• Leo Rex

Thwarting the Negative Feedback Signal

Updated: Apr 27, 2020

This blog post is a continuation in a series on the recovery of men’s natural testosterone production and fertility after the use of anabolic and androgenic steroids.

To watch the video that accompanies this article, click here.

To review the previous article in this series, click here.


So far, we have learned that the brain’s hypothalamus signals to the pituitary to produce the gonadotropins LH and FSH. LH increases intratesticular testosterone (ITT) and FSH promotes the differentiation and maturation of sperm. When testosterone and estrogen levels are high, they produce a feedback signal that instructs the hypothalamus to cease signaling to the pituitary to produce gonadotropins.

In the previous blog post, we discussed hCG, hMG, and rFSH, which improve spermatogenesis by simulating the behavior of endogenous LH and FSH. We noted that hCG has been successful as a monotherapy, but that overall, better results are seen when rFSH is added subsequent to hCG administration.

In this blog post, we will discuss the two categories of drugs that are used to lessen the negative feedback signal that results from heightened estrogen levels.


While hCG and hMG/rFSH are used to mimic the role of endogenous LH and FSH in the body, SERMs block estrogen feedback, which is a reason for the lack of activity at the hypothalamus that leads to the initial cessation of LH and FSH production at the pituitary. While hCG and hMG bypass the brain, which is the root of the problem, and try to mimic its signaling, SERMS (and AIs) go to the root of the problem.

SERMs can therefore increase GnRH at the hypothalamus, leading to production of endogenous LH and FSH at the pituitary and resulting in increases in intratesticular testosterone (ITT)[1]. For this purpose, tamoxifen and clomiphene citrate (CC) have been used extensively.

CC (brand names Clomid and Serophene) is a mix of the short acting enclomiphene, which is purely an estrogen antagonist, and the long-acting zuclomiphene, which has antagonist and agonist characteristics. CC has a half-life of 5 days[2]. Recently, enclomiphene citrate (EC), the pure antagonist, has been used alone at doses of 25 mg daily in several promising trials, but the FDA has yet to approve it[3][4][5].

In the clinic, CC is used at doses of 25-100mg daily or every other day. Although it is routinely shown to improve serum testosterone levels and alleviate hypogonadal symptoms, its efficacy for improving fertility as a monotherapy is less clear, though there is evidence to support it[6]. Its effect on sperm count is unpredictable, as there are case reports of it reducing sperm count[7]. It is tempting to speculate that EC would produce more uniform results due to a lack of agonism at the estrogen receptors.

Although women experience severe mental side effects from CC, it is tolerated better by men[8][9].


The aromatase enzyme synthesizes estrogen from testosterone. Aromatase inhibitors, which are continually being made more specific, can decrease estrogen levels in men, thereby reducing the feedback inhibition to the HPG axis. In a manner similar to that which results from SERM use, AIs can increase production of LH and FSH from the pituitary. Usually, AIs are prescribed to obese men and those that exhibit a testosterone to estrogen ratio less than 10, though they are also prescribed to limit the estrogen increase that results from hCG monotherapy[10].

At 1 mg a day, the AI anastrozole has been shown to improve spermatogenesis in men with low sperm count and low sperm motility[11], although its effect on men with low sperm motility is less clear[12]. The newer, more selective letrozole, administered at 2.5 mg daily as a monotherapy, has been shown to improve spermatogenesis in about 20% of men with low sperm count or sperm motility[13].


While SERMs are usually well-tolerated and can even be protective[14][15], AIs elevate liver enzymes in nearly 20% of patients and may be causal in the development of pulmonary embolisms[16]. They can also worsen bone mineral density[17].

A study comparing CC (at 25 mg daily) and anastrozole (at 1 mg daily) showed that CC had a greater impact on testosterone levels, while anastrozole, naturally, had a better impact on testosterone-to-estrogen ratios[18]. For this reason, it has been postulated that a combination of the two may be ideal.

Having discussed the problem, and the tools, we shall next discuss speculative solutions.

To read the next article in this series, click here.

To return to the previous article in this series, click here.

[1] Goldstein, S. R., Siddhanti, S., Ciaccia, A. V., & Plouffe Jr, L. (2000). A pharmacological review of selective oestrogen receptor modulators. Human reproduction update, 6(3), 212-224. [2] Shelly, W., Draper, M. W., Krishnan, V., Wong, M., & Jaffe, R. B. (2008). Selective estrogen receptor modulators: an update on recent clinical findings. Obstetrical & gynecological survey, 63(3), 163-181. [3] Kaminetsky, J., Werner, M., Fontenot, G., & Wiehle, R. D. (2013). Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. The journal of sexual medicine, 10(6), 1628-1635. [4] Wiehle, R., Cunningham, G. R., Pitteloud, N., Wike, J., Hsu, K., Fontenot, G. K., ... & Podolski, J. (2013). Testosterone restoration using enclomiphene citrate in men with secondary hypogonadism: a pharmacodynamic and pharmacokinetic study. BJU international, 112(8), 1188-1200. [5] Wiehle, R. D., Fontenot, G. K., Wike, J., Hsu, K., Nydell, J., Lipshultz, L., & ZA-203 Clinical Study Group. (2014). Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone. Fertility and sterility, 102(3), 720-727. [6] Hussein, A., Ozgok, Y., Ross, L., & Niederberger, C. (2005). Clomiphene administration for cases of nonobstructive azoospermia: a multicenter study. Journal of andrology, 26(6), 787-791. [7] Pasqualotto, F. F., Fonseca, G. P., & Pasqualotto, E. B. (2008). Azoospermia after treatment with clomiphene citrate in patients with oligospermia. Fertility and sterility, 90(5), 2014-e11. [8] Kaminetsky, J., & Hemani, M. L. (2009). Clomiphene citrate and enclomiphene for the treatment of hypogonadal androgen deficiency. Expert opinion on investigational drugs, 18(12), 1947-1955. [9] Moskovic, D. J., Katz, D. J., Akhavan, A., Park, K., & Mulhall, J. P. (2012). Clomiphene citrate is safe and effective for long‐term management of hypogonadism. BJU international, 110(10), 1524-1528. [10] Kim, E. D., Crosnoe, L., Bar-Chama, N., Khera, M., & Lipshultz, L. I. (2013). The treatment of hypogonadism in men of reproductive age. Fertility and sterility, 99(3), 718-724. [11] Ramasamy, R., Ricci, J. A., Palermo, G. D., Gosden, L. V., Rosenwaks, Z., & Schlegel, P. N. (2009). Successful fertility treatment for Klinefelter's syndrome. The Journal of urology, 182(3), 1108-1113. [12] Raman, J. D., & Schlegel, P. N. (2002). Aromatase inhibitors for male infertility. The Journal of urology, 167(2 Part 1), 624-629. [13] Saylam, B., Efesoy, O., & Çayan, S. (2011). The effect of aromatase inhibitor letrozole on body mass index, serum hormones, and sperm parameters in infertile men. Fertility and sterility, 95(2), 809-811. [14] Lewis, J. S., & Jordan, V. C. (2005). Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 591(1-2), 247-263. [15] Yoshikawa, Y., Miyashita, T., Higuchi, S., Tsuneyama, K., Endo, S., Tsukui, T., ... & Yokoi, T. (2012). Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries. Toxicology and applied pharmacology, 264(1), 42-50. [16] Burnett‐Bowie, S. A. M., Roupenian, K. C., Dere, M. E., Lee, H., & Leder, B. Z. (2009). Effects of aromatase inhibition in hypogonadal older men: a randomized, double‐blind, placebo‐controlled trial. Clinical endocrinology, 70(1), 116-123. [17] Burnett-Bowie, S. A. M., McKay, E. A., Lee, H., & Leder, B. Z. (2009). Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels. The Journal of Clinical Endocrinology & Metabolism, 94(12), 4785-4792. [18] Helo, S., Ellen, J., Mechlin, C., Feustel, P., Grossman, M., Ditkoff, E., & McCullough, A. (2015). A randomized prospective double‐blind comparison trial of clomiphene citrate and anastrozole in raising testosterone in hypogonadal infertile men. The journal of sexual medicine, 12(8), 1761-1769.

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