The Diagnosis of Polycystic Ovary Syndrome during Adolescence

Hormone Research in Paediatrics

Volumn 83, Issue 6, 2015, Pages 376-389

  Witchel, Selma F ^a   Oberfield, Sharon ^b   Rosenfield, Robert L ^c   Codner, Ethel ^d   Bonny, Andrea ^e   Ibáñez, Lourdes ^f   Pena, Alexia ^g   Horikawa, Reiko ^h   Gomez Lobo, Veronica ⁱ   Joel, Dipesalema ^j   Tfayli, Hala ^k   Arslanian, Silva ^a   Dabadghao, Preeti ^l   Garcia Rudaz, Cecilia ^m   Lee, Peter A ⁿ  

^a CHILDREN S HOSPITAL OF PITTSBURGH   (United States)

^b NEW YORK PRESBYTERIAN HOSPITAL   (United States)

^c UNIVERSITY OF CHICAGO   (United States)

^d UNIVERSITY OF CHILE   (Chile)

^e OHIO STATE UNIVERSITY   (United States)

^f UNIVERSITY OF BARCELONA   (Spain)

^g UNIVERSITY OF ADELAIDE   (Australia)

^h NATIONAL CENTER FOR CHILD HEALTH AND DEVELOPMENT   (Japan)

ⁱ GEORGETOWN UNIVERSITY   (United States)

^j PRINCESS MARINA HOSPITAL   (Botswana)

^k AMERICAN UNIVERSITY OF BEIRUT   (Lebanon)

^l SANJAY GANDHI POSTGRADUATE INSTITUTE OF MEDICAL SCIENCES   (India)

^m MONASH CHILDREN S HOSPITAL   (Australia)

ⁿ PENN STATE MILTON S HERSHEY MEDICAL CENTER   (United States)

more..

Author keywords

Hyperandrogenism; Ovarian hyperandrogenism; Ovary; Polycystic ovary syndrome; Puberty

Indexed keywords

TESTOSTERONE;

ADOLESCENT; AMENORRHEA; ANOVULATION; ARTICLE; BIOCHEMICAL ANALYSIS; COMORBIDITY; DIAGNOSTIC ERROR; FEMALE; HORMONE DETERMINATION; HUMAN; HYPERANDROGENISM; HYPERINSULINEMIA; INSULIN RESISTANCE; LABORATORY TEST; MEDICAL HISTORY; MENSTRUATION; OBESITY; OVARY POLYCYSTIC DISEASE; PHYSICAL EXAMINATION; PRACTICE GUIDELINE; PREVALENCE; PRIORITY JOURNAL; PUBERTY;

EID: 84937519689     PISSN: 16632818     EISSN: 16632826     Source Type: Journal    
DOI: 10.1159/000375530     Document Type: Article

References (163)

1. Fauser BC, Tarlatzis RW, Rebar RS, et al: Consensus on women's health aspects of polycys-tic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril 2012; 97:28-38.e25.
2. Azziz R, Sanchez ES, Knochenhauer C, et al: Androgen excess in women: experience with over 1, 000 consecutive patients. J Clin Endo-crinol Metab 2004; 89:453-462.
3. Carmina E, Rosato F, Janni A, Rizzo M, Longo RA: Extensive clinical experience: relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism. J Clin Endocrinol Metab 2006; 91:2-6.
4. Rosenfield RL: Identifying children at risk of polycystic ovary syndrome. J Clin Endocrinol Metab 2007; 92:787-796.
5. Franks S: Polycystic ovary syndrome in adolescents. Int J Obes (Lond) 2008; 32:1035-1041.
6. Stein IF, Leventhal ML: Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935; 29:181-191.
7. Nelson VL, Legro RS, Strauss JF, McAllister JM: Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. Mol Endo-crinol 1999; 13:946-957.
8. McAllister JM, Modi B, Miller BA, et al: Over-expression of a DENND1A isoform produces a polycystic ovary syndrome theca pheno-type. Proc Natl Acad Sci USA 2014; 111: 1519-E1527.
9. Ibáñez L, Ong KK, López-Bermejo A, Dunger DB, de Zegher F: Hyperinsulinaemic andro-gen excess in adolescent girls. Nat Rev Endo-crinol 2014; 10:499-508.
10. Zawadzki J, Dunaif A: Diagnostic criteria for polycystic ovary syndrome: towards a rational approach; in Dunaif A, Givens JR, Haseltine FP, Merriam GR (eds): Polycystic Ovary Syndrome. Boston, Blackwell Scientific Publications 1992, vol 4, pp 377-384.
11. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81:19-25.
12. Azziz R, Carmina E, Dewailly D, et al: The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009; 91: 456-488.
13. Johnson T, Kaplan L, Ouyang P, Rizza R: National Institutes of Health Evidence-Based Methodology Workshop on Polycystic Ovary Syndrome (PCOS). NIH EbMW Report. Bethesda, National Institutes of Health, 2012, vol 1, pp 1-14.
14. Barber TM, Wass JA, McCarthy I, Franks S: Metabolic characteristics of women with polycystic ovaries and oligo-amenorrhoea but normal androgen levels: implications for the management of polycystic ovary syndrome. Clin Endocrinol (Oxf) 2007; 66:513-517.
15. Guastella E, Longo RA, Carmina E: Clinical and endocrine characteristics of the main polycystic ovary syndrome phenotypes. Fertil Steril 2010; 94:2197-2201.
16. Panidis D, Tziomalos K, Misichronis G, et al: insulin resistance and endocrine characteristics of the different phenotypes of polycystic ovary syndrome: a prospective study. Hum Reprod 2012; 27:541-549.
17. Conway G, Dewailly D, Diamanti-Kandara-kis E, Escobar-Morreale HF, Franks S, Gam-bineri A, Kelestimur F, Macut D, Micic D, Pasquali R, Pfeifer M, Pignatelli D, Pugeat M, Yildiz BO; ESE PCOS Special Interest Group: The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur J Endocrinol 2014; 171:P1-P29.
18. Carmina E, Oberfield SE, Lobo RA: the diagnosis of polycystic ovary syndrome in adolescents. Am J Obstet Gynecol 2010; 203:e201-e205.
19. Legro RS, Arslanian SA, Ehrmann DA, et al: diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2013; 98:4565-4592.
20. Azziz R, Carmina E, Dewailly D, et al: Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperan-drogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91:4237-4245.
21. AGREE Collaboration: Development and validation of an International appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project. Qual Saf Health Care 2003; 12:18-23.
22. Escobar-Morreale HF, Carmina E, Dewailly D, et al: Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update 2012; 18:146-170.
23. Deplewski D, Rosenfield RL: Role of hormones in pilosebaceous unit development. Endocr Rev 2000; 21:363-392.
24. Martin KA, Chang RJ, Ehrmann DA, et al: Evaluation and treatment of hirsutism in pre-menopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93:1105-1120.
25. Merino PM, Codner E, Cassorla F: A rational approach to the diagnosis of polycystic ovarian syndrome during adolescence. Arq Bras Endocrinol Metabol 2011; 55:590-598.
26. Yildiz BO, Bolour S, Woods K, Moore A, Azziz R: Visually scoring hirsutism. Hum Re-prod Update 2010; 16:51-64.
27. Li R, Qiao J, Yang D, et al: Epidemiology of hirsutism among women of reproductive age in the community: a simplified scoring system. Eur J Obstet Gynecol Reprod Biol 2012; 163:165-169.
28. Sadat HM, Ramezani TF, Azizi F: The lack of association between idiopathic hirsutism and metabolic disturbances: Iranian PCOS Prevalence Study. Gynecol Endocrinol 2013; 29: 821-825.
29. Chen WC, Zouboulis CC: Hormones and the pilosebaceous unit. Dermatoendocrinol 2009; 1:81-86.
30. Hawryluk EB, English JC 3rd: Female adolescent hair disorders. J Pediatr Adolesc Gynecol 2009; 22:271-281.
31. Souter I, Sanchez A, Perez M, Bartolucci A, Azziz R: The prevalence of androgen excess among patients with minimal unwanted hair growth. Am J Obstet Gynecol 2004; 191:1914-1920.
32. Di Fede G, Mansueto P, Pepe G, Rini B, Car-mina E: High prevalence of polycystic ovary syndrome in women with mild hirsutism and no other significant clinical symptoms. Fertil Steril 2010; 94:194-197.
33. Ko JH, Huang YH, Kuo TT: Hair counts from normal scalp biopsy in Taiwan. Dermatol Surg 2012; 38:1516-1520.
34. Sperling LC: Hair density in African Americans. Arch Dermatol 1999; 135:656-658.
35. Yaprohm P, Manonukul J, Sontichai V, Poo-liam J, Srettabunjong S: Hair follicle counts in Thai population: a study on the vertex scalp area. J Med Assoc Thai 2013; 96:1578-1582.
36. Zhao X, Ni R, Li L, et al: Defining hirsutism in Chinese women: a cross-sectional study. Fer-til Steril 2011; 96:792-796.
37. DeUgarte CM, Woods KS, Bartolucci AA, Azziz R: Degree of facial and body terminal hair growth in unselected black and white women: toward a populational definition of hirsutism. J Clin Endocrinol Metab 2006; 91: 1345-1350.
38. Archer JS, Chang RJ: Hirsutism and acne in polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 2004; 18:737-754.
39. Franks S: The investigation and management of hirsutism. J Fam Plann Reprod Health Care 2012; 38:182-186.
40. Lucky AW, Biro FM, Daniels SR, Cedars MI, Khoury PR, Morrison A: The prevalence of upper lip hair in black and white girls during puberty: a new standard. J Pediatr 2001; 138: 134-136.
41. Ferriman D, Gallwey JD: Clinical assessment of body hair growth in women. J Clin Endo-crinol Metab 1961; 21:1440-1447.
42. Lucky AW, Biro FM, Simbartl LA, Morrison JA, Sorg NW: Predictors of severity of acne vulgaris in young adolescent girls: results of a five-year longitudinal study. J Pediatr 1997; 130:30-39.
43. Eichenfield LF, Krakowski AC, Piggott C, et al: Evidence-based recommendations for the diagnosis and treatment of pediatric acne. Pediatrics 2013; 131:S163-S186.
44. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H: Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin En-docrinol Metab 2007; 92:405-413.
45. Rosner W, Vesper H: Toward excellence in testosterone testing: a consensus statement. J Clin Endocrinol Metab 2010; 95:4542-4548.
46. Legro RS, Schlaff WD, Diamond MP, et al: Total testosterone assays in women with poly-cystic ovary syndrome: precision and correlation with hirsutism. J Clin Endocrinol Metab 2010; 95:5305-5313.
47. Auchus RJ: Steroid assays and endocrinology: best practices for basic scientists. Endocrinology 2014; 155:2049-2051.
48. Salameh WA, Redor-Goldman MM, Clarke NJ, Mathur R, Azziz R, Reitz RE: Specificity and predictive value of circulating testosterone assessed by tandem mass spectrometry for the diagnosis of polycystic ovary syndrome by the National Institutes of Health 1990 criteria. Fertil Steril 2014; 101:1135-1141.
49. 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; 84:3666-3672.
50. O'Reilly MW, Taylor AE, Crabtree NJ, Hughes BA, Capper F, Crowley RK, Stewart PM, Tomlinson JW, Arlt W: Hyperandrogen-emia predicts metabolic phenotype in poly-cystic ovary syndrome: the utility of serum androstenedione. J Clin Endocrinol Metab 2014; 99:1027-1036.
51. Moll G Jr, Rosenfield RL: Plasma free testosterone in the diagnosis of adolescent polycys-tic ovary syndrome. J Pediatr 1983; 102:461-464.
52. van Hooff MH, Voorhorst FJ, Kaptein MB, Hirasing RA, Koppenaal C, Schoemaker J: Insulin, androgen, and gonadotropin concentrations, body mass index, and waist to hip ratio in the first years after menarche in girls with regular menstrual cycles, irregular menstrual cycles, or oligomenorrhea. J Clin Endo-crinol Metab 2000; 85:1394-1400.
53. Mortensen M, Ehrmann DA, Littlejohn E, Rosenfield RL: Asymptomatic volunteers with a polycystic ovary are a functionally distinct but heterogeneous population. J Clin Endocrinol Metab 2009; 94:1579-1586.
54. Rosenfield RL: Clinical review: adolescent an-ovulation: maturational mechanisms and implications. J Clin Endocrinol Metab 2013; 98: 3572-3583.
55. Apter D, Vihko R: Serum pregnenolone, progesterone, 17-hydroxyprogesterone, testosterone, and 5 alpha-dihydrotestosterone during female puberty. J Clin Endocrinol Metab 1977; 45:1039-1048.
56. Venturoli S, Porcu E, Fabbri R, et al: Menstrual irregularities in adolescents: hormonal pattern and ovarian morphology. Horm Res 1986; 24:269-279.
57. Apter D, Raisanen I, Ylostalo P, Vihko R: Fol-licular growth in relation to serum hormonal patterns in adolescent compared with adult menstrual cycles. Fertil Steril 1987; 47:82-88.
58. van Hooff MH, Voorhorst FJ, Kaptein MB, Hirasing RA, Koppenaal C, Schoemaker J: Endocrine features of polycystic ovary syndrome in a random population. Hum Reprod 1999; 14:2223-2229.
59. Apter D, Vihko R: Endocrine determinants of fertility: serum androgen concentrations during follow-up of adolescents into the third decade of life. J Clin Endocrinol Metab 1990; 71: 970-974.
60. Venturoli S, Porcu E, Fabbri V, et al: Longitudinal change of sonographic ovarian aspects and endocrine parameters in irregular cycles of adolescence. Pediatr Res 1995; 38:974-980.
61. Gambineri A, Fanelli F, Prontera O, Repaci A, Di Dalmazi G, Zanotti L, Pagotto U, Flacco ME, Guidi J, Fava GA, Manzoli L, Pasquali R: Prevalence of hyperandrogenic states in late adolescent and young women: epidemiologi-cal survey on Italian high-school students. J Clin Endocrinol Metab 2013; 98:1641-1650.
62. Metcalf MG, Skidmore DS, Lowry GF, Mackenzie JA: Incidence of ovulation in the years after the menarche. J Endocrinol 1983; 97: 213-219.
63. Apter D: Endocrine and metabolic abnormalities in adolescents with a PCOS-like condition: consequences for adult reproduction. Trends Endocrinol Metab 1998; 9:58-61.
64. Treloar AE, Boynton RE, Behn BG, Brown BW: Variation of the human menstrual cycle through reproductive life. Int J Fertil 1967; 12: 77-126.
65. Vollman RF: The menstrual cycle. Major Probl Obstet Gynecol 1977; 7:1-193.
66. Gardner J: Adolescent menstrual characteristics as predictors of gynaecological health. Ann Hum Biol 1983; 10:31-40.
67. Zhang K, Pollack S, Ghods A, Dicken C, Isaac B, Adel G, Zeitlian G, Santoro N: Onset of ovulation after menarche in girls: a longitudinal study. J Clin Endocrinol Metab 2008; 93: 1186-1194.
68. 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 poly-cystic ovaries at age 15 years for oligo-amen-orrhoea at age 18 years. Hum Reprod 2004; 19: 383-392.
69. Legro RS, Lin HM, Demers LM, Lloyd T: Rapid maturation of the reproductive axis during perimenarche independent of body composition. J Clin Endocrinol Metab 2000; 85:1021-1025.
70. Wiksten-Almströmer M, Hirschberg AL, Hagenfeldt K: Prospective follow-up of menstrual disorders in adolescence and prognostic factors. Acta Obstet Gynecol Scand 2008; 87:1162-1168.
71. Southam AL, Richart RM: The prognosis for adolescents with menstrual abnormalities. Am J Obstet Gynecol 1966; 94:637-645.
72. Chumlea WC, Schubert CM, Roche AF, Kulin HE, Lee PA, Himes JH, Sun SS: Age at men-arche and racial comparisons in US girls. Pediatrics 2003; 111:110-113.
73. Marshall WA, Tanner JM: Variations in pattern of pubertal changes in girls. Arch Dis Child 1969; 44:291-303.
74. Widholm O, Kantero RL: A statistical analysis of the menstrual patterns of 8, 000 Finnish girls and their mothers. Acta Obstet Gynecol Scand Suppl 1971; 14:1-36.
75. Diaz A, Laufer MR, Breech LL: Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Pediatrics 2006; 118:2245-2250.
76. World Health Organization multicenter study on menstrual and ovulatory patterns in adolescent girls. I. A multicenter cross-sectional study of menarche. World Health Organization Task Force on Adolescent Reproductive Health. J Adolesc Health Care 1986; 7: 229-235.
77. Flug D, Largo RH, Prader A: 1984 Menstrual patterns in adolescent Swiss girls: a longitudinal study. Ann Hum Biol 1984; 11:495-508.
78. Franks S: Adult polycystic ovary syndrome begins in childhood. Best Pract Res Clin En-docrinol Metab 2002; 16:263-272.
79. Dewailly D, Lujan ME, Carmina E, et al: Definition and significance of polycystic ovarian morphology: a task force report from the An-drogen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update 2014; 20: 334-352.
80. Hickey M, Doherty DA, Atkinson H, Sloboda DM, Franks S, Norman RJ, Hart R: Clinical, ultrasound and biochemical features of poly-cystic ovary syndrome in adolescents: implications for diagnosis. Hum Reprod 2011; 26: 1469-1477.
81. Adams J, Franks Sl, Polson DW, et al: Multi-follicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone. Lancet 1985; 2:1375-1379.
82. Codner E, Villarroel C, Eyzaguirre FC, et al: Polycystic ovarian morphology in postmen-archal adolescents. Fertil Steril 2011; 95:702-706, e701-702.
83. Ersen A, Onal H, Yildirim D, Adal E: Ovarian and uterine ultrasonography and relation to puberty in healthy girls between 6 and 16 years in the Turkish population: a cross-sectional study. J Pediatr Endocrinol Metab 2012; 25:447-451.
84. Hagen CP, Mouritsen A, Mieritz MG, Tinggaard J, Wohlfart-Veje C, Fallentin E, Brocks V, Sundberg K, Jensen LN, Anderson RA, Juul A, Main KM: Circulating AMH reflects ovarian morphology by magnetic resonance imaging and 3D ultrasound in 121 healthy girls. J Clin Endocrinol Metab 2015; 100:880-890.
85. Kelsey TW, Dodwell SK, Wilkinson AG, Greve T, Andersen CY, Anderson RA, Wallace WH: Ovarian volume throughout life: a validated normative model. PLoS One 2013; 8:e71465.
86. Radivojevic UD, Lazovic GN, Kravic-Stevovic TK, et al: Differences in anthropometric and ultrasonographic parameters between adolescent girls with regular and irregular menstrual cycles: a case-study of 835 cases. J Pediatr Adolesc Gynecol 2014; 27:227-231.
87. Barber TM, Alvey C, Greenslade M, et al: Patterns of ovarian morphology in polycystic ovary syndrome: a study utilising magnetic resonance imaging. Eur Radiol 2010; 20: 1207-2013.
88. Brown M, Park AS, Shayya RF, Wolfson T, Su HI, Chang RJ: Ovarian imaging by magnetic resonance in adolescent girls with polycystic ovary syndrome and age-matched controls. J Magn Reson Imaging 2013; 38:689-993.
89. Ibáñez L, López-Bermejo A, Díaz M, Marcos MV, de Zegher F: Early metformin therapy (age 8-12 years) in girls with precocious pubarche to reduce hirsutism, androgen excess, and oligomenorrhea in adolescence. J Clin Endocrinol Metab 2011; 96:E1262-E1267.
90. Rosenfield RL, Wroblewski K, Padmanabhan V, Littlejohn E, Mortensen M, Ehrmann DA: Antimüllerian hormone levels are independently related to ovarian hyperandrogenism and polycystic ovaries. Fertil Steril 2012; 98: 242-249.
91. Hart R, Doherty DA, Norman RJ, et al: Serum antimullerian hormone (AMH) levels are elevated in adolescent girls with polycystic ovaries and the polycystic ovarian syndrome (PCOS). Fertil Steril 2010; 94:1118-1121.
92. Villarroel C, Merino PM, Lopez P, et al: Poly-cystic ovarian morphology in adolescents with regular menstrual cycles is associated with elevated anti-Mullerian hormone. Hum Reprod 2011; 26:2861-2868.
93. Dewailly D, Andersen CY, Balen A, Broek-mans F, Dilaver N, Fanchin R, Griesinger G, Kelsey TW, La Marca A, Lambalk C, Mason H, Nelson SM, Visser JA, Wallace WH, Anderson RA: The physiology and clinical utility of anti-Mullerian hormone in women. Hum Reprod Update 2014; 20:370-385.
94. Pawelczak M, Kenigsberg L, Milla S, Liu YH, Shah B: Elevated serum anti-Müllerian hormone in adolescents with polycystic ovary syndrome: relationship to ultrasound features. J Pediatr Endocrinol Metab 2012; 25: 983-989.
95. Cengiz H, Ekin M, Dagdeviren H, Yildiz S, Kaya C, Kanawati A: Comparison of serum anti-Müllerian hormone levels in normal weight and overweight-obese adolescent patients with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2014; 180C:46-50.
96. Sopher AB, Grigoriev G, Laura D, Cameo T, Lerner JP, Chang RJ, McMahon DJ, Oberfield SE: Anti-Mullerian hormone may be a useful adjunct in the diagnosis of polycystic ovary syndrome in nonobese adolescents. J Pediatr Endocrinol Metab 2014; 27:1175-1179.
97. Trapp CM, Oberfield SE: Recommendations for treatment of nonclassic congenital adrenal hyperplasia (NCCAH): an update. Steroids 2012; 77:342-346.
98. Witchel SF, Azziz R: Nonclassic congenital adrenal hyperplasia. Int J Pediatr Endocrinol 2010; 2010:625105.
99. Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI: High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet 1985; 37:650-667.
100. Miller WL, Auchus RJ: The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. En-docr Rev 2011; 32:81-151.
101. Draper N, Walker EA, Bujalska IJ: Mutations in the genes encoding 11beta-hy-droxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. Nat Genet 2003; 34:434-439.
102. Charmandari E, Kino T, Ichijo T, Chrousos GP: Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder. J Clin Endocrinol Metab 2008; 93:1563-1572.
103. Unluhizarci K, Kaltsas G, Kelestimur F: Non-polycystic ovary syndrome-related endocrine disorders associated with hirsutism. Eur J Clin Invest 2012; 42:86-94.
104. Filho RB, Domingues L, Naves L, Ferraz E, Alves A, Casulari LA: Polycystic ovary syndrome and hyperprolactinemia are distinct entities. Gynecol Endocrinol 2007; 23:267-272.
105. Ghazi AA, Mofid D, Salehian MT, et al: Functioning adrenocortical tumors in children-secretory behavior. J Clin Res Pediatr Endocrinol 2013; 5:27-32.
106. New MI, Lorenzen F, Lerner AJ, et al: Geno-typing steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 1983; 57:320-326.
107. Deneux C, Tardy V, Dib A, et al: Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin En-docrinol Metab 2001; 86:207-213.
108. Azziz R, Hincapie LA, Knochenhauer ES, Dewailly D, Fox L, Boots LR: Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study. Fertil Steril 1999; 72:915-925.
109. Speiser PW, Azziz R, Baskin LS, et al: Congenital adrenal hyperplasia due to steroid 21-hydroxylase due to steroid 21-hydroxy-lase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95:4133-4160.
110. Pall M, Azziz R, Beires J, Pignatell D: The phenotype of hirsute women: a comparison of polycystic ovary syndrome and 21-hy-droxylase-deficient nonclassic adrenal hy-perplasia. Fertil Steril 2010; 94:684-689.
111. Finkielstain GP, Chen W, Mehta SP, et al: Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hy-perplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2011; 96:E161-E172.
112. Sultan C, Paris F: Clinical expression of polycystic ovary syndrome in adolescent girls. Fertil Steril 2006; 86(suppl 1):S6.
113. Ibáñez L, Potau N, Zampolli M, Prat N, Vir-dis R, Vicens-Calvet E, Carrascosa A: Hy-perinsulinemia in postpubertal girls with a history of premature pubarche and functional ovarian hyperandrogenism. J Clin Endocrinol Metab 1996; 81:1237-1243.
114. Lewy VD, Danadian K, Witchel SF, Arsla-nian S: Early metabolic abnormalities in adolescent girls with polycystic ovarian syndrome. J Pediatr 2001; 138:38-44.
115. Apter D, Butzow T, Laughlin GA, et al: Metabolic features of polycystic ovary syndrome are found in adolescent girls with hy-perandrogenism. J Clin Endocrinol Metab 1995; 80:2966-2973.
116. Ibáñez L, Díaz R, López-Bermejo A, Marcos MV: Clinical spectrum of premature pubarche: links to metabolic syndrome and ovarian hyperandrogenism. Rev Endocr Metab Disord 2009; 10:63-76.
117. Ibáñez L, Potau N, Marcos MV, de Zegher F: Exaggerated adrenarche and hyperinsu-linism in adolescent girls born small for ges-tational age. J Clin Endocrinol Metab 1999; 84:4739-4741.
118. Ibáñez L, Potau N, Zampolli M, Riqué S, Saenger P, Carrascosa A: Hyperinsulinemia and decreased insulin-like growth factor-binding protein-1 are common features in prepubertal and pubertal girls with a history of premature pubarche. J Clin Endocrinol Metab 1997; 82:2283-2288.
119. Gungor N, Saad R, Janosky J, Arslanian S: Validation of surrogate estimates of insulin sensitivity and insulin secretion in children and adolescents. J Pediatr 2004; 144:47-55.
120. Glueck CJ, Morrison JA, Friedman LA, Goldenberg N, Stroop DM, Wang P: Obesity, free testosterone, and cardiovascular risk factors in adolescents with polycystic ovary syndrome and regularly cycling adolescents. Metabolism 2006; 55:508-514.
121. 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: 492-497.
122. Lee S, Gungor N, Bacha F, Arslanian S: Insulin resistance: link to the components of the metabolic syndrome and biomarkers of endothelial dysfunction in youth. Diabetes Care 2007; 30:2091-2097.
123. Leibel NI, Baumann EE, Kocherginsky M, Rosenfield RL: Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome. J Clin Endocrinol Metab 2006; 91:1275-1283.
124. Rossi B, Sukalich S, Droz J, Griffin A, Cook S, Blumkin A, Guzick DS, Hoeger KM: Prevalence of metabolic syndrome and related characteristics in obese adolescents with and without polycystic ovary syndrome. J Clin Endocrinol Metab 2008; 93: 4780-4786.
125. Chin V, Censani M, Lerner S, Conroy R, Oberfield S, McMahon D, Zitsman J, Fen-noy I: Gonadal dysfunction in morbidly obese adolescent girls. Fertil Steril 2014; 101: 1142-1148.
126. Roe AH, Prochaska E, Smith M, Sammel M, Dokras A: Using the androgen excess-PCOS society criteria to diagnose polycystic ovary syndrome and the risk of metabolic syndrome in adolescents. J Pediatr 2013; 162: 937-941.
127. Hart R, Doherty DA, Mori T, Huang RC, Norman RJ, Franks S, Sloboda D, Beilin L, Hickey M: Extent of metabolic risk in adolescent girls with features of polycystic ovary syndrome. Fertil Steril 2011; 95:2347-2353.
128. Palmert MR, Gordon CM, Kartashov AI, et al: Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. J Clin Endocrinol Metab 2002; 87: 1017-1023.
129. Fruzzetti F, Perini D, Lazzarini V, Parrini D, Genazzani AR: Hyperandrogenemia influences the prevalence of the metabolic syndrome abnormalities in adolescents with the polycystic ovary syndrome. Gynecol En-docrinol 2009; 25:335-343.
130. Barbieri RL, Makris A, Randall RW, Daniels G, Kistner RW, Ryan KJ: Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 1986; 62:904-909.
131. Dunaif A: Insulin resistance and the poly-cystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997; 18:774-800.
132. Witchel SF, Arslanian S: Ovarian responses to hCG stimulation: insulin resistance/hy-perinsulinaemia vs. insulin deficiency. Clin Endocrinol (Oxf) 1999; 51:127-130.
133. Arslanian SA, Lewy V, Danadian K, Saad R: Metformin therapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance: amelioration of exaggerated adrenal response to adrenocor-ticotropin with reduction of insulinemia/insulin resistance. J Clin Endocrinol Metab 2002; 87:1555-1559.
134. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L: Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS). J Adolesc Health 2001; 29:160-169.
135. De Leo V, Musacchio MC, Morgante G, Pi-omboni P, Petraglia F: Metformin treatment is effective in obese teenage girls with PCOS. Hum Reprod 2006; 21:2252-2256.
136. Tfayli H, Ulnach JW, Lee S, Sutton-Tyrrell K, Arslanian S: Drospirenone/ethinyl estra-diol versus rosiglitazone treatment in overweight adolescents with polycystic ovary syndrome: comparison of metabolic, hormonal, and cardiovascular risk factors. J Clin Endocrinol Metab 2011; 96:1311-1319.
137. Reinehr T, de Sousa G, Roth CL, Andler W: Androgens before and after weight loss in obese children. J Clin Endocrinol Metab 2005; 90:5588-5595.
138. Ibáñez L, Valls C, Ferrer A, Marcos MV, Ro-driguez-Hierro F, de Zegher F: Sensitization to insulin induces ovulation in nonobese adolescents with anovulatory hyperan-drogenism. J Clin Endocrinol Metab 2001; 86:3595-3598.
139. Jaquet D, Leger J, Chevenne D, Czernichow P, Levy-Marchal C: Intrauterine growth retardation predisposes to insulin resistance but not to hyperandrogenism in young women. J Clin Endocrinol Metab 1999; 84: 3945-3949.
140. Abbott DH, Bacha F: Ontogeny of polycys-tic ovary syndrome and insulin resistance in utero and early childhood. Fertil Steril 2013; 100:2-11.
141. Ong KK, Potau N, Petry CJ, Jones R, Ness AR, Honour JW, de Zegher F, Ibáñez L, Dunger DB; Avon Longitudinal Study of Parents and Children Study Team: Opposing influences of prenatal and postnatal weight gain on adrenarche in normal boys and girls. J Clin Endocrinol Metab 2004; 89: 2647-2651.
142. Neville KA, Walker JL: Precocious pubarche is associated with SGA, prematurity, weight gain, and obesity. Arch Dis Child 2005; 90: 258-261.
143. Littlejohn EE, Weiss RE, Deplewski D, Edi-din DV, Rosenfield R: Intractable early childhood obesity as the initial sign of insulin resistant hyperinsulinism and precursor of polycystic ovary syndrome. J Pediatr En-docrinol Metab 2007; 20:41-51.
144. McCartney CR, Prendergast KA, Blank SK, Helm KD, Chhabra S, Marshall JC: Maturation of luteinizing hormone (gonadotropin-releasing hormone) secretion across puberty: evidence for altered regulation in obese peripubertal girls. J Clin Endocrinol Metab 2009; 94:56-66.
145. McCartney CR, Blank SK, Prendergast KA, Chhabra S, Eagleson CA, Helm KD, Yoo R, Chang RJ, Foster CM, Caprio S, Marshall JC: Obesity and sex steroid changes across puberty: evidence for marked hyperandrogen-emia in pre-and early pubertal obese girls. J Clin Endocrinol Metab 2007; 92:430-436.
146. Dokras A, Witchel SF: Are young adult women with polycystic ovary syndrome slipping through the healthcare cracks? J Clin Endocrinol Metab 2014; 99:1583-1585.
147. Teede HJ, Misso ML, Deeks AA, et al: Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline. Med J Aust 2011; 195:S65-S112.
148. Allen HF, Mazzoni C, Heptulla RA, et al: Randomized controlled trial evaluating response to metformin versus standard therapy in the treatment of adolescents with poly-cystic ovary syndrome. J Pediatr Endocrinol 2005; 18:761-768.
149. Bridger T, MacDonald S, Baltzer F, Rodd C: Randomized placebo-controlled trial of metformin for adolescents with polycystic ovary syndrome. Arch Pediatr Adolesc Med 2006; 160:241-246.
150. Hoeger K, Davidson K, Kochman L, et al: The impact of metformin, oral contraceptives, and lifestyle modification on polycys-tic ovary syndrome in obese adolescent women in two randomized-placebo controlled trials. J Clin Endocrinol Metab 2008; 93:4299-4306.
151. Chung JP, Yiu AK, Chung TK, Chan SS: A randomized crossover study of medroxy-progesterone acetate and Diane-35 in adolescent girls with polycystic ovarian syndrome. J Pediatr Adolesc Gynecol 2014; 27: 166-171.
152. Ibáñez L, Valls C, Ferrer A, et al: Sensitiza-tion to insulin induces ovulation in non-obese adolescents with anovulatory hyper-androgenism. J Clin Endocrinol Metab 2001; 86: 3595-3598.
153. Rofey D, Szigethy E, Noll RB, et al: Cognitive behavioral therapy for physical and emotional disturbances in adolescent with polycystic ovarian syndrome: a pilot study. J Pediatr Psychol 2009; 34:156-163.
154. Harris-Glocker M, Davidson K, Kotchman L, et al: Improvement in quality of life questionnaire measures in obese adolescent females with polycystic ovarian syndrome treated with lifestyle changes and oral contraceptives with or without metformin. Fertil Steril 2010; 93:1006-1019.
155. Ladson G, Dodson WC, Sweet SD, et al: Effects of metformin in adolescents with poly-cystic ovary syndrome undertaking lifestyle therapy: a pilot randomized double-blind study. Fertil Steril 2011; 95:2595-2598.
156. El-Sharkawy AA, Abdelmoaleb GS, Aly MK, Kabel AM: Effect of metformin on sleep disorders in adolescent girls with poly-cystic ovarian syndrome. J Pediatr Adolesc Gynecol 2014; 27:347-352.
157. Bredella MA, McManus S, Misra M: Impact of metformin monotherapy versus metfor-min with oestrogen-progesterone on lipids in adolescent girls with polycystic ovarian syndrome. Clin Endocrinol 2013; 79:199-203.
158. Ibáñez L, de Zegher F: Ethinylestradiol-drospirenone, flutamide-metformin, or both for adolescents and women with hyperinsu-linemic hyperandrogenism: opposite effects on adipocytokines and body adiposity. J Clin Endocrinol Metab 2004; 89:1592-1597.
159. 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; 96:3533-3540.
160. Loverro G, Lorusso F, De Pergola G, et al: Clinical and endocrinological effects of 6 month of metformin treatment in young hyperinsulinemic patients affected by poly-cystic ovary syndrome. Gynecol Endocrinol 2002; 16:217-224.
161. Díaz MR, Chacón M, López-Bermejo A, et al: Ethinyl estradiol-cyproterone acetate versus low-dose pioglitazone-flutamide-metformin for adolescent girls with andro-gen excess: divergent effects on CD163, TWEAK Receptor, ANGPTL4 and LEPTIN expression in subcutaneous adipose tissue. J Clin Endocrinol Metab 2012; 97: 3630-3638.
162. Ibáñez L, Díaz M, Sebastiani G, Marcos MV, Ló pez-Bermejo A, de Zegher F: Oral contraception vs insulin sensitization for 18 months in nonobese adolescents with an-drogen excess: posttreatment differences in c-reactive protein, intima-media thickness, visceral adiposity, insulin sensitivity, and menstrual regularity. J Clin Endocrinol Metab 2013; 98:E902-E907.
163. Mastorakos G, Koliopoulos C, Creatsas G: Androgen and lipid profiles in adolescents with polycystic ovary syndrome who were treated with two forms of combined oral contraceptives. Fertil Steril 2002; 77: 919-927.