Testosterone Cypionate Fertility Suppression: Alternatives Without This Side Effect

Why testosterone cypionate suppresses fertility

The Depo-Testosterone label describes the mechanism directly: during exogenous administration of androgens, endogenous testosterone release is inhibited through feedback inhibition of pituitary luteinizing hormone, and at large doses of exogenous androgens spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle stimulating hormone [1]. Oligospermia at high dosages appears in the same label's list of adverse reactions [1]. The label also lists testicular atrophy, subfertility and infertility among the effects reported in men who abuse anabolic steroids [1].

Is any testosterone product fertility-sparing?

The Depo-Testosterone label attributes the gonadotropin suppression to exogenous androgens generally, not to cypionate specifically [1]. In the hCG recovery series, recovery did not differ significantly by the type of testosterone used [3], and in the hCG-plus-testosterone series, semen parameters did not differ by testosterone formulation [2]. In the contraception analysis, sperm recovery after stopping was faster with shorter-acting testosterone preparations [8]. The approaches studied for protecting sperm production are hCG added to ongoing testosterone [2], hCG combined with other fertility drugs [3][4], and the two non-testosterone drugs, clomiphene and enclomiphene [5][6].

What the guidelines say

The Endocrine Society's 2018 clinical practice guideline recommends against starting testosterone therapy in men planning fertility in the near term [7].

hCG added to ongoing testosterone

In a retrospective review of 26 hypogonadal men of mean age 35.9 years who stayed on testosterone (19 on injections, 7 on gel) and added hCG 500 IU intramuscularly every other day, no patient became azoospermic [2]. Mean follow-up was 6.2 months, no differences in semen parameters were observed during follow-up extending beyond a year, and 9 of the 26 men contributed to a pregnancy with their partner [2]. Mean serum testosterone rose from 207.2 to 1,055.5 ng/dL during treatment [2].

That was a single-centre chart review without a control group, so it cannot show how much of the result is due to hCG. It speaks to maintaining semen parameters during treatment.

hCG combined with another fertility treatment

A series from two tertiary infertility clinics tracked 49 men who had azoospermia or severe oligospermia (under 1 million/mL) while taking exogenous testosterone. All were on hCG 3,000 units subcutaneously every other day plus clomiphene, tamoxifen, anastrozole or recombinant FSH (or a combination), according to physician preference. Spermatogenesis returned or improved in 47 men (95.9%), with an average of 4.6 months and a mean first sperm density of 22.6 million/mL, and there was no significant difference in recovery by the type of testosterone used [3].

A second series followed 66 men with infertility after testosterone use who stopped testosterone and started high-dose hCG plus a selective estrogen receptor modulator; 46 of 66 (70%) reached a total motile count above 5 million within 12 months [4]. Success was lower in azoospermic men (64.8%) than in cryptozoospermic men (91.7%), and both older age and longer testosterone use were associated with slower recovery [4].

Clomiphene

A prospective series followed 86 men with hypogonadism confirmed by two consecutive early-morning testosterone levels below 300 ng/dL, mean age 29 [5]. Clomiphene started at 25 mg every other day and was titrated to 50 mg every other day against a target testosterone of 550 ng/dL, plus or minus 50, with a mean treatment duration of 19 months; infertility was the most common reason for seeking treatment, cited by 64% [5].

The authors described clomiphene as a safe and efficacious alternative to exogenous testosterone in hypogonadal men [5]. The series tracked testosterone, other hormone levels and symptom scores in men taking clomiphene; it did not compare fertility outcomes with testosterone injections.

Enclomiphene

Enclomiphene is the trans-isomer of clomiphene. A phase II trial compared oral enclomiphene citrate with 1% topical testosterone gel in men with secondary hypogonadism. Enclomiphene raised morning testosterone and estradiol to levels similar to those with the gel, FSH and LH increased with enclomiphene, and sperm counts were conserved [6]. Hormone and semen outcomes were measured during treatment [6].

How long recovery takes with no add-on treatment

An integrated analysis of 30 hormonal male contraception studies, covering 1,549 healthy eugonadal men aged 18 to 51, found a median 3.4 months for sperm concentration to recover to 20 million/mL after treatment stopped; 67% reached that threshold within 6 months, 90% within 12, 96% within 16 and 100% within 24 [8]. Faster recovery was associated with shorter-acting testosterone preparations, shorter treatment, older age and a higher baseline sperm count [8].

These were healthy volunteers suppressing normal fertility, not men with hypogonadism, so the numbers are a reference point rather than a forecast for a particular patient. In the series of men who had become infertile on testosterone, age and duration of use both slowed recovery [4].

Putting the options in order

For a man who wants a child in the near term, the guideline position is that testosterone therapy should not be started [7]. For a man already on cypionate who wants to preserve fertility, the studied route is adding hCG to continued testosterone [2]. For men who have already lost sperm production on testosterone, the studied routes are hCG combined with other fertility drugs [3], or stopping testosterone and using hCG with a SERM [4]. Clomiphene and enclomiphene were studied as alternatives to testosterone that raise the body's own testosterone while sperm production is retained [5][6].

Each of these rests on small, mostly retrospective studies. Semen analysis is the measure those studies used to track whether sperm production held or returned [2][4][6].