There is a study in the male contraception literature that is quietly remarkable, and largely unknown outside specialist circles. It involves a gel applied to the shoulders daily by a male partner, a gel applied to the abdomen daily by a female partner, and an unconventional trial design that tested whether two people sharing the contraceptive burden could actually make it work.
The concept is the NES/T gel. NES stands for Nestorone — a progestogen, also known by its chemical name segesterone acetate. T stands for testosterone. Together, applied transdermally, they suppress spermatogenesis through the dual mechanism described throughout this series. The trial that tested this most rigorously is a Phase IIb study whose results were published in 2023, representing the culmination of roughly 15 years of development by the Population Council, the National Institutes of Health, and USAID.
Before getting to what it showed, it is worth understanding why transdermal delivery for male contraception has been such an attractive target, and why the NES/T formulation specifically represents an advance.
Why Gels for Men
The appeal of transdermal delivery is obvious: no needles. A gel applied once daily to a skin surface achieves steady-state testosterone levels without the peak-and-trough pharmacokinetics of weekly injections. The practicality problem that plagued the WHO injection trials — who is going to go to a clinic every week for a contraceptive injection? — dissolves with a self-applied gel.
Testosterone gels for hypogonadism (Androgel, Testim, Axiron, and others) have demonstrated that transdermal testosterone delivery is feasible at scale. Men use them. They work. The absorption is predictable enough for clinical use. The question for contraception was whether a transdermal regimen could achieve suppression levels deep enough, and consistently enough, to work as a contraceptive.
The problem with testosterone gel alone at contraceptive doses is the same problem as injectable testosterone alone: you need supraphysiologic levels to reliably suppress spermatogenesis, and supraphysiologic testosterone brings side effects. Adding a progestogen allows lower testosterone doses while maintaining or improving suppression — and transdermal progestogen gels have been developed specifically for this purpose.
Nestorone: The Progestogen That Cannot Be Taken Orally
Nestorone (segesterone acetate) is a synthetic progestogen developed by the Population Council. Its key pharmacological properties are that it has no androgenic, estrogenic, or glucocorticoid activity — which means it adds progestogenic HPT suppression without layering in additional hormonal effects. It is also, notably, active transdermally but not orally: it is extensively metabolized in the gut on first pass, which makes it impractical as a pill but effective as a gel or patch.
This is actually a relevant safety feature. Nestorone applied to the male partner’s skin does not meaningfully transfer to female partners through skin contact (at normal application and drying intervals), reducing the concern about partner exposure to a progestogen.
The combination of nestorone gel (applied to male partner) plus testosterone gel (also applied to male partner) was the basic concept. A pilot study published in 2012 (Ilani et al.) showed that this gel-only regimen — both hormones applied to the man — was effective and well tolerated, with 89% of men in the active treatment group achieving sperm suppression to below 1 million/mL.
The Phase IIb Trial Design
The Phase IIb study — the most substantial trial of the NES/T gel — had an unusual twist. The trial design involved both partners. Men applied a combination gel (NES/T, combining both hormones in one product) to the upper arm and shoulder area. Women — the female partners — were enrolled and monitored as part of the study, a design feature that allowed tracking of any potential gel transfer to female partners via skin contact.
The study was sponsored by the National Institutes of Health and was multicenter, enrolling couples at sites in the United States, Chile, Kenya, and Sweden. The target enrollment was 420 couples, with a 24-week suppression phase followed by a 52-week efficacy phase (no other contraception).
Results from the Phase IIb, published in a 2023 paper in EClinicalMedicine (Page et al.), showed:
- Of men who completed the full treatment course, approximately 86% achieved sperm suppression to below 1 million/mL, which is the threshold for the contraceptive efficacy phase.
- LH and FSH were substantially suppressed in the majority of participants.
- Testosterone levels in male partners showed appropriate androgen exposure — not the supraphysiologic spikes of the old injection regimens, but maintained physiologic-range levels.
- Female partners showed no clinically significant changes in androgen levels attributable to gel transfer.
- The most commonly reported side effects in men were acne and weight gain, consistent with other androgen-containing regimens.
The 86% suppression rate is meaningful. It is well above the ~70% from testosterone-only injection regimens, and reasonably close to the 95%+ seen in some combination injection studies.
What Went Wrong — Or Didn’t, Depending How You Look at It
Here is where the trial’s story gets complicated in the familiar male-contraception way.
The study did not complete its planned efficacy phase. Enrollment was significantly disrupted by COVID-19, which halted clinical trial activity globally from early 2020 onward. Many couples could not complete the full protocol. The study did not accumulate the person-years of contraceptive efficacy phase data originally planned, meaning the pregnancy prevention rate data are limited.
Additionally, retention and adherence — getting couples to apply gel every single day for a year and a half — presented challenges. Daily topical application requires habitual compliance in a way that an injection every few months does not. Adherence rates varied across sites and couples.
The result is a trial that proved the regimen works for suppression in most men, established that transdermal delivery is pharmacologically sound, and documented an acceptable safety profile — but could not deliver the large-scale pregnancy prevention data that would be needed for regulatory review.
This is the recurring pattern in male contraception research. The science advances. The trials demonstrate feasibility. Then some combination of logistics, funding, COVID, recruitment challenges, and adherence difficulties prevents the clean efficacy dataset that would enable a regulatory submission.
Why This Still Matters
Despite its incomplete efficacy data, the NES/T Phase IIb study is significant in several ways.
It is the most clinically advanced transdermal male contraceptive to date. It uses approved-class compounds (testosterone is already approved; segesterone acetate is the active ingredient in the female contraceptive implant Annovera). It has a plausible regulatory pathway. The manufacturing and formulation challenges are real but not unprecedented.
Perhaps most importantly, it demonstrates that the suppression science is robust across different delivery methods — injections, gels, slow-release formulations. When you combine an appropriate androgen with an appropriate progestogen, you can reliably shut down spermatogenesis in the large majority of men. The variation in delivery method does not change the fundamental endocrinology.
What the NES/T trial story ultimately illustrates is that male contraceptive science is not failing at the hypothesis level. The hypothesis — testosterone plus progestogen suppresses spermatogenesis reversibly and effectively — has been confirmed in multiple trial formats over 30 years. What is failing is the system that would take a validated scientific finding and turn it into a product that pharmacists stock, insurers cover, and men can pick up at a drugstore.
That system failure is the subject of the final post in this series.
Next up: Post 5 — Why Male Contraception Still Does Not Exist: the pharmaceutical economics, the side effect double standard, the cultural assumptions, and what the field would actually need to succeed.
