Pregnancy outcomes in women with polycystic ovary syndrome in two Latin American populations.

Pregnancy complications and obstetric outcomes were compared in 80 Chilean (PPCOSCh) and 70 Argentinian (PPCOSAr) pregnant women. Reference groups of Chilean and Argentinian normal pregnant women from the same antenatal care units were also compared. PPCOSCh showed a higher prevalence of gestational diabetes mellitus (GDM) (OR, 2.28, 95% CI: 1.08-4.77, p = .030) and a lower prevalence of pregnancy-induced hypertension (PIH) (OR, 0.20, 95% CI: 0.07-0.54, p = .001) compared to PPCOSAr. In the normal pregnant groups, the prevalence of PIH was lower in Chilean women compared to Argentinian women (OR, 0.24, 95% CI: 0.10-0.62, p = .001). Similar to the pattern observed in the normal populations, newborns from PPCOSCh had higher birth weight and length compared with the newborns of PPCOSAr (p = .006 and .014, respectively). In conclusion, differences in pregnancy complications and obstetric outcomes between Chilean and Argentinian pregnant women with PCOS could be determined by ethnic diversity together with environmental factors of both populations. Impact Statement What is already known on this subject: The reproductive and metabolic phenotypes of women with polycystic ovary syndrome vary between different populations, which could significantly influence the obstetric and neonatal outcomes in this syndrome. What the results of this study add: Pregnant women with PCOS from two Latin American countries (Chile and Argentina) exhibit differences in the prevalence of gestational diabetes and pregnancy-induced hypertension, and in the birth weight of their newborns. What the implications are of these findings for clinical practice and/or further research: Ethnic diversity together with environmental factors are fundamental elements that must be considered in the management of pregnant women with PCOS.

Hirsutism and oligomenorrhea are appropriate screening criteria for polycystic ovary syndrome in adolescents.

We evaluated the association of hirsutism and oligomenorrhea (persistent menstrual cycles > 45 days) as screening criteria for the detection of biochemical hyperandrogenism (BH) and polycystic ovaries (PCOM) during adolescence and determined which androgens, granulosa cell hormone, ultrasonographic parameters have the best association with polycystic ovary syndrome (PCOS). Hirsute girls with oligomenorrhea (N = 26 Hirs/Oligo group) and non-hirsute girls with regular cycles (N = 63, C group) were studied. Prevalence of BH and PCOM, diagnostic performance of androgens and ultrasound parameters for PCOS diagnosis were analyzed. BH and PCOM prevalence were higher in the Hirs/Oligo girls than in the C girls (76.9% versus 25.5%; 92.3% versus 33.3%, respectively; p < 0.0001). A complete PCOS phenotype (Hirs/Oligo with BH and PCOM) was observed in 73.1% of the Hirs/Oligo group. The presence of both BH and PCOM was observed in 7.9% of the C group. The parameters with the best diagnostic performance were free androgen index ≥6.1, testosterone ≥2.4 nmol/L, follicle number ≥12 and ovarian volume ≥10 ml anti-Müllerian hormone (AMH) exhibited a low diagnostic accuracy. Hirsutism and persistent menstrual cycle over 45 days are highly associated with BH and PCOM suggesting that the presences of both criteria are necessary for the diagnosis of PCOS during adolescence.

[Effects of pregnancy and changes in body weight on polycystic ovary syndrome phenotypes according to the Rotterdam criteria]. / Clasificación de los fenotipos de síndrome de ovario poliquístico de acuerdo a los criterios de Rotterdam: ¿una condición estática o variable?

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

Pituitary and testis responsiveness of young male sheep exposed to testosterone excess during fetal development.

Prenatal exposure to excess testosterone induces reproductive disturbances in both female and male sheep. In females, it alters the hypothalamus-pituitary-ovarian axis. In males, prenatal testosterone excess reduces sperm count and motility. Focusing on males, this study tested whether pituitary LH responsiveness to GNRH is increased in prenatal testosterone-exposed males and whether testicular function is compromised in the testosterone-exposed males. Control males (n=6) and males born to ewes exposed to twice weekly injections of 30  mg testosterone propionate from days 30 to 90 and of 40  mg testosterone propionate from days 90 to 120 of gestation (n=6) were studied at 20 and 30 weeks of age. Pituitary and testicular responsiveness was tested by administering a GNRH analog (leuprolide acetate). To complement the analyses, the mRNA expression of LH receptor (LHR) and that of steroidogenic enzymes were determined in testicular tissue. Basal LH and testosterone concentrations were higher in the testosterone-exposed-males. While LH response to the GNRH analog was higher in the testosterone-exposed males than in the control males, testosterone responses did not differ between the treatment groups. The testosterone:LH ratio was higher in the control males than in the testosterone-exposed males of 30 weeks of age, suggestive of reduced Leydig cell sensitivity to LH in the testosterone-exposed males. The expression of LHR mRNA was lower in the testosterone-exposed males, but the mRNA expression of steroidogenic enzymes did not differ between the groups. These findings indicate that prenatal testosterone excess has opposing effects at the pituitary and testicular levels, namely increased pituitary sensitivity to GNRH at the level of pituitary and decreased sensitivity of the testes to LH.

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.

[Polycystic ovary syndrome and pregnancy]. / 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.

Insulin sensitivity in male sheep born to ewes treated with testosterone during pregnancy.

In animal models, exposure to excess testosterone during gestation induces polycystic ovary syndrome (PCOS)-like reproductive and metabolic traits in female offspring, suggesting that the hyperandrogenemic intrauterine environment may have a role in the etiology of PCOS. Additionally, few studies have also addressed metabolic and reproductive outcomes in male offspring. In the present study, the intravenous glucose tolerance test (IGTT) was used to assess the insulin-glucose homeostasis at various ages during sexual development in male sheep born to testosterone-treated ewes. To further analyze the programming effect of testosterone on insulin-glucose homeostasis, indexes of insulin sensitivity were assessed in orchidectomized post-pubertal males born to testosterone-treated ewes (Torq-males) and orchidectomized post-puberal controls (Corq-males) before and 48 h after a testosterone injection. There was no difference in insulin sensitivity indexes between males born to testosterone-treated ewes (T-males) and control males born to control ewes (C-males) at 5, 10, 20 and 30 weeks of age, representing the infantile, early and late pre-pubertal, and early post-pubertal stage of sexual development, respectively. In orchidectomized males, basal levels of insulin and glucose were not different between both groups before and after the testosterone injection; however, Torq-males released more insulin before and after T challenge during the first 20 min of the test. Despite this, plasma glucose concentrations were not different in both groups during IVGTT, resulting in an insulin sensitivity index composite similar between groups. We concluded that the effect of prenatal exposure to excess testosterone may reprogram the pancreatic ß-cells insulin release in ovine males, with effects more evident in castrated males versus intact males.

Prenatal testosterone excess alters Sertoli and germ cell number and testicular FSH receptor expression in rams.

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-ß type I receptor (TßR-I), and two members of the TGF-ß superfamily, transforming growth factor-ß3 (TGFß3) 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 TßR-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 TGFß3. 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.

Serological markers of autoimmunity in pregnant women with polycystic ovary syndrome: a pilot study.

BACKGROUND: 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. AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Prenatal Testosterone Exposure Disrupts Insulin Secretion And Promotes Insulin Resistance.

Hyperandrogenemia and metabolic disturbances during postnatal life are strongly linked both to polycystic ovary syndrome and other conditions that arise from prenatal exposure to androgen excess. In an animal model of this condition, we reported that insulin sensitivity (IS) was lower in young female sheep born to testosterone-treated mothers versus sheep born to non-exposed mothers (control). This lower insulin sensitivity remains throughout reproductive life. However, it is unknown whether abnormal postnatal levels of testosterone (T) further decrease IS derived from prenatal exposure to testosterone. Therefore, we assessed the effects of an acute testosterone administration (40 mg) on IS and insulin secretion during an intravenous glucose tolerance test performed at 40 weeks of age (adulthood) in previously ovariectomized sheep at 26 weeks of age (prepuberty), that were either prenatally exposed to testosterone (T-females, n = 6) or not (C-females, n = 6). The incremental area under the curve of insulin was greater in C-females both with or without the acute testosterone treatment (P < 0.05). The ISI-Composite was lower after an acute testosterone treatment, only in T-females. We conclude that prenatal exposure to testosterone disrupts pancreatic insulin secretion in response to glucose and that in this setting further hyperandrogenemia may predispose to lower insulin sensitivity.

DNA methylation in promoter regions of genes involved in the reproductive and metabolic function of children born to women with PCOS.

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

Cardiometabolic health in offspring of women with PCOS compared to healthy controls: a systematic review and individual participant data meta-analysis.

BACKGROUND: Women diagnosed with polycystic ovary syndrome (PCOS) suffer from an unfavorable cardiometabolic risk profile, which is already established by child-bearing age. OBJECTIVE AND RATIONALE: The aim of this systematic review along with an individual participant data meta-analysis is to evaluate whether cardiometabolic features in the offspring (females and males aged 1-18 years) of women with PCOS (OPCOS) are less favorable compared to the offspring of healthy controls. SEARCH METHODS: PubMed, Embase and gray literature databases were searched by three authors independently (M.N.G., M.A.W and J.C.) (last updated on 1 February 2018). Relevant key terms such as 'offspring' and 'PCOS' were combined. Outcomes were age-specific standardized scores of various cardiometabolic parameters: BMI, blood pressure, glucose, insulin, lipid profile and the sum scores of various cardiometabolic features (metabolic sum score). Linear mixed models were used for analyses with standardized beta (ß) as outcome. OUTCOMES: Nine relevant observational studies could be identified, which jointly included 1367 children: OPCOS and controls, originating from the Netherlands, Chile and the USA. After excluding neonates, duplicate records and follow-up screenings, a total of 885 subjects remained. In adjusted analyses, we observed that OPCOS (n = 298) exhibited increased plasma levels of fasting insulin (ß = 0.21(95%CI: 0.01-0.41), P = 0.05), insulin-resistance (ß = 0.21(95%CI: 0.01-0.42), P = 0.04), triglycerides (ß = 0.19(95%CI: 0.02-0.36), P = 0.03) and high-density lipoprotein (HDL)-cholesterol concentrations (ß = 0.31(95%CI: 0.08-0.54), P < 0.01), but a reduced birthweight (ß = -116(95%CI: -195 to 38), P < 0.01) compared to controls (n = 587). After correction for multiple testing, however, differences in insulin and triglycerides lost their statistical significance. Interaction tests for sex revealed differences between males and females when comparing OPCOS versus controls. A higher 2-hour fasting insulin was observed among female OPCOS versus female controls (estimated difference for females (ßf) = 0.45(95%CI: 0.07 to 0.83)) compared to the estimated difference between males ((ßm) = -0.20(95%CI: -0.58 to 0.19)), with interaction-test: P = 0.03. Low-density lipoprotein-cholesterol differences in OPCOS versus controls were lower among females (ßf = -0.39(95%CI: -0.62 to 0.16)), but comparable between male OPCOS and male controls (ßm = 0.27(95%CI: -0.03 to 0.57)), with interaction-test: P < 0.01. Total cholesterol differences in OPCOS versus controls were also lower in females compared to the difference in male OPCOS and male controls (ßf = -0.31(95%CI: -0.57 to 0.06), ßm = 0.28(95%CI: -0.01 to 0.56), interaction-test: P = 0.01). The difference in HDL-cholesterol among female OPCOS versus controls (ßf = 0.53(95%CI: 0.18-0.88)) was larger compared to the estimated mean difference among OPCOS males and the male controls (ßm = 0.13(95%CI: -0.05-0.31), interaction-test: P < 0.01). Interaction test in metabolic sum score revealed a significant difference between females (OPCOS versus controls) and males (OPCOS versus controls); however, sub analyses performed in both sexes separately did not reveal a difference among females (OPCOS versus controls: ßf = -0.14(95%CI: -1.05 to 0.77)) or males (OPCOS versus controls: ßm = 0.85(95%CI: -0.10 to 1.79)), with P-value < 0.01. WIDER IMPLICATIONS: We observed subtle signs of altered cardiometabolic health in OPCOS. Therefore, the unfavorable cardiovascular profile of women with PCOS at childbearing age may-next to a genetic predisposition-influence the health of their offspring. Sensitivity analyses revealed that these differences were predominantly observed among female offspring aged between 1 and 18 years. Moreover, studies with minimal risk of bias should elucidate the influence of a PCOS diagnosis in mothers on both sexes during fetal development and subsequently during childhood.

Long-term testosterone treatment during pregnancy does not alter insulin or glucose profile in a sheep model of polycystic ovary syndrome.

The administration of testosterone to pregnant sheep to resemble fetal programming of the polycystic ovary syndrome could alter other hormones/factors of maternal origin with known effects on fetal growth. Hence, we studied the weekly profile of insulin, progesterone and glucose during a treatment with testosterone propionate given biweekly from weeks 5 to 17 of pregnancy (term at 21 weeks) and checked the outcome of their fetuses at 17 weeks of gestation after C-section. Control dams were only exposed to the vehicle of the hormone. The testosterone administration did not cause any significant change in the maternal weekly profile of insulin, progesterone or glucose concentration, although the plasma levels of testosterone in the treated dams were inversely correlated to the levels of progesterone. Testosterone treatment also induced an inverse correlation between mean maternal insulin levels and fetal insulin levels; however, the fetal zoometric parameters, body weight, or insulin levels did not differ between exposed and not exposed fetuses. Therefore, treatment with testosterone during pregnancy does not cause significant impact on insulin levels in the mother, leading to less effect on the programming of fetal growth.

Higher luteinizing hormone levels associated with antimüllerian hormone in postmenarchal daughters of women with polycystic ovary syndrome.

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

Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome.

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

Prenatal testosterone excess reduces sperm count and motility.

The reproductive system is extremely susceptible to insults from exposure to exogenous steroids during development. Excess prenatal testosterone exposure programs neuroendocrine, ovarian, and metabolic deficits in the female, features seen in women with polycystic ovary disease. The objective of this study was to determine whether prenatal testosterone excess also disrupts the male reproductive system, using sheep as a model system. The extent of reproductive disruption was tested by assessing sperm quantity and quality as well as Leydig cell responsiveness to human chorionic gonadotropin. Males born to mothers treated with 30 mg testosterone propionate twice weekly from d 30 to 90 and with 40 mg testosterone propionate from d 90 to 120 of pregnancy (T-males) showed a significant reduction (P < 0.05) in body weight, scrotal circumference, and sperm count compared with control males. Mean straight line velocity of sperms was also lower in T-males (P < 0.05). Circulating testosterone levels in response to the human chorionic gonadotropin did not differ between groups. These findings demonstrate that exposure to excess testosterone during fetal development has a negative impact on reproductive health of the male offspring, raising concerns relative to unintended human exposure to steroidal mimics in the environment.

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.

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.

Enlarged adipocytes in subcutaneous adipose tissue associated to hyperandrogenism and visceral adipose tissue volume in women with polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is an androgen excess disorder associated with obesity and adipose tissue disturbances. Our aim was to evaluate gene expression of adipocytokines and adipocyte characteristics in abdominal subcutaneous adipose tissue (SAT) of PCOS women. DESIGN: Twelve PCOS (PCOSw) and 12 control (Cw) premenopausal women (BMI 20-35 kg/m2) were included, with measurements of whole-body composition assessed by dual-energy X-ray absorptiometry, and abdominal subcutaneous and visceral adipose tissue (VAT) volume, by magnetic resonance imaging. An oral glucose tolerance test was performed with measurements of glucose and insulin, and sex steroids, lipid profile and serum adipocytokines were determined in the fasting sample. Adipocytokine gene expression, mean adipocyte area and macrophage infiltration were evaluated in SAT biopsies. RESULTS: Both groups were comparable in age and BMI. Trunk fat mass amount (p = .043), serum and SAT leptin/adiponectin ratio (p = .034 and p = .028, respectively) and adipocyte area (p = .015) were higher in PCOSw compared to Cw. Interestingly, trunk fat mass was positively correlated with adipocyte area in PCOSw (r = 0.821, p = .023), while the inverse correlation was found in Cw (r = -0.786, p = .021). Only in PCOSw, adipocyte area was positively correlated with serum testosterone (r = 0.857, p = .014) and visceral adipose tissue volume (r = 0.857, p = .014). CONCLUSIONS: Our results indicate that PCOS women present adipose tissue dysfunction in the subcutaneous compartment, characterized by an alteration in adipocyte size and leptin/adiponectin expression and secretion, probably associated with higher androgen concentrations.

Anti-Müllerian hormone levels in peripubertal daughters of women with polycystic ovary syndrome.

CONTEXT: 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. OBJECTIVE: 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. DESIGN: 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. RESULTS: 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). CONCLUSIONS: 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.