Testosterone Cypionate and Fertility Suppression: The Biology of Why It Happens

Why does injected testosterone switch off sperm production?

The Depo-Testosterone label states the mechanism plainly: during exogenous administration of androgens, endogenous testosterone release is inhibited through feedback inhibition of pituitary luteinizing hormone (LH), and at large doses of exogenous androgens, through feedback inhibition of pituitary follicle stimulating hormone (FSH) [1].

LH is the pituitary signal that stimulates the Leydig cells of the testis to make testosterone. FSH acts on the Sertoli cells that support developing sperm. As LH falls, the testes make much less testosterone locally, and the high intratesticular concentration that sperm production depends on drops: in the enanthate study, testosterone inside the testes fell 94% in the group that did not receive hCG [2].

How far does intratesticular testosterone actually fall?

The clearest measurement in men comes from a randomized study of 29 men with normal reproductive physiology [2]. The men received 200 mg of testosterone enanthate weekly plus either saline placebo or 125, 250 or 500 IU of hCG every other day, for 3 weeks; testicular fluid was sampled by fine needle aspiration at baseline and at the end of treatment [2].

At baseline, serum testosterone was 14.1 nmol/L, which was 1.2% of the intratesticular concentration of 1174 nmol/L [2]. In the group given testosterone alone, LH fell to 5% and FSH to 3% of baseline, and intratesticular testosterone fell 94%, from 1234 to 72 nmol/L [2]. The study used enanthate rather than cypionate.

Does estradiol made from testosterone carry part of the feedback?

At least partly. In a study of 16 normal men, 9 took the aromatase inhibitor anastrozole 10 mg daily for 5 days; estradiol fell from 33 to 14 pg/mL, testosterone rose from 563 to 817 ng/dL, and gonadotropin levels increased significantly [5]. Twelve men in the same study had medical castration with ketoconazole, which lowered both estradiol and testosterone, and gonadotropins rose in that group as well [5]. Estradiol, made from testosterone by the enzyme aromatase, is part of what restrains gonadotropin secretion.

What the label lists for sperm and testes

The Depo-Testosterone adverse reactions section lists oligospermia at high dosages [1]. Its drug abuse section lists testicular atrophy, subfertility and infertility among reactions reported in men using anabolic androgenic steroids [1].

Recovery after stopping

The sperm recovery data come from two kinds of men: healthy volunteers in contraception trials [4], and men who became infertile on testosterone and were then treated with hCG-based regimens [6][7].

The largest dataset is an integrated analysis of 30 hormonal male contraception studies, 1549 healthy men with normal testosterone production, on androgen or androgen-progestin regimens. Median time for sperm concentration to return to 20 million/mL was 3.4 months. Recovery to that threshold was 67% within 6 months, 90% within 12 months, 96% within 16 months and 100% within 24 months. Recovery was faster with shorter-acting testosterone, shorter treatment and higher baseline sperm counts [4].

A different picture comes from a retrospective study of 66 men who presented with infertility after testosterone use. All stopped testosterone and received high-dose hCG plus a selective estrogen receptor modulator; 46 (70%) reached a total motile count above 5 million within 12 months. Only 64.8% of the azoospermic men reached that count, compared with 91.7% of the cryptozoospermic men. Older age and longer testosterone use correlated with longer time to recovery [7]. The contraception analysis found faster recovery in older men [4], while this infertility series found the opposite [7].

Can hCG keep the testes working while testosterone continues?

In the same 3-week study, intratesticular testosterone rose linearly with hCG dose (P < 0.001). After treatment it was 25% below baseline at 125 IU, 7% below baseline at 250 IU, and 26% above baseline at 500 IU every other day [2]. The study measured testosterone inside the testes, so it cannot show whether hCG preserved sperm production [2].

In a retrospective case series, 49 men with azoospermia or severe oligospermia (under 1 million/mL) while on exogenous testosterone were treated with hCG 3,000 units subcutaneously every other day plus clomiphene, tamoxifen, anastrozole or recombinant FSH. Spermatogenesis returned or improved in 47 (95.9%), average time 4.6 months, mean first sperm density 22.6 million/mL. Recovery did not differ significantly by the type of testosterone used [6]. There was no control group.

Clomiphene instead of testosterone

A 2019 review describes clomiphene citrate as a selective estrogen receptor modulator that acts centrally to increase LH and FSH secretion, raising testosterone production. Unlike testosterone replacement, it does not suppress the hypothalamic-pituitary-gonadal axis, so intratesticular testosterone production and spermatogenesis are preserved, which is the basis for its use in hypogonadal men interested in fertility. The review notes that a meta-analysis of the few fertility studies shows significant improvement in fertility rates, and that several studies show improvement in semen parameters. Reported adverse effects include headache, dizziness, gynecomastia and exacerbation of psychiatric illness [8].

The guideline position

The Endocrine Society's 2018 clinical practice guideline recommends against starting testosterone therapy in men planning fertility in the near term [3].