The Pathophysiological Mechanism and Clinical Treatment of Polycystic Ovary Syndrome: A Molecular and Cellular Review of the Literature.

Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder among women of reproductive age, characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. The pathogenesis of PCOS involves a complex interplay of genetic and environmental factors, including insulin resistance (IR) and resultant hyperinsulinemia. Insulin receptors, primarily in skeletal muscle, liver, and adipose tissue, activate downstream signaling pathways like PI3K-AKT and MAPK-ERK upon binding. These pathways regulate glucose uptake, storage, and lipid metabolism. Genome-wide association studies (GWASs) have identified several candidate genes related to steroidogenesis and insulin signaling. Environmental factors such as endocrine-disrupting chemicals and lifestyle choices also exacerbate PCOS traits. Other than lifestyle modification and surgical intervention, management strategies for PCOS can be achieved by using pharmacological treatments like antiandrogens, metformin, thiazolidinediones, aromatase inhibitor, and ovulation drugs to improve insulin sensitivity and ovulatory function, as well as combined oral contraceptives with or without cyproterone to resume menstrual regularity. Despite the complex pathophysiology and significant economic burden of PCOS, a comprehensive understanding of its molecular and cellular mechanisms is crucial for developing effective public health policies and treatment strategies. Nevertheless, many unknown aspects of PCOS, including detailed mechanisms of actions, along with the safety and effectiveness for the treatment, warrant further investigation.

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Polycystic ovary syndrome (PCOS) is one of the most common gynecological endocrine disorders. Most pathophysiological changes of PCOS begin in the peripubertal phase, and these pathophysiological changes will continuously affect women's health in the later stages of their lives. The pathogenic mechanisms of PCOS remain unclear, involving key aspects such as the regulation of hypothalamic-pituitary function, ovarian cellular functions, androgen levels, and insulin resistance. Herein, we summarized the latest findings on the pathogenesis of PCOS from the perspectives of the genetic background, intrauterine development, neuroendocrine function, inflammatory factors, gut microbiome, and environmental factors. This review will help provide new ideas for a deeper understanding of the disease, as well as its clinical diagnosis and treatment.

Obesity and risk of female reproductive conditions: A Mendelian randomisation study.

BACKGROUND: Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Thus, we aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders. METHODS AND FINDINGS: Logistic regression, generalised additive models, and Mendelian randomisation (MR) (2-sample, non-linear, and multivariable) were applied to obesity and reproductive disease data on up to 257,193 women of European ancestry in UK Biobank and publicly available genome-wide association studies (GWASs). Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI were observationally (odds ratios [ORs] = 1.02-1.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06-2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Genetically predicted visceral adipose tissue (VAT) mass was associated with the development of HMB (OR [95% CI] per 1-kg increase in predicted VAT mass = 1.32 [1.06-1.64], P = 0.0130), PCOS (OR [95% CI] = 1.15 [1.08-1.23], P = 3.24 × 10-05), and pre-eclampsia (OR [95% CI] = 3.08 [1.98-4.79], P = 6.65 × 10-07). Increased waist circumference posed a higher genetic risk (ORs = 1.16-1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06-1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% and 50% of the total genetically predicted association of obesity with pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. This study was limited in power by the low prevalence of female reproductive conditions among women in the UK Biobank, with little information on pre-diagnostic anthropometric traits, and by the susceptibility of MR estimates to genetic pleiotropy. CONCLUSIONS: We found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, large-scale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions. Our results suggest the utility of exploring the mechanisms mediating the causal associations of overweight and obesity with gynaecological health to identify targets for disease prevention and treatment.

Polycystic ovary syndrome as a plausible evolutionary outcome of metabolic adaptation.

As a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. It is linked with insulin resistance through preferential abdominal fat accumulation that is worsened by obesity. Over the past two millennia, menstrual irregularity, male-type habitus and sub-infertility have been described in women and confirm that these clinical features of PCOS were common in antiquity. Recent findings in normal-weight hyperandrogenic PCOS women show that exaggerated lipid accumulation by subcutaneous (SC) abdominal stem cells during development to adipocytes in vitro occurs in combination with reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This PCOS phenotype may be an evolutionary metabolic adaptation to balance energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction. This review integrates fundamental endocrine-metabolic changes in healthy, normal-weight PCOS women with similar PCOS-like traits present in animal models in which tissue differentiation is completed during fetal life as in humans to support the evolutionary concept that PCOS has common ancestral and developmental origins.

Is there any association between migraine headache and polycystic ovary syndrome (PCOS)? A review article.

BACKGROUND: Polycystic ovary syndrome (PCOS) and migraine headaches are considered to be common health problems that may share some risk factors. This study aimed to discuss the possible association between migraine headache and polycystic ovary syndrome. METHODS AND RESULTS: In this narrative review, PubMed, Scopus, Web of Science, and Google Scholar were systematically searched for retrieving and summarizing published studies up to January 2021 to explore the possible interplay between migraine headache and PCOS. We discuss the possible pathways that may explain the association between migraine headaches and PCOS signs/symptoms and complications. While genetic factors have profound effects on the pathogenesis of migraine headaches, sex hormones, including estrogen and progesterone may also play an important role in inducing migraine headaches. Some disorders, such as sleep apnea, amenorrhea, and vascular disease that are more likely to occur in women with PCOS, may cause or exacerbate migraine headaches in women with PCOS. CONCLUSIONS: Future comprehensive studies are needed to investigate the exact underlining mechanisms related to the association between PCOS and migraine headaches.

Polycystic Ovary Syndrome: A Comprehensive Review of Pathogenesis, Management, and Drug Repurposing.

Polycystic ovary syndrome (PCOS) is an endocrine-gynecology disorder affecting many women of childbearing age. Although a part of the involved mechanism in PCOS occurrence is discovered, the exact etiology and pathophysiology are not comprehensively understood yet. We searched PubMed for PCOS pathogenesis and management in this article and ClinicalTrials.gov for information on repurposed medications. All responsible factors behind PCOS were thoroughly evaluated. Furthermore, the complete information on PCOS commonly prescribed and repurposed medications is summarized through tables. Epigenetics, environmental toxicants, stress, diet as external factors, insulin resistance, hyperandrogenism, inflammation, oxidative stress, and obesity as internal factors were investigated. Lifestyle modifications and complementary and alternative medicines are preferred first-line therapy in many cases. Medications, including 3-hydroxy-3-methyl-3-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, thiazolidinediones, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucose-like peptide-1 receptor agonists, mucolytic agents, and some supplements have supporting data for being repurposed in PCOS. Since there are few completed clinical trials with a low population and mostly without results on PCOS repurposed medications, it would be helpful to do further research and run well-designed clinical trials on this subject. Moreover, understanding more about PCOS would be beneficial to find new medications implying the effect via the novel discovered routes.

Controversies in the Pathogenesis, Diagnosis and Treatment of PCOS: Focus on Insulin Resistance, Inflammation, and Hyperandrogenism.

Polycystic ovary syndrome (PCOS) is a heterogeneous and extremely common disease with symptoms that vary with the age of the patient, typically characterized by hyperandrogenism, chronic oligo-anovulation, and/or several metabolic disorders. The syndrome includes various phenotypes, and the pathogenesis is multifactorial, often involving insulin resistance. This feature is closely related to ovarian dysfunction, inflammation, hyperandrogenism, and metabolic disorders, which characterize and complicate the syndrome. Therapy currently considers both lifestyle improvements and medications, and must be tailored on a case-by-case basis. To date, the published studies have not arrived at a definition of the most suitable therapy for each individual case and many of the drugs used are still off-label. In this review, we discuss some controversial diagnostic and therapeutic aspects of PCOS, such as the role of insulin resistance, inflammation, and hyperandrogenism. We also evaluated the advantages and disadvantages of contraceptive therapy and antiandrogens.

The role of androgen and its related signals in PCOS.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women at reproductive age. However, the underlying pathogenic mechanisms have not been completely understood. Hyperandrogenism is an important clinic feature in patients with PCOS, suggesting its pathologic role in the development and progression of PCOS. However, the actual role of androgen and the related signals in PCOS and PCOS-related complications have not yet been clarified. In this review, we surveyed the origin and effects of androgen on PCOS and the related complications, highlighted the cellular signals affecting androgen synthesis and summarized the pathological processes caused by hyperandrogenism. Our review well reveals the important mechanisms referring the pathogenesis of PCOS and provides important clues to the clinic strategies in patients with PCOS.

Obesity and polycystic ovary syndrome.

The increased global prevalence of obesity over the last 40-years has driven a rise in prevalence of obesity-related co-morbidities, including polycystic ovary syndrome (PCOS). On a background of genetic susceptibility, PCOS often becomes clinically manifest following weight gain, commonly during adolescence. A common endocrinopathy affecting between 6%-10% of reproductive-age women, PCOS presents with the cardinal features of hyperandrogenism, reproductive and metabolic dysfunction. PCOS associates with insulin resistance, independently of (but amplified by) obesity. Insulin resistance in PCOS is characterized by abnormal post-receptor signalling within the phosphatidylinositol-kinase (PI3-K) pathway. Multiple factors (including most notably, weight gain) contribute towards the severity of insulin resistance in PCOS. Compensatory hyperinsulinaemia ensues, resulting in over-stimulation of the (intact) post-receptor mitogen-activated protein kinase (MAP-K) insulin pathway, with consequent implications for steroidogenesis and ovarian function. In this concise review, we explore the effects of weight gain and obesity on the pathogenesis of PCOS from the perspective of its three cardinal features of hyperandrogenism, reproductive and metabolic dysfunction, with a focus on the central mediating role of the insulin pathway. We also consider key lifestyle strategies for the effective management of obese and overweight women with PCOS.

Contribution of high-fat diet-induced PCSK9 upregulation to a mouse model of PCOS is mediated partly by SREBP2.

The incidence of polycystic ovary syndrome (PCOS) due to high-fat diet (HFD) consumption has been increasing significantly. However, the mechanism by which a HFD contributes to the pathogenesis of PCOS has not been elucidated. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein that regulates cholesterol metabolism. Our previous study revealed abnormally high PCSK9 levels in serum from patients with PCOS and in serum and hepatic and ovarian tissues from PCOS model mice, suggesting that PCSK9 is involved in the pathogenesis of PCOS. However, the factor that induces high PCSK9 expression in PCOS remains unclear. In this study, Pcsk9 knockout mice were used to further explore the role of PCSK9 in PCOS. We also studied the effects of a HFD on the expression of PCSK9 and sterol regulatory element-binding protein 2 (SREBP2), a regulator of cholesterol homeostasis and a key transcription factor that regulates the expression of PCSK9, and the roles of these proteins in PCOS pathology. Our results indicated HFD may play an important role by inducing abnormally high PCSK9 expression via SREBP2 upregulation. We further investigated the effects of an effective SREBP inhibitor, fatostain, and found that it could reduce HFD-induced PCSK9 expression, ameliorate hyperlipidemia and improve follicular development in PCOS model mice. Our study thus further elucidates the important role of an HFD in the pathogenesis of PCOS and provides a new clue in the prevention and treatment of this disorder.

A review on inositol's potential in cyclic disturbances of adipose-endocrinology-associated polycystic ovary syndrome.

Since the lack of certainty in identifying polycystic ovary syndrome (PCOS) demonstrates confusion regarding the disorder's pathophysiology and its therapeutic approaches, systematic screening of women under diagnostic guidelines of the NIH reported that about 4-10 percent of reproductive women aged 20-44 years suffer from PCOS. Not all females with PCOS-defining biochemical and clinical characteristics and about 22% of PCOS women have no symptoms. PCOS is a heterogeneous phenotypic and clinical condition, combined with metabolic implications. The root cause of PCOS is the major issue of IR or irregular androgen secretion and constant effort is being made in identifying the dynamic pathogenic network underlying the syndrome. Regardless of PCOS initiating cause, IR therapy and hyperinsulinemia can restore metabolic and hormonal homeostasis, and minimize ovarian dysfunction. Thus, the impact of insulin on ovaries in hyperinsulinemic individuals can account for many of the PCOS characteristics and is important for developing treatment strategies. Therefore, our primary aim is to investigate the proper understanding of endocrine disruption during PCOS and secondary to the therapeutic potential of inositol in reestablishing the equilibrium of ovarian dysfunction, anovulation, and eventually infertility.

Polycystic ovarian syndrome in Nigerian women with epilepsy on carbamazepine/levetiracetam monotherapy.

OBJECTIVE: The study is aimed at comparing effects of older drugs like carbamazepine (CBZ) and newer agent like levetiracetam (LEV) on polycystic ovarian syndrome (PCOS) in women with epilepsy (WWE). METHODS: An interviewer-based questionnaire was used to obtain relevant clinical information from 50 WWE on CBZ and LEV monotherapy, respectively, and 50 age-matched controls. The diagnosis of epilepsy was clinical with electroencephalographic features taken into consideration and the seizures classified using the 2017 International League Against Epilepsy classification. The diagnosis of PCOS was based on the European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine. RESULTS: The frequency of PCOS and its subcomponent were higher among WWE compare to controls. PCOS was present in 22 (44%) of LEV group compare to 8 (16%) CBZ group. The frequency of its subcomponent was higher among those on LEV except for comparable effect with regard to oligomenorrhea. The levels of the sex steroid hormone were comparable in both groups of WWE except luteal phase luteinizing hormone, which was lower among the LEV group (P .001). The follicular phase estradiol level was lower (P .021), and follicle-stimulating hormone level was about 2-fold higher (P .03) among WWE compare to controls. The mean value testosterone was significantly lower among controls compared to WWE. CONCLUSIONS: The increased frequency of PCOS and its subcomponent and the unsatisfactory effect of LEV compared to CBZ on reproductive endocrine function underscore the need for routine reproductive endocrine evaluation to improve overall quality of life.

Role of 14-3-3ß protein on ovarian folliculogenesis, steroidogenesis and its correlation in the pathogenesis of PCOS in mice.

This study was designed to assess for the first time the circulating and ovarian level of 14-3-3ß protein in the PCOS mice and the possible correlation between 14-3-3ß protein with PCOS related increase in testosterone (HA), insulin levels (HI) and reduced insulin sensitivity in the ovary. PCOS was induced in mice using treatment of letrozole (by oral gavage) for 21 days. Immunohistochemical study showed increased expression of 14-3-3ß protein in PCOS ovary compared to the control ovary. The circulating testosterone and insulin levels, together with circulating and ovarian levels of 14-3-3ß protein also showed significant increase in PCOS mice compared to the control mice. An increase in 14-3-3ß protein was observed positively correlated with circulating testosterone and insulin levels but showed a negative correlation with ovarian expression of insulin receptor protein in PCOS mice. The treatment of 14-3-3ß protein in vitro to the normal ovary showed a significant increase in testosterone synthesis but a significant decline in insulin receptor protein expression compared to the vehicle-treated ovary of adult mice. The present study showed the direct role of 14-3-3ß protein in increasing testosterone synthesis along with decreasing insulin sensitivity. Thus, 14-3-3ß protein may be playing possible role in PCOS pathogenesis.

Pyroptosis and inflammasomes in obstetrical and gynecological diseases.

Pyroptosis, an inflammatory form of programmed cell death, takes an essential part in a wide variety of physiological activities, for instance, implantation, placentation and the body's defense against infection. However, once excessively activated, pyroptosis mediated by the activation of inflammasomes can be highly pathological. It can cause inflammatory and autoimmune diseases including a variety of obstetrical and gynecological diseases, such as endometriosis, gestational diabetes mellitus, insulin resistance in polycystic ovary syndrome, and multiple obstetric complications including preeclampsia. Although the role of pyroptosis in the pathogenesis of the above mentioned diseases has not been fully elucidated, we try to tap its therapeutic potential by targeting pyroptosis signaling and inflammasome formation. Pyroptosis and inflammasomes are confirmed to be involved in endometriosis and gynecological malignant tumors, therefore, medical approachs inducing pyroptosis of the ectopic endometrium and tumor cells can be feasible treatments for endometriosis and gynecological cancers. On the maternal-fetal interface, although a certain level of the innate immune response activation is required for a successful implantation and placentation, maternal and fetal injury may occur once the inflammasomes are over-activated. Besides, since gestational diabetes mellitus and insulin resistance in polycystic ovary syndrome share common pathogenesis with metabolic diseases, this domain research sheds light on future study of some obstetrical and gynecological diseases.

Environmental Influences and Polycystic Ovarian Syndrome.

Polycystic ovarian syndrome (PCOS) is a complex endocrine-metabolic disorder whose pathogenesis is not well-understood. While genetic insults have been hypothesized as possible causes, there are a large number of environmental chemicals known to have detrimental effects on the endocrine system and may be irreversible, especially when exposure occurs early in development. Many of these chemicals have been investigated as causes of PCOS by measuring serum and urinary levels of common endocrine disruptors in women and adolescents with PCOS as well as using animal models for PCOS induction with chemical exposures.

Oxidative Stress and Low-Grade Inflammation in Polycystic Ovary Syndrome: Controversies and New Insights.

The pathophysiology of Polycystic Ovary Syndrome (PCOS) is quite complex and different mechanisms could contribute to hyperandrogenism and anovulation, which are the main features of the syndrome. Obesity and insulin-resistance are claimed as the principal factors contributing to the clinical presentation; in normal weight PCOS either, increased visceral adipose tissue has been described. However, their role is still debated, as debated are the biochemical markers linked to obesity per se. Oxidative stress (OS) and low-grade inflammation (LGI) have recently been a matter of researcher attention; they can influence each other in a reciprocal vicious cycle. In this review, we summarize the main mechanism of radical generation and the link with LGI. Furthermore, we discuss papers in favor or against the role of obesity as the first pathogenetic factor, and show how OS itself, on the contrary, can induce obesity and insulin resistance; in particular, the role of GH-IGF-1 axis is highlighted. Finally, the possible consequences on vitamin D synthesis and activation on the immune system are briefly discussed. This review intends to underline the key role of oxidative stress and low-grade inflammation in the physiopathology of PCOS, they can cause or worsen obesity, insulin-resistance, vitamin D deficiency, and immune dyscrasia, suggesting an inverse interaction to what is usually considered.

Influence of Vitamin D on the Vasoactive Effect of Estradiol in a Rat Model of Polycystic Ovary Syndrome.

We examined the vasoactive effect of estradiol in a rat model of early PCOS and the influence of vitamin D deficiency (VDD). We created a model of chronic hyperandrogenism and VDD in adolescent female Wistar rats (N = 46) with four experimental groups: vitamin D supplemented (T-D+), VDD (T-D-), hyperandrogenic and vitamin D supplemented (T+D+), and hyperandrogenic and VDD (T+D-). T+ groups received an 8-week-long transdermal Androgel treatment, D-animals were on vitamin D-reduced diet and D+ rats were supplemented orally with vitamin D3. Estrogen-induced vasorelaxation of thoracic aorta segments were measured with a wire myograph system with or without the inhibition of endothelial nitric oxide synthase (eNOS) or cyclooxygenase-2 (COX-2). The distribution of estrogen receptor (ER), eNOS and COX-2 in the aortic wall was assessed by immunohistochemistry. VDD aortas showed significantly lower estradiol-induced relaxation independently of androgenic status that was further decreased by COX-2 inhibition. COX-2 inhibition failed to alter vessel function in D+ rats. Inhibition of eNOS abolished the estradiol-induced relaxation in all groups. Changes in vascular function in VDD were accompanied by significantly decreased ER and eNOS staining. Short-term chronic hyperandrogenism failed to, but VDD induced vascular dysfunction, compromised estrogen-dependent vasodilatation and changes in ER and eNOS immunostaining.

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.

Subfatin and asprosin, two new metabolic players of polycystic ovary syndrome.

Asprosin and subfatin are recently discovered two new hormones of adipocyte origin that play a role in the regulation of glucose metabolism. Polycystic ovary syndrome (PCOS) is a gynaecological syndrome presenting with energy turbulence. The aim of this study was to investigate whether asprosin and subfatin play a role in PCOS disease. Thirty participants with a diagnosis of PCOS and thirty control group participants were included in this case-control study. Hormone profiles of the participants (subfatin, asprosin, insulin, prolactin, thyroid-stimulating hormone (TSH), oestradiol (E2), follicle-stimulating hormone (FSH), luteinising hormone (LH), dehydroepiandrosterone sulphate (DHEA-SO4), lipid profiles [(total testosterone, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride, cholesterol)], fasting blood sugar (FBS) and high-sensitivity C-reactive protein (hs-CRP) values were measured. While the levels of asprosin, LDL and triglyceride, TSH, E2, FSH, LH, DHEA-SO4 were found to be significantly higher in patients with PCOS compared to controls (p = .005; p = .01), subfatin and HDL levels were found to be low. Significantly decreasing subfatin and increasing asprosin levels in circulation in PCOS may play a role in the etiopathology of this disease and that they may also be new candidate molecules in addition to classical laboratory parameters in the diagnosis and follow-up of PCOS in the future.Impact statementWhat is already known on this subject? The studies investigating the relationship between PCOS and asprosin are contradictory. Although subfatin has been studied in many metabolic diseases, it has not been studied yet whether it is associated with PCOS. Furthermore, whether there is a mutual relationship between subfatin and asprosin in patients with PCOS has not been studied yet.What do the results of this study add? This available data indicates that significantly decreasing subfatin and increasing asprosin levels in the circulation in PCOS may play a role in the etiopathology of this disease.What are the implications of these findings for clinical practice and/or further research? The findings are promising in that decreasing subfatin and increasing asprosin levels will shed new light on reproductive endocrinology changes caused by PCOS and may help to clarify the pathophysiology of PCOS. Furthermore, in our study, the asprosin/subfatin ratio was above three in PCOS disease. This ratio reported here is anticipated to contribute to the course or follow-up of the disease in the future. Also, subfatin has been investigated here for the first time, may also be a new candidate molecule in addition to classical laboratory parameters in the diagnosis and follow-up of PCOS.

Electroacupuncture alleviates polycystic ovary syndrome-like symptoms through improving insulin resistance, mitochondrial dysfunction, and endoplasmic reticulum stress via enhancing autophagy in rats.

BACKGROUND: Electroacupuncture (EA), a treatment derived from traditional Chinese medicine, can effectively improve hyperandrogenism and insulin resistance in patients with polycystic ovary syndrome (PCOS), however, its underlying mechanisms remain obscure. This study aimed to investigate whether EA could mitigate PCOS-like symptoms in rats by regulating autophagy. METHODS: A rat model of PCOS-like symptoms was established by subcutaneous injection with dehydroepiandrosterone (DHEA), and then EA treatment at acupoints (ST29 and SP6) was carried out for 5 weeks. To inhibit autophagy in rats, intraperitoneal injection with 0.5 mg/kg 3-MA (an autophagy inhibitor) was performed at 30 min before each EA treatment. RESULTS: EA intervention alleviated PCOS-like symptoms in rats, which was partly counteracted by the combination with 3-MA. Moreover, DHEA-exposure-induced deficient autophagy in skeletal muscle was improved by EA treatment. EA-mediated improvements in insulin resistance, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in PCOS-like rats were counteracted by 3-MA pretreatment. Mechanically, EA attenuated autophagy deficiency-mediated insulin resistance in PCOS-like rats via inactivating mTOR/4E-BP1 signaling pathway. CONCLUSIONS: Taken together, our findings indicate that EA treatment ameliorates insulin resistance, mitochondrial dysfunction, and ER stress through enhancing autophagy in a PCOS-like rat model. Our study provides novel insight into the mechanisms underlying the treatment of EA in PCOS, which offers more theoretic foundation for its clinical application.