Progesterone Modulator May Offer PMDD Relief

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Ulipristal acetate (UPA), a progesterone-modulating drug used as an emergency contraceptive and treatment for uterine fibroids, might help alleviate the psychological symptoms of premenstrual dysphoric disorder (PMDD), according to a study in AJP in Advance. An estimated 3% to 5% of women of reproductive age are believed to experience PMDD, which is characterized by mood swings, irritability, anxiety, depression, and physical symptoms in the days preceding menstruation.

Current medication options for PMDD are limited. Selective serotonin reuptake inhibitors (SSRIs) can improve PMDD symptoms, such as depression or irritability, but up to 40% of women do not respond to these medications.

Erika Comasco, Ph.D., an associate professor of neuroscience at Sweden’s Uppsala University, and colleagues tested UPA as another option for treating PMDD after studies revealed many women prescribed low-dose UPA for fibroids did not experience menstruation because their egg release was blocked (known as anovulation). PMDD manifests in the period between ovulation and menstruation, and it is believed that anovulation may be a mechanism to reduce PMDD symptoms.

Comasco and colleagues recruited women aged 18 to 46 who were diagnosed with PMDD, as determined by scores on the Daily Record of Severity of Problems (DRSP) over a two-month period. This scale measures the time course and severity of 11 common PMDD symptoms. A total of 95 participants were given either 5 mg UPA or placebo pills daily over the course of three menstrual cycles. At the end of the study, average DRSP scores for the five days prior to menstruation had fallen by an average of 41% among women taking UPA compared with 22% among women taking placebo. In addition, half of the women taking UPA achieved full remission (defined as no individual DRSP symptom above a score of 3) compared with 21% in the placebo group.

Among specific symptoms, women taking UPA reported greater improvements in symptoms of depression, anger, and fatigue relative to women taking placebo. UPA was not associated with improvements in anxiety or guilt, and it did not significantly improve any physical symptoms, such as headache or feeling bloated.

“As this study was not designed to capture ovulation and progesterone levels during treatment, we cannot ascertain whether the effect of UPA is mediated by anovulation, leading to low progesterone and allopregnanolone levels, or via specific actions at the progesterone receptor,” Comasco and colleagues wrote. However, they noted that only 27% of women taking UPA experienced loss of menstruation, a much lower rate than reported by women in fibroid studies. “For this reason, we speculate that both factors are likely involved.”

The UPA was well tolerated and there were similar dropout rates in the UPA and placebo groups (eight women taking UPA and nine taking placebo dropped out of the study). There were no serious adverse events reported during the study, and the only side effect more pronounced in the UPA group compared with the placebo group was nausea.

The authors acknowledged that since this was the first controlled study to assess UPA as a PMDD therapy, it is too soon to recommend this drug for any patients. One outstanding issue is that some women taking UPA for fibroids have experienced liver damage, and the European Medicines Agency is reviewing if UPA was responsible. In 2018, the Food and Drug Administration rejected UPA for fibroid treatment in the United States, citing safety concerns. (Women with any history of liver problems were not allowed to enroll in the study by Comasco and colleagues.) But as more safety data emerges, UPA could become a viable option for some women who do not respond or tolerate SSRI therapy, the researchers noted. In this study 36% of the participants had tried and failed SSRIs already.

“This is a novel and interesting study that showcases the potential of reproductive hormones as part of the armamentarium for treating mood disorders,” said David Rubinow, M.D., a distinguished professor of psychiatry and medicine at the University of North Carolina and the founder of UNC’s Women’s Mood Disorders Program.

“As UPA can alter the length of a woman’s cycle, it is difficult to conduct a truly blinded study and that might have skewed the results,” he continued. “But, overall the findings were solid.”

Rubinow, who was not involved in the study, said UPA is intriguing since it is a selective progesterone modulator; that is, it only blocks hormonal activity in tissues where the equilibrium is off, which reduces the risk of undesirable side effects. (Selective estrogen modulators are widely used for osteoporosis and breast cancer.) He noted that it would be important to show whether UPA stabilizes progesterone levels in women and if that stabilization is related to overall efficacy.

This study was supported by grants from the Swedish Research Council and the Swedish Society of Medicine. Some of the authors reported relationships with Gedeon Richter Nordics, which manufactures UPA. ■