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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1707
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 4 1275-1283
Copyright © 2006 by The Endocrine Society

Relationship of Adolescent Polycystic Ovary Syndrome to Parental Metabolic Syndrome

Natasha I. Leibel, Elizabeth E. Baumann, Masha Kocherginsky and Robert L. Rosenfield

Departments of Pediatrics (N.I.L., E.E.B., R.L.R.), Medicine (R.L.R.), and Health Studies (M.K.), The University of Chicago Pritzker School of Medicine, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Robert L. Rosenfield, University of Chicago Comer Children’s Hospital, Section of Pediatric Endocrinology, 5841 South Maryland Avenue (M/C 5053), Chicago, Illinois 60637. E-mail: robros{at}peds.bsd.uchicago.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: We determined the relationship of metabolic syndrome (MBS) to polycystic ovary syndrome (PCOS).

Objective: We tested the hypothesis that parental MBS is related to the PCOS phenotype in their offspring.

Design/Setting: We phenotyped for MBS and PCOS in our General Clinical Research Center.

Patients: Girls with PCOS, 12–19 yr old (n = 36, including one pair of siblings), and their parents (35 mothers, 19 fathers) were recruited from the Pediatric Endocrinology Clinic. Healthy girls, 12–19 yr old (n = 21), were recruited as a reference population.

Interventions: We measured anthropometrics, blood pressure, fasting lipids and androgens, oral glucose tolerance, and ultrasonographically determined polycystic ovary status.

Main Outcome Measures: MBS in parents, and PCOS features in mothers, were related to the presence of PCOS features in probands.

Results: Fathers had strikingly high prevalence of excess adiposity (94% were obese or overweight) and MBS (79%). Premenopausal mothers more commonly had MBS (36%) than features of PCOS (≤22%). Polycystic ovaries in proband offspring of premenopausal mothers were associated with maternal polycystic ovaries only in a minority of cases. Proband polycystic ovary status was completely concordant to fathers’ MBS status (P = 0.008), but not their own or their mothers’ MBS status, in families whose premenopausal mothers lacked polycystic ovaries. Proband prevalence of MBS was 27.8%, 3-fold greater than expected for obesity status.

Conclusion: Familial factors related to paternal MBS seem to be fundamental to the pathogenesis of PCOS.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARY SYNDROME (PCOS) is a syndrome of chronic anovulatory androgen excess that becomes symptomatic during adolescence and affects about 5% of adult women (1, 2). Adult women with PCOS are at an increased risk for obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and the metabolic syndrome (MBS) (3, 4, 5, 6, 7, 8, 9, 10). Considerable evidence indicates that PCOS is a multifactorial complex trait with polygenic components (11). The evidence points to autosomal dominant transmission of polycystic ovaries and elevated testosterone levels (12, 13, 14, 15); premature balding has been suggested to be the male equivalent of polycystic ovaries (12, 13). In addition, first-degree relatives of women with PCOS have an increased prevalence of glucose intolerance and insulin resistance (14, 16). Nevertheless, the parental phenotype, particularly the paternal phenotype, is incompletely understood.

MBS, a variably expressed cluster of glucose abnormalities, central (android) obesity, hypertension, and dyslipidemia, is the result of insulin resistance interacting with obesity and age (17, 18). Given that both PCOS and the MBS have insulin resistance and obesity at the core of their pathophysiology and have heritable components, we tested the hypotheses that parental MBS would be related to the PCOS phenotype in their offspring and that MBS prevalence would be increased in adolescents with PCOS.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Thirty-six postmenarcheal adolescent girls with PCOS, including one pair of siblings, and their parents were recruited from The University of Chicago Children’s Hospital Pediatric Endocrinology Clinics. This represents 66% of adolescents with PCOS who were evaluated by us for MBS during the study period. Thirty-five mothers and 19 fathers participated. The medical records of probands also included a history of estimated height and weight on 12 of the 16 nonparticipating fathers. As a reference population, 21 healthy, postmenarcheal, adolescent volunteer girls were recruited by advertisement during the same time period.

PCOS was defined consistent with Rotterdam criteria: otherwise unexplained biochemical evidence of hyperandrogenism (specifically, plasma free testosterone above the upper limit of normal for reproductive age women, 10 pg/ml) and menstrual irregularity and/or a polycystic ovary (9). A polycystic ovary was defined according to volume criteria (over 10.5 ml in volume in adults and 10.8 ml in adolescents, according to the formula for a prolate ellipsoid), whether or not an excessive number of follicles was present (9, 19, 20). Congenital adrenal hyperplasia, adrenal tumors, Cushing’s syndrome, hyperprolactinemia, and thyroid disease were excluded.

For comparison with previously published national prevalence data, MBS was defined in adults according to National Cholesterol Education Program Adult Treatment Panel III criteria (ATP-III) in adults (21), and in adolescents by criteria extrapolated from ATP-III criteria in line with national recommendations for lipid and blood pressure levels in children (C-III criteria) (Table 1Go) (22). Similarly, the prevalence of the individual MBS features in all groups was compared with published national prevalence data representative of the general U.S. population, the third National Health and Nutrition Examination Survey (NHANES III) (22, 23, 24, 25, 26). These data were adjusted for significant age, sex, ethnic, and body mass index (BMI) differences as indicated. For all other data analyses, the updated 2004 criteria of the National Heart, Lung, and Blood Institute/American Heart Association (NHA-04) were applied (17). These are ATP-III criteria modified to encompass current American Diabetes Association criteria for glucose abnormalities, including impaired glucose tolerance (IGT) (a 2-h plasma glucose 140–199 mg/dl) or a 2-h glucose of at least 200 mg/dl as a T2DM criterion. Similarly, the C-III criteria for children were modified (C-04) by aligning the criteria for glucose abnormalities with the NHA-04 recommendations; we also defined increased waist circumference as at least 88 cm, i.e. the critical level of risk for adult women, although this is somewhat lower (approximately 85th percentile NHANES III) than the cut-point of C-III criteria [www.cdc.gov/nchs/about/major/nhanes/datatblelink.htm (27)] (28). Any subject on a medication for diabetes, dyslipidemia, or hypertension was considered to meet that MBS criterion.


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  		TABLE 1. Criteria for MBS

 
Excessive weight was divided into obesity and overweight categories; obesity was defined as a BMI of 30 kg/m2 or more in adults (≥95th percentile for adolescents), overweight as a BMI between 25 and 29.9 kg/m2 (85–94.9th percentile for adolescents). Waist circumference was obtained at the narrowest part of the torso (29). Sitting blood pressure was recorded as the mean of one to three measurements. Fasting blood samples were obtained at approximately 0800 h (during d 3–11 of the menstrual cycle in regularly menstruating females) for total and free testosterone, estradiol, and SHBG (30, 31); LH and FSH (Delphia, Wallach, Finland); and a lipid panel (homogenous enzymatic colorimetric assay; Roche, Indianapolis, IN). Then an oral glucose tolerance test was performed according to American Diabetes Association guidelines (32). Plasma glucose was measured using a glucose analyzer (YSI model 23; Yellow Springs, OH). Serum insulin was measured by double-antibody RIA (33). The females had real-time pelvic ultrasound examinations; abdominal imaging was performed in probands and endovaginal imaging in mothers using an Acuson Sequoia with a 4-Mhz transducer (Acuson, Mountain View, CA) and Philips ATL 3000 or 5000 with an 8- to 10-Mhz transducer (Philips Medical Systems, Bothell, WA), respectively. Insulin resistance was indexed by homeostatic model assessment (HOMA); higher scores indicate greater insulin resistance (34). It was not computed in parents who were on antidiabetic treatment.

Oral contraceptive medications were discontinued in probands for at least 2 months before participation in the study; regularly menstruating females were studied on d 3–10 of their menstrual cycle. The Institutional Review Board of the University of Chicago approved the study, and all patients gave informed consent. All studies were conducted in the General Clinical Research Center of The University of Chicago.

Statistical methods

Fisher’s exact test was used to test independence of two categorical variables because the expected frequencies were low for most variables (35), and t tests were used to identify differences in continuous measurements (e.g. HOMA, BMI, testosterone, and SHBG) between two groups; P values are given for two-tailed tests. To reduce the effect of outliers and to account for unequal variability in the MBS feature groups, the nonparametric trend test (36) was used to determine whether BMI and HOMA scores were significantly increasing as the number of metabolic features went up. Because there was only one pair of proband siblings, the within-family correlation could not be estimated, and the two siblings with PCOS were treated in the analyses as if they had come from different families. In the analyses involving both probands and their parents, the parents of the two siblings were counted twice.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Characteristics of study groups

The 36 probands averaged 16 yr of age (range, 12–19 yr); 73.6% were Caucasian (W) and 26.4% were African-American (AA). Ninety-seven percent had irregular menses, and 72% had a polycystic ovary; 44% were hirsute. One proband had preexisting type 1 diabetes. Seventy-four percent of the mothers and 89% of the fathers were W; 26% of the mothers and 11% of the fathers were AA. The mothers averaged 45.2 yr of age (range, 31–54 yr); 10 (29%) were postmenopausal on both clinical and endocrinological grounds. Their PCOS features are discussed below. The fathers averaged 48.5 yr of age (range, 39–58 yr). Of the fathers studied, 10.5% were on oral antidiabetic medications, 10.5% were on medications for dyslipidemia, and 26% were on antihypertensive medications. Eleven percent of the mothers were on antihypertensive medications. The adolescent reference group was 12–19 yr of age; two thirds were AA, one third W. All had monthly menstrual cycles of 22–35 d.

Information was not available for waist circumference in two mothers and two fathers, lipids in one proband and one father, and blood pressure in seven mothers and three fathers. Two premenopausal mothers declined pelvic ultrasound examination. No ultrasound was performed on a mother who was surgically postmenopausal. Insulin levels were not available on two fathers, both of whom were known diabetics.

Relationship of adolescent PCOS to MBS

Sixty-one percent of probands were obese, and 14% were overweight (Fig. 1AGo). By C-III criteria, MBS was present in 19.4%; all were obese. Seventy-two percent of probands had central adiposity, 31% had low high-density lipoprotein cholesterol (HDL-C), 22% had hypertension, 20% had elevated triglycerides, and 8.6% had glucose abnormalities (exclusive of the type 1 diabetic) by C-III criteria. By C-04 criteria, 27.8% had MBS and 20% had T2DM-related glucose abnormalities; during this study, three probands (8.6%) were diagnosed with T2DM, one had impaired fasting glucose (IFG) alone (3%), two IGT alone (5.7%), and one both IFG and IGT (3%).


Figure 1
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  		FIG. 1. Prevalence of excessive weight, MBS, and MBS features in study groups compared with that expected in the U.S. population according to ATP-III criteria. Prevalence in adults is compared with that expected from age-, sex-, and ethnicity-adjusted prevalence rates of obesity and overweight (26 ) and MBS features (24 ) in the general U.S. population. BMI status of fathers was determined by a combination of history and examination, whereas MBS status was determined only on the examined subgroup, which was entirely obese (Ob) or overweight (Ow). Prevalence of excessive weight in adolescents is compared with that expected from age-, sex-, and ethnicity-adjusted prevalence rates of obesity and overweight (26 ) in the general U.S. population. The prevalence of MBS and MBS features in the adolescent female groups was compared with that expected for BMI category in addition to adjusting for that expected on the basis of their ethnicity (22 ). Checkmark indicates a difference between a study and comparison group of at least 1.5-fold. Adip, Adiposity; Abn, abnormality.

 
Excessive weight was more common in the probands than in the general U.S. population of adolescents, as expected, because of a greater prevalence of obesity (26) (Fig. 1AGo). PCOS adolescents had a MBS prevalence 3-fold higher than expected from BMI- and ethnicity-adjusted prevalence rates for adolescents in the U.S. population (22). Central adiposity, hypertension, and glucose abnormality prevalence rates were similarly 1.5- to 2-fold higher than expected for BMI in the PCOS adolescents (22) (Fig. 1AGo). All of the obese probands had abdominal adiposity, and 32% had MBS (45% by C-04 criteria). Abdominal adiposity was the only MBS feature seen in our overweight subjects, affecting 60% of overweight probands.

The healthy adolescent reference group had a prevalence of MBS and MBS features similar to that expected for their BMI and ethnicity (22), differing from that expected by less than 7% and 1.5-fold (Fig. 1BGo). All had normal glucose tolerance. Their prevalence of polycystic ovaries was unexpectedly high (61.9%).

Probands with MBS had significantly higher BMI, HOMA score, and free testosterone than those without MBS (Table 2Go). However, SHBG level and polycystic ovaries were not significantly related to the presence of MBS, although there was a tendency to lower SHBG levels in the subgroup with MBS. The number of MBS features was significantly related to BMI and the HOMA index of insulin resistance in the probands (P < 0.0001). The adolescent reference population all proved to be free of MBS.


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  		TABLE 2. MBS-related features in PCOS proband adolescents with and without MBS, and non-PCOS reference population (mean ± SD)

 
MBS and PCOS features of parents

The majority of mothers were either obese (54.4%) or overweight (11.4%) (Fig. 1CGo). By ATP-III criteria, 34% had MBS. Central adiposity was the most common MBS feature; it was present in 70% of mothers, followed by 48% with hypertension, whereas 17.1% had glucose abnormalities, 43% low HDL-C, and 26% elevated triglycerides. Using NHA-04 criteria hardly changed the prevalence of MBS (37.1%), although T2DM-related glucose abnormalities were much more frequent (48.6%). The latter consisted of T2DM in five (14.3%), three previously undiagnosed; IFG alone was found in 11.4%, IGT alone in 8.6%, and both IFG and IGT in 14.3%.

The maternal prevalence of obesity was 1.5-fold greater than that expected for age and ethnicity in the general U.S. population, but the combined prevalence of obesity and overweight was similar (26). Although the prevalence of MBS and central adiposity in mothers was not substantially higher than that in the general U.S. population, the maternal prevalence of hypertension and glucose abnormalities was 1.5- to 2.0-fold greater than expected (24).

Fathers were obese or overweight in 94% of cases by a combination of history (n = 12) and examination (n = 19) (Fig. 1DGo). Unexamined fathers were overweight or obese in 25 and 58%, respectively, of cases; there was a history of diabetes in 17% of cases, hypertension in 25%, and dyslipidemia in 8%. All examined fathers were overweight (31.5%) or obese (68.5%). According to ATP-III criteria, 53% of the examined group had MBS. Eighty-eight percent of these fathers on whom data were available had hypertension, 42.1% glucose abnormalities, 76.5% central adiposity, 50% low HDL-C, and 42.1% elevated triglycerides. Using NHA-04 criteria in examined fathers, MBS (79%) and T2DM-related glucose abnormalities (84.3%) were much more frequent. The latter included T2DM in six (31.6%), three previously undiagnosed, IFG alone in 31.6%, IGT alone in 15.8%, and both IFG and IGT in 5.3%. The examined fathers’ prevalence of obesity, MBS, central adiposity, hypertension, and glucose abnormalities, including T2DM and IGT, were all about 1.5- to 2-fold greater than expected in the age- and ethnicity-adjusted general U.S. population (24, 25).

As expected, the number of MBS features was significantly related to BMI and the HOMA index of insulin resistance in mothers (P < 0.001 and P < 0.0001, respectively) and to BMI in fathers (P = 0.006). A relationship to HOMA could not be demonstrated in fathers, because the great majority (79%) for whom HOMA scores were available already had at least three MBS features.

Parental features previously linked to PCOS were less common than the prevalence of obesity and MBS (Table 3Go). One or more polycystic ovaries were found in five of the 23 (22%) premenopausal mothers on whom pelvic ultrasonography was performed. Increased free testosterone was found in three (12%) of the 25 premenopausal women. Two of these three met criteria for PCOS, having both irregular periods and polycystic ovaries; both were obese and had MBS (the third, who was obese and had abdominal adiposity, but not a history of anovulatory symptoms, declined the ultrasound). Two other mothers reported a history of relative infertility because of PCOS, one of whom was postmenopausal, and the other declined pelvic ultrasound because of a history suggestive of a wedge resection for PCOS. Thus, approximately 14% (four of 35) of the mothers had evidence of PCOS. The prevalence of MBS among the premenopausal mothers was 36%, and the presence of MBS and PCOS was not associated (P = 0.1).


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  		TABLE 3. Prevalence of excessive weight, metabolic syndrome, and PCOS-related features in parents

 
Information on balding was available by self-report in 14 of the fathers. One father reported balding before age 30 yr, seven between age 30 and 40 yr, and six (with an average age of 47 yr) reported that they were not yet balding. Thus, only 7% reported premature male pattern balding. The average plasma free testosterone level of the fathers was 129 ± 44.1 pg/dl (normal, 80–280 pg/dl for men aged 40–60 yr). Two of the fathers had clearly low plasma free testosterone levels, 42 and 54 pg/ml.

Relationship between proband and parental phenotype

Table 4Go shows the relationship between parental features of MBS and the presence of MBS, HOMA scores, and the PCOS features of their offspring in the 19 families that underwent complete study. SHBG in the probands significantly decreased as the number of parents with the MBS increased (P = 0.008), and HOMA scores and free testosterone increased marginally, although to a lesser extent (P = 0.09 and P = 0.06, respectively). However, no association was found between the presence of polycystic ovaries in the probands and the number of parents affected with the MBS.


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  		TABLE 4. Relationship between the proband phenotype and the number of MBS-affected parents.

 
Table 5Go demonstrates the relationship between the presence of polycystic ovaries in the probands and the 23 premenopausal mothers for whom ultrasound studies were available. No significant association was found (P value = 1.0, Fisher’s exact test); mothers and daughters had different ovarian morphology in over half of the cases (63%). Nevertheless, four of the five mothers with polycystic ovaries had a daughter with polycystic ovaries.


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  		TABLE 5. Polycystic ovary (PCO) status of premenopausal mothers vs. PCO status of probands

 
The relationship of parental MBS to proband polycystic ovaries was then explored by analyzing complete families in which the premenopausal mothers were known to lack polycystic ovaries to exclude the possibility of polycystic ovary transmission from mother to proband. Table 6Go shows that the presence of MBS in fathers was completely concordant as well as highly significantly associated with probands’ polycystic ovary status (P = 0.008, Fisher’s exact test). Such a relationship was not found between the entire cohort of premenopausal mother-proband pairs, where the presence of MBS in mothers and polycystic ovaries in daughters was discordant in the majority (79%, not significant) (Table 7Go). In addition, among the six probands with postmenopausal mothers whose fathers were examined, five probands had polycystic ovaries and all six fathers had MBS. The significant relationship of paternal MBS to proband polycystic ovaries contrasts with the lack of significance of a relationship of proband polycystic ovaries to their own MBS. Although the number of complete parent-proband units studied was smaller than the number of maternal-proband units studied, there were no significant differences in the characteristics of probands or mothers of these two subgroups (data not shown).


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  		TABLE 6. Paternal MBS status vs. polycystic ovary (PCO) status of proband offspring of premenopausal mothers known to lack PCO

 

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  		TABLE 7. Maternal MBS status vs. polycystic ovary (PCO) status of proband offspring of all premenopausal mothers known to lack PCO

 
There were four complete families in which the probands were of normal weight (Fig. 2Go). Three of these had polycystic ovaries (families B–D); each had an obese father with MBS. The mothers were more likely to have MBS than a polycystic ovary or elevated testosterone. Only one of these probands had any feature of MBS.


Figure 2
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  		FIG. 2. Pedigrees of the four families in which the PCOS probands were of normal weight. Quadrants show status regarding BMI (Ow, overweight; Ob, obese), free testosterone (fT) and polycystic ovaries (PCO) in females, MBS (number of features), and glucose tolerance; H, high; L, low; N, normal. It can be seen that all these probands had an overweight or obese parent. Each obese parent had MBS, but the only proband to have any MBS feature (abnormal glucose tolerance) was the one with two diabetic parents. However, all three probands who had a father with MBS had polycystic ovaries.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The most common phenotypes in parents of adolescents with PCOS were found to be excessive weight and MBS. This was particularly the case in fathers, in whom the prevalences of MBS and central obesity were 1.5- to 2-fold greater than expected in the general population. Remarkably, paternal MBS was found to be more closely related to proband polycystic ovary status than any maternal or proband phenotypic feature, including MBS.

Obesity and metabolic syndrome features of PCOS families

The prevalence of excessive weight in our adolescents with PCOS, 14% of whom were overweight and 61% obese, was over 2-fold greater than expected in the general population. This is at the upper end of that reported in a U.S. series of adolescents with PCOS (50–75%) (37, 38, 39, 40). Nevertheless, MBS prevalence in our adolescent PCOS cohort was at least 3-fold higher than expected from either national prevalence data or a local reference population when adjusted for BMI status. MBS prevalence has not previously been documented in adolescence, although obesity, insulin resistance, and glucose intolerance are frequent at this early stage of PCOS (37, 39, 41, 42, 43). The MBS prevalence in our adolescents with PCOS was about half as great as in 20- to 29-yr-old adults with PCOS (10). The prevalence of all component features of MBS except triglyceride levels was at least 1.5-fold greater than expected for BMI in the population or in a local reference group. As in the general population (22), the prevalence of MBS features in these girls increased with increasing BMI. Probands with MBS were significantly more obese and insulin resistant, as indexed by BMI and HOMA score, and had a higher free testosterone level than those without MBS, although they did not have a lower SHBG level.

Fathers had an unexpectedly high prevalence of obesity (about two thirds) and excessive weight (94%), more so than anticipated from the population or from the known degree of correlation of adiposity of fathers and daughters (44). This was more striking than in mothers, in whom obesity was found in about half and the prevalence of excessive weight (65%) was similar to that expected in the general population of similar sex, age, and ethnicity. In parallel with excessive weight, MBS was considerably more frequent than expected in fathers (53–79% according to ATP-III and 2004 criteria, respectively) but not in mothers (34–37%). In parents, as in probands, central obesity (70–76% of parents), hypertension (48–88%), and glucose abnormalities (48–84% by current criteria) were the major features of MBS. It has been noted before that mothers of young women with PCOS have increased abdominal adiposity; on the contrary, an increased prevalence of central adiposity was not found in the fathers in that study (14). However, another study found that fathers of young women with PCOS were more obese than those of healthy controls and had higher HOMA scores than the mothers, even when controlled for BMI (45). Our data are consistent with the recent report of increased MBS prevalence in hyperandrogenic sisters of PCOS patients (46).

Familial factors in PCOS

Polycystic ovaries, testosterone levels, and T2DM-related defects in insulin secretion and action have previously been identified as heritable factors in PCOS (4, 12, 13, 15, 16, 47, 48). In premenopausal mothers, we found excessive weight and MBS to be more common than documented polycystic ovaries (22%), testosterone excess (12%), or PCOS (9%). Evidence exists that polycystic ovaries can be inherited as an autosomal dominant trait (12, 13). Testosterone is elevated in 23–46% of sisters of women with PCOS, and about half of these, in turn, have PCOS (13, 48). PCOS was reported to occur in 35% of premenopausal mothers of women with PCOS, using less objective criteria than we used, namely, menstrual irregularity and hirsutism as a surrogate for hyperandrogenemia (15). However, other studies documented only 7–8% of premenopausal mothers of women with PCOS to have an elevated free or total testosterone level (13, 14). Although our criteria for ovarian enlargement and androgen elevation may underestimate the incidence in premenopausal mothers because these values normally decrease with age, this is likely to be small because most studies indicate that the fall in these parameters with age is closely related to menopause (49, 50, 51, 52).

There has been considerable interest in identifying a possible heritable paternal component that may contribute to the PCOS phenotype. This is particularly relevant to our study because the majority of our PCOS adolescents did not have a mother with PCOS, an elevated testosterone level, or polycystic ovaries, and the maternal prevalence of excessive weight and MBS did not seem unusual. It has been suggested that premature male pattern baldness is the paternal phenotype (12, 13, 53). We could not confirm this in our family histories, which is not surprising in view of the complexity of this phenotypic trait (54). We did not find hyperandrogenism in the fathers, consistent with some, but not other, previous studies (12, 14). Indeed, about 10% of the fathers had low testosterone levels. Slightly elevated dehydroepiandrosterone sulfate levels have been reported in one series of brothers of PCOS women (55), but not in another (14).

Notably, however, in examining the phenotype of parent-daughter trios, we found that the presence of MBS in fathers, according to either ATP-III or current criteria, was strongly associated with the presence of polycystic ovaries in daughters, in the absence of polycystic ovaries in the mother. Such a relationship of MBS to proband polycystic ovary status did not pertain in premenopausal mothers or in the probands themselves. This was the only aspect of MBS in either probands or parents that was associated with polycystic ovaries. Our admittedly limited number of pedigrees of normal-weight probands showed these same relationships. These data strongly suggest that MBS in fathers is closely related to their daughters’ polycystic ovary status independently of the proband’s MBS status. Although we cannot exclude an environmental basis for the relationship between paternal MBS and polycystic ovaries in probands, these findings are most compatible with the genetic determinants of this aspect of PCOS being closely linked to paternal MBS.

Although there was no additive effect of paternal and maternal MBS on proband polycystic ovary status, we found a weakly additive effect on their offsprings’ HOMA index of insulin resistance. This combined effect is not surprising in view of insulin resistance being a major factor underlying MBS and having a significant heritable component (56). Paternal and maternal MBS also had a strongly additive effect on the suppression of offspring SHBG levels and a marginally additive one on free testosterone levels; this suggests complimentary effects of heredity (57, 58) and the compensatory hyperinsulinemia of insulin resistance (59, 60) on SHBG and free testosterone levels.

Study limitations

The applicability of this study is limited by the ascertainment bias inherent in the process of recruiting patients, their families, and volunteers. It is possible that adolescents whose parents had obesity, diabetes, or other MBS-related problems preferentially enrolled for this family evaluation. Although we observed the same relationship between paternal MBS and polycystic ovary status in probands with or without excessive weight, our proband group had a high prevalence of excessive weight (75%), which was nevertheless within the range of overweight and obesity reported for PCOS in the United States (30–75%) (10, 37, 38, 39, 40, 60, 61, 62). However, PCOS is clearly a multifactorial disorder; although excessive weight is increased in prevalence in PCOS in the United States, it is not necessarily a feature in all PCOS populations (62, 63, 64). Nevertheless, it is noteworthy that increased upper body fat accumulation seems to be characteristic of most lean PCOS patients (65), suggesting that an increase in central adiposity is fundamental to the disorder. Similar considerations pertain to our reference population of adolescent volunteers, who are not necessarily representative of the general adolescent population. Although the prevalence of MBS features in this healthy volunteer reference group was similar to that expected from national prevalence data, the high percentage of polycystic ovaries in this group was unexpected. Although polycystic ovaries have been reported in 23–43% or more of normal adult volunteers (66, 67, 68), the true prevalence in the general population is probably lower (69). The transabdominal visualization approach that is standard and appropriate for studies in adolescents probably underestimates the prevalence of polycystic ovaries (70), even though the prevalence of polycystic ovaries in our probands was similar to that reported in other series of PCOS patients. However, there is reason to believe that ovarian size may be greater in the perimenarcheal period than at any other stage of development; the number of large antral follicles reaches its maximum at that time, as the result of the combination of mature gonadotropin output and a higher population of follicles than in adults (71, 72).

Conclusions

With the reservations noted above, our results link adolescent polycystic ovaries with paternal MBS and add to a growing body of evidence suggesting that PCOS is fundamentally related to insulin resistance and additionally suggest a familial relationship to central obesity that warrants additional study.


   Acknowledgments
 
We give our special thanks to the pediatric ultrasonographers Drs. Kate Feinstein and David Yousefzadeh.


   Footnotes
 
This work was supported in part by U.S. Public Health Service Grants HD-39267, U54-041859, and RR-00055 (to R.L.R.) and a grant from Pfizer Pharmaceuticals (to N.L.).

The authors have nothing to declare.

First Published Online January 31, 2006

Abbreviations: AA, African-American; ATP-III, National Cholesterol Education Program Adult Treatment Panel III criteria; BMI, body mass index; C-III, extrapolated from ATP-III for children; HDL-C, high-density lipoprotein cholesterol; HOMA, homeostatic model assessment; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; MBS, metabolic syndrome; NHA-04, 2004 criteria of the National Heart, Lung, and Blood Institute/American Heart Association; NHANES III, third National Health and Nutrition Examination Survey; PCOS, polycystic ovary syndrome; T2DM, type 2 diabetes mellitus; W, Caucasian.

Received August 1, 2005.

Accepted January 20, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Ehrmann DA, Barnes RB, Rosenfield RL 1995 Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev 16:322–353[CrossRef][Medline]
  2. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO 2004 The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 89:2745–2749[Abstract/Free Full Text]
  3. Dunaif A, Segal KR, Futterweit W, Dobrjansky A 1989 Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38:1165–1174[Abstract]
  4. Ehrmann DA, Jeppe S, Byrne M, Karrison T, Rosenfield RL, Polonsky K 1995 Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J Clin Invest 96:520–527[Medline]
  5. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J 1999 Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 22:141–146[Abstract/Free Full Text]
  6. Legro RS, Kunselman AR, Dodson WC, Dunaif A 1999 Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 84:165–169[Abstract/Free Full Text]
  7. Glueck CJ, Papanna R, Wang P, Goldenberg N, Sieve-Smith L 2003 Incidence and treatment of metabolic syndrome in newly referred women with confirmed polycystic ovarian syndrome. Metabolism 52:908–915[CrossRef][Medline]
  8. Orio F, Jr., Palomba S, Spinelli L, Cascella T, Tauchmanova L, Zullo F, Lombardi G, Colao A 2004 The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study. J Clin Endocrinol Metab 89:3696–3701[Abstract/Free Full Text]
  9. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2004 Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81:19–25[Medline]
  10. Apridonidze T, Essah PA, Iuorno MJ, Nestler JE 2005 Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 90:1929–1935[Abstract/Free Full Text]
  11. Legro RS, Strauss JF 2002 Molecular progress in infertility: polycystic ovary syndrome. Fertil Steril 78:569–576[CrossRef][Medline]
  12. Carey AH, Chan KL, Short F, White D, Williamson R, Franks S 1993 Evidence for a single gene effect causing polycystic ovaries and male pattern baldness. Clin Endocrinol (Oxf) 38:653–658[Medline]
  13. Govind A, Obhrai MS, Clayton RN 1999 Polycystic ovaries are inherited as an autosomal dominant trait: analysis of 29 polycystic ovary syndrome and 10 control families. J Clin Endocrinol Metab 84:38–43[Abstract/Free Full Text]
  14. Yildiz BO, Yarali H, Oguz H, Bayraktar M 2003 Glucose intolerance, insulin resistance, and hyperandrogenemia in first degree relatives of women with polycystic ovary syndrome. J Clin Endocrinol Metab 88:2031–2036[Abstract/Free Full Text]
  15. Kahsar-Miller MD, Nixon C, Boots LR, Go RC, Azziz R 2001 Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS. Fertil Steril 75:53–58[CrossRef][Medline]
  16. Colilla S, Cox NJ, Ehrmann DA 2001 Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their first degree relatives. J Clin Endocrinol Metab 86:2027–2031[Abstract/Free Full Text]
  17. Grundy SM, Brewer Jr HB, Cleeman JI, Smith Jr SC, Lenfant C 2004 Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 109:433–438[Free Full Text]
  18. Eckel RH, Grundy SM, Zimmet PZ 2005 The metabolic syndrome. Lancet 365:1415–1428[CrossRef][Medline]
  19. Balen AH, Laven JS, Tan SL, Dewailly D 2003 Ultrasound assessment of the polycystic ovary: international consensus definitions. Hum Reprod Update 9:505–514[Abstract/Free Full Text]
  20. Venturoli S, Porcu E, Fabbri R, Pluchinotta V, Ruggeri S, Macrelli S, Paradisi R, Flamigni C 1995 Longitudinal change of sonographic ovarian aspects and endocrine parameters in irregular cycles of adolescence. Pediatr Res 38:974–980[Medline]
  21. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults 2001 Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285:2486–2497[Free Full Text]
  22. Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH 2003 Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988–1994. Arch Pediatr Adolesc Med 157:821–827[Abstract/Free Full Text]
  23. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS 2003 Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 289:76–79[Abstract/Free Full Text]
  24. Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB 2003 The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch Intern Med 163:427–436[Abstract/Free Full Text]
  25. Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE, Little RR, Wiedmeyer HM, Byrd-Holt DD 1998 Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988–1994. Diabetes Care 21:518–524[Abstract]
  26. Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM 2004 Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA 291:2847–2850[Abstract/Free Full Text]
  27. National Center for Health Statistics 2004 National Health and Nutrition Examination Survey III. Anthropometric reference data, United States, 1988–1994. Hyattsville, MD: U.S. Department of Health and Human Services
  28. Fernandez JR, Redden DT, Pietrobelli A, Allison DB 2004 Waist circumference percentiles in nationally representative samples of African-American, European-American, and Mexican-American children and adolescents. J Pediatr 145:439–444[CrossRef][Medline]
  29. Callaway CW, Chumlea WC, Bouchard C, Himes JH, Lohman TG, Martin AD, Mitchell CD, Mueller WH, Roche AF, Seefeldt VD 1988 Circumferences. In: Lohman TG, Roche AF, Martorell R, eds. Anthropometric standardization reference manual. Champaign, IL: Human Kinetics Books; 39–54
  30. Rosenfield RL, Perovic N, Ehrmann DA, Barnes RB 1996 Acute hormonal responses to the gonadotropin releasing hormone agonist leuprolide: dose-response studies and comparison to nafarelin. J Clin Endocrinol Metab 81:3408–3411[Abstract]
  31. Moll Jr G, Rosenfield R 1979 Testosterone binding and free plasma androgen concentrations under physiological conditions: characterization by flow dialysis technique. J Clin Endocrinol Metab 49:730–736[Medline]
  32. American DA 2004 Diagnosis and classification of diabetes mellitus. Diabetes Care 27(Suppl 1):S5–S10
  33. Faber O, Binder C, Markussen J, Heding L, Naithani V, Kuzuga H, Blix P, Horwitz D, Rubenstein A 1978 Characterization of seven C-peptide antisera. Diabetes 27:170–177
  34. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC 1985 Homeostasis model assessment: insulin resistance and ß-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419[CrossRef][Medline]
  35. Altman DG 1999 Practical statistics for medical research. Boca Raton, FL: CRC Press
  36. Cuzick J 1985 A Wilcoxon-type test for trend. Stat Med 4:87–90[Medline]
  37. Apter D, Bützow G, Laughlin A, Yen SSC 1995 Metabolic features of polycystic ovary syndrome are found in adolescent girls with hyperandrogenism. J Clin Endocrinol Metab 80:2966–2973[Abstract/Free Full Text]
  38. Rosenfield RL, Ghai K, Ehrmann DA, Barnes RB 2000 Diagnosis of polycystic ovary syndrome in adolescence. Comparison of adolescent and adult hyperandrogenism. J Pediatr Endocrinol Metab 13:1285–1289
  39. Silfen ME, Denburg MR, Manibo AM, Lobo RA, Jaffe R, Ferin M, Levine LS, Oberfield SE 2003 Early endocrine, metabolic, and sonographic characteristics of polycystic ovary syndrome (PCOS): comparison between nonobese and obese adolescents. J Clin Endocrinol Metab 88:4682–4688[Abstract/Free Full Text]
  40. Trent M, Austin SB, Rich M, Gordon CM 2005 Overweight status of adolescent girls with polycystic ovary syndrome: body mass index as mediator of quality of life. Ambul Pediatr 5:107–111[CrossRef][Medline]
  41. Arslanian SA, Lewy VD, Danadian K 2001 Glucose intolerance in obese adolescents with polycystic ovary syndrome: roles of insulin resistance and ß-cell dysfunction and risk of cardiovascular disease. J Clin Endocrinol Metab 86:66–71[Abstract/Free Full Text]
  42. Lewy VD, Danadian K, Witchel SF, Arslanian S 2001 Early metabolic abnormalities in adolescent girls with polycystic ovarian syndrome. J Pediatr 138:38–44[CrossRef][Medline]
  43. Palmert MR, Gordon CM, Kartashov AI, Legro RS, Emans SJ, Dunaif A 2002 Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. J Clin Endocrinol Metab 87:1017–1023[Abstract/Free Full Text]
  44. Figueroa-Colon R, Arani RB, Goran MI, Weinsier RL 2000 Paternal body fat is a longitudinal predictor of changes in body fat in premenarcheal girls. Am J Clin Nutr 71:829–834[Abstract/Free Full Text]
  45. Sir-Petermann T, Angel B, Maliqueo M, Carvajal F, Santos JL, Perez-Bravo F 2002 Prevalence of type II diabetes mellitus and insulin resistance in parents of women with polycystic ovary syndrome. Diabetologia 45:959–964[CrossRef][Medline]
  46. Sam S, Legro RS, Bentley-Lewis R, Dunaif A 2005 Dyslipidemia and metabolic syndrome in the sisters of women with polycystic ovary syndrome. J Clin Endocrinol Metab 90:4797–4802[Abstract/Free Full Text]
  47. Franks S, Gharani N, Waterworth D, Batty S, White D, Williamson R, McCarthy M 1998 Genetics of polycystic ovary syndrome. Mol Cell Endocrinol 145:123–128[CrossRef][Medline]
  48. Legro RS, Driscoll D, Strauss 3rd JF, Fox J, Dunaif A 1998 Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci USA 95:14956–14960[Abstract/Free Full Text]
  49. Giacobbe M, Pinto-Neto AM, Costa-Paiva LH, Martinez EZ 2004 Ovarian volume, age, and menopausal status. Menopause 11:180–185[Medline]
  50. Tufan E, Elter K, Durmusoglu F 2004 Assessment of reproductive ageing patterns by hormonal and ultrasonographic ovarian reserve tests. Hum Reprod 19:2484–2489[Abstract/Free Full Text]
  51. Winters SJ, Talbott E, Guzick DS, Zborowski J, McHugh KP 2000 Serum testosterone levels decrease in middle age in women with the polycystic ovary syndrome. Fertil Steril 73:724–729[CrossRef][Medline]
  52. Davison SL, Bell R, Donath S, Montalto JG, Davis SR 2005 Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 90:3847–3853[Abstract/Free Full Text]
  53. Ferriman D, Purdie A 1979 The inheritance of polycystic ovarian disease and a possible relationship to premature balding. Clin Endocrinol (Oxf) 11:291–300[Medline]
  54. Nyholt DR, Gillespie NA, Heath AC, Martin NG 2003 Genetic basis of male pattern baldness. J Invest Dermatol 121:1561–1564[Medline]
  55. Legro RS, Kunselman AR, Demers L, Wang SC, Bentley-Lewis R, Dunaif A 2002 Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome. J Clin Endocrinol Metab 87:2134–2138[Abstract/Free Full Text]
  56. Hong Y, Weisnagel SJ, Rice T, Sun G, Mandel SA, Gu C, Rankinen T, Gagnon J, Leon AS, Skinner JS, Wilmore JH, Bergman RN, Bouchard C, Rao DC 2001 Familial resemblance for glucose and insulin metabolism indices derived from an intravenous glucose tolerance test in Blacks and Whites of the HERITAGE Family Study. Clin Genet 60:22–30[Medline]
  57. An P, Rice T, Gagnon J, Borecki IB, Rankinen T, Gu C, Leon AS, Skinner JS, Wilmore JH, Bouchard C, Rao DC 2001 Population differences in the pattern of familial aggregation for sex hormone-binding globulin and its response to exercise training: the HERITAGE Family Study. Am J Hum Biol 13:832–837[CrossRef][Medline]
  58. Hong Y, Gagnon J, Rice T, Perusse L, Leon AS, Skinner JS, Wilmore JH, Bouchard C, Rao DC 2001 Familial resemblance for free androgens and androgen glucuronides in sedentary black and white individuals: the HERITAGE Family Study. Health, Risk Factors, Exercise Training and Genetics. J Endocrinol 170:485–492[Abstract]
  59. Nestler J, Powers L, Matt D, Steingold K, Plymate S, Rittmaster R, Clore J, Blackard W 1991 A direct effect of hyperinsulinemia on serum sex-hormone binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 72:83–89[Abstract]
  60. Ehrmann DA 2004 Medical progress: polycystic ovary syndrome. N Engl J Med 352:1223–1236
  61. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R 1998 Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 83:3078–3082[Abstract/Free Full Text]
  62. Carmina E, Legro RS, Stamets K, Lowell J, Lobo RA 2003 Difference in body weight between American and Italian women with polycystic ovary syndrome: influence of the diet. Hum Reprod 18:2289–2293[Abstract/Free Full Text]
  63. Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S, Escobar-Morreale HF 2000 A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 85:2434–2438[Abstract/Free Full Text]
  64. Ibañez L, Valls C, Potau N, Marcos M, De Zegher F 2001 Polycystic ovary syndrome after precocious pubarche: ontogeny of the low-birthweight effect. Clin Endocrinol (Oxf) 55:667–672[CrossRef][Medline]
  65. Kirchengast S, Huber J 2001 Body composition characteristics and body fat distribution in lean women with polycystic ovary syndrome. Hum Reprod 16:1255–1260[Abstract/Free Full Text]
  66. Polson D, Adams J, Wadsworth J, Franks S 1988 Polycystic ovaries: a common finding in normal women. Lancet 1:870–872[CrossRef][Medline]
  67. Legro RS, Chiu P, Kunselman AR, Bentley CM, Dodson WC, Dunaif A 2005 Polycystic ovaries are common in women with hyperandrogenic chronic anovulation but do not predict metabolic or reproductive phenotype. J Clin Endocrinol Metab 90:2571–2579[Abstract/Free Full Text]
  68. Adams JM, Taylor AE, Crowley Jr WF, Hall JE 2004 Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome. J Clin Endocrinol Metab 89:4343–4350[Abstract/Free Full Text]
  69. van Hooff MH, Voorhorst FJ, Kaptein MB, Hirasing RA, Koppenaal C, Schoemaker J 2004 Predictive value of menstrual cycle pattern, body mass index, hormone levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum Reprod 19:383–392[Abstract/Free Full Text]
  70. Mendelson EB, Bohm-Velez M, Joseph N, Neiman HL 1988 Gynecologic imaging: comparison of transabdominal and transvaginal sonography. Radiology 166:321–324[Abstract/Free Full Text]
  71. Block E 1953 A quantitative morphological investigation of the follicular system in newborn female infants. Acta Anat 17:201–206[Medline]
  72. Baker T 1963 A quantitative and cytological study of germ cells in human ovaries. Proc Roy Soc Biol 158:417–433



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