Polycystic ovary syndrome (PCOS) is frequently seen in females of reproductive age and is associated with metabolic disorders that are exacerbated by obesity. Although body weight reduction programs via diet and lifestyle changes are recommended for modifying reproductive and metabolic phenotypes, the drop-out rate is high. Thus, an efficacious, safe, and continuable treatment method is needed. Recent studies have shown that oxytocin (OT) reduces body weight gain and food intake, and promotes lipolysis in some mammals, including humans (especially obese individuals), without any adverse effects. In the present study, we evaluated the changes in endogenous OT levels, and the effects of acute and chronic OT administration on body weight changes, food intake, and fat mass using novel dihydrotestosterone-induced PCOS model rats. We found that the serum OT level was lower in PCOS model rats than in control rats, whereas the hypothalamic OT mRNA expression level did not differ between them. Acute intraperitoneal administration of OT during the dark phase reduced the body weight gain and food intake in PCOS model rats, but these effects were not observed in control rats. In contrast, chronic administration of OT decreased the food intake in both the PCOS model rats and control rats. These findings indicate that OT may be a candidate medicine that is efficacious, safe, and continuable for treating obese PCOS patients. Full article

As in women with polycystic ovary syndrome (PCOS), hyperinsulinemia is associated with anovulation in PCOS-like female rhesus monkeys. Insulin sensitizers ameliorate hyperinsulinemia and stimulate ovulatory menstrual cycles in PCOS-like monkeys. To determine whether hyperinsulinemia (>694 pmol/L), alone, induces PCOS-like traits, five PCOS-like female rhesus monkeys with minimal PCOS-like traits, and four control females of similar mid-to-late reproductive years and body mass index, received daily subcutaneous injections of recombinant human insulin or diluent for 6–7 months. A cross-over experimental design enabled use of the same monkeys in each treatment phase. Insulin treatment unexpectedly normalized follicular phase duration in PCOS-like, but not control, females. In response to an intramuscular injection of 200 IU hCG, neither prenatally androgenized nor control females demonstrated ovarian hyperandrogenic responses while receiving insulin. An intravenous GnRH (100 ng/kg) injection also did not reveal evidence of hypergonadotropism. Taken together, these results suggest that experimentally induced adult hyperinsulinemia, alone, is insufficient to induce PCOS-like traits in female rhesus monkeys and to amplify intrinsic PCOS-like pathophysiology. Full article

Polycystic ovary syndrome (PCOS), which affects 5–10% of women of reproductive age, is associated with reproductive and metabolic disorders, such as chronic anovulation, infertility, insulin resistance, and type 2 diabetes. However, the mechanism of PCOS is still unknown. Therefore, this study used a letrozole-exposed mouse model in which mice were orally fed letrozole for 20 weeks to investigate the effects of letrozole on the severity of reproductive and metabolic consequences and the expression of cysteine–cysteine motif chemokine receptor 5 (CCR5) in letrozole-induced PCOS mice. The letrozole-treated mice showed a disrupted estrous cycle and were arrested in the diestrus phase. Letrozole treatment also increased plasma testosterone levels, decreased estradiol levels, and caused multicystic follicle formation. Furthermore, histological analysis of the perigonadal white adipose tissue (pgWAT) showed no significant difference in the size and number of adipocytes between the letrozole-treated mice and the control group. Further, the letrozole-treated mice demonstrated glucose intolerance and insulin resistance during oral glucose and insulin tolerance testing. Additionally, the expression of CCR5 and cysteine-cysteine motif ligand 5 (CCL5) were significantly higher in the pgWAT of the letrozole-treated mice compared with the control group. CCR5 and CCL5 were also significantly correlated with the homeostasis model assessment of insulin resistance (HOMA-IR). Finally, the mechanisms of insulin resistance in PCOS may be caused by an increase in serine phosphorylation and a decrease in Akt phosphorylation. Full article

The susceptibility and the severity of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with hyperandrogenism, obesity, and preexisting pulmonary, metabolic, renal, and cardiac conditions. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with obesity, hyperandrogenism, and cardiometabolic dysregulations. We analyzed cardiac, renal, circulatory, and urinary SARS-CoV-2 viral entry proteins (ACE2, TMPRSS2, TMPRSS4, furin, cathepsin L, and ADAM17) and androgen receptor (AR) expression, in a peripubertal androgen exposure model of PCOS. Peripubertal female mice were treated with dihydrotestosterone (DHT) and low (LFD) or high (HFD) fat diet for 90 days. HFD exacerbated DHT-induced increase in body weight, fat mass, and cardiac and renal hypertrophy. In the heart, DHT upregulated AR protein in both LFD and HFD, ACE2 in HFD, and ADAM17 in LFD. In the kidney, AR protein expression was upregulated by both DHT and HFD. Moreover, ACE2 and ADAM17 were upregulated by DHT in both diets. Renal TMPRSS2, furin, and cathepsin L were upregulated by DHT and differentially modulated by the diet. DHT upregulated urinary ACE2 in both diets, while neither treatment modified serum ACE2. Renal AR mRNA expression positively correlated with Ace2, Tmprss2, furin, cathepsin L, and ADAM17. Our findings suggest that women with PCOS could be a population with a high risk of COVID-19-associated cardiac and renal complications. Furthermore, our study suggests that weight loss by lifestyle modifications (i.e., diet) could potentially mitigate COVID-19-associated deleterious cardiorenal outcomes in women with PCOS. Full article

Administration of 1000–1500 mg/day D-Chiro-Inositol (DCIns) or a combination of Myo-Inositol (MyoIns) and DCIns in their plasma molar ratio (40:1) for three or more months are among recommended treatments for metabolic syndrome and/or Polycystic Ovary Syndrome (PCOS). We previously confirmed the efficacy of this formulation (8.2 mg/day MyoIns and 0.2 mg/day DCIns for 10 days) in a mouse PCOS model, but also observed negative effects on ovarian histology and function of formulations containing 0.4–1.6 mg/day DCIns. We therefore analyzed effects of higher doses of DCIns, 5, 10 and 20 mg/day, administered to young adult female mice for 21 days, on ovarian histology, serum testosterone levels and expression of the ovarian enzyme aromatase. Five mg/day DCIns (human correspondence: 1200 mg/day) altered ovarian histology, increased serum testosterone levels and reduced the amount of aromatase of negative controls, suggesting the induction of an androgenic PCOS model. In contrast, 10–20 mg/day DCIns (human correspondence: 2400–4800 mg/day) produced ovarian lesions resembling those typical of aged mice, and reduced serum testosterone levels without affecting aromatase amounts, suggesting a failure in steroidogenic gonadal activity. Notwithstanding physiological/biochemical differences between mice and humans, the observed pictures of toxicity for ovarian histology and function recommend caution when administering DCIns to PCOS patients at high doses and/or for periods spanning several ovulatory cycles. Full article

SARS-CoV-2, the causative agent of COVID-19, infects host cells using the angiotensin I converting enzyme 2 (ACE2) as its receptor after priming by host proteases, including TMPRSS2. COVID-19 affects multiple organ systems, and male patients suffer increased severity and mortality. Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is associated with obesity and cardiometabolic comorbidities, both being risk factors associated with severe COVID-19 pathology. We hypothesize that elevated androgens in PCOS regulate SARS-CoV-2 entry proteins in multiple tissues increasing the risk for this population. Female mice were treated with dihydrotestosterone (DHT) for 90 days. Body composition was measured by EchoMRI. Fasting glucose was determined by an enzymatic method. mRNA and protein levels of ACE2, Tmprss2, Cathepsin L, Furin, Tmprss4, and Adam17 were quantified by RT-qPCR, Western-blot, or ELISA in tissues, serum, and urine. DHT treatment increased body weight, fat and lean mass, and fasting glucose. Ace2 mRNA was upregulated in the lung, cecum, heart, and kidney, while downregulated in the brain by DHT. ACE2 protein was upregulated by DHT in the small intestine, heart, and kidney. The SARS-CoV-2 priming proteases Tmprss2, Cathepsin L, and Furin mRNA were upregulated by DHT in the kidney. ACE2 sheddase Adam17 mRNA was upregulated by DHT in the kidney, which corresponded with increased urinary ACE2 in DHT treated mice. Our results highlight the potential for increased cardiac, renal, and gastrointestinal dysfunction in PCOS women with COVID-19. Full article

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have a high prevalence of obesity, insulin resistance (IR), increased blood pressure (BP), and activation of the renin angiotensin system (RAS). Effective evidence-based therapeutics to ameliorate the cardiometabolic complications in PCOS are lacking. The sodium-glucose cotransporter-2 (SGLT2) inhibitor Empagliflozin (EMPA) reduces BP and hyperglycemia in type 2 diabetes mellitus. We hypothesized that hyperandrogenemia upregulates renal SGLT2 expression and that EMPA ameliorates cardiometabolic complications in a hyperandrogenemic PCOS model. Four-week-old female Sprague Dawley rats were treated with dihydrotestosterone (DHT) for 90 days, and EMPA was co-administered for the last three weeks. DHT upregulated renal SGLT2, SGLT4, and GLUT2, but downregulated SGLT3 mRNA expression. EMPA decreased DHT-mediated increases in fat mass, plasma leptin, and BP, but failed to decrease plasma insulin, HbA1c, or albuminuria. EMPA decreased DHT-mediated increase in renal angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), and angiotensin II type 1 receptor (AGT1R) mRNA and protein expression. In summary, SGLT2 inhibition proved beneficial in adiposity and BP reduction in a hyperandrogenemic PCOS model; however, additional therapies may be needed to improve IR and renal injury. Full article

Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is associated with an adverse metabolic profile including reduced postprandial thermogenesis. Although abnormalities in adipose tissue function have been widely reported in women with PCOS, less is known about direct effects of androgen on white and, particularly, brown adipocytes. The purpose of this study was to investigate the effect of the nonaromatizable androgen dihydrotestosterone (DHT) on (1) lipid accumulation and expression of adipogenic markers in immortalized mouse brown adipose cell lines (IMBATs), (2) mitochondrial respiration in IMBATs, (3) mitochondrial DNA content and gene expression, (4) expression of brown adipose tissue (BAT) markers and thermogenic activation. In addition, we profiled the relative levels of 38 adipokines secreted from BAT explants and looked at androgen effects on adipokine gene expression in both IMBATs and immortalized mouse white adipose (IMWATs) cell lines. Androgen treatment inhibited IMBAT differentiation in a dose-dependent manner, reduced markers of adipogenesis, and attenuated the β-adrenoceptor-stimulated increase in uncoupling protein-1 (UCP1) expression. In explants of mouse interscapular BAT, androgen reduced expression of UCP1, peroxisome proliferator-activated receptor-γ coactivator-1 (PCG-1) and Cidea. Significantly, as well as affecting genes involved in thermogenesis in BAT, androgen treatment reduced mitochondrial respiration in IMBATs, as measured by the Seahorse XF method. The results of this study suggest a role for excess androgen in inhibiting brown adipogenesis, attenuating the activation of thermogenesis and reducing mitochondrial respiration in BAT. Together, these data provide a plausible molecular mechanism that may contribute to reduced postprandial thermogenesis and the tendency to obesity in women with PCOS. Full article

Women with polycystic ovary syndrome (PCOS) are reported to have greater lean mass and insulin resistance. To examine muscular changes in a prenatally androgenized (PNA) rat model for PCOS, Sprague–Dawley rats were exposed to 5 mg testosterone or vehicle daily on gestational days 16–19. At 15 weeks of age, endurance on a rota-rod treadmill was measured. At 16 weeks of age, fasting blood glucose and insulin, hindlimb skeletal muscle mass, muscle fiber cross-sectional area (CSA) and composition, and intra- and peri-muscular lipid droplets were examined. Expression of mitochondrial marker ATP synthase and insulin signaling proteins were also investigated. Compared with controls, PNA female rats demonstrated greater total body and hindlimb muscle weights, greater muscle fiber CSA, and trending reduced time on the rota-rod. An increase in fibers co-expressing the slow and fast isoforms of myosin (90 vs. 86%, p < 0.05) and greater expression of ATP synthase (6-fold, p < 0.005) were observed in the gastrocnemius (GN) muscle. More lipid content was observed in GN and tibialis anterior (TA) muscles. PNA rats had elevated fasting serum insulin (1.9 vs. 1.2 ng/mL, p < 0.005) but comparable fasting glucose. Expression of total and Ser^636/9-phosphorylated IRS1 were altered in PNA rat hindlimb muscles. Together, skeletal muscle alterations in hindlimb muscles of a PNA rat model for PCOS may represent consequences of, or adaptations to, insulin resistance in this model. Full article

Polycystic ovarian syndrome (PCOS) is the main cause of female infertility. It is a multifactorial disorder with varying clinical manifestations including metabolic/endocrine abnormalities, hyperandrogenism, and ovarian cysts, among other conditions. D-Chiro-inositol (DCI) is the main treatment available for PCOS in humans. To address some of the mechanisms of this complex disorder and its treatment, this study examines the effect of DCI on reproduction during the development of different PCOS-associated phenotypes in aged females and two mouse models of PCOS. Aged females (8 months old) were treated or not (control) with DCI for 2 months. PCOS models were generated by treatment with dihydrotestosterone (DHT) on Days 16, 17, and 18 of gestation, or by testosterone propionate (TP) treatment on the first day of life. At two months of age, PCOS mice were treated with DCI for 2 months and their reproductive parameters analyzed. No effects of DCI treatment were produced on body weight or ovary/body weight ratio. However, treatment reduced the number of follicles with an atretic cyst-like appearance and improved embryo development in the PCOS models, and also increased implantation rates in both aged and PCOS mice. DCI modified the expression of genes related to oocyte quality, oxidative stress, and luteal sufficiency in cumulus-oocyte complexes (COCs) obtained from the aged and PCOS models. Further, the phosphorylation of AKT, a main metabolic sensor activated by insulin in the liver, was enhanced only in the DHT group, which was the only PCOS model showing glucose intolerance and AKT dephosphorylation. The effect of DCI in the TP model seemed mediated by its influence on oxidative stress and follicle insufficiency. Our results indicate that DCI works in preclinical models of PCOS and offer insight into its mechanism of action when used to treat this infertility-associated syndrome. Full article

Women with polycystic ovary syndrome (PCOS) are more likely to develop endometrial cancer (EC). The molecular mechanisms which increase the risk of EC in PCOS are unclear. Derangements in lipid metabolism are associated with EC, but there have been no studies, investigating if this might increase the risk of EC in PCOS. This was a cross-sectional study of 102 women in three groups of 34 (PCOS, EC and controls) at Nottingham University Hospital, UK. All participants had clinical assessments, followed by obtaining plasma and endometrial tissue samples. Lipidomic analyses were performed using liquid chromatography (LC) coupled with high resolution mass spectrometry (HRMS) and the obtained lipid datasets were screened using standard software and databases. Using multivariate data analysis, there were no common markers found for EC and PCOS. However, on univariate analyses, both PCOS and EC endometrial tissue samples showed a significant decrease in monoacylglycerol 24:0 and capric acid compared to controls. Further studies are required to validate these findings and investigate the potential role of monoacylglycerol 24:0 and capric acid in the link between PCOS with EC. Full article

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and post-menopausal women. PCOS is a multifactorial heterogeneous disorder associated with a variety of etiologies, outcomes, and clinical manifestations. However, the pathophysiology of PCOS is still unclear. Heat shock proteins (HSPs) have recently been investigated for their role in the pathogenesis of PCOS. HSPs are a class of proteins that act as molecular chaperones and maintain cellular proteostasis. More recently, their actions beyond that of molecular chaperones have highlighted their pathogenic role in several diseases. In PCOS, different HSP family members show abnormal expression that affects the proliferation and apoptotic rates of ovarian cells as well as immunological processes. HSP dysregulation in the ovaries of PCOS subjects leads to a proliferation/apoptosis imbalance that mechanistically impacts follicle stage development, resulting in polycystic ovaries. Moreover, HSPs may play a role in the pathogenesis of PCOS-associated conditions. Recent studies on HSP activity during therapeutic interventions for PCOS suggest that modulating HSP activity may lead to novel treatment strategies. In this review, we summarize what is currently known regarding the role of HSPs in the pathogenesis of PCOS and their potential role in the treatment of PCOS, and we outline areas for future research. Full article

Insulin resistance is documented in clamp studies in 75% of women with polycystic ovary syndrome (PCOS). Although it is not included in the diagnostic criteria of PCOS, there is a crucial role of this metabolic impairment, which along with hormonal abnormalities, increase each other in a vicious circle of PCOS pathogenesis. Insulin resistance in this group of patients results from defects at the molecular level, including impaired insulin receptor-related signaling pathways enhanced by obesity and its features: Excess visceral fat, chronic inflammation, and reactive oxygen species. While lifestyle intervention has a first-line role in the prevention and management of excess weight in PCOS, the role of anti-obesity pharmacological agents in achieving and maintaining weight loss is being increasingly recognized. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) not only act by reducing body weight but also can affect the mechanisms involved in insulin resistance, like an increasing expression of glucose transporters in insulin-dependent tissues, decreasing inflammation, reducing oxidative stress, and modulating lipid metabolism. They also tend to improve fertility either by increasing LH surge in hypothalamus-pituitary inhibition due to estrogen excess connected with obesity or decreasing too high LH levels accompanying hyperinsulinemia. GLP1-RAs seem promising for effective treatment of obese PCOS patients, acting on one of the primary causes of PCOS at the molecular level. Full article

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. Full article

Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities. Moreover, besides metabolic activity, myo-Ins and D-chiro-Ins deeply influence steroidogenesis, regulating the pools of androgens and estrogens, likely in opposite ways. Given the complexity of inositol-related mechanisms of action, many of their beneficial effects are still under scrutiny. Therefore, continuing research aims to discover new emerging roles and mechanisms that can allow clinicians to tailor inositol therapy and to use it in other medical areas, hitherto unexplored. The present paper outlines the established evidence on inositols and updates on recent research, namely concerning D-chiro-Ins involvement into steroidogenesis. In particular, D-chiro-Ins mediates insulin-induced testosterone biosynthesis from ovarian thecal cells and directly affects synthesis of estrogens by modulating the expression of the aromatase enzyme. Ovaries, as well as other organs and tissues, are characterized by a specific ratio of myo-Ins to D-chiro-Ins, which ensures their healthy state and proper functionality. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations usually occur in association with medical conditions, such as PCOS, or as a consequence of some pharmacological treatments. Based on the physiological role of inositols and the pathological implications of altered myo-Ins to D-chiro-Ins ratios, inositol therapy may be designed with two different aims: (1) restoring the inositol physiological ratio; (2) altering the ratio in a controlled way to achieve specific effects. Full article

Polycystic ovarian syndrome (PCOS) is the most prevalent endocrinopathy of reproductive years. Salient features in presentation of patients PCOS include menstrual dysfunction, hyperandrogenism and/or polycystic appearance of ovaries on ultrasound. While the diagnosis of PCOS depends on presence of specified criteria, misdiagnoses are common. Despite years of extensive research, the exact aetiology of PCOS remains largely unknown. In the past decade, apart from insulin resistance and hyperandrogenemia, anti-mullerian hormone (AMH), an important marker of ovarian reserve, and vascular endothelial growth factor (VEGF), a crucial factor in angiogenesis, have been examined as plausible players of causative relevance for PCOS. Vitamin D, a sex-steroid hormone that is universally known for its relevance for skeletal health, has received increasing attention due to growing evidence supporting its pivotal in reproductive physiology and in PCOS. In this review we summarize our current understanding of the mechanisms relevant to the pathophysiology of PCOS and examine the role of vitamin D signalling in this context. Full article

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. Full article

Polycystic ovary syndrome (PCOS) is a major anovulatory infertility affecting a great proportion of women of childbearing age and is associated with obesity, insulin resistance and chronic inflammation. Poor endometrial receptivity and recurrent implantation failure are major hurdles to the establishment of pregnancy in women with PCOS. The accumulating body of evidence obtained from experimental and clinical studies suggests a link between inherent adaptive and innate immune irregularities and aberrant endometrial features in PCOS. The use of conventional therapeutic interventions such as lifestyle modification, metformin and ovarian stimulation has achieved limited clinical success in restoring ovulation and endometrial receptivity in women with PCOS. Unlike other immunosuppressive drugs prescribed in the clinical management of autoimmune and inflammatory disorders that may have deleterious effects on fertility and fetal development, preclinical studies in mice and in women without PCOS but with repeated implantation failure revealed potential therapeutic benefits for the use of low-dose tacrolimus in treating female infertility. Improved systemic and ovarian immune functions, endometrial progesterone receptor and coreceptor expressions and uterine vascular adaptation to pregnancy were among features of enhanced progesterone-receptor sensitivity in the low-dose tacrolimus-treated mouse model of the disease. In this review, we have compiled available experimental and clinical data in literature on endometrial progesterone resistance and current therapeutic options, as well as mechanisms of actions and reported outcomes relevant to the potential therapeutic benefits for the use of low-dose tacrolimus in treating PCOS-associated female infertility. Full article

Although the current literature associates polycystic ovarian syndrome (PCOS) with chronic inflammation, the evidence for this link remains inconclusive and its causal nature remains unclear. The purpose of this systematic review was to assess the inflammatory status in PCOS women and to determine whether it is related to PCOS or to its associated adiposity. We searched electronic databases including PUBMED, EMBASE and MEDLINE, SCOPUS, DynaMed plus, TRIP, ScienceDirect and Cochrane Library, for studies investigating C-reactive protein (CRP) and other inflammatory makers in PCOS women versus healthy controls. Quality and risk of bias for selected studies were assessed using the modified Newcastle–Ottawa scale. CRP data were extracted and pooled using RevMan for calculation of the standardized mean difference (SMD) and 95% confidence interval (CI). Eighty-five eligible studies were included in the systematic review, of which 63 were included in the meta-analysis. Pooled analysis of the 63 studies revealed significantly higher circulating CRP in PCOS women (n = 4086) versus controls (n = 3120) (SMD 1.26, 95%CI, 0.99, 1.53). Sensitivity meta-analysis of 35 high quality studies including non-obese women showed significantly higher circulating CRP in PCOS women versus controls (SMD 1.80, 95%CI, 1.36, 2.25). In conclusion, circulating CRP is moderately elevated in PCOS women independent of obesity, which is indicative of low-grade chronic inflammation. Full article

Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disease. The hypothesis that alterations in the microbiome are involved in the genesis of PCOS has been postulated. Aim of this review is to summarize the available literature data about the relationship between microbiome and PCOS. A search on PubMed and Medline databases was performed from inception to November 20Most of evidence has focused on the connection of intestinal bacteria with sex hormones and insulin-resistance: while in the first case, a relationship with hyperandrogenism has been described, although it is still unclear, in the second one, chronic low-grade inflammation by activating the immune system, with increased production of proinflammatory cytokines which interfere with insulin receptor function, causing IR (Insulin Resistance)/hyperinsulinemia has been described, as well as the role of gastrointestinal hormones like Ghrelin and peptide YY (PYY), bile acids, interleukin-22 and Bacteroides vulgatus have been highlighted. The lower genital tract microbiome would be affected by changes in PCOS patients too. The therapeutic opportunities include probiotic, prebiotics and synbiotics, as well as fecal microbiota transplantation and the use of IL-22, to date only in animal models, as a possible future drug. Current evidence has shown the involvement of the gut microbiome in PCOS, seen how humanized mice receiving a fecal transplant from women with PCOS develop ovarian dysfunction, immune changes and insulin resistance and how it is capable of disrupting the secondary bile acid biosynthesis. A future therapeutic approach for PCOS may involve the human administration of IL-22 and bile acid glycodeoxycholic acid. Full article

PCOS as the most common endocrine disorder of women in their reproductive age affects between 5–15% of the female population. Apart from its cardinal symptoms, like irregular and anovulatory cycles, hyperandrogenemia and a typical ultrasound feature of the ovary, obesity, and insulin resistance are often associated with the disease. Furthermore, PCOS represents a status of chronic inflammation with permanently elevated levels of inflammatory markers including IL-6 and IL-18, TNF-α, and CRP. Inflammation, as discovered only recently, consists of two processes occurring concomitantly: active initiation, involving “classical” mediators including prostaglandins and leukotrienes, and active resolution processes based on the action of so-called specialized pro-resolving mediators (SPMs). These novel lipid mediator molecules derive from the essential ω3-poly-unsaturated fatty acids (PUFAs) DHA and EPA and are synthesized via specific intermediates. The role and benefits of SPMs in chronic inflammatory diseases like obesity, atherosclerosis, and Diabetes mellitus has become a subject of intense research during the last years and since PCOS features several of these pathologies, this review aims at summarizing potential roles of SPMs in this disease and their putative use as novel therapeutics. Full article

Polycystic ovary syndrome (PCOS) is characterized by elevated androgen production and subclinical changes in cardiovascular and metabolic risk markers. Total cholesterol, high-density lipoprotein (HDL) cholesterol, fasting glucose, and fasting insulin appear to increase specifically in PCOS compared with fertile women. PCOS also confers an increased risk of cardiometabolic disease in later life. Novel biomarkers such as serum’s cholesterol efflux capacity and blood-derived macrophage activation profile may assist in more accurately defining the cardiometabolic risk profile in these women. Aldosterone antagonists, androgen receptor antagonists, 5α-reductase inhibitors, and synthetic progestogens are used to reduce hyperandrogenism. Because increased insulin secretion enhances ovarian androgen production, short-term treatment with metformin and other hypoglycemic agents results in significant weight loss, favorable metabolic changes, and testosterone reduction. The naturally occurring inositols display insulin-sensitizing effects and may be also used in this context because of their safety profile. Combined oral contraceptives represent the drug of choice for correction of androgen-related symptoms. Overall, PCOS management remains focused on specific targets including assessment and treatment of cardiometabolic risk, according to disease phenotypes. While new options are adding to established therapeutic approaches, a sometimes difficult balance between efficacy and safety of available medications has to be found in individual women. Full article

Polycystic ovary syndrome (PCOS) is an endocrine condition associated with reproductive and psychiatric disorders, and with obesity. Eating disorders, such as bulimia and recurrent dieting, are also linked to PCOS. They can lead to the epigenetic dysregulation of the hypothalamic–pituitary–gonadal (HPG) axis, thereby impacting on ovarian folliculogenesis. We postulate that PCOS is induced by psychological distress and episodes of overeating and/or dieting during puberty and adolescence, when body dissatisfaction and emotional distress are often present. We propose that upregulated activation of the central HPG axis during this period can be epigenetically altered by psychological stressors and by bulimia/recurrent dieting, which are common during adolescence and which can lead to PCOS. This hypothesis is based on events that occur during a largely neglected stage of female reproductive development. To date, most research into the origins of PCOS has focused on the prenatal induction of this disorder, particularly in utero androgenization and the role of anti-Müllerian hormone. Establishing causality in our peripubertal model requires prospective cohort studies from infancy. Mechanistic studies should consider the role of the gut microbiota in addition to the epigenetic regulation of (neuro) hormones. Finally, clinicians should consider the importance of underlying chronic psychological distress and eating disorders in PCOS. Full article

Human sex hormone-binding globulin (SHBG) is a glycoprotein produced by the liver that binds sex steroids with high affinity and specificity. Clinical observations and reports in the literature have suggested a negative correlation between circulating SHBG levels and markers of non-alcoholic fatty liver disease (NAFLD) and insulin resistance. Decreased SHBG levels increase the bioavailability of androgens, which in turn leads to progression of ovarian pathology, anovulation and the phenotypic characteristics of polycystic ovarian syndrome (PCOS). This review will use a case report to illustrate the inter-relationships between SHBG, NAFLD and PCOS. In particular, we will review the evidence that low hepatic SHBG production may be a key step in the pathogenesis of PCOS. Furthermore, there is emerging evidence that serum SHBG levels may be useful as a diagnostic biomarker and therapeutic target for managing women with PCOS. Full article

Polycystic ovary syndrome (PCOS) is a common endocrinopathy, characterized by chronic anovulation, hyperandrogenism, and multiple small subcapsular cystic follicles in the ovary during ultrasonography, and affects 5–10% of women of reproductive age. PCOS is frequently associated with insulin resistance (IR) accompanied by compensatory hyperinsulinemia and, therefore, presents an increased risk of type 2 diabetes mellitus (DM). The pathophysiology of PCOS is unclear, and many hypotheses have been proposed. Among these hypotheses, IR and hyperandrogenism may be the two key factors. The first line of treatment in PCOS includes lifestyle changes and body weight reduction. Achieving a 5–15% body weight reduction may improve IR and PCOS-associated hormonal abnormalities. For women who desire pregnancy, clomiphene citrate (CC) is the front-line treatment for ovulation induction. Twenty five percent of women may fail to ovulate spontaneously after three cycles of CC treatment, which is called CC-resistant PCOS. For CC-resistant PCOS women, there are many strategies to improve ovulation rate, including medical treatment and surgical approaches. Among the various surgical approaches, one particular surgical method, called laparoscopic ovarian drilling (LOD), has been proposed as an alternative treatment. LOD results in an overall spontaneous ovulation rate of 30–90% and final pregnancy rates of 13–88%. These benefits are more significant for women with CC-resistant PCOS. Although the intra- and post-operative complications and sequelae are always important, we believe that a better understanding of the pathophysiological changes and/or molecular mechanisms after LOD may provide a rationale for this procedure. LOD, mediated mainly by thermal effects, produces a series of morphological and biochemical changes. These changes include the formation of artificial holes in the very thick cortical wall, loosening of the dense and hard cortical wall, destruction of ovarian follicles with a subsequently decreased amount of theca and/or granulosa cells, destruction of ovarian stromal tissue with the subsequent development of transient but purulent and acute inflammatory reactions to initiate the immune response, and the continuing leakage or drainage of “toxic” follicular fluid in these immature and growth-ceased pre-antral follicles. All these factors contribute to decreasing local and systemic androgen levels, the following apoptosis process with these pre-antral follicles to atresia; the re-starting of normal follicular recruitment, development, and maturation, and finally, the normalization of the “hypothalamus–pituitary–ovary” axis and subsequent spontaneous ovulation. The detailed local and systematic changes in PCOS women after LOD are comprehensively reviewed in the current article. Full article

The presence of abnormal ovarian ratios of myo-inositol (MI) to D-chiro-inositol (DCI) is a recurrent feature in PCOS. Available evidence suggests that MI and DCI may modulate steroid biosynthesis, likely in an opposite manner. Specifically, MI seems to induce estrogen production, while DCI has a role in the synthesis of androgens. Elevated insulin levels, generally associated with PCOS, alter the physiological MI/DCI ratio, increasing MI-to-DCI conversion through activation of a specific epimerase enzyme. DCI directly increases testosterone biosynthesis in thecal cells and reduces its conversion to estradiol by downregulating aromatase enzyme in granulosa cells. This manuscript reviews the literature that supports the connection between altered MI/DCI ratios and pathological steroidogenesis observed in PCOS women. Furthermore, it discusses the application of inositol-based treatment protocols in managing PCOS symptoms and improving the quality of patients’ life. Full article

In a healthy female reproductive system, a subtle hormonal and metabolic dance leads to repetitive cyclic changes in the ovaries and uterus, which make an effective ovulation and potential implantation of an embryo possible. However, that is not so in the case of polycystic ovary syndrome (PCOS), in which case the central mechanism responsible for entraining hormonal and metabolic rhythms during the menstrual cycle is notably disrupted. In this review we provide a detailed description of the possible scenario of PCOS pathogenesis. We begin from the analysis of how a set of genetic disorders related to PCOS leads to particular malfunctions at a molecular level (e.g., increased enzyme activities of cytochrome P450 (CYP) type 17A1 (17$\alpha$-hydroxylase), 3$\beta$-HSD type II and CYP type 11A1 (side-chain cleavage enzyme) in theca cells, or changes in the expression of aquaporins in granulosa cells) and discuss further cellular- and tissue-level consequences (e.g., anovulation, elevated levels of the advanced glycation end products in ovaries), which in turn lead to the observed subsequent systemic symptoms. Since gene-editing therapy is currently out of reach, herein special emphasis is placed on discussing what kinds of drug targets and which potentially active substances seem promising for an effective medication, acting on the primary causes of PCOS on a molecular level. Full article

Pre-eclampsia is the most common pregnancy complication affecting 1 in 20 pregnancies, characterized by high blood pressure and signs of organ damage, most often to the liver and kidneys. Metabolic network analysis of published lipidomic data points to a shortage of Coenzyme A (CoA). Gene expression profile data reveal alterations to many areas of metabolism and, crucially, to conflicting cellular regulatory mechanisms arising from the overproduction of signalling lipids driven by CoA limitation. Adverse feedback loops appear, forming sphingosine-1-phosphate (a cause of hypertension, hypoxia and inflammation), cytotoxic isoketovaleric acid (inducing acidosis and organ damage) and a thrombogenic lysophosphatidyl serine. These also induce mitochondrial and oxidative stress, leading to untimely apoptosis, which is possibly the cause of CoA restriction. This work provides a molecular basis for the signs of pre-eclampsia, why polycystic ovary syndrome is a risk factor and what might be done to treat and reduce the risk of disease. Full article