Increasing numbers of men in the United States are initiating TST for the treatment of hypogonadism [3]. The majority of prescriptions for testosterone supplements come from endocrinologists (23.73%), followed by general practitioners (16.95%), and thirdly urologists (15.25%) [45]. Perhaps more alarming is the finding that up to 25% of urologists surveyed by the American Urological Association reported using testosterone therapy as a treatment for the indication of infertility despite the known contraceptive effect of testosterone supplementation [46]. Exogenous testosterone induces negative feedback inhibition on the hypothalamic-pituitary-gonadal axis, thus leading to atrophy of the germinal epithelium in otherwise normal men and suppressing spermatogenesis, with azoospermia inducible by 10 weeks of testosterone use [47]. Testicular atrophy is common with loss in volume due to both suppressed spermatogenesis and decreased Leydig cell function. While otherwise healthy men may demonstrate rebound of spermatogenesis after 6–18 months of abstinence from exogenous testosterone [47], up to 4–10% of patients with impaired spermatogenesis prior to TST may remain azoospermic after cessation of therapy, with significant implications for their future fertility [48]. Thus, in any patient who desires to maintain fertility and is considering TST, a semen analysis should be obtained prior to initiation of treatment to rule out idiopathic infertility or an undiagnosed hypogonadal state (e.g., Klinefelter’s syndrome ). Also previously discussed is the increasing population of men on anabolic-androgenic steroids (AAS) [4], many of whom are in their reproductive years, who may present with subfertility as a result of steroid-induced hypogonadism.

In the previous tion, hCG therapy was discussed as a means of replacing LH in hypogonadal men to promote restoration of intratesticular testosterone production. Intramuscular hCG has also been shown to reduce the impact of exogenous testosterone on intratesticular T levels, though data is scarce on its use in men previously on TST/AAS. A RCT was conducted with 29 healthy men receiving 200 mg per week of testosterone enanthate, who were also randomized to receive intramuscular saline placebo, 125, 250, or 500 IU hCG every other day for 3 weeks. Intratesticular testosterone levels and gonadotropins were assessed at days 0 and 21. Intratesticular T levels were suppressed by 94% in the T enanthate/placebo group, 25% in the T enanthate/125 IU hCG treatment group, and 7% in the T enanthate/250 IU hCG treatment group, and were actually increased 26% from baseline levels in the T enanthate/500 IU hCG treatment group [49]. Endogenous LH and FSH levels were not surprisingly suppressed to 5% and 3% of baseline, respectively, in the T enanthate/placebo group. This demonstrated that even supraphysiologic doses of TST can be countered by low-dose hCG to maintain normal levels of intratesticular testosterone. The effect on spermatogenesis was later shown in a retrospective study conducted on 26 hypogonadal men treated with TST via transdermal patches or intramuscular injections, as well as low-dose hCG. Serum total and free T, serum estradiol, semen parameters, and pregnancy rates were assessed. Pretreatment semen parameters included an average volume of 2.9 mL, concentration of 35.2 million/mL, motility of 49.0%, and forward progression of 2.3. There were no observed changes in semen parameters regardless of T formulation over more than 1 year of follow-up, none of the men became azoospermic during the treatment course, and 9 of 26 contributed to a pregnancy with their partners [50]. A recent multi-institutional series of men previously on TST with subsequent azoospermia or severe oligospermia were treated with hCG 3000 IU every other day and supplemented with either FSH, clomiphene citrate, tamoxifen, or anastrozole. Patients on these hCG-based combination therapies demonstrated a recovery of spermatogenesis to a mean density of 22 million/mL in 4 months [51]. These studies suggest a beneficial role for hCG therapy in hypogonadal men who desire both symptomatic relief via TST and preservation of fertility potential during their reproductive years. Data is even more limited on the use of hCG therapy for men with hypogonadism ondary to AAS use. Case reports have documented that hCG alone at doses of 2000 IU three times weekly to 10,000 IU once weekly can restore spermatogenesis and lead to clinical pregnancy [52–54]. hCG and FSH combination therapy (10,000 IU weekly and 75 IU daily, respectively) has also been reported with clinical success in restoring spermatogenesis [55].

The role of SERMs was previously discussed in the treatment of symptomatic hypogonadism via suppression of estrogenic negative feedback inhibition on the hypothalamic-pituitary-gonadal axis, thus promoting increased gonadotropins and downstream intratesticular testosterone production. Data on the use of clomiphene citrate for restoration of spermatogenesis is scarce. Case reports on the use of high-dose clomiphene (100 mg daily) in men with AAS-induced hypogonadism documented restoration of the normal hormonal axis within 2–3 months, but spermatogenesis was not assessed [56, 57]. Also, as mentioned in the previous paragraph, clomiphene in combination with hCG has demonstrated efficacy in recovery of spermatogenesis in men previously on TST [51]. Enclomiphene citrate is a more potent and shorter acting trans-isomer of clomiphene citrate that was evaluated in a randomized, open-label, controlled, phase IIB study designed to assess fertility in 12 men with ondary hypogonadism previously treated with 1% testosterone gel for a minimum of 6 months. After cessation of TST, morning total T values averaged 165 ± 66 pg/dL. The treatment group was then given 25 mg enclomiphene citrate and the control group received 1% testosterone gel with results compared at 3 and 6 months including serum total T, FSH, LH, and semen parameters. In follow-up, only enclomiphene citrate therapy was observed to restore both serum T levels and sperm counts while also elevating LH and FSH in the treatment group [58]. A later randomized, phase IIB, placebo-controlled, parallel, multicenter study of 73 men with ondary hypogonadism was conducted using two oral doses of enclomiphene citrate or 1% topical T gel. All men had either discontinued prior TST for at least 6 months or never been treated. This particular study population was notable for more severe hypogonadism and lower baseline serum T levels than prior studies. Again, enclomiphene was demonstrated to reverse low serum T and gonadotropins compared to placebo while preserving sperm production compared to the TST treatment group [59]. These findings have since been further validated in a phase III RCT [10]. As of this time, enclomiphene is not yet FDA approved for the treatment of male hypogonadism and further phase III studies are pending.

There are no prospective trials in the literature evaluating the use of aromatase inhibitors in men with hypogonadism ondary to TST or AAS use. The previously mentioned retrospective series by Wenker et al. evaluating hCG-based combination therapies (including AI) in men with azoo- or oligospermia following TST demonstrated a 98% success rate at restoring spermatogenesis with no differences noted between supplemental therapy administered with hCG and the type of TST used [51]. Patients who stand to benefit most from therapy with these agents will have low serum T and have a T/E₂ ratio of <10 [11, 13, 15, 16]; thus their role in restoration and maintenance of spermatogenesis in men previously on TST/AAS or who wish to continue TST/AAS will be limited and likely adjunctive.