Classic Polycystic Ovarian Syndrome Research Articles

Polycystic Ovarian Syndrome among Young Women of a University in Central Gujarat - A Cross-sectional Study.

Polycystic ovarian syndrome (PCOS) is one of the most common reproductive endocrinological disorders affecting 6%-8% of women in reproductive years. An early liberal PCOS screening appears to be a cost-effective strategy, benefiting earlier diagnosis and intervention. The objectives are to measure the prevalence of PCOS and factors associated with PCOS among young girl students of a University in Central Gujarat. All consenting girl medical students enrolled in MBBS curriculum during 2013-2017 were given a self-administered questionnaire (for signs and symptoms of PCOS), taking due prior permissions; during January 2018-June 2019. Using Rotterdam (2006) criteria, those who were screened for PCOS were subjected to abdominal ultrasonography (USG) and if required, laboratory investigations (random blood sugar, thyroid-stimulating hormone, and free testosterone). The proportion of young women having PCOS as per the Rotterdam and European Society for Human Reproduction and Embryology (EHSRE) Criteria are reported. The study enrolled 308 girl medical students. More than one-tenth of the study participants (11.7%, 36/308) had confirmed PCOS (Rotterdam Criteria). As per the EHSRE criteria, 24/36 had classic PCOS, 11/36 had ovulatory phenotype, and 01/36 had the non-hyperandrogenic phenotype PCOS. USG was required in 123/308 (39%); of which 91 consented and 16/91 (18%) had conclusive PCOS. Twenty-three girls required laboratory investigations, of which two had abnormal values suggestive of PCOS. Irregular menses and hirsutism were significantly associated with the PCOS (P < 0.05). The proportion of young medical students with PCOS was 12%. Irregular menses and hirsutism were significantly associated with PCOS.

THE HAIRY TRUTH: AMH, BMI, AND HYPERANDROGENISTIC SYMPTOMS IN PCOS WOMEN

Women with polycystic ovarian syndrome (PCOS) often present with elevated serum AMH levels as well as a higher BMI as a result of metabolic dysfunction. While both AMH and BMI have been strongly linked to fertility outcomes in PCOS patients, previous studies correlating the two have been controversial. Better understanding the link between AMH and BMI may provide important insight to the widely misunderstood metabolic and endocrine etiology of PCOS’ impacts on fertility. Hyperandrogenism and altered steroidogenesis is one of the defining features of PCOS that may play a key role in the relationship between BMI and AMH levels. Thus, we sought to better understand the relationship between hyperandrogenistic characteristics, BMI, and AMH levels in PCOS patients, compared to classical PCOS presentations. The purpose of this study was to determine the relationship between hyperandrogenism, AMH, and BMI levels in PCOS patients. Retrospective chart review at a private multi-site infertility center. Patients who underwent in-vitro fertilization (IVF) cycles between April 2017 and October 2020 with a diagnosis of PCOS, defined by the Rotterdam Criteria, were included. Patients were divided into two groups: those with hyperandrogenism and those without. Hyperandrogenic PCOS and classical PCOS subgroups were defined based on the presence or absence of self-reported adult acne and hair growth. Baseline characteristics were evaluated, and linear regression analysis was performed on PCOS patients to detect correlations between BMI, AMH, and clinical hyperandrogenism. Two sample t-tests and chi square analysis were used to analyze the data using SPSS (SPSS Inc., Chicago, IL, USA). A total of 330 patients were analyzed. We did not find a statistically significant correlation between BMI and AMH. While there was no statistically significant difference in BMI between the classical and hyperandrogenic PCOS groups, of note, there was a significantly higher AMH in the hyperandrogenic group, with a mean of 5.89, compared to 4.56 in the classical PCOS group (p = 0.008). However, when separated based on whether patients exhibited clinical hyperandrogenism, patients with no increased testosterone levels did exhibit a statistically significant negative correlation between BMI and AMH (p = .001). Comparatively, while there was a negative correlation between AMH and BMI in the clinical hyperandrogenism group, it was not statistically significant (p = .605). Our results demonstrate that there is an overall negative correlation between BMI and AMH amongst both classical and hyperandrogenic PCOS populations. Although this is only statistically significant in the classical PCOS group, these preliminary results may demonstrate a peek into the etiology of hyperandrogenic PCOS, as well as the relationship between BMI and AMH in this subgroup. Further research is needed to clarify the correlation between BMI and AMH and how testosterone, or lack thereof, may influence these levels.

Insulin resistance and high molecular weight adiponectin in obese and non-obese patients with Polycystic Ovarian Syndrome (PCOS)

BackgroundPolycystic ovarian syndrome (PCOS) is the most common endocrinopathy among young women. Insulin resistance is a key feature in the pathogenesis of PCOS; also high molecular weight adiponectin is a marker of insulin resistance. The aim of this study was to evaluate the insulin resistance, metabolic and androgenic profiles and high molecular weight adiponectin in obese and non-obese PCOS patients.MethodsIn this cross-sectional study in outpatient endocrinology clinics of Shiraz University of Medical Sciences, 80 women aged 17–43 years old with PCOS were enrolled. Biochemical and hormonal assay was done on fasting blood sample on the third day of follicular phase.ResultsThe individuals had a mean age of 28.39 ± 6.56 years, mean weight of 65.41 ± 12.59 Kg, mean BMI of 25.5 ± 4.9, and mean waist circumference of 88.0 ± 13.1 cm. Of all individuals 20% had frank insulin resistance with HOMA-IR > 3.8. Although the obese PCOS patients had lower levels of high molecular weight adiponectin (P = 0.03) than the normal weight PCOS individuals, the level of insulin and insulin resistance was not different in them (P = 0.13, 0.13). Patients with classic PCOS phenotype significantly had higher levels of insulin resistance and free androgen index (P < 0.001, 0.001). We found a significant correlation between the insulin level and free androgen index (correlation coefficient: 0.266 and P = 0.018) after adjusting for BMI.ConclusionThis cross-sectional study showed a high incidence of insulin resistance in PCOS patients independent of obesity, and determined BMI related lower level of high molecular weight adiponectin in obese PCOS individuals. More detailed studies are warranted for evaluation of insulin resistance and its pathophysiologic role in PCOS.

Animal Models in Polycystic Ovarian Syndrome.

The pathogenesis of polycystic ovarian syndrome (PCOS) in women is poorly understood. With its varied endocrine and metabolic effects, it is unlikely a single genetic mutation or biological insult is the cause of the disease. Animals have been the proposed model for further studying the pathogenesis of PCOS and many modalities can be used to induce PCOS-like phenotypes in animals, most often with rodents. While there is not yet an animal model that perfectly recapitulates the classic PCOS phenotype in human women, many models allow for a better understanding of the complex disease process as well as possible treatments.

Bifurcation analysis of a menstrual cycle model reveals multiple mechanisms linking testosterone and classical PCOS

A system of 16 differential equations is described which models hormonal regulation of the menstrual cycle focusing on the effects of the androgen testosterone (T) on follicular development and on the synthesis of luteinizing hormone (LH) in the pituitary. Model simulations indicate two stable menstrual cycles – one cycle fitting data in the literature for normal women and the other cycle being anovulatory because of no LH surge. Bifurcations with respect to sensitive model parameters illustrate various characteristics of polycystic ovarian syndrome (PCOS), a leading cause of female infertility. For example, varying one parameter retards the growth of preantral follicles and produces a “stockpiling” of these small follicles as observed in the literature for some PCOS women. Modifying another parameter increases the stimulatory effect of T on LH synthesis resulting in reduced follicular development and anovulation. In addition, the model illustrates how anovulatory and hyperandrogenic cycles which are characteristic of PCOS can be reproduced by perturbing both pituitary sensitivity to T and the follicular production of T. Thus, this model suggests that for some women androgenic activity at the levels of both the pituitary and the ovaries may contribute to the etiology of PCOS.

Preantral follicular development is not accelerated in women with polycystic ovarian syndrome compared with normal controls

OBJECTIVE: To establish the ovarian preantral follicular developmental patterns of women with polycystic ovarian syndrome (PCOS) and those with normal ovaries. DESIGN: Prospective observational study. MATERIALS AND METHODS: IRB approval was obtained. Patients were undergoing surgery for other gynecologic reasons. Subjects with PCOS, meeting all three Rotterdam criteria, were recruited. Normal controls were normal cycling, without diabetes or hyperandrogenism, had no evidence of PCO morphology on ultrasound, and had not used any hormonal therapy in the preceding six months. Ovarian cortex biopsies were obtained. Biopsy samples underwent enzymatic digestion and follicle release in a mixture of Collagenase Type IA and DNase. All follicles were microscopically assessed and classified by a single investigator (TWM) according to preantral follicular developmental stage (primordial, transitional, primary, secondary, multilaminar). RESULTS: Three patients with classic PCOS and five normal controls were analyzed. Groups did not differ by age, however the PCOS group had a significantly higher BMI compared with controls (40.0 vs 22.9). A total of 5,904 follicles were analyzed, 3,171 from normal controls, and 2,733 from PCOS. Follicle distributions according to stage are shown in the table. Multinomial logit modeling was used to compare the proportions at each stage. All stage distributions were similar with no significant variation between normals and those with PCOS.Tabled 1Ovarian Preantral Follicle DistributionNormal n=3171PCOS n=2733Primordial1382 (43.6)1317 (48.2)Transitional1242 (39.2)765 (28.0)Primary432 (13.6)482 (17.6)Secondary86 (2.7)131 (4.8)Multilaminar27 (0.9)29 (1.1)Antral22 (0.1)9 (0.3)All comparisons non-significant. Open table in a new tab All comparisons non-significant. CONCLUSION: In this large analysis of preantral follicles, we found that there is no difference in the pattern of early ovarian follicular growth among normal women or those with PCOS.

Oligomenorrhoea in Exercising Women

To date, the predominant mechanism underlying menstrual disturbances in exercising women supports an underlying energy deficiency-related aetiology, in which a failure to compensate dietary intake for the energy cost of exercise suppresses reproductive function. Increasing evidence demonstrates that energy deficiency plays a causal role in the induction of amenorrhoea in exercising women, and consistent with this mechanism are findings of glucoregulatory perturbations such as low triiodothyronine, reduced insulin secretion and elevated cortisol, growth hormone and ghrelin levels. The menstrual disturbance that may differ in its energetic characteristics and, perhaps in its androgenic and ovarian steroid environment, is oligomenorrhoea. We conducted a systematic review of the literature to begin to understand whether oligomenorrhoea in exercising women is a mild subclinical phenotype of polycystic ovarian syndrome (PCOS) in which exercise is conferring beneficial effects in protecting women from the classic PCOS phenotype, or whether oligomenorrhoea is part of the spectrum of menstrual disturbances caused by an energy deficiency that is often reported in exercising women with menstrual disturbances. We included observational, randomized controlled trials and cross-sectional studies that reported clinical, hormonal and metabolic profiles in exercising women with amenorrhoea or oligomenorrhoea and in women with PCOS. Previous studies examining the underlying mechanisms and consequences of exercise-associated menstrual disturbances have grouped exercising amenorrhoeic and oligomenorrhoeic women into a single group, and have relied primarily on self-reported menstrual history. Although scarce, the data available to date suggest that hyperandrogenism, such as that observed in PCOS, may likely be associated with oligomenorrhoea in exercising women, and may not always represent hypothalamic inhibition secondary to an energy deficiency. It is critical to closely examine the metabolic and endocrine status of women with menstrual disturbances because the treatment strategies for energy deficiency-related menstrual disturbances differ from that of disturbances traceable to hyperandrogenaemia. Further investigation is necessary to explore whether different endocrine aetiologies underly menstrual disturbances, particularly oligomenorrhoea, in physically active women.

Mild androgen phenotypes

Mild androgen phenotypes are found in 30-40% of patients referred to an endocrine clinic because of suspected hyperandrogenic syndrome. These disorders are characterized by clinical or biological signs of hyperandrogenism in women with normal ovulatory menstrual cycles. Three main mild androgen disorders may be distinguished: ovulatory polycystic ovarian syndrome (PCOS), idiopathic hyperandrogenism, and idiopathic hirsutism. Ovulatory PCOS includes ovulatory hyperandrogenic patients presenting with polycystic ovaries. Using ESHRE/ASRM criteria for diagnosis of PCOS, this disorder is now part of PCOS spectrum. While in vivo and in vitro studies have confirmed the similarities between the two forms of PCOS, ovulatory PCOS presents clinicians with some unique problems. In fact, fertility is not a problem, but insulin resistance is present, and although milder than in classic PCOS it may be associated with an increased cardiovascular and metabolic risk. Because of this, an ovarian sonography should be performed in all ovulatory hyperandrogenic patients, and when polycystic ovaries are found cardiovascular and metabolic risk should be carefully evaluated. Ovulatory PCOS patients with altered glucose tolerance and/or with dyslipidaemia may need treatment with insulin-sensitizing agents. Idiopathic hyperandrogenism regroups ovulatory patients with increased androgen levels and normal ovaries, while idiopathic hirsutism includes ovulatory patients presenting with hirsutism but normal circulating androgens and normal ovaries. The differentiation between these two disorders may be difficult because commercial assays of androgen levels are generally unreliable. While idiopathic hyperandrogenism may be associated with insulin resistance, neither disorder is associated with an increased cardiovascular risk. The main clinical problem is hirsutism, and this may be approached by aesthetic or pharmacological therapies.

Insulin Resistance in Polycystic Ovarian Disease

The classic polycystic ovarian syndrome (PCOS) was originally described by Stein and Leventhal as the association of amenorrhea with polycystic ovaries and, variably, hirsutism and/or obesity. It is estimated that 5 to 10% of women of reproductive age have PCOS. Although insulin resistance is not part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS can not be denied. PCOS is associated with insulin resistance, independent of total or fat-free body mass. Postreceptor defects in the action of insulin have been described in PCOS that are similar to those found in obesity and type 2 diabetes. Treatment with insulin sensitizers, metformin, and thiazolidinediones (TZDs) improve both metabolic and hormonal patterns and also improve ovulation in PCOS. Recent studies have shown that women who have PCOS have higher circulating levels of inflammatory mediators such as C-reactive protein, tumor necrosis factor, tissue plasminogen activator, and plasminogen activator inhibitor-1 (PAI-1). It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation.

Adipocyte insulin action following ovulation in polycystic ovarian syndrome.

The role of anovulation and insulin resistance in the pathogenesis of polycystic ovarian syndrome (PCOS) remains to be determined. The aim of this study was to investigate whether the metabolic abnormality of insulin resistance in PCOS reflects, rather than causes, the ovarian dysfunction. Eight subjects with classical PCOS were studied on two occasions. Adipocyte insulin sensitivity together with hormonal and metabolic changes were investigated in patients with PCOS following prolonged amenorrhoea and then again in the early follicular phase after ovulation. Insulin receptor binding in amenorrhoeic subjects with PCOS was low at 0.78 +/- 0.08% and this increased to 1.18 +/- 0.19% after an ovulatory cycle (P < 0.05). Maximal insulin stimulated 3-O-methylglucose uptake was 0.70 +/- 0. 14 during amenorrhoea and increased to 1.08 +/- 0.25 pmol/10 cm(2) cell membrane (P < 0.05). Plasma testosterone fell (4.0 +/- 0.4 to 2. 3 +/- 0.2 nmol/l; P < 0.001), luteinizing hormone fell (17.6 +/- 2.3 to 6.7 +/- 0.8 IU/l; P < 0.001) but plasma insulin concentrations remained unchanged following ovulation (14.6 +/- 1.9 and 15.7 +/- 3. 8 pmol/l during amenorrhoea and after ovulation respectively). The results of this study suggest that chronic anovulation per se appears to modify the factors contributing to cellular insulin resistance seen in PCOS.

Responses of polycystic ovarian syndrome and related variants to low-dose follicle stimulating hormone

Objective: To determine whether patients with classical polycystic ovarian syndrome (PCOS) respond differently to low-dose FSH therapy in comparison with anovulatory patients (PCOS-like) where only some features of PCOS are present. Methods: Two groups of patients were studied. The PCOS group (25 patients, 51 cycles) and the PCOS-like group (38 patients, 57 cycles) were treated with the same protocol of purified FSH, commencing with an initial dosage of 75 IU/day and increasing by 37.5 IU/day after 14 days, where necessary. Estradiol levels and ultrasonographic evidence of follicular development were used for monitoring. Results: PCOS patients required more ampules of FSH, needed more days of gonadotropin stimulation, secreted higher levels of E 2 and had increased numbers of intermediate follicles compared to the PCOS-like group. Conclusions: This study demonstrated significant differences between PCOS and other PCOS-like conditions when treated with low-dose FSH. Classification of the subvariants of PCOS may have therapeutic implications.

Effect of bromocriptine on LH pulsatility in the polycystic ovary syndrome.

The effects were studied of bromocriptine, 10 mg daily for 1 year, on luteinizing hormone (LH) pulse characteristics in patients with classical polycystic ovarian syndrome (PCOS). All patients were hirsute, had been oligomenorrhoeic since menarche, had LH: FSH ratios of greater than 3:1, and either elevated serum testosterone (T) or dehydroepiandrosterone sulphate (DHAS) concentrations. In 10 subjects who completed the study menstrual frequency increased from an average of 3.6 to 8 per year but few of the cycles were ovulatory. Mean (SE) serum testosterone fell from 4.4 (0.5) nmol/l pretreatment to 2.8 (0.3) nmol/l (P less than 0.01) and DHAS from 7.9 (1.1) mumol/l to 5.4 (1.1) mumol/l (P less than 0.05). Serum delta 4 androstenedione and oestradiol did not change with bromocriptine treatment. Mean serum LH fell from 17.4 (2.4) IU/l to 11.2 (1.8) IU/l (P less than 0.03) after 12 months of bromocriptine. No pattern of LH pulsatility specific to PCOS was detected during 10 min sampling for an 8 h period prior to dopamine agonist treatment. LH interpeak interval (58 (5.2) min) and peak amplitude (156 (7.2%) of mean nadir) in untreated PCOS were similar to that of the mid-follicular stage of ovulatory cycles, and bromocriptine for 1 year did not alter these variables. We conclude that while bromocriptine reduces serum androgen levels and increases menstrual frequency it has no effect centrally to modify hypothalamic GnRH secretion. The reduction in LH levels by bromocriptine may be the result of diminished gonadotroph sensitivity to GnRH or reduced pituitary stores of LH available for release. Despite the return towards normal of various hormonal characteristics of PCOS, bromocriptine has little place in the management of this condition.