While many women experience physical symptoms prior to the onset of their period or premenstrual syndrome (PMS), a smaller subset of women suffer from Premenstrual Dysphoric Disorder (PMDD), a more severe form of premenstrual syndrome.  Serotonergic antidepressants have been established as the first-line treatment option for PMDD; however, some women either do not tolerate or fail to respond to this class of medications.  Some women may benefit from treatment with oral contraceptives; however, a significant proportion of women, especially those with more severe symptoms, may not respond to either of  these interventions.  

In a recent study, researchers investigated continuous treatment with a selective progesterone receptor modulator, ulipristal acetate (UPA), as a potential treatment for PMDD.  In this multicenter, double-blind, randomized clinical trial, women with PMDD (N=95) were randomly assigned to receive either 5 mg/day of UPA (N=48) or placebo (N=47) during three 28-day treatment cycles.   One-third of the participant had previously failed treatment with an SSRI.

Premenstrual symptoms were measured using  the Daily Record of Severity of Problems (DRSP) from baseline to end of treatment. DRSP scores were captured daily using a smartphone application.  

Results

Women in the UPA group experienced a mean improvement in DRSP score after 3 months of 41% (SD=18), compared to 22% (SD=27) in the placebo group (mean difference -18%). UPA treatment was associated with improvements in DRSP depressive symptom subscale (42% compared with 22%) and DRSP anger/irritability subscale (47% compared with 23%).  No differences were observed for the DRSP physical symptom subscale. 

Remission based on DRSP score was attained by 20 women in the UPA group (50.0%) and eight women in the placebo group (21.1%).  Seven women treated with UPA discontinued because of mild or moderate side effects. The most commonly reported side effects leading to discontinuation were headache, fatigue, and nausea; one woman discontinued because of worsening of depressive symptoms.Among women in the placebo group, three discontinued because of depressive symptoms or anxiety

Will UPA Be a Viable Treatment Option?

The current study suggests that UPA is an effective treatment for PMDD.  While it does improve the physical symptoms observed in women with PMDD, UPA treatment leads to significant reductions in the psychological symptoms of depression and anger/irritability, which are the hallmark of PMDD.  Complete or partial remission of PMDD symptoms was attained by 85% of the women treated with UPA. 

Exactly how UPA works is not completely understood.  UPA is a selective progesterone receptor modulator which acts as a progesterone antagonist in progesterone responsive tissues.  In the brain, progesterone receptors are found throughout the amygdala, hippocampus, hypothalamus, thalamus, and frontal cortex, areas involved in mood regulation.  

While direct modulation of progesterone receptors may contribute to the reduction of PMDD symptoms observed with UPA in this study, treatment with progesterone receptor modulators, including UPA, results in anovulation.  Thus, UPA may provide relief by shutting down ovulation and preventing the cyclical fluctuations in the levels of estrogen and progesterone which are thought to trigger premenstrual symptoms.  This mechanism of action is similar to what is observed in women treated with GnRH agonists like leuprolide or Lupron.  However, the big advantage with UPA is that, unlike GnRH agonists, UPA does not lead to such a profound reduction in estrogen levels and hypoestrogenism.  In women treated with UPA, levels of estrogen remain stable in the mid-follicular phase range.  

While UPA appears to be effective for PMDD symptoms, it is important to note that 15% of the women in the UPA group discontinued treatment because of side effects, most commonly headaches, nausea and fatigue. There is limited information on the long-term safety of UPA. This medication was  introduced in 2012 for the treatment of uterine fibroids.  More than 750,000 women have been treated for uterine fibroids with UPA; however, treatment does not typically extend beyond three months.  One study suggested increased risk of liver injury with long term use; thus, the FDA has requested more data regarding the safety of long-term use and for now recommends periodic monitoring of liver function.  

UPA is not quite ready for primetime.  However, it is exciting to see a new medication that works differently from standard treatment approaches.  Moreover, the fact that about one-third of the participants failed treatment with an SSRI prior to entry into the study but responded to UPA, suggests that UPA, and perhaps other progesterone receptor modulators, may be a reasonable alternative for patients who do not tolerate or respond to SSRIs.

Ruta Nonacs, MD PhD

Comasco E, Kopp Kallner H, Bixo M, Hirschberg AL, Nyback S, de Grauw H, Epperson CN, Sundström-Poromaa I.  Ulipristal Acetate for Treatment of Premenstrual Dysphoric Disorder: A Proof-of-Concept Randomized Controlled Trial.  Am J Psychiatry. 2020 Dec 10.