Impaired carotid viscoelastic properties in women with polycystic ovaries

Background-The purpose of this study was to assess the elastic properties of the carotid arteries in women with polycystic ovarian syndrome, asymptomatic women with polycystic ovaries. and healthy controls.Methods and Results-We recruited the following 60 subjects: 20 symptomatic women with polycystic ovaries attending the reproductive endocrinology clinics, 20 asymptomatic women with polycystic ovaries attending the family planning clinic, and 20 staff volunteers as healthy controls with normal ovaries on transvaginal scan. Compliance and stiffness index were assessed in the common and internal carotid arteries using duplex ultrasound equipped with an echo-locked arterial wall-tracking system. Compliance was significantly lower in the common carotid artery in symptomatic and asymptomatic women with polycystic ovaries than in the controls (10.7, 14.1, and 19.2%mm Hg-1 x 10(-2), respectively). The arterial stiffness index was correspondingly increased (12.3, 10.2, and 6.7, respectively). Similar results were obtained in the internal carotid artery for compliance (10.1. 11.0, and 16.9 %mm Hg-1 x 10(-2), respectively) and stiffness index (14.8, 16.2, and 8.7, respectively).Conclusions-The results of this study provide additional evidence of vascular dysfunction in women with polycystic ovaries and are compatible with the hypothesis that they are at increased risk from coronary artery disease and stroke

Divergences in insulin resistance between the different phenotypes of the polycystic ovary syndrome

Context/Objective: Current diagnostic criteria for polycystic ovary syndrome (PCOS) have generated distinct PCOS phenotypes, based on the different combinations of diagnostic features found in each patient. Our aim was to assess whether either each single diagnostic feature or their combinations into the PCOS phenotypes may predict insulin resistance in these women. Patients/Design: A total of 137 consecutive Caucasian women with PCOS, diagnosed by the Rotterdam criteria, underwent accurate assessment of diagnostic and metabolic features. Insulin sensitivity was measured by the glucose clamp technique. Results: Among women with PCOS, 84.7% had hyperandrogenism, 84.7% had chronic oligoanovulation, and 89% had polycystic ovaries. According to the individual combinations of these features, 69.4% of women had the classic phenotype, 15.3% had the ovulatory phenotype, and 15.3% had the normoandrogenic phenotype. Most subjects (71.4%) were insulin resistant. However, insulin resistance frequency differed among phenotypes, being 80.4%, 65.0%, and 38.1%, respectively, in the 3 subgroups (P < .001). Although none of the PCOS diagnostic features per se was associated with the impairment in insulin action, after adjustment for covariates, the classic phenotype and, to a lesser extent, the ovulatory phenotype were independently associated with insulin resistance, whereas the normoandrogenic phenotype was not. Metabolic syndrome frequency was also different among phenotypes (P = .030). Conclusions: There is a scale of metabolic risk among women with PCOS. Although no single diagnostic features of PCOS are independently associated with insulin resistance, their combinations, which define PCOS phenotypes, may allow physicians to establish which women should undergo metabolic screening. In metabolic terms, women belonging to the normoandrogenic phenotype behave as a separate group

Association between circulating adiponectin levels and polycystic ovarian syndrome

Background: Low adiponectin levels in polycystic ovarian syndrome (PCOS) have been largely attributed to obesity which is common among these patients. In addition, evidence also suggests that low adiponectin in PCOS may be related to insulin resistance (IR) in these women. However, studies on the role of adiponectin in younger and lean patients are limited. Therefore, the aim of the present study was to examine the association of adiponectin levels in young and lean women with PCOS.&lt;p&gt;&lt;/p&gt; Methods: A case–control study was conducted at the Dow University of Health Sciences, Karachi, Pakistan. Cases were 75 patients of PCOS with Body Mass Index (BMI) &#38;23 aged 16–35 years and 75 healthy age and BMI matched controls were selected from family and friends of the cases. Demographic details, family history and past medical history were obtained through interview by a physician. Anthropometric measurements included weight and height of the participants. Fasting glucose, total cholesterol, high-density lipoprotein (HDL), insulin, adiponectin, and androgen levels were determined. IR was calculated using homeostasis model assessment for insulin resistance (HOMA-IR). Logistic regression models were used to assess the association between adiponectin and PCOS after adjusting for co-variates.&lt;p&gt;&lt;/p&gt; Results: On multivariable analysis, PCOS cases were 3.2 times more likely to have low adiponectin level (OR = 3.2, 95% CI 1.49-6.90, p-value 0.003) compared to the controls after adjustment for age, BMI, family history, marital status, total cholesterol, HDL level and IR. Females with a family history of PCOS were significantly more likely to have lower adiponectin (OR = 3.32, 95% CI 1.27-8.67, p-value 0.014) compared to those who did not have a family history of PCOS. The associations of IR and family history with low adiponectin level also remained statistically significant after adjustments for covariates.&lt;p&gt;&lt;/p&gt; Conclusion: Serum adiponectin levels are independently associated with PCOS and are only partly explained by IR. Adiponectin level may serve as a potential independent biomarker for diagnosis of PCOS in young and lean women with fewer symptoms, or women with a family history of PCOS

The Role of the Brain in the Pathogenesis and Physiology of Polycystic Ovary Syndrome (PCOS).

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder, affecting at least 10% of women of reproductive age. PCOS is typically characterized by the presence of at least two of the three cardinal features of hyperandrogenemia (high circulating androgen levels), oligo- or anovulation, and cystic ovaries. Hyperandrogenemia increases the severity of the condition and is driven by increased luteinizing hormone (LH) pulse secretion from the pituitary. Indeed, PCOS women display both elevated mean LH levels, as well as an elevated frequency of LH pulsatile secretion. The abnormally high LH pulse frequency, reflective of a hyperactive gonadotropin-releasing hormone (GnRH) neural circuit, suggests a neuroendocrine basis to either the etiology or phenotype of PCOS. Several studies in preclinical animal models of PCOS have demonstrated alterations in GnRH neurons and their upstream afferent neuronal circuits. Some rodent PCOS models have demonstrated an increase in GnRH neuron activity that correlates with an increase in stimulatory GABAergic innervation and postsynaptic currents onto GnRH neurons. Additional studies have identified robust increases in hypothalamic levels of kisspeptin, another potent stimulator of GnRH neurons. This review outlines the different brain and neuroendocrine changes in the reproductive axis observed in PCOS animal models, discusses how they might contribute to either the etiology or adult phenotype of PCOS, and considers parallel findings in PCOS women

Dual mTOR/PI3K inhibition limits PI3K-dependent pathways activated upon mTOR inhibition in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of kidney cysts leading to kidney failure in adulthood. Inhibition of mammalian target of rapamycin (mTOR) slows polycystic kidney disease (PKD) progression in animal models, but randomized controlled trials failed to prove efficacy of mTOR inhibitor treatment. Here, we demonstrate that treatment with mTOR inhibitors result in the removal of negative feedback loops and up-regulates pro-proliferative phosphatidylinositol 3-kinase (PI3K)-Akt and PI3K-extracellular signal-regulated kinase (ERK) signaling in rat and mouse PKD models. Dual mTOR/PI3K inhibition with NVP-BEZ235 abrogated these pro-proliferative signals and normalized kidney morphology and function by blocking proliferation and fibrosis. Our findings suggest that multi-target PI3K/mTOR inhibition may represent a potential treatment for ADPKD

The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study

To evaluate the cardiovascular risk of polycystic ovary syndrome (PCOS), we investigated lipid profile, metabolic pattern, and echocardiography in 30 young women with PCOS and 30 healthy age- and body mass index (BMI)-matched women. PCOS women had higher fasting glucose and insulin levels, homeostasis model assessment score of insulin sensitivity, total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels, and TC/high density lipoprotein cholesterol (HDL-C) ratio and lower HDL-C levels than controls. Additionally, PCOS women had higher left atrium size (32.0 +/- 4.9 vs. 27.4 +/- 2.1 mm; P &lt; 0.0001) and left ventricular mass index (80.5 +/- 18.1 vs. 56.1 +/- 5.4 g/m(2); P &lt; 0.0001) and lower left ventricular ejection fraction (64.4 +/- 4.1 vs. 67.1 +/- 2.6%; P = 0.003) and early to late mitral flow velocity ratio (1.6 +/- 0.4 vs. 2.1 +/- 0.2; P &lt; 0.0001) than controls. When patients and controls were grouped according to BMI [normal weight (BMI, &gt;18 and &lt;25 kg/m(2)), overweight (BMI, 25.1-30 kg/m(2)), and obese (BMI, &gt;30 kg/m(2))], the differences between PCOS women and controls were maintained in overweight and obese women. In normal weight PCOS women, a significant increase in left ventricular mass index and a decrease in diastolic filling were observed, notwithstanding no change in TC, LDL-C, HDL-C, TC/HDL-C ratio, and TG compared with controls. In conclusion, our data show the detrimental effect of PCOS on the cardiovascular system even in young women asymptomatic for cardiac disease

Effect of androgen treatment during foetal and/or neonatal life on ovarian function in prepubertal and adult rats

We investigated the effects of different windows of testosterone propionate (TP) treatment during foetal and neonatal life in female rats to determine whether and when excess androgen exposure would cause disruption of adult reproductive function. Animals were killed prepubertally at d25 and as adults at d90. Plasma samples were taken for hormone analysis and ovaries serial sectioned for morphometric analyses. In prepubertal animals, only foetal+postnatal and late postnatal TP resulted in increased body weights, and an increase in transitory, but reduced antral follicle numbers without affecting total follicle populations. Treatment with TP during both foetal+postnatal life resulted in the development of streak ovaries with activated follicles containing oocytes that only progressed to a small antral (smA) stage and inactive uteri. TP exposure during foetal or late postnatal life had no effect upon adult reproductive function or the total follicle population, although there was a reduction in the primordial follicle pool. In contrast, TP treatment during full postnatal life (d1-25) resulted in anovulation in adults (d90). These animals were heavier, had a greater ovarian stromal compartment, no differences in follicle thecal cell area, but reduced numbers of anti-Mullerian hormone-positive smA follicles when compared with controls. Significantly reduced uterine weights lead reduced follicle oestradiol production. These results support the concept that androgen programming of adult female reproductive function occurs only during specific time windows in foetal and neonatal life with implications for the development of polycystic ovary syndrome in women

Increased expression of circulating miRNA-93 in women with polycystic ovary syndrome may represent a novel, non-invasive biomarker for diagnosis

MicroRNAs (miRNA) are a novel class of small noncoding single-stranded RNA molecules that regulate gene expression. There is increasing evidence of their importance in polycystic ovary syndrome (PCOS). The objective was to determine if miRNA-93 and miRNA-223 are differentially expressed in the circulation of women with PCOS compared to age matched women. A case–control study comparing women with PCOS (n = 25) to age and weight matched controls (n = 24) without PCOS was performed. MiRNA-93 and miRNA-223 were determined by total RNA reverse transcription. Both miRNA-93 and miRNA-223 were significantly increased relative to the control group (p &lt; 0.01, p = 0.029 respectively). In both groups there was no correlation of either miRNA-93 or miRNA-223 with insulin, HOMA-IR, HOMA-β or testosterone levels. The area under the receiver operator characteristic curve for miR-223 and miR-93 was 0.66 and 0.72 respectively, suggesting miR-93 is a more efficient biomarker than miR-223 for diagnosis of PCOS. The combination of the two miRNAs together, tested using multiple logistic regression analysis, did not improve the diagnostic potential. In conclusion, circulating miRNA-93 and miRNA-223 were higher in women with PCOS compared to age and weight matched controls independent of insulin resistance and testosterone levels, and miR-93 may represent a novel diagnostic biomarker for PCOS

Rodent Models of Polycystic Ovary Syndrome

Rodents are clearly valuable models for assessing disruption of fertility. The effects of different steroid treatments at different stages of reproductive life through from fetal to adult have been assessed for effects on fertility, ovarian morphology, hypothalamic- pituitary function or metabolic consequences. The results show that steroid treatments do disrupt fertility in many cases, but the underlying mechanisms are complicated by the effects of the different treatments at multiple sites. As models for PCOS at the ovarian level however, there are a number of problems particularly related to the fact that rodents are multi-ovular species. Apart from an absence of ovulation and corpora lutea, many of the different steroid regimes result in an increase in large atretic, or cystic follicles that do not parallel PCOS in women. Indeed a number of treatments are given at times when they will cause disruption of the positive feedback effects of estradiol, thus blocking ovulation in adult life. The resulting ovarian morphology thus appears to be like that of PCOS but is in fact not a clear mimic. This review of the various studies highlights parallels and problems with the use of rodents to study the mechanisms underlying the development of PCOS in women