FRI424 Allopregnanolone Levels Are Elevated in the Follicular Phase and Predict Premenstrual Depression and Anxiety Symptom Severity in Women with Menstrually Related Mood Disorder

Disclosure: A. Kimball: None. J. Bourassa: None. M. Chicote: None. A.V. Gerweck: None. L.E. Dichtel: Other; Self; Dr. Dichtel is a Mass General Brigham (MGB) Innovation Fellow hosted by Third Rock Ventures. Financial interests were reviewed and are managed by MGH and MGB in accordance with their COI policies. K.K. Miller: None. Menstrually related mood disorder (MRMD), which includes premenstrual dysphoric disorder (PMDD) and subthreshold PMDD, is marked by severe psychiatric impairment in the late luteal phase of the menstrual cycle, but little is known about the mechanisms responsible. Allopregnanolone is a neuroactive metabolite of progesterone and a potent GABA(A) receptor allosteric activator with antidepressant and anxiolytic properties. We have shown that allopregnanolone levels increase, while the allopregnanolone/progesterone ratio decreases, from the follicular to luteal phase in healthy women. We hypothesized that allopregnanolone levels would decrease in association with the increase in depression severity experienced in the late luteal phase by women with MRMD. We studied 23 women with regular menses [MRMD (n=9) and healthy controls with no premenstrual symptoms or psychiatric history (HC) (n=14)] in the mid-follicular (cycle day 6-10), mid-luteal (5-9 days after LH surge), and late luteal (9-13 days after LH surge) phases. No subjects took gonadal steroids or psychotropic medications. The Daily Record of Severity of Problems was used to diagnosed PMDD (≥5 symptoms) and subthreshold PMDD (1-4 symptoms). Depression and anxiety symptom severity were assessed using the Quick Inventory of Depressive Symptomatology and Generalized Anxiety Disorder 7-item Scale, respectively. Fasting plasma hormone levels were measured by GC/MS. Data are presented as median(95% CI). Normal ranges were calculated as the 95% CI of HC. Median age [30(28,33) years] and BMI [23.8(22.9,29.0) kg/m(2)] were similar between groups. Depression severity was greater in MRMD vs HC [7(3,13) vs 2(1,4), p=0.005) in the late luteal phase only, as expected. In the follicular phase, the median allopregnanolone level was higher in MRMD vs HC [86(40,148) vs 29(24,73) pg/mL, p=0.05] and frankly elevated in 6 of 9 (67%) MRMD women. The median allopregnanolone/progesterone ratio in the follicular phase was higher in MRMD vs HC [0.8(0.4,2.2) vs 0.4 (0.3,0.8), p=0.03] and elevated in 4 of 9 (44%) MRMD women. There were no differences in neuroactive steroid levels between groups during the luteal phase. Higher allopregnanolone levels in the follicular phase were associated with greater depression severity in the mid-luteal (r=0.51, p=0.01) and late luteal (r=0.54, p=0.007) phase and greater anxiety severity in the late luteal phase (r=0.41, p=0.05). Conclusion: Contrary to our hypothesis, we found that levels of neuroactive steroids, which have antidepressant effects, were higher in the follicular phase in women with MRMD – who experience depression in the late luteal phase – compared with HC. This suggests that increased conversion of progesterone to allopregnanolone in the follicular phase, resulting in elevated allopregnanolone levels, may be a compensatory response to premenstrual depression and anxiety in some women with MRMD. Presentation Date: Friday, June 16, 2023