scholarly journals Erbb4 regulates the oocyte microenvironment during folliculogenesis

2020 ◽  
Vol 29 (17) ◽  
pp. 2813-2830
Author(s):  
Ville Veikkolainen ◽  
Nsrein Ali ◽  
Milena Doroszko ◽  
Antti Kiviniemi ◽  
Ilkka Miinalainen ◽  
...  
Keyword(s):  
Ovarian Function ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Reproductive Function ◽  
Intercellular Junctions ◽  
Ovary Development ◽  
Endocrine Disorders ◽  
Metabolic Systems ◽  
Reproductive Endocrine

Abstract Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders leading to infertility in women affecting reproductive, endocrine and metabolic systems. Recent genomewide association studies on PCOS cohorts revealed a single nucleotide polymorphism (SNP) in the ERBB4 receptor tyrosine kinase 4 gene, but its role in ovary development or during folliculogenesis remains poorly understood. Since no genetic animal models mimicking all PCOS reproductive features are available, we conditionally deleted Erbb4 in murine granulosa cells (GCs) under the control of Amh promoter. While we have demonstrated that Erbb4 deletion displayed aberrant ovarian function by affecting the reproductive function (asynchronous oestrous cycle leading to few ovulations and subfertility) and metabolic function (obesity), their ovaries also present severe structural and functional abnormalities (impaired oocyte development). Hormone analysis revealed an up-regulation of serum luteinizing hormone, hyperandrogenism, increased production of ovarian and circulating anti-Müllerian hormone. Our data implicate that Erbb4 deletion in GCs leads to defective intercellular junctions between the GCs and oocytes, causing changes in the expression of genes regulating the local microenvironment of the follicles. In vitro culture assays reducing the level of Erbb4 via shRNAs confirm that Erbb4 is essential for regulating Amh level. In conclusion, our results indicate a functional role for Erbb4 in the ovary, especially during folliculogenesis and its reduced expression plays an important role in reproductive pathophysiology, such as PCOS development.

scholarly journals Androgens and ovarian function: translation from basic discovery research to clinical impact

2019 ◽  
Vol 242 (2) ◽  
pp. R23-R50 ◽  
Author(s):  
K A Walters ◽  
V Rodriguez Paris ◽  
A Aflatounian ◽  
D J Handelsman
Keyword(s):  
Future Development ◽  
Molecular Mechanisms ◽  
Ovarian Function ◽  
Polycystic Ovary ◽  
Reproductive Function ◽  
Poor Responders ◽  
Discovery Research ◽  
The Future ◽  
The Impact

In the last decade, it has been revealed that androgens play a direct and important role in regulating female reproductive function. Androgens mediate their actions via the androgen receptor (AR), and global and cell-specific Ar-knockout mouse models have confirmed that AR-mediated androgen actions play a role in regulating female fertility and follicle health, development and ovulation. This knowledge, along with the clinical data reporting a beneficial effect of androgens or androgen-modulating agents in augmenting in vitro fertilization (IVF) stimulation in women termed poor responders, has supported the adoption of this concept in many IVF clinics worldwide. On the other hand, substantial evidence from human and animal studies now supports the hypothesis that androgens in excess, acting via the AR, play a key role in the origins of polycystic ovary syndrome (PCOS). The identification of the target sites of these AR actions and the molecular mechanisms involved in underpinning the development of PCOS is essential to provide the knowledge required for the future development of novel, mechanism-based therapies for the treatment of PCOS. This review will summarize the basic scientific discoveries that have enhanced our knowledge of the roles of androgens in female reproductive function, discuss the impact these findings have had in the clinic and how a greater understanding of the role androgens play in female physiology may shape the future development of effective strategies to improve IVF outcomes in poor responders and the amelioration of symptoms in patients with PCOS.

scholarly journals Family-Based Quantitative Trait Meta-Analysis Implicates Rare Noncoding Variants in DENND1A in Polycystic Ovary Syndrome

2019 ◽  
Vol 104 (9) ◽  
pp. 3835-3850 ◽  
Author(s):  
Matthew Dapas ◽  
Ryan Sisk ◽  
Richard S Legro ◽  
Margrit Urbanek ◽  
Andrea Dunaif ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Quantitative Trait ◽  
Rare Variants ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Meta Analysis ◽  
Premenopausal Women ◽  
Endocrine Disorders ◽  
Genome Wide Association Studies ◽  
Ovary Syndrome

AbstractContextPolycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5% to15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date.ObjectiveThe objective of this study was to test whether rare genetic variants contribute to PCOS pathogenesis.Design, Patients, and MethodsWe performed whole-genome sequencing on DNA from 261 individuals from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis.ResultsWe found rare variants in DENND1A (P = 5.31 × 10−5, adjusted P = 0.039) that were significantly associated with reproductive and metabolic traits in PCOS families.ConclusionsCommon variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.

scholarly journals Family-based quantitative trait meta-analysis implicates rare noncoding variants in DENND1A in pathogenesis of polycystic ovary syndrome

2018 ◽  
Author(s):  
Matthew Dapas ◽  
Ryan Sisk ◽  
Richard S. Legro ◽  
Margrit Urbanek ◽  
Andrea Dunaif ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Quantitative Trait ◽  
Rare Variants ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Meta Analysis ◽  
Premenopausal Women ◽  
Endocrine Disorders ◽  
Genome Wide Association Studies ◽  
Ovary Syndrome

ABSTRACTPolycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5-15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. PCOS is a leading risk factor for type 2 diabetes in young women. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date. To test the hypothesis that rare genetic variants contribute to PCOS pathogenesis, we performed whole-genome sequencing on DNA from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis. We found rare variants in DENND1A (P=5.31×10−5, Padj=0.019) that were significantly associated with reproductive and metabolic traits in PCOS families. Common variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.

GPR120 agonist ameliorated insulin resistance and improved ovarian function

Zygote ◽  
2021 ◽  
pp. 1-6
Author(s):  
Yang Liu ◽  
Jiayi Ding ◽  
Xiaofang Tan ◽  
Ya Shen ◽  
Li Xu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Rat Model ◽  
Lipid Accumulation ◽  
Ovarian Function ◽  
Polycystic Ovary ◽  
Vital Role ◽  
Expression Levels ◽  
Glucose And Lipid Metabolism

Summary GPR120 is implicated in the regulation of glucose and lipid metabolism, and insulin resistance. In the current study, we aimed to investigate the role of GPR120 in polycystic ovary syndrome (PCOS). With the adoption of dehydroepiandrosterone, a rat model was established to simulate PCOS in vitro. mRNA and protein expression levels of GPR120 were measured using RT-qPCR and western blot, respectively. In addition, expression levels of testosterone, estradiol, luteinizing hormone and follicle-stimulating hormone, serum total cholesterol and triglyceride were assessed using the corresponding kits. Moreover, haematoxylin and eosin staining was used to detect pathological changes in ovary or liver and oil red staining was utilized to evaluate lipid accumulation. In the present study, GPR120 was downregulated in plasma, liver and ovary in the PCOS rat model. In addition, the GPR120 agonist regulated lipid metabolism in the liver and weight in the PCOS rat model. Furthermore, the GPR120 agonist decreased insulin resistance in the PCOS rat model but improved the ovarian function. It is suggested that GPR120 plays a vital role in suppressing insulin resistance, regulating ovary function and decreasing lipid accumulation in the liver, demonstrating that targeting GPR120 could be an effective method for the improvement of PCOS.

scholarly journals Prevalence of thyroid dysfunction in patients with polycystic ovarian syndrome: a cross sectional study

2018 ◽  
Vol 7 (8) ◽  
pp. 3055 ◽  
Author(s):  
Deepa Shanmugham ◽  
Sindhu Natarajan ◽  
Arun Karthik
Keyword(s):  
Thyroid Dysfunction ◽  
Polycystic Ovarian Syndrome ◽  
Polycystic Ovary ◽  
Reproductive Function ◽  
Thyroid Stimulating Hormone ◽  
Endocrine Disorders ◽  
Free T4 ◽  
Cross Sectional ◽  
The Mean ◽  
Ovarian Syndrome

Background: Polycystic ovary syndrome (PCOS) and thyroid disorders are two of the most common endocrine disorders in the general population. Both of these endocrine disorders share common predisposing factors, gynaecological features and have profound effect on reproductive function in women. The aim of this study is to study the prevalence of thyroid dysfunction in patients with polycystic ovarian syndrome and to evaluate the relationship between polycystic ovarian syndrome and thyroid dysfunction.Methods: This is a cross sectional observational study done on 100 patients with Poly Cystic Ovarian Syndrome based on Rotterdam’s criteria. The exclusion criteria was hyperprolactinemia, congenital adrenal hyperplasia and virilising tumour. Thyroid function was evaluated by measurement of fasting serum thyroid stimulating hormone (TSH), free thyroxine levels (free T3 and free T4).Results: The mean age of the study patients was 26±4.2 years. Among the study patients, 11% of them had goitre. 18% of the patients with presented with subclinical hypothyroidism. The mean TSH levels in the study patients was 4.62±2.12 mIU/ml. The overall prevalence of thyroid dysfunction was 33% in the study patients with PCOS.Conclusions: This study concludes that the prevalence of hypothyroidism is increased in women with PCOS patients.

scholarly journals Effect of androgen treatment during foetal and/or neonatal life on ovarian function in prepubertal and adult rats

Reproduction ◽  
2012 ◽  
Vol 143 (1) ◽  
pp. 21-33 ◽  
Author(s):  
Victoria Tyndall ◽  
Marie Broyde ◽  
Richard Sharpe ◽  
Michelle Welsh ◽  
Amanda J Drake ◽  
...  
Keyword(s):  
Ovarian Function ◽  
Polycystic Ovary ◽  
Time Windows ◽  
Reproductive Function ◽  
Antral Follicle ◽  
Female Rats ◽  
Postnatal Life ◽  
Adult Rats ◽  
Stromal Compartment ◽  
Neonatal Life

We investigated the effects of different windows of testosterone propionate (TP) treatment during foetal and neonatal life in female rats to determine whether and when excess androgen exposure would cause disruption of adult reproductive function. Animals were killed prepubertally at d25 and as adults at d90. Plasma samples were taken for hormone analysis and ovaries serial sectioned for morphometric analyses. In prepubertal animals, only foetal+postnatal and late postnatal TP resulted in increased body weights, and an increase in transitory, but reduced antral follicle numbers without affecting total follicle populations. Treatment with TP during both foetal+postnatal life resulted in the development of streak ovaries with activated follicles containing oocytes that only progressed to a small antral (smA) stage and inactive uteri. TP exposure during foetal or late postnatal life had no effect upon adult reproductive function or the total follicle population, although there was a reduction in the primordial follicle pool. In contrast, TP treatment during full postnatal life (d1–25) resulted in anovulation in adults (d90). These animals were heavier, had a greater ovarian stromal compartment, no differences in follicle thecal cell area, but reduced numbers of anti-Mullerian hormone-positive smA follicles when compared with controls. Significantly reduced uterine weights lead reduced follicle oestradiol production. These results support the concept that androgen programming of adult female reproductive function occurs only during specific time windows in foetal and neonatal life with implications for the development of polycystic ovary syndrome in women.

Is there a role for vitamin D in human reproduction?

2016 ◽  
Vol 25 (1) ◽  
Author(s):  
Anindita Nandi ◽  
Nandita Sinha ◽  
Erwyn Ong ◽  
Halis Sonmez ◽  
Leonid Poretsky
Keyword(s):  
Vitamin D ◽  
Polycystic Ovary ◽  
Reproductive Function ◽  
Human Reproduction ◽  
Bone Modeling ◽  
Metabolizing Enzymes ◽  
Vitro Fertilization ◽  
Vitamin D Levels ◽  
Autoimmune Conditions

AbstractVitamin D is a steroid hormone with canonical roles in calcium metabolism and bone modeling. However, in recent years there has been a growing body of literature presenting associations between vitamin D levels and a variety of disease processes, including metabolic disorders such as diabetes and prediabetes and autoimmune conditions such as thyroid disease. This review focuses on the potential role of vitamin D in both male and female reproductive function. The vitamin D receptor (VDR) is expressed throughout central and peripheral organs of reproduction. VDR is often co-localized with its metabolizing enzymes, suggesting the importance of tissue specific modulation of active vitamin D levels. Both animal and human studies in males links vitamin D deficiency with hypogonadism and decreased fertility. In females, there is evidence for its role in polycystic ovary syndrome (PCOS), endometriosis, leiomyomas, in-vitro fertilization, and pregnancy outcomes. Studies evaluating the effects of replacing vitamin D have shown variable results. There remains some concern that the effects of vitamin D on reproduction are not direct, but rather secondary to the accompanying hypocalcemia or estrogen dysregulation.

scholarly journals Inositol Treatment and ART Outcomes in Women with PCOS

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Deepika Garg ◽  
Reshef Tal
Keyword(s):  
Ovarian Stimulation ◽  
Ovarian Function ◽  
Current Knowledge ◽  
Polycystic Ovary ◽  
Mature Oocyte ◽  
Reproductive Age ◽  
Vitro Fertilization ◽  
Ovulatory Dysfunction ◽  
Ovarian Morphology

Polycystic ovary syndrome (PCOS) affects 5–10% of women in reproductive age and is characterized by oligo/amenorrhea, androgen excess, insulin resistance, and typical polycystic ovarian morphology. It is the most common cause of infertility secondary to ovulatory dysfunction. The underlying etiology is still unknown but is believed to be multifactorial. Insulin-sensitizing compounds such as inositol, a B-complex vitamin, and its stereoisomers (myo-inositol and D-chiro-inositol) have been studied as an effective treatment of PCOS. Administration of inositol in PCOS has been shown to improve not only the metabolic and hormonal parameters but also ovarian function and the response to assisted-reproductive technology (ART). Accumulating evidence suggests that it is also capable of improving folliculogenesis and embryo quality and increasing the mature oocyte yield following ovarian stimulation for ART in women with PCOS. In the current review, we collate the evidence and summarize our current knowledge on ovarian stimulation and ART outcomes following inositol treatment in women with PCOS undergoing in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI).

scholarly journals Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

2021 ◽  
Vol 14 (1) ◽  
pp. 42
Author(s):  
Alexander O. Shpakov
Keyword(s):  
Diabetes Mellitus ◽  
Pregnancy Outcomes ◽  
Hormonal Regulation ◽  
Ovarian Function ◽  
Assisted Reproductive Technologies ◽  
Polycystic Ovary ◽  
Health Effect ◽  
Reproductive Technologies ◽  
Male Reproduction ◽  
Endocrine Disorders

Metformin (MF), a first-line drug to treat type 2 diabetes mellitus (T2DM), alone and in combination with other drugs, restores the ovarian function in women with polycystic ovary syndrome (PCOS) and improves fetal development, pregnancy outcomes and offspring health in gestational diabetes mellitus (GDM) and T2DM. MF treatment is demonstrated to improve the efficiency of in vitro fertilization and is considered a supplementary drug in assisted reproductive technologies. MF administration shows positive effect on steroidogenesis and spermatogenesis in men with metabolic disorders, thus MF treatment indicates prospective use for improvement of male reproductive functions and fertility. MF lacks teratogenic effects and has positive health effect in newborns. The review is focused on use of MF therapy for restoration of female and male reproductive functions and improvement of pregnancy outcomes in metabolic and endocrine disorders. The mechanisms of MF action are discussed, including normalization of metabolic and hormonal status in PCOS, GDM, T2DM and metabolic syndrome and restoration of functional activity and hormonal regulation of the gonadal axis.

scholarly journals PCOS and Assisted Reproduction Technique: Role and Relevance of Inositols

Endocrines ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 515-522
Author(s):  
Paolo Giovanni Artini ◽  
Elisa Malacarne ◽  
Vito Cela
Keyword(s):  
Ovarian Function ◽  
Polycystic Ovary ◽  
Obese Women ◽  
Assisted Reproduction Technique ◽  
Positive Role ◽  
Vitro Fertilization ◽  
Beneficial Effects ◽  
Insulin Sensitizers

Polycystic ovary syndrome is an endocrine disorder often characterized by insulin resistance and hyperinsulinemia, especially in overweight/obese women. Among insulin sensitizers, the positive role of inositols has been increasingly established in recent years. The action of inositols not only concerns the metabolic parameters of these patients, but also the hormonal profile, resulting in beneficial effects on ovarian function. For this reason, many studies have tried to recognize their role in PCOS infertile women who underwent in vitro fertilization (IVF) procedures.

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