Adiposity is associated with anovulation independent of serum free testosterone: A prospective cohort study.

BACKGROUND: Obesity, a body mass index (BMI) ≥30 kg/m2 , is linked to infertility, potentially through a greater risk of anovulation due to elevated androgens. Yet, previous studies have not directly assessed the impact of adiposity, or body fat, on anovulation in the absence of clinical infertility. OBJECTIVE: To characterise the associations between adiposity and anovulation among women menstruating on a regular basis. METHODS: Women from the EAGeR trial (n = 1200), a randomised controlled trial of low-dose aspirin and pregnancy loss among women trying to conceive, were used to estimate associations between adiposity and incident anovulation. Participants completed baseline questionnaires and anthropometry, and provided blood specimens. Women used fertility monitors for up to six consecutive menstrual cycles, with collection of daily first morning voids for hormone analysis in the first two menstrual cycles for prospective assessment of anovulation. Anovulation was assessed by urine pregnanediol glucuronide or luteinising hormone concentration or the fertility monitor. Weighted mixed-effects log-binomial regression was used to estimate associations between measures of adiposity and incident anovulation, adjusted for free (bioavailable) testosterone, anti-Mullerian hormone (AMH), serum lipids, and demographic and life style factors. RESULTS: 343 (28.3%) women experienced at least one anovulatory cycle. Anovulation risk was higher per kg/m2 greater BMI (relative risk [RR] 1.03, 95% confidence interval (CI) 1.01, 1.04), cm waist circumference (RR 1.01, 95% CI 1.00, 1.02), mm subscapular skinfold (RR 1.02, 95% CI 1.01, 1.03), and mm middle upper arm circumference (RR 1.04, 95% CI 1.01, 1.06) adjusted for serum free testosterone, AMH, lipids, and other factors. CONCLUSIONS: Adiposity may be associated with anovulation through pathways other than testosterone among regularly menstruating women. This may account in part for reported associations between greater adiposity and infertility among women having menstrual cycles regularly. Understanding the association between adiposity and anovulation might lead to targeted interventions for preventing infertility.

Prevalence and risk factors related to anovular phenotypes in dairy cows.

The objective of the current study was to evaluate the relationship of body condition score (BCS) at 35 d in milk (DIM), milk production, diseases, and duration of the dry period with prevalence of anovulation at 49 DIM and then, specifically, with the prevalence of each anovular phenotype. We hypothesized that anovular follicular phenotypes, classified based on maximal size of the anovular follicle, have different etiologies. A total of 942 lactating Holstein cows (357 primiparous and 585 multiparous) from 1 herd had ovaries evaluated by ultrasonography at 35 ± 3 and 49 ± 3 DIM to detect the absence of a corpus luteum (CL), and to measure the diameter of the largest follicle. Cows were classified as cyclic at 49 DIM if a CL was observed in at least 1 of the 2 examinations, or anovular if no CL was observed at either examination. Cows considered anovular were divided into 3 groups based on the largest diameter of the largest follicle as follows: ranging from 8 to 13 mm, 14 to 17 mm, or ≥18 mm. Cows were evaluated for the following diseases: retained placenta, metritis, hyperketonemia, mastitis, lameness, respiratory problem, and digestive problem. At 35 DIM, BCS was determined, and milk yield for individual cows was recorded. A total of 28.5% (268/942) of cows were classified as anovular. Anovular cows had longer dry periods (90 vs. 71 d) and smaller BCS than cyclic cows (2.83 vs. 2.99). Cows with a single disease or multiple diseases had 2 and 3-fold increase in odds of being anovular, respectively. Anovular cows had follicles that ranged from 4 to 50 mm. The prevalence of anovular phenotype, among anovular cows, that had the diameter of the largest follicle ranging from 8 to 13 mm, 14 to 17 mm, and ≥18 mm was 29.9 (79/264), 37.5 (99/264), and 32.6% (86/264), respectively. Anovular cows with follicles of 8 to 13 mm had longer dry periods than those with follicles ≥18 mm (104 vs. 74 d), whereas anovular cows with medium size follicles had intermediate days dry (99 d). Cows with small and medium anovular follicles had smaller BCS and greater prevalence of multiple diseases than cyclic cows. For almost all risk factors, the cows with large anovular follicles (≥18 mm) were similar to cyclic cows and different from cows with smaller anovular follicles (8-13 mm). Thus, longer dry periods, less BCS at 35 DIM, and diseases were risk factors for anovulation. Moreover, the risk factors for the 3 distinct anovular follicle phenotypes differed.

Lifestyle and environmental contributions to ovulatory dysfunction in women of polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common reason of anovulatory infertility. Environmental factor is one of the main causes of PCOS, but its contribution to ovulatory dysfunction in PCOS remains unknown. METHODS: A total of 2217 infertile women diagnosed as PCOS according to Rotterdam criteria were recruited, including 1979 women with oligo-anovulation (OA group) and 238 women with normal -anovulation (non OA group). Besides, 279 healthy control women of reproductive age were enrolled as controls. RESULTS: Frequencies of snoring (PCOS-OA group, PCOS-non-OA group, control group: 29.30% vs 18.10% vs 11.50%, P < 0.01), smoking (37.70% vs 28.10% vs 12.20%, P < 0.01), plastic tableware usage (38.30% vs 28.10% vs 25.40%, P < 0.01) and indoor decoration (32.10% vs 24.80% vs 16.80%, P < 0.01) were highest in PCOS-OA group. After adjusted for multivariable, difference remained significant between PCOS-OA group and the other two groups. PCOS-OA women preferred a meat favorable diet compared to PCOS-non-OA group (54.60% vs 41.30%, P < 0.01). There was no difference between three groups in exercise, frequency of insomnia, and alcohol consumption. CONCLUSIONS: Smoking, snoring, hyper-caloric diet, plastic tableware usage and indoor decoration were found to be associated with an increased risk for ovulatory dysfunction in women suffering from PCOS.

Laparoscopic ovarian drilling for ovulation induction in women with anovulatory polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common condition affecting 8% to 13% of reproductive-aged women. In the past clomiphene citrate (CC) used to be the first-line treatment in women with PCOS. Ovulation induction with letrozole should be the first-line treatment according to new guidelines, but the use of letrozole is off-label. Consequently, CC is still commonly used. Approximately 20% of women on CC do not ovulate. Women who are CC-resistant can be treated with gonadotrophins or other medical ovulation-induction agents. These medications are not always successful, can be time-consuming and can cause adverse events like multiple pregnancies and cycle cancellation due to an excessive response. Laparoscopic ovarian drilling (LOD) is a surgical alternative to medical treatment. There are risks associated with surgery, such as complications from anaesthesia, infection, and adhesions. OBJECTIVES: To evaluate the effectiveness and safety of LOD with or without medical ovulation induction compared with medical ovulation induction alone for women with anovulatory polycystic PCOS and CC-resistance. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group (CGFG) trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers up to 8 October 2019, together with reference checking and contact with study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of women with anovulatory PCOS and CC resistance who underwent LOD with or without medical ovulation induction versus medical ovulation induction alone, LOD with assisted reproductive technologies (ART) versus ART, LOD with second-look laparoscopy versus expectant management, or different techniques of LOD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risks of bias, extracted data and evaluated the quality of the evidence using the GRADE method. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. Pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS), ovulation, costs, and quality of life were secondary outcomes. MAIN RESULTS: This updated review includes 38 trials (3326 women). The evidence was very low- to moderate-quality; the main limitations were due to poor reporting of study methods, with downgrading for risks of bias (randomisation and allocation concealment) and lack of blinding. Laparoscopic ovarian drilling with or without medical ovulation induction versus medical ovulation induction alone Pooled results suggest LOD may decrease live birth slightly when compared with medical ovulation induction alone (odds ratio (OR) 0.71, 95% confidence interval (CI) 0.54 to 0.92; 9 studies, 1015 women; I2 = 0%; low-quality evidence). The evidence suggest that if the chance of live birth following medical ovulation induction alone is 42%, the chance following LOD would be between 28% and 40%. The sensitivity analysis restricted to only RCTs with low risk of selection bias suggested there is uncertainty whether there is a difference between the treatments (OR 0.90, 95% CI 0.59 to 1.36; 4 studies, 415 women; I2 = 0%, low-quality evidence). LOD probably reduces multiple pregnancy rates (Peto OR 0.34, 95% CI 0.18 to 0.66; 14 studies, 1161 women; I2 = 2%; moderate-quality evidence). This suggests that if we assume the risk of multiple pregnancy following medical ovulation induction is 5.0%, the risk following LOD would be between 0.9% and 3.4%. Restricting to RCTs that followed women for six months after LOD and six cycles of ovulation induction only, the results for live birth were consistent with the main analysis. There may be little or no difference between the treatments for the likelihood of a clinical pregnancy (OR 0.86, 95% CI 0.72 to 1.03; 21 studies, 2016 women; I2 = 19%; low-quality evidence). There is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage (OR 1.11, 95% CI 0.78 to 1.59; 19 studies, 1909 women; I2 = 0%; low-quality evidence). OHSS was a very rare event. LOD may reduce OHSS (Peto OR 0.25, 95% CI 0.07 to 0.91; 8 studies, 722 women; I2 = 0%; low-quality evidence). Unilateral LOD versus bilateral LOD Due to the small sample size, the quality of evidence is insufficient to justify a conclusion on live birth (OR 0.83, 95% CI 0.24 to 2.78; 1 study, 44 women; very low-quality evidence). There were no data available on multiple pregnancy. The likelihood of a clinical pregnancy is uncertain between the treatments, due to the quality of the evidence and the large heterogeneity between the studies (OR 0.57, 95% CI 0.39 to 0.84; 7 studies, 470 women; I2 = 60%, very low-quality evidence). Due to the small sample size, the quality of evidence is not sufficient to justify a conclusion on miscarriage (OR 1.02, 95% CI 0.31 to 3.33; 2 studies, 131 women; I2 = 0%; very low-quality evidence). Other comparisons Due to lack of evidence and very low-quality data there is uncertainty whether there is a difference for any of the following comparisons: LOD with IVF versus IVF, LOD with second-look laparoscopy versus expectant management, monopolar versus bipolar LOD, and adjusted thermal dose versus fixed thermal dose. AUTHORS' CONCLUSIONS: Laparoscopic ovarian drilling with and without medical ovulation induction may decrease the live birth rate in women with anovulatory PCOS and CC resistance compared with medical ovulation induction alone. But the sensitivity analysis restricted to only RCTs at low risk of selection bias suggests there is uncertainty whether there is a difference between the treatments, due to uncertainty around the estimate. Moderate-quality evidence shows that LOD probably reduces the number of multiple pregnancy. Low-quality evidence suggests that there may be little or no difference between the treatments for the likelihood of a clinical pregnancy, and there is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage. LOD may result in less OHSS. The quality of evidence is insufficient to justify a conclusion on live birth, clinical pregnancy or miscarriage rate for the analysis of unilateral LOD versus bilateral LOD. There were no data available on multiple pregnancy.

Defining polycystic ovary syndrome phenotype in Vietnamese women.

AIM: This study aimed to evaluate the unique phenotype of the Vietnamese polycystic ovarian syndrome (PCOS) population. METHODS: In this multicenter cross-sectional descriptive study, a total of 901 reproductive-age women were recruited at three medical centers in Vietnam from June 2016 to May 2018. Group I included 479 patients with PCOS (Rotterdam 2003 consensus) and Group II included 422 non-PCOS women, consisted of women with regular menstrual cycle, collected at the same time of PCOS recruitment, without ovarian disease or ovarian failure. Main outcome measures were anthropomorphic, serum hormone, ultrasound and physical characteristics of PCOS. RESULTS: The Vietnamese PCOS population was lean, but with a higher weight and body mass index compared to controls. About 34.4% of PCOS subjects had hirsutism, primarily confined to the leg, arm and pubis. The PCOS population had higher serum luteinizing hormone (LH), LH : follicle stimulating hormone ratio, anti-Mullerian hormone and testosterone. The PCOS population had double the ovarian volume compared to controls. PCOS subjects had no increase in metabolic disease history and had on average optimal serum markers for low metabolic disease risk. Group D (O + polycystic ovary morphology [PCOM]) was the most prevalent phenotype noted in our Vietnamese PCOS cohort (67.6%). Modified Ferriman-Gallwey, levels of LH, testosterone and anti-Mullerian hormone were highest in Group A (O + H + PCOM) and lowest in Group D (O + PCOM). CONCLUSION: The Vietnamese PCOS population is characterized by a lean body type, nonfacial hirsutism, anovulatory, enlarged ovaries and typical PCOS serum hormone markers, low risk factors for metabolic syndrome. Nonclassical phenotypes for PCOS were more frequent than the classic phenotype.

Lysyl oxidase blockade ameliorates anovulation in polycystic ovary syndrome.

STUDY QUESTION: Is overexpression of lysyl oxidase (LOX), an enzyme responsible for the cross-linking of collagens, a cause of anovulation in polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: LOX overexpression was present in PCOS ovaries, due at least in part to interleukin-1ß (IL-1ß), and inhibition of LOX activity with ß-aminopropionitrile (BAPN) ameliorated polycystic ovary morphology and anovulation. WHAT IS KNOWN ALREADY: Aberrant ovarian extracellular matrix (ECM) remodeling and inflammation may contribute to the development of PCOS. It remains unknown whether proinflammatory IL-1ß is a contributing factor for LOX overexpression in PCOS ovaries and whether inhibition of LOX can improve PCOS conditions. STUDY DESIGN, SIZE, DURATION: LOX and IL-1ß abundance in the granulosa cells and follicular fluid was compared between non-PCOS (n = 30) and PCOS (n = 39) patients. The effect and mechanism of IL-1ß on LOX expression was examined in cultured primary human granulosa cells. The improvements in PCOS conditions by LOX inhibition with BAPN was investigated in a dehydroepiandrosterone (DHEA)-induced PCOS rat model. PARTICIPANTS/MATERIALS, SETTING, METHODS: The abundance of LOX and IL-1ß was measured with quantitative real-time polymerase chain reaction (qRT-PCR), LOX activity assays and enzyme-linked immunosorbent assays (ELISA), respectively. The effect of IL-1ß on LOX expression was examined in the presence or absence of inhibitors for signaling molecules and small interfering RNA-mediated knockdown of the putative transcription factor. Chromatin immunoprecipitation assays were conducted to further identify the responsible transcription factor. The role of LOX in ovulation was investigated in a DHEA-induced PCOS rat model with administration of the LOX inhibitor BAPN. The numbers of retrieved total oocytes and MII oocytes were recorded upon ovarian stimulation. MAIN RESULTS AND THE ROLE OF CHANCE: Increased abundance of LOX (P < 0.05) and IL-1ß (P < 0.05) was observed in the granulosa cells and follicular fluid in PCOS patients. IL-1ß increased LOX expression via activation of ERK1/2 and JNK and subsequent activation of the transcription factor c-Jun. Inhibition of LOX with BAPN ameliorated irregular estrous cyclicity (P < 0.05), polycystic ovary morphology and anovulation (P < 0.05) in PCOS rats, but appeared to be ineffective in the improvement of oocyte quality. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Ovarian tissue-directed specific inhibition of LOX in combination with oocyte quality-improving drugs may be more effective in the treatment of PCOS. WIDER IMPLICATIONS OF THE FINDINGS: Inflammation of the ovary is a contributing factor for the aberrant expression of LOX in the PCOS ovary, and inhibition of LOX together with anti-inflammatory therapy may improve the core features of PCOS. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by National Key R & D Program of China (2017YFC1001403) and Doctorial Innovation Fund of Shanghai Jiao Tong University School of Medicine (BXJ201718). The authors declare no competing financial interests.

Low-dose gonadotropin induction of ovulation in anovulatory women: still needed in the age of IVF.

Low-dose, step-up gonadotropin is the treatment of choice for women with polycystic ovary syndrome (PCOS) who have not conceived after anti-oestrogen treatment and as an effective alternative to pulsatile GnRH in women with hypogonadotropic hypogonadism (HH). There has been, however, no large-scale, comparative study between the two groups using low-dose gonadotropins. Here, we performed a retrospective, comparative analysis, in a single clinic database, of efficacy and safety of induction of ovulation using low-dose gonadotropins in 364 women with PCOS and 80 women with HH. The rate of ovulation was high in both PCOS (83%) and HH (84%) but mono-follicular, ovulatory cycles were more prevalent in PCOS than in HH (77% vs 53%, P < 0.0001) and the proportion of cycles that were abandoned was higher in HH than in PCOS (25% vs 15%, P < 0.0001). The median threshold dose of gonadotropin required to induce ovulation was 75 IU/day in PCOS and 113 IU/day in HH (P < 0.001) and the range of doses was greater in HH women. Forty-nine percent of women with PCOS and 65% of those with HH conceived (more than 90% within 6 cycles of treatment) and had at least one pregnancy. Multiple pregnancies (all twins) occurred in only 4% of women with PCOS and 5% of those with HH. These findings emphasise the efficacy and safety of low-dose gonadotropin treatment for both clomiphene-resistant women with PCOS and those with HH. These results highlight the importance of choosing the more physiological approach of gonadotropin induction of ovulation in both groups as the most appropriate treatment, in preference to IVF.

High level of C-type natriuretic peptide induced by hyperandrogen-mediated anovulation in polycystic ovary syndrome mice.

Polycystic ovary syndrome (PCOS), which is characterized by hyperandrogenism, is a complex endocrinopathy that affects the fertility of 9-18% of reproductive-aged women. However, the exact mechanism of PCOS, especially hyperandrogen-induced anovulation, is largely unknown to date. Physiologically, the natriuretic peptide type C/natriuretic peptide receptor 2 (CNP/NPR2) system is essential for sustaining oocyte meiotic arrest until the preovulatory luteinizing hormone (LH) surge. We therefore hypothesized that the CNP/NPR2 system is also involved in PCOS and contributes to arresting oocyte meiosis and ovulation. Here, based on a dehydroepiandrosterone (DHEA)-induced PCOS-like mouse model, persistent high levels of CNP/NPR2 were detected in anovulation ovaries. Meanwhile, oocytes arrested at the germinal vesicle stage correlated with persistent high levels of androgen and estrogen. We further showed that ovulation failure in these mice could be a result of elevated Nppc/Npr2 gene transcription that was directly increased by androgen (AR) and estrogen (ER) receptor signaling. Consistent with this, anovulation was alleviated by administration of either exogenous human chorionic gonadotropin (hCG) or inhibitors of AR or ER to reduce the level of CNP/NPR2. Additionally, the CNP/NPR2 expression pattern in the anovulated follicles was, to some extent, consistent with the clinical expression in PCOS patients. Therefore, our study highlights the important role an overactive CNP/NPR2 system caused by hyperandrogenism in preventing oocytes from maturation and ovulation in PCOS mice. Our findings provide insight into potential mechanisms responsible for infertility in women with PCOS.

Inositol treatment of anovulation in women with polycystic ovary syndrome: a meta-analysis of randomised trials.

Polycystic ovary syndrome is a common cause of anovulation and infertility, and a risk factor for development of metabolic syndrome and endometrial cancer. Systematic review and meta-analysis of randomised controlled trials (RCT) that evaluated the effects of inositol as an ovulation induction agent. We searched MEDLINE, EMBASE, Cochrane and ISI conference proceedings, Register and Meta-register for RCT and WHO trials' search portal. We included studies that compared inositol with placebo or other ovulation induction agents. Quality of studies was assessed for risk of bias. Results were pooled using random effects meta-analysis and findings were reported as relative risk or standardised mean differences. We included ten randomised trials. A total of 362 women were on inositol (257 on myo-inositol; 105 on di-chiro-inositol), 179 were on placebo and 60 were on metformin. Inositol was associated with significantly improved ovulation rate (RR 2.3; 95% CI 1.1-4.7; I2 = 75%) and increased frequency of menstrual cycles (RR 6.8; 95% CI 2.8-16.6; I2 = 0%) compared with placebo. One study reported on clinical pregnancy rate with inositol compared with placebo (RR 3.3; 95% CI 0.4-27.1), and one study compared with metformin (RR 1.5; 95% CI 0.7-3.1). No studies evaluated live birth and miscarriage rates. Inositol appears to regulate menstrual cycles, improve ovulation and induce metabolic changes in polycystic ovary syndrome; however, evidence is lacking for pregnancy, miscarriage or live birth. A further, well-designed multicentre trial to address this issue to provide robust evidence of benefit is warranted. TWEETABLE ABSTRACT: Inositols improve menstrual cycles, ovulation and metabolic changes in polycystic ovary syndrome.

Therapeutic approach for metabolic disorders and infertility in women with PCOS.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting 5-10% of women of reproductive age. It generally shows with oligo/amenorrhea, anovulatory cycles, clinical o biochemical hirsutism, polycystic ovaries and, in a significant percentage of cases, insulin resistance. PCOS is defined as a multifactorial pathology, determined by the association of many factors: genetic, endocrine and environmental. The first and most effective treatment of PCOS is to change life-style and lose weight. The use of oral contraceptives has been shown effective in reducing acne and hirsutism and regulates the menstrual cycle. For women with severe hirsutism, the addition of antiandrogens to estrogen-progestin therapy has significantly improved the results. In cases of anovulatory infertility, the drug of first choice is clomiphene citrate, followed by low-dose gonadotropins. Recently, insulin-sensitizing drugs have been widely prescribed for PCOS patients. They are particularly effective in reducing insulin resistance and improving ovulatory performance. Besides insulin-sensitizing drugs, natural substances, such as inositol, seems to have good efficacy, similar to metformin with fewer side effects. New substances that could be used include statins and natural statins, such as monakolin, alone or combined with myo-inositol. These substances do not have side effects and greatly reduce the hyperandrogenic component in these patients.

The cardiometabolic effect of current management of polycystic ovary syndrome: strategies of prevention and treatment.

Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder amongst women of reproductive age, which is characterized by reproductive and cardiometabolic disturbances with long-term health repercussions. Insulin resistance (IR), impaired glucose tolerance, type 2 diabetes mellitus (DM2), obesity and dyslipidemia occur more in women with PCOS than in age-comparable women without PCOS. Long term data regarding risks or benefits of medical intervention for metabolic dysfunction of PCOS are lacking. Therapies, such as oral contraceptives (OCPs) and anti-androgenic medications used to manage the reproductive manifestations of PCOS, may themselves be the cause of cardiometabolic perturbations. Hence, strategies regarding the management of reproductive issues in PCOS encompass a patient-specific tailored approach. Factors that influence the cardiometabolic side effects arising during treatment of the reproductive manifestations of PCOS (hirsutism/anovulation) are also discussed in this paper in order to build future strategies to minimize the overall cardiometabolic risk.

High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process.

Metabolic disorders, such as PCOS (polycystic ovarian syndrome) and T2DM (type 2 diabetes mellitus), are associated with menstrual dysfunction, anovulation, infertility, and early pregnancy loss. Ovarian dysfunction is not only related to low pregnancy rates but also to the increased risk of miscarriage. Women with PCOS or T2DM, characterized by hyperinsulinemia, commonly experience ovarian dysfunction. In this study, we first explored whether high insulin levels directly affected ovarian functioning during embryo implantation. Mice in the insulin-treated group were given a subcutaneous injection of human recombinant insulin. After insulin treatment, serum levels of E2 (estrogen), PROG (progesterone), LH (luteinizing hormone), and FSH (follicle-stimulating hormone) were obviously lower, and there was a significant decrement of ovarian GDF9 (growth differentiation factor 9) mRNA. H&E (hematoxylin and eosin) staining showed a greater number of immature follicles and less luteinization in the insulin group. Further autophagy was studied in this process. A significant increase of P62 (SQSTM1/Sequestosome1) and a decrease of Cathepsin B, BECN1 (Beclin 1), and ULK1 (Unc-51-like kinase 1) mRNA in ovary was found in the insulin group. Western blot analysis showed that the expressions of LC3 (microtubule-associated protein 1 light chain 3), BECN1, and Cathepsin B proteins in ovaries from insulin group were obviously reduced, while P62 proteins were significantly increased. All these results illustrated that insulin could directly impair ovarian function during embryo implantation and the imbalance of ovarian autophagy due to insulin. Autophagy could enhance the impaired ovarian function results from insulin.

Extension of the clomiphene citrate stair-step protocol to gonadotropin treatment in women with clomiphene resistant polycystic ovarian syndrome.

Our objective was to evaluate the safety and efficacy of direct initiation of gonadotropin ovarian stimulation without prior withdrawal bleeding in anovulatory clomiphene citrate (CC) resistant polycystic ovarian syndrome (PCOS) patients. Eighteen PCOS patients underwent ovulation induction with CC using a stair-step regimen. Patients who failed to respond to the maximal dose of CC initiated gonadotropin stimulation without inducing withdrawal bleeding, using the chronic low dose regimen. The primary outcome measure was the time to ovulation from the beginning of CC treatment until the day of ovulatory trigger. This was compared with the time to ovulation calculated according to the traditional approach, which includes inducing progesterone withdrawal bleeding between each CC dose increment and before gonadotropin therapy. The time to ovulation in the study group was 67.0 ± 6.8 days. The estimated time to ovulation according to the traditional approach was approximately 110 days. The clinical pregnancy rate was 44% (8/18), and all pregnancies were singletons. One patient miscarried; hence the live birth rate was 38.9% (7/18). Direct initiation of gonadotropin therapy without prior induction of withdrawal bleeding in clomiphene resistant PCOS patients results in considerable reduction of the time to ovulation and is both safe and efficacious.

Phenotypic variation in anti-Mullerian hormone (AMH) production per follicle in women with polycystic ovary syndrome (PCOS) and isolated polycystic ovarian morphology (PCOM): an observational cross-sectional study.

This observational study compares the ratio of serum anti-Mullerian hormone (AMH) to the total antral follicle count (AFC) (as a marker of AMH production per follicle) in the various phenotypes of women with polycystic ovary syndrome (PCOS) and isolated polycystic ovarian morphology (PCOM). Two hundred and sixty-two women were recruited. Women with PCOS were divided into four phenotypes based on the diagnostic inclusion criteria of oligo-anovulation (OA), hyperandrogenism (HA) and polycystic ovarian morphology (PCOM). These included Group A (OA + HA + PCOM), Group B (OA + HA), Group C (HA + PCOM) and Group D (OA + PCOM). A ratio of serum AMH to total AFC was calculated and expressed as the AMH/AFC ratio which was compared in the phenotypes of PCOS and isolated PCOM. The median AMH/AFC ratios in PCOS-A, PCOS-D, PCOS-C and PCOM were 1.5, 1.6, 1.2 and 1.1, respectively. There were significant differences in the groups compared [F(3, 238) = 6.14, p = 0.000)]. The ratios were significantly higher in the oligo-anovulatory phenotypes PCOS-A and PCOS-D than the PCOM (p = 0.004 and 0.002, respectively). There was no significant difference in the ratio between ovulatory phenotype PCOS-C and PCOM (p = 0.59). The role of androgens and LH in per-follicle AMH production remains limited. The findings support the hypothesis of a key role for AMH in the mechanism of anovulation in PCOS.

The mare as a model for luteinized unruptured follicle syndrome: intrafollicular endocrine milieu.

Luteinized unruptured follicle (LUF) syndrome is a recurrent anovulatory dysfunction that affects up to 23% of women with normal menstrual cycles and up to 73% with endometriosis. Mechanisms underlying the development of LUF syndrome in mares were studied to provide a potential model for human anovulation. The effect of extended increase in circulating LH achieved by administration of recombinant equine LH (reLH) or a short surge of LH and decrease in progesterone induced by prostaglandin F2α (PGF2α) on LUF formation (Experiment 1), identification of an optimal dose of COX-2 inhibitor (flunixin meglumine, FM; to block the effect of prostaglandins) for inducing LUFs (Experiment 2), and evaluation of intrafollicular endocrine milieu in LUFs (Experiment 3) were investigated. In Experiment 1, mares were treated with reLH from Day 7 to Day 15 (Day 0=ovulation), PGF2α on Day 7, or in combination. In Experiment 2, FM at doses of 2.0 or 3.0 mg/kg every 12 h and human chorionic gonadotropin (hCG) (1500 IU) were administered after a follicle ≥32 mm was detected. In Experiment 3, FM at a dose of 2.0 mg/kg every 12 h plus hCG was used to induce LUFs and investigate the intrafollicular endocrine milieu. No LUFs were induced by reLH or PGF2α treatment; however, LUFs were induced in 100% of mares using FM. Intrafollicular PGF2α metabolite, PGF2α, and PGE2 were lower and the ratio of PGE2:PGF2α was higher in the induced LUF group. Higher levels of intrafollicular E2 and total primary sex steroids were observed in the induced LUF group along with a tendency for higher levels of GH, cortisol, and T; however, LH, PRL, VEGF-A, and NO did not differ between groups. In conclusion, this study reveals part of the intrafollicular endocrine milieu and the association of prostaglandins in LUF formation, and indicates that the mare might be an appropriate model for studying the poorly understood LUF syndrome.

Role of cortisol and superoxide dismutase in psychological stress induced anovulation.

Stress has been identified as a potential trigger for reproductive dysfunctions, but the psycho-physiological pathway behind the effect of stress on ovulation remains unexplored. The present research work highlights the plausible mechanism of psychological stress on ovulation in mice by targeting superoxide dismutase (SOD), an enzyme involved in ovulation. For this, three consecutive studies were carried out. The first study aimed to determine the effect of psychological stress induced change in cortisol level, behavioral parameters and normal estrous cyclicity. The effect on mRNA expression of SOD subtypes, follicular growth in histological sections of ovaries and the difference in oocyte quality and number, upon superovulation were assessed in the subsequent studies. The results indicate that psychological stress model causes an increase in cortisol level (p⩽0.05) with development of anhedonia, depression and anxiety. An irregular estrous cycle was observed in stressed mice with an upregulation in mRNA expression of SOD subtypes. Histological sections revealed an increase in atretic antral follicle with an impaired follicular development. Moreover, immature oocytes were obtained from superovulated stressed mice. The study concludes that psychological stress results in anovulation which may be due to increase in cortisol level and SOD activity in stressed mice.

Effect of a low glycemic diet in patients with polycystic ovary syndrome and anovulation - a randomized controlled trial.

OBJECTIVE: To determine whether a low glycemic index diet is better than a normal glycemic index diet in producing ovulatory cycles in women with polycystic ovary syndrome (PCOS) and anovulation. MATERIALS AND METHODS: A randomized controlled clinical trial involving 37 women with PCOS and anovulation. The authors randomly assigned low glycemic index diets (n = 19) and normal glycemic index (n = 18) diets, and analyzed the number of ovulatory cycles for three months. RESULTS: In patients who consumed a low glycemic index diet, 24.6% (14/57) of the cycles were ovulatory. In those who consumed a normal glycemic index diet, only 7.4% (4/54) of the cycles were ovulatory (p = 0.014). CONCLUSIONS: The difference observed in the number of ovulatory cycles could be related to a decrease in the serum levels of circulating androgens, secondary to an improvement in insulin resistance.

Menstrual preconditioning for the prevention of major obstetrical syndromes in polycystic ovary syndrome.

The presence of multiple ovarian cysts, anovulation, and endometrial progesterone resistance in the neonate seems remarkably similar to ovarian and endometrial features of the polycystic ovary syndrome (PCOS) of adolescent and adult women. In fact, in the absence of cyclic menstruations after menarche, the neonatal progesterone resistance is likely to persist and adversely affect young women with PCOS at the time of pregnancy after induction of ovulation, because any persisting defect in progesterone response can interfere with the process of decidualization and trophoblast invasion. The primigravid woman with PCOS therefore is likely to be at risk of defective deep placentation as manifested by the increased risk of major obstetric syndromes. A recent, large epidemiologic study has demonstrated that the risk of preeclampsia and preterm delivery is elevated in the 13- to 15-year old group, although it does not persist in the 16- to 17-year old group. It is proposed therefore that induction of ovulation in the infertile nulligravid woman with PCOS should be preceded by a period of progesterone withdrawal bleedings to achieve full endometrial progesterone response by the time of pregnancy. The cyclic administration of clomiphene citrate for a period to be determined by vascular response may be an appropriate tool to reduce the risk of major obstetric syndromes by menstrual preconditioning.

Prevalence of conditions causing chronic anovulation and the proposed algorithm for anovulation evaluation.

AIM: This study investigated the prevalence of disease-causing chronic anovulation and proposes a logical investigation flowchart to facilitate diagnosis in women presenting with chronic anovulation. MATERIAL AND METHODS: The cross-sectional retrospective study was performed using 293 reproductive-aged women who were diagnosed with chronic anovulation at the Gynecologic Endocrinology Unit, Faculty of Medicine, Chiang Mai University between January 2008 and December 2012. The demographic data, laboratory investigations and diagnoses were collected. RESULTS: Among 293 patients recruited into the study, the common causes of anovulation were polycystic ovary syndrome (PCOS) (73.4%), prolactin disorder (13.3%) and unexplained chronic anovulation (7.5%). The less common causes were thyroid disorders, congenital adrenal hyperplasia, adrenal tumors and Cushing's disease. There was a strong positive association between the levels of 17-hydroxyprogesterone and/or dehydroepiandrosterone sulfate with the levels of testosterone and androstenedione. The sensitivity and specificity of serum luteinizing hormone to accurately diagnose PCOS were 29.38% and 55.56% (P = 0.03). The luteinizing hormone/follicle-stimulating hormone ratio ≥ 3 had a sensitivity and specificity at 18.56% and 92.86% (P = 0.03) for PCOS diagnosis. CONCLUSION: Serum androstenedione, testosterone, thyroid-stimulating hormone, prolactin levels and pelvic ultrasonography should be included in the initial investigations for anovulation. The 17-hydroxyprogesterone and dehydroepiandrosterone sulfate levels can be used for secondary anovulation evaluations.