Bárbara Echiburú

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.

Placental steroidogenesis in pregnant women with polycystic ovary syndrome

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.

Metabolic Profile in Sons of Women with Polycystic Ovary Syndrome

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 (PCOS(S)) and 56 sons of control women without hyperandrogenism (C(S)), 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, PCOS(S) showed higher weight (P = 0.038) and weight sd score (P = 0.031) than C(S). 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 PCOS(S) compared with C(S), but after adjusting for BMI, these differences were nonsignificant. During adulthood, PCOS(S) exhibited higher weight (P = 0.022), BMI (P = 0.046), and waist circumference (P = 0.028) than C(S). 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 PCOS(S) than in C(S) (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.

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.

Effects of Birth Weight on Anti-Müllerian Hormone Serum Concentrations in Infant Girls

CONTEXT 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. OBJECTIVE 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. DESIGN 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. RESULTS 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). CONCLUSIONS 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.

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.

Pituitary and Testicular Function in Sons of Women with Polycystic Ovary Syndrome from Infancy to Adulthood

CONTEXT 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. OBJECTIVE 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. DESIGN 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. RESULTS 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. CONCLUSIONS 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.

Gonadal function in low birth weight infants: a pilot study.

OBJECTIVE To evaluate gonadal function and anti-Müllerian 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.

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.

Sex Steroids Modulate Uterine-Placental Vasculature: Implications for Obstetrics and Neonatal Outcomes

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.