Testosterone and male contraception

madman

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Purpose of review

Rates of unintended pregnancy have remained relatively stagnant for many years, despite a broad array of female contraceptive options. Recent restrictions on access to abortion in some countries have increased the urgency for expanding contraceptive options. Increasing data suggest men are keen to utilize novel reversible male contraceptives.


Recent findings

Despite decades of clinical research in male contraception, no reversible hormonal product currently exists. Nestorone/testosterone, among other novel androgens, shows promise to finally move to pivotal Phase 3 studies and introduction to the marketplace.


Summary

Hormonal male contraception utilizes androgens or androgen-progestin combinations to exploit negative feedback that regulates the hypothalamic-pituitary-testicular axis. By suppressing release of gonadotropins, these agents markedly decrease endogenous testosterone production, lower intratesticular testosterone and suppress spermatogenesis. The addition of a progestin enhances the degree and speed of sperm suppression. The androgen component preserves a state of symptomatic eugonadism in the male. There is growing demand and acceptance of male contraceptive options in various forms. As these formulations progress through stages of drug development, regulatory oversight and communication with developers around safety and efficacy standards and garnering industry support for advancing the production of male contraceptives will be imperative.




* PHYSIOLOGY OF MALE REPRODUCTION


* HORMONAL MALE CONTRACEPTIVE EFFICACY TRIALS


* ADDITIONAL HORMONAL CONTRACEPTIVE METHODS USING TESTOSTERONE OR NOVEL ANDROGENS


- Gonadotropin-releasing hormone antagonists

- 7-Alpha-methyl-19-nortestosterone

- Dimethandrolone undecanoate and 11-betamethyl-19-nortestosterone





CONCLUSION: FUTURE DEVELOPMENT OF HORMONAL MALE CONTRACEPTIVES

Clinical trials over the last 50 years have demonstrated the effectiveness and safety of androgen based HMC. Importantly, recent data from older men has provided additional reassurance regarding the safety of exogenous testosterone when given at physiologic dosing [54–56], the backbone of combined androgen-progestin HMC. So why is there no HMC on the market? To perform pivotal Phase 3 studies, both funding and regulatory guidance is required to allow developers to appropriately evaluate longer term safety and efficacy. Surveys of men and women suggest a rapidly expanding desire for male contraceptive options and interest in sharing the burden of contraception [57]. Co-ordinated efforts between investigators, regulators, investors and the public are required to get male contraceptives to the market, a need that is increasingly urgent in the face of the economic and health impacts of unplanned pregnancies. Such efforts will hopefully result in novel, reversible male contraceptives in the next decade.
 

Attachments

FIGURE 1. Hypothalamic-pituitary-gonadal axis physiology and with contraceptive agents. FSH, follicle-stimulating hormone;GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; T, testosterone. (a) shows the normal functioning of the axis with the feedback inhibition exerted by T to keep the loop in check. (b) shows the functioning of the axis under the effects of a male hormonal contraceptive regimen, whereby the production of endogenous T and sperm is inhibited, yet maintaining peripheral actions of T. Figure reused with permission from Thirumalai and Page [16] (License number: 5815380841177).
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* Most recently, a large phase 2b efficacy trial of a combined testosterone and segesterone acetate(Nestorone) transdermal gel, spanning 17 sites across 4 continents, is expected to conclude in 2024 [29&]. A prior 24-week study compared sperm suppression in men receiving either testosterone gel alone or testosterone gel in combination with Nestorone gel (8–12 mg/day) found that 23% of men in the testosterone-alone arm suppressed sperm production to less than 1 million/ml, while in the combination group, more than 88% of men achieved this threshold [30]. Adverse events were minimal, and only 5 of 99 enrolled men discontinued due to (possibly) drug-related side effects. This novel regimen is the first user-administered HMC to be evaluated in a multisite efficacy study. User-driven methods may appeal to some men given the ease of use; however, user-administered methods may increase nonadherence and complicate interpretation of method failure. Concerns regarding hormone transfer to nonusers with transdermal hormone delivery have been raised [31] prompting evaluation of transfer of Nestorone/Testosterone gel. Similar to testosterone transdermal gels (prescribed to treat male hypogonadism), users of Nestorone/Testosterone gel wearing a shirt during prolonged, intense skin to skin contact or showering 2 h after gel application mitigates transfer to others[32]. Results of the Phase 2b efficacy trial are expected in early 2025, with positive results perhaps supporting the first Phase 3 HMC trial.





 
KEY POINTS

* There is an unmet need for novel methods to prevent unplanned pregnancy; male hormonal contraceptive methods which are reversible and effective could help fill this gap within the next decade.

* Male hormonal contraception utilizes exogenous androgen, usually testosterone, plus a progestin to interrupt normal hypothalamic-pituitary-testes endocrine homeostasis resulting in suppression of spermatogenesis.

* Clinical efficacy trials of more than 2000 couples have demonstrated the male hormonal methods are well tolerated, effective, reversible and acceptable to users; a pivotal Phase 3 study involving 5–10 000 couples will likely be required to get these methods to the market.

* Exogenous testosterone, or an equivalent androgen, is a necessary component of male hormonal contraceptive regimens and can be given at physiologic dosing; data support that dosing in the physiologic range is well tolerated and effective formen using these methods.
 

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