ARTICLE. Primary Amenorrhea as a Manifestation of Polycystic Ovarian Syndrome in Adolescents

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1 ARTICLE Primary Amenorrhea as a Manifestation of Polycystic Ovarian Syndrome in Adolescents A Unique Subgroup? Marianna Rachmiel, MD; Sari Kives, MD; Eshetu Atenafu, MSc; Jill Hamilton, MD, MSc Objective: To compare clinical and metabolic features of adolescents having primary amenorrhea () and polycystic ovarian syndrome (PCOS) with those having oligomenorrhea or secondary amenorrhea () and PCOS. Design: Retrospective case-control study. Setting: Endocrine Gynecology Clinic at The Hospital for Sick Children, Toronto, Ontario, Canada. Patients: Girls and young women aged 14 to 18 years having and PCOS (n=9) seen during a year period were compared with control subjects having and PCOS (n=18) randomly selected during the same period. Intervention: Medical record review was performed to assess clinical, biochemical, and ultrasonographic measures, as well as response to a progesterone challenge. Main Outcome Measures: Differences in response to the progesterone challenge, hyperandrogenism, and the presence of features of the metabolic syndrome. Results: Compared with adolescents having, adolescents having demonstrated older age at pubarche, higher androstenedione levels, greater prevalence of family history of obesity, a tendency toward no withdrawal bleeding in response to the progesterone challenge, and more features associated with the metabolic syndrome (acanthosis nigricans, higher diastolic blood pressure, and lower high-density lipoprotein cholesterol level). No significant correlation was demonstrated between response to the progesterone challenge, metabolic features, and androstenedione levels. Conclusion: Adolescents with and PCOS exhibit increased features of the metabolic syndrome and higher androstenedione levels and may represent a more severe spectrum of a common condition. Arch Pediatr Adolesc Med. 2008;162(6): Author Affiliations: Division of Pediatrics, Assaf Harofeh Medical Center, Tel Aviv University, Zerifin, Israel (Dr Rachmiel); and Division of Endocrinology (Drs Rachmiel and Hamilton), Section of Gynecology (Dr Kives), and Child Health Evaluative Sciences (Mr Atenafu), The Hospital for Sick Children, Toronto, Ontario, Canada. POLYCYSTIC OVARIAN SYNdrome (PCOS) is a heterogeneous condition with a spectrum of clinical and biochemical features, including symptoms of anovulation, hyperandrogenism, and polycystic ovaries. Obesity is a feature in 35% to 50% of cases. 1-3 There is evidence that insulin resistance, hyperinsulinism, and typical features of the metabolic syndrome (MS) are associated with the development of PCOS and its late metabolic implications. 1,4-6 Many of the features appear during early adolescence as secondary amenorrhea (SA) or oligomenorrhea (OM) and as symptoms of hyperandrogenism such as acne and hirsutism. 1,7-9 Primary amenorrhea () is an uncommon manifestation of PCOS. 10,11 Literature regarding and PCOS is scant. The reported percentage of as an initial feature in PCOS among small cohorts has varied between 1.4% 12 and 14%. 9,13 Nduwayo et al 14 described 9 patients with PCOS and, all of whom had signs of hyperandrogenism. Dramusic et al 9,13 noted that most obese adolescents with PCOS had or prolonged SA, while girls of normal weight had OM. To our knowledge, no studies have compared specific clinical and biochemical features in adolescents with and PCOS vs those with and PCOS. We hypothesized that adolescents with PCOS and may represent a more severe spectrum of the PCOS disorder and exhibit a greater degree of hyperandrogenemia and metabolic disturbances. The objective of this study was to compare the clinical, biochemical, and radiologic features of adolescents having and PCOS with those having and PCOS. 521

2 Table 1. Clinical Characteristics of Subjects With Polycystic Ovarian Syndrome and Primary Amenorrhea () vs Oligomenorrhea or Secondary Amenorrhea () Characteristic Patients With (n=9) METHODS DEFINITIONS Primary amenorrhea was defined as no menstrual bleeding by age 16 years or older or no menarche at least 4 years after initiation of secondary sexual signs. Oligomenorrhea was defined as fewer than 9 menses per year. Secondary amenorrhea was defined as no menses for 6 months. 8 To decrease the possible confounder of physiologic anovulatory cycles occurring after menarche, OM and SA were only considered if present at least 2 years after menarche. Polycystic ovarian syndrome was defined according to the revised 2003 Rotterdam ESHRE/ASRM Sponsored PCOS Consensus Workshop Group statement. 15 Metabolic syndrome was defined according to criteria by Weiss et al. 16 STUDY POPULATION Control Subjects With (n=18) P Value a Age, mean (SD), y 15.6 (1.0) 15.8 (1.1).65 Family history, % (No. of Hirsutism 50 (3/6) 25 (3/12).34 Menstrual abnormalities 0 (0/8) 27 (4/15).26 Obesity 67 (6/9) 22 (4/18).04 Type 2 diabetes mellitus 67 (6/9) 100 (18/18).68 Age at pubarche, mean (SD), y 11.2 (2.1) 9.8 (1.1).03 Age at thelarche, mean (SD), y 11.2 (1.7) 10.0 (1.2).06 Body mass index z score, 2.1 (0.4) 1.5 (1.0).08 mean (SD) Age at menarche, mean (SD), y (1.2)... Cycle length, mean (SD), d (1.6)... Acanthosis nigricans, % (No.) 67 (6) 22 (4).04 Hirsutism, % (No.) None 0 28 (5) Mild 33 (3) 33 (6) Moderate 33 (3) 28 (5).26 Severe 33 (3) 11 (2) Acne, % (No.) None 22 (2) 33 (6) Mild 33 (3) 28 (5) Moderate 33 (3) 17 (3).80 Severe 11 (1) 22 (4) Blood pressure percentile, mean (SD) Systolic 74.2 (20.6) 69.5 (20.1).43 Diastolic 85.3 (16.0) 70.8 (17.8).04 Metabolic syndrome, % (No. of 38 (3/8) 19 (3/16).36 Abbreviation: Ellipses, not applicable. a Fisher exact test for discrete variables expressed as percentages and nonparametric Kruskal-Wallis test for continuous variables expressed as mean (SD). This was a case-control study. All medical records of adolescents referred to the Endocrine Gynecology Clinic at The Hospital for Sick Children, Toronto, Ontario, Canada, from November 1, 2003, to May 31, 2006, with were reviewed. Inclusion criteria for the cases included and PCOS. Investigations to rule out other causes of included prolactin level, Table 2. Metabolic Characteristics, Hormonal Profiles, Pelvic Ultrasonography Findings, and Responses to Progesterone Challenge (PC) Variable Patients With thyroid function, evaluation of the hypothalamic-pituitaryovarian axis, ultrasonography to detect structural genitourinary anomalies, and screening for congenital adrenal hyperplasia and Cushing syndrome. The control group (2 controls for every case) included adolescents with and PCOS who were seen during the same year period. This group was randomly collected as the first 2 patients seen at the clinic during the same month as each patient with. DATA COLLECTION Control Subjects With P Value a Luteinizing hormone level, mean 9.2 (3.8) 10.2 (4.4).44 (SD), miu/ml Follicle-stimulating hormone level, 5.7 (1.9) 5.8 (2.0).80 mean (SD), miu/ml Dehydroepiandrosterone sulfate 204 (96) 230 (93).60 level, mean (SD), µg/dl Testosterone level, mean (SD), 130 (46) 84 (32).07 ng/dl Free testosterone level, mean 15.5 (8.6) 9.9 (4.6).13 (SD), pmol/l Androstenedione level, mean 350 (149) 221 (92).05 (SD), ng/dl Triglyceride level, mean (SD), 133 (35) 115 (53).49 Cholesterol level, mean (SD), Low-density lipoprotein 93 (12) 108 (43).42 High-density lipoprotein 31 (4) 43 (12).04 Oral glucose tolerance test Fasting glucose level, mean 92 (18) 81 (11).07 (SD), 2-h Glucose level, mean (SD), 115 (16) 130 (47).93 Fasting insulin level, mean 45.0 (32.1) 20.4 (17.0).06 (SD), µiu/ml Pelvic ultrasonography findings Polycystic ovaries, % (No. of 50 (4/8) 27 (3/11).38 Endometrium thickness, mean 2.8 (1.1) 4.2 (1.8).13 (SD), mm Response to PC, % (No. of 40 (2/5) 100 (6/6).06 Abbreviations: OM, oligomenorrhea;, primary amenorrhea; SA, secondary amenorrhea. SI conversion factors: To convert luteinizing hormone level and follicle-stimulating hormone level to international units per liter, multiply by 1.0; dehydroepiandrosterone sulfate level to micromoles per liter, multiply by 0.027; testosterone level to nanomoles per liter, multiply by ; androstenedione level to nanomoles per liter, multiply by ; triglyceride level to millimoles per liter, multiply by ; cholesterol level to millimoles per liter, multiply by ; glucose level to millimoles per liter, multiply by ; insulin level to picomoles per liter, multiply by a Fisher exact test for discrete variables expressed as percentages and nonparametric Kruskal-Wallis test for continuous variables expressed as mean (SD). Data collected included the following: (1) Demographic characteristics (age, race/ethnicity, and family history). (2) Coexisting medical illness and medications. (3) Clinical and physical findings (acne, obesity, hirsutism, elevated blood pressure, 522

3 Level, ng/dl 300 Level, pmol/l Androstenedione Testosterone Free Testosterone Figure. Comparison of serum levels of androstenedione, testosterone, and free testerone between the study groups. To convert androstenedione to nanomoles per liter, multiply by ; and testosterone to nonomoles per liter, multiply by , A, For comparisons between the 2 groups, P=.05 for androstenedione and P=.07 for testosterone. B, For comparison between the 2 groups for free testosterone, P=.13. OM indicates oligomenorrhea;, primary amenorrhea; SA, secondary amenorrhea; lines within boxes, median; limits of boxes, 25th and 75th percentiles; extensions of boxes, minimum and maximum; and plus signs, means. and acanthosis nigricans). (4) Laboratory results (lipid profile, the levels of fasting and 2-hour glucose following an oral glucose tolerance test, and the levels of insulin, androstenedione [Diagnostic Products, Los Angeles, California], 17- hydroxyprogesterone [Diagnostic Products], estradiol [DiaSorin Diagnostics, Saluggia, Italy], free testosterone [Coat-A- Count, Diagnostic Products], dehydroepiandrosterone sulfate [Immulite, Diagnostic Products], serum gonadotropins [luteinizing hormone and follicle-stimulating hormone], and testosterone [Chemiluminescence Immunoassay; Bayer Corporation, West Haven, Connecticut]). (5) Ultrasonographic variables based on 2003 Rotterdam ESHRE/ASRM Sponsored PCOS Consensus Group criteria for PCOS. 15 (6) Withdrawal bleeding in response to progesterone challenge (PC). The study was approved by the Institutional Ethics Review Board of The Hospital for Sick Children. STATISTICAL ANALYSIS Statistical analysis was performed using commercially available software (SAS version 9.1; SAS Institute Inc, Cary, North Carolina). The nonparametric Kruskal-Wallis test for continuous variables and the Fisher exact test for categorical variables were used to evaluate differences between the and groups. Spearman rank correlation was performed to evaluate associations between variables. P.05 was considered significant. RESULTS There were 9 subjects aged 14 to 18 years with and PCOS, matched to 18 subjects with. Subjects represented various racial/ethnic backgrounds. Adolescents with and PCOS had statistically significantly increased family history of obesity and more features associated with MS (acanthosis nigricans, higher diastolic blood pressure, and lower high-density lipoprotein cholesterol level) (P=.04 for all) (Table 1 and Table 2). The association between MS and obesity was statistically significant (P=.002). Subjects with had pubarche and thelarche later than subjects with ; however, both were within the normal range. Features of hyperandrogenism were similar in the 2 groups. There was no significant difference in the hormonal profiles except for androstenedione levels (Figure). Ultrasonography findings were similar between the 2 groups. A subset of subjects underwent PC. All 6 in the group exhibited a large amount of withdrawal bleeding; only 2 of 5 in the group responded to PC (P=.06). No association was detected between response to PC, androstenedione levels, and ultrasonography findings. COMMENT We hypothesized that the group of adolescents having PCOS and would exhibit a greater degree of hyperandrogenism and metabolic dysfunction compared with adolescents having PCOS and. The prevalence of MS among youth in the United States varies between 4.2% and 8.4% in the general population but rises to 28% to 39% among obese adolescents (body mass index, 95th 523

4 percentile) depending on the definition criteria used The incidence of the MS was similar in the present study, at 25% among the cohort. In contrast, Coviello et al 20 reported MS rates of 11% in overweight girls and 63% in obese girls with PCOS. Differences in the results may be accounted for by differences in the number of subjects, duration of symptoms, degree of obesity among the subjects assessed, or definitions used of the MS and PCOS during adolescence. Although the group did not have a higher prevalence of MS compared with the group, the group demonstrated more acanthosis nigricans, higher diastolic blood pressure, slightly elevated fasting insulin levels, slightly higher body mass index z score, and lower high-density lipoprotein cholesterol levels. Together, this suggests that adolescents with PCOS and may have a higher risk for features of MS than those with PCOS and. Further prospective study among larger numbers of adolescent patients is warranted. Adult women with PCOS have higher rates of MS and type 2 diabetes mellitus and increased risk factors for cardiovascular disease, linked to the role of hyperinsulinism in the pathogenesis of PCOS, and it would be valuable to identify young women at greatest risk for these comorbidities. 21 The group had higher androstenedione levels compared with the group. Higher serum androstenedione levels have been previously described in adolescents with PCOS, related to the hypothesis of isolated functional ovarian hyperandrogenism as being causative. 3,22,23 We did not find evidence of a history of premature adrenarche or elevation of dehydroepiandrosterone sulfate levels, which have been reported in patients with PCOS. 23 Although hyperandrogenism is a core feature of PCOS, most adolescents with PCOS exhibit elevated estrogen levels with thickened endometrial lining, anovulatory cycles, and OM or SA. 24 Hyperandrogenism has been suggested as a rare cause of negative withdrawal response to PC due to a persistently decidualized endometrium induced by a prolonged anovulatory state. 24 Our study results support this assumption because the adolescents with had laboratory evidence of higher serum androstenedione levels and lack of response to PC. This study has some limitations. First, the study included a small number of subjects and a retrospective nature of evaluation, leading to potential bias in recall of puberty onset. However, all patients attended a specialized clinic and likely had heightened concerns about puberty, potentially improving the accuracy of patient recall. Second, PCOS can be difficult to diagnose in this age group because girls may indeed have acne, irregular bleeding, and physiologic anovulatory cycles following menarche. 9,25,26 By including those with for comparison at least 2 years after menarche, we minimized this potential confounder. Third, the use of the free testosterone assay, rather than the calculated free androgen index, may underestimate the degree of hyperandrogenemia. The free testosterone assay has been criticized for representing only 20% to 60% of the free testosterone measured by equilibrium dialysis. 27 Although the link between and PCOS has been mentioned briefly in the literature, PCOS is rarely listed as a differential diagnosis for. Although PCOS is becoming more prevalent in parallel with rising obesity rates, studies 9-14 have not evaluated the clinical features of this subgroup of patients with -PCOS. We conclude that adolescents with -PCOS are similar in many respects to those with, but they demonstrate more features of MS and have higher androstenedione levels and lower frequency of response to PC. Accordingly, this may indicate elevated androgen levels or enhanced sensitivity to androgen with persistent decidualization of the endometrium. Further studies in a larger cohort of patients to determine the frequency of this finding are warranted. Finally, it is important for health care providers to recognize that may be due to PCOS so that appropriate investigative and management strategies may be undertaken. Accepted for Publication: November 16, Correspondence: Marianna Rachmiel, MD, Division of Pediatrics, Assaf Harofeh Medical Center, Tel Aviv University, Zerifin, Israel (rmarianna@gmail.com). Author Contributions: Drs Rachmiel and Hamilton had complete access to all data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Rachmiel, Kives, and Hamilton. Acquisition of data: Rachmiel. Analysis and interpretation of data: Rachmiel, Atenafu, and Hamilton. Drafting of the manuscript: Rachmiel and Hamilton. Critical revision of the manuscript for important intellectual content: Kives, Atenafu, and Hamilton. Statistical analysis: Atenafu and Hamilton. Administrative, technical, and material support: Rachmiel. Supervision: Kives and Hamilton. Financial Disclosure: None reported. REFERENCES 1. Franks S. Adult polycystic ovary syndrome begins in childhood. Best Pract Res Clin Endocrinol Metab. 2002;16(2): Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998;83(9): Buggs C, Rosenfield RL. Polycystic ovary syndrome in adolescence. Endocrinol Metab Clin North Am. 2005;34(3): Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18(6): Legro RS, Kunselman AR, Dodson WC, Dunaif A. 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. 1999;84(1): Macut D, Micić D, Cvijović G, et al. Cardiovascular risk in adolescent and young adult obese females with polycystic ovary syndrome (PCOS). J Pediatr Endocrinol Metab. 2001;14(suppl 5): van Hooff MH, Voorhorst FJ, Kaptein MB, Hirasing RA, Koppenaal C, Schoemaker J. Endocrine features of polycystic ovary syndrome in a random population sample of year old adolescents. Hum Reprod. 1999;14(9): Rosenfield RL, Ghai K, Ehrmann DA, Barnes RB. Diagnosis of the polycystic ovary syndrome in adolescence: comparison of adolescent and adult hyperandrogenism. J Pediatr Endocrinol Metab. 2000;13(suppl 5): Dramusic V, Rajan U, Chan P, Ratnam SS, Wong YC. Adolescent polycystic ovary syndrome. Ann N Y Acad Sci. 1997;816: Franks S. Polycystic ovary syndrome. N Engl J Med. 1995;333(13): Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril. 2004;82(suppl 1):S33-S Obhrai M, Lynch SS, Holder G, Jackson R, Tang L, Butt WR. Hormonal studies 524

5 on women with polycystic ovaries diagnosed by ultrasound. Clin Endocrinol (Oxf ). 1990;32(4): Dramusic V, Goh VH, Rajan U, Wong YC, Ratnam SS. Clinical, endocrinologic, and ultrasonographic features of polycystic ovary syndrome in Singaporean adolescents. J Pediatr Adolesc Gynecol. 1997;10(3): Nduwayo L, Despert F, Lecomte C, Lecomte P. Primary amenorrhea revealing micropolycystic ovary syndrome [in French]. Presse Med. 1992;21(23): Rotterdam ESHRE/ASRM Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1): Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. 2004;350(23): Cook S. The metabolic syndrome: antecedent of adult cardiovascular disease in pediatrics. J Pediatr. 2004;145(4): Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, Arch Pediatr Adolesc Med. 2003; 157(8): Goodman E, Daniels SR, Morrison JA, Huang B, Dolan LM. Contrasting prevalence of and demographic disparities in the World Health Organization and National Cholesterol Education Program Adult Treatment Panel III definitions of metabolic syndrome among adolescents. J Pediatr. 2004;145(4): 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(2): Teede HJ, Hutchison S, Zoungas S, Meyer C. Insulin resistance, the metabolic syndrome, diabetes, and cardiovascular disease risk in women with PCOS. Endocrine. 2006;30(1): Harwood K, Vuguin P, DiMartino-Nardi J. Current approaches to the diagnosis and treatment of polycystic ovarian syndrome in youth. Horm Res. 2007;68 (5): Ibáñez L, de Zegher F, Potau N. Premature pubarche, ovarian hyperandrogenism, hyperinsulinism and the polycystic ovary syndrome: from a complex constellation to a simple sequence of prenatal onset. J Endocrinol Invest. 1998; 21(9): Speroff LGR, Kase NG. Clinical Gynecology, Endocrinology and Infertility. 6th ed. Baltimore, MD: Lippincott Williams & Wilkins; 1999: Apter D, Viinikka L, Vihko R. Hormonal pattern of adolescent menstrual cycles. J Clin Endocrinol Metab. 1978;47(5): Driscoll DA. Polycystic ovary syndrome in adolescence. Ann N Y Acad Sci. 2003; 997: Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999; 84(10): Announcement Trial Registration Required. In concert with the International Committee of Medical Journal Editors (ICMJE), Archives of Pediatrics and Adolescent Medicine will require, as a condition of consideration for publication, registration of all trials in a public trials registry (such as ClinicalTrials.gov). Trials must be registered at or before the onset of patient enrollment. This policy applies to any clinical trial starting enrollment after July 1, For trials that began enrollment before this date, registration will be required by September 13, 2005, before considering the trial for publication. The trial registration number should be supplied at the time of submission. For details about this new policy, and for information on how the ICMJE defines a clinical trial, see the editorials by DeAngelis et al in the September 8, 2004 (2004; 292: ) and June 15, 2005 (2005;293: ) issues of JAMA. Also see the Instructions to Authors on our Web site: 525

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