Using Dose Titration to Resolve Fertility Suppression on Testosterone Cypionate

What testosterone cypionate does to sperm, per its label

Depo-Testosterone is testosterone cypionate in oil, injected deep into the gluteal muscle at 50 to 400 mg every 2 to 4 weeks for replacement in hypogonadal men, with a half-life of about 8 days after intramuscular injection [1].

The label's mechanism line is short: exogenous androgens inhibit endogenous testosterone release through feedback inhibition of pituitary LH, and at large doses spermatogenesis may also be suppressed through feedback inhibition of pituitary FSH [1]. Its adverse reactions section lists oligospermia at high dosages, without a rate, and its abuse section lists testicular atrophy, subfertility and infertility among reactions reported in men who abuse anabolic steroids [1].

The Azmiro (cypionate in a prefilled syringe) and Xyosted (subcutaneous enanthate) labels go further: they state that reduced fertility is seen in some men on testosterone replacement and that the effect on fertility may be irreversible.

What the guideline says before the first injection

The 2018 Endocrine Society guideline recommends against starting testosterone therapy in men who are planning fertility in the near term [2].

What has and has not been tested about dose

The label adjusts the dose according to the patient's response and adverse reactions within the 50 to 400 mg range every 2 to 4 weeks [1]. The only link the label draws between dose and sperm is that FSH suppression is described at large doses and oligospermia at high dosages [1].

The recovery studies in the next section looked at stopping testosterone, with or without hCG-based treatment. None of them tested slowing the increase, lowering the dose, pausing injections or splitting the dose into more frequent shots [3][4][5].

What the recovery studies show

Stopping hormonal suppression in healthy men. An integrated analysis of 30 studies and 1,549 healthy eugonadal men using androgen or androgen-progestin contraception found a median of 3.4 months for sperm concentration to return to 20 million per mL; 67% reached that threshold within 6 months, 90% within 12, 96% within 16 and 100% within 24 [5]. Recovery was faster with shorter-acting testosterone preparations, shorter treatment, older age and a higher baseline sperm count [5]. These were fertile men suppressing normal sperm production, not men with hypogonadism on replacement therapy.

hCG-based combination therapy. A retrospective series from two fertility clinics described 49 men who presented with azoospermia or severe oligospermia (under 1 million per mL) while on testosterone. All received hCG 3,000 units subcutaneously every other day plus clomiphene, tamoxifen, anastrozole or recombinant FSH; spermatogenesis returned or improved in 47 (95.9%), with an average of 4.6 months and a mean first density of 22.6 million/mL, and no difference by type of testosterone used [4]. It is a case series without a control group, and its abstract does not say whether testosterone was continued during treatment [4].

Stopping testosterone plus hCG and a SERM. A retrospective study of 66 men with infertility after testosterone use tracked whether they reached a total motile count above 5 million within 12 months of stopping testosterone and starting high-dose hCG plus a selective estrogen receptor modulator. Forty-six men (70%) did; 64.8% of the azoospermic men and 91.7% of the cryptozoospermic men reached that threshold, and older age and longer testosterone use predicted slower recovery [3].