Neuroactive steroid hormone trajectories across the menstrual cycle in premenstrual dysphoric disorder (PMDD): the PHASE study.

It is presently not known whether endogenous neuroactive steroid hormone trajectories across the menstrual cycle are distinguishable in women with premenstrual dysphoric disorder (PMDD). To improve the rigor in this area of research, we implemented a validated study methodology, involving blood sample collection at 8 key menstrual cycle timepoints, following which the study data is realigned so that all women are compared at the same biological window (i.e., menstrual cycle subphase). Using liquid chromatography-mass spectrometry (LC-MS), we analyzed serum levels of nine steroid hormones previously implicated in the etiology of PMDD, including allopregnanolone. Other than progesterone (p ≤ 0.001), none of the steroid hormones displayed significant changes across menstrual cycle subphases when comparing participants with PMDD to the healthy controls. A thorough investigation of the progesterone trajectory showed that its left shift in the luteal phase (e.g., earlier rise in progesterone) exposes women with PMDD to a higher periovulatory progesterone and a more acute withdrawal in the late luteal subphase. Results of the present study indicate that the largely overlooked brief periovulatory subphase should be thoroughly examined in PMDD and agree with prior conclusions that rapid progesterone withdrawal associates with the development of negative affect.

Blunted Cortisol Response to Acute Psychosocial Stress in Women With Premenstrual Dysphoric Disorder.

BACKGROUND: Despite being considered a stress-related condition, it is not known whether the hypothalamic-pituitary-adrenal (HPA) axis is dysfunctional in response to acute psychosocial stress in premenstrual dysphoric disorder (PMDD). This is problematic because many women with PMDD report that they are not able to control their stress levels, and a blunted cortisol output has been identified in women with related psychiatric conditions, such as anxiety and depression. The present study is a part of the Premenstrual Hormonal and Affective State Evaluation (PHASE) project, and it aimed to characterize the cortisol trajectory in response to an acute psychosocial stress challenge. METHODS: Women with PMDD and healthy controls with confirmed ovulatory cycles underwent the Trier Social Stress Test (TSST) procedure in the mid-late luteal phase of the menstrual cycle, throughout which we collected serum samples of cortisol that we analyzed using ultra-performance liquid chromatography tandem mass spectrometry. RESULTS: The linear mixed model analysis indicated a significant time*diagnosis interaction (P = .008) such that women with PMDD displayed significantly lower serum cortisol levels at +40 through +90 minutes from the time of stress induction. CONCLUSION: This is the first study to show that women with PMDD have a blunted cortisol response to psychosocial stress. Combined with our earlier finding showing a greater parasympathetic nervous system withdrawal on heart oscillations in PMDD during acute stress, these and other results show that the dysregulated processing of stress in PMDD may be captured using objective study measures.

Peripheral Blood Mononuclear Cell Expression of Cation-Chloride Cotransporter (CCC) Genes in Premenstrual Dysphoric Disorder (PMDD) across the Menstrual Cycle-A Preliminary Study.

Premenstrual Dysphoric Disorder (PMDD) is a psychiatric condition characterized by debilitating affective symptomatology in the luteal phase of the menstrual cycle. Based on the previous reports that PMDD may be related to GABAergic cellular dysfunction(s), we assessed whether cation-chloride cotransporter (CCC) gene expression across the menstrual cycle is altered in PMDD. As there are limitations in accessing the human CNS to study CCC-encoding genes, we utilized peripheral blood mononuclear cells (PBMCs) as an alternative model. We first sought to replicate previous reports characterizing CCC gene expression patterns in PBMCs of reproductive age women. We subsequently investigated potential distinct CCC mRNA expression patterns in women with PMDD. We collected blood samples across 8 menstrual cycle visits for PBMC separation/RNA extraction to study mRNA expression of four KCCs (KCC1, KCC2, KCC3, KCC4) and two NKCCs (NKCC1, NKCC2) cotransporters. We mostly replicated the earlier gene expression pattern findings, and found that the expression levels of KCC1 were significantly downregulated during the mid-follicular and periovulatory subphases of the menstrual cycle in women with PMDD. The present study shows that PBMCs is a valid model for studying GABAergic mechanisms underlying PMDD.

Mid-Luteal Progesterone Is Inversely Associated with Premenstrual Food Cravings.

It is not clear whether progesterone and estradiol associate with premenstrual food cravings, which significantly contribute to cardiometabolic adverse effects associated with obesity. We sought to investigate this question in the present study based on the prior literature showing a protective effect of progesterone on drug craving and extensive neurobiological overlaps between food and drug cravings. We enrolled 37 non-illicit drug- or medication-using women in the study to provide daily ratings of premenstrual food cravings and other symptoms across two-three menstrual cycles, based on which we classified them as premenstrual dysphoric disorder (PMDD) or control participants. In addition, the participants provided blood samples at eight clinic visits across the menstrual cycle. We aligned their mid-luteal progesterone and estradiol using a validated method which relies upon the peak serum luteinizing hormone and analyzed estradiol and progesterone using ultraperformance liquid chromatography tandem mass spectrometry. Hierarchical modeling, adjusted for BMI, showed a significant inverse effect of progesterone (p = 0.038) but no effect of estradiol on premenstrual food cravings. The association was not unique to PMDD or control participants. Results of research to date in humans and rodents showing that progesterone has dampening effects on the salience of the reinforcer translate to premenstrual food cravings.

Periovulatory Subphase of the Menstrual Cycle Is Marked by a Significant Decrease in Heart Rate Variability.

(1) Background: High-frequency heart rate variability (HF-HRV) is an essential ultradian rhythm that reflects the activity of the PNS to decelerate the heart. It is unknown how HF-HRV varies across the menstrual cycle (MC), and whether progesterone mediates this potential variation. (2) Methods: We enrolled 33 women in the study to attend eight clinic visits across the MC, during which we measured their resting HF-HRV and collected samples for the analysis of luteinizing hormone (LH) and progesterone. We realigned the study data according to the serum LH surge to the early follicular, mid-follicular, periovulatory, early luteal, mid-luteal and late luteal subphases. (3) Results: Pairwise comparisons between all the subphases showed significant differences between the early follicular and periovulatory subphases (ß = 0.9302; p ≤ 0.001) and between the periovulatory and early luteal subphases (ß = -0.6955; p ≤ 0.05). Progesterone was positively associated with HF-HRV in the early follicular subphase but not the periovulatory subphase (p ≤ 0.05). (4) Conclusions: The present study shows a significant drop in HF-HRV in the anticipation of ovulation. Further research in this area is critical given the marked cardiovascular disease mortality in women.

Trajectories of Allopregnanolone and Allopregnanolone to Progesterone Ratio across the Six Subphases of Menstrual Cycle.

Background: Allopregnanolone is one of the most studied neuroactive steroids; yet, despite its relevance to neuropsychiatric research, it is not known how it, as well as its ratio to progesterone, varies across all six subphases of the menstrual cycle. Two enzymes-5α-dihydroprogesterone and 5α-reductase-convert progesterone to allopregnanolone, and, based on immunohistochemical studies in rodents, the activity of 5α-reductase is considered the rate-limiting step in the formation of allopregnanolone. It is not clear, however, whether the same phenomenon is observed across to the menstrual cycle, and, if so, at what point this takes place. Methods: Thirty-seven women completed the study during which they attended eight clinic visits across one menstrual cycle. We analyzed their allopregnanolone and progesterone serum concentrations using ultraperformance liquid chromatography-tandem mass spectrometry, and we implemented a validated method to realign the data from the original eight clinic study visits, following which we imputed the missing data. Hence, we characterized allopregnanolone concentrations, and the ratio of allopregnanolone:progesterone at six menstrual cycle subphases: (1) early follicular, (2) mid-follicular, (3) periovulatory, (4) early luteal, (5) mid-luteal, and (6) late luteal. Results: There were significant differences in allopregnanolone levels between (1) early follicular and early luteal, (2) early follicular and mid-luteal, (3) mid-follicular and mid-luteal, (4) periovulatory and mid-luteal, and (5) mid-luteal and late luteal. We detected a sharp drop in allopregnanolone:progesterone ratio in the early luteal subphase. Within the luteal subphase, the ratio was the lowest in the mid-luteal subphase. Conclusions: Allopregnanolone concentrations are the most distinct, relative to the other subphases, in the mid-luteal subphase. The shape of the allopregnanolone trajectory across the cycle is similar to that of progesterone; however, the proportion of the two neuroactive steroid hormones is drastically different due to enzymatic saturation, which takes place at the start of the early luteal subphase, but continuing through, and peaking, in the mid-luteal subphase. Hence, the estimated activity of 5α-reductase decreases, but does not cease, at any point across the menstrual cycle.

Allopregnanolone Is Associated with a Stress-Induced Reduction of Heart Rate Variability in Premenstrual Dysphoric Disorder.

Human survival and wellbeing require appropriate responses to stress, including a highly coordinated and efficient nervous system control of the heart rhythm. During stress, a greater disinhibition of the vagal nerve is reflective of poor stress adaptability, which may be relevant in premenstrual dysphoric disorder (PMDD)-a debilitating affective condition thought to be marked by dysregulated stress processing and sensitivity to allopregnanolone. In the present study, women with PMDD (n = 17) and healthy controls (n = 18), who did not take medication, smoke, or consume illicit drugs, and who were free of other psychiatric conditions, participated in the Trier Social Stress Test, during which we measured the high frequency of the heart rate (HF-HRV) and allopregnanolone using ultra-performance liquid chromatography tandem mass spectrometry. Relative to their baseline, women who have PMDD, but not the healthy controls, experienced a reduction in HF-HRV during stress anticipation (p ≤ 0.05) and stress (p ≤ 0.01). Their recovery from stress was significantly delayed (p ≤ 0.05). Absolute peak HF-HRV change from baseline was significantly predicted by baseline allopregnanolone only in the PMDD group (p ≤ 0.01). The present study shows how an interaction between stress and allopregnanolone-which have both been separately implicated in PMDD-underlies PMDD expression.

Waist Circumference and Its Association With Premenstrual Food Craving: The PHASE Longitudinal Study.

Visceral adiposity is a significant marker of all-cause mortality. Reproductive age women are at a considerable risk for developing visceral adiposity; however, the associated factors are poorly understood. The proposed study evaluated whether food craving experienced during the premenstrual period is associated with waist circumference. Forty-six women (mean BMI = 24.36) prospectively provided daily ratings of food craving across two-three menstrual cycles (122 cycles total). Their premenstrual rating of food craving was contrasted against food craving in the follicular phase to derive a corrected summary score of the premenstrual food craving increase. Study groups were divided into normal (n = 26) and obese (n = 20) based on the 80 cm waist circumference cutoff signifying an increase in risk. Waist circumference category was significantly associated with premenstrual food cravings [F (1,44) = 5.12, p = 0.028]. Post hoc comparisons using the Tukey HSD test (95% family-wise confidence level) showed that the mean score for the food craving effect size was 0.35 higher for the abdominally obese vs. normal study groups (95% CI: 0.039 to 0.67). The result was statistically significant even following inclusion of BMI in the model, pointing to a particularly dangerous process of central fat accumulation. The present study establishes an association between temporal vulnerability to an increased food-related behavior and a marker of metabolic abnormality risk (i.e., waist circumference), thereby forming a basis for integrating the premenstruum as a viable intervention target for this at-risk sex and age group.

Behavioral Symptomatology in the Premenstruum.

OBJECTIVE: Sleep and eating behaviors are disturbed during the premenstrual phase of the menstrual cycle in a significant number of reproductive-age women. Despite their impact on the development and control of chronic health conditions, these behaviors are poorly understood. In the present study, we sought to identify affective and psychological factors which associate with premenstrual changes in sleeping and eating behaviors and assess how they impact functionality. METHODS: Fifty-seven women provided daily ratings of premenstrual symptomatology and functionality across two-three menstrual cycles (156 cycles total). For each participant and symptom, we subtracted the mean day +5 to +10 ("post-menstruum") ratings from mean day -6 to -1 ("pre-menstruum") ratings and divided this value by participant- and symptom-specific variance. We completed the statistical analysis using multivariate linear regression. RESULTS: Low interest was associated with a premenstrual increase in insomnia (p ≤ 0.05) and appetite/eating (p ≤ 0.05). Furthermore, insomnia was associated with occupational (p ≤ 0.001), recreational (p ≤ 0.001), and relational (p ≤ 0.01) impairment. CONCLUSIONS: Results of the present analysis highlight the importance of apathy (i.e., low interest) on the expression of behavioral symptomatology, as well as premenstrual insomnia on impairment. These findings can inform treatment approaches, thereby improving care for patients suffering from premenstrual symptomatology linked to chronic disease conditions.

Reduced Dehydroepiandrosterone-Sulfate Levels in the Mid-Luteal Subphase of the Menstrual Cycle: Implications to Women's Health Research.

The regulation of DHEA-sulfate by steroid sulfotransferase (SULT) and steryl-sulfatase (STS) enzymes is a vital process for the downstream formation of many steroid hormones. DHEA-sulfate is the most abundant steroid hormone in the human body; thus, DHEA-sulfate and its hydrolyzed form, DHEA, continue to be evaluated in numerous studies, given their importance to human health. Yet, a basic question of relevance to the reproductive-age female population-whether the two steroid hormones vary across the menstrual cycle-has not been addressed. We applied a validated, multi-step protocol, involving realignment and imputation of study data to early follicular, mid-late follicular, periovulatory, and early, mid-, and late luteal subphases of the menstrual cycle, and analyzed DHEA-sulfate and DHEA serum concentrations using ultraperformance liquid chromatography tandem mass spectrometry. DHEA-sulfate levels started to decrease in the early luteal, significantly dropped in the mid-luteal, and returned to basal levels by the late luteal subphase. DHEA, however, did not vary across the menstrual cycle. The present study deep-mapped trajectories of DHEA and DHEA-sulfate across the entire menstrual cycle, demonstrating a significant decrease in DHEA-sulfate in the mid-luteal subphase. These findings are relevant to the active area of research examining associations between DHEA-sulfate levels and various disease states.