Estradiol in Men on TRT: Impact on Brain and Heart

What are Estradiol and Aromatase?

Estradiol is a form of the female hormone estrogen. Although estradiol production is typically considered a female concern, men also need to maintain healthy levels of this hormone for optimal health. Since men lack ovaries (where most estradiol is produced in women), estradiol in men is created by a process that uses an enzyme called aromatase (1) in testicles, liver and fat cells.

Aromatase converts a very small portion of testosterone levels into estradiol, and health problems can arise when aromatase levels are too high or too low (1).

When aromatase is unbalanced, estradiol becomes an issue

As men age, they can experience excess aromatase activity, raising estradiol levels and reducing testosterone to unhealthy levels. Low T levels will adversely impact quality of life by reducing libido, ability to maintain an erection, mood, and muscle mass, among other health factors (2).

However, when the body produces too little aromatase, men can experience other, potentially serious health problems.

Men with diminished aromatase levels will have an estradiol deficit, which can create problems similar to low-T; diminished sex drive, loss of bone mass, and increased body fat (3). Men on testosterone replacement therapy (TRT) taking higher doses of aromatase inhibitors can also experience estradiol deficit.

Let’s look at recent studies finding that low estradiol can play a critical role in increasing the risk of cognitive decline and increase the odds of experiencing cardiovascular disease.

Low estrogen levels in men, not testosterone increases risk of heart disease

A study led by Elaine Yu, MD, MSc, addresses the suspicion held by many medical professionals that testosterone can promote cardiovascular disease in men, and that estradiol provides protection against it (4).

The researchers sought to determine whether it was estradiol or testosterone that regulated men’s cardiovascular risk factors by comparing two groups whose hormone levels were changed using a combination of medications (4).

They looked at 400 healthy men, between the ages of 20 and 50. Study participants were weighed, had fasting blood tests for markers of heart disease and diabetes, and also had a thigh scan using quantitative computed tomography (CT scan) to measure muscle fat content before and after the study (4).

Yu’s team found that while higher levels of testosterone reduced these men’s levels of healthy (HDL) cholesterol, changes in estradiol levels had no effect at all on HDL(4).

However, they also discovered that low estradiol levels did increase the markers for diabetes, like increased insulin resistance, increased fat in the muscles, and higher fasting blood sugar levels(4). Diabetes is a major risk factor for heart disease (5).

Additionally, the study found that neither estradiol nor testosterone affected the levels of LDL (unhealthy) cholesterol.

According to Yu, these findings indicate that in men, it’s higher testosterone levels combined with lower estradiol levels that can worsen cardiovascular risk factors, somewhat explaining differences in the incidence of heart disease between men and women. Some studies have shown that it is the ratio of testosterone to estradiol that is important, not just the level of each of those hormones. As testosterone increases with TRT, so does estradiol to balance the effects of testosterone on lipids, mood and insulin action.

Androgen deprivation therapy can cause cognitive decline

Androgen deprivation therapy (ADT) is an often used method to slow the growth of prostate cancer. It’s also used for men transitioning to women (6, 7).

ADT is typically prescribed on an open-ended (no fixed period) basis to help treat advanced prostate cancer. An estimated 44 percent of men with prostate cancer will undergo ADT at some point as part of a strategy to slow tumor growth (6).

ADT therapy is used specifically to block the male hormones, particularly testosterone, from stimulating prostate cancer cell growth. Research has confirmed that ADT can cause significant cognitive decline in women with breast cancer (8), but few studies have investigated cognitive impairment following ADT for men being treated for prostate cancer.

Using formal tests, scientists recently compared the cognitive ability of 58 prostate cancer patients receiving androgen deprivation therapy to 84 prostate cancer patients who did not receive ADT, and 88 cancer-free men (9). They found that those treated with ADT were 70 percent more likely to develop cognitive impairment after six months, and over twice as likely to have significant cognitive impairment after one year(9).

 

Does estradiol restore cognitive function during ADT?

A 2018 study published in Current Neuropharmacology has examined whether estradiol supplementation is an effective way to prevent this side effect (9). Researchers performed a literature search using PubMed and Google Scholar to identify studies on this topic and discover any evidence that estradiol supplementation has a cognitive benefit for men on ADT.

They examined studies involving the effects of estradiol treatment on cognitive function in three androgen-deprived male populations; prostate cancer patients, male-to-female transsexuals, and castrated male animals (9).

A review of the literature found that while some studies show that estradiol supplementation resulted in cognitive improvement (especially in spatial ability), They couldn’t determine (9):

• Whether estradiol will improve cognition after long-term ADT
• How early or delayed estradiol treatment post-castration will affect cognition
• If estradiol affects memory retention

They conclude that for androgen-deprived males, there is some evidence that estradiol supplementation may improve both verbal and visual memory (9). However the variability between the reviewed studies resulted in significant inconsistencies, making further study necessary to determine what estradiol treatment protocol can best maximize cognitive improvement for men using ADT (9).

Should high estradiol levels be treated?

Men on testosterone replacement therapy can experience an increase in estradiol that can sometimes reach clinically elevated levels (10).

A study published in the Journal of Sexual Medicine (11) looks at the phenomenon of increased estradiol levels in men undergoing TRT to discover whether high estradiol levels in this population should be treated.

Researchers comprehensively reviewed the published literature on the role of estradiols in male sexual function and testosterone deficiency to answer this question.

The study findings reveal that (11):

• Although estradiol have been used at pharmacologic doses to suppress serum testosterone, there is no evidence that naturally occurring elevations of estradiol will cause a reduction in testosterone levels

• Absent testosterone deficiency, study findings suggest that elevated estradiol levels don’t seem to be harmful. Once again, monitoring and treating the ratio of testosterone to estradiol may be more important than either hormone alone.

• Estradiol could help maintain some sexual function in castrated men

Given the evidence uncovered by this review study, researchers report that, although further research is needed, the existing evidence doesn’t support the treatment of elevated estradiol for men on testosterone therapy (11).

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References

1) Stocco, Carlos. “Tissue Physiology and Pathology of Aromatase.” Steroids 77.1-2 (2012): 27–35. PMC. Web. 11 June 2018.

2) Araujo, Andre B., and Gary A. Wittert. “Endocrinology of the Aging Male.” Best practice & research. Clinical endocrinology & metabolism 25.2 (2011): 303–319. PMC. Web. 11 June 2018.

3) Bulun, Serdar E. “AROMATASE DEFICIENCY.” Fertility and sterility 101.2 (2014): 323–329. PMC. Web. 11 June 2018.

4) Men's heart disease risk linked to high testosterone and low estrogen. The Endocrine Society.

5) Zhang PY. Cardiovascular disease in diabetes. Eur Rev Med Pharmacol Sci. 2014;18(15):2205-14.

6) Perlmutter, Mark A, and Herbert Lepor. “Androgen Deprivation Therapy in the Treatment of Advanced Prostate Cancer.” Reviews in Urology 9.Suppl 1 (2007): S3–S8. Print.

7) Unger, Cécile A. “Hormone Therapy for Transgender Patients.” Translational Andrology and Urology 5.6 (2016): 877–884. PMC. Web. 11 June 2018.

8) Wu, Lisa M., and Ali Amidi. “Cognitive Impairment Following Hormone Therapy: Current Opinion of Research in Breast and Prostate Cancer Patients.” Current opinion in supportive and palliative care 11.1 (2017): 38–45. PMC. Web. 11 June 2018.

9) Wibowo E. Cognitive Impacts of Estrogen Treatment in Androgen-Deprived Males: What Needs to be Resolved. Curr Neuropharmacol. 2017;15(7):1043-1055.

10) Tan RS, Cook KR, Reilly WG. High estrogen in men after injectable testosterone therapy: the low T experience. Am J Mens Health. 2015 May;9(3):229-34. doi: 10.1177/1557988314539000. Epub 2014 Jun 13.

11) Ravi Kacker, Abdulmaged M. Traish, Abraham Morgentaler. Estrogens in Men: Clinical Implications for Sexual Function and the Treatment of Testosterone Deficiency. The Journal of Sexual Medicine. (2012): Volume 9, Issue 6, Pages 1681–1696