Medications to Manage Fertility Suppression on Testosterone Cypionate: First-Line and Beyond

Why testosterone cypionate suppresses sperm

The Depo-Testosterone label states that during exogenous androgen administration, the body's own testosterone release is inhibited through feedback inhibition of pituitary luteinizing hormone (LH), and that at large doses this extends to follicle stimulating hormone (FSH) [3]. The same label lists oligospermia among adverse reactions, noting it may occur at high dosages [3].

Sperm production depends on testosterone inside the testicle, not just in the blood. In a study of 29 healthy men receiving weekly testosterone enanthate, intratesticular testosterone fell 94%, from 1234 to 72 nmol/L, in the group given saline instead of hCG [6]. At baseline, serum testosterone was only about 1.2% of the intratesticular concentration [6].

First-line: decide about fertility before the first injection

The Endocrine Society's 2018 guideline recommends against starting testosterone therapy in men who are planning fertility in the near term [1].

For men who became azoospermic or severely oligospermic on testosterone, two treatment approaches have been reported. One added clomiphene, tamoxifen, anastrozole or recombinant FSH to hCG [2]. The other was a retrospective study of men who stopped testosterone and received high-dose hCG plus a selective estrogen receptor modulator (SERM) [4].

hCG: the drug with the most data

hCG substitutes for the LH signal that testosterone suppresses. In a randomized study of 29 healthy men, all received 200 mg of testosterone enanthate weekly plus either saline or hCG at 125, 250 or 500 IU every other day for three weeks [6]. Intratesticular testosterone fell 94% in the saline group and rose in a straight line with hCG dose (P<0.001) [6]. After three weeks, intratesticular testosterone was 25% below baseline at 125 IU, 7% below at 250 IU, and 26% above baseline at 500 IU [6].

The endpoint in that study was intratesticular testosterone sampled by fine needle aspiration, not sperm. It shows that fairly small hCG doses maintained the testicular testosterone pool while exogenous testosterone was given.

The clinical series used a much larger dose. Forty-nine men from two infertility clinics who had azoospermia or severe oligospermia (under 1 million sperm/mL) while taking exogenous testosterone were started on hCG 3,000 units subcutaneously every other day, plus clomiphene citrate, tamoxifen, anastrozole or recombinant FSH according to physician preference [2]. Spermatogenesis returned or improved in 47 men (95.9%), with one additional pregnancy recorded without a follow-up semen analysis [2]. Average time to return was 4.6 months and mean first sperm density was 22.6 million/mL [2]. There was no significant difference in recovery by type of testosterone used [2].

That series is retrospective, has no control group, and let the treating physician pick the add-on drug, so it cannot show which component did the work. Its abstract does not say whether testosterone was continued during treatment, and the 3-week hCG study did not measure sperm production [2][6].

Beyond hCG: what the add-on drugs contribute

The four add-ons in that series (clomiphene, tamoxifen, anastrozole and recombinant FSH) were chosen per physician preference, and the report does not give their doses or compare them [2]. Anastrozole belongs to a different class (an aromatase inhibitor) than the SERMs clomiphene and tamoxifen, and recombinant FSH acts directly on the FSH receptor rather than on estrogen feedback.

Stopping testosterone: what recovery looks like

Some men stop testosterone rather than add drugs to it. In a retrospective study of 66 men with infertility after testosterone use, all stopped testosterone and started high-dose hCG plus a SERM; 46 (70%) reached a total motile count above 5 million within 12 months [4]. Recovery was less likely in men who started with azoospermia (64.8% reached that threshold versus 91.7% of men with cryptozoospermia), and both older age and longer duration of testosterone use predicted slower recovery [4].

Recovery is also possible without drug treatment, but the best numbers come from a different population. An integrated analysis of 30 studies covering 1,549 healthy eugonadal men on androgen or androgen-progestin contraception found a median of 3.4 months for sperm concentration to return to 20 million/mL [5]. Recovery to that threshold was 67% within 6 months, 90% within 12 months, 96% within 16 months and 100% within 24 months [5]. Faster recovery was associated with shorter-acting testosterone, shorter treatment, older age and a higher baseline sperm count [5]. These men were fertile volunteers suppressing normal sperm production, not men with hypogonadism on replacement therapy, so the timelines are a reference point rather than a prediction.