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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 10 4682-4688
Copyright © 2003 by The Endocrine Society

Early Endocrine, Metabolic, and Sonographic Characteristics of Polycystic Ovary Syndrome (PCOS): Comparison between Nonobese and Obese Adolescents

Miriam E. Silfen, Michelle R. Denburg, Alexandra M. Manibo, Rogerio A. Lobo, Richard Jaffe, Michel Ferin, Lenore S. Levine and Sharon E. Oberfield

Department of Pediatrics, Division of Pediatric Endocrinology (M.E.S., M.R.D., A.M.M., L.S.L., S.E.O.), and Department of Obstetrics and Gynecology (R.A.L., R.J., M.F.), Columbia University, College of Physicians and Surgeons, New York, New York 10032

Address all correspondence and requests for reprints to: Sharon E. Oberfield, M.D., Columbia University, College of Physicians and Surgeons, Division of Pediatric Endocrinology, 630 West 168th Street, PH 5 East-522, New York, New York 10032. E-mail: seo8{at}columbia.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Approximately half of all women with polycystic ovary syndrome (PCOS) are overweight or obese, and studies have reported endocrine and metabolic differences between lean and obese women with PCOS. PCOS has not been as extensively investigated in the adolescent population.

The objectives of our study were to further characterize early endocrine and metabolic alterations in adolescents with PCOS and to determine whether differences between nonobese and obese women with PCOS are present early in its course.

We studied an ethnically heterogeneous group of 48 adolescents: 11 nonobese with PCOS [age, 16.1 ± 1.9 yr; body mass index (BMI), 22.5 ± 1.5 kg/m2], 22 obese with PCOS (age, 15.5 ± 1.4 yr; BMI, 35.9 ± 6.2 kg/m2), and 15 obese controls (age, 14.4 ± 1.5 yr; BMI, 35.8 ± 7.1 kg/m2). Fasting levels of glucose, insulin, proinsulin, hemoglobin A1c, testosterone, SHBG, {Delta}4-androstenedione ({Delta}4-A), dehydroepiandrosterone sulfate (DHEAS), LH, FSH, IGF-I, IGF binding protein-1, free IGF-I, and lipids were measured. Six of the 11 nonobese PCOS subjects, 11 of the 22 obese PCOS subjects, and six of the 15 controls underwent standard oral glucose tolerance testing. The insulin response to the oral glucose tolerance test was measured by the insulin area under the curve (IAUC120). Measures of insulin sensitivity were calculated as the fasting glucose to insulin ratio, quantitative insulin sensitivity check index, and composite insulin sensitivity index.

The nonobese adolescents with PCOS demonstrated higher levels of LH, SHBG, {Delta}4-A, DHEAS, dihydrotestosterone, free IGF-I, and high-density lipoprotein, and lower low-density lipoprotein, compared with the obese PCOS group. Fasting levels of insulin and proinsulin, IAUC120, and log IAUC120 were higher, and the fasting glucose to insulin ratio, quantitative insulin sensitivity check index, and composite insulin sensitivity index were lower in the obese compared with the nonobese PCOS subjects. Greater levels of LH and androgens, including total and free testosterone, {Delta}4-A, and DHEAS, and lower SHBG levels were found in the obese PCOS group compared with the obese controls.

Adolescents with PCOS manifest clinical, metabolic, and endocrine features similar to those of adult women, and differences between nonobese and obese women with PCOS may be detected in adolescence. Our findings indicate a more pronounced alteration in the hypothalamo-pituitary-adrenal axis in nonobese adolescents with PCOS and a more marked dysregulation of insulin levels and impairment of insulin sensitivity in their obese counterparts. Our data also suggest differences in the IGF system between nonobese and obese adolescents with PCOS.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARY SYNDROME (PCOS) is the most common endocrinopathy in women, present in 5–7% of women of reproductive age. PCOS is characterized by hyperandrogenism and chronic anovulation, and its morbidity may include hyperinsulinemia, insulin resistance, early onset of type 2 diabetes mellitus (DM), dyslipidemia, cardiovascular disease, and infertility (1, 2, 3, 4, 5). Women with PCOS demonstrate marked clinical heterogeneity; the commonly associated features of hirsutism, acne, polycystic-appearing ovaries, obesity, and acanthosis nigricans are neither uniform nor universal (6, 7).

Approximately half of all women with PCOS are overweight or obese (8). Several studies have reported endocrine and metabolic differences between lean and obese women with PCOS. These studies have demonstrated, in addition to alterations in insulin sensitivity that were independent of obesity (9, 10, 11, 12), more marked hyperinsulinemia and insulin resistance, relative hyperglycemia, and lower SHBG in the obese compared with lean women with PCOS (7, 13, 14, 15, 16, 17, 18, 19, 20). Obesity has been shown to be an independent predictor of conversion to impaired glucose tolerance or type 2 DM in women with PCOS (21). Obese women with PCOS were found to have similar levels of IGF-I and IGF-binding protein 3 (IGFBP-3), but lower IGFBP-1, decreased GH pulse amplitude, a blunted response to GH-releasing hormone, and elevated GH-binding protein compared with their lean counterparts (13, 14). Although a similarly increased LH pulse frequency has been reported in both lean and obese PCOS, an attenuated LH pulse amplitude has been noted in obese women (13, 22). Some studies have also detected differences in lipid profile in obese compared with lean women with PCOS, with elevated triglycerides and lower high-density lipoprotein (HDL) cholesterol being the most consistently described (7, 14, 17, 19).

The etiology of PCOS remains unclear. The syndrome is often perimenarcheal in onset, and similarities between the physiological changes of puberty and the pathological features of PCOS have been noted, such as the hyperpulsatile gonadotropin secretion, increased ovarian and adrenal steroidogenesis, menstrual irregularity, reduced levels of SHBG and IGFBP-1, hyperinsulinemia, and insulin resistance that develop in both conditions (23, 24, 25). Decreased levels of SHBG, hyperinsulinemia, insulin resistance, and unfavorable lipid profiles have also been demonstrated in prepubertal girls with premature adrenarche (PA) and pubertal girls with a history of PA, a condition that may herald the later development of anovulation and functional ovarian hyperandrogenism, including PCOS (26, 27, 28, 29, 30, 31). Nonetheless, PCOS has not been as extensively investigated in the adolescent population. Studies have demonstrated disturbances in insulin sensitivity and insulin secretion early in the course of PCOS and indicate that similar to their adult counterparts, both lean and obese adolescent girls with PCOS are at increased risk for impaired glucose tolerance and DM (32, 33, 34, 35, 36). Decreased SHBG and IGFBP-1 levels and abnormalities of LH secretion, similar to those observed in adults with PCOS, have also been reported in adolescent girls with hyperandrogenism and PCOS, and a recent study found amplified GH secretion in nonobese adolescents with PCOS (37, 38, 39, 40).

The primary objectives of our study were to further characterize early endocrine and metabolic alterations in adolescents with PCOS and to determine whether differences between nonobese and obese women with PCOS are present early in its course. We sought to thereby gain insight into possible pathogenetic differences between nonobese and obese subgroups of women with PCOS and its resultant clinical heterogeneity.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

We studied 48 subjects: 11 nonobese and 22 obese adolescents with PCOS and 15 obese controls. For the PCOS subjects, the criteria for entry into the study were the presence of hyperandrogenism [free testosterone > 6.3 pg/ml, testosterone > 55 ng/dl, {Delta}4-androstenedione ({Delta}4-A) > 245 ng/dl, and/or dehydroepiandrosterone sulfate (DHEAS) > 248 µg/dl] and oligomenorrhea or amenorrhea (41). All subjects were euthyroid without hyperprolactinemia or evidence of an adrenal enzyme defect, established by either normal morning 17-hydroxyprogesterone or ACTH stimulation testing. The criteria for entry into the obese control group included regular menses and the absence of hyperandrogenism. None of the subjects was taking any medications known to affect hormone, lipid, or insulin levels at the time of the study. Obesity was defined as a body mass index (BMI) greater than the 85th percentile for age and sex, based on 1 SD reference data from the National Health and Nutrition Examination Survey (NHANES) I (42). All obese subjects had BMI values greater than 25 kg/m2, whereas all nonobese subjects had BMI values less than 25 kg/m2. The degree of hirsutism was quantified using the Ferriman-Gallwey (F-G) score (43). All subjects were examined for the presence of acanthosis nigricans. Clinical characteristics of the subjects are presented in Table 1Go. Informed consent was obtained from a legal guardian of each subject less than 18 yr of age and from those subjects 18 yr or older before participation in the study. Assent from subjects less than 18 yr of age was also obtained before their participation in the study. The study was approved by the Institutional Review Board (IRB) of the Columbia-Presbyterian Medical Center.


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  		TABLE 1. Clinical characteristics

 
Procedures

Basal levels of glucose (G0), insulin (I0), proinsulin (P0), IGF-I, free IGF-I, IGFBP-1, DHEAS, {Delta}4-A, SHBG, testosterone, free testosterone, dihydrotestosterone (DHT), LH, FSH, hemoglobin A1c (HgbA1c), and lipids were measured in all subjects after an overnight fast. Six of 11 nonobese PCOS subjects, 11 of 22 obese PCOS subjects, and six of 15 controls underwent a standard 1.75 g/kg body weight (maximum 75 g) oral glucose tolerance test (OGTT). Not all subjects underwent OGTT because our original IRB application did not include this procedure. Therefore, the first 23 patients were not offered the OGTT. Of the remaining 25 patients, two patients refused OGTT. Before and 30, 60, 90, and 120 min after the ingestion of oral glucose, blood was sampled for plasma glucose and serum insulin and proinsulin levels. Transabdominal pelvic sonography was performed on all of the 11 nonobese and 20 of the 22 obese PCOS subjects and 13 of 15 controls.

Measures of insulin sensitivity and hyperinsulinemia

The fasting plasma glucose was divided by the fasting serum insulin to calculate the fasting glucose to insulin ratio (FGIR), a measure that has been validated in obese, white PCOS women using the oral and frequently sampled iv glucose tolerance tests and in obese adolescents with PCOS using the hyperinsulinemic-euglycemic clamp (32, 44). The quantitative insulin sensitivity check index (QUICKI) and the composite whole-body insulin sensitivity index [ISI(composite)], both previously validated against the euglycemic insulin clamp, were also calculated (45, 46). QUICKI was calculated as 1/(log I0 + log G0), and ISI(composite) was calculated according to the following formula: 10,000/square root of [(G0) (I0) (mean serum insulin during OGTT) (mean blood glucose during OGTT)]. The insulin area under the curve (IAUC120) was calculated using the trapezoidal rule (47).

Assays

Insulin (by immunochemiluminometric assay), IGF-I, IGFBP-1, DHEAS, {Delta}4-A, testosterone, free testosterone, DHT, SHBG, FSH, LH, and HgbA1c levels were measured by Esoterix Endocrinology (Calabasas Hills, CA). Plasma glucose levels were assayed by the glucose hexokinase method. Plasma total cholesterol, HDL cholesterol, and triglycerides were measured using the Hitachi analyzer in the Core Laboratory of the General Clinical Research Center (GCRC) at Columbia-Presbyterian Medical Center. Low-density lipoprotein (LDL) cholesterol was calculated according to the Friedewald formula (48). Free IGF-I levels were determined using a two-site immunoradiometric assay (Diagnostic Systems Laboratories, Inc., Webster, TX). The intra- and interassay coefficients of variation were 6.5 and 12.5% respectively. A single assay was performed to include all of the samples in triplicate.

Data analysis

Comparisons between groups on continuous measures were made using the Student’s t test with an F test to determine the equality of two sample variances. Comparisons between groups on nominal measures used Fischer’s exact test. The IAUC120 in response to glucose challenge was log-transformed to normalize the distribution of the data. Results are reported as the mean ± SD unless otherwise noted. P values < 0.05 were considered to represent statistical significance.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical and sonographic characteristics

The nonobese and obese PCOS groups were comparable in age (Table 1Go). The obese controls were slightly younger than the obese PCOS subjects, but this difference, although statistically significant, was not clinically relevant. The mean BMI was virtually identical in the two obese study groups. The mean age at menarche was similar in all groups. In terms of ethnicity, the groups included white, Hispanic, and non-Hispanic black subjects, with some variation in the representations among the groups. The PCOS groups had similar F-G scores, and the mean F-G score in the obese controls was lower than that of the obese PCOS group. Acanthosis nigricans was observed more commonly in the obese groups and was present in 36% of the nonobese PCOS group. A family history of adult-onset diabetes and/or cardiovascular disease was frequently elicited in all three study groups.

All of the nonobese and the majority of the obese subjects with PCOS had polycystic-appearing ovaries (PAO) on pelvic sonography, i.e. multiple peripherally oriented ovarian follicles, and the difference in frequency between the PCOS groups was not statistically significant (Table 2Go). Consistent with existing literature, some of the control subjects were also found to have PAO, although as expected, these subjects comprised a smaller proportion of the study group than in the PCOS groups (2, 49). No statistically significant differences were detected in mean ovarian volume.


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  		TABLE 2. Sonographic findings

 
Hormonal characteristics (Table 3Go)

The mean LH level was higher in the nonobese PCOS group compared with the obese PCOS group, whereas their mean FSH levels were comparable (Table 3Go). The PCOS groups had similar total and free testosterone levels, but the nonobese adolescents with PCOS demonstrated higher levels of {Delta}4-A, DHEAS, and DHT. The SHBG level was lower in the obese than in the nonobese PCOS group. As expected, higher mean levels of LH and androgens, including total and free testosterone, {Delta}4-A, and DHEAS, lower SHBG levels, and a trend toward elevated DHT were found in the obese PCOS group compared with the obese controls.


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  		TABLE 3. Hormonal characteristics

 
Lipid profiles (Table 4Go)

Lower LDL and higher HDL cholesterol was noted in the nonobese compared with the obese adolescents with PCOS. No differences in lipid levels were detected between the obese study groups.


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  		TABLE 4. Lipid profiles

 
IGF system

Total IGF-I was comparable in the three study groups (Table 5Go). Ten of 11 nonobese PCOS and all of the obese PCOS and control subjects had IGFBP-1 levels below the normal fasting range (10–150 ng/ml) (41), and a trend toward a less suppressed IGFBP-1 level was observed in the nonobese PCOS group. The mean free IGF-I level was significantly higher in the nonobese compared with the obese adolescents with PCOS.


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  		TABLE 5. IGF system

 
Glucose- and insulin-related parameters and measures of insulin sensitivity

Fasting glucose and HgbA1c levels were similar in the three study groups, and none of the subjects had impaired fasting glucose or diabetes (Table 6Go). Three of the 11 obese PCOS subjects who underwent glucose tolerance testing, but none of the nonobese PCOS or obese control subjects, demonstrated impaired glucose tolerance. I0 and P0 were significantly increased in the obese compared with the nonobese PCOS subjects. The obese adolescents with PCOS also demonstrated a greater insulin response to an oral glucose load (IAUC120, log IAUC120) compared with the nonobese PCOS group. All measures of insulin sensitivity, the FGIR, QUICKI, and ISI(composite), were significantly reduced in the obese group compared with the nonobese PCOS group. With the exception of a trend toward higher log IAUC120 in the obese PCOS subjects compared with the obese controls, no statistically significant differences in glucose- and insulin-related parameters or the measures of insulin sensitivity were detected between the two obese groups.


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  		TABLE 6. Glucose- and insulin-related parameters and measures of insulin sensitivity

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In our study, as anticipated, the sonographic finding of PAO was observed in most of the PCOS subjects. Of the 13 obese controls who had pelvic ultrasounds, 31% had PAO. The prevalence of PAO was somewhat higher than that reported (16–25%) in the general population; it is possible that some of these obese adolescents with PAO may evolve into the full syndrome, with obesity as a risk factor for its development (2, 49). These asymptomatic women without baseline hyperandrogenism may nonetheless demonstrate subclinical characteristics similar to those of PCOS, for example in response to GnRH-agonist testing (49). Mean ovarian volume did not differ between the nonobese and obese adolescents and was similar to volumes in adult women with PCOS, confirming previously reported results in women with PCOS (14, 15, 18, 19, 20). The mean ovarian volume was somewhat higher in the obese PCOS compared with the obese control group, although this difference was not statistically significant. The absence of this expected difference could be attributable in part to the degree of hyperinsulinemia observed in the control group. Although ovarian size has been shown to be largely dependent on LH, insulin has also been found to contribute to ovarian volume (23). The independent effects of LH and insulin on ovarian size could also explain the comparable ovarian volumes seen in the nonobese and obese PCOS groups, because the former had higher LH and the latter greater fasting and stimulated insulin levels.

We found differences in gonadotropin and androgen levels between nonobese and obese adolescents with PCOS. The elevated LH and comparable FSH levels of the nonobese compared with the obese PCOS group is consistent with prior reports in the adult population of attenuated LH pulse amplitude in obese PCOS. As has been hypothesized, the hyperinsulinemia in obese PCOS may be responsible for the diminished LH levels (7, 13, 22). Some studies have reported increased hyperandrogenism in obese compared with nonobese women with PCOS, as evidenced by a higher total and/or free testosterone or free androgen index, but comparable {Delta}4-A and DHEAS levels (17, 18, 20). Holte et al. (50) demonstrated significant positive interactions between obesity and PCOS on SHBG, testosterone, free androgen index, and DHEAS, but found that obesity counteracted the effect of PCOS on LH and {Delta}4-A. In our population of adolescents with PCOS, the nonobese subjects had higher mean levels of {Delta}4-A and DHEAS, but similar total and free testosterone, suggestive of increased adrenal hyperandrogenism. In addition, the concentration of DHT was shown to be higher in the nonobese than in the obese PCOS group, possibly indicating increased peripheral conversion of testosterone. The higher DHT levels also likely reflect the higher SHBG levels in the nonobese group, because DHT has a very high affinity for SHBG (51). Despite higher levels of DHT in the nonobese group, the degree of hirsutism was not different, which likely reflects the higher SHBG levels and/or relatively less sensitivity to DHT at the level of the skin (51). The obese PCOS group demonstrated greater suppression of SHBG than the nonobese group, confirming previous results in women with PCOS (7, 13, 15, 17, 18, 20). The low mean level in the nonobese PCOS group suggests that decreased SHBG, secondary to hyperandrogenism and/or hyperinsulinemia, is an early finding in PCOS.

Consistent with the diagnosis, the obese PCOS group had higher levels of total and free testosterone, {Delta}4-A, and DHEAS compared with BMI-matched controls. Elevated LH and reduced SHBG, characteristic alterations of PCOS, were also observed in the obese PCOS adolescents compared with the obese controls (1). The trend toward higher DHT in the obese PCOS group compared with the obese control group, despite lower SHBG levels, is consistent with the greater degree of hirsutism observed in the former and prior evidence of enhanced 5{alpha}-reductase activity in PCOS (52).

It has been suggested that obesity is often associated with a more atherogenic lipid profile in women with PCOS (8). Specifically, elevated triglycerides and lower HDL cholesterol comprise the most consistently reported alterations in obese compared with nonobese subgroups (7, 14, 17, 19). In this study, the obese adolescents with PCOS similarly demonstrated a more atherogenic lipid profile, with higher LDL and lower HDL cholesterol, than their nonobese counterparts. Although the comparable lipid levels in the two obese groups could be attributable to the small sample sizes, we speculate that abnormalities in fasting lipid levels may be a later finding of the disorder. In addition, dyslipidemia, although a complication of PCOS, is not a consistent feature of the disorder. Larger studies are needed to clarify whether dyslipidemia complicates PCOS in adolescence.

A dysregulation of the insulin/IGF system has been implicated in the pathophysiology of PA and PCOS. IGF-I and insulin have been shown to stimulate the proliferation of theca-interstitial cells (53) and to potentiate LH-stimulated androgen synthesis in these cells (54). In cultures of ovarian stromal tissue obtained from hyperandrogenic women, high concentrations of insulin alone induce androgen accumulation (55). Physiological levels of insulin and IGF-I also induce steroidogenic enzymes in cultured human adrenocortical cells (56, 57), and insulin and IGF-I have been shown to suppress production of SHBG in a human hepatoma cell line (58). Studies by Horton et al. (59) indicate that induction of 5{alpha}-reductase in skin may be mediated by IGF-I. Women with PCOS and girls with PA have reduced concentrations of IGFBP-1, and IGFBP-1 levels are inversely correlated with fasting serum insulin levels (27, 60, 61, 62, 63, 64). Elevated total IGF-I has been reported in prepubertal girls with PA (27), and in a small study of nonobese women with PCOS, levels of free IGF-I were shown to be elevated using a Sep-Pak extraction procedure (63). Thierry van Dessel et al. (64) demonstrated elevated free IGF-I levels, determined by the same immunoradiometric assay used in our study, in a cohort of both obese and nonobese PCOS subjects. Our group has recently demonstrated elevated total and free IGF-I levels in prepubertal Hispanic girls with PA (65).

Consistent with previous studies in adult women with PCOS, we found similar levels of total IGF-I in the nonobese and obese PCOS adolescents (13, 14) as well as in the obese controls (62, 64, 66). IGFBP-1 was suppressed in all three study groups, but whereas virtually identical in the obese groups, the mean IGFBP-1 level was approximately 3-fold higher in the nonobese PCOS group. The relative suppression of IGFBP-1 in the obese compared with the nonobese adolescents with PCOS, previously reported in their adult counterparts (13), can be accounted for by the more marked hyperinsulinemia demonstrated in the obese group. We found elevated free IGF-I levels in the nonobese compared with the obese PCOS group. Although the previous reports of elevated free IGF-I in PCOS did not involve comparison of nonobese and obese subjects, Thierry van Dessel et al. (64) found a statistically significant inverse correlation between free IGF-I and BMI. The mechanism behind the relative increase in free IGF-I in nonobese PCOS is unclear from our data. Given the more pronounced hyperinsulinemia and lower IGFBP-1 levels observed in the obese PCOS group, the higher free IGF-I level in the nonobese group argues against the hypothesis that the suppression of IGFBP-1 by hyperinsulinemia alone is responsible for the increased bioavailability of IGF-I in PCOS. We propose that the increased adrenal hyperandrogenism and peripheral androgen conversion in nonobese PCOS may be mediated by free IGF-I.

Another possible explanation for the elevated free IGF-I in the nonobese PCOS group is that relatively increased IGFBP-3 proteolysis in the nonobese PCOS group may result in increased IGF-I bioavailability. In vivo studies in type 1 diabetics support the role of insulin in the regulation of IGFBP-3 proteolysis (67, 68). Bereket et al. (67) have demonstrated a normalization of the increased IGFBP-3 proteolysis that is observed before insulin therapy in children with type 1 DM, suggesting that insulin suppresses IGFBP-3 proteolysis. Insulin may also be involved in the control of IGFBP-3 protease inhibitor synthesis (68). We speculate that the relative hyperinsulinemia in our obese PCOS subjects compared with our nonobese PCOS subjects suppresses IGFBP-3 proteolysis and thereby lowers the free IGF-I level in this group.

Similar to reports in obese and nonobese women with PCOS (7, 13, 14, 15, 16, 17, 18, 19), the obese adolescents with PCOS demonstrated comparative hyperinsulinemia, including a more than 2-fold higher mean fasting insulin level and a greater insulin response to glucose challenge as reflected by the IAUC120 data. Decreased insulin sensitivity in the obese compared with the nonobese PCOS group was evidenced by statistically significant differences in FGIR, QUICKI, and ISI(composite), confirming previous findings in adults with PCOS (13, 16, 17). These metabolic differences between nonobese and obese adolescents with PCOS were corroborated clinically by the increased frequency of acanthosis nigricans observed in the obese PCOS group. We also found higher P0 in the obese compared with the nonobese PCOS group. Elevated P0 has been associated with type 2 DM and impaired glucose tolerance in adults and has been shown to predict the development of type 2 DM (69, 70). Finally, despite normal fasting glucose levels, 27% of the obese PCOS subjects who underwent testing had impaired glucose tolerance compared with none of their nonobese counterparts, although this difference was not statistically significant most likely due to the small sample size. This corroborates the limited sensitivity of fasting glucose levels in predicting glucose intolerance in PCOS (34).

The absence of statistically significant differences in measures of hyperinsulinemia and insulin sensitivity between the obese PCOS and control groups would seem to contrast with previous reports of disturbances in insulin secretion and sensitivity early in the course of PCOS (32, 33). Although not statistically significant, the insulin response to glucose challenge was increased, all measures of insulin sensitivity were decreased in the obese PCOS group compared with the obese controls, and a trend was detected in the difference in log IAUC120. Therefore, we suggest that we may have lacked sufficient power to detect differences in these measures due to the small sample size of 23 subjects who underwent glucose tolerance testing. We also cannot exclude the possibility that the ethnic diversity of the groups minimized the difference in insulin levels (71, 72). Finally, although our study lacked a nonobese control group, the proportion of nonobese adolescents with PCOS noted to have acanthosis nigricans on physical exam (36%) greatly exceeded previous estimates of the prevalence of this skin lesion in an unselected population (73), suggesting that PCOS itself contributes to the clinical manifestation of insulin resistance.

Adolescents with PCOS manifest clinical, metabolic, and endocrine features similar to those of adult women, and differences between nonobese and obese women with PCOS may be detected in adolescence. Our findings indicate a more pronounced alteration in the hypothalamo-pituitary-adrenal axis in nonobese adolescents with PCOS, but a more marked dysregulation of insulin levels and impairment of insulin sensitivity in their obese counterparts. Our data also suggest differences in the IGF system between nonobese and obese adolescents with PCOS. Thus, the clinical heterogeneity of PCOS is reflected in a biochemical and hormonal heterogeneity, which may be appreciated early in the evolution of the disorder and may arise from distinct pathogenetic mechanisms.


   Acknowledgments
 
We thank members of the Pediatric Endocrine Division at Columbia-Presbyterian Medical Center (New York, NY) for their kind referral of subjects, as well as the subjects for agreeing to participate. We also thank the nurses and staff of the Pediatric GCRC for their outstanding help and the sonographers of the Department of Obstetrics and Gynecology for performing the pelvic sonograms. We acknowledge and thank Genentech, Inc., Eli Lilly & Co., and Pharmacia & Upjohn, Inc. for grant support. We gratefully acknowledge Esoterix Endocrinology (Calabasas Hills, CA) and the GCRC laboratory for performing laboratory measurements.


   Footnotes
 
This work was supported in part by grants from the National Institutes of Health (RR-00645), Eli Lilly & Co., Pharmacia & Upjohn, Inc., and Genentech, Inc.

Current address for M.E.S.: Jacobi Medical Center and Albert Einstein College of Medicine, Bronx, New York 10461.

Current address for R.J.: Columbia University, Department of Obstetrics/Gynecology, St. Luke’s-Roosevelt Hospital, 1000 10th Avenue, New York, New York 10019.

This work was presented in part at the Annual Meeting of the Lawson Wilkins Pediatric Endocrine Society in Baltimore, MD, May 2002.

Abbreviations: {Delta}4-A, {Delta}4-Androstenedione; BMI, body mass index; DHEAS, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; DM, diabetes mellitus; F-G, Ferriman-Gallwey; FGIR, fasting glucose to insulin ratio; G0, basal glucose level; GCRC, General Clinical Research Center; HDL, high-density lipoprotein; HgbA1c, hemoglobin A1c; I0, basal insulin level; IAUC120, insulin area under the curve; IGFBP, IGF-binding protein; ISI(composite), composite insulin sensitivity index; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test; P0, basal proinsulin level; PA, premature adrenarche; PAO, polycystic- appearing ovaries; PCOS, polycystic ovary syndrome; QUICKI, quantitative insulin sensitivity check index.

Received April 9, 2003.

Accepted July 24, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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