An influence of menopausal symptoms on mental health, emotion perception, and quality of life: a multi-faceted approach.

PURPOSE: The menopausal transition brings with it many physical, cognitive, and affective changes in a woman's life, impacting quality of life. Whereas prior work has examined impact on general mental health and cognitive function, research on basic affective processing during menopause remains scarce. METHODS: Using a median-split procedure, this pre-registered study examined the impact of stronger (N = 46 women) vs. milder (N = 47 women) menopausal symptoms using a behavioural task of subjective emotion perception (embody) and a passive eye tracking viewing task of emotional faces in addition to self-report questionnaires. After 3 months, participants completed the questionnaires again to examine whether objective measures of emotion perception (eye tracking) might predict mental health at follow-up. RESULTS: As anticipated, women with stronger vs. milder menopausal symptoms reported increased symptoms of anxiety, depression, stress, emotion regulation difficulties, and lower quality of life during both time points. While no evidence was found in the behavioural task, eye tracking data indicated blunted emotion perception in women with high menopausal symptoms, while women with low symptoms spent more time looking at happy faces relative to fearful or surprised faces. Although eye tracking or hormonal data did not predict mental health at follow-up, a higher estradiol/FSH ratio indicated a higher quality of life. CONCLUSIONS: This study documented an impact of the menopausal transition and strength of menopausal symptoms in particular on objective emotion perception as well as mental health and quality of life in women suffering from stronger vs. milder menopausal symptoms. Clinical implications are discussed.

Exome sequencing to explore the possibility of predicting genetic susceptibility to the joint occurrence of polycystic ovary syndrome and Hashimoto's thyroiditis.

A large body of evidence indicates that women with polycystic ovary syndrome (PCOS) have a higher risk of developing Hashimoto's thyroiditis (HT) than healthy individuals. Given the strong genetic impact on both diseases, common predisposing genetic factors are possibly involved but are not fully understood. Here, we performed whole-exome sequencing (WES) for 250 women with sporadic PCOS, HT, combined PCOS and HT (PCOS+HT), and healthy controls to explore the genetic background of the joint occurrence of PCOS and HT. Based on relevant comparative analyses, multivariate logistic regression prediction modeling, and the most informative feature selection using the Monte Carlo feature selection and interdependency discovery algorithm, 77 variants were selected for further validation by TaqMan genotyping in a group of 533 patients. In the allele frequency test, variants in RAB6A, GBP3, and FNDC7 genes were found to significantly (padjusted < 0.05) differentiated the PCOS+HT and PCOS groups, variant in HIF3A differentiated the PCOS+HT and HT groups, whereas variants in CDK20 and CCDC71 differentiated the PCOS+HT and both single disorder groups. TaqMan genotyping data were used to create final prediction models, which differentiated between PCOS+HT and PCOS or HT with a prediction accuracy of AUC = 0.78. Using a 70% cutoff of the prediction score improved the model parameters, increasing the AUC value to 0.87. In summary, we demonstrated the polygenic burden of both PCOS and HT, and many common and intersecting signaling pathways and biological processes whose disorders mutually predispose patients to the development of both diseases.

Bones and Hormones: Interaction between Hormones of the Hypothalamus, Pituitary, Adipose Tissue and Bone.

The bony skeleton, as a structural foundation for the human body, is essential in providing mechanical function and movement. The human skeleton is a highly specialized and dynamic organ that undergoes continuous remodeling as it adapts to the demands of its environment. Advances in research over the last decade have shone light on the various hormones that influence this process, modulating the metabolism and structural integrity of bone. More recently, novel and non-traditional functions of hypothalamic, pituitary, and adipose hormones and their effects on bone homeostasis have been proposed. This review highlights recent work on physiological bone remodeling and discusses our knowledge, as it currently stands, on the systemic interplay of factors regulating this interaction. In this review, we provide a summary of the literature on the relationship between bone physiology and hormones including kisspeptin, neuropeptide Y, follicle-stimulating hormone (FSH), prolactin (PRL), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), leptin, and adiponectin. The discovery and understanding of this new functionality unveils an entirely new layer of physiologic circuitry.

Coping profiles, depression, and body image anxiety during the Covid-19 pandemic: Comparative analysis of females with thyroid diseases and a non-clinical sample.

OBJECTIVES: This study aimed to compare profiles of coping among females with thyroid disorders and females from a healthy control group regarding depression levels and body image anxiety. We also wanted to check whether subjectively experienced Covid-19-related psychological distress moderated the above-mentioned association in both groups of participants. METHOD: The study sample comprised 564 females, of which 329 were diagnosed with a thyroid disease and 235 formed the healthy control group. Participants filled out paper-and-pencil or online versions of psychometric questionnaires to assess coping strategies, depression, and body image anxiety. RESULTS: In general, we observed higher depression intensity and a higher level of body image anxiety among females with thyroid diseases than among the healthy control group. Latent profile analysis revealed adaptive vs. maladaptive coping profiles from both study samples. Depression symptoms were significantly higher if coping was maladaptive in both the clinical and control groups. Still, there were no significant differences in body image anxiety between participants with adaptive and maladaptive coping profiles. Covid-19-related distress did not moderate the link between coping profiles, depression, and body image anxiety in either group. CONCLUSION: Greater focus should be placed on the role of body image in females struggling with thyroid diseases. Bodily therapy may help these patients to cope better with co-occurring thyroid diseases and mental disorders, whose relationship is still not fully understood.

The most common problems in lactation in the first days postpartum in Polish women - a cross-sectional study.

Breastfeeding is the primal form of feeding new-borns and has multiple benefits to mothers and children. However, often introduction of infant formula is necessary due to breastfeeding cessation or infant's inability to thrive on human milk. AIM: The aim of the study was to analyse elementary lactation problems in the first days postpartum leading up to feeding new-borns with infant formula. MATERIALS AND METHODS: The diagnostic survey that consisted of 28 questions was performed on a group of 194 patients staying at the Obstetrics and New-borns Department of the Duchess Anna Mazowiecka Clinical Hospital in Warsaw from September until December 2018. RESULTS: Most of respondents that gave birth naturally didn't give the infant formula after birth (62.4%, n=58/93), whereas patients giving birth by caesarean section 69.0% (n=69/100) fed infant formula to new-borns after birth. The administration of infant formula significantly depended on the mode of delivery (p<0.01) and on whether the baby had suckled on the first contact (p<0.01). Moreover, patients with prepregnancy diabetes (81.8%, n=9/11, p<0.05) and obesity (76.2%, n=16/21, p<0.05) were more likely to give children infant formula. CONCLUSIONS: Feeding with infant formula is more frequent after caesarean section and when there is coexistence of diseases with pregnancy. Suckling the breast during the first skin-to-skin contact has a positive effect on the duration of lactation.

Lactational Amenorrhea: Neuroendocrine Pathways Controlling Fertility and Bone Turnover.

Lactation is a physiological state of hyperprolactinemia and associated amenorrhea. Despite the fact that exact mechanisms standing behind the hypothalamus-pituitary-ovarian axis during lactation are still not clear, a general overview of events leading to amenorrhea may be suggested. Suckling remains the most important stimulus maintaining suppressive effect on ovaries after pregnancy. Breastfeeding is accompanied by high levels of prolactin, which remain higher than normal until the frequency and duration of daily suckling decreases and allows normal menstrual function resumption. Hyperprolactinemia induces the suppression of hypothalamic Kiss1 neurons that directly control the pulsatile release of GnRH. Disruption in the pulsatile manner of GnRH secretion results in a strongly decreased frequency of corresponding LH pulses. Inadequate LH secretion and lack of pre-ovulatory surge inhibit the progression of the follicular phase of a menstrual cycle and result in anovulation and amenorrhea. The main consequences of lactational amenorrhea are connected with fertility issues and increased bone turnover. Provided the fulfillment of all the established conditions of its use, the lactational amenorrhea method (LAM) efficiently protects against pregnancy. Because of its accessibility and lack of additional associated costs, LAM might be especially beneficial in low-income, developing countries, where modern contraception is hard to obtain. Breastfeeding alone is not equal to the LAM method, and therefore, it is not enough to successfully protect against conception. That is why LAM promotion should primarily focus on conditions under which its use is safe and effective. More studies on larger study groups should be conducted to determine and confirm the impact of behavioral factors, like suckling parameters, on the LAM efficacy. Lactational bone loss is a physiologic mechanism that enables providing a sufficient amount of calcium to the newborn. Despite the decline in bone mass during breastfeeding, it rebuilds after weaning and is not associated with a postmenopausal decrease in BMD and osteoporosis risk. Therefore, it should be a matter of concern only for lactating women with additional risk factors or with low BMD before pregnancy. The review summarizes the effect that breastfeeding exerts on the hypothalamus-pituitary axis as well as fertility and bone turnover aspects of lactational amenorrhea. We discuss the possibility of the use of lactation as contraception, along with this method's prevalence, efficacy, and influencing factors. We also review the literature on the topic of lactational bone loss: its mechanism, severity, and persistence throughout life.

Two consecutive pregnancies in a patient with premature ovarian insufficiency in the course of classic galactosemia and a review of the literature.

AIM: To present a case report of a patient with classic galactosemia and the Q188R/K285N GALT mutation, who conceived spontaneously twice despite severe ovarian failure. A review of the literature is included. MATERIALS AND METHODS: A 20-year-old patient with classic galactosemia and premature ovarian insufficiency (POI) came to our attention. We performed a routine hormonal and ultrasound examination confirming low ovarian reserve. Due to low rates of pregnancies in individuals with POI (5%-10%), we were almost certain of the infeasibility of pregnancy. RESULTS: Surprisingly, several months after hospitalization, the patient conceived without any medical intervention and less than a year after the first birth she became pregnant again. While reviewing the literature, 90 pregnancies among galactosemic patients were identified. CONCLUSIONS: Ovarian failure is a long-term diet-independent complication of classic galactosemia, pertaining to about 90% of affected individuals. This case confirms its unpredicted course, as even the presence of unfavorable factors (absence of spontaneous puberty, early diagnosis of POI, undetectable AMH) may not preclude the chance for conception.

Two successful pregnancies after in vitro fertilisation with oocyte donation in a patient with Swyer syndrome - a case report.

Diagnosis of complete XY gonadal dysgenesis exposes the patient to the prospect of infertility and many years of medical treatment in order to avoid the development of diseases associated with this condition. However, sufficiently early diagnosis followed by the implementation of proper therapy improves the prognosis for enabling future pregnancies after IVF through the development of reproductive organs and prevention of health complications of hypoestrogenism such as cardiovascular problems and osteoporosis. This syndrome is very rare and affects 1 in 80,000 women. Due to the high risk of developing a gonadal tumour, prophylactic bilateral gonadectomy is one of the main procedures performed in a relatively brief time after diagnosis. Unfortunately, despite characteristic symptoms like primary amenorrhoea and underdeveloped breasts, the diagnosis is often made quite late. We report the case of a 45-year-old woman who had been diagnosed with Swyer syndrome at the age of 16 years. The patient underwent bilateral gonadectomy one year after the diagnosis due to the associated risk of developing malignancy and was treated since with hormone replacement therapy. At the age of 32 and 34 years, 2 successful IVF procedures were performed with oocyte donations. The pregnancies proceeded without any complications and both were resolved by caesarean section. The healthy sons' weights were 3600 g and 3700 g, respectively.

Body Image During Pregnancy in the Era of Coronavirus Disease 2019: The Role of Heterogeneous Patterns of Perceived Social Support.

Objective: The aim of this study was to explore the profiles of pregnant women on perceived social support with regard to sociodemographic variables, coronavirus disease 2019 (COVID-19)-related distress issues, and body image. We compared the aforementioned relationships within the study variables between pregnant women and a control group of non-pregnant women. Method: The study sample comprised 345 women, 157 pregnant women, and 188 women in the control group. Participants filled out paper-and-pencil or online psychometric questionnaires to assess the variables analyzed in our research. Results: Latent profile analysis revealed six profiles of pregnant women based on perceived social support, which varied in terms of body image evaluation. The high-support profile differed from the profiles with the lowest scores in all support domains. Significant differences in body image between the profiles of pregnant women and the control group were noted. Conclusion: Understanding the mechanisms through which women can attain more body satisfaction during pregnancy is an important research topic that can inspire planning for more effective psychological help, especially in the context of the COVID-19 pandemic and related psychological distress.

18-Year-old patient with Klinefelter syndrome (47, XXY) and complete androgen insensitivity syndrome (CAIS) - case report.

AIMS: The aims of the presented case report are to emphasize the importance of a proper diagnostics and treatment in the case of the coexistence of Klinefelter syndrome (KS, 47 XXY) and complete androgen insensitivity syndrome (CAIS). Since there is no causal treatment it is necessary to provide the patient with a good quality of life, including psychological and sexological support. MATERIALS AND METHODS: The presented case report is the retrospective analysis of the patient's medical history over the 3 years. RESULTS: At the age of 15, the patient was directed to genetic testing due to primary amenorrhea. The results of the patient showed an incorrect male karyotype with the SRY gene present (47, XXY). A molecular diagnostics revealed a very rare variant of the androgen receptor (AR) mutation responsible for tissue insensitivity to androgens. The detected mutation has not been described in the available databases so far. Following a diagnosis of the presence of Klinefelter syndrome (KS, 47 XXY) together with complete androgen insensitivity syndrome (CAIS), the patient underwent a bilateral gonadectomy. CONCLUSIONS: In women with KS and CAIS physiological reproduction and maintenance of normal sex, hormone levels are not possible. A gonadectomy is performed due to the risk of malignant testicular tumors.

Autoimmune Diseases in Patients with Premature Ovarian Insufficiency-Our Current State of Knowledge.

Premature ovarian insufficiency (POI), previously known as premature ovarian failure or premature menopause, is defined as loss of ovarian function before the age of 40 years. The risk of POI before the age of 40 is 1%. Clinical symptoms develop as a result of estrogen deficiency and may include amenorrhea, oligomenorrhea, vasomotor instability (hot flushes, night sweats), sleep disturbances, vulvovaginal atrophy, altered urinary frequency, dyspareunia, low libido, and lack of energy. Most causes of POI remain undefined, however, it is estimated that anywhere from 4-30% of cases are autoimmune in origin. As the ovaries are a common target for autoimmune attacks, an autoimmune etiology of POI should always be considered, especially in the presence of anti-oocyte antibodies (AOAs), autoimmune diseases, or lymphocytic oophoritis in biopsy. POI can occur in isolation, but is often associated with other autoimmune conditions. Concordant thyroid disorders such as hypothyroidism, Hashimoto thyroiditis, and Grave's disease are most commonly seen. Adrenal autoimmune disorders are the second most common disorders associated with POI. Among women with diabetes mellitus, POI develops in roughly 2.5%. Additionally, autoimmune-related POI can also present as part of autoimmune polyglandular syndrome (APS), a condition in which autoimmune activity causes specific endocrine organ damage. In its most common presentation (type-3), APS is associated with Hashomoto's type thyroid antibodies and has a prevalence of 10-40%. 21OH-Antibodies in Addison's disease (AD) can develop in association to APS-2.

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis.

BACKGROUND: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. METHODS: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 µmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. FINDINGS: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35-3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04-2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86-1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39-0·91; p=0·016). INTERPRETATION: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. FUNDING: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.

Chronic Low Grade Inflammation in Pathogenesis of PCOS.

Polycystic ovary syndrome (PCOS) is a one of the most common endocrine disorders, with a prevalence rate of 5-10% in reproductive aged women. It's characterized by (1) chronic anovulation, (2) biochemical and/or clinical hyperandrogenism, and (3) polycystic ovarian morphology. PCOS has significant clinical implications and can lead to health problems related to the accumulation of adipose tissue, such as obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. There is also evidence that PCOS patients are at higher risk of cardiovascular diseases, atherosclerosis, and high blood pressure. Several studies have reported the association between polycystic ovary syndrome (PCOS) and low-grade chronic inflammation. According to known data, inflammatory markers or their gene markers are higher in PCOS patients. Correlations have been found between increased levels of C-reactive protein (CRP), interleukin 18 (IL-18), tumor necrosis factor (TNF-α), interleukin 6 (IL-6), white blood cell count (WBC), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) in the PCOS women compared with age- and BMI-matched controls. Women with PCOS present also elevated levels of AGEs and increased RAGE (receptor for advanced glycation end products) expression. This chronic inflammatory state is aggravating by obesity and hyperinsulinemia. There are studies describing mutual impact of hyperinsulinemia and obesity, hyperandrogenism, and inflammatory state. Endothelial cell dysfunction may be also triggered by inflammatory cytokines. Many factors involved in oxidative stress, inflammation, and thrombosis were proposed as cardiovascular risk markers showing the endothelial cell damage in PCOS. Those markers include asymmetric dimethylarginine (ADMA), C-reactive protein (CRP), homocysteine, plasminogen activator inhibitor-I (PAI-I), PAI-I activity, vascular endothelial growth factor (VEGF) etc. It was also proposed that the uterine hyperinflammatory state in polycystic ovary syndrome may be responsible for significant pregnancy complications ranging from miscarriage to placental insufficiency. In this review, we discuss the most importance evidence concerning the role of the process of chronic inflammation in pathogenesis of PCOS.

Hormonal Effects on Hair Follicles.

The hair cycle and hair follicle structure are highly affected by various hormones. Androgens-such as testosterone (T); dihydrotestosterone (DHT); and their prohormones, dehydroepiandrosterone sulfate (DHEAS) and androstendione (A)-are the key factors in terminal hair growth. They act on sex-specific areas of the body, converting small, straight, fair vellus hairs into larger darker terminal hairs. They bind to intracellular androgen receptors in the dermal papilla cells of the hair follicle. The majority of hair follicles also require the intracellular enzyme 5-alpha reductase to convert testosterone into DHT. Apart from androgens, the role of other hormones is also currently being researched-e.g., estradiol can significantly alter the hair follicle growth and cycle by binding to estrogen receptors and influencing aromatase activity, which is responsible for converting androgen into estrogen (E2). Progesterone, at the level of the hair follicle, decreases the conversion of testosterone into DHT. The influence of prolactin (PRL) on hair growth has also been intensively investigated, and PRL and PRL receptors were detected in human scalp skin. Our review includes results from many analyses and provides a comprehensive up-to-date understanding of the subject of the effects of hormonal changes on the hair follicle.

The World Health Organization (WHO) approach to healthy ageing.

The ageing of the global population is the most important medical and social demographic problem worldwide. The World Health Organization (WHO) has defined healthy ageing as a process of maintaining functional ability to enable wellbeing in older age. The WHO, Member States and Partners for Sustainable Development Goals have created a Global Strategy and Action Plan for Ageing and Health for 2016-2020 and its continuation with the WHO programme The Decade of Healthy Ageing 2020-2030. The WHO has established main priorities such as supporting country planning and action, collecting better global data and promoting research on healthy ageing, aligning health systems to the needs of older people, laying the foundations and ensuring the human resources necessary for long-term integrated care, undertaking a global campaign to combat ageism, and enhancing the global network for age-friendly cities and communities. There are several reports of coordinated preventive health and social health initiatives in well developed countries. However, there is little evidence on the application of the active ageing frameworks in developing countries. Greater national capacities and closer monitoring of the progress through age-disaggregated data is needed to effectively implement the intended programmes on healthy ageing.

POI after chemotherapy and bone marrow transplant may mimic disorders of sexual differentiation - a case report of a patient with primary amenorrhea and 46, XY karyotype.

Cytogenetic examination may be useful in determining the reason for primary amenorrhea in phenotypically female patients. The result 46, XY usually indicates two syndromes: complete androgen insensitivity or pure gonadal dysgenesis. We report a case of a patient, who due to acute lymphoblastic leukemia in childhood was treated with total body irradiation and bone marrow transplantation. Later on the patient presented with symptoms typical for premature ovarian failure and male karyotype in peripheral lymphocytes. The cytogenetic examination for peripheral cells showed normal female karyotype. Therefore, it has been concluded that ovarian function impairment resulted rather from the gonadotoxic effect of oncological treatment than as a disorder of sexual differentiation. The survival rates of childhood cancer are very high and some of the patients will experience premature ovarian failure. It must be remembered that after bone marrow transplantation karyotype of peripheral lymphocytes may be misleading.

Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses.

BACKGROUND: Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth. METHODS: We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134. FINDINGS: We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163 947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73-2·89]; I2=59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74-0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35-0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02-0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 µmol/L versus four (0·28%; 0·08-0·72) of 1412 cases with total bile acids of 40-99 µmol/L (hazard ratio [HR] 2·35 [95% CI 0·52-10·50]; p=0·26), and versus 18 (3·44%; 2·05-5·37) of 524 cases for bile acids of 100 µmol/L or more (HR 30·50 [8·83-105·30]; p<0·0001). INTERPRETATION: The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 µmol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery. FUNDING: Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust.

Premature ovarian insufficiency - aetiopathology, epidemiology, and diagnostic evaluation.

Premature ovarian insufficiency (POI) is defined as a cessation of ovarian function before the age of 40 years. It is associated with hypoestrogenism and loss of residual follicles, both of which lead to menstrual abnormalities, pregnancy failures, and decreased health-related quality of life. The prevalence of POI is estimated at 1% in the general population. Current European Society of Human Reproduction and Embryology (ESHRE) diagnostic criteria include: amenorrhoea or oligomenorrhoea for at least four months and increased follicle-stimulating hormone (FSH) levels > 25 IU/l measured twice (with a four-week interval). The aetiopathogenesis of the disease in most cases remains unexplained. Nevertheless, in some patients with POI, genetic abnormalities, metabolic disorders, autoimmunity, iatrogenic procedures, infections, or environmental factors have been established as underlying causes of the syndrome.

Signs and symptoms, evaluation, and management of genitourinary tract consequences of premature ovarian insufficiency.

Premature ovarian insufficiency (POI) occurs in 1% of women under 40 years old. Hypoestrogenism associated with this condition may result in vaginal atrophy and urine incontinence, called genitourinary syndrome. The symptoms include: vaginal dryness, irritation, dyspareunia, and dysuria. There is relative lack of studies on the occurrence and treatment of genitourinary problems in women with POI. Prevalence rates vary from 17 to 54% depending on cause, duration of oestrogen depletion, and the treatment used. Patients with POI gain lower scores in tests measuring vaginal health or sexual function in comparison to healthy peers. Hormonal treatment in premature ovarian insufficiency is recommended until the natural age of menopause. The vaginal route of oestrogen administration is supposed to be the criterion standard in treating genitourinary symptoms. Androgen supplementation is not routinely recommended.