Pituitary-ovarian Axis Research Articles

Association between Metal(loid) Exposure and Risk of Polycystic Ovary Syndrome Mediated by Anti-Müllerian Hormone among Women Undergoing In Vitro Fertilization and Embryo Transfer

ObjectiveTo investigate the relationship and potential pathways between metal(loid) exposure and the risk of polycystic ovary syndrome (PCOS) in women of childbearing age. MethodsThis case-control study included 200 patients with PCOS (cases) and 896 non-PCOS controls with the age of 25–37 years. The concentrations of 29 metal(loid)s in the follicular fluid (FF) and clinical indicators in the serum were measured in all participants. Logistic regression analysis and mediation analysis were conducted to evaluate the associations between metal(loid) exposure and PCOS risk and investigate the possible roles of clinical indicators, respectively. ResultsLogistic regression analysis revealed an association between high copper levels in FF and increased PCOS risk (highest vs. lowest quartile: adjusted odds ratio = 2.94, 95% confidence interval: 1.83–4.72). A high luteinizing hormone/follicle-stimulating hormone ratio and elevated levels of testosterone and anti-Müllerian hormone (AMH) were strongly associated with increased PCOS risk induced by high copper exposure. The mediation analysis indicated a mediating effect of AMH in the association between copper exposure and PCOS risk. ConclusionCopper may affect PCOS risk through the hypothalamic–pituitary–ovarian axis, mediated by AMH. Copper exposure and internal AMH levels are important indicators for early warning of PCOS development.

Restorative effects of melatonin on bisphenol a-induced interference of gene expression in hypothalamic pituitary axis following early exposure

Bisphenol-A is a standard monomer used in manufacturing plastics and epoxy resins, and it is widely used in food preservation and packaging. It is an endocrine-disrupting chemical miming the endogenous estradiol hormone. Melatonin regulates sleep-wake cycles and plays essential physiological roles in the body through its antioxidative properties. This research aims to ascertain the impact of Bisphenol A on the hypothalamic-pituitary-ovarian axis and determine melatonin's function on possible BPA-induced effects. Six adult male Wistar rats and 12 adult female Wistar rats of proven fertility were bred and organized into groups. These animals were subjected to subcutaneous injections of high and low doses of bisphenol A from postnatal days 0-3, then oral melatonin. The rats were allowed to mature into full-grown adults and euthanized at 120 ±4 days. The serum and hypothalamic-pituitary-ovarian tissues were collected for various assays. Compared to the control groups, groups administered varying doses of bisphenol A showed significant overexpression of estrogen and androgen receptors. Administration of Melatonin showed some reversal and reparative effects on damage of the hypothalamic pituitary ovarian axis. Elevated estrogen receptor levels induced by Bisphenol A altered receptor function. Melatonin showed some promising reparative effects.

P10-18 Bayesian benchmark dose modelling of hypothalamic–pituitary–ovarian axis endpoints to assess DEHP exposure effects in female mice

P10-18 Bayesian benchmark dose modelling of hypothalamic–pituitary–ovarian axis endpoints to assess DEHP exposure effects in female mice

TO STUDY ASSOCIATION OF OBESITY WITH HORMONAL IMBALANCE IN PRIMARY INFERTILITY AND EARLY PREGNANCY LOSS

Objectives: The study aimed to assess follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, and thyroid-stimulating hormone in obese patients with primary infertility and early pregnancy loss (EPL) and compare with normal fertile patients. Methods: Patients were divided into two groups. Group A consists of 50 patients with a history of infertility and EPL with a body mass index of more than 30 kg/m2. Group B consists of 50 normal fertile patients. Informed written consent was taken from all the patients. Blood samples were taken and hormone levels in two groups were measured and compared statistically. Results: Comparison and statistical analysis of FSH levels in obese infertile and normal fertile groups showed the difference to be statistically highly significant. LH levels in both groups were statistically highly significant. When compared statistically, the difference between prolactin levels of both groups was highly significant. Conclusion: This study supports the impact of obesity on infertility and pregnancy outcomes. Obesity affects dysfunction of the hypothalamus, pituitary ovarian axis, and results in a higher risk of infertility and EPL.

Characteristics of polycystic ovary syndrome rat models induced by letrozole, testosterone propionate and high-fat diets

Research questionWhat are the long-term effects of different models of polycystic ovary syndrome (PCOS), and which model could be used in future research? DesignPCOS models induced by letrozole, letrozole plus a high-fat diet (LE+HFD), testosterone propionate (TP) or testosterone propionate plus an HFD (TP+HFD) were established in rats. Body weight, energy intake, blood glucose, sex hormone concentrations, lipid profiles and the oestrus cycle were observed. Histology of the ovaries, large intestine and fat was displayed using haematoxylin–eosin or Oil Red O staining. Protein and mRNA levels relating to hormone synthesis, oocyte maturation, the gut barrier, lipid metabolism and inflammation were evaluated using western blotting, immunohistochemistry and PCR. The composition of the microbial community was measured using 16S RNA sequencing. ResultsLetrozole treatment induced hyperandrogenaemia, polycystic ovarian morphology, a disrupted oestrus cycle and impaired ovarian function. However, these effects could be reversed within 42 days. Concurrently, letrozole enhanced excess fat storage, diminished adipocyte browning and energy expenditure, led to the development of insulin resistance, affected the inflammatory state and compromised intestinal homeostasis. HFD could amplify the disturbances in the metabolism and intestinal microenvironment, and the pituitary–ovarian axis was more efficiently and consistently affected by testosterone propionate. Testosterone propionate and TP+HFD treatment also disturbed the intestinal microenvironment. Although the metabolic effects of testosterone propionate metabolism were not as profound as those of letrozole, they were enhanced by an HFD. ConclusionsLetrozole is useful for studies on metabolic disturbances in PCOS, and LE+HFD treatment is suitable for investigations on PCOS metabolic abnormalities and the gut–PCOS link. Testosterone propionate injection is appropriate for studying reproductive abnormalities in PCOS, while TP+HFD treatment is the most comprehensive for studying PCOS reproductive abnormalities, metabolic disturbances and the gut–PCOS link.

Clinicopathological Evaluation of Thyroid Dysfunction in Women with Abnormal Uterine Bleeding

Introduction: Abnormal uterine bleeding describes any variation from normal bleeding patterns in nonpregnant, reproductive-aged women beyond menarche lasting for at least 6 months. Regular cyclic menstruation results the choreographed relationship between the endometrium and its regulating factors. Any type of disturbance between the regulatory mechanism of pituitary ovarian axis or pelvic diseases results in abnormal uterine bleeding. Thyroid hormones play a key role in the menstrual and reproductive function of women. It is recognized universally that menstrual disturbances may accompany clinical alterations in thyroid function. Objectives: To evaluate the thyroid dysfunction in patients with abnormal uterine bleeding. Materials and Methods: This cross sectional study was conducted in Department of obstetrics & gynaecology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Shahbag, Dhaka from April 2023 to December 2023. Women with abnormal uterine bleeding were included in the study. Sample was selected by purposive sampling. Sample size was 100. Detail demographic data were collected from the informant and recorded in structured case report form. Clinical examination and relevant investigation were done meticulously. Data was collected by using a semi-structured questionnaire. Data was processed and analysed with the help of computer program SPSS and Microsoft excel. Quantitative data expressed as mean and standard deviation and qualitative data as frequency and percentage. Result was presented in the form of tables, pie chart, graphs, bar diagrams, histogram & charts etc. Results: In this study, the maximum numbers of cases (43.0%) were between 26-35 years age group. Mean age was 29.57 ± 8.27 years. Large numbers of respondents came from urban area (58%). On evaluation of types & causes of AUB, maximum patient belongs to AUB-L (leiomyoma) group (53%) followed by AUB-A (adenomyosis) (28%); AUB-P (polyp) (8%); AUB-O (ovulatory) (9%) and AUB-M (malignancy) (2%). Present study showed that prevalence of thyroid disorders is 26% in AUB patients. The prevalence of Hypothyroidism was 18% and Hyperthyroidism was 8%. Thyroid dysfunction is associated with menstrual abnormalities in females of all age groups. Conclusion: Abnormal uterine bleeding has a strong association with thyroid disorders. The most common type of disorder is subclinical hypothyroidism. Thus, all patient of AUB must be evaluated for thyroid dysfunction. Medicine Today 2023 Vol.36 (1): 1-6

Effects of quercetin on polycystic ovary syndrome in animal models: a systematic review and meta-analysis.

Metformin is an insulin sensitizer that is widely used for the treatment of insulin resistance in polycystic ovary syndrome patients. However, metformin can cause gastrointestinal side effects. This study showed that the effects of quercetin are comparable to those of metformin. Therefore, this study aimed to systematically evaluate the efficacy of quercetin in treating PCOS. The present systematic search of the Chinese National Knowledge Infrastructure (CNKI), Wanfang Data Information Site, Chinese Scientific Journals Database (VIP), SinoMed, Web of Science, and PubMed databases was performed from inception until February 2024. The methodological quality was then assessed by SYRCLE's risk of bias tool, and the data were analyzed by RevMan 5.3 software. Ten studies were included in the meta-analysis. Compared with those in the model group, quercetin in the PCOS group had significant effects on reducing fasting insulin serum (FIS) levels (P = 0.0004), fasting blood glucose (FBG) levels (P = 0.01), HOMA-IR levels (P < 0.00001), cholesterol levels (P < 0.0001), triglyceride levels (P = 0.001), testosterone (T) levels (P < 0.00001), luteinizing hormone (LH) levels (P = 0.0003), the luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio (P = 0.01), vascular endothelial growth factor (VEGF) levels (P < 0.00001), malondialdehyde (MDA) levels (P = 0.03), superoxide dismutase (SOD) levels (P = 0.01) and GLUT4 mRNA expression (P < 0.00001). This meta-analysis suggested that quercetin has positive effects on PCOS treatment. Quercetin can systematically reduce insulin, blood glucose, cholesterol, and triglyceride levels in metabolic pathways. In the endocrine pathway, quercetin can regulate the function of the pituitary-ovarian axis, reduce testosterone and luteinizing hormone (LH) levels, and lower the ratio of LH to follicle-stimulating hormone (FSH). Quercetin can regulate the expression of the GLUT4 gene and has antioxidative effects at the molecular level.

Primary Amenorrhoea

The amenorrhoea is the normal physiological feature in prepubertal girls, failure to commence menstruation is primary amenorrhea. A normal uterovaginal anatomy and functional hypothalamic pituitary ovarian (HPO) axis is essential for menstruation. The detailed relevant medical and family history along with thorough physical examination adds in for requesting relevant investigations to find out the cause. In the absence of secondary sexual characteristics, hormonal disturbances are the most likely cause while anatomical problems are more common in the presence of secondary sexual characteristics, along with physiological delays and endocrinopathies. Investigate primary amenorrhoea without secondary sexual development at 13 years and with secondary sexual development at 15 years of age, consider early referral if suspicion of chromosomal abnormality, hyperandrogenemia, anatomical abnormalities or primary amenorrhoea persists for five years after thelarche. The multidisciplinary team approach, to support patient and parents with evidence base knowledge for decision-making is the corner stone. It is important to address patient and their family needs, individually for the best outcome.

Heavy menstrual bleeding in adolescence: who to investigate and how to manage it

Key content Adolescent heavy menstrual bleeding (HMB) is commonly related to hypothalamic pituitary ovarian axis immaturity, which improves with age. This article outlines when and how to investigate for underlying pathological causes. Medical treatment for adolescent HMB consists predominantly of hormonal contraceptives. Preparation choice depends upon patient preference, comorbidities and co‐existing conditions. Acute adolescent HMB is rare; a suggested framework for assessing and managing such cases is provided within this article. Learning objectives To understand how to clinically evaluate adolescent HMB. To understand when and how to investigate adolescent HMB. To understand the different medical treatment options for HMB, their efficacy, risks and alternatives. To understand the management of acute adolescent HMB. Ethical issues Duties of confidentiality must be balanced against safeguarding concerns.

The Relationship between Leptin Hormone and Central Obesity in the Women Suffers from Polycystic Ovary Syndrome: A Case–Control Study

Abstract Background: One of the hallmarks of polycystic ovarian syndrome (POCS) is central obesity (CO), and conditions brought on by PCOS are likely to worsen when CO is present. The hormone leptin acts as a conduit to transmit metabolic signals from the brain’s neural networks to the pituitary-ovarian axis. Objective: It is to find the correlation between central adiposity and blood levels of leptin in women with PCOS. Materials and Methods: For this study, 150 women were recruited: 75 were control (n = 75) and 75 were PCOS (n = 75). The body mass index (BMI); waist circumference; hip circumference; waist/hip ratio and level of circulating serum leptin were assessed for each individual. The data analysis was conducted utilizing SPSS software (version 23). Results: Leptin hormone, a higher significant in the group of PCOS when compared with the control group (P &gt; 0.05). A positive significance correlation was found between the level of leptin with BMI, waist circumference, and hip circumference (P &lt; 0.05). Leptin level showed an AUC of 0.93 at a cutoff point of 10 ng/mL, giving a sensitivity (93%) and specificity (96%). Conclusion: The positive association between serum leptin and CO with BMI could be the cause of the increased leptin levels in the PCOS women.

Heartache to Happiness: Managing a Six Year Hormonal Subfertility with a Successful Rate of Conception

Background: The inability to conceive is emotionally distressing and indeed a very painful struggle in which the pain stays with the individual every day. Hormonal disorders are the leading cause of infertility globally. They do not only include the hypothalamic pituitary ovarian axis but also the none-reproductive endocrine glands. Hormonal management helps promote ovum maturation, which triggers ovulation, increasing the likelihood of conception. Case presentation: We report a 36-year-old African lady who presented with an inability to conceive for six years since marriage and it was associated with an irregular menstruation cycle length of twenty-four to thirty-six days. She had anovulatory cycles for seven years, and high Prolactin levels. Her body mass index was 34.4kg/m2. She had visited several hospitals in and outside Tanzania without success in conceiving. At Bugando Medical Centre we managed her case by diet, fertility awareness, and medical management. She conceived after three months of treatment. Conclusion: Anovulatory cycles with abnormal bleeding patterns are a major cause of infertility in reproductive woman. Basic hormonal profiles are essential to confirm where the problem is. Prolactinemia and insulin resistance affects ovulation. Fertility awareness, lifestyle changes, and medical management will bring back happiness to most women with subfertility secondary to hormonal disorders.

Current Insights in Prolactin Signaling and Ovulatory Function.

Prolactin (PRL) is a pleiotropic hormone released from lactotrophic cells of the anterior pituitary gland that also originates from extrapituitary sources and plays an important role in regulating lactation in mammals, as well as other actions. Acting in an endocrine and paracrine/autocrine manner, PRL regulates the hypothalamic-pituitary-ovarian axis, thus influencing the maturation of ovarian follicles and ovulation. This review provides a detailed discussion of the current knowledge on the role of PRL in the context of ovulation and ovulatory disorders, particularly with regard to hyperprolactinemia, which is one of the most common causes of infertility in women. Much attention has been given to the PRL structure and the PRL receptor (PRLR), as well as the diverse functions of PRLR signaling under normal and pathological conditions. The hormonal regulation of the menstrual cycle in connection with folliculogenesis and ovulation, as well as the current classifications of ovulation disorders, are also described. Finally, the state of knowledge regarding the importance of TIDA (tuberoinfundibular dopamine), KNDγ (kisspeptin/neurokinin B/dynorphin), and GnRH (gonadotropin-releasing hormone) neurons in PRL- and kisspeptin (KP)-dependent regulation of the hypothalamic-pituitary-gonadal (HPG) axis in women is reviewed. Based on this review, a rationale for influencing PRL signaling pathways in therapeutic activities accompanying ovulation disorders is presented.

Hormonal-metabolic trajectory of menopausal transition in a normoglycemic cohort of women with different blood pressure levels

Introduction. The gradual clustering of cardio-metabolic factors in women depending on age and decline of ovarian function justifies attention to the phenotype of the formation of the metabolic syndrome during the menopausal transition depending on the presence of hypertension without dysglycemia. Aim: to evaluate the association of indicators of the functional state of the pituitary-ovarian axis with markers of metabolic syndrome (MetS) and parameters of insulin resistance (IR) in a cohort of normoglycemic women aged 35-59 years with different levels of blood pressure (BP). Patients and methods. In a cohort of women 35–59 years old without dysglycemia (n = 88), 58 women had hypertension, 30 were normotensive. It was determined: body mass index (BMI), waist circumference (WC), levels of BP, triglycerides (TG), HDL-C, insulin, follicle-stimulating hormone (FSH) and estradiol, fasting glucose (FG); TyG and HOMA2-IR indices. Using SPSS (version 17) assessed the median (25; 75%); intergroup differences using the Mann-Whitney test; correlation analyzes: Spearman (R) and partial correlation (R рс ) to level out the influence of age. Results. In the general cohort of women, the influence of postmenopausal duration (PMD), FSH and E2 levels on MetS and TyG parameters depended on age, except for the correlation of PMD with FG (R pc = 0.313; p = 0.004). The range of associations of MetS markers with each other and TyG in the group of patients with hypertension is similar to those in the general cohort of women. In both cohorts, the interrelations between FG, OT, insulin and TyG remained relevant with partial correlation. The TyG index, associated with HOMA2-IR (R=0.600; p&lt;0.001; R pc =0.426; p&lt;0.001), had a greater range of connections with MetS components, as well as with FSH (R=0.312; p=0.017; R pc =0.286; p=0.030) and E2 (R= -0.393; p=0.002; R pc = -0.376; p=0.004) in the presence of hypertension. Conclusion. The influence of indicators of the functional state of the pituitary-ovarian axis on MetS and TyG markers was revealed, along with a spectrum of associations of parameters and factors in the formation of menopausal MetS with IR indices, especially TyG. Correlation relations between FG with PMD and MetS components, as well as estradiol in case of hypertension, reflect a high risk of progression to dysglycemia.

Epilepsy and Anti-Seizure Medications: Secret Agents for Endocrine Disruption.

There is a reciprocal relationship between epilepsy and reproductive endocrine disorders. Seizures and anti-seizure medications (ASMs) can contribute to reproductive and endocrine dysfunction and reproductive dysfunction may exacerbate seizures. Epilepsy via neuroendocrine mechanisms affects the hypothalamic-pituitary-ovarian (HPO) axis, disrupting the regulation of gonadotropin secretion, and resulting in dystrophic effects on the ovaries and early menopause. Anti-seizure medications have endocrine-related side effects on sexual function and bone health. Long-term use of ASMs may result in menstrual irregularities, sexual dysfunction, anovulatory cycles, polycystic ovaries, and reduced fertility. Some ASMs also interfere with bone metabolism. Epilepsy patients treated with ASMs are at risk for bone loss and fractures. This article explores the endocrine and hormonal effects of seizures and ASMs.

Primary Amenorrhea in Adolescents: Approach to Diagnosis and Management

Primary amenorrhea (PA) describes the complete absence of menses by the age of 15 years. It is a devastating diagnosis that can affect the adolescent’s view of her femininity, sexuality, fertility and self-image. A normal menstrual cycle can occur only in the presence of: a properly functioning hypothalamus–pituitary axis, well-developed and active ovaries, outflow tract without abnormalities. Any dysfunction in any of these players can result in amenorrhea. PA evaluation includes the patient’s medical history, physical examination, pelvic ultrasonography and initial hormone evaluation, limited to the serum-follicle-stimulating hormone (FSH) and luteinizing hormone, testosterone and prolactin. A karyotype should be obtained in all adolescents with high FSH serum levels. The main causes of PA, whether or not accompanied by secondary sexual characteristics, include endocrine defects of the hypothalamus–pituitary–ovarian axis, genetic defects of the ovary, metabolic diseases, autoimmune diseases, infections, iatrogenic causes (radiotherapy, chemotherapy), environmental factors and Müllerian tract defects. PA management depends on the underlying causes. Estrogen replacement therapy at puberty has mainly been based on personal experience. PA can be due to endocrine, genetic, metabolic, anatomical and environmental disorders that may have severe implications on reproductive health later in life. In some complex cases, a multidisciplinary team best manages the adolescent, including a pediatrician endocrinologist, gynecologist, geneticist, surgeon, radiologist, and psychologist.

Current approaches in managing pregnancy in kidney transplant recipients

End-stage renal disease impacts fertility, causing functional menopause in female patients. Within 3 months of successful renal transplant, menstrual function normalizes, ovulation recommences due to improved hypothalamic–pituitary–ovarian axis function, and, thereby, fertility is restored in 80–90% of women in the childbearing age group. In such circumstances, any unplanned pregnancy poses a significant risk to the mother and the child, and the allograft. Pregnancy, in general, does not negatively impact long-term allograft function or survival if the baseline function of the allograft is excellent. Risk predictors of clinical adverse outcomes and graft loss during pregnancy include short transplant–pregnancy interval, preconception graft function, hypertension, preconception proteinuria, and preeclampsia. The recommended and safer maintenance immunosuppressive regimen during pregnancy is calcineurin inhibitors (CNI) (tacrolimus/cyclosporine), azathioprine, and steroids. Sirolimus/everolimus and mycophenolate mofetil should be withdrawn 6 weeks before planned conception. To avoid acute rejections, drug levels should be monitored closely, and the dosage should be modified to reach the recommended target level. Addressing contraception must be a crucial component of the pretransplant counseling process to prevent premature unplanned pregnancies. Mechanical contraceptives are safe for transplant recipients, convenient, and easy to use, with no concerns regarding interaction with immune suppressants; nevertheless, their efficacy depends on user compliance which is difficult to achieve in most cases. However, combined oral contraceptives and progestin-only contraceptives have an inhibitory effect on P 450 3A4, thus increasing the concentration of CNIs particularly cyclosporine. Furthermore, CNIs, in particular, tacrolimus, have an inductive effect on P 450 3A4, potentially reducing the contraceptive efficacy. Therefore, successful pregnancy depends on thorough prepregnancy counseling, careful family planning, and multidisciplinary teamwork. Breastfeeding is not contraindicated and should not be discouraged.

P-429 Transcriptomic heterogeneity within cortical ovarian follicle pool in child and adult

Abstract Study question What are the transcriptomic differences between child and adult ovarian follicles in the human cortex? Summary answer Our results suggest that human ovarian cortical follicles show marked differences before and after puberty, with the greatest differences being present in the secondary stage. What is known already The ovaries and their main functional structures, follicles, are important for determining the reproductive health. Follicle growth and maturation are controlled by multiple mechanisms, including the hypothalamus pituitary ovarian axis and local paracrine signalling. Although dormant primordial follicles are activated to grow even in infancy, all growing follicles before the first menarche are bound to undergo atresia. Follicle growth activation in infancy and adulthood remains poorly understood. Additionally, child and adult follicles behave differently during in vitro culture suggesting differing biology, raising many questions e.g., about their suitability for fertility preservation. Study design, size, duration Ovarian cortical tissues from children were collected through fertility preservation program at the Helsinki Children’s hospital (Finland). Families of underage patients signed an informed written consent. Adult ovarian tissue was collected from gender reassignment patients at the Helsinki University hospital and Karolinska university hospital after informed written consent. Follicles at different maturation stages were isolated from ovarian cortex for single follicle transcriptomic analysis. Freshly-fixed cortical biopsies (3x3x1 mm3) were used for validation of transcriptomic analysis. Participants/materials, setting, methods Single viable follicles (n = 120, 60/age group) were mechanically and enzymatically isolated from frozen-thawed ovarian tissue from four adults (age &amp;gt;18 yrs) and five children (age 1-11 yrs) and processed for RNA-sequencing. Individual follicles were lysed, prepared for RNA libraries following Smart-Seq2 protocol and sequenced using NextSeq 500 platform. After quality assessment, 109 follicles were analysed (Adult n = 54, Child n = 55). DDX4, AMH, FOXL2 and DAZL transcripts and proteins localization were evaluated via immunodetection and RNA-FISH assay. Main results and the role of chance Principal component analysis (PCA) of all sequenced follicles demonstrated an expected timely progression of their stages based on maturation, and an overall similarity between child and adult. Interestingly, PCA displayed two distinct clusters of follicles in both adult and child samples. The first group contained only growing follicles and, after differentially expressed gene (DEG) analysis, demonstrated lower expression of traditional oocyte markers (group 1). The second group consisted of primordial and growing follicles and had lower expression of traditional granulosa marker (group 2). Group-related differential expression of main oocyte (DDX4, DAZL) and granulosa (FOXL2, AMH) marker genes were validated in tissue sections with RNA-FISH. Downstream analyses focused on group 2 follicles. When child and adult follicles were compared to each other, the highest number of DEGs were found in the secondary stage (primordial n = 32, primary n = 14, secondary n = 387). Pathway analysis of DEG displays enrichment of oestrogen-related related pathways in adult secondary follicles. Furthermore, we analysed DEGs between the follicular stages per age group, finding high number of DEGs between primordial and primary follicles (Adult n = 1663, Child n = 1914). The majority of those genes are unique to the age group (common=512). Limitations, reasons for caution Adult ovarian tissue is obtained from gender reassignment patients, who receive androgen treatments prior to surgery. Child ovarian tissue was collected from fertility preservation programme where some patients were exposed to chemotherapy prior to tissue collection. Wider implications of the findings The differences between child and adult follicles encourage further investigation of the suitability of child ovarian tissue in current fertility preservation protocols. Understanding transcriptomic changes during early folliculogenesis and reasons for follicle degeneration can help tailor protocols for in vitro growth of follicles. Trial registration number not applicable

Ovaries out of control – hormonal strategies

The perimenopausal transition represents a therapeutic challenge for clinicians as the follicular activity of the ovaries does not decline gradually and evenly, but is accompanied by a pronounced up and down of hormone production. The female menstrual cycle involves a highly regulated chain of neuro-endocrine phenomena, maintained by a constant dialogue between the hypothalamus, the pituitary gland and the ovaries. Besides FSH, LH, estradiol and progesterone, other components of this dialogue are inhibin A and B, AMH as well as the KNDy neurons in the arcuate nucleus. Approaching menopause the number of primordial follicles declines to a critically low level. As a result a series of endocrine changes occur and the highly coordinated feed-back loops between the regulating levels is increasingly disturbed. The pituitary-ovarian axis is no longer subject to the laws of the fertile phase: Follicular activity fluctuates and there are periods of estrogen excess alternating with periods of estrogen deficiency. Luteal insufficiencies and anovulation increasingly occur and asynchronous maturation of follicles can lead to so-called "LOOP-events" = "luteal out of phase-events. The strongly fluctuating levels of steroidal hormones can lead to pronounced bleeding disorders and may be responsible for sleep disturbances and depressive moods, both typical symptoms of the early and mid perimenopausal transition.

Effects of pulsatile intravenous follicle-stimulating hormone treatment on ovarian function in women with obesity

To establish conditions for effective hypothalamic suppression in women with normal and high body mass index (BMI) and test the hypothesis that intravenous (IV) administration of pulsatile recombinant follicle-stimulating hormone (rFSH) can overcome the clinically evident dysfunctional pituitary-ovarian axis in women with obesity. Prospective interventional study. Academic medical center. Twenty-seven normal-weight women and 27 women with obesity, who were eumenorrheic and aged 21-39 years. Two-day frequent blood sampling study, in early follicular phase, before and after cetrorelix suppression of gonadotropins and exogenous pulsatile IV rFSH administration. Serum inhibin B and estradiol (E2) levels (basal and rFSH stimulated). A modified gonadotropin-releasing hormone antagonism protocol effectively suppressed production of endogenous gonadotropins in women with normal and high BMIs, providing a model to address the functional role of FSH in the hypothalamic-pituitary-ovarian axis. The IV rFSH treatment resulted in equivalent serum levels and pharmacodynamics in normal-weight women and those with obesity. However, women with obesity exhibited reduced basal levels of inhibin B and E2 and a significantly decreased response to FSH stimulation. The BMI was inversely correlated with serum inhibin B and E2. In spite of this observed deficit in ovarian function, pulsatile IV rFSH treatment in women with obesity resulted in E2 and inhibin B levels comparable with those in normal-weight women, in the absence of exogenous FSH stimulation. Despite normalization of FSH levels and pulsatility by exogenous IV administration, women with obesity demonstrate ovarian dysfunction with respect to E2 and inhibin B secretion. Pulsatile FSH can partially correct the relative hypogonadotropic hypogonadism of obesity, thereby providing a potential treatment strategy to mitigate some of the adverse effects of high BMI on fertility, assisted reproduction, and pregnancy outcomes. ClinicalTrials.gov #NCT02478775.

Genital epithelial barrier function is conserved by intravaginal rings releasing etonogestrel and ethinyl estradiol

ABSTRACT The injectable progestin depot-medroxyprogesterone acetate (DMPA) is a popular contraceptive choice in sub-Saharan Africa although mouse models indicate it weakens genital epithelial integrity and barrier function and increases susceptibility to genital infection. The intravaginal ring NuvaRing® is another contraceptive option that like DMPA suppresses hypothalamic pituitary ovarian (HPO) axis function with local release of progestin (etonogestrel) and estrogen (ethinyl estradiol). As we previously reported that treating mice with DMPA and estrogen averts the loss of genital epithelial integrity and barrier function induced by DMPA alone, in the current investigation we compared genital levels of the cell-cell adhesion molecule desmoglein-1 (DSG1) and genital epithelial permeability in rhesus macaques (RM) treated with DMPA or a NuvaRing®re-sized for RM (N-IVR). While these studies demonstrated comparable inhibition of the HPO axis with DMPA or N-IVR, DMPA induced significantly lower genital DSG1 levels and greater tissue permeability to intravaginally administered low molecular mass molecules. By identifying greater compromise of genital epithelial integrity and barrier function in RM administered DMPA vs. N-IVR, our results add to the growing body of evidence that indicate DMPA weakens a fundamental mechanism of anti-pathogen host defense in the female genital tract.