Best Way To Control Estradiol On TRT

Men naturally have some Estrogen in their bodies, but too much can be detrimental, and even cause Gyno. What is the best way to control Estradiol On TRT?

Most men think of estrogen as an exclusively female hormone, but You know what?! men also produce it. Testosterone is the precursor of estradiol, an estrogen, and the primary female sex hormone.

Testosterone is converted into estradiol via the aromatase enzyme and therefore being on testosterone replacement therapy (TRT) can potentially elevate estrogen levels.

Fortunately, most men on standard TRT dosages do not experience high estradiol levels. Nevertheless, genetically predisposed men may experience symptoms associated with high levels, which may lead to certain unwanted side effects.

Want to know more on the Best Way To Control Estradiol On TRT? Here you go…

What is Estrogen?

Best Way To Control Estradiol On TRT

Key Takeaways

  • Estrogens may contribute to the persistence of sexually stimulated erectile function when serum testosterone is severely depressed
  • Naturally occurring elevations in E2 are harmful with respect toconcerning testosterone levels or sexual function
  • E2 may increase during TRT, but elevations above the normal range are uncommon
  • Elevations in E2 may resolve with prolonged TRT
  • Symptoms of estrogen excess, such as gynecomastia or nipple tenderness, are rare
  • Men who experience such symptoms should consider temporary or permanent discontinuation of TRT
  • The routine use of aromatase inhibitors with TRT is not recommended, unless needed
  • When an aromatase inhibitor is used, it should be titrated so that E2 levels remain above 40 pmol/L to preserve bone health

While estrogens are defined by their feminizing effects, they are found in both genders. Estrogen is a hormone that is not only prevalent in females but also plays an important role in male physiology. [1]

Estrogens have been known to be present in substantial concentrations in men for several decades, yet their role in male physiology remains an area of considerable uncertainty and controversy. [1]

Because of the increased interest in testosterone (T) deficiency and testosterone replacement therapy (TRT), there has been renewed interest in estrogens, particularly their role in sexual function. [1]

It is well known that men on testosterone replacement therapy will have a corresponding rise in their estrogen level. Therefore, Monitoring and managing estrogen levels are paramount to optimizing testosterone therapy results. [1]

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 investigated. [1]

In men on Testosterone replacement therapy who look to optimize performance, sex drive, muscle growth, and weight loss, estrogen management must also be a component of therapy. [1]

Testosterone and estrogen are strongly linked, as testosterone is a major source of estradiol (E2) via aromatization. [1]

Endogenous estrogens in humans are found as estrone (E1), 17b-estradiol (E2), and estriol (E3).

Of all known estrogens, E2 has the highest affinity for the estrogen receptors (ERs) and is the most biologically active. [2]

Estrogen Production In Men

In men, E2 is primarily produced via peripheral aromatization of serum testosterone. However, about 20% of serum E2 in men is produced by Leydig cells in the testes. [1]

Aromatization of the adrenal androgen androstenedione produces E1, a small portion of which is converted to E2 [3].

As with testosterone, a substantial fraction of E2 is bound to sex-hormone binding globulin (SHBG) and this fraction is not considered to be biologically active. [1]

Factors Affecting Estrogen Production In Men

Aging

As men age testosterone production declines and the ratio of estrogen to testosterone rises in favor of estrogen.

Testosterone Concentrations

Serum estrogen levels in men are mediated byseveralf factors. As testosterone is the substrate for approximately 80% of serum E2, changes in serum testosterone concentrations will affect E2 levels. [1]

Body Mass Index (BMI) and Obesity

Multiple studies have reported higher E2 levels in obese men and a direct relationship between E2 and BMI [4].

Men with Low testosterone who are on TRT are expected to experience rises in estrogen levels. This is more pronounced in obese males who have a significant amount of fat cells that have a lot of aromatase.

Men who are obese tend to have higher estradiol levels than men of normal weight.

Vermeulen et al. determined that subcutaneous fat as measured by computed tomography in obese men aged 30–60 was significantly and strongly associated with free E2, whereas abdominal fat was not [5].

Obese men usually suffer from a metabolic syndrome which is presented with obesity, high blood pressure, high blood sugar, and high cholesterol.

Obese men with metabolic syndrome have low testosterone levels and elevated estrogen levels. They also tend to have lower Sex Hormone Binding Globin (SHBG) levels.

Given the higher density of adipose (fat cells) in obese men, which is the primary source for aromatase, obese men tend to aromatize estrogen more than the normal weight individuals, leading to more testosterone being broken down into estrogen.

Aromatase Activity and Adipose Tissue (Fat Cells)

Aromatase is mainly found in adipose tissues (the central fat deposits of the abdomen). The more central fat cells a man has the more aromatase enzyme that is present.

Role of Estrogen in Men

The Role of Estrogen in Testosterone Production

Estrogen is a breakdown product of testosterone. It controls the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus and the release of Luteinizing Hormone (LH) from the pituitary gland.

GnRH and LH, are necessary for testosterone production. Estrogen can act to block the release of these signaling hormones and halt testosterone production. Therefore, monitoring and managing Estrogen levels during TRT are crucial.

High estrogen levels lead to a decrease in testosterone production.

Bone Health

The impact of estrogens on bone health in men is well studied. Longitudinal studies have shown that low total and bioavailable E2 levels are associated with an increased rate of bone loss, with increased risk at a threshold of 40 pmol/L [6].

Males with low E2 levels from congenital aromatase deficiency exhibited tall stature, persistent linear growth, and delayed bone age, and osteopenia/osteoporosis. [1]

Cardiovascular Health and Metabolism

Testosterone and E2 together may facilitate endothelial-dependent vasodilation and prevent atherogenesis [1].

Men with congenital aromatase deficiency exhibited symptoms of metabolic syndrome including abdominal fat accumulation and impaired insulin sensitivity. [1]

Causes of Elevated Estrogens in Men

The upper limit of normal for E2 in men is not clinically defined. Laboratory reference ranges are assay dependent, but the upper bound is often stated as approximately 50 pg/mL or 160 pmol/L. [1]

Obesity

Obesity is associated with an increase in E2 [1], likely secondary to increased aromatase activity in subcutaneous and gluteal fat [5].

Interestingly, E2 was reduced in obese men 2 years after gastric bypass surgery, and SHBG was increased, resulting in an even greater decrease in bioavailable E2 [1].

Antiepileptic Drugs

Antiepileptic drugs, such as phenytoin and carbamazepineof, are associated with high E2 levels in men with sexual dysfunction [1]. It has been suggested that this is secondary to increased aromatase activity.

Elevated Estrogen Levels and Testosterone Deficiency

Administration of exogenous estrogen at pharmacologic doses and, in rare cases, estrogen hypersecretion from adrenal tumors are known to down-regulate testosterone through gonadotropin suppression [1].

Anabolic Steroids

Administration of Anabolic Steroids that do interact with the Aromatase enzyme can lead to great elevations of Estrogen in the body.

Symptoms of High Estrogen in Men on TRT

  • Fat gain around the stomach
  • Puffy ankles (look for sock marks)
  • Puffy or sensitive nipples
  • Unexplained emotions (sad, crying, etc)
  • Erectile dysfunction

Estrogen Modulators in Testosterone Deficient Men

Clomiphene citrate and tamoxifen are classified as selective ER modulators (SERMs). The SERMs and their metabolites modulate ER activation by inducing conformation changes to the ER and selectively altering signal transduction. [1]

Clomiphene Citrate (Clomid)

Clomiphene citrate or Clomid is a selective estrogen receptor modulator particularly when maintenance of fertility is desired, as treatment does not reduce gonadotropins or sperm concentration. [1]

It has been primarily used for infertility treatment in both genders for over 50 years. [7]

It selectively blocks estrogen receptors in the hypothalamus and pituitary, thereby increasing gonadotropin-releasing hormone, luteinizing hormone, and follicle-stimulating hormone release. This boosts endogenous testosterone levels. [7]

A previous study reported that clomiphene achieved testosterone levels comparable to those of testosterone gels. [8]

Other studies have shown improvement in erectile function with clomiphene citrate in men with secondary testosterone deficiency [10] and a recent nonrandomized study showed similar improvement in ADAM scores with clomiphene citrate compared with topical TTh [11].

Another study found that clomiphene significantly increased testosterone levels without changing prostate-specific antigen or hematocrit values. [9]

Clomiphene is a less expensive alternative to testosterone replacement with the added benefit on fertility. [7]

Tamoxifen (Nolvadex)

Elevated estrogen levels can stimulate male breast enlargement (gynecomastia). Tamoxifen or Nolvadex has and can be used in men on TRT who experience gynecomastia, as it will block estrogen at the breast tissue.

Tamoxifen can decrease bone turnover and increase bone mineral density. [1]

Tamoxifen has also been shown to raise testosterone levels and may be effective in the treatment of male infertility. [1]

Aromatase Inhibitor

Anastrozole (Arimidex)

The use of aromatase inhibitors such as Arimidex or Anastrozole can stop this conversion and breakdown of testosterone.

Arimidex is an aromatase inhibitor. Aromatase acts upon testosterone and breaks it down by a process called aromatization into estradiol. The aromatase enzyme has been found to be present in the testicles, brain, fat tissue, muscle, hair, and vascular tissues.

Many clinicians prescribed Arimidex by TRT to reduce the breakdown of testosterone and eventually reduce estrogen production and as a treatment for gynecomastia.

Aromatase inhibitors such as Arimidex can be used in men with elevated estrogen levels for the primary treatment of hypogonadism and increase testosterone levels without impairing fertility.

Aromatase inhibitors 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 Aromatase inhibitors.

While Arimidex is known to reduce estrogen in men by inhibiting aromatase. It can also increase testosterone production.

Unlike TRT, patients who use Arimidex as monotherapy do not experience an increase in hematocrit and hemoglobin levels or an elevation in prostate-specific antigen (PSA).

Estrogen Response To TRT

The response of estrogen to TRT was studied by Lakshman et al. In a group of young men and another group of older men. [1]

Both total and free E2 levels increased with TRT. There was a higher rate of aromatization in the group of older men which was explained by greater fat mass [1].

These results suggest that in Testosterone-deficient men, TRT increases serum E2, possibly with greater increases in older or obese men. [1]

Men who are receiving injectable TRT such as testosterone cypionate or testosterone enanthate will have a higher rise in estradiol levels than other testosterone formulations.

Elevated E2 During TRT: To Treat or Not To Treat?

TRT may lead to elevations in serum E2 and some cases to levels above the upper limit of normal. [1]

The development of nipple or breast tenderness or frank gynecomastia has been reported in association with TRT. [1]

In these cases, there is a clear indication for the use of aromatase inhibitors to reduce E2. Some authors recommend withdrawal first of TRT with subsequent resolution of symptoms, followed by the use of aromatase inhibitors together with reinitiation of TTh [1].

Some clinicians, particularly in the antiaging community, advocate the routine use of aromatase inhibitors with TRT even in the absence of symptoms of estrogen excess. [1]

These clinicians believe that maintaining a relatively low estrogen concentration improves male health and the efficacy of TRT. [1]

Conclusion

There is some evidence that estrogens may contribute to the persistence of sexually stimulated erectile function when serum testosterone is severely depressed, such as in men who have undergone castration for advanced prostate cancer men.

It does not appear that naturally occurring elevations in E2 are harmful concerning testosterone levels or sexual function. E2 may increase during TRT, but elevations above the normal range are uncommon.

Elevations in E2 may resolve with prolonged TRT.

Symptoms of estrogen excess, such as gynecomastia or nipple tenderness, are rare. Men who experience such symptoms should consider temporary or permanent discontinuation of TRT, or the addition of an aromatase inhibitor.

We do not recommend the routine use of aromatase inhibitors with TRT. In the absence of signs of estrogen excess, we also find no reason to recommend the use of aromatase inhibitors in men who experience positive benefits from TTh despite elevated or high-normal E2 concentrations.

When an aromatase inhibitor is used, it should be titrated so that E2 levels remain above 40 pmol/L to preserve bone health, and monitoring of bone mineral density with DXA is recommended.

Kacker, Ravi, Abdulmaged M. Traish, and Abraham Morgentaler. "Estrogens in men: clinical implications for sexual function and the treatment of testosterone deficiency." The journal of sexual medicine 9.6 (2012): 1681-1696.

Boothby L. Bioidentical hormone therapy: A review. Menopause 2004;11:356–67.

Saez JM, Morera AM, Dazard A, Bertrand J. Adrenal and testicular contribution to plasma oestrogens. J Endocrinol 1972;55:41–4.

Muller M, den Tonkelaar I, Thijssen JH, Grobbee DE, van der Schouw YT. Endogenous sex hormones in men aged 40–80 years. Eur J Endocrinol 2003;149:583–9.

Vermeulen A, Goemaere S, Kaufman JM. Sex hormones, body composition and aging. Aging Male 1999;2:8–11.

Khosla S, Melton J, Atkinson EJ, O’Fallon WM. Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J Clin Endocrinol Metab 2001;86:3555–61.

Francisco, Roshirl, et al. "Clomiphene for hypogonadism complicated by polycythemia." Baylor University Medical Center Proceedings. Vol. 32. No. 1. Taylor & Francis, 2019.

Ramasamy, Ranjith, et al. "Testosterone supplementation versus clomiphene citrate for hypogonadism: an age-matched comparison of satisfaction and efficacy." The Journal of urology 192.3 (2014): 875-879.

Chandrapal, Jason C., et al. "Characterising the safety of clomiphene citrate in male patients through prostate‐specific antigen, hematocrit, and testosterone levels." BJU international 118.6 (2016): 994-1000.

Guay AT, Bansal S, Heatley GJ. Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism. A double blind placebo-controlled trial with clomiphene citrate. J Clin Endocrinol Metab 1995;80:3546– 52

Taylor F, Levine L. Clomiphene citrate and testosterone gel replacement therapy for male hypogonadism: Efficacy and treatment cost. J Sex Med 2010;7:269–76.

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