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Sarah uses kitchen measuring spoons to dispense just the right dose—between a pinch and a smidge—of testosterone gel formulated for men to treat her low sexual desire. “This is an absurd way for women to get testosterone therapy,” acknowledged 58-year-old Sarah’s physician, Sharon Parish, MD, a professor of clinical medicine at Weill Cornell Medical College in New York City. But with no female-tailored testosterone product on the market, it’s a necessary workaround.
Parish and an international group of researchers recently published a position statement on female testosterone therapy. In line with these first global recommendations, Parish advises some of her postmenopausal patients with low libido like Sarah to use one-tenth of a male dose to approximate their premenopausal testosterone levels.
Many clinicians aren’t as judicious. Juliana Kling, MD, an associate professor of medicine at the Mayo Clinic in Phoenix, said she cringes each time a new patient tells her that she’s had testosterone pellets implanted into her buttocks by another clinician, often a naturopath or alternative medicine practitioner. “It’s very difficult or impossible to get a physiologic level of testosterone with pellets,” Kling said. She’s seen women whose off-label, high-dose testosterone use for low libido and other concerns has led to hair loss, voice changes, and even an enlarged clitoris. In some cases, the adverse effects are irreversible.
The new recommendations, endorsed by 11 international professional societies—including the North American Menopause Society, the Endocrine Society, and the International Society for the Study of Women’s Sexual Health (ISSWSH)—aim to clarify which women may benefit from testosterone treatment and to protect patients from harmful androgen concentrations.
The statement, published in The Journal of Clinical Endocrinology & Metabolism, summarizes the evidence for physicians contemplating prescribing testosterone to women, according to Michael Irwig, MD, director of the Center for Andrology at George Washington University in Washington, DC, who was not involved with the recommendations. Because so much is unknown about female androgen deficiency, “there is a considerable uncertainty about which women could potentially benefit from testosterone therapy,” he said.
Although physicians have been treating women with testosterone for decades, consensus recommendations like these haven’t been available until now. The guideline is largely based on evidence from randomized clinical trials, including a recent systematic review and meta-analysis of 36 trials (some unpublished) involving a total of 8480 women.
It “coalesces the world’s data into a single statement,” said James Simon, MD, a clinical professor at George Washington University who coauthored the recommendations.
The position statement is emphatic that testosterone therapy should be used only for postmenopausal women and only to treat hypoactive sexual desire disorder (HSDD). This type of female sexual dysfunction is defined as a persistent lack of sexual fantasies and desire for sex that causes distress to the woman or her intimate relationship. Lacking evidence, the statement’s task force couldn’t recommend testosterone therapy for female sexual arousal disorder, a condition in which women can’t achieve or maintain an adequate genital response during sex. But the researchers found a moderate treatment effect of testosterone for HSDD, which is diagnosed based on an assessment of biological and social factors.
“That is the only indication for which we have truly good evidence,” said Susan Davis, MD, the statement’s lead author and a professor of clinical epidemiology at Monash University in Melbourne, Australia. Nevertheless, some physicians, particularly in the United States, promote the use of high-dose testosterone among women for indications such as hot flashes, fatigue, headache, depression, and low mood. Davis, who is president of the International Menopause Society, called the liberal prescribing “complete cowboy stuff.”
Due to a dearth of evidence, the statement doesn’t recommend testosterone therapy for common off-label uses like improving mood, cognition, or general well-being. The data also don’t reflect a beneficial effect on musculoskeletal tissues, despite keen interest in using testosterone for female bone health. In addition, high-dose testosterone’s safety for women hasn’t been established, so the new guidance recommends using small amounts to boost a woman’s testosterone to her approximate premenopausal testosterone concentrations, which is typically in the upper quartile of the reference range.
The other side of the coin is that testosterone also can be underprescribed to women. Experts said that underuse has been a problem since the Women’s Health Initiative trial linked hormone replacement therapy—specifically estrogen and progestin—with cardiovascular disease and breast cancer in 2002. “Hormone therapy has a very bad rap—unnecessarily,” said Simon, who is president of the ISSWSH.
The panel of experts, who received no external funding for the report, concluded that among postmenopausal women, low-dose testosterone’s moderate effect translated to 1 additional satisfying sexual event per month on average, along with increases in sexual desire, arousal, orgasm, and sexual responsiveness and a reduction in a woman’s distress from sexual dysfunction.
“While one additional satisfying sexual event per month doesn’t sound like much, it was both statistically significant and a clinically relevant change to the study subjects,” Simon said.
However, not all women respond to testosterone therapy. “About 60% of women will have real improvement that will make a difference to them, about 20% won’t change, and about 20% will get worse because low testosterone has nothing to do with their sexual dysfunction,” said Davis, who also coauthored the recent meta-analysis.
The treatment appears to have a good, albeit limited, safety profile. In its review, the task force found no evidence of major adverse events, but only 2 years of safety data were available. Clinical trials of testosterone also haven’t included women at high risk of cardiometabolic disease. The panel’s recommendations therefore don’t extend to women with high cardiovascular disease risk or to long-term therapy.
“The decision to use testosterone in any patient, including those with increased cardiovascular risk or for longer duration, involves a benefit-risk discussion between the clinician and the patient,” Parish said.
Although testosterone therapy hasn’t been associated with increased breast cancer risk, the authors urged caution in prescribing the therapy to women with hormone-sensitive breast cancer. Clinicians are also warned against using oral testosterone for women, which can adversely affect cholesterol levels. The statement recommends nonoral testosterone therapies, such as topical creams and gels, which don’t appear to negatively influence lipid profiles over the short-term. Patients should also avoid injectables, pellets, or other formulations that create androgen excess. And testosterone prepared in compounding pharmacies, which aren’t rigorously regulated, should also be avoided.
Considering the statement’s many cautions, Ekta Kapoor, MBBS, said that she is wary about prescribing testosterone for HSDD. “By virtue of being older, these women have a higher risk of cardiovascular disease and breast cancer,” she said.
Kapoor, who is assistant director of the Mayo Clinic Center for Women’s Health in Rochester, Minnesota, prescribes testosterone therapy to postmenopausal women only if she can’t find other reasons for low sexual desire, which she asserted is typically not the case. “Giving testosterone to a postmenopausal woman is like tampering with nature,” she said.
Simon disagreed: “Women have had testosterone all their adult lives,” he said. He acknowledged that more long-term data are needed. But he prescribes low-dose testosterone every day to patients in his practice, which is focused on treating problems of menopause and sexual dysfunction.
According to the new guidance, testosterone therapy shouldn’t be initiated until a clinician rules out potentially reversible biopsychosocial factors that may contribute to a woman’s low sexual desire, like a medical condition or medications, depression, relationship issues, or sexually repressive cultural or religious values. Parish recommended that clinicians follow the ISSWSH’s process of care for HSDD management.
“Only after reaching the conclusion that a woman’s distressing low sexual desire is the result of age-related decline of testosterone do I consider using an off-label testosterone product, potentially in conjunction with other lifestyle and educational interventions,” she said.
Although there’s no specific blood testosterone threshold for diagnosing HSDD in women, getting a baseline level is recommended to ensure that it’s in the lower quartile of the reference range, which varies based on the laboratory conducting the test. According to Parish, the therapy is unlikely to help women whose baseline testosterone is already in the upper quartile. If patients don’t see a benefit at 3 to 6 months, she stops the treatment.
Although the new statement wasn’t created to spur the development of women’s testosterone products, the authors and other physicians said they want the pharmaceutical industry to take notice.
“There was unanimous agreement by all the societies that endorsed the position statement that there is a desperate need for products for women,” Davis said.
There are currently about 30 testosterone products on the US market to treat male hypogonadism, but no testosterone products specifically formulated for women. In fact, Australia is the only country with an approved female testosterone product. (Two nonhormonal products for HSDD are available— flibanserin [Addyi] and bremelanotide [Vyleesi]—but neither is approved for postmenopausal women.)
Sexual dysfunction has been studied much more extensively in men than in women, according Davis, which explains why no testosterone products exist for women. Due to prevalent sexism and ageism, “women’s sexual needs are completely dismissed,” she said.
Simon also cited a double standard at the US Food and Drug Administration (FDA). The last time a drug company brought a testosterone product for women before the FDA was in 2004, when Procter & Gamble introduced its transdermal testosterone patch. An FDA advisory committee agreed that the testosterone patch was efficacious but raised concerns about potential cardiovascular and breast cancer risks.
“The FDA asked for a 5-year study to document the safety of the product for cardiovascular disease and for breast cancer—a $1 billion trial,” Simon said. Procter & Gamble withdrew its application and another pharmaceutical company that attempted the safety study ran out of money, he explained.
The FDA’s criteria for approving testosterone products for men is much lower: the product simply must demonstrate that it can bring a man with low testosterone levels up to the normal range and do that safely for 6 months, according to Simon. Although he said that he’s hopeful, he isn’t betting on pharmaceutical companies to develop testosterone products for women. “I’m pessimistic that the FDA will make changes to the pathway to approval for women’s testosterone products,” he said.
Meanwhile, there’s still much to learn about testosterone therapy for women, the consensus panel concluded. In particular, the experts called for more randomized trials to study testosterone for musculoskeletal health and cognitive performance, and to establish its long-term safety.
A more basic necessity is a method to diagnose HSDD. “We don’t even have a good validated instrument to assess sexual dysfunction in women to discern what is a problem and what isn’t,” Irwig said. “That has to be improved.”
Slomski A. Which Postmenopausal Women Should Use Testosterone for Low Sexual Desire? JAMA. 2020;323(6):493–495. doi:10.1001/jama.2019.22070
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