Search

Disturbances during intrauterine life have been implicated in the origin of polycystic ovary syndrome (PCOS) and may modify the endocrine and metabolic function of a child born to a mother with PCOS independently of genetic inheritance and sex. Daughters of women with PCOS show 4 components of the syndrome (ovarian dysfunction, neuroendocrine dysfunction, hyperandrogenism, and hyperinsulinemia) that appear in a sequential pattern during infancy, childhood, and puberty increasing the chance for developing PCOS during adulthood. Sons born to mothers with PCOS show few reproductive but important metabolic disturbances. These metabolic features, both in girls and boys, have early cardiovascular effects that may put these children at risk for later cardiovascular disease. Recent combined animal/human models have been able to identify common markers that will help us elucidate the precise mechanisms involved in the transgenerational transmission of this syndrome and provide possible therapies to prevent it.

How obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring is unclear. In a Swedish nationwide register-based cohort and a clinical case–control study from Chile, we found that daughters of mothers with PCOS were more likely to be diagnosed with PCOS. Furthermore, female mice (F0) with PCOS-like traits induced by late-gestation injection of dihydrotestosterone, with and without obesity, produced female F1–F3 offspring with PCOS-like reproductive and metabolic phenotypes. Sequencing of single metaphase II oocytes from F1–F3 offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case–control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of mothers with PCOS and identify possible candidate genes for the prediction of a PCOS phenotype in future generations. Prenatal androgen exposure causes transgenerational increases in offspring susceptibility to polycystic ovary syndrome in adulthood.

Objective To study the reproductive and metabolic differences between daughters of women with polycystic ovary syndrome (PCOSd) and control women (Cd) after menarche. Design Case-control study. Setting Clinical endocrinology unit. Patient(s) We studied 43 PCOSd and 28 Cd 1.5–6 years after menarche. Intervention(s) Determination of anthropometry, pubertal development, hirsutism, oral glucose tolerance test, and GnRH analogue test. Main Outcome Measure(s) Ferriman score, sex steroids, gonadotropins, antimullerian hormone (AMH), ovarian volumes, and glucose and insulin levels. Result(s) The groups were similar in chronologic, gynecologic, and menarchal ages and anthropometric variables. Ferriman score, ovarian volumes, and AMH were higher in PCOSd. Propensity score analysis showed that there were significant differences in LH, LH-FSH ratio, T and free androgen index, post-stimulated LH and LH-FSH ratio, and 2-hour insulin that could be attributed only to the fact of being a PCOS daughter. The generalized linear model showed that higher LH levels were positively associated with AMH and T levels. Conclusion(s) We found that higher LH, androgen, and insulin levels are present in PCOSd during the postmenarchal period, which may establish the basis for the development of PCOS during adulthood. Moreover, LH levels were associated with AMH levels, which supports that the neuroendocrine feedback proposed for AMH and LH is present in humans and that this feature is probably programed in utero, as recently shown in mice.

Clinical and experimental evidences indicate that epigenetic modifications induced by the prenatal environment are related to metabolic and reproductive derangements in polycystic ovary syndrome (PCOS). Alterations in the leptin and adiponectin systems, androgen signalling and antimüllerian hormone (AMH) levels have been observed in PCOS women and in their offspring. Using a targeted Next-Generation Sequencing (NGS), we studied DNA methylation in promoter regions of the leptin (LEP), leptin receptor (LEPR), adiponectin (ADIPOQ), adiponectin receptor 1 and 2 (ADIPOR1 and ADIPOR2), AMH and androgen receptor (AR) genes in 24 sons and daughters of women with PCOS (12 treated with metformin during pregnancy) and 24 children born to non-PCOS women during early infancy (2–3 months of age). Genomic DNA was extracted from whole blood, bisulphite converted and sequenced by NGS. Girls showed differences between groups in 1 CpG site of LEPR, 2 of LEP, 1 of ADIPOR2 and 2 of AR. Boys showed differences in 5 CpG sites of LEP, 3 of AMH and 9 of AR. Maternal metformin treatment prevented some of these changes in LEP, ADIPOR2 and partially in AR in girls, and in LEP and AMH in boys. Maternal BMI at early pregnancy was inversely correlated with the methylation levels of the ChrX-67544981 site in the whole group of girls (r = −0.530, p = 0.008) and with the global Z-score in all boys (r = −0.539, p = 0.007). These data indicate that the intrauterine PCOS environment predisposes the offspring to acquire certain sex-dependent DNA methylation patterns in the promoter regions of metabolic and reproductive genes.

Background: Granulomatous disease secondary to cosmetic injection of silicone is an uncommon cause of hypercalcemia. Transgender persons with limited access to appropriate surgery commonly use this procedure as an alternative, which can cause serious complications. Clinical Case: Forty year old transgender women with a 7-year history of nephrolithiasis treated with lithotripsy, pyelotomy and requiring the installation of a pig tail. She is admitted at the emergency room due to renal failure. Non-contrast CT rules out acute obstruction and lab tests conclude terminal kidney failure so she is started with dialysis and discharged. Two months later she returns with fever, she is diagnosed with central venous catheter-related bloodstream infection associated to the dialysis catheter and is started with antibiotics. Physical exam reveals pigmented, indurated nodular areas in her buttocks, hips and legs. The patient is re-interrogated and admits to have had injections of industrial silicone at the age of 22 in the described nodular areas. Regarding her transition process she had a vaginoplasty at 25 years old and was started with estrogens at that time but abandoned controls thereafter. Laboratory: Calcium 10, 8 (8,6-10,2 mg/dl), P 6 (2,5-4,5 mg/dl), PTH 17 (12-88 pg / ml), 25OHVD 3 (30ng / ml). Abdominal and thorax CT showed multiple pulmonary nodules, hilar, axillar and retroperitoneal adenopathies, hepatosplenomegaly, and subcutaneous granulomas with calcification in the buttocks and lumbar areas. HVB, HVC, VDRL and HIV serologies were negative as were ANA, pANCA and Rheumatoid Factor. Myelogram was normal. Biopsy of the involved skin and axillary lymph nodes revealed foreign body granulomatous reaction. Real Time PCR determination of the CYP27B1 mRNA showed a positive expression of this gene in the lesions confirming increased 1 alpha-hydroxylase activity as the cause of hypercalcemia. Tc-99m MDP scintigraphy showed increased activity in the soft tissue of the hips, buttocks and legs. Currently she maintains dialysis with normal values of calcium and is following regular controls in our gender program. Conclusion: Granulomatous disease due to cosmetic injection of silicone is a cause of hypercalcemia that should be suspected in the appropriate context. It is important to educate the transgender community about the possible severe adverse effects of these not authorized procedures.

Obesity reduces maternal insulin sensitivity and alters sex steroid serum concentrations. However, it is not clear if these changes are reflected in the fetal circulation. On the other hand, similar to other metabolic tissues, modifications in sex steroid concentrations and metabolic parameters could modify the transport and metabolism of fatty acids (FA) in the placenta increasing their availability for the fetus. Therefore, we aimed to study, in pregnant women with normal-weight and obesity, sex steroid serum concentrations in cord blood and their relationship with the gene expression of FA transporters and of molecules related with FA metabolism in the placenta. We included 26 pregnant women with normal-weight and 26 pregnant women with obesity without pregnancy complications. At term of pregnancy, mixed cord blood and placenta samples were collected and stored at -80°C. Serum concentrations of dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione, testosterone, estrone, estradiol, estriol, insulin and TNF-α were measured by RIA or ELISA. Glycemia and lipid profile were also analyzed. In placental samples, the gene expression of MFSD2A, CD36, FABP4, SLC27A4, PPARG, LPL and DGAT were determined by quantitative PCR. No differences were observed in sex steroid concentrations and metabolic parameters between groups. On the other hand, the gene expression of MFSD2A, CD36 and FABP4 were higher in placentas from women with obesity compared to women with normal-weight (P = 0.050, P = 0.037 and P = 0.038, respectively). When distributed according to fetal sex, cholesterol levels were higher in cord blood of women with obesity and female fetuses (P = 0.005), whereas glycemia was lower in women with obesity and male fetuses (P = 0.045). In turn, the gene expression of CD36 and FABP4 were higher (P = 0.024 and P = 0.034, respectively), whereas MFSD2A tended to be higher (P = 0.092) only in placentas from women with obesity and male fetuses. Moreover, in women with obesity and male fetuses, glycemia was positively correlated with MFSD2A (r = 0.650; P = 0.022), and in women with obesity and female fetuses FABP4 was inversely correlated with triglyceride levels (r = -0.580; P = 0.048). In conclusion, these data suggest that modifications in placental steroidogenesis do not affect sex steroid serum concentrations in the fetal circulation. On the other hand, metabolic parameters in cord blood of pregnant women with obesity are associated with an abnormal expression of FA transporters in placental tissue.

BACKGROUND Women diagnosed with polycystic ovary syndrome (PCOS) suffer from an unfavorable cardiometabolic risk profile, which is already established by child-bearing age. OBJECTIVE AND RATIONALE The aim of this systematic review along with an individual participant data meta-analysis is to evaluate whether cardiometabolic features in the offspring (females and males aged 1–18 years) of women with PCOS (OPCOS) are less favorable compared to the offspring of healthy controls. SEARCH METHODS PubMed, Embase and gray literature databases were searched by three authors independently (M.N.G., M.A.W and J.C.) (last updated on 1 February 2018). Relevant key terms such as ‘offspring’ and ‘PCOS’ were combined. Outcomes were age-specific standardized scores of various cardiometabolic parameters: BMI, blood pressure, glucose, insulin, lipid profile and the sum scores of various cardiometabolic features (metabolic sum score). Linear mixed models were used for analyses with standardized beta (β) as outcome. OUTCOMES Nine relevant observational studies could be identified, which jointly included 1367 children: OPCOS and controls, originating from the Netherlands, Chile and the USA. After excluding neonates, duplicate records and follow-up screenings, a total of 885 subjects remained. In adjusted analyses, we observed that OPCOS (n = 298) exhibited increased plasma levels of fasting insulin (β = 0.21(95%CI: 0.01–0.41), P = 0.05), insulin-resistance (β = 0.21(95%CI: 0.01–0.42), P = 0.04), triglycerides (β = 0.19(95%CI: 0.02–0.36), P = 0.03) and high-density lipoprotein (HDL)-cholesterol concentrations (β = 0.31(95%CI: 0.08–0.54), P WIDER IMPLICATIONS We observed subtle signs of altered cardiometabolic health in OPCOS. Therefore, the unfavorable cardiovascular profile of women with PCOS at childbearing age may—next to a genetic predisposition—influence the health of their offspring. Sensitivity analyses revealed that these differences were predominantly observed among female offspring aged between 1 and 18 years. Moreover, studies with minimal risk of bias should elucidate the influence of a PCOS diagnosis in mothers on both sexes during fetal development and subsequently during childhood.

Polycystic ovary syndrome (PCOS) is an androgen excess disorder associated with obesity and adipose tissue disturbances. Our aim was to evaluate gene expression of adipocytokines and adipocyte characteristics in abdominal subcutaneous adipose tissue (SAT) of PCOS women.Twelve PCOS (PCOSw) and 12 control (Cw) premenopausal women (BMI 20-35 kg/mBoth groups were comparable in age and BMI. Trunk fat mass amount (p = .043), serum and SAT leptin/adiponectin ratio (p = .034 and p = .028, respectively) and adipocyte area (p = .015) were higher in PCOSw compared to Cw. Interestingly, trunk fat mass was positively correlated with adipocyte area in PCOSw (r = 0.821, p = .023), while the inverse correlation was found in Cw (r = -0.786, p = .021). Only in PCOSw, adipocyte area was positively correlated with serum testosterone (r = 0.857, p = .014) and visceral adipose tissue volume (r = 0.857, p = .014).Our results indicate that PCOS women present adipose tissue dysfunction in the subcutaneous compartment, characterized by an alteration in adipocyte size and leptin/adiponectin expression and secretion, probably associated with higher androgen concentrations.

Context Hyperandrogenic states and obesity in women are associated with insulin-resistance. Androgens reduce glucose uptake in adipose cells and increase TNFα production in peripheral monocytes. Inflammatory cytokines have a known detrimental effect on insulin resistance. The aim of the present study was to explore the role of testosterone in local cytokine production in visceral adipose tissue from women of reproductive age. Design Twenty-four women 18–40 years old, undergoing elective abdominal surgery for benign and non-inflammatory conditions, were recruited for the study. Women with clinical hyperandrogenism, diabetes, hepatic or renal dysfunction, hypothyroidism, BMI> 40 or drugs known to interfere with hormonal levels or fat metabolism were excluded. Women were classified into two groups according to BMI, non-obese (N O; BMI Results Expression of CCL-2 and IL-6 at 24 h in CTLs was significantly higher in the obese group compared to the non-obese group (2.81 ± 0.43 fold for CCL-2; p = 0.005 and 3.26 ± 0.73 fold for IL-6; p = 0.03). At 48 and 72 h there were no differences between both groups in any of the markers. In the total group without T stimulation (CTL) there were significant correlations between: TNFα expression at 24 h and BMI (r = 0.708; p = 0.005), TGC levels (r = 0.904; p = 0.004), total Cholesterol (r = 0.904; p = 0.0046) and IL-6 expression at 24 h (r = 0.642; p = 0.015). CCL-2 expression at 24 h was correlated with BMI (r = 0.637; p = 0.007) and TGC levels (r = 0.700; p = 0.02). Stimulation with T 10−6 M for 72 h produced an increase in CCL-2 expression, which was significantly larger in the obese group compared to the non-obese group (2.04 ± 0.44 in obese vs 0.82 ± 0.11 in non-obese; p = 0.015). Moreover, in the whole group there was a positive correlation between CCL-2 expression in T-treated tissues (10−6 M 72 h) and BMI (r = 0.514; p = 0.017). Cytokine determinations followed the same pattern as mRNA but without significant differences. Conclusions Testosterone increases CCL-2 expression in visceral adipose tissue from obese women of reproductive age. This response is associated to BMI. These results show new possible mechanisms connecting androgens to insulin resistance and chronic inflammation.

To assess insulin sensitivity, insulin secretion and metabolic profile in women with polycystic ovary syndrome (PCOS) in different stages of reproductive life.In a cross-sectional study, 190 PCOS women (PCOSw) and 99 controls (Cw) aged between 18 and 55years were included. PCOSw and Cw were distributed into 3 stages of reproductive life: early reproductive age (18-34years old), late reproductive age (35-40years old) and perimenopausal period (41-55years old). Waist circumference (WC), body mass index (BMI) and blood pressure (BP) were recorded. An oral glucose tolerance test (OGTT) with measurement of glucose and insulin was performed. Sex steroids and lipid profile were also determined in the fasting sample. Insulin sensitivity was assessed by HOMA-IR and ISI composite, and insulin secretion by HOMA-β and insulinogenic index. Visceral adiposity index (VAI) and lipid accumulation product (LAP) were also calculated. Metabolic syndrome (MS) was assessed by the IDF and ATPIII criteria.At early reproductive age, PCOSw showed higher BMI, WC, and VAI and a higher prevalence of MS compared to Cw (p0.05). In addition, at late reproductive age PCOSw also showed elevated total cholesterol, triglycerides, insulin secretion, LAP and BP. At perimenopausal period, these parameters were not different between Cw and PCOSw. Within the PCOSw group, HOMA-β was lower at late reproductive and perimenopausal periods compared to the early reproductive age. Regarding control women, a deterioration of anthropometric and metabolic parameters was observed in perimenopausal women compared to early and late reproductive women.Our results suggest that metabolic derangements associated with PCOS are more evident at the early and late reproductive ages. On the other hand, during perimenopause, there is no further deterioration of metabolic parameters. Nevertheless, a disruption in pancreatic β-cell function is evidenced at this stage.

Obesity is a major concern in public health because it is one of the main risk factors for the development of non-transmissible chronic diseases. The fact that there is a clear sex dimorphism in normal body fat distribution points out the role of sex steroids as key factors in the regulation and function of the adipose cell. Androgens affect adipogenesis and fat metabolism in the adipose tissue of males and females. Hormonal disorders during pregnancy may affect the fetal tissues, with long-term implications leading to the development of pathologies during adult life. Obesity and metabolic disease are among these. In this regard, animal models have demonstrated an abnormal fat distribution and modifications in the size and function of adipose cells in the female and male offspring of mothers exposed to androgen excess during pregnancy.

Context Intrauterine life may be implicated in the origin of polycystic ovary syndrome (PCOS) modifying the endocrine and metabolic functions of children born to PCOS mothers independently of the genetic inheritance and gender. The aim of the present study was to evaluate the reproductive and metabolic functions in sons of women with PCOS during puberty. Methods Sixty-nine PCOS sons (PCOSs) and 84 control sons of 7–18 years old matched by the Tanner stage score were studied. A complete physical examination was conducted including anthropometric measurements (weight, height, waist, hip and body mass index). An oral glucose tolerance test was performed and circulating concentrations of luteinizing hormone, follicle-stimulating hormone (FSH), sex hormone-binding globulin, testosterone, androstenedione (A4), 17α-hydroxyprogesterone (17-OHP) and AMH were determined in the fasting sample. Results Waist-to-hip ratio, FSH and androstenedione levels were significantly higher in the PCOSs group compared to control boys during the Tanner stage II–III. In Tanner stages II–III and IV–V, PCOSs showed significantly higher total cholesterol and LDL levels. Propensity score analysis showed that higher LDL levels were attributable to the PCOSs condition and not to other metabolic factors. AMH levels were comparable during all stages. The rest of the parameters were comparable between both groups. Conclusions Sons of women with PCOS show increased total cholesterol and LDL levels during puberty, which may represent latent insulin resistance. Thus, this is a group that should be followed and studied looking for further features of insulin resistance and cardiovascular risk markers. Reproductive markers, on the other hand, are very similar to controls.

It is not clear whether maternal obesity along with fetal gender affect sex steroid metabolism during pregnancy. Therefore, we compared sex steroid concentrations and placental expression of steroidogenic enzymes between non-obese and obese pregnant women with non-pathological pregnancies, and investigated the influence of fetal gender on these parameters. In 35 normal weight (body mass index (BMI) 20–24.9 kg m−2) (controls) and 36 obese women (BMI 30–36 kg m−2) (obese), a fasting blood sample was obtained at first and at third trimester of gestation to measure progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate, androstenedione, testosterone and estradiol by liquid chromatography-tandem mass spectrometry and estrone by radioimmunoassay. In a subset of women, placental mRNA and protein expression of steroidogenic enzymes was measured by quantitative PCR and western blot, respectively. The comparisons were primarily made between controls and obese, and then separately according to fetal gender. At first and third trimesters of gestation serum progesterone was lower whereas testosterone was higher in obese women (P

Background: Polycystic Ovary Syndrome (PCOS) is tightly associated with insulin resistance and obesity and characterized by hyperandrogenism, chronic oligo-anovulation and polycystic ovarian morphology when fully expressed. The 2003 Rotterdam consensus proposed that two or three of these features were necessary to make the diagnosis, which generated four phenotypes. Several studies have suggested that these phenotypes could differ in their metabolic and endocrine characteristics and that they could vary in the same patient when analyzed throughout life. Aim: To determine if the initial classification of PCOS phenotypes is modified by different physiological conditions. Material and Methods: We performed a non-concurrent prospective analysis of 88 women with PCOS according to the Rotterdam criteria. The effect of physiological conditions such as changes in body weight, pregnancy and ageing more than five years on PCOS phenotype expression was analyzed. Results: Twenty four percent of women became pregnant, 37% decreased and 24% increased their body weight during follow up. These conditions modified significantly the proportion of the different phenotypes (c2 = 32.2, p < 0.001). For instance, weight reduction was associated with a change to a better phenotype (p = 0.047) and even a normalization of the PCOS condition in 27% of the patients. On the other hand, an increase in body weight modifying body mass index in one unit, conferred an 8% probability of changing to a worst phenotype. Conclusions: Pregnancy and changes in body weight significantly modify PCOS phenotypes.

Adequate blood supply to the uterine-placental region is crucial to ensure the transport of oxygen and nutrients to the growing fetus. Multiple factors intervene to achieve appropriate uterine blood flow and the structuring of the placental vasculature during the early stages of pregnancy. Among these factors, oxygen concentrations, growth factors, cytokines, and steroid hormones are the most important. Sex steroids are present in extremely high concentrations in the maternal circulation and are important paracrine and autocrine regulators of a wide range of maternal and placental functions. In this regard, progesterone and estrogens act as modulators of uterine vessels and decrease the resistance of the spiral uterine arteries. On the other hand, androgens have the opposite effect, increasing the vascular resistance of the uterus. Moreover, progesterone and estrogens modulate the synthesis and release of angiogenic factors by placental cells, which regulates trophoblastic invasion and uterine artery remodeling. In this scenario, it is not surprising that women with pregnancy-related pathologies, such as early miscarriages, preterm delivery, preeclampsia, and fetal growth restriction, exhibit altered sex steroid concentrations.

We have previously described increased serum levels of anti-Müllerian hormone (AMH) and stimulated insulin in daughters of women with polycystic ovary syndrome (PCOS), suggesting that these girls may have an altered ovarian follicular development which may be modulated by insulin. However, the specific relationship between serum AMH and insulin levels during each Tanner stage of puberty in this cohort has not been established.The aim of our study was to establish the relationship between AMH and poststimulated insulin serum concentrations during each stage of puberty in daughters of women with PCOS (PCOSd), compared to daughters of control women (Cd).We studied 135 PCOSd and 93 Cd classified according to their Tanner stage. Gonadotrophins, sex steroids, sex hormone-binding globulin (SHBG), and AMH were determined in a fasting sample. Ovarian volume was measured by pelvic ultrasound. In addition, in both groups we performed an oral glucose tolerance test with measurements of glucose and insulin.Anti-Müllerian hormone levels were significantly higher in PCOSd compared to Cd at all Tanner stages. Daughters of women with PCOS having AMH concentrations greater than 2 standard deviation (SD) above the mean AMH value for the Cd group showed decreased serum follicle-stimulating hormone (FSH) concentrations and increased stimulated levels of insulin during Tanner stages I, II, and III.Anti-Müllerian hormone levels are increased in PCOSd during all stages of puberty. We suggest that those PCOSd with the highest AMH levels probably represent a group of girls with more severe ovarian dysfunction and metabolic derangements.

Developmental programming refers to processes that occur during early life that may have long-term consequences, modulating adult health and disease. Complex diseases, such as diabetes, cancer and cardiovascular disease, have a high prevalence in different populations, are multifactorial, and may have a strong environmental component. The environment interacts with organisms, affecting their behaviour, morphology and physiology. This interaction may induce permanent or long-term changes, and organisms may be more susceptible to environmental factors during certain developmental stages, such as the prenatal and early postnatal periods. Several factors have been identified as responsible for inducing the reprogramming of various reproductive and nonreproductive tissues. Among them, both natural and synthetic steroids, such as endocrine disruptors, are known to have either detrimental or positive effects on organisms depending on the dose of exposure, stage of development and biological sexual background. The present review focuses on the action of steroids and endocrine disruptors as agents involved in developmental programming and on their modulation and effects on female neuroendocrine functions. Fil: Abruzzese, Giselle Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Crisosto, Nicolás. Facultad de Medicina de la Universidad de Chile; Chile. Clinica Las Condes; Chile Fil: De Grava Kempinas, Wilma. Universidade Estadual Paulista Julio de Mesquita Filho; Brasil Fil: Sotomayor Zárate, Ramón. Universidad de Valparaiso; Chile

Polycystic ovary syndrome (PCOS) is characterized by the presence of hyperandrogenism and an increased follicular mass probably determined by deregulation of locally produced factors. Anti-Müllerian hormone (AMH) is a glycoprotein that inhibits follicular recruitment and determines the size of the follicular pool. To evaluate the role of androgens in the regulation of AMH expression in bovine granulosa cells from small follicles, granulosa cells from 3 to 4 mm follicles were isolated and incubated in basal culture media, or in media containing testosterone (T) at 10(-5)M, T 10(-8)M, or estradiol (E2) at 150 ng/ml for 48 h. AMH mRNA levels of these cells were determined using real-time PCR (RT PCR). AMH protein levels and E2 were determined in cell-conditioned media. A 3.4-fold decrease in AMH mRNA levels was observed in granulosa cells exposed to T 10(-5)M (P = 0.03, n = 5), but not in cells exposed to T 10(-8)M. AMH protein levels showed a 1.8-fold reduction in cell-conditioned media from cells exposed to T 10(-5)M (P = 0.01, n = 5), without significant changes in the group exposed to T 10(-8)M. Cells treated with E2 150 ng/ml showed no change in AMH protein levels. We propose that AMH expression is modulated by androgens in bovine granulosa cells from small follicles. Thus, it is possible to speculate that androgens, by inhibiting AMH expression, may promote follicle recruitment, increasing the early growing follicular pool. This new mechanism may have implications for the understanding of PCOS pathophysiology.

Objective To assess metabolic parameters in the cord blood of newborns of women with polycystic ovary syndrome (PCOS) and to correlate these parameters with those of mothers with PCOS during midgestation. Design Case-control study. Setting Unit of Endocrinology and Reproductive Medicine. Patient(s) Thirty newborns of mothers with PCOS (PCOSn) and 34 newborns of control mothers (Cn) were studied. Intervention(s) A sample of cord blood was obtained at delivery. In all mothers, an oral glucose tolerance test (oGTT) with measurement of glucose and insulin was performed at 22–28 weeks of gestation. In cord blood and in the fasting sample of the oGTT, serum leptin, adiponectin, insulin, glucose, and lipids (triglycerides, cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol) were determined. Result(s) PCOSn showed significantly higher leptin concentrations than Cn. Moreover, in PCOSn, leptin concentrations in cord blood were correlated with birth weight ( r = 0.495) and body mass index of the mother at midpregnancy ( r = 0.644). Conclusion(s) The metabolic parameters in the cord blood of PCOSn are similar to those observed in controls, except for leptin concentrations, which are significantly higher. The latter could be related to the fetal adiposity or the metabolic condition of the mother.

Polycystic ovary syndrome (PCOS) is a familial endocrine-metabolic dysfunction, increasingly recognized in adolescent girls with hyperandrogenism. However, it is difficult to establish whether the metabolic abnormalities described in PCOS are present before the onset of hyperandrogenism. In children, a strong association of adiponectin levels with metabolic parameters of insulin resistance has been described.The objective of the study was to evaluate adiponectin serum concentrations and metabolic parameters in prepubertal and pubertal daughters of women with PCOS to identify girls with increased metabolic risk.Fifty-three prepubertal and 22 pubertal (Tanner stages II-V) daughters of PCOS women (PCOSd) and 32 prepubertal and 17 pubertal daughters of control women (Cd) were studied. In both groups, an oral glucose tolerance test was performed with measurement of glucose and insulin. Adiponectin, leptin, C-reactive protein, SHBG, sex steroids, and lipids were determined in the fasting sample.Both groups had similar chronological ages, body mass index sd score, and Tanner stage distribution. In the prepubertal girls, 2-h insulin was higher (P = 0.023) and adiponectin levels were lower (P = 0.004) in the PCOSd group, compared with the Cd group. In the pubertal girls, triglycerides (P = 0.03), 2-h insulin (P = 0.01), and serum testosterone concentrations were higher (P = 0.012) and SHBG lower (P = 0.009) in PCOSd, compared with Cd, but adiponectin levels were similar in both groups.Some of the metabolic features of PCOS are present in daughters of PCOS women before the onset of hyperandrogenism. Adiponectin appears to be one of the early markers of metabolic derangement in these girls.

Polycystic Ovary Syndrome (PCOS) is tightly associated with insulin resistance and obesity and characterized by hyperandrogenism, chronic oligo-anovulation and polycystic ovarian morphology when fully expressed. The 2003 Rotterdam consensus proposed that two or three of these features were necessary to make the diagnosis, which generated four phenotypes. Several studies have suggested that these phenotypes could differ in their metabolic and endocrine characteristics and that they could vary in the same patient when analyzed throughout life.To determine if the initial classification of PCOS phenotypes is modified by different physiological conditions.We performed a non-concurrent prospective analysis of 88 women with PCOS according to the Rotterdam criteria. The effect of physiological conditions such as changes in body weight, pregnancy and ageing more than five years on PCOS phenotype expression was analyzed.Twenty four percent of women became pregnant, 37% decreased and 24% increased their body weight during follow up. These conditions modified significantly the proportion of the different phenotypes (c2 = 32.2, p0.001). For instance, weight reduction was associated with a change to a better phenotype (p = 0.047) and even a normalization of the PCOS condition in 27% of the patients. On the other hand, an increase in body weight modifying body mass index in one unit, conferred an 8% probability of changing to a worst phenotype.Pregnancy and changes in body weight significantly modify PCOS phenotypes.

Objective To assess gonadotrophin secretion, ovarian steroid production and ovarian reserve in PCOS women during the onset of reproductive decline, in order to characterize their ovarian function at this age. Study design Forty PCOS patients and 35 healthy women (35–40 years of age) were included. Clinical history, anthropometry, transvaginal ultrasound and a leuprolide acetate test (10 μg/kg s.c.) were performed. Gonadotrophins, steroid hormones, SHBG, inhibin B and AMH were determined. Results Basal and peak LH levels were similar in both groups. Basal and peak FSH levels were significantly higher in the control group. Androgens, peak oestradiol, ovarian volume, antral follicle count and AMH levels were significantly higher in PCOS patients. Conclusion These observations suggest that during late reproductive age, gonadotrophin secretion in women with PCOS is clearly different from that observed in control women and may also differ from that of younger PCOS patients. New features like normal LH and lower FSH levels associated with a higher ovarian reserve may give a different reproductive profile to these women.

Objective To evaluate the placental activity of steroid sulfatase (STS), 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD-1) and P450 aromatase (P450arom) in polycystic ovarian syndrome (PCOS) compared to normal pregnant women. Design Twenty pregnant women with PCOS and 30 control pregnant women who delivered at term were studied. Samples of placental tissue and cord blood were obtained after delivery. A maternal blood sample was obtained during the 34th week of gestation. In placental tissue, the activities of STS, 3β-HSD-1 and P450arom were evaluated. In the blood samples, progesterone, DHEAS, DHEA, androstenedione, testosterone, estrone, estradiol and total estriol were determined. Result In placental tissue from women with PCOS, higher 3β-HSD-1 and lower P450 aromatase activities were observed compared to control women. Moreover, women with PCOS showed higher androstenedione and testosterone concentrations compared to normal pregnant women ( p = 0.016 and p = 0.025, respectively). In cord blood, female newborns of women with PCOS exhibited lower androstenedione and higher estriol concentrations compared to daughters of control women ( p = 0.038; p = 0.031, respectively). Conclusion These data suggest that placental tissue from women with PCOS shows changes in the activities of two important enzymes for steroid synthesis, higher 3β-HSD-1 and lower P450, which could increase androgen production during pregnancy.

Objective To evaluate the ovarian function during early infancy in daughters of women with polycystic ovary syndrome (PCOS) treated with metformin throughout pregnancy (PCOSd+M), as a means to reduce androgen and insulin levels, compared with daughters of nontreated PCOS women (PCOSd−M) and daughters of women who belong to a healthy comparison group (HCd). Design Descriptive and analytic study. Setting Unit of endocrinology and reproductive medicine. Patient(s) Fifteen PCOSd+M, 23 PCOSd−M, and 35 HCd were studied at 2–3 months of age. Intervention(s) A GnRH analogue test was performed with determinations of gonadotropins, sex steroids, SHBG, and anti-Mullerian hormone (AMH). Main Outcome Measure(s) Differences in AMH levels between PCOSd+M, PCOSd−M and HCd. Result(s) AMH and peak E 2 concentrations were significantly higher in PCOSd−M compared with HCd, whereas PCOSd+M exhibited AMH concentrations and peak E 2 levels similar to those observed in HCd. Conclusion(s) The improvement of the altered endocrine-metabolic environment of PCOS mothers reduces AMH levels in their daughters, which might reflect a decrease in their follicular mass.

Objective To evaluate in a cross-sectional study adiponectin and leptin levels in prepubertal and pubertal daughters of women with PCOS and their relationship to insulin sensitivity and reproductive features. Study design We studied 92 daughters of PCOS women (PCOSd) and 76 daughters of control women (Cd) matched by age and body mass index SD scores and distributed according to breast Tanner stage: prepuberty (Tanner 1), early puberty (Tanner 2–3) or late puberty (Tanner 4–5). In all girls an oral glucose tolerance test was performed. Leptin, adiponectin, sex steroids, SHBG, glucose, insulin and lipid profile were determined. Leptin–adiponectin ratio, free androgen index and insulin sensitivity (HOMA-IR and ISI composite) were then calculated. Results Prepubertal PCOSd showed lower serum adiponectin compared to Cd ( p = 0.028), whereas during puberty no differences were observed between the groups. Leptin concentrations were similar in both groups in all Tanner stages. In addition, in PCOSd during early puberty, adiponectin showed a negative correlation with testosterone and leptin showed a negative correlation with ISI composite, which were independent of BMI SDS ( r = −0.39; p = 0.02 and r = −0.42; p = 0.01). Conclusion These observations suggest that during the prepubertal period PCOSd exhibit abnormal adiponectin levels, independently of BMI. Moreover, leptin and adiponectin may be related to metabolic and reproductive abnormalities observed in PCOSd during the early stages of sexual development.

We previously demonstrated that low birth weight (BW) infant girls show increased serum anti-Müllerian hormone (AMH) concentrations and poststimulated estradiol levels compared to normal-BW infants, suggesting an altered follicular development. However, the impact of high BW on reproductive function is less known.To evaluate the effect of BW on AMH, we determined the concentrations of this hormone in low-BW, normal-BW, and high-BW female infants during the first 3 months of life.Twenty-seven low-BW, 29 normal-BW, and 28 high-BW infant girls were studied. We measured serum gonadotropins, steroid hormones, AMH, glucose, insulin, free fatty acids, IGF-I, and adiponectin in a fasting blood sample. In addition, in a subgroup of normal-BW (n = 23) and high-BW infants (n = 10), a GnRH analog leuprolide acetate test was performed.Serum concentrations of AMH were higher in low-BW and high-BW infants compared to normal-BW infants (P = 0.028 and 0.022, respectively). In addition, in high-BW infants, adiponectin concentrations were lower (P = 0.018), and poststimulated FSH and estradiol levels were higher compared to normal-BW infants (P = 0.024 and 0.047, respectively).Serum AMH and poststimulated estradiol concentrations are increased in low-BW and high-BW female infants, suggesting that these girls may show evidence of an altered follicular development. However, the increased poststimulated FSH levels and low adiponectin concentrations observed in high-BW infants suggest that ovarian function is perturbed through a different mechanism from that in low-BW infants.

Context: In some patients, PCOS may develop as a consequence of an exaggerated adrenarche during pubertal development. Objective: The aim of the study was to assess adrenal function during childhood and pubertal development in daughters of women with PCOS (PCOSd). Design: We included 98 PCOSd [64 during childhood (ages 4–8 yr) and 34 during the peripubertal period (ages 9–13 yr)] and 51 daughters of control women (Cd) [30 during childhood and 21 during the peripubertal period]. In both groups, an acute ACTH-(1–24) stimulation test (0.25 mg) and an oral glucose tolerance test were performed. Bone age and serum concentrations of cortisol, androstenedione, 17-hydroxyprogesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), glucose, and insulin were determined. Results: PCOSd and Cd were similar in age and body mass index. During the peripubertal period, basal and poststimulated DHEAS concentrations were higher in PCOSd compared to Cd. Among PCOSd, 12.5% of girls in childhood and 32.4% in peripuberty presented biochemical evidence of exaggerated adrenarche. Stimulated insulin was higher in PCOSd compared to Cd during childhood (P = 0.03) and peripuberty (P = 0.03). An advancement of 8 months between bone and chronological age was observed in peripubertal PCOSd compared to Cd. Conclusions: In PCOSd, basal and stimulated DHEAS concentrations were higher during the onset of puberty. Around 30% of the PCOSd demonstrated an exacerbated adrenarche, which may reflect increased P450c17 activity. In addition, a modest advance in bone age was observed, probably secondary to the hyperinsulinemia and/or adrenal hyperandrogenism. Daughters of women with PCOS exhibit increased dehydroepiandrosterone sulfate serum concentrations and biochemical evidence of an exacerbated adrenarche.

We have previously observed increased anti-Müllerian hormone (AMH) levels in prepubertal daughters of polycystic ovary syndrome (PCOS) women, suggesting that these girls may have an altered follicular development. However, it is not known whether AMH levels remain increased during puberty.The aim was to establish whether the increased AMH levels observed in prepubertal daughters of PCOS women persist during the peripubertal period, a stage during which the gonadal axis is activated and PCOS may become clinically manifested.We studied 28 daughters (8-16 yr old) of PCOS women (PCOSd) and 33 daughters (8-16 yr old) of control women (Cd). In both groups, an oral glucose tolerance test was performed. Gonadotropins, sex hormones, and AMH were determined in a fasting sample.Both groups were comparable in age, body mass index, and breast Tanner stage. Free androgen index, testosterone, AMH (Cd 14.4 +/- 8.0 pM vs. PCOSd 24.0 +/- 19.0 pM; P = 0.012), and 2-h insulin levels were significantly higher in the PCOSd group compared with the control group. The average ovarian volume was significantly higher in the PCOSd group. In both groups a positive correlation between 2-h insulin and AMH concentrations was observed (PCOSd: r = 0.530, P = 0.007; Cd: r =0.561, P = 0.008).AMH concentrations are increased in peripubertal PCOSd. These findings, along with the results of our previous study, suggest that PCOSd appear to show an increased follicular mass that is established during early development, and persists during puberty.

Objective To evaluate the metabolic profile of Chilean and Argentinian women with polycystic ovary syndrome (PCOS) according to the Rotterdam criteria. Design Observational cross-sectional study. Setting Academic centers. Patient(s) Women with PCOS, aged 18–39 years: 220 Chilean (PCOS Ch ) and 206 Argentinian (PCOS Ar ). Intervention(s) Physical examination, fasting blood samples for androgens, gonadotropins, metabolic parameters, and a transvaginal ultrasound. Main Outcome Measure(s) Comparative analysis of the metabolic profile in both populations divided into four phenotypes. Result(s) The distribution of the different phenotypes was different in both populations. PCOS Ch women showed a higher body mass index and a higher percentage of metabolic syndrome in all phenotypes compared with the PCOS Ar women. The PCOS Ar women exhibited a statistically significantly higher diastolic blood pressure in phenotypes A, B, and C and a higher percentage of hypertension in phenotypes A and D compared with the PCOS Ch women. Conclusion(s) The data show differences in the metabolic profile of both populations. PCOS Ch women presented with greater metabolic alterations such as dysglycemia and dyslipidemia and a higher prevalence of metabolic syndrome, independent of the phenotype. The PCOS Ar patients showed more elevated blood pressure. Ethnic diversity associated with environmental factors are fundamental elements in the analysis of the PCOS phenotypes.