Effect of progesterone and its 5 α and 5β metabolites on symptoms of premenstrual syndrome according to route of administration

Orally administered progesterone may have advantages over other routes of administration in the treatment of premenstrual syndrome (PMS) because of substantially higher levels of the anxiolytic metabolites 5α and 5β pregnanolone. The only previous placebo-controlled trial which used oral progesterone reported beneficial effects in the treatment of PMS. The present study, a double-blind crossover trial, compared the administration of 300mg daily oral progesterone with 200 mg daily vaginal progesterone and matched placebos for 10 days premenstrually. Although there was a significant treatment effect on symptoms, no difference between active treatments and placebo was found. The trial was terminated with 25 women completing treatment as it was evident that no clinically significant effect of either form of progesterone was likely to be detected even with twice the sample size. Serum levels of progesterone and metabolites showed that oral administration resulted in supra physiological levels of 5α and 5β metabolites and there was a negative correlation between 5α pregnanolone levels and anxiety. However this did not translate to overall reduction in premenstrual distress or anxiety beyond that achieved by placebo, as measured by validated questionnaires.