Premenstrual dysphoric disorder (PMDD) affects about 5% of menstruating individuals and is related to significant negative mood symptoms throughout the luteal phase of the menstrual cycle. For many years, the treatment of PMDD has primarily consisted of two distinct approaches. Treatments that suppress ovulation, including oral contraceptives and GnRH antagonists (Lupron), can improve premenstrual symptoms, but many ladies cannot tolerate these hormonal interventions. More commonly, women with PMDD are treated with serotonergic reuptake inhibitor (SRI) antidepressants, corresponding to fluoxetine (Prozac) and sertraline (Zoloft).

Recently other options have emerged. The appearance of a novel class of antidepressants — neuroactive steroids that modulate the results of the inhibitory neurotransmitter GABA at GABA-A receptors — have led to the event of two recent treatments for postpartum depression, brexanolone and zuranolone. This has led researchers to invest that these neuroactive steroids may additionally be effective for the treatment of other hormone-mediated mood disorders, including PMDD. 

While SRIs proceed to be the primary line treatment for PMDD, exactly how they work to alleviate PMDD symptoms will not be well understood. A brand new study from Miller and colleagues asks whether SRI treatment affects the degrees of neuroactive steroids that act at GABA-A receptors and in that case, whether increases in levels of neurosteroids are related to improvement in PMDD symptoms.

This study included 32 individuals with PMDD confirmed with prospective rankings of PMDD symptoms using the Each day Record of Severity of Problems (DRSP) and 38 unaffected controls. At baseline, serum levels of nine neuroactive steroids were measured (3?,5?-THP; 3?5?-THP; pregnenolone; 3?,5?-androsterone; 3?,5?-androsterone; 3?,5?-A-diol; 3?5?-A-diol; 3?,5?-THDOC; 3?5?-THDOC) throughout the follicular (before ovulation) and luteal (after ovulation) phases of the participants’ menstrual cycles. 

In the next menstrual cycle, participants within the PMDD group were treated with 50 mg sertraline throughout the luteal phase (from ovulation to the onset of menses), and levels of neuroactive steroids were again measured.

Treatment with SSRI Alters Luteal Levels of Neuroactive Steroids

At baseline, there have been no significant differences in levels of neuroactive steroid levels between participants with PMDD and controls throughout the luteal phase of the cycle (p > 0.05). After treatment with sertraline, nonetheless, participants within the PMDD group had significantly increased levels of pregnenolone, increases within the pregnenolone:progesterone ratio, and decreased levels of three?,5?-androsterone.

A complete of 27 participants within the PMDD group were treated with sertraline. Inside the PMDD group, 12 participants (44.4%) were considered sertraline treatment responders, while 15 were non-responders. The researchers observed no significant association between changes in neuroactive steroid levels and changes in luteal phase PMDD symptoms amongst individuals treated with sertraline (p > .05). Amongst non-responders, 3?,5?-androsterone levels decreased with SSRI treatment; in contrast the responders showed a rise in 3?,5?-androsterone levels with SSRI treatment. 

What’s the Role of Neuroactive Steroids within the Pathophysiology of PMDD?

This can be a small but thought-provoking study, the primary to look at the impact of SSRI treatment on luteal phase levels of neuroactive steroids in individuals with confirmed PMDD. Treatment with sertraline throughout the luteal phase was related to increased pregnenolone levels, in addition to increases within the pregnenolone:progesterone ratio.

The findings of this study suggest that pregnenolone may play a job within the pathophysiology of PMDD. Progesterone is converted to the metabolite allopregnenolone, in addition to pregnenolone (first to five?-DHP by 5?-reductase after which to pregnenolone by 3?-HSD). Thus, elevated pregnenolone levels, and particularly a rise within the ratio of pregnenolone relative to progesterone, suggests that the enzymes 5?-reductase or 3?-HSD are more efficiently converting progesterone to pregnenolone consequently of SSRI treatment. That is consistent with previous studies finding that SSRIs increase the efficiency of the enzyme 3?-HSD, leading to increased conversion of progesterone to pregnenolone. 

The findings suggest a possible mechanism of motion for serotonergic reuptake inhibitors within the treatment of PMDD. Clinically we see that girls with PMDD often experience rapid relief after initiating treatment with SRIs–in days versus weeks, as is the case when SRIs are used to treat depressive symptoms. This more rapid onset of motion suggests that SRIs may go in another way for the treatment of PMDD than for major depressive disorder. The authors hypothesize that in individuals with PMDD, SRIs may ameliorate premenstrual symptoms by increasing levels of neuroactive steroids with GABA-ergic effects. The rapid motion of SRIs on this setting may reflect more rapid changes in neuroactive steroid levels, much like those observed when brexanolone or zuranolone are used to treat postpartum depression.

Several studies have checked out the efficacy of neuroactive steroids for the treatment of PMDD. One example is sepranolone (or isoallopregnanolone), a metabolite of allopregnanolone that acts as an antagonist on the GABA-A receptor. In a double-blind randomized controlled trial from Bäckström and colleagues, sepranolone was shown to be effective for the treatment of PMDD symptoms and well-tolerated. 

Stay tuned…

Ruta Nonacs, MD PhD

References

Miller KN, Standeven L, Morrow AL, Payne JL, Epperson CN, Hantsoo L. GABAergic neuroactive steroid response to sertraline in premenstrual dysphoric disorder. Psychoneuroendocrinology. 2024 Feb; 160:106684.