emotional and behavioral problems, and reductions in IQ that persist into adulthood. Heavy metals typically target the prefrontal cortex area of the brain responsible for (hyper)activity, attention, learning and (anti-)social behavior. Children born to mothers with high mercury exposure during pregnancy, and/or high lead exposure postnatally had higher rates of ADHD, substantiating the fact that these heavy metals are shifting children’s behavior.

Heavy metals contributing to ADHD symptomatology is an example of how genetic, together with environmental factors, can come together to create “the perfect storm” for a neurodevelopmental disorder to establish its roots. A recent study showed that it is children with mutations in genes responsible for neuropsychological function, lead contributed to detriments in the executive function, such as inattention, impulsivity and processing speed [32].

Diet, Sleep & Exercise Considerations

Perhaps the ultimate goal in managing ADHD is to do it in such a way that life at home and at school becomes easier and more rewarding for children and their families, while at the same time working with the strengths and positive attributes that ADHD offers.

Diet is an important factor in managing ADHD. Dietary approaches to improving ADHD symptoms are beginning to emerge and gain traction in the clinical science community with multi-nutrient intervention studies [33, 34] and clinical trials (clinical trial identifier number NCT03252522).

Besides a multi-nutrient supplement, a diet full of healthy fats, healthy protein and complex carbohydrates may help balance blood sugar and help maintain stable mood and improve focus and concentration. In some instances an elimination diet may help reduce ADHD symptoms, especially if a food allergy is suspected [35]. Additionally, restricting synthetic food coloring may relieve some of the symptoms as well [36]. Small improvements in ADHD symptoms were also reported in studies using omega-3 supplementation [37 -39].

Sleep disturbances are reported in upwards of 70% of children with ADHD. Evaluating circadian rhythm abnormalities and correcting them with behavioral interventions and/or melatonin supplementation may be useful in helping achieve the sought-after relief with sleep problems [40]. Reducing screen time throughout the day and especially at bedtime also belongs in this subsection, because the blue light-emitting devices can interfere with melatonin production and likely exacerbate existing problems with sleep.

Lastly, exercise can help improve sympathetic tone and cognitive inhibition in ADHD, improve mood and tire out the little, but very active body. Team and group dynamics can be especially challenging for young people with ADHD, so it’s important to explore the activities they enjoy to find the right fit, often finding a fit in individual sports such as swimming, running, biking and martial arts.

In Conclusion

All the information presented above is intended to enrich the toolkit that health care providers and parents can use to supplement current doctor-recommended approaches to ADHD. Because ADHD is so heterogenous and varies greatly from patient to patient, not one single approach is expected to provide significant symptom relief, but rather to serve as a guide for things to try to see what brings the most symptom relief for a given individual and their family. Even if the improvements in symptoms are small with a specific intervention, the hope is that with a number of slight improvements, the added effect will help ease the burden of the disorder and help foster positive family and peer relationships, successes in the school and work environment, and the positive self-esteem that comes from exploring one’s strengths and interests.

ZRT Laboratory is here to help – samples for many of the tests mentioned above can be collected from finger stick blood collected on filter paper (dried blood spot or DBS). The advantage of collecting blood samples from a finger stick is autonomy for the patient (blood can be collected at home), minimal distress (small blood volumes), which is important in pediatric diagnostics, exceptional sample stability and minimal costs during the shipping of the sample. Talk to your doctor or contact us to help you find a health care provider 1.866.600.1636 info@zrtlab.com to order a test.

Related Resources

References

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McCarthy S, Neubert A, Man K, et al. Effects of long-term methylphenidate use on growth and blood pressure: results of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS). BMC Psychiatry. 2018;18(1):327.
Hennissen L, Bakker MJ, Banaschewski T, et al. Cardiovascular effects of stimulant and non-stimulant medication for children and adolescents with ADHD: a systematic review and meta-analysis of trials of methylphenidate, amphetamines and atomoxetine. CNS Drugs. 2017;31(3):199-215.
Storebø OJ, Ramsstad E, Krogh HB, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev. 2015;(11): CD009885.
Schelleman H, Bilker WB, Kimmel SE, et al. Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry. 2012;169(2):178-185.
Swanson JM, Arnold LE, Molina BSG, et al. Young adult outcomes in the follow-up of the multimodal treatment study of attention-deficit/hyperactivity disorder: symptom persistence, source discrepancy, and height suppression. J Child Psychol Psychiatry. 2017;58(6):663-678.
Corkum P, Davidson F, Macpherson M. A framework for the assessment and treatment of sleep problems in children with attention-deficit/hyperactivity disorder. Pediatr Clin North Am. 2011;58(3):667-683.
Hart AB, de Wit H, Palmer AA. Genetic factors modulating the response to stimulant drugs in humans. Curr Top Behav Neurosci. 2012;12:537-577.
Luo Y, Weibman D, Halperin JM, et al. A review of heterogeneity in attention deficit/hyperactivity disorder (ADHD). Front Hum Neurosci. 2019;13:42.
Nigg JT, Karalunas SL, Gustafsson HC, et al. Evaluating chronic emotional dysregulation and irritability in relation to ADHD and depression genetic risk in children with ADHD. J Child Psychol Psychiatry. 2020;61(2):205-214.
Arnold LE. Editorial: A special tree in the forest: from oak to acorn to oak. J Am Acad Child Adolesc Psychiatry. 2021;60(1):26-28.
Sucksdorff M, Brown AS, Chudal R, et al. Maternal vitamin D levels and the risk of offspring attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2021;60(1)142-151.e2.
Gan J, Galer P, Ma D , et al. The effect of vitamin D supplementation on attention-deficit/hyperactivity disorder: a systematic review and meta-analysis of randomized controlled trials. J Child Adolesc Psychopharmacol. 2019;29(9):670-687.
Wang Y, Huang L, Zhang L, et al. Iron status in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. PLoS One. 2017;12(1):e0169145.
Tseng PT, Cheng YS, Yen CF, et al. Peripheral iron levels in children with attention-deficit hyperactivity disorder: a systematic review and meta-analysis. Sci Rep. 2018;8(1):788.
Pivina L, Semenova Y, Dosa MD, et al. Iron deficiency, cognitive functions, and neurobehavioral disorders in children. J Mol Neurosci. 2019;68(1):1-10.
Cortese S, Azoulay R, Castellanos FX, et al. Brain iron levels in attention-deficit/hyperactivity disorder: a pilot MRI study. World J Biol Psychiatry. 2012;13(3):223-231.
Hare D, Ayton S, Bush A, et al. A delicate balance: Iron metabolism and diseases of the brain. Front Aging Neurosci. 2013;5(34).
Konofal E, Lecendreux M, Arnulf I, et al. Iron deficiency in children with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med. 2004;158(12):1113-1115.
Konofal E, Lecendreux M, Deron J, et al. Effects of iron supplementation on attention deficit hyperactivity disorder in children. Pediatr Neurol. 2008;38(1):20-26.
Andersen SL, Laurberg P, Wu CS, et al. Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study. BJOG. 2014;121(11):1365-1374.
Ahmed OM, El-Bakry AM, Abd El-Tawab SM, et al. Thyroid hormones states and brain development interactions. Int J Dev Neurosci. 2008;26(2):147-209.
Zader SJ, Williams E, Buryk MA. Mental health conditions and hyperthyroidism. Pediatrics. 2019;144(5):e20182874.
Arnold LE, Votolato NA, Kleykamp D, et al. Does hair zinc predict amphetamine improvement of ADD/hyperactivity? Int J Neurosci. 1990;50(1-2):103-107.
Yorbik O, Ozdag MF, Olgun A, et al. Potential effects of zinc on information processing in boys with attention deficit hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(3):662-667.
Skalny AV, Mazaletskaya AL, Ajsuvakova OP, et al. Serum zinc, copper, zinc-to-copper ratio, and other essential elements and minerals in children with attention deficit/hyperactivity disorder (ADHD). J Trace Elem Med Biol. 2020;58:126445.
Effatpanah M, Rezaei M, Effatpanah H, et al. Magnesium status and attention deficit hyperactivity disorder (ADHD): a meta-analysis. Psychiatry Res. 2019;274:228-234.
Huang YH, Zeng BY, Li DJ, et al. Significantly lower serum and hair magnesium levels in children with attention deficit hyperactivity disorder than controls: a systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2019;90:134-141.
Robberecht H, Verlaet AA, Breynaert A, et al. Magnesium, iron, zinc, copper and selenium status in attention-deficit/hyperactivity disorder (ADHD). Molecules. 2020;25(19):4440.
Black LJ, Allen KL, Jacoby P, et al. Low dietary intake of magnesium is associated with increased externalising behaviours in adolescents. Public Health Nutr. 2015;18(10):1824-1830.
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Choi JW, Jung AH, Nam S, et al. Interaction between lead and noradrenergic genotypes affects neurocognitive functions in attention-deficit/hyperactivity disorder: a case control study. BMC Psychiatry. 2020;20(1):407.
Rucklidge JJ, Eggleston MJF, Johnstone MJ, et al. Vitamin-mineral treatment improves aggression and emotional regulation in children with ADHD: a fully blinded, randomized, placebo-controlled trial. J Child Psychol Psychiatry. 2018: 59(3):232-246.
Gordon HA, Rucklidge JJ, Blampied NM, et al. Clinically significant symptom reduction in children with attention-deficit/hyperactivity disorder treated with micronutrients: an open-label reversal design study. J Child Adolesc Psychopharmacol. 2015: 25(10):783-798.
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Nigg JT, Lewis K, Edinger T, et al. Meta-analysis of attention-deficit/hyperactivity disorder or attention-deficit/hyperactivity disorder symptoms, restriction diet, and synthetic food color additives. J Am Acad Child Adolesc Psychiatry. 2012;51(1):86-97.e8.
Bloch MH, Qawasmi A. Omega-3 fatty acid supplementation for the treatment of children with attention-deficit/hyperactivity disorder symptomatology: systematic review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2011;50(10):991-1000.
Chang JP-C, Su KP, Mondelli V, et al. Omega-3 polyunsaturated fatty acids in youths with attention deficit hyperactivity disorder: a systematic review and meta-analysis of clinical trials and biological studies. Neuropsychopharmacology. 2018;43(3):534-545.
Hawkey E, Nigg JT. Omega-3 fatty acid and ADHD: blood level analysis and meta-analytic extension of supplementation trials. Clin Psychol Rev. 2014;34(6):496-505.
Esposito S, Laino D, D'Alonzo R, et al. Pediatric sleep disturbances and treatment with melatonin. J Transl Med. 2019;17(1):77.

Understanding a Broken Heart – The Physiology of Grief

Fri, 28 Aug 2020 10:58:51 -0700

Last weekend I went whitewater rafting. A particularly turbulent patch of the rapids caught me off guard, when I tumbled off the raft into the water. It all happened so quickly. We hit a big rock, the raft turned vertical and I fell into the river. I was swept under and spat back out, my body tossed around like a tiny paper boat. I was gasping for air with the whitewater waves rising in front of me, crashing over my face, flooding my nose, my mouth, choking me. All I could hear was water rushing past me – stubborn, relentless, ferocious. And loud. So deafeningly loud. Breathe, I told myself, breathe the tiny breaths in between the waves, feet forward, lean back, trust the lifejacket. Helpless, I surrendered to the current, all the while making futile attempts to grasp what had happened, only to feel vastly unprepared in a seemingly familiar landscape. Then I heard someone’s shouting voice, and the raft suddenly appeared just within reach. A strong pair of hands reached out and dragged me into the raft – safe again.

Events Outside our Control – Whether Rafting or being Bereaved

The experience of being swept by the river is emblematic to me of losing a loved one through death. The overwhelming sensation of being at a complete loss, flooded with sorrow, incapacitated with aching. Consciously breathing, but not sensing any oxygen. Feeling like a poisoned dart pierced my heart, spreading gnawing, dark and sticky pain to the extremities. I’ve been told that grief is like an emotional roller coaster – some days are good, some are bad, and some days you just feel numb. For me, grief was more like a monstrous whirlpool of overwhelming feelings, pulling me under and spitting me back out, over and over, with an intention to suffocate and crumble my spirit.

I felt surprised by the intensity and the duration of my anguish, and by the fierce yearning for my loved one. I had time to prepare myself for the loss yet felt completely unprepared when it actually happened. I felt clueless, searching for thoughtful answers to deep questions that I have not yet formulated, frustrated at not being able to make meaning out of something so consuming, powerful and paralyzing.

Physical Manifestations of Grief

Grief is an extraordinarily powerful constellation of emotions that can initiate a chain reaction of biochemical events in the body.

Although we think we know what to expect of mourning, the details of every story of loss are individual. While we ponder new ways of comprehending death in life, bereavement researchers study the biochemistry of grief and offer insights into the mechanisms of what happens to our bodies when we’re left with forlorn impermanence.

Interest in bereavement has grown in recent years, recognizing the profound impact of grief on the health of bereaved individuals. Physical manifestations of grief are common – powerful emotions can elicit a wide range of physiological responses in our bodies [1]. For example, changes in sleep patterns – difficulty getting to sleep, waking up in the middle of the night, or wanting to sleep all the time – as well as exhaustion (grief requires a lot of energy) are all too common. Others can include changes in appetite, headaches, muscle stiffness, and stomach upsets. Some can become jumpy and restless, while others, overly sensitive to loud noises or other people. Bottom line is that grief is an extraordinarily powerful constellation of emotions that can initiate a chain reaction of biochemical events in the body.

Physiological Mechanisms for Effects of Grief on Health

Although increased health risks associated with grief are well documented, the mechanisms remain somewhat ambiguous. Research implicates changes in the endocrine, immune, autonomic nervous, and cardiovascular systems in bereaved individuals [2]. The significance of these changes, and why in some these are primarily adaptive physiologic responses while in others these become maladaptive and physiologically deleterious, is not well-understood. But here are some things that clinical science does explain.

Can a Heart Truly be Broken?

A broken heart is a globally accepted metaphor that describes intense emotional suffering. Actually, modern medicine recognizes that a broken heart is as much a physical experience as it is an emotional one. A relatively new disease classification takotsubo or stress cardiomyopathy is just that – a broken heart [3].

Is it actually “broken”? Yes and no. A broken heart is not physically shattered into a million pieces, although it surely feels like it; but it certainly is damaged. Stress insults can injure the heart, inducing loss or damage to the cardiac muscle cells [4]. Because adult hearts cannot effectively repair and regenerate themselves, such damage can manifest as heart disease, hallmarked by dysfunction of cardiac muscle cells, diminished pump function, arrhythmias, and even death.

How Does Stress Injure the Heart?

Numerous studies show persistently elevated cortisol levels in bereaved individuals.

You’ve already gathered that it all comes down to stress. More importantly, it all comes down to experiencing a lot of stress for prolonged periods of time. Let’s dissect this – one stress molecule at a time.

Cortisol

Released from the adrenal cortex, cortisol promotes arousal and energy mobilization, and it actually increases our capacity to cope with acute stress. Cortisol levels are highest upon waking and reach their nadir in the late evening (Fig. 1). In doing so, cortisol facilitates catabolic processes consistent with its role in anticipation of wakefulness, increased activity and regulation of the stress response.

Fig. 1 An example of a normal 24-hour circadian cortisol pattern (green) with 4 urine collections first morning, several hours later, evening, and night before bed (black dots). When measured in urine, cortisol levels in healthy individuals are highest in the 2nd morning collection, capturing the morning peak, and drop steadily throughout the day to low levels at night. High stress can result in high cortisol levels at night and may disrupt sleep.

In the presence of chronic stressors, however, cortisol release becomes sustained throughout the day and the negative feedback mechanism, so important to the self-regulation of the hypothalamic-pituitary-adrenal (HPA) axis, is lost. Persistent stress drives cortisol to higher levels, sustaining this heightened cortisol tone throughout the day and at night, without allowing the cortisol surge to subside.

Numerous studies show persistently elevated cortisol levels in bereaved individuals [5]. Moreover, as the levels of dehydroepiandrosterone-sulphate (DHEA-S) decrease with age (an important immune enhancer) and cortisol levels rise, the newly lopsided cortisol:DHEA-S ratio may have an impact on the health of elderly bereaved, with greater potential for immune dysfunction [6].

This type of a scenario has been associated with increased cardiac risk, reduced immune function and reduced quality of life (reviewed in [2]). Why? Because cortisol increases heart rate and blood pressure – it’s really good at keeping the heart working overtime without allowing it to rest.

Fig. 2 The normal fluctuations of norepinephrine and epinephrine throughout the day show a distinct “inverted-U” fingerprint compared to cortisol’s diurnal pattern. Under basal conditions of little to no stress, norepinephrine and epinephrine levels are low in the first morning urine, reflecting their low levels throughout the night. With the normal stressors of awakening and activity, levels increase, and peak mid-day, and decrease by bedtime returning to low during the night. This normal diurnal pattern is disrupted with excessive stressors (emotional, physical, chemical, pathogenic) resulting in much higher, erratic high to low, or all together suppressed low levels of these catecholamines throughout the day.

The Role of Norepinephrine and Epinephrine

Stress insults can injure the heart, inducing loss or damage to the cardiac muscle cells.

In a stressful event, the sympathetic nerves and the adrenal glands release the “fight or flight” chemicals – norepinephrine and epinephrine (collectively called catecholamines) (Fig. 2). Rising heart rate, escalating blood pressure, increasing respiration rate and activation of sweat secretion are sure signs that the body is pumping out massive amounts of norepinephrine and epinephrine to prepare us for action. This system, however, is only intended for acute situations of immediate threat. If the stressors persist, and the body continues to be bathed in supraphysiological levels of catecholamines day after day, heart injury can eventually occur [7].

Research shows that profound emotional activation as seen in times of grief is accompanied by high catecholamine levels [8]. Bereaved individuals have been reported to have increased heart rate [9], high blood pressure [10], stress cardiomyopathy [11] and even sudden cardiac death [12].

Stress and a Broken Heart in a Nutshell

Physical symptoms of a broken heart are preceded by an emotionally traumatic event accompanied by markedly increased HPA axis activity and catecholamine levels (Fig. 3). Chronic stress, by inducing autonomic dysfunction through disrupting HPA axis (cortisol) and sympathetic nervous system activities (catecholamines), can contribute to the development of cardiovascular diseases [7].

Fig. 3 Emotional trauma can precipitate heart dysfunction through a series of dysregulated neuroendocrine and autonomic responses. Adapted from [13].

How Does this Affect My Ability to Deal with Grief?

Oddly enough, understanding the physiology of grief helps me cope. Every article of every research study is like putting together a little square inch snapshot of one massive mural in my own story of bereavement. I guess, if I’m not spending time checking off the stages of denial, anger, bargaining, depression, and acceptance, I may be seeking validation that what I feel is real. Perhaps this is all about me trying to grasp and process the difficulty of loss, and how to further structure my life around it. Reading and talking about the deleterious effects of grief also serves as a reminder for me to be more patient and kind towards myself during this time. In the midst of a global COVID-19 pandemic, we all have something that we’re grieving for. I hope this reminds you to be patient and kind towards yourself too.

Related Resources

[1] Institute of Medicine. Bereavement: Reactions, Consequences, and Care. 1984, Washington, DC: The National Academies Press.

[2] Buckley, T., et al., Physiological correlates of bereavement and the impact of bereavement interventions. Dialogues Clin Neurosci, 2012. 14(2):129-39.

[3] Efferth, T., M. Banerjee, and N.W. Paul, Broken heart, tako-tsubo or stress cardiomyopathy? Metaphors, meanings and their medical impact. Int J Cardiol, 2017. 230:262-268.

[4] Xin, M., E.N. Olson, and R. Bassel-Duby, Mending broken hearts: cardiac development as a basis for adult heart regeneration and repair. Nat Rev Mol Cell Biol, 2013. 14(8):529-41.

[5] Buckley, T., et al., Prospective study of early bereavement on psychological and behavioural cardiac risk factors. Internal medicine journal, 2009. 39(6):370-378.

[6] Khanfer, R., J.M. Lord, and A.C. Phillips, Neutrophil function and cortisol:DHEAS ratio in bereaved older adults. Brain Behav Immun, 2011. 25(6):1182-6.

[7] Kastaun, S., et al., Psychosocial and psychoneuroendocrinal aspects of Takotsubo syndrome. Nat Rev Cardiol, 2016. 13(11):688-694.

[8] Jacobs, S.C., et al., Bereavement and catecholamines. J Psychosom Res, 1986. 30(4): p. 489-96.

[9] Buckley, T., et al., Effect of early bereavement on heart rate and heart rate variability. Am J Cardiol, 2012. 110(9):1378-83.

[10] Buckley, T., et al., Haemodynamic changes during early bereavement: potential contribution to increased cardiovascular risk. Heart Lung Circ, 2011. 20(2):91-8.

[11] Wittstein, I.S., Stress cardiomyopathy: a syndrome of catecholamine-mediated myocardial stunning? Cell Mol Neurobiol, 2012. 32(5):847-57.

[12] Stroebe, M., H. Schut, and W. Stroebe, Health outcomes of bereavement. Lancet, 2007. 370(9603):1960-73.

[13] Fioranelli, M., et al., Stress and Inflammation in Coronary Artery Disease: A Review Psychoneuroendocrineimmunology-Based. Front Immunol, 2018. 9:2031.

Are Hormones to Blame for My Acne?

Fri, 01 May 2020 16:15:58 -0700

I was in teenage hell. Overnight, I went from being completely oblivious to what I looked like, to being obsessed with my appearance. And let me tell you, I did not like what I saw in the mirror. Too tall and too skinny, with an awkward toothy grin, uncoordinated and gangly, and I didn’t seem to know where my limbs were supposed to be around me. I wanted pretty hair and a semblance of curves, like many of my friends; instead I was a bean pole with a grease mop on my head. I wanted clear glowing skin; instead I was covered in acne. I felt miserable. I detested being a teenager. Thanks, puberty!

I had to deal with acne for the duration of middle school, high school and college. During that time, at all times, there was a crop rotation of pimples in various stages of sprouting development in plain sight. I spent hours obsessively picking at my face in the mirror, or mindlessly digging at those under-the-skin painful cysts while doing homework. Many nights I showered my pillow with tears of frustration and dread over getting up in the morning and showing up to class with the damage from the night before glaring on my face. And nothing really helped make it better. My mom and her friends, bathing in confidence from having skin worthy of a Neutrogena commercial, would shake their heads empathetically at me in disbelief ascribing it to my changing hormones: “don’t worry,” they would say “it will get better.” “When?” I would sigh back. But they would avert their eyes without a good answer on hand. All the while I carried a sense of doom and shame over not being able to control my seemingly raging hormones that wreaked havoc on my face.

Acne & “the Pill” – a Complicated Relationship

My terrible acne situation didn’t improve until graduate school when I finally decided to take birth control pills for this specific reason. And it helped my skin clear up tremendously (but resulted in a slew of other undesirable side effects that I will address in a different blog post). So I walked around, blissfully happy about having clear skin for the first time in my life, working on my confidence of looking more like a grown woman than a gawky teenager, with all of my hormones effectively suppressed. Fast forward a few years from receiving my PhD when my husband and I decided we were ready to start a family, and I stopped taking my birth control pills. By that point, I had already forgotten about the emotional damage that acne had caused me. Much to my dismay, it came back with a vengeance. When I went off “the pill,” almost instantly I developed a full-on zit beard that spread all the way along my chin to my ears and down my neck (apparently this is a very common pattern in females [2]).

Skin is an Endocrine Organ

As I sit here diligently recalling and writing about my frustrating acne history, I contemplate the complexity and the deep beauty of skin, an organ with its own plethora of endocrine commitments. Specifically, because skin is a tireless endocrine organ; our hormones play a major role in its healthful and youthful appearance. Women are all too familiar that as they age and estrogen levels decline towards menopause, skin loses elasticity, leaving them prone to developing wrinkles. What about acne? Were my mom and her friends right about hormonal shifts giving rise to my ever-so-frustrating adolescence? The short answer is – yes, they were right! The long answer is somewhat more complicated. So, I’m going to try and break it down into digestible parts.

What is Acne? And What Makes it so Terrible?

Acne (medical name “acne vulgaris”) is an inflammatory condition (or a disease of the pilosebaceous unit if you ask a Dermatologist [2]), where the balance among the skin microbiome, hormones, and a proper inflammatory response is lost. The hair follicles on the skin basically become clogged with dead cells and oil from the skin – a medium so rich and fertile that a variety of bacteria claim it as their bed and breakfast. This results in pimples or bumps that heal ever so slowly, and when one seems to start going away, the others crop up. The factors driving this process are multifactorial, and in the majority of cases include:

Increased androgens, or “androgen dominance” (in puberty, adolescence, right before a period, or in perimenopause) trigger an increase in oil (sebum) production and stimulate abnormally rapid shedding of skin cells and subsequent entrapment of the oil and the dead cells inside the pores. This also leads to an enlargement of the sebaceous gland. Note that even when androgen levels are normal, with low estradiol and progesterone, androgens can appear “elevated” in a functional sense, giving rise to acne
Skin microbiome changes that “help” with colonization and proliferation of the duct with pathogenic bacteria
The immune system, always in vigilant surveillance mode, detects the newly formed acne unit and attacks it, resulting in inflammation, redness, swelling and pus-like fluid buildup

Fig. 1 Overview of the skin pilosebaceous unit, the bacterial population within it, and acne formation. Adapted from [1].

Let’s Talk About Androgens

Androgens (e.g., Testosterone (T) and dihydrotestosterone (DHT), the more potent metabolite of T), are historically pegged as intrinsically “male.” Men have about 10-times more T than women. While women have less T, they also have and need androgens to maintain a sense of well-being, elevate mood, improve libido, see a decent response to exercise, and give rise to estrogens. Androgens also play a role in regulating normal dermal physiology, via their actions on the androgen receptors, expressed at the surface of our skin [3].

An imbalance in androgen metabolism and levels can set forth a series of events that inadvertently end up presenting on our face as acne. Because the skin is highly expressive in androgen receptors, persistent activation of these receptors with high levels of androgens in the sebaceous glands results in a dramatically revved up output of sebum. Both testosterone and DHT can bind to the androgen receptors in the skin; however, DHT is much more potent. Research suggests that elevated androgens in puberty initiate acne symptoms, especially in girls, and accompany the persistent progression of acne into adulthood [4, 5]. So, in a sense, high androgens in puberty can prime androgen receptors to be more sensitive to even normal androgen levels later in life [6]. Estrogens and progesterone also play a role in how androgens affect the skin. They are both anti-androgenic and account for the pregnancy glow in the skin and hair when estradiol, estriol, and progesterone levels skyrocket to very high levels and androgens decrease, or at least don’t increase.

The strong androgen-acne connection is especially evident in disorders like polycystic ovarian syndrome (PCOS), in which acne, scalp hair loss and increased facial and body hair are common [7]. Other disorders, such as congenital adrenal hyperplasia or CAH can present with similar symptoms to PCOS. Saliva LC-MS/MS testing can help differentiate between the two disorders. Additionally, hyperprolactinemia is another common disorder that leads to PCOS/CAH-type acne symptoms, easily missed if not looking for it specifically, and ZRT’s serum test covers that territory.

A simple saliva test can assess the levels of bioavailable androgens (DHEA and testosterone) and a dried urine test can assess DHT levels to see if abnormal androgen metabolism is to blame. Anti-androgen therapies have now been developed to help manage androgen-triggered acne [8].

When it Comes to Skin Health, Does Food Matter?

In addition to hormonal imbalances, diet plays a big role in the development and propagation of acne. The Western diet, which is characterized by a high intake of hyperglycemic carbohydrates and dairy products, increases insulin and insulin-like growth factor-1 (IGF-1). Together, through a series of biochemical events, they drive androgen levels higher and thus promote more oil production and induce inflammation [9].

Diet doesn’t just induce changes in the housekeeping molecules that regulate glucose – diet also shapes the gut microbiota, which can then influence skin microbiota. Research suggests that a low fiber/high saturated fat Western diet causes fundamental changes in the intestinal microbiota, producing metabolic and inflammatory skin conditions [10].

Dietary modifications aimed at reducing high glycemic index carbohydrates, dairy protein, and saturated fat and the introduction of sea fish, green tea, resveratrol and vitamin D-rich foods may help attenuate acne [9].

What Role Does Our Microbiome Play in Our Acne?

Our skin is a rich ecosystem, inhabited by billions of diverse microorganisms. Most of the time, there is a healthy and concerted balance between our skin and the microorganisms living on it. However, if skin conditions are permissive, pathogenic bacteria can attach and proliferate, forming entire colonies. Skin oil (sebum) is a major influential factor in controlling microbial diversity at the skin level. In sebum-rich areas lipophilic bacteria are more dominant and drier skin may promote a more diverse microbiome. Therefore, skin that is more oily is more likely to experience a switch from commensal to pathogenic bacterial populations, resulting in acne and its accompanying inflammatory response (redness and swelling) – clinical signs of imbalance between our skin and the microbiota [9]. Some authors present preliminary evidence that certain probiotic species can also help control the population of pathogenic skin bacteria [1].

Perhaps my hormones aren’t as revved up as they used to be when I was thirteen, and that’s what has helped my face clear up; or perhaps I’ve cleaned up my diet enough to see a difference on my face – the point is that there is a reason behind acne pathology, and today there are many resources available to help understand what is driving this irritating condition for each individual patient. Additionally, treating your skin with love and consideration may ease the anxiety over having acne. Now that I am in my late thirties, I am finally beginning to view my skin as a friend and not a foe. I am careful to recognize patterns when certain products or activities make my skin break out, and subsequently treat it with gentleness and care; appreciating every bit of it, even the patches with scars from previous battles.

ZRT Laboratory’s saliva and dried urine testing can help you determine if your androgen levels are out of balance and a possible cause of your uncontrollable acne. Order your next test today to find your way back to clear skin.

References

Lee, Y.B., E.J. Byun, and H.S. Kim, Potential Role of the Microbiome in Acne: A Comprehensive Review. J Clin Med, 2019. 8(7).
Tan, A.U., B.J. Schlosser, and A.S. Paller, A review of diagnosis and treatment of acne in adult female patients. Int J Womens Dermatol, 2018. 4(2): p. 56-71.
Lai, J.J., et al., The role of androgen and androgen receptor in skin-related disorders. Arch Dermatol Res, 2012. 304(7): p. 499-510.
Williams, C. and A.M. Layton, Persistent acne in women : implications for the patient and for therapy. Am J Clin Dermatol, 2006. 7(5): p. 281-90.
Preneau, S. and B. Dreno, Female acne - a different subtype of teenager acne? J Eur Acad Dermatol Venereol, 2012. 26(3): p. 277-82.
Kim, M.H., et al., Integrated targeted serum metabolomic profile and its association with gender, age, disease severity, and pattern identification in acne. PLoS One, 2020. 15(1): p. e0228074.
Gersh, F., PCOS SOS. A Gynecologist's Lifeline To Naturally Restore Your Rhythms, Hormones, and Happiness. 2018: Integrative Medical Group of Irvine.
Dreno, B., Treatment of adult female acne: a new challenge. J Eur Acad Dermatol Venereol, 2015. 29 Suppl 5: p. 14-9.
Melnik, B.C., Acne vulgaris: The metabolic syndrome of the pilosebaceous follicle. Clin Dermatol, 2018. 36(1): p. 29-40.
Bowe, W., N.B. Patel, and A.C. Logan, Acne vulgaris, probiotics and the gut-brain-skin axis: from anecdote to translational medicine. Benef Microbes, 2014. 5(2): p. 185-99.

The Importance of Hormone Balance for a Healthy Immune System During COVID-19 Outbreak

Fri, 17 Apr 2020 11:10:48 -0700

For the past 4 weeks, each morning for me starts with a cup of coffee and a side of news about the global health pandemic in which we’re living. Invading our world rapidly, forcing everything to look different today compared to just a month ago, COVID-19 has everyone on high alert! Throughout the rest of my day, I allow myself to be interrupted by articles about the virus, nurturing the feelings of surrealism and unease. Quarantined together with my family, my new reality has been reduced to a filtrate of information through the COVID-19 prism. It’s disorienting how quickly the normalcy of our regular lives have been swept away with the state-mandated stay at home orders. This is starting to feel like the opening scenes of a post-apocalyptic film, rather than reality. As a scientist, I grapple with uncertainty – there are so many questions about what is happening right now, with only few answers, as we’re all witnessing this epidemic unfold. So below is a list of things that I found helpful in understanding the widespread COVID-19 infection, the immune response, and the reasons behind social and physical distancing.

CORONAVIRUSES = umbrella term for many different viruses, which include SARS, MERS, and the current one that everyone is talking about - SARS‐CoV‐2.
SARS‐CoV‐2 = type of coronavirus.
COVID-19 = COrona VIrus Disease – the name for the actual infection or disease caused by SARS‐CoV‐2.

Naming Semantics

Many things can be confusing during a health crisis, so let’s start with the language we use when talking about the current state of affairs. Coronaviruses (also known as CoV in medical jargon) belong to the same family of viruses as Severe Acute Respiratory Syndrome (SARS) and Middle East respiratory syndrome (MERS), but usually cause only mild illnesses (e.g., common cold). On February 11^th 2020 the coronavirus study group of the International Committee on Taxonomy of Viruses named the novel coronavirus as severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2); and the World Health Organization (WHO) formally named the disease triggered by SARS‐CoV‐2 as coronavirus disease 2019 (COVID‐19).

Crown-Like

Coronaviruses are called “corona” because of the crown-like projections that protrude from their surface – on the outside the virus structure is enveloped in a casing of lipid molecules with protein spikes [3]. This oily lipid structure falls apart on contact with soap; this is why washing your hands is important to prevent or at least minimize the spread of illness.

How does it Work?

For a great explanation on how viruses enter and hijack cells inside a human body, the following illustrations from the New York Times are helpful. In a nutshell, SARS‐CoV‐2 is transmitted from human to human, via respiratory droplets or close contact [4]. It freely enters the body through the airway, the spike proteins of the “crown” associating with the angiotensin-converting enzyme 2 (ACE2) surface receptors on alveolar (lung) cells, and the virus is ushered inside (Fig. 1) [5]. Once inside the cells, the virus releases its genetic material (RNA) and hijacks the human cell machinery to make viral proteins. So, in a sense, the virus overrides the cell’s normal programming and forces it to become a virus-making factory.

How Does It Feel?

As the infection continues to progress, fever and cough might develop – a sign that the immune system is fighting back. If the infection continues, it can damage alveolar cells and further stimulate a systemic inflammatory reaction. If this happens, it becomes harder for the lungs to supply oxygen for the blood to carry to various organs. Instead, lungs can fill up with fluid, making it hard to breathe. If the infection is severe enough, some may even need a ventilator.

Fig. 1 Proposed model for the host immune response to SARS-CoV-2 infection. Adapted from [1] & [2].

The infection process and the immune defense are extremely complicated [3]. A case report for a moderate COVID-19 infection highlights the complexity of the immune response dynamics in a 47-year-old female patient [6]. Based on a good number of recent reports and the CDC, common symptoms of COVID-19 are [7]:

98% of the patients in the study had fevers
78% had a temperature higher than 38°C (100.4 ^oF)
76% of the patients had coughs
44% of patients experienced fatigue and muscle pain
55% of patients had difficulty breathing
28% developed phlegmy coughs
8% had headaches
3% had diarrhea
100% of patients showed abnormalities in chest computed tomography - grinding glass‐like and consolidation areas were found in 98% of the infected patients' lungs bilaterally

Why Social Distancing?

Just a short while ago, the terms “flatten the curve” and “social distancing” didn’t mean much to any of us. Today, on the other hand, that’s all we hear on the news and through social media. So why exactly do we bother with all this self-isolation business; why not just have a COVID party, be sick all at once, and get over it all at once? Ok, let’s break this down, using stats from the Chinese Center for Disease Control and Prevention [8]:

By rough approximation there are 350,000,000 people in the US, and we all have a “COVID PARTY” → all get infected all at once
80% of us are going to be “just fine” with mild pneumonia or nothing at all → no big deal
14% or 49,000,000 of us are going to develop severe disease (difficulty breathing, not enough oxygen) → not great
5% or 17,500,000 will develop critical disease with respiratory failure, shock and multiorgan dysfunction. So that’s roughly 350,000 people per state → that’s a problem. According to OPB, Oregon has only 6,601 staffed hospital beds. So…
And that’s precisely why we don’t want to get infected all at once

There’s No Treatment (Yet) - But Here’s What You Need to Know

The burst of confirmed cases worldwide shows how detrimental SARS‐CoV‐2 can be to human health. With no preventative vaccine and no curative treatment for COVID-19, relying on our own immune system to protect us from the threat of COVID is one of our best options for now. Just to be clear, there's no magic food or pill that is guaranteed to boost your immune system and protect you against the virus. However, there are ways to keep your immune system functioning optimally, which can help to keep you healthy and give you a sense of control in an uncertain time.

Estradiol is a female sex steroid and its actions extend way beyond reproduction – it plays an important role in modulating immune events as well [9, 10]. It seems appropriate to talk about sex steroids in the context of SARS-CoV-2 as it appears that men and women are equally likely to contract the virus, but men have a harder time fighting off the infection. Clinical studies reveal stark inequality between how men and women’s bodies handle infections. Women have evolved to be particularly robust – fast and strong immune responses, likely to protect them during pregnancy and the postpartum period. (This immune protection, however, comes at a cost – women are also more likely than men to develop autoimmune diseases). Estradiol equips the body with potent protective anti-inflammatory effects, which could certainly come in handy during the “cytokine storm” resulting from the SARS-CoV-2 infection (Fig. 1) [11]. Estrogen-responsive immune parameters are going to be especially important during hormonal transition times like menopause when estradiol levels decrease and the body loses its protective effects, now being exposed to a ravaging onslaught of inflammatory processes [12].

Cortisol tends to get a bad rap, receiving the blame for anxiety, weight gain, insomnia, high blood pressure, you name it. It does all these bad things, but only when chronically high and not following a normal circadian rhythm. But we often forget that our bodies need cortisol to survive and having just enough cortisol around at the right time of day optimizes and boosts immunity while limiting inflammation [13, 14]. When stress doesn’t abate, however, too much cortisol can become destructive, opening the door for chronic immunosuppression. We are witnessing the COVID-19 pandemic unfold on a global scale, so it’s not surprising that all of us are affected and experience “empathetic stress” as we watch so many other people out there in distress and our own anxiety over the uncertainty of the situation. Keeping stress levels and, with that, normal circadian cortisol levels throughout the day, in check is going to be very important to maintaining a healthy immune response [15].

Vitamin D – typically called a “vitamin”, vitamin D is a precursor to a fat-soluble hormone – a substance that our skin produces in response to being out in sunlight. Vitamin D is best known to keep our bones healthy and strong by helping to assimilate calcium from our diet into skeletal tissues. At the gene level, the active form of vitamin D regulates the expression of hundreds of genes. Research shows that vitamin D is protective against acute respiratory infections [16].

Minerals like Zinc and Selenium – zinc can inhibit viral replication and shorten the duration of a common cold caused by a virus [17]; while selenium, forming part of selenoproteins including the antioxidant glutathione, contributes to our biggest defense system against the reactive oxygen species that viruses generate and contribute to the destructive inflammatory conditions in the lungs and heart at the late stages of COVID-19 infection.

As we wait for vaccine development against and testing for SARS-CoV-2 to ramp up, taking care of your health, starting with a healthy immune system, is going to be very important. Currently many doctors are transitioning from in-person appointments to telemedicine visits which presents an inherent problem in obtaining objective information like physical exams and labs. ZRT Laboratory is here to help by providing simple, minimally invasive lab testing from samples that patients can collect from the comfort (and necessity) of their own home.

Testing for Estradiol

Testing for Cortisol

Testing for Vitamin D

Testing for Elements

References

Prompetchara, E., C. Ketloy, and T. Palaga, Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol, 2020. 38(1): p. 1-9.
Li, X., et al., Molecular immune pathogenesis and diagnosis of COVID-19. Journal of Pharmaceutical Analysis, 2020.
Li, G., et al., Coronavirus infections and immune responses. J Med Virol, 2020. 92(4): p. 424-432.
Chan, J.F., et al., A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet, 2020. 395(10223): p. 514-523.
Zhao, Y., et al., Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov. bioRxiv, 2020: p. 2020.01.26.919985.
Thevarajan, I., et al., Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nature Medicine, 2020.
Huang, C., et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, 2020. 395(10223): p. 497-506.
Wu, Z. and J.M. McGoogan, Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA, 2020.
Bouman, A., M.J. Heineman, and M.M. Faas, Sex hormones and the immune response in humans. Hum Reprod Update, 2005. 11(4): p. 411-23.
Moulton, V.R., Sex Hormones in Acquired Immunity and Autoimmune Disease. Front Immunol, 2018. 9: p. 2279.
Khan, D. and S. Ansar Ahmed, The Immune System Is a Natural Target for Estrogen Action: Opposing Effects of Estrogen in Two Prototypical Autoimmune Diseases. Front Immunol, 2015. 6: p. 635.
Ghosh, M., M. Rodriguez-Garcia, and C.R. Wira, The immune system in menopause: pros and cons of hormone therapy. J Steroid Biochem Mol Biol, 2014. 142: p. 171-5.
Venneri, M.A., et al., Circadian Rhythm of Glucocorticoid Administration Entrains Clock Genes in Immune Cells: A DREAM Trial Ancillary Study. J Clin Endocrinol Metab, 2018. 103(8): p. 2998-3009.
Bahrami-Nejad, Z., et al., A Transcriptional Circuit Filters Oscillating Circadian Hormonal Inputs to Regulate Fat Cell Differentiation. Cell Metab, 2018. 27(4): p. 854-868 e8.
Gamble, K.L., et al., Circadian clock control of endocrine factors. Nat. Rev. Endocrinol, 8/2014. 10(8): p. 466-475.
Martineau, A.R., et al., Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ, 2017. 356: p. i6583.
Science, M., et al., Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials. CMAJ, 2012. 184(10): p. E551-61.

Haunted by Spooky Things in Your Candy?

Thu, 31 Oct 2019 16:08:46 -0700

It’s that time of year when my favorite sinkhole that is Pinterest overflows with HALLOWEEN EVERYTHING! Lines between reality and mystical foggy autumn things get blurry – spooky treats, homemade costumes, pranks to scare your friends, the perfect eerie soundtracks – all helpful suggestions for your ghastly transition from the normal human self into that monstrous creepy being. And I love ALL OF IT! My house is covered with a 2-story sized spider web with a giant furry tarantula right smack in the middle of it. Outdoor lights have been swapped for ominous reddish-orange ones, casting a macabre glow on various tombstones and protruding skeleton bones scattered in the yard. There is a witch hanging on my front door, making a cackling sound every time someone walks by – annoying? Perhaps. But very effective!

My feral monstrosity of a sweet tooth is just beginning to come out of a year-long hibernation, enticed by the allure of everything sweet and colorful. Let’s face it, Halloween candy is a staple that is hard to resist. Since becoming a parent, however, I’ve become more cognizant about exactly how much candy my family eats, partly because candy can make parenting that much harder. I’ve literally watched my children go from acting like unhinged lunatics, wild-eyed, sniffing out more candy that I’ve put away like truffle-seeking pigs; to the tearful crash that often follows – the epic post-Halloween candy binge hangovers are real! And they’re not fun for anyone involved.

What’s Hiding in Your Kids' Candy?

More than 10,000 chemicals are allowed as additives in food (including candy) in the United States.

As a parent and a researcher, I approach candy with caution – not necessarily because of the legendary sugar highs and lows, or being annoyed over empty calories, or thinking of cavities developing in real-time, or sweets-induced bellyache – but primarily because of all the other ingredients in it. More than 10,000 chemicals are allowed as additives in food (including candy) in the United States [1]. Some of them, such as synthetic artificial food colors (AFCs) are added to foods for aesthetic reasons to make food more colorful and thus particularly appealing to young children. Originally derived from coal tar and now from petroleum, AFCs are easily identifiable at the end of the ingredients list by a color name and a number. In the last 6 decades, their use has increased more than fivefold [2]. Over the years, many AFCs have been banned because of their adverse effects on laboratory animals, and research is just beginning to address how these impact human health [3].

So What’s the Big Deal?

Diet quality plays a very important role in mood and neurological health, especially in children [4,5]. Specifically, diet low in healthy foods and/or high in unhealthy foods may increase a child’s risk for developing mental health problems later in life [5]; and can be particular triggering for those who carry a genetic lability for Attention Deficit Hyperactivity Disorder (ADHD) [6].

Children with ADHD appear to be more sensitive to the nutrient composition in their food with regard to symptom presentation compared to their non-ADHD peers [6,7]. The reason for this is not clear; however, the authors speculate that perhaps it is the inappropriate absorption and utilization of micronutrients in ADHD, rather than low dietary intake, that’s to blame.

A number of recent studies show that supplementation with micronutrients, such as vitamins and minerals, can be an effective way to manage symptoms of hyperactivity, inattention, and aggression [8,9]. In fact, some of these broad-spectrum nutrient interventions are now in clinical trials.

Now Back to the Impact of AFCs on the Health of ADHD Children

Experts suggest that AFCs may play a role in hyperactivity, especially for some children with ADHD [3]. Double-blind placebo-controlled studies confirm that artificial dyes can contribute to hyperactivity [10,11]. The mechanism of exactly how AFCs contribute to hyperactivity are not known; however, some of them do cross the blood-brain barrier. Elimination of AFCs from the diet may provide benefits to children with ADHD, who seem to be particularly sensitive to certain dyes [12].

It’s a good idea to arm yourself against the annual assault by developing a Halloween-candy strategy to carry you through the next few weeks. In the same vein, I promise you – I am not that kind of parent who wants to ruin all the fun, and I certainly don’t advocate for ditching candy altogether by confiscating your child’s jubilantly collected loot. However, Halloween for someone with ADHD may be a recipe for trouble; so here’s how not to ruin your child’s Halloween:

Remember the old trick of a healthy diet – starting with Halloween and leading all the way through the holiday season. Nutritious breakfast and a healthy lunch can help prevent crashing after the post-sugar high.
Along those lines, avoid too much sugar and whenever possible, steer clear of artificial coloring.
Keep up with a consistent bedtime routine to get a good night’s rest and maintain those circadian rhythms.
Lastly, teach your child to pay attention to their own body and recognize how certain foods make them feel afterwards.

Related Resources

References

[1] Trasande, L., et al., Food Additives and Child Health. Pediatrics, 2018. 142(2).

[2] Stevens, L.J., et al., Amounts of artificial food colors in commonly consumed beverages and potential behavioral implications for consumption in children. Clin Pediatr (Phila), 2014. 53(2): p. 133-40.

[3] Arnold, L.E., N. Lofthouse, and E. Hurt, Artificial food colors and attention-deficit/hyperactivity symptoms: conclusions to dye for. Neurotherapeutics, 2012. 9(3): p. 599-609.

[4] Jacka, F.N., et al., A prospective study of diet quality and mental health in adolescents. PLoS One, 2011. 6(9): p. e24805.

[5] Dimov, S., et al., Diet quality and mental health problems in late childhood. Nutr Neurosci, 2019: p. 1-9.

[6] Holton, K.F., et al., Evaluation of dietary intake in children and college students with and without attention-deficit/hyperactivity disorder. Nutr Neurosci, 2018: p. 1-14.

[7] Jacobson, M.F., Diet, ADHD & Behavior: a quarter-century review. . 1999, Center for Science in the Public Interest: Washington, DC.

[8] Gordon, H.A., et al., Clinically Significant Symptom Reduction in Children with Attention-Deficit/Hyperactivity Disorder Treated with Micronutrients: An Open-Label Reversal Design Study. J Child Adolesc Psychopharmacol, 2015. 25(10): p. 783-98.

[9] Rucklidge, J.J., et al., Vitamin-mineral treatment improves aggression and emotional regulation in children with ADHD: a fully blinded, randomized, placebo-controlled trial. J Child Psychol Psychiatry, 2018. 59(3): p. 232-246.

[10] Bateman, B., et al., The effects of a double blind, placebo controlled, artificial food colourings and benzoate preservative challenge on hyperactivity in a general population sample of preschool children. Arch Dis Child, 2004. 89(6): p. 506-11.

[11] Schab, D.W. and N.H. Trinh, Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta-analysis of double-blind placebo-controlled trials. J Dev Behav Pediatr, 2004. 25(6): p. 423-34.

[12] Nigg, J.T., et al., Meta-analysis of attention-deficit/hyperactivity disorder or attention-deficit/hyperactivity disorder symptoms, restriction diet, and synthetic food color additives. J Am Acad Child Adolesc Psychiatry, 2012. 51(1): p. 86-97 e8.

Your Guide to PMDD: Causes and Treatment

Thu, 29 Aug 2019 12:43:14 -0700

When I turned 12, all of a sudden all of my friends were getting their periods, and I just couldn’t wait to get mine! I was so ready to join the ranks of glamorous women who had the privilege of being initiated into the menstruating club. I wanted to belong with them - everything about periods was synonymous with femininity for me at the time. I had to endure witnessing so many of my classmates get the special treatment and be sent home to deal with their cramps, meanwhile staying behind to suffer through boring physics or math classes. Periods seemed to have been happening to everyone around me, just not me. Until one day, seemingly a miracle, I got it! I remember my hands shaking with excitement – I did it – I was in the club! I was becoming a woman! I was beyond thrilled. My 12-year-old dreams were coming true!

My overwhelming excitement lasted for about 10 minutes. What I realized once I got my period was that it wasn’t at all glamorous. It was a messy project in need of careful management. A nuisance really. Once a month for about a week, I had to strategically plan my time around bathroom breaks in between class times in order to deal with the relentless crimson river escaping my body. There was no internet at the time to help me understand what was normal and what wasn’t. I relied on my friends for knowledge about managing cramps and on my parents to let me know just how crabby I’d been during the days leading up to my period.

Is PMDD Worse than PMS? Hint: It Is.

It wasn’t until college that I learned about premenstrual syndrome (PMS), and that it was a real thing. Meaning it happened to many women (not just me) because of specific endocrine fluctuations related to the menstrual cycle. What I also learned in college was that I had the “easy” version – a small percentage of women suffered from something even worse than PMS, called premenstrual dysphoric disorder (PMDD). At the time, this news seemed unfathomable to me – how can you feel even worse? Turns out, you can! And clinical science is just beginning to understand the differences between PMS and PMDD and governing the distressing etiology of the disorder.

What is PMDD?

PMS symptoms can range from abdominal pain to mood issues, and if they are severe enough to cause functional impairment and interfere with life’s normal activities, they can be classified as PMDD. PMDD is a luteal phase-specific syndrome on the severe end of the PMS spectrum. And it is debilitating! Approximately 3-8% of menstruating women suffer from the same constellation of symptoms as PMS but experienced at a much higher intensity. The burden of PMDD is a cyclical and predictable detriment to the quality of life for the patient and to those around them.

Due to a particular set of cycle-dependent core symptoms, PMDD has recently been outlined as a new diagnostic category in DSM-5 [1]. PMDD is typically defined by having at least 5 symptoms in most menstrual cycles that have to do with severe mood changes and physical symptoms. These symptoms need to occur during the week before and improve shortly after the onset of menses.

How Does PMDD Occur?

The etiology of PMDD is still largely unclear, but it likely has a lot to do with hormonal shifts across the menstrual cycle. Because PMDD is a luteal phase-specific disorder, it is important to recognize what hormonal changes take place in the luteal phase compared to the follicular phase. One distinguishing feature of the luteal phase is the high levels of progesterone that pick up momentum right after ovulation. This makes sense, as it is the follicle, matured at ovulation, that is responsible for progesterone production to prepare the body for pregnancy, should fertilization take place. Women with PMDD seem to feel relatively well in the follicular phase when progesterone is low, and feel terrible once ovulation occurs and progesterone levels start to rise. So, what exactly could be going on when progesterone – typically regarded as the calming, anxiety-relieving hormone – all of a sudden triggers the opposite reaction in some individuals?

The Answer May Lie with Progesterone Metabolism

The answer may be found in the neuroactive steroid allopregnanolone – a metabolite of progesterone, rather than in progesterone itself. Allopregnanolone levels rise in tandem with progesterone across the luteal phase of the menstrual cycle, and by virtue of targeting the GABA A receptor, produce anxiolytic and sedative effects [2]. In fact, some practitioners recommend progesterone supplementation to manage PMS symptoms. Additionally, IV infusions of allopregnanolone (called Brexanolone) has recently been approved for use in postpartum depression with clinically meaningful improvements in mood [3]. Unfortunately, not everyone responds to allopregnanolone the same way, and in women vulnerable to mood changes in the pre-menstrual period, allopregnanolone can induce negative mood states.

The Inverted U-shaped Effect

The curious thing about PMDD is that symptomatology can be relieved when ovarian hormones are suppressed altogether, because it is the physiological levels of progesterone-turned-allopregnanolone that are particularly triggering, or when allopregnanolone levels are pushed higher to beyond physiological luteal levels. In other words, at the heart of the disorder are luteal levels of progesterone and allopregnanolone.

Although the levels of allopregnanolone between PMDD and non-PMDD groups are not that different [4,5], it turns out that what distinguishes individuals with PMDD from those without is dysregulated GABA A receptor organization. The GABA-A receptor has to mix-and-match the 5 subunits throughout the menstrual cycle in different ways to adapt to the ever-changing hormonal flux [6]. Women with PMDD have previously been reported to exhibit differences in GABA-A subunit structure and abnormal patterns of neural activation [7-9].

The clinical research on PMDD, therefore, points to a role for allopregnanolone in the symptoms of the disorder, with numerous studies finding that allopregnanolone levels typical of the luteal phase (top of an inverted U-shaped curve) trigger adverse symptoms in women with PMDD.

PMDD Therapeutic Management

Management of PMDD requires a careful approach, and unfortunately treatments aiming directly at PMDD are lacking. Instead, focusing on symptom management has been the primary goal of a successful treatment strategy, and clinical research has highlighted a few such approaches. The gist of the therapeutic strategy is to avoid progesterone levels equivalent to normal physiological luteal levels and either bring them down lower or higher than what’s seen in the luteal phase (inverted U-shaped effect). Here are few examples:

Oral contraceptives – aimed at suppressing ovarian steroids altogether to bring relief for PMDD symptoms [10].
Selective Serotonin Reuptake Inhibitors (SSRIs) – initiated as soon as symptoms begin and discontinued at menstruation. The short onset of therapeutic action in PMDD could potentially be explained with SSRIs’ ability to enhance formation of allopregnanolone from progesterone by increasing the levels of 5α-reductase in the brain [11], and thus pushing the right side of the U-shaped curve.
Progesterone – sure, paradoxical and counter-intuitive, but studies show that the maximum concentration of allopregnanolone observed during the luteal phase of the cycle typically worsens the symptoms, yet with a further increase in allopregnanolone with progesterone supplementation, the symptoms decrease in severity [12,13].
5α-reductase inhibitors – because allopregnanolone levels observed during the luteal phase of the cycle typically worsens the symptoms, women receiving a 5α-reductase inhibitor to prevent formation of allopregnanolone from progesterone experience a profound reduction in several core PMDD symptoms [4].

The sole comfort of PMDD is that it doesn’t last. It goes away, yet, as sure at it leaves, it comes back the following month. The hope is to make it manageable for patients whose quality of life is compromised with PMDD.

ZRT Laboratory offers a Menstrual Cycle Mapping kit designed to assess cases of PMS and PMDD. Tracking estrogen and progesterone levels throughout the cycle allows us to highlight when the levels are too high or too low, pointing to the root of the problem. Get your Menstrual Cycle Mapping kit today to see if there can be help for your debilitating PMDD symptoms!

Related Resources

References

[1] Diagnostic and statistical manual of mental disorders DSM-5, fifth edition ed. 2013: APA, Washington, DC.

[2] Bixo, M., et al., Effects of GABA active steroids in the female brain with a focus on the premenstrual dysphoric disorder. J Neuroendocrinol, 2018. 30(2).

[3] Kanes, S., et al., Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet, 2017. 390(10093): p. 480-489.

[4] Martinez, P.E., et al., 5alpha-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder. Neuropsychopharmacology, 3/2016. 41(4): p. 1093-1102.

[5] Timby, E., et al., Women with premenstrual dysphoric disorder have altered sensitivity to allopregnanolone over the menstrual cycle compared to controls-a pilot study. Psychopharmacology. (Berl. ), 6/2016. 233(11): p. 2109-2117.

[6] Bixo, M., et al., Treatment of premenstrual dysphoric disorder with the GABAA receptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial. Psychoneuroendocrinology, 6/2017. 80: p. 46-55.

[7] Rapkin, A.J., et al., Neuroimaging evidence of cerebellar involvement in premenstrual dysphoric disorder. Biol. Psychiatry, 2/15/2011. 69(4): p. 374-380.

[8] Berman, S.M., et al., Elevated gray matter volume of the emotional cerebellum in women with premenstrual dysphoric disorder. J Affect. Disord, 4/5/2013. 146(2): p. 266-271.

[9] Gingnell, M., et al., Social stimulation and corticolimbic reactivity in premenstrual dysphoric disorder: a preliminary study. Biol. Mood. Anxiety. Disord, 2014. 4(1): p. 3.

[10] Lopez, L.M., A.A. Kaptein, and F.M. Helmerhorst, Oral contraceptives containing drospirenone for premenstrual syndrome. Cochrane Database Syst Rev, 2012(2): p. CD006586.

[11] Hantsoo, L. and C.N. Epperson, Premenstrual Dysphoric Disorder: Epidemiology and Treatment. Curr. Psychiatry. Rep, 11/2015. 17(11): p. 87.

[12] Andreen, L., et al., Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone. Psychoneuroendocrinology, 2/2005. 30(2): p. 212-224.

[13] Andreen, L., et al., Allopregnanolone concentration and mood--a bimodal association in postmenopausal women treated with oral progesterone. Psychopharmacology (Berl), 2006. 187(2): p. 209-221.

The Connection Between Low Vitamin D and Sleep Disturbances

Thu, 01 Aug 2019 15:34:49 -0700

Here in the Pacific Northwest we love talking about the sun! We grumble about it being hidden away behind heavy rain clouds for months at a time in the winter; we delight in the first breakthrough rays in the spring, realizing our pagan longing for it, watching, as if for the first time, as everything around us wakes up from a deep slumber; we marvel at its delightful, almost intoxicating warmth in the early summer; and yes, we find it irritating when the temperature goes a dash over 80 degrees, or if stays too hot for too long into the fall. Our enthusiasm for the sun’s activities makes sense - after all, humans have evolved to rely on sunlight and center many of our activities around its presence. And we Oregonians, are no different.

The “Sunshine Vitamin”

Not unlike stimulating photosynthesis in plants, inside our human bodies sunlight sets in motion a series of biochemical events that are essential to our wellbeing. Proclaimed as a vitamin, vitamin D is actually a precursor to a fat-soluble hormone – a substance that our skin produces in response to being out and about, all the while soaking up those rays of sun. Vitamin D is best known to keep our bones healthy and strong by helping to assimilate calcium from our diet into skeletal tissues.

And it does so much more! At the DNA level, the active form of vitamin D regulates the expression of hundreds of genes, turning them on or off at precisely the right time. It’s no wonder that if humans don’t get enough of this “sunshine vitamin”, deficiencies can be linked to or exacerbate a variety of disorders, such as seasonal affective disorder, mania [1], psychosis [2], depression [3], metabolic syndrome [4], irritable bowel disease [5], chronic back pain [6], increased severity of PMS symptoms [7], and sleep disorders [8].

Shining Some Light on Low Vitamin D

Emphasized by dermatologists, the danger of ultraviolet radiation is now embedded into our psyche. Going out into the fierce midday light without first slathering on full-strength sunscreen feels plain wrong. We have become really good at blocking harmful sun’s rays to prevent solar souvenirs that can angrily inflame our skin. However, at the same time it is also so easy to forget about those pathways that are nourished by sunlight. Vitamin D biosynthesis is one such pathway. Without adequate doses of unblocked sunlight, foods fortified with the vitamin or just straightforward supplementation, one risks falling into the low vitamin D zone. Unfortunately, there is no one symptom that indicates an overt vitamin D deficiency. But one way that such a deficiency can manifest is through sleep disturbances.

Vitamin D and Sleep

Sleep is something we often take for granted and discuss frequently in the context of its absence. After all, humans are wired that way – we have a physiological need to sleep. And when we don’t get enough good quality sleep, we just don’t feel right. What many folks don’t realize is just how important vitamin D is for sleep.

In a recent study, sleep quality was assessed in participants with sleep disorders. The authors reported that vitamin D improved sleep quality, reduced sleep latency, raised sleep duration and improved subjective sleep quality [9]. This and other studies highlight the important and powerful connection between vitamin D and sleep [10, 11, 12, 13, 14, 15].

Vitamin D and Melatonin

The mechanism of exactly how vitamin D contributes to a healthy slumber is not quite elucidated; however, clinical science is just beginning to address this enigmatic process. At least in part, it appears that it might have something to do with vitamin D’s regulation of tryptophan hydroxylase (TRPH) expression – the rate-limiting enzyme in serotonin (and consequently melatonin) production [16]. Vitamin D potentiates the expression of neuronal TRPH to stimulate the appropriate production of serotonin in the brain [17, 18]. Without sufficient serotonin production, melatonin levels will not rise appropriately to give the body that signal to go to sleep at night.

How to Get Enough Vitamin D

A balanced approach to direct sun exposure (too much sun is damaging to skin cells and can increase the risk of skin cancer), eating foods rich in vitamin D (eggs, liver, fatty fish, red meat), and maybe even supplements may be helpful for people who are looking to increase their vitamin D levels. Whether to choose supplements or sunlight to get your vitamin D quota might be worth discussing with your doctor. Vitamin D adequacy can easily be assessed by a simple blood spot test.

Related Resources

References

[1] Altunsoy, N., et al., Exploring the relationship between vitamin D and mania: correlations between serum vitamin D levels and disease activity. Nord J Psychiatry, 2018: p. 1-5.

[2] Hedelin, M., et al., Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33 000 women from the general population. BMC Psychiatry, 2010. 10: p. 38-38.

[3] Bahrami, A., et al., High Dose Vitamin D Supplementation Is Associated With a Reduction in Depression Score Among Adolescent Girls: A Nine-Week Follow-Up Study. J Diet Suppl, 2017: p. 1-10.

[4] Schmitt, E.B., et al., Vitamin D deficiency is associated with metabolic syndrome in postmenopausal women. Maturitas, 2018. 107: p. 97-102.

[5] Branco, J.C., et al., Vitamin D Deficiency in a Portuguese Cohort of Patients with Inflammatory Bowel Disease: Prevalence and Relation to Disease Activity. GE Port J Gastroenterol, 2019. 26(3): p. 155-162.

[6] Ghai, B., et al., Vitamin D Supplementation in Patients with Chronic Low Back Pain: An Open Label, Single Arm Clinical Trial. Pain Physician, 2017. 20(1): p. E99-E105.

[7] Jarosz, A.C. and A. El-Sohemy, Association between Vitamin D Status and Premenstrual Symptoms. J Acad Nutr Diet, 2019. 119(1): p. 115-123.

[8] Zhao, K., et al., Low serum 25-hydroxyvitamin D concentrations in chronic insomnia patients and the association with poor treatment outcome at 2months. Clin Chim Acta, 2017. 475: p. 147-151.

[9] Majid, M.S., et al., The effect of vitamin D supplement on the score and quality of sleep in 20-50 year-old people with sleep disorders compared with control group. Nutr Neurosci, 2018. 21(7): p. 511-519.

[10] Kim, J.H., et al., Association between self-reported sleep duration and serum vitamin D level in elderly Korean adults. J Am Geriatr Soc, 2014. 62(12): p. 2327-32.

[11] Bozkurt, N.C., et al., The relation of serum 25-hydroxyvitamin-D levels with severity of obstructive sleep apnea and glucose metabolism abnormalities. Endocrine, 2012. 41(3): p. 518-25.

[12] Gominak, S.C. and W.E. Stumpf, The world epidemic of sleep disorders is linked to vitamin D deficiency. Med Hypotheses, 2012. 79(2): p. 132-5.

[13] Gong, Q.H., et al., 25-Hydroxyvitamin D Status and Its Association with Sleep Duration in Chinese Schoolchildren. Nutrients, 2018. 10(8).

[14] Gao, Q., et al., The Association between Vitamin D Deficiency and Sleep Disorders: A Systematic Review and Meta-Analysis. Nutrients, 2018. 10(10).

[15] Dogan-Sander, E., et al., Association of serum 25-hydroxyvitamin D concentrations with sleep phenotypes in a German community sample. PLoS One, 2019. 14(7): p. e0219318.

[16] Muscogiuri, G., et al., The lullaby of the sun: the role of vitamin D in sleep disturbance. Sleep Med, 2019. 54: p. 262-265.

[17] Patrick, R.P. and B.N. Ames, Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB. J, 6/2014. 28(6): p. 2398-2413.

[18] Patrick, R.P. and B.N. Ames, Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior. Faseb J, 6/2015. 29(6): p. 2207-2222.

Understanding the Connection Between Hormones and Hair Loss

Thu, 25 Jul 2019 15:22:13 -0700

A symbol of femininity for so many women, our hair demands attention. Both deeply personal and superficially public, changes in the looks of our hair can inspire a range of emotions, driving us to willingly partake in its cutting, straightening, curling, bleaching, darkening, or other aggressive chemical treatments. Hair is part of who we are and how we present ourselves to the world. This is why thinning hair is kind of a big deal – it can be a very frustrating topic for many women as there is no quick solution to getting more hair instantly.

Losing hair is utterly dreaded and distressing, and unfortunately something we all eventually come to face as we get older. As hair thins over the years and the shower drain clogs almost on a daily basis, the scalp becomes so vivid when hair is a dash too oily, and now the hair part has been moved over to a different spot, thereby concealing the thinned out patches next to the temples – you find yourself on the internet in search of answers, bombarded with innumerable articles offering anywhere between 3 and 33+ helpful tips on how to get your luscious mane back. Some are obvious – eat right and exercise to provide nutrients and stimulate blood flow, while others are less straightforward like sleeping on a silk pillowcase or wrapping your hair in a T-shirt. Whatever the suggestions may be, achieving strong and healthy hair extends way beyond keeping your locks away from heat and dyes.

Ironically the phrase “beauty is only skin deep” is not entirely appropriate in conversations about hair. Thinning, dry hair is actually a symptom of internal changes in the body. Perhaps viewed by some as a normal, inevitable sign of aging or response to stress, losing hair is oftentimes related to endocrine imbalances. This blog is going to review the role that hormones play in hair health.

Hair Follicles Cycle Between Rest and Growth

Before we jump into endocrine logistics, let’s review some anatomical considerations. Hair changes can occur due to alterations of the hair fiber itself, the hair cycle, and/or the hair follicle – the portion of hair beneath the surface of the skin. This human hair follicle is an intriguing structure! Hair follicles are incredibly productive, constantly undergoing cyclical rounds of rest (telogen), regeneration (anagen) and degeneration (catagen), and they are unique in this ability to dynamically alternate between rest and active growth.

The Stress - Tress Connection

We all know that stress is bad for you, including your hair. Bluntly speaking, stress makes your hair fall out. This is largely because stress puts you in survival mode, diverting resources away from good skin blood flow, adequate digestion, sleep, growth, etc. so the energy can be used instead for fight or flight. And let’s be honest, your body doesn’t regard hair as being essential to your survival.

Stress molecules like cortisol can target and damage the hair follicle [1]. You don’t even have to wait till menopause for stress-induced pony tail circumference shrinkage – many women in their 20s and 30s start losing hair due to stress-related issues [2].

Symptoms of sudden bouts of hair shedding with little to no hair growth are suggestive of telogen effluvium – a condition where hair in the anagen (growing) phase prematurely enters the telogen (resting) phase (Fig. 1) [3]. Furthermore, stress resulting from the hair loss itself (which for many people carries a significant psychological burden) aggravates and perpetuates the vicious cause-and-effect cycle that is doomed to keep repeating itself like “Groundhog Day”.

So take a moment to assess your stress burden and try to incorporate stress-reduction strategies in your daily life. For laboratory measures, diurnal cortisol testing in saliva or urine can help understand underlying biochemistry.

Sex Hormones – Not Just for Reproduction

PREGNANCY: Remember all that hair that you didn’t lose when you were pregnant? I loved my luxurious pregnancy hair – so strong, thick and shiny. It wasn’t me who had the “pregnancy glow”, it was my hair! Pregnancy increases the number of hair follicles in the anagen (translation: massive growth) phase. The enhanced supply of estradiol and progesterone in pregnancy are particularly nurturing to hair, expanding the growth phase and preventing shedding. Little did I know that at about 3 months postpartum, when my hormones were trying to re-equilibrate themselves and adjust to a “new normal”, my hair would all come out in clumps, washing down the drain, falling out so fast it was a seeming miracle any of it actually remained attached to my head.

Hair changes in pregnancy are common; however, every woman is different and therefore hair changes are all individual. If hair loss is experienced in the postpartum period, most women will experience a full recovery, although the process may be slow.

MENOPAUSE: Along those lines, when the levels of estradiol and progesterone fall in menopause, hot flashes and night sweats are not the only symptoms that seemingly appear out of nowhere. What many women are unaware of and unprepared for is the fact that they may also find themselves facing hair thinning. And just like the postpartum hair loss, it has everything to do with hormones. However, unlike the postpartum period, hair loss in menopause is irreversible, unless hormone replacement therapy is introduced.

Estrogen increases the amount of time that hair spends in the growing phase, so when estrogen declines, hair loses these protective effects.

Estrogen increases the amount of time that hair spends in the growing phase, so when estrogen declines, hair (and skin, brain, heart, bones and many other tissues!) loses these protective effects. Additionally, androgenic effects of testosterone can also be intensified – where testosterone’s metabolite dihydrotestosterone (DHT) can produce progressively weaker hair due to the follicle’s failure to thrive [4]. When menopausal symptoms are present, a simple-to-collect saliva test can assess the levels of estradiol, progesterone, and testosterone, and help both patient and practitioner decide on the best therapeutic strategy.

PCOS: This is a common female endocrine disorder based on a cluster of symptoms, with hyperandrogenism taking center stage [5]. In PCOS, the “Alice in Wonderland” equivalent reality of elevated androgens, women lose scalp hair, while simultaneously growing hair in places where men usually get it and where women certainly don’t want it – face, chest and back. Although there is no cure for PCOS, treatment is usually focused on managing symptoms. A laboratory workup is typically performed for saliva steroids and blood levels of HbA1c and fasting insulin.

Ferritin – Not That Kind of Store

If you think of iron as the merchandise in the front of the store, ferritin is the storage warehouse in the back. Serum ferritin is a powerful screening tool for iron deficiency. Low serum ferritin gives rise to a condition called anemia.

For those of us who’ve been anemic at one point or another (thanks, heavy periods), we are all too familiar with the symptoms of being really tired and pale. While hair loss is not the most common symptom of iron-deficiency anemia, it does affect approximately half of those with low ferritin stores [6]. Hair follicles actually hang on to ferritin. When the body is low in iron, it can pull ferritin from places like hair follicles, deemed not as important as, let’s say, red blood cell production. The resulting effect is diffuse hair loss.

If hair loss is related to insufficient iron in the body, correcting anemia should allow for hair to grow back. But first, screening for low serum ferritin levels is very important, because supplementing with iron when iron levels are normal or high can result in iron overload and toxicity [7].

Thyroid Hormone

Thyroid hormone regulates pretty much every process in our body. When the thyroid system becomes underactive, like with hypothyroidism for example, our metabolism slows down, and the lesser important body functions get less attention. Sadly, hair (and skin) typically suffer first [8]. In hypothyroidism, hair tends to be dry, brittle, dull, and diffusely thinned out – even eyebrow hair can fall out [9]! When the reverse is true and there’s too much thyroid hormone (Graves’ disease), hair will also fall out.

Accompanying symptoms of thyroid disease are noticeably in energy levels and mood. Hypothyroidism tends to make people feel tired, sluggish, depressed, and constipated. Hyperthyroidism can manifest in anxiety, problems sleeping, restlessness, and irritability. If symptoms are present, check your thyroid levels and talk to your doctor about thyroid hormone therapy. In most cases, hair grows back once thyroid abnormalities are treated.

Vitamin D – the “Sunshine” Vitamin and so Much More!

Vitamin D is an important nutrient that is essential to our immunity, bone health and many other processes. With regard to hair, it actually helps create new hair follicles by initiating the anagen phase. It does so by regulating the expression of genes that are required for hair follicle cycling. A number of symptoms, such as hair loss, can occur when the body lacks enough vitamin D. It’s not surprising then when researchers found suboptimal serum vitamin D levels in women with telogen effluvium or female pattern hair loss [10]. Moreover, patients with alopecia areata, an autoimmune condition which gives rise to hair loss, also have low serum vitamin D levels [11]. Emerging clinical research is putting forward recommendations to evaluate serum vitamin D levels in patients with hair loss [12].

Most people can get the bulk of their vitamin D through sunlight exposure or through diet. Some foods are naturally rich in this nutrient, such as fatty fish (salmon, mackerel), mushrooms, or foods fortified with vitamin D (certain cereals and milk). Vegan or vegetarian diets tend to provide less vitamin D, so supplements may be needed. Additionally, finding a balance between protecting skin from sun exposure and absorbing the vitamin may be essential to achieving optimal vitamin D levels.

Vitamin B12 – the “Energy Vitamin”

To keep hair follicles active, you need healthy blood flow – the oxygen-rich red blood cells feed the hair follicles. Vitamin B12, also known as cobalamin, does exactly that – it promotes healthy hair growth by assisting in the production of these red blood cells.

Vitamin B12 is nicknamed “the energy vitamin”, and it makes sense that its deficiency can manifest as weakness and fatigue – symptoms that appear to overlap with other types of deficiencies described in this blog. If you're worried you may be deficient, a serum vitamin B12 test can rule out abnormalities. B12 deficiency is usually more prominent in folks with digestive issues (low stomach acid, gastritis, or celiac disease), in older adults, vegans, vegetarians, and with excessive alcohol intake. Vitamin B12 is found in animal-sourced foods such as meat and dairy, and in some fermented veggies. Plants don’t make vitamin B12, but during the fermentation process, certain types of bacteria can supply some of this nutrient.

Clinical Evaluation – Talk to Your Doctor!

A laboratory workup for hair loss is commonly performed. Additional questions that you may be asked to help narrow down differential diagnosis are [13]:

When did the hair loss start? A sudden onset of hair loss may be suggestive of a disruption of the hair cycle.
Where is the hair loss most prominent? Hair loss can be patchy, diffuse or patterned. Diffuse shedding may indicate disruption of the hair cycle, while patterned thinning could be attributed to hormonal dysregulation.
What is the normal hair care routine? Certain hair care practices can have a tremendous impact on the loss of hair health.

With proper evaluation and appropriate testing for hormonal imbalances or nutritional deficiencies, help is on the way!

Related Resources

References

[1] Shin, H., et al., Acute Stress-Induced Changes in Follicular Dermal Papilla Cells and Mobilization of Mast Cells: Implications for Hair Growth. Ann Dermatol, 2016. 28(5): p. 600-606.

[2] Dinh, Q.Q. and R. Sinclair, Female pattern hair loss: current treatment concepts. Clin Interv Aging, 2007. 2(2): p. 189-99.

[3] Thom, E., Stress and the Hair Growth Cycle: Cortisol-Induced Hair Growth Disruption. J Drugs Dermatol, 2016. 15(8): p. 1001-4.

[4] Ramos, P.M. and H.A. Miot, Female Pattern Hair Loss: a clinical and pathophysiological review. An Bras Dermatol, 2015. 90(4): p. 529-43.

[5] Gersh, F., PCOS SOS. A Gynecologist's Lifeline To Naturally Restore Your Rhythms, Hormones, and Happiness. 2018: Integrative Medical Group of Irvine.

[6] Deloche, C., et al., Low iron stores: a risk factor for excessive hair loss in non-menopausal women. Eur J Dermatol, 2007. 17(6): p. 507-12.

[7] Trost, L.B., W.F. Bergfeld, and E. Calogeras, The diagnosis and treatment of iron deficiency and its potential relationship to hair loss. J Am Acad Dermatol, 2006. 54(5): p. 824-44.

[8] Contreras-Jurado, C., et al., Thyroid hormone signaling controls hair follicle stem cell function. Mol Biol Cell, 2015. 26(7): p. 1263-72.

[9] van Beek, N., et al., Thyroid hormones directly alter human hair follicle functions: anagen prolongation and stimulation of both hair matrix keratinocyte proliferation and hair pigmentation. J Clin Endocrinol Metab, 2008. 93(11): p. 4381-8.

[10] Rasheed, H., et al., Serum ferritin and vitamin d in female hair loss: do they play a role? Skin Pharmacol Physiol, 2013. 26(2): p. 101-7.

[11] Lee, S., et al., Increased prevalence of vitamin D deficiency in patients with alopecia areata: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol, 2018. 32(7): p. 1214-1221.

[12] Banihashemi, M., et al., Serum Vitamin D3 Level in Patients with Female Pattern Hair Loss. Int J Trichology, 2016. 8(3): p. 116-20.

[13] Mirmirani, P., Managing hair loss in midlife women. Maturitas, 2013. 74(2): p. 119-22.

My Thyroid Story

Wed, 26 Jun 2019 15:26:57 -0700

I was so tired. I needed a new word for tired. I felt exhausted and incapacitated, utterly drained and hollowed out. It was like my brain and body were fading. And yet, these words are still not descriptive enough to relate how I felt. Getting out of bed felt grueling, punishing. I was 24 at the time, in my 4^th year of my PhD program at Purdue University. I was newly engaged and so in love with my soon-to-be husband. Really good things were happening in my life. And I could barely function.

On the weekends, I slept in till noon, got out of bed to have a bite of breakfast and would go back to bed until 4 in the afternoon. I could only stay up with my fiancé for a little while in the early evenings, just to go back to bed around 8. This went on for months. At some point, he even asked me if I enjoyed my weekends and I distinctly remember saying “well of course, that’s when I get to sleep in.” During those days, he liked to tease me, saying I was the human equivalent of a sloth. [I did not find that amusing].

Not That Many Symptoms

I refused to believe that there was anything actually wrong with me, after all, I was young and supposed to be healthy. I attributed my fatigue to the high demands of graduate school, rather than to something internal. Plus, my blood tests for all the typical CBC parameters were normal-ish, with the exception of mildly reduced iron stores. I didn’t have all the typical symptoms of thyroid dysfunction – I’ve always felt cold for as long as I could remember, my hair was always pretty thin and skin on the dry side. I didn’t gain weight. In fact, my “bad” lipid parameters were all on the low end, and “good” cholesterol received a whopping A++ from the student center doctor. Also, I didn’t feel that depressed. In fact, I didn’t feel much of anything, except debilitating fatigue. Eventually, I did go to the doctor once more, to say that I thought I was fine, but my fiancé wanted to spend more time with me, so he insisted that I try to figure out why I was sleeping so much.

Diagnosis

After a few additional tests, I learned that my Thyroid Stimulating Hormone (TSH) level was hovering in the mid-thirties. And so, I received my diagnosis of insufficient thyroid function called hypothyroidism. And what a difference a little bit of levothyroxine (synthetic thyroid hormone replacement) did for me! I felt like a new person!

No Known Cause

Who knows why I developed hypothyroidism. In most cases, the medical community agrees that causes of hypothyroidism are idiopathic, meaning without a known cause. In retrospect, thyroid disease is not all that uncommon for someone who grew up 200-some miles away from Chernobyl [1] or for a young woman taking birth control pills [2]. I can’t change my past. But what I can focus on right now is making sure I take levothyroxine in the morning on an empty stomach [3] and monitoring thyroid function regularly.

Laboratory Measures

Although I felt much better shortly after initiating thyroid replacement, it took me years to feel like I’ve regained that vigor or zest for life. My endocrinologist tells me that’s normal. At the time of my diagnosis, the accepted reference range for normal serum TSH went up to 10 mIU/L. For me personally, being closer to 10 meant that I would get out of bed in the morning, no problem, but I also fatigued easily, mentally and physically, not completely wiped out, but sufficiently lethargic. It took some time for my medication dosage, TSH levels and symptoms to achieve their optimal balance, where I felt best.

In the third National Health and Nutrition Examination Survey (NHANES III, 1988-1994), of 17,353 people evaluated, 80.8% had a serum TSH below 2.5 mIU/L with a mean serum TSH of 1.50 mIU/L [4]. For women trying to become or already pregnant, the American Thyroid Association recommends TSH intervals to be 0.2-2.5 mIU/L [5], while other reports recommend the TSH cutoff to be less than 2.5 mIU/L to control depressive symptoms [6]. Surely enough, when I got pregnant, my levothyroxine dosage was doubled right away, and my TSH levels were monitored on a regular basis.

TSH Alone May Not Be Enough

In many cases, measuring TSH alone to diagnose hypothyroidism is not enough [7]. Free T4 and Free T3 measurements when low alongside a normal TSH may still suggest hypothyroidism [8]. Elevated thyroid peroxidase (TPO) antibodies typically indicate autoimmune thyroiditis (Hashimoto’s disease), a condition in which the body produces antibodies that attack the thyroid gland. The levels of these antibodies in blood can help diagnose this condition and indicate the extent of the disease. Lastly, thyroglobulin, a protein concentrated in the thyroid gland that is rich in iodine-bound tyrosine to ensure formation of thyroid hormone, can show up in the bloodstream at elevated levels when iodine status is very low [9].

Conclusions

If you suffer from the common symptoms of hypothyroidism, check your thyroid levels and talk to your doctor about thyroid hormone therapy. Even with normal levels of thyroid hormone, there are instances in which thyroid hormone activity can be affected at the molecular level by things like stress hormones or heavy metals. ZRT Laboratory offers a simple, at-home collection test from a finger-stick for thyroid parameters, where blood collected on a filter card and allowed to dry can be sent directly to us for testing of thyroid hormones.

Related Resources

References

[1] Zablotska LB, et al. Risk of thyroid follicular adenoma among children and adolescents in Belarus exposed to iodine-131 after the Chornobyl accident. Am J Epidemiol 2015:182:781-90.

[2] Wiegratz I, et al. Effect of four oral contraceptives on thyroid hormones, adrenal and blood pressure parameters. Contraception 2003:67:361-6.

[3] Leung AM. Levothyroxine Dosing: Morning, Night, or In Between? Medscape 2019; March 22.

[4] Hollowell JG, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III), J Clin. Endocrinol. Metab 2002:87:489-499.

[5] Soldin OP, et al. The Use of TSH in Determining Thyroid Disease: How Does It Impact the Practice of Medicine in Pregnancy?, J Thyroid Res 2013 (2013):148157.

[6] Talaei A, et al. TSH cut off point based on depression in hypothyroid patients, BMC Psychiatry 2017:17:327.

[7] Ling C, et al. Does TSH Reliably Detect Hypothyroid Patients? Ann Thyroid Res 2018:4:122-125.

[8] Persani L, et al. 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism. Eur Thyroid J 2018:7:225-237.

[9] Vejbjerg P, et al. Thyroglobulin as a marker of iodine nutrition status in the general population, Eur J Endocrinol 2009:161:475-481.

Glycine – A Small Molecule with a Big Impact on Sleep

Fri, 10 Aug 2018 10:35:00 -0700

Glycine has a calming effect on the brain – it helps you wind down and prepare for sleep. Its role as an inhibitory neurotransmitter has been unfolding over many years of ongoing research efforts.

Easily one of the most versatile amino acids, glycine serves as a building block to proteins (collagen, the most abundant protein in our body, is one-third glycine), and is heavily utilized for the production of heme, DNA and RNA synthesis, glutathione formation, and for enriching the body’s capacity for methylation reactions [1] [2].

Sleep Problems

People need sleep. It is our basic human need. Too many of us experience sleep problems. Laying there restless, counting sheep, watching the hostile glow of the green numbers, fearing the absence of sleep – this dreaded scenario of sleep-deprived desperation is all too familiar. Needless to say, sleep issues have become a pervasive health problem, and research shows that lack of sleep affects everything from mental competence to increased risk of chronic diseases and cancer.

Glycine Promotes Sleep Without Altering Sleep Architecture

When human volunteers who have continuously experienced unsatisfactory sleep were given 3 g glycine before bedtime, their sleep improved [3]. Using polysomnography, a type of diagnostic tool in sleep studies, glycine was shown to shorten the amount of time to fall asleep and stabilize sleep state, with no alterations in sleep architecture, unlike with traditional hypnotic drugs. Glycine promoted normal nocturnal sleep cycles, from deeper to shallower with very few interruptions.

Glycine Lowers Core Body Temperature

So what is it about this tiny amino acid that could be so powerful in contributing to regulating such a complex process as sleep? First of all, glycine taken orally has easy access to the brain – it readily crosses the blood brain barrier via glycine transporters [4]. Once in the brain, glycine targets glutamate NMDA receptors in the suprachiasmatic nucleus (SCN) – the 24-hour biological clock in the central nervous system that controls when we want to be asleep and awake.

By modulating NMDA receptors in the SCN, glycine induces vasodilation throughout the body to promote lowering of core body temperature [5]. Sleep and body temperature are intertwined – in its circadian oscillation, body temperature decreases before the onset of sleep and continues to decrease throughout the night, reaching its nadir about 2 hours after sleep onset, and gradually rising as a person wakes [6]. Temperature is just one of many 24-hour rhythms our bodies experience throughout the day and as nighttime approaches – the drop is important for initiating sleep. Glycine’s effect on thermoregulation is similar to that of common prescription sleep medications that also work by reducing core body temperature to promote sleep [7] [8].

Unlike many sleep aids out there, nutraceutical or pharmaceutical, that promote sleep and leave you groggy the next day, glycine actually corrects feelings of fatigue and sleepiness during the day.

Additional mechanisms that glycine may rely on to promote sleep include inhibiting orexin neurons – the “wakefulness” neurons (the absence of which is implied in narcolepsy) [9]. However, more research is needed to fully elucidate this process.

Glycine Improves Daytime Performance

Here’s the exciting part – unlike many sleep aids out there, nutraceutical or pharmaceutical, that promote sleep and leave you groggy the next day, glycine actually corrects feelings of fatigue and sleepiness during the day [10]. Sleep-restricted volunteers receiving glycine, after waking, showed improved reaction times in in the psychomotor vigilance test compared to the placebo group and reported feeling refreshed.

Glycine Regulates Daytime Wakefulness

Glycine was found to contribute to yet another circadian process – stimulating the expression of arginine vasopressin – a neuropeptide produced in the SCN. Animal studies show that the expression levels of arginine vasopressin were increased during the day in the glycine treatment group [10].

Arginine vasopressin serves as an output signal of the hypothalamic biological clock, an important modulator of circadian processes involving the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes and the autonomic nervous system [11]. Specifically to the HPA axis, arginine vasopressin synergizes signaling with corticotropin releasing hormone (CRH) to facilitate the release of adrenocorticotropic hormone (ACTH) to ultimately trigger the production of cortisol from the adrenal glands, thus contributing to the state of wakefulness [12].

Sleep isn’t just a time to rest. It’s an active process of cleaning out toxins and repairing brain cells damaged by free radicals [13]. Think about sleep as a form of neural sanitization – during sleep, waste products of brain metabolic processes are removed from the tiny spaces between brain cells where they can accumulate [14]. Sleep, therefore, is a kind of a power cleanse that restores and rejuvenates our brain for optimal function [15]. Considering glycine's prominent role in detoxifications processes, as future research studies unfold, it would be exciting to see what additional processes glycine helps regulate to support a healthy brain.

Related Resources

References

[1] M.A. Razak, P.S. Begum, B. Viswanath, S. Rajagopal, Multifarious Beneficial Effect of Nonessential Amino Acid, Glycine: A Review, Oxid Med Cell Longev 2017 (2017) 1716701.

[2] M.F. McCarty, J.H. O'Keefe, J.J. DiNicolantonio, Dietary Glycine Is Rate-Limiting for Glutathione Synthesis and May Have Broad Potential for Health Protection, Ochsner J 18(1) (2018) 81-87.

[3] W.I. Yamadera, K.; Chiba, S.; Bannai, M.; Takahashi, M., Nakayama, K., Glycine ingestion improves subjective sleep quality in human volunteers, correlating with polysomnographic changes, Sleep and Biological Rhythms 5 (2007).

[4] A. Kurolap, A. Armbruster, T. Hershkovitz, K. Hauf, A. Mory, T. Paperna, E. Hannappel, G. Tal, Y. Nijem, E. Sella, M. Mahajnah, A. Ilivitzki, D. Hershkovitz, N. Ekhilevitch, H. Mandel, V. Eulenburg, H.N. Baris, Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine, Am J Hum Genet 99(5) (2016) 1172-1180.

[5] N. Kawai, N. Sakai, M. Okuro, S. Karakawa, Y. Tsuneyoshi, N. Kawasaki, T. Takeda, M. Bannai, S. Nishino, The sleep-promoting and hypothermic effects of glycine are mediated by NMDA receptors in the suprachiasmatic nucleus, Neuropsychopharmacology 40(6) (2015) 1405-16.

[6] M. Bannai, N. Kawai, New therapeutic strategy for amino acid medicine: glycine improves the quality of sleep, J Pharmacol Sci 118(2) (2012) 145-8.

[7] R.R. Markwald, T.L. Lee-Chiong, T.M. Burke, J.A. Snider, K.P. Wright, Jr., Effects of the melatonin MT-1/MT-2 agonist ramelteon on daytime body temperature and sleep, Sleep 33(6) (2010) 825-31.

[8] E.E. Elliot, J.M. White, The acute effects of zolpidem compared to diazepam and lorazepam using radiotelemetry, Neuropharmacology 40(5) (2001) 717-21.

[9] M. Hondo, N. Furutani, M. Yamasaki, M. Watanabe, T. Sakurai, Orexin neurons receive glycinergic innervations, PLoS One 6(9) (2011) e25076.

[10] M. Bannai, N. Kawai, K. Ono, K. Nakahara, N. Murakami, The effects of glycine on subjective daytime performance in partially sleep-restricted healthy volunteers, Front Neurol 3 (2012) 61.

[11] A. Kalsbeek, E. Fliers, M.A. Hofman, D.F. Swaab, R.M. Buijs, Vasopressin and the output of the hypothalamic biological clock, J Neuroendocrinol 22(5) (2010) 362-72.

[12] H.K. Caldwell, E.A. Aulino, K.M. Rodriguez, S.K. Witchey, A.M. Yaw, Social Context, Stress, Neuropsychiatric Disorders, and the Vasopressin 1b Receptor, Front Neurosci 11 (2017) 567.

[13] A.R. Eugene, J. Masiak, The Neuroprotective Aspects of Sleep, MEDtube Sci 3(1) (2015) 35-40.

[14] L. Xie, H. Kang, Q. Xu, M.J. Chen, Y. Liao, M. Thiyagarajan, J. O'Donnell, D.J. Christensen, C. Nicholson, J.J. Iliff, T. Takano, R. Deane, M. Nedergaard, Sleep Drives Metabolite Clearance from the Adult Brain, Science 342(6156) (10/18/2013) 373-377.

[15] A.R. Mendelsohn, J.W. Larrick, Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging and neurodegenerative diseases, Rejuvenation Res 16(6) (2013) 518-23.

New Study Links Testosterone & Desire For Luxury Goods

Tue, 10 Jul 2018 12:28:00 -0700

Testosterone, so meaningful to a man’s behavior, is the evolutionary force behind everything intrinsically “male.”

Historical stereotypes peg testosterone as the macho elixir of legendary magnitude – the “chest-thumping hormone of aggression.” New research, however, is beginning to tease out previously unknown subtleties of testosterone’s effects on behavior. Testosterone is non-trivial for social functioning – increasing levels enhance generosity [1], cooperation [2], and honesty [3], thereby emphasizing that its effects in shaping male psychological makeup are infinitely more complex than previously thought.

New Study Points to Altered Consumer Preferences after Testosterone Dosing

A new study published in Nature Communications, resulting from ongoing collaborations between ZRT Laboratory and several academic institutions, explored the effects of testosterone supplementation on young men’s preference for luxury products [4]. It turns out that men in the testosterone group had a much stronger preference for goods perceived as having higher status, compared to men that received placebo, suggesting that consumption of status goods may stem from neuroendocrine motives. The surge in testosterone, established by testing these men’s salivary hormones by liquid chromatography-mass spectrometry (LC-MS), highly suggests that some region in the brain was stimulated to promote stronger attitudes toward status-enhancing goods, and not those associated with power or high quality – thereby reinforcing a sort of nuanced “consumer aggression,” as a means to gain social status.

The results of this “buying under the influence” study implicate testosterone’s role in social adaptation, highlighting its role in status-enhancing behaviors. The pursuit of status enhancement appears to be hardwired into the male neurophysiology. Human males no longer have a need for indiscriminate aggression, which, when it boils down to it, is just one of the means to achieve status. Men who are knowledgeable or skilled in a particular area can nowadays achieve social dominance without physically conquering their adversaries.

Testosterone Affects Attitudes to Competition

Whether physical or mental, testosterone surges propagate the desire to dominate – its levels spike as an individual embarks upon a task that may significantly affect status.

Whether physical or mental, testosterone surges propagate the desire to dominate – its levels spike as an individual embarks upon a task that may significantly affect status. The motivation to continue after losing a competition seems to be strongly affected by the rise in testosterone – losers with more testosterone are more likely to compete again [5]. In a real-life scenario, prior to performing a particularly challenging and demanding task testosterone levels have been shown to rise to the occasion [6].

What is it about testosterone that makes it seem to mimic the feel-good reward-enhancing actions of the neurotransmitter dopamine? Turns out, a downstream metabolite of testosterone, referred to as 5α-androstanediol, binds to dopamine receptors in the brain and enhances its actions [7]. Being at the top triggers the feel-good dopamine surge in the brain, which is amplified by this testosterone metabolite. Testosterone is prominently featured within the reward pathways – stimulating dopamine biosynthesis and potentiating its signaling throughout the brain [7] [8]. Not only can circulating testosterone and its more potent metabolite readily cross the blood-brain barrier to access dopaminergic neurons, but local synthesis can raise androgens in specific brain areas as well.

If testosterone propels men to seek status, research into the theoretical frameworks of neuroeconomics might improve our understanding of gender-specific social behaviors. Psychometrics behind behavioral tests provide a glimpse into the multi-dimensional neurobehavioral labyrinth. The gamut of structural and functional endpoints affected by testosterone is further broadened when testosterone metabolism is considered. Future studies should probe deeper into the role of testosterone metabolism in reward-based behavior of status seeking. Approaching this challenge will only be feasible using noninvasive body fluids, such as saliva or urine, and testing them for hormones like testosterone and its metabolites by state-of-the-art mass spectrometry developed at ZRT Laboratory and used in the recently reported study [4].

Related Resources

References

[1] C. Eisenegger, M. Naef, R. Snozzi, M. Heinrichs, E. Fehr, Prejudice and truth about the effect of testosterone on human bargaining behaviour, Nature 463(7279) (2010) 356-9.

[2] J. van Honk, E.R. Montoya, P.A. Bos, M. van Vugt, D. Terburg, New evidence on testosterone and cooperation, Nature 485(7399) (2012) E4-5; discussion E5-6.

[3] M. Wibral, T. Dohmen, D. Klingmuller, B. Weber, A. Falk, Testosterone administration reduces lying in men, PLoS One 7(10) (2012) e46774.

[4] G. Nave, A. Nadler, D. Dubois, D. Zava, C. Camerer, H. Plassmann, Single-dose testosterone administration increases men's preference for status goods, Nat Commun 9(1) (2018) 2433.

[5] P.H. Mehta, R.A. Josephs, Testosterone change after losing predicts the decision to compete again, Horm. Behav 50(5) (12/2006) 684-692

[6] P.A. Brennan, M.K. Herd, R. Puxeddu, R. Anand, L. Cascarini, J.S. Brown, C.M. Avery, R.T. Woodwards, D.A. Mitchell, Serum testosterone levels in surgeons during major head and neck cancer surgery: a suppositional study, Br J Oral Maxillofac Surg 49(3) (2011) 190-3.

[7] D.J. Tobiansky, K.G. Wallin-Miller, S.B. Floresco, R.I. Wood, K.K. Soma, Androgen Regulation of the Mesocorticolimbic System and Executive Function, Front Endocrinol (Lausanne) 9 (2018) 279.

[8] T.D. Purves-Tyson, S.J. Owens, K.L. Double, R. Desai, D.J. Handelsman, C.S. Weickert, Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway, PLoS One 9(3) (2014) e91151.

Heavy Metals, Nutrients & Mental Health

Wed, 23 May 2018 08:48:00 -0700

Influenced by our environment, we are constantly being exposed to elements, whether nutritional or toxic. They are a big contribution to the yin yang dualism of health and disease.

With heavy metals, contamination is so extensive nowadays that it is no longer a question of whether exposure took place, but rather what the level of exposure was or continues to be.

Toxicity from low levels of exposure can lead to a wide array of neurological disturbances and can be much more insidious in presentation than acute toxicity, which is, in contrast, rather obvious in its presentation. While the effects of heavy metal exposure may be superficially innocuous at first, over time the body distributes and stores heavy metals (“bioaccumulation”), and neurotoxic effects become inevitable.

One protein at a time, these minuscule toxic monsters hijack our brain proteins, displacing the elements that we really need for proper neuronal function, and replacing them with ones that permanently propagate oxidative stress—meanwhile stripping the body of important defensive mechanisms. Living with a haunting legacy of chronic exposure to arsenic, bromine, cadmium, and mercury from industrial pollution can have grave consequences, masked by seemingly unrelated symptoms of depression, anxiety, insomnia, headaches, memory problems, aggression, developmental issues, and many others.

Exposure to moderate contamination levels is implicated in cognitive and neurological deficits associated with poorer mental health quality, that can symptomatically be difficult to decipher.

In other words, exposure to moderate contamination levels is implicated in cognitive and neurological deficits associated with poorer mental health quality, that can symptomatically be difficult to decipher.

On the flip side, diet is becoming increasingly recognized as a potentially modifiable factor that is inherently intertwined with human cognition, behavior and emotions. Insufficient dietary intake of certain minerals has been associated with neurocognitive deficits, especially in vulnerable populations like children, whose nervous systems continue to develop for many years before reaching maturity [1].

Starting this month, ZRT will be offering an option to test elements together with neurotransmitters. This powerful combination offers an opportunity to confirm a clinical suspicion and glean a deeper understanding of how a patient's micronutrient or perhaps toxic element exposure is contributing to a shifting mood balance. Below is a brief synopsis of ZRT's elements test in dried urine, offering a literature-based rationale for their importance for the health of the nervous system.

Iodine

As an essential component of the active thyroid hormone triiodothyronine (T3), a deficiency of iodine impacts thyroid hormone synthesis and severely compromises thyroid function throughout the body. Adequate thyroid function is required for proper neurological development and iodine’s role in brain development and growth has long been recognized [2]. Children born to mothers residing in even moderately iodine-deficient areas develop behavioral, psychoneurological and intellectual difficulties [1] [3].

Bromine

In high amounts through exposure to environmental pollutants (e.g., brominated flame retardants), bromine can induce neurotoxicity by inappropriately modifying glycine, glutamate, and GABA signaling. Additionally, excessive bromine levels can interfere with iodine uptake into the thyroid gland, thereby preventing thyroid hormone synthesis. Neurological abnormalities from excessive bromine exposure can include detrimental changes in cognition and mood [4].

Selenium

Anti-inflammatory and neuroprotective in nature, selenium is an essential trace element that combats mercury and cadmium toxicity. Selenium is vital for proper functioning of several selenoproteins involved in antioxidant defenses in the brain and the rest of the body. Selenoproteins play an essential role in the activation of thyroid hormone and in glutathione production [5], those biochemical systems, dysregulation of which is associated with neuropsychiatric manifestations.

There appears to be an optimal selenium range in relation to depressive symptoms. Studies show that both too low and too high selenium levels are linked with oxidative and inflammatory pathways, offering a potential mechanistic explanation for the link between selenium levels and depression [6].

Specifically with regard to neurotransmission, selenium displays selective inhibition of monoamine oxidase A (MAO A), an enzyme that breaks down serotonin (and dopamine to a certain extent) [7]. Selectively inhibiting MAO A would have a serotonin-elevating effect, and for patients afflicted with mood issues rooted in serotonin deficiency, increased serotonin may be key to feeling better. Furthermore, in dopaminergic neurons, which are particularly vulnerable to oxidative stress, selenium plays a protective role and prevents neurodegeneration [8].

Arsenic

Arsenic disrupts serotonin and dopamine metabolism, thus compromising neuronal health. Even at low-level exposure, arsenic predisposes to cognitive dysfunction and susceptibility to mood disorders. Additionally, arsenic can induce neuronal death by stimulating processes implicated in Alzheimer’s disease [9] [10] [11].

Cadmium

Cadmium upsets the delicate balance between glycine, glutamate, and GABA to negatively impact memory and cognition by being especially destructive to white matter in the brain. Cadmium exposure has detrimental effects on neurocognitive development in children, and is associated with learning disabilities, lower IQ, attention deficits, behavioral problems, and hearing loss [10] [12] [13] [14] [15].

Mercury

“Mad as a hatter” cases of mercury poisoning are historically-documented examples of gold and silver mining casualties [16]. Mercury is well-known as a potent neurotoxin, which increases oxidative stress by permanently inhibiting glutathione function, thereby stripping neurons of their defensive mechanisms. Mercury radically skews neurotransmission – it stimulates excitatory signaling (e.g., glutamate, dopamine) and decreases inhibitory signaling (e.g., GABA). Mercury exposure can cause a variety of neurological symptoms, including irritability, mood swings, headaches, concentration and memory difficulties, and sleep disturbances [5] [17] [18].

Lithium

Lithium, in trace amounts, has been shown to improve mood and slow the progression of dementia. Overall, lithium’s effects on the brain are neuroprotective, antioxidant and regenerative. Lithium can modulate monoamine oxidase activity to appropriately break down serotonin, dopamine, and phenethylamine [19] [20].

Laboratory testing in addition to exposure history, clinical signs, and symptoms must all be taken into account during diagnosis of heavy metal toxicity or mineral nutrient deficiency. The body is an intricate system of checks and balances shaped by nutritional elements or heavy metals engaging one another and other molecules in the body in a complex biochemical waltz to control many body processes.

Monitoring exposure to heavy metals alerts to insidious exposure before too much bioaccumulation can occur, helping to prevent more severe damage. And testing for dietary deficiencies of the nutrients allows the opportunity to rectify these by supplementation or dietary changes, while preventing excessive intake that can also have undesired effects. Combining neurotransmitters and elements testing gives a clearer picture of how elements can be contributing to neurotransmitter imbalances or mood disorders.

Related Resources

References

[1] I. Velasco, S.C. Bath, M.P. Rayman, Iodine as Essential Nutrient during the First 1000 Days of Life, Nutrients 10(3) (2018).

[2] S. Henjum, I. Aakre, A.M. Lilleengen, L. Garnweidner-Holme, S. Borthne, Z. Pajalic, E. Blix, E.L.F. Gjengedal, A.L. Brantsaeter, Suboptimal Iodine Status among Pregnant Women in the Oslo Area, Norway, Nutrients 10(3) (2018).

[3] F. Vermiglio, V.P. Lo Presti, M. Moleti, M. Sidoti, G. Tortorella, G. Scaffidi, M.G. Castagna, F. Mattina, M.A. Violi, A. Crisa, A. Artemisia, F. Trimarchi, Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries, J Clin Endocrinol Metab 89(12) (2004) 6054-60.

[4] M.M. Dingemans, M. van den Berg, R.H. Westerink, Neurotoxicity of brominated flame retardants: (in)direct effects of parent and hydroxylated polybrominated diphenyl ethers on the (developing) nervous system, Environ Health Perspect 119(7) (2011) 900-7.

[5] H.A. Spiller, Rethinking mercury: the role of selenium in the pathophysiology of mercury toxicity, Clin Toxicol (Phila) (2017) 1-14.

[6] J. Wang, P. Um, B.A. Dickerman, J. Liu, Zinc, Magnesium, Selenium and Depression: A Review of the Evidence, Potential Mechanisms and Implications, Nutrients 10(5) (2018).

[7] C.A. Bruning, M. Prigol, J.A. Roehrs, C.W. Nogueira, G. Zeni, Involvement of the serotonergic system in the anxiolytic-like effect caused by m-trifluoromethyl-diphenyl diselenide in mice, Behav Brain Res 205(2) (2009) 511-7.

[8] N.D. Solovyev, Importance of selenium and selenoprotein for brain function: From antioxidant protection to neuronal signalling, J Inorg Biochem 153 (2015) 1-12.

[9] Y.C. Lin, C.T. Su, H.S. Shiue, W.J. Chen, Y.H. Chen, C.S. Choy, H.Y. Chiou, B.C. Han, Y.M. Hsueh, The Methylation Capacity of Arsenic and Insulin Resistance are Associated with Psychological Characteristics in Children and Adolescents, Sci Rep 7(1) (2017) 3094.

[10] V. Karri, M. Schuhmacher, V. Kumar, Heavy metals (Pb, Cd, As and MeHg) as risk factors for cognitive dysfunction: A general review of metal mixture mechanism in brain, Environ Toxicol Pharmacol 48 (2016) 203-213.

[11] L.L. Wu, W. Gong, S.P. Shen, Z.H. Wang, J.X. Yao, J. Wang, J. Yu, R. Gao, G. Wu, Multiple metal exposures and their correlation with monoamine neurotransmitter metabolism in Chinese electroplating workers, Chemosphere 182 (2017) 745-752.

[12] C. Marchetti, Interaction of metal ions with neurotransmitter receptors and potential role in neurodiseases, Biometals 27(6) (2014) 1097-113.

[13] M. Mendez-Armenta, C. Rios, Cadmium neurotoxicity, Environ Toxicol Pharmacol 23(3) (2007) 350-8.

[14] K. Gustin, F. Tofail, M. Vahter, M. Kippler, Cadmium exposure and cognitive abilities and behavior at 10years of age: A prospective cohort study, Environ Int 113 (2018) 259-268.

[15] Y. Liu, X. Huo, L. Xu, X. Wei, W. Wu, X. Wu, X. Xu, Hearing loss in children with e-waste lead and cadmium exposure, Sci Total Environ 624 (2018) 621-627.

[16] K. Schofield, The Metal Neurotoxins: An Important Role in Current Human Neural Epidemics?, Int J Environ Res Public Health 14(12) (2017).

[17] S. Caito, M. Aschner, Neurotoxicity of metals, Handb Clin Neurol 131 (2015) 169-89.

[18] F. Woimant, J.M. Trocello, Disorders of heavy metals, Handb Clin Neurol 120 (2014) 851-64.

[19] M.A. Nunes, T.A. Viel, H.S. Buck, Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease, Curr Alzheimer Res 10(1) (2013) 104-7.

[20] G.N. Schrauzer, E. de Vroey, Effects of nutritional lithium supplementation on mood. A placebo-controlled study with former drug users, Biol Trace Elem Res 40(1) (1994) 89-101.

The Role of Estrogen & the Microbiome in Preserving Bone Health

Sat, 12 May 2018 12:10:00 -0700

I remember my great-grandmother’s hands. So capable, big and warm, covered in freckles, ready to comfort, unbending the clawed rigidity to softly wipe my tears.

I remember her powerful, beautiful mind, endless with patience, tirelessly reading my favorite story over and over from a tattered book. I remember her, trapped in a creaky body, moving slowly around the kitchen in a sort of graceful dance with pain, cooking, cleaning, all the while humming, singing to herself.

In that time and space, to my child eyes, she seemed timeless and invincible. Now all I have are the sweetest memories of her. And the photographs of her looking so lovely and so fragile. She was one of the lucky ones – no falls, no breaks, no fractures. Instead, she quietly, silently, withered, shrank onto herself, rounded back and all.

Estrogen helps keep our bones healthy and strong. In menopause, when estrogen levels are very low, its protective effects on bone tissue are lost, predisposing women to fractures and disability. Postmenopausal osteoporosis is an estrogen deficiency-induced metabolic bone disease, characterized by reduced bone strength, increased bone loss and extensive structural destruction. Until a fracture event happens, osteoporosis silently devours bone tissues without any apparent symptoms. After a fracture, pain, malformation, and dysfunction can all contribute to the high morbidity of the disease. The National Osteoporosis Foundation estimates 10 million Americans over the age of 50 live with osteoporosis.

Major research efforts have been focused on understanding osteoporosis pathology. May is osteoporosis prevention month and is a good time to share what’s new in the frontier of science that addresses bone health.

Estrogen Works Directly on Bone Tissue to Elicit Protective Effects

Scientists have long known that estrogen works directly on estrogen receptors located within bone tissue to elicit its protective effects. Exciting new research is now beginning to explore the endocrine landscape of estrogen’s actions, illuminating new, previously unexplored, relationships between estrogen and the microbiome, and the impact these interactions have on bone health.

The Importance of a Diverse Microbiome

Loss of estrogen is associated with unfavorable changes in the microflora, weakening of the gut barrier’s integrity, increased intestinal permeability, decreased calcium absorption, and increased inflammatory response.

Surely the microorganisms that we host in our gastrointestinal tract are important for digestive health – they break down complex carbohydrates to improve energy extraction from food, produce vitamins and minerals, aid in digestion and absorption, and ferment dietary fibers. Turns out that these tiny microbial passengers residing in our digestive tract are also very important for bone health. Recent studies help illuminate the relationship between the intestinal microbiota and bone health, suggesting that the microbiome may serve as a potential therapeutic target for osteoporosis [1].

A diverse microbiome ensures that calcium and vitamin D – the dominant mineral and vitamin in bone formation and integrity – are absorbed adequately. These microbes also help safeguard the gut barrier to maintain its integrity. The integrity of the gut epithelial barrier is critical for regulating nutrient, electrolyte, and water absorption, and preventing the entry of pathogenic microorganisms and cytokines that are detrimental to bone health, from the gut into the rest of the body.

Additionally, a healthy microbiome can favorably shift the host’s immunity, where “osteoimmunity” [2] can protect from “immunoporosis [3].” Germ-free animals have decreased osteoclast precursor cells in the bone marrow, an effect that was counteracted by the introduction of gut microbiota from mice raised in a conventional environment [3]. The authors concluded that the increase in bone mass following colonization of gut bugs into germ free animals was associated with the reduction in the expression of pro-inflammatory cytokines.

What About Estrogen?

Estrogen engages the microbiome in an interplay geared to prevent the loss, and promote growth and proliferation, of beneficial bacteria [4]. Yes, estrogen is key to maintaining the diversity of our gut bugs! Research shows that animals treated with estrogen have significantly higher microbial diversity than controls [5].

And Now for That Estrogen-Microbiome-Bone Connection

Loss of estrogen is associated with unfavorable changes in the microflora, weakening of the gut barrier’s integrity, increased intestinal permeability, decreased calcium absorption, and increased inflammatory response [5] [6]. In menopause when estrogen is low, not only are estrogen’s direct protective effects on bone tissue lost (not enough estrogen to active its receptors on bone tissue), but also its indirect effects, via compromised microbial ecosystems and diminishing gastrointestinal health [7]. All of these consequences of estrogen deficiency compromise bone health.

Bone Loss is an Estrogen & a Gut Problem

Gut microbes regulate the systemic immune response critical for bone homeostasis. Occurrence of dysbiosis, when the gut bacterial population is askew, is sufficient to aggravate intestinal pathologies related to the immune system. When the immune system is triggered in the absence of estrogen’s potent anti-inflammatory effects, bone health — already compromised by the lack of estrogen — may suffer additional consequences due to detrimental changes in gut health. Importantly, the inflammatory response from gastrointestinal inflammation and dysbiosis, which estrogen protects against, can lead to an immune cascade that can hinder vitamin D receptor expression and activity, wounding not only the immune system but hindering the skeleton’s ability to retain its calcium.

Relevance to Patients

Overall, a balanced hormonal clinical picture is important for maintaining healthy bones. In addition, therapeutic approaches to preserve the integrity of the gut would offer a promising therapy to prevent estrogen depletion-induced bone loss. Estrogen therapy (if not contraindicated) together with probiotics may be worth considering for patients approaching menopause to maintain estrogen and bone health.

Related Resources

References

[1] Xu X, et al. Intestinal microbiota: a potential target for the treatment of postmenopausal osteoporosis. Bone Res 5 2017;5:17046.

[2] Crotti TN, et al. Osteoimmunology: Major and costimulatory pathway expression associated with chronic inflammatory induced bone loss. J Immunol Res 2015;2015:281287.

[3] Srivastava RK, et al. Immunoporosis: Immunology of osteoporosis - role of T cells. Front Immunol. 2018;9:657.

[4] Chen KL, et al. Estrogen and microbiota crosstalk: should we pay attention? Trends Endocrinol Metab 2016;27:752-755.

[5] Baker JM, et al. Estrogen-gut microbiome axis: Physiological and clinical implications. Maturitas 2017;103:45-53.

[6] Braniste V, et al. Oestradiol decreases colonic permeability through oestrogen receptor beta-mediated up-regulation of occludin and junctional adhesion molecule-A in epithelial cells. J Physiol. 2009;587(Pt 13):3317-28.

[7] Jones RM, et al. Osteomicrobiology: The influence of gut microbiota on bone in health and disease. Bone. 2017 Apr 27. [Epub ahead of print]

Collection Timing Matters for Urine Testing

Fri, 02 Mar 2018 10:48:00 -0800

Urine is rapidly becoming the preferred medium for neurotransmitter testing to ensure objective neurobiological assessment. This is because a) urine is the primary route of peripherally-produced neurotransmitter elimination; and b) it is non-invasive and cost-effective. This blog takes a look at how dried urine testing provides a superior advantage over standard liquid urine collection methods.

Is a 24-hour collection necessary – or even desirable?

The gold standard of neurotransmitter testing in urine involves an inconvenient and mildly embarrassing collection of liquid urine over a period of 24 hours into a jug. The awkwardness of this type of collection is further compounded by the fact that in certain circumstances during the day, it is nearly impossible to get every last drop of the sample into the collection device, and a patient may even miss some collections altogether. To circumvent these issues associated with the 24-hour liquid collection, dried urine can be used in place of the liquid sample, offering many advantages. Collecting urine on filter cards at 4 time points throughout the day is non-invasive, simple, straightforward and discreet – which allows the clinician and patient to get an accurate 24-hour clinical picture without the enormous hassle.

For the neurotransmitter test, ZRT recommends collecting urine 4 times throughout the day - the first void of the morning; the second void, approximately 2 hours after waking; in the early evening around dinner time; and at bedtime. This method ensures both ease of obtaining the sample for the patient and stability of the sample during shipping and handling.

When samples are received in the lab, the 4 dried urine strips are processed together to get an average value for neurotransmitters excreted throughout the day. An additional advantage of dried urine is that the strips can be processed separately as 4 individual samples to evaluate diurnal rhythms of the first-line stress responders, norepinephrine and epinephrine, in addition to cortisol, cortisone and melatonin – all critical to the clinical evaluation of the stress response.

Diurnal Rhythms

Every now and then, providers and patients ask ZRT if the first morning collection or the second morning collection alone can be used as a substitute for the 4 time-point collection. And the short answer is no. With good reason.

Neurotransmitter levels do fluctuate dramatically during the day, with some neurotransmitters having very distinct circadian fingerprints.

Averaged throughout the day, neurotransmitter levels, as determined by the 4 time-point collection, are a stable measure of the individual’s neurotransmitter status. Meaning that if you measure the average daily excretion of neurotransmitters over a period of a few days, the numbers will be approximately the same from one day to the next (assuming no changes in medications or supplements, and no interfering foods). However, neurotransmitter levels do fluctuate dramatically during the day, with some neurotransmitters having very distinct circadian fingerprints.

Norepinephrine and epinephrine display specific diurnal rhythms – levels are low when we sleep and steadily increase over the course of the day to regulate blood pressure, heart rate and blood sugar and adjust the body’s response to stressors accordingly. This diurnal fluctuation in norepinephrine and epinephrine levels is part of the body’s normal physiological response.

Specifically, the levels of norepinephrine and epinephrine are lowest in the first urine collection of the day and reflect the body’s production of these catecholamine molecules during the night. Levels begin to increase towards mid-morning – a normal physiological response, thus the second urine collection captures norepinephrine and epinephrine production during that morning time period since the first collection. Levels then continue to increase towards mid-morning, peak in the afternoon, and decrease by bedtime with low levels during the night, so a graph of the levels over a typical 24-hour period would take the shape of an inverted U. It is because of these diurnal fluctuations that one cannot reliably exchange the first or second morning samples for the 24-hour one without first developing reference ranges from samples collected at very specific time points.

The first and second morning samples are different

On a similar note, it is precisely because of these diurnal fluctuations that laboratories testing urine collected at a single time point in the morning ought not to advise their patients to interchange the first and second morning urine samples. Without reference ranges developed from samples collected at specific time points to account for circadian rhythmicity, the clinical result will likely to be grossly inaccurate.

ZRT Study

In a ZRT study, 30 healthy volunteers donated their first and second morning urine and the results were compared for epinephrine. Epinephrine levels in the second morning void (orange line), as a general rule, run higher than the first morning void (blue line). And for some of the volunteers, the second morning urine showed dramatically higher levels of epinephrine than the first morning sample. This means that if a patient collects their first morning sample, and the range for epinephrine was established based on the second morning values, then this patient’s result will fall into the "low" clinical range, yet that may not be a valid result for that individual.

Additional analysis of these data shows that epinephrine values in the 1^st and 2^nd morning voids do not correlate with an extremely low value for the coefficient of variation of R²=0.0324 (if things correlate, then the R²value ought to be closer to 1).

Dried urine represents a tremendous advantage over liquid 24-hour urine collections for both patients and clinicians, but it is important to be aware of these timing issues and ensure that samples are properly collected. When testing is done right, it gives not just a blurry snapshot of a patient’s neurotransmitter status but instead a focused assessment that can really help pinpoint abnormalities in a diurnal rhythm, as well as an accurate assessment of overall neurotransmitter production without all the fuss of a liquid collection.

Related Resources

The Impact of Hormones on Serotonin in Depression

Fri, 09 Feb 2018 10:57:00 -0800

Serotonin, or rather its deficiency, frequently steals the spotlight in conversations regarding depression. Initially discovered as a component of serum in 1948 to regulate vasoconstriction (serotonin = serum + tone), the role of serotonin in depressive disorders wasn't implied until a few years later. Since then, much effort has been dedicated by scientists and clinicians alike to understand the wondrous complexity of the seemingly inscrutable code that is serotonin neurotransmission. In fact, some of the major breakthroughs in psychopharmacology happened with serotonin in mind – the discovery of selective serotonin reuptake inhibitors (SSRIs) prominently expanded the therapeutic toolbox for mental health practitioners.

The appearance of SSRIs, however, was just the beginning of the arduous journey to understand and treat the intricate disorder that is depression. Providing valuable relief for some by offering mood improvement and stability, the treatment of depression has fallen short of optimal for others [1]. As brilliant research minds continue to unravel the mysteries of depression, what is becoming clearer is that depression is prolific in complexity, painting a picture of inappropriate entanglement of neural and somatic pathways as they respond to a variety of insults. It is this complexity that makes it difficult to understand where and how the intrinsic program has gone off the rails, leaving practitioners without significant leverage in the plight to increase a patient’s emotional reserve.

Recent explosions of interest in brain studies are actively driving research in depression to the next league. But the enormity of the task to uncover relevant underpinnings of depression still remains overwhelming. And that probably has to do with the fact that at its most fundamental level, depression is excruciatingly heterogeneous. An astounding number of factors could be responsible for the derailed mood infrastructure - dysregulation of inflammatory, metabolic, neuroendocrine, growth factor and of course, neurotransmitter systems, just to name a few [1].

Time for Pie

To describe this in simpler terms, let’s think of depression for a moment as a pumpkin pie. Each slice within the pie represents a particular system which, when dysregulated, contributes to the pathology of the disorder. In this over-simplified model of depression, neurotransmitters are just one slice of the pie, and within that slice, there are even smaller slices that could be any or all of the following – serotonin, dopamine, norepinephrine, glutamate - you name it! What does this mean for serotonin in particular? Well, serotonin happens to be the piece that gets talked about a lot because historically it’s the most-studied piece. In the monoamine theory of depression, serotonin is a prominent player. But unlike this two-dimensional model of pie slices that are nestled comfortably in their own pie framework, the real “pie pieces” are dynamic and frequently affect how and what the other “pie pieces” are doing.

This blog is going to focus on a small but significant aspect of serotonin biology that pertains to depression. If prominent serotonin lowering is to blame for the depressive symptoms in a subset of patients, then what are some of the endocrine factors that could be driving and perpetuating this dearth of neurochemicals? The mechanisms behind hormonal regulation of serotonin levels are key to our understanding of the patient’s mood pathology.

The "Housekeeping" Functions of Serotonin

A small molecule with such profound impact, serotonin fulfills an impressive number of critical roles throughout the body – above and below the neck. Serotonin is our body’s housekeeping chemical –it promotes feelings of well-being, hence the nickname “happiness molecule”. Serotonin also arms us against adversity, providing us with resilience. And it does so much more! Serotonin regulates appetite, temperature, energy balance, platelet coagulation, bone remodeling, sleep cycles, emesis, the inflammatory response and sexual behavior, just to name a few [2]. To make all these processes happen, serotonin works in a dynamic equilibrium relying on communication from other molecules – estradiol, testosterone, cortisol, vitamin D and many others that help shape its molecular behavior. In this context, hormones play a very important role in modulating serotonin signaling.

To properly address insufficient serotonin levels, we need to understand how the body makes this neuro-chemical.

A Word About How Serotonin is Made...

To synthesize serotonin in the brain and the rest of the body, humans start with tryptophan, an amino acid found in foods like meats and fish, dairy and tofu, nuts and seeds [3]. Conversion of tryptophan to serotonin is a two-step process. First, tryptophan is converted to its downstream metabolite, 5-HTP. Tryptophan hydroxylase (TRPH) is the enzyme in charge of this process – type 1 does the job in the gut (where upwards of 90% of all serotonin is manufactured in the body), and type 2 reigns in the brain. Sufficient biopterin and iron are required to facilitate the activity of TRPH and get over the hurdle of this rate-limiting step [4] [5].

Once 5-HTP is formed, the path to serotonin is smooth sailing. Sure, there’s still a need for vitamin B6 in order for the reaction to proceed, but typically 5-HTP to serotonin is a straightforward biochemical transaction. This is why for serotonin-deficient individuals, 5-HTP supplementation can be an effective therapeutic strategy to elevate mood either as a stand-alone treatment [6] or in conjunction with SSRIs [7] [8].

... and How Serotonin is Broken Down

Serotonin is broken down to its inactive metabolite 5-HIAA via a 2-step process, one of which is governed by monoamine oxidase A (MAO A). (Note that not all serotonin metabolites are inactive; for example, melatonin is derived from serotonin to regulate sleep). There has to be enough MAO A to assist with keeping serotonin levels “just right” – too much MAO A activity and the serotonin pool will be zealously depleted, leaving the individual vulnerable to afflictions such as insomnia, excessive worry, and perhaps even depressive mood. Not enough MAO A activity, and serotonin levels may build up, potentially contributing to a multifaceted array of aggressive and impulsive behaviors [9].

To get a glimpse at MAO A activity in a patient, assaying serotonin and 5-HIAA together is imperative. The levels of both species – the neurotransmitter and its metabolite – are analyzed together to make the most informed therapeutic decision. Unlike a straight-lined seesaw, the levels of serotonin and 5HIAA don’t always change in a linear fashion in relation to each other and utilizing that discrepancy can be of important clinical value.

To summarize, TRPH is important for serotonin biosynthesis, and MAO A is important for its metabolism. These steps in the biosynthesis and breakdown of serotonin are precisely the check-points where hormones can step in and acutely regulate serotonin levels. Below is a summary of how different hormones modulate serotonin levels through biosynthesis and breakdown.

The Nurturing Nature of Estradiol Towards Serotonin

Estradiol is especially nurturing towards serotonin – it stimulates TRPH expression to ensure that enough serotonin is made and suppresses MAO A levels to prolong the longevity of the neurotransmitter. This relationship between estradiol and serotonin is prominently featured in perimenopause, when estradiol levels eventually plummet, leaving serotonin down in the dumps as well. This is one of the reasons why mood disorders are common in menopause – when estradiol goes away, so can serotonin [10].

Hormone replacement therapy can effectively manage existing depression in menopause as it aims to restore estradiol to pre-menopausal physiological levels [11]. Moreover, a recent double-blind, placebo-controlled randomized trial published in JAMA Psychiatry provides some of the first evidence that depressive symptoms can actually be prevented with hormone replacement therapy, thus protecting women from developing mood disorders as a consequence of extreme estradiol fluctuations/withdrawal [12]. SSRIs can also help take the edge off low mood, although some women may be unwilling to comply because of a smothered libido (which is already low because of low estradiol).

Menopause is not the only time when the estradiol/serotonin connection becomes critical with respect to mood. In pregnancy, estradiol levels increase by upward of 30-fold compared to levels prior to conception. Shortly after birth, with the loss of the placenta, estradiol is rapidly cleared to usher in the lactation period, leaving some women particularly vulnerable to developing postpartum depression. In the United States alone, approximately 1 in 9 women experience depressive symptoms after giving birth [13]. Persistent depressive symptoms that develop after having a baby, also called postpartum depression, range in prevalence – from a low of 8% to a high of 20% in some states with an average of 13% across the country [13].

So now for that connection with serotonin. A recent study utilized imaging techniques to look at MAO A levels in the postpartum period. Women with postpartum depression had elevated MAO A density in the brain areas responsible for emotion compared to asymptomatic women in the postpartum period [14].(Note: the higher the levels of MAO A, the lower the levels of monoamine neurotransmitters, including serotonin. Elevated MAO A activity has been reported in other types of depression [15].) As estradiol drops rapidly in the first few days postpartum, there is a temporary rise in MAO A levels and activity. But for some women, MAO A levels fail to return to normal, and remain elevated, all the while hastily burning through available serotonin. Without adequate normalization, these elevated MAO A levels, compounded by the challenges that motherhood brings, renders some women overtly prone to developing postpartum mood disorders.

In summary, the serotonin system learns to rely heavily on estradiol from the onset of puberty and beyond. In circumstances when estradiol levels decrease profoundly, such as in postpartum when estradiol goes from high to physiological, or in menopause when estradiol drops from normal to essentially non-existent, the serotonin system can struggle to adjust. Loss of equilibrium in the serotonin system can then manifest as mood disorders.

The Caveat of Serotonin Lowering by Testosterone

First isolated 80-some years ago, testosterone’s influence on the brain is finally getting much needed research attention rather than being largely a matter of creative speculation.

The relationship between testosterone and serotonin has not been fleshed out as well as it has for estradiol. However, experimental evidence suggests that testosterone does the opposite of estradiol – it potentiates MAO expression. In the presence of an aromatase inhibitor to prevent testosterone metabolism to estradiol, testosterone actively elevates MAO A levels, consequently lowering precursor neurotransmitters (serotonin) and elevating metabolites (5-HIAA) [16].

But this is where the old-fashioned dualism of the line dividing androgens and estrogens becomes blurry and not well-defined. Many of testosterone’s effects on the brain are paradoxically estrogenic in nature. This is because the rapid generation of estrogen from its yangian counterpart testosterone in the brain, an organ which is rich in aromatase, results in suppression of MAO A.

Nature abhors absolutes and this testosterone-estradiol push-pull in regulating one of the most prominent monoamine metabolizing enzymes is a prime example of how it keeps a balance in a system as delicate as the brain.

An Unexpected Kinship Between Cortisol and Serotonin

Stress is one of the primary risk factors for developing mood pathologies. When threats are chronic, unrelenting and intense in nature, vulnerable individuals respond by the consequent hyperactivation of the HPA axis resulting in persistently elevated cortisol levels. The stress cascade becomes a wrecking crew, spearheaded by cortisol, that targets neurotransmitters with utmost ferocity. Studies show that a subset of patients suffering from depressive disorders display a hyper-aroused HPA axis with higher levels of cortisol compared to individuals who are not depressed [17] [18]. (Note: although elevated cortisol is observed in some depressed patients, it is not a defining feature for all types of depression.) And the functional consequence of elevated cortisol may just be diminished serotonin levels, because cortisol is yet another member of the neuroendocrine family with MAO A-potentiating capabilities [19]. Very exciting!

Yet the plot thickens even more when serotonin emerges not merely as an innocent passive bystander, simply receiving inputs from a devouring MAO A governed by an elevated glucocorticoid tone, but as an active, prominent modulator of the HPA axis in and of itself. The serotonin system (serotonin + serotonin receptors) acts directly in the hypothalamus to stimulate the production of CRH, corticotropin-releasing hormone, an essental part of the cortisol-activation cascade [19]. In fact, 5-HTP administration triggers an impressive increase in salivary cortisol levels compared to placebo [20]. This spike in salivary cortisol in response to 5-HTP may be tolerated, without adverse symptomatology, by many individuals. However, in patients with panic disorder, cortisol levels spike even higher than in controls [20]. Thus, the subsidiary effect of increased agitation with 5-HTP supplements in sensitive individuals may be explained by a rapid rise in cortisol.

The Low Down on Vitamin D and Serotonin

Interest in vitamin D has been growing exponentially as large swaths of the population are not getting enough of this "sunshine vitamin." Biologically a hormone, produced in the skin in response to sunlight, vitamin D is important for mood health. Disappearance of vitamin D has been linked to mood disorders, such as seasonal affective disorder, mania [21], psychosis [22], and depression [23].

With respect to serotonin, adequate vitamin D levels are essential for appropriate serotonin biosynthesis. Like estradiol, vitamin D potentiates the expression of neuronal TRPH to stimulate the appropriate production of serotonin in the brain [24] [25]. But remember how there are two types of TRPH and type 1 is present in the gut to regulate the majority of the body’s serotonin production? Well, vitamin D inhibits the expression of TRPH 1 to suppress serotonin biosynthesis [24].

What does this mean for a patient testing their urinary serotonin who is concurrently deficient in vitamin D? Without sufficient vitamin D, this individual may be suffering from low brain serotonin (not enough TRPH 2 stimulation) all the while having high serotonin production in the gut (not enough TRPH 1 suppression). This can explain why a patient who checks depression on the symptom portion of the ZRT requisition form may have a high serotonin result.

In Conclusion

As with all biochemical systems, none can be viewed in isolation. Hormonal changes are as involved with neurotransmitter systems as they are with the other physiological systems they impact. A better understanding of the interplay between these systems can go a long way to helping practitioners view their patients with depression by getting to the source of the imbalance rather than treating only the end result.

Related Resources

References

[1] Strawbridge, R., A.H. Young, and A.J. Cleare, Biomarkers for depression: recent insights, current challenges and future prospects. Neuropsychiatr Dis Treat, 2017. 13: p. 1245-1262.

[2] Shajib, M.S. and W.I. Khan, The role of serotonin and its receptors in activation of immune responses and inflammation. Acta Physiol (Oxf), 3/2015. 213(3): p. 561-574.

[3] Strasser, B., J.M. Gostner, and D. Fuchs, Mood, food, and cognition: role of tryptophan and serotonin. Curr. Opin. Clin Nutr Metab Care, 1/2016. 19(1): p. 55-61.

[4] Hasegawa, H. and K. Nakamura, CHAPTER 2.3 - Tryptophan Hydroxylase and Serotonin Synthesis Regulation, in Handbook of Behavioral Neuroscience, C.P. Müller and B.L. Jacobs, Editors. 2010, Elsevier. p. 183-202.

[5] Kim, J. and M. Wessling-Resnick, Iron and mechanisms of emotional behavior. J Nutr Biochem, 2014. 25(11): p. 1101-1107.

[6] Boadle-Biber, M.C., Regulation of serotonin synthesis. Prog Biophys Mol Biol, 1993. 60(1): p. 1-15.

[7] Kious, B.M., et al., An Open-Label Pilot Study of Combined Augmentation With Creatine Monohydrate and 5-Hydroxytryptophan for Selective Serotonin Reuptake Inhibitor- or Serotonin-Norepinephrine Reuptake Inhibitor-Resistant Depression in Adult Women. J Clin Psychopharmacol, 2017. 37(5): p. 578-583.

[8] Jacobsen, J.P.R., et al., Adjunctive 5-Hydroxytryptophan Slow-Release for Treatment-Resistant Depression: Clinical and Preclinical Rationale. Trends Pharmacol Sci, 2016. 37(11): p. 933-944.

[9] Godar, S.C., et al., The role of monoamine oxidase A in aggression: Current translational developments and future challenges. Prog. Neuropsychopharmacol. Biol. Psychiatry, 8/1/2016. 69: p. 90-100.

[10] Bromberger, J.T. and H.M. Kravitz, Mood and menopause: findings from the Study of Women's Health Across the Nation (SWAN) over 10 years. Obstet. Gynecol. Clin. North Am, 9/2011. 38(3): p. 609-625.

[11] Fischer, B., C. Gleason, and S. Asthana, Effects of hormone therapy on cognition and mood. Fertil. Steril, 4/2014. 101(4): p. 898-904.

[12] Gordon, J.L., et al., Efficacy of transdermal estradiol and micronized progesterone in the prevention of depressive symptoms in the menopause transition: A randomized clinical trial. JAMA Psychiatry, 2018.

[13] Ko, J.Y., et al., Trends in Postpartum Depressive Symptoms - 27 States, 2004, 2008, and 2012. MMWR Morb Mortal Wkly Rep, 2017. 66(6): p. 153-158.

[14] Sacher, J., et al., Relationship of monoamine oxidase-A distribution volume to postpartum depression and postpartum crying. Neuropsychopharmacology, 2015. 40(2): p. 429-35.

[15] Meyer, J.H., et al., Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch. Gen. Psychiatry, 11/2006. 63(11): p. 1209-1216.

[16] Bethea, C.L., et al., Androgen metabolites impact CSF amines and axonal serotonin via MAO-A and -B in male macaques. Neuroscience, 2015. 301: p. 576-89.

[17] Gupta, S., et al., Evaluation of Endocrine Parameters as Predictor of Major Depressive Disorder. Indian J Psychol Med, 2017. 39(6): p. 766-769.

[18] Duval, F., et al., Interaction between the serotonergic system and HPA and HPT axes in patients with major depression: implications for pathogenesis of suicidal behavior. Dialogues Clin Neurosci, 2002. 4(4): p. 417.

[19] Higuchi, Y., T. Soga, and I.S. Parhar, Regulatory Pathways of Monoamine Oxidase A during Social Stress. Front Neurosci, 2017. 11: p. 604.

[20] Schruers, K., et al., L-5-hydroxytryptophan induced increase in salivary cortisol in panic disorder patients and healthy volunteers. Psychopharmacology (Berl), 2002. 161(4): p. 365-9.

[21] Altunsoy, N., et al., Exploring the relationship between vitamin D and mania: correlations between serum vitamin D levels and disease activity. Nord J Psychiatry, 2018: p. 1-5.

[22] Hedelin, M., et al., Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33 000 women from the general population. BMC Psychiatry, 2010. 10: p. 38-38.

[23] Bahrami, A., et al., High Dose Vitamin D Supplementation Is Associated With a Reduction in Depression Score Among Adolescent Girls: A Nine-Week Follow-Up Study. J Diet Suppl, 2017: p. 1-10.

[24] Patrick, R.P. and B.N. Ames, Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB. J, 6/2014. 28(6): p. 2398-2413.

[25] Patrick, R.P. and B.N. Ames, Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior. Faseb J, 6/2015. 29(6): p. 2207-2222.

Mood and Menopause – Going Through "The Change"

Fri, 01 Dec 2017 10:04:00 -0800

Not quite menopause. Throwing blankets off at night, keeping awake. Fatigue and irritation punctuated throughout the day by heat dissipating from every pore, clouding thoughts, reinforcing forgetfulness. Hair falling out so stubbornly fast. Clothes choosing when to fit. Flooding periods coming sporadically, unexpectedly. They call it “the change of life” – but I feel like a different person altogether. What is happening?

In perimenopause, the physiological landscape is subject to tremendous change with estradiol and progesterone at the heart of the transition. Progesterone levels fall quickly – no ovulation – no corpus luteum – no progesterone. Estradiol, on the other hand, does not give up so easily. Estradiol levels continue to rise and fall – reliable, steady, wave-like – a biological rollercoaster – approaching the halting rhythms of reproductive senescence. In the context of very low progesterone, these dramatic peaks and troughs in estradiol levels, give rise to systemic consequences and unrelenting symptoms of the menopausal transition.

Hot flashes, synonymous with menopause, commonly co-occur with other neurological symptoms – mood changes, sleep disturbances and decline in cognitive function [1]. Many of these are naturally attributed to the shifting hormonal milieu. Although historically ascribed to strictly reproductive functions, hormones serve as important neural substrates. For example, adequate estradiol levels are essential to neuronal health with its neuroprotective and antioxidant properties [2]. As estradiol levels plummet in menopause, neurological dysfunction arises from the impaired glucose homeostasis, mitochondrial dysregulation, and attenuated ATP production.

Estradiol and Serotonin

Fig. 2. The importance of estradiol in modulating serotoninergic tone.

Specific to neurotransmitter systems, estradiol has a close-knit relationship with serotonin, aptly nicknamed "the happiness molecule." Estradiol directly modulates just about everything about serotonin biology:

Upregulates the expression of tryptophan hydroxylase, the enzyme in charge of the rate-limiting step in the serotonin biosynthesis pathway;
Helps augment serotonin receptor activation and subtype expression;
Blocks re-uptake; slows down degradation by suppressing monoamine oxidase expression – the enzyme that rapidly breaks down serotonin into inactive form. In other words, in order to have enough serotonin around, you need adequate estradiol levels.

So What Happens in Menopause?

When the maestro steps off the podium, despite years of exquisite discipline and arduous practice, the permanence of the loss drives the symphony to disarray. As estradiol firmly sets a course to wind down (albeit not without a fight), the serotonin system experiences this deficiency first-hand. With little estradiol left to stimulate tryptophan hydroxylase expression, this translates to reduced intrinsic serotonin production. Serotonin production is further reduced by increased monoamine oxidase expression (no more estradiol to keep suppressing its overexpression) – rapidly metabolizing what little serotonin there is to begin with.

The newly acquired low serotonin tone perpetuates the tenacity of unremitting sleepless nights, hot flashes, mood swings, and brain fog. This is why some women can be helped with SSRI therapy – blocking the reuptake of what's left of serotonin to help take the edge off the severity of hot flashes or mood swings [3] [4]. However, SSRI therapy comes with a slew of its own side effects especially lowered libido (also worsened by low estrogen) and GI side effects. Plus, without estradiol in the picture, all the other symptoms of menopause – bone loss, vaginal dryness, glucose dysregulation, metabolic changes, cardiovascular health – remain unaddressed.

A Common Picture in Perimenopause

Below is an example of a laboratory work-up for a perimenopausal patient presenting with a clinical picture of symptoms and results, commonly observed at ZRT. Weight gain, sleep disturbances, fatigue, and decreased libido can be explained in part by the low levels of estradiol and progesterone despite normal levels of testosterone.

Low estradiol plays a role in steering neurotransmitter levels. Although this patient's serotonin levels are normal (she is not in menopause yet), the levels of the serotonin metabolite, 5-HIAA are above the optimal range, suggesting that she is starting down the path of increased serotonin metabolism. There is a discordance in the results – serotonin, the precursor is lower in the clinical range than 5-HIAA, the metabolite. Without intervention, as time goes by, the gap between the two may widen – as estradiol levels continue to decline, further accentuating existing symptoms and allowing for new symptoms to develop.

Keeping an eye on emerging hot flashes, night sweats and changes in bleeding patterns is important when looking for imminent signs of menopause. Low progesterone and fluctuating estradiol as part of the normal physiological change are expected during the transition and can be picked up by a non-invasive saliva test. Low estradiol, driving serotonin and 5HIAA into discordant clinical ranges, is also typical and can be observed with urinary neurotransmitter analysis.

What's a Woman to Do?

As perimenopausal signs emerge, working with a practitioner who uses low-dose, bio-identical hormone replacement therapy judiciously to alleviate symptoms and rectify hormonal balance is crucial to maintaining mood and reducing debilitating symptoms. Of course, regular hormone testing to ensure levels remain in physiological ranges is important. Nurturing mental health during this time of transition is not only a matter of addressing hormonal balance; women also benefit from the support and understanding of their loved ones as they begin to behave in uncharacteristic ways, and from taking time to care for themselves and acknowledging their bodies’ altered needs.

Related Resources

References

[1] Brinton, R.D., et al., Perimenopause as a neurological transition state. Nat. Rev. Endocrinol, 7/2015. 11(7): p. 393-405.

[2] Fischer, B., C. Gleason, and S. Asthana, Effects of hormone therapy on cognition and mood. Fertil. Steril, 4/2014. 101(4): p. 898-904.

[3] Freedman, R.R., Menopausal hot flashes: mechanisms, endocrinology, treatment. J Steroid Biochem. Mol. Biol, 7/2014. 142: p. 115-120.

[4] Krause, M.S. and S.T. Nakajima, Hormonal and nonhormonal treatment of vasomotor symptoms. Obstet. Gynecol. Clin. North Am, 3/2015. 42(1): p. 163-179.

Clinical Pearls - Getting the Most Out of Your Neurotransmitter Test

Fri, 29 Sep 2017 13:45:00 -0700

Learning how to use a new test can be overwhelming, especially when it goes back to neurology which you might not have thought of since medical school.

To assist health care providers in approaching neurotransmitter testing as a functional assessment, ZRT has outlined a series of key concepts below.

As with any functional test that measures physiological function, the challenge lies in the interpretation of subclinical levels of measured parameters. However, it is within those subclinical levels that the neurotransmitter test becomes a powerful tool to identify what is contributing to a specific patient's health issues and how to map toward a successful outcome based on an individual treatment plan.

Before looking at specific neurotransmitters, let's review some important fundamentals needed for neurotransmitter interpretation.

Patterns are just as important as numbers
It is important to look at the relative levels of neurotransmitters and their relationships with one another. Patterns are just as important, if not more important, as the numbers themselves. For example, a low serotonin with a high 5HIAA can suggest sluggish MAO A activity; GABA and glutamate should balance each other; and serotonin and dopamine should both increase or decrease together.
Treatment considerations for generally low levels of neurotransmitters
With generally low-normal or low neurotransmitter results, treatment considerations include, but are not limited to, precursor amino acid supplementation and cofactor support such as B vitamins, magnesium, zinc, vitamin C, and folate.
Treatment considerations for generally elevated levels of neurotransmitters

Treatment strategies should focus on reducing potentially neurotoxic excitatory damage with anti-oxidants, anti-inflammatory support, and neuroprotective therapies. These include: omega 3 fatty acids, glutathione, and N-acetyl cysteine.
Devising the treatment plan
Address inhibitory neurotransmitter support first (for example – 5HTP, GABA) and then excitatory support (for example – tyrosine, glutamine), otherwise undesirable side effects such as anxiety and agitation may arise. It is typically safe to introduce excitatory support after approximately a week of inhibitory support.

Now, let’s look at some common patterns that we see in neurotransmitter testing and review some facts that are pertinent when interpreting results.

Low serotonin with SSRI therapy
Low urinary serotonin levels are not uncommon in patients on prolonged SSRI use. Over time, SSRIs deplete serotonin from platelets [1], which could be reflected in the low urinary serotonin result. This is commonly why SSRI treatments will require increasing dosages or stop working over time.
Unexpectedly high serotonin levels
High serotonin in urine could result from many conditions including, but not limited to, food allergies, post infectious IBS, low vitamin D levels, and use of medications or supplements geared to boost serotonin, such as 5HTP. Fun fact: the GI tract makes a lot of serotonin when GI inflammation is triggered [2].
PEA is the only neurotransmitter that crosses the blood brain barrier freely and bidirectionally
Low PEA in urine serves as a recognized biomarker in ADHD [3]. ADHD patients that respond well to treatment typically show marked increases in urinary PEA levels. On the flip side, high PEA (it can be very high) is associated with anxiety. High PEA can be addressed by supplementing with SAMe, vitamin B2, copper with zinc, or nutritional lithium.
GABA does not need to cross the blood brain barrier to exert calming effects
The literature has been inconsistent regarding whether or not GABA crosses the blood brain barrier when taken as a supplement. However, since GABA taken as a supplement can be very effective in relieving symptoms of anxiety for a sizeable cohort of patients, this begs the question of its mechanism of action. Recent studies from animals begin to shed light into peripheral mechanisms of GABA action. Specifically, within the adrenal glands, GABA regulates epinephrine (and a small amount of norepinephrine) release to make sure the anxiety-provoking “fight or flight” response is not overdone [4]. That could certainly serve as one of the calming mechanisms of GABA action in the periphery. Therefore, when interpreting a neurotransmitter report, determining the relationship between GABA levels and norepinephrine/epinephrine levels is important. With low GABA, it may be that much more challenging to bring down the sympathetic/adrenal overdrive.
Urinary norepinephrine is a product of the sympathetic nervous system
Most urinary norepinephrine originates from the sympathetic nerve endings, giving us an idea of how the peripheral nerves are firing. Because of the involvement of the nervous system, abnormal norepinephrine results could be addressed by introducing herbal nervines (e.g., Melissa officinalis, Passiflora officinalis) and biofeedback in the treatment protocol.
Epinephrine is adrenal in origin
Urinary epinephrine measured by the test, on the other hand, is mostly adrenal in origin, therefore treatment typically involves adrenal adaptogens and lifestyle interventions to reduce stress.
Utility of a diurnal norepinephrine and epinephrine assessment
Sometimes when patients report being under a lot of stress and self-report moderate to severe anxiety, sleep disturbances, and irritability, dysfunctions in the HPA axis and/or sympathetic nervous system may be suspected. However, their average urinary norepinephrine and epinephrine levels fall within the normal range. This seeming discrepancy in symptoms and test results could be addressed by running a distribution pattern at 4 time points during the day to see if these catecholamines are following a normal diurnal rhythm. Being able to determine alterations from a normal predictable circadian pattern could help the practitioner establish a better-tailored treatment plan, supporting when levels are low and suppressing when levels are high.

It takes experience and really knowing and integrating the subjective and objective aspects of a case to achieve a successful interpretation of the results. Learning to “speak the language” is the first step in incorporating the neurotransmitter test into everyday practice. As with any language, the initial building blocks are key to becoming fluent. Until then, we are here to help you as always. Feel free to call ZRT's clinicians for provider-to-provider consultation at 1-866-600-1636.

Related Resources

References

[1] Siesser WB, Sachs BD, Ramsey AJ, Sotnikova TD, Beaulieu JM, Zhang X, Caron MG, Gainetdinov RR: Chronic SSRI treatment exacerbates serotonin deficiency in humanized Tph2 mutant mice. ACS Chem Neurosci 2013;4:84-88.

[2] Spiller RC, Jenkins D, Thornley JP, Hebden JM, Wright T, Skinner M, Neal KR: Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut 2000;47:804-811.

[3] Irsfeld M, Spadafore M, Pruss BM: beta-phenylethylamine, a small molecule with a large impact. Webmedcentral 2013;4:9.

[4] Harada K, Matsuoka H, Fujihara H, Ueta Y, Yanagawa Y, Inoue M: GABA Signaling and Neuroactive Steroids in Adrenal Medullary Chromaffin Cells. Front Cell Neurosci 2016;10:100

Estrogen: The Link Between Microbiome, Menopause & Metabolic Health

Sat, 23 Sep 2017 08:33:00 -0700

The diversity of the microbiome has profound implications for metabolic health. The micro-organisms that we host in our gastrointestinal tract maintain our gut integrity, break down complex carbohydrates to improve energy extraction from food, produce vitamins and minerals, aid in digestion and absorption, ferment dietary fibers and protect us against pathogens. Maintaining a delicate balance in the diversity of the host-microbiome relationship is crucial for disease prevention and healthy aging.

Studies on the microbiome are emerging as a new and exciting frontier of science. However, how the microbiome interacts with the endocrine system to modulate metabolic health is still one of the less explored avenues in microbiome research. This blog aims to shed light on the intertwined roles of gut microbiota and estrogen on metabolic health for women as they transition into menopause.

Estrogen, Microbiome and Metabolic Health

Estrogen and the microbiome regulate weight gain and lipid deposition independent of each other.

By increasing the density of small intestinal villi capillaries, gut microbiota influence gastrointestinal physiology and gut motility, and thus promote caloric extraction from the diet. Studies in humans show that a drastic reduction in the diversity of gut microbes (also called dysbiosis) is enough to cause functional changes related to weight gain [1]. Owing to the essential role of the gut ecosystem in maintaining host physiology, unfavorable alterations in the composition of the microbial make up can trigger a wide range of physiological disorders, including low-grade inflammation, metabolic disorders, excess lipid accumulation, and loss of insulin sensitivity, which increase the risk of developing metabolic diseases.

Estrogen, in proper amounts, is also recognized as a key element in preserving metabolic health, by keeping weight down, reducing abdominal fat and improving glucose tolerance. Recent studies help illuminate another, less recognized role of estrogen in metabolic health, and it has to do with the gut.

Estrogen is Protective for Microbial Diversity

Adequate estrogen levels are important for a multitude of functions outside of its reproductive role. Specific to the microbiome, estrogen and estrogen-like compounds prevent the loss of and promote growth and proliferation of beneficial bacteria [2]. For example, animals treated with estrogen have significantly higher microbial diversity than controls [3].

Research shows that microbial diversity is key for maintaining a healthy metabolic profile [1]. The study by Turnbaugh (2009) specifically illuminates how dysbiosis can preferentially turn on genes and inappropriately activate pathways involved in sugar and carbohydrate metabolism in overweight but not in lean individuals. The aberrant upregulation of these genes is suspected to contribute to the metabolic profile observed in overweight persons.

Estrogen Helps Maintain the Integrity of the Gut

Cells that line the gut comprise a barrier, so that large molecules (food particles, digestive enzymes, cytokines, etc.) stay where they ought to – inside the gastrointestinal tract. A healthy and diverse microbiome ensures that the gut barrier maintains its integrity. So does estrogen! Sufficient estrogen levels are needed to form the epithelial layer of the gut and keep it healthy, elastic and impervious to the contents of the gut [4]. Gut barrier integrity is critical in the context of metabolic health because any changes to intestinal permeability are likely to be detrimental to a healthy weight profile and may play a role in T-cell activation leading to the development of food sensitivities, adipose inflammation and autoimmune diseases.

Estrogen Decreases Inflammation

Disturbances in the microbiota composition in dysbiosis can impair the process of deconjugating estrogen, resulting in reduced circulating free estrogen levels.

Additionally, estrogen decreases pathogenic populations of bacteria and reduces lipopolysaccharide (LPS) -induced inflammation. LPS, produced by Gram-negative bacteria, can impair the lining of the gut, cross into the rest of the body and elicit a strong immune response. Estrogen working against enteric pathogens is yet another example of estrogen’s protective functions on the gut.

Microbiome Regulates Free Estrogen Levels

The gut microbiome impacts estrogen levels through the secretion of β-glucoronidase, an enzyme which deconjugates estrogen to its free, biologically active form available for tissue uptake [4]. It is the free fraction of estrogen hormone that has activity at the level of estrogen receptors a and b (ERα and ERβ, respectively), giving rise to subsequent physiological downstream effects. Specific to metabolic health, estrogen is key for keeping weight down, reducing abdominal fat and improving glucose tolerance.

Characterized by diminished microbial diversity, dysbiosis is an event that may lead to an inflammatory response and metabolic profile that is detrimental to health [1]. Disturbances in the microbiota composition in dysbiosis can impair the process of deconjugating estrogen, resulting in reduced circulating free estrogen levels.

Connection to Menopause

Lack of estrogen and alteration of the gut microbiota are important in driving metabolic issues in menopause. Although the formula for the optimal composition of the gut microbiota may be individual, a balanced community is crucial for cultivating homeostasis of estrogen-modulated physiology. Maintaining physiological levels of estrogen with the help of hormone replacement therapy becomes even more important in menopause when dysbiosis events are suspected.

For perimenopausal patients experiencing decreases in basal metabolic rate with concurrent gastrointestinal health issues, a combination of estrogen replacement therapy together with digestive support might have a profound impact on restoring gut health and improving metabolic function.

A convenient and noninvasive test to assess the bioavailable fraction of hormone available for tissue uptake can be done with saliva. Routine testing, done as part of a hormone replacement program, can help your patients achieve their best metabolic health during menopause.

Related Resources

References

[1] Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI: A core gut microbiome in obese and lean twins. Nature 2009;457:480-484.

[2] Chen KL, Madak-Erdogan Z: Estrogen and Microbiota Crosstalk: Should We Pay Attention? Trends Endocrinol Metab 2016;27:752-755.

[3] Benedek G, Zhang J, Nguyen H, Kent G, Seifert HA, Davin S, Stauffer P, Vandenbark AA, Karstens L, Asquith M, Offner H: Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells. J Neuroimmunol 2017;310:51-59.

[4] Baker JM, Al-Nakkash L, Herbst-Kralovetz MM: Estrogen-gut microbiome axis: Physiological and clinical implications. Maturitas 2017;103:45-53.

Examining the "Warrior Gene" - MAOA & Aggression

Fri, 02 Jun 2017 11:20:00 -0700

Aggression is deeply rooted in our genetic foundation. Yet it is a double-edged sword: on one side, aggression communicates dominance, an exaggerated hostile manifestation and a willful attempt to harm. On the other, aggression is innate and essential to the human condition, even instrumental to our survival as a species for attainment of resources, determent of competitors, and organization of social hierarchies.

Considerable pressure has been placed on scholars studying cultural paradigms of aggression and how to prevent its excess. In recent years, scientists have begun to shed light on individual variance in genetic factors that have important implications contributing to aggression. These scientific attempts have allowed mapping of the aberrant genotypes onto a larger framework of underlying neurobiology and the resulting personality. And what we have learned is that a genetic mutation in the monoamine oxidase A (MAOA) gene may in part be to blame.

The Warrior Gene

MAOA is an enzyme that breaks down the neurotransmitters serotonin, dopamine, and norepinephrine [1]. The rapid degradation of these neurotransmitters is essential for their proper functioning during synaptic transmission in the central nervous system and in the periphery. Certain types of mutations in the MAOA gene give rise to a sluggish MAOA enzyme, slowing down the metabolism in the above-mentioned neurotransmitters, thereby causing higher levels of serotonin, dopamine, and norepinephrine and lower levels of their respective metabolites. This MAOA variant, characterized by low activity, offers an illustrating example of a minor DNA change that can result in the alteration of certain behaviors.

This slow-acting MAOA mutant serves as the best-validated genetic basis of aggression and is widely known as the "warrior gene." Saddled with the label of "warrior," the name is rather incongruous. "Warrior" conjures a strong, stoic man who can protect and provide for his people. However, "warrior gene" is commonly associated with violent behavior that hides behind an appealing masculine archetype.

Insight from Animal Studies

Regardless of naming nuances, studies in animals show that mice completely lacking MAOA have increased brain levels of serotonin, dopamine, and norepinephrine and increased aggressive behaviors [2]. Restoring MAOA levels to normal in those animals reduced aggressiveness to basal levels.

Why are Males Affected More than Females?

MAOA is an X-linked gene. Therefore, in males, with only a single copy of the X chromosome, the effects of an underactive MAOA enzyme are much more prominent than in females. The general consensus is that the warrior gene predisposes susceptible rage-aholics to excess impulsivity, risky decision-making, violent behavior, and yes, aggression [3]. Some studies mention that gene carriers for the sluggish MAOA may be predisposed to anxiety and neuroticism, while others mention exacerbated antisocial, solitary behavior [1].

Below is an example of what a neurotransmitter report may look like in a patient with a suspected MAOA mutation. This particular patient self-reported symptoms of aggression, anxiety, mania, insomnia and mental fatigue, among others, indicating them as severe. His levels of serotonin, dopamine, norepinephrine and normetanephrine are high, while respective metabolite levels are low, overall resulting from, what appears to be sluggish MAO activity.

It is important to mention here that the opposite effect is seen when MAO is not mutated but levels are high enough that the body burns through all the neurotransmitters, resulting in low neurotransmitter levels and high metabolites levels. When this happens, profoundly unpleasant psychological symptoms can be expected to manifest in the form of depression, anxiety, nervousness, etc.

Extreme Cases

The presence of the gene has also been reported in extremely violent offenders [4]. Moreover, carriers of the warrior gene tend to become profoundly aggressive upon provocation, according to Brown University researchers [5]. Not surprising, as deficient MAOA activity appears to influence predisposition toward hyperreactivity to a threat [6].

A "Perfect Storm"

Sometimes it takes a "perfect storm" of genetic and environmental factors to exert influence on the behavior of an individual. Without structure in upbringing, the effects of the gene can go unchecked. Past research found a pronounced connection among warrior gene carriers between exposure to abuse in childhood and engagement in significantly higher levels of violent behavior as adults [7].

Born to Rage?

In 2010, National Geographic released a documentary called "Inside The Warrior Gene." Men from diverse and sometimes violent backgrounds, self-admitting to impulsive, aggressive behavior, were tested for the warrior gene – bikers, mixed martial arts athletes, ex-gang members. Some questioned the anger inside them, admitting that their anger always simmers just below the surface: "I react violently to violent situations. And I like it." Some of the guys self-identified themselves as "warriors" and expected to carry the mutation. One man, upon receiving the result that he is the warrior gene carrier, said "it makes sense" as he is always "battling a demon." Another with an impulsive, aggressive nature but who does not carry the mutated gene expressed disappointment: "you want to be the warrior, you want to be the man!"

Genes are Not your Destiny

We have the power to overcome our evolutionary impulses. Through our understanding of the MAOA gene, we can come to understand our behaviors better.

Genes, themselves, don't necessarily dictate behavioral outcomes. Not everyone with the warrior gene is aggressive. Three Buddhist monks, interviewed in the above-mentioned documentary, who were all from violent or difficult backgrounds, all carry the warrior gene. So you see how a predisposition reflects an association and not necessarily a predestination. Violence is not always the outcome if we learn how to channel our genetics.

Frydman and colleagues discuss a different angle of the warrior gene phenomenon. In their study, they saw that those individuals with the warrior gene were seemingly better at making a decision based on risk/reward [8]. So perhaps, although the carriers are viewed as more aggressive or impulsive, they may just be responding to good opportunities.

Regardless of whether this mutation of the MAOA gene results in aggressive behaviors, better decision-making, or both, it clearly has an effect on behavior. However, just having the warrior gene by itself doesn’t make things happen. We have the power to overcome our evolutionary impulses and change outcomes. Through our understanding of the MAOA gene, we can come to understand our behaviors better. And remembering that our genes are only a rather small part of the big picture is imperative as we strive to curb the sweeping and dangerous generalizations that categorize people based on genetic information alone.

Related Resources

References

[1] Harro J, Oreland L: The role of MAO in personality and drug use. Prog Neuropsychopharmacol Biol Psychiatry 2016;69:101-111.

[2] Shih JC, Thompson RF: Monoamine oxidase in neuropsychiatry and behavior. Am J Hum Genet 1999;65:593-598.

[3] Godar SC, Fite PJ, McFarlin KM, Bortolato M: The role of monoamine oxidase A in aggression: Current translational developments and future challenges. Prog Neuropsychopharmacol Biol Psychiatry 2016;69:90-100.

[4] Tiihonen J, Rautiainen MR, Ollila HM, Repo-Tiihonen E, Virkkunen M, Palotie A, Pietilainen O, Kristiansson K, Joukamaa M, Lauerma H, Saarela J, Tyni S, Vartiainen H, Paananen J, Goldman D, Paunio T: Genetic background of extreme violent behavior. Mol Psychiatry 2015;20:786-792.

[5] McDermott R, Tingley D, Cowden J, Frazzetto G, Johnson DD: Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation. Proc Natl Acad Sci U S A 2009;106:2118-2123.

[6] Morell V: Evidence found for a possible 'aggression gene'. Science 1993;260:1722-1723.

[7] Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R: Role of genotype in the cycle of violence in maltreated children. Science 2002;297:851-854.

[8] Frydman C, Camerer C, Bossaerts P, Rangel A: MAOA-L carriers are better at making optimal financial decisions under risk. Proc Biol Sci 2011;278:2053-2059.

L-Theanine in Green Tea Stimulates Neurotransmitter Production & Reduces Anxiety

Fri, 19 May 2017 13:25:00 -0700

Capable of generating higher consciousness, the human brain is truly impressive in its complexity. The brain not only controls how we feel and what we think, but also manages all aspects of our health. To understand the fundamentals of a healthy brain, we ought to first take the time to understand how it works. In so many ways, our understanding of brain function evolved from studies on electricity.

The Brain’s Electrical Network

Neurons are the signaling cells in the brain. Each neuron is connected to many other neurons to create the brain’s own electrical network. The inside of a neuronal cell is negatively charged, because of sequestration of negative ions, such as chloride. On the outside, the neurons are positively charged because positive ions, such as sodium, are actively pumped out. This creates a voltage difference in a resting neuron – the outside is positive, the inside is negative. Electrical activity begins with a stimulus – a reaction from any of the five senses – which causes the positive ions to rush inside the neuron through specific ion channels, changing the voltage across the membrane. Once initiated, this voltage change moves down the membrane of the neuron to the end, eventually triggering a release in neurotransmitters [1]. The released neurotransmitters can then activate or inhibit receptors on adjacent neurons and propagate the message.

Electrical Impulses Translate Into Brain Waves

So you see how every thought, emotion, decision, reaction or impulse is merely a set of electrical impulses orchestrated to work harmoniously with one another. The union of all of these impulses is synchronized to form a “brain wave.” Brain waves are cyclic and “wave-like” in nature in that they oscillate according to the intensity of the continuous electrical activity. These oscillations in the electricity levels in the brain can be detected and recorded by an electroencephalogram (EEG).

A Simplified Overview of Normal Adult Brain Waves

BETA - awake and alert
ALPHA - awake and resting
THETA - sleeping
DELTA - deep sleep

Brain Waves Define Mood

There are four types of brainwaves – beta, alpha, delta and theta (some but not all also recognize a fifth type, called gamma) [2]. Each type of wave describes a certain type of brain activity and is characterized by a different amplitude and frequency. Although one brainwave state may predominate at any given time, depending on the activity level of the individual, the remaining brain states are present in the mix of brainwaves at all times. It is the relationship between the brain waves that defines various mood states.

Delta-beta Waves & Anxiety

Positive interplay (called “coupling” in expert lingo) between delta and beta waves is associated with anxiety. One study showed that increases in cortisol levels strengthen the relationship between delta and beta waves [3]. In other words, increased cortisol impulses in the brain orchestrate a set of brain waves that manifest as anxiety to the person and can be recorded as strong delta-beta recordings on an EEG. This means that as anxiety increases and gives rise to escalating cortisol levels, the brain activity changes reflect the state of stress by adjusting brain wave patterns.

Alpha Waves & Quieting the Mind

Meditation allows the brain to relax by inducing the oscillation of the so-called alpha waves in the brain. These alpha waves arise in the wakeful relaxation state – a state of composure, alertness and improved concentration without the edge of anxiety. In a way, alpha waves are a brain’s way to shift the “oscillating balance of power” between the two general brain systems – the task-oriented beta (the one that worries, calculates, plans, etc.) and the default alpha (i.e., daydreaming) system [1].

With alpha waves predominating, we simply become aware of our surroundings. Neuroscientists who study brain waves call this the “optimal inattention” state [4]. Through mindfulness, by harnessing this “power to ignore” [distracting stimuli] one specifically enhances the alpha brain state.

What does that mean for a physiological anxiety response, you may ask? Remember those cortisol levels increasing as beta-delta coupling strengthened? Alpha wave activity is inversely correlated with cortisol levels – as alpha waves become predominant, cortisol levels decrease [5]. This is important for those individuals whose anxiety (among many other symptoms) is driven and perpetuated by high cortisol levels.

Additional Ways to Induce Alpha Waves

As it turns out, meditation is not the only practice that can induce alpha wave activity in the brain. Yoga also stimulates alpha waves and concurrently induces a reduction in circulating cortisol levels [6]. But did you know that something you can buy for about $5 or perhaps already residing in your cupboard at the moment can also induce a powerful shift in brain activity toward alpha waves? That cupboard resident is green tea. One specific green tea constituent worthy of discussion and its influence on alpha waves is L-theanine.

L-theanine is an amino acid that reduces anxiety by promoting relaxation – slows down the heartbeat, reduces blood pressure, diminishes the acuteness of stress – all the while improving focus, attention and concentration. It does so by inducing resting state alpha wave activity without causing drowsiness due to unchanged theta waves [7].

Structurally, L-theanine resembles glutamate and GABA, the brain’s major excitatory and inhibitory neurotransmitter systems, respectively. By virtue of these structural similarities, L-theanine targets glutamate receptors – the fast-acting ion channels NMDA and AMPA, and the slower acting mGLURs [8].

L-theanine Resembles the Body’s Own Neurotransmitters

L-theanine Stimulates Neurotransmitter Production

L-theanine induces profound changes in neurotransmission by upregulating the levels of inhibitory and modulatory neurotransmitters. Shortly after the stimulation of the glutamate receptors, levels of the inhibitory neurotransmitters GABA and glycine are increased in the brain. In their turn, GABA and glycine, acting through their respective receptors, trigger increases in dopamine and serotonin in select brain regions. In other words, L-theanine appears to reduce excitatory pathways by activating and channeling the brain’s calming and anxiolytic mechanisms [8]. Additionally, L-theanine administration reduces cortisol levels and increases BDNF levels [9]. It is because of this modulating activity that L-theanine has profound effects on improving neurogenesis and neuroplasticity and is able to positively regulate mood, motivation, cognition and memory.

NEUROMODULATORY EFFECTS OF L-THEANINE

↑ GABA

↑ Glycine

↑ Serotonin

↑ Dopamine

↓ Cortisol

L-Theanine Therapy

L-theanine can be administered in supplement form or in tea – one cup of green tea contains anywhere from 25 - 60 mg of L-theanine. L-theanine readily crosses the blood-brain barrier within 30 minutes and continues to increase, reaching maximum levels after approximately 5 hours. Typical dosing for supplementation starts at 200 mg of L-theanine every 4-6 hours; however, alpha waves have been shown to be induced after as little as 50 mg of L-theanine [10].

It's good to know that something as simple as a cup of tea can work wonders for our brain health and help reduce anxiety – and might just save a trip to the doctor.

Related Resources

References

[1] Churchland PA: Touching A Nerve. New York, W.W. Norton & Company, 2013.

[2] Basar E, Basar-Eroglu C, Karakas S, Schurmann M: Gamma, alpha, delta, and theta oscillations govern cognitive processes. Int J Psychophysiol 2001;39:241-248.

[3] Schutter DJ, van HJ: Salivary cortisol levels and the coupling of midfrontal delta-beta oscillations. Int J Psychophysiol 2005;55:127-129.

[4] Sacchet MD, LaPlante RA, Wan Q, Pritchett DL, Lee AK, Hamalainen M, Moore CI, Kerr CE, Jones SR: Attention drives synchronization of alpha and beta rhythms between right inferior frontal and primary sensory neocortex. J Neurosci 2015;35:2074-2082.

[5] Kamei T, Toriumi Y, Kimura H, Ohno S, Kumano H, Kimura K: Decrease in serum cortisol during yoga exercise is correlated with alpha wave activation. Percept Mot Skills 2000;90:1027-1032.

[6] Kamei T, Toriumi Y, Kimura H, Ohno S, Kumano H, Kimura K: Decrease in serum cortisol during yoga exercise is correlated with alpha wave activation. Percept Mot Skills 2000;90:1027-1032.

[7] Williams J, Kellet J, Roach PD, McKune A, Mellor D, Thomas J, Naumovski N: L-Theanine as a functional food additive: its role in disease prevention and health promotion. Beverages 2016;2.

[8] Lardner AL: Neurobiological effects of the green tea constituent theanine and its potential role in the treatment of psychiatric and neurodegenerative disorders. Nutr Neurosci 2014;17:145-155.

[9] White DJ, de KS, Woods W, Gondalia S, Noonan C, Scholey AB: Anti-Stress, Behavioural and Magnetoencephalography Effects of an L-Theanine-Based Nutrient Drink: A Randomised, Double-Blind, Placebo-Controlled, Crossover Trial. Nutrients 2016;8.

[10] Nobre AC, Rao A, Owen GN: L-theanine, a natural constituent in tea, and its effect on mental state. Asia Pac J Clin Nutr 2008;17 Suppl 1:167-168.

A Dynamic Duo: When to Test Neurotransmitters with Sex Hormones

Thu, 06 Apr 2017 10:29:00 -0700

The nervous system and its communication with peripheral organs is under the continuous dynamic influence of hormones, neuroactive steroids, and neurotransmitters. This is why the underlying pathology of mood disorders can often be varied and complex.

The hormonal piece is critical to our understanding of the imbalances when it comes to the complete neurotransmitter assessment. Hormones regulate key processes pertaining to neurotransmitter biosynthesis, signaling, and degradation. It is important to recognize that disturbances in the relationships between hormones and neurotransmitters can shape normal physiology toward a maladaptive state leading to suboptimal psychological wellbeing.

HPA axis dysfunction, anxiety, depression, low libido, PCOS, lack of appetite, and menstrual cycle disorders are just a few examples of what happens when the equilibrium within the neuroendocrine system is disrupted. Without information yielded from objective clinical testing, selection of the most effective treatment for each particular patient with a mood disorder continues to be a challenge. Testing neurotransmitters together with hormones allows health care practitioners to enhance their neuroendocrine tool kit by delineating hormone-governed neurotransmitter dysregulation, and provides a deeper understanding of how individual biochemistry alters neurotransmitter homeostasis.

Diurnal Urinary Hormones

What is measured: cortisol, cortisone, norepinephrine, epinephrine, melatonin

Sample type: dried urine

Diurnal rhythms of cortisol, norepinephrine, and epinephrine reflect HPA axis function; the addition of diurnal melatonin provides a useful measure of circadian rhythm regulation. Detailed characterization of these biochemical parameters may aid in identifying specific imbalances in an individual’s response to stress. This diurnal test uses the same urine cards on which the neurotransmitter sample was collected without any extra additional steps.

Saliva Hormones

What is measured: estradiol, progesterone, testosterone, DHEA-S, cortisol

Sample type: saliva

The saliva hormones add-on is an excellent way to assess the initial “big picture” of overall sex and adrenal hormone status in female and male patients. The test provides clinical information regarding the bioavailable fraction of hormones. For those Individuals who produce very little saliva or who use supplementary sublingual hormones, this test may not be appropriate.

Urinary Hormone Metabolites

What is measured: estradiol, testosterone, DHEA, pregnanediol, allopregnanolone, androstenedione, 5a-dihydrotestosterone (DHT), 5a,3a-androstanediol

Sample type: dried urine

The hormonal profile in dried urine features two main progesterone metabolites and five major androgens, along with estradiol. Assessment of sex steroids and metabolites in dried urine is a convenient option for those patient who are unable to collect sufficient saliva for the salivary test. While the salivary hormones add-on provides an overall glance at the major hormones, the metabolites add-on expands the evaluation to the major sex steroid metabolites and is specifically geared to those patients who present with low or high androgen symptoms or symptoms of estrogen dominance.

When to Test Neurotransmitters Alone	When to Combine Neurotransmitters with Diurnal Urinary Hormones	When to Combine Neurotransmitters with Saliva Hormones	When to Combine Neurotransmitters with Urine Hormone Metabolites
Managing psychiatric interventions Establish a baseline Patients unable to use HRT Children and Adolescents Hormone levels recently tested	Suspected HPA axis dysfunction Sleep problems PCOS Pre-menopause & Menopause Andropause ADHD	PMS/PMDD Symptoms of estrogen dominance High or low androgen symptoms Pre-menopause & menopause Irregular cycles PCOS Suspected HPA axis dysfunction	Low androgen symptoms: fatigue, foggy thinking, decreased stamina High androgen symptoms: acne, scalp hair loss, facial hair growth PCOS Symptoms of estrogen dominance Suspected HPA axis dysfunction
Considerations Regarding Hormone Supplementation
Suitable for testing with any route of hormone administration	Suitable for testing with any route of hormone administration	Only suitable for oral, topical, vaginal, patch, injectable, pellet forms of hormone administration; Not suitable for troche/sublingual supplementation	Only suitable for oral, topical, patch, injectable, pellet forms of hormone administration; Not suitable for vaginal supplementation

Within the neuroendocrine system, both hormones and neurotransmitters serve as key modulators of psychological wellbeing. The targeted neuroendocrine assessment provides clinicians with a focused individualized biochemical platform to guide treatment interventions.

Learn More about Neurotransmitter Testing

How to Address Low Libido in Peri-Menopausal Patients

Fri, 24 Feb 2017 10:12:00 -0800

Providers routinely call ZRT for support in addressing low libido for their patients during the menopausal transition.

Busy lifestyles, everyday stress, not enough or poor quality sleep and many other factors can all contribute to putting sex at the bottom of the to-do list, well after laundry, scrubbing the floor, and taking the dog to the vet.

Low libido is a multidimensional issue that can have a little bit of everything infused into its mosaic. It's not uncommon that the symptom of low libido is accompanied by fatigue, sleep disturbances, mood swings, and perhaps even mild depression. Helping patients with waning libido is attainable, and one just needs to know where to look. There are a number of factors that appear to be intimately linked to libido that can be divided into three broad categories – endocrine, lifestyle, and physical.

Endocrine Factors

What Happens to Libido When Hormones Fall Out Of Balance

As women approach perimenopause and transition into menopause, declining levels of estrogen, progesterone, DHEA and testosterone may have a negative effect on libido. Not always intuitive, but adrenal, thyroid, and growth hormones can contribute to sexual dysfunction as well.

Estrogen dominance – in perimenopause, the delicate balance between estrogen and progesterone is disrupted by fewer and fewer ovulatory cycles – progesterone plummets and estradiol levels fluctuate erratically. When estradiol levels are high, symptoms of estrogen dominance arise, such as water retention, breast tenderness, bloating, and irritability. When estradiol levels plummet, hot flashes, night sweats and vaginal dryness typically emerge. In the context of these endocrine changes without the body’s natural balance between estradiol and progesterone, low libido can commonly be experienced by many patients. Natural progesterone therapy can help restore the balance and bring relief to those women who suffer from unopposed estrogen [1].

Adrenal dysfunction – with increasing age, the levels of DHEA decrease steadily, but the amount of cortisol either remains constant or actually increases, giving rise to an essentially skewed DHEA/cortisol ratio. The unbalanced relationship between DHEA and cortisol can make some patients experience low androgen symptoms – fatigue, foggy thinking, decreased stamina, and low libido. On the flip side, when the body doesn’t make enough cortisol, as is the case with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, extreme fatigue, low blood pressure, and low blood sugar can make the patient feel perpetually drained. Not surprisingly, lack of desire also surfaces prominently in cases of HPA axis dysfunction.

DHEA replacement therapy appears to be an effective strategy to balance out the cortisol and additionally address low libido along with a number of other accompanying symptoms. Adrenal adaptogens (e.g., Rhodiola, Ashwagandha) can work with the body to balance the HPA axis and promote a return to normal physiologic function [2]. Moreover, because the adrenal glands synthesize progesterone, adrenal health becomes an important focus in combating estrogen dominance in peri- and post-menopause. In other words, by supporting adrenal health, we support progesterone balance.

Hypothyroidism, characterized by low or low-normal T4 and T3 levels along with high TSH, affects the entire body with profound mental and physical symptoms. It is not uncommon for patients with an underactive thyroid to discover that they have a decrease in sexual interest [3]. Selenium and iodine can help support the conversion of the thyroid hormone (T4) into its active form (T3), improve hypothyroid symptoms and generally contribute to a sense of wellbeing [4].

Metabolic syndrome – metabolic disturbances associated with a myriad of endocrine changes in perimenopause may predispose some patients to developing metabolic syndrome. Women with metabolic syndrome report having lower sexual drive – symptoms specifically related to having higher triglyceride levels [5]. Abnormalities in the lipid profile, fasting insulin, hemoglobin A1c and IGF-1 levels can provide useful insight into the basic cardiometabolic status for a given patient and track progress after intervention.

Physical Factors

How to Approach Dyspareunia

Ovarian production of estradiol, the master hormone of female reproductive maturity, begins to decline during perimenopause. With decreasing estrogen, vaginal dryness and atrophy can occur. Even if desire remains, pain during intercourse can be especially unappealing. Thankfully, there are a number of hormonal and non-hormonal approaches to treating the physical aspect of low libido.

Estrogen therapy helps alleviate some of the somatic symptoms associated with the perimenopausal transition. Specifically, low-dose estradiol cream applied vaginally, estrogen receptor modulators (e.g., Osphena), or vaginal creams or suppositories containing estriol or DHEA can be an effective therapeutic approach to help prevent or treat vaginal dryness, vulvodynia, and atrophy.

Testosterone – not just for men – plays a prominent role in the physiology of both sexes. In women, testosterone specifically plays a key role in the physical aspect of libido. As the levels of testosterone decline with age, topical androgen therapy can help maintain physical sensation by improving blood flow to the target organs. Systemic testosterone can also improve mental aspects of libido as well. Low testosterone is a particular concern for women who have undergone surgical menopause, in whom androgen replacement is often necessary.

A non-hormonal approach works for those patients who can't take hormones or present only with vaginal dryness. Hyaluronic acid suppositories with cocoa butter or vaginal application of vitamin E can work wonders. For patients with suspected pelvic organ prolapse, a non-hormonal approach in the form of pelvic floor therapy and/or tonic herbs to strengthen the muscles in the pelvic floor may be very effective too.

Lifestyle Factors

Focus on Supporting a Healthy Brain

Addressing brain health when discussing libido issues becomes especially important for patients in perimenopause and menopause.

The female brain is one of the most powerful erogenous zones. Addressing brain health when discussing libido issues becomes especially important for patients in perimenopause and menopause. When considering lifestyle factors for a healthy brain, consider in particular those that increase blood flow and include them in everyday life, while at the same time reducing or eliminating the ones that decrease blood flow and deprive the brain of vital nutrients. After all, as Dr. Daniel Amen says, "Whatever is good for your brain is good for your genitals [6]."

Avoid smoking, nicotine, and excessive alcohol, as they constrict blood flow and reduce the overall health of the vascular system.

Exercise – strengthens the heart, floods the body with endorphins, increases serotonin levels, tones the body, and facilitates blood flow to all tissues.

Good fats – omega 3 fatty acids are essential to the integrity and function of cell membranes. Cholesterol (yes, cholesterol!) is needed to make adequate levels of sex hormones [7].

Hydration – drinking enough water throughout the day helps keep tissues hydrated, including those below the belt. Plus a dehydrated brain (which is 80% water!) makes it difficult to think, yet alone feel amorous.

Nutrition – healthy foods supply the body with adequate vitamins and minerals – B vitamins, magnesium, zinc, and iron are necessary for neurotransmitter synthesis in the brain and periphery. Dopamine, for example, the brain’s so-called "pleasure center" requires both iron and vitamin B6 for its production.

Sleep – an adequate amount of good-quality sleep is essential for a healthy libido [8].

Supplements – Asian ginseng (Panax ginseng), the Peruvian herb Maca (Lepidium meyenii), and Ginkgo (Ginkgo biloba) are examples of supplements used in traditional medicine to improve blood flow and sexual function [9].

For some women, particularly those in mid-life whose partner's hormones are similarly declining, the waning of desire may be accepted as a natural consequence of aging, with physical sexuality transitioning into more emotional expressions of intimacy. For others, however, low libido may have a negative impact on the quality of life, emotional satisfaction, and general happiness. For those menopausal women seeking help from their health care providers, hormone balance and lifestyle improvements are key areas to address.

Related Resources

References

[1] Lee JR: What Your Doctor May Not Tell You About Menopause. ed revised edition, New York, Hachette Book Group, 2004.

[2] Head KA, Kelly GS: Nutrients and botanicals for treatment of stress: adrenal fatigue, neurotransmitter imbalance, anxiety, and restless sleep. Altern Med Rev 2009;14:114-140.

[3] Pamela Wartian Smith: What You Must Know About Vitamins, Minerals, Herbs & More. Choosing The Nutrients That Are Right For You. Square One Publishers, 2008.

[4] Kelly Brogan M: A Mind of Your Own. HarperCollins Publishers, 2016.

[5] Trompeter SE, Bettencourt R, Barrett-Connor E: Metabolic Syndrome and Sexual Function in Postmenopausal Women. Am J Med 2016;129:1270-1277.

[6] Amen DG: Magnificent Mind at Any Age. New York, Harmony Books, 2008.

[7] Schmidt MA: Brain-Building Nutrition. ed 3rd, Berkeley, Frog Books, 2007.

[8] Kling JM, Manson JE, Naughton MJ, Temkit M, Sullivan SD, Gower EW, Hale L, Weitlauf JC, Nowakowski S, Crandall CJ: Association of sleep disturbance and sexual function in postmenopausal women. Menopause 2017.

[9] Muskin PR: Complementary and Alternative Medicine and Psychiatry. Washington, DC, American Psychiatric Press, Inc., 2005.

The Distinction Between DHEA and DHEA-S & Why Both Are Important For a Healthy Brain

Wed, 08 Feb 2017 13:00:00 -0800

Everything we do, feel, think – it all starts with the brain. A balanced, healthy brain helps lay the essential foundation for optimal wellbeing. A small but significant aspect of brain health is regulated by a specific class of steroid molecules called neurosteroids.

That the brain is a steroidogenic organ is widely accepted, and neurosteroids are woven into its very fabric. In fact, the term “neurosteroid” refers to cholesterol-derived steroid compounds that play critical roles in the nervous system - its development, maintenance and survival. “Neurosteroids: of the nervous system, by the nervous system, for the nervous system” as Baulieu said a decade and a half following the remarkable discovery of the very first neurosteroid - DHEA-S [1] [2].

As the levels of DHEA and DHEA-S decline with age, the brain loses their protective properties and becomes more sensitive to the ravages of neurological decline. This blog is going to focus on DHEA and its sulfated form DHEA-S and their relevance to brain health.

Terms used commonly throughout this blog post:

DHEA = dehydroepiandrosterone

DHEA-S = dehydroepiandrosterone sulfate

DHEA(S) = total pool of DHEA and DHEA-S in the body

Dehydroepiandrosterone (DHEA) is plentiful in the human body - together with its sulfated form (DHEA-S), DHEA comprises the most abundant form of steroid hormones [3]. In fact, the average concentration of DHEA-S in the bloodstream is about 10,000 times higher than the most potent estrogen - estradiol (typical estradiol levels around 0.1 ng/mL vs 1000 ng/mL for DHEA-S). Derived from cholesterol, DHEA is produced by the adrenal glands, brain, ovaries and testes, and is a precursor for the major sex steroids (estrogen, progesterone, and testosterone). Sometimes called the "anti-aging hormone" or even the "fountain of youth," it is no wonder that supplementation with DHEA to its mid-normal physiologically youthful levels appears to engender a sense of wellbeing and reestablish that "zest for life"[4].

DHEA-S levels peak around mid-twenties and gradually decrease to around 20% by age 70. Unfortunately, once DHEA levels begin to wind down, there are no feedback mechanisms to help restore it. As DHEA and downstream metabolites decrease, the brain loses the protective effects of sex steroids and becomes increasingly vulnerable to neurotoxic effects of cortisol and other potentially damaging factors. With declining DHEA-S levels, cortisol levels remain constant, resulting in an increased cortisol/DHEA-S ratio. The unbalanced relationship between the too high cortisol and not enough DHEA-S is serious enough that it can create potentially harmful conditions for the hippocampus and contribute to neurodegenerative disease pathology. Specifically, brain imaging studies show that the decreased DHEA-S levels are closely associated with decreased hippocampal function in Alzheimer’s disease [5].

This is why DHEA is commonly prescribed to female and male patients presenting with low androgen symptoms in combination with low circulating DHEA-S and/or low testosterone levels. DHEA replacement therapy can certainly impede the ravages of aging - adequate levels help ramp up the levels of downstream sex steroids, enhance the ability to adapt to stress, increase libido, improve the body fat ratio, and boost the immune system [6]. However, it is important to monitor the levels of the sex steroid hormones as well as DHEA-S during supplementation – just like with too little DHEA, too much DHEA (and/or DHEA-S) can have its own set of distressing symptoms.

Low Androgen Symptoms

Fatigue
Foggy thinking
Decreased stamina
Decreased muscle size
Decreased libido
Rapid aging

High Androgen Symptoms

Irritability
Weight gain (hip and/or breast area)
Acne
Oily skin
Scalp hair loss
Growth of facial hair

Why Measure DHEA-S?

At ZRT we test for DHEA-S, the sulfated form of DHEA. Providers often call with questions regarding the difference between DHEA and DHEA-S. The difference in structure of the two molecules is the presence of a sulfate group – DHEA-S is the sulfated form of DHEA. Approximately 98% of circulating DHEA in the bloodstream is the sulfated form (DHEA-S). DHEA-S binds more strongly to albumin, its carrier protein, than DHEA, thus contributing to the slower metabolic clearance from circulation [7]. In addition to the longer biological half-life, DHEA-S does not exhibit a strong diurnal rhythm as seen with cortisol and DHEA, nor does it vary from day to day [8]. Additionally, the levels of DHEA-S run in parallel to those of DHEA, and correlate very closely with clinical symptoms of androgen deficiency and excess.

Consequently, DHEA-S represents a more stable index of adrenocortical activity and stress accumulated over time, whereas DHEA may better reflect the response to acute stressors. So when we measure DHEA-S, we gain an understanding of the body’s systemic biological reservoir of DHEA. All of the above reasons make DHEA-S the ideal molecular testing candidate.

When it comes to function, both DHEA and DHEA-S molecules have profound physiological effects on the body. One particular role I would like to focus on may often get overlooked – the actions of both DHEA and DHEA-S in the nervous system.

DHEA-S & the Central Nervous System

For many years, DHEA has been regarded as inactive and merely a forerunner of androgens and estrogens in the periphery – this observation was based on the inability to detect classical nuclear DHEA receptors observed those for other steroid hormones (estrogens – ER, progestogens – PR, androgens – AR, glucocorticoids – GR, mineralocorticoids – MR). However, more recent evidence sheds the light on DHEA not just as a pro-hormone, but rather an active hormone in its own right. Nowadays, not only DHEA, but DHEA-S as well are recognized for regulating a myriad of biological processes, with a remarkable tropism especially for the central nervous system. DHEA and DHEA-S play important roles in the development, maintenance and survival of the central nervous system. Both hormones modulate neurotransmitter synthesis and release, immunity and inflammation, endothelial and cognitive function, and neurogenesis and neuronal survival.

Independent of age, serum levels of DHEA-S appear to be positively correlated with healthier psychological profiles - executive function, working memory, attention, concentration, enjoyment of leisure activities and overall stress-buffering effect [3]. Imbalance in the DHEA pool tends to be associated with distress and psychopathology, such as depression, anxiety, bipolar disorder, eating disorders, PTSD and perceived stress [9] [10] [11]. Specifically, DHEA-S levels are inversely correlated with hyperactivity, suggesting a possible protective role in the etiology of ADHD [12]. Low DHEA-S levels have been reported in young patients with anorexia nervosa. Moreover, lower DHEA levels go hand-in-hand with the degree in severity of depression [13]. And on the flip-side, too-high levels have been detected in patients with mania [14]. Elevated DHEA-S and reduced cortisol have also been reported in patients with PTSD [3].

Mechanisms of Action

"Typical" steroid molecules (such as estradiol, testosterone and progesterone) modulate their effects by entering target cells, binding to their receptors and initiating cascades that either activate or inhibit the expression of various downstream proteins (some non-genomic mechanisms have been described as well by modulating fast-acting membrane receptors). The fascinating thing about neurosteroids is that they work in a slightly different fashion.

There is considerable ambiguity regarding whether a DHEA receptor does, in fact, exist. What is known, however, is that DHEA and DHEA-S act directly on neurotransmitter systems to regulate synaptic transmission. Specifically, these neurosteroids modulate neuronal excitability by directly interacting with neurotransmitter systems, such as dopamine, serotonin, glutamate, and GABA amongst others [15].

DHEA and DHEA-S bind to and both activate and modulate the NMDA glutamate receptor, potentiate dopamine and serotonin signaling, and inhibit the GABA A receptor activity. Crudely, all of this means that DHEA-S helps keep that fire going – that the excitatory neurons are firing properly, but also that the fire is burning "just right" and is not out of control.

Same But Different

Here comes the really cool part – there are many functions that DHEA and DHEA-S perform in similar ways; however, they have their own distinct mechanisms as well [15]. For example, both molecules can stimulate dopamine release, a neurotransmitter well-known for being the "pleasure center" of the brain. However, the paths to raise dopamine are different. DHEA-S uses genomic, slow, long-lasting mechanisms to do so by upregulating tyrosine hydroxylase levels, the enzyme responsible for dopamine production. DHEA, on the other hand, signals to increase dopamine levels in rapid, intense, short-lived bursts. For a more complete story on what neurotransmitter processes DHEA and DHEA-S regulate together and separately, please see the figure above.

Treatment Considerations

While DHEA is available over the counter in health food stores, it is best used under medical supervision with the goal of restoring low levels to the physiological range. When treating a patient with low androgen symptoms and low DHEA-S levels, it is important to consider the route of hormone administration (e.g., most common routes are oral, sublingual, topical, and vaginal) and testing options for measuring DHEA or DHEA-S (saliva, blood spot, serum, or urine).

Topical DHEA

If personal biochemistry does not allow for DHEA-S to be readily converted to DHEA, the topical route may be preferred.

When administered topically, DHEA restores skin elasticity, relieves symptoms of vaginal dryness and atrophy (with vaginal application), and generally improves many low-androgen symptoms [16]. The caveat with topical DHEA administration is that it does not undergo first-pass metabolism through the liver (no liver passage - no sulfation), so although a subsequent increase in salivary and blood spot DHEA is observed, DHEA-S levels remain unchanged. The levels of the hormone in saliva represent the "free" hormone fraction, available for tissue uptake. Animal studies show that with topical DHEA treatment, the unsulfated DHEA crosses into the brain and gives rise to DHEA-S right on site. With topical DHEA supplementation, the practitioner has to rely on monitoring the patient’s progress with improving symptomatology, which may be a challenge in and of itself. If low androgen symptoms persist with topical DHEA treatment, switching to oral dosing may prove to be a more effective strategy. It is important to know that topical DHEA therapy will raise serum and salivary DHEA levels, but have little effect on DHEA-S levels in these body fluids.

The advantage of topical DHEA administration, however, is for those patients with known sulfatase SNPs. If personal biochemistry does not allow for DHEA-S to be readily converted to DHEA, the topical route may be preferred.

Oral DHEA

With oral DHEA administration we see a substantial spike in DHEA-S levels in all commonly tested body fluids (saliva, blood spot, serum, or urine) (undergoes first-pass metabolism and gets sulfated), and a marked improvement in symptoms as well. However, once DHEA becomes sulfated to DHEA-S, it is unable to cross the blood-brain barrier (DHEA is non-polar and crosses the blood-brain barrier easily, whereas DHEA-S is polar and does not cross into the brain from periphery). It is plausible to assume that DHEA-S that arises from first-pass metabolism after oral DHEA administration behaves in a similar manner to endogenous DHEA-S and contributes to the body’s biological reservoir of DHEA, readily converting to DHEA when the need arises.

Troche DHEA

How you take DHEA definitely impacts how much gets into the brain and how fast. For example, troche (sublingual) DHEA goes directly into the bloodstream (measured in serum) and because it’s not sulfated, it crosses directly into the brain and other tissues. Some patients are particularly sensitive even to small amounts (5 mg) of DHEA administered this way - with agitation being a common side effect. In this case, taking DHEA orally could have a more gentle uplifting sensation of wellbeing.

Clinical Utility of Neurosteroids

Since the discovery of neurosteroids in the early 80s, significant efforts have been poured into studying the role they play in brain-related disorders. Gleaning insight into the mechanisms that underlie neurosteroid involvement in mood pathologies may extend their clinical utility to treatment of mood and anxiety disorders, alcoholism, sleep disorders, chronic pain, traumatic brain injury, neurodegenerative disorders and many others [17]. Specifically for DHEA, it has been exciting to see the evolution of knowledge regarding this molecule’s behavior in the brain. Overall, DHEA is well-poised in clinical development for its therapeutic potential in helping the aging brain retain its regenerative capacity.

References

[1] Baulieu EE, Robel P: Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids. Proc Natl Acad Sci U S A 1998;95:4089-4091.

[2] Baulieu EE: Neurosteroids: of the nervous system, by the nervous system, for the nervous system. Recent Prog Horm Res 1997;52:1-32.

[3] Maninger N, Wolkowitz OM, Reus VI, Epel ES, Mellon SH: Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol 2009;30:65-91.

[4] Muskin PR: Complementary and Alternative Medicine and Psychiatry. Washington, DC, American Psychiatric Press, Inc., 2005.

[5] Murialdo G, Nobili F, Rollero A, Gianelli MV, Copello F, Rodriguez G, Polleri A: Hippocampal perfusion and pituitary-adrenal axis in Alzheimer's disease. Neuropsychobiology 2000;42:51-57.

[6] Lee JR, Zava DT, Hopkins V: What Your Doctor May Not Tell You About Breast Cancer. New York, Hachette Book Group, 2003.

[7] Kamin HS, Kertes DA: Cortisol and DHEA in Development and Psychopathology. Horm Behav 2016.

[8] Starka L, Duskova M, Hill M: Dehydroepiandrosterone: a neuroactive steroid. J Steroid Biochem Mol Biol 2015;145:254-260.

[9] Sripada RK, Marx CE, King AP, Rajaram N, Garfinkel SN, Abelson JL, Liberzon I: DHEA enhances emotion regulation neurocircuits and modulates memory for emotional stimuli. Neuropsychopharmacology 2013;38:1798-1807.

[10] Buoli M, Caldiroli A, Cumerlato MC, Serati M, de NJ, Altamura AC: Biological aspects and candidate biomarkers for psychotic bipolar disorder: A systematic review. Psychiatry Clin Neurosci 2016;70:227-244.

[11] Strous RD, Maayan R, Weizman A: The relevance of neurosteroids to clinical psychiatry: from the laboratory to the bedside. Eur Neuropsychopharmacol 2006;16:155-169.

[12] Strous RD, Spivak B, Yoran-Hegesh R, Maayan R, Averbuch E, Kotler M, Mester R, Weizman A: Analysis of neurosteroid levels in attention deficit hyperactivity disorder. Int J Neuropsychopharmacol 2001;4:259-264.

[13] Michael A, Jenaway A, Paykel ES, Herbert J: Altered salivary dehydroepiandrosterone levels in major depression in adults. Biol Psychiatry 2000;48:989-995.

[14] Dubrovsky BO: Steroids, neuroactive steroids and neurosteroids in psychopathology. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:169-192.

[15] Perez-Neri I, Montes S, Ojeda-Lopez C, Ramirez-Bermudez J, Rios C: Modulation of neurotransmitter systems by dehydroepiandrosterone and dehydroepiandrosterone sulfate: mechanism of action and relevance to psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:1118-1130.

[16] Labrie F, Belanger A, Belanger P, Berube R, Martel C, Cusan L, Gomez J, Candas B, Chaussade V, Castiel I, Deloche C, Leclaire J: Metabolism of DHEA in postmenopausal women following percutaneous administration. J Steroid Biochem Mol Biol 2007;103:178-188.

[17] Zorumski CF, Paul SM, Izumi Y, Covey DF, Mennerick S: Neurosteroids, stress and depression: potential therapeutic opportunities. Neurosci Biobehav Rev 2013;37:109-122.

Goodbye 2016! Comfort Foods for Your New Year’s Celebration

Fri, 30 Dec 2016 12:48:00 -0800

When you think of comfort foods, what comes to mind?

For me, it’s all about the firsts of the season. Sitting on the floor by the fireplace with its warmth permeating the room, it’s that first sip of eggnog – yes, the real stuff made from scratch. It’s the time when my house fills with the sweetness of a baking apple pie for the first time in many months. It’s also about the unending damp drizzle of Pacific Northwest winters and the haven of dry comfort on the inside enveloping my family and friends with a sense of belonging, connection and gratitude.

The Clinical Consultants group at ZRT hopes you enjoy these comfort food recipes and wishes you a Happy New Year!

Comfort food is as much about the indulgence and richness of the bite, overwhelming yet satisfying the senses, as it is about with whom you chose to share the food. For my family, there are only a few rules that apply to comfort food - it has to be kid and adult friendly alike, and it has to be simple to prepare with room for spontaneity and creativity. This way adults and children can enjoy the food together and every creation comes out with a slight twist and no two are ever the same.

Homemade Mac'n Cheese

The ultimate comfort food for my family is homemade mac’n cheese. I experiment with various kinds of cheeses for extra creamy decadence, spices for the element of surprise, and am prepared to try different ones next time around. Pair it with wine, green salad or baked squash for adults and homemade apple sauce for the kiddos. There are only so many firsts each season holds, allow yourself to give in to your senses and covet those moments. – Dr. Kate Placzek

Ingredients:

1 lb elbow macaroni, cavatappi, or any other pasta curls that will hold on to the sauce
1 quart organic whole milk
6 tbsp butter
½ cup unbleached flour
6 oz gruyère cheese, grated
4-6 oz smoked gouda cheese, grated
4 oz mozzarella cheese, grated
6 oz extra sharp cheddar cheese, grated
½ - 1 tsp ground nutmeg
¾ cup Panko breadcrumbs
½ cup grated parmesan
1 tbsp Italian seasoning
Sea salt to taste
Optional: for an extra kick, consider adding cayenne pepper

Instructions:

Preheat oven to 375 F.
Boil water, add the macaroni and cook according to the instructions to al dente. Drain well.
Meanwhile, heat the milk in a small saucepan, but don't boil it. Melt 6 tbsp of butter in a large (4 qt.) pot and add the flour. Cook over low heat for 3-4 minutes, stirring with a whisk. While whisking, add the hot milk and cook for a minute or two more, until thickened and smooth. Add pepper, salt, nutmeg, and Italian seasoning (and cayenne if using). Off the heat, add the grated cheeses. Add the cooked macaroni and stir well. Pour into a 3 quart baking dish.
Combine Panko bread crumbs and parmesan, sprinkle on top. Bake 30-35 minutes, or until the sauce is bubbly and macaroni is browned on the top.

Delicious Roasted Brussels Sprouts Medley

I’m someone who enjoys balance in life. This dish is a little sweet and a little savory – a little healthy and a little indulgent. It’s converted at least two people I know into Brussels sprout lovers. Just as important, it’s a lovely dish to look at with its reds, browns, golds and greens so it packs up and presents beautifully at parties and dinners. I hope you enjoy it as much as our family has! – Dr. Allison Smith

Roasted Brussels Sprouts:

3 cups Brussels sprouts, ends trimmed, yellow leaves removed, and cut in half
2 tbsp olive oil
Salt, to taste

Toss together in a bowl then spread out in a single layer with cut sides down on a foil covered, EVOO greased cookie sheet.

Roasted Butternut Squash:

1 ½ lb butternut squash, peeled, seeded, and cubed into 1-inch cubes (Yields about 4 cups of uncooked cubed butternut squash)
1 tbsp olive oil
2 tbsp maple syrup
1 tsp ground cinnamon

Toss together in a separate bowl then spread out in a single layer on a foil covered, EVOO greased cookie sheet.

Pecans:

1 tbsp packed brown sugar
2 tbsp maple syrup
2 tbsp organic butter
2 cups pecan halves

Follow directions below to candy pecans OR skip this step and buy some already candied pecans.

Other Ingredients:

1 cup dried cranberries

Instructions:

On 2 separate cookie sheets side by side in a 400 F oven, roast Brussels sprouts and butternut squash for 20-25 minutes and turn them half-way through cooking so they don’t get too brown on one side.
For the pecans: While those are cooking, heat a 12” skillet and melt the butter, then add brown sugar and maple syrup. Stir constantly until mixed and bubbly then add pecans. Cook for 2-3 minutes and keep stirring until coated. Remove from heat.
When the Brussels sprouts and squash are done, pull them out and let them cool. Drop the temp in the oven to 350. Spread the pecans on a parchment-covered cookie sheet and bake for 8 minutes or so. Cool for 20 minutes.
In a large serving bowl, incorporate the Brussels sprouts, the butternut squash cubes, the pecans and 1 cup of dried cranberries. Enjoy!!

Roasted Kabocha Squash, Carrot & Ginger Soup With Lamb Meatballs

Is there anything better than a warm cup of soup, but one made of a vegetable makes it even better. This is your typical yummy squash soup, but with a bit of an added kick with limes and cilantro. Although the recipe calls for lamb meatballs, leftovers were eaten with spicy sausage without complaints. I am lucky enough to have an instant pot, so I was able to cook the squash in 17 min shaving more time off of this awesome recipe. – Dr. Alison McAllister

Soup:

2 tbsp coconut oil, melted
1 medium kabocha squash, seeded and sliced into chunks
5 medium orange carrots, quartered
1 yellow onion, peeled and chopped
3 cloves of garlic, peeled and left whole
Salt & pepper (to taste)
2 tsp ground ginger
1 tsp ground cloves
4 cups chicken broth (learn how to make your own here)
1 13.5 oz can of full fat coconut milk
1 inch ginger root, peeled and grated

Meatballs:

1 lb grass fed ground lamb
1 tsp granulated garlic
1/2 tsp ground ginger
1/2 tsp oregano flakes
1/2 tsp cinnamon
1/2 tsp salt
1/4 tsp pepper
1 tbsp coconut oil (for frying)

Garnish:

Fresh cilantro
Fresh cut limes

Instructions:

Preheat your oven to 375 degrees F.
Line two baking sheets with tin foil and set aside. Cut up your carrots, onions, and seeded kabocha squash into large chunks. Toss with melted coconut oil, salt, pepper, ginger, and cloves. Make sure all of the veggies are coasted evenly. Lay out the veggies onto the baking sheets along with the whole cloves or garlic and allow to roast in the oven for 45-60 minutes or until the veggies are fork tender. You should be able to scoop the squash away from the skin easily. Once the veggies are done take them out and allow them to cool until they are no longer too hot to handle with your hands.
Add the carrots, onions and garlic to a heavy bottomed soup pot. Scoop out the meat of the kabocha squash, discarding the skins. Add the scooped out cooked flesh of the squash to the soup pot with the other roasted veggies. Add the chicken broth, coconut milk and freshly grated ginger to the pot with the veggies. Allow to simmer over a medium heat for 20 minutes or so in order to allow the flavors to marry.
While the soup is simmering, start on your lamb meatballs. Add the ground lamb and spices to a bowl and combine well with clean hands. Once the lamb and spices are well combined, portion the lamb into 12 equal portions and roll them into small meatballs. Place a pan on the stove and heat a tbsp of coconut oil over medium heat. Once the oil is hot, add the meatballs to the pan. Allow them to cook, rotating every couple of minutes in order to cook them fully.
Once your soup has simmered for 20 minutes, remove it from the heat and using an immersion blender, blend the soup until it is completely smooth and creamy.
After the meatballs are cooked through, you are ready to serve! Fill a bowl with soup, add a couple of meatballs to your bowl of soup and garnish with cilantro and the juice of half a lime (trust me on the lime juice, it's amazing). Enjoy!

Carrot and Parsnips Mash

It’s a simple but bright and colorful dish, as easy to make and as comforting as mashed potatoes but a little more unusual. Particularly good with poultry or roast beef.
– Lindsay Nyre.

Ingredients:

1lb carrots, peeled and chopped
1lb parsnips, peeled and chopped
Half stick of butter
3 tbsp heavy whipping cream
Handful chopped fresh parsley
Salt & pepper to taste

Instructions:

Boil carrots and parsnips for 30 mins or until soft and easily pierced with a fork
Mash with cream and butter, adding half of parsley, salt & pepper to taste
Sprinkle remaining parsley on top

Original Kentucky Whiskey Cake

On a different note of comfort…a recipe for the Original Kentucky Whiskey Cake will make a special holiday treat. Although the recipe is chock-full of fruit, it’s no ordinary fruit cake. The sweet, buttery denseness of moist cake is combined with the distinctive, earthy sweetness of cherries and dates infused with bourbon whiskey. Pecans give a nutty flavor and crunchy texture to this delightful, comfort treat. Enjoy! – Dr. Sherry LaBeck

Ingredients:

1 lb candied cherries, cut in half (I substitute fresh or frozen cherries for the candied variety)
½ lb dates or raisins
1 pint Kentucky Bourbon
1 ½ cups butter, softened
2 cups white sugar
1 cup brown sugar
6 egg yolks, beaten
5 cups sifted flour
1 lb shelled pecans
2 tsp nutmeg
1 tsp baking powder
6 egg whites, stiffly beaten

Instructions:

Soak cherries and dates/raisins in bourbon overnight.
Cream butter and sugar until fluffy, add egg yolks, beat well.
Add soaked fruit and the rest of the liquid.
Mix pecans with ½ cup of flour.
Add the rest of the flour, nutmeg and baking powder to mixture.
Fold in egg whites and floured pecans.
Bake in a large greased tube pan lined with greased paper for 3-4 hours in a slow oven (250-275 F).
When cool, stuff center hole with cheese cloth soaked in bourbon and wrap in heavy waxed paper.
Place in a tightly covered container and refrigerate (freezes well).