The use of transdermal testosterone in the treatment of hypoactive sexual desire disorder (HSDD) in postmenopausal women is effective and existing studies show no apparent association with breast cancer.

However, reliable studies are lacking and caution is urged, particularly for women with hormone-sensitive breast cancer, say the authors of a new systematic review, led by Ritika Gera of the London Breast Institute, Princess Grace Hospital, UK.

Transdermal testosterone, used as a gel or patch, is commonly prescribed for HSDD in postmenopausal women. Testosterone is also frequently used in women, off-label, for general menopausal symptoms.

“A consensus is yet to be reached on the safety of transdermal testosterone use for postmenopausal women and the nature of its relationship with breast cancer,” say Gera and colleagues.

“Our systematic review aims to tackle this uncertainty.”

Only Three Studies Could Be Reviewed but Provide Important Insights

The researchers initially identified more than 200 studies by searching PubMed and Ovid, but only three randomized controlled trials sufficiently met their criteria, and even those could not be compared because of substantial differences in age groups and the number of women who were also taking estrogen.

The trials were “too heterogeneous for a meta-analysis. A systematic review was deemed the most appropriate analysis of the data available,” they note in their review, published in the December issue of Anticancer Research.

However, the studies “did offer some important insights,” they add.

The first study (Gynecol Endocrinol. 2011;27:39-48), of 641 women who became menopausal as a result of surgery and received transdermal testosterone therapy and estrogen, found no significant increase in the occurrence of major adverse effects over an approximately 4-year follow-up; however, the study did not include women who were naturally post-menopausal. There were three cases of invasive breast cancer, which is consistent with age-appropriate expected rates.

The second study (Climacteric. 2010;13:121-131), of the randomized, placebo-controlled ADORE trial, included 272 naturally menopausal women who received transdermal testosterone (300 µg) or placebo for HSDD twice a week for 6 months, and most participants were not taking other hormone therapy. No occurrences of breast cancer, myocardial infarction, or death were reported during the trial; however, there was no post-termination follow-up.

There were significant improvements in various measures of satisfying sexual episodes in the testosterone-treated group.

The third study (N Engl J Med. 2008;359:2005-2017) was a double-blind, placebo-controlled 52-week trial of 464 postmenopausal women with low libido who were not taking estrogen and received transdermal testosterone (150 or 300 µg/day) or placebo.

In that study, four cases of breast cancer occurred in the testosterone group; however, one case developed within the first 4 months of the study and one case had symptoms prior to randomization. One of the patients reported having a sister who was also at risk of breast cancer, and one patient took 300 µg/day of testosterone for 104 weeks as part of a treatment extension. There were no occurrences of breast cancer in the placebo group.

Compared with placebo, there was a significantly greater increase in satisfying sexual episodes in the testosterone 300 µg/day group (P < .001) but not the testosterone 150 µg/day group (P = .11).

“The findings from the New England Journal of Medicine study were slightly alarming since four cases of breast cancer were seen in the transdermal testosterone group and none in the control group,” senior author Kefah Mokbel, MBBS MS, also of the London Breast Institute, told Medscape Medical News.

Overall, he said, “We were surprised by the paucity of studies in this field. By contrast, there are numerous studies looking at testosterone and prostate cancer risk.”

Mokbel also noted that the review focused on the medical indication of HSDD with transdermal testosterone because evidence is conflicting or lacking of the benefits of testosterone for other postmenopausal symptoms, including fatigue, insomnia, and mood swings.

Randomized, Placebo-Controlled Trials Needed

The review underscores the fact that more research is needed to determine the safety of the widespread use of transdermal testosterone in postmenopausal women, the authors assert.

“There is clearly a need to further investigate any potential safety risks related with the use of transdermal testosterone, particularly by using randomized prospective trials,” the authors write.

“A double-blind prospective trial with a large cohort of postmenopausal women who do not have any previous history of cancer should be conducted.”

They offer key recommendations for the design of clinical trials that will more effectively assess the relationship between use of transdermal testosterone and breast cancer in postmenopausal women, as follows.

• Participants who have previously taken systemic estrogen/estrogen-progestin in the previous 3 months or have testosterone implants should be excluded.
• Adjust for confounding risk factors for breast cancer such as body mass index and ethnicity. Participants should subsequently be randomized to placebo or varying concentrations of transdermal testosterone.
• Follow-up should be for at least a year and participants should be checked for the development of breast cancer in the years following study termination.
• The development of breast cancer throughout the trial should be assessed using a standard method.
• Mammography should be conducted prior to study initiation and upon study termination. The presence of symptoms of breast cancer prior to study initiation should be an exclusion factor.
• A Pap smear must also be conducted prior to study initiation to determine the risk of cervical cancer, and those with suspicious results should be excluded.
• Randomization should include varying concentrations of transdermal testosterone or placebo.
• Participants should be asked to keep a sexual desire and activity journal to document any increase in their arousal levels because of the transdermal testosterone treatment.

Treatment in Women Who Have Already Had Breast Cancer

Finally, the authors add that more research is needed into the use of transdermal testosterone among different groups of women who have already had breast cancer.

“Further experimentation is required to determine the long-term effects of transdermal testosterone therapy on women with estrogen receptor-positive breast cancer.”

And caution should be also exercised when considering use of transdermal testosterone in patients with triple-negative breast cancer that is positive for androgen receptor expression, they conclude.