The ZRT Laboratory Blog

A Perimenopausal Game Plan

Fri, 06 Dec 2019 16:52:41 -0800

Having just entered my forties, my radar’s perked for solid information coming out of the research community on the perimenopausal transition. What can I do to make this 10 or so years of transition useful and even helpful to the future postmenopausal me? As women, we’re no strangers to functioning in some level of consistent discomfort – whether cycle-related, birth control related, pregnancy or post-partum related, or multiple-role related. We just manage through it one way or another with the idea that the pain is for a purpose. That said, perimenopause may be different: for instance, we now know that a highly symptomatic perimenopause may be directly associated with cardiovascular risk, suddenly turning that “pain for a purpose” attitude we’ve had for decades into something different. And with coronary heart disease being the leading cause of death for humans on this planet, perhaps our perimenopausal experience should prompt more than just a symptoms management approach. Perhaps a lot more.

What is Perimenopause?

Before we stop having periods for good, hormones like estrogen and progesterone fall out of their expected rhythms because the perimenopausal time directly links with our declining ovarian reserve. As we run low on viable follicles or eggs, the signals from the brain to the ovary – that’s LH and FSH – begin to amplify little by little (to a lot). The less follicular estrogen and inhibin the ovary produces, the louder FSH gets. Similarly, the fewer successful ovulations, the higher that LH signal becomes in its effort to make ovulation happen. Ovulation is where we get most of our progesterone, so when we’re not ovulating we have basically no progesterone and thus end up fluctuating between estrogen dominant and estrogen deficient states, which leads to irregular bleeding. For some women, this phase is rather short, going from regular cycles to no longer cycling seemingly overnight and with few to no attributable symptoms. Other women take the scenic route through perimenopause over many, many years of bleeding changes, hot flashes, mood swings, and shifts in body composition.

Perimenopause may be the most important time to squirrel away resources and get your hormone status, body composition, and nutrition in order to prepare for the coming famine.

With my personal family history being full of typical postmenopausal afflictions like osteopenia, cardiovascular disease, uterine prolapse, autoimmune disease, and thyroid problems, I really have to look at this perimenopausal time period as a runway to takeoff. It’s a silly metaphor but I’ve got to gas up because I want to fly for a long, long time! Perimenopause may be the most important time to squirrel away resources and get the hormonal (sex, adrenal, and thyroid especially), body composition, and nutritional statuses in order to prepare for the coming famine because I don’t trust the ground work I laid in my teens and twenties to carry me through.

So, I’ve devised a plan. A perimenopausal game plan.

Step One: Replace

The decision to replace estrogen and progesterone in menopause is truly such an individual one. Some in the naturopathic community may feel we should embrace the natural senescence on the other side of menopause. Some in the anti-aging community probably feel like folks should be knee deep in injectable peptides and hormone replacement by their mid-30s for max benefit. I’m somewhere in the middle, I suppose, and my rationale is this: as we live in a world in which cardiovascular disease will usher more folks to the morgue than breast cancer, I’m pretty locked on to the idea of using hormone replacement therapy as early on in menopause as possible for the biggest benefit to my heart, brain, and bones (the things that, without estrogen, are most likely to rob me of my health or kill me). And without knowing what the future holds from a hormone research standpoint or for my own future health at this point, I do plan to remain on HRT for decades in an effort to increase my health span [1,2]. I don’t see myself slathering on 10 or 20 mg of topical estradiol every day or anything, I’m more of the mind of using a low to mid-dosed transdermal or topical. As for progesterone; none of that progestin business, especially medroxyprogesterone acetate that links up with cardiovascular events and breast cancer, but good old bioidentical progesterone for breast, bone, brain, and endometrium [3]. Maybe I’ll cycle it using rhythmic dosing for the potential cardiovascular benefit if that ends up fleshing out in the research – I haven’t decided yet. It’s early. That’s for tomorrow.

Today, I’m zeroed in on Step 2 and 3: BUILD and FAST, also known as exercise and diet – admittedly the two greatest medical treatment clichés of American culture. I can do that starting right now, even before that first perimenopausal symptom sets in. I’m really inspired by the research coming out on the circadian rhythms of the body and how dependent our cardiovascular and metabolic health is on the proper diurnal excursions of our hormones, peptides, and inflammatory cytokines. After all, in women, the menstrual cycle both governs (with estradiol) and is governed by (with light/dark) the circadian rhythm ultimately set by the suprachiasmatic nucleus (SCN) – so yes, hormone replacement is a part of keeping the clocks synchronized. But that’s not the end of the story. We also have peripheral clocks that have to stay coordinated with that master central clock for our brain hormone signals to stay in sync with the tissues. Cortisol is that coordinator between peripheral and central. Its diurnal rhythm is constantly adjusted by the master (central) clock primarily through the HPA axis and by direct splanchnic innervation from the SCN. But secondarily, cortisol rhythms are heavily regulated by the times of day in which our bodies are moving and eating. I’m sufficiently convinced that if I can actively synchronize and reinforce these diurnal rhythms through my lifestyle choices, that groundwork will define my perimenopausal experience. So let’s look closer at steps 2 and 3.

Step Two: Build

Through Movement: Walking + Resistance Training

Blue Zone research says walking 6 hours a week will decrease the risk of dying from cardiovascular disease.

To build a resource cache in my bones and muscles, I have to move them enough to make it a habit. Blue Zone research says walking 6 hours a week will decrease the risk of dying from cardiovascular disease [4]. Check plus. This, I can do and enjoy. Of course, while aerobic exercise like walking carries the cardiovascular benefit, with my family history I’m also interested in bone health. I tend to put most stock into research looking at increased femoral neck, hip, and lumbar bone mineral densities. And from perusing studies linking greater bone density with exercise, the take home message for me has been this: incorporate resistance training [5,6]. Use my own body weight like squats (easy while I’m brushing my teeth) push-ups and planks (while watching a show), but also incorporate weights like bench press, bicep curls, and – seriously I want to do this – dead lifts. So, get stronger. This is not a weight loss thing; rather it’s a way to build resources within my own body. I’m certain I will not be a 90-year old body builder, but the idea is I’ll be less likely to suffer spinal compression fractures or – goodness forbid – a broken hip on my way to an early cardiovascular-related grave.

Benefit to perimenopausal symptoms

Outside of the cardiovascular and bone benefits, several studies have identified resistance training as an effective strategy for reducing the frequency and severity of perimenopausal hot flashes. Additional research on aerobic exercise – that’s your walking, dancing, and shaking – found that it decreased night sweats, urinary problems, headaches, irritability, mood swings, and increased overall quality of life in postmenopausal women even at just 2.5 hours a week [7,8,9].

Step Three: Fast (and then Break-fast)

The irony of titling the diet section Fast is not lost on me. But the research on calorie restriction, time restricted feeding (TRF) schedules, and fasting mimicking diets (FMDs) just keeps getting more interesting, yielding a growing list of compelling health implications.

I’ve always proselytized the idea of eating breakfast everyday regardless of level of hunger in the early hours, based on a preponderance of research relating breakfast-skipping to metabolic syndrome in adolescents and adults alike. But now we know that the fasting portion of the daily schedule, the times in which we’re not eating, matters just as much as the eating part for other parameters of health.

Time restricted feeding (sometimes referred to as intermittent fasting or IF, but is just one of many types of IF) essentially means eating for a 6-8 hour block of the day and then fasting for the rest of it. Early time restricted feeding (eTRF) concentrates the eating hours into the hours of the day just following morning waking. An eTRF schedule can strengthen and synchronize those circadian rhythms by advancing the sleep phase, influencing our gut microbiome, adjusting our hormonal rhythms that signal hunger/satiety/adipose functions, honing hormone receptor sensitivities, and reducing inflammatory markers like TNFα, IL-6, and IL-1β [10].

FMDs work on the same underlying mechanism and have gained notoriety for influencing many of the same health parameters as the TRF diets, as well as lowering systolic blood pressure, CRP, IGF-1, and potentially engaging some of the same anti-aging/anti-cancer benefits of autophagy/apoptosis/cell regeneration, including neuro-regeneration [11]. Instead of compressing the eating period on a diurnal feeding/fasting schedule on a daily basis, FMDs usually entail an intense caloric restriction phase (500-800 calories a day) for some period of time – these protocols may vary from 2-7 days a month to 2 consecutive days a week (aka the 5:2 plan) to every other day.

For me, I’ll probably start out with one of the expensive pre-packaged FMD plans until I get comfortable with it (I really don’t even know how to wrap my mind around 600 calories a day yet) and see how my body feels on it. I’m not big on repressive regimens and happen to believe in the health benefits of social eating, so there will have to be a lifestyle balance for it to work for me.

Benefit to perimenopausal symptoms

No real direct studies have looked at menopausal symptoms and intermittent fasting exactly, but it’s not hard to extrapolate the effects of the diet by its known effects on different blood markers also known to be attributed to perimenopausal symptoms and imagine there could be a benefit. For instance, because higher levels of inflammatory cytokines like TNFα, IL-8, and IL-6 are associated with hot flashes in menopause [12], an eating schedule that includes a fasting component may reduce those cytokines, alleviating those hot flashes [13]. You could say the same thing about cognitive changes and BDNF, or night sweats and systolic blood pressure, or body composition and adiponectin:leptin ratio.

Ladies, perimenopause serves a purpose. It’s our time to take our health into our own hands and plan for the next phase, not just weather through drenched sheets and “brain fog”. If perimenopause turns your life upside down, it may be worth taking a hard look at your cardiovascular system – that means teaming up with your health care providers to perhaps get some baselines for coronary artery calcium (CAC) score and look at modifiable markers like homocysteine and BDNF, sex hormones, and diurnal cortisol patterns. I can’t help but think that if we started thinking of perimenopause as 10+ years of heavy cardiovascular prevention work, there would have to be a huge benefit to our health care system, not to mention to ourselves and our families. That’s my perimenopausal plan, what’s yours?

Related Resources

References

[1] Palacios, S, et al. Hormone therapy for first-line management of menopausal symptoms: Practical recommendations. Womens Health (Lond). 2019;15:1745506519864009.

[2] Velarde, MC. Mitochondrial and sex steroid hormone crosstalk during aging. Longev Healthspan. 2014;3:2.

[3] Lobo, RA, et al. Prevention of diseases after menopause. Climacteric. 2014;17:540-56.

[4] https://www.bluezones.com/2018/07/research-says-walking-this-much-per-week-extends-your-life/

[5] Berin, E, et al. Resistance training for hot flushes in postmenopausal women: A randomised controlled trial. Maturitas. 2019;126:55-60.

[6] Bailey, TG, et al. Exercise training reduces the frequency of menopausal hot flushes by improving thermoregulatory control. Menopause. 2016;23:708-18.

[7] Moilanen, JM, et al. Effect of aerobic training on menopausal symptoms--a randomized controlled trial. Menopause. 2012;19:691-6.

[8] Mansikkamäki K, et al. Sleep quality and aerobic training among menopausal women--a randomized controlled trial. Maturitas. 2012;72:339-45.

[9] Courneya KS, et al. Dose-Response Effects of Aerobic Exercise on Quality of Life in Postmenopausal Women: Results from the Breast Cancer and Exercise Trial in Alberta (BETA). Ann Behav Med. 2017;51:356-364.

[10] Jamshed, H, et al. Early Time-Restricted Feeding Improves 24-Hour Glucose Levels and Affects Markers of the Circadian Clock, Aging, and Autophagy in Humans. Nutrients. 2019;11:1234.

[11] Paoli, A., et al. The influence of meal frequency and timing on health in humans: the role of fasting. Nutrients. 2019;11:E719.

[12] Huang, WY, et al. Circulating interleukin-8 and tumor necrosis factor-α are associated with hot flashes in healthy postmenopausal women. PLoS One. 2017;12:e0184011

[13] Franco, OH, et al. Vasomotor symptoms in women and cardiovascular risk markers: Systematic review and meta-analysis. Maturitas. 2015;81:353-61.

Guide: How to Treat Iodine Deficiency

Thu, 25 Oct 2018 09:02:00 -0700

The decision to start a regimen of iodine supplementation should be based on a detailed nutritional, physical, and laboratory assessment. Once the need is established, some clinicians go straight for supraphysiologic dosing while others may implement a diet rich in sea vegetables to get the job done. How do you decide where to start? The first step is understanding the different supplement forms of iodine.

Supplementation

Iodine exists in several oxidative states in the body which perform vastly different actions. That said, there are a couple of forms of iodine to understand before starting to prescribe iodine. A working knowledge of these forms is needed before diving into testing the markers of iodine status because as those markers inform the course, the form and dose will determine the outcome.

Iodide

You’ll find it in supplements typically as potassium iodide (KI). Iodine, in the form of iodide, concentrates in the thyroid gland and any other tissue with the right sodium iodine symporter (NIS) protein to bring it in – NIS concentrates iodide not only in the thyroid, but also in the cervix, the ovaries, placenta, eyes, skin, and lactating breast [1]. This is the form of iodine that gets incorporated into thyroid hormones which transport iodine around to the entire body by T4 to T3 conversion intracellularly thereby supporting a myriad of processes from basal metabolism to ovulation to the immune system. This is the form used to support the thyroid primarily along with the rest of the body. So, if you’re looking to support the thyroid and its T3 and iodine delivery service, KI may be a good choice.

Dosing range is typically 150 µg – 1100 µg (0.150 mg – 1.1 mg) daily.

I₂(Molecular Iodine)

Quite different from iodide, I₂ (aka molecular iodine as referred to in the literature), passes into body tissues in a NIS-independent fashion by facilitated diffusion. It lends more of an antioxidant, anti-proliferative effect to tissues by virtue of its structure and ability to form protective iodolactones and iodinated lipids - rather than concentrating in only the NIS-rich tissues as iodide would [1]. You’ll notice when you read the label of any “molecular iodine” supplement that I₂ is supplemented as a mixture of potassium iodide (KI) and iodate (KIO₃) or potassium iodide and free iodine. And free iodine may be referred to as elemental iodine or even molecular iodine depending on where you read about it. The mixture of KI and KIO₃ forms molecular iodine (I₂) “in solution” in the low pH of the stomach as it’s absorbed; the mixtures of free iodine and KI work from the premise that KI improves solubility/absorption of the free iodine portion, and transdermally-applied free iodine seems to be taken up locally as molecular iodine [2].

Once absorbed and taken up into the body, some studies show I₂ doesn’t affect thyroid markers (which is good news for some patients) but does enter the breast, the prostate, tumor sites, and cystic areas, acting at the mitochondrial level to attenuate benign and cancerous growths [3]. So, this is the form to use when attempting to avoid thyroid uptake and to push the reactive oxygen species (ROS) scavenging and cell cycle-limiting effects of iodine in other parts of the body.

Dosing range is typically 1100 µg – 12,500 µg (1.1 mg – 12.5 mg) daily.

*Supraphysiologic dosing is anything over 1100 µg (1.1 mg) although a 2013 paper exploring some of the extrathyroidal actions of iodine recommended at least a 3 mg daily intake of I₂[3].

Here are some examples of such forms currently available to patients – this is in no way an exhaustive list, just an idea of what’s out there.

Caveat(s): It is possible that any of the iodine Rx options listed above will have some iodide effect on the thyroid and caution should be exercised even with the ones that claim 100% conversion to I₂. Regarding iodine testing, when supraphysiologic doses of iodine are used (even transdermally), urinary iodine excretion skyrockets into the thousands. For instance, with a 12.5 mg dose, expect to see lab results between 1,000 and 3000 µg/g Cr! Higher doses yield even higher lab results even days after a dose. For sufficiency, the normal laboratory range for general thyroid health is 100 – 380 µg/g Cr.

Hashimoto’s

When anti-thyroid antibodies contribute to thyroid dysfunction, recommending iodine supplementation may feel like a dangerous undertaking. Many providers don’t recommend it at all. As a matter of fact, it’s not uncommon for ZRT to see someone with Hashimoto’s have urinary iodine labs in the severely deficient range of less than 30 µg/g Cr. That said, there are some providers treating autoimmune thyroiditis with mega-doses of molecular iodine sometimes upwards of 100 mg per day. Yes, that’s milligrams! And amazingly, these doses don’t seem to put the average patient’s thyroid into a storm (not reliably anyway) and some case reports tout complete resolution despite the inherent risk. For those of us worried about hurting the one person that does react negatively to a high dose of iodine, perhaps there’s a middle ground.

It makes good clinical sense to ensure that even our autoimmune patients receive properly monitored nutrition for their thyroids and the rest of their iodine-sensitive tissues. After all, those iodine levels can be monitored for sufficiency in the urine while other work is underway to quiet the immune system and relieve the oxidative stress of autoimmune disease [4]. It makes sense that the supplemented form be mostly molecular iodine to minimize the impact on thyroid hormones and keep the thyroid as quiet and happy as possible. And of course, using the thyroid hormone prescription to keep TSH within the normal range (NOT LOW!) ensures the NIS system will still be working hard to bring nutritionally acquired iodine into the body tissues, and any supplemented T4 will support the transport of iodine around the body where it’s needed.

Dosing range is conservative with frequent monitoring: 150 µg – 1100 µg (0.150 mg – 1.1 mg) molecular iodine with the general rule of start low, go slow. Even a low dose can cause slight changes in the thyroid hormones [5].

Final Thought on Iodine: Support and Thwart

Iodine performs some crucial roles in the body within multiple systems but it never acts alone. Depending on the environment, iodine can oxidize, reduce, and form complexes. Without stacking the deck in favor of reduction, too much iodine in the body can be destructive and may even increase the risk of autoimmune thyroiditis [6]. Once you identify low iodine status in an individual, it is absolutely imperative to assess and support iodine’s equal partners - selenium, iron, magnesium, zinc, B6, cortisol, glutathione - and consciously work to identify and thwart the endocrine disruptors like bromine, cadmium, mercury, and arsenic in order to get the best outcome [7].

Related Resources

References

1 Kaczor, T. Iodine and cancer: a summary of the evidence to date. NMJ June 2014: 6(6).

2 Gottardi W. The uptake and release of molecular iodine by the skin: chemical and bactericidal evidence of residual effects caused by povidone-iodine preparations. J Hosp Infect. 1995;29(1):9-18.

3 Aceves C, et al. The extrathyronine actions of iodine as antioxidant, apoptotic, and differentiation factor in various tissues. Thyroid. 2013; 23(8): 938–946.

4 Soriguer F, et al., Iodine intakes of 100-300 μg/d do not modify thyroid function and have modest anti-inflammatory effects. Br J Nutr. 2011;105(12):1783-90.

5 Reinhardt W. Effect of small doses of iodine on thyroid function in patients with Hashimoto's thyroiditis residing in an area of mild iodine deficiency. Eur J Endocrinol. 1998;139(1):23-8.

6 Palaniappan S. Improving iodine nutritional status and increasing prevalence of autoimmune thyroiditis in children. Indian J Endocrinol Metab. 2017;21(1):85-89.

7 Chen A, et al. Thyroid hormones in relation to lead, mercury, and cadmium exposure in the National Health and Nutrition Examination Survey, 2007-2008. Environ Health Perspect. 2013;121(2):181-6.

Guide: How to Assess Iodine Deficiency

Fri, 28 Sep 2018 12:14:00 -0700

I’m excited to do this practical piece on iodine therapy because I field a lot of questions on the matter of assessing iodine status, implementing the right iodine supplement, and monitoring that therapy.

Iodine performs some crucial roles in the body, but it never acts alone. Therefore, to assess iodine deficiency, it’s imperative to test iodine and its partners - selenium, iron, magnesium, zinc, B6, cortisol, and glutathione. To assure optimal outcomes, it’s also important to check for endocrine disruptors like bromine, cadmium, mercury, and arsenic.

Iodine's Relationship to Health

If you do an online search for information on “iodine supplementation,” you’re bound to find most of the articles focused on the thyroid and on the iodide form of the mineral. But many providers are now thinking about iodine’s relationship to the breast, to ovarian health, to ovulation and fertility, and even in the context of cancer prevention and treatment.

Even beyond nutritional sufficiency, many are using iodine in supraphysiologic doses to get more of a drug-like effect. I think much of the information out there on iodine, while exciting and informative, can be confusing when it comes to discerning a clear treatment for a patient’s unique presentation.

Given that, this guide will focus on the “how to” of assessing for and treating iodine deficiency rather than the “why you should,” and I’ll connect you with the various ZRT resources already available to help you implement this assessment in practice.

Iodine Intake

The first part of any good nutritional evaluation – assess for adequate intake. As clinicians, we may gloss over this part or take patients at their word. It’s great when patients give their assurance that they have a “clean diet” or “only eat a diet rich in whole, organic foods” but that doesn’t necessarily tell you what exactly they’re eating on a regular basis. This is where a diet recall during the visit followed up by a 7-day diet diary can be helpful. And what key foods should you be looking for? Check out these two resources below.

Even if someone eats an excellent diet that should yield an adequate daily iodine intake, unfortunately natural food sources may vary somewhat in nutritional content which affects dietary intake. We should also consider assessing for consumption of toxic elements that disrupt iodine uptake like bromine and arsenic [1][2].

Key Symptoms

While it’s tempting to rely on nutritional intake for information about a patient’s overall iodine status, it’s important to consider an individual’s symptom profile. Is she presenting with fibrocystic breasts? Is he suffering with benign prostatic hypertrophy (BPH)? Some examples of presentations that may warrant an investigation into low iodine status are:

Athletes (sweating clears more iodine, increases requirement)
Breast cancer - Family or personal history
Fibrocystic breast changes (and breast pain)
Gastric cancer
Hypometabolism/hypothyroidism - Weight gain, low body temps, constipation, fatigue, dry skin, brittle nails
Hypochlorhydria or Gastric Bypass (may decrease absorption)
Infertility - Ovulation – Women; Semen quality - Men
Lactation
Menstrual cycle irregularities - Mid-cycle pain
Ovarian cysts (luteal cysts)
Pregnancy
Urinary symptoms in men due to prostate problems (including prostate cancer)

Physical Examination

I don’t know of a clear “tell” when it comes to identifying an early iodine deficiency, but perhaps the first sign would be decreased sweating as the body tries to decrease iodine clearance. Once that low status reaches the thyroid, clear signs begin to emerge.

Hypothyroidism symptoms

Brittle fingernails
Hair loss, diffuse
Puffy eyes
Subnormal body temp
Decreased sweating
Hoarse speech
Skin dry/coarse
Thyroid enlargement
Edema (non-pitting)
Lateral 1/3 eyebrow loss
Slow heartrate
Hair dry/coarse
Overweight
Slow reflex return

Other signs that may suggest a low extrathyroidal iodine status (or a need for supplemental iodine):

Breast exam may reveal bilateral diffuse bumpiness or focal areas that are often tender to palpation.
Prostate exam may reveal diffuse, bilateral bogginess.

Laboratory Assessment: 3 Parts

1. Thyroid Function Panel

Essential Components: TSH, Total T4, Free T4, Free T3

How does a thyroid function panel tell us about iodine status? Well, to answer that, here’s a super basic look at the pertinent physiology as we follow the iodine after dietary consumption over to the thyroid and then to the rest of the body. After being absorbed into the thyroid tissue, iodine accumulates and incorporates into the structure of the main thyroid hormone, thyroxine (T4). With iodine deficiency, T4 levels fall (total T4 drops earlier than free T4) and TSH levels rise to increase iodine absorption capability [3].

T4, as the body’s main source of metabolic potential energy, in true endocrine fashion travels through the body attached to thyroid binding globulins (total T4) to target tissues where it becomes free T4. When T4 is “activated” in the tissues to T3, iodine is liberated into the intracellular space.

In this way, the thyroid is in large part responsible for the dissemination of iodide to the body through conversion of T4 to T3 far from the thyroid itself. Several nutritional cofactors such as zinc, selenium, and vitamin B6 make the conversion of T4 to T3 possible, and deficiencies in these diet-acquired cofactors can lead to low T3 levels, low intracellular iodine levels, and symptoms. So, for this reason, when assessing intracellular, extrathyroidal iodine status, it is absolutely insufficient to test only T4 and TSH. We must look to free T3 for that additional piece.

Notes for testing: When initiating supplemental iodine (and the same goes for thyroid hormone replacement), monitoring a thyroid function panel at 6-8 weeks is recommended for reassessment.

2. Thyroglobulin (+ Antibodies to TPO and TG)

When thyroglobulin (Tgbn) is higher in the context of an otherwise normally functioning thyroid, it’s likely the thyroid is laboring to overcome an iodine deficiency. The scarcer iodide is to the thyroid, the more the thyroid gland enlarges due to increased stimulation from TSH. The denser the thyroid tissue, the more thyroglobulin. Likewise, when thyroglobulin is optimal (3 – 10 ng/mL), iodine has been sufficiently available for adequate thyroid hormone production and any variations in dietary iodine intake has likely been well-sustained by the thyroid [4][5].

Caveat: When using thyroglobulin to assess iodine status, it is important to either have previously confirmed or simultaneously test for anti-TPO and especially anti-Tgbn antibodies because autoimmune thyroid tissue destruction can also cause increases in thyroglobulin unrelated to iodine status. Importantly, if you’re considering molecular iodine-only supplementation, this information influences the level of monitoring necessary during that treatment.

3. Urinary Iodine and Bromine

Urinary iodine measured via ICP-MS is a direct and simple way to test for recent iodine sufficiency without the interference from bromine found with ion electrode testing. Traditional ion electrode testing can’t tell the difference between iodine and bromine. But even ICP-MS iodine testing is inappropriate for discerning longer-term iodine status without putting it together with the aforementioned thyroid markers.

Other methods of testing for functional iodine deficiency have frustratingly fallen short of the scientific bar. In particular, the “iodine loading test” can no longer be recommended due to its premise being based on a long-propagated misapplication of earlier literature exploring the expected iodine clearance after a high dose of iodine and very low sensitivity as a result. Dr. Zava has written about the flaws associated with the iodine loading test in a white paper you can find here and ZRT actually did a small study to assess the iodine clearance and kinetics after a 50 mg dose of iodine/iodide mixture you can read about here.

Notes for testing: For a baseline urinary iodine level for those previously supplementing, the recommendation varies by the previous dose. After stopping supraphysiologic dosing (1100 µg – 6.0 mg), 7-10 days is usually enough time to return to baseline. For those using physiologic doses (150 µg – 1100 µg), 3 days off is recommended. After a CT scan with iodine contrast or dosages > 6.0 mg, it can take 4 – 6 weeks to clear that iodine. Lab values can reach the tens of thousands for those who test too early afterward!

Urinary Bromine via ICP-MS tells us about iodine status because bromine impedes iodine’s entry into the thyroid gland. That means even when urinary iodine levels are normal, if bromine is elevated, tissue iodine levels may actually be inadequate. As such, this element should always be assessed side by side with iodine.

Overview: Laboratory Clues of Low Iodine Status

Analyte	Finding	ZRT Range
TSH	↑	0.5 – 3.0 µU/mL
Total T4	↓	5 – 10.8 µg/dL
Free T4	↓	0.7 – 2.5 ng/dL
Free T3	↓ (or low compared to fT4)	2.4 – 4.2 pg/mL
Thyroglobulin	↑ (when negative anti-thyroid antibodies)	3-40 ng/mL ZRT Optimal 3-10 ng/mL
Urinary Iodine	↓	100 – 380 µg/g Cr
Urinary Bromine	↑	<4800 µg/g Cr

Note: Free T4 and Free T3 may be within normal ranges for a period of time as the body works to accommodate for an iodine deficiency

Final Thought on Iodine

In a world full of endocrine disruptors, misguided diets, and daily stressors, it is very easy for people to fall below their individual nutritional intake requirements. Given iodine’s responsibilities inside and outside the thyroid, its sufficiency is so important for all of our patients. When symptoms of iodine deficiency start to emerge, follow these guidelines to investigate the signs. Once a clinical pattern materializes to correlate with those symptoms, the next step involves choosing an iodine supplement regimen.

Related Resources

References

1 Lee KW, et al. Food Group Intakes as Determinants of Iodine Status among US Adult Population. Nutrients. 2016.

2 Shengwen S, et al. Arsenic binding to proteins. Chem Rev. 2013; 113(10): 7769–7792.

3 Pearce, EN, et al. Urinary iodine, thyroid function, and thyroglobulin as biomarkers of iodine status. Am J Clin Nutr. 2016; 104(Suppl 3): 898S–901S.

4 Andersen S, et al. Reliability of thyroglobulin in serum compared with urinary iodine when assessing individual and population iodine nutrition status. Br J Nutr. 2017;117(3):441-449.

5 Ma ZF. Thyroglobulin as a biomarker of iodine deficiency: a review. Thyroid. 2014;24(8):1195-209.

The Connection Between GABA & Sleep Disturbances

Wed, 20 Jun 2018 09:42:00 -0700

Gamma-aminobutyric acid, better known as GABA, is the neurotransmitter known for its affinity for GABA receptors throughout the central nervous system (CNS). It acts to inhibit excitatory processes – whether they be normal or pathological.

It's synthesized from the excitatory neurotransmitter glutamate in a process that requires vitamin B6 as a cofactor. The delicate balance in the brain between GABA and glutamate is orchestrated by shuttle systems from the Krebs Cycle, the presence of NMDA and GABA receptor modulators, enzyme cofactors, and reuptake mediators.

In the rest of the body, GABA plays a myriad of important protective roles. It modulates the adrenal response to stress by acting as the gate-keeper of norepinephrine and epinephrine release (catecholamines responsible for the adrenaline surge) [1]. It regulates the activity and regeneration of β-islet cells in the pancreas which are responsible for insulin secretion and blood sugar regulation [2]. GABA made and stored in the nerves of the enteric nervous system acts to mediate the upper gastrointestinal tract’s secretion and emptying mechanisms and modulate the sensation of visceral pain there. The guts are absolutely covered in GABA receptors of all types. When synthesized in the small intestine by Lactobacillus and Bifidobacterium species, GABA influences the HPA axis and up-regulates GABA receptor expression in the CNS, thanks to the vagus nerve [3]. Any imbalance in this body-wide system, whether it be in the CNS or in the periphery, may lead to sleep disturbances.

Low GABA & Sleep Problems

We see sleep disturbances not only in those with low GABA but also in those with high GABA excretion, and while the presentation may be quite similar, the underlying cause is very different.

Applying what we know about GABA's function in the CNS and in the periphery, how do we think the absolute GABA levels we find in the urine correlate to the reported symptom of sleep disturbance? The low hanging fruit in the thought process is that low GABA levels correlate with sleep problems. Not enough inhibitory activity to get the job done – not enough brakes, so to speak, to let our busy minds absorb the halting rhythms of the day and ease into much needed rest. And in some cases, that's definitely true – for example, in the presence of oxidative stress, glutamate resources prioritize glutathione production at the expense of GABA's and leave us low in GABA, or even a simple B6 deficiency can lead to lower activity of the enzyme that turns glutamate into GABA, glutamate decarboxylase (GAD), and as a result lower GABA levels. Those with minor genetic mutations in the GAD enzyme system or those with autoantibodies against GAD may have lower GABA levels in the urine along with the symptom of disturbed sleep.

High GABA & Sleep Problems

In clinical practice though, the reality is that we see sleep disturbances reported not only in those with low GABA but also in those with high GABA excretion, and while the presentation may be quite similar, the underlying cause is really very different. Circle back to what we know about GABA’s job in the adrenal medulla as a stress modulator and it starts to make sense. GABA production and release is a reactive measure in the presence of a stressor; its release is not directly centrally mediated. In fact, it acts in an autocrine/paracrine manner when released from adrenal chromaffin cells, which live in close vicinity to the excitatory catecholamine-releasing sympathetic neurons. Without GABA's modulatory activity in the adrenal medulla, norepinephrine and epinephrine release would become a runaway train. So, this compensatory mechanism is a clue to help us get to the bottom of what’s actually disturbing sleep.

High GABA Excretion’s Link to Acute Stress

A study in 2013 [4] looked at kids with obstructive sleep apnea (hypoxia being the ultimate stressor) and found elevated overnight levels of urinary GABA, norepinephrine, and epinephrine – strengthening the idea that excessive fight or flight activity has close ties with higher GABA levels. And that extra GABA may be absolutely necessary for an individual with a ramped-up sympathetic nervous system.

Gabapentin is an excellent example of a drug that uses this mechanism to blunt the norepinephrine/epinephrine stress response at the level of the adrenal gland. Gabapentin was designed to mimic GABA while not binding to GABA receptors, and is commonly used for neuropathic pain and epilepsy. Gabapentin raises GABA levels centrally and we also find significantly elevated GABA levels in the urine in Gabapentin users. And like GABA, it does this while concurrently attenuating norepinephrine and epinephrine secretion from the adrenal medulla, modulating the response to stress [5]. This is probably a big part of why it is also effective at treating anxiety and insomnia [6]. Certainly, more sustainable interventions than a gabapentin prescription to retrain the body to respond to stress in a healthy manner are preferred – dietary interventions, biofeedback, adaptogen therapies, and regular exercise, to name a few – and the cornerstone of any therapy is still a regular good night’s sleep. To get there, the terrain must be cleared.

The takeaway here is to assess and address the adrenal stress response first in patients with high GABA and sleep problems. Don't assume that because it’s a "good" neurotransmitter that more is better. More may actually be the smoking gun of a trigger-happy, overwhelmed sympathetic nervous system.

Related Resources

References

[1] Harada, K, et al. GABA signaling and neuroactive steroids in adrenal medullary chromaffin cells. Front Cell Neurosci. 2016;10:100.

[2] Soltani, N, et al. GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proc Natl Acad Sci U S A. 2011; 108: 11692–11697.

[3] Leo, G. The gut microbiome and the brain. J Med Food. 2014; 17: 1261–1272.

[4] Kheirandish-Gozal L , et al. Urinary neurotransmitters are selectively altered in children with obstructive sleep apnea and predict cognitive morbidity. Chest. 2013;143:1576-1583.

[5] Todd, Robert D, et al. Gabapentin inhibits catecholamine release from adrenal chromaffin cells. Anesthesiology. 2012; 116: 1013–1024.

[6] Lo HS, et al. Treatment effects of gabapentin for primary insomnia. Clin Neuropharmacol. 2010;33:84-90.

Norway, for the win!

Fri, 23 Feb 2018 12:16:00 -0800

Amidst all the hullabaloo about norovirus in the Olympic village, doping in the Russian curling community, and wipeouts of truly epic proportions, the 2018 Games have certainly elevated the entertainment quotient. Norway quietly tops the list for Olympic medals in Pyeongchang this year and as a team, has steadily stepped up their game every 4 years since 2010 which for me raises the question: What can we learn from the Norwegians?

Don’t do drugs.

For such a contender, you won't find a single Norwegian winter athlete on the doping lists for Olympics dating back to the inception of testing in 1968. I find this fascinating. The use of performance enhancing drugs and supplements (PEDs) became such a foregone conclusion in the 80's and 90’s for its influence on the medal counts that the International Olympic Committee finally had to act. Today, even under the strict scrutiny of the World Anti-Doping Agency, invariably, many athletes are still testing positive for PEDs.

Norwegians learn very early in life how to incorporate frequent journeys into nature into their everyday lives.

Eat brown cheese and fish for breakfast.

If you can't load up on supplements and medications to optimize your athletic performance, your diet had better be stellar. Made from cow's or sometimes goat's milk, Brunost (or brown cheese) is a defining food in the Norwegian diet and said to taste both nutty and tangy. Many varieties of fish including cod, haddock, mackerel and halibut – those cold water fish that are full of eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) – swim the waters around Norway and make up a significant part of the Norwegian diet.

Live for the outdoors.

Perhaps part of the reason Norway performs so well in winter sports, Norwegians learn very early in life how to incorporate frequent journeys into nature into their everyday lives – ‘friluftsliv’. Even their work culture supports this understanding of the fundamental need for outdoor living and recreation. Thus, outdoor activities are literally a way of life in Norway and people don’t expect the long winters to keep them indoors. Sports like skiing, skating, and hiking go on through the seasons.

Perhaps ‘friluftsliv’ underlies the foundation of Norway’s winter team: it’s their super power. If so, we all have much to learn from the Norwegian way of living, not just to win more Olympic medals, but maybe even to win at life.

Related Resources

Evidence Shows Placentophagy (Placenta Encapsulation) Works

Thu, 28 Dec 2017 11:03:00 -0800

The practice of placentophagy – a woman consuming her placenta after she gives birth – is a bit of a hot topic these days. For those of you not familiar with the practice, if you're imagining the Dothraki queen devouring the giant, bleeding heart of a horse with her bare hands, you're probably not alone. In reality, there's much less of a "yuck" factor associated with the process when consuming an encapsulated placenta, which entails heating, dehydrating, pulverizing and then placing the resulting placenta powder into capsules. The result looks more like a vitamin supplement than a bleeding heart.

Cultural and personal interpretations aside, what would inspire someone to consume their placenta after birth? What's in it and what’s the therapeutic potential for a mom who’s riding the hormone roller coaster after giving birth or to a new baby who's exclusively breastfed? All of this attention on the placenta has classically been based on anecdotal evidence that consumption of it in the postpartum period leads to improved mood, more energy, increased iron stores and more milk production. ZRT Lab has been involved in some fascinating research on postpartum human placenta consumption to help answer some of these questions. And now we're happy to say that there’s a small body of research to back up some of these claims.

Study Design

In the studies referenced herein, the placentas were all prepared in the same manner and dosed on the same schedule. The placentas were either frozen or refrigerated upon retrieval from birth, heated to 160^oC, dehydrated, ground up in a food processor and then encapsulated in capsules that hold up to 550 mg of dehydrated placenta. The maximum daily dose studied was 3300 mg; (two 550-mg capsules taken 3 times daily) for the first 4 days after birth, then 2200 mg for the next 8 days, and finally 1100 mg for the final 9 days. The studies assessed hormone, mineral and element content and maternal quality of life. Women were either in the control group with encapsulated beef or in the study group with encapsulated dried placenta. All the hormone testing for these studies was performed at ZRT Laboratory using mass spectrometry (LC-MS/MS).

What's in the Placenta?

Minerals

The first of this series of studies [1] found that the encapsulated placenta at the 3300 mg dose provided about 2.2 mg of a particularly absorbable form of iron called heme iron, roughly four times the amount provided in the same dose of encapsulated beef. 2.2 mg certainly isn’t a high enough dose to be considered an iron supplement alone for the anemic new mom; however, in the world of foods, it would be considered a good iron source. A less significant showing of copper, selenium and zinc and even smaller detections of manganese, molybdenum, strontium, and rubidium rounded out the trace mineral content. Still, in the follow-up study [2] that analyzed postpartum iron status, no measurable benefit to iron status markers in the new mom emerged by week 3 of placenta supplementation vs beef supplementation. So, just like beef, placenta acts to maintain iron status over a 3-week period, not boost it [2].

Below Threshold Toxic Elements

Concern that toxic elements like cadmium, lead, and mercury might concentrate in the placenta diminished, with surprisingly relatively small, insignificant levels reported in the 28 placentas analyzed. This study [1] looked at some of the more common toxic exposures but it is entirely possible that the placenta concentrates other environmental toxins not tested in this research.

Elements found in modest amounts	Elements found only at low levels
Copper	Arsenic
Iron	Cadmium
Selenium	Lead
Zinc	Mercury
	Uranium

Streptococcus agalactiae (Group B Strep)

A common finding in late pregnancy, vaginal group B Streptococcus (GBS) bacterial infection usually signals extra precautions to protect the baby from transmission during delivery. In these studies, one out of the 28 women studied was positive for GBS at delivery. Certainly, the presence of GBS wouldn't necessarily render the placenta positive, but the risk should certainly be considered higher. This is a real concern based on a case report of GBS sepsis in a twice-infected infant exclusively breastfed by a mom ingesting her GBS-positive placenta. It's not clear how the oral consumption of the GBS in the placenta capsules was making it to the baby but perhaps additional safety steps in delivery and preparation should be considered. To me, it’s much like consuming a meat product. If it's "tainted", mother and child could potentially be harmed.

Hormones!

If these hormones are getting into the circulation, are they at least in part responsible for the purported beneficial effects on mood and bonding – all the things so important when the baby arrives?

Just before delivery, hormones like estrogens and progesterone were very high, as expected. Within a few days after birth, hormone levels dropped steeply to help adjust the body to the new baby and to urge the system into the lactation period. With this rapid drop in estrogens and progesterone, some women experience the "baby blues". Researchers took an interest in studying placentophagy because human placentas amass a rich concentration of different steroid hormones, which when reintroduced after birth could help attenuate postpartum symptoms. When dosed as a supplement (taken in small pieces), the typical maximum daily dose of placenta was found to yield varying amounts of 17 different hormones tested [3], the ones in highest concentration being those typically used in hormone replacement therapy - about 2.5 µg of estriol, 0.3 µg of estradiol, 1.1 µg of estrone, 37.3 µg of progesterone (and of interest for postpartum depression, a 0.37 µg dose of allopregnanolone) which raised the question: do the hormones taken orally in capsules have any chance of making their way into circulation and from there to the brain, where they can influence behavior and prevent postpartum depression?

Researchers sought to find out [4] and the short answer is yes, but…! Yes, this study actually found a small increase in absolute levels of the hormones tested in moms’ saliva in the placenta consuming group compared to no change in the beef group, but that’s not the end of the story. In further analysis, they uncovered a significant increase in the volume of distribution (V_d) of the hormones present in the placenta group, not the beef group. V_d is a measure of how much hormone was expected to have made it into the body tissues (the higher the V_d, the higher the distribution to all tissues). These findings hold the key to future clinical research to develop new treatments for postpartum problems. Amazingly, the natural concentrations of the different hormones in the human placenta as shown in this study [4] lends itself to use during breastfeeding with higher levels of progesterone and allopregnanolone and lower levels of androgens, all the while softening that rapid postpartum drop in estrogens and progestogens – which may be how this all works. So, if these hormones are getting into the circulation, are they at least in part responsible for the purported beneficial effects on mood and bonding – all the things so important when the baby arrives?

How Did Moms Feel?

Improvement in Mood and Fatigue in the Placenta Group

To try to answer that question, pilot study number 2 [5] assessed the effect of placenta consumption on mood, bonding and fatigue with the same group of participants. Using that same decreasing dosage schedule from 3300 mg daily to 1100 mg daily, they found decreasing benefits from the high dose days to the low dose days. So, again, perhaps the dose matters. Depression scores (mood) improved significantly in the placenta group over the beef group only when they were taking the higher doses (3300 mg and 2200 mg) but dropped to match their beef counterparts by the end of the study after taking 9 days of the lowest dose (1100 mg). Overall, fatigue scores improved in the placenta group over the beef group from beginning to end of study. Suffice it to say, I was surprised to read the actual study and find that the negative news headlines about these results were rather misleading.

Further Study?

I, for one, am thrilled to see more work being done in this area of study. In 2014, when I was contemplating having my placenta prepared for consumption after the birth of my third child, I did a PubMed search on human placentophagy to investigate some of these beliefs about the benefits, and at that time there were only a few articles. Most of them covered cultural factors leading to the practice and one or two that presented clinician and patient "perspectives" on the practice. So, anecdotal evidence (or REALLY old research) was as good as it got in 2014. Given the research available to us now, I'm still not sure I’d be overwhelmingly swayed one way or the other. As it goes for most pilot studies, they just lack the power – if we could look at a thousand women in the treatment arm and as many in the placebo arm with a look at safety over a longer period of time, we’d all be a little more confident on both sides of this conversation. So, while placentophagy can’t yet be officially recommended by obstetricians until more research develops, women must rely on that "woman's intuition" as we always have. It truly is a personal choice. It's good to know there are researchers out there who are curious about how this disposable organ may be of help to some of us while shedding light on the scientific basis for all our collective, historical experiences with the practice.

Related Resources

References

[1] Young SM, et al. Human placenta processed for encapsulation contains modest concentrations of 14 trace minerals and elements. Nutrition Research 2016;36(8): 872-8.

[2] Gryder LK, et al. Effects of human maternal placentophagy on maternal postpartum iron status: A randomized, double-blind, placebo controlled pilot study. Journal of Midwifery and Women’s Health 2017;62:68-79.

[3] Young SM, et al. Presence and concentration of 17 hormones in human placenta processed for encapsulation and consumption. Placenta 2016;43: 86-9.

[4] Young SM, et al. Effects of placentophagy on maternal salivary hormones: A pilot trial, part 1. Women Birth 2017; Nov 23 [in press].

[5] Young SM, et al. Placentophagy’s effects on mood, bonding, and fatigue: A pilot trial, part 2. Women Birth 2017; Nov 23 [in press]

Shorter Days: A SAD Pattern

Fri, 03 Nov 2017 11:27:00 -0700

It feels like winter is officially looming now that we’ve all turned our clocks back and the days are getting shorter. In the Pacific Northwest, this also brings darkness and rain for many months and for some of us, it brings seasonal affective disorder (SAD).

Whether or not symptoms of SAD eclipse your normal disposition, there’s a good chance the sun's vacation this time of year will affect four key areas of your health.

Vitamin D

Ultraviolet rays from the sun catalyze the synthesis of vitamin D on contact in the human skin, and to a smaller degree we consume it in fish, eggs and mushrooms. This little hormone carries some big distinctions. It's been studied extensively in research for its roles in modulating the immune system, insulin sensitivity, neurotransmitter synthesis, calcium uptake and bone resorption, and may have a place in preventing devastating diseases like cancer and multiple sclerosis. The vitamin D receptor (VDR), present in almost every tissue of the body, ushers in vitamin D so it can enhance gene transcription at the vitamin D response element (VDRE) on the DNA itself to carry out these functions.

What Contributes to Lower Vitamin D Status in the Body?

Low production

With fewer daylight hours and cold temperatures, the likelihood of getting enough vitamin D from sunshine starts to diminish. For those with more melanin pigment in the skin to block out this UV catalyst, expect even lower production during this time.

Low intake

A fat-soluble vitamin, D's bioavailability depends on proper administration. Taking all fat-soluble vitamins with a meal helps get them into the body. Vitamin D-containing supplements like cod liver oil and cholecalciferol will raise circulating vitamin D levels. Tuna, mackerel, sardines and salmon also pack a vitamin D punch delivered appropriately for its solubility – as a fatty meal.

High cortisol

High cortisol and its pharmaceutical analogues are known to reduce VDR expression and thus limit vitamin D uptake and activity in the body. People who use corticosteroids or otherwise have high cortisol levels, especially during the yearly winter vitamin D famine, may want to take extra precautions to protect vitamin D status.

Vitamin D & the Serotonin Seesaw

If you don’t have enough vitamin D to bind VDREs, serotonin synthesis plummets and people really feel the domino effect of that drop in serotonin.

An important reason why the discussion of SAD focuses so much on vitamin D is because the VDREs present in the brain, when bound by vitamin D, act to up-regulate the synthesis of 5-HTP — the precursor to serotonin. Another important piece of the emotional wellness puzzle, serotonin acts in a variety of ways in the body – as a modulator of inflammation and the allergic response, as a signal for almost every type of immune cell imaginable, in gut function, and in the central nervous system as an inhibitory neurotransmitter that gives us emotional flexibility.

Enzymes change one molecule into another – in order to make serotonin anywhere in the body, the enzyme tryptophan hydroxylase (TRPH) must transform tryptophan (an amino acid obtained from the protein we eat) into 5-HTP. 5-HTP can then be turned into serotonin by another enzyme. Because vitamin D binding to the VDREs in the brain increases the activity of the TRPH (TRPH2) enzyme there, you get more serotonin. That’s the good news. The bad news is if you don’t have enough vitamin D to bind to those VDREs, serotonin synthesis plummets and some people really feel the domino effect of that drop in serotonin.

The rest of the body feels the effects as well! In the absence of vitamin D, the activity of TRPH1 (the non-neuronal form) that is responsible for peripheral serotonin production is enhanced (in contrast to the brain TRHP2), which contributes to an exaggerated immune response, gut motility and bone resorption.

So, in effect, it acts in the complete opposite way of the TRPH2 in the brain. This is why peripheral serotonin levels measured in the urine may look normal or high while brain levels are simultaneously quite low. So, knowing Vitamin D status colors our understanding of potential serotonin levels in different compartments of the body. If vitamin D is low and there are symptoms of serotonin deficiency, it’s likely out of balance in the upstairs compartment.

Cortisol Awakening Response

Sunlight influences the diurnal rhythm and when it becomes scarce, those rhythms can become dysregulated. The adrenal hormone, cortisol, reacts to stressors in the body like inflammation, illness and low blood sugar; however, outside of its first-response job, it follows a very typical diurnal rhythm. It can be measured upon waking and throughout the day with results in saliva that look a lot like the graph below.

Normally, in the morning as the sun begins its ascent, cortisol charts its course toward the highest level of our 24-hour day. Within 30 minutes of waking up, cortisol should continue to rise by about 50% from the waking level. When the mornings are dark, in susceptible individuals the diurnal rhythm of cortisol flattens out and it becomes difficult to shake off sleep and function normally. Another helpful measure of the HPA axis that captures that 50% rise (or absence of it) is called the cortisol awakening response (CAR) which measures cortisol in response to the “stress” of waking.

Here's a normal CAR — observe the 2^nd black dot in the graph below showing the cortisol level at 30 minutes after the initial waking sample:

Here’s an example of a CAR in someone struggling with SAD:

Notice the morning, noon, evening and night cortisol levels are roughly within normal ranges while the attenuated CAR is the finding of interest. Overall, the defect in cortisol regulation in SAD may be missed if the CAR isn’t assessed along with the diurnal rhythm.

Altered Melatonin Rhythm

The defect in cortisol regulation in SAD may be missed if the CAR isn’t assessed along with the diurnal rhythm.

Even the absence of sunlight affects diurnal rhythms – this is where melatonin comes into play. Darkness signals the nightly melatonin flood in the central nervous system, and with darkness creeping in more and more during autumn and winter, we naturally find more and prolonged central melatonin production. There are some researchers who theorize that the increased melatonin production during the winter steals tryptophan from other parts of the brain that normally use it to build serotonin, leaving those parts of the brain at a serotonin deficit. Put this possible tryptophan-steal scenario together with a vitamin D deficiency, and it’s easy to see how a neural serotonin imbalance propagates.

Here’s a normal diurnal melatonin curve:

Remember, in urine the first morning void contains the melatonin metabolite (MT6s) that has accumulated in the bladder during sleep, so the highest levels of the day are expected in that first morning result on the graph (as measured in ZRT's Sleep Balance profile).

Contrast that with this demonstrative example of a melatonin diurnal curve of a patient with SAD:

Notice MT6s is within the normal range (higher than median) during the night as evidenced by the level in the first morning void; but instead of dropping significantly after awakening, it remains at the overnight level. It's a groggy start to the morning with continued night-time melatonin production on board. Since this absence of light has such an effect on the body clock, natural light therapy has been studied quite a bit for helping combat SAD. It has long been used to clear out morning melatonin, stimulate cortisol production and improve mood overall.

The good news is the dark days of winter can give us a reason to turn inward, get the sleep we desperately need after a busy summer and start to the school year, and to gather up energy for the holiday season. The clocks wind back soon — are you ready?

Related Resources

Avoiding 3 Common Interpretation Pitfalls for Salivary Cortisol Tests

Tue, 08 Aug 2017 09:27:00 -0700

One of ZRT's most popular tests includes diurnal assessment of a patient's salivary cortisol levels. On the surface, these tests seem easy enough to interpret, but experienced clinicians know there can sometimes be pitfalls.

Patients testing cortisol in a clinical setting may take undisclosed medications, live under stressful conditions, have inflammation, genetic variations, tumors, and diseases. Sleuthing out the cause of cortisol elevations and depressions can be a real challenge.

To avoid unnecessary work-ups, there are a few areas to consider when interpreting a salivary cortisol test – Contamination, Suppression, and Comorbidities.

Collecting & Processing Samples

The general collection for a diurnal cortisol curve assessment requires drooling into a plastic tube upon waking, another before lunch, again before dinner and a final sample taken before bed.

When the samples arrive at the lab, they're labeled, tested for blood, and centrifuged. Samples are then mechanically pipetted onto separate plates and tested on their own assays. Using an ELISA method, cortisol is quantified using 2 different antibodies and an enzyme marker. In this method, the capture antibody binds to cortisol in the sample with 100% affinity, and the other antibody attached to a special enzyme designed to fluoresce in the spectrophotometer binds to the antibody/cortisol complex and provides the means for quantifying cortisol in the sample.

Contamination

Occasionally, cortisol levels in a sample are grossly elevated beyond what we would expect to see in a Cushing’s patient. Remember that capture antibody with such high affinity to cortisol? It also has a lower affinity to other molecules that have structures very similar to cortisol. If you have direct introduction of hydrocortisone into the saliva sample from the fingers holding the collection tube for example, the high level of substrate overrides that low affinity leading to extremely high reported values that don’t represent endogenous cortisol production at all. Corticosteroid products are so widely available over the counter and many patients don’t even realize they’re using them. So, before reflexing to more diagnostic tests, consider the following case examples demonstrating contamination of the samples.

Both of these patients were found to be using a 1% OTC hydrocortisone cream for a rash on the day of collection:

Patient #1:

Patient #2:

Suppression

Suppression looks very different than contamination in the cortisol results and we see this typically in patients either using daily prednisone therapy or who have had a recent intraarticular steroid injection. So, this may look like an Addison’s case, but it’s really a case of transient adrenal suppression from recent steroid treatment.

If prednisone therapy is discontinued, a period of 4-6 weeks is recommended before testing adrenal function. This is the period of time before the HPA axis is functioning normally again. The same testing window is true for intraarticular steroid injections.

Comorbidities

This one’s obvious, but easy to forget when looking at free cortisol levels in saliva. Some conditions can affect levels of cortisol-binding globulin (CBG) and affect free cortisol levels directly or indirectly. Really understanding the patient’s health status, concurrent medications, and comorbidities will help frame the results for proper interpretation. It may make sense, in addition to saliva testing, to also assess total cortisol levels in serum or capillary blood, or urinary free cortisol levels, for a full 24-hour comparison to aid decision-making. It may also be a good idea to test other aspects of the endocrine system for clues such as thyroid function, sex steroid levels, and insulin, and relate them back to liver and HPA axis function.

Practice Take-Aways

Remind patients that hydrocortisone can influence their testing even if it is just for that 1 little bug bite.
When you see extremely high levels > 20 ng/mL – chances are that your patient was using some sort of steroid and does not have Cushing's. Rule that out before worrying about tumors.
If you have a patient on a steroid therapy and want to check the health of his or her HPA axis, delaying the test for 4-6 weeks after discontinuation is an excellent rule of thumb. For shorter courses, a shorter window may make sense.

Once all of these areas are considered and the pitfalls ruled out, then interpretation of a diurnal cortisol rhythm is a snap! When in doubt, give us a call here at the lab.

Related Resources

How Exercise Can Turn the Tide in ADHD

Thu, 13 Apr 2017 12:34:00 -0700

“Our sons were both diagnosed with ADHD by kindergarten. More than just dealing with the disciplinary and academic issues at school, my husband and I struggled to maintain a productive and nurturing household with the kids having regular meltdowns and outbursts. Our ability to connect with them became compromised. We were at our wits’ end considering medications and home school. We agonized over the long-term repercussions of both of those choices. We turned inward and analyzed our habits and routines. One thing we noticed with both the boys was that a strict routine in the mornings and in the evenings seemed to help and that physical interventions (rather than reasoning or time-outs) worked best to correct behavioral problems – getting them outside, running them around, engaging them in a physical activity. There were particularly frenetic times when we would take them to the track at the local middle school and have them run laps. The more we intervened in that way, the fewer the outbursts and behavior issues and ironically, the better they’d sleep; but we were concerned that they would start seeing exercise as a punishment and decided to take a different approach.

We figured if we were all involved in a healthy movement regimen, it would be more of a lifestyle than a penalty. We became a running family. We started with an early morning jog around our neighborhood before school and work – all of us, the whole family. At ages 8 and 5, our boys loved it. When they got home from school in the afternoons after snack and before homework, we jogged again. The rest of the evening, we tightly structured homework, dinner, bath and bed. We even ran on the weekends on the same schedule around extra-curricular activities. The results were immediate. Behavior at home and at school improved drastically, our parent-teacher conferences became a pleasure, and even their little personalities shifted from quick emotion to much more flexibility and understanding. It has changed our family for the better. Not only are our kids not on stimulants or anti-depressants, we all feel fit and healthy and we get to do it together every day.”

I find this case and others like it fascinating. How can such a simple lifestyle change make such an impact on ADHD outcome? It turns out, there are a number of reasons.

ADHD, with its many subtypes, affects the lives of around 10% of American kids. Inattentive type, hyperactive/impulsive type (rare) and the combined type all have their own clinical features and findings but kids with ADHD, in general, may have problems with controlling impulses, concentrating, focusing, sleeping, sitting still, paying attention and listening. Inappropriate emotional outbursts can present and often anger is associated.

A diagnosis typically leads to a trial of one of several medications to "wake the brain up" to increase concentration and focus. Probably the most popular drugs for ADHD today are stimulants such as amphetamine-salts (Adderall) and methylphenidate (Ritalin) – both work to increase norepinephrine and dopamine activity in the brain. Atomoxetine (Strattera) increases serotonin and norepinephrine activity in the brain. All of these drugs excite the brain and as such have similar common side effects even though each one has a unique mechanism of action.

What’s going on in the body and the brain with ADHD?

Daydream-State Brain Waves

First, we have learned from EEG studies that there may be different brain wave patterns in different subtypes of ADHD. The theme, however, seems to be a higher ratio of theta to beta waves than in a non-ADHD brain. [1] Theta waves are normally higher during sleep just before waking and beta waves are highest when we're concentrating and processing information. So, a child with ADHD is literally asleep at the wheel when he or she is expected to concentrate and function at school.

Low Sympathetic Tone

Second, urinary phenethylamine (PEA) tends to be low in kids with untreated ADHD. [2] As a modulator of norepinephrine transmission in the central nervous system, it enhances sympathetic tone. A normal sympathetic tone gives us the baseline function that enables our bodies to appropriately react and respond to stressors and provides the terrain for brain activity, wakefulness, and concentration. This may be an isolated finding but more often than not, we will see this low urinary PEA in concert with a low urinary dopamine in patients with ADHD. In cases where urinary dopamine is within the normal range, it is most often low compared to urinary serotonin in the same specimen. What is this telling us? Urinary dopamine (along with norepinephrine, discussed below) and PEA give us information about sympathetic tone and when it's low, it explains much of the symptomatology associated with ADHD. The result of effective treatment, whether conventional or alternative, is to raise dopamine, serotonin and PEA levels in the urine.

Urinary dopamine and PEA give us information about sympathetic tone and when it’s low, it explains much of the symptomatology associated with ADHD

Abnormal Stress Response

Third, the urinary diurnal rhythms of free cortisol, norepinephrine and epinephrine are often dysfunctional in ADHD, and HPA axis dysfunction is common in the inattentive type. [3] Cortisol, norepinephrine, and epinephrine are all normally released from the adrenal glands at a baseline level and in response to all sorts of stressors. Cortisol production responds to signaling from the pituitary gland and the norepinephrine in the urine comes straight from the sympathetic nervous system (well, 80% of it with the rest from adrenal production) and positively correlates with our sympathetic tone. Epinephrine (also known as adrenaline) in the urine is the direct result of adrenal production and should be thought of as an adrenal stress indicator. When these diurnal markers are out of rhythm, symptoms such as anxiety, nervousness, insomnia, and that "over-tired" burned out emotional feeling start to emerge. Typically, a child with a combined-type ADHD will show elevated or normal pooled cortisol levels with an abnormal diurnal rhythm, low norepinephrine (or low by comparison) with an inverted diurnal rhythm, and a high pooled epinephrine with an inverted diurnal curve.

An example of the abnormal urinary circadian curves often seen in a child with ADHD and an anxiety component is shown in the purple lines on the graphs below (keep in mind the blue-shaded area would be considered "in the normal range" and represents the shape of the normal expected curve):

Hyperexcitation & Neurotoxicity

Finally, urinary glutamate may be elevated alongside a functionally low urinary GABA in kids with ADHD who have the perfect storm of diet and a susceptible biochemistry. Glutamate is one of the major on-switches in the brain and its rise in the body may be either representing a compensatory mechanism in ADHD to counter a low sympathetic tone, or simply the result of genetic mutations leading to glutamatergic dysfunction. In either case, taking steps to protect the brain from neurotoxicity as a result of overexcitation is key to good clinical outcomes. In the body’s infinite wisdom, glutamate’s inhibitory counterpart, GABA, is synthesized from glutamate and it’s an important reminder that absolute levels of urinary neurotransmitters are probably less important than the balance between them. Outside the brain, GABA is synthesized in the adrenal glands and acts as the gatekeeper of norepinephrine and epinephrine synthesis, an important modulator of the stress response. Levels in the urine mainly reflect that adrenal contribution and so as much as it's important to assess the balance with glutamate, assessing for its balance with norepinephrine and epinephrine may even be more telling.

Drop down and give me 20!

It turns out, there is a therapy after all that can rouse the ADHD brain and raise PEA and norepinephrine levels to improve sympathetic tone and it’s not administered in a pill. It’s exercise! For those who need more than common sense to get behind this treatment option, physical activity for ADHD has also been well studied. A recent study that looked at kids with ADHD given an 8-week yoga intervention twice a week for 40 minutes found that the kids in the yoga group significantly improved from baseline on cognitive inhibition and attention tests. [4] The FITKids Trial in 2014 randomized kids between the ages of 7 and 9 to a 9-month afterschool physical activity regimen or a wait-list. They found that the kids that engaged in the physical activity program performed significantly better on attention and cognitive inhibition testing than their wait-listed counterparts. [5]

The take-home is this:

Exercise changes brain waves and improves cognitive inhibition in kids with ADHD.[6] [7] [8]
Exercise improves sympathetic tone. [9] [10]
Exercise influences glutamate and GABA balance in the brain and in the body. [11] [12]

Exercise is not a punishment! To teach our kids the power of it is to give them a gift for life. For kids with ADHD, you could be empowering them to modulate their moods and impulses with a tool they can control.

I hope that parents searching for answers other than supplements and medications for their kids with ADHD, or who seek adjunct lifestyle therapies for their kids already being managed on medications, consider talking to their pediatricians about incorporating physical activity into the regimen. There are lots of options. And perhaps even better, like the family's story featured here, find a way to involve everyone in daily physical activity because half the battle is setting a good example. After all, exercise rules for supporting cardiovascular, mental, immune, and endocrine health – and what's more, it raises the levels of hormones (like oxytocin) and neurotransmitters in the body that make us feel closer and more connected. It’s exactly the physical help families need to work together to weather through some of the more difficult challenges of ADHD. [13] [14] [15]

Related Resources

References

[1] Clin EEG Neurosci. 2017 Jan;48(1):20-32. Epub 2016 May 11. Quantitative EEG in Children and Adults With Attention Deficit Hyperactivity Disorder: Comparison of Absolute and Relative Power Spectra and Theta/Beta Ratio. Markovska-Simoska S1, Pop-Jordanova N2.

[2] No To Hattatsu. 2002 May;34(3):243-8. Decreased beta-phenylethylamine in urine of children with attention deficit hyperactivity disorder and autistic disorder. Kusaga A1.

[3] Child Psychiatry Hum Dev. 2008 Mar;39(1):27-38. Epub 2007 Jun 13. The stress response in adolescents with inattentive type ADHD symptoms. Randazzo WT1, Dockray S, Susman EJ.

[4] PeerJ. 2017 Jan 12;5:e2883. doi: 10.7717/peerj.2883. eCollection 2017. Effects of an 8-week yoga program on sustained attention and discrimination function in children with attention deficit hyperactivity disorder. Chou CC1, Huang CJ1.

[5] Pediatrics. September 2014. Effects of the FITKids Randomized Controlled Trial on Executive Control and Brain Function. Charles H. Hillman, et al.

[6] Exp Brain Res. 2015 Apr;233(4):1069-78. doi: 10.1007/s00221-014-4182-8. Epub 2014 Dec 24. The relationship between aerobic fitness and neural oscillations during visuo-spatial attention in young adults. Wang CH1, Liang WK, Tseng P, Muggleton NG, Juan CH, Tsai CL.

[7] Neural Plast. 2015;2015:717312. doi: 10.1155/2015/717312. Epub 2015 Feb 10. Effects of physical exercise on individual resting state EEG alpha peak frequency. Gutmann B1, Mierau A1, Hülsdünker T1, Hildebrand C1, Przyklenk A1, Hollmann W2, Strüder HK1.

[8] Int J Dev Neurosci. 2014 May;34:1-8. doi: 10.1016/j.ijdevneu.2013.12.009. Epub 2014 Jan 8. Acute exercise induces cortical inhibition and reduces arousal in response to visual stimulation in young children. Mierau A1, Hülsdünker T2, Mierau J2, Hense A2, Hense J2, Strüder HK2.

[9] Pediatr Res. 2003 May;53(5):756-61. Epub 2003 Mar 5. Catecholamine response to exercise in children with attention deficit hyperactivity disorder. Wigal SB1, Nemet D, Swanson JM, Regino R, Trampush J, Ziegler MG, Cooper DM.

[10] Behav Neurosci. 2015 Jun;129(3):361-7. doi: 10.1037/bne0000054. Physical exercise affects attentional orienting behavior through noradrenergic mechanisms. Robinson AM1, Buttolph T2, Green JT2, Bucci DJ1.

[11] J Altern Complement Med. 2010 Nov;16(11):1145-52. doi: 10.1089/acm.2010.0007. Epub 2010 Aug 19. Effects of yoga versus walking on mood, anxiety, and brain GABA levels: a randomized controlled MRS study. Streeter CC1, Whitfield TH, Owen L, Rein T, Karri SK, Yakhkind A, Perlmutter R, Prescot A, Renshaw PF, Ciraulo DA, Jensen JE.

[12] Applied Physiology , Nutrition and Metabolism. 2106. doi: 10.1139/apnm-2016-0033. Exercise increases mitochondrial glutamate oxidation in the mouse cerebral cortex. Herbst EAF, Holloway GP.

[13] Psychiatry Res. 2015 Aug 30;228(3):746-51. doi: 10.1016/j.psychres.2015.05.029. Epub 2015 Jun 15. Decreased levels of serum oxytocin in pediatric patients with Attention Deficit/Hyperactivity Disorder. Sasaki T1, et al.

[14] Eur J Endocrinol. 2008 Dec;159(6):729-37. doi: 10.1530/EJE-08-0064. Epub 2008 Sep 15. Acute changes in endocrine and fluid balance markers during high-intensity, steady-state, and prolonged endurance running: unexpected increases in oxytocin and brain natriuretic peptide during exercise. Hew-Butler T1, Noakes TD, Soldin SJ, Verbalis JG.

[15] Eur J Sport Sci. 2017 Apr;17(3):343-350. doi: 10.1080/17461391.2016.1260641. Epub 2016 Dec 7. The importance of cohesion and enjoyment for the fitness improvement of 8-10-year-old children participating in a team and individual sport school-based physical activity intervention. Elbe AM1, Wikman JM1, Zheng M1, Larsen MN1, Nielsen G1, Krustrup P2,3.

5 Steps to a Healthier Brain in 2017

Tue, 31 Jan 2017 12:25:00 -0800

We're in a new year now and it seems like everyone's weighing in on the 5 or 10 or 20 things you and I should be doing to improve our health and wellness this year.

It is January, after all, and it’s time to start setting priorities. There are tons of great ideas out there! Here are my top 5 for 2017.

If you want to improve brain health, you need to make sure it gets enough oxygen, nutrition, and anti-oxidant support so that’s the unifying theme. I have a feeling if everyone did these, in 20 years we’d have fewer cases of psychological dysfunction and of neurodegenerative disease.

1. Eat fish at least twice a week and consider supplementing fish oils (EPA and DHA). There’s a lot of consensus out there on this one. Getting enough EPA and DHA (omega 3 fatty acids) in the diet improves not only brain health but heart health as well. If it’s too much to grill a wild salmon on a maple plank for dinner, consider packing sardines or tuna for lunch. For the sensitive palate, Atlantic cod isn’t too fishy-tasting and seasons up to make excellent fish tacos. Algae sources of EPA and DHA are available in over-the-counter supplements for those who do not use animal products.

Rationale: Nourish the cell membrane and limit neuroinflammation [1], influence neurotransmitter synthesis [2] and regeneration of neurons [3]. Our brains and every other tissue in the body are made up of cells which must interact and communicate with one another, both near and far. Our diets play a significant role in the make-up of our cell membranes. Cholesterol and saturated fats render our membranes rigid and hardened whereas omega 3 fats keep them fluid and functional. EPA and DHA may also nourish the “gut friendlies,” our commensal intestinal bacterial population [4] which does everything from support neurotransmitter balance in the brain to synthesizing vitamins we absorb to training our immune systems when to mobilize and when to quiet.

2. Get your sleep. To assess your sleep, ask yourself some questions. Do you go to bed tired? Do you sleep the night through? Do you get enough hours? Do you wake rested? If you snore, are overweight and/or have many of the symptoms on the Berlin Questionnaire, ask your doctor about doing a sleep study and if you have sleep apnea, treat it faithfully. Sleep apnea and the low-oxygen state it induces changes the way the brain signals hormone production, in general, predisposing those afflicted to cardiovascular disease and diabetes. Importantly, make sure you produce enough melatonin. You can test for this too. Consider supplementing if you don't have a nice showing of MT6S in your first morning urine sample. Melatonin is integral in calming the central nervous system, reducing oxidation, and helping with DNA repair/maintenance. Additionally, cortisol and the catecholamines epinephrine and norepinephrine (also easily assessed in the urine) should be within the appropriate ranges while we sleep so our brains and bodies can rest and repair. [5] [6]

Rationale: A brain without proper sleep oxidizes without reducing, excites without inhibiting, and accumulates toxins without clearing them out. Imbalances that arise from not regularly getting enough sleep can become pathologies and give rise to neurodegenerative disorders down the road.

Because methylation cycles are also so intricately woven into our oxidation and reduction pathways, their function in the brain is crucial.

3. Check for methylation defects and supplement to correct them. Perhaps the best-studied set of single nucleotide polymorphisms (SNPs) is in the MTHFR gene, which encodes the enzyme that activates folic acid to its usable form in the body by methylating it. The links between several MTHFR mutations and neuro and psychological conditions like ADD/ADHD, autism, OCD, depression, anxiety and even some cancers are just coming to light. [7] For some, the answer’s as simple as supplementing methyltetrahydrofolate (MTHF). For others, a more complex protocol is required. Before you go down the genetic rabbit hole with a laboratory, it’s important to link up with a health care professional who understands this type of testing and who can walk you through the process and interpretation. Test for a few or order the raw data on your whole genome.

Rationale: Many SNPs affect the way we metabolize our own hormones, neurotransmitters and drug therapies. Some of them (or combinations of them) have effects that are largely reversible with the right types of supplementation and without treatment can in some cases contribute to serious health problems while others are phenotypically silent. Because methylation cycles are also so intricately woven into our oxidation and reduction pathways, their function in the brain is crucial.

4. Nourish your mitochondria. Tiny bacterial remnants that exist in every cell of the human body, the mitochondria function to manufacture ATP (energy currency in a cell), transfer this energy, and undergo constant oxidative processes in so doing. The mitochondria have their own DNA (inherited from your mother) and they function rather independently within each cell, have their own DNA replication, repair and maintenance capabilities, and must themselves divide (fission) and can even fuse together (fusion) as the need arises. Mitochondrial DNA is susceptible to damage and can occur secondarily to hormone and nutrient metabolism, therapeutic drug use, chemical exposures, and radiation. Antioxidant therapies may limit oxidative damage and prevent DNA adduct formation. Resveratrol, N-acetyl-cysteine, L-carnitine, coenzyme Q10, R-alpha lipoic acid, vitamin E, and the carotenoid family are a few examples of nutritional supplements that have been studied as mitochondria-targeting therapeutics for oxidation reduction. [8]

Rationale: Mitochondrial dysfunction and mitochondrial DNA damage is implicated in several neurodegenerative diseases including Alzheimer’s disease and this is a major area for drug and nutritional research right now. [9]

5. Discover yoga. Decades of studies tell us that exercise improves these important functions of the brain and body: neuroplasticity, mitochondrial function, vascular function, adrenal sensitivity, cognition, and working memory. [10] [11] [12] Yoga provides more than just the stretching and cardio aspect of exercise. The breathing technique (or Pranayama) associated with yoga seems to drive the brain benefit here. So, don’t leave that part out.

Rationale: I chose to highlight yoga here because of the multitude of studies out there that have observed a regular yoga practice’s effect on the HPA axis, the sympathetic nervous system and on the symptoms of depression and anxiety. It is also very accessible to many Americans, whether done with a prescription as physical therapy, at home with video instruction, in a class with a yoga therapist, or for free at a community center.

References

[1] Nutr Health Aging. 2004;8(3):163-74. Roles of unsaturated fatty acids (especially omega-3 fatty acids) in the brain at various ages and during ageing. Bourre JM.

[2] FASEB J. 2015 Jun;29(6):2207-22. doi: 10.1096/fj.14-268342. Epub 2015 Feb 24. Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior. Patrick RP, Ames BN.

[3] Curr Med Chem. 2013;20(24):2953-63. n-3 fatty acids: role in neurogenesis and neuroplasticity. Crupi R, Marino A, Cuzzocrea S.

[4] Lipid Technology Volume 27, Issue 8, pages 179–182, August 2015 How fish oils could support our friendly bacteria. Bentley-Hewitt KL, et al.

[5] J Gerontol A Biol Sci Med Sci. 2015 Dec;70(12):1569-77. doi: 10.1093/gerona/glv088. Epub 2015 Aug 11. Association of Urinary 6-Sulfatoxymelatonin (aMT6s) Levels and Objective and Subjective Sleep Measures in Older Men: The MrOS Sleep Study. Saksvik-Lehouillier I, et al.

[6] Science. 2016 Aug 12;353(6300):687-90. doi: 10.1126/science.aad2993. Local modulation of human brain responses by circadian rhythmicity and sleep debt. Muto V, et al.

[7] NIH Genetics Home Reference: MTHFR - https://ghr.nlm.nih.gov/gene/MTHFR#synonyms

[8] Curr Neuropharmacol. 2016;14(2):143-54. Mitochondrial Biology and Neurological Diseases. Arun S, Liu L, Donmez G.

[9] Neurol Res. 2017 Jan;39(1):73-82. Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. Islam MT.

[10] Curr Alzheimer Res. 2017 Jan 11. Resilience to Alzheimer's disease: the role of physical activity. Anna P, et al.

[11] J Psychiatr Res. 2015 Sep;68:270-82. doi: 10.1016/j.jpsychires.2015.07.013. Epub 2015 Jul 13. A systematic review of randomised control trials on the effects of yoga on stress measures and mood. Pascoe MC, Bauer IE.

[12] J Altern Complement Med. 2010 Jan;16(1):3-12. doi: 10.1089/acm.2009.0044. The health benefits of yoga and exercise: a review of comparison studies. Ross A, Thomas S.

Testing Urinary Neurotransmitters? Avoid the Big 5.

Thu, 06 Oct 2016 11:25:00 -0700

It’s well understood that the food we eat provides the amino acids, micronutrients (eg., vitamins and minerals) and macronutrients (proteins, fats and carbohydrates) we need to sustain our lives. However, it may come as a surprise to know that some foods contain more than just the amino acid precursors to neurotransmitters and actually contain high levels of some neurotransmitters themselves like serotonin¹ and dopamine².

For some people, a diet rich in those foods that are high in neurotransmitters lends just the balance they need to feel well in lieu of psychotropic medication. As an example, someone who struggles with irritability and a low mood might try a diet rich in serotonin and vitamin B6-containing foods like bananas, walnuts and pineapples. But when you’re testing neurotransmitters in the urine, these foods in fact can cause problems with the testing.

We want to measure the neurotransmitters the body is making overall that end up in the urine (sourced from the adrenals, brain, gut, etc) and the balance (or lack of it) that exists in the body. An important variable that’s easy to control, yet can significantly and artificially increase urinary neurotransmitter levels is the food you eat.

There are 5 specific foods that are known to produce the biggest shifts, creating what’s known as a false positive result. These 5 foods will send your urinary neurotransmitter levels to the moon for hours after you eat them. It’s essential to avoid the following on the day prior to and the day of your urine collection:

Bananas and plantains
Nuts (especially walnuts)
Nut butters
Pineapples
Avocadoes

In some cases, the elevations are so significant that they can lead to misinterpretation of the test

When testing urinary neurotransmitters within 4 or so hours after consuming these particular foods, we see an entirely food-induced elevation in serotonin, dopamine, and 5-HIAA.² In some cases, the elevations are so significant that they can lead to misinterpretation of the test and raise suspicion of carcinoid syndrome or pheochromocytoma.

Think of it like a fasting blood sample for glucose. If you have a pancake breakfast instead of fasting and check glucose just afterward, there’s a good chance you’d be mistaken for a diabetic. Your treatment advice would be based upon a false-positive result or rather a non-fasting result instead of a fasting one. If you just can’t abstain from that banana bread with walnuts for a those couple of days around your urine test collection, please remember to mark it down on your requisition form that comes in with your sample. Identify the forbidden food and jot down what time you ate it. If it shows up in your urine sample, it’ll help with the interpretation.

A urinary neurotransmitter test is a functional test which means the interpretation can be tricky – the providers who are using this test are doing more than just observing highs and lows (that’s easy), they’re putting weight into the high-normals, the low-normals, the ratios, appreciating the dominance of excitatory or inhibitory neurotransmitters, assessing enzyme activity and cofactor availability in those biochemical pathways by looking at the downstream metabolites, and then trying to discern and control the factors contributing to your unique symptom constellation.

We're all excited to be offering urinary neurotransmitter testing at ZRT. For some, it may answer big questions. For others, it may only fill in some of the missing pieces of the puzzle. Either way, the human body's an intricate machine. The more tools we have to assess its function, the more comprehensive the treatment options become.

Related Resources

References

¹Feldman, J M and Lee, E M. Serotonin content of foods: effect on urinary excretion of 5-hydroxyindoleacetic acid. Am J Clin Nutr October 1985 vol. 42 no. 4 639-643.

²Kema IP, Schellings AM, Meiborg G, Hoppenbrouwers CJ, Muskiet FA. Influence of a serotonin- and dopamine-rich diet on platelet serotonin content and urinary excretion of biogenic amines and their metabolites. Clin Chem. 1992 Sep;38(9):1730-6.

3 Keys to Preventing Prostate Cancer

Fri, 24 Jun 2016 00:08:00 -0700

Getting an early jump on a disease process like cancer makes treatment exponentially easier and outcomes generally better.

Under the current guidelines, that early jump on prostate cancer starts at age 55 for men at low to moderate risk and 40-45 for men at high risk. It takes years for cancer to grow to a detectable point after the tumor's initial induction from a normal cell to a cancerous one.

There's been a lot of research done to determine what those inducers are and how they work. Three of these inducers are simple to test for and completely modifiable with treatment and/or avoidance:

Bisphenol A
Arsenic
Catechol estrogens

Bisphenol A (BPA)

It may come as a surprise to know that BPA, a chemical found in plastics and linings of food containers has hormonal activity and could be correlated with your risk of prostate cancer down the road. A study that looked at urinary BPA levels in men with and without prostate cancer found more than a 2 fold increase in BPA in the urine of the men with prostate cancer.¹ Here at ZRT, we also routinely see elevated urinary BPA levels in testers with prostate cancer, a result consistent with what the research is bearing out to date.

BPA Affects Prostate Specific Antigen (PSA) Testing

Individuals with a high body burden of BPA were likely to have false negative results for PSA

Even though it's infamous for leading younger men to needless biopsies and missing some cancers when levels are within normal range, we nonetheless use the less-than-perfect PSA test to screen patients for prostate problems including cancer and also to monitor prostate cancer treatment to the end point of lowering PSA as much as possible. To add insult to injury, the same study mentioned above¹ found that high BPA levels may cause PSA levels to look low when they shouldn't be.

In other words, individuals with a high body burden of BPA were likely to have false negative results for PSA. Particularly, they found high urinary BPA levels associated with low PSA levels in prostate cancer patients, a population where we expect to see much higher PSA levels with increasing statistical significance in men under the age of 65.¹ "Under the age of 65" here is important because this is the group of men in which most of our prostate cancer diagnoses are made (and missed). So, not only could BPA be responsible for increasing prostate cancer risk, it also decreases the chances of an early diagnosis. It may make sense then that an individual with an elevated BPA and an allegedly normal PSA should be counseled on proper avoidance of BPA and have their PSA retested in 4-6 weeks.

Arsenic

In hefty amounts arsenic is poisonous, having killed scores of literary characters and famous historical figures. Most people think of arsenic this way, probably. But in small amounts, arsenic finds its way naturally into our air, soil, food and water. It's used in industrial processes and more than occasionally concentrates in areas around those industries that use it. I was amazed to see this first hand here in environmentally-conscious Portland, OR when elevated arsenic levels were discovered around a neighborhood glass blowing business – one tiny example of a possibly much larger issue across the nation and certainly the world.

Without a doubt, chronic arsenic exposure is associated with increased risk of many cancers including prostate. A most compelling research article I came across on the matter of hazardous effects of arsenic studied a community of people who lived on the southwestern coast of Taiwan. The residents lived on and consumed water from a well contaminated with arsenic for 50+ years. This group of people had a very high prostate cancer incidence and mortality that only began to decrease once the source of that arsenic exposure was removed with treatment of the water supply.²

Urinary arsenic levels should be taken into consideration when assessing a patient for prostate cancer risk

The Strong Heart Study published in 2013 followed nearly 4,000 Native American men for almost 20 years and concluded that higher urinary arsenic levels were associated with prostate cancer mortality. Studies performed in vitro show that under arsenic exposure, prostate cancer cell lines are transformed from normal to malignant and can progress a tumor from androgen-sensitive to androgen-independent.³

In case you're still not worried, a recent study that was just published assessed arsenic levels in drinking water in areas of Illinois along with prostate cancer rates in those counties and found that counties with higher arsenic levels had a higher incidence of prostate cancer.⁴

Certainly, individual urinary arsenic levels should be taken into consideration when assessing a patient for prostate cancer risk. Avoiding arsenic means breathing clean air and drinking and using clean water, steering clear of second-hand smoke or quitting smoking, educating yourself on high-arsenic foods, and managing any workplace exposure.

Catechol Estrogens

Men's bodies make estrogens from androgens like testosterone and androstenedione. Estrogen has both protective and proliferative effects in the body so estrogen balance is crucial. This means estrogen biosynthesis should be in balance with estrogen metabolism and excretion from the body. In order to leave the body, estrogens are further modified through a 2-part "detoxification" pathway.

The first part yields the catechol estrogens – they're more water soluble and closer to being ready for excretion but they can be dangerous because by virtue of their new structure, they're more susceptible to oxidation (or quinone formation). In the proper cell environment in the absence of oxidative stress, those catechol estrogens are methylated by the COMT enzyme complex to form the inert final products that enter the urine and stool for elimination.

What if oxidative stress transforms catechol estrogens to quinones?

Catechol estrogens that have been oxidized instead of methylated can bind to areas of DNA and create sites of altered genes that in some cases can become mutations that initiate cancer. High urinary catechol estrogens (in particular high levels of 2-hydroxyestrone, 4-hydroxyestradiol and 16-hydroxyestrone), have been tied to increased prostate cancer risk.^5,6 The way estrogens are metabolized can be influenced by the health of the rest of the endocrine system, body composition, smoking status, diet, and an individual’s genetics.

Catechol estrogen activity in the body can be attenuated by treating endocrine imbalances (like hypothyroidism, for instance), promoting and supporting proper methylation pathways, improving nutrition, decreasing inflammation and most of all reducing oxidation.

When should prostate cancer prevention start?

It's always a great time to avoid chemicals and poisons and to adopt a healthful lifestyle. It's worth a conversation between doctor and patient – identify those areas of susceptibility. ZRT's Estrogen Metabolites testing, which tests for2-hydroxy, 4-hydroxy and 16-hydroxy estrogens, is also something to consider.

Related Resources

References

¹Tarapore P, et al. Exposure to bisphenol A correlates with early-onset prostate cancer and promotes centrosome amplification and anchorage-independent growth in vitro. PLoS One. 2014;9(3):e90332.

²Yang CY, et al. Does arsenic exposure increase the risk for prostate cancer? J Toxicol Environ Health A. 2008;71(23):1559-63.

³ García-Esquinas E, et al. Arsenic exposure and cancer mortality in a US-based prospective cohort: the strong heart study. Cancer Epidemiol Biomarkers Prev. 2013;22(11):1944-53.

⁴ Bulka CM, et al. Arsenic in drinking water and prostate cancer in Illinois counties: An ecologic study. Environ Res. 2016;148:450-6.

⁵ Barba M, et al. Urinary estrogen metabolites and prostate cancer: a case-control study and meta-analysis. J Exp Clin Cancer Res. 2009;28:135.

⁶ Mosli HA, et al. Catechol estrogens induce proliferation and malignant transformation in prostate epithelial cells. Toxicol Lett. 2013;220(3):247-58.

How to Use the Cortisol Awakening Response (CAR) in Addressing Adrenal Function

Fri, 04 Mar 2016 09:14:00 -0800

Treatment Takeaway

On awakening cortisol should increase about 50% in the first 30 minutes then begin to progressively drop the remainder of the day. Three, rather than one, early morning collections are what is needed to accurately assess the CAR; one immediately on waking, one 30 minutes later, and another at 1 hour.

Diurnal Cortisol Curve Assessment

Thirty minutes after awakening from a good night's sleep, cortisol levels are at the highest they'll be all day. Following the morning peak, cortisol levels then fall to less than half that peak level by noon. They continue to drop to very low levels at night where they stay low during the sleep hours. Some individuals have a sharp rise to reach morning levels, others a more gradual incline. Looking at cortisol levels graphed during the day, any abnormal elevation, or depression of levels, or a loss of the expected curve with its characteristic morning peak and swooping decline towards evening may suggest HPA axis dysfunction – which is what we're most interested in assessing when we're looking at a diurnal cortisol curve (i.e. a 4-point cortisol test).

Looking at the diurnal curve of saliva cortisol levels plotted against time of day can give us some useful information about the body's response to chronic stress and the ultimate downregulation of pituitary ACTH, but an altered diurnal cortisol curve could also be due to more acute stressors. Some examples of things that affect the 24-hour cortisol pattern include:

Dysglycemia or even fasting a little too long between meals
Sleep
Exercise
Pain
A recent cortisone injection or regular topical, inhaled or oral steroid use

We expect onslaughts to the HPA axis to yield predictable results – the highs and lows following each challenge should tell us the HPA axis is functioning properly. In the face of severe chronic stress, we expect to see high cortisol levels throughout the day. When we see normal or low cortisol levels instead, we suspect HPA axis dysfunction. We do our best to put together an individual's symptoms with what the 4-point cortisol curve is telling us to help guide treatment decisions. But sometimes it just doesn't add up and we need more information. What if you could add several more saliva collections to see how cortisol is changing in the first hour or so upon awakening?

A Second Measure of HPA Axis Tuning

CAR gives us even more clues to pin down the reason for a hyperactive or hypoactive HPA axis.

How can we assess the response capacity of the HPA axis? We have a built-in mechanism governed by the hippocampus and the light-sensitive suprachiasmatic nucleus of the hypothalamus wherein cortisol levels show a temporary boost between the moment of waking and 30 or so minutes after rising, returning to the initial waking level at 60 minutes after waking.

This transient rise in cortisol levels is unique to the stimulus of morning waking. It doesn't happen when we are woken from sleep in the middle of the night or after we take an afternoon nap. It happens in the first hour or so after waking up, and it's called the Cortisol Awakening Response (CAR). The magnitude of the CAR gives us some idea of the HPA axis's ability to activate and respond to the magnitude of all the stressors (normal physiological stress, self-perceived emotional stress, physical stress, etc.) that face us as we awaken and begin the day.

CAR gives us even more clues to pin down the reason for a hyperactive or hypoactive HPA axis. So, what is a NORMAL CAR response? On awakening cortisol should increase about 50% in the first 30 minutes then begin to progressively drop the remainder of the day. Three, rather than one, early morning collections are what is needed to accurately assess the CAR; one immediately on waking, one 30 minutes later, and another at 1 hour. The other three collections are done as usual – before lunch, dinner, and bedtime.

Clinical Use of CAR

Decreased CAR has been associated with the following conditions:^1,2

PTSD
Chronic Pain
Systemic hypertension
High CIMT (carotid intima media thickness) in women
Functional GI diseases
Postpartum depression
Chronic Fatigue Syndrome
Major depression
Insomnia (but not isolated night waking)
Autoimmune diseases
Atopic and allergic conditions
Low frequency noise exposure
Low socioeconomic status
Perceived high stress
Cushing's Disease
Addison's Disease

Increased CAR is associated with the following conditions:

Visceral obesity in men
Major depressive episodes
Upper respiratory illnesses
Bipolar disorder
Fibromyalgia in women reporting abuse during childhood
Women with BPD (borderline personality disorder)
Smoking (to a small degree)
Light exposure during waking
Chronic stress and worrying
Work overload

CAR Use in Monitoring Therapy

CAR may even be applicable in monitoring the efficacy of drug therapies used to treat these diseases. A recent study on the effects of the SSRI paroxetine on salivary cortisol in major depressive disorder reported a "robust CAR increase especially when patients became remitters versus no change in non-remitters during paroxetine treatment" so CAR may additionally be used to assess clinical response to antidepressant therapy.³Given the results of this study, it makes sense that CAR could be a powerful marker to monitor during treatment of a dysfunctional HPA axis.

Problems with the CAR

As with anything that potentially gives us more information, interpretation can be tricky. Most people (about 75%) have a normal CAR and the remaining 25% do not. Different types of stressors affect CAR in different ways – chronic stress as opposed to acute, perceived, or social stress, or work overload, for instance.

Additionally, many normal things can affect the CAR. For example collecting saliva on a less stressful non-work day very likely will yield a lower CAR. Finally, and perhaps most importantly, those individuals who have great difficulty conjuring the 1 mL volume of saliva required for the test may run into problems appreciating the CAR, because a single waking sample collected over a 15 or 30 minute time frame would actually represent more of an average. Comparing average waking cortisol within the first 5 minutes with a second measure at 30 minutes and a third at 60 min could result in underestimation of CAR and compromise the usefulness of this test.

Sample Collection for Determining CAR

Simple to collect, all in all, the CAR could be a very useful addition to a salivary diurnal cortisol test.

From a laboratory perspective, the sampling required to determine the CAR is rather simple. It requires a saliva collection of about 1 mL without bubbles upon morning waking within the first 5 minutes, a second sample also of 1 mL without bubbles at 30 minutes, and a third sample at 60 minutes. Samples should be collected as quickly as possible (within a 5 minute time frame). The rest of the diurnal rhythm can be assessed at the normal time intervals (noon, evening and night), making a total of 6 collection tubes.

Alternatively, when using a 4-tube collection, collect samples on waking, waking + 30 min, noon or evening, and night. For assessing CAR most accurately remember we're looking for the delta from morning waking to + 30 min and then + 60 min.

When monitoring the CAR in patients with conditions correlated with prolonged CARs, it may make sense to observe free cortisol at an additional time point 60 minutes after waking.

The ZRT report always provides cortisol levels both numerically and graphically with results plotted against time of collection. Simple to collect, all in all, the CAR could be a very useful addition to a salivary diurnal cortisol test. The only thing left is to order some extra vials!

Take the Next Step

Contact ZRT's Customer Service team at 866.600.1636 or info@zrtlab.com to order Adrenal Stress Profile kits marked to test the Cortisol Awakening Response.

Related Resources

References

¹Fries, E., Dettenborn, L., Kirschbaum, C. 2009. The cortisol awakening response (CAR): Facts and future directions. Int J of Psychophysiology 72 (2009) 67-73.

²Dedovic, K. and Ngiam, J. 2015. The cortisol awakening response and major depression: examining the evidence. Neuropsychiatr Dis Treat (2015) 11: 1181-1189.

³Henricus, R., Khoenkhoen, S., Ottenhof, K., Koeter, M., Mocking, R., Schene, A. 2015. Longitudinal effects of the SSRI paroxetine on salivary cortisol in Major Depressive Disorder. Psychoneuroendocrinology (2015) 52, 261-271.

Could Zombies Survive on Today's Brain?

Fri, 30 Oct 2015 10:00:00 -0700

Everyone knows zombies are hungry.

Naturally, brains are on the menu, and occasionally my six-year-old daughter expresses her concern that a zombie might eat her brain as she sleeps (thanks, ParaNorman).

But the nerd in me can’t help but wonder why a zombie would want to eat today’s brain.

Eeeeww. We’ve literally turned into the human equivalent of potato chips.

Nutrient-Poor & Toxin-Rich Environment

Today’s brain is full of aspartame, SSRI’s, cadmium, arsenic and mercury, phthalates, benzene metabolites, DDE and BPA. Scientific American even tells us we have fewer memories stored in our brains now that we can rely on “the cloud.”

If we truly look at a zombie apocalypse situation and consider the eventuality of a world without cigarettes, diet sodas, combustion engines, pesticides and herbicides, plastics and EMFs, we’re still left with the mess that’s become of our soil and water supply – which, let’s face it, has become increasingly nutrient-poor and toxin-rich.

Today’s brain is full of aspartame, SSRI’s, cadmium, arsenic and mercury, phthalates, benzene metabolites, DDE and BPA...the human equivalent of potato chips.

We eat food grown in the soil, animals made up of food from that same soil, and drink the water. Our bodies are designed to take in that substrate from the environment and assimilate it into the body for life functions.

Even in the best of situations, our bodies take in the bad with the good and sequester it away from the vital organs – usually sending it over to the liver or kidneys to try to modify it for excretion (if possible), or ultimately to the fat or bone for long term storage depending on what it is. Lead looks enough like calcium to incorporate into the bones. Methylmercury complexed to L-cysteine looks enough like L-methionine to pass through the blood-brain barrier and deposit in the brain.

You Are What You Eat

Needless to say, while on the run from zombies, we’d all be on a pretty serious calorie restricted diet. If our body fat is full of safely sequestered lipid-soluble toxins and other undesirables, what happens when we’re spending our nights running from zombies? I’d imagine some serious lipolysis would be liberating organophosphates and PCBs from fat stores – we might all go just a little bit crazy not only from fear for our lives, but from acute exposure to the poisons within.

How about those high BPA levels in the body from all the super convenient water bottles we’ve been sucking dry for years? Our BPA-altered stress response would most certainly keep cortisol levels elevated for very long periods of time and ultimately lead to dysregulation. Bone remodeling would favor resorption in our calorie-restricted state and we’d have a lot of lead pumping through our blood as a result. We’d be a bunch of tired and wired, hungry, angry and depressed, fatigued and desperate sacks of flesh moving slowly and aimlessly across the countryside in search of...

Wait a minute. We’re not the zombies. Or are we? I kiss my daughter’s forehead reassuringly as I wonder about such things.

Read More About Environmental Toxins:

SHBG – A Modulator to be Modulated

Tue, 21 Jul 2015 10:50:00 -0700

SHBG, or Sex Hormone Binding Globulin, controls testosterone effect in both men and women by modulating changes in sex steroid levels. When SHBG goes up, free testosterone goes down.

I like to think of SHBG as a sponge that soaks up androgens and to some degree estrogens as well.

Since it binds so specifically and tightly to testosterone, it makes up part of the equation that equals androgen excess or androgen deficiency. Knowing how to manipulate SHBG can be a useful tool in a number of scenarios.

Role: Bind to and carry testosterone (and less strongly E2 and DHT) through the blood stream to target tissues and to the liver for modification and removal from the body. This bond is very strong. The bound testosterone is not easily removed from the SHBG and is therefore considered inactive.

Production Sites: Liver mostly, testes, brain

Production Signals: Estradiol, triiodothyronine (T3)

Down-Regulated by: Insulin

Aliases: ABP (androgen binding protein), SSBG (sex steroid binding globulin), TEBG (testosterone binding beta globulin), GBG (gonadal steroid binding globulin)

Action: Controls clearance and bioavailability of testosterone

Prescription Drugs & SHBG Levels

Some drugs such as Spironolactone alter binding of androgens to the receptor sites on SHBG, therefore leading to increased clearance of testosterone and to the rise of estrogen and SHBG. Other medications can cause a sustained increase in prolactin levels that suppress testosterone and raise SHBG. Safe to say, most if not all oral drugs have some effect on the liver and SHBG levels. Listed are some of the ones that make the most impact.

Drugs that Raise SHBG via Increasing Prolactin:

Antipsychotics (both typical and atypical)
Antidepressants (SSRIs, Tricyclics, MAO-Is)
Xanax and Buspar
H2 Antagonists (Cimetidine, Ranitidine)
Morphine
Some Antihypertensives

Drugs that Raise SHBG:

Raloxifene (Evista)
Tamoxifen
Spironolactone
Anticonvulsants (Phenytoin)
Oral (but not transdermal) estradiol
Ethinyl estradiol (oral contraceptives)
Metformin
Exogenous insulin in Type 2 DM
Coffee!

Drugs that Suppress SHBG:

Progestins
Glucocorticoids
Exogenous insulin in Type I DM

Genetics

Some people have a genetic variation in their SHBG structure that slows or speeds its degradation leading to high or low levels. Current research projects are studying specific SHBG SNPs with regard to risk of Type 2 diabetes

Areas of Application:

How to Influence SHBG:
Pinpoint the cause of the imbalance whenever possible and instead of trying to lower a high SHBG and raise a low SHBG, zoom out to support balance in the system. If SHBG is high or low, look deeper. Always consider the main endocrine inputs: INSULIN, ESTRADIOL, THYROID.

Accompanying Tests:

Fasting Insulin
HgbA1c
Sex Steroids (E2, T, DHEA-S)
Thyroid Panel (TSH, fT3, fT4)
LH and FSH
IGF-1
Prolactin
Liver function tests

Some Treatment Examples:

Continue the discussion:

Topical Testosterone & the U-Shaped Curve

Thu, 11 Jun 2015 08:53:00 -0700

The testicles of a man in his 20s are known to contribute about 5-10mg of testosterone per 24-hour day and levels of total testosterone in the venous blood with that amount are observed to yield roughly 300-1200 ng/dL in the morning at the diurnal peak.

Testosterone, whether endogenous or given exogenously, negatively feeds back on the hypothalamus, limiting GnRH and thus LH and FSH from the pituitary. A man taking supraphysiological doses of testosterone can expect to have very low or undetectable levels of LH and FSH in the serum. What happens when the prescription dose overshoots the patient's optimal dose? Certainly, we see LH and FSH practically disappear.

Additionally, there can be a return of all or some of the original hypogonadal symptoms which could be due to down regulation of the tissue receptors. This is something we see demonstrated quite a bit here in the lab, especially with doses of topical testosterone gels over 50mg per day. An interesting area of research right now is androgen receptor sensitivity measured by a genetic finding (CAG repeat polymorphism), the increasing degree of which is negatively correlated to testosterone tissue uptake.

Illustration 1: Topical Testosterone Dose vs Symptom Severity VAS 1-10 in Men

What is Andropause?

Andropause can have different presentations for each individual patient. Late onset hypogonadism (LOH) is a form of secondary hypogonadism appearing in men over 40. Estimated prevalence climbs as high as 30% in men over 70 and its symptoms seem to embody the term of andropause the best. Interestingly, there’s a higher prevalence in men with type II diabetes and sleep apnea. Though there are quite a few general afflictions associated with LOH, the key symptoms are sexual and the clinical sign is low total and free testosterone in the serum. All of the above are needed for diagnosis of LOH. Psychological and physical symptoms are supportive but not diagnostic alone.

Low T – sexual symptoms

Frequency of morning erections (<1 per month)
Sexual thoughts (<2-3 times a month)
Erectile function suitable for intercourse (almost never)

Low T – psychological symptoms

Sadness
Low energy
Fatigue

Low T – physical symptoms

Inability to walk more than 1 km
Decreased flexibility – can’t bend or kneel
Not able to engage in vigorous activity

Most men with age-related low testosterone levels are asymptomatic. Clearly, there are other factors at play. Common drug therapies and nutritional deficiencies like low vitamin D levels are associated with lower levels of free testosterone. The endocrine system has intricate ins and outs, and dysfunction in one part can change the way the whole system functions. Adrenal and thyroid functions are altered by stress and changes in cortisol, T3 and T4, LH, FSH, SHBG and prolactin may be the beginning of where we see low free and total testosterone levels in a lab test turn into noticeable symptoms.

Recent studies have shown that dosing with supraphysiological amounts of topical testosterone may actually be involved in increasing the risk of cardiovascular events in elderly men rather than preventing them as seen endogenously when testosterone levels are replete.

Why are we even seeing prescribing in doses higher than normal physiological production? Larger than physiologic doses of topical testosterone are often needed in order to see total testosterone in serum studies rise and when dosing is started too high to begin with, it can be confusing to follow the symptom picture. For instance, if the starting prescription is 50mg and the patient's optimal zone (bottom of the U) is 10-20mg, even if the patient initially improves, we'll eventually see mood and sexual symptoms return. Starting at low doses and increasing them over time will help create a patient's own U-shaped curve and prevent diminishing returns.

What to check when the numbers look good but symptoms remain while on TRT:

Estradiol levels. Testosterone becomes estradiol with the help of aromatase. This enzyme exists in nearly all body tissues including fat tissue, the gonads, blood vessels, brain and the skin. If estradiol is rising with testosterone therapy, an aromatase inhibitor may be required.
SHBG levels. Testosterone circulates bound to SHBG at a high percentage. If SHBG is becoming elevated, free testosterone will decrease and symptoms usually appear.
DHT levels. Testosterone metabolizes down to DHT at the tissue level via 5-alpha reductase. Elevation in DHT seems to be correlated with an increase in erythrocytosis so also assess hematocrit.
DHEA-S levels. It could be that low androgen symptoms are attributable to low levels of this largely adrenal androgen.
Thyroid function. Symptoms often overlap with symptoms of low testosterone.
Diurnal free cortisol to assess for physiological stress response which may be playing a role in symptom development.

Treat the Lab or Treat the Person?

Is there a risk associated with NOT treating a low testosterone level in the asymptomatic (according to the diagnosis criteria) man? I would argue that the answer is yes. This doesn’t necessarily mean give everyone testosterone when it's low in the serum. For instance, imbalances in estradiol, free testosterone and DHEA can profoundly affect a man’s cardiovascular risk profile. After all, he is more likely to die of heart disease than any other disease. We have learned how strongly endogenous testosterone is involved in cardiovascular autonomic tone and lower T levels are associated with incidence of atrial fibrillation, type 2 diabetes, obesity, and peripheral artery disease.

Perhaps the popularization of treating menopause with hormonal therapies has encouraged men to see their own age-related decline in sex hormones as an imbalance to be corrected, but men in their 50s are seeking medical care looking for testosterone. It isn’t surprising to see that men over 40 are not okay with a hampered or discontinued sex life, low energy and mood, or muscle weakness and the eventuality of a sedentary remaining existence – a terrible lifestyle combination for cardiovascular risk.

The symptoms of low testosterone are shared with other conditions and this can be a major pitfall for patients and clinicians alike. In these cases, correcting a low serum testosterone to normal levels through testosterone prescription won't make the symptoms improve. Sorting all of this out can be a huge challenge but is often a solvable problem by digging further into the sex hormones and remembering the U-shaped curve.

Related Resources

Melatonin's Role in the Gut "Brain"

Thu, 12 Mar 2015 09:30:00 -0700

Last week, I discussed Melatonin's Role in Sleep. By focusing on MT6s, we may be focusing on the tip of the melatonin iceberg.

We see very high levels of MT6s in the urine as a result of pineal synthesis and release of melatonin in response to dark stimulation.

Melatonin is released, fulfills its role as central nervous system sedative, resets our cellular clocks and is then sulfated and to a much smaller degree glucoronidated in the liver. The sulfated melatonin then hits the kidneys for disposal. Though important for assessing the circadian rhythm, that’s not the end of the story for melatonin.

In the gastrointestinal tract, melatonin is synthesized in the enterochromaffin cells that exist in the epithelia that line the lumen and acts more in a paracrine manner – affecting nearby cells.

Melatonin performs several roles in the gut:

Helps control immune reactions
Regulates GI motility (reduces the tone of GI muscles)
Modulates local inflammation
Moderates visceral sensation

Research suggests the gut manufactures 500x higher melatonin levels than the brain.

Why doesn’t it show up in the urine as MT6s? It turns out melatonin, by virtue of its structure, can directly neutralize oxidative species like hydroxyl radicals, nitrites, peroxynitrites and peroxides. In so doing, melatonin descends down pathways that change its structure depending on what it’s reducing. Those metabolites, such as N1-acetyl-5-methoxykynuramine (AMK) and N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), may represent an emerging field of study for developing a way to assess the body’s ability to handle oxidative stress and general inflammation.

So, we do see some baseline low levels of MT6s in the urine during the day from extra-pineal melatonin production sites that may represent a small portion of the body’s melatonin status. It remains to be seen what conclusions we can draw from looking at daytime MT6s alone for more than sleeping status.

Learn more about testing Melatonin.

Melatonin's Role in Sleep

Sat, 07 Mar 2015 10:00:00 -0800

Melatonin is a ubiquitous little hormone that comes in an indolamine package similar to serotonin, its precursor. Thanks to its unique structure, it can travel easily through the blood stream and readily crosses the blood-brain and placental barriers. It is synthesized and used all over the body to perform a number of indispensable roles. It’s the main reason our bodies know what time it is and what it’s supposed to be doing at any given moment. It signals the transcription of genes that regulate the cell cycle, neutralize free radicals, and decrease inflammation. Its claim to fame, however, is its role in promoting sleep.

Melatonin's Daily Curve

If we were to look at a curve representing production of melatonin over a 24 hour period, we would see a steep rise to peak levels within the first hour of sleep with a plateau lasting until about 3-4AM followed by a drastic reduction to its daytime baseline level by around 7AM.

Darkness stimulates the production of melatonin and sustains its peak level via signals that relay from the retina in the back of the eye to the suprachiasmatic nucleus of the hypothalamus in the brain sending norepinephrine to the pineal gland to ramp up melatonin manufacture. When melatonin is released, it floods the cerebrospinal fluid, the blood stream and surrounding tissues and acts as a potent sedative to the nervous system. It can readily enter all cells in all tissues – for some purposes, it rings the doorbell, entering via membrane receptors and setting off a cascade of phosphorylation events. For other purposes, it diffuses through the cell membrane and heads straight to the mitochondria for antioxidant duty or to the nucleus for promoting DNA transcription of specific proteins and enzymes. With high levels of melatonin on board, the body rests and repairs. At sunrise or the retina’s detection of light stimulation, melatonin production ramps down quickly to daytime levels – this is why it’s imperative we sleep in the dark and take care not to turn on lights in the middle of the night.

In the urine, we measure melatonin’s metabolite MT6s first thing in the morning to assess the overnight production of melatonin. MT6s shows up in the urine about 3 hours after the appearance of melatonin in the blood stream and thus persists for about 3 hours after melatonin’s morning decline making it a simple and accurate marker of melatonin production.

See the image to the right for an example of a urine MT6s curve. By looking at the first morning melatonin level (5AM), we can see that overnight melatonin levels were quite low. Certainly, if there are reported symptoms of delayed sleep onset or other sleep disturbances as well, we could make the assessment that addressing melatonin levels might be an important part of the treatment plan.

Related Resources

The Role of Hormones in Sleep Disturbances - Webinar Q&A

Thu, 28 Aug 2014 00:40:00 -0700

Thanks to everyone who joined in for the Role of Hormones in Sleep Disturbances webinar! We had a great turnout and I was so happy to be able to share this information with everyone.

There were a number of questions I wasn’t able to address due to time constraints but they were all excellent questions. I thought at least someone would be interested in a follow-up as I speak to the rest of the questions just as a little wrap-up.

Q: Wouldn't it be nice to include Dried Urine Melatonin in your ZRT Comprehensive Profile, to be able to evaluate Morning Cortisol when low? Maybe it is low while Melatonin is high?

A: It would be nice! We’ve had a flurry of inquiries about this. Stay tuned for updates on it. Currently, melatonin testing is included with the Urine Hormone Metabolites Profile and the Sleep Balance Profile. Both of these are dried urine collection profiles.

Q: Do you start with 0.3mg for children, also?

A: With kids and adults alike, I prefer to start with a low dose and work up to the minimum effective dose from there. With melatonin, the lowest effective dose for most people has been established at 0.3mg. That said, there are plenty of studies with exclusively children as subjects that used pre-bedtime doses of up to 12mg. There seems to be some latitude in dosing here. As a matter of fact, there is even a trial that was done with septic newborns showing favorable study outcomes at an oral dose of 20mg! So, there you go.

Q: What dose for 5HTP do you use?

A: Here’s another case of starting low dose and working up. 100mg is an excellent 5HTP starting dose, but patients rarely get much clinical effect at this dose. Generally speaking, 300mg at bedtime is the sweet spot for most. I’ve found over the years that there are just some people who don’t seem to respond to 5HTP at all in the normal dosing range and many times, these folks do better on tryptophan (or melatonin itself). Remember though, that there is always some potential for serotonin syndrome if your patients are using 5HTP with SSRIs or other antidepressants and though there are conflicting schools of thought on whether or not they should be used together, if the benefits outweigh the risks, it’s always best to proceed with caution.

Q: Are there recommended foods that have high melatonin?

A: Apparently, there ARE foods high in melatonin! If you like kiwi, goji berries, tart cherries and walnuts, you’re eating foods that provide you with this sleep hormone. Current research is looking at animal (meat) sources of melatonin – lamb, chicken, beef, pork and fish – so far melatonin makes a good showing there too. There are also high-tryptophan foods. Tryptophan heads up the pathway to 5HTP, serotonin and melatonin. It’s an essential amino acid which means it’s necessary for life, and we can’t make it endogenously so good food sources are a must. Protein-rich foods are the main focus, but they don’t have to be animal source proteins. I’ll link to Wikipedia here for a nice chart on food sources of tryptophan that the average person actually eats: http://en.wikipedia.org/wiki/Tryptophan.

Q: Will multiple nocturnal diuresis affect the results?

A: This is a great question, and one I had to really wrap my mind around because you would think you couldn’t actually quantify melatonin production if you weren’t sampling the entire overnight production. But in fact, because of the 3-hour lag between melatonin production and the appearance of its major urinary metabolite MT6s, added to the 7-hour overnight plateau of melatonin production, it’s hard to miss it. Of course, if you’re ever concerned about a patient with a unique set of circumstances getting a good sample, you could always have him or her use a vessel to collect urine overnight and dip the urine strip in the morning after the “first morning void.” That works too.

Q: Does use of melatonin over time reduce the natural production of melatonin?

A: This is a good myth-buster question, and the answer seems to be no. You can increase your melatonin production nutritionally by feeding the body the building blocks to make it, and supplementation with melatonin itself will boost serum and urine levels but it will not change the underlying endogenous production of melatonin. This means that if you take melatonin for a period of time and then discontinue it, your body’s melatonin production will go back to the pre-treatment state.

It does seem to be safe long-term; and while there are some studies that show melatonin loses its effectiveness over time, many others demonstrate its safety and efficacy over several years of use. This lack of pineal suppression of endogenous melatonin production by exogenous melatonin supplementation may be partially due to its constant baseline production throughout the body all the time. It’s also (maybe more importantly) likely related to the fact that there is no negative feedback loop involving melatonin to the pineal gland – light/dark stimulation provides the feedback here.

If you'd like to view the webinar recording, click here.

Related Resources

Melatonin’s Importance Is So Much Bigger Than Sleep

Thu, 17 Jul 2014 01:10:00 -0700

I've been up to my elbows in melatonin research for a week now.

I always felt like I had a pretty good working knowledge of where melatonin came from in the body, roughly how it was synthesized, the signals that propagate its production, and where it acts. Like most clinicians, I tended to think of it for sleep problems in general and as an adjunct treatment for some of the comorbidities associated with different cancers.

I was also vaguely aware that there was a physical reason my colitis patients usually presented with depression and sleep problems – the gut really is the bigger of our two brains after all, but I’m not sure I was able to put it all together until this intensive synthesis of information.

Hormonally Speaking, Melatonin is a Major Player

While I’m not ready to say that melatonin or any one hormone is a panacea, I will say it truly is a hormone with far-reaching potential to be a major player in resolving a myriad of health issues. If you are someone who thought melatonin was just that sleep hormone, consider this short list of melatonin’s strengths:

Resolving sleep disorders
Decreasing pain in chronic pain conditions, even neuropathic pain
Improving quality of life in depressed patients
Reducing oxidative damage
Acting as an anti-inflammatory agent by inhibiting 5-LOX and COX-2
Ramping up both humoral and cellular immune responses
Maintaining the circadian rhythm by day (from the gut) and by night (from the brain)
Healing damaged tissues

This is all compelling, but to really understand melatonin’s importance and potential for improving health, we should start with what we know about its biochemistry and physiology.

About Melatonin Production

It might be surprising to hear that melatonin is synthesized from L-tryptophan at 500x greater concentrations in the gastrointestinal tract than in the pineal gland of the brain. The gut is responsible for most of our daytime synthesis of melatonin and its release increases significantly in response to food intake, particularly protein-rich foods with high tryptophan content, or tryptophan administration. At night, the pineal gland takes over production by responding to light deprivation in the form of a huge surge of melatonin peaking around 2am and dropping steadily until waking. The enzymes for synthesis of melatonin can also be found in the skin, lymphocytes, various epithelia throughout the body including airway passages, reproductive organs, endothelial cells, and in the thyroid.

The 101 on Melatonin Synthesis

The first two steps in the pathway from tryptophan require the help of nutritional cofactors niacin, iron, folate, zinc, B6, magnesium, and vitamin C, resulting in serotonin. Once melatonin is formed, its versatile structure allows it to penetrate nearby and distant tissues very quickly for a near immediate effect. The melatonin production pathway starts with tryptophan, an essential amino acid found in high-protein foods like chicken, fish, nuts and spinach. It’s always important to remember that proper stomach acid and pancreatic function is required to break down and assimilate proteins into amino acids for absorption.

Circulating melatonin is hydroxylated and conjugated with sulfate in the liver to form its primary metabolite, melatonin 6-sulfatoxy (MT6s), and excreted into urine.

Where Does Melatonin Act? In Short, Everywhere!

Not surprisingly, melatonin has its own special membrane receptors – MT1, MT2 and MT3 that are found in almost every cell and tissue in the body from epithelia to neurons to smooth muscle.

“In humans, melatonin receptors were also detected in several organs, including brain and retina, cardiovascular system, liver and gallbladder, intestine, kidney, immune cells, adipocytes, prostate and breast epithelial cells, ovary/granulosa cells, myometrium, and skin.” The nuclear melatonin receptors, RZR/ROR, are as ubiquitous throughout the body as the membrane receptors and may be responsible for its apoptotic effects on cancer cells.

Related Resources

References

Dai, J, Ram, PT, Yaun, L, Spriggs, LL, Hill, SM. Transcriptional repression of RORa, activity in human breast cancer cells by melatonin. Mol Cell Endocrinol 2001; 176: 111-120.
Ekmekcioglu, C. Melatonin receptors in humans: biological role and clinical relevance. Biomed Pharmacother. 2006; 60:97-108.
Karasek, M, Winczyk, K. Melatonin in Humans. J Physiol Pharmacol. 2006;57 Suppl 5:19-39.
Konturek, SJ, Konturek, PC, Brzozowski, T, Bubenik, GA. Role of melatonin in upper gastrointestinal tract. J Physiol Pharmacol. 2007; 58 Suppl 6:23-52.

Breast Cancer: Fear & Preventative Double Mastectomies An Unnecessary Mix

Thu, 29 May 2014 01:26:00 -0700

The recent news about a study regarding women who get mastectomies to prevent breast cancer is stunning.

This study finds most women who get double mastectomies don’t need it. They react out of fear. And this has many doctors puzzled.

Breast Cancer & Biochemistry

Can we prevent breast cancer occurrence through primary care means? The short answer is yes, we can.

We can identify breast cancer risks. We can do functional lab testing to assess nutritional and endocrine balance and test for products of hormone metabolism. We can treat the imbalances we find and monitor progress through lab work and imaging. We can achieve this by understanding some pretty basic biology and biochemistry, and applying it to our patients to help them overturn early cancerous processes in the body and improve overall health.

Expendable Body Parts?

This idea that certain body parts are expendable is not a new one. Modern medicine has been guilty of prophylactically removing the appendix, unfortunately before we knew it was the hot house of probiotic inoculation for the entire gut (oops).

The gallbladder is routinely removed when its dysfunction could be treated by non-surgical means. Who needs one of those (aside from the countless numbers of cholecystectomy patients who now live with chronic diarrhea, who have figured it out the hard way)?

We routinely see hysterectomies performed prophylactically in women beyond their childbearing years, because you can’t get cancer in it if it’s not there to begin with. But that involves major abdominal surgery and impairs blood flow to the ovaries, which reduces ovarian function resulting in hormonal deficiencies they didn't bargain for..

It’s really not that difficult to apply the same logic to the breasts. It’s no wonder we are seeing women push for elective bilateral mastectomies in an effort to prevent breast cancer, and I’m trying to figure out why this trend is surprising.

Patients Seeking Peace of Mind

It would seem that these patients are acting from the standpoint of proactive resolve when no other agreeable options are presented. It is nightmarishly expensive and emotionally horrifying to undergo cancer treatment, and our patients are hip to that. Not to mention better informed on breast cancer prevention research and updates than some of their own primary care doctors.

Really, what are the options doctors present to their patients wanting to prevent cancer but who are not in the high risk category? Watch and wait? Paradoxically more relaxed practice guidelines on clinical breast exams? That doesn’t exactly lend peace of mind to an educated patient who wants to prevent cancer down the road with or without surgery.

Providers Can Take Positive Steps

There are solid preventive strategies for breast cancer that doctors can implement with their patients right now, and it starts by asking these 5 questions:

Is this patient getting adequate/optimal nutrition every day? Especially fiber from green vegetables in the cruciferous family? Are there adequate sources of B vitamins, magnesium, iodine and selenium?
How balanced is this patient’s endocrine system? Are the sex hormones in balance? Are there symptoms of estrogen dominance? In women, what are the cycles like? Is the circadian rhythm in balance? Is blood sugar in balance? Is the thyroid functioning optimally?
How well does the liver metabolize the sex hormones into safe metabolic products? Is this patient making excessive known breast cancer-promoting metabolites? Is proper methylation happening?
How well is this patient eliminating hormonal metabolites? Is there a (healthy) bowel movement 1-2 times a day? Or is there potential for excreted estrogen metabolite re-absorption in a sluggish, toxic digestive tract? Is the creatinine clearance and kidney function normal? Is this person exercising and sweating regularly?
How does this patient handle stress? What are their stress-reducing strategies and are they effective? Stress is well-correlated with tumor induction and may play a much larger role in its development than we know.

Addressing the 5 Questions

Nutrition going into the body, and how the body uses that nutrition to circulate nutrients and build hormones, and their elimination coming out should be big indicators of what’s going on at the cellular level. So, how do we address these 5 questions? Much of this can be evaluated in the subjective portion of any medical encounter. The rest can be assessed using existing lab tests.

Saliva or blood spot testing for estriol, estradiol, estrone, progesterone, testosterone, DHEA-S, and diurnal cortisol levels are a good start for assessing the sex hormones and the circadian rhythm.
Functional laboratory analyses on the market for assessing intracellular vitamin/mineral status and looking at traditional CBC/CMP with a “functional eye” can also tell you something about metabolic imbalances.
Serum or blood spot HgbA1c, fasting insulin and fasting blood glucose will assess blood sugar balance.
Thyroid function can be assessed by looking at serum or blood spot TSH, free T3 and free T4.
ZRT Dried Urine Elements Profile that tests iodine and selenium status as well as bromine, arsenic and mercury excretion can show deficiencies in vital elements for cancer protection (iodine and selenium) and excesses in toxic elements.
Healthy vs. cancer-promoting metabolites and proper methylation can be assessed using the ZRT Estrogen Metabolites Plus Profile, which is geared toward identifying breast and prostate cancer risks. There are also tests on the market that check for specific genetic SNPs if there is concern about a wider genetic methylation issue.

Learning More About Breast Cancer

If it’s hard to imagine how all of this fits together into one giant breast cancer prevention picture, don’t worry. Some researchers have made it their life’s work to comb through countless studies, conduct their own research, develop cutting-edge laboratory tests, and educate the provider community about ALL of it. Dr. David Zava’s 6-part Metabolites series of webinars are specific to the content here and are available to view. I think all medical providers on the front lines should be aware of the preventive care they could be providing their patients beyond the bare minimum screening guidelines currently set forth. Patients simply are demanding more.

That said, this approach may not be for everyone. There will always be a number of women who will opt for the prophylactic double mastectomy despite having no genetic or family history basis to justify it. For the rest of the women out there searching for real preventive strategies who may be researching the highly publicized prophylactic double mastectomy but reaching out for other solid options first, a real cooperative effort with their primary care physician may be the game changer. With this approach, doctors and patients can assess risk, make nutritional, lifestyle, supplement and hormonal adjustments based on the risk assessments, monitor the changes through lab work and feel confident breast cancer risk is decreasing.

The ZRT Laboratory Blog

A Perimenopausal Game Plan

What is Perimenopause?

Step One: Replace

Step Two: Build

Step Three: Fast (and then Break-fast)

Related Resources

References

Guide: How to Treat Iodine Deficiency

Supplementation

Iodide

I2 (Molecular Iodine)

Hashimoto’s

Final Thought on Iodine: Support and Thwart

Related Resources

References

Guide: How to Assess Iodine Deficiency

Iodine's Relationship to Health

Iodine Intake

Key Symptoms

Physical Examination

Laboratory Assessment: 3 Parts

Overview: Laboratory Clues of Low Iodine Status

Final Thought on Iodine

Related Resources

References

The Connection Between GABA & Sleep Disturbances

Low GABA & Sleep Problems

We see sleep disturbances not only in those with low GABA but also in those with high GABA excretion, and while the presentation may be quite similar, the underlying cause is very different.

High GABA & Sleep Problems

High GABA Excretion’s Link to Acute Stress

Related Resources

References

Norway, for the win!

Norwegians learn very early in life how to incorporate frequent journeys into nature into their everyday lives.

Related Resources

Evidence Shows Placentophagy (Placenta Encapsulation) Works

Study Design

What's in the Placenta?

If these hormones are getting into the circulation, are they at least in part responsible for the purported beneficial effects on mood and bonding – all the things so important when the baby arrives?

How Did Moms Feel?

Further Study?

Related Resources

References

Shorter Days: A SAD Pattern

Vitamin D

What Contributes to Lower Vitamin D Status in the Body?

Vitamin D & the Serotonin Seesaw

If you don’t have enough vitamin D to bind VDREs, serotonin synthesis plummets and people really feel the domino effect of that drop in serotonin.

Cortisol Awakening Response

Altered Melatonin Rhythm

The defect in cortisol regulation in SAD may be missed if the CAR isn’t assessed along with the diurnal rhythm.

Related Resources

Avoiding 3 Common Interpretation Pitfalls for Salivary Cortisol Tests

Contamination

Suppression

Comorbidities

Practice Take-Aways

Related Resources

How Exercise Can Turn the Tide in ADHD

What’s going on in the body and the brain with ADHD?

Urinary dopamine and PEA give us information about sympathetic tone and when it’s low, it explains much of the symptomatology associated with ADHD

Related Resources

References

5 Steps to a Healthier Brain in 2017

Because methylation cycles are also so intricately woven into our oxidation and reduction pathways, their function in the brain is crucial.

Related Content

References

Testing Urinary Neurotransmitters? Avoid the Big 5.

In some cases, the elevations are so significant that they can lead to misinterpretation of the test

Related Resources

References

3 Keys to Preventing Prostate Cancer

Bisphenol A (BPA)

BPA Affects Prostate Specific Antigen (PSA) Testing

Individuals with a high body burden of BPA were likely to have false negative results for PSA

Arsenic

Urinary arsenic levels should be taken into consideration when assessing a patient for prostate cancer risk

Catechol Estrogens

What if oxidative stress transforms catechol estrogens to quinones?

I₂(Molecular Iodine)