AUA2021 Second Opinion Cases: Role of Medical Therapy in the Treatment of Azoospermia Following Testosterone Therapy

By: Larry I. Lipshultz, M.D.; Sarah Vij, MD; Peter N. Schlegel, MD | Posted on: 03 Sep 2021

Case Study

Historically, testosterone is a bad contraceptive–unreliable, inconsistent and with poor compliance. Ironically, its use as a performance-enhancing drug leaves many younger men seeking medical advice for their infertility and resultant substandard semen quality following testosterone use. Exogenous testosterone and its aromatized byproduct, estradiol, suppress spermatogenesis, with 65% of men from one contemporary contraceptive series experiencing azoospermia.1 All testosterone preparations can do this–topicals, oral and injectables–some more quickly and more effectively than others. As serum testosterone and estradiol increase with exogenous testosterone use, there is a resultant negative feedback on the androgen and estradiol receptors in the hypothalamus and pituitary, resulting in decreased concentrations of FSH and LH. Spermatogenesis is primarily regulated by the synergistic action of FSH on Sertoli cells combined with high intratesticular levels of testosterone. Interestingly, the Sertoli cells alone contain receptors for both FSH and testosterone.

There are 2 general approaches to treating azoospermia secondary to testosterone or other exogenous androgen-suppressed cases of impaired spermatogenesis. Both include reversal of the gonadotropin-suppressive effects of testosterone or other androgens. The cessation of testosterone as well as the manipulation of direct or indirect pathways for reestablishing gonadotropin stimulation of spermatogenesis will be addressed by our 2 treating physicians.

Opinion 1: Sarah C. Vij, MD

Allow the hypothalamic-pituitary-gonadal (HPG) axis to reestablish a baseline by offering only symptomatic care.

Fortunately, the great majority of men on exogenous testosterone therapy will recover spermatogenesis without intervention apart from withdrawing therapy. The recovery process may be somewhat prolonged which can pose a problem in a couple where the female partner is of advanced age. In this scenario, supplementation to hasten recovery is sensible. The challenge of simply withdrawing therapy and allowing for recovery of the HPG axis and sperm production is that many men are symptomatic when testosterone replacement therapy is stopped. In men whose symptoms are absent or not significant, observation off therapy is a very reasonable pathway. Liu et al reviewed an aggregate of studies examining time to recovery and predictors of timely recovery in healthy men on testosterone replacement therapy who were observed off therapy.2 Predictors for rapid recovery included older age, Asian origin, shorter treatment duration, shorter acting testosterone replacement preparations, higher sperm concentrations at baseline, faster suppression of spermatogenesis and lower baseline luteinizing hormone levels. The probability of recovery to 20M/ml was 67% by 6 months and 100% by 24 months. Based on these data, observation is an acceptable pathway in men who are asymptomatic and whose partners have reasonable fertility potential.

Opinion 2: Peter N. Schlegel, MD

Reestablish normal gonadotropin production with either direct replacement or indirect stimulation.

The primary adverse effect of exogenous androgens on spermatogenesis is via the suppression of LH and FSH production by the pituitary. Intervention is intended to increase LH production by the pituitary or LH-like action through hCG treatment. This can be provided with hCG injections while testosterone/exogenous androgens are still being received or to induce pituitary production of LH by manipulating estrogen stimulation of the pituitary with selective estrogen receptor modulators (SERMs; eg clomiphene) or aromatase inhibitors (eg anastrozole). The induction of LH production is possible because the pituitary senses circulating testosterone levels (and hence affects LH production) by detection of circulating estrogens. SERMs block estrogen action, so the pituitary senses lower circulating estrogen levels and increases LH production. Aromatase inhibitors decrease testosterone-to-estrogen conversion, resulting in lower estrogen levels in circulation, again enhancing pituitary production of LH. These agents will shorten time to recovery of spermatogenesis after exogenous testosterone has been stopped, but they can also be used for men receiving exogenous testosterone,3 allowing increased LH and FSH production.

For men who do not symptomatically tolerate withdrawal of exogenous testosterone, hCG can be provided while continuing exogenous androgens to stimulate return of spermatogenesis.4 hCG monotherapy treatment has the disadvantage of effecting suppression of FSH production, which limits spermatogenic potential to some degree. FSH replacement can also be used, but that treatment is expensive, although less so with compounded FSH.

Monitoring of endogenous testosterone production is more complicated with maintenance of exogenous testosterone treatment, but it is possible to detect endogenous testosterone production by measuring circulating 17-OH progesterone levels, which reflects the endogenous testosterone pathway and is the best measure of intratesticular testosterone production.5 Measurement of 17-OH progesterone allows earlier monitoring of the efficacy of treatment for men being treated to enhance return of spermatogenesis; hormonal changes can be detected within a month or less, far before changes in semen analysis. For men who cease exogenous testosterone use, measurement of serum testosterone concentration following SERM or aromatase inhibitor treatment provides early feedback on the adequacy of endogenous testosterone production. Doses used for hCG may vary from 500 IU daily to 2500 IU twice a week, with 50 mg every other day for clomiphene and 1 mg daily for anastrozole. A wide variety of treatment doses have been used clinically, and treatment may need to be adjusted based on individual patient hormonal response.

Conclusion

The case described herein will doubtlessly become increasingly common. Several additional interventions are suggested. If you are the treating physician who first starts the testosterone therapy, try to get a baseline semen analysis in all men in their reproductive years. This serves as a target when starting a reboot protocol and makes it much easier to know when you have reached maximal semen quality for this individual. More aggressive treatment should be instituted if the partner is over 35, especially if she is demonstrating decreased ovarian reserve. It should also be appreciated that spermatogenesis following testosterone suppression will return in a progressive manner. Therefore, if the patient is finding the symptoms of hypogonadism extremely unbearable, or again if the partner is over 35, one can suggest going to IVF early during the course of the reboot protocol, since many fewer sperm are necessary to produce an IVF pregnancy. By incorporating the 2 pathways suggested by our “second opinion” physicians, as well as the suggestions found in the conclusion, the treating physician will experience a more successful therapeutic outcome for these difficult patients, many of whom will become some of your most appreciative parents.

  1. Patel AS, Leong JY, Ramnos L et al: Testosterone is a contraceptive and should not be used in men who desire fertility. World J Mens Health 2019; 37: 45.
  2. Liu P, Swerdloff RS and Christenson P: Rate, extent and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet 2006; 367: 1412.
  3. Mehta A, Bolyakov A, Roosma J et al: Successful testicular sperm retrieval in adolescents with Klinefelter syndrome treated with at least 1 year of topical testosterone and aromatase inhibitor. Fertil Steril 2013; 100: 970.
  4. Wenker EP, Dupree JM, Langille GM et al: The use of HCG-based combination therapy for recovery of spermatogenesis after testosterone use. J Sex Med 2015; 12: 1334.
  5. Amory JK, Coviello AD, Page ST et al: Serum 17-hydroxyprogesterone strongly correlates with intratesticular testosterone in gonadotropin-suppressed normal men receiving various dosages of human chorionic gonadotropin. Fertil Steril 2008; 89: 380.
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