Polycystic ovary syndrome.

Despite affecting ~11-13% of women globally, polycystic ovary syndrome (PCOS) is a substantially understudied condition. PCOS, possibly extending to men's health, imposes a considerable health and economic burden worldwide. Diagnosis in adults follows the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome, requiring two out of three criteria - clinical or biochemical hyperandrogenism, ovulatory dysfunction, and/or specific ovarian morphological characteristics or elevated anti-Müllerian hormone. However, diagnosing adolescents omits ovarian morphology and anti-Müllerian hormone considerations. PCOS, marked by insulin resistance and hyperandrogenism, strongly contributes to early-onset type 2 diabetes, with increased odds for cardiovascular diseases. Reproduction-related implications include irregular menstrual cycles, anovulatory infertility, heightened risks of pregnancy complications and endometrial cancer. Beyond physiological manifestations, PCOS is associated with anxiety, depression, eating disorders, psychosexual dysfunction and negative body image, collectively contributing to diminished health-related quality of life in patients. Despite its high prevalence persisting into menopause, diagnosing PCOS often involves extended timelines and multiple health-care visits. Treatment remains ad hoc owing to limited understanding of underlying mechanisms, highlighting the need for research delineating the aetiology and pathophysiology of the syndrome. Identifying factors contributing to PCOS will pave the way for personalized medicine approaches. Additionally, exploring novel biomarkers, refining diagnostic criteria and advancing treatment modalities will be crucial in enhancing the precision and efficacy of interventions that will positively impact the lives of patients.

Proteomic analysis shows decreased type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS.

Background: Polycystic ovary syndrome's (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead to changes in protein levels and biological function. Methods: To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry, and analyzed gene expression and methylation. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation. Results: Perilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. A mouse model was used to corroborate that androgen exposure leads to a shift in muscle fiber type in controls but not in skeletal muscle-specific androgen receptor knockout mice. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue. Conclusions: Our results suggest that hyperandrogenic women with PCOS have higher levels of extra-myocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading to insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective. Funding: Swedish Research Council (2020-02485, 2022-00550, 2020-01463), Novo Nordisk Foundation (NNF22OC0072904), and IngaBritt and Arne Lundberg Foundation. Clinical trial number NTC01457209.

Elevated circulating adiponectin levels do not prevent anxiety-like behavior in a PCOS-like mouse model.

Polycystic ovary syndrome (PCOS) is associated with symptoms of moderate to severe anxiety and depression. Hyperandrogenism is a key feature together with lower levels of the adipocyte hormone adiponectin. Androgen exposure leads to anxiety-like behavior in female offspring while adiponectin is reported to be anxiolytic. Here we test the hypothesis that elevated adiponectin levels protect against the development of androgen-induced anxiety-like behavior. Pregnant mice overexpressing adiponectin (APNtg) and wildtypes were injected with vehicle or dihydrotestosterone to induce prenatal androgenization (PNA) in the offspring. Metabolic profiling and behavioral tests were performed in 4-month-old female offspring. PNA offspring spent more time in the closed arms of the elevated plus maze, indicating anxiety-like behavior. Intriguingly, neither maternal nor offspring adiponectin overexpression prevented an anxiety-like behavior in PNA-exposed offspring. However, adiponectin overexpression in dams had metabolic imprinting effects, shown as lower fat mass and glucose levels in their offspring. While serum adiponectin levels were elevated in APNtg mice, cerebrospinal fluid levels were similar between genotypes. Adiponectin overexpression improved metabolic functions but did not elicit anxiolytic effects in PNA-exposed offspring. These observations might be attributed to increased circulating but unchanged cerebrospinal fluid adiponectin levels in APNtg mice. Thus, increased adiponectin levels in the brain are likely needed to stimulate anxiolytic effects.

International evidence-based guideline on assessment and management of PCOS-A Nordic perspective.

Polycystic ovary syndrome (PCOS) affects about 12% of women of reproductive age. In 2018, the first evidence-based guideline on assessment and management of PCOS was published, and an updated extended guideline was released in August 2023. These guidelines followed best practice and are endorsed by 39 organizations worldwide, making them the most robust source of evidence to guide clinical practice. In the 2023 guideline, diagnostic criteria have been further refined as polycystic ovary morphology can now be assessed with gynecological ultrasound or elevated anti-Müllerian hormone levels. A healthy lifestyle should be at the focus of care for all women with PCOS; however, with no specific diet or physical exercise recommended. The latest evidence on medical treatments and fertility management are reviewed, including special considerations regarding long-term follow-up of metabolic and psychiatric comorbidities and pregnancy in women with PCOS. Here we summarize the recommendations from a Nordic perspective.

Body image concerns in women with polycystic ovary syndrome: a systematic review and meta-analysis.

OBJECTIVE: To assess differences in body image concerns among women with and without polycystic ovary syndrome (PCOS). DESIGN: This is a systematic review and meta-analysis. METHODS: Electronic databases (MEDLINE, EMBASE, APA PsychInfo, PUBMED, Web-of-Science Core Collection, and Cochrane Controlled Register of Trials [CENTRAL]) were searched from inception through July 2022. Outcome measures included validated questionnaires reporting on body image concerns. Methodological quality was assessed by the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system, and included studies were assessed for risk of bias. Meta-analyses were performed using the inverse variance method based on random or fixed effects models (Review Manager, Version 5). RESULTS: A total of 918 women with PCOS and 865 women without PCOS from 9 studies were included. Meta-analysis of 3 studies using Multidimensional Body-Self Relations Questionnaire Appearance Scale (MBSRQ-AS) showed those with PCOS reported higher dissatisfaction with appearance evaluation and appearance orientation compared to those without PCOS (mean difference [MD] = -0.78, I2 = 0%, P < .00001, and MD = 0.22, I2 = 54%, P = .004, respectively). Meta-analysis of 2 studies showed higher dissatisfaction with overweight preoccupation, lower body area satisfaction, and body weight classification on MBSRQ-AS subscales in those with PCOS compared to those without PCOS (all P < .001). Meta-analysis of 2 studies using the Body Esteem Scale for Adolescents and Adults (BESAA) showed significantly lower scores for the weight subscale in those with PCOS compared to those without PCOS (P = .03). CONCLUSIONS: Those with PCOS experience more significant body image concerns, emphasising the importance of awareness in the clinical care of PCOS. Considering the limited evidence, further studies are warranted to identify drivers and mitigating factors.

The role of B cells in immune cell activation in polycystic ovary syndrome.

Variations in B cell numbers are associated with polycystic ovary syndrome (PCOS) through unknown mechanisms. Here, we demonstrate that B cells are not central mediators of PCOS pathology and that their frequencies are altered as a direct effect of androgen receptor activation. Hyperandrogenic women with PCOS have increased frequencies of age-associated double-negative B memory cells and increased levels of circulating immunoglobulin M (IgM). However, the transfer of serum IgG from women into wild-type female mice induces only an increase in body weight. Furthermore, RAG1 knockout mice, which lack mature T- and B cells, fail to develop any PCOS-like phenotype. In wild-type mice, co-treatment with flutamide, an androgen receptor antagonist, prevents not only the development of a PCOS-like phenotype but also alterations of B cell frequencies induced by dihydrotestosterone (DHT). Finally, B cell-deficient mice, when exposed to DHT, are not protected from developing a PCOS-like phenotype. These results urge further studies on B cell functions and their effects on autoimmune comorbidities highly prevalent among women with PCOS.

Polycystic ovary syndrome is a lifelong condition associated with disrupted hormone levels, which affects around 15-20% of women. Characterised by increased levels of male sex hormones released by ovaries and adrenal glands, the condition affects menstrual cycles and can cause infertility and diabetes. Alongside the increase in male sex hormones, changes in the number of B cells have recently been observed in polycystic ovary syndrome. B cells produce antibodies that are important for fighting infection. However, it is thought that they might aggravate the condition by releasing antibodies and other inflammatory molecules which instead attack the body. It remained unclear whether changes in the B cell numbers were a result of excessive hormone levels or whether the B cells themselves were responsible for increasing the levels of male sex hormones. Ascani et al. showed that exposing female mice to excess male sex hormones leads to symptoms of polycystic ovary syndrome and causes the same changes to B cell frequencies as observed in women. This effect was prevented by simultaneously treating mice with a drug that blocks the action of male sex hormones. On the other hand, transferring antibodies from women with polycystic ovary syndrome to mice led to greater body weight and variation in B cell numbers. However, it did not result in clear symptoms of polycystic ovary syndrome. Furthermore, mice without B cells still developed symptoms when exposed to male sex hormones, showing that B cells alone are not solely responsible for the development of the condition. Taken together, the experiments show that B cells are not central mediators of polycystic ovary syndrome and the variation in their numbers is due to excess male sex hormones. This raises the question of whether B cells are an appropriate target for the treatment of this complex condition and paves the way for studies on how other immune cells are altered by hormones. Future work should also investigate how B cell function affects symptoms associated with polycystic ovary syndrome, given the association between antibody transfer and weight gain in mice.

Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome.

The transgenerational maternal effects of polycystic ovary syndrome (PCOS) in female progeny are being revealed. As there is evidence that a male equivalent of PCOS may exists, we ask whether sons born to mothers with PCOS (PCOS-sons) transmit reproductive and metabolic phenotypes to their male progeny. Here, in a register-based cohort and a clinical case-control study, we find that PCOS-sons are more often obese and dyslipidemic. Our prenatal androgenized PCOS-like mouse model with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in first-generation (F1) male offspring are passed down to F3. Sequencing of F1-F3 sperm reveals distinct differentially expressed (DE) small non-coding RNAs (sncRNAs) across generations in each lineage. Notably, common targets between transgenerational DEsncRNAs in mouse sperm and in PCOS-sons serum indicate similar effects of maternal hyperandrogenism, strengthening the translational relevance and highlighting a previously underappreciated risk of transmission of reproductive and metabolic dysfunction via the male germline.

Transcriptomic survey of key reproductive and metabolic tissues in mouse models of polycystic ovary syndrome.

Excessive androgen production and obesity are key to polycystic ovary syndrome (PCOS) pathogenesis. Prenatal androgenized (PNA), peripubertal androgenized, and overexpression of nerve growth factor in theca cells (17NF) are commonly used PCOS-like mouse models and diet-induced maternal obesity model is often included for comparsion. To reveal the molecular features of these models, we have performed transcriptome survey of the hypothalamus, adipose tissue, ovary and metaphase II (MII) oocytes. The largest number of differentially expressed genes (DEGs) is found in the ovaries of 17NF and in the adipose tissues of peripubertal androgenized models. In contrast, hypothalamus is most affected in PNA and maternal obesity models suggesting fetal programming effects. The Ms4a6e gene, membrane-spanning 4-domains subfamily A member 6E, a DEG identified in the adipose tissue in all mouse models is also differently expressed in adipose tissue of women with PCOS, highlighting a conserved disease function. Our comprehensive transcriptomic profiling of key target tissues involved in PCOS pathology highlights the effects of developmental windows for androgen exposure and maternal obesity, and provides unique resource to investigate molecular mechanisms underlying PCOS pathogenesis.

Transcriptome-wide association analyses identify an association between ARL14EP and polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, which is accompanied by a variety of comorbidities including metabolic, reproductive, and psychiatric disorders. Genome-wide association studies have identified several genetic variants that are associated with PCOS. However, these variants often occur outside of coding regions and require further investigation to understand their contribution to PCOS. A transcriptome-wide association study (TWAS) was performed to uncover heritable gene expression profiles that are associated with PCOS in two independent cohorts. Causal gene prioritization was subsequently performed and expression of genes prioritized through these analyses was examined in 49 PCOS patients and 30 controls. TWAS analyses revealed that increased expression of ARL14EP was significantly associated with PCOS risk in the discovery (P = 1.6 × 10-6) and replication cohorts (P = 2.0 × 10-13). Gene prioritization pipelines provided further evidence that ARL14EP is the most likely causal gene at this locus. ARL14EP gene expression was shown to be significantly different between PCOS cases and controls, after adjusting for body mass index, age and testosterone levels (P = 1.2 × 10-13). This study has provided evidence for the role of ARL14EP in PCOS. Given that ARL14EP has been reported to play an important role in chromatin remodeling, variants affecting the expression of ARL14EP may also affect the expression of other genes that contribute to PCOS pathogenesis.

Update on Animal Models of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a complex disease affecting up to 15% of women of reproductive age. Women with PCOS suffer from reproductive dysfunctions with excessive androgen secretion and irregular ovulation, leading to reduced fertility and pregnancy complications. The syndrome is associated with a wide range of comorbidities including type 2 diabetes, obesity, and psychiatric disorders. Despite the high prevalence of PCOS, its etiology remains unclear. To understand the pathophysiology of PCOS, how it is inherited, and how to predict PCOS, and prevent and treat women with the syndrome, animal models provide an important approach to answering these fundamental questions. This minireview summarizes recent investigative efforts on PCOS-like rodent models aiming to define underlying mechanisms of the disease and provide guidance in model selection. The focus is on new genetic rodent models, on a naturally occurring rodent model, and provides an update on prenatal and peripubertal exposure models.

Circulating Anti-Müllerian hormone in a cohort-study of women with severe obesity with and without polycystic ovary syndrome and the effect of a one-year weight loss intervention.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) have high circulating anti-Müllerian hormone (AMH) levels which is correlated with antral follicle count and polycystic ovarian morphology and negatively correlated with body mass index (BMI). Moreover, diet-induced weight loss in women with PCOS and overweight or obesity, reduce or normalize AMH-levels. There is, however, no previous study investigating the circulating AMH levels in women with severe obesity and how a structured diet-induced weight loss program affects circulating AMH levels in these women. Therefore, this study aims to investigate circulating AMH levels in a population of women with severe obesity (BMI ≥ 35 kg/m2) with and without PCOS, as diagnosed by the NIH-criteria, and to investigate the effect of a one-year weight loss program with a very low-energy diet (VLED) on circulating levels of AMH. METHODS: In a prospective cohort-study, were 246 women with severe obesity were screened for PCOS diagnosis with the NIH-criteria, circulating AMH and anthropometry were measured at baseline and after a 12-month weight loss intervention with very low-energy diet (VLED). RESULTS: Mean BMI was 39.9 ± 4.7 (PCOS), 39.6 ± 4.3 (non-PCOS) P = 0.960. Circulating AMH was higher in women with PCOS (5.47 ± 4.89 µg/L) compared with non-PCOS (2.66 ± 3.71 µg/L) P < 0.001 and was positively correlated with circulating total testosterone in both groups. Next, we performed ROC-analyses, and show that circulating AMH could not discriminate women with PCOS and severe obesity from non-PCOS women with severe obesity. Finally, a one-year weight reduction program does not affect circulating AMH levels despite significant weight loss neither in women with PCOS, nor without PCOS and severe obesity. CONCLUSION: Women with severe obesity and PCOS have elevated levels of circulating AMH compared to women without the syndrome. AMH-levels could not discriminate women with PCOS from non-PCOS because of low sensitivity and specificity. Significant weight loss was not associated with changes in circulating AMH levels, neither in women with, nor without PCOS and severe obesity. These results imply that in women with severe obesity, a greater weight loss may be needed to improve reproductive features, independent of PCOS diagnosis. TRIAL REGISTRATION NUMBER: Clinical trial.gov: NCT01319162.

Polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) affects 5-18% of women, and is a reproductive, metabolic, and psychological condition with impacts across the lifespan. The cause is complex, and includes genetic and epigenetic susceptibility, hypothalamic and ovarian dysfunction, excess androgen exposure, insulin resistance, and adiposity-related mechanisms. Diagnosis is recommended based on the 2003 Rotterdam criteria and confirmed with two of three criteria: hyperandrogenism (clinical or biochemical), irregular cycles, and polycystic ovary morphology. In adolescents, both the criteria of hyperandrogenism and irregular cycles are needed, and ovarian morphology is not included due to poor specificity. The diagnostic criteria generates four phenotypes, and clinical features are heterogeneous, with manifestations typically arising in childhood and then evolving across adolescent and adult life. Treatment involves a combination of lifestyle alterations and medical management. Lifestyle optimisation includes a healthy balanced diet and regular exercise to prevent excess weight gain, limit PCOS complications and target weight reduction when needed. Medical management options include metformin to improve insulin resistance and metabolic features, combined oral contraceptive pill for menstrual cycle regulation and hyperandrogenism, and if needed, anti-androgens for refractory hyperandrogenism. In this Review, we provide an update on the pathophysiology, diagnosis, and clinical features of PCOS, and discuss the needs and priorities of those with PCOS, including lifestyle, and medical and infertility treatment. Further we discuss the status of international evidence-based guidelines (EBG) and translation, to support patient self management, healthcare provision, and to set research priorities.

A genome-wide cross-trait analysis identifies shared loci and causal relationships of type 2 diabetes and glycaemic traits with polycystic ovary syndrome.

AIMS/HYPOTHESIS: The link underlying abnormal glucose metabolism, type 2 diabetes and polycystic ovary syndrome (PCOS) that is independent of BMI remains unclear in observational studies. We aimed to clarify this association using a genome-wide cross-trait approach. METHODS: Summary statistics from the hitherto largest genome-wide association studies conducted for type 2 diabetes, type 2 diabetes mellitus adjusted for BMI (T2DMadjBMI), fasting glucose, fasting insulin, 2h glucose after an oral glucose challenge (all adjusted for BMI), HbA1c and PCOS, all in populations of European ancestry, were used. We quantified overall and local genetic correlations, identified pleiotropic loci and expression-trait associations, and made causal inferences across traits. RESULTS: A positive overall genetic correlation between type 2 diabetes and PCOS was observed, largely influenced by BMI (rg=0.31, p=1.63×10-8) but also independent of BMI (T2DMadjBMI-PCOS: rg=0.12, p=0.03). Sixteen pleiotropic loci affecting type 2 diabetes, glycaemic traits and PCOS were identified, suggesting mechanisms of association that are independent of BMI. Two shared expression-trait associations were found for type 2 diabetes/T2DMadjBMI and PCOS targeting tissues of the cardiovascular, exocrine/endocrine and digestive systems. A putative causal effect of fasting insulin adjusted for BMI and type 2 diabetes on PCOS was demonstrated. CONCLUSIONS/INTERPRETATION: We found a genetic link underlying type 2 diabetes, glycaemic traits and PCOS, driven by both biological pleiotropy and causal mediation, some of which is independent of BMI. Our findings highlight the importance of controlling fasting insulin levels to mitigate the risk of PCOS, as well as screening for and long-term monitoring of type 2 diabetes in all women with PCOS, irrespective of BMI.

Genomic correlation, shared loci, and causal relationship between obesity and polycystic ovary syndrome: a large-scale genome-wide cross-trait analysis.

BACKGROUND: The comorbidity between polycystic ovary syndrome (PCOS) and obesity has long been observed in clinical settings, but their shared genetic basis remains unclear. METHODS: Leveraging summary statistics of large-scale GWAS(s) conducted in European-ancestry populations on body mass index (adult BMI, Nfemale=434,794; childhood BMI, N=39,620), waist-to-hip ratio (WHR, Nfemale=381,152), WHR adjusted for BMI (WHRadjBMI, Nfemale=379,501), and PCOS (Ncase=10,074, Ncontrol=103,164), we performed a large-scale genome-wide cross-trait analysis to quantify overall and local genetic correlation, to identify shared loci, and to infer causal relationship. RESULTS: We found positive genetic correlations between PCOS and adult BMI (rg=0.47, P=2.19×10-16), childhood BMI (rg=0.31, P=6.72×10-5), and WHR (rg=0.32, P=1.34×10-10), all withstanding Bonferroni correction. A suggestive significant genetic correlation was found between PCOS and WHRadjBMI (rg=0.09, P=0.04). Partitioning the whole genome into 1703 nearly independent regions, we observed a significant local genetic correlation for adult BMI and PCOS at chromosome 18: 57630483-59020751. We identified 16 shared loci underlying PCOS and obesity-related traits via cross-trait meta-analysis including 9 loci shared between BMI and PCOS (adult BMI and PCOS: 5 loci; childhood BMI and PCOS: 4 loci), 6 loci shared between WHR and PCOS, and 5 loci shared between WHRadjBMI and PCOS. Mendelian randomization (MR) supported the causal roles of both adult BMI (OR=2.92, 95% CI=2.33-3.67) and childhood BMI (OR=2.76, 95% CI=2.09-3.66) in PCOS, but not WHR (OR=1.19, 95% CI=0.93-1.52) or WHRadjBMI (OR=1.03, 95% CI=0.87-1.22). Genetic predisposition to PCOS did not seem to influence the risk of obesity-related traits. CONCLUSIONS: Our cross-trait analysis suggests a shared genetic basis underlying obesity and PCOS and provides novel insights into the biological mechanisms underlying these complex traits. Our work informs public health intervention by confirming the important role of weight management in PCOS prevention.

Effect of acupuncture and metformin on insulin sensitivity in women with polycystic ovary syndrome and insulin resistance: a three-armed randomized controlled trial.

STUDY QUESTION: Does acupuncture improve insulin sensitivity more effectively than metformin or sham acupuncture in women with polycystic ovary syndrome (PCOS) and insulin resistance (IR)? SUMMARY ANSWER: Among women with PCOS and IR, acupuncture was not more effective than metformin or sham acupuncture in improving insulin sensitivity. WHAT IS KNOWN ALREADY: Uncontrolled trials have shown that acupuncture improved insulin sensitivity with fewer side effects compared with metformin in women with PCOS and IR. However, data from randomized trials between acupuncture and metformin or sham acupuncture are lacking. STUDY DESIGN, SIZE, DURATION: This was a three-armed randomized controlled trial enrolling a total of 342 women with PCOS and IR from three hospitals between November 2015 and February 2018, with a 3-month follow-up until October 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged from 18 to 40 years with PCOS and homeostasis model assessment of insulin resistance (HOMA-IR) ≥2.14 were randomly assigned (n = 114 per group) to receive true acupuncture plus placebo (true acupuncture), metformin plus sham acupuncture (metformin, 0.5 g three times daily) or sham acupuncture plus placebo (sham acupuncture) for 4 months, with an additional 3-month follow-up. True or sham acupuncture was given three times per week, and 0.5 g metformin or placebo was given three times daily. The primary outcome was change in HOMA-IR from baseline to 4 months after baseline visit. Secondary outcomes included changes in the glucose AUC during an oral glucose tolerance test, BMI and side effects at 4 months after baseline visit. MAIN RESULTS AND THE ROLE OF CHANCE: After 4 months of treatment, the changes of HOMA-IR were -0.5 (decreased 14.7%) in the true acupuncture group, -1.0 (decreased 25.0%) in the metformin group and -0.3 (decreased 8.6%) in the sham acupuncture group, when compared with baseline. True acupuncture is not as effective as metformin in improving HOMA-IR at 4 months after baseline visit (difference, 0.6; 95% CI, 0.1-1.1). No significant difference was found in change in HOMA-IR between true and sham acupuncture groups at 4 months after baseline visit (difference, -0.2; 95% CI, -0.7 to 0.3). During the 4 months of treatment, gastrointestinal side effects were more frequent in the metformin group, including diarrhea, nausea, loss of appetite, fatigue, vomiting and stomach discomfort (31.6%, 13.2%, 11.4%, 8.8%, 14.0% and 8.8%, respectively). Bruising was more common in the true acupuncture group (14.9%). LIMITATIONS, REASONS FOR CAUTION: This study might have underestimated the sample size in the true acupuncture group with 4 months of treatment to enable detection of statistically significant changes in HOMA-IR with fixed acupuncture (i.e. a non-personalized protocol). Participants who withdrew because of pregnancy did not have further blood tests and this can introduce bias. WIDER IMPLICATIONS OF THE FINDINGS: True acupuncture did not improve insulin sensitivity as effectively as metformin in women with PCOS and IR, but it is better than metformin in improving glucose metabolism (which might reduce the risk of type 2 diabetes) and has less side effects. Metformin had a higher incidence of gastrointestinal adverse effects than acupuncture groups, and thus acupuncture might be a non-pharmacological treatment with low risk for women with PCOS. Further studies are needed to evaluate the effect of acupuncture combined with metformin on insulin sensitivity in these women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants 2017A020213004 and 2014A020221060 from the Science and Technology Planning Project of Guangdong Province. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov number: NCT02491333. TRIAL REGISTRATION DATE: 8 July 2015. DATE OF FIRST PATIENT'S ENROLLMENT: 11 November 2015.

Epigenetic inheritance of polycystic ovary syndrome - challenges and opportunities for treatment.

Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and is associated with a substantially increased lifetime risk of comorbidities, including type 2 diabetes mellitus, psychiatric disorders and gynaecological cancers. Despite its high prevalence (~15%) and substantial economic burden, the aetiology of PCOS remains elusive. The genetic loci linked to PCOS so far account for only ~10% of its heritability, which is estimated at 70%. However, growing evidence suggests that altered epigenetic and developmental programming resulting from hormonal dysregulation of the maternal uterine environment contributes to the pathogenesis of PCOS. Male as well as female relatives of women with PCOS are also at an increased risk of developing PCOS-associated reproductive and metabolic disorders. Although PCOS phenotypes are highly heterogenous, hyperandrogenism is thought to be the principal driver of this condition. Current treatments for PCOS are suboptimal as they can only alleviate some of the symptoms; preventative and targeted treatments are sorely needed. This Review presents an overview of the current understanding of the aetiology of PCOS and focuses on the developmental origin and epigenetic inheritance of this syndrome.

Transmission of Polycystic Ovary Syndrome via Epigenetic Inheritance.

A recent study by Mimouni et al. shows that late gestation exposure to anti-Müllerian hormone (AMH) results in transgenerational transmission of a polycystic ovary syndrome (PCOS)-like phenotype in mice. Altered DNA methylation underlies transmission and was also observed in women with PCOS. Epigenetics-based therapy reversed some PCOS-like phenotypic traits when applied to F3 female mice.

Prenatal androgen exposure causes a sexually dimorphic transgenerational increase in offspring susceptibility to anxiety disorders.

If and how obesity and elevated androgens in women with polycystic ovary syndrome (PCOS) affect their offspring's psychiatric health is unclear. Using data from Swedish population health registers, we showed that daughters of mothers with PCOS have a 78% increased risk of being diagnosed with anxiety disorders. We next generated a PCOS-like mouse (F0) model induced by androgen exposure during late gestation, with or without diet-induced maternal obesity, and showed that the first generation (F1) female offspring develop anxiety-like behavior, which is transgenerationally transmitted through the female germline into the third generation of female offspring (F3) in the androgenized lineage. In contrast, following the male germline, F3 male offspring (mF3) displayed anxiety-like behavior in the androgenized and the obese lineages. Using a targeted approach to search for molecular targets within the amygdala, we identified five differentially expressed genes involved in anxiety-like behavior in F3 females in the androgenized lineage and eight genes in the obese lineage. In mF3 male offspring, three genes were dysregulated in the obese lineage but none in the androgenized lineage. Finally, we performed in vitro fertilization (IVF) using a PCOS mouse model of continuous androgen exposure. We showed that the IVF generated F1 and F2 offspring in the female germline did not develop anxiety-like behavior, while the F2 male offspring (mF2) in the male germline did. Our findings provide evidence that elevated maternal androgens in PCOS and maternal obesity may underlie the risk of a transgenerational transmission of anxiety disorders in children of women with PCOS.

Excess of ovarian nerve growth factor impairs embryonic development and causes reproductive and metabolic dysfunction in adult female mice.

Nerve growth factor (NGF) is critical for the development and maintenance of the peripheral sympathetic neurons. NGF is also involved in the ovarian sympathetic innervation and in the development and maintenance of folliculogenesis. Women with the endocrine disorder, polycystic ovary syndrome (PCOS), have an increased sympathetic nerve activity and increased ovarian NGF levels. The role of ovarian NGF excess in the PCOS pathophysiology and in the PCOS-related features is unclear. Here, using transgenic mice overexpressesing NGF in the ovarian theca cells (17NF mice), we assessed the female embryonic development, and the reproductive and metabolic profile in adult females. Ovarian NGF excess caused growth restriction in the female fetuses, and a delayed gonocyte and primary oocyte maturation. In adulthood, the 17NF mice displayed irregular estrous cycles and altered ovarian expression of steroidogenic and epigenetic markers. They also exhibited an increased sympathetic output with increased circulating dopamine, and metabolic dysfunction reflected by aberrant adipose tissue morphology and function, impaired glucose metabolism, decreased energy expenditure, and hepatic steatosis. These findings indicate that ovarian NGF excess leads to adverse fetal development and to reproductive and metabolic complications in adulthood, mirroring common features of PCOS. This work provides evidence that NGF excess may be implicated in the PCOS pathophysiology.