The Next Longevity Revolution: Estrogen Metabolism in Men

by Filomena Trindade, MD, MPH

What do we think about when we consider anti-aging and men’s health? Testosterone replacement? Prostate health? Cardiovascular risk prevention? All of these are no doubt important aspects of men’s health; however, there is one detail that has been neglected: estrogen metabolism. Its impact on wellness and disease prevention is rarely considered in men’s health. Most anti-aging experts assume that when I address estrogen metabolism, it is my aim to simply balance hormones to increase a man’s sense of well-being and to delay aging. Although this is indeed helpful, I see the metabolism of estrogen as being influential in deeper layers of a man’s physiology. For instance, it has the power to affect the likelihood of a man’s developing osteoporosis, cancer (prostate and other hormone related cancers), glaucoma, cardiovascular disease and impaired detoxification, among many other ailments.¹ In this article, I will focus on estrogen metabolism as it pertains to hormone optimization, cardiovascular risk prevention, and detoxification in men.

In today’s world, we are constantly exposed to toxins. These toxins can affect our hormones and hormone metabolism in several ways. One way is by binding to the hormone receptor. Another way is by upregulating androgen, or testosterone receptors (a process that increases the number of receptors on the surface of the cell). A third way is referred to as posttranslational genetic, or epigenetic, changes to our actual genes. In the instance of epigenetic changes, alterations occur because toxins cause different biochemical groups to attach to our DNA thereby changing its chemical nature. In other words, they can cause changes in DNA methylation, which ultimately disrupts estrogen receptor activity. This is risky business not only because it impairs our ability to metabolize, process, and eliminate our own hormones and neurotransmitters, but epigenetic changes can also be inherited genetically by future generations. If that isn’t enough, it also compromises our capacity to repair our own DNA! An especially important type of genetic change is called single nucleotide polymorphisms (SNPs). There are two ways that SNPs develop: either via genetic inheritance or environmental toxic exposure. SNPs signify a change in one single DNA building block, or nucleotide, within one larger gene (or a regulatory region near a gene). The reason that SNPs are important is because they disrupt one particular building block within the gene. Depending on which building block is affected, an individual may develop an increased risk for certain diseases, begin experiencing adverse responses to certain drugs, have difficulty in processing certain nutrients, or suffer from impaired efficiency in detoxifying environmental pollutants. This is of key importance in men’s health and longevity.

One form of imminent toxic exposure that we are all confronted with is the presence of xenoestrogens in our environment. The risks that xenoestrogens pose to the human physiology are numerous. Xenoestrogens are foreign estrogens. In other words, they are human-produced compounds that mimic the effects of natural estrogen in the body but tend to be much stronger. Because of this, they can occupy the estrogen or testosterone/androgen receptor with much higher affinity than the natural equivalent, thereby blocking the action of natural hormones. So clinically, if a male patient has a hormone imbalance – let’s say low testosterone – administering more testosterone is not going to be an effective treatment, because his receptor is already blocked due to the xenoestrogens circulating in his body However, xenoestrogens can have the opposite effect; they can increase, rather than replace or block, the overall effects of natural estrogen in the body. This is also harmful because it can lead to estrogen dominance. Estrogen dominance is associated with various diseases including benign prostatic hypertrophy in men, fibroids and fibrocystic breast disease in women, and potential cancer in both sexes. In addition, xenoestrogens may alter the feedback loops in organs such as the brain, pituitary, gonads, and thyroid. This of course will lead to hormone imbalances and miscommunication between the command center (the brain) and the organ.

To make matters worse, xenoestrogens can both modify and upregulate members of the cytochrome P450 (CYP) enzyme family and to preferentially produce a higher ratio of the 4 and 16 hydroxylated estrogen derivatives intermediates that are even more genotoxic than the xenoestrogens themselves! Lastly, xenoestrogens can also lead to general disorders of metabolism such as weight gain, obesity, hyperglycemia, insulin resistance, diabetes, and dyslipidemia .² Gong et al. have shown in two recent studies as well as other researchers in earlier studies the importance that these metabolic deficiencies have in affecting androgen levels in men as well as how they contribute to or affect cardiovascular and cerebrovascular health.^3–8 In short, the way that the body processes and uses these synthetic estrogens will affect not only a man’s longevity but also his risk for chronic diseases, cardiovascular health, brain function, and cancer.^9,10,14,15

As we can see, xenoestrogen toxins are powerful and create a cascade of harmful effects in the body, but perhaps their most villainous attribute is the fact that they undermine the two main detoxification pathways. Phase 1 and phase 2 detoxification occur in the liver. It is here that toxins and our own sex hormones should be metabolized and later move on to be expelled. Phase 1 in the liver is a series of CYP450 enzymes that are aimed at making a toxin more water soluble. But the problem is that the breakdown of lipid soluble toxins creates an interim environment of increased toxicity. Now with regard to estrogen, it must go through one of the 3 pathways in phase 1 in order to be metabolized (2-hydroxylation, 4-hydroxylaton, or 16-hydroxylation). The 2-hydroxylation step in phase 1 is the healthiest and most preferable route for an estrogen to pass though. Unfortunately, though, xenoestrogens choose the other two options: the 4-hydroxylation or the 16-hydroxylation pathways.²

Moving on to phase 2 detoxification, we see a series of reactions to neutralize or further metabolize and eliminate the intermediate from phase 1. The problem is that most SNPs in phase 1 increase the activity of the enzymes, causing more toxic intermediates. On the other hand, SNPs in phase 2 downregulate the activity of the enzyme. This is just the opposite of what we want. It is definitely preferable to increase the activity of phase 2 in order to fully process and eliminate a toxin instead of having that more toxic intermediate (formed from phase 1) in circulation. When those partially processed toxins circulate, the body cannot further metabolize or eliminate them, so they lodge in the body, particularly the adipose tissue, where they’re stored indefinitely.

In short, to address the root cause of hormonal imbalance in men, it is not enough just to examine hormone levels. Rather, we must confront estrogen metabolism and the genomics of detoxification in each patient. Plus, it is essential that when examining the detoxification of estrogens, whether natural or xenoestrogens, we focus on phase 2 to ensure the breakdown of any toxic intermediates. This way, we can provide men with a treatment plan that will truly recover their health instead of further exacerbating their symptoms.

As is evident, toxins affect all aspects of our well-being, but particularly our hormone balance. More specifically, how effectively we process or metabolize endogenous and exogenous hormones determines exactly how much of a toxic load we bear. One example of a toxin that is highly detrimental to our hormones and is difficult to detoxify is the xenoestrogen bisphenol A (BPA). BPA is an environmental endocrine disruptor used extensively in the production of polycarbonate plastics, in the epoxy linings of some canned food and beverage containers, as well as in many dental products.^11,12 Exposure to BPA is nearly universal. In a recent study, BPA was detected in urine samples from 92.6% of a sample population in the US.¹³ One reason for its unmitigated presence is that BPA can be found in many common household products. BPA lives in kitchen regulars such as plastic storage containers for dinner leftovers, or cans that hold refried beans or soda. At work, it can be found in the thermal paper used for cash register receipts. Wherever its location, it can detrimentally affect our health and particularly our hormone balance. As with other xenoestrogens, BPA has been shown to exert endocrine-disrupting effects on reproduction, development, metabolism, and cancer in humans and other species.^14,15 Recent findings linked exposure to BPA with several male reproductive disorders and prostate diseases.^16–23 Other studies have demonstrated that administration of low doses of BPA during early life (when tissues are specially sensitive to endocrine disrupting chemicals) significantly affects several aspects of prostate development, including an increase in the number and hyperplasia of the prostate gland ducts and urethral constriction.^24,25 Strikingly, BPA can lead to permanent hyperplasia of the prostate and upregulation of prostatic androgen receptors in adults many months after exposure.

Although all the specific mechanisms that cause BPA to have such harmful effects have yet to be completely elucidated, it is clear that given certain SNPs, BPA do in fact adversely affect estrogen metabolism. Both in vitro and in vivo, BPA has been documented to disrupt the endocrine system. It is able to do this in a large part due to its estrogenlike properties. Prolonged exposure to BPA causes an increase of 4-hydroxyestrogens, which may lead to higher rates of hormone related cancers through the formation of DNA adducts. So, not surprisingly, a study by Kim el al. found significant differences of estrogen metabolism in patients due to exposure to BPA.²⁶ We know that this is possible because BPA can bind to estrogen receptors and androgen receptors in the prostate. We also know that testosterone is converted to dihydrotestosterone (DHT) by 5alpha-reductase isozymes, which is present in tissues such as the prostate. Castro et al. found that BPA modifies 5alpha-reductase isozymes in the rat prostate.²⁵ This is significant because it means that BPA is binding to hormone receptors with higher affinity than natural hormones, thus competing with testosterone for receptor sites. In turn, this alters the downstream metabolites of testosterone; namely, the conversion of testosterone to DHT and estradiol. This is one explanation for the low levels of testosterone that we are seeing in men, particularly young men. There seems to be an epidemic of low testosterone in the young men I see in my practice, and I strongly believe that endocrine disruption due to toxic exposure is the cause. Therefore, the solution to this problem is not to give hormone replacement, but to deal with the root cause: toxicity and impaired estrogen metabolism due to an accumulation of environmental toxins. This can only be addressed with diet, nutrition, lifestyle modification, gut restoration, and careful and appropriate detoxification.

I have focused mostly on BPA because it is so ubiquitous in our environment. However, there are many other bisphenols that continue to exist in plastics that have not been brought to question by consumers. This is not even to mention other xenoestrogens that we are constantly in contact with in our daily lives. Fertilizers, chemical pesticides (such as DDT), cosmetics, laundry detergent, fabric softeners, growth hormones fed to cattle, electromagnetic radiation, heavy metals such as mercury in dental amalgams, or industrial compounds such as phthalates are a few examples. Or take the case of brominated flame retardants; they are documented to cause hormone disruption in men by altering the thyroid hormones including TSH, T3, and T4 as well as reproductive hormones such as FSH, LH testosterone, SHBG, and estradiol.²⁷ Follicle stimulating hormone (FSH) and luteinizing hormone (LH) are made in the brain and stimulate the gonads to secrete hormones such as testosterone and estradiol. Sex hormone binding globulin (SHBG) is a glycoprotein that binds testosterone and estradiol and transports them in the blood stream. So it is evident that the consequence of these toxins exists not only at the tissue or receptor level but also at the level of communication with our master command center: the brain.

We must remember that when we combine a man’s total toxic load along with the genetic predispositions or any SNPs inherited or caused by toxic exposure, hormone metabolism is likely compromised. Since each patient will have different rates of xenoestrogenic exposure and thus a different variation in the SNPs affected, it is important to assess estrogen metabolism as well as genomic profiles in each individual patient. If we want to address a man’s unique needs and decrease his disease risk, it is crucial to do this before starting him on bioidentical hormone replacement.

Now onto the subject of men’s health and cardiovascular disease (CVD). There has been intense debate regarding the role of testosterone in vascular function and cardiovascular disease. For instance, low testosterone is associated with the progression of atherosclerosis, the production of pro-inflammatory cytokines, an increase in arterial thickness and blood glucose levels, as well as an elevation in total cholesterol and low-density lipoprotein. All of these physiological reactions are documented contributors to CVD.^6–8 Conversely, however, high testosterone has been associated with sudden cardiac death, liver disease, and suicidal behavior.⁵ In fact, simply being male is a risk factor for CVD (males have an earlier occurrence and higher prevalence of many cardiovascular and metabolic-related diseases).

Recent scientific publications may be able to help us understand why there has been so much confusion and debate surrounding this topic. In respect to estrogen and a man’s vascular health, it is clear that low quantities of naturally occurring estrogens are significantly associated with higher risk of disease. We are all well aware of this in regard to women, whose cardiovascular risk becomes much higher after menopause.^28,29 The recent Nurses’ Health Study, WISE Study, and the Women’s Health Initiative have demonstrated that young women who go into early menopause (due to ovarian dysfunction or bilateral oophorectomy) are at an increased risk of CVD compared with women exhibiting normal endogenous estrogen levels.^30,31 But does estrogen have this same effect on men? Studies show that endogenous, naturally occurring estrogen may be cardioprotective in men as well.^3,32–34 In fact, significant amounts of estrogen in men are produced by the aromatase enzyme, which converts C19 androgenic steroids into 17beta-estradiol (E2). In healthy young men, aromatase inhibition lowers plasma estradiol (E2), and this decrease is associated with less flow-mediated dilatation of the brachial artery⁾.³ This fact is highly important to consider for young men who are taking aromatase inhibitors, especially for alopecia concerns. We need to make sure not to decrease the estradiol level too drastically for these men. Furthermore, the estradiol to testosterone balance (T/E2) plays a key role in the relationship between sex hormones and the risk of cerebrovascular disease for men. Interestingly, the balance between these two hormones, T and E2, may actually be more important than either of their individual absolute quantities. This partly explains why studies focusing solely on androgens or estrogens alone have produced inconclusive results regarding cardiovascular disease prevention in men. Both extremely low T/E2 relative proportions and inappropriately high T/E2 ratios can harm brain blood vessels. Luckily the reverse is also true; we know that optimizing the T/E2 balance in elderly men is a good way to protect blood vessels in the brain.^3,34 You do not want a man’s estradiol level too high or too low. Consequently, it’s all about balance.

Now that we know about toxins and how they affect hormones and estrogen metabolism as well as how suboptimal estrogen metabolism affects the T/E ratio, how do we apply it to increase longevity in men? My approach has been to develop an individually tailored treatment protocol for each patient. This is based on a detailed history, a thorough physical examination, and appropriate laboratory tests (based on my clinical suspicions) to identify the nutrient status, hormonal state, and metabolic imbalances present. At that point, I can address all underlying dysfunctions and thus reach the root cause of the problem. Then the patient is able achieve his main goal of slowing the aging process and improving quality of life. What is unique about this approach is the focus on “connecting the dots,” so to speak. I take several seemingly unrelated symptoms and/or findings and examine how they may have a common cause or connection. In the case of longevity in men, this means measuring and optimizing estrogen metabolism and promoting proper detoxification (based on individualized genomics) in each patient. The specifics of how to actually do this lie in optimizing gastrointestinal health, correcting oxidative stress when present, treating underlying chronic or reactivated infections, optimizing nutrient levels, developing appropriate and safe detoxification protocols for each patient, and balancing all hormones. Simply suppressing symptoms or accepting the “Band-Aid” approach without going the extra mile to fully understand the root cause of a man’s complaints is arguably negligent. Instead, we have the opportunity to offer men optimal health and longevity by working with their bodies to identify and treat the underlying imbalances present. In my experience, optimizing estrogen metabolism is key to a man’s longevity and must not be overlooked.

Notes

1. Pasquale et al. Estrogen pathway polymorphisms in relation to primary open angle glaucoma: an analysis accounting for gender from the United States. Mol Vis. 2013 Jul 12;19:1471–81.

2. Alonso-Magdalena et al. Endocrine disruptors in the etiology of type 2 diabetes mellitus. Nat Rev Endocrinol. 2011 Jun;7(6):346–353.

3. Gong Y, Xiao H, Li C, et al. Elevated T/E2 ratio is associated with an increased risk of cerebrovascular disease in elderly men. PLoS One. 2013 Apr 24;8(4):e61598.

4. Gong Y, Xiao H, Bai J, et al. Association between sex hormone levels and abnormal metabolism in a population of elderly Chinese men. Aging Male. 2013;16:8–16.

5. Sher L. High and low testosterone levels may be associated with suicidal behavior in young and older men, respectively. Aust N Z J Psychiatry. 2012.

6. Francomano D, Bruzziches R, Natali M, Aversa A, Spera G. Cardiovascular effect of testosterone replacement therapy in aging male. Acta Biomed. 2010;81 Suppl 1:101–106.

7. Svartberg J, von Muhlen D, Mathiesen E, et al. Low testosterone levels are associated with carotid atherosclerosis in men. J Intern Med. 2006;259:576–582.

8. Vlachopoulos C, Ioakeimidis N, Terentes-Printzios D, et al. Plasma total testosterone and incident cardiovascular events in hypertensive patients. Am J Hypertens. 2013;26:373–381.

9. René Viñas, Cheryl S Watson Mixtures of xenoestrogens disrupt estradiol-induced non-genomic signaling and downstream functions in pituitary cells. Environ Health. 26 March 2013;12:26.

10. Yow-Jiun Jeng, Mikhail Kochukov, Cheryl S Watson. Combinations of physiologic estrogens with xenoestrogens alter calcium and kinase responses, prolactin release, and membrane estrogen receptor trafficking in rat pituitary cells. Environ Health. 15 October;2010;9:61.

11. Olea N, Pulgar R, Perez P, Olea-Serrano F, Rivas A, et al. Estrogenicity of resin-based composites and sealants used in dentistry. Environ Health Perspect. 1996;104:298–305.

12. 12. Goodson A, Robin H, Summerfield W, Cooper I. Migration of bisphenol A from can coatings – effects of damage, storage conditions and heating. Food Addit Contam. 2004;10: 1015–1026.

13. Rubin BS, Soto AM. Bisphenol A: perinatal exposure and body weight. Mol Cell Endocrinol. 2009;25:55–62.

14. Rubin BS. Bisphenol A: an endocrine disruptor with widespread exposure and multiple effects. J Steroid Biochem Mol Biol. 2011;127:27–34.

15. Soto AM, Sonnenschein C. Environmental causes of cancer: endocrine disruptors as carcinogens. Nat Rev Endocrinol. 6:363–370.

16. Richter CA, Birnbaum LS, Farabollini F, et al. In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol. 2007;24: 199–224.

17. Walker DM, Gore AC (2011) Transgenerational neuroendocrine disruption of reproduction. Nat Rev Endocrinol. 7:197–207.

18. Takao T, Nanamiya W, Nagano I, et al. Exposure with the environmental estrogen bisphenol A disrupts the male reproductive tract in young mice. Life Sci. 1999;65:2351–2357.

19. Chitra KC, Latchoumycandane C, Mathur PP (2003) Induction of oxidative stress by bisphenol A in the epididymal sperm of rats. Toxicology 14: 119–127.

20. De Flora S, Micale RT, La Maestra S, et al. Upregulation of clusterin in prostate and DNA damage in spermatozoa from bisphenol A-treated rats and formation of DNA adducts in cultured human prostatic cells. Toxicol Sci. 2011;122: 45–51.

21. Ho SM, Tang WY, Belmonte de Frausto J, Prins GS. Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant. Cancer Res. 2006;1:5624–5632.

22. Taylor JA, Richter CA, Ruhlen RL, vom Saal FS. Estrogenic environmental chemicals and drugs: mechanisms for effects on the developing male urogenital system. J Steroid Biochem Mol Biol. 2011;127:83–95.

23. Welshons WV, Nagel SC, vom Saal FS. Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology. 2006;147:56–69.

24. Vandenberg LN, Colborn T, Hayes TB. Hormones and endocrine-disrupting chemicals: low-dose effects and non mono-tonic dose responses. Endocr Rev. 2012;33:378–455.

25.Castro B, Sánchez P, Torres JM, Preda O, del Moral RG, Ortega E. Bisphenol A exposure during adulthood alters expression of aromatase and 5α-reductase isozymes in rat prostate. PLoS One. 2013;8(2):e55905.

26. Kim EJ, Lee D, Chung BC, Pyo H, Lee J. Association between urinary levels of bisphenol-A and estrogen metabolism in Korean adults. Sci Total Environ. 2013 Aug 15. pii:S0048-9697(13)00808-5. doi:10.1016/j.scitotenv.2013.07.040.

27. Johnson PI et al. Associations between brominated flame retardants in house dust and hormone levels in men. Sci Total Environ. 2013 Feb 15;445–446:177–84.

28. Brett KM. Can hysterectomy be considered a risk factor for cardiovascular disease? Circulation. 2005;111:1456–1458.

29. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ. 2012;345:e6409.

30. Gierach GL, Johnson BD, Bairey Merz CN, et al. Hypertension, menopause, and coronary artery disease risk in the Women’s Ischemia Syndrome Evaluation (WISE) Study. J Am Coll Cardiol. 2006;47:S50–S58.

31. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291:1701–1712.

32. Wenner MM, Stachenfeld N. Blood pressure and water regulation: understanding sex hormone effects within and between men and women. J Physiol. 2012.

33. Gardner JD, Murray DB, Voloshenyuk TG, et al. Estrogen attenuates chronic volume overload induced structural and functional remodeling in male rat hearts. Am J Physiol Heart Circ Physiol. 2010;298:H497–H504.

34. Naessen T, Bergquist J, Lind L, Kushnir MM. Higher endogenous estrogen levels in 70-year-old women and men: an endogenous response to counteract developing atherosclerosis? Menopause. 2012.

Filomena Trindade, MD, MPH, is a teacher, author, and internationally sought-after speaker in functional medicine. She is a graduate of the fellowship in Anti-Aging, Regenerative and Functional Medicine and teaches in the Fellowship (a master’s program through the University of South Florida). After obtaining her BA degree in biology, she went on to finish a master’s degree in public health in the area of environmental health and epidemiology before starting medical school. She graduated first in her class in family practice from the University of California Davis School of Medicine and did her residency training in family practice at the UC San Francisco/Santa Rosa Program. She has been in clinical practice for over 18 years. Before starting her own private practice in 2004 in functional medicine, she was the medical director of a large nonprofit organization that catered to the underserved. She is currently very active in developing teaching programs in functional medicine in the US, Latin America, and Europe.