How to Manage Estrogen Levels in Men on Testosterone Replacement Therapy (TRT)

· How to manage estrogen levels in men on TRT

· Estrogen response in men on TRT

· Use of selective estrogen receptor modulators (SERMS): Tamoxifen and Clomid

· How estrogen is affected on testosterone replacement therapy

· Importance of estrogen in sexual function

Keywords: High estrogen, Estrogen in men, symptoms of high estrogen in men, what causes high estrogen levels in men, estrogen imbalance, gynecomastia, Tamoxifen, Clomid, SERM, Arimidex, Anastrozole,

Estrogen

Estrogen is a hormone that is not only prevalent in females, but also plays an important role in male physiology. The role of estrogen in men has received much attention since the evolving popularity of testosterone replacement therapy (TRT). It is well known that men on TRT will have a corresponding rise in their estrogen level. Monitoring and managing estrogen levels is paramount to optimizing testosterone therapy results.

Estrogen has long been known as an important hormone for bone and vascular health in both males and females, but its role in sexual function, erectile function, sex drive, weight loss, and performance are becoming more well known. In men on Testosterone therapy who look to optimize performance, sex drive, muscle growth and weight loss, estrogen management must also be a component of therapy.

Estrogen circulates in the body in three forms: E1, E2, E3. The most prominent form of estrogen in males is E2 (Estradiol). Estradiol is most important form of estrogen to manage during TRT.

Estrogen Production in Men

The majority of estrogen in the male body is a breakdown product of testosterone. Other sources and production of estrogen in men include the Leydig Cells in the testicles, adrenal glands and peripheral tissues (adipocytes: fat cells).

Men with Low-T who use exogenous testosterone are subject rises in estrogen levels. Testosterone acts a substrate for estrogen production, the more testosterone administered into the body the me that can be converted into estrogen. This is especially true in obese males who have significant amount of fat cells that house aromatase. Men who are obese tend to have higher estradiol levels than men of normal weight. Elevated estrogen levels can stimulate male breast enlargement (gynecomastia). As men age testosterone production declines and the ratio of estrogen to testosterone rises in favor of estrogen. It is often the ratio and balance of estrogen to testosterone that effects male physiology.

The use of an aromatase inhibitors, (Arimidex or Anastrozole) can stop this conversion and breakdown of testosterone. Arimidex has been used in coordination with TRT in many men’s health testosterone clinics to reduce the breakdown of testosterone, reduce estrogen production and as a treatment for gynecomastia.

Estrogen in Overweight Men

Overweight men commonly suffer from metabolic syndrome; a combination of obesity, high blood pressure, elevated blood sugar and high cholesterol. This collection of conditions increases the risk for cardiovascular disease and diabetes. Obese men with metabolic syndrome have a low testosterone level and elevated estrogen levels. Obese men with metabolic syndrome tend to have lower Sex Hormone Binding Globin (SHBG) levels. While one would think this would provide more bioavailable testosterone, it does not. Obese men tend to aromatize estrogen more than the normal weight individuals. Given the higher density of adipose (fat cells) in obese men, which is the primary source for aromatase, more testosterone is broken down into estrogen. Elevated estrogen, via negative feedback on the pituitary gland prevents testosterone production. Furthermore, elevated Leptin levels in obese men prevents LH release from the pituitary gland further reducing testosterone levels. Men with reduced testosterone levels are subject to increasing weight gain, depression, loss of muscle mass and erectile dysfunction among others.

Aromatase Activity and Adipose Tissue (Fat Cells)

Aromatase is predominately found in adipose tissues, principally in the central fat deposits of the abdomen. Obesity is one of most common conditions associated with low testosterone (Low-T). Large amount of fat cells convert testosterone into estradiol. The more fat cells a man has centrally located, the more aromatase enzyme that is present. Furthermore, fat cells release pro-inflammatory markers that promote cholesterol build up in arteries (plaque) and reduce pituitary signals that normally raise testosterone levels. Fat cells also release Leptin, a molecule that inhibits the release of GnRH (Gonadotropin Releasing Hormone). Lower levels of GnRH reduces LH and FSH secretion from the pituitary gland thereby reducing testosterone production and release from the testicles.

The Role of Estrogen in Testosterone Production

Estrogen is a breakdown product of testosterone. Estrogen plays a pivotal role in controlling the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus and the release of Luteinizing Hormone (LH) from the pituitary gland. Both of these signalizing hormones, GnRH and LH, are necessary for testosterone production. Estrogen can act to block the release of these signaling hormones and halt testosterone production. This is the principle reason why monitoring and managing Estrogen levels during TRT is important.

When estrogen levels are too high in men the result can be a decrease in testosterone production. When men undergo testosterone replacement therapy, aromatase will act to breakdown newly injected testosterone into estrogen. Blocking the aromatizing enzyme can improve and maintain injected testosterone.

In fact, aromatase inhibitors such as Arimidex (Anastrozole) can be used in men with elevated estrogen levels for the primary treatment of hypogonadism and increase testosterone levels without impairing fertility.

Estrogen Response during Testosterone Replacement Therapy (TRT)

Men who are administered testosterone in any formulation (injection, topical gel, topical cream, pellet, or patch) will have a corresponding rise in estradiol levels. In particular, testosterone injections, such as testosterone cypionate or testosterone enanthate, will have a higher rise in estradiol levels than other testosterone formulations. A study by Amory et. al also found that men on combined Testosterone enanthate and Finasteride had a greater increase in estradiol levels than man on Testosterone enanthate by itself. This may be a result of finasteride blocking the conversion of Testosterone to DHT and providing more substrate for aromatase to act upon.

There is a greater increase in estradiol levels in older men and more obese men on testosterone. As thus, this particular population of men and men on finasteride who are on TRT should have their estradiol monitored and advised.

The Role of Estrogen and Erectile Function

Estrogen may play a role in male orgasm, penile detumescent and penile erection. Estrogen receptors and the aromatase enzyme do reside in penile tissue. Studies have confirmed that penile development is also an estrogen dependent process in addition to testosterone. While the exact mechanism and pathway estrogen plays during an erection is still be understood, through clinical observation men with very low or even very high estrogen levels can have erectile dysfunction and decreased sexual desire. The goal of estrogen monitoring and treatment is to keep estrogen levels stable and within a specific and tailored range.

Sexual desire is an androgen dependent process, principally a result of testosterone. Much less is known about the role of estrogen in male sexual desire. It is believed that the ratio of testosterone to estrogen is the important factor in male sexual behavior rather than the presence of one individual hormone alone. In an interesting observational study in men who do not have the aromatase enzyme (aromatase-deficient men), estrogen supplementation increased sexual behavior.

It is important for any man who is undergoing to undergo testosterone replacement therapy (TRT) or estrogen management, to understand that estrogen (principally estradiol) plays a pivotal role during treatment. The goal of therapy should not be to lower estradiol levels to undetectable levels as this could affect male sexual behavior, desire and erectile function. The balance should be focused on the ratio of testosterone to estradiol levels in addition to keeping estradiol within a specific therapeutic range.

Arimidex

The most widely used medication to manage estrogen levels during TRT is Arimidex. Arimidex is an aromatase inhibitor (AI). Aromatase acts upon testosterone and breaks it down by a process called aromatization into estradiol (a form of estrogen). The aromatase enzyme has found to be present in the testicles, brain, fat tissue, muscle, hair, and vascular tissues. In men Arimidex is used off -label.

AI’s are classified into two categories, either steroidal and non-steroidal and by generation (first, second and third generations). Steroidal aromatase inhibitors are commonly not utilized in men on TRT. Steroidal aromatase inhibitors bind to aromatase strongly (irreversibly). Non-steroidal aromatase inhibitors, such as Anastrozole (Arimidex) reversibly bind to aromatase.

Arimidex is a third generation AI. Third generation AI’s do not completely inhibit the aromatase enzyme completely. This partial inhibition of aromatase may impart some benefit when used in men because it allows some degree of estrogen production. Complete absence or very low levels of estrogen in men can be detrimental affecting sexual function vascular health, and weight gain.

While Arimidex is known to reduce estrogen in men by inhibiting aromatase, the medication can also increase testosterone production. Arimidex prevents estrogen from blocking pituitary signals that stimulate testosterone production, mainly LH and FSH. In several clinical studies Arimidex given 1mg daily has been shown to increase, often double, bioavailable testosterone. Unlike TRT, patients who use Arimidex as mono therapy do not experience a rise in hematocrit and hemoglobin levels or an elevation in prostate- specific antigen (PSA).

A study in 2004 by Leder et al. reveled that anastrozole was able to in raise testosterone levels in men with Low-T. Also, a randomized placebo-controlled study by Massachusetts General Hospital and Harvard Medical School to assess the effects of anastrozole on testosterone levels found testosterone values peaked at 3 months compared to the placebo group and estradiol levels decreased significantly in men on anastrozole mono therapy. During the study clinicians found no change in PSA, worsening of lower urinary tract symptoms (LUTS) , hemoglobin and hematocrit levels. Of primary importance, despite a rise in testosterone levels the body composition and strength improvements normally accompanied by TRT was not witnessed in men on anastrozole mono therapy.

To Learn more about Arimidex click here.

According to the American Urologic Association guideline Arimidex, for off label use in men, Arimidex is dosed at 0.05 to 1mg every three days. Side effects of the medication include hot flashes, dyspnea, peripheral edema, and bone pain.

Selective Estrogen Receptor Modulators (SERMS)

Pharmaceutical medications such as Clomid (Clomiphene Citrate) and Tamoxifen are selective estrogen receptor modulators (SERM’S). SERMs act to block the estrogen receptor in target tissues and glands. This is different that Anastrozole which inhibits the enzymes that converts testosterone in to estrogen. By blocking the estrogen receptor in the pituitary or hypothalamus, estrogen is unable to impact signaling hormones that stimulate testosterone production. Furthermore, SERM’s act to decrease tissue responses to estrogen. For instance in men on TRT, the increase in estrogen can stimulate breast tissue enlargement (Gynecomastia). The use of SERM’s can prevent male breast tissue from enlarging or shrink breast tissue that has enlarged.

Tamoxifen

Tamoxifen is an off-label medication used in men to prevent and treat gynecomastia. Tamoxifen exerts an effect by binding to estradiol (E2) receptors in estrogen sensitive tissues (such as the male breast) and prevents estrogen from exerting an effect. Tamoxifen has and can be used in men on TRT who experience gynecomastia. Gynecomastia is enlargement of male breast tissue and is a result of an imbalance between testosterone and estradiol levels. The use of Tamoxifen (20mg daily) can reduce breast tissue enlargement in men on TRT. Arimidex can also be used in combination with Tamoxifen to combat male breast tissue enlargement.

According to the American Urologic Association guideline Tamoxifen, for off label use in men, is dosed at 20mg orally daily. Side effects of the medication include liver enzyme changes, ocular (eye) changes and increased risked of thromboembolic events.

Clomid

Clomiphene Citrate (Brand name Clomid) is a selective estrogen receptor modulator. Initially developed in the 1960’s to treat female infertility, Clomid is commonly used off-label in men to treat male infertility and low testosterone. In men with Low-T, Clomid is an excellent and effective oral medication to raise serum testosterone levels and improve the testosterone to estradiol ratio. Clomid can improve and raise testosterone. In some men Clomid can raise testosterone above 1000 ng/dL. Clomid works by blocking the estrogen receptor leading to an increase in both FSH and LH. These two signaling hormones released by the pituitary stimulate the testis to raise testosterone levels and enhance spermatogenesis (sperm production).

For more information on Clomid click here.

When to Measure Estrogen in Patients on Testosterone Replacement Therapy

According to the American Urologic Association guidelines for testosterone replacement therapy, there are specific instances and situations estrogen levels should be measured.

In men with low testosterone who present with breast symptoms or gynecomastia., a clinician should check an estradiol level at baseline.

Optional to measure Estradiol levels in all patients with testosterone deficiency at baseline to assess pre-testosterone therapy level.

Optional to measure Estradiol in all patients who are using SERMs.

Treating Elevated Estrogen (Estradiol/ E2) in Men on TRT.

In men who use testosterone there is evidence that a corresponding rise in estradiol levels will result. A clear indication for the treatment of estradiol levels in men on TRT is the development of breast tenderness or enlargement of breast tissue while on therapy. In some clinical practices, men who are on Testosterone therapy also provided Arimidex form the start. This practice may be performed secondary to prior research that men on combination Testosterone therapy and Arimidex compared to Testosterone alone had greater sexual drive and interests. Other clinical practices have preferred to observe the rise in estradiol while on testosterone therapy before treating.

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Sources

Nieschlag et al. Testosterone Action, Deficiency, Substitution. Fourth Edition, Published 2004.

Tan et. al. Clinical use of Aromatase Inhibitors in Adult Males. Journal of Sexual Medicine. April 2014. Vol. 2. Iss. 2. Pages 79-90.

Wheeler et. al. Clomiphene Citrate for the Treatment of Hypogonadism. Journal of Sexual Medicine. April 2019 Vol. 7, Iss 2, Pages 272-276.

Kacker et. al. Estrogens in Men: Clinical Implications for Sexual Function and the Treatment of Testosterone Deficiency. June 2012 Volume 9. Issue 6 Pages 1681-1696.