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Female suicide attempts peak peri-menstrually—around the onset of menses—when the ovarian steroids estradiol (E2) and progesterone (P4) fall rapidly. Given preclinical evidence that withdrawal from either E2 or P4 can provoke behaviors consistent with elevated suicide risk, we hypothesized that withdrawal from one or both of these steroids contributes to perimenstrual exacerbation of suicidal ideation (SI) and related symptoms. In a randomized, controlled, double-blind crossover experiment (NCT03720847), a transdiagnostic sample of naturally cycling, medically healthy psychiatric outpatients reporting past-month SI completed two conditions during two different 14-day experimental intervals (days 7–20 where the luteinizing hormone surge = day 0), separated by a monthlong washout cycle. In the E2 and P4 (EP) condition, participants received transdermal E2 (0.1 mg/day) plus oral micronized P4 (200 mg/day as 100 mg twice daily) to buffer perimenstrual steroid withdrawal. A matched placebo (PBO) condition allowed natural perimenstrual steroid withdrawal. Participants reported daily SI and planning (primary outcomes) and indices of depression (low mood, hopelessness), threat sensitivity (anxiety, perceived stress), executive functioning (difficulty concentrating, impulsivity), and social cognitive bias (rejection sensitivity, perceived burdensomeness). In baseline cycles, no participant met prospective criteria for DSM-5 premenstrual dysphoric disorder, but 59% met all criteria except full follicular symptom remission, and 93% showed the highest SI in the perimenstrual phase. Of 29 randomized, 28 were analyzed (14 EP-PBO, 14 PBO-EP). Experimental administration of E2 and P4 (relative to PBO) reduced perimenstrual exacerbation of SI, suicide planning, depression, hopelessness, perceived stress, rejection sensitivity, and perceived burdensomeness, particularly in the perimenstrual (natural E2 and P4 withdrawal) days. Further, delayed withdrawal from experimental E2 and P4 (but not PBO) recapitulated SI, hopelessness, and rejection sensitivity. Acute perimenstrual withdrawal from ovarian steroids may play a causal role in perimenstrual worsening of depression and SI.

Altered fear conditioning and extinction learning are discussed as key etiological features in anxiety disorders. Women have an increased risk for anxiety disorders and fear conditioning has been shown to be influenced by the menstrual cycle phase and circulating gonadal hormones. The objective of our study was to investigate the effects of separate and combined estradiol and progesterone administration on fear extinction in healthy women. We conducted a placebo-controlled, randomized study in healthy women, who completed a fear conditioning paradigm on three consecutive days: fear acquisition training on day 1, fear extinction training on day 2, and return of fear test on day 3. Skin conductance responses (SCRs) served as main outcome variable. Two hours before testing on day 2, participants received pills containing either placebo, estradiol (2 mg), progesterone (400 mg) or the combination of both. We examined 116 women (mean age 25.7 ± 6.0 years), who showed significantly stronger conditioned SCRs to the CS+ than CS- during fear acquisition training indicating successful fear learning. At the beginning of the fear extinction training, estradiol administration reduced the differentiation between the conditioned stimuli. In the return of fear test, the estradiol groups showed heightened SCR responses to the previously extinguished stimulus, i.e., impaired extinction recall. Administration of progesterone did not have any significant influence on SCRs. There were also no effects on fear potentiated startle response. In our interpretation, exogenous estradiol administration affected the extinction of the conditioned fear response which led subsequently to a stronger return of fear. From a clinical perspective our findings suggest that estradiol levels may have an influence on the success of exposure therapy and could be taken into consideration when planning exposure sessions.

PurposeTo investigate the impact of letrozole administration on follicular steroid hormones during controlled ovarian hyperstimulation for fertility preservation.MethodsOne hundred and nineteen women with cancer undergoing oocytes retrieval for fertility preservation were recruited. All women underwent ovarian hyperstimulation according to a random start protocol. Those with hormone-sensitive tumors also received letrozole, an aromatase inhibitor aimed at keeping peripheral estrogen levels low. At the time of oocytes retrieval, a sample of follicular fluid was collected and frozen. All samples were assayed concomitantly after thawing, by liquid chromatography tandem mass spectrometry. The concentration of 15 steroid hormones was determined and results were compared between women who did and did not receive letrozole.ResultsFifty-two women were treated with letrozole, while 67 were not. Statistically significant differences emerged for 12 of the 15 tested steroids. They were the following: cortisol, 11-deoxycortisol, 21-deoxycortisol, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), estradiol, androstenedione, testosterone, dihydrotestosterone (DHT), 17-hydroxyprogesterone, progesterone and corticosterone. The most striking differences were observed for testosterone that showed a more than 200-time increase in women receiving letrozole. Estradiol was conversely reduced to a third.ConclusionsThe endocrine microenvironment surrounding oocytes is markedly perturbed by the concomitant assumption of letrozole. Robust clinical evaluation is pressingly needed to rule out any detrimental effect on the chance of live birth with the use of these oocytes.

Abstract Background Oral administration of estradiol (E2) generally increases GH secretion in postmenopausal women. Oral administration of E2 is associated with a decrease in IGF-1, whereas parenteral or transdermally administered E2 may have no effect on GH. The effect of progesterone (P4) on GH secretion has rarely been studied. We hypothesized that moderately increased serum E2 levels stimulate GH and that P4 modulates E2-stimulated GH secretion. Study Design Four parallel groups of randomly assigned postmenopausal women (n = 40). Treatments were saline placebo and oral placebo, saline placebo and oral micronized P4 (3 × 200 mg/d IM), E2 (5 mg IM) and oral placebo, and E2 IM and oral micronized P4. Outcome measures were overnight GH secretion (10 hours), stimulated (ghrelin, 0.3 µg/kg IV bolus) GH secretion, and CT-estimated visceral fat. Results Intramuscular E2 administration did not alter nocturnal and ghrelin-stimulated GH secretion. Nocturnal GH secretion was not changed by P4 administration. However, P4 diminished ghrelin-stimulated pulsatile GH release with or without E2 (average, 7.20 ± 2.14 and 9.58 ± 1.97 µg/L/2 h, respectively; P = 0.045). Respective outcomes for mean GH concentrations and GH peak amplitudes were 0.97 ± 0.31 and 1.52 μg/L ± 0.29 (P = 0.025) and 2.76 ± 1.04 and 3.95 μg/L ± 0.90 (P = 0.031). Ghrelin-stimulated GH secretion correlated negatively with P4 concentration with or without correction for visceral fat area in the regression equation (R = 0.49, P = 0.04, β = −0.040 ± 0.016). Conclusions Low-range physiological E2 concentrations do not affect spontaneous or ghrelin-stimulated pulsatile GH secretion. Conversely, P4 inhibits ghrelin-stimulated GH secretion in a concentration-dependent fashion. The mechanistic aspects and physiological significance of natural P4’s regulation of ghrelin-evoked GH secretion require further study. Low-range physiological E2 concentrations do not affect spontaneous or ghrelin-stimulated pulsatile GH secretion. P4 inhibits ghrelin-stimulated GH secretion in a concentration-dependent fashion.

Antenatal progesterone prevents preterm birth (PTB) in women with a short cervix or prior PTB in daily vaginal or weekly injectable formulations, respectively. Neither has been tested for the indication of maternal HIV, which is associated with an elevated risk of PTB. The Vaginal Progesterone (VP) Trial was a pilot feasibility study of VP to prevent HIV-related PTB in Lusaka, Zambia. Using mixed methods, we concurrently evaluated the acceptability of the trial and the study product among participants. Over a 1-year period, we enrolled 140 pregnant women living with HIV into a double-masked, placebo-controlled, randomized trial of daily self-administered VP or placebo. We administered an endline questionnaire to all participants and conducted in-depth interviews with 30 participants to assess barriers and facilitators to uptake and retention in the trial and to study product adherence. All interviews were audiotaped, transcribed, translated into English as needed, and independently coded by two analysts to capture emerging themes. Of 131 participants who completed the questionnaire, 128 (98%) reported that nothing was difficult when asked the hardest part about using the study product. When given a hypothetical choice between vaginal and injectable progesterone, 97 (74%) chose vaginal, 31 (24%) injectable, and 3 (2%) stated no preference. Most interviewees reported no difficulties with using the study product; others cited minor side effects and surmountable challenges. Strategies that supported adherence included setting alarms, aligning dosing with antiretrovirals, receiving encouragement from friends and family, sensing a benefit to their unborn baby, and positive feedback from study staff. Participants who reported preference of a vaginal medication over injectable described familiarity with the vaginal product, a fear of needles and resulting pain, and inconvenience of a weekly clinic visit. Those who would prefer weekly injections cited fewer doses to remember. Perceived barriers to study participation included mistrust about the motivations behind research, suspicion of Satanism, and futility or possible harm from a placebo. We report key influences on acceptability of a randomized trial of VP to prevent PTB among HIV-infected women in Zambia, which should inform methods to promote uptake, adherence, and retention in a full-scale trial.

To compare the efficacy and safety of PPOS and CPOS in high-responder patients undergoing COS for IVF. This one-year prospective, randomized, controlled trial included 86 high-responder patients. They were divided into PPOS (n=44) and CPOS (n=42). Both groups underwent COS with hormonal injections, and various parameters, such as LH surge, cycle cancellation rates, birth rates, implantation rates, and more, were measured and compared. The study revealed that LH surge occurred in 2.3% of the PPOS group and 2.5% of the CPOS group, with no significant difference (p=0.9). The cycle cancellation rates were 9.1% for PPOS and 10% for CPOS. Birth rates were 57% for PPOS and 54% for CPOS. Implantation rates were 45% for PPOS and 49% for CPOS. There was no significant difference in the duration of stimulation (PPOS: 11.30±1.96 days, CPOS: 11.41±2.02 days, p=0.807) or the total FSH used (PPOS: 2888.95±791.80IU, CPOS: 2808±834.52IU, p=0.655). The PPOS group had a mean of 19.58±8.07 retrieved oocytes, while the CPOS group had a mean of 21.87±10.02, showing no significant difference (p=0.807). Similarly, there was no significant difference (p=0.376) in the number of mature (MII) oocytes between the PPOS group (15.67±6.23) and the CPOS group (17.08±7.96). Post-trigger LH levels were significantly lower in the PPOS group (PPOS: 49.68±27.54IU/L, CPOS: 71.83±43.43IU/L, p-value 0.007), indicating LH surge suppression. Neither group reported cases of ovarian hyperstimulation syndrome (OHSS). PPOS and CPOS offer similar outcomes in high-responder individuals undergoing COS for IVF, except for lower post-trigger LH levels in the PPOS group. Importantly, neither group experienced ovarian hyperstimulation syndrome (OHSS).

Abstract Introduction Postpartum smoking relapse is a highly prevalent public health problem. Mood and breast feeding are significantly associated with smoking relapse, although less is known about the temporality of these relationships. Therefore, this study utilized ecological momentary assessments (EMA) to prospectively examine changes in mood and smoking-related symptomatology in relationship to three events—childbirth, termination of breast feeding, and smoking relapse. We expected all three events to significantly alter mood and smoking-related symptomatology. Methods We enrolled a sample of pregnant women who had recently quit smoking and intended to remain quit during the postpartum. Participants were randomized to active/placebo progesterone to prevent postpartum relapse. Participants also completed daily EMA to collect data mood and smoking-related symptomatology as well as our three events of interest. Results Participants (n = 46) were, on average, 26.5 ± 0.8 years old and, prior to pregnancy, smoked 10.1 ± 0.7 cigarettes/day. We noted a number of significant within- and between-subject relationships. For example, participants reported a 24% decline in negative affect after childbirth (p = .0016). Among those who relapsed to smoking (n = 23), participants randomized to placebo had a significant increase in cigarette craving after relapse (β = 1.06, 95% confidence interval [CI] = 0.62 to 1.49, p value = .0003), whereas participants randomized to active progesterone did not (β = 0.63, 95% CI = −0.35 to 1.62, p value = .1824). Conclusions These observations suggest that mood and smoking-related symptomatology are influenced by childbirth, breast feeding, smoking relapse, and use of exogenous progesterone. Future research should explore how these observations may inform novel postpartum smoking relapse-prevention interventions. Implications Postpartum smoking relapse has been a persistent public health problem for more than 40 years. Although a number of significant predictors of postpartum smoking relapse have been identified (eg, depression and breast feeding), much of these analyses have relied on cross-sectional and/or self-reported retrospective data. Therefore, for the first time, we utilized ecological momentary assessment to explore the effect of childbirth, termination of breast feeding, and smoking relapse on mood and smoking-related symptomatology (eg, craving). Numerous significant relationships were observed, including a 96% increase in craving after smoking relapse. These novel observations can inform new and effective postpartum smoking relapse-prevention programs.

Clinical evidence suggests that symptoms in premenstrual dysphoric disorder (PMDD) reflect abnormal responsivity to ovarian steroids. This differential steroid sensitivity could be underpinned by abnormal processing of the steroid signal. We used a pharmacometabolomics approach in women with prospectively confirmed PMDD ( n =15) and controls without menstrual cycle-related affective symptoms ( n =15). All were medication-free with normal menstrual cycle lengths. Notably, women with PMDD were required to show hormone sensitivity in an ovarian suppression protocol. Ovarian suppression was induced for 6 months with gonadotropin-releasing hormone (GnRH)-agonist (Lupron); after 3 months all were randomized to 4 weeks of estradiol (E2) or progesterone (P4). After a 2-week washout, a crossover was performed. Liquid chromatography/tandem mass spectrometry measured 49 steroid metabolites in serum. Values were excluded if >40% were below the limit of detectability ( n =21). Analyses were performed with Wilcoxon rank-sum tests using false-discovery rate ( q <0.2) for multiple comparisons. PMDD and controls had similar basal levels of metabolites during Lupron and P4-derived neurosteroids during Lupron or E2/P4 conditions. Both groups had significant increases in several steroid metabolites compared with the Lupron alone condition after treatment with E2 (that is, estrone-SO 4 ( q =0.039 and q =0.002, respectively) and estradiol-3-SO 4 ( q =0.166 and q =0.001, respectively)) and after treatment with P4 (that is, allopregnanolone ( q =0.001 for both PMDD and controls), pregnanediol ( q =0.077 and q =0.030, respectively) and cortexone ( q =0.118 and q =0.157, respectively). Only sulfated steroid metabolites showed significant diagnosis-related differences. During Lupron plus E2 treatment, women with PMDD had a significantly attenuated increase in E2-3-sulfate ( q =0.035) compared with control women, and during Lupron plus P4 treatment a decrease in DHEA-sulfate ( q =0.07) compared with an increase in controls. Significant effects of E2 addback compared with Lupron were observed in women with PMDD who had significant decreases in DHEA-sulfate ( q =0.065) and pregnenolone sulfate ( q =0.076), whereas controls had nonsignificant increases (however, these differences did not meet statistical significance for a between diagnosis effect). Alterations of sulfotransferase activity could contribute to the differential steroid sensitivity in PMDD. Importantly, no differences in the formation of P4-derived neurosteroids were observed in this otherwise highly selected sample of women studied under controlled hormone exposures.

To evaluate the value of vaginal progesterone therapy for reduction of preterm labor in asymptomatic women with twin pregnancies and sonographic short cervix. This randomized controlled study was conducted in Mansoura University Hospital and private practice settings in Mansoura, Egypt. Of 322 women with dichorionic twin pregnancy, 250 asymptomatic women with cervical length of 20-25 mm at 20-24 weeks of gestation were included in the study. All women were randomly divided into two groups; the study group (n = 125) received vaginal progesterone suppositories in a dose of 400 mg daily starting at 20-24 weeks of gestation while the control group (n = 125) received no treatment. The primary outcome measure was preterm labor before 34 weeks of gestation and the secondary outcome measures were neonatal respiratory distress syndrome (RDS) and early neonatal death (END). 224 women (116 in the study group and 108 in the control group) were subjected to final analysis. The duration of pregnancy was significantly longer in the study group and the incidence of preterm labor before 34 and 32 weeks of gestation was significantly lower in the study group. The neonatal morbidities and mortality were significantly lower in the study group as shown by lower incidence of very low (<1500 gm) birth weight, neonatal RDS, the need for mechanical ventilation and END. Vaginal progesterone administration in asymptomatic twin pregnancies with sonographic short cervix (20-25 mm) at 20-24 weeks of gestation is effective and safe treatment for reducing the incidence of preterm labor with subsequent reduction in the neonatal morbidities and mortality associated with preterm birth.

Prediction models for patients with traumatic brain injury (TBI) are important for multiple reasons, including case-mix adjustment, trial design, and benchmarking for quality-of-care evaluation. Models should be generalizable and therefore require regular external validation. We aimed to validate the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) prognostic models for moderate and severe TBI in a recent randomized controlled trial. We studied 1124 patients enrolled in the multi-center randomized placebo-controlled Study of the Neuroprotective Activity of Progesterone in Severe Traumatic Brain Injuries (SyNAPSe) trial that evaluated the efficacy of progesterone in TBI. Treatment and placebo groups were combined for analysis. We evaluated the predictive performance of the three prognostic models (core, extended, and lab) from the IMPACT study with regard to discrimination (area under the receiver operating characteristic curve [AUC]) and calibration (comparison of observed to predicted risks). Substantial differences were found in case-mix and outcome distribution between IMPACT and SyNAPSe. In line with the more homogeneous case-mix of a clinical trial, the discriminative performance was reasonable. For the core model, an AUC of 0.677 and 0.684 was obtained for 6-month mortality and unfavorable outcome, respectively. Performance was slightly better for the extended model (0.693 and 0.705) and for the lab model (0.689 and 0.711, respectively). For calibration, we found overestimation of mortality, especially at higher risk predictions, and underestimation of unfavorable outcome, especially at lower risk predictions. This pattern of miscalibration was consistent across all three models. In a contemporary trial setting, the IMPACT models have reasonable discrimination if enrollment restrictions apply. Observed changes in outcome distribution necessitate updating of previously developed prognostic models.