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

Abstract

Premenstrual dysphoric disorder (PMDD) symptoms are eliminated by ovarian suppression, stimulated by administration of ovarian steroids, yet appear in the context of levels of ovarian steroids indistinguishable from those in women without PMDD. Thus PMDD symptoms could be precipitated by either an acute change in the levels of ovarian steroids, or that stable levels of ovarian steroids above a critical threshold play a permissive role in the expression of an underlying infradian affective “pacemaker.” In this study, we attempted to define the kinetics of the ovarian steroid event relevant to triggering of PMDD symptoms. We studied 22 women with PMDD, aged 30 to 50 years. Twelve women who experienced symptom remission after 2–3 months of GnRH agonist-induced ovarian suppression (leuprolide) then received one month of single-blind(participant only) placebo and then three months of continuous combined estradiol/progesterone. Primary outcome measure was the Rating for Premenstrual Tension observer rater- and self-ratings completed every two weeks during clinic visits. Multivariate repeated measure ANOVA for mixed models was employed. Both Premenstrual Tension -self and –rater scores were significantly increased (more symptomatic) during the first month of combined estradiol/progesterone compared with all other months (i.e., last month of leuprolide alone (p=.0003,p<.0001, respectively), placebo(p=.0015,p=.0013, respectively), and 2nd month of estradiol/progesterone (p=.0014,p<.0001, respectively), and 3rd month of estradiol/progesterone (p=.0006,p<.0001, respectively). There were no significant differences in symptom severity scores (Premenstrual Tension -self, –rater)between the last month of leuprolide alone and the placebo month(p=.609, p=.106, respectively), 2nd month of estradiol/progesterone (p=.639, p=.524, respectively) and 3rd month of estradiol/progesterone (p=.99, p=.812, respectively). Finally, Premenstrual Tension scores in the 2nd and 3rd estradiol/progesterone months did not significantly differ. We demonstrated that the change in levels of estradiol/progesterone from low to high, and not the steady state levels, was associated with the onset of PMDD symptoms. Therapeutic efforts to modulate the change in steroid levels proximate to ovulation merit further study.

Epigenetic intersection of BDNF Val66Met genotype with premenstrual dysphoric disorder transcriptome in a cross-species model of estradiol add-back

“…Curiously, intact Het-Met female mice display cognitive deficits that are corrected by ovariectomy alone [6]. Together with our report, these findings suggest that, similar to PMDD women, behavioral impairment in Met carriers arise from the presence of E2 [16,30].…”

“…This mouse paradigm sheds light from an epigenetic perspective on PMDD in humans, where ovarian suppression has been used to treat negative symptoms associated with PMDD, such as depressive mood, anxiety, irritability, and other somatic symptoms [16]. Women with PMDD display recurrence of negative symptoms when treated with E2 [16,30]. Besides parallels in the lability of behavior under E2 in Het-Met female mice and women with PMDD, we also found parallels between expression of epigenetic regulatory genes in the vHpc of OVX WT and OVX Het-Met mice and in LCL cultures from healthy women and women with PMDD, respectively.…”

Sex differences and the neurobiology of affective disorders

“…As it was unclear whether the precipitating event was a change (increase) in the hormone or the exceeding of a threshold level of hormone, a study was designed to administer reproductive steroids continuously for 3 months in association with ovarian suppression. Following the initial precipitation of depression in concert with hormone exposure, the affective state resolved and failed to reappear during the remaining 3 months of the stabilized hormone administration, thus demonstrating that the change in hormone (rather than the level achieved) was the inciting stimulus [350]. Similarly, prevention of the luteal phase-related increase in the progesterone metabolite allopregnanolone by the administration of dutasteride, a blocker of allopregnanolone synthesis, prevented the switch into the PMDD-related dysphoric state [351], thus mirroring the stresslike behavioral state observed following changes in allopregnanolone in rodents [345].…”

<p>Comorbid Premenstrual Dysphoric Disorder in Women with Bipolar Disorder: Management Challenges</p>

“…30 The rapid changes of progesterone levels during the different phases of the menstrual cycle and the estrogen influence on serotonin may result in premenstrual symptoms even in case of normal ovarian function. [31][32][33] Hormonal fluctuations during the menstrual cycle may influence the clinical course of BD: women with BD and premenstrual exacerbation of mood symptoms have a poorer outcome and shorter time to relapse. 34 In patients affected by BD, low levels of estrogen were found during episodes of post-partum psychosis.…”