- Email: [email protected]
Using the Androgen Excess–PCOS Society Criteria to Diagnose Polycystic Ovary Syndrome and the Risk of Metabolic Syndrome in Adolescents
Using the Androgen Excess–PCOS Society Criteria to Diagnose Polycystic Ovary Syndrome and the Risk of Metabolic Syndrome in Adolescents Andrea Hsu Roe, MD1, Erica Prochaska, BS1, Matthew Smith, BS1, Mary Sammel, ScD2, and Anuja Dokras, MD, PhD1 Objectives To use the Androgen Excess–PCOS Society (AE-PCOS) criteria in adolescents to diagnose polycystic ovary syndrome (PCOS) and identify the prevalence of metabolic risk factors. Study design Retrospective chart review of adolescents (>2 years postmenarche) presenting at a specialty clinic from 2008 through 2010 with complete evaluation for PCOS and metabolic risk were reviewed. Metabolic risk in adolescents with PCOS was compared with those with #1 AE-PCOS criteria. Results Of the 205 adolescents evaluated, 66% were found to have PCOS based on the AE-PCOS criteria. The most common presenting symptom was menstrual irregularity, followed by acne, hirsutism, and weight gain. Adolescents with PCOS had a significantly higher prevalence of obesity, hypertension, and low level of highdensity lipoprotein cholesterol. Subjects with PCOS had $1 metabolic risk factor compared with the subjects without PCOS (63.6% vs 33.3%, P = .002). More adolescents with PCOS had $2 abnormal metabolic risk factors excluding body mass index compared with those without PCOS (P < .02). The prevalence of metabolic syndrome ($3 risk factors) was 10.8% in adolescents with PCOS compared with 1.7% in those without PCOS (P < .04). Conclusions Adolescents diagnosed with PCOS based on the AE-PCOS criteria are at a significantly increased risk of $1 metabolic abnormality. Our data underscore the need to accurately diagnose PCOS in the adolescent population instead of delaying the diagnosis to adulthood. Further, using similar criteria for the diagnosis of PCOS in adolescents (>2 years postmenarche) and adults will be more convenient for the clinician. (J Pediatr 2013;162:937-41).
W
ith increasing awareness and clarity in diagnostic criteria for polycystic ovary syndrome (PCOS), a number of adult women are evaluated for this condition. There are currently 3 diagnostic sets of criteria used for adults: the National Institutes of Health (NIH), Rotterdam, and Androgen Excess–PCOS Society (AE-PCOS) criteria. The NIH criteria define PCOS as the presence of oligomenorrhea/anovulation and clinical or biochemical hyperandrogenism. The Rotterdam criteria include women with any 2 of the following 3 criteria: oligomenorrhea/anovulation, clinical or biochemical hyperandrogenism, and polycystic ovaries on ultrasound. The AE-PCOS criteria include women with oligomenorrhea/oligoovulation or polycystic ovaries on ultrasound and clinical or biochemical hyperandrogenism. In all cases, other conditions such as hypothyroidism, hyperprolactinemia, and adrenal disorders that mimic the symptoms of PCOS need to be excluded. As adolescents transition through puberty, they commonly have symptoms mimicking all of the diagnostic criteria for PCOS such as oligomenorrhea/anovulation, signs of clinical hyperandrogenism, and the appearance of polycystic ovaries on ultrasound. Irregular menses are commonly present during the first few years after menarche. By 2 years postmenarche, the majority of adolescent menstrual cycles are normal according to adult standards.1 Based on these findings, it has been suggested that the diagnosis of PCOS should be deferred during the first 2 years after menarche.2 Clinical hyperandrogenism is also difficult to evaluate during adolescence as there is no standardized grading system targeted specifically to this age group for either acne or hirsutism. Proposed risk factors for PCOS, including prenatal exposure to androgens, low birth weight, and premature pubarche, are not well established.3 As a result of these limitations, some women diagnosed with PCOS in adolescence do not meet the established criteria for PCOS on further evaluation as adults. Given the challenges for diagnosis of PCOS in adolescents, some investigators have suggested use of different criteria specific to the adolescent period. On the other hand, it has been argued that accurate diagnosis of PCOS may not be essential during the transitional adolescent period, because clinical management of the patient is usually unaltered.
AE-PCOS BMI BP FG HDL-C NIH PCOS TG
Androgen Excess–PCOS Society Body mass index Blood pressure Ferriman–Gallwey High-density lipoprotein cholesterol National Institutes of Health Polycystic ovary syndrome Triglycerides
From the 1Division of Reproductive Endocrinology and Infertility, and 2Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA The authors declare no conflicts of interest. Portions of the study were presented at the annual meeting of the American Society of Reproductive Medicine, Orlando, FL, October 17-19, 2011. 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.11.019
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The AE-PCOS guidelines consider hyperandrogenism as the core abnormality in PCOS and define the syndrome by the presence of clinical or biochemical hyperandrogenism and irregular menses/anovulation or polycystic appearing ovaries on ultrasound.4 The aims of our study were to determine the usefulness of the adult AE-PCOS criteria in the diagnosis of adolescent subjects referred to a specialty practice. Second, we wanted to determine the metabolic risk in adolescents with AE-PCOS–defined PCOS compared with those adolescents who were referred to our practice but did not meet these criteria.
Methods A retrospective chart review was performed of medical records of all adolescents (#20 years) presenting to a specialty gynecology clinic from 2008 through 2010 for evaluation of PCOS. Medical records were reviewed for demographic information, clinical history, and laboratory data. This study was approved by the Institutional Review Board at the University of Pennsylvania. Diagnosis of PCOS was confirmed by the AE-PCOS criteria4 as follows: hyperandrogenism was defined as biochemical (total testosterone $55 ng/mL) or clinical (Ferriman–Gallwey [FG] score $8), irregular menses were defined as menses #9 times per year, and polycystic appearing ovaries were defined as either ovary having a volume of $10 cm3 on abdominal or transvaginal ultrasound.5 Only volume criteria were used for ultrasound measurements, recognizing that antral follicle counts are not a reliable finding for PCOS in adolescents.2 We obtained an ultrasound when the diagnosis of PCOS could not be clearly established based on menstrual frequency history and hyperandrogenism. All subjects with only hyperandrogenism or only menstrual irregularity had ultrasound results. All oligomenorrheic subjects were at least 2 years postmenarche. If a subject was taking combined oral contraceptives, she was asked to stop for 8 weeks before testosterone measurements. The turbulent-flow liquid chromatography–mass spectrometry method was used to measure total testosterone levels (ARUP Laboratories, University of Utah Research Park, Salt Lake City, Utah). Additional laboratory tests abstracted from the medical records to establish the diagnosis of PCOS included thyroid-stimulating hormone, prolactin, dehydroepiandrosterone sulphate, and 17-hydroxyprogesterone levels. Adolescents who presented to our center and did not meet the earlier AE-PCOS criteria (who had none or only 1 criterion) were compared with the PCOS group. Of 400 charts reviewed, 205 adolescents had adequate data to be accurately classified according to the AE-PCOS criteria and had laboratory testing to define metabolic risk and the presence or absence of metabolic syndrome. Subjects were classified as having metabolic syndrome if they met 3 of the following 5 criteria based on the modified Cook criteria: body mass index (BMI) >90th percentile, serum triglycerides (TG) level $150 mg/dL, serum high-density lipoprotein 938
Vol. 162, No. 5 cholesterol (HDL-C) #40 mg/dL, blood pressure (BP) $90th percentile for age (http://www.nhlbi.nih.gov/ guidelines/hypertension/child_tbl.pdf) or taking antihypertensive medication, and fasting blood glucose $100 mg/dL or the presence of type 2 diabetes mellitus.6 Statistical Analyses Pearson c2 test was performed to compare differences with categorical variables. The 2-sample t tests were used to compare differences between means of the biochemical variables. The differences in the overall metabolic risk (1-4) criteria was analyzed using the Wilcoxon rank sum test. Logistic regression analysis was used to control for variables such as age and race. ORs along with 95% CIs measure the association between PCOS diagnosis and each metabolic risk factor and metabolic syndrome.
Results Of the 205 subjects who met the inclusion criteria of our study, 34.6% did not meet the AE-PCOS criteria for PCOS. Table I shows the demographic information for the 148 adolescents with PCOS with both AE-PCOS criteria and 57 subjects without PCOS (#1 AE-PCOS criteria). The majority of the adolescents with PCOS in our study (140/148) also met the NIH criteria. The mean age at presentation at our center was similar for the 2 groups. The majority of the subjects were white. A higher proportion of adolescents with PCOS had a family history of PCOS, diabetes, hypertension, coronary artery disease, and hyperlipidemia. All subjects were screened for other endocrine conditions that mimic the features of PCOS, such as hypothyroidism, hyperprolactinemia, and adrenal conditions (Table II). Six adolescents with PCOS Table I. Demographic information for adolescents with and without PCOS based on the AE-PCOS criteria Demographics
PCOS (2 criteria)
No PCOS (£1 criteria)
No. Age at presentation, y Age range, y Age at menarche, y Race, % White Black Asian Unknown Other Ethnicity, % Hispanic Non-Hispanic Unknown
148 16.9 1.9 13-20 12.2 1.6
57 16.6 2.5 14-20 12.4 1.4
73.7 14.5 4.6 0.7 6.6
83.0 5.7 1.9 0.0 9.4
3.3 89.5 7.2
1.9 98.1 0.0
Family history, % PCOS Diabetes mellitus Hypertension Coronary artery disease Hyperlipidemia
Maternal
Paternal
Maternal
Paternal
9 26* 21* 10* 14*
0 16* 18* 10* 12*
0 1 1 0 0
0 0 0 0 0
Values for age are mean SD. *P < .01.
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Table II. Endocrine profile in adolescents evaluated for the diagnosis of PCOS
Thyroid-stimulating hormone, mIU/mL Prolactin, ng/mL 17-OH progesterone, ng/dL Dihydroepiandrosterone sulphate, ng/mL
PCOS (2 criteria)
No PCOS (£1 criteria)
2.2 1.5 11.6 6.4 80.2 62.2 266 141
1.8 0.9 8.9 3.6* 66.7 86.7 241.4 126.2
Values are mean SD. *P < .05.
were receiving treatment for hypothyroidism compared with 3 adolescents without PCOS. The most common presenting symptom in the adolescents diagnosed with PCOS was menstrual irregularities (98%), followed by acne, hirsutism, and weight gain. Of the subjects with PCOS and menstrual irregularities, 68.3% had oligomenorrhea, 27.7% presented with secondary amenorrhea (no menses during the preceding 6 months), and 4% presented with primary amenorrhea (no menses up to the age of 16). Of the subjects with PCOS and clinical hyperandrogenism, 37% complained of acne only, 40% had hirsutism only, and 23% had both acne and hirsutism. About one-half of the adolescents with acne had seen a dermatologist and used prescription medications. In addition, 34% of adolescents diagnosed with PCOS complained of recent weight gain as one of their presenting symptoms. Of the adolescents who did not have PCOS, 48% had only irregular menses, 28% had only biochemical hyperandrogenemia, 4% had only polycystic appearing ovaries based on volume criteria, and the remaining met neither criterion after applying the AE-PCOS definition. Fifty percent of the adolescents without PCOS had acne and 15% of these girls were using medications for the treatment of acne. Compared with the adolescents with PCOS, fewer adolescents without PCOS complained of hirsutism (13%, P < .01) and weight gain (11.3%, P < .01). Of the adolescents diagnosed with PCOS, 55% had an ultrasound compared with 80% of the adolescents without PCOS. The mean ovarian volume was 9.62 5.3 cm3 in the PCOS subjects compared with 6.25 2.8 cm3 in the adolescents without PCOS (P < .01). The biomarkers measured for assessing the metabolic risk profile in the 2 groups are shown in Table III. Adolescents with PCOS had a significantly higher BMI compared with the adolescents without PCOS (P < .01), and a larger proportion of adolescents with PCOS were overweight and obese (based on adult definitions). The mean systolic BP was significantly higher in the adolescents with PCOS (P < .01), and 1 subject with PCOS was receiving antihypertensive medications. The mean HDL-C levels were significantly lower in adolescents with PCOS (P < .05). Four adolescents with PCOS and 1 without PCOS had an impaired fasting glucose level (>100 mg/dL). No subjects were diagnosed with diabetes in this cohort. Table IV shows the prevalence of each metabolic risk factor in the 2 groups. The OR for abnormal BMI and BP were significantly higher in the PCOS group.
Table III. Metabolic risk factors in adolescents with and without PCOS
Systolic BP, mm Hg Diastolic BP, mm Hg Fasting glucose, mg/dL Total cholesterol, mg/dL HDL-C, mg/dL Low-density lipoprotein cholesterol, mg/dL TG, mg/dL BMI, kg/m2 <25 25-30 >30
PCOS (2 criteria)
No PCOS (£1 criteria)
117.3 13.3 70.1 8.8 81.1 13.8 178 38.8 52.8 15.7 105 35.9
111.4 11.6† 70.8 6.7 80.8 10.2 179.25 43.9 57.8 13.8* 101 33.1
108.4 85 28.5 7.4 38% 21% 38%
94.8 56.2 24.7 7.1† 77% 9% 9%
Values are mean SD. *P < .05. †P < .01.
A higher percentage of adolescents with PCOS (63.6%) had $1 metabolic risk factor as defined by the Cook criteria for metabolic syndrome compared with the subjects without PCOS (33.3%, P = .002). Also, the distribution of 1-4 risk factors was significantly higher in the PCOS group (P < .02). No adolescent subject had all 5 metabolic risk factors. The prevalence of metabolic syndrome ($3 risk factors) was 10.8% in adolescents with PCOS compared with 1.7% in those without PCOS (P < .04). The unadjusted OR for metabolic syndrome in adolescents with PCOS was 6.7 (95% CI 0.9-52.4, P < .06). The adjusted OR (age and race) was 5.8 (95% CI 0.73-46.6, P < .09). BMI is one of the variables used to calculate the risk of metabolic syndrome; it was not included in the logistic regression model. Only one subject with PCOS and normal BMI (n = 71) had metabolic syndrome and no subjects without PCOS and normal BMI (n = 44) had metabolic syndrome. Of the subjects with BMI >95th percentile for age, 20% of adolescents with PCOS and 7% of adolescents without PCOS had metabolic syndrome (P = .2). Because the groups with only obese or only lean subjects were small, we also analyzed the risk of metabolic abnormalities excluding BMI. Adolescents with PCOS had a significantly higher number of the remaining metabolic risk factors (than the adolescents without PCOS Table IV. Prevalence of metabolic syndrome and its individual components in adolescents with and without PCOS
BMI $90th percentile BP $90th percentile TG $150 mg/dL TG $110 mg/dL (Ford criteria) Glucose $100 mg/dL HDL #40 mg/dL Metabolic syndrome (Cook criteria)
PCOS (2 criteria)
No PCOS (£1 criteria)
OR (95% CI)
50.3% 27.7% 16.2% 28.3%
22.8% 14% 7% 17.5%
3.6 (1.8-7.1) 2.3 (1.03-5.2) 2.6 (0.9-7.1) 1.8 (0.9-3.8)
2.7% 17.4% 10.8%
1.7% 5.5% 1.7%
1.5 (0.6-7.79) 3.14 (1-10.2) 6.7 (0.9-52.7)
14.8%
7.02%
2.3 (0.8-6.7)
Using the Androgen Excess–PCOS Society Criteria to Diagnose Polycystic Ovary Syndrome and the Risk of Metabolic Syndrome in Adolescents
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(P < .01). More adolescents with PCOS had $2 abnormal metabolic risk factors not including BMI compared with those without PCOS (P < .02)). The majority of the adolescents with PCOS in our study (140/148) met the NIH criteria. Of the 8 subjects with PCOS who did not meet the NIH criteria (high androgen levels and polycystic ovaries), 6 had an elevated BMI, 2 had elevated BP, 1 had low HDL-C, and 1 had high TG based on the Cook criteria. One subject met the Cook criteria of metabolic syndrome.
Discussion Most gynecologists treat irregular menses in adolescents with hormonal regulation or observation for a few years. Similarly, acne is commonly treated with topical medications and combination contraceptive pills. It has therefore been proposed that the diagnosis of PCOS should perhaps be delayed to the postadolescent years. On the contrary, our findings underscore the need to accurately diagnose PCOS at an early age and thereby allow for timely metabolic risk evaluation and early intervention for prevention of cardiovascular disease. We also evaluated the unique group of adolescents who mimic features of PCOS but do meet both AE-PCOS criteria and found a low metabolic risk profile in this group. Milder PCOS phenotypes may be more difficult to identify in the adolescent transition, and waiting to confirm the diagnosis would be prudent given their metabolic findings. Irregular menses is a common presentation in the adolescent girl. Because persistent oligomenorrhea (for >2 years postmenarche) is a stronger predictor of continued irregular menses,7 it has been suggested to defer the diagnosis of PCOS during this time period.2 In our study, all subjects were post spontaneous menarche for >2 years except for 4 subjects who presented with primary amenorrhea. A large proportion of subjects had no menses for >6 months at the time of presentation. It has been reported that hirsutism is not a common presentation in adolescents with PCOS.8,9 In our cohort, hirsutism was one of the presenting symptoms in 65% of adolescents diagnosed with PCOS, but the FG score was elevated in only 37%. Most adolescents in our study described hirsutism as excessive facial hair but minimal hair on other androgensensitive areas of the body. Generalized hirsutism may take longer to develop and our data suggest that an evaluation of serum androgens, in the absence of an abnormal FG score, is essential in this population. In the adult population, one study describes the endocrine evaluation of oligomenorrheic women with minimal hirsutism (FG score <5).10 Interestingly, 50% (94/188) of these women were diagnosed with PCOS and the authors concluded that routine endocrine workup should be performed in all women with minimal unwanted hair. Acne is common in the adolescent age group; however, its validity as a surrogate clinical marker for hyperandrogenism in this population is not established. Several subjects with PCOS in our study were using topical medications and had consulted with a dermatologist regarding the treatment of severe acne. Not surprisingly, nearly one-half of the adolescents 940
Vol. 162, No. 5 who did not have PCOS also presented with acne, confirming that acne is a common complaint during the adolescent period. Further studies are needed to evaluate incorporation of an acne scoring scale into diagnostic PCOS criteria, especially in the adolescent group.11 Given the technical and diagnostic limitations of ultrasound evaluation of polycystic ovaries in the adolescent2 and the ongoing debate regarding the criteria for polycystic ovaries in adults,4 we found that this criterion is better used for confirming the absence of PCOS. For example, for adolescents with hyperandrogenism where the menstrual history did not satisfy the AE-PCOS criteria, we obtained an ultrasound. As a result, 80% of subjects without PCOS had an ultrasound to evaluate their ovaries. Our study has some limitations. We used BMI as a surrogate for waist circumference in the definition of metabolic syndrome. A high correlation between waist circumference and BMI has been reported in the adolescent population6 (r = 0.94). In this study, the 95th percentile for BMI was used as the threshold criterion for obesity, and we used the same cut-off in our study. Also, we did not include a geographically matched control group. Other studies have compared adolescents with PCOS to controls and evaluated the risk of metabolic syndrome. The aim of our study was to identify differences between adolescents with PCOS and those who may have some features that mimic PCOS. Of the controls, 48% had only irregular menses and 28% had only biochemical hyperandrogenemia. The remaining adolescents presented with some irregularity of menses or severe acne but did not meet either AE-PCOS criteria by strict definitions. A few studies have examined the prevalence of metabolic risk in adolescents with PCOS. The risk of metabolic syndrome was reported to be increased in adolescents with PCOS in studies from the US (N = 4912 and N = 3613), India (N = 51),14 and China (N = 128).15 Other studies reported no difference in risk in adolescents with and without PCOS from the US (N = 43)16 and Italy (N = 71).17 The disparity in the prevalence of metabolic syndrome in adolescents is likely due to application of differing diagnostic criteria for both PCOS and metabolic syndrome. In community-based study of adolescent Australian girls with PCOS,9 there was an increased clustering of recognized metabolic risk factors 35.3% in PCOS by NIH criteria and 26.2% in PCOS by Rotterdam criteria compared with 15.4% in adolescents who did not meet either definition of PCOS. In another study, it has been reported that adolescents with different Rotterdam phenotypes may not have a similar metabolic risk.18 Our study includes one of the largest groups of adolescents with PCOS and we report a significantly increased metabolic risk profile. The use of metabolic risk cluster compared with the established metabolic syndrome criteria recognizes that the sequence of events leading to metabolic syndrome begins with obesity and/or insulin resistance and then continues by varying pathways to manifest as clinical disease. In the longitudinal Bogalusa Heart Study, an increase in the number of cardiovascular risk factors in childhood predicted the severity of asymptomatic coronary and aortic atherosclerosis in young people.19 Roe et al
ORIGINAL ARTICLES
May 2013 There are different definitions used to diagnose metabolic syndrome in adolescents involving the same 5 criteria but differing cut-offs. This has resulted in variation in the range of metabolic syndrome prevalence to vary between 2% and 10%. It has been proposed that metabolic syndrome can be used as a marker for intervention in overweight and obese youth. Longitudinal studies of adolescent girls have shown persistence of multiple cardiovascular risk markers from childhood to adulthood.20 In another longitudinal cohort, childhood metabolic syndrome and abnormal metabolic risk factors predict adult type 2 diabetes.20,21 Based on these findings, it seems prudent to screen all adolescents with PCOS for diabetes and lipid abnormalities and provide them with treatment options. In our study, a large proportion of adolescents with PCOS were overweight and obese. The American Heart Association recommends treatment options for childhood obesity based on the presence or absence of comorbidities.21 There are very few studies examining the effects of weight loss on cardiovascular end points in adolescents with PCOS.22,23 We found a higher proportion of metabolic abnormalities in subjects with PCOS compared with adolescents without PCOS even after excluding BMI. These findings indicate screening of all adolescents with PCOS for metabolic risk. Using broad definitions and accommodating different phenotypes of PCOS may be problematic in the adolescent.2 These data underscore the importance of accurate identification of PCOS in the adolescent population. Using similar criteria in the adolescent ($2 years postmenarche) and adult for the diagnosis of PCOS will be more convenient for the clinician. n Submitted for publication Jun 19, 2012; last revision received Oct 11, 2012; accepted Nov 2, 2012. Reprint requests: Anuja Dokras, MD, PhD, Division of Reproductive Endocrinology and Infertility, University of Pennsylvania, 3710 Market St, Philadelphia, PA 19104. E-mail: [email protected]
References 1. Vollman RF. The menstrual cycle. Major Probl Obstet Gynecol 1977;7: 72-123. 2. Carmina E, Oberfield SE, Lobo RA. The diagnosis of polycystic ovary syndrome in adolescents. Am J Obstet Gynecol 2010;203:201.e1-e5. 3. Rosenfield RL. Clinical review: identifying children at risk for polycystic ovary syndrome. J Clin Endocrinol Metab 2007;92:787-96. 4. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, EscobarMorreale HF, Futterweit W , et al., Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009;91:456-88. 5. Porter MB, Brown R, Goldstein SR, Paushter D, Puscheck E, Coutifaris C, et al. AIUM practice guideline for ultrasonography in reproductive medicine. J Ultrasound Med 2009;28:128-37. 6. Johnson WD, Kroon JJ, Greenway FL, Bouchard C, Ryan D, Katzmarzyk PT. Prevalence of risk factors for metabolic syndrome in adolescents: National Health and Nutrition Examination Survey (NHANES), 2001-2006. Arch Pediatr Adolesc Med 2009;163:371-7.
7. van Hooff MH, Voorhorst FJ, Kaptein MB, Hirasing RA, Koppenaal C, Schoemaker J. 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 2004; 19:383-92. 8. van Hooff MH, Voorhorst FJ, Kaptein MB, Hirasing RA, Koppenaal C, Schoemaker J. Polycystic ovaries in adolescents and the relationship with menstrual cycle patterns, luteinizing hormone, androgens, and insulin. Fertil Steril 2000;74:49-58. 9. Hart R, Doherty DA, Mori T, Huang RC, Norman RJ, Franks S, et al. Extent of metabolic risk in adolescent girls with features of polycystic ovary syndrome. Fertil Steril 2011;95:2347-53. 10. Souter I, Sanchez LA, Perez M, Bartolucci AA, Azziz R. The prevalence of androgen excess among patients with minimal unwanted hair growth. Am J Obstet Gynecol 2004;191:1914-20. 11. Ozdemir S, Ozdemir M, G€ orkemli H, Kiyici A, Bodur S. Specific dermatologic features of the polycystic ovary syndrome and its association with biochemical markers of the metabolic syndrome and hyperandrogenism. Acta Obstet Gynecol Scand 2010;89:199-204. 12. Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. J Clin Endocrinol Metab 2006;91:492-7. 13. Leibel NI, Baumann EE, Kocherginsky M, Rosenfield RL. Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome. J Clin Endocrinol Metab 2006;91:1275-83. 14. Bhattacharya SM, Jha A. Prevalence and risk of metabolic syndrome in adolescent Indian girls with polycystic ovary syndrome using the 2009 ‘joint interim criteria’. J Obstet Gynaecol Res 2011;37:1303-7. 15. Huang J, Ni R, Chen X, Huang L, Mo Y, Yang D. Metabolic abnormalities in adolescents with polycystic ovary syndrome in south China. Reprod Biol Endocrinol 2010;8:142. 16. Rossi B, Sukalich S, Droz J, Griffin A, Cook S, Blumkin A, et al. Prevalence of metabolic syndrome and related characteristics in obese adolescents with and without polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93:4780-6. 17. Fulghesu A, Magnini R, Portoghese E, Angioni S, Minerba L, Melis GB. Obesity-related lipid profile and altered insulin incretion in adolescents with polycystic ovary syndrome. Adolesc Health 2010; 46:474-81. 18. Fruzzetti F, Perini D, Lazzarini V, Parrini D, Genazzani AR. Adolescent girls with polycystic ovary syndrome showing different phenotypes have a different metabolic profile associated with increasing androgen levels. Fertil Steril 2009;92:626-34. 19. Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med 1998;338:1650-6. 20. Bao W, Srinivasan SR, Wattigney WA, Berenson GS. Persistence of multiple cardiovascular risk clustering related to syndrome X from childhood to young adulthood: the Bogalusa Heart Study. Arch Intern Med 1994;154:1842-7. 21. Daniels SR, Amett DK, Eckel RH, Gidding SS, Hayman LL, Kumanyika S, et al. Overweight in children and adolescents: pathophysiology, consequences, prevention, and treatment. Circulation 2005;111: 1999-2012. 22. Lass N, Kleber M, Winkel K, Wunsch R, Reinehr T. Effect of lifestyle intervention on features of polycystic ovarian syndrome, metabolic syndrome, and intima-media thickness in obese adolescent girls. J Clin Endocrinol Metab 2011;96:3533-40. 23. Geller DH, Pacaud D, Gordon CM, Misra M , of the Drug and Therapeutics Committee of the Pediatric Endocrine Society. State of the art review: emerging therapies: the use of insulin sensitizers in the treatment of adolescents with polycystic ovary syndrome (PCOS). Int J Pediatr Endocrinol 2011;2011:9.
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ith increasing awareness and clarity in diagnostic criteria for polycystic ovary syndrome (PCOS), a number of adult women are evaluated for this condition. There are currently 3 diagnostic sets of criteria used for adults: the National Institutes of Health (NIH), Rotterdam, and Androgen Excess–PCOS Society (AE-PCOS) criteria. The NIH criteria define PCOS as the presence of oligomenorrhea/anovulation and clinical or biochemical hyperandrogenism. The Rotterdam criteria include women with any 2 of the following 3 criteria: oligomenorrhea/anovulation, clinical or biochemical hyperandrogenism, and polycystic ovaries on ultrasound. The AE-PCOS criteria include women with oligomenorrhea/oligoovulation or polycystic ovaries on ultrasound and clinical or biochemical hyperandrogenism. In all cases, other conditions such as hypothyroidism, hyperprolactinemia, and adrenal disorders that mimic the symptoms of PCOS need to be excluded. As adolescents transition through puberty, they commonly have symptoms mimicking all of the diagnostic criteria for PCOS such as oligomenorrhea/anovulation, signs of clinical hyperandrogenism, and the appearance of polycystic ovaries on ultrasound. Irregular menses are commonly present during the first few years after menarche. By 2 years postmenarche, the majority of adolescent menstrual cycles are normal according to adult standards.1 Based on these findings, it has been suggested that the diagnosis of PCOS should be deferred during the first 2 years after menarche.2 Clinical hyperandrogenism is also difficult to evaluate during adolescence as there is no standardized grading system targeted specifically to this age group for either acne or hirsutism. Proposed risk factors for PCOS, including prenatal exposure to androgens, low birth weight, and premature pubarche, are not well established.3 As a result of these limitations, some women diagnosed with PCOS in adolescence do not meet the established criteria for PCOS on further evaluation as adults. Given the challenges for diagnosis of PCOS in adolescents, some investigators have suggested use of different criteria specific to the adolescent period. On the other hand, it has been argued that accurate diagnosis of PCOS may not be essential during the transitional adolescent period, because clinical management of the patient is usually unaltered.
AE-PCOS BMI BP FG HDL-C NIH PCOS TG
Androgen Excess–PCOS Society Body mass index Blood pressure Ferriman–Gallwey High-density lipoprotein cholesterol National Institutes of Health Polycystic ovary syndrome Triglycerides
From the 1Division of Reproductive Endocrinology and Infertility, and 2Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA The authors declare no conflicts of interest. Portions of the study were presented at the annual meeting of the American Society of Reproductive Medicine, Orlando, FL, October 17-19, 2011. 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.11.019
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The AE-PCOS guidelines consider hyperandrogenism as the core abnormality in PCOS and define the syndrome by the presence of clinical or biochemical hyperandrogenism and irregular menses/anovulation or polycystic appearing ovaries on ultrasound.4 The aims of our study were to determine the usefulness of the adult AE-PCOS criteria in the diagnosis of adolescent subjects referred to a specialty practice. Second, we wanted to determine the metabolic risk in adolescents with AE-PCOS–defined PCOS compared with those adolescents who were referred to our practice but did not meet these criteria.
Methods A retrospective chart review was performed of medical records of all adolescents (#20 years) presenting to a specialty gynecology clinic from 2008 through 2010 for evaluation of PCOS. Medical records were reviewed for demographic information, clinical history, and laboratory data. This study was approved by the Institutional Review Board at the University of Pennsylvania. Diagnosis of PCOS was confirmed by the AE-PCOS criteria4 as follows: hyperandrogenism was defined as biochemical (total testosterone $55 ng/mL) or clinical (Ferriman–Gallwey [FG] score $8), irregular menses were defined as menses #9 times per year, and polycystic appearing ovaries were defined as either ovary having a volume of $10 cm3 on abdominal or transvaginal ultrasound.5 Only volume criteria were used for ultrasound measurements, recognizing that antral follicle counts are not a reliable finding for PCOS in adolescents.2 We obtained an ultrasound when the diagnosis of PCOS could not be clearly established based on menstrual frequency history and hyperandrogenism. All subjects with only hyperandrogenism or only menstrual irregularity had ultrasound results. All oligomenorrheic subjects were at least 2 years postmenarche. If a subject was taking combined oral contraceptives, she was asked to stop for 8 weeks before testosterone measurements. The turbulent-flow liquid chromatography–mass spectrometry method was used to measure total testosterone levels (ARUP Laboratories, University of Utah Research Park, Salt Lake City, Utah). Additional laboratory tests abstracted from the medical records to establish the diagnosis of PCOS included thyroid-stimulating hormone, prolactin, dehydroepiandrosterone sulphate, and 17-hydroxyprogesterone levels. Adolescents who presented to our center and did not meet the earlier AE-PCOS criteria (who had none or only 1 criterion) were compared with the PCOS group. Of 400 charts reviewed, 205 adolescents had adequate data to be accurately classified according to the AE-PCOS criteria and had laboratory testing to define metabolic risk and the presence or absence of metabolic syndrome. Subjects were classified as having metabolic syndrome if they met 3 of the following 5 criteria based on the modified Cook criteria: body mass index (BMI) >90th percentile, serum triglycerides (TG) level $150 mg/dL, serum high-density lipoprotein 938
Vol. 162, No. 5 cholesterol (HDL-C) #40 mg/dL, blood pressure (BP) $90th percentile for age (http://www.nhlbi.nih.gov/ guidelines/hypertension/child_tbl.pdf) or taking antihypertensive medication, and fasting blood glucose $100 mg/dL or the presence of type 2 diabetes mellitus.6 Statistical Analyses Pearson c2 test was performed to compare differences with categorical variables. The 2-sample t tests were used to compare differences between means of the biochemical variables. The differences in the overall metabolic risk (1-4) criteria was analyzed using the Wilcoxon rank sum test. Logistic regression analysis was used to control for variables such as age and race. ORs along with 95% CIs measure the association between PCOS diagnosis and each metabolic risk factor and metabolic syndrome.
Results Of the 205 subjects who met the inclusion criteria of our study, 34.6% did not meet the AE-PCOS criteria for PCOS. Table I shows the demographic information for the 148 adolescents with PCOS with both AE-PCOS criteria and 57 subjects without PCOS (#1 AE-PCOS criteria). The majority of the adolescents with PCOS in our study (140/148) also met the NIH criteria. The mean age at presentation at our center was similar for the 2 groups. The majority of the subjects were white. A higher proportion of adolescents with PCOS had a family history of PCOS, diabetes, hypertension, coronary artery disease, and hyperlipidemia. All subjects were screened for other endocrine conditions that mimic the features of PCOS, such as hypothyroidism, hyperprolactinemia, and adrenal conditions (Table II). Six adolescents with PCOS Table I. Demographic information for adolescents with and without PCOS based on the AE-PCOS criteria Demographics
PCOS (2 criteria)
No PCOS (£1 criteria)
No. Age at presentation, y Age range, y Age at menarche, y Race, % White Black Asian Unknown Other Ethnicity, % Hispanic Non-Hispanic Unknown
148 16.9 1.9 13-20 12.2 1.6
57 16.6 2.5 14-20 12.4 1.4
73.7 14.5 4.6 0.7 6.6
83.0 5.7 1.9 0.0 9.4
3.3 89.5 7.2
1.9 98.1 0.0
Family history, % PCOS Diabetes mellitus Hypertension Coronary artery disease Hyperlipidemia
Maternal
Paternal
Maternal
Paternal
9 26* 21* 10* 14*
0 16* 18* 10* 12*
0 1 1 0 0
0 0 0 0 0
Values for age are mean SD. *P < .01.
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Table II. Endocrine profile in adolescents evaluated for the diagnosis of PCOS
Thyroid-stimulating hormone, mIU/mL Prolactin, ng/mL 17-OH progesterone, ng/dL Dihydroepiandrosterone sulphate, ng/mL
PCOS (2 criteria)
No PCOS (£1 criteria)
2.2 1.5 11.6 6.4 80.2 62.2 266 141
1.8 0.9 8.9 3.6* 66.7 86.7 241.4 126.2
Values are mean SD. *P < .05.
were receiving treatment for hypothyroidism compared with 3 adolescents without PCOS. The most common presenting symptom in the adolescents diagnosed with PCOS was menstrual irregularities (98%), followed by acne, hirsutism, and weight gain. Of the subjects with PCOS and menstrual irregularities, 68.3% had oligomenorrhea, 27.7% presented with secondary amenorrhea (no menses during the preceding 6 months), and 4% presented with primary amenorrhea (no menses up to the age of 16). Of the subjects with PCOS and clinical hyperandrogenism, 37% complained of acne only, 40% had hirsutism only, and 23% had both acne and hirsutism. About one-half of the adolescents with acne had seen a dermatologist and used prescription medications. In addition, 34% of adolescents diagnosed with PCOS complained of recent weight gain as one of their presenting symptoms. Of the adolescents who did not have PCOS, 48% had only irregular menses, 28% had only biochemical hyperandrogenemia, 4% had only polycystic appearing ovaries based on volume criteria, and the remaining met neither criterion after applying the AE-PCOS definition. Fifty percent of the adolescents without PCOS had acne and 15% of these girls were using medications for the treatment of acne. Compared with the adolescents with PCOS, fewer adolescents without PCOS complained of hirsutism (13%, P < .01) and weight gain (11.3%, P < .01). Of the adolescents diagnosed with PCOS, 55% had an ultrasound compared with 80% of the adolescents without PCOS. The mean ovarian volume was 9.62 5.3 cm3 in the PCOS subjects compared with 6.25 2.8 cm3 in the adolescents without PCOS (P < .01). The biomarkers measured for assessing the metabolic risk profile in the 2 groups are shown in Table III. Adolescents with PCOS had a significantly higher BMI compared with the adolescents without PCOS (P < .01), and a larger proportion of adolescents with PCOS were overweight and obese (based on adult definitions). The mean systolic BP was significantly higher in the adolescents with PCOS (P < .01), and 1 subject with PCOS was receiving antihypertensive medications. The mean HDL-C levels were significantly lower in adolescents with PCOS (P < .05). Four adolescents with PCOS and 1 without PCOS had an impaired fasting glucose level (>100 mg/dL). No subjects were diagnosed with diabetes in this cohort. Table IV shows the prevalence of each metabolic risk factor in the 2 groups. The OR for abnormal BMI and BP were significantly higher in the PCOS group.
Table III. Metabolic risk factors in adolescents with and without PCOS
Systolic BP, mm Hg Diastolic BP, mm Hg Fasting glucose, mg/dL Total cholesterol, mg/dL HDL-C, mg/dL Low-density lipoprotein cholesterol, mg/dL TG, mg/dL BMI, kg/m2 <25 25-30 >30
PCOS (2 criteria)
No PCOS (£1 criteria)
117.3 13.3 70.1 8.8 81.1 13.8 178 38.8 52.8 15.7 105 35.9
111.4 11.6† 70.8 6.7 80.8 10.2 179.25 43.9 57.8 13.8* 101 33.1
108.4 85 28.5 7.4 38% 21% 38%
94.8 56.2 24.7 7.1† 77% 9% 9%
Values are mean SD. *P < .05. †P < .01.
A higher percentage of adolescents with PCOS (63.6%) had $1 metabolic risk factor as defined by the Cook criteria for metabolic syndrome compared with the subjects without PCOS (33.3%, P = .002). Also, the distribution of 1-4 risk factors was significantly higher in the PCOS group (P < .02). No adolescent subject had all 5 metabolic risk factors. The prevalence of metabolic syndrome ($3 risk factors) was 10.8% in adolescents with PCOS compared with 1.7% in those without PCOS (P < .04). The unadjusted OR for metabolic syndrome in adolescents with PCOS was 6.7 (95% CI 0.9-52.4, P < .06). The adjusted OR (age and race) was 5.8 (95% CI 0.73-46.6, P < .09). BMI is one of the variables used to calculate the risk of metabolic syndrome; it was not included in the logistic regression model. Only one subject with PCOS and normal BMI (n = 71) had metabolic syndrome and no subjects without PCOS and normal BMI (n = 44) had metabolic syndrome. Of the subjects with BMI >95th percentile for age, 20% of adolescents with PCOS and 7% of adolescents without PCOS had metabolic syndrome (P = .2). Because the groups with only obese or only lean subjects were small, we also analyzed the risk of metabolic abnormalities excluding BMI. Adolescents with PCOS had a significantly higher number of the remaining metabolic risk factors (than the adolescents without PCOS Table IV. Prevalence of metabolic syndrome and its individual components in adolescents with and without PCOS
BMI $90th percentile BP $90th percentile TG $150 mg/dL TG $110 mg/dL (Ford criteria) Glucose $100 mg/dL HDL #40 mg/dL Metabolic syndrome (Cook criteria)
PCOS (2 criteria)
No PCOS (£1 criteria)
OR (95% CI)
50.3% 27.7% 16.2% 28.3%
22.8% 14% 7% 17.5%
3.6 (1.8-7.1) 2.3 (1.03-5.2) 2.6 (0.9-7.1) 1.8 (0.9-3.8)
2.7% 17.4% 10.8%
1.7% 5.5% 1.7%
1.5 (0.6-7.79) 3.14 (1-10.2) 6.7 (0.9-52.7)
14.8%
7.02%
2.3 (0.8-6.7)
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(P < .01). More adolescents with PCOS had $2 abnormal metabolic risk factors not including BMI compared with those without PCOS (P < .02)). The majority of the adolescents with PCOS in our study (140/148) met the NIH criteria. Of the 8 subjects with PCOS who did not meet the NIH criteria (high androgen levels and polycystic ovaries), 6 had an elevated BMI, 2 had elevated BP, 1 had low HDL-C, and 1 had high TG based on the Cook criteria. One subject met the Cook criteria of metabolic syndrome.
Discussion Most gynecologists treat irregular menses in adolescents with hormonal regulation or observation for a few years. Similarly, acne is commonly treated with topical medications and combination contraceptive pills. It has therefore been proposed that the diagnosis of PCOS should perhaps be delayed to the postadolescent years. On the contrary, our findings underscore the need to accurately diagnose PCOS at an early age and thereby allow for timely metabolic risk evaluation and early intervention for prevention of cardiovascular disease. We also evaluated the unique group of adolescents who mimic features of PCOS but do meet both AE-PCOS criteria and found a low metabolic risk profile in this group. Milder PCOS phenotypes may be more difficult to identify in the adolescent transition, and waiting to confirm the diagnosis would be prudent given their metabolic findings. Irregular menses is a common presentation in the adolescent girl. Because persistent oligomenorrhea (for >2 years postmenarche) is a stronger predictor of continued irregular menses,7 it has been suggested to defer the diagnosis of PCOS during this time period.2 In our study, all subjects were post spontaneous menarche for >2 years except for 4 subjects who presented with primary amenorrhea. A large proportion of subjects had no menses for >6 months at the time of presentation. It has been reported that hirsutism is not a common presentation in adolescents with PCOS.8,9 In our cohort, hirsutism was one of the presenting symptoms in 65% of adolescents diagnosed with PCOS, but the FG score was elevated in only 37%. Most adolescents in our study described hirsutism as excessive facial hair but minimal hair on other androgensensitive areas of the body. Generalized hirsutism may take longer to develop and our data suggest that an evaluation of serum androgens, in the absence of an abnormal FG score, is essential in this population. In the adult population, one study describes the endocrine evaluation of oligomenorrheic women with minimal hirsutism (FG score <5).10 Interestingly, 50% (94/188) of these women were diagnosed with PCOS and the authors concluded that routine endocrine workup should be performed in all women with minimal unwanted hair. Acne is common in the adolescent age group; however, its validity as a surrogate clinical marker for hyperandrogenism in this population is not established. Several subjects with PCOS in our study were using topical medications and had consulted with a dermatologist regarding the treatment of severe acne. Not surprisingly, nearly one-half of the adolescents 940
Vol. 162, No. 5 who did not have PCOS also presented with acne, confirming that acne is a common complaint during the adolescent period. Further studies are needed to evaluate incorporation of an acne scoring scale into diagnostic PCOS criteria, especially in the adolescent group.11 Given the technical and diagnostic limitations of ultrasound evaluation of polycystic ovaries in the adolescent2 and the ongoing debate regarding the criteria for polycystic ovaries in adults,4 we found that this criterion is better used for confirming the absence of PCOS. For example, for adolescents with hyperandrogenism where the menstrual history did not satisfy the AE-PCOS criteria, we obtained an ultrasound. As a result, 80% of subjects without PCOS had an ultrasound to evaluate their ovaries. Our study has some limitations. We used BMI as a surrogate for waist circumference in the definition of metabolic syndrome. A high correlation between waist circumference and BMI has been reported in the adolescent population6 (r = 0.94). In this study, the 95th percentile for BMI was used as the threshold criterion for obesity, and we used the same cut-off in our study. Also, we did not include a geographically matched control group. Other studies have compared adolescents with PCOS to controls and evaluated the risk of metabolic syndrome. The aim of our study was to identify differences between adolescents with PCOS and those who may have some features that mimic PCOS. Of the controls, 48% had only irregular menses and 28% had only biochemical hyperandrogenemia. The remaining adolescents presented with some irregularity of menses or severe acne but did not meet either AE-PCOS criteria by strict definitions. A few studies have examined the prevalence of metabolic risk in adolescents with PCOS. The risk of metabolic syndrome was reported to be increased in adolescents with PCOS in studies from the US (N = 4912 and N = 3613), India (N = 51),14 and China (N = 128).15 Other studies reported no difference in risk in adolescents with and without PCOS from the US (N = 43)16 and Italy (N = 71).17 The disparity in the prevalence of metabolic syndrome in adolescents is likely due to application of differing diagnostic criteria for both PCOS and metabolic syndrome. In community-based study of adolescent Australian girls with PCOS,9 there was an increased clustering of recognized metabolic risk factors 35.3% in PCOS by NIH criteria and 26.2% in PCOS by Rotterdam criteria compared with 15.4% in adolescents who did not meet either definition of PCOS. In another study, it has been reported that adolescents with different Rotterdam phenotypes may not have a similar metabolic risk.18 Our study includes one of the largest groups of adolescents with PCOS and we report a significantly increased metabolic risk profile. The use of metabolic risk cluster compared with the established metabolic syndrome criteria recognizes that the sequence of events leading to metabolic syndrome begins with obesity and/or insulin resistance and then continues by varying pathways to manifest as clinical disease. In the longitudinal Bogalusa Heart Study, an increase in the number of cardiovascular risk factors in childhood predicted the severity of asymptomatic coronary and aortic atherosclerosis in young people.19 Roe et al
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May 2013 There are different definitions used to diagnose metabolic syndrome in adolescents involving the same 5 criteria but differing cut-offs. This has resulted in variation in the range of metabolic syndrome prevalence to vary between 2% and 10%. It has been proposed that metabolic syndrome can be used as a marker for intervention in overweight and obese youth. Longitudinal studies of adolescent girls have shown persistence of multiple cardiovascular risk markers from childhood to adulthood.20 In another longitudinal cohort, childhood metabolic syndrome and abnormal metabolic risk factors predict adult type 2 diabetes.20,21 Based on these findings, it seems prudent to screen all adolescents with PCOS for diabetes and lipid abnormalities and provide them with treatment options. In our study, a large proportion of adolescents with PCOS were overweight and obese. The American Heart Association recommends treatment options for childhood obesity based on the presence or absence of comorbidities.21 There are very few studies examining the effects of weight loss on cardiovascular end points in adolescents with PCOS.22,23 We found a higher proportion of metabolic abnormalities in subjects with PCOS compared with adolescents without PCOS even after excluding BMI. These findings indicate screening of all adolescents with PCOS for metabolic risk. Using broad definitions and accommodating different phenotypes of PCOS may be problematic in the adolescent.2 These data underscore the importance of accurate identification of PCOS in the adolescent population. Using similar criteria in the adolescent ($2 years postmenarche) and adult for the diagnosis of PCOS will be more convenient for the clinician. n Submitted for publication Jun 19, 2012; last revision received Oct 11, 2012; accepted Nov 2, 2012. Reprint requests: Anuja Dokras, MD, PhD, Division of Reproductive Endocrinology and Infertility, University of Pennsylvania, 3710 Market St, Philadelphia, PA 19104. E-mail: [email protected]
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7. van Hooff MH, Voorhorst FJ, Kaptein MB, Hirasing RA, Koppenaal C, Schoemaker J. 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 2004; 19:383-92. 8. van Hooff MH, Voorhorst FJ, Kaptein MB, Hirasing RA, Koppenaal C, Schoemaker J. Polycystic ovaries in adolescents and the relationship with menstrual cycle patterns, luteinizing hormone, androgens, and insulin. Fertil Steril 2000;74:49-58. 9. Hart R, Doherty DA, Mori T, Huang RC, Norman RJ, Franks S, et al. Extent of metabolic risk in adolescent girls with features of polycystic ovary syndrome. Fertil Steril 2011;95:2347-53. 10. Souter I, Sanchez LA, Perez M, Bartolucci AA, Azziz R. The prevalence of androgen excess among patients with minimal unwanted hair growth. Am J Obstet Gynecol 2004;191:1914-20. 11. Ozdemir S, Ozdemir M, G€ orkemli H, Kiyici A, Bodur S. Specific dermatologic features of the polycystic ovary syndrome and its association with biochemical markers of the metabolic syndrome and hyperandrogenism. Acta Obstet Gynecol Scand 2010;89:199-204. 12. Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. J Clin Endocrinol Metab 2006;91:492-7. 13. Leibel NI, Baumann EE, Kocherginsky M, Rosenfield RL. Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome. J Clin Endocrinol Metab 2006;91:1275-83. 14. Bhattacharya SM, Jha A. Prevalence and risk of metabolic syndrome in adolescent Indian girls with polycystic ovary syndrome using the 2009 ‘joint interim criteria’. J Obstet Gynaecol Res 2011;37:1303-7. 15. Huang J, Ni R, Chen X, Huang L, Mo Y, Yang D. Metabolic abnormalities in adolescents with polycystic ovary syndrome in south China. Reprod Biol Endocrinol 2010;8:142. 16. Rossi B, Sukalich S, Droz J, Griffin A, Cook S, Blumkin A, et al. Prevalence of metabolic syndrome and related characteristics in obese adolescents with and without polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93:4780-6. 17. Fulghesu A, Magnini R, Portoghese E, Angioni S, Minerba L, Melis GB. Obesity-related lipid profile and altered insulin incretion in adolescents with polycystic ovary syndrome. Adolesc Health 2010; 46:474-81. 18. Fruzzetti F, Perini D, Lazzarini V, Parrini D, Genazzani AR. Adolescent girls with polycystic ovary syndrome showing different phenotypes have a different metabolic profile associated with increasing androgen levels. Fertil Steril 2009;92:626-34. 19. Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med 1998;338:1650-6. 20. Bao W, Srinivasan SR, Wattigney WA, Berenson GS. Persistence of multiple cardiovascular risk clustering related to syndrome X from childhood to young adulthood: the Bogalusa Heart Study. Arch Intern Med 1994;154:1842-7. 21. Daniels SR, Amett DK, Eckel RH, Gidding SS, Hayman LL, Kumanyika S, et al. Overweight in children and adolescents: pathophysiology, consequences, prevention, and treatment. Circulation 2005;111: 1999-2012. 22. Lass N, Kleber M, Winkel K, Wunsch R, Reinehr T. Effect of lifestyle intervention on features of polycystic ovarian syndrome, metabolic syndrome, and intima-media thickness in obese adolescent girls. J Clin Endocrinol Metab 2011;96:3533-40. 23. Geller DH, Pacaud D, Gordon CM, Misra M , of the Drug and Therapeutics Committee of the Pediatric Endocrine Society. State of the art review: emerging therapies: the use of insulin sensitizers in the treatment of adolescents with polycystic ovary syndrome (PCOS). Int J Pediatr Endocrinol 2011;2011:9.
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