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.

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 <5 and the absence of symptom cyclicity on Daily Rating Form (i.e., weekly [7-day] average daily scores for irritability, sadness or anxiety of < 3 (indicating less than moderate severity of a particular symptom) (52;53) were selected to continue on leuprolide for an additional 4 months. Women not meeting these criteria were considered non-responders and were not included in the statistical analysis. Responders to leuprolide continued to receive monthly leuprolide injections for another four months and received one month of single blind (to participant only) placebo (patch and suppository) followed by three months of combined estradiol (100 ug daily by skin patch) and progesterone (200 mg vaginal suppository twice daily) replacement. Functional impairment was assessed through self-reports of distress and functional impairment on the Daily Rating Form (23). The Daily Rating Form criteria for functional impairment were as follows: a score of 2 (minimal) or higher on one of 4 questions related to functional impairment (i.e., stayed at home or avoided social activities, had conflicts or problems with people, symptoms interfered with relationships at work or home, or symptoms interfered with work productivity) in at least 3 days out of 7 days pre-menses. (B) Study Patient Flow Chart

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.