Testosterone isocaproate and male fertility

The paradox of testosterone is that a hormone considered a symbol of male strength, when introduced from outside, can make a man temporarily infertile. Studies of male hormonal contraception were even built on this effect. The editors examine how testosterone isocaproate and other esters affect spermatogenesis and what is known about recovery.

How spermatogenesis is regulated

The formation of spermatozoa takes place in the convoluted seminiferous tubules of the testes and lasts approximately 70-75 days from a stem cell to a mature spermatozoon. This process requires two signals from the pituitary gland: luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

LH stimulates the Leydig cells to produce testosterone. The key detail: spermatogenesis requires a very high concentration of testosterone specifically inside the testis - many times higher than in the blood. FSH acts on the Sertoli cells, which 'nourish' the developing germ cells.

The entire system works on the principle of negative feedback. The hypothalamus releases gonadotropin-releasing hormone, the pituitary responds with LH and FSH, and testosterone and its metabolite estradiol signal back that there is enough hormone. Inhibin B, produced by the Sertoli cells, additionally inhibits FSH.

This mechanism is usually described as the 'hypothalamic-pituitary-gonadal' (HPG) axis. Understanding how it works explains why the introduction of any testosterone ester, in particular isocaproate, inevitably affects fertility.

Why exogenous testosterone 'switches off' the testes

The brain does not distinguish where the testosterone in the blood came from - from the testes or from an injection. When the hormone level rises, the hypothalamus and pituitary reduce the production of releasing hormone, LH and FSH. Against the background of testosterone esters in doses exceeding physiological ones, LH and FSH can drop to almost undetectable values.

The consequence is twofold. First, the Leydig cells stop receiving the signal and sharply reduce their own synthesis of testosterone. Second, the intratesticular concentration of the hormone falls, even though there is plenty of testosterone in the blood. Without high intratesticular testosterone and FSH, spermatogenesis stops.

Clinically this manifests as a reduction in testicular volume and a decrease in sperm concentration, up to their complete absence from the ejaculate (azoospermia). Libido may remain normal or even increased, so many men do not suspect a problem until they face infertility.

Mixed preparations such as 'Sustanon', where isocaproate is combined with the long-acting decanoate, provide prolonged exposure. The total duration of action determines how long the axis remains suppressed after the last injection.

What contraception studies showed

The most reliable data on the effect of testosterone on spermatogenesis were obtained not from sports medicine, but from WHO studies of male contraception. In multicenter trials in 1990 and 1996, healthy men were given testosterone enanthate at a dose of 200 mg intramuscularly weekly.

In the first study (Lancet, 1990) most participants developed azoospermia within a few months, and in its presence pregnancies in their partners occurred very rarely. However, some men - especially in the European centers - achieved only pronounced oligospermia rather than the complete disappearance of spermatozoa.

The integrated analysis by Liu and co-authors (Lancet, 2006), which combined data from more than 1,500 men from hormonal contraceptive studies, showed that after cessation of administration spermatogenesis recovered in the vast majority of participants. The median time to recovery was measured in months, and the probability of complete recovery increased over time.

It is important to understand the limitations: these studies were conducted on healthy volunteers, with a single substance, in controlled doses and for a limited period. Real non-medical use often involves higher doses, several substances at once and many years of use, so the prognosis there is worse and less predictable.

Recovery: what it depends on

After discontinuing testosterone esters, the HPG axis gradually 'wakes up': first LH and FSH rise, then one's own testosterone, and only later - the concentration of spermatozoa. Since a full cycle of spermatogenesis lasts more than two months, the improvement in the semen analysis lags behind the hormonal changes.

The review by Rahnema and co-authors (2014) described hypogonadism caused by anabolic steroids as a common cause of male infertility and hypogonadism in young men. The authors emphasize that in some patients recovery takes more than a year, and in some the function does not fully return.

Additional risks to fertility are created by concomitant factors: varicocele, infections, obesity, smoking, overheating. If they were present before the use of androgens, they will not disappear after discontinuation.

Examination and help

For men planning parenthood after the use of testosterone, the editors advise starting with a consultation with a urologist-andrologist. The doctor will assess the medical history, the size and consistency of the testes and prescribe a basic set of examinations.

• A semen analysis (preferably twice, with an interval of a few weeks).
• LH, FSH, total testosterone, SHBG, estradiol, prolactin.
• Ultrasound of the scrotal organs.
• As indicated - inhibin B, genetic testing, assessment of sperm DNA fragmentation.

If recovery drags on, andrologists have pharmacological approaches to stimulate the axis. The choice of drugs, doses and duration of treatment is solely within the doctor's competence, since these agents have their own risks and contraindications, and using them on your own can mask the real problem.

In complex cases, when spermatozoa do not appear in the ejaculate, surgical retrieval of spermatozoa from the testis and assisted reproductive technologies are considered. For men who do receive testosterone for medical indications, doctors may suggest cryopreservation of sperm in advance.

Editors' conclusions

Testosterone isocaproate, like any testosterone ester, suppresses the production of LH and FSH and thereby stops spermatogenesis. This effect is so reliable that it was studied as a method of contraception.

In healthy volunteers in controlled studies, spermatogenesis mostly recovered, but it took months. In real non-medical use, recovery can be prolonged or incomplete.

If you are planning to have children, the best step is an examination by an andrologist, not independent experiments with drugs.

We also recommend our materials on the body's recovery after the use of testosterone isocaproate, on its metabolism and on the legal status of the drug in Ukraine and the EU.

References

1. World Health Organization Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia in normal men. Lancet. 1990;336(8721):955–959.
2. World Health Organization Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril. 1996;65(4):821–829.
3. Liu PY, Swerdloff RS, Christenson PD, et al. Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet. 2006;367(9520):1412–1420.
4. Rahnema CD, Lipshultz LI, Crosnoe LE, et al. Anabolic steroid-induced hypogonadism: diagnosis and treatment. Fertil Steril. 2014;101(5):1271–1279.
5. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744.
6. Nieschlag E, Behre HM, Nieschlag S (eds). Andrology: Male Reproductive Health and Dysfunction. 3rd ed. Springer; 2010.