Testosterone replacement and fertility

Testosterone replacement therapy restores energy, libido, and quality of life in men with hypogonadism. But it has a side effect that patients are often not told about right away: exogenous testosterone suppresses sperm production. The editors explain why this happens, how reversible it is, and how medicine resolves the conflict between TRT and the desire to have children.

Paradox: more testosterone means less sperm

It seems intuitive that testosterone as a “male hormone” should improve fertility. In fact, spermatogenesis does not require a high concentration of the hormone in the blood, but a very high concentration inside the testicles themselves. According to research, the intratesticular testosterone level is ten times higher than the serum level, and it is he who supports the maturation of spermatozoa.

This local testosterone is produced by Leydig cells under the influence of luteinizing hormone (LH) of the pituitary gland. In parallel, follicle-stimulating hormone (FSH) acts on Sertoli cells, the "nannies" of the spermatogenic epithelium. Both hormones are required for normal sperm production, and both are regulated in a negative feedback fashion.

When testosterone comes from the outside, the hypothalamus and pituitary "see" a sufficient level of the hormone in the blood and reduce the secretion of gonadoliberin, LH and FSH. The testicles lose their stimulus: Leydig cells almost stop working, intratesticular testosterone drops, and spermatogenesis ceases. At the same time, the level of testosterone in the blood can be quite normal.

This mechanism is so reliable that in the 1990s the World Health Organization investigated testosterone enanthate injections as a male contraceptive. In multicentre WHO studies, most healthy men developed azoospermia (absence of sperm in the ejaculate) or marked oligozoospermia within several months.

So, TRT with testosterone is actually a hormonal contraception, albeit an unreliable one: in some men, suppression is incomplete, and pregnancy of the partner is possible. Therefore, it is not worth counting on TRT as protection, nor hoping that it will not affect plans for children.

How reversible suppression is

The good news is that in most men, spermatogenesis resumes after stopping testosterone. The largest set of data was provided by an integrated analysis by Liu et al. (Lancet, 2006), which combined the results of studies of hormonal male contraception. The authors showed that the vast majority of participants returned to baseline sperm concentration over time.

At the same time, recovery is not instantaneous: the spermatogenic cycle in a person lasts about 70-74 days, and the hormonal axis needs time to "wake up". In this analysis, the median time to return to threshold values ​​was measured in months, and for some men, over a year.

The speed of recovery depended on several factors. It occurred more slowly in older men, after a longer duration of hormonal exposure and when using long-acting drugs. It is faster in individuals with a higher initial concentration of sperm and in certain ethnic groups.

It is important to distinguish between healthy volunteers in contraceptive studies and patients with hypogonadism. If a person has primary testicular insufficiency or severe damage to the pituitary gland, then after the withdrawal of TRT there is simply nowhere to go back: the actual production of hormones and sperm was low even before treatment.

The situation is even more complicated for those who have been using supraphysiological doses of anabolic steroids outside of medicine for years. Review by Rahnema et al. (2014) describes persistent androgen-induced hypogonadism, in which recovery may take a long time or be incomplete.

What clinical guidelines say

The Endocrine Society clinical guideline (Bhasin et al., 2018) explicitly states that testosterone should not be prescribed to men planning to become pregnant in the near future. A similar position is taken by the American Urological Association (AUA, 2018) and the European Association of Urologists (EAU).

AUA separately emphasizes: the doctor is obliged to discuss with the patient of reproductive age the effect of therapy on fertility before its initiation. This is not a formality - many men learn about the problem only after the couple has been trying unsuccessfully to conceive for several months.

For men with hypogonadism who want to have children now, guidelines suggest other approaches—those that stimulate their own hormonal axis rather than replacing it. The choice of a specific method depends on the cause of hypogonadism (primary or secondary) and is an exclusively medical decision.

Below is a summary of what strategies are discussed in the medical literature. The table is not a treatment scheme: it only shows the logic by which endocrinologists and andrologists think.

The study of Coviello et al. should be mentioned separately. (2005), which showed that low doses of human chorionic gonadotropin maintained intratesticular testosterone in men in the face of suppression by exogenous testosterone. This work became the scientific basis for combined approaches, but the decision about them is made only by the doctor.

What to check before starting TRT

If a man of reproductive age is considering TRT, the editors advise asking the doctor several direct questions even before the first injection or application of the gel. This approach saves months and sometimes years.

• Semen analysis before the start of therapy. It captures the initial state and helps to later assess the recovery.
• LH and FSH. It allows distinguishing primary hypogonadism from secondary, and this determines all further options.
• Cryopreservation of sperm. A relatively simple way to "insure" future fertility, especially if plans for children are uncertain.
• Planning horizon. Whether children are planned within the next 1-2 years — the very expediency of TRT depends on this.
• Cause of low testosterone. Obesity, sleep apnoea, taking opioids or other drugs are sometimes corrected without hormone replacement.

The experience of clinics shows that cryopreservation is often underestimated. It does not guarantee pregnancy, but gives a choice if the recovery after TRT is delayed. This is especially true for men with already low sperm count.

It is also important to understand that the form of the drug (gel, injections, long-term depots) affects suppression slightly: any effective exogenous testosterone suppresses gonadotropins. The only difference is how quickly the hormone is excreted after withdrawal.

Finally, self-experimentation with over-the-counter fertility "protecting" drugs is not an alternative. They carry their own risks and do not replace a controlled semen analysis and the supervision of a specialist.

Common myths

There are many beliefs surrounding the topic of TRT and children that are not supported by data. Let's analyze the most frequent ones.

"If libido is high, everything is fine with fertility." Libido and erection depend on serum testosterone, which is normal on TRT. Spermatogenesis depends on the intratesticular level and FSH, which are suppressed. One does not indicate the other.

"Gel does not affect sperm, but injections do." Any form that effectively increases testosterone triggers a negative feedback loop. Transdermals are not "fertility safe."

"After discontinuation, everything will return in a month." Even in a favourable scenario, it takes at least several months for a complete cycle of spermatogenesis to pass, and for some men it takes much longer.

"TRT — reliable contraception." No: suppression in individual men is incomplete, and cases of pregnancy of female partners against the background of therapy have been described. Contraception requires proven methods.

Editorial conclusions

Testosterone replacement therapy and fertility are in physiological conflict: the exogenous hormone turns off the signals the testes need to produce sperm.

In most men, this suppression is reversible, but recovery takes months, sometimes longer, and depends on age, duration of therapy, and baseline reproductive status.

If children are planned, this should be discussed with the doctor before starting TRT: evaluate the semen analysis, gonadotropins, consider cryopreservation or alternative strategies that stimulate the own axis.

For a deeper understanding of the topic, we recommend our materials "TRT monitoring: analyzes and frequency", "How TRT differs from a sports course" and "TRT in men after 40".

List of used literature

1. 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.
2. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA guideline. J Urol. 2018;200(2):423–432.
3. 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.
4. 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.
5. Coviello AD, Matsumoto AM, Bremner WJ, et al. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J Clin Endocrinol Metab. 2005;90(5):2595–2602.
6. Rahnema CD, Lipshultz LI, Crosnoe LE, et al. Anabolic steroid-induced hypogonadism: diagnosis and treatment. Fertil Steril. 2014;101(5):1271–1279.
7. Nieschlag E, Behre HM, Nieschlag S (eds). Testosterone: Action, Deficiency, Substitution. 4th ed. Cambridge University Press; 2012.