Professor Ada Cheung

Sublingual minoxidil improved testosterone-associated hair loss in transgender people without compromising masculinisation in the first placebo-controlled trial to address a major evidence gap in gender-affirming care, Australian researchers report.

The randomised, double-blind trial, published in the Journal of the American Academy of Dermatology [link here], found objective improvements in scalp hair counts in trans people receiving testosterone therapy, without reducing testosterone levels or causing major cardiovascular adverse effects.

Lead investigator, endocrinologist Professor Ada Cheung from the Trans Health Research Group at the University of Melbourne and Austin Health, and colleagues said androgenetic alopecia represented a growing but under-recognised issue in gender-affirming hormone care.

“While embodiment goals may differ, hair remains deeply tied to how a substantial proportion of people express and experience their identity,” the investigators wrote.

“Beard hair growth may be desirable but AGA is a potentially undesirable and distressing effect of testosterone therapy.”

The challenge for clinicians, the authors noted, is that conventional anti-androgen therapies such as finasteride may potentially interfere with masculinisation goals.

The 48-week Australian study enrolled 46 transgender and gender-diverse adults recorded female at birth who were receiving standard-dose testosterone therapy and had concerns about hair loss. Participants had a mean age of 31 years and had been taking testosterone for a mean of almost five years. Most had relatively mild androgenetic alopecia at baseline.

Participants were randomised to receive either sublingual minoxidil or placebo for 24 weeks before all participants entered a 24-week open-label extension phase. During the blinded phase, minoxidil was escalated to 1.35 mg twice daily, while the extension phase increased dosing to 2.5 mg twice daily.

The primary endpoint was change in hair counts in the midfrontal and vertex scalp regions measured using tattoo-directed phototrichograms.

At 24 weeks, the lower 1.35 mg twice-daily dose produced significantly greater improvement in midfrontal scalp hair counts than placebo:

• Midfrontal total hair count improved by 15.7 hairs/cm² more than placebo (P=0.03).
• Midfrontal non-vellus hair count improved by 12.7 hairs/cm² more than placebo (P=0.04).

However, the investigators did not observe a significant between-group improvement in the vertex/crown region during the initial placebo-controlled phase.

Longer treatment duration and dose escalation appeared more important for crown response. Participants who received continuous minoxidil from baseline and escalated to 2.5 mg twice daily demonstrated significant gains by week 48 in both frontal and vertex scalp regions, including a 37.9 hairs/cm² increase in vertex total hair count and a 29.9 hairs/cm² increase in vertex terminal hair count.

By contrast, participants who crossed over from placebo to 2.5 mg twice daily minoxidil at week 24 did not demonstrate statistically significant changes in overall hair counts during the shorter exposure period, although increases in anagen-phase hairs were observed.

Investigators said the differing response between frontal and vertex scalp regions may reflect a female-pattern distribution of alopecia despite ongoing testosterone exposure, while continued androgen exposure during treatment may also have counterbalanced minoxidil’s hair-growth effects.

“Despite testosterone therapy, it may be possible that the AGA observed follows female pattern hair loss typically seen in cis women where there is predominant diffuse midfrontal hair thinning,” they wrote.

The delayed vertex response may also reflect ongoing testosterone exposure during the study, which the authors said continued driving androgen-mediated alopecia pathways despite treatment.

At the same time, increases in anagen-phase hairs alongside reductions in telogen hairs suggested sublingual minoxidil was actively promoting follicular cycling.

“Minoxidil may have promoted anagen in existing follicles and recruited kenogen follicles into new growth as well,” the investigators suggested.

Importantly, the treatment did not appear to compromise gender-affirming hormone therapy goals. The study found no significant differences in testosterone concentrations between groups and no signal for serious cardiovascular adverse events.

One participant withdrew from the study because of concerns about body hypertrichosis. The authors said hypertrichosis – excessive hair growth outside the scalp – was “a potential side-effect from minoxidil that needs to be considered when counseling trans and nonbinary people given varying goals for masculinization”.

However, they noted the effect may not always be undesirable.

“Conversely, hypertrichosis inducing increase in body or facial hair may be perceived as promoting masculinization and beneficial in some trans people starting testosterone, supporting the need for an individualized approach to treatment,” the investigators wrote.

While objective hair counts improved, the cosmetic impact was less clear.

Blinded dermatologist reviewers did not identify significant visible changes in global scalp photographs, although participants themselves were more likely to report improvement in vertex hair appearance and frontal hairline satisfaction.

“These subjective outcomes are particularly meaningful in the context of gender affirmation where hair changes may have psychological and social impacts beyond clinical metrics,” the investigators countered.

They suggested the discrepancy between objective hair counts and visible photographic change may partly reflect the mild baseline severity of alopecia in many participants, as well as the relatively short blinded study duration.

The authors said larger and longer studies would now be needed to determine whether ongoing testosterone exposure eventually attenuated minoxidil efficacy over time and whether the objective hair-count gains translated into meaningful long-term cosmetic improvement.