Amanda Ladrón de Guevara

Metabolic and Reproductive Features before and during Puberty in Daughters of Women with Polycystic Ovary Syndrome

CONTEXT A significant proportion of the first-degree female relatives of women with polycystic ovary syndrome (PCOS) may be at risk for developing PCOS. However, it is not known at which stage of pubertal development the hormonal and metabolic abnormalities ensue in PCOS. OBJECTIVE The aim of the study was to assess the reproductive and metabolic profiles of daughters of women with PCOS (PCOSd) during the peripubertal period, a stage during which the gonadal axis is activated and PCOS may become clinically manifest. DESIGN Ninety-nine PCOSd [30 prepubertal and 69 pubertal (Tanner II-V)] and 84 daughters of control women (Cd) (20 prepubertal and 64 pubertal) were studied. An oral glucose tolerance test, a GnRH agonist test (leuprolide acetate, 10 microg/kg sc), and a transabdominal ultrasound were performed. Gonadotropins, sex steroids, SHBG, glucose, insulin, and lipids were determined. RESULTS Both groups had similar chronological ages and body mass index sd scores according to Tanner stage distribution. Ovarian volume and 2-h insulin were significantly higher in PCOSd compared to Cd at all Tanner stages. In Tanner stages IV and V, basal testosterone and poststimulated LH, testosterone, and 17-hydroxyprogesterone concentrations were significantly higher in PCOSd compared to Cd. CONCLUSIONS Hyperinsulinemia and an increased ovarian volume are present in PCOSd before the onset of puberty and persist during pubertal development. The biochemical abnormalities of PCOS appear during late puberty. Considering the early onset and the nature of the alterations, PCOSd constitute a high-risk group for metabolic and reproductive derangements.

Adrenal function during childhood and puberty in daughters of women with polycystic ovary syndrome.

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.

Improvement of hyperandrogenism and hyperinsulinemia during pregnancy in women with polycystic ovary syndrome: possible effect in the ovarian follicular mass of their daughters

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-Müllerian 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.

Relationship Between Anti-Müllerian Hormone (AMH) and Insulin Levels During Different Tanner Stages in Daughters of Women with Polycystic Ovary Syndrome

Context: 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. Objective: 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). Design: 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. Results: 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. Conclusions: 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.

Metabolic profile of the different phenotypes of polycystic ovary syndrome in two Latin American populations

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 (PCOSCh) and 206 Argentinian (PCOSAr). 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. PCOSCh women showed a higher body mass index and a higher percentage of metabolic syndrome in all phenotypes compared with the PCOSAr women. The PCOSAr 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 PCOSCh women. CONCLUSION(S) The data show differences in the metabolic profile of both populations. PCOSCh women presented with greater metabolic alterations such as dysglycemia and dyslipidemia and a higher prevalence of metabolic syndrome, independent of the phenotype. The PCOSAr patients showed more elevated blood pressure. Ethnic diversity associated with environmental factors are fundamental elements in the analysis of the PCOS phenotypes.

Metabolic profile in women with polycystic ovary syndrome across adult life

OBJECTIVE To assess insulin sensitivity, insulin secretion and metabolic profile in women with polycystic ovary syndrome (PCOS) in different stages of reproductive life. MATERIALS AND METHODS 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. RESULTS At early reproductive age, PCOSw showed higher BMI, WC, and VAI and a higher prevalence of MS compared to Cw (p<0.05). 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. CONCLUSIONS 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.

Relationship of serum adipocyte-derived proteins with insulin sensitivity and reproductive features in pre-pubertal and pubertal daughters of polycystic ovary syndrome women

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.

Síndrome de ovario poliquístico y embarazo

Polycystic ovary syndrome (PCOS) is a common endocrine metabolic dysfunction closely associated with insulin resistance and obesity, which predisposes to pregnancy complications and prenatal programming of the offspring. The aim of this review is to report our experience in PCOS patients who became pregnant and were followed during the whole pregnancy. Firstly, we analyzed the effect of pregnancy on PCOS pathophysiology and secondly the role of PCOS in pregnancy outcomes. Regarding the firstpoint, during normal pregnancy a progressive insulin resistance, serum lipid changes and an increase in androgen levels is observed, which is exacerbated in the PCOS condition. This adverse intrauterine environment could have a prenatal programming effect with detrimental consequences for female or male fetuses. Regarding the second point, PCOS is associated with an increased risk for maternal complications such as gestational diabetes (GDM) and pregnancy-induced hypertension. Moreover, these adverse pregnancy outcomes are more frequently associated with an increase in low birth weight and high birth weight newborns. According to our clinical experience, PCOS patients who became pregnant and were not treated with metformin during the whole pregnancy, showed a higher prevalence of gestational diabetes and SGA newborns, which was improved with metformin treatment. In summary, pregnancy may constitute a period in which an abnormal condition is established or aggravated in the fetus of a PCOS mother. Moreover, PCOS enhanced adverse obstetric and neonatal outcomes

CAG repeat polymorphism of androgen receptor gene and X-chromosome inactivation in daughters of women with polycystic ovary syndrome (PCOS): relationship with endocrine and metabolic parameters.

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 in PCOSd.

Evaluation of ovarian function in 35–40-year-old women with polycystic ovary syndrome

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.