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Laboratory of Animal Physiology and Endocrinology (S.E.R., P.R.), Faculty of Veterinary Medicine, University of Concepción, Chillán 3801061, Chile; and Laboratory of Endocrinology and Metabolism West Division (M.M., B.E., T.S.-P.) and Institute of Maternal and Child Research (R.S., R.R., E.C., F.C.), School of Medicine, University of Chile, Santiago 8360160, Chile
Address all correspondence and requests for reprints to: Prof. T. Sir-Petermann, Laboratory of Endocrinology, Department of Medicine West Division, School of Medicine, Las Palmeras 299, Interior Quinta Normal, Casilla 33052, Correo 33, Santiago, Chile. E-mail: tsir{at}med.uchile.cl.
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Abstract |
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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.
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Introduction |
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In view of the high prevalence of affected individuals within families of PCOS women, a genetic basis for this syndrome has been suggested (15). This has been evaluated in different populations (16) through phenotypic and family aggregation studies. These studies have demonstrated that a significant number of female relatives are affected with this condition (17, 18, 19, 20, 21, 22, 23, 24). However, the male phenotype of PCOS is not well defined, so it has been difficult to establish whether male relatives are also affected. Multiple possible phenotypes have been proposed including increased hair growth (15), abnormalities in male hair distribution such as premature male balding (18, 25), and metabolic abnormalities such as insulin resistance (26, 27). Insulin resistance appears to have a genetic basis, because the abnormality is perpetuated in tissue culture (26, 28). Therefore, it is possible that a proportion of the males in an affected family with PCOS might also manifest insulin resistance.
In previous studies, we demonstrated that parents and brothers of PCOS women exhibit insulin resistance and related metabolic defects more often than control subjects (29, 30). Recently, Yildiz et al. (31) reported that first-degree relatives of women with PCOS have more insulin resistance and glucose intolerance than control subjects. On the other hand, it has been proposed that PCOS has an environmental component and that intrauterine life, as an environmental factor, is implicated in the origin of PCOS (32, 33). Therefore, intrauterine life may affect the endocrine/metabolic function of a child born to a PCOS mother, independent of genetic inheritance and sex. However, no studies have evaluated the metabolic characteristics of sons of women with PCOS from the early stages of sexual development into adulthood to establish whether metabolic abnormalities are present and, if so, the stage of life at which they develop.
Therefore, the aim of the present study was to assess the metabolic profiles in sons of women with PCOS during three different stages of life: early infancy (2–3 months), childhood (4–7 yr), and adulthood (18–30 yr).
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Subjects and Methods |
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We studied 80 boys (20 infants, 31 children, and 29 adults) born to PCOS mothers [PCOS sons (PCOSS]. As a control group, we included 56 boys (20 infants, 17 children, and 19 adults) born to mothers with regular menses and without hyperandrogenism [control sons (CS)]. The PCOSS and CS were matched for age.
PCOS mothers were recruited from patients attending the Unit of Endocrinology and Reproductive Medicine at the University of Chile. This group of PCOS mothers is part of an unselected group of patients that has attended our clinic because they were diagnosed with PCOS. Diagnosis of PCOS was made according to the National Institutes of Health consensus criteria (34). PCOS women were evaluated before pregnancy, and they exhibited chronic oligomenorrhea or amenorrhea, hirsutism, serum testosterone more than 0.6 ng/ml and/or free androgen index more than 5.0, and androstenedione more than 3.0 ng/ml. In addition, PCOS women showed the characteristic ovarian morphology of PCO on ultrasound, based on the criteria described by Adams et al. (35). PCOS women were normoglycemic, with varying degrees of hyperinsulinemia that were evaluated by an oral glucose tolerance test. All patients had an elevated waist-to-hip ratio, greater than 0.85. We excluded patients with hyperprolactinemia, androgen-secreting neoplasms, Cushing’s syndrome, and late-onset 21-hydroxylase deficiency as well as thyroid disease.
All PCOSS were born at term after spontaneous conceptions that led to singleton pregnancies. The prevalence of gestational diabetes for PCOS mothers, according to the World Health Organization criteria (36), was 17.5%, and the incidence of pregnancy-induced hypertension was 13.6%. In addition, 57.5% of PCOS patients and 42.8 of control mothers were primiparous.
As control mothers, we selected 56 women of similar socioeconomic level as the PCOS patients, with a history of singleton pregnancies, regular 28- to 32-d menstrual cycles, absence of hirsutism and other manifestations of hyperandrogenism, and no history of infertility or pregnancy complications.
There were no siblings included in the groups studied.
The protocol was approved by the institutional review boards of the San Juan de Dios and San Borja Arriarán Hospitals and the University of Chile. All parents and boys older than 8 yr signed an informed consent before entering the study.
Study protocol
Infants and children were admitted with their mothers to the pediatric unit of our Clinical Research Center at approximately 0830 h. We performed a complete physical examination on each boy, including anthropometric measurements [weight, height, waist, hip, BMI, and BMI SD score (SDS) calculated by the Growth Analyzer Program using the U.S. Growth Charts BMI for age). Adult males were admitted to our Clinical Research Center at approximately 0830 h, and we obtained a clinical history and performed a complete physical examination, including anthropometric measurements.
In children and adults, after a 12-h overnight fast, an oral glucose tolerance test (1.75 g/kg, up to a maximum of 75 g glucose in 250 ml water) was performed. In children, blood samples (5 ml) were obtained at baseline and 120 min after glucose administration. In adults, blood was withdrawn before and 30, 60, 90, and 120 min after the glucose load. In infants, a blood sample (3 ml) was obtained in the fasting state. Serum glucose and insulin were determined in each sample. Circulating concentrations of adiponectin, leptin, C-reactive protein (CRP), SHBG, and serum lipids were determined in the fasting sample.
Assays
Serum glucose was determined by the glucose oxidase method (Photometric Instrument 4010; Roche, Basel, Switzerland). The intraassay coefficient of variation of this method was less than 2.0%. The lipid profile was determined by standard colorimetric assays (Photometric Instrument 4010). Serum low-density lipoprotein (LDL)-cholesterol concentration was calculated by Friedewald’s formula [LDL-cholesterol = total cholesterol – high-density lipoprotein (HDL)-cholesterol – (triglycerides/5)].
Serum adiponectin was assayed by RIA (Linco Research Inc., St. Charles, MO) with a sensitivity of 1.0 ng/ml and intra- and interassay coefficients of variation of 1.8 and 9.0%, respectively. Leptin concentrations were measured by RIA (Linco) with a sensitivity of 0.5 ng/ml and intra- and interassay coefficients of variation of 3.9 and 4.7%, respectively. CRP concentrations were determined by an ultrasensitive immunoturbidimetric assay (CRP Latex HS; Roche Diagnostics, Mannheim, Germany) with a sensitivity of 0.03 mg/liter and intra- and interassay coefficients of variation of 1.3 and 5.7%, respectively. Serum insulin was assayed by RIA (Diagnostic Systems Laboratories, Inc., Webster, TX). The intra- and interassay coefficients of variation were 5 and 8%, respectively. SHBG was determined by radioimmunometric assay (Diagnostic Products Corp., Los Angeles, CA) with intra- and interassay coefficients of variation of 3.8 and 7.9%, respectively.
Data analysis
The measurements derived from the oral glucose tolerance test included the following: 1) serum fasting glucose, serum fasting insulin, and homeostatic model assessment for insulin resistance (HOMA-IR) (37); 2) serum 2-h glucose and insulin; 3) whole-body insulin sensitivity index (ISI) composite (38); 4) serum lipid profile, total cholesterol, triglycerides, LDL-cholesterol, and HDL-cholesterol; and 5) serum adiponectin, leptin, CRP, and SHBG.
Statistical evaluation
Data are expressed as median and range. Normal distribution was assessed by the Kolmogorov-Smirnov test. Differences between study groups were assessed with the Student’s t test when data were normally distributed or Mann-Whitney U test when not normally distributed. The effect of body weight or BMI on continuous variables was evaluated using multivariate analysis (multiple linear regression techniques). Spearman correlations analysis was used to evaluate the relationship among the variables of interest. Statistical analysis was performed with STATA 7.0 package. A P value of <0.05 was considered to be statistically significant.
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Results |
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. Control mothers were comparable in age with PCOS mothers in the three study periods. At the time when their sons were evaluated, PCOS mothers were more obese than control mothers of infants and children. Regarding pregnancy history, gravity and parity were similar between control mothers and PCOS mothers. BMI at term of pregnancy was significantly higher in PCOS mothers of children compared with control mothers. Gestational age and birth weight were similar between newborns of PCOS mothers and of control mothers in the three groups studied. There were no small for gestational age newborns (<2.0 SD of weight) in the PCOS groups or the control groups. However, a small number of large for gestational age children (>2.0 SD of weight) was observed only in the PCOS groups (two in the infant group; two in the childhood group, and one in the adult group). The correlation between the weight of the mothers at term of pregnancy and the weight of their sons at time of study was evaluated. A positive correlation between the weight of the PCOS mothers at term of pregnancy and the weight of the sons was observed during childhood (r = 0.440; P = 0.02) and adulthood (r = 0.637; P = 0.001). Moreover, during childhood, there was a positive correlation between BMI of the mothers and BMI of their sons in the PCOS group (r = 0.425; P = 0.02).
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. During early infancy, PCOSS showed a greater weight (P = 0.038) and weight SDS (P = 0.031) than CS. Serum glucose, insulin, HOMA-IR, and lipids were similar in both groups. Adiponectin, leptin, SHBG, and CRP protein serum concentration were also similar in both groups.
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). Adiponectin, leptin, CRP serum concentration, and SHBG were not different between groups.
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). Adiponectin, leptin, and CRP serum concentration were not different between groups. SHBG serum concentrations tended to be lower in PCOSS compared with CS (P = 0.067).
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Discussion |
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In the present study, PCOSS exhibited a higher body weight than CS. During early infancy and childhood, PCOSS showed higher weight and weight SDS than CS but no other metabolic changes were observed after the data were corrected by BMI. Finally, during adulthood, insulin resistance was present independent of body weight, indicating that sons of PCOS women showed an abnormal metabolic profile that was more evident as the subjects became older.
Interestingly, an increased body weight during infancy was the earliest sign that was observed in our PCOSS and persisted during the different stages of life. This may represent an important finding that may underscore the crucial role of early excess weight gain in the development of metabolic changes in these boys. As mentioned previously, approximately 50% of PCOS women are overweight or obese, and most of them exhibit an abdominal phenotype (4, 5). It has been proposed that obesity may play a pathogenetic role in the development of this syndrome in susceptible individuals (4, 39, 40). It is possible that a similar phenomenon occurs in the sons of PCOS women.
The origin of obesity in these boys is probably the consequence of several factors, which include genetic susceptibility, environmental factors, and eating habits. In this regard, it is interesting to point out that PCOS mothers were more obese than control mothers at the time when these boys were evaluated. In addition, we have demonstrated that during pregnancy, PCOS mothers are more obese and exhibit an altered metabolic profile with high insulin and low adiponectin levels (41). Moreover, in the present study, a positive correlation between the weight of the PCOS mother at term of pregnancy and the weight of their sons was observed in children and adults Therefore, prenatal environmental factors and/or abnormal eating habits of the mother may be important for promoting weight gain. On the other hand, sisters of PCOS patients have higher BMI than sisters of normal women, suggesting a genetic component for PCOS-associated obesity in these subjects (22).
Considering that numerous studies confirm that childhood obesity is associated with insulin resistance, hyperinsulinemia, and an increased risk of developing diabetes, PCOSS constitute a high risk group for metabolic abnormalities. Interventions aimed at reducing body fat through dietary modifications and exercise are likely to improve insulin resistance, reducing the risk of developing type 2 diabetes and cardiovascular disease, similar to what has been proposed for women with PCOS (42).
Several studies have reported a high prevalence of insulin resistance in PCOS women. Few studies, however, have systematically examined possible metabolic abnormalities in male relatives of PCOS women, and none have included a concurrently studied control group. The present study demonstrates for the first time that adult sons of women with PCOS exhibit insulin resistance according to ISI composite values, independent of body weight. Several methods have been proposed to evaluate insulin sensitivity from data obtained by the oral glucose tolerance test. Most of them rely on the ratio of plasma glucose to insulin concentrations during the oral glucose tolerance test. In the present study, we chose two methods, HOMA-IR (37) and ISI composite (38). Fasting plasma glucose, fasting plasma insulin, and HOMA-IR index are poor predictors of insulin resistance and glucose intolerance in young subjects or in studies where a small number of subjects are included (43, 44). In the case of the ISI composite, basal and poststimulated values of glucose and insulin are integrated, differing from HOMA-IR, which considers only the fasting values of glucose and insulin. Therefore, ISI composite offers more advantages than HOMA-IR and is a better method to assess individual insulin resistance in young subjects (45). After the data were adjusted by BMI, ISI composite was the only measurement of insulin resistance that persisted as significantly different between control and PCOSS during adulthood. However, we were not able to assess insulin resistance by more sensitive methods to establish whether insulin resistance is present since childhood, because multiple blood sampling at this age was not possible.
The presence of insulin resistance in adult sons of PCOS women is a novel finding, which suggests that insulin resistance may constitute part of the male PCOS phenotype, as previously proposed (27). Our findings confirm the results of Norman et al. (26), who proposed that hyperinsulinemia may be an important marker of the condition in family members of PCOS patients. Insulin resistance is central to the pathogenesis of both type 2 diabetes and PCOS, with a strong genetic basis and important implications for the management of both disorders. Insulin resistance and hyperinsulinemia are common precursors of impaired glucose tolerance and type 2 diabetes (46, 47). In this context, the presence of insulin resistance in early-adulthood sons of women with PCOS could be the first step in the development of type 2 diabetes. Therefore, its detection and the employment of therapeutic tools might be useful for the prevention of this disorder.
It is difficult, however, to establish whether insulin resistance in PCOSS is a genetic trait, the result of fetal programming, or both. There are relatively few studies studying this hypothesis in males. Recently, we have demonstrated that female sheep treated prenatally with testosterone exhibited reduced birth weight and impaired insulin sensitivity in early postnatal life (48). In adult male rhesus monkeys treated prenatally with testosterone, a similar phenomenon was observed (49). On the other hand, in humans, we demonstrated a significant increase in androgen concentrations during pregnancy in PCOS women, suggesting that these androgens could provide a potential source of androgen excess for the fetus (50). In sum, it is possible that prenatal androgen excess may influence insulin sensitivity in the offspring of PCOS mothers, which may act in concert with an inherited genetic predisposition for a reduced insulin sensitivity in these patients.
Other metabolic variables measured in the present study, such as leptin, adiponectin, CRP, and SHBG, were similar in both groups. Recently, we observed that normal weight prepubertal daughters of PCOS women showed significantly lower concentrations of adiponectin and higher levels of poststimulated insulin compared with control daughters (51). Normal-weight pubertal PCOS daughters exhibited higher levels of triglycerides and poststimulated insulin and lower levels of SHBG compared with controls, suggesting that some metabolic features of PCOS are also present in these girls (51). However, in comparison with the data of the present study, some interesting differences were observed. The boys were relatively more obese than the girls, and surrogate markers of insulin resistance such as circulating concentrations of adiponectin and SHBG were affected in girls but not in boys. It is possible that gender differences and body weight may partly explain these differences. However, based on our studies, we should point out that both daughters and sons of PCOS women appear to constitute high-risk groups for possible metabolic derangements.
In conclusion, our results suggest that some of the metabolic alterations described in PCOS women are present in their sons. In addition, sons of PCOS women exhibit higher body weight since early life. In addition, insulin resistance became evident as the subjects got older. We propose that insulin resistance may be part of the male PCOS phenotype and that this metabolic feature should be investigated in males born to PCOS mothers.
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Acknowledgments |
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Footnotes |
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This work was presented in part at the 46th meeting of the European Society for Pediatric Endocrinology (ESPE), Helsinki, 2007.
Disclosure Statement: S.E.R., R. S., R.R., M.M., B.E., E.C., P.R., and T.S-P. have nothing to disclose. F.C. has received lecture fees from Pfizer and Novo-Nordisk.
First Published Online January 29, 2008
Abbreviations: CRP, C-reactive protein; CS, control sons; HOMA-IR, homeostatic model assessment for insulin resistance; ISI, insulin sensitivity index; PCOS, polycystic ovary syndrome; PCOSS, PCOS sons; SDS, SD score.
Received October 9, 2007.
Accepted January 23, 2008.
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