Use of testosterone by women, especially menopausal women, continues to expand, despite the lack of long-term safety data and the lack of an approved product for women in the US, according to experts.

During a public workshop on testosterone use in menopausal women hosted by the FDA Office of Women’s Health and the Center for Drug Evaluation and Research, clinicians and researchers reviewed the current evidence and called on the FDA for additional research and expanded approvals of testosterone products for women.

The risks associated with testosterone use in women could be addressed in part by the approval of a product formulated for women specifically, said Pelin Batur, MD, MSCP, at the meeting. Evidence supports testosterone as a safe and effective product for many menopausal women, said Batur, professor of obstetrics and gynecology & reproductive biology at the Cleveland Clinic Lerner College of Medicine, Case Western Reserve University in Cleveland. Ultimately, the lack of FDA approval of testosterone for women complicates prescribing and leads to delays and errors in care, she emphasized.

A global consensus statement on the use of testosterone in women was published in 2019 in The Journal of Clinical Endocrinology & Metabolism, said Rajita Patil, MD, MSCP, associate clinical professor and director of the UCLA Comprehensive Menopause Program.

The goal of the consensus was to establish evidence-based guidance about which women would benefit from testosterone, which treatments might help, and which treatments might carry risks, and it was a response to the “clinical reality” of off-label testosterone prescribing for women, Patil said.

“Importantly, the final document was not simply the opinion of a small group of experts; it was endorsed by numerous leading organizations all over the world,” she emphasized.

Consensus Limited to a Single Condition

The international panel determined that the current evidence was only sufficient to support testosterone for treatment of hypoactive sexual desire disorder (HSDD) in postmenopausal women, with studies showing a modest therapeutic benefit. The statement did not endorse the use of testosterone in women for any other condition, citing insufficient data to assess effects on cognitive enhancement or the prevention of cognitive decline. The experts also found no demonstrated benefits of testosterone for improving general well-being or depressed mood, she said.

Although the experts also found insufficient data regarding associations between testosterone use and myocardial infarction or mortality in women, oral testosterone has been associated with adverse lipid profiles and is not recommended for use by women, said Patil. Testosterone in non-oral forms showed no significant adverse effects on lipid profiles, blood pressure, glucose, or HbA1c when used with physiologic dosing levels, based on data from short-term randomized, controlled trials, she said.

Given the lack of an FDA-approved testosterone product for women, clinicians must rely on off-label male formulations, which require dose modification and bring variability in exposure, Patil said. In addition, although data from short-term randomized controlled trials have been mainly reassuring, long-term data are lacking, as are data on special populations including perimenopausal women and breast cancer survivors, she said.

Patil also highlighted a clinical practice guideline for the use of testosterone specifically for HSDD published by the International Society for the Study of Women’s Sexual Health (ISSWSH) in 2021.

The ISSWSH guideline specifies the off-label use of one tenth of the male FDA-approved version of transdermal testosterone gel, which translates to 3-5 mg/d, the equivalent of three tubes per month, Patil said. Patients must provide informed consent because the product is off-label, and patients should apply the gel to the skin of the leg, back of calf, upper outer thigh, or buttock, according to the ISSWSH guideline.

Clinical Conundrums

In clinical practice, prescriptions of testosterone for women have approximately tripled in the past 5 years, said Batur, who also serves as center director of the Women’s Comprehensive Health and Research Center at the Cleveland Clinic.

Batur described a typical patient as a 55-year-old woman complaining of low sexual desire who has failed typical behavioral therapy. She understands the risks and benefits and might be a good candidate for testosterone, said Batur.

However, currently, “we are being asked to take a prescription suited for somebody with testicles and adapt to it to somebody with ovaries,” Batur said. That means adapting a lower dose of the products available and approved for men or compounding a product, which introduces another potential layer of human error, she said.

Compounding testosterone products for women can lead to unreliable dosing and supraphysiologic exposure, although metered devices can help with measuring, Batur noted. Side effects often go unreported, she said.

Other clinical challenges include differing absorption rates, application on unstudied body locations, and the addition of boosters to products meant for men, which can affect how much product is actually absorbed, she noted. Variability in cost remains a concern, as many health insurance plans do not cover testosterone for women because of the lack of an approved product, Batur said. The classification of testosterone as a Schedule III controlled substance further complicates prescribing, she noted.

Approval by the FDA of testosterone for women would help standardize delivery methods, which would allow for studies to determine the best body application locations and how to determine optimal dosing, Batur said. She called on the FDA to follow the lead of Australia, which has an approved testosterone cream formulated for women (AndroFeme). The product is officially approved only for HSDD and does not contain the absorption boosters found in male testosterone products.

Although the current evidence supports the use of testosterone in women for HSDD only, the large amount of insufficient evidence for other domains, including other sexual dysfunction entities, must be considered, Patil said during a Q&A session at the FDA workshop.

“As a clinician seeing patients who complain of an array of symptoms, I think it is important not to be dismissing these symptoms and to acknowledge and understand a patient’s treatment goals,” she said.

Be transparent with patients about the existing evidence for management of HSDD but also acknowledge that insufficient data does not mean there is no evidence for other indications, said Patil. There are observational data and small studies, but “we don’t have all the answers,” she said.

“Ultimately, it comes down to clinical shared decision-making, with the patients understanding the risks and limitations, as well as the possible benefits, before making a treatment plan,” Patil emphasized.

Patil and Batur had no financial conflicts to disclose.