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PubMed2005

Serum anti-Müllerian hormone levels remain high until late reproductive age and decrease during metformin therapy in women with polycystic ovary syndrome.

BACKGROUND: Anti-Müllerian hormone (AMH) is secreted by granulosa cells of ovarian early developing follicles and its serum levels have been shown to correlate with small antral follicle number. Since the pronounced androgen secretion from follicles/stroma in women with polycystic ovary syndrome (PCOS) remains until late reproductive age, and since AMH reflects the number of antral follicles, it was of interest to study the possible age-related relationship between AMH, androgens and follicle number in women with PCOS and in control women. Moreover, the possible effect of metformin on serum AMH levels and the relationship to follicle count and volume were studied. METHODS: Forty-four healthy women (aged 21-44 years) and 65 women with previously diagnosed PCOS (aged 16-44 years) participated in the study. Serum basal AMH levels were correlated with those of serum androstenedione, testosterone, estradiol (E2), LH, FSH and inhibin B, and with follicle number. The effect of metformin on serum AMH concentrations, follicle number and ovarian volume was studied in 26 women (aged 20-41 years) with PCOS after 6 months of treatment. RESULTS: Serum AMH levels were 2- to 3- fold higher in PCOS women than in healthy women. In control women, serum AMH levels correlated positively with those of serum androstenedione (r = 0.564, P < 0.001) and testosterone (r = 0.328, P = 0.036) and negatively with serum FSH concentrations (r = -0.374, P = 0.012) and age (r = -0.691, P<0.001). In women with PCOS, serum AMH levels correlated positively with those of androstenedione (r = 0.311, P = 0.011) and testosterone (r = 0.310, P = 0.011) and with follicle count (r = 0.352, P = 0.012), and negatively with age (r = -0.300, P = 0.014). Serum AMH levels, the number of antral follicles and ovarian volume decreased significantly during metfromin treatment. CONCLUSIONS: Serum AMH levels decreased with age both in healthy women and in women with PCOS, although they were always 2- to 3-fold higher and remained elevated until 40 years of age in PCOS subjects. Thus, since serum AMH levels correlate well with antral follicle count and serum androgen levels, the measurement of AMH could be used as a tool to assess ovarian ageing, to diagnose polycystic ovaries/PCOS and to evaluate treatment efficacy.

Adult↗

PubMed2005

Comparison of ovarian stromal blood flow between fertile women with normal ovaries and infertile women with polycystic ovary syndrome.

BACKGROUND: Conflicting information exists in the literature with respect to ovarian stromal blood flow in women with polycystic ovary syndrome (PCOS). We compared the ovarian stromal blood flow and serum vascular endothelial growth factor (VEGF) concentration between fertile women with normal ovaries and infertile women with PCOS. METHODS: In the second to fourth day of the menstrual period, they underwent transvaginal scanning with three-dimensional (3D) power Doppler to determine total antral follicle count (AFC), total ovarian volume, total ovarian vascularization index (VI), flow index (VFI) and vascularization flow index (VFI). Serum FSH, LH and VEGF concentrations were also checked. RESULTS: 107 fertile controls and 32 PCOS women were recruited. Fertile controls and PCOS women had similar total ovarian VI/FI/VFI after controlling for age of the woman, although PCOS women had significantly higher total AFC, total ovarian volume and serum LH concentration than fertile controls. Total ovarian VI/FI/VFI were significantly higher in normal weight (BMI < 25 kg/m2) PCOS women than their overweight (> or = 25 kg/m2) counterparts. CONCLUSIONS: Fertile controls and PCOS women had similar total ovarian 3D power Doppler flow indices. Normal weight PCOS women had significantly higher total ovarian 3D power Doppler flow indices than their overweight counterparts.

Adult↗

PubMed2005

Microvascular dysfunction in women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with multiple cardiovascular risk factors and an increased prevalence of arterial dysfunction. However, microvascular dysfunction in PCOS has not been assessed. METHODS: Subjects comprised 12 women with PCOS and 12 age-matched controls with normal ovaries. Microvascular function was assessed by observing forearm skin microvascular erythrocyte flux responses, to cumulative iontophoretic doses of 1% (w/v) acetylcholine (ACh) and 1% (w/v) sodium nitroprusside (SNP), using laser Doppler imaging. RESULTS: Basal microvascular perfusion was comparable in PCOS and controls. The increase in skin microvascular perfusion in response to ACh was however generally blunted in PCOS women (P = 0.018). Peak ACh-induced erythrocyte flux was also less (p < 0.04) in PCOS women (125.1 +/- 21.7, i.e. 5.3-fold basal flux) than in controls (200.8 +/- 28.5, i.e. 8.3-fold basal flux). Analysis of covariance indicated this effect was unrelated to differences in body mass index or serum testosterone but serum insulin may be a weak confounder. No differences were noted between the PCOS and control groups in their response to SNP. CONCLUSION: Despite its limited sample size studied, this is the first demonstration that women with PCOS exhibit microvascular endothelial dysfunction, indicated by an inhibited vasodilatory response to ACh.

Acetylcholine↗

PubMed2006

The (TAAAA)n microsatellite polymorphism in the SHBG gene influences serum SHBG levels in women with polycystic ovary syndrome.

BACKGROUND: Hyperandrogenaemia is a common feature of polycystic ovary syndrome (PCOS). The sex hormone-binding globulin (SHBG) gene was proposed as being a PCOS candidate gene. A possible influence of the microsatellite polymorphism (TAAAA)(n) in the SHBG gene on serum SHBG levels in PCOS patients was investigated. METHODS: One hundred and twenty-three PCOS patients and 110 age-matched controls were included in the study. Peripheral blood samples were obtained. Genotyping of the (TAAAA)(n) polymorphism in the SHBG gene was performed. Serum LH, FSH, SHBG and total testosterone concentrations were determined. RESULTS: SHBG alleles with 6-11 TAAAA repeats were found. None of the SHBG alleles or genotypes were present at a significantly more frequent rate in PCOS patients compared with controls. Serum SHBG levels were significantly lower (P < 0.001) in PCOS patients compared with controls and were found to be strongly influenced by the (TAAAA)(n) SHBG polymorphism, in both the PCOS (55.3%) and control (33.1%) groups of patients. CONCLUSIONS: The (TAAAA)(n) SHBG gene polymorphism might be an important predictor for serum SHBG levels and, consequently, for hyperandrogenaemic clinical presentation of PCOS.

Adult↗

PubMed2007

Adipocyte resistin mRNA levels are down-regulated by laparoscopic ovarian electrocautery in both obese and lean women with polycystic ovary syndrome.

BACKGROUND: The aim of this study was to investigate serum and adipocyte mRNA expression of resistin in lean and obese women with polycystic ovary syndrome (PCOS) before and 3 months after laparoscopic ovarian electrocauterization (LOE). METHODS: Adipose tissue obtained from 12 women with PCOS (six obese and six lean, body mass index > 27 kg m(-1) as threshold point) before and after LOE was analysed. Gene expression of resistin was measured by semi-quantitative RT-PCR. Ten lean, age-matched healthy women served as controls. RESULTS: Both lean and obese women with PCOS had significantly higher fasting and 2 h insulin and homeostasis model insulin resistance index (HOMA(IR)) values and lower fasting glucose-to-insulin ratios (G(0)/I(0)) than did the controls. The serum levels of glucose and insulin and HOMA(IR) were significantly decreased, and the G(0)/I(0) ratio was significantly increased 3 months after LOE. No difference was found in serum resistin levels between controls and either obese or lean women with PCOS before LOE, nor between PCOS patients before and after LOE. However, resistin mRNA expression levels in both lean and obese women with PCOS before LOE were significantly higher than that in controls and were decreased significantly after LOE back to control levels. CONCLUSION: Local resistin activity may be actively involved in the pathogenesis of PCOS. LOE reduces insulin resistance and down-regulates resistin mRNA expression in lean and obese women with PCOS.

Adipocytes↗

PubMed1998

Aromatase mRNA expression in individual follicles from polycystic ovaries.

Polycystic ovary syndrome (PCOS) is a common reproductive disorder characterized by arrested follicular development prior to selection of a dominant follicle. Dominant follicles produce large amounts of oestradiol but PCOS follicles do not. With several potential aromatase (P450AROM) inhibitors in follicular fluid, the question arises whether P450AROM is expressed in PCOS granulosa cells, but the activity is inhibited, or whether P450AROM is not expressed in PCOS. The purpose of the present study was to determine whether P450AROM mRNA expression is altered in PCOS and to correlate P450AROM mRNA expression in individual follicles with aromatase stimulatory bioactivity and oestradiol in the follicular microenvironments. P450AROM mRNA was measured in individual follicles from 16 PCOS and 48 regularly cycling control women by quantitative polymerase chain reaction (PCR) and correlated with follicular fluid oestradiol concentrations and aromatase stimulating bioactivity measured by the rat granulosa cells aromatase bioassay. Follicular fluid oestradiol was low in all control follicles <7 mm in diameter. Some follicles > or = 7 mm contained elevated oestradiol values (P < 0.01) and all had an androstenedione:oestradiol ratio of <4. Only in granulosa cells from follicles > or = 7 mm with an androstenedione:oestradiol ratio of <4 were P450AROM mRNA levels increased (P < 0.05). These same follicles also contained increased levels of aromatase stimulating bioactivity whereas follicles <7 mm or with androstenedione:oestradiol ratio of >4 contained little or no bioactivity. All PCOS follicles contained low levels of oestradiol, P450AROM mRNA and aromatase stimulating bioactivity similar to size-matched control follicles. These data indicate that P450AROM mRNA expression and oestradiol production begin in developing follicles when they reach approximately 7 mm in diameter. Oestradiol production is low in PCOS follicles because there is insufficient aromatase stimulating bioactivity to increase P450AROM mRNA expression.

Androstenedione↗

PubMed1996

Normal serum uric acid concentrations in women with polycystic ovary syndrome.

Recently, an inverse correlation between serum uric acid concentrations and insulin sensitivity has been described in subjects with varying degrees of metabolic syndrome, suggesting that measurement of serum uric acid may provide a simple marker of insulin resistance. Several biochemical and clinical features of polycystic ovary syndrome (PCOS) resemble those of metabolic syndrome: women with PCOS are often obese; they are also at increased risk for the development of coronary artery disease, hypertension and diabetes mellitus. The objective of the present study was to analyse the usefulness of serum uric acid measurement in screening for the metabolic syndrome in women with PCOS. For that purpose serum concentrations of uric acid, insulin and triglycerides were measured in 38 women with PCOS and 20 weight-matched control women with regular menstrual cycles. No differences were found in the uric acid concentrations between the PCOS and control groups. The mean concentrations of triglycerides and fasting insulin were higher in the women with PCOS than in the healthy controls. Serum uric acid concentrations were inversely related to serum hormone-binding globulin (SHBG) concentrations, and positively with body mass index (BMI), insulin concentrations and testosterone:SHBG ratio in the PCOS group. Our results suggest that measurement of serum uric acid does not provide new means for identification of metabolic syndrome in patients with PCOS.

Adult↗

PubMed1995

Insulin-like growth factor binding proteins in a natural pre-ovulatory follicle from a woman with polycystic ovary syndrome.

Insulin-like growth factor binding protein (IGFBP) concentrations in the follicular fluid of ovarian follicles have been shown to correlate with dominance and atresia. IGFBP-2 and IGFBP-4 are increased in atresia, and IGFBP-3 is decreased in dominant follicles. The purpose of this study was to compare the IGFBP concentration in follicular fluid from a natural pre-ovulatory follicle of a woman with polycystic ovarian syndrome (PCOS) with other PCOS follicles and dominant follicles from normally cycling women. Follicular fluid was collected from 5-7 mm diameter follicles and a natural pre-ovulatory follicle from women with PCOS, and healthy and atretic follicles from normal women. The IGFBP profiles were analysed using Western ligand blotting. The IGFBP concentrations in the 5-7 mm diameter follicles from the polycystic ovaries containing a pre-ovulatory follicle were similar to those in follicles from other women with PCOS, and comparable with androgenic cohort follicles from normal women. In particular, the IGFBP-2 and IGFBP-4 concentrations were elevated significantly compared with the oestrogenic cohort follicles. The concentrations of all IGFBP detected in the follicular fluid from the PCOS pre-ovulatory follicle were significantly less than those of the 5-7 mm diameter follicles from the same subject. The IGFBP concentrations were within the range of normal dominant follicles, and IGFBP-2 and IGFBP-3 were at the lower end of the normal range. The results indicate that the PCOS pre-ovulatory follicle contained a normal pattern of IGFBP expression even though the other follicles exhibited a pattern typical of PCOS. These data support the hypothesis that decreased concentrations of IGFBP, in particular IGFBP-3, may be involved in selection of the dominant follicle, and that when a spontaneous pre-ovulatory follicle develops in PCOS, the underlying cause of the polycystic ovaries is not resolved but the rest of the ovary remains polycystic.

Adult↗

PubMed1995

Subjects with polycystic ovaries without hyperandrogenaemia exhibit similar disturbances in insulin and lipid profiles as those with polycystic ovary syndrome.

Polycystic ovaries (PCO) are detected using ultrasonography in a proportion of women who do not have clinical symptoms of the polycystic ovary syndrome (PCOS). The aim of this study was to compare the metabolic and endocrine differences between women with such ultrasound-detected PCO and women with PCOS, and to relate these changes to clinical presentation with particular reference to cycle irregularity. A group of 118 women showing PCO on vaginal ultrasound scan was divided into those who had no hyperandrogenaemia (n = 21) and those who had increased androgens and a clinical presentation normally associated with PCOS (n = 97). These were compared with a reference group of 26 normal subjects. Glucose tolerance, lipid concentrations and endocrine profiles were compared between groups. Apart from higher concentrations of androgens in the PCOS group, there were no significant differences between the PCO and PCOS groups in either fasting and stimulated insulin and glucose or in concentrations of sex hormone-binding globulin, gonadotrophins and blood lipids or in ovarian volume. Both PCO and PCOS subjects with cycle irregularity had significantly higher concentrations of serum fasting and stimulated insulin independent of androgens and body mass index than those with normal cycles. It was concluded that: (i) PCO and PCOS patients have equivalent disturbances in relation to insulin and glucose metabolism as well as lipid and lipoprotein disturbances compared to reference subjects; (ii) higher serum insulin values are associated with menstrual irregularity in both groups; (iii) ultrasound evidence for PCO predicts similar metabolic sequelae to PCOS and can therefore be used for studies of the genetics and long term risks for this condition.

Androgens↗

PubMed2001

Insulin action and insulin secretion in polycystic ovary syndrome treated with ethinyl oestradiol/cyproterone acetate.

Polycystic ovary syndrome (PCOS) is associated with abnormalities of insulin action and insulin secretion. Ethinyl oestradiol/cyproterone acetate is a common agent used to treat the symptoms of PCOS, but its effects on insulin action and insulin pulsatility have not been examined. We investigated the relationship between insulin action and insulin secretion in 11 patients with PCOS, at diagnosis and after 3 months of treatment with ethinyl oestradiol/cyproterone acetate, and in 13 controls. Insulin action was assessed using the euglycaemic hyperinsulinaemic clamp (2 mU/kg/min for 2 h). Insulin pulsatility was examined over 90 min by 2 min sampling. Short-term insulin pulses were identified using PULSAR. Treatment with ethinyl oestradiol/cyproterone acetate resulted in significant reductions in testosterone (3.3+/-0.7 vs. 1.9+/-0.2 nmol/l, p<0.05), free androgen index (10.2+/-0.7 vs. 1.2+/-0.2, p<0.05) and LH/FSH ratio (2.6+/-0.5 vs. 1.0+/-0.2, p<0.05). During hyperinsulinaemic clamps, the glucose infusion rate (GIR) required to maintain euglycaemia was lower in PCOS compared to controls (33.6+/-2.7 vs. 45.1+/-3.5 micromol/kg/min, p<0.05) but similar in PCOS before and after treatment (33.6+/-2.8 vs. 33.6+/-2.7 micromol/kg/min, p=0.9). Numbers of pulses identified in PCOS and controls were similar and unaltered by ethinyl oestradiol/cyproterone acetate. There was no correlation between GIR and frequency of insulin pulses in PCOS before or after treatment (r=0.2, p=0.6; post r=-0.5, p=0.1) unlike controls (r=-0.6, p=0.04). Despite considerable improvement in androgen profile, treatment with ethinyl oestradiol/cyproterone acetate did not alter insulin action in PCOS, and this insulin resistance does not appear to be determined by insulin pulse frequency.

Adult↗

PubMed2005

Impaired uterine perfusion associated with metabolic disorders in women with polycystic ovary syndrome.

BACKGROUND: Risk factors for cardiovascular disease, including chronic anovulation, obesity, hyperandrogenism, hyperinsulinemia, and dyslipidemia, are commonly observed in women with polycystic ovary syndrome (PCOS). We evaluated uterine perfusion and its correlation with clinical and biochemical parameters in women with PCOS. METHODS: We performed a pulsed Doppler study on uterine arterial blood flow in 25 women with PCOS and 45 control women with regular menstrual cycles. PCOS was diagnosed based on oligomenorrhea, polycystic ovaries determined by means of ultrasonography, and elevated luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratio. RESULTS: Women with PCOS had a significantly higher body mass index (BMI) and serum testosterone, and showed insulin resistance and dyslipidemia, including increased total cholesterol, triglyceride, low-density lipoprotein-cholesterol (LDL-C), and decreased high-density lipoprotein-cholesterol (HDL-C). The uterine arterial pulsatility index (PI) in women with PCOS was significantly higher than that in the control women during the follicular phase. The PI was correlated with BMI, LH/FSH ratio, or LDL-C/HDL-C ratio, whereas it was inversely correlated with the HDL-C level. Women with PCOS had reduced endometrial thickness and elevated uterine arterial PI in the luteal phase, in which implantation occurs. CONCLUSIONS: Elevation of uterine arterial blood flow resistance is associated with risk factors for cardiovascular events. Furthermore, the impaired uterine perfusion in the luteal phase may cause endometrial dysfunction in women with PCOS.

Adult↗

PubMed1992

Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome.

OBJECTIVE: The evidence that some women with the polycystic ovary syndrome (PCOS) are hyperinsulinaemic has brought into question their risk of developing early coronary artery disease. We have focused on three cardiac risk factors which have been associated with hyperinsulinaemia by measuring glucose tolerance, fasting serum lipid concentrations and blood pressure in women with PCOS. DESIGN: Comparison of clinical and biochemical measurements in lean and obese women with PCOS and in women with normal ovaries. Determinants of the risk factors for coronary artery disease were assessed by multiple regression analysis. PATIENTS: One hundred and two women with ultrasound diagnosed PCOS and 19 lean women with normal ovaries were studied. Patients were recruited from a reproductive endocrine clinic. MEASUREMENTS: Fasting total cholesterol, triglycerides, high density lipoproteins (HDL), HDL2, glucose tolerance, fasting and stimulated insulin, gonadotrophins, testosterone and androstenedione were measured during a 2-hour oral glucose tolerance test. Recumbent blood pressure was measured automatically. RESULTS: Lean women with PCOS were found to be hyperinsulinaemic and have reduced serum HDL and HDL2 concentrations compared to women with normal ovaries; serum insulin concentrations correlated positively with plasma glucose and blood pressure measurements in multiple regression analysis. Obese women with PCOS were in addition found to have higher systolic blood pressure, serum triglyceride and plasma glucose concentration than lean women with PCOS and controls. CONCLUSIONS: These results support the evidence that hyperinsulinaemic women with PCOS have an increased risk of developing cardiovascular disease and therefore form a population in whom metabolic screening is advisable.

Adult↗

PubMed2005

The peroxisome proliferator activated receptor gamma Pro12Ala polymorphism is associated with a lower hirsutism score and increased insulin sensitivity in women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and chronic anovulation. The genetic background of the insulin resistance frequently associated with PCOS is unclear. OBJECTIVES: To examine the influe nce of the Pro12Ala polymorphism of the peroxisome proliferator activated receptor gamma (PPARgamma), which is thought to play a role in the regulation of insulin sensitivity, on endocrine and metabolic parameters in PCOS patients. METHODS: PPARgamma alleles were analysed in 102 PCOS patients (age 27 +/- 5.3 years) and 104 age matched control women. PCOS was defined by the NIH-criteria as the presence of chronic oligo- or anovulation and hyperandrogenism. Family history and clinical parameters were evaluated by personal interview and physical examination, parameters of insulin resistance [homeostasis model assessment (HOMA) and Matsuda-index] were evaluated with a glucose tolerance test. RESULTS: Seventy-nine (77.5%) PCOS patients were carriers of the wild-type PPARgamma allele (Pro/Pro), while 23 (22.5%) had at least one Ala allele (X/Ala), with an equal distribution in controls. X/Ala PCOS women were more insulin-sensitive, evidenced by lower fasting insulin, HOMA index and insulin secretion. Differences in insulin resistance did not depend on body mass index. The genotype had no influence on lipid status, leptin, adiponectin, ghrelin, or family history of type 2 diabetes. A significantly lower proportion of Pro/Ala patients had hirsutism and they had on average lower hirsutism scores than Pro/Pro patients. No relationship was found between the Pro/Ala polymorphism and other signs of hyperandrogenism. CONCLUSION: The Pro12Ala polymorphism of the PPARgamma gene is associated with increased insulin sensitivity and lower hirsutism scores in PCOS women.

Adult↗

PubMed2006

Inflammatory and endothelial markers in women with polycystic ovary syndrome.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) carry a pattern of cardiovascular risk factors. Endothelial dysfunction and chronic inflammation are early findings in the atherosclerotic process. The purpose of the study was to investigate the coexistence of active inflammation markers and endothelial dysfunction in young women with PCOS, and their relationship with metabolic and hormonal abnormalities of the syndrome. MATERIALS AND METHODS: Twenty-five young women with PCOS and 25 controls of similar age and body mass index (BMI) were studied. Endothelial function was assessed by flow-mediated dilatation (FMD) on the brachial artery and smooth muscle cells injury was excluded by nitrate-induced dilatation (NID). Plasma levels of endothelin-1 (ET-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and high sensitivity C-reactive protein (hsCRP) were measured. Hormonal and metabolic profiles were determined in both groups. RESULTS: Flow-mediated dilatation (FMD) was statistically lower in PCOS (P < 0.001), whereas nitrate-induced dilatation (NID) was similar within the two groups. Polycystic ovary syndrome (PCOS) had statistically higher levels of ET-1 (P = 0.03), sICAM-1 (P = 0.01), sVCAM-1 (P = 0.02) and hsCRP (P = 0.01). Furthermore FMD was statistically higher in PCOS population with hsCRP 1 mg L(-1) when compared with PCOS population with hsCRP > 1 mg L(-1) (P = 0.02). Flow-mediated dilatation (FMD) was negatively related to hsCRP (r = -0.512, P = 0.015); ET-1 was positively related to free androgen index (r = 0.27, P = 0.05) and negatively to sex hormone-binding globulin (r = -0.465, P = 0.022); sVCAM-1 was positively related to total testosterone (r = 0.431, P = 0.036); hsCRP was positively related to BMI (r = 0.647, P = 0.001), and negatively related to FMD (r = -0.512, P = 0.015), quantitative insulin sensitivity check index (QUICKI) (r = -0.499, P = 0.018), and MATSUDA index (r = -0.445, P = 0.038). CONCLUSIONS: The present study demonstrates that endothelial dysfunction coexists and is influenced by the presence of increased serum levels of inflammation and endothelial activation markers in young women with PCOS. These parameters appear to be interrelated with hyperandrogenaemia in this insulin-resistant population.

Adult↗

PubMed2005

Development of polycystic ovary syndrome: involvement of genetic and environmental factors.

We have recently proposed that polycystic ovary syndrome (PCOS) has its origin in fetal life. This hypothesis is based on data from animal models (rhesus monkey or sheep that have been exposed prenatally to high doses of androgen) and is supported by clinical studies. It is suggested that, in human females, exposure to excess androgen, at any stage from fetal development of the ovary to the onset of puberty, leads to many of the characteristic features of PCOS, including abnormalities of luteinizing hormone secretion and insulin resistance. It is likely that, in humans with PCOS, the development of the PCOS phenotype results primarily from a genetic predisposition for the fetal ovary to hypersecrete androgen. At present, it is unclear whether the maternal environment directly influences the development of PCOS in the offspring. Maternal androgen excess is unlikely to affect the fetus, because the placenta presents an effective barrier, but metabolic disturbances during pregnancy could affect development of the syndrome in the fetus. In postnatal life, the natural history of PCOS can be further modified by factors affecting insulin secretion and/or action, most importantly, nutrition. We now have evidence for a disorder of early follicular development in the polycystic ovary that is consistent with an increased population of primordial follicles in the fetal ovary. It remains to be determined whether this phenomenon is the cause or the effect of increased exposure to androgen within the ovary. PCOS is the commonest endocrine disorder in women. It is not only a very prevalent cause of anovulatory infertility, menstrual disturbances and hirsutism, but it is also a major risk factor for the development of type 2 diabetes mellitus in later life. The aetiology of the syndrome remains uncertain but there is increasing evidence for a genetic basis. PCOS very often becomes clinically manifest during adolescence with maturation of the hypothalamic-pituitary-ovarian axis but the genesis of the syndrome may be during very early development - perhaps even in utero. In this review, this hypothesis is explored in the light of clinical, biochemical and genetic research.

Androgens↗

PubMed2006

The impact of obesity on reproduction in women with polycystic ovary syndrome.

The polycystic ovary syndrome (PCOS) is one of the most common causes of infertility due to anovulation in women. The clinical features of PCOS are heterogeneous and may change throughout the lifespan, starting from adolescence to postmenopausal age. This is largely dependent on the influence of obesity and metabolic alterations, including an insulin-resistant state and the metabolic syndrome, which consistently affect most women with PCOS. Obesity does in fact have profound effects on both the pathophysiology and the clinical manifestation of PCOS, by different mechanisms leading to androgen excess and increased free androgen availability and to alterations of granulosa cell function and follicle development. Notably, simple obesity per se represents a functional hyperandrogenic state. These mechanisms involve early hormonal and metabolic factors during intrauterine life, leptin, insulin and the insulin growth factor system and, potentially, the endocannabinoid system. Compared with normal weight women with PCOS, those with obesity are characterised by a worsened hyperandrogenic and metabolic state, poorer menses and ovulatory performance and, ultimately, poorer pregnancy rates. The importance of obesity in the pathogenesis of PCOS is emphasised by the efficacy of lifestyle intervention and weight loss, not only on metabolic alterations but also on hyperandrogenism, ovulation and fertility. The increasing prevalence of obesity among adolescent and young women with PCOS may partly depend on the increasing worldwide epidemic of obesity, although this hypothesis should be supported by long-term prospective epidemiological trials. This may have great relevance in preventive medicine and offer the opportunity to expand our still limited knowledge of the genetic and environmental background favouring the development of the PCOS.

Adipose Tissue↗

PubMed2002

Association of insulin gene VNTR polymorphism with polycystic ovary syndrome.

Variability in the number of tandem repeats of the insulin gene (INS VNTR) is known to influence several phenotypes, including polycystic ovary syndrome (PCOS), diabetes mellitus type 1, diabetes mellitus type 2, and birth weight. The presence of the class III allele of INS VNTR has been reported to be protective in diabetes mellitus type 1, but in contrary it increases the disease risk of PCOS and diabetes mellitus type 2. PCOS is a very common endocrinopathy in women of reproductive age. The etiology of PCOS is uncertain, but family history of this syndrome suggests a major genetic cause. The aim of this pilot study was to investigate the possible association of INS VNTR polymorphism with PCOS in Czech women. In PCOS, significantly higher WHR, BMI, G(0), G(180), I(30), Cp(0), Cp(30), Cp(60), AUC-I, AUC-Cp, and insulinogenic index and significantly lower AUC-G/AUC-I were found. No significant differences in INS VNTR genotype, phenotype, or allele frequencies were found between PCOS and controls. In spite of several differences in anthropometric and biochemical parameters (abdominal fat localization, increased beta-cell function, and lower insulin sensitivity in PCOS women), no effect of INS VNTR polymorphism was found on insulin secretion, insulin action, or any other screened parameter.

Base Sequence↗

PubMed2004

Exaggerated 17-hydroxyprogesterone response to intravenous infusions of recombinant human LH in women with polycystic ovary syndrome.

Studies using pharmacological gonadotropin stimulation suggest that ovarian steroidogenesis is abnormal in the polycystic ovary syndrome (PCOS). We assessed ovarian steroid secretion in response to near-physiological gonadotropin stimuli in 12 ovulatory controls and 7 women with PCOS. A gonadotropin-releasing hormone-receptor antagonist (ganirelix, 2 mg sc) was given to block endogenous LH secretion, followed by dexamethasone (0.75 mg orally) to suppress adrenal androgen secretion. After ganirelix injection (12 h), intravenous infusions of recombinant human LH (0, 10, 30, 100, and 300 IU; each over 8 min) were administered at 4-h intervals in a pseudorandomized (highest dose last) manner. Plasma LH, 17-hydroxyprogesterone (17-OHP), androstenedione, and testosterone were measured concurrently. LH dose-steroid response relationships (mean sex-steroid concentration vs. mean LH concentration over 4 h postinfusion) were examined for each subject. Linear regression of 17-OHP on LH yielded a higher (mean +/- SE) slope in PCOS (0.028 +/- 0.010 vs. 0.005 +/- 0.005, P < 0.05), whereas extrapolated 17-OHP at zero LH was similar. The slopes of other regressions did not differ from zero in either PCOS or controls. We conclude that near-physiological LH stimulation drives heightened 17-OHP secretion in patients with PCOS, suggesting abnormalities of early steps of ovarian steroidogenesis. With the exception of 17-OHP response in PCOS, no acute LH dose-ovarian steroid responses were observed in controls or PCOS. Defining the precise mechanistic basis of heightened precursor responsiveness to LH in PCOS will require further clinical investigation.

17-alpha-Hydroxyprogesterone↗