Search

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.

Although signs and symptoms of polycystic ovary syndrome (PCOS) usually occur after adolescence in most girls, early clinical features of PCOS may develop in some girls during the peripubertal years. Early features in prepubertal girls may be considered to be normal "physiological" changes and may delay diagnosis and treatment of PCOS until adulthood. Previous studies have found that some of the metabolic abnormalities of PCOS were present before the onset of hyperandrogenism in daughters of women with PCOS (PCOSd) during prepubertal and pubertal stages. It is unclear, however, at which pubertal stage these abnormalities occur. During the peripubertal period, the gonadal axis is activated and PCOS may become clinically evident. Two studies have suggested that a significant proportion of the first-degree female relatives of a PCOS woman may be at risk for developing PCOS. To test this possibility, this cross-sectional study compared reproductive and metabolic profiles in daughters of women with and without PCOS during prepubertal and pubertal stages. The study subjects were 99 PCOSd at Tanner stage II-V 30 prepubertal [ages 7-10 years] and 69 pubertal [ages 8-15 years] and 84 matched daughters of control women (Cd) (20 prepubertal and 64 pubertal) born to mothers with regular menstrual cycles and without hyperandrogenism. Participants in both groups were given an oral glucose tolerance test, evaluated for hormonal response to a gonadotropin releasing hormone agonist (leuprolide acetate) and examined with transabdominal ultrasound. Fasting blood samples were drawn for the measurement of plasma glucose and insulin concentrations before and after the glucose load. Serum concentrations of gonadotropins (LH and FSH), sex steroids (testosterone, androstenedione,17a-hydroxyprogesterone (17-OHP) and estradiol), as well as SHBG and lipids were also determined. There was no significant difference between the Cd and PCOSd groups in chronological age or body mass index standard deviation scores during any Tanner stage. Compared to the Cd women, those in the PCOSd group had significantly higher ovarian volume and 2-hour insulin at all Tanner stages. Basal testosterone and poststimulated LH, testosterone, and 17-OHP concentrations were significantly higher in Tanner stages IV and V among PCOSd compared to Cd. These findings indicate that PCOSd are at high-risk for metabolic and reproductive abnormalities associated with PCOS during prepuberty and puberty.

An important proportion of male members of polycystic ovary syndrome (PCOS) families exhibit insulin resistance and related metabolic defects. However, the reproductive phenotypes in first-degree male relatives of PCOS women have been described less often.The objective of the study was to evaluate the pituitary-testicular function in sons of women with PCOS during different stages of life: early infancy, childhood, and adulthood.Eighty sons of women with PCOS (PCOS(S)) and 56 sons of control women without hyperandrogenism (C(S)), matched for age, were studied. In all subjects, the pituitary-gonadal axis was evaluated by a GnRH agonist test (leuprolide acetate, 10 microg/kg sc). Serum anti-Müllerian hormone (AMH) and inhibin B were used as Sertoli cell markers. Serum concentrations of gonadotropins, steroid hormones, and SHBG were also determined. A semen analysis was performed.Basal concentrations of gonadotropins, sex steroids, and inhibin B were comparable between PCOS(s) and C(S) during early infancy, childhood, and adulthood. Similar results in stimulated gonadotropin and sex steroid concentrations were observed. However, AMH serum concentrations were higher in PCOS(s) compared with C(S) during early infancy [925.0 (457.3-1401.7) vs. 685.6 (417.9-1313.2) pmol/liter, P = 0.039] and childhood [616.3 (304.6-1136.9) vs. 416.5 (206.7-801.2) pmol/liter, P = 0.007). Sperm-count analysis was similar between both groups.AMH concentrations are increased in prepubertal sons of women with PCOS, suggesting that these boys may show an increased Sertoli cell number or function during infancy and childhood. However, this does not seem to have a major deleterious effect on sperm production.

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.

We aimed to evaluate the serum adiponectin and lipid concentrations in normal and polycystic ovary syndrome (PCOS) women during pregnancy in order to establish whether PCOS induces abnormal lipid and adiponectin levels that could constitute potential metabolic risk factors for pregnancy complications. Women with singleton pregnancies and of similar age were included (48 pregnant PCOS and 51 normal pregnant women). During gestational weeks 10-16 and 22-28 a 2 h 75 g oral glucose tolerance test was performed with measurement of glucose and insulin in each sample. Adiponectin and lipid concentrations were determined in the fasting sample. The incidence of gestational diabetes mellitus (GDM) was significantly higher in the PCOS group (12.2%) compared with the control group (2%). In PCOS patients triglyceride (TG) concentrations and area under the curve of glucose and insulin were higher in both study periods and adiponectin concentrations were significantly lower in the second period compared with normal women. Moreover adiponectin concentrations were lower in women with GDM than in those with normal glucose tolerance in the two study periods. Low adiponectin and high insulin levels are associated with GDM in pregnant PCOS patients. High TG levels seem not to be directly related to pregnancy complications in these patients. (authors)

During pregnancy, women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring. This study investigated whether maternal androgen excess causes anxiety-like behavior in offspring mimicking anxiety disorders in PCOS. The PCOS phenotype was induced in rats following prenatal androgen (PNA) exposure. PNA offspring displayed anxiety-like behavior in the elevated plus maze, which was reversed by flutamide [androgen receptor (AR) blocker] and tamoxifen [selective estrogen receptor (ER) modulator]. Circulating sex steroids did not differ between groups at adult age. The expression of serotonergic and GABAergic genes associated with emotional regulation in the amygdala was consistent with anxiety-like behavior in female, and partly in male PNA offspring. Furthermore, AR expression in amygdala was reduced in female PNA offspring and also in females exposed to testosterone in adult age. To determine whether AR activation in amygdala affects anxiety-like behavior, female rats were given testosterone microinjections into amygdala, which resulted in anxiety-like behavior. Together, these data describe the anxiety-like behavior in PNA offspring and adult females with androgen excess, an impact that seems to occur during fetal life, and is mediated via AR in amygdala, together with changes in ERα, serotonergic, and GABAergic genes in amygdala and hippocampus. The anxiety-like behavior following testosterone microinjections into amygdala demonstrates a key role for AR activation in this brain area. These results suggest that maternal androgen excess may underpin the risk of developing anxiety disorders in daughters and sons of PCOS mothers.

Accurate measurement of sex steroid concentrations in rodent serum is essential to evaluate mouse and rat models for sex steroid-related disorders. The aim of the present study was to develop a sensitive and specific gas chromatography-tandem mass spectrometry (GC-MS/MS) method to assess a comprehensive sex steroid profile in rodent serum. A major effort was invested in reaching an exceptionally high sensitivity for measuring serum estradiol concentrations. We established a GC-MS/MS assay with a lower limit of detection for estradiol, estrone, T, DHT, progesterone, androstenedione, and dehydroepiandrosterone of 0.3, 0.5, 4.0, 1.6, 8, 4.0, and 50 pg/mL, respectively, whereas the corresponding values for the lower limit of quantification were 0.5, 0.5, 8, 2.5, 74, 12, and 400 pg/mL, respectively. Calibration curves were linear, intra- and interassay coefficients of variation were low, and accuracy was excellent for all analytes. The established assay was used to accurately measure a comprehensive sex steroid profile in female rats and mice according to estrous cycle phase. In addition, we characterized the impact of age, sex, gonadectomy, and estradiol treatment on serum concentrations of these sex hormones in mice. In conclusion, we have established a highly sensitive and specific GC-MS/MS method to assess a comprehensive sex steroid profile in rodent serum in a single run. This GC-MS/MS assay has, to the best of our knowledge, the best detectability reported for estradiol. Our method therefore represents an ideal tool to characterize sex steroid metabolism in a variety of sex steroid-related rodent models and in human samples with low estradiol levels.

Does polycystic ovary syndrome (PCOS) in women without pregnancy complications affect placental signal transducer and activator of transcription 3 (STAT3) and mechanistic target of rapamycin (mTOR) signaling?Placental STAT3 signaling is activated but mTOR signaling is unaffected in PCOS.Women with PCOS have increased risk of poor pregnancy outcomes (e.g. restricted or accelerated fetal growth), indicating placental dysfunction. Placental STAT3 and mTOR pathways regulate placental function and indirectly affect fetal growth.In a case-control study, placental tissue and maternal blood were collected at delivery from 40 control pregnant women and 38 PCOS women with uncomplicated pregnancy.Women with PCOS were recruited at two medical centers and pregnant controls were recruited at one of these centers. Placental mRNA expression of genes encoding proteins related to steroid action, metabolic pathways and cytokines was analyzed by quantitative RT-PCR. Phosphorylated placental STAT3 (P-STAT3) and mTOR targets was measured by western blot. Levels of sex steroids in serum were determined by mass spectrometry.Placental P-STAT3 (Tyr-705) was increased in women with PCOS (P0.05) versus controls. Placental mTOR signaling was not affected in PCOS women when compared with controls. Circulating levels of androstenedione, androst-5-ene-3β, 17β-diol, testosterone, 5α-dihydrotestosterone and etiocholanolone glucuronide were higher and estradiol lower in women with PCOS than in controls (all P0.05). No correlation between sex steroid levels in serum and P-STAT3 was observed.Women with PCOS and pregnancy complications were excluded to avoid the confounding effects of placental pathologies, which could modify STAT3 and mTOR signaling. Moreover, 97.4% of women with PCOS in the study displayed oligoamenorrhea at diagnosis. Thus, the current findings could be restricted to PCOS women with the oligo-anovulatory phenotype without pregnancy complications.Phosphorylation of STAT3 is increased in the placenta from women with PCOS and uncomplicated pregnancies, indicating that specific metabolic placental pathways are activated in the absence of obstetric and perinatal complications.The work was supported by the Swedish Medical Research Council (Project No. 2011-2732 and 2014-2775); Jane and Dan Olsson Foundation, Wilhelm and Martina Lundgrens's Science Fund; Hjalmar Svensson Foundation (E.S.-V and M.M.); Adlerbert Research Foundation; Swedish federal government under the LUA/ALF agreement ALFFGBG-136481 and 429501 and the Regional Research and Development agreement (VGFOUREG-5171, -11296 and -7861). MM thanks the Becas Chile Programme (Chile) and University of Chile for financial support through a postdoctoral fellowship. There are no competing interests.

Context: Anti-Müllerian hormone (AMH) is produced by the granulosa cells and reflects follicular development. Adult women with polycystic ovary syndrome (PCOS) have increased levels of AMH associated with an excessive number of growing follicles. However, it is not known whether these abnormalities are present before the clinical onset of PCOS.Objective: Our objective was to investigate whether prepubertal daughters of women with PCOS have increased AMH levels.Design: Fourteen female infants (2–3 months old) and 25 prepubertal girls (4–7 yr old) born to PCOS mothers were studied. As a control group, we studied 21 female infants and 24 prepubertal girls born to mothers with regular menses and without hyperandrogenism. The group with PCOS mothers and the control group had normal birth weight and were born from spontaneous singleton pregnancies. Circulating concentrations of gonadotropins, testosterone, androstenedione, estradiol, 17-OH-progesterone, SHBG, inhibin B, and AMH were determined by specific assays.Results: Serum concentrations of AMH were significantly higher in the PCOS group compared with the control group during early infancy (20.4 ± 15.6 vs. 9.16 ± 8.6 pmol/liter; P = 0.024) and during childhood (14.8 ± 7.7 vs. 9.61 ± 4.4 pmol/liter; P = 0.007). Gonadotropin and serum sex steroid concentrations were similar in both groups during the two study periods, except for FSH, which was lower during childhood in girls born to PCOS mothers.Conclusions: We conclude that serum AMH concentrations are increased in prepubertal daughters of PCOS women, suggesting that these girls appear to show evidence of an altered follicular development during infancy and childhood.

BACKGROUND The aim of this study was to evaluate the effect of a single dose of leuprolide acetate on gonadotrophin and gonadal steroid secretion in brothers of women with polycystic ovary syndrome (PCOS), in order to assess P450c17alpha activity. An oral glucose tolerance test (OGTT) and a lipid profile were also performed. METHODS Twenty-two unrelated brothers of women with PCOS (PCOS(b)) and 14 brothers of normal cycling women (C(b)), matched for age, underwent a leuprolide acetate test (10 microg/kg s.c.) and an OGTT with measurement of circulating concentrations of gonadotrophins, steroid hormones, glucose, insulin and lipids. RESULTS Clinical and basal hormonal parameters were similar in both groups. After leuprolide administration, PCOS(b) exhibited a significant increase of 17alpha-hydroxyprogesterone (17-OHP) compared to C(b) (P

We evaluated metabolic parameters in Chilean women with polycystic ovary syndrome (PCOS) who were carriers and non-carriers of the glycine-to-arginine substitution at codon 972 (Gly972Arg) variant of insulin receptor substrate-1 and to assess insulin response after oral high- and low-glycemic loadsIn 146 women with PCOS and 97 healthy women (HW), Gly972Arg genotypes were obtained by polymerase chain reaction, and an oral glucose tolerance test was performed with glucose and insulin measurements. An insulinogenic index, a homeostasis model assessment for insulin resistance, and whole-body insulin sensitivity index (composite) were calculated. Eight carriers and eight non-carriers (four PCOS and four HW, respectively) underwent a 50-g glucose (high glycemic) or 50-g fructose (low glycemic) load with serum glucose and insulin measurements at 15-min intervals for 3 h.The frequency of the Gly972Arg variant was higher in PCOS patients than in HW (P0.05). The insulinogenic index was lower in HW carriers than in non-carriers (P0.05). In PCOS carriers, 2-h insulin was higher than in those without the mutation. In overweight PCOS carriers, the homeostasis model assessment for insulin resistance was higher and the insulin sensitivity index was lower than in PCOS patients without the mutation. In HW carriers, a delay in the maximal response of insulin secretion was observed, with a decrease of 26.7% in insulin concentrations 30 to 60 min after the 50-g glucose load. Glucose concentrations increased by 19.7% between 60 and 120 min. Glucose concentrations between 0 and 120 min were 14.9% higher in PCOS carriers than in non-carriers after the 50-g glucose load.In HW, this polymorphism appears to be associated with a decrease in insulin secretion; in PCOS women, this polymorphism interacts with obesity to influence insulin resistance, thus contributing to the pathogenesis of the metabolic component of PCOS.

Objective To investigate the presence of caspase-3 and Bcl-2 concentration in human endometrial tissue throughout the menstrual cycle, and study the effect of nitric oxide (NO) on cell proliferation and apoptosis during culture. Design Expression of caspase-3 and Bcl-2 concentration in endometrial explants, and examination of L-arginine (L-Arg) effect on epithelial and stromal cell proliferation and apoptosis in vitro. Setting Prospective study. Patient(s) Twenty-seven eumenorrheic women (37 ± 1.2 years). Intervention(s) Endometrial samples were obtained with Pipelle suction curette from the corpus of the uterus. Main outcome measure(s) Apoptosis (annexin V–FITC binding), Bcl-2 concentration (ELISA), caspase-3 (immunohistochemistry), cell proliferation (spectrophotometric assay), and gene expression (RT-PCR). Result(s) Caspase-3 was detected by immunoassay in epithelial tissue throughout the menstrual cycle and in stroma during secretory phase. The Bcl-2 concentration was similar in endometrial homogenates obtained throughout the menstrual cycle, but L-Arg decreased Bcl-2 only in endometrium from the proliferative phase. In epithelial cells, NO increased apoptosis by 2.1 ± 0.2-fold, augmented mRNA expression of Bax, and reduced expression of Bcl-2 compared with basal cultures. In stromal cells, NO increased cell proliferation in a dose-dependent manner, an effect that was blocked by a NO synthase inhibitor. Conclusion(s) These data indicate that NO has a differential regulatory function on endometrial cell survival, as indicated by the results on stromal cell proliferation and epithelial cell apoptosis during culture, which suggests paracrine interactions between both cell types.

Objective To evaluate the expression of steroid hormone receptors, proteins related to apoptosis, and cell proliferation in endometria from women with polycystic ovary syndrome (PCOS). Design Case-control study. Setting Hospital research unit. Patient(s) Eight women with PCOS and 12 fertile healthy women of similar age to those with PCOS. Intervention(s) Endometrial samples were obtained from women with PCOS (PCOSE) and normal (NE) women during the proliferative phase of the menstrual cycle. Main outcome measure(s) Expression studies (immunohistochemistry and reverse transcription–polymerase chain reaction) and DNA fragmentation [TdT-mediated dUTP nick end labeling (TUNEL)]. Result(s) In stroma, protein expression of estrogen receptor α, Bcl-2, and Bax was higher in PCOSE than in NE; epithelial cells had a greater expression of androgen receptor in the nucleus and a lower expression in the cytoplasm of PCOSE. Cell proliferation was higher in the epithelia of NE, while the expression of caspase-3 and DNA fragmentation was similar in both groups. The bax mRNA expression was higher in PCOSE, and bcl-2 mRNA expression was similar between groups. A higher bcl-2/bax relative ratio in PCOSE was observed. Conclusion(s) An alternating expression of proteins related to cell survival in endometria from PCOSE may potentially be associated with the disruption of their endometrial cell cycle.

Aims/hypothesis. Insulin resistance with increased risk of Type II (non-insulin-dependent) diabetes is a common feature of polycystic ovary syndrome (PCOS). To investigate antecedents of metabolic disorders in family members of patients with PCOS, we evaluated glucose tolerance and insulin resistance in parents of patients with PCOS compared to parents of healthy women. Methods. A total of 200 parents of women with clinical and hormonal evidence of PCOS (PCOSp) and 120 parents of healthy normally cycling women (HWp) were studied. A 75-g OGGT was performed and subjects were classified according to the World Health Organization (WHO) criteria (1999). Serum glucose and insulin were measured before the glucose load and 30, 60 and 120 min after. C-peptide and sex hormone-binding globulin were also determined before the glucose load. Insulin resistance was assessed by HOMA model and ISI composite. Results. The prevalence of Type II diabetes was 1.89-(1.06–3.38)-fold higher in PCOSp compared to HWp. Insulin resistance, evaluated by HOMAIR and ISI composite was also significantly higher in the PCOSp group compared to the HWp group. After both study groups were distributed by sex, and adjusted by age and BMI, the metabolic parameters were still significantly different between PCOSp and HWp. Conclusions/interpretation. The data suggest that parents of PCOS women exhibit insulin resistance and Type II diabetes more frequently than those of healthy women, thus constituting a high-risk group but an ideal cohort to detect and prevent the development of Type II diabetes.

To compare the effect of a single session of acupuncture with either low-frequency electrical or manual stimulation on insulin sensitivity and molecular pathways in the insulin-resistant dihydrotestosterone-induced rat polycystic ovary syndrome (PCOS) model. Both stimulations cause activation of afferent nerve fibers. In addition, electrical stimulation causes muscle contractions, enabling us to differentiate changes induced by activation of sensory afferents from contraction-induced changes. Control and PCOS rats were divided into no-stimulation, manual-, and electrical stimulation groups and insulin sensitivity was measured by euglycemic hyperinsulinemic clamp. Manually stimulated needles were rotated 180° ten times every 5 min, or low-frequency electrical stimulation was applied to evoke muscle twitches for 45 min. Gene and protein expression were analyzed by real-time PCR and Western blot. The glucose infusion rate (GIR) was lower in PCOS rats than in controls. Electrical stimulation was superior to manual stimulation during treatment but both methods increased GIR to the same extent in the post-stimulation period. Electrical stimulation decreased mRNA expression of Adipor2, Adrb1, Fndc5, Erk2, and Tfam in soleus muscle and increased ovarian Adrb2 and Pdf. Manual stimulation decreased ovarian mRNA expression of Erk2 and Sdnd. Electrical stimulation increased phosphorylated ERK levels in soleus muscle. One acupuncture session with electrical stimulation improves insulin sensitivity and modulates skeletal muscle gene and protein expression more than manual stimulation. Although electrical stimulation is superior to manual in enhancing insulin sensitivity during stimulation, they are equally effective after stimulation indicating that it is activation of sensory afferents rather than muscle contraction per se leading to the observed changes.

Antenatal exposure to testosterone (T) has a series of consequences on postnatal reproductive parameters in females of several animal species. In sheep born under this condition the ovaries are characterized by an increased number of growing follicles. If such disruptions are manifested early in life or involve changes in follicular recruitment and ovary paracrine environment, it remains unclear. This study addressed the impact of prenatal T on ovarian morphometry and the mRNA expression of ovarian anti-müllerian hormone (AMH), FSH receptor (FSHR) and nuclear factor kappa B (NFkB, a transcription factor for AMH), factors that are involved in the growth and selection of the dominant follicle. At 4 weeks of age, female lambs born to dams treated with 30 mg of T propionate twice weekly from day 30 to day 90, followed by 40 mg of T propionate from day 90 to day 120 of pregnancy (T females), showed similar number of primordial, primary, secondary and antral follicles than control females (C females) born to dams treated with the vehicle. In the pool of secondary follicles (< 0.5 mm) the expression of the FSHR was slightly higher in the T females, while AMH and NFkB expression were lower than C females. Instead, the pool of small antral follicles (between 0.5 and 1 mm) showed a higher expression of FSHR and a slight increase in AMH in T females, while NFkB expression remained lower than C females. These findings provide evidence that the prenatal exposure to T impacts the expression of key local factors governing the folliculogenesis before histological alterations occur. &nbsp, La exposición prenatal a testosterona (T) tiene consecuencias postnatales en parámetros reproductivos en hembras de varias especies. En ovejas, los ovarios presentan alteraciones en el mecanismo de selección folicular, caracterizándose por un aumento del número de folículos en crecimiento. No se sabe si este tipo de trastorno se manifiesta en etapas tempranas del desarrollo y si implica cambios en el reclutamiento folicular y en el ambiente paracrino del ovario. Este estudio abordó el impacto de la T prenatal en la morfología ovárica y en la expresión de hormona antimülleriana (AMH), receptor de FSH (FSHR) y factor nuclear kappa B (NFkB, un factor de transcripción de AMH). A las 4 semanas de edad, las hembras nacidas de madres tratadas con 30 mg de propionato de T dos veces por semana desde el día 30 a 90, seguido de 40 mg desde los 90 a 120 días de preñez (hembras-T), presentaron un número similar de folículos primordiales, primarios, secundarios y antrales que hembras control (hembras-C) nacidas de madres tratadas con el vehículo. En el pool de folículos secundarios la expresión del FSHR fue ligeramente mayor en las hembras-T, mientras que la expresión de AMH y NFkB fue menor. En cambio, en el pool de folículos antrales pequeños de hembras-T, la expresión del FHSR fue mayor, mientras que la expresión de NFkB se mantuvo baja. AMH fue levemente mayor. Estos resultados sugieren que la exposición prenatal a T modifica la expresión de factores locales que rigen la foliculogénesis. &nbsp

Several studies have suggested that leptin modulates hypothalamic-pituitary-gonadal axis function. A synchronicity of LH and leptin pulses has been described in healthy women and in patients with polycystic ovarian syndrome (PCOS), suggesting that leptin may modulate the episodic secretion of LH. The aim of the present investigation was to assess the episodic fluctuations of circulating LH and leptin during lactational amenorrhoea in fully breastfeeding normal and PCOS women at 4 and 8 weeks postpartum, in order to establish LH-leptin interactions in the reactivation of the gonadal axis during this period. Six lactating PCOS patients and six normal lactating women of similar age and body mass index were studied. During a 12 h period on the 4th and 8th weeks postpartum, blood samples were collected at 10 min intervals for 12 h (22:00-10:00). Serum LH and leptin concentrations were measured in all samples. For pulse analysis, the cluster algorithm was used. To detect an interaction between LH and leptin pulses, an analysis of co-pulsatility was employed. LH concentrations tended to increase in both groups between the 4th and 8th weeks postpartum; however, serum leptin concentrations were not modified. Leptin pulse frequencies were similar at the 4th and 8th weeks postpartum, and did not differ between groups. Moreover, leptin pulse frequency was higher than LH pulse frequency in both groups, and in the two study periods. There was no synchronicity between LH and leptin pulses, and there were no increments in leptin concentration during the night. The fact that leptin concentrations were not modified and no synchronicity between LH and leptin pulses was observed suggests that, during lactational amenorrhoea, circulating leptin is probably not involved as a primary signal in promoting the reactivation of pulsatile LH secretion.

Several studies suggest that leptin modulates hypothalamic-pituitary-gonadal axis functions. Leptin may stimulate release of gonadotrophin releasing hormone (GnRH) from the hypothalamus and of gonadotrophins from the pituitary. A synchronicity of luteinizing hormone (LH) and leptin pulses has been described in healthy women and in patients with polycystic ovarian syndrome, suggesting that leptin may modulate the episodic secretion of LH. However, it has not been established whether LH regulates the episodic secretion of leptin. To further examine LH-leptin interactions, we studied the episodic fluctuations of circulating LH and leptin in two patients with Kallmann's syndrome (KS) before and on day 7 of pulsatile GnRH administration, and compared these with those observed in the early follicular phase of 10 regularly menstruating women divided into two control groups according to the body mass index of each patient. To assess episodic hormone secretion, blood samples were collected at 10 min intervals for 6 h, before and on day 7 of GnRH administration in KS patients, and during days 3-7 of the follicular phase in normally cycling women. LH and leptin concentrations were measured in all samples. For pulse analysis, the cluster algorithm was used. Before treatment, an apulsatile pattern with no endogenous LH pulsations was observed in both KS patients. However, leptin pulses were assessed in both women. During GnRH administration, pulsatile LH activity was achieved in both patients with pulse characteristics similar to those of the respective control group. Serum leptin concentrations and leptin pulsatile patterns were not modified. These results suggest that circulating leptin is probably not modulated by pulsatile GnRH-LH secretion.

The conserved brain design that primates inherited from early mammals differs from the variable adult brain size and species-specific brain dominances observed across mammals. This variability relies on the emergence of specialized cerebral cortical regions and sub-compartments, triggering an increase in brain size, areal interconnectivity and histological complexity that ultimately lies on the activation of developmental programs. Structural placental features are not well correlated with brain enlargement; however, several endocrine pathways could be tuned with the activation of neuronal progenitors in the proliferative neocortical compartments. In this article, we reviewed some mechanisms of eutherians maternal-fetal unit interactions associated with brain development and evolution. We propose a hypothesis of brain evolution where proliferative compartments in primates become activated by 'non-classical' endocrine placental signals participating in different steps of corticogenesis. Changes in the inner placental structure, along with placenta endocrine stimuli over the cortical proliferative activity would allow mammalian brain enlargement with a concomitant shorter gestation span, as an evolutionary strategy to escape from parent-offspring conflict.

Here, we tested the hypothesis that excess maternal androgen in late pregnancy reduces placental and fetal growth, increases placental steroidogenesis, and adversely affects glucose and lipid metabolism in adult female offspring. Pregnant Wistar rats were randomly assigned to treatment with testosterone (daily injections of 5 mg of free testosterone from gestational days 16 to 19) or vehicle alone. In experiment 1, fetal and placental weights, circulating maternal testosterone, estradiol, and corticosterone levels, and placental protein expression and distribution of estrogen receptor-α and -β, androgen receptor, and 17β-hydroxysteroid dehydrogenase 2 were determined. In experiment 2, birth weights, postnatal growth rates, circulating testosterone, estradiol, and corticosterone levels, insulin sensitivity, adipocyte size, lipid profiles, and the presence of nonalcoholic fatty liver were assessed in female adult offspring. Treatment with testosterone reduced placental and fetal weights and increased placental expression of all four proteins. The offspring of testosterone-treated dams were born with intrauterine growth restriction; however, at 6 wk of age there was no difference in body weight between the offspring of testosterone- and control-treated rats. At 10–11 wk of age, the offspring of the testosterone-treated dams had less fat mass and smaller adipocyte size than those born to control rats and had no difference in insulin sensitivity. Circulating triglyceride levels were higher in the offspring of testosterone-treated dams, and they developed nonalcoholic fatty liver as adults. We demonstrate for the first time that prenatal testosterone exposure alters placental steroidogenesis and leads to dysregulation of lipid metabolism in their adult female offspring.

Background: The polycystic ovary syndrome (PCOS) is a hyperandrogenic disorder that arise from a combination of genetic and environmental factors. Aim: To assess the role of the androgen receptor (AR) CAG repeat polymorphism in the metabolic and reproductive features in daughters of women with PCOS (PCOSd). Methods: Sixty-seven PCOSd and 60 daughters of control women (Cd) were studied in early stages of sexual development. Sex steroids, glucose, insulin and lipids were determined. The AR CAG repeat sizes and X-chromosome inactivation (XCI) were analyzed. Results: PCOSd and Cd had similar mean number of CAG repeats and XCI pattern. In PCOSd and Cd, methylation-weighted biallelic means CAGn (mwCAGn) was not associated with androgen levels. In infants and pubertal PCOSd, mwCAGn was associated with a low concentration of HDL-cholesterol. Conclusions: AR CAG repeat polymorphism appears to be unrelated with serum androgen levels. However, the short mwCAGn variant may have a possible impact on the lipid profile ...

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.

Exposure to excess testosterone (T) during fetal life has a profound impact on the metabolic and reproductive functions in the female's postnatal life. However, less is known about the effects of excess testosterone in males. The aim of the present study was to evaluate the impact (consequences) of an excess of T during fetal development on mature male testis. The testicular evaluation was by histological analysis and by determination of mRNA expression of the FSH receptor (FSH-R), transforming growth factor-β type I receptor (TβR-I), and two members of the TGF-β superfamily, transforming growth factor-β3 (TGFβ3) and anti-Müllerian hormone (AMH) in males born to mothers receiving an excess of T during pregnancy. At 42 wk of age, postpubertal males born to mothers treated with 30 mg of T propionate twice weekly from day 30 to 90, followed by 40 mg of T propionate from day 90 to 120 of pregnancy (T males), showed higher concentrations of FSH in response to a GnRH analog, a higher number of Sertoli cells/seminiferous tubule cross-section, and a lower number of germ cells/tubules (P < 0.05) than control males (C males) born to mothers treated with the vehicle. The mRNA expression of FSH-R and of TβR-I was higher in T males compared with C males (P < 0.05). Moreover, in T males, AMH expression level correlated negatively with the expression level of TGFβ3. In C males, this latter correlation was not observed. These results suggest that prenatal exposure to an excess of T can negatively modify some histological and molecular characteristics of the mature testis. Fil: Rojas García, Pedro P.. Universidad de Concepción; Chile Fil: Recabarren, Mónica. Universidad de Concepción; Chile Fil: Sarabia, Luis. Universidad de Chile; Chile Fil: Schön, Jennifer. Freie Universität; Alemania Fil: Gabler, Christoph. Freie Universität; Alemania Fil: Einspanier, Ralf. Freie Universität; Alemania Fil: Maliqueo, Manuel. Universidad de Chile; Chile Fil: Sir Petermann, Teresa. Universidad de Chile; Chile Fil: Rey, Rodolfo Alberto. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Biología Celular e Histología; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Recabarren, Sergio E.. Universidad de Concepción; Chile

Gestational diabetes mellitus (GDM) is highly prevalent in women with polycystic ovary syndrome (PCOS). Women with GDM have considerable risk for developing both type 1 and type 2 diabetes.To evaluate the prevalence of anti-GAD65 and anti-IA2 auto-antibodies in Chilean pregnant women with GDM, normal pregnancy (NP) and with PCOS (PPCOS) to establish whether in PCOS women GDM is partially induced by auto-antibodies.Women with singleton pregnancies matched by age and gestational age were included: 50 GDM, 59 NP and 50 PPCOS. During gestational weeks 22-28, a 2-h, 75 g oral glucose tolerance test was performed, with measurement of glucose, insulin, lipids and auto-antibodies.A highly prevalence of anti-GAD65 antibodies (12%) was observed in women with GDM. PPCOS and NP women showed a similar distribution of anti-GAD65 antibodies (2.0% and 1.7%, respectively). Anti-IA2 antibodies were present in 4.0% of women with GDM, in 1.7% of NP women and 2.0% PPCOS women.A highly prevalence of anti-GAD65 was observed in women with GDM which is in agreement with previous studies. Nevertheless, the frequency of these auto-antibodies was very low in NP and PPCOS women.

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.

Polycystic ovary syndrome (PCOS) is an endocrine metabolic dysfunction closely associated with insulin resistance and obesity, which predisposes to pregnancy complications.To report a prospective clinical experience in PCOS patients who became pregnant after diet, exercise and metformin treatment intervention, and were followed up during the whole pregnancy.Seventy pregnant PCOS (PPCOS) women and forty normal pregnant (NP) women of similar age and with singleton pregnancies were included in the study. During gestational ages 10-16 and 22-28 weeks, a 2h, 75 g oral glucose tolerance test (OGTT) was performed with measurement of glucose and insulin in each sample.No differences were found in duration of gestation, weight gain during pregnancy, or systolic and diastolic blood pressure between PPCOS and NP women. There were significant differences in body mass index (BMI) at the initiation and in the third trimester of pregnancy between both groups. The incidence of gestational diabetes was significantly higher (p0.01) in the PCOS group (35.2%) compared to the control group (5.0%). The prevalence of small for gestational age (SGA) infants tended to be higher (p =0.09) in the PCOS group. During pregnancy, 2h glucose and insulin were significantly higher in PPCOS than in NP women.PCOS mothers showed a higher prevalence of gestational diabetes and SGA newborns, which cannot be attributed to the weight gain during pregnancy, and seems to be more related to the BMI at the initiation of pregnancy, and to the PCOS condition of the mother.

Context: Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder with strong familial aggregation. It has been demonstrated that parents and brothers of PCOS women exhibit insulin resistance and related metabolic defects. However, metabolic phenotypes in sons of PCOS women have not been described. Objective: Our objective was to assess the metabolic profiles in sons of women with PCOS during different stages of life: early infancy, childhood, and adulthood. Design: Eighty sons of women with PCOS (PCOSS) and 56 sons of control women without hyperandrogenism (CS), matched for age, were studied. In early infancy, glucose and insulin were determined in the basal sample. In children and adults, a 2-h oral glucose tolerance test was performed with measurements of glucose and insulin. Adiponectin, leptin, C-reactive protein, SHBG, and serum lipids were determined in the basal sample during the three periods. Results: During early infancy, PCOSS showed higher weight (P = 0.038) and weight sd score (P = 0.031) than CS. During childhood, weight (P = 0.003), body mass index (BMI) (P < 0.001), BMI sd score (P < 0.001), waist circumference (P = 0.001), total cholesterol (P = 0.007), and low-density lipoprotein cholesterol (P = 0.022) were higher in PCOSS compared with CS, but after adjusting for BMI, these differences were nonsignificant. During adulthood, PCOSS exhibited higher weight (P = 0.022), BMI (P = 0.046), and waist circumference (P = 0.028) than CS. Fasting insulin (P = 0.030), homeostasis model assessment for insulin resistance (P = 0.034), total cholesterol (P = 0.043), low-density lipoprotein cholesterol (P = 0.034), and 2-h insulin (P = 0.006) were also significantly higher and insulin sensitivity index composite significantly lower in PCOSS than in CS (P = 0.003). After adjusting for BMI, only 2-h insulin and insulin sensitivity index composite remained significantly different. Conclusions: This study indicates that sons of PCOS women exhibit higher body weight from early infancy. In addition, insulin resistance became evident as the subjects got older, which may place them at risk for the development of type 2 diabetes and cardiovascular disease.

Background: Polycystic ovary syndrome (PCOS) is an endocrine metabolic dysfunction closely associated with insulin resistance and obesity, which predisposes to pregnancy complications. Aim: To report a prospective clinical experience in PCOS patients who became pregnant after diet, exercise and metformin treatment intervention, and were followed up during the whole pregnancy. Patients and Methods: Seventy pregnant PCOS (PPCOS) women and forty normal pregnant (NP) women of similar age and with singleton pregnancies were included in the study. During gestational ages 10-16 and 22-28 weeks, a 2h, 75 g oral glucose tolerance test (OGTT) was performed with measurement of glucose and insulin in each sample. Results: No differences were found in duration of gestation, weight gain during pregnancy, or systolic and diastolic blood pressure between PPCOS and NP women. There were significant differences in body mass index (BMI) at the initiation and in the third trimester of pregnancy between both groups. The incidence of gestational diabetes was significantly higher (p

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 gonadal function and anti-Mullerian hormone (AMH) serum concentrations during the first 3 months of life in low birth weight (low-BW) and normal birth weight (normal-BW) infants. INFANTS: Twenty low-BW and 29 normal-BW infants were studied. Methods The pituitary-gonadal axis was evaluated by a GnRH agonist test (leuprolide acetate, 10 microg/kg s.c.). Circulating concentrations of gonadotropins, steroid hormones, sex hormone binding globulin, inhibin B and AMH were determined by specific assays. Results In both sexes, basal concentrations of gonadotropins, sex steroids, sex hormone binding globulin and inhibin B were similar between low-BW and normal-BW infants. However, AMH concentrations were significantly higher in low-BW compared to normal-BW females (p = 0.004). This was not observed in males. After leuprolide administration, estradiol concentrations were higher in low-BW compared to normal-BW females (p = 0.043). In males, post-stimulated sex steroid concentrations were similar in both groups except for 17-OHP, which was significantly higher after leuprolide in the low-BW group (p = 0.023). Conclusions An increase in AMH and post-stimulated estradiol serum concentrations suggests altered follicular development in low-BW girls. In contrast, the normal circulating levels of AMH and inhibin B seem to indicate that Sertoli cell function is normal in low-BW boys. We suggest that ovarian function seems to be more vulnerable than testicular function in infants with intrauterine growth restriction.

Both epidemiological and clinical evidence suggest a relationshipbetween the prenatal environment and the risk of developing diseases during adulthood. The firstobservations about this relationship showed that prenatal growth retardation or stress conditionsduring fetal life were associated to cardiovascular, metabolic and other diseases in later life.However, not only those conditions may have lasting effects after birth. Growing evidence suggeststhat prenatal exposure to steroids (either of fetal or maternal origin) could be another source ofprenatal programming with detrimental consequences during adulthood. We have recentlydemonstrated that pregnant women with polycystic ovary syndrome exhibit elevated androgenlevels compared to normal pregnant women, which could provide an androgen excess for bothfemale or male fetuses. We have further tested this hypothesis in an animal model of prenatalandrogenization, finding that females born from androgenized mothers have a low birth weightand high insulin resistance, that starts at an early age. On the other hand, males have lowtestosterone and LH secretion in response to a GnRH analogue test compared to control males andalterations in seminal parameters. We therefore propose that our efforts should be directed tomodify the hyperandrogenic intrauterine environment to reduce the potential development ofreproductive and metabolic diseases during adulthood (Rev Med Chile 2006; 134: 101-8).(

Summary Objective To establish the frequency of the Trp64Arg polymorphism of the β3 adrenergic receptor (ADRB3) in women with polycystic ovary syndrome (PCOS) from a Chilean population, focusing particularly on the interaction with body weight. In addition, we evaluated the relationship of the Trp64Arg variant with other metabolic components of this syndrome. Patients and Design In a case–control design study, a total of 106 women with clinical and hormonal evidence of PCOS and 82 healthy women (HW) were evaluated. Measurements An oral glucose tolerance test (OGTT) was performed and serum glucose and insulin were measured before the glucose load and 30, 60, 90 and 120 min after. Lipid profile was determined in the basal sample. Insulin resistance was assessed by the homeostatic model assessment (HOMAIR) and insulin sensitivity index (ISI) composite. A polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis was performed to determine the Trp64Arg polymorphism of ADRB3. Results The frequency of the heterozygous condition was similar between PCOS and HW (39%vs. 35%). Only two subjects were homozygous for arginine, both belonging to the PCOS group and having a body mass index (BMI) > 30 kg/m2. In the crude analysis, hypothesis tests and odds ratios show that there is no evidence of association between the ADRB3 Trp64Arg variant and PCOS (P = 0·47). Moreover, when data were stratified by BMI categories, the statistical test for interaction between Trp64 carrier status and obesity was not significant (P = 0·29). This variant was present in 52% of the obese PCOS patients and 40% of the obese HW. In normal weight and obese PCOS carriers, the presence of the Trp64Arg variant was associated with high triglyceride (TG) levels. A major effect of the Trp64Arg variant on insulin resistance parameters could not be demonstrated. Conclusions The frequency of the Trp64Arg polymorphism was similar in healthy women and PCOS women, and a possible interaction between the effect of this variant and obesity in PCOS could not be demonstrated. However, our results showed an association between triglyceride levels and the presence of this genetic variant in PCOS women.

BACKGROUND: The aim of this study was to establish the effect of polycystic ovary syndrome (PCOS) adjusted for adiposity on proinsulin concentrations. METHODS: Ninety-one women with PCOS and 72 normal cycling (NC) women were recruited. A 2 h, 75 g oral glucose tolerance test was performed. Glucose and insulin were measured in each sample. Proinsulin and C-peptide were determined at 0 and 30 min and the fasting proinsulin/insulin ratio (PI/I) was calculated. Insulin sensitivity was estimated by insulin sensitivity index (ISI) composite, and beta-cell function was estimated by insulinogenic index. RESULTS: Insulin, proinsulin and C-peptide concentrations were higher in women with PCOS than in NC women (P < 0.05). PI/I and insulinogenic index were similar in both groups. Proinsulin concentrations increased with body mass index (P < 0.05) only in women with PCOS; therefore, proinsulin concentrations were higher in obese PCOS patients compared with obese control women (P < 0.05). Moreover, a positive association between proinsulin concentrations and waist diameter adjusted for C-peptide (P < 0.05) and a negative association between proinsulin concentrations and ISI composite values were observed in PCOS patients (P < 0.05). CONCLUSIONS: Data suggest that in PCOS patients an elevated proinsulin concentration could reflect insulin resistance more than beta-cell dysfunction. However, the elevated concentration of proinsulin in these patients could also result from impaired beta-cell function resulting from intra-abdominal obesity independently of insulin resistance.

BACKGROUND: The aim of this study was to evaluate the peripheral serum androgen concentrations in normal and polycystic ovarian syndrome (PCOS) women during pregnancy, in order to establish if PCOS may induce gestational hyperandrogenism and therefore constitute a potential source of androgen excess for the fetus. METHODS: Twenty pregnant PCOS (PPCOS) women and 26 normal pregnant (NP) women of similar age with singleton pregnancies were selected for the study. During gestational weeks 10-16 and 22-28, a 2 h, 75 g oral glucose tolerance test (OGTT) was performed. For the OGTT, glucose and insulin were measured in each sample and testosterone, androstenedione, dehydroepiandrosterone sulphate (DHEAS), estradiol, progesterone and sex hormone-binding globulin were determined in the fasting sample. RESULTS: In the first study period (gestational weeks 10-16), the levels of androstenedione, testosterone and DHEAS and the free androgen index tended to be higher in the PCOS group. These differences became significant in the second study period (gestational weeks 22-28). In this second period, 2 h insulin concentrations were also significantly higher in PPCOS than in NP women. CONCLUSIONS: The present study demonstrates a significant increase in androgen concentrations during pregnancy in PCOS women. We propose that these androgen concentrations could provide a potential source of androgen excess for the fetus, without leading to fetal virilization.

BACKGROUND Polycystic ovarian syndrome (PCOS) is a common endocrine-metabolic disorder in women, a high percentage of whom exhibit peripheral insulin resistance. After delivery, in normal women, lactation imposes a metabolic adaptation, the impact of which on the insulin resistance of PCOS patients is not known. The aim of this study was to evaluate the effect of lactation on insulin resistance, glucose and insulin metabolism, and sex hormone-binding globulin (SHBG) and insulin-like growth factor binding protein-1 (IGFBP)-1 concentrations in fully breast-feeding normal and PCOS women during the postpartum period (lactational amenorrhoea) and also after weaning. METHODS Twelve lactating PCOS (LPCOS) women and six normal lactating (NL) women of similar age and body mass index (BMI) were selected for the study. At the 4th and the 8th week postpartum (pp), and 8 weeks after weaning, a 2 h, 75 g oral glucose tolerance test (oGGT) was performed, followed by an insulin tolerance test 2 days later. For the oGGT, glucose and insulin were measured in each sample and SHBG and IGFBP-1 were determined in the fasting sample. RESULTS During lactation, fasting insulin levels were similar in both groups. In LPCOS women 2 h insulin concentrations were significantly higher, and SHBG and IGFBP-1 concentrations were significantly lower, than those observed in NL women. In both groups, insulin sensitivity evaluated by the insulin tolerance test was not modified. After weaning, in LPCOS women, SHBG and IGFBP-1 concentrations remained lower and insulin concentrations remained higher than those observed in NL women ( P < 0.05 ). CONCLUSIONS In PCOS women, insulin resistance is not modified during lactation. Lactation has a transitory beneficial effect on insulin levels and biological markers of insulin resistance.

Polycystic ovary syndrome (PCOS) is a very common disorder that occurs up to 10% of premenopausal women. Although PCOS is known to be associated with a higher reproductive morbility and increased risk of hormone dependent-cancer, its diagnosis is particularly important because PCOS is strongly linked to insulin resistance. This involves a major risk of early metabolic and cardiovascular complications. On the other hand, the prevalence of metabolic disorders associated with insulin resistance is higher in family members of patients with PCOS than in those of normal women, which suggests that the treatment of this syndrome should be preventive rather than symptomatic. For that reason, PCOS might be considered a signal of a family disorder, a route to diabetes and a public health problem (Rev Med Chile 2001; 129: 805-12).

Background: Several studies suggest that leptin modulates the reproductive axis function. Leptin may stimulate release of GnRH from hypothalamus and of gonadotrophins from the pituitary. A synchronicity of LH and leptin pulses has been described in healthy women and in patients with polycystic ovarian syndrome (PCOS), suggesting a relationship between the episodic secretion of LH and leptin. In vitro experimental studies have demonstrated that leptin administration promotes GnRH-LH release. However it is not established whether GnRH promotes the episodic secretion of leptin. Aim: To assess the response of LH and leptin to the administration of a GnRH bolus in hyperandrogenic and healthy women. Patients and methods: Eleven hyperandrogenic and eleven healthy women of similar age and body mass index (BMI) were studied. Under basal conditions three blood samples were collected every 30 min before and after the administration of a GnRH bolus (100 µg). LH and leptin concentrations were measured in all samples. Testosterone, SHBG and estradiol were determined in the first sample. For data analysis, the increment of LH and leptin between 0-30 and 0-60 min. was calculated. The LH and leptin areas under the curve (AUC) before and after GnRH administration were also calculated in both groups. Results: After GnRH administration. an increment in LH concentrations was observed in both groups; however, leptin concentrations were not modified. In both groups LH area under the curve increased after GnRH administration; however, the leptin area was not modified. Conclusions: These results suggest that circulating leptin concentration is not modulated by GnRH-LH. (Rev Méd Chile 2000; 128: 460-6)

Animal and human studies suggest that leptin modulates hypothalamic-pituitary-gonadal axis functions. Leptin may stimulate gonadotrophin-releasing hormone (GnRH) release from the hypothalamus and luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion from the pituitary. A synchronicity of LH and leptin pulses has been described in healthy women, suggesting that leptin probably also regulates the episodic secretion of LH. In some pathological conditions, such as polycystic ovarian syndrome (PCOS), LH-leptin interactions are not known. The aim of the present investigation was to assess the episodic fluctuations of circulating LH and leptin in PCOS patients compared to regularly menstruating women. Six PCOS patients and six normal cycling (NC) women of similar age and body mass index (BMI) were studied. To assess episodic hormone secretion, blood samples were collected at 10-min intervals for 6 h. LH and leptin concentrations were measured in all samples. For pulse analysis the cluster algorithm was used. To detect an interaction between LH and leptin pulses, an analysis of copulsatility was employed. LH concentrations were significantly higher in the PCOS group in comparison to NC women, however serum leptin concentrations and leptin pulse characteristics for PCOS patients did not differ from NC women. A strong synchronicity between LH and leptin pulses was observed in NC women; 11 coincident leptin pulses were counted with a phase shift of 0 min (P = 0.027), 18 pulses with a phase shift of -1 (P = 0.025) and 24 pulses with a phase shift of -2 (P = 0.028). PCOS patients also exhibited a synchronicity between LH and leptin pulses but weaker (only 20 of 39 pulses) and with a phase shift greater than in normal women, leptin pulses preceding LH pulses by 20 min (P = 0.0163). These results demonstrate that circulating leptin and LH are synchronized in normal women and patients with PCOS. The real significance of the apparent copulsatility between LH and leptin must be elucidated, as well as the mechanisms that account for the ultradian leptin release.

Summary Multiple skin tags appear associated with abnormalities in glucose/insulin metabolism. Clinical and metabolic glucose/insulin characteristics of men with multiple (8 or more) skin tags on the neck were compared with a control group with few or none. Both groups were divided in two subgroups according to normal or abnormal laboratory findings. In the study subgroup with normal laboratory findings the number of skin tags varied from 8–33, whereas in those with abnormal laboratory findings the range was 9–65. Eight or more skin tags were related with statistically significant laboratory glucose/insulin abnormalities: basal hyperinsulinemia (p