It is worth noting that unintended pregnancies account for nearly 40% of all pregnancies worldwide. Pregnancies often lead to adverse outcomes such as maternal mortality, societal burdens, and child abuse. While numerous female contraceptive methods exist, many are discontinued due to side effects or contraindications. Furthermore, for men, contraceptive options remain limited to withdrawal during coitus, condoms (barrier methods), and vasectomy. Unfortunately, these methods have significant drawbacks. For example, condoms are often used inconsistently, while vasectomy, though effective, is a surgical procedure that is not reliably reversible. Indeed, some men object to surgical interventions like vasectomy.
Figure 1. Methods of Male Contraception
Despite these limitations, studies show strong interest among men globally in adopting new contraceptive methods. Surveys indicate that many men are willing to use such methods, and female partners are generally supportive of male involvement in family planning. However, the lack of a safe, effective, and reversible male contraceptive method continues to hinder progress in this area.
Indeed, surveys conducted over the past two decades reveal that attitudes toward male contraception are generally positive. Interestingly, about half of men indicate a willingness to use new contraceptive methods.
Furthermoe, acceptance varies by country and demographic factors, such as education and income levels. Conventionally preferred methods include daily pills, implants, and injections. Of the men surveyed in most of these studies, non-hormonal and relatively convenient delivery methods such as yearly injections were preferred over other methods. Despite widespread interest, cultural norms and concerns about health risks and reliability continue to influence the adoption of male contraception. There is certainly a need for male contraceptive methods in a time where men have developed a desire to have autonomy in family planning.
Advancements in Male Hormonal Contraception
Recent research has demonstrated the potential of male hormonal contraception. Studies have validated the efficacy, safety, and reversibility of methods that combine testosterone (T) with progestins. Testosterone undecanoate injections, for instance, have shown efficacy rates comparable to female hormonal contraceptives in a two-year study involving over 1,000 Chinese men. However, monthly injections are inconvenient and less effective in non-Asian populations.
To address these challenges, researchers have explored combining testosterone with progestins, which significantly enhance the suppression of spermatogenesis. Progestins used in these studies include 19-nortestosterone derivatives such as levonorgestrel and etonogestrel, as well as pregnane-derived medroxyprogesterone acetate.
The Promise of Transdermal Contraception
A promising development is the use of transdermal gels to deliver both testosterone and progestin. This approach avoids the peaks and troughs associated with pills or injections, providing steady-state hormone delivery. A pilot study using transdermal gels containing testosterone and Nestorone (NES), a novel progestin, showed effective suppression of gonadotropins without significant adverse effects. NES, derived from 19-norprogesterone, is notable for its lack of androgenic, estrogenic, or glucocorticoid activity, reducing potential side effects compared to other progestins.
By directly inhibiting gonadotropins and possibly local testosterone production in the testes, NES offers a unique mechanism of action. This innovation could streamline male contraceptive methods, improving user compliance and acceptability.
Mechanism of Action of Segesterone Acetate (Nestorone) and Testosterone in Male Contraceptive Gel:
1. Segesterone Acetate (Nestorone):
- Primary Function: Suppresses gonadotropin release.
- Mechanism:
- Acts as a potent progestin.
- Inhibits the secretion of gonadotropins (LH and FSH) by binding to progesterone receptors in the hypothalamus and pituitary gland.
- This reduces stimulation of the testes to produce testosterone and sperm.
- Outcome: Decreased intratesticular testosterone levels, leading to suppression of spermatogenesis.
2. Testosterone:
- Primary Function: Maintains androgen-dependent physiological functions while complementing spermatogenesis suppression.
- Mechanism:
- Provides exogenous testosterone to replace the reduced endogenous testosterone caused by gonadotropin suppression.
- Maintains physiological testosterone levels to support normal sexual function, libido, and secondary male characteristics.
- Outcome: Balances the effects of spermatogenesis suppression while ensuring normal androgenic activity.
Figure 2. Mechanism of action of Nestorone (Segesterone Acetate)
A recent study showed that combining testosterone (T) gel with Nestorone (NES) gel effectively suppressed spermatogenesis, making it a promising male contraceptive option. By weeks 20–24, sperm concentrations were reduced to less than 1 million/ml in 89% of men using the NES 8 mg dose and 88% of those using the NES 12 mg dose, with the 8 mg dose emerging as the optimal choice. Remarkably, suppression began rapidly, with over 60% of participants experiencing significant reductions in sperm concentration within just eight weeks. Azoospermia, or complete absence of sperm, was achieved in 78% of men in the NES 8 mg group, with no added benefit observed at the higher dose.
Crucially, all participants returned to normal sperm levels after treatment cessation, with recovery times averaging 115–116 days for the NES-treated groups. The treatment was generally well-tolerated, with acne being the most common side effect, reported by 21% of participants. Minor mood changes, slight increases in weight, and modest rises in fasting glucose levels were also observed, though all hormone levels remained within physiological ranges throughout the study.
Adherence was a challenge for some participants, underscoring the need for a more user-friendly, single-application gel. Despite these issues, the study’s results highlight the potential of this method as a safe, effective, and reversible male contraceptive option. Researchers recommend further exploration to refine dosing, improve compliance, and ensure long-term safety, paving the way for broader acceptance of male hormonal contraception.
A new male contraceptive gel combining segesterone acetate (Nestorone) and testosterone has shown faster sperm suppression compared to previous hormone-based methods. In an ongoing phase 2b trial funded by the NIH, 86% of participants reached effective sperm suppression (≤1 million sperm/ml) within 15 weeks, with a median suppression time of less than 8 weeks—significantly quicker than the 9–15 weeks required for injection-based methods.
This daily gel application not only accelerates sperm suppression but also reduces the testosterone dose needed while maintaining physiological testosterone levels to support normal sexual function. The trial’s sperm suppression phase is complete, and further research is ongoing to evaluate the gel’s safety, effectiveness, acceptability, and reversibility after treatment ends.
References
Martin CW, Anderson RA, Cheng L, Ho PC, van der Spuy Z, Smith KB, Glasier AF, Everington D, Baird DT. 2000. Potential impact of hormonal male contraception: cross-cultural implications for development of novel preparations. Human Reproduction 15(3):637-645.
Page ST, Amory JK, Blithe D, Sitruk-Ware R, Swerdloff R, Bremner W, Liu P, Anawalt BD, Thirumalai A, Nguyen B, Dart C, Lee M, Wang C. FRI436 Design Of An International Male Contraceptive Efficacy Trial Using A Self-administered Daily Topical Gel Containing Testosterone And Nestoroneâ„¢. J Endocr Soc. 2023 Oct 5;7(Suppl 1):bvad114.1627.
