Cortical morphology variations during the menstrual cycle in individuals with and without premenstrual dysphoric disorder.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is hypothesized to stem from maladaptive neural sensitivity to ovarian steroid hormone fluctuations. Recently, we found thinner cortices in individuals with PMDD, compared to healthy controls, during the symptomatic phase. Here, we aimed at investigating whether such differences illustrate state-like characteristics specific to the symptomatic phase, or trait-like features defining PMDD. METHODS: Patients and controls were scanned using structural magnetic resonance imaging during the mid-follicular and late-luteal phase of the menstrual cycle. Group-by-phase interaction effects on cortical architecture metrics (cortical thickness, gyrification index, cortical complexity, and sulcal depth) were assessed using surface-based morphometry. RESULTS: Independently of menstrual cycle phase, a main effect of diagnostic group on surface metrics was found, primarily illustrating thinner cortices (0.3 < Cohen's d > 1.1) and lower gyrification indices (0.4 < Cohen's d > 1.0) in patients compared to controls. Furthermore, menstrual cycle-specific effects were detected across all participants, depicting a decrease in cortical thickness (0.4 < Cohen's d > 1.7) and region-dependent changes in cortical folding metrics (0.4 < Cohen's d > 2.2) from the mid-follicular to the late luteal phase. LIMITATIONS: Small effects (d = 0.3) require a larger sample size to be accurately characterized. CONCLUSIONS: These findings provide initial evidence of trait-like cortical characteristics of the brain of individuals with premenstrual dysphoric disorder, together with indications of menstrual cycle-related variations in cortical architecture in patients and controls. Further investigations exploring whether these differences constitute stable vulnerability markers or develop over the years may help understand PMDD etiology.

Neonatal outcome following metformin-treated gestational diabetes mellitus: A population-based cohort study.

INTRODUCTION: Neonatal hypoglycemia is a common complication associated with gestational diabetes and therefore relevant to consider in evaluations of maternal treatment. We aimed to investigate the risk of neonatal hypoglycemia in offspring exposed to metformin treatment alone (MT) or combined with insulin (MIT) in comparison with nutrition therapy alone (NT), and insulin treatment alone (IT). In addition, we investigated MT in comparison with MIT. Secondary outcomes included neonatal anthropometrics, respiratory morbidity, hyperbilirubinemia, 5-min Apgar score, and preterm birth. MATERIAL AND METHODS: This Swedish population-based cohort included 16 181 women diagnosed with gestational diabetes, and their singleton offspring born in 2019-2021. We estimated risk as adjusted odds ratio (aOR) with 95% confidence interval (CI), using individual-level, linkage register-data in multivariable logistic regression models. RESULTS: In the main analysis, MT was associated with a lower risk of neonatal hypoglycemia vs NT (aOR 0.85, 95% CI: 0.74-0.96), vs MIT (0.74 [0.64-0.87]), and vs IT (0.47 [0.40-0.55]), whereas MIT was associated with a similar risk of neonatal hypoglycemia vs NT (1.14 [0.99-1.30]) and with lower risk vs IT (0.63 [0.53-0.75]). However, supplemental feeding rates were lower for NT vs pharmacological treatments (p < 0.001). In post hoc subgroup analyses including only exclusively breastfed offspring, the risk of neonatal hypoglycemia was modified and similar among MT and NT, and higher in MIT vs NT. Insulin exposure, alone or combined with metformin, was associated with increased risk of being large for gestational age. Compared with NT, exposure to any pharmacological treatment was associated with significantly lower risk of 5-min Apgar score < 4. All other secondary outcomes were comparable among the treatment categories. CONCLUSIONS: The risk of neonatal hypoglycemia appears to be comparable among offspring exposed to single metformin treatment and nutrition therapy alone, and the lower risk that we observed in favor of metformin is probably explained by a difference in supplemental feeding practices rather than metformin per se. By contrast, the lower risk favoring metformin exposure over insulin exposure was not explained by supplemental feeding. However, further investigations are required to determine whether the difference is an effect of metformin per se or mediated by other external factors.

Menopausal hormone therapy and risk of sarcoidosis: a population-based nested case-control study in Sweden.

Sarcoidosis incidence peaks in women between 50 and 60 years old, which coincides with menopause, suggesting that certain sex hormones, mainly estrogen, may play a role in disease development. We investigated whether menopausal hormone therapy (MHT) was associated with sarcoidosis risk in women and whether the risk varied by treatment type. We performed a nested case-control study (2007-2020) including incident sarcoidosis cases from the Swedish National Patient Register (n = 2593) and matched (1:10) to general population controls (n = 20,003) on birth year, county, and living in Sweden at the time of sarcoidosis diagnosis. Dispensations of MHT were obtained from the Swedish Prescribed Drug Register before sarcoidosis diagnosis/matching. Adjusted odds ratios (aOR) of sarcoidosis were estimated using conditional logistic regression. Ever MHT use was associated with a 25% higher risk of sarcoidosis compared with never use (aOR 1.25, 95% CI 1.13-1.38). When MHT type and route of administration were considered together, systemic estrogen was associated with the highest risk of sarcoidosis (aOR 1.51, 95% CI 1.23-1.85), followed by local estrogen (aOR 1.25, 95% CI 1.11-1.42), while systemic estrogen-progestogen combined was associated with the lowest risk compared to never users (aOR 1.12, 95% CI 0.96-1.31). The aOR of sarcoidosis did not differ greatly by duration of MHT use. Our findings suggest that a history of MHT use is associated with increased risk of sarcoidosis, with women receiving estrogen administered systemically having the highest risk.

Pregnancy-related maternal physiological adaptations and fetal chemical exposure.

Prenatal life represents a susceptible window of development during which chemical exposures can permanently alter fetal development, leading to an increased likelihood of disease later in life. Therefore, it is essential to assess exposure in the fetus. However, direct assessment in human fetuses is challenging, so most research measures maternal exposure. Pregnancy induces a range of significant physiological changes in women that may affect chemical metabolism and responses. Moreover, placental function, fetal sex, and pregnancy complications may further modify these exposures. The purpose of this narrative review is to give an overview of major pregnancy-related physiological changes, including placental function and impacts of pregnancy complications, to summarize existing studies assessing chemical exposure in human fetal organs, and to discuss possible interactions between physiological changes and exposures. Our review reveals major knowledge gaps in factors affecting fetal chemical exposure, highlighting the need to develop more sophisticated tools for chemical health risk assessment in fetuses.

Emotion-induced brain activation across the menstrual cycle in individuals with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids.

Premenstrual dysphoric disorder (PMDD) is a debilitating disorder characterized by severe mood symptoms in the luteal phase of the menstrual cycle. PMDD symptoms are hypothesized to be linked to an altered sensitivity to normal luteal phase levels of allopregnanolone (ALLO), a GABAA-modulating progesterone metabolite. Moreover, the endogenous 3ß-epimer of ALLO, isoallopregnanolone (ISO), has been shown to alleviate PMDD symptoms through its selective and dose-dependent antagonism of the ALLO effect. There is preliminary evidence showing altered recruitment of brain regions during emotion processing in PMDD, but whether this is associated to serum levels of ALLO, ISO or their relative concentration is unknown. In the present study, subjects with PMDD and asymptomatic controls underwent functional magnetic resonance imaging (fMRI) in the mid-follicular and the late-luteal phase of the menstrual cycle. Brain responses to emotional stimuli were investigated and related to serum levels of ovarian steroids, the neurosteroids ALLO, ISO, and their ratio ISO/ALLO. Participants with PMDD exhibited greater activity in brain regions which are part of emotion-processing networks during the late-luteal phase of the menstrual cycle. Furthermore, activity in key regions of emotion processing networks - the parahippocampal gyrus and amygdala - was differentially associated to the ratio of ISO/ALLO levels in PMDD subjects and controls. Specifically, a positive relationship between ISO/ALLO levels and brain activity was found in PMDD subjects, while the opposite was observed in controls. In conclusion, individuals with PMDD show altered emotion-induced brain responses in the late-luteal phase of the menstrual cycle which may be related to an abnormal response to physiological levels of GABAA-active neurosteroids.

Altered GABAA receptor function in women with endometriosis: a possible pain-related mechanism.

INTRODUCTION: The mechanism underlying endometriosis-related pain remains poorly understood. Previous studies have indicated that γ-aminobutyric acid (GABA) type A (GABAA ) receptors and GABAergic substances (eg endogenous neurosteroids) play important mechanistic roles in various pain conditions. Our primary objective was to compare GABAA receptor function between women with endometriosis and healthy controls by performing a challenge test with diazepam, a GABAA receptor agonist, using the saccadic eye velocity as the main outcome. The secondary objective was to investigate the relation between GABAA receptor function and serum levels of allopregnanolone, an endogenous positive modulator of the GABAA receptor, in the participating women. MATERIAL AND METHODS: 15 women with pelvic pain and laparoscopically confirmed endometriosis and 10 healthy, symptom-free, control women, aged 18-40 years, underwent the diazepam challenge test during the follicular phase of the menstrual cycle. Basal serum allopregnanolone levels were measured prior to diazepam injection. RESULTS: Compared with healthy controls, women with pelvic pain and confirmed endometriosis had a significantly smaller change in saccadic eye velocity after GABAA receptor stimulation with diazepam, indicating lower sensitivity to diazepam. The saccadic eye velocity response was not correlated with the serum allopregnanolone levels. CONCLUSIONS: Women with painful endometriosis show altered GABAA receptor function, depicted as a muted response to an exogenous GABAA receptor agonist.

Differential grey matter structure in women with premenstrual dysphoric disorder: evidence from brain morphometry and data-driven classification.

Premenstrual dysphoric disorder (PMDD) is a female-specific condition classified in the Diagnostic and Statical Manual-5th edition under depressive disorders. Alterations in grey matter volume, cortical thickness and folding metrics have been associated with a number of mood disorders, though little is known regarding brain morphological alterations in PMDD. Here, women with PMDD and healthy controls underwent magnetic resonance imaging (MRI) during the luteal phase of the menstrual cycle. Differences in grey matter structure between the groups were investigated by use of voxel- and surface-based morphometry. Machine learning and multivariate pattern analysis were performed to test whether MRI data could distinguish women with PMDD from healthy controls. Compared to controls, women with PMDD had smaller grey matter volume in ventral posterior cortices and the cerebellum (Cohen's d = 0.45-0.76). Region-of-interest analyses further indicated smaller volume in the right amygdala and putamen of women with PMDD (Cohen's d = 0.34-0.55). Likewise, thinner cortex was observed in women with PMDD compared to controls, particularly in the left hemisphere (Cohen's d = 0.20-0.74). Classification analyses showed that women with PMDD can be distinguished from controls based on grey matter morphology, with an accuracy up to 74%. In line with the hypothesis of an impaired top-down inhibitory circuit involving limbic structures in PMDD, the present findings point to PMDD-specific grey matter anatomy in regions of corticolimbic networks. Furthermore, the results include widespread cortical and cerebellar regions, suggesting the involvement of distinct networks in PMDD pathophysiology.

Long-term outcome after routine surgery for pelvic organ prolapse-A national register-based cohort study.

INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) is common, and women have an estimated 12-19% lifetime risk for needing POP surgery. Aims were to measure re-operation rates up to 10 years after POP surgery and patient-reported outcomes (PROMs) 5 years after a first-time operation for POP. METHODS: This is a cohort study using the Swedish National Quality Register for Gynaecological Surgery (GynOp). We retrieved information from 32,086 POP-operated women up to 10 years later. After validation, a web-based PROM questionnaire was sent to 4380 women who 5 years previously had standard POP surgery. Main outcome measures were reoperations due to a relapse of prolapse and PROMs 5 years after the primary operation. RESULTS: Among women operated for all types of POP, 11% had re-operations 5 years later and an additional 4% 10 years later, with similar frequencies for various compartments/types of surgery. PROMs yielded a 75% response rate after 5 years. Cure rate was 68% for anterior, 70% for posterior, and 74% for combined anterior-posterior native repairs. Patient satisfaction exceeded 70%, and symptom reduction was still significant after 5 years (p < 0.0001). CONCLUSIONS: Following primary prolapse surgery, re-operation rates are low, even after 10 years. A web-based survey for follow-up of PROMs after POP surgery is feasible and yields a high response rate after 5 years. The subjective cure rate after primary POP operations is high, with reduced symptoms and satisfied patients regardless of compartment. Standard prolapse surgery with native tissue repair produces satisfactory long-term results.

White matter microstructure and volume correlates of premenstrual dysphoric disorder.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is a mood disorder characterized by psychological and physical symptoms. Differences in white matter have been associated with affective and anxiety disorders, which share some symptoms with PMDD. However, whether white matter structure differs between the brains of individuals with PMDD and healthy controls is not known, nor is its relation to symptom severity. METHODS: We performed tract-based spatial statistics and voxel-based morphometry analyses of diffusion tensor imaging metrics and white matter volume, using 2 neuroimaging data sets (n = 67 and n = 131) and a combined whole-brain and region-of-interest approach. We performed correlation analyses to investigate the relationship between regions with different white matter microstructure and volume and PMDD symptom severity. RESULTS: We found greater fractional anisotropy in the left uncinate fasciculus (d = 0.69) in individuals with PMDD compared to controls. Moreover, the volume of the right uncinate fasciculus was higher in individuals with PMDD compared to controls (d = 0.40). As well, the severity of premenstrual depression was positively correlated with fractional anisotropy in the right superior longitudinal fasciculus (r = 0.35). LIMITATIONS: It is challenging to interpret group differences in diffusion tensor imaging metrics in terms of their underlying biophysical properties. The small size of the control group in the diffusion tensor imaging study may have prevented effects of interest from being detected. CONCLUSION: The findings of the present study provide evidence of differential cerebral white matter structure associated with PMDD and its symptoms.

Prevalence and correlates of current suicidal ideation in women with premenstrual dysphoric disorder.

BACKGROUND: Although previous studies report an association between Premenstrual Dysphoric Disorder (PMDD) and suicidal ideation, most studies have only established a provisional and retrospective diagnosis of PMDD fundamentally invalidating the diagnosis. Therefore, the aim of this study was to describe the prevalence and to explore correlates of current suicidal ideation in the late luteal phase in women with prospectively assessed and confirmed PMDD. METHODS: Participants were 110 women who attended the pre-randomization baseline visit of two randomized placebo-controlled clinical trials between January 15, 2017 and October 19, 2019. PMDD was diagnosed prospectively in line with DSM-5 criteria. Current suicidal ideation was measured by the MADRS-S in the late luteal phase. Descriptive statistics were presented and logistic regression analyses were carried out to explore the association between psychosocial and health characteristics and current suicidal ideation, presenting unadjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Current suicidal ideation was reported by nearly 40% of women with confirmed PMDD (n = 43, 39.1%). Previous psychological treatment for PMDD and higher depressive symptoms in the late luteal phase were positively associated with current suicidal ideation (OR 5.63, 95% CI 1.07-29.49, and OR 1.17, 95% CI 1.10-1.25, respectively), whereas higher ratings of self-rated health were associated with lower odds ratios for current suicidal ideation (OR 0.98, 95% CI 0.96-0.99). CONCLUSIONS: A substantial proportion of women with confirmed PMDD report current suicidal ideation in the late luteal phase. Results point to a need for better awareness and screening of suicidal ideation in women with PMDD.

Positive GABAA receptor modulating steroids and their antagonists: Implications for clinical treatments.

GABA is the main inhibitory neurotransmitter in the brain and GABAergic transmission has been shown to be of importance for regulation of mood, memory and food intake. The progesterone metabolite allopregnanolone (Allo) is a positive GABAA receptor modulating steroid with potent effects. In humans, disorders such as premenstrual dysphoric disorder (PMDD), hepatic encephalopathy and polycystic ovarian syndrome are associated with elevated Allo levels and increased negative mood, disturbed memory and increased food intake in some individuals. This is surprising because Allo shares many properties with benzodiazepines and is mainly considered to be anxiolytic and anti-depressant. However, it is well established that, in certain individuals, GABAA receptor activating compounds could have paradoxical effects and thus be anxiogenic in low physiological plasma concentrations but anxiolytic at high levels. We have demonstrated that isoallopregnanolone (Isoallo), the 3ß-OH sibling of Allo, functions as a GABAA receptor modulating steroid antagonist (GAMSA) but without any effects of its own on GABAA receptors. The antagonistic effect is noted in most GABAA subtypes investigated in vitro to date. In vivo, Isoallo can inhibit Allo-induced anaesthesia in rats, as well as sedation or saccadic eye velocity in humans. Isoallo treatment has been studied in women with PMDD. In a first phase II study, Isoallo (Sepranolone; Asarina Pharma) injections significantly ameliorated negative mood in women with PMDD compared with placebo. Several GAMSAs for oral administration have also been developed. The GAMSA, UC1011, can inhibit Allo induced memory disturbances in rats and an oral GAMSA, GR3027, has been shown to restore learning and motor coordination in rats with hepatic encephalopathy. In humans, vigilance, cognition and pathological electroencephalogram were improved in patients with hepatic encephalopathy on treatment with GR3027. In conclusion GAMSAs are a new possible treatment for disorders and symptoms caused by hyperactivity in the GABAA system.

Gestational weight gain, appetite regulating hormones, and metformin treatment in polycystic ovary syndrome: A longitudinal, placebo-controlled study.

OBJECTIVE: To explore mechanisms that modulate gestational weight gain (GWG) in women with polycystic ovary syndrome (PCOS) and healthy controls. DESIGN: Sub-sample of randomised controlled trials (PCOS) combined with a prospective cohort (controls). SETTING: Eleven Norwegian, Swedish, and Icelandic hospitals. POPULATION: Pregnant women with PCOS treated with metformin (PCOS-M, n = 36) or placebo (PCOS-P, n = 37), and healthy pregnant women (HC, n = 15). METHODS: Serum levels of the appetite regulating hormones leptin, ghrelin, allopregnanolone, and soluble leptin receptor (sOB-R) were determined in the first and third trimesters. MAIN OUTCOME MEASURES: Excessive GWG (eGWG) relative to body mass index according to Institute of Medicine (IOM) guideline. Serum leptin/sOB-R ratio, or free-leptin-index (FLI), as biomarker of leptin sensitivity. Serum ghrelin and allopregnanolone levels. RESULTS: The overall prevalence of eGWG was 44% (38/86). Women with eGWG had higher first and third trimester FLI (P < 0.001), and lower third trimester allopregnanolone levels (P = 0.003) versus women with non-eGWG. The prevalence of eGWG was lower in PCOS-M versus PCOS-P (28% versus 62%, odds ratio = 0.4, 95% CI 0.2-0.8, P = 0.005). FLI decreased during pregnancy in PCOS-M (P = 0.01), but remained unaltered in PCOS-P and HC. Ghrelin and allopregnanolone levels were comparable in PCOS-M, PCOS-P and HC throughout pregnancy. CONCLUSION: Excessive GWG is associated with enhanced leptin resistance, and attenuated physiological increase in serum allopregnanolone levels during pregnancy. Metformin reduces the risk for eGWG and improves leptin sensitivity in pregnant women with PCOS. TWEETABLE ABSTRACT: Metformin counteracts excessive weight gain and leptin resistance in pregnant women with polycystic ovary syndrome.

A randomized, double-blind study on efficacy and safety of sepranolone in premenstrual dysphoric disorder.

Women with premenstrual dysphoric disorder (PMDD) experience mood symptoms related to the increase in progesterone and the neuroactive steroid allopregnanolone. Our hypothesis is that allopregnanolone is the symptom provoking factor. The rationale for the present study was to treat PMDD patients with the GABAA receptor modulating steroid antagonist, sepranolone (isoallopregnanolone). Patients (n = 206) with PMDD from 12 European centers were randomized in a parallel double-blind study and treated with placebo, sepranolone 10 mg and 16 mg. Patients administered sepranolone subcutaneously every 48 h during the 14 premenstrual days of three consecutive menstrual cycles. After obtaining informed consent, the PMDD diagnosis was confirmed according to DSM-5 and verified with two menstrual cycles of daily symptom ratings using the Daily Record of Severity of Problems (DRSP) scale in an eDiary. Inclusion and exclusion criteria stipulated that the women should be essentially healthy, not pregnant, have no ongoing psychiatric disorder or take interfering medications, and have regular menstrual cycles. The study's primary endpoint was the Total symptom score (Sum21, the score for all 21 symptom questions in the DRSP). In the prespecified statistical analysis the average score of the 5 worst premenstrual days in treatment cycles 2 and 3 were subtracted from the corresponding average score in the two diagnostic cycles. The treatment effects were tested using analysis of variance in a hierarchal order starting with the combined active sepranolone treatments vs. placebo. The prespecified analysis of Sum21 showed a large treatment effect of all three treatments but no statistically significant difference to placebo. However, the ratings of distress showed a significant treatment effect of sepranolone compared to placebo (p = 0.037) and the ratings of impairment showed a trend to greater treatment effect of sepranolone compared to placebo. Many women with PMDD had symptoms during a longer period than the late luteal phase. It has previously been shown that 9 premenstrual days may be more representative for comparison of PMDD symptom periods than the 5 worst premenstrual days. A post hoc analysis was undertaken in the per protocol population investigating the treatment effect during 9 premenstrual days in the third treatment cycle. The Sum21 results of this analysis showed that the sepranolone 10 mg was significantly better than placebo (p = 0.008). Similar significant treatment effects were found for the impairment and distress scores. A significantly larger number of individuals experienced no or minimal symptoms (Sum21 <42 points) with the 10 mg sepranolone treatment compared to placebo (p = 0.020). The results indicate that there is an attenuating effect by sepranolone on symptoms, impairment, and distress in women with PMDD especially by the 10 mg dosage. Sepranolone was well tolerated, and no safety concerns were identified.

Neurosteroid involvement in threatened preterm labour.

Introduction: The neurosteroid allopregnanolone modulates oxytocin expression in the brain, and its effects arise from its action on the GABAA receptor. Whether neurosteroid levels and the function of the GABAA receptor are involved in the risk of preterm labour in pregnant women is unknown. Methods: Pregnant women with (n = 16) or without (n = 20) threatened preterm labour (TPL) in gestational week 33 + 6 days to 37 + 0 days were studied prospectively with procedures including foetal heart rate monitoring, vaginal examination, ultrasound examination and blood tests to determine allopregnanolone, progesterone and oxytocin levels. The GABAA receptor function in both groups was measured with a saccadic eye velocity test (SEVT). Results: Plasma oxytocin levels were higher in the TPL group than in the control group (41.5 vs. 37.0 pmol/L, respectively, p = .021). Although the allopregnanolone and progesterone levels in both groups did not differ, there was a negative association between blood oxytocin and allopregnanolone (as predictor) levels in the TPL group (B: -3.2, 95% confidence interval (CI): -5.5 to -0.9, p = .012). As a predictor of TPL, progesterone was associated with cervix maturity (odds ratio: 1.02, 95% CI: 1.00-1.04, p = .038). SEVT showed that the women in both groups had similar GABAA receptor functions. In both groups, body mass index correlated with peak saccadic eye velocity (r = .34, p = .044) and negatively with allopregnanolone (r = -.41, p = .013). Conclusions: Neurosteroid levels were unchanged in the peripheral blood of women with TPL, despite the increase in available oxytocin. Although the function of the GABAA receptor was unchanged in women with TPL, to ensure reliable results, saccadic eye velocity should be investigated during a challenge test with a GABAA receptor agonist.

Towards individualised contraceptive counselling: clinical and reproductive factors associated with self-reported hormonal contraceptive-induced adverse mood symptoms.

OBJECTIVE: The study aim was to establish which demographic, clinical, reproductive and psychiatric factors are associated with self-reported hormonal contraceptive (HC)-induced adverse mood symptoms. STUDY DESIGN: We compiled baseline data from two Swedish studies: one cross-sectional study on combined oral contraceptive (COC)-induced adverse mood symptoms (n=118) and one randomised controlled trial on adverse mood symptoms on COC (n=184). Both included women eligible for COC use, aged over 18 years. All women answered a questionnaire on HC use and associated mood problems. The Mini-International Neuropsychiatric Interview (M.I.N.I.) was used to capture mood and anxiety disorders. Women who acknowledged HC-induced adverse mood symptoms, ongoing or previously (n=145), were compared with women without any such experience (n=157). RESULTS: Compared with women without self-reported HC-induced adverse mood symptoms, women with these symptoms were younger at HC start (adjusted odds ratio (aOR) 0.83, 95% CI 0.72 to 0.95), had more often undergone induced abortion (OR 3.36, 95% CI 1.57 to 7.23), more often suffered from an ongoing minor depressive disorder (n=12 vs n=0) and had more often experienced any previous mental health problem (aOR 1.90, 95% CI 1.01 to 3.59). CONCLUSIONS: In line with previous research, this study suggests that women with previous or ongoing mental health problems and women who are younger at HC start are more likely to experience HC-induced adverse mood symptoms. Former and current mental health should be addressed at contraceptive counselling, and ongoing mental health disorders should be adequately treated. IMPLICATIONS: This study adds valuable knowledge for identification of women susceptible to HC-induced adverse mood symptoms. It should facilitate the assessment of whether or not a woman has an increased risk of such symptoms, and thus enable clinicians to adopt a more personalised approach to contraceptive counselling.

Ulipristal Acetate for Treatment of Premenstrual Dysphoric Disorder: A Proof-of-Concept Randomized Controlled Trial.

OBJECTIVE: Premenstrual dysphoric disorder (PMDD) is a common mood disorder, characterized by distressing affective, behavioral, and somatic symptoms in the late luteal phase of the menstrual cycle. The authors investigated continuous treatment with a selective progesterone receptor modulator, ulipristal acetate (UPA), as a potential treatment for PMDD. METHODS: The authors conducted an investigator-initiated, multicenter, double-blind, randomized, parallel-group clinical trial in which women with PMDD (N=95) were treated with either 5 mg/day of UPA or placebo during three 28-day treatment cycles. The primary outcome was the change in premenstrual total score on the Daily Record of Severity of Problems (DRSP) from baseline to end of treatment. DRSP scores were captured by daily ratings using a smartphone application and were analyzed with linear mixed models for repeated measures. RESULTS: The mean improvement in DRSP score after 3 months was 41% (SD=18) in the UPA group, compared with 22% (SD=27) in the placebo group (mean difference -18%; 95% CI=-29, -8). Treatment effects were also noted for the DRSP depressive symptom subscale (42% [SD=22] compared with 22% [SD=32]) and the DRSP anger/irritability subscale (47% [SD=21] compared with 23% [SD=35]), but not for the DRSP physical symptom subscale. Remission based on DRSP score was attained by 20 women in the UPA group (50.0%) and eight women in the placebo group (21.1%) (a statistically significant difference). CONCLUSIONS: If these results are replicated, UPA could be a useful treatment for PMDD, particularly for the psychological symptoms associated with the disorder.

Safety and Efficacy of an Oxytocin Gel and an Equivalent Gel but Without Hormonal Ingredients (Vagivital® Gel) in Postmenopausal Women with Symptoms of Vulvovaginal Atrophy: A Randomized, Double-Blind Controlled Study.

PURPOSE: The primary objective was to compare the efficacy of 12 weeks of daily treatment with Aqueous Hypromellose-based vaginal (Vagivital®) gel versus Aqueous Hypromellose-based vaginal gel plus 400 IU oxytocin gel in reducing the severity of the most bothersome vulvovaginal atrophy symptoms (MBS: itching, dysuria, bleeding, and pain/discomfort during vaginal sexual activity) observed at baseline. The secondary objectives were to evaluate the other vulvovaginal atrophy symptoms, vaginal pH, superficial squamous cells, and the safety and tolerability of both gels. PATIENTS AND METHODS: This double-blind, randomized study evaluated the safety and efficacy of subjects randomly assigned to 12 weeks of daily intravaginal oxytocin gel (n=79) or Aqueous Hypromellose-based vaginal gel (n=78). The efficacy evaluation was performed using data from all included subjects who fulfilled entry criteria. RESULTS: Both treatments induced statistically significant reductions in the severity of the MBS from baseline until 4 weeks (Vagivital mean reduction 0.90, p=0.0000; Oxytocin mean reduction 0.82, p=0.0000) and 12 weeks post baseline (Vagivital mean reduction 1.28, p=0.0000; Oxytocin mean reduction 1.16, p=0.0000), but the reduction of MBS severity was not significantly different between the treatment groups at either time point. No serious adverse events were reported in the Aqueous Hypromellose-based vaginal gel group during the treatment period, but one (breast cancer) was reported in the oxytocin gel group (assessed as unlikely related to the study compound). CONCLUSION: Significant reductions in the severity of the MBS were seen in both the Aqueous Hypromellose-based vaginal gel and the oxytocin gel groups, but with no significant differences in severity reduction seen between the groups. Both gels were safe and well tolerated. Given the benefits of avoiding the use of hormones, Aqueous Hypromellose-based vaginal gel is an attractive first choice in the treatment of postmenopausal women with vulvovaginal atrophy symptoms.

Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) have an increased risk of pregnancy complications. Epi-analysis of two previous randomised controlled trials that compared metformin with placebo during pregnancy in women with PCOS showed a significant reduction in late miscarriages and preterm births in the metformin group. The aim of this third randomised trial (PregMet2) was to test the hypothesis that metformin prevents late miscarriage and preterm birth in women with PCOS. METHODS: PregMet2 was a randomised, placebo-controlled, double-blind, multicentre trial done at 14 hospitals in Norway, Sweden, and Iceland. Singleton pregnant women with PCOS aged 18-45 years were eligible for inclusion. After receiving information about the study at their first antenatal visit or from the internet, women signed up individually to participate in the study. Participants were randomly assigned (1:1) to receive metformin or placebo by computer-generated random numbers. Randomisation was in blocks of ten for each country and centre; the first block had a random size between one and ten to assure masking. Participants were assigned to receive oral metformin 500 mg twice daily or placebo during the first week of treatment, which increased to 1000 mg twice daily or placebo from week 2 until delivery. Placebo tablets and metformin tablets were identical and participants and study personnel were masked to treatment allocation. The primary outcome was the composite incidence of late miscarriage (between week 13 and week 22 and 6 days) and preterm birth (between week 23 and week 36 and 6 days), analysed in the intention-to-treat population. Secondary endpoints included the incidence of gestational diabetes, preeclampsia, pregnancy-induced hypertension, and admission of the neonate to the neonatal intensive care unit. We also did a post-hoc individual participant data analysis of pregnancy outcomes, pooling data from the two previous trials with the present study. The study was registered with ClinicalTrials.gov, number NCT01587378, and EudraCT, number 2011-002203-15. FINDINGS: The study took place between Oct 19, 2012, and Sept 1, 2017. We randomly assigned 487 women to metformin (n=244) or placebo (n=243). In the intention-to-treat analysis, our composite primary outcome of late miscarriage and preterm birth occurred in 12 (5%) of 238 women in the metformin group and 23 (10%) of 240 women in the placebo group (odds ratio [OR] 0·50, 95% CI 0·22-1·08; p=0·08). We found no significant differences for our secondary endpoints, including incidence of gestational diabetes (60 [25%] of 238 women in the metformin group vs 57 [24%] of 240 women in the placebo group; OR 1·09, 95% CI 0·69-1·66; p=0·75). We noted no substantial between-group differences in serious adverse events in either mothers or offspring, and no serious adverse events were considered drug-related by principal investigators. In the post-hoc pooled analysis of individual participant data from the present trial and two previous trials, 18 (5%) of 397 women had late miscarriage or preterm delivery in the metformin group compared with 40 (10%) of 399 women in the placebo group (OR 0·43, 95% CI 0·23-0·79; p=0·004). INTERPRETATION: In pregnant women with PCOS, metformin treatment from the late first trimester until delivery might reduce the risk of late miscarriage and preterm birth, but does not prevent gestational diabetes. FUNDING: Research Council of Norway, Novo Nordisk Foundation, St Olav's University Hospital, and Norwegian University of Science and Technology.

Repair of recurrent rectocele with posterior colporrhaphy or non-absorbable polypropylene mesh-patient-reported outcomes at 1-year follow-up.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to compare the results of repair of isolated, recurrent, posterior vaginal wall prolapse using standard posterior colporrhaphy versus non-absorbable polypropylene mesh in a routine health care setting. METHODS: This cohort study was based on prospectively collected data from the Swedish National Register for Gynaecological Surgery. All patients operated for recurrent, posterior vaginal wall prolapse in Sweden between 1 January 2006 and 30 October 2016 were included. A total of 433 women underwent posterior colporrhaphy, and 193 were operated using non-absorbable mesh. Data up to 1 year were collected. RESULTS: The 1-year patient-reported cure rate was higher for the mesh group compared with the colporrhaphy group, with an odds ratio (OR) of 2.06 [95% confidence interval (CI) 1.03-4.35], corresponding to a number needed to treat of 9.7. Patient satisfaction (OR = 2.38; CI 1.2-4.97) and improvement (OR = 2.13; CI 1.02-3.82) were higher in the mesh group. However, minor surgeon-reported complications were more frequent with mesh (OR = 2.74; CI 1.51-5.01). Patient-reported complications and re-operations within 12 months were comparable in the two groups. CONCLUSIONS: For patients with isolated rectocele relapse, mesh reinforcement enhances the likelihood of success compared with colporrhaphy at 1-year follow-up. Also, in our study, mesh repair was associated with greater patient satisfaction and improvement of symptoms, but an increase in minor complications. Our study indicates that the benefits of mesh reinforcement may outweigh the risks of this procedure for women with isolated recurrent posterior prolapse.