The month of June is a time in which fathers are celebrated, so it is fitting that June is also the time in which we honor men’s health.
A health issue on the forefront of male health is the depletion of testosterone. The litany of symptoms that are associated with low testosterone can be what makes a man feel like less of the man he once was. There are multiple life threatening consequences of low levels of testosterone in combination with other hormonal imbalances and unfortunately, many are unaware of the serious associated health risks.
The primal instinct to not show signs of weakness is oftentimes what causes men to minimize symptoms and can be what prevents them from seeking medical attention. The early recognition of signs and symptoms and appropriate actions can prevent serious health consequences in older age.
TESTOSTERONE FUNCTION & IMBALANCE
- Functions of Testosterone²⁻⁴
muscle mass development, bone growth, body and facial hair growth, deepening of the voice, penis and testicle growth, sperm production, sex drive², red blood cell formation³, increased HDL performance⁴
- Symptoms of Low Testosterone¹
low sex drive, erectile dysfunction, gynecomastia (male breasts), decreased body hair, fatigue, loss of muscle strength/mass, increased body fat, infertility, depressed mood, irritability, poor concentration/memory, decreased sense of well-being, decreased hemoglobin/mild anemia, osteoporosis
- Causes of Low Testosterone¹
aging, excess estrogen (via enhanced aromatase activity), obesity, metabolic disorders, decreased blood supply to the testes by injury or infection, chemotherapy/radiation, pituitary gland dysfunction, medications (i.e. opioids, steroids, prostate cancer hormones, statins²⁴), alcohol abuse, liver/kidney disease, HIV/AIDS, genetic predisposition, congenital defects, sleep apnea, anabolic steroid use
Cholesterol begins the process of testosterone production. Cholesterol is converted to pregnenolone which can then be made into either DHEA or progesterone in separate pathways to become testosterone.
The current medical approach to treating low testosterone is to prescribe testosterone, but there may be other approaches that can prevent the downstream effects that result in low testosterone that may lead to further serious health complications.
The Delicate Balance Between Hormones
The intertwining of androgen/hormone producing pathways makes it easy for unchecked imbalances to occur and can be tricky for some doctors to find where the downstream effects stem from. This exquisite balance is necessary for one to express optimal health given that hormones affect every aspect of human physiology.
Pregnenolone (Cortisol) Steal
In states of stress, the body will shunt pregnenolone down the pathway to become cortisol. This is a natural process that should occur in acute situations. The theory of cortisol steal states that when chronic stress persists, resources are continuously pulled into the cortisol production pathway and away from the pathways that produce testosterone, estrogen and aldosterone. In this situation, commonly ordered hormone lab values may show low levels of progesterone, DHEA-S, Estrogens and/or Testosterone. Some theorize that stress may reduce the production of DHEA rather than the idea that elevated cortisol “steals” pregnenolone.⁵
A 24-hour cortisol test will be able to evaluate cortisol production throughout the day, which is far more informative than a one time cortisol test taken at a random time.
The natural levels of cortisol should show an elevation just before rising with a peak early morning and a decline throughout the day. Any shift from this normal flux of cortisol can have detrimental effects on not only hormone production but also immune function, blood sugar regulation and much more. It is imperative to address all sources of stress, both mental and physical, when trying to balance hormone levels.
Enhanced Aromatase Activity: Testosterone to Estrogen Conversion
Androgens can be converted into estrogens (testosterone into estradiol) by the enzyme aromatase. This process known as aromatization functions to maintain the balance between hormones. Naturally, as testosterone production declines in older men, aromatase activity increases, enhancing the conversion of testosterone to estrogen, causing further decline of testosterone levels. Another significant cause of increased aromatase activity is adipose tissue, most notably, abdominal fat. Poor nutrition, weight gain, stress and lack of exercise are also contributors to aromatase activity enhancement. Elevation of estradiol in combination with low testosterone in males can increase the risk of significant health crises such as stroke⁶, cardiovascular events⁷, colon cancer, prostate cancer and male breast cancer. ⁸ ⁹ ¹º
Oftentimes in conventional medicine, testosterone is prescribed to men with low levels without checking estrogens. Men given testosterone replacement may run the risk of converting testosterone to estradiol with elevated aromatase activity which can place them at higher risk for the aforementioned conditions.
Excess levels of estrogens are a more common occurrence in males, but low estrogens also pose a risk to men’s health. The way in which men synthesize estrogen is through the aromatase enzyme, mostly occurring in adipose tissue. Some men may lack the aromatase enzyme whereas others may have inadequate levels of testosterone to convert to estrogen. Low levels have shown to increase the likelihood of developing osteoporosis and associated bone fractures.¹¹ ¹²
A study published in JAMA found that men with chronic heart failure whose estradiol levels fell outside of the range of 21.80-30.11 pg/mL showed increased rates of mortality. Those in the highest and the lowest quintile of estradiol levels were significantly more at risk.¹³ Perhaps checking estrogen levels in male cardiovascular patients is a huge missing piece in the current mainstream approach to assessing cardiovascular disease risk.
FACTORS IN HORMONE REGULATION
The Testosterone and Cholesterol Connection
High Density Lipoprotein (HDL), the “good” cholesterol, is the only lipoprotein that scavenges cholesterol in the blood vessels and tissues and returns it to the liver for processing and removal. Testosterone increases the activity of hepatic lipase, an enzyme that cleaves HDL derived cholesterol and also increases B1 receptor sites in the liver that uptake cholesterol for processing and removal.¹⁴ ¹⁵ The relationship between testosterone and HDL is one that should be further considered by practitioners for the prevention and removal of arterial plaques and for overall cardiovascular health in men.
How Does Vitamin D Play a Role?
Vitamin D receptors as well as Vitamin D metabolizing enzymes are found throughout the male reproductive system, which includes the Leydig cells that produce testosterone. Because of this, it has been theorized that vitamin D may play a role in the production of hormones and thus studies have been performed to assess the effects of vitamin D supplementation on androgen levels. A provocative study¹⁶ published in 2012 found that 2,069 males who were referred for coronary angiography with low free testosterone or vitamin D had a 60% increased risk of mortality due to non-cardiovascular related causes. If there was a deficiency in both Free T and vitamin D, the risk of death due to a cardiovascular event was 77%. Even worse, those with low levels of both markers had a 133% increased risk in non-cardiovascular related mortality.
Interestingly enough, recent studies have hypothesized that vitamin D supplementation may have positive effects on the production of androgens (testosterone), but current testing models show no apparent connection between the two resulting in unchanged levels of androgens between the two groups of participants.¹⁷ Given that the anatomy/physiology of the male reproductive system is flooded with vitamin D receptors and enzymes, there must be a role that vitamin D plays in hormone production that goes beyond our current understanding or testing methodology. The ubiquitous nature of vitamin D in human health would warrant obtaining optimal levels regardless of the condition(s) being assessed and treated.
Magnesium and Testosterone¹⁹
Often with aging comes muscle wasting/decline of muscle mass which can be linked to not only low testosterone but also low levels of magnesium. Studies have shown a positive response in muscle mass and activity as well as testosterone levels when supplementing with magnesium along with exercise. Animal models have shown a clear improvement in measured physiologic, cytologic, morphologic parameters and cellular architecture of the testes following magnesium supplementation.
The decline in testosterone related to aging, reduced physical activity, poor nutrition and inflammation should be addressed with a focus on magnesium status. Inflammatory cytokines reduce LH production in the pituitary which leads to less output of testosterone and sensitivity to LH secretion. Magnesium helps to control oxidative stress and maintain antioxidant capacity, both significant contributors to inflammation. Dosage of 420mg/day of magnesium is adequate for healthy men. Some studies have seen more improvement when administering 500mg/day.
Mitochondria and Sex Hormones²⁰
The mitochondrial membrane is involved in the first, rate limiting step in sex hormone production. Cholesterol passes through the membrane and is converted to pregnenolone which is then transferred out of the mitochondria to be converted into differing sex hormones. The need for a healthy mitochondrial membrane is relevant in the downstream manufacture of adequate testosterone levels. Animal studies have looked at the presence of increased ROS within mitochondria of Leydig cells in older rats compared to younger subjects and in these studies, the elevation of ROS inhibited the production of testosterone.
Inversely, studies have shown the positive impact of sex hormones on the health of mitochondria. Although testosterone and progesterone have been less studied, estrogen has shown to modulate gene expression for mitochondrial function, i.e. mitochondrial respiration, mitochondrial protein synthesis and mitochondrial biogenesis. Sex steroid receptors have been shown to protect mitochondria from damage caused by reactive oxygen species. More investigation needs to be done on the direct effects of testosterone on mitochondria, but our current understanding of the presence of estrogen has shown favorable results in mitochondrial functionality. Men who lack sufficient levels of testosterone necessary to convert to estrogen (low estrogen) may perhaps suffer a negative outcome on mitochondrial function and preservation.
Testosterone, Insulin Sensitivity and Obesity ²⁰ ²¹
Research has found a connection between low levels of testosterone, decreased insulin sensitivity and visceral adipose tissue (abdominal fat) although the connecting factors still remain unclear. There are theories that low testosterone leads to the development of abdominal fat via inability to metabolize triglycerides properly, leading to insulin resistance. What has been seen in animal studies is that castration of male rats leads to the development of insulin resistance and subsequent testosterone supplementation corrects the insulin response.
Some human trials have shown testosterone administration to be beneficial with insulin resistance whereas others have seen no correlation between the two. The correlation was stronger in studies looking at obese men with diabetes. Diabetes can also create microvascular complications which have been associated with low testosterone, low DHEA and elevated estrogen.²² These findings should encourage a healthy lifestyle to avoid the onset of diabetes and obesity, specifically visceral fat, to negate the potential association between low testosterone, insulin resistance and obesity.
There are numerous compounds, both natural and manmade, that affect the endocrine system and thus interfere with hormone production. These endocrine disruptors are found throughout our environment, in our food, water, household products, hygiene products, furniture, insecticides and medications, to name a few. Some of the more commonly known ECDs are BPA and phthalates found in plastics, perfluoroalkyl substances (PFAS) in industrial products like textiles, furniture upholstery and paper, butylated hydroxyanisole (BHA) a food preservative, and in medications such as ketoconazole, an antifungal, medroxyprogesterone acetate prescribed for abnormal sexuality in males, etomidate a general anesthetic. Even food compounds like resveratrol, flavones and isoflavones have been shown to affect hormone production.
These compounds can cause androgen producing enzyme inhibition (HSD3B), cause disruption in Leydig cell development, can bind to estrogen and androgen receptors acting as estrogens and androgens respectively, inhibit testosterone synthesis and can inhibit androgen production.
Many of these endocrine disruptors remain in the body for quite some time due to their long half life, all the while, their synergistic effects remain unknown. Many of these compounds have effects within the mitochondria as well, altering mitochondrial function which can be problematic in hormone production as previously stated.
A systematic review has shown an association between cholesterol lowering statins and their negative effects on the production of testosterone. Unfortunately, numerous physicians ignore the detrimental effects of low cholesterol with the mere focus on lowering cholesterol levels. Optimal total cholesterol levels are between 150-199 mg/dL. Cholesterol plays a significant role in so much of human physiology and thus it stands to reason that lowering cholesterol levels to an unhealthy range may be detrimental to not only hormone production, but to so many other physiologic processes in the body.
The Copper/Zinc Imbalance²⁵ ²⁶
A 2011 study found that men with elevated copper and low levels of zinc had lower levels of testosterone. Zinc plays a significant role in the activation of testosterone producing Leydig cells. With aging and inflammatory states, mechanisms are set in place to decrease zinc concentrations and elevate copper, altering the repair and maintenance status of an individual, most notably in aging populations. This alteration in the copper to zinc ratio can also play a significant role in the development of cardiovascular disease, malignancy and all-cause mortality. Other contributing factors to the imbalance of these two nutrients are oxidative stress, dietary deficiencies, and elevated insulin levels. A serum/plasma copper to zinc ratio above 2.0 is indicative of an inflammatory state and a zinc deficiency.
PROMOTE HEALTHY TESTOSTERONE LEVELS
Summary & Action Steps
1. Reduce cortisol production to reduce the potential cortisol/pregnenolone steal by developing stress coping mechanisms, avoiding stress triggers and/or finding an outlet to release built up negative emotion.
Adaptogenic herbs to negate the effects of stress: ashwagandha, ginseng, rhodiola, astragalus, holy basil, milk thistle, licorice root. Caution is advised with licorice root as it can also have effects on blood pressure. In this case, deglycyrrhized licorice root can help to avoid any potential unwanted effects.
2. Reduce aromatase activity with changes in diet, increased physical activity and reduction of stress. Addressing these lifestyle factors can help with weight loss which is also a contributor to increased aromatase activity.
Dietary recommendations: cruciferous vegetables (i.e. broccoli, cabbage, brussel sprouts, kale, arugula, cauliflower, collard greens, turnip, radish); members of the allium family (i.e. garlic, onion, leek, green onion, chive; flavones found in the citrus family, passionflower and chamomile; healthy fats (i.e. coconut oil, raw nuts and seeds, EV olive oil, avocado); fermented foods (i.e. sauerkraut, kimchi, apple cider vinegar).
3. Elevate low estrogen levels to reduce the risk of developing osteoporosis and associated fractures. Increasing the production of testosterone to convert to estrogen via aromatase should be the approach given the concerns in research that lie in the uncertainty of the mental effects of phytoestrogens (specifically genistein found in soy) in male populations. Some studies have shown improvement in cognitive function while others have shown decline with soy/genistein administration.¹⁸
4. Estradiol levels between 21.80-30.11 pg/mL showed to have the best health outcomes for those with cardiovascular disease.
5. Increase low HDL levels with healthy fat consumption and omega-3 supplementation to enhance the antiatheroscelrotic role that testosterone plays in relation to HDL activity and cardiovascular health.
6. Maintain healthy levels of total cholesterol between 150-199 mg/dL for optimal conversion through hormone production pathways.
7. Increase vitamin 25-OH vitamin D levels to a [bare] minimum of 50-60 ng/mL through safe exposure to sunlight, vitamin D3 supplementation and diet.
Dietary Sources of Vitamin D: Cod liver oil, wild caught salmon, sardines, mushrooms, egg yolk, beef liver
8. Test serum magnesium levels and supplement accordingly. Adequate levels should be between 0.75–0.95 mmol/L or 1.7–2.5 mg/dL.¹⁹ One particular study found the most improvement in testosterone levels when 500 mg/d¹⁹ was administered to those with low levels.
Dietary Sources of Magnesium: Dark leafy greens, nuts, seeds, legumes, avocado, banana, dark chocolate, fatty fish (i.e. salmon mackerel, halibut) and whole grains
9. Maintain mitochondrial integrity to allow for the conversion of cholesterol to progesterone which can then be converted to other sex hormones outside of the mitochondria. Adequate levels of estrogen are needed for mitochondrial protection from reactive oxygen species.
10. Control weight and blood sugar with proper diet and exercise to reduce the role they may play in hormone synthesis.
11. Reduce or eliminate the exposure to endocrine disrupting substances while promoting detoxification and mitochondrial health to eliminate previous toxin exposure stored in body tissues.
12. Maintain a serum copper to zinc ratio below 2.0 with adequate intake of dietary and/or supplemental zinc, reduction in systemic inflammation, insulin stabilization and oxidative stress reduction.
Dietary Sources of Zinc: Oysters, crab, lobster, grass-fed meats, beans, nuts, pumpkin seeds, yogurt and peas
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