Premenstrual Dysphoric Disorder Symptoms Following Ovarian Suppression: Triggered by Change in Ovarian Steroid Levels But Not Continuous Stable Levels

Abstract

Objective: Premenstrual dysphoric disorder (PMDD) symptoms are eliminated by ovarian suppression and stimulated by administration of ovarian steroids, yet they appear with ovarian steroid levels indistinguishable from those in women without PMDD. Thus, symptoms could be precipitated either by an acute change in ovarian steroid levels or by stable levels above a critical threshold playing a permissive role in expression of an underlying infradian affective "pacemaker." The authors attempted to determine which condition triggers PMDD symptoms.

Method: The study included 22 women with PMDD, ages 30 to 50 years. Twelve women who experienced symptom remission after 2-3 months of GnRH agonist-induced ovarian suppression (leuprolide) then received 1 month of single-blind (participant only) placebo and then 3 months of continuous combined estradiol/progesterone. Primary outcome measures were the Rating for Premenstrual Tension observer and self-ratings completed every 2 weeks during clinic visits. Multivariate repeated-measure ANOVA for mixed models was employed.

Results: Both self- and observer-rated scores on the Rating for Premenstrual Tension were significantly increased (more symptomatic) during the first month of combined estradiol/progesterone compared with the last month of leuprolide alone, the placebo month, and the second and third months of estradiol/progesterone. There were no significant differences in symptom severity between the last month of leuprolide alone, placebo month, or second and third months of estradiol/progesterone. Finally, the Rating for Premenstrual Tension scores in the second and third estradiol/progesterone months did not significantly differ.

Conclusions: The findings demonstrate that the change in estradiol/progesterone levels from low to high, and not the steady-state level, was associated with onset of PMDD symptoms. Therapeutic efforts to modulate the change in steroid levels proximate to ovulation merit further study.

Trial registration: ClinicalTrials.gov NCT00005011.

Keywords: Premenstrual Syndrome; estradiol; progesterone.

Conflict of interest statement

Disclosures:

The Authors have no potential conflicts of interest or financial support regarding this manuscript.

Figures

Figure 1

(A) Study Design Schematic: After a baseline cycle in which the diagnosis of PMDD was established all women received open label leuprolide. Between 2 and 6 days after onset of menses, women received six monthly intramuscular injections of 3.75 mg leuprolide After two - three months of leuprolide alone, those women whose PMDD symptoms were in remission (responders to leuprolide) (i.e., self-reported improvement confirmed by Premenstrual Tension scores

Figure 2

Upper Panel: Plasma estradiol (A) and progesterone (B) were significantly increased in the three months of estradiol/progesterone addback compared with the last month of leuprolide and the month of single-blind placebo. There were no significant differences in plasma levels between the first month of estradiol/progesterone addback compared with the second and third months of estradiol/progesterone addback. Lower Panel: The pattern of between month differences in symptom severity reflects the presence of significantly increased Premenstrual Tension-self (C) and –rater (D) scores during the first month of estradiol/progesterone (E/P in figure) addback (Month 5) compared with all other months (i.e., last month of leuprolide alone, placebo, and the second and third months of estradiol/progesterone addback). In contrast, there were no significant differences in symptom severity scores in either Premenstrual Tension-self or –rater scores between the last month of leuprolide alone (Month 3) and scores during placebo, second and third month of estradiol/progesterone addback. Finally, Premenstrual Tension scores in the second and third months of estradiol/progesterone addback also were not significantly different.