Abnormal Ovarian Function Research Articles

Analysis of risk factors in diabetics resulted from polycystic ovary syndrome in women by EDA analysis and machine learning techniques

This study discusses the relationship between Polycystic Ovary Syndrome (PCOS) and diabetes in women, which has become increasingly prevalent due to changing lifestyles and environmental factors. The characteristic that distinguishes women with PCOS is hyperandrogenism which results from abnormal ovarian or adrenal function, which leads to the overproduction of androgens. Excessive androgens in women increase the risk of Type 2 diabetes (T2D) and insulin resistance (IR). Nowadays, diabetes affects people of all ages and is linked to factors such as lifestyle, genetics, stress, and aging. Diabetes, the uncontrolled high blood sugar level can potentially harm kidneys, nerves, eyes, and other organs and there is no cure, making it a concerning disease in developing nations. This research tried to submit the evidence through feature-wise correlation analyses between PCOS and diabetes. Hence, this model utilized the Exploratory Data Analysis (EDA) and the Elbow clustering algorithms for the experimental purpose in which the EDA deeply analyzed the features of PCOS and diabetes and recorded a positive correlation of 95%. The Elbow clustering technique is employed for verifying the correlations identified through EDA. Although limited research exists on this specific disease, this work provides potential evidence for the research community by evaluating the clustering results using Silhouette Score, Calinski-Harabasz Index, and Davies-Bouldin Index.

Subacute high-refined carbohydrate diet leads to abnormal reproductive control of the hypothalamic-pituitary axis in female rats

We previously reported that female rats placed on a diet containing refined carbohydrates (HCD) resulted in obesity and reproductive abnormalities, such as high serum LH concentration and abnormal ovarian function. However, the impacts at the hypothalamic-pituitary (HP) function, specifically regarding pathways linked to reproductive axis modulation are unknown. In this study, we assessed whether subacute feeding with HCD results in abnormal reproductive control in the HP axis. Female rats were fed with HCD for 15 days and reproductive HP axis morphophysiology was assessed. HCD reduced hypothalamic mRNA expression (Kiss1, Lepr, and Amhr2) and increased pituitary LHβ+ cells. These changes likely contribute to the increase in serum LH concentration observed in HCD. Blunted estrogen negative feedback was observed in HCD, with increased kisspeptin protein expression in the arcuate nucleus of the hypothalamus (ARH), lower LHβ+ cells and LH concentration in ovariectomized (OVX)+HCD rats. Thus, these data suggest that HCD feeding led to female abnormal reproductive control of HP axis.

The ovarian-related effects of polystyrene nanoplastics on human ovarian granulosa cells and female mice

Nanoplastics (NPs) have recently emerged in the context of global plastic pollution. They may be more toxic than macroplastics litter and microplastic fragments due to its abundances, tiny sizes, and cellular accessibility. The female reproductive toxicity of NPs has been widely documented for aquatic animals, but their effects and underlying mechanisms remain poorly understood in mammals. This study aimed to explore the effects of NPs on female reproduction using human ovarian granulosa cells (GCs) and female mice. The accumulation of polystyrene NPs (PS-NPs) in human granulosa-like tumor cells (KGN cells) and the ovaries of female Balb/c mice were evaluated by exposure to fluorescent PS-NPs. Proliferation and apoptosis, reactive oxygen species (ROS), and Hippo signaling pathway-related factors were analyzed in KGN cells. In addition, fertility rate, litter size, ovarian weight and microstructure, follicle development, serum level of anti-Mullerian hormone, and apoptosis in ovaries were examined in female mice. Here, the PS-NPs can penetrate the KGN cells and accumulate in the ovaries. In vitro, 100 μg/ml PS-NPs inhibited proliferation, induced apoptosis, accumulated ROS, activated three key regulators of the Hippo signaling pathway (MST1, LATS1, and YAP1), and downregulated the mRNA levels of CTGF and Cyr61 in KGN cells. Furthermore, salidroside, an antioxidative compound extracted from Rhodiola rosea, alleviated the damage of PS-NPs to KGN and inhibited the activation of the Hippo signal pathway. In vivo, exposure to 1 mg/day PS-NPs resulted in decreased fertility, abnormal ovarian function, and increased ovarian apoptosis in female mice. Overall, our data suggest that PS-NPs cause granulosa cell apoptosis and affect ovarian functions, leading to reduced fertility in female mice, by inducing oxidative stress and dysregulating the Hippo pathway.

Effects of Mindfulness-Based Therapy on Clinical Symptoms and DNA Methylation in Patients with Polycystic Ovary Syndrome and High Metabolic Risk

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder affecting women of reproductive age. Research has shown that epigenetic alterations such as DNA methylation may play a role in the development and progression of abnormal ovarian function and metabolic disorders in PCOS. Studies have identified specific genes (related with insulin signaling and steroid hormone metabolism) that are methylated in women with PCOS. DNA methylation appears to respond to various interventions aimed at altering health and lifestyle factors. We tested the efficacy of a mindfulness-based stress reduction program (MBSR) in PCOS patients. We examined its effects on anthropometric measurements, mental health and wellbeing, and alterations in DNA methylation in peripheral blood. MBSR was associated with a reduction in body mass index, waist circumference and blood glucose level, an improvement in subjectively perceived general health, emotional role limitation, and levels of pain, as well as mindfulness-like traits. MBSR reduced the expression of anxious symptomatology and subjectively perceived stress. Methylation changes were observed in four genes: COMT, FST, FKBP51, and MAOA. We conclude that MBSR may be a useful supplementary therapy to mitigate the deleterious effects of PCOS on mental health.

The effects of natural products and bioactive ingredients of traditional Chinese medicine on apoptosis of ovarian granulosa cells.

Abnormal ovarian function is the main manifestation of female reproductive toxicity. Granulosa cells (GCs) play an important role in determining the fate of follicles and are the main effector cells of the female reproductive system. Excessive apoptosis of GCs leads to pathological folliculogenesis and further reproductive damage. However, drugs available for treatment of female reproductive toxicity are limited. Recent studies have confirmed that various natural products and bioactive ingredients of traditional Chinese medicine (TCM) can inhibit apoptosis of GCs and protect ovarian function. In this review, the mechanisms underlying the proapoptotic and antiapoptotic effects of natural products and bioactive ingredients of TCM on the proliferation, function, and apoptosis of GCs are summarized based on the findings of reports published over the past 10years as reference for the treatment of female reproductive toxicity.

MicroRNA-7a2 Contributes to Estrogen Synthesis and Is Modulated by FSH via the JNK Signaling Pathway in Ovarian Granulosa Cells.

MicroRNA-7a2 (miR-7a2) plays fundamental roles in the female reproductive axis, and estrogen is indispensable for maintaining ovary function. However, the interaction between miR-7a2 and ovarian function is unclear. The present study aimed to determine whether and how miR-7a2 functions in estrogen synthesis. Firstly, the results verified that miR-7a was highly expressed in ovarian granulosa cells. The knockout (KO) of miR-7a2 caused infertility and abnormal ovarian function in mice. Concomitantly, the Cyp19a1 expression and estrogen synthesis were significantly inhibited, which was validated in primary granulosa cells. The mice transplanted with miR-7a2 KO ovaries showed similar results; however, estrogen supplementation reversed infertility. In the in vitro experiment, follicle-stimulating hormone (FSH) significantly improved the expression of miR-7a and Cyp19a1 and the synthesis of estrogen. However, the miR-7a2 KO markedly reversed the function of FSH. Also, FSH upregulated miR-7a by activating the (c-Jun N-terminal kinase) JNK signaling pathway. In addition, Golgi apparatus protein 1 (Glg1) was shown to be the target gene of miR-7a2. These findings indicated that miR-7a2 is essential for ovarian functions with respect to estrogen synthesis through the targeted inhibition of the expression of Glg1 and then promoting Cyp19a1 expression; the physiological process was positively regulated by FSH via the JNK signaling pathway in granulosa cells.

Loss of abnormal spindle-like, microcephaly-associated (Aspm) disrupts female folliculogenesis in mice during maturation and aging

The abnormal spindle-like, microcephaly-associated (ASPM) gene is a causative gene of autosomal recessive primary microcephaly (MCPH) 5 in humans, which is characterized by a reduction in brain volume. It was previously reported that truncated Aspm proteins in transgenic mice caused major defects in the germline, a severe reduction in ovary weight and the number of follicles accompanied by reduced fertility. However; it remains unknown whether a loss of Aspm induces abnormal ovarian function, resulting in female infertility. In order to assess the ovary function, we examined vaginal smear cytology from the age of 7 weeks to 100 weeks in CAG-mediated Cre-loxP conditional Aspm-/- knockout mice and control female mice. In addition, we evaluated the ovarian size, fibrosis ratio and the number of follicles (primordial, primary, secondary, antral and atretic follicles) in mice from 15 weeks to 100 weeks old by image analyses. Mann-Whitney U-test was used for statistical analysis. The size of the ovary was significantly reduced in Aspm knockout mice at 15–20 weeks, 40–50 weeks and 70–80 weeks old compared with the control mice. Furthermore, at all stages, we found a severe decrease in the number of developing follicles at 10–15 weeks, 40–50 weeks and 70–80 weeks old, accompanied by disrupted cyclic changes of vaginal cytology and an aberrant upregulation of Foxo3, Kitl, and Lhcgr in Aspm knockout female. These results suggested that Aspm might play an important role in the folliculogenesis and estrous cyclicity of the postnatal ovary during maturation and aging.

Evaluation of Serum AMH, INHB Combined with Basic FSH on Ovarian Reserve Function after Laparoscopic Ovarian Endometriosis Cystectomy.

ObjectiveThe value of serum AMH, INHB, and bFSH levels in assessing postoperative ovarian reserve function was analyzed by measuring serum anti-Mullerian hormone (AMH), inhibin B (INHB), and basal follicle-stimulating hormone (bFSH) levels in patients after laparoscopic cystectomy for endometrioma.MethodsFrom June 2019 to December 2021, 124 patients underwent laparoscopic cystectomy for endometrioma in our hospital were selected, and the serum AMH, INHB, bFSH level, antral follicle count (AFC) of all patients before and after operation were detected and compared. According to the results of postoperative testing, all the patients were divided into normal group (n = 86), diminished ovarian reserve (DOR) group (n = 27), and premature ovarian failure (POF) group (n = 11). Pearson correlation model and subject operating characteristic curve (ROC) were used to analyze the correlation and diagnostic value of serum AMH, INHB and bFSH levels with postoperative ovarian reserve function, respectively.ResultsAfter operation, the levels of serum AMH, INHB and AFC in the DOR group and POF group decreased compared with those before the operation, and the serum bFSH levels increased (p < 0.05). After operation, the levels of serum AMH, INHB and AFC in DOR group and POF group were lower than those in normal group,and the serum bFSH levels were higher than the normal group; the levels of serum AMH, INHB and AFC in POF group were lower than those in DOR group, and the serum bFSH levels were higher than the DOR group (p < 0.05). Pearson analysis showed that serum AMH and INHB levels were negatively correlated with bFSH, and positively correlated with the number of AFC, the serum bFSH level was negatively correlated with the number of AFC (p < 0.05). The diagnostic values of serum AMH, bFSH, INHB and the combination of the three tests for postoperative abnormal ovarian reserve function were 0.866 (95% CI, 0.801–0.923), 0.810 (95% CI, 0.730–0.890), 0.774 (95% CI, 0.687–0.860) and 0.940 (95% CI, 0.900–0.981), respectively.ConclusionSerum AMH and INHB levels decreased and bFSH levels increased in patients after laparoscopic cystectomy for endometrioma, both of which were closely related to postoperative ovarian reserve function, and both could evaluate ovarian reserve function after ovarian cyst debulking, and the combined test could significantly improve the detection rate.

Obesity and oocyte quality: significant implications for ART and emerging mechanistic insights.

The prevalence of obesity in adults worldwide, and specifically in women of reproductive age, is concerning given the risks to fertility posed by the increased risk of type 2 diabetes, metabolic syndrome, and other noncommunicable diseases. Obesity has a multi-systemic impact in female physiology that is characterized by the presence of oxidative stress, lipotoxicity, and the activation of pro-inflammatory pathways, inducing tissue-specific insulin resistance and ultimately conducive to abnormal ovarian function. A higher body mass is linked to Polycystic Ovary Syndrome, dysregulated menstrual cycles, anovulation, and longer time to pregnancy, even in ovulatory women. In the context of assisted reproductive technology (ART), compared to women of normal body mass index, obese women have worse outcomes in every step of their journey, resulting in reduced success measured as live birth rate. Even after pregnancy is achieved, obese women have a higher chance of miscarriage, gestational diabetes, pregnancy complications, birth defects, and most worryingly, a higher risk of stillbirth and neonatal death. The potential for compounding effects of ART on pregnancy complications and infant morbidities in obese women has not been studied. There is still much debate in the field on whether these poorer outcomes are mainly driven by defects in oocyte quality, abnormal embryo development, or an unaccommodating uterine environment, however the clinical evidence to date suggests a combination of all three are responsible. Animal models of maternal obesity shed light on the mechanisms underlying the effects of obesity on the peri-conception environment, with recent findings pointing to lipotoxicity in the ovarian environment as a key driver of defects in oocytes that have not only reduced developmental competence but long-lasting effects in offspring health.

Patterns of menstrual cycle length over the menopause transition are associated with subclinical atherosclerosis after menopause.

Longer menstrual cycles have been associated with greater risk of cardiovascular disease, supporting a contribution of abnormal ovarian function. We aimed to characterize trajectories of menstrual cycle length over the menopause transition (MT) and test whether these trajectories are associated with postmenopausal markers of subclinical atherosclerosis. Women from the Study of Women's Health Across the Nation Daily Hormone Study were included if they had an observed date of the final menstrual period (FMP), recorded cycle lengths from ≥2 annual menstrual cycles (mean±SD: 4.22 ± 1.91 cycles), and had measurements of postmenopausal carotid intima-media thickness (cIMT) and/or brachial-ankle pulse wave velocity (baPWV). Trajectories of cycle length over the MT were identified using group-based trajectory modeling and linked with cIMT and baPWV using linear regression. We studied 428 women who had 1,808 cycles over the MT (45.1 ± 2.3 y old at baseline visit), and of whom 263 had cIMT, and 213 had baPWV measured postmenopausally (after 13.88 ± 0.42 and 15.25 ± 0.70 y since baseline visit, respectively). Three distinct trajectories of cycle length were identified: stable (no changes in cycle length over the MT among 62.1% of women), late increase (a late increase 2 y before the FMP among 21.8%), and early-increase (an early increase 5 y before the FMP among 16.2%). Women with the late-increase pattern had significantly lower postmenopausal cIMT (0.72 mm) and baPWV (1392 cm/s) levels than the stable group (0.77 mm and 1508 cm/s, respectively) adjusting for race, concurrent age, socioeconomic status, physical activity level, and premenopausal cardiovascular risk profile. Patterns of cycle length over the MT seem to be a marker of future vascular health that may help identify groups at greater or lesser risk of atherosclerosis after menopause.

The Role of AIRE Deficiency in Infertility and Its Potential Pathogenesis.

The increasing number of patients with infertility is recognized as an emerging problem worldwide. However, little is known about the cause of infertility. At present, it is believed that infertility may be related to genetic or abnormal immune responses. It has long been indicated that autoimmune regulator (AIRE), a transcription factor, participates in immune tolerance by regulating the expression of thousands of promiscuous tissue-specific antigens in medullary thymic epithelial cells (mTECs), which play a pivotal role in preventing autoimmune diseases. AIRE is also expressed in germ cell progenitors. Importantly, the deletion of AIRE leads to severe oophoritis and age-dependent depletion of follicular reserves and causes altered embryonic development in female mice. AIRE-deficient male mice exhibit altered apoptosis during spermatogenesis and have a significantly decreased breeding capacity. These reports suggest that AIRE deficiency may be responsible for infertility. The causes may be related to the production of autoantibodies against sperm, poor development of germ cells, and abnormal ovarian function, which eventually lead to infertility. Here, we focus on the potential associations of AIRE deficiency with infertility as well as the possible pathogenesis, providing insight into the significance of AIRE in the development of infertility.

The Efficacy and Safety of the mTOR Signaling Pathway Activator, MHY1485, for in vitro Activation of Human Ovarian Tissue

BackgroundPremature ovarian insufficiency (POI) is characterized by abnormal ovarian function before the age of 40. POI showed that primordial follicles developed in disorder. mTOR signaling plays a vital role in the process of follicle development. It has been verified that the mTOR signaling pathway activator, MHY1485, can promote primordial follicle development in mice. We considered that MHY1485 would be a promising fertility preservation method for POI patients.MethodsThe fragmented ovarian tissues of normal woman was cultured with activator MHY1485 in vitro, and then the control and activated ovaries were transplanted into the kidney capsules of ovariectomized mice. We then used the Infinium Human Methylation EPIC BeadChip to verify the DNA methylation level of ovarian tissues, thus exploring the effectiveness of them.ResultsMHY1485 stimulated mTOR, S6K1, and rpS6 phosphorylation. Cultured with MHY1485, ovarian weights increased and endocrine function was restored. The number of growing follicles was increased. The in vitro activation process did not induce histological changes or abnormal DNA methylation occurrence.ConclusionMHY1485 for in vitro activation (IVA) is effective for ovarian rejuvenation and is a potential therapeutic treatment for POI patients.

Homoeopathic Management in a Case of Infertility with PCOS

AbstractInfertility is the inability of a sexually active couple, not using any birth control, to get pregnant after 1 year of trying. About one-quarter of female infertility is caused by a problem with ovulation. Polycystic ovary syndrome (PCOS) accounts for more than 75% of cases of anovulatory infertility. PCOS is a disorder of chronically abnormal ovarian function and hyperandrogenism (abnormally elevated androgen levels) manifested by irregular menstrual cycles, polycystic ovaries, excess unwanted hair, obesity etc. A case of a female aged 21 years with irregular menses for the past 2 years diagnosed with PCOS and inability to conceive has been reported here. The case was worked out as per homoeopathic principles and individualised homoeopathic medicine, Pulsatilla nigricans (Puls. nig.) was prescribed and the patient responded positively and conceived

Bisphenol A promotes autophagy in ovarian granulosa cells by inducing AMPK/mTOR/ULK1 signalling pathway

BackgroundBisphenol A (BPA) is a widespread endocrine-disrupting chemical with estrogen like effects, which could interfere with the human reproductive system by disrupting the normal function of granulosa cells (GCs) leading to abnormal ovarian function. However, the mechanism of its toxicity on human GCs has not been clearly described thus far. Methods106 normogonadotropic infertile women undergoing their first in-vitro fertilization-embryo transfer (IVF-ET) cycle were recruited. Urinary BPA level and the early outcomes of IVF-ET were analysed. Patients were divided to low and high BPA exposure groups using the median urinary BPA concentration as the cut-off value. In-vivo and in-vitro studies were conducted using mice and human granulosa cell line (KGN cells). Female Kunming mice approximately 6–8 weeks of age were poisoned with BPA at different dosages (1, 10 or 100 μg/kg) by oral gavage once daily for 2 weeks, while KGN cells were exposed to BPA at the concentration of 1, 10 or 100 nM for 24 h, 48 h or 72 h. BPA-induced ovarian morphologic changes were analysed by histopathology investigation. Cell viability and apoptosis were evaluated using CCK-8, TUNEL and flowcytometric, respectively. Hormone levels were determined using ELISA and the molecular mechanism studies were conducted using immunofluorescence, RT-PCR and western blots. ResultsThe oocyte retrieval rate, maturation rate and embryo implantation rate significantly decreased with the higher level of urinary BPA concentration. Peak E2 level was lower in high BPA group, but no statistical significance could be observed. In BPA treated mice, cystic dilation of the follicles with a decreased number of GCs could be observed histopathologically. Decreased E2, P4 and AMH level and GCs autophagy could be detected both in-vivo and in-vitro with the activation of AMPK/mTOR/ULK1 signalling pathway. As being confirmed in KGN cells, phosphorylated AMPK and ULK1 increased while phosphorylated mTOR decreased, and by inhibition autophagy using knockdown of AMPK or 3-MA, adverse effects of BPA exposure in-vitro could be reversed. ConclusionBPA exposure might abnormally influence human ovarian functions leading to abnormal folliculogenesis by activation of autophagy in GCs through AMPK/mTOR/ULK1 pathway.

Salt-inducible Kinases Are Critical Determinants of Female Fertility.

Follicle development is the most crucial step toward female fertility and is controlled mainly by follicle-stimulating hormone (FSH). In ovarian granulosa cells (GCs), FSH activates protein kinase A by increasing 3',5'-cyclic adenosine 5'-monophosphate (cAMP). Since cAMP signaling is impinged in part by salt-inducible kinases (SIKs), we examined the role of SIKs on the regulation of FSH actions. Here, we report that SIKs are essential for normal ovarian function and female fertility. All SIK isoforms are expressed in human and rodent GCs at different levels (SIK3>SIK2>SIK1). Pharmacological inhibition of SIK activity potentiated the stimulatory effect of FSH on markers of GC differentiation in mouse, rat, and human GCs and estradiol production in rat GCs. In humans, SIK inhibition strongly enhanced FSH actions in GCs of patients with normal or abnormal ovarian function. The knockdown of SIK2, but not SIK1 or SIK3, synergized with FSH on the induction of markers of GC differentiation. SIK inhibition boosted gonadotropin-induced GC differentiation in vivo, while the genomic knockout of SIK2 led to a significant increase in the number of ovulated oocytes. Conversely, SIK3 knockout females were infertile, FSH insensitive, and had abnormal folliculogenesis. These findings reveal novel roles for SIKs in the regulation of GC differentiation and female fertility, and contribute to our understanding of the mechanisms regulated by FSH. Furthermore, these data suggest that specific pharmacological modulation of SIK2 activity could be of benefit to treat ovulatory defects in humans and to increase the propagation of endangered species and farm mammals.

Subcutaneous grafting of ovaries from newborn rabbits into adult ovariectomized mice does not result in normal folliculogenesis

About 10% (6.1 million) of women in the United States ages 15–44 have difficulty becoming pregnant or staying pregnant. About 1/3 are fertility problems in women. Abnormal ovarian function is a major contributor. A greater understanding of ovarian function and especially follicular development would improve treatment. Follicles form when germ cells arrive in the primitive sex cords, which are derived from the coelomic epithelium. In most species, these cords fragment and the germ cells become covered by precursors of the granulosa cells. Thus primordial follicles form. Pools of these follicles are eventually recruited and undergo maturation; a series of functional and morphological transformations that lead to ovulatory follicles. In species like humans, cattle and pigs, follicles form during the embryonic phase of gestation, while maturation takes place after birth. In contrast, both phases occur postnatally in rabbits and makes them an excellent model to study folliculogenesis. Laboratory studies using non‐rodent species are logistically more difficult and even prohibitive. One alternative is ovarian grafting into immunocompromised mice. When adult ovarian tissue is transplanted from large animals into mice, some primordial follicles survive and undergo maturation. We investigated the rabbit model by transplantation of immature rabbit ovaries under the dorsal skin of adult ovariectomized NCr N ude mice (1 ovary / mouse). At 4 – 5 weeks, growth of the grafted ovaries was evident. Macroscopically, 50% of the grafts (5/10) had one or two follicle‐like structures on their surface. Histologically the structures were cysts lined by cuboidal cells and contained cells with the germ cell phenotype. In conclusion, ovaries grafted subcutaneously from newborn rabbits into ovariectomized adult mice developed cystic primordial follicles. Normal follicle formation and maturation did not occur.Support or Funding InformationMidwestern University intramural funds

Is melatonin, leptin or their combination more effective on oxidative stress and folliculogenesis in the obese rats?

In this study, we evaluated the effects of melatonin (Mel), leptin (Lep) or melatonin and leptin treatment on ovaries in control and obese rats. The animals were divided into control (NC), melatonin (NM), leptin (NL), melatonin–leptin (NML), obese (OC), obese–melatonin (OM), obese–leptin (OL), obese–melatonin–leptin (OML) groups. Body weights, peri-ovarian fat pads, volumetric parameters and numerical values of follicles were estimated. Also, the LH receptor (LHr) immune-positivity, catalase (CAT) and the myeloperoxidase (MPO) levels were determined. The body weight and peri-ovarian fat pads were significantly decreased following Mel (p < .05) treatment and, especially, Lep (p < .01) treatment. But, the ovarian weights were significantly increased following Lep (p < .05) and Mel (p < .01) treatment, in particular. The ovarian and cortex volume decreased in the OC group, and the cortex volume of the OC group was significantly higher than the Ob + Mel, Ob + Lep and Ob + Mel + Lep groups (p < .01). Besides, the volume of the cortex in the NL group was significantly higher than in the other groups (except for the NC group) (p < .01). Although, the total numbers of primordial and primary follicles in NC group were significantly higher than in the OC group (p < .001), the number of the primordial and primary follicles in OC group was significantly higher than in the OL (p < .05), OM (p < .05) and, especially, the OML groups (p < .001). Likewise, the number of the secondary follicles in the OML group was significantly less than that in the OC group (p < .05). The CAT and MPO activity of the OC group was significantly higher than in the NC group (p < .05) and also granulosa cell apoptosis had increased in obese rats; but it was decreased after Lep and Mel treatment. Otherwise, Lep and, in particular, Mel increased LHr positivity. We concluded that obesity could trigger abnormal ovarian function and polycystic ovary via inducing LHr apoptosis and suppressing ovarian folliculogenesis. Also, melatonin could be better for inhibition of apoptosis and modulation of folliculogenesis than leptin. These observations suggest that melatonin may act to reduce fertility in obese patients.Impact statementWhat is already known on this subject? Hormonal changes during reproductive cycle in obese women are particularly studied and there is not any study that evaluates the effects of melatonin and leptin, together.What the results of this study add? The study has shown that obese rats have increased granulosa cell apoptosis and MPO activities but melatonin and leptin reduces the apoptosis and inflammation. Moreover, the obesity decreased, but melatonin and leptin increased LHR immunoreactivity in both the granulosa and theca cells.What the implications are of these findings for clinical practice and/or further research? The results suggest that leptin and melatonin could decrease excess body weight in obese persons. Also, these hormones modulate the ovarian turn-over by regulating developing follicles. Therefore, leptin and especially melatonin could be used as a supplement to ovulation therapy.

SUN-263 Evidence for Diminished Ovarian Reserve in Youth with Trisomy X

Background: An additional X chromosome occurs in 1 in 1,000 females resulting in a 47,XXX karyotype also known as Trisomy X. Abnormal ovarian function was suggested from a cohort of 10 females with Trisomy X followed from birth through young adulthood who had later age of menarche and one girl who developed secondary amenorrhea with elevated gonadotropin levels (1). There have since been several case reports of premature menopause in women with Trisomy X, and 3.8% of women with premature ovarian insufficiency (POI) have been reported to have Trisomy X (2). Ovarian reserve can be estimated by serum anti-mullerian hormone (AMH) concentrations, with low AMH concentrations concerning for diminished ovarian reserve and poor fertility prospects. Ovarian function in youth with Trisomy X has not been evaluated. The purpose of this study was to evaluate AMH as a marker of ovarian reserve in girls with Trisomy X. Methods: Parents and youth with Trisomy X seen at a tertiary care referral center were counselled on the risk for POI and AMH was offered as a screen for ovarian reserve. All participants provided informed consent to use their clinical data for research purposes. A total of 11 girls with a non-mosaic 47,XXX karyotype had AMH measured by chemiluminescent assay (Esoterix Laboratory Services) between December 2015 and October 2018. Results: The median age of participants was 13.3 years (IQR 12.4 – 17.9) and 9 of 11 girls had experienced menarche at a median age of 12.5 years (IQR 11.5-12.6); none had primary or secondary amenorrhea. The median AMH concentration was 0.7 ng/ml (IQR 0.2-1.7), significantly lower than the laboratory provided median of 5.23 ng/ml (one sample Wilcoxin Signed Rank Test p=0.001). 72% had an AMH below 1.05 ng/ml, the lower limit of normal for age. Discussion: Despite normal menarchal timing and ongoing menses, the majority of youth with Trisomy X had a low AMH concerning for diminished ovarian reserve and potentially impaired fertility. Although there is great interest in fertility preservation for girls with oncological diagnoses and Turner syndrome, there is limited awareness of ovarian dysfunction in Trisomy X. Research on ovarian function and fertility in Trisomy X is needed across the lifespan, as well as investigation into the mechanisms of the additional X chromosome leading to the diminished ovarian reserve observed in this adolescent sample. (1) Ratcliffe et al, 1990, Birth Defects: Original Article Series, 26(4): 1-44. (2) Goswami et al, 2003, Fertil Steril, 80(4): 1052-4.

The incidence of unexpected poor ovarian response in Chinese young women.

Unexpected poor ovarian response (UPOR) is a problem for both clinicians and infertile couples, because our understanding of this situation is limited. This article investigated incidence of UPOR in women <35 years with normal ovarian reserve function with further analysis.This is a retrospective study, which included 567 women who accepted their first IVF-ET/ICSI. Based on the number of oocytes retrieved, clinic pregnancy rate of fresh cycle, and cycle cancellation rate of fresh cycle, the included cycles were divided into three groups namely unexpected poor ovarian response (UPOR) (n = 120), for which number of oocytes retrieved was not more than 6; normal ovarian response (NOR) (n = 223), for which number of oocytes retrieved was between 7 and 12; and unexpected high ovarian response (UHOR) (n = 224), for which the number of oocytes retrieved was 13 at least. The comparisons of clinical outcomes and correlated hormones among groups were carried out.The incidence of UPOR in Chinese women is 21.16%. Patient age (χ2 = 6.177, P = .0129), basic FSH (χ2 = 20.585, P < .0001), basic LH (χ2 = 11.689, P = .0006), and AFC (χ2 = 8.053, P = .0045) might be helpful for diagnosis of UPOR.The basic evaluation of ovarian function may no longer be simplified into normal and abnormal ovarian reserve function; rather, by using a detailed numerical analysis, such as basal FSH and LH levels, the ovarian response to ovulation induction may be predicted to some extent.

Diabetes Induces Abnormal Ovarian Function via Triggering Apoptosis of Granulosa Cells and Suppressing Ovarian Angiogenesis.

Diabetes triggers abnormal ovarian follicular development and consequently leads to infertility. Here, we established a type 2 diabetes mouse model by feeding with high fat diet (HFD) for 15/20 weeks and assessed the effect of diabetes on follicular development and ovarian angiogenesis. After fed with HFD for 15 weeks, mice had the characteristics of type 2 diabetes, which was much more serious after 20 weeks on HFD. After 20 weeks on HFD, the mice had shown abnormal ovarian morphology with hyaline appearance, much less blood vessel, follicular development arrest and less of granulosa cells (GCs) in mature follicles, but not in ovaries from 15 weeks on HFD. Elevated makers of DNA damage, ER stress and apoptosis of GCs were observed in ovaries from HFD for 20 weeks. Additionally, diabetes significantly suppressed ovarian angiogenesis with the evidence of down-regulation of CD31 via inhibiting HIF1α-VEGF signaling pathway in time-dependent. We concluded that diabetes triggers abnormal ovarian function via inducing GCs apoptosis and suppressing ovarian angiogenesis.