Short-Acting Testosterone Replacement Therapy Better for Spermatogenesis

Study authors hypothesized that longer-acting testosterone replacement therapy will have significant impact on suppressing HPG axis compared with short-acting TRT preparations.

The following article is part of our coverage of the Endocrine Society’s annual meeting (ENDO 2021) that is being held virtually from March 20-23, 2021. Endocrinology Advisor‘s staff will report on the top research in hormone science and clinical care. Check back for the latest news from ENDO 2021.


Short-acting testosterone replacement therapy (TRT) may be more effective than long-acting TRT at helping hypogonadal men maintain intratesticular testosterone essential for spermatogenesis, according to study results presented at ENDO 2021, held virtually from March 20 to 23, 2021.

Long-acting TRT has been linked to infertility in a large number of men due to suppression of the hypothalamic-pituitary-gonadal axis. However, short-acting TRT may have less of an impact on the hypothalamic-pituitary-gonadal axis than long-acting TRT in the context of improving spermatogenesis. The objective of this study was to compare the effects of short-acting vs long-acting TRT on fertility using serum 17-hydroxyprogesterone (17-OHP) as a biomarker.

In this study, researchers evaluated data from two open-label, randomized, two-arm clinical trials in which hypogonadal men aged 18 through 65 years received different types of short- or long-acting TRT. In one trial, 47 men received 800 mg subcutaneous Testopel testosterone pellets.

In the other trial, 20 men received either 11 mg intranasal testosterone (n=10) or 200 mg of intramuscular testosterone cypionate (n=10) every 2 weeks for 2 months. Researchers collected serum testosterone and 17-OHP at baseline and at 2 months into therapy.

Results revealed there was a statistically significant decrease among each of the testosterone preparations in 17-OHP, with the greatest decrease observed in longer-acting preparations, including pellets and testosterone cypionate (41 ng/mL [range, 20.3-65.6] to 14 ng/mL [range, 10.3-20.8]; 80 ng/mL [range, 48-121] to 20 ng/mL [range, 17-36], respectively; P <.001).

A statistically significant decrease in 17-OHP was also observed in shorter-acting testosterone preparations (52.5 ng/mL [range, 26-67]; 26.5 ng/mL [range, 18-39.8], respectively; P =.007), but to a lesser extent compared with longer-acting preparations.

The study researchers concluded that short-acting forms of TRT may be more effective than long-acting forms of TRT at helping men maintain spermatogenesis and that this finding should be considered when treating hypogonadal men who want to preserve their fertility or the size of their testis.

Disclosure: One study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of author’s disclosures.

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Kresch E, Gonzalez D, Ory J, et al. Impact of short-acting vs long-acting testosterone therapy on intratesticular testosterone using data from two open-label randomized clinical trials of testosterone pellets, injections, and intranasal gel in hypogonadal men. Presented at: ENDO 2021; March 20-23, 2021. Session P42.