The ZRT Laboratory Blog

Athletic Performance and the Menstrual Cycle: How to Tailor Workouts to Achieve Optimal Performance

Thu, 10 Jun 2021 10:54:49 -0700

Overview of Hormones and the Menstrual Cycle

Training for athletic competition or exercising to stay healthy is already hard, but the unique physiology of hormone fluctuation due to the menstrual cycle can make it downright tough at times. Women can take advantage of understanding their hormones to optimize their training to their advantage and this is being used by the US Women’s World Cup Championship teams who use specialized training approaches that conform to the different phases of the cycle [1]. I hope after reading this blog, you can better understand what changes happen at the hormonal level and how to better harness these changes to perform your best.

The menstrual cycle starts on day one with menses or more commonly known as the “period,” which lasts between three to seven days. The full first half of the menstrual cycle is called the follicular phase and averages 13 days. This phase includes menses and ends with ovulation. Ovulation is the middle phase of the menstrual cycle and ends when the egg is released from the ovary. After ovulation ends, the luteal phase begins, which typically lasts 13 days as well and ends when menses begins again.

Oral contraceptives (OCs) are common among elite female athletes, with about half of the women competing at the Rio Olympic Games using some form of oral birth control [2]. While this is useful in preventing the cyclic nature of hormones during the menstrual cycle, it appears the OCs interfere with normal immune homeostasis. Data from the 2012 London Olympic Games showed women were 60% more likely to get sick, which affected training or competition. This increase in illness is likely a result of OC use with studies showing elevated C-reactive protein (CRP) levels among women using OCs than the women who were naturally cycling [2]. Another study also showed that cortisol levels were higher in the same high school women athletes 10 months after starting OCs than before they began taking them [3]. This increase in both CRP and cortisol in OC elite athletes is likely the cause of increased illness.

Let us look closer at the different phases and see how the change in hormones during each phase can be used advantageously for performance.

Follicular Phase

Periodic rises in estrogen levels to physiological levels are good as they provide a protective effect on tendon and muscle health.

The follicular phase is highlighted by menses. Approximately 75% of women athletes have negative side effects in relation to their menses [4]. However, this phase is not all bad for athletic performance, as a spike in estrogen after menses typically brings with it a boost of energy. During this part of the cycle, the female body is primed for high-intensity workouts and it is the best time for strength training. This is because of the effect estrogen has on the muscle, which will be detailed later in the blog. The rise in estrogen also increases the body’s ability to recover in between workouts. During this state of increased estrogen, it is also important to not overdo your activities. Estrogen increases type III collagen mRNA. This is in part responsible for decreased tendon stiffness during maximal muscle loading in women and decreases stiffness of the sinew, causing an increase in elasticity of the knee [5,6]. Studies have shown that there is an increased risk of anterior cruciate ligament (ACL) injuries during the late follicular phase [5 ,6]. The flip side of this is that women have much lower incidence of muscle strains and Achilles ruptures due to this decreased sinew stiffness. In professional soccer, women are 54% less likely than men to suffer a muscle strain or Achilles rupture [6]. This mostly translates to fewer groin and hamstring strains [6]. However, when taking OCs these risks change. OCs will decrease the ACL risk, but increase the Achilles tendon rupture risk [6]. OCs have also been linked to increased muscle damage and delayed muscle soreness [6]. Periodic rises in estrogen levels to physiological levels are good as they provide a protective effect on tendon and muscle health [6]. Finally, during this period women utilize stored carbs (glucose) much better, which allows for better endurance. Once estrogen levels spike, the body can’t utilize the glucose stores as efficiently due to the suppression of gluconeogenesis in the liver by estrogen and progesterone. During this time, carb loading is very important as these external carbs are the main source of fuel for female athletes. The follicular phase ends upon ovulation.

Ovulation

Ovulation begins when luteinizing hormone (LH) levels spike, the egg is released, and estrogen levels drop rapidly. However, during the three-to-five-day window prior to the ovulation portion of the cycle, estrogen levels remain very high, as well as a spike in LH. and it is an ideal time for strength training. But the body switches to fat as a fuel rather than glucose, which results in less available energy for high-intensity activities and carb loading is more important. As the luteal phase begins, estrogen declines and progesterone begins to rise.

Luteal Phase

The luteal phase is highlighted by a large increase in progesterone and a rebound of estrogen levels. With both estrogen and progesterone levels high, the body is not primed for high-intensity workouts. Endurance can also be affected at the end of this phase as there can be a drop in blood plasma volume, decreasing oxygen levels to the muscles [1]. Estrogen results in fluid retention and as estrogen levels begin to drop before menstruation, the fluid is redistributed causing this decrease in volume. It is very important to up protein intake during this time as the body increases protein catabolism due to the increased progesterone levels [1]. There could also be a slight disadvantage due to higher basal body temperatures, although this would only occur under extreme heat conditions.

Estrogen’s Role on Muscles

There is no difference in relation to sex when looking at force in relation to muscle cross-sectional areas. Simply put, the bigger the muscle the more force it generates, regardless of gender.

When people think of muscle, they usually think of testosterone. However, estrogen plays a very important part in muscle structure and function and is usually overlooked. In fact, there is no difference in relation to sex when looking at force in relation to muscle cross-sectional areas (CSAs). Simply put, the bigger the muscle the more force it generates, regardless of gender. In one study of collegiate swimmers, there was found to be no difference in force-CSA between men and women [7]. Estrogen is an important factor in this because it is important for maintaining proper muscle conformations. This means the muscle fibers are aligned properly and the myosin heads are primed to bind with the strong binding site of the actin filament rather than the weak binding site [8]. Estrogen is responsible for more strong-binding reactions of myosin heads to actin, resulting in more force generation [8]. This is also suggestive of why women respond better to strength workouts during the late follicular phase when estrogen is highest.

Estrogen is also important in decreasing pro-inflammatory cytokines that can increase muscle breakdown [5]. Estrogen acts as an antioxidant and sarcolemma membrane stabilizer [5]. The sarcolemma is the muscular membrane and is responsible for the depolarization potential that makes muscles contract. Estrogen is important for myosatellite cell expansion, differentiation, and self-renewal [9]. Myosatellite cells act as stem cells for muscles and are important in muscle recovery and function [9]. These are very important because muscle cell nuclei do not replicate so to build new muscle or repair injured muscle, myosatellite cells are needed. When estrogen levels are higher, myofibrillar protein synthesis is higher and the decline of estrogen and progesterone levels as people age led to muscle weakness [6,8]. This age-related muscle weakness is a response by the muscle to lower estrogen levels that don’t allow for the proper muscular conformation [8].

Muscle fatigue is a common phenomenon that affects women more often than men, as well as longer recovery times [10]. The anti-fatigue protein, orosomucoid (ORM), is produced in the liver and exhibits many biological activities such as immunity modulation, binding and carrying drugs, maintaining the capillary barrier, and acts as a disease marker. ORM is significantly elevated in sera, liver, and muscle tissues of fatigued rodents [10]. ORM works by increasing glycogen storage and muscle endurance. The increase in muscle fatigue in women is tied to reduced ORM induction in response to fatigue. ORM is downregulated by estrogen via estrogen receptors and the p38 mitogen-activated protein kinase [10]. This suggests the best time for endurance activities is when estrogen is at it lowest during menses.

Now you may be asking yourself, estrogen is high in both late-follicular as well as mid-luteal phases, why does this increase in muscle strength and growth only occur in the late-follicular phase? This is a great question and progesterone itself is important for protein synthesis. But animal data has indicated that when estrogen and progesterone are present together, like in the mid-luteal phase, they may counteract each other [9]. Therefore, resistance training is best during the late-follicular phase only.

For OC users, a triphasic OC with low progestogen in the first two weeks also showed this same increase in resistance training response [9]. It has also been shown that women using OCs that contain constant amounts of ethinyl estradiol (EE) and progestins showed lower protein synthesis [9]. This suggest that progestins have an anti-androgen effect on protein synthesis when paired with estrogens.

Testing

How can you use all this information to enhance your training and performance? For women who are naturally cycling, it is important to understand the exact timeline of your cycle so you know when you are in each phase and can get the most out it. ZRT offers a menstrual cycle mapping kit that allows for accurate mapping of the menstrual cycle through testing of LH, and metabolites of progesterone and estradiol in urine. For women on hormonal birth control, it may be important to understand where your hormone levels are at while on the contraceptives. This is best done using our LCMS saliva profile. This profile tests for 18 hormones, melatonin, three steroid synthesis inhibitors, and most importantly, the synthetic estrogen EE. It is important to understand your EE levels to fully understand your full estrogen load on top of your estradiol (E2) levels. EE binds stronger to the estrogen receptor than estradiol and is therefore much more potent. The full estrogen load is a calculation of EE and E2 values to understand the estrogen receptor binding capacity.

Related Resources

References

Introducing ZRT’s new Fitness Metrics and Elite Athletic Metrics profiles

Wed, 06 Jan 2021 09:21:27 -0800

The balance of hormones is essential for all aspects of human health and the same plays true for athletes. Whether you are a beginner working on getting into shape and losing weight, or a seasoned veteran with many competitions under your belt, understanding your hormones and how they change with intense exercise is essential to getting as much as possible out of your training. ZRT Laboratory is launching 2 new kits that will enable athletes to track their hormones and help them better understand the changes happening to their body. In my previous blog, I spoke about why laboratory testing is important for hormone tracking to prevent injury and achieve optimal performance. Here, I am going to introduce ZRT Laboratory’s new kits and explain why these particular biomarkers were selected and how they tie into each other.

Fitness Metrics Profile

Our first kit, designed more for the beginner athlete, is called the Fitness Metrics profile. This profile is designed to measure the levels of the 4 main sex steroid hormones estradiol, progesterone, testosterone, and DHEA-S, plus cortisol, from a small amount of fingerstick blood dried on a filter card (dried blood spot – DBS). Both estradiol and testosterone can be useful tools in diagnosing overtraining syndrome (OTS) [1]. During exercise, testosterone levels are depleted, but generally rebound after a good night’s rest. However, if testosterone (and estradiol in women) stay low, an athlete’s susceptibility to injury increases.

DHEA is an important marker as it decreases with age and is viewed as the anti-aging hormone. DHEA helps reduce recovery time, protects joints and bones, and increases stamina [2]. DHEA also reduces bad cholesterol, increases good cholesterol, and neutralizes the effects of cortisol, the stress hormone. In this kit we look at the sulfate form of DHEA, DHEA-S, which is the form in which the body stores DHEA. Progesterone doesn’t fluctuate in response to activity like the other hormones, but is still important to track, especially for female athletes. If your progesterone levels are low, this can have negative effects on your health and wellbeing such as anxiety and poor moods, increased susceptibility to PMS, and the possibility of irregular periods, decreased fertility, poor sleep, and less muscular development.

Whether you are a beginner working on getting into shape and losing weight, or a seasoned veteran with many competitions under your belt, understanding your hormones and how they change with intense exercise is essential to getting as much as possible out of your training.

This kit also tests for cortisol, discussed in my previous blog. Cortisol is the stress hormone, released as the end-product of HPA axis activity as it regulates the stress response, and is important for shunting resources where they are needed in stressful situations. The fluctuations in cortisol tend to be limited to short bursts but with increased stress or increased physical activity, these bursts can last longer and longer, making the body less sensitive to these small changes and causing long-term effects. These long-term effects of too much cortisol can reduce protein synthesis, increase abdominal fat, suppress levels of anabolic hormones like growth hormone, estradiol, progesterone, testosterone, and DHEA-S, affecting fertility and libido, and can lessen glucose usage predisposing to diabetes. This kit takes only one cortisol measurement in the morning about 30 minutes after awakening, when the level should normally be at the peak of the cortisol awakening response, which helps you get out of bed each day. If this level is elevated, it could mean your overall cortisol is high throughout the day and your sleep cycles are not enough to lower it properly. If cortisol is low shortly after awakening your energy level will likely be low and it may have significant effects on your athletic performance. (To get a better understanding of the effects on cortisol, a 4 time point circadian reading gives more information).

The final piece of the puzzle that is important when analyzing steroid hormones in blood, is sex hormone binding globulin (SHBG). SHBG binds free steroids in the blood and keeps them bound and soluble allowing for transport through the blood vasculature. If sex steroid levels are decreasing while SHBG is increasing, this can be a sign of OTS and should be monitored closely [3].

Monitoring thyroid hormone levels is critical in endurance athletes as most thyroid hormone levels increase right after an event and can take 1-4 days to return to normal afterwards.

Moving on from the sex steroids, we also look at thyroid-stimulating hormone (TSH). TSH is an important indicator of thyroid health. Thyroid hormones regulate the size and performance of muscles. To boost thyroid hormone levels during exercise, the thyroid needs to be working properly. Over-exercising can increase catabolic hormones like cortisol and adrenaline (epinephrine), and reduce the thyroid’s capacity to make thyroid hormone, making daily tasks such as focusing and remembering things more difficult. Underactive thyroid in athletes can reduce blood volume pumped by the heart, decrease fat consumption during muscle contraction, reduce insulin sensitivity, interfere with bone metabolism, and slow down muscle recovery [2]. Thyroid health becomes especially important after sustaining an injury; doctors recommend measuring thyroid levels before resuming activity. Monitoring thyroid hormone levels is critical in endurance athletes as most thyroid hormone levels increase right after an event and can take 1-4 days to return to normal afterwards.

Blood lipids are another important set of biomarkers tested in this profile. Blood lipids are useful in understanding cardiovascular disease risk and how it can be improved by fitness training and diet. Aerobic exercise has been shown to increase HDL cholesterol, the “good” cholesterol, and decrease triglyceride levels. Being able to set a baseline and see your blood lipid levels improve can be an effective strategy for starting and keeping a workout routine.

The final standard test of this profile and probably one of the most important, especially during the COVID-19 pandemic, is vitamin D. Vitamin D is important in immune regulation, protein synthesis, inflammatory response, cell growth, and skeletal muscle strength and function. Surprisingly, vitamin D deficiency is not uncommon in athletes due to the body’s utilization of vitamin D for muscle repair and recovery. Many studies have shown a link between hospitalization from COVID-19 and vitamin D levels [4]. While vitamin D can’t prevent you from getting COVID-19, it may help decrease symptomatology and hopefully prevent a hospital stay.

There are a few add-ons available to the fitness metrics kit that can round out the health picture. These include free T3, free T4 (thyroxine), and thyroid peroxidase antibodies (TPOab), completing the thyroid picture; insulin and hemoglobin A1c (HbA1c), giving insight into insulin resistance and predisposition to diabetes; C-reactive protein (hsCRP), an indicator of inflammation; and luteinizing hormone (LH). LH plays an important role in the production of estrogens and androgens by stimulating their production. LH steadily declines over time in athletes under an intense training regimen but can rebound quickly during periods of rest and recovery.

Elite Athlete Metrics

Surprisingly, vitamin D deficiency is not uncommon in athletes due to the body’s utilization of vitamin D for muscle repair and recovery.

The second new kit offered by ZRT is the Elite Athlete Metrics profile. This is very similar to the Fitness Metrics profile, but adds a 4-point saliva collection in addition to the DBS and offers a few extra goodies. The reason we chose to assess sex hormones and cortisol in saliva rather than blood for this profile is that it gives a better picture of the bioavailable hormones, those not tied up by SHBG and available to be utilized by the target cells. Another benefit of measuring hormones in saliva is that samples can be collected throughout the day non-invasively, so we can make sure that cortisol is following a normal circadian pattern. Looking at cortisol levels throughout the day in this manner allows for a better understanding of whether cortisol patterns are normal after vigorous physical activity to allow for optimal recovery to take place.

This profile also includes all the thyroid hormones together to give a full picture of how the thyroid system is performing. Thyroid levels will increase as a response to training increase and should recover to normal levels once this new training level is stabilized. Just remember that the more you push yourself, the harder your thyroid has to work, so it is important to understand the state of your thyroid health both before beginning a training regimen as well as once fully ensconced in one.

Similarly to the Fitness Metrics profile, this profile provides Vitamin D measurements, which are vital to overall health, especially with winter fast approaching, and allows for the add-on of the blood lipids (which are included as standard in the Fitness Metrics profile) as an option.

Which Profile do I choose?

Choosing the right kit and testing frequency can be tough. I will throw in my 2 cents here as to how I envision this information being used, but you may also consult with your training coach or physical therapist as well to see if they have any insight.

As an athlete that trains year-round, it may be difficult to find a time to establish a baseline. This is best done during a time of prolonged rest, preferably 2 weeks or more. As for myself, I have had very few periods of no activity in the last year that amounts to 2 weeks or more, but it is important to have this baseline established. It can help diagnose injuries before they occur as well allow you to get more out of your training in the future, so it is time well invested. For the baseline test, especially for seasoned athletes, I recommend the Elite Athlete profile. If you are a seasoned athlete you probably don’t need the add-on blood lipids, but if you are just beginning your journey or working to shed some weight, then I would recommend the add-ons. If you are new to training, the Fitness Metrics profile will also work well, but make sure to get all the add-ons. The add-ons will help you track your progress toward health and give you the ability to see progress you may not be seeing in the mirror.

If you are coming up on a competition, it could be helpful to get an idea of the state of your hormones to determine the amount of rest that may be needed to perform optimally at the competition.

As for frequency, I would recommend retesting every 3 months at a minimum. After having established a baseline, it is less imperative to get all the add-ons if you are an elite athlete. I would either recommend the basic Elite Athlete Metrics profile or the basic Fitness Metrics profile for these “maintenance” measurements. These are more to ensure everything is still in line and nothing is slowly getting out of whack. If you are a beginner looking more to increase your overall health and lose weight, I would recommend the Fitness Metrics, which includes the blood lipids. This will allow you to track your progress to help keep the motivation there. For any type of athlete, if there were areas of concern with the baseline test, I would recommend making sure those hormones are tested again at the next 3 month “maintenance” test. Once everything is in the healthy range, it is ok to only do the basic tests every 3 months. However, if you are injured or a feeling like you are hitting a wall and can’t seem to break through with your training, it may be good to get your testing done more frequently. This will enable you to see why exactly you are hitting a wall and hopefully help prevent any injuries. If you are injured, it would be good to do a “maintenance” test before resuming your activities to make sure you are back to baseline and may want to do the “maintenance” testing a little more frequently thereafter. Finally, if you are coming up on a competition, it could be helpful to get an idea of the state of your hormones to determine the amount of rest that may be needed to perform optimally at the competition. I would suggest testing yourself at least 2 weeks prior to competition so you have adequate time to rest and recover as needed before the competition.

So, whether you are a beginner or a seasoned athlete, hormone testing can be a useful tool to help you achieve your goals and continue to be the best you. Contact a customer service representative at ZRT today to find out how to get started tracking your hormones today!

Related Resources

References

How Your Hormones Affect Athletic Performance and Why You Need to Start Testing

Fri, 31 Jan 2020 15:43:47 -0800

Growing up, I never thought of myself as a runner, or really a good athlete in general. I played every sport possible as a kid, but I was never great and didn’t play high school sports. As an adult, I started playing team sports again and eventually was convinced to run a 5k. I ended up running the Warrior Dash and enjoyed it, so I continued doing 3.2-mile training runs. For the rest of my 20s I continued running 5k races with friends and played volleyball, softball, and some casual intramural sports, but was there more to my athletic prospects?

Going the Extra Mile

In 2015, my wife came up with the crazy idea of running the Chicago Triathlon. Running was fun and all, but the prospect of doing multiple sports in one race really appealed to me. We trained together, swimming in Lake Michigan and running and biking on the lakefront trail. In June of 2016 I completed my first sprint distance triathlon and I instantly wanted to do it again! However, as life happens, triathlons got put on hold. After our first child was born, my wife promptly set a goal to complete another triathlon before she was a year post-partum and did 2 sprint triathlons in 2018. My next goal was an Olympic distance triathlon, which I completed in 3:12:58. Two weeks later I did another Olympic tri and my worst nightmare came true as I got a flat tire on my bike 0.25 miles in. I managed to change the tire on the side of the road, but it set the tone for a rough day.

Since starting at ZRT I started tracking my hormones and studying how they change and affect my training and performance. Having another tool in my training toolbox has improved my performance by being able to optimize my workload and recovery balance. Never in my life did I think I would enjoy running, let alone be as much of an athlete as I am. I am currently training for a half-marathon between triathlon seasons and have used the data from my hormone tracking to get my times down to under 8 minutes per mile.

Laboratory Medicine and Athletics – Which Hormones are Involved?

It has been established that healthy athletes have adaptations to their hormonal conditioning.

Laboratory medicine in sport is an important preventative and protective science, fundamental for evaluating the condition of an athlete. The balance between workload and recovery is important for athletes to prevent injury while maintaining the highest level of competition. This balance can be monitored and optimized using laboratory medicine, particularly through the prevention of overtraining. It has been established that healthy athletes have adaptations to their hormonal conditioning [1].

Thyroid hormones regulate energy metabolism and can influence energy processes during physical exercise [2]. Thyroid hormones are also important regulators of cardiac function, protein synthesis, and calcium homeostasis. Hypothyroidism causes a decrease in athletic performance and capacity while hyperthyroidism can also cause a decrease in athletic performance through weight loss and tachycardia [2]. Analysis of thyroid hormone levels can help prevent issues and allow an athlete to reach optimal athletic performance.

Steroid hormones endogenously produced by the body are important in maintaining energy stores, building muscle, increasing oxygen capacity, decreasing fatigue and recovery time, and optimizing hand-eye coordination. The main hormone responsible for these effects is testosterone, the main sex hormone in males. Testosterone is found in both men and women. Progesterone, estradiol, and cortisol are also important hormones regarding athletic performance and must be balanced along with testosterone. Progesterone helps maintain proper activity of the thyroid, which can help increase energy availability and helps keep inflammation in check. Estradiol is the main sex hormone in women, but also important in men as well and is responsible for controlling inflammation, reducing muscle damage, and helping break down fat for fuel. Cortisol and aldosterone help in regulating metabolism, blood sugar, and water/salt balance. Excess cortisol can cause muscle breakdown and fatigue.

Now that you know about the hormones that affect you while exercising, how can you use this information to increase athletic performance? There are many ways to monitor these hormones that will give insight into whether you have the correct diet, are overtraining, or possibly have other health issues.

Hormones and Overtraining Syndrome

Overtraining syndrome (OTS) happens when the balance between training and recovery get out of sync. This is a result of the body not being able to return to homeostasis after physical exercise. Recovery is just a short way of saying the regenerative process of re-establishing homeostasis. If exercise continues before recovery completes, an accumulation of fatigue occurs. At early stages of OTS, often called overreaching, only fatigue and decreased performance present themselves, which can be overcome with a longer recovery period. If OTS continues, more long-term problems occur that change the physiology of the body and can take months to overcome [3]. Gonadal and adrenal steroids have been used as biomarkers of overtraining in athletes and can be used to assess whether an athlete is in early or late stage OTS [4].

Estradiol and testosterone levels and their ratio have shown to be diagnostic in OTS [5]. Testosterone is shown to have a slight increase at the start of exercise but declines thereafter [3]. Normally, testosterone levels rebound overnight with rest, but after severe exercise this rebound can be delayed [3,6]. However, in trained endurance athletes, basal levels of total testosterone and free androgens are decreased over time [7,8]. This decrease in testosterone can increase the susceptibility to OTS as well as decrease sperm quality [8]. This can be assessed by looking at sex hormone binding globulin (SHBG), which binds free steroids in the blood and keeps them bound and soluble allowing for transport through the blood vasculature. Increasing SHBG in response to the lowering levels of testosterone over time can be indicative of OTS [6]. Overtraining in female athletes can lead to low estrogen levels and menstrual disorders [4]. Dehydroepiandrosterone (DHEA) levels are associated with muscular enzyme activity and are associated with muscular traction during exercise [2]. Cortisol is increased during high-intensity exercises in many sports but rapidly decreases after exercise and is not suitable for monitoring for OTS.

Growth hormone (GH) levels are higher in athletes than in sedentary people, but with no increase in insulin-like growth factor I (IGF-1) [1]. Usually the liver secretes IGF-1 based on how much GH it receives, which is secreted from the pituitary gland. This is important because IGF-1 is the mediator of GH activity, stimulating systematic growth, whereas GH has very specific individual actions [9]. Increases in GH in athletes help by promoting more targeted growth in areas that are important for athletes. These effects include calcium retention, direct muscle mass growth, increased protein synthesis, enhanced gluconeogenesis for energy production, and increased conversion of T4 to T3, the active thyroid hormone [9].

A surprising find is that athletes have a prevalence of vitamin D insufficiency, despite the fact they can spend a lot of time outside training.

A surprising find is that athletes have a prevalence of vitamin D insufficiency, despite the fact they can spend a lot of time outside training [1,10]. This insufficiency is due to the expression of vitamin D receptors in muscles causing a decrease in circulating vitamin D due to high muscle activity [1,10]. In addition to its role in bone health, vitamin D is also important in immune regulation, protein synthesis, inflammatory response, cell growth, and skeletal muscle strength and function [11]. One of the main clinical indicators of vitamin D deficiency is muscle weakness and myopathy [11]. A few studies showed that vitamin D supplementation increased musculoskeletal performance especially with regard to vertical jump height, as well as hand strength, aerobic power and capacity, and sprinting ability [12]. Vitamin D also plays a big role in muscle regeneration following injury [12].

Catecholamines can also be effective in measuring the degree of OTS [8]. Catecholamines are neurotransmitters that include dopamine, norepinephrine (noradrenaline) and epinephrine (adrenaline). Dopamine is involved in reward and pleasure in the brain and as a vasodilator in the rest of the body. Norepinephrine is part of the sympathetic nervous system (fight-or-flight response) and is involved in alertness, focus, and readiness. Epinephrine is important in receptor-dependent vasoconstriction, which allows for greater cardiac output. The surge of adrenalin at the start of athletic activity increases alertness and boosts the heart rate allowing for more available oxygen for working muscles. Studies show that during recovery periods before competitions, norepinephrine levels typically are lower in well-trained athletes than in over-trained athletes [13]. Monitoring norepinephrine levels during training or when athletes feel as if they aren’t getting the most out of their workouts can help identify the early stages of OTS.

How Does Menstruation Affect Women Athletes?

Research is being conducted to optimize female training and performance while decreasing injury with regard to menstruation status.

Men and women vary in many ways when it comes to sports and exercise, but the biggest difference, which can have far reaching effects, is the cyclical change in hormones that occur in women throughout the menstrual cycle. Almost half of all women believe their menstrual cycle has a negative impact on their training and performance [14]. Research is being conducted to optimize female training and performance while decreasing injury with regard to menstruation status. Women use carbohydrates more efficiently in the follicular phase and are better at using fats and amino acids in the luteal phase [14]. While exercise is touted to have many beneficial effects, intense exercise can lead to problems if not monitored closely. Intense exercise has an effect on the hypothalamic-pituitary-gonadal axis as well as inducing a state of energy deficiency which can inhibit the release of gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH), both of which direct the body in how much hormone to make. Lactate levels in the blood are lower during physical activities in the luteal phase when progesterone is high, delaying the onset of fatigue [15,16].

Energy deficiency or availability (EA) is one of the pillars of the female athlete triad which explains the interrelationship between EA, menstrual function, and bone mineral density (BMD) and their clinical manifestation in eating disorders, osteoporosis, and amenorrhea [17]. These effects can be ameliorated by adjusting training protocols to be more in sync with the menstrual cycle, or through the use of oral hormonal contraceptives. The US Women’s National Soccer Team tracked their cycles and tailored their workouts to coincide with their menstruation status. Research suggests strength training is more advantageous during the first half of the cycle due to better recovery and adaptation of the body [14]. However, due to higher estrogen levels, the risk of injury can be higher during this time as well. Again, these effects are only present in intense exercise or sports that necessitate low weight. Moderate exercise is beneficial for both men and women.

Fluctuations in hormones can increase the risk of certain types of injuries during different phases of the menstrual cycle. One study found that anterior cruciate ligament (ACL) injuries are more common in the follicular and ovulatory phases [14,18]. This is unique to ligaments, specifically the ACL because the ACL has estrogen receptors, which inhibit synthesis of type I collagen synthesis [19]. Another study found that concussions were more likely and the symptoms more severe during late luteal/early menstruation when both estrogen and progesterone are at their lowest levels [20]. Estrogen and progesterone have both shown neuroprotective effects as well as modulating the inflammatory response to injury. Progesterone has a thermogenic effect, raising basal body temperature by around 0.5°C, which can lead to a thermoregulatory disadvantage for female athletes in extreme heat and humidity during the luteal phase [18].

The International Olympic committee (IOC) recommends periodic testing of serum ferritin and hemoglobin to assess iron status.

Iron deficiency is another issue that can plague female athletes, as well as men, and is one of the most common deficiencies in sports [21]. Female athletes are particularly at risk due to the loss of iron during menstrual bleeding. Athletes require more iron to build up their red blood cells due to the requirements of regular exercise. Athletes require higher aerobic output and one of the physiological adaptations to promote delivery of oxygen-rich blood to muscles is to increase blood volume or red cell mass along with increased cardiac size and function and enhanced off-loading of oxygen at the tissue level [21]. Iron is also an important factor in the electron transport chain which is one of the main producers of energy in the body [21]. Iron is essential for thyroid hormone synthesis (2). Iron is also important in brain development and cognition. Deficiencies can lead to impairment of concentration, motivation, and decision-making [21]. The International Olympic Committee (IOC) recommends periodic testing of serum ferritin and hemoglobin [21] to assess iron status.

Post-menopause athletes don’t have to worry about the cyclical nature of their hormones, but they do have to be aware of the lower levels of hormones. While exercise is very important for post-menopausal women to help control the issues that arise from lower hormone levels such as muscle loss and osteoporosis, it will be important to monitor hormone levels in case hormone replacement therapy (HRT) may be needed. Exercise has been shown to increase muscle mass, help prevent bone density loss, decrease risk of coronary heart disease, and may help reduce hot flashes [22].

Testing Your Hormones and Nutrients to Improve Your Performance

Now that you know how your hormones and nutritional status play into athletic performance, what can you do about getting tested? Most of the parameters I discussed can be tested in a clinical laboratory like ZRT. It is important to get a general health baseline of your hormonal and nutritional status before beginning an intense training regime. This will allow you to address areas of need before they have a chance to become a problem and throw you into OTS. ZRT has simplified hormone testing by allowing you to noninvasively collect various body fluids that can be used for hormone testing. Here is an outline of a basic testing option I recommend with some add-on options.

Start with the Comprehensive Female/Male Profile I. This panel tests saliva for the important parent hormones as well as dried blood spot (DBS) for thyroid hormones. I would add-on vitamin D in DBS. I like looking at saliva for the steroid hormones because saliva gives you a better picture of what the cells are seeing rather than what is just being circulated, bound and unbound, throughout the body.

I would recommend getting a baseline test before beginning a training regimen, but if you have already begun training, it would be best to test during one of the recovery periods to get values as close to baseline as possible. I would consider retesting periodically throughout your training program or anytime you feel like you are “hitting the wall” to help understand why this is happening to allow for changes in training to prevent it in the future.

Related Resources

References

[1] Luger A, et al. Acute Hypothalamic-Pituitary-Adrenal responses to the stress of treadmill exercise. N Engl J Med. 1987;316:1309-1315.

[2] Lombardo B, et al. Laboratory medicine: health evaluation in elite athletes. Clin Chem Lab Med. 2019;March 5:ePub.

[3] Kuipers H, and Keizer HA. Overtraining in elite athletes. Sport Med. 1988;6:79-92.

[4] Cadegiani FA, et al. Basal hormones and biochemical markers as predictors of overtraining syndrome in male athletes: the EROS-BASAL study. J Athl Train. 2019;54:ePub.

[5] Cadegiani FA. Et al. Novel insights of overtraining syndrome discovered from the EROS study. BMJ Open SP Ex Med. 2019;5:1-11.

[6] Urhausen A, et al. Blood hormones as markers of training stress and overtraining. Sport Med. 1995;20:251-276.

[7] Maimoun L, et al. Testosterone is significantly reduced in endurance athletes without impact on bone mineral density. Horm Res. 2003;59:285-292.

[8] Lucía A, et al. Reproductive function in male endurance athletes: sperm analysis and hormonal profile. J appl physiol. 1996;81:2627-2636.

[9] Holt RIG, et al. The use and abuse of growth hormone in sports. Endo Review. 2019;40:1163-1185.

[10] Lanteri P, et al. Vitamin D in exercise: physiologic and analytical concerns. Clin Chim Acta. 2013;415:45-53.

[11] Alimoradi K, et al. Efficacy of vitamin D supplementation in physical performance of Iranian elite athletes. Int j prev med. 2019;10:100

[12] Wiciński M, et al. Impact of vitamin D on physical efficiency and exercise performance – A review. Nutrients. 2019;11:2826.

[13] Hooper SL, et al. Hormonal responses of elite swimmers to overtraining. Med Sci in Sport and Excise. 1993;25:714-747.

[14] Oleka CT. Use of the menstrual cycle to enhance female sports performance and decrease sports-related injury. J Ped Adol Gyn. 2019; pii:S1083-3188(19)30319-5.

[15] Lagowska K, et al. Testosterone concentrations in female athletes and ballet dancers with menstrual disorders. Euro j sport sci. 2016;16:490-497.

[16] Orio F, et al. Effects of physical exercise on the female reproductive system. Minerva Endo. 2013;38:305-319.

[17] Weiss Kelly AK, et al. The female athlete triad. Pediatrics. 2016;137:e20160922.

[18] Constantini NW, et al. The menstrual cycle and sport performance. Clin sports med. 2005;24:e51-e82.

[19] Balachandar V, et al. Effects of the menstrual cycle on lower-limb biomechanics, neuromuscular control, and anterior cruciate ligament injury risk: a systematic review. Muscles ligaments tendons J. 2017;7(1):136-146.

[20] La Fountaine MF, et al. Preliminary evidence for a window of increased vulnerability to sustain a concussion in females: A brief report. Front neurol. 2019;10:691.

[21] Pedlar CR, et al. Iron balance and iron supplementation for female athlete: A practical approach. Euro j sport sci. 2018;18:295-305.

[22] Shangold MM, et al. Exercise and menopause. Physician sport med. 1998;26(12):45-52.

The Effects of Cannabis - Part 2: Cannabidiol

Thu, 22 Aug 2019 14:31:28 -0700

In my previous blog, I discussed how the psychoactive component of marijuana (cannabis), mainly tetrahydrocannabinol (THC), can have a negative impact on your hormones. In this blog, I will delve into the world of cannabidiol (CBD), which has been making quite a buzz lately as a therapeutic panacea.

Although they are derived from the same plant and have quite similar molecular structures, CBD is very different than THC from a clinical perspective, primarily because CBD doesn’t elicit the “high”. Despite its lack of psychoactive effects, CBD has potent anti-inflammatory and anti-seizure properties and an array of other benefits for the body that I will discuss below.

Biochemical Differences Between CBD and THC

CBD is closely related to THC, but with its own unique biochemistry. Although derived from the same plant, CBD is quite different from THC in its actions in the body, mostly the brain. For example, CBD has a lower affinity for the CB1 cannabinoid receptors that bind and are activated by THC. CBD is most closely associated with cannabinoid receptor CB2. CB2 receptors are found primarily in the immune system and blood cells, hence explaining CBD’s ability to help with the inflammatory response [1]. This difference in location between CB1 and CB2 receptors is one of the reasons why CBD doesn’t have the psychotropic effect of THC, or “high”. The other reason is that it acts differently, as an inverse agonist [2]. An agonist is a molecule that activates a receptor, providing the expected effect. An inverse agonist activates the receptor, but creates the inverse, or opposite of the effect expected. This inverse effect allows CBD to counter the effects of THC and other endocannabinoids in the brain and elsewhere in the body.

Another possible mechanism for CBD’s beneficial actions is its indirect effect on the endocannabinoid (cannabinoid-like molecules made naturally within the body) system whereby it blocks anandamide reuptake, which inhibits its enzymatic degradation, allowing it to be retained longer in circulation. Anandamide is the most abundant natural endocannabinoid produced by the body.

First Modern Uses of CBD

CBD really broke onto the scene in 2006 in association with its use in treatment of refractory epilepsy. “Patient zero” is a girl from Colorado named Charlotte who suffers from a rare, lifelong form of epilepsy called Dravet syndrome. Charlotte’s story, propelled to the level of national prominence, featured a wheelchair-bound 5-year-old girl with a feeding tube, whose seizures almost entirely disappeared after her mom gave her CBD extract.

Since then, cannabinoids have been made into multiple FDA-approved drug products. These include Epidiolex, a CBD prescription drug to treat epileptic seizures; Marinol and Cesamet, two synthetic THC medications used to combat the side effects of chemotherapy and wasting disease; and a pain medication using a 1:1 ratio of CBD to THC called Sativex. These drugs are just the tip of the iceberg of what cannabis, and more specifically, CBD, can be used to treat.

CBD works to reduce inflammation by decreasing adenosine uptake by immune cells.

Current Medicinal Applications

Pain: One of the most common uses of CBD currently is for treatment of pain. This is generally achieved by the reduction of inflammation. CBD works to reduce inflammation by decreasing adenosine uptake by immune cells, thus down regulating their ability to trigger inflammation through the release of inflammatory cytokines [3]. CBD has also been found experimentally to reduce transcription levels of receptors found in the inflammation pathway in the brain [3].

Bone Loss: CBD may also help reduce bone loss and osteoporosis resulting from loss of estrogens at menopause and with aging. CBD acts on bone by stimulating CB2 expression in osteoblasts and osteoclasts, which can inhibit bone resorption and stimulate bone formation [4,5].

Cancer Treatment: CBD has also been shown to be beneficial in the treatment of certain cancers. These effects are seen through the increase of reactive oxygen species (ROS) in some cancer cell lines [6,7,8]. ROS are extremely reactive and can cause significant damage to healthy tissues and cells within the body if not scavenged almost immediately by antioxidants before they have a chance to do said damage. CBD appears to selectively increase ROS in cancer cells more than normal cells, leading to their death. The mechanism by which this occurs is still unknown. The other important function of CBD in the treatment of cancer is its ability to inhibit breast cancer resistance protein (BCRP) in the cell membranes of cancer cells [9]. BCRP is an efflux pump that is responsible for flushing xenobiotics, compounds not found endogenously in the body, out of cells. Cancer cells, especially those being treated with chemotherapy, upregulate the production of BCRPs, causing the cells to become resistant to chemotherapy, thus rendering the chemotherapy ineffective. By inhibiting BCRP, CBD can therefore enhance the effects of chemotherapeutic agents on cancer cells.

Epilepsy: I wouldn’t be doing CBD justice if I didn’t talk about how it is an effective treatment for some forms of epilepsy [10]. Seizure activity in the hippocampus leads to increased levels of CB1 receptors. In one study blocking CB1 receptors caused an increase in frequency and duration of seizures in rats but did not cause seizures in control rats not prone to seizures [10]. This suggests that CB1 activation is a response to seizures rather than a cause. Studies also show that endocannabinoid levels peak 20 minutes after a seizure, suggesting cannabinoids are important in the protection against seizure activity [10]. The enhancement of the endocannabinoid system by CBD can have beneficial effects in certain types of seizures.

Effects on the Immune System – Both Good and Bad

The biggest effect CBD has in the body lies within the immune system. Immune cells have the highest concentration of CB2 receptors, allowing CBD to play a role in inflammation as mentioned above. Briefly, the immune system involves two types of immunity, cellular and humoral. Cellular immunity guards against infected cells from bacteria, fungus, and viruses and foreign tissue. This is how the body attacks cancer and rejects transplants. Humoral immunity is the body’s antibody response to infection. Antibodies are produced by B cells. Leukocytes (white blood cells) are also part of the humoral immune system and produce interleukins as a response.

CBD inhibits various immune response factors in both B-cells and T-cells [2,11]. This can have beneficial but also negative effects. For example, the actions of CBD on B-cells can increase a person’s risk of HIV-1 and other infectious disease organisms. This inhibitory effect is cell line specific though, as CBD increases some factors in eosinophils, which play a key role in allergic inflammatory responses [11]. This means that CBD can make the symptoms of some allergic responses worse. In lymphocytes and monocytes, CBD is shown to inhibit the release different inflammatory cytokines, which is the mode of action that allows CBD to have an anti-inflammatory effect [11].

CBD is being looked at as a possible treatment for depression and anxiety through its effects on the CB1 receptors in the brain.

Possibilities for the Future: Mood Disorders and Alzheimer’s

CBD is being looked at as a possible treatment for depression and anxiety through its effects on the CB1 receptors in the brain. Studies show that CBD acts through the modulation of the serotonin 5-HT_1A receptors to work as a fast-acting antidepressant and anxiolytic (anti-anxiety) [12]. A reduced number/affinity of 5-HT_1A receptors has been found in the brains of depressed individuals [13]. This is highly significant because these receptors help facilitate the release of brain-derived neurotrophic factor (BDNF) and are responsible for some of the neuroprotective abilities of the 5-HT receptors [13]. BDNF is present in nearly all brain regions as well as the peripheral nervous system and is important in regulation of developmental processes, neuroprotection, synaptogenesis, and mechanisms of memory and cognition [14]. With low numbers of serotonin receptors in the brain BDNF levels are also likely to be low, thus partially stripping the brain from its nourishing protector. Not surprisingly, low serum BDNF levels are a biomarker for depression [15]. An increase in BDNF is seen with antidepressant behavior modification and is found in response to CBD and the common antidepressant drug, imipramine. High stress situations can also negatively impact BDNF levels. The increase in BDNF after CBD administration is rapid and is not sustained long term [16]. However, long-term, frequent administration of CBD will continue to keep BDNF levels elevated above the baseline [16].

Closely related to serotonin, the sex steroid estrogen also stimulates serotonin as well as BDNF production. Estrogen up-regulates serotonin receptors and enzymes responsible for serotonin synthesis, thereby increasing levels [17]. Fluctuating levels of estrogens that occur with transitions to puberty, throughout menstrual cycles during the fertile years, and then into perimenopause and finally menopause, can play a major role in a woman’s overall feeling of happiness during her life-cycles.

CBD has also been shown to rapidly increase dendritic spines in the brain which is also indicative of its antidepressant activity [16]. Several studies in rats showed that low doses of CBD had anxiolytic (calming) effects, whereas higher doses did not have the same effect [15]. CBD is being shown as a promising treatment/preventative treatment for Alzheimer’s disease. In Alzheimer’s disease there is an accumulation of β-amyloid plaques. However, it is unknown whether these plaques are the cause or a symptom of Alzheimer’s disease. Decreased levels of BDNF has also been shown in Alzheimer’s patients [18]. CBD has been shown to prevent cell death caused by these β-amyloid plaques and to facilitate hippocampal neurogenesis [19].

Side Effects of CBD

Like most natural products, CBD influences your cytochrome P450 (CYP) family of enzymes responsible for the body’s ability to metabolize both natural endogenous and exogenous molecules to prepare them for excretion. Natural products, foods, and pharmaceutical drugs can up- or down-regulate the activities of the CYP enzymes. Generally, these effects don’t have major impacts on the body. However, when taking pharmaceutical drugs or natural products to treat ailments or diseases, the ability of these enzymes to affect the clearance of these products can be detrimental to your health. A classic example is grapefruit juice. A small glass of grapefruit juice can inhibit some of the CYP enzymes that are important in metabolizing prescription medications. This reduces the clearance of these medications and can lead to an unhealthy accumulation of these drugs. Because of this, it is extremely important to tell your doctor if you are taking CBD so they can adjust the doses of your medications as necessary to ensure they are working as effectively as possible and that no negative side effects occur.

The other side effect of CBD use affects the fetus. As mentioned earlier, CBD inhibits BCRP efflux pumps in cancer cells, but BCRP are also very important in the placenta and are responsible for protecting the fetus from toxins that could be passed from the mother. Endocannabinoids have also shown to have a regulatory role in the placenta by removing damaged cells through apoptosis, and thus CB1 and CB2 receptors are found in the placenta throughout the first 10 weeks of gestation [20]. There is also a high concentration of fatty acid amide hydrolase (FAAH) which is responsible for the metabolism of endocannabinoids and is important in maintaining a very stable concentration in the placenta. When concentrations get too high, cell growth is reduced and cell numbers are too low, which can lead to increased risk of 1^st trimester pregnancy loss [21].

The Need for Further Research

Ongoing research suggests CBD has many therapeutic uses, from epilepsy to providing neuroprotective benefits in the brain. CBD has been less studied than THC so there is a lot of research that has not been done yet. While preliminary work looks promising, as CBD starts gaining more attention and undergoing safety trials regulated by the FDA, the picture of our interactions with CBD will become clearer.

If you are interested in using CBD here are some pointers to help in the process. First, you should always consult with your doctor before trying new treatments, especially if you are on other medications. Second, make sure you are getting your CBD from a trusted source. CBD is not treated as a dietary supplement (yet) and is not regulated as such, meaning there are very few controls in place for the manufacture of CBD products. As such, you want to make sure the manufacturer is doing things the right way. Things to look for are GMP certification, clear labeling of potency and purity, and published quality documents. A lot of quality CBD manufacturers will post their quality documents online showing that the CBD oil extracted from the hemp is free of microbial, heavy metal, pesticide, and residual solvent contamination. Third, make sure to start at a low dosage and slowly increase over time to find the correct dosage for you. Since CBD amounts vary (even from what is on the label, see second point), it is important to find the most appropriate dosage. The amount your friend takes for their symptoms might not be enough for you, or it may be too much. Finally, finding a “full-spectrum” product will be more beneficial as it contains all the other cannabinoids and terpenes found in the plant, not just the isolated compound. I am a firm believer that all compounds in a plant are there working in conjunction with each other and will result in a better treatment than just cherry-picking the compounds that have been studied and determined to be active.

Related Resources

References

[1] Pagotto U, et al. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocrine Reviews. 2006;27(1):73-100.

[2] Bergamaschi MM, et al. Safety and side effects of cannabidiol, a cannabis sativa Curr Drug Safety. 2011;6(4)237-249.

[3] Burstein S. Cannabidiol (CBD) and its analogs: a review of their effects on inflammation. Bioorganic Med Chem. 2015;23:1377-1385.

[4] Bab I, et al. Cannabinoids and the skeleton: From marijuana to reversal of bone loss. Annals of Med. 2009;41:560-567.

[5] Kogan NM, et al. Cannabidiol, a major non-psychotropic cannabis constituent enhances fracture healing and stimulates lysyl hydroxylase activity in osteoblasts. J Bone Miner Res. 2015;30(10):1905-1913.

[6] Iffland K et al. An update on the safety and side effects of cannabidiol: A review of clinical data and relevant animal studies. Cannabis and cannabidiol research. 2017;2(1):139-154.

[7] McAllister SD, et al. The antitumor activity of plant-derived non-psychoactive cannabinoids. J Neuroimmune Pharmacol. 2015;10(2):255-267.

[8] Singer E, et al. Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma. Cell Death Dis. 2015;6(1):e1601.

[9] Nakanishi T, et al. Breast cancer resistance protein (BCRP/ABCG2): its tole in multidrug resistance and regulation of its gene expression. Chin J Cancer. 2012;31(2):73-99.

[10] Wallace MJ, et al. Cannabinoids: Defending the epileptic brain. J Pharmacol Exp Ther. 2003;307:129-137.

[11] Srivastava MD, et al. Δ⁹ Tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology. 1998;40:179-185.

[12] Linge R, et al. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT_1a Neuropharmacology. 2016;103:16-26.

[13] Zanelati TV, et al. Antidepressant-like effects of cannabidiol in mice: Possible involvement of 5-HT_1A Brit J Pharmacology. 2010; 159:122-128.

[14] Kowianski P, et al. BDNF: A key factor with multipotent impact on brain signaling and synaptic plasticity. Cell Mol Neurobiol. 2018;38:579-593.

[15] de Mello Schier AR, et al. Antidepressant-like and anxiolytic-like effects of cannabidiol: A chemical compound of Cannabis sativa. CNS & Neuro Disorder – Drug Targets. 2014;13:953-960.

[16] Sales AJ, et al. Cannabidiol induces rapid and sustained antidepressant-like effects through increased BDNF signaling and synaptogenesis in the prefrontal cortex. Mol Neurobiol. 2019;56(2):1070-1081.

[17] Carbone DL and Handa RJ. Sex and stress hormone influences on the expression and activity of brain-derived neurotrophic factor. Neurosci. 2013;239:295-303.

[18] Budni J, et al. The involvement of BDNF, NGF, and GDNF in aging and Alzheimer’s disease. Aging Dis. 2015;6(5):331-341.

[19] Campos AC, et al. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res. 2016;112:119-127.

[20] Feinshtein V, et al. Cannabidiol enhances xenobiotic permeability through the human placental barrier by direct inhibition of breast cancer resistance protein: an ex vivo study. AM J Obstet Gynecol. 2013;209(6):573.e1-573.e15.

[21] Habayeb OMH, et al. Expression of the endocannabinoid system in human first trimester placenta and its role in trophoblast proliferation. Endocrinology. 2008;149(10):5052-5060.

The Effects of Cannabis on Your Hormones

Thu, 20 Jun 2019 15:52:45 -0700

While cannabis is being legalized in more and more states, both the adverse and beneficial effects of its use are starting to be better understood. The active compound in cannabis, THC (tetrahydrocannabinol) is widely known to have effects on the brain, producing the “high” that many users are seeking. However, the other more adverse effects cannabis can have on the body are less widely known. In this blog, I want to focus mainly on how cannabis can affect your hormones, primarily through the pituitary, thyroid, and adrenal glands, and the reproductive system.

The Endocannabinoid System (ECS) and How It Works

Endocannabinoids are molecules naturally produced in the body in small amounts that act on cannabinoid receptors and play important roles in various processes. There are 2 types of cannabinoid receptors in the body, CB1 and CB2, and a few orphan receptors that also bind with the endocannabinoids. These are the same receptors that THC binds and activates (and CBD, which I won’t cover here). The ECS is involved in regulating fertility, pregnancy, appetite, pain-sensation, mood, memory, energy balance, homeostasis, and the immune system. The ECS is also responsible for “runner’s high” through spikes in endocannabinoids circulating in the blood to the brain, where it is involved in locomotor activity through interactions with the cerebellum and affects the reward center of the brain through transduction of dopamine release.

Cannabis’s Effects on the Hypothalamus-Pituitary-Adrenal (HPA) Axis

The HPA axis controls the stress response ultimately through the release of cortisol. When different regions of the brain sense a stressor (whether emotional, chemical, physical, or pathogenic), neural signals are sent to the hypothalamus which triggers the release of corticotropin-releasing factor (CRF) and vasopressin (VP) which couple to stimulate the pituitary to manufacture and release adrenocorticotropic hormone (ACTH) into the bloodstream. When ACTH reaches the adrenal glands it binds to receptors in specific regions of the gland to stimulate the release of cortisol into the bloodstream. When the stressor is removed (e.g., low blood glucose returns to normal, emotional stress is resolved, and physical exercise, chemical, or pathogenic stressors are reduced), cortisol negatively feeds back to the hypothalamus and pituitary to shut down further stimulation of CRF and ACTH.

Acute high cortisol is essential for optimal health, since cortisol helps control blood sugar levels, regulates metabolism, reduces inflammation, controls salt and water balance which influences blood pressure, and assists with memory formation. However, persistent high cortisol caused by excessive stressors will eventually have a negative impact on health. Prolonged release of high levels of cortisol reduces the sensitivity of the negative feedback loop that controls cortisol levels and reduces its effectiveness [1].

It has been shown that THC increases circulating cortisol levels after use [2][3]. For infrequent cannabis users, this increase in cortisol can cause increases in blood pressure and anxiety [4]. In long-term users, sustained increase of cortisol blunts the body’s natural reactions to changes in cortisol and can affect a woman’s libido and menstrual cycle [3][4]. Long-term use also has the potential to blunt the morning spike of cortisol, referred to as the Cortisol Awakening Response (CAR). Upon waking, cortisol levels spike, slowly declining throughout the day. This spike of cortisol is important in facilitating the body to wake up. If this spike is blunted, it becomes difficult to shake off sleep and function normally.

Cannabis’s Effects on the Hypothalamus-Pituitary-Thyroid (HPT) Axis

The HPT axis is responsible for maintaining metabolic rate, heart and digestive functions, muscle control, brain development, and bone health. Briefly, the hypothalamus releases thyrotropin-releasing hormone (TRH) which then binds with the pituitary gland, stimulating the release of thyroid-stimulating hormone (TSH). TSH then stimulates the release of thyroxine (T4) and triiodothyronine (T3) from the thyroid. T4 exerts a negative feedback with the hypothalamus to regulate how much is circulating in the bloodstream.

THC inhibits secretion of TSH from the pituitary gland mostly through regulation of TRH release in the hypothalamus [5][6]. This effect is dose-dependent, meaning the more you consume, the more it depresses the TSH levels [5][6]. This decrease in TSH levels causes a decrease in synthesis of T4 and T3 in the thyroid gland and consequent lower circulating T4 and T3 levels [5][6]. Low circulating T4 and TSH levels can lead to symptoms of pituitary hypothyroidism including fatigue, weight gain, cold intolerance, depression, decreased libido, and abnormal menstrual cycles.

Cannabis’s Effects on the Hypothalamus-Pituitary-Gonadal (HPG) Axis

The HPG axis oversees the body’s functions related to reproductive health and regulates our hormones to maintain optimal function and health of all tissues throughout the body (brain, connective tissue, cardiovascular, reproductive organs, immune system, etc.). Briefly, the hypothalamus secretes gonadotrophin-releasing hormone (GnRH) which stimulates the pituitary to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

FSH and LH are important in regulating gonadal function in both sexes. In women, FSH and LH are important for pubertal development and ovarian function and play an important role during the menstrual cycle. In men, FSH is essential to the function of the testes and their production of sperm (spermatogenesis) and LH stimulates the production of testosterone. Cannabis use directly impacts many parts of the HPG axis. THC indirectly decreases the secretion of GnRH by the hypothalamus through regulation of the neurotransmitters glutamate and gamma-aminobutyric acid (GABA) [7][8], and through the transduction of dopamine, which is shown to decrease GnRH signaling [9]. In women, THC inhibits folliculogenesis, the maturation of the ovarian follicle, and ovulation, through the regulation of cellular energy produced in the mitochondria, cAMP [7]. During ovulation, the body releases a surge of endocannabinoids in the ovary; excess cannabinoids from cannabis consumption can disrupt the ovulatory surge and lead to an irregular cycle [7][8]. THC also inhibits steroidogenesis by preventing the conversion of pregnenolone to progesterone [7]. In men, THC has been shown to decrease sperm count, reduce serum testosterone and LH levels, reduce sperm motility, and inhibit the processes needed to facilitate sperms’ ability to achieve conception [7][10][11]. These effects can lead to a decrease in fertility in both men and women, but fertility can return with cessation of use.

In summary, chronic cannabis consumption can have effects on the adrenal, thyroid, and reproductive systems that can potentially affect energy, behavior, and reproductive health. Fortunately, after stopping long-term, chronic use, the body can restore normal function, hopefully mitigating these effects. THC also has an impact on the developing fetus so stopping cannabis use while trying to conceive will help both you and your developing child [12].

In this blog, I only addressed the THC component of cannabis. In a future blog, I will address cannabidiol (CBD), the other major cannabinoid without the psychotrophic effects of THC, that is showing great promise as a medicine.

If you are a habitual cannabis user and your energy level and sex-drive are lackluster, it may be wise to periodically test your levels of adrenal hormones (cortisol, DHEA-S), sex hormones (estradiol, progesterone, and testosterone), and thyroid hormones (T4, T3, TSH, TPOab) to make sure THC isn’t blunting your edge. Simple and convenient saliva and blood spot tests can help determine if cannabis use is impacting your overall health.

Related Resources

References

[1] Hill MN, et al. Endogenous cannabinoid signaling is essential for stress adaptation. Proc Natl Acad Sci USA. 2010;107:9406-11.

[2] Hilliard CJ, et al. Endocannabinoid signaling and the hypothalamic-pituitary-adrenal axis. Compr Physiol. 2018;7: 1-15.

[3] Ranganathan M, et al. The effects of cannabinoids on serum cortisol and prolactin in humans. Psychopharmacology. 2009;203:737-44.

[4] Cservenka A, et al. Cannabis use and hypothalamic-pituitary-adrenal axis functioning in humans. Front. Psychiatry 2018;9:472.

[5] Malhotra S, et al. Effect of cannabis use on thyroid function and autoimmunity. Thyroid. 2017;27:167-73.

[6] Hillard CJ, et al. The effects of Δ⁹-Tetrahydrocannabinol on serum thyrotropin levels in the rat. 1984;20:547-50.

[7] Walker OS, et al. The role of the endocannabinoid system in female reproductive tissue. J Ovarian Res. 2019;12:3.

[8] Brown TT, Dobs AS. Endocrine effects of marijuana. J Clin Pharmacol. 2002;42:90S-96S.

[9] Liu X, Herbison AE. Dopamine regulation of gonadotropin-releasing hormone excitability in male and female mice. 20113;154O:340-50.

[10] Kolodny RC, et al. Depression of plasma testosterone levels after chronic intensive marihuana use. N Engl J Med. 1974;290:872-4.

[11] Gundersen TD, et al. Association between use of cannabis and male reproductive hormones and semen quality: a study among 1215 healthy young men. Am J Epidemiol. 2015;182:473-81.

[12] Velez ML, et al. Cannabis use disorders during perinatal period. In: cannabis use disorders. 2018:177-188.