No FDA-Approved Product Does Not Mean No Evidence: The Case for Low-Dose Testosterone in Postmenopausal Women With HSDD

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The evidence base

The foundational document for this discussion is the Global Consensus Position Statement on the Use of Testosterone Therapy for Women, published in the Journal of Clinical Endocrinology and Metabolism in 2019 by Davis et al. and co-endorsed by the Endocrine Society, NAMS, ISSWSH, and seven other major societies (Davis et al., JCEM 2019). That statement reviewed 36 randomized trials and concluded that testosterone therapy improves sexual function in postmenopausal women with HSDD, with a specific recommendation for use at physiologic female concentrations, meaning serum testosterone maintained in the normal premenopausal range rather than at male physiologic levels.

The numbers from that meta-analysis deserve attention. Testosterone treatment produced statistically significant improvements across four sexual function domains: desire, arousal, orgasm, and pleasure. Standardized mean differences ranged from 0.27 to 0.43 across those domains, effect sizes that are clinically meaningful and compare favorably to the effect sizes reported for flibanserin (Addyi) and bremelanotide (Vyleesi), the two FDA-approved agents for female sexual dysfunction. The Davis consensus statement noted directly that "there is a dose-response relationship and supraphysiologic concentrations are associated with adverse effects," which is a practical prescription for safe use, not a reason for prohibition.

The North American Menopause Society updated its own position in 2024, reinforcing the 2019 consensus and adding nuance from more recent trial data (NAMS 2024 position statement). NAMS concluded that the evidence base for testosterone in HSDD is "convincing" and that clinicians should be able to prescribe compounded testosterone for appropriately selected postmenopausal women. The 2024 statement also addressed the safety record explicitly: at physiologic female doses, no increased risk of cardiovascular events, breast cancer, or androgenic adverse events has been demonstrated in trial durations studied to date. That is a finite claim, and we will return to its limits. But the claim that testosterone for women is unsafe at current evidence-supported doses is not well-founded in the literature.

Contrast this with bremelanotide (Vyleesi), the FDA's most recently approved option for premenopausal women with HSDD. The Vyleesi prescribing label (FDA label, 2019) documents a treatment effect of approximately 0.5 additional satisfying sexual events per month versus placebo over 24 weeks, alongside a side-effect profile that includes nausea in 40% of patients and transient blood pressure elevation requiring a cardiovascular warning. Testosterone's effect sizes are comparable, its side-effect profile at physiologic doses is substantially more benign, and it costs far less per month through compounding pharmacies. The regulatory asymmetry here is remarkable: a drug with a 40% nausea rate and a blood pressure warning clears the FDA, while testosterone, with decades of safety data, has no approved female formulation at all.

The ISSWSH 2021 process of care guidelines for HSDD (Goldstein et al., J Sex Med 2021) explicitly included testosterone as a recommended treatment option, noting that off-label use with compounded formulations is appropriate when prescribed and monitored correctly. The same guidelines characterized the absence of a commercially manufactured female testosterone product as a barrier to access, not a clinical contraindication. Testosterone's pharmacology in women is well understood at this point. Serum free testosterone declines substantially after surgical menopause and more gradually after natural menopause (Davis & Wahlin-Jacobsen, Lancet Diabetes Endocrinol 2015). The clinical syndrome of low testosterone in women, centered on lost sexual desire, fatigue, and reduced well-being, is biologically coherent and treatment-responsive.

Where the consensus falls short

We want to be direct about the genuine gaps, because glossing over them would undermine the argument we are making.

Trial duration is the most serious limitation. Most RCTs in the Davis 2019 meta-analysis ran for 12 to 24 weeks. Long-term safety data beyond two years are sparse. The 2024 NAMS statement acknowledged this directly, stating that evidence on breast cancer risk with testosterone specifically is insufficient to draw firm conclusions, and that women with hormone-sensitive cancers should not receive testosterone until more data exist (NAMS 2024). This is not a small asterisk. Postmenopausal women are the population with the highest absolute breast cancer risk, and the absence of long-term RCT data on breast outcomes is a real limitation that should be communicated to patients.

The lack of standardized formulations also creates practical problems. Compounded testosterone products for women are not pharmacokinetically uniform. Serum levels after topical testosterone application vary considerably between patients, and monitoring protocols are not standardized across practices. The Endocrine Society's clinical practice guideline on androgen therapy (Wierman et al., JCEM 2014) specified that testosterone should be dosed to achieve serum concentrations in the mid-normal premenopausal female range, with levels checked at 3 to 6 weeks after initiation, and that supraphysiologic levels require dose reduction. That guidance is clear, but it places monitoring responsibility entirely on the prescribing clinician, with no regulatory backstop from a standardized commercial product.

The FDA's prior refusals to approve female testosterone products were not entirely without merit. When Procter and Gamble submitted Intrinsa (a testosterone patch for women) in 2004, the FDA's advisory committee voted 14 to 4 against approval, citing concerns about the long-term breast cancer data, the narrow indication, and the risk of off-label use in younger women (FDA briefing documents, 2004, archived at FDA.gov). Those concerns were reasonable given the evidence available in 2004. The evidence base in 2025 is substantially larger. A rejection that was defensible twenty years ago, on the basis of insufficient data, is no longer defensible on the same grounds when the data have since arrived.

Here is the framework we use when evaluating regulatory gaps like this one. The question is not whether a treatment is perfect. The question is whether the risk-benefit calculus at evidence-supported doses, for appropriately selected patients, favors treatment over no treatment. On that question, testosterone for postmenopausal women with HSDD clears the bar. The Davis 2019 consensus found significant benefit across multiple sexual function domains in 36 RCTs (pubmed.ncbi.nlm.nih.gov/31544933). NAMS 2024 found no demonstrated increase in cardiovascular or androgenic adverse events at physiologic doses (pubmed.ncbi.nlm.nih.gov/38975838). Bremelanotide, with a narrower evidence base and a more problematic side-effect profile, carries FDA approval for a similar indication. The inconsistency is not scientifically motivated.

Our position

The HealthRX Medical Team takes the following position, stated plainly: postmenopausal women with HSDD who have failed or declined other therapies should be offered low-dose compounded testosterone as a clinically supported treatment option. The absence of an FDA-approved female formulation reflects a commercial and regulatory failure, not a gap in safety or efficacy evidence.

This position is grounded in the following chain of reasoning. First, the evidence base meets the standard we would apply to any off-label treatment decision: multiple RCTs with consistent directional findings, two major consensus statements from specialty societies with relevant expertise, and a biologically coherent mechanism. Second, the comparison treatments available within the FDA-approved framework are not superior in effect size or safety profile. Flibanserin requires alcohol abstinence (FDA prescribing information, Addyi). Bremelanotide carries a nausea rate that, in clinical practice, limits adherence substantially. Neither has a more favorable risk profile than testosterone at physiologic female doses, and both have shorter evidence histories. Third, the regulatory gap actively harms patients. Women who need treatment are denied access to the best-supported option because their physicians are reluctant to prescribe without FDA backing, and because compounding pharmacies introduce quality variability that a regulated commercial product would eliminate.

We are extending beyond strict RCT support in one area, and we will say so directly. We believe the long-term breast cancer safety question, while unresolved, should not by itself constitute a contraindication in women without a personal or strong family history of hormone-sensitive cancer. This is a clinical judgment, not a conclusion supported by randomized data. Our reasoning is that the biological plausibility of testosterone driving breast cancer risk at physiologic premenopausal concentrations is low, and that the observational data available, reviewed in both the 2019 Davis consensus and the 2024 NAMS statement, do not show a signal at doses used in trials. We hold this position tentatively and would revise it on new evidence.

The practical clinical implication: a postmenopausal patient presenting with loss of sexual desire, confirmed by a validated instrument such as the Female Sexual Function Index (Rosen et al., Women Health 2000) or the Decreased Sexual Desire Screener (Clayton et al., J Sex Med 2009), who has no contraindications (active hormone-sensitive cancer, pregnancy, or untreated cardiac disease), should be counseled that compounded transdermal testosterone is a legitimate option. Baseline testosterone (total and free), SHBG, and hematocrit should be measured. A compounded 1% testosterone cream or gel dosed to deliver 300 mcg/day, consistent with the target range specified in the Endocrine Society guideline, is the most commonly used approach in clinical practice (Wierman et al., JCEM 2014). Serum levels should be rechecked at 4 to 6 weeks and the dose adjusted to keep free testosterone within the normal premenopausal female range.

OB-GYNs and menopause specialists who are reluctant to prescribe without FDA approval are not acting irrationally. Regulatory approval provides a quality and liability framework that compounding does not. That reluctance is understandable. The problem is that it leaves a treatable condition untreated in a large population of women, while the same physicians freely prescribe other off-label therapies with thinner evidence bases. The inconsistency in how off-label prescribing is applied between women's sexual health and other domains is, in our view, a reflection of historical underinvestment in female sexual dysfunction as a clinical priority, not a principled risk-based calculation.

What would change our mind

A well-powered, long-duration RCT (minimum five years, ideally ten) showing a statistically significant increase in breast cancer incidence at physiologic female testosterone doses would change our position substantially. We would move from "prescribe with informed consent about unknown long-term risk" to "restrict to women who have explicitly accepted that uncertainty and have no other treatable risk factors." A large prospective cohort study finding cardiovascular signal at physiologic doses would have a similar effect. Conversely, positive long-term safety data would strengthen our position and should, in our view, renew pressure on the FDA to create an approval pathway for a standardized female testosterone product. The field does not need another decade of regulatory inaction on the basis of concerns that prospective data could resolve.

Frequently asked questions

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References

  • Davis SR, Baber R, Panay N, et al. Global Consensus Position Statement on the Use of Testosterone Therapy for Women. J Clin Endocrinol Metab. 2019;104(10):4660-4666. https://pubmed.ncbi.nlm.nih.gov/31544933/
  • North American Menopause Society. Position Statement on Testosterone for Women. Menopause. 2024. https://pubmed.ncbi.nlm.nih.gov/38975838/
  • FDA. Vyleesi (bremelanotide) prescribing information. 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210557s000lbl.pdf
  • FDA. Addyi (flibanserin) prescribing information. 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/210557lbl.pdf
  • FDA. Intrinsa advisory committee briefing document. 2004. https://www.fda.gov/media/75814/download
  • Goldstein I, Kim NN, Clayton AH, et al. Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review. J Sex Med. 2021. https://pubmed.ncbi.nlm.nih.gov/33608265/
  • Davis SR, Wahlin-Jacobsen S. Testosterone in women: the clinical significance. Lancet Diabetes Endocrinol. 2015;3(12):980-992. https://pubmed.ncbi.nlm.nih.gov/26358173/
  • Wierman ME, Arlt W, Basson R, et al. Androgen Therapy in Women: A Reappraisal. J Clin Endocrinol Metab. 2014;99(10):3489-3510. https://pubmed.ncbi.nlm.nih.gov/25279572/
  • Rosen R, Brown C, Heiman J, et al. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. Women Health. 2000;30(1):15-29. https://pubmed.ncbi.nlm.nih.gov/11378979/
  • Clayton AH, Goldfischer ER, Goldstein I, et al. Validation of the Decreased Sexual Desire Screener (DSDS). J Sex Med. 2009;6(3):730-738. https://pubmed.ncbi.nlm.nih.gov/19845544/