A Brief Review of Hormone Physiology

In men, estrogen is important for the growth and maturity of sperm, libido, bone health, cardiovascular health, and prostate health.5  After the age of 30, testosterone levels slowly decline, partly due to increased aromatase activity and partly due to the fact that estrogen also binds to androgen receptors. This binding inhibits gonadotropin-releasing hormone (GnRH), which would otherwise tell the body to make more testosterone by increasing production of luteinizing hormone (LH) in the testes.

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Estrogen is made in the adrenal glands, fat cells (adipose tissue), and testes. There are two receptors for estrogen – alpha and beta – with alpha exerting stronger estrogenic effects than beta. Alpha receptors are found in the prostate (stroma), testes (Leydig cells), epididymis, bone, brain, liver, and white adipose tissue; beta receptors are expressed in the colon, prostate (epithelium), testes, bone marrow, salivary gland, vascular epithelial, and brain.6

 

Estrogen metabolites, such as 2-hydroxy (OH), 4-OH, and 16α-OH, derive from the parent hormones, estradiol, and estrone. These two estrogens can convert back and forth into each other via hepatic hydroxylases and are then metabolized through glucuronidation, sulfation, and/or methylation. The enzyme responsible for methylation – catechol-O-methyltransferase (COMT) – converts 2-OH-estrogen to 2-methoxy-estrogen, which is a protective form of estrogen. The metabolites 4-OH and 16α-OH are generally not regarded as favorable estrogens, especially in terms of cancer risk. Estrogen is bound to carrier proteins such as sex hormone-binding globulin (SHBG) and, to a lesser extent, albumin. Bound hormone is not active.

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Sources of Additional Estrogens

Although the body employs a number of dedicated processes to keeping estrogens in balance, (both production and metabolism), exogenous estrogens have become prevalent in our society, especially through diet and environment. Xenoestrogens, which bind to estrogen alpha receptors, are non-physiological compounds that can also evoke estrogen responses. They are present in diethylstilbestrol (DES), coumestrol (a phytoestrogen), bisphenol A (BPA), dichlorodiphenylethylene (DDE, a metabolite of DDT), nonylphenol, endosulfan, and dieldrin. Xenoestrogens can interfere with endogenous estrogen actions and may also cause increased prolactin secretion.8 These endocrine disruptors are prevalent in skin, cleaning, and beauty products; plastic food containers; orthodontia materials9 (eg, clear aligners, retainers, adhesives), pollution; pesticides; and artificial preservatives. Research suggests that these environmental estrogens may contribute to increased risks in men of testicular cancer, cryptorchidism, hypospadia, and decreased semen quality.10

 

Hormone Interrelationships

Hormones are pulsatile but are well regulated in the body. Progesterone has a role in balancing estrogen dominance in men as well as women. Progesterone, which derives mostly from the adrenals in men,11 is a precursor to both estrogens and androgens, and has an influence on testosterone production, sperm function, and several other functions in the body.12 Estrogen (and possibly xenoestrogens) may be a driving force in prostate cancer, and progesterone has been identified as a protective factor.13,14

 

Elevated estrogen can also contribute to obesity by increasing the concentration of thyroid-binding globulin (TBG), which binds thyroid hormone. Lower thyroid activity slows metabolism, leading to weight gain. Because aromatase in fat cells converts testosterone into estrogen, an increase in adipose tissue exacerbates the problem.

 

Melatonin can help counteract estrogen’s actions. However, a stressful lifestyle, bright lights at night (including electronic devices), and dietary factors such as alcohol, sugar, and caffeine15 can decrease melatonin production and therefore its protective effects. Melatonin has been found in animals to modulate steroid synthesis in Leydig cells (eg, increase testosterone production and inhibit aromatase activity), and may have similar effects in humans.16

 

COMT, the enzyme that converts estrogen into 2-methoxy-estrogen, is also responsible for degrading dopamine, norepinephrine, and epinephrine. Since COMT mutations may contribute to higher serum estradiol levels due to a less efficient degradation of estrogens, and because of its role in degrading catecholamines, variations in COMT may predispose individuals toward high estrogen and anxiety.17 Needless to say, someone who’s constantly anxious will not sleep well. Sleep also regulates the hormones related to satiety, so poor sleep can place people at risk of eating unhealthier foods, which can lead to weight gain and insulin resistance – another factor possibly linked to elevated estrogen in men.18

 

Hormone Testing

Hormone testing can be performed using serum, saliva, or urine. Blood is convenient in that it can also be used for other basic blood work (eg, CBC, CMP, vitamin D) that provides additional information about the patient’s health that can affect hormone imbalance, such as blood sugar or thyroid issues. However, a blood test for hormones is only a snapshot in time. It also often only reflects total sex hormone levels, which don’t differentiate between bound hormone and free (unbound) hormone. This means that hormone levels may appear normal despite the patient being symptomatic. Measuring “free” fractions of hormone and/or adding SHBG and cortisol-binding globulin (CBG; transcortin) can provide a more accurate picture.

 

Saliva and urine are non-invasive tests that measure the unbound hormones, and the latter goes a step further to reflect hormone metabolites, as well as cortisol and melatonin. Salivary testing provides a more accurate read of the pulsatile nature of hormones relative to diurnal rhythm and when four small samples are taken over the course of a day – the average provides a more accurate view of hormone levels. Urinary options can be limited by significant liver or kidney disease; urine testing is also limited by dehydration or excessive fluid intake.19 Genetic tests for MTHFR, COMT, SULT, and CYP can offer a more in-depth picture and understanding of various hormone metabolites. One of the significant disadvantages of urine testing is that it cannot directly measure progesterone levels.

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Therapeutic Approach

1. Reduce exposure to xenoestrogens and work to detox existing levels. Vitamin and mineral-rich foods such as avocados can help support liver detox pathways including methylation; high-fiber foods can also help regulate bowel movements. Ground flax seeds (have weak estrogen content, promote healthy gut bacteria, and bind estrogen in the liver), nuts, wild-caught fish, and olive oil all help optimize production (they provide nutrients for detox pathways and testosterone production, and promote healthy cell membrane function), as well as provide satiety and help balance blood sugar.

2. Increase consumption of dark leafy greens and cruciferous vegetables that will help reduce estrogen and promote more optimal metabolites. Due to their selenium content (also a great nutrient for thyroid), indole-3-carbinol (helps promote production of the 2-OH metabolite), glucosinolate hydrolysis, and sulforaphane (binds, then inactivates estrogen), cruciferous vegetables are highly protective against cancer, possibly more than the total intake of fruits and vegetables.20 Furthermore, crucifers’ high vitamin and mineral content promotes competent phase I and phase II liver detox pathways that ensure the safe excretion of compounds.

3. Cholesterol is the building block of sex hormones, so healthy, cholesterol-rich foods should be encouraged. 

4. Have patients aim for water intake that equals at least half their body weight in ounces. 

5. Encourage a regular bedtime, ideally before 11 PM, in order to optimize melatonin production, as most of it is produced between 11 PM and 3 AM.

6. Resistance training is an effective way to boost testosterone,21 reduce body fat, increase basal metabolic rate, and improve insulin sensitivity.22 Mix resistance training with more vigorous-intensity exercise to further reduce the effects of insulin resistance and promote weight loss.23

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Supplementation

Supplements to focus on for balancing hormones include those that act on hormone production and metabolism, and which support hepatic health, as the liver is such an important organ in hormone health. 

1. Progesterone with chrysin.  Chrysin acts as an aromatase inhibitor to reduce conversion of testosterone to estradiol. Progesterone has also been shown to be protective of the brain and cardiovascular functions. Progesterone is especially important for prostate health. Like saw palmetto berry, prostate inhibits 5-alpaha reductase, and in turn, inhibits the conversion of testosterone to DHT. Progesterone helps burn fat for energy and as a result, can help prevent obesity. Men who have less body fat, produce less estrone.  Since progesterone and testosterone stimulate the (tumor suppressor) gene p53, protection from the oncogene Bcl-2 is provided and healthy apoptosis is stimulated. Use 12mg of topical progesterone plus 30 mg of chrysin daily, applied to the thin areas of the skin for fast absorption (avoid fatty tissue as steroid hormones are lipophilic).  

2. Calcium-D-glucarate (inhibits bacterial beta-glucuronidase in the gut,24 which would otherwise cleave estrogen from a bound molecule, allowing it to recirculate), 

3. Saw palmetto (decreases 5α-reductase),25 grapeseed extract (decreases aromatase26), and Vitex agnus castus (boosts progesterone). 

4. Support the liver with bitter herbs, as well as quercetin, alpha-lipoic acid, and N-acetylcysteine. 

5. Optimize 25-OH-vitamin D levels to around 70 ng/mL, and perhaps higher in patients with cancer or autoimmune conditions.