Semin Reprod Med 2022; 40(01/02): 003-015
DOI: 10.1055/s-0041-1735892
Review Article

Disorders of Puberty in Girls

1   Division of Endocrinology, Diabetes and Metabolism, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York
,
Sharon E. Oberfield
1   Division of Endocrinology, Diabetes and Metabolism, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York
,
Selma F. Witchel
2   Division of Endocrinology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
› Author Affiliations

Abstract

Puberty is the process through which reproductive competence is achieved and comprises gonadarche and adrenarche. Breast development is the initial physical finding of pubertal onset in girls and typically occurs between 8 and 13 years. Menarche normally occurs 2 to 3 years after the onset of breast development. Pubertal onset is controlled by the gonadotropin-releasing hormone pulse generator in the hypothalamus; however, environmental factors such as alterations in energy balance and exposure to endocrine-disrupting chemicals can alter the timing of pubertal onset. Improvement in nutritional and socioeconomic conditions over the past two centuries has been associated with a secular trend in earlier pubertal onset. Precocious puberty is defined as onset of breast development prior to 8 years and can be central or peripheral. Delayed puberty can be hypogonadotropic or hypergonadotropic and is defined as lack of breast development by 13 years or lack of menarche by 16 years. Both precocious and delayed puberty may have negative effects on self-esteem, potentially leading to psychosocial stress. Patients who present with pubertal differences require a comprehensive assessment to determine the underlying etiology and to devise an effective treatment plan.



Publication History

Article published online:
24 September 2021

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  • References

  • 1 Grumbach MM. The neuroendocrinology of human puberty revisited. Horm Res 2002; 57 (Suppl. 02) 2-14
  • 2 Morris DH, Jones ME, Schoemaker MJ, Ashworth A, Swerdlow AJ. Familial concordance for age at natural menopause: results from the Breakthrough Generations Study. Menopause 2011; 18 (09) 956-961
  • 3 Wohlfahrt-Veje C, Mouritsen A, Hagen CP. et al. Pubertal onset in boys and girls is influenced by pubertal timing of both parents. J Clin Endocrinol Metab 2016; 101 (07) 2667-2674
  • 4 Madsen A, Bruserud IS, Bertelsen BE. et al. Hormone references for ultrasound breast staging and endocrine profiling to detect female onset of puberty. J Clin Endocrinol Metab 2020; 105 (12) dgaa679
  • 5 Susman EJ, Houts RM, Steinberg L. et al; Eunice Kennedy Shriver NICHD Early Child Care Research Network. Longitudinal development of secondary sexual characteristics in girls and boys between ages 91/2 and 151/2 years. Arch Pediatr Adolesc Med 2010; 164 (02) 166-173
  • 6 Granados A, Gebremariam A, Lee JM. Relationship between timing of peak height velocity and pubertal staging in boys and girls. J Clin Res Pediatr Endocrinol 2015; 7 (03) 235-237
  • 7 Carlson LJ, Shaw ND. Development of ovulatory menstrual cycles in adolescent girls. J Pediatr Adolesc Gynecol 2019; 32 (03) 249-253
  • 8 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 (03) 1021-1025
  • 9 Treloar AE, Boynton RE, Behn BG, Brown BW. Variation of the human menstrual cycle through reproductive life. Int J Fertil 1967; 12 (1, Pt 2): 77-126
  • 10 Gottschalk MS, Eskild A, Hofvind S, Gran JM, Bjelland EK. Temporal trends in age at menarche and age at menopause: a population study of 312 656 women in Norway. Hum Reprod 2020; 35 (02) 464-471
  • 11 Eckert-Lind C, Busch AS, Petersen JH. et al. Worldwide secular trends in age at pubertal onset assessed by breast development among girls: a systematic review and meta-analysis. JAMA Pediatr 2020; 174 (04) e195881
  • 12 Biro FM, Greenspan LC, Galvez MP. et al. Onset of breast development in a longitudinal cohort. Pediatrics 2013; 132 (06) 1019-1027
  • 13 Day FR, Thompson DJ, Helgason H. et al; LifeLines Cohort Study, InterAct Consortium, kConFab/AOCS Investigators, Endometrial Cancer Association Consortium, Ovarian Cancer Association Consortium, PRACTICAL Consortium. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat Genet 2017; 49 (06) 834-841
  • 14 Goldberg M, D'Aloisio AA, O'Brien KM, Zhao S, Sandler DP. Pubertal timing and breast cancer risk in the Sister Study cohort. Breast Cancer Res 2020; 22 (01) 112
  • 15 Cousminer DL, Mitchell JA, Chesi A. et al. Genetically determined later puberty impacts lowered bone mineral density in childhood and adulthood. J Bone Miner Res 2018; 33 (03) 430-436
  • 16 Albright F, Smith PH, Fraser R. A syndrome characterized by primary ovarian insufficiency and decreased stature: report of 11 cases with a digression on hormonal control of axillary and pubic hair. Am J Med Sci 1942; 204: 625-648
  • 17 Nakamura Y, Gang HX, Suzuki T, Sasano H, Rainey WE. Adrenal changes associated with adrenarche. Rev Endocr Metab Disord 2009; 10 (01) 19-26
  • 18 Dhom G. The prepuberal and puberal growth of the adrenal (adrenarche). Beitr Pathol 1973; 150 (04) 357-377
  • 19 Oberfield SE, Sopher AB, Gerken AT. Approach to the girl with early onset of pubic hair. J Clin Endocrinol Metab 2011; 96 (06) 1610-1622
  • 20 Witchel SF, Pinto B, Burghard AC, Oberfield SE. Update on adrenarche. Curr Opin Pediatr 2020; 32 (04) 574-581
  • 21 Weber A, Toppari J, Harvey RD. et al. Adrenocorticotropin receptor gene mutations in familial glucocorticoid deficiency: relationships with clinical features in four families. J Clin Endocrinol Metab 1995; 80 (01) 65-71
  • 22 Herbison AE. The gonadotropin-releasing hormone pulse generator. Endocrinology 2018; 159 (11) 3723-3736
  • 23 Livadas S, Chrousos GP. Molecular and environmental mechanisms regulating puberty initiation: an integrated approach. Front Endocrinol (Lausanne) 2019; 10: 828
  • 24 Moore AM, Coolen LM, Porter DT, Goodman RL, Lehman MN. KNDy cells revisited. Endocrinology 2018; 159 (09) 3219-3234
  • 25 Maione L, Bouvattier C, Kaiser UB. Central precocious puberty: recent advances in understanding the aetiology and in the clinical approach. Clin Endocrinol (Oxf) 2021; ; (online ahead of print) DOI: 10.1111/cen.14475.
  • 26 Renault CH, Aksglaede L, Wøjdemann D, Hansen AB, Jensen RB, Juul A. Minipuberty of human infancy - a window of opportunity to evaluate hypogonadism and differences of sex development?. Ann Pediatr Endocrinol Metab 2020; 25 (02) 84-91
  • 27 Conte FA, Grumbach MM, Kaplan SL. A diphasic pattern of gonadotropin secretion in patients with the syndrome of gonadal dysgenesis. J Clin Endocrinol Metab 1975; 40 (04) 670-674
  • 28 Terasawa E, Fernandez DL. Neurobiological mechanisms of the onset of puberty in primates. Endocr Rev 2001; 22 (01) 111-151
  • 29 Lehman MN, He W, Coolen LM, Levine JE, Goodman RL. Does the KNDy model for the control of gonadotropin-releasing hormone pulses apply to monkeys and humans?. Semin Reprod Med 2019; 37 (02) 71-83
  • 30 Witchel SF, Plant TM. Neurobiology of puberty and its disorders. Handbookelin Neurol 2021; 181: 463-496 DOI: 10.1016/13978-0-12-8206836.00033-6.
  • 31 Eaves L, Silberg J, Foley D. et al. Genetic and environmental influences on the relative timing of pubertal change. Twin Res 2004; 7 (05) 471-481
  • 32 de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 2003; 100 (19) 10972-10976
  • 33 Seminara SB, Messager S, Chatzidaki EE. et al. The GPR54 gene as a regulator of puberty. N Engl J Med 2003; 349 (17) 1614-1627
  • 34 Topaloglu AK, Reimann F, Guclu M. et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat Genet 2009; 41 (03) 354-358
  • 35 Chan YM, Broder-Fingert S, Paraschos S. et al. GnRH-deficient phenotypes in humans and mice with heterozygous variants in KISS1/Kiss1. J Clin Endocrinol Metab 2011; 96 (11) E1771-E1781
  • 36 Lomniczi A, Ojeda SR. The emerging role of epigenetics in the regulation of female puberty. Endocr Dev 2016; 29: 1-16
  • 37 Plant TM, Durrant AR. Circulating leptin does not appear to provide a signal for triggering the initiation of puberty in the male rhesus monkey (Macaca mulatta). Endocrinology 1997; 138 (10) 4505-4508
  • 38 Kaplowitz PB. Link between body fat and the timing of puberty. Pediatrics 2008; 121 (Suppl. 03) S208-S217
  • 39 Harley KG, Berger KP, Kogut K. et al. Association of phthalates, parabens and phenols found in personal care products with pubertal timing in girls and boys. Hum Reprod 2019; 34 (01) 109-117
  • 40 Stoker TE, Gibson EK, Zorrilla LM. Triclosan exposure modulates estrogen-dependent responses in the female Wistar rat. Toxicol Sci 2010; 117 (01) 45-53
  • 41 Ramsey JT, Li Y, Arao Y. et al. Lavender products associated with premature thelarche and prepubertal gynecomastia: case reports and endocrine-disrupting chemical activities. J Clin Endocrinol Metab 2019; 104 (11) 5393-5405
  • 42 Lee JE, Jung HW, Lee YJ, Lee YA. Early-life exposure to endocrine-disrupting chemicals and pubertal development in girls. Ann Pediatr Endocrinol Metab 2019; 24 (02) 78-91
  • 43 Eugster EA. Update on precocious puberty in girls. J Pediatr Adolesc Gynecol 2019; 32 (05) 455-459
  • 44 Pasquino AM, Tebaldi L, Cioschi L. et al. Premature thelarche: a follow up study of 40 girls. Natural history and endocrine findings. Arch Dis Child 1985; 60 (12) 1180-1182
  • 45 Farello G, Altieri C, Cutini M, Pozzobon G, Verrotti A. Review of the literature on current changes in the timing of pubertal development and the incomplete forms of early puberty. Front Pediatr 2019; 7: 147
  • 46 Söderström HF, Carlsson A, Börjesson A, Elfving M. Vaginal bleeding in prepubertal girls: etiology and clinical management. J Pediatr Adolesc Gynecol 2016; 29 (03) 280-285
  • 47 Sømod ME, Vestergaard ET, Kristensen K, Birkebæk NH. Increasing incidence of premature thelarche in the Central Region of Denmark - challenges in differentiating girls less than 7 years of age with premature thelarche from girls with precocious puberty in real-life practice. Int J Pediatr Endocrinol 2016; 2016: 4
  • 48 Palmert MR, Malin HV, Boepple PA. Unsustained or slowly progressive puberty in young girls: initial presentation and long-term follow-up of 20 untreated patients. J Clin Endocrinol Metab 1999; 84 (02) 415-423
  • 49 Utriainen P, Laakso S, Liimatta J, Jääskeläinen J, Voutilainen R. Premature adrenarche–a common condition with variable presentation. Horm Res Paediatr 2015; 83 (04) 221-231
  • 50 Bräuner EV, Busch AS, Eckert-Lind C, Koch T, Hickey M, Juul A. Trends in the incidence of central precocious puberty and normal variant puberty among children in Denmark, 1998 to 2017. JAMA Netw Open 2020; 3 (10) e2015665
  • 51 Abreu AP, Macedo DB, Brito VN, Kaiser UB, Latronico AC. A new pathway in the control of the initiation of puberty: the MKRN3 gene. J Mol Endocrinol 2015; 54 (03) R131-R139
  • 52 Macedo DB, Abreu AP, Reis AC. et al. Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. J Clin Endocrinol Metab 2014; 99 (06) E1097-E1103
  • 53 Valadares LP, Meireles CG, De Toledo IP. et al. MKRN3 mutations in central precocious puberty: a systematic review and meta-analysis. J Endocr Soc 2019; 3 (05) 979-995
  • 54 Ioannides Y, Lokulo-Sodipe K, Mackay DJ, Davies JH, Temple IK. Temple syndrome: improving the recognition of an underdiagnosed chromosome 14 imprinting disorder: an analysis of 51 published cases. J Med Genet 2014; 51 (08) 495-501
  • 55 Roberts SA, Kaiser UB. Genetics in Endocrinology: genetic etiologies of central precocious puberty and the role of imprinted genes. Eur J Endocrinol 2020; 183 (04) R107-R117
  • 56 Dauber A, Cunha-Silva M, Macedo DB. et al. Paternally inherited DLK1 deletion associated with familial central precocious puberty. J Clin Endocrinol Metab 2017; 102 (05) 1557-1567
  • 57 Silveira LG, Noel SD, Silveira-Neto AP. et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab 2010; 95 (05) 2276-2280
  • 58 Teles MG, Bianco SD, Brito VN. et al. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med 2008; 358 (07) 709-715
  • 59 Brandberg G, Raininko R, Eeg-Olofsson O. Hypothalamic hamartoma with gelastic seizures in Swedish children and adolescents. Eur J Paediatr Neurol 2004; 8 (01) 35-44
  • 60 Chan YM, Fenoglio-Simeone KA, Paraschos S. et al. Central precocious puberty due to hypothalamic hamartomas correlates with anatomic features but not with expression of GnRH, TGFalpha, or KISS1. Horm Res Paediatr 2010; 73 (05) 312-319
  • 61 Cukier P, Castro LH, Banaskiwitz N. et al. The benign spectrum of hypothalamic hamartomas: infrequent epilepsy and normal cognition in patients presenting with central precocious puberty. Seizure 2013; 22 (01) 28-32
  • 62 Stephen MD, Zage PE, Waguespack SG. Gonadotropin-dependent precocious puberty: neoplastic causes and endocrine considerations. Int J Pediatr Endocrinol 2011; 2011: 184502
  • 63 Cho EK, Kim J, Yang A. et al. Clinical and endocrine characteristics and genetic analysis of Korean children with McCune-Albright syndrome: a retrospective cohort study. Orphanet J Rare Dis 2016; 11 (01) 113
  • 64 Nabhan ZM, West KW, Eugster EA. Oophorectomy in McCune-Albright syndrome: a case of mistaken identity. J Pediatr Surg 2007; 42 (09) 1578-1583
  • 65 Tufano M, Ciofi D, Amendolea A, Stagi S. Auxological and endocrinological features in children with McCune Albright syndrome: a review. Front Endocrinol (Lausanne) 2020; 11: 522
  • 66 Cavlan D, Bharwani N, Grossman A. Androgen- and estrogen-secreting adrenal cancers. Semin Oncol 2010; 37 (06) 638-648
  • 67 Parikshaa G, Ariba Z, Pranab D. et al. Juvenile granulosa cell tumor of the ovary: a comprehensive clinicopathologic analysis of 15 cases. Ann Diagn Pathol 2021; 52: 151721
  • 68 Wyk JJ, Grumbach M. Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism: an example of hormonal overlap in pituitary feedback. J Pediatr 1960; 57: 416-435
  • 69 Hannah-Shmouni F, Morissette R, Sinaii N. et al. Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians. Genet Med 2017; 19 (11) 1276-1279
  • 70 Witchel SF. Nonclassic congenital adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes 2012; 19 (03) 151-158
  • 71 Claahsen-van der Grinten HL, Speiser PW, Ahmed SF. et al. Congenital adrenal hyperplasia - current insights in pathophysiology, diagnostics and management. Endocr Rev 2021; bnab016
  • 72 Kaplowitz PB. Do 6-8 year old girls with central precocious puberty need routine brain imaging?. Int J Pediatr Endocrinol 2016; 2016: 9
  • 73 Martins WP, Nastri CO. Ultrasonographic measurement of ovarian volume in the diagnosis of central precocious puberty. Ultrasound Obstet Gynecol 2009; 34 (04) 484-485
  • 74 Eugster EA. Treatment of central precocious puberty. J Endocr Soc 2019; 3 (05) 965-972
  • 75 Lazar L, Lebenthal Y, Yackobovitch-Gavan M. et al. Treated and untreated women with idiopathic precocious puberty: BMI evolution, metabolic outcome, and general health between third and fifth decades. J Clin Endocrinol Metab 2015; 100 (04) 1445-1451
  • 76 Howard SR, Dunkel L. Delayed puberty-phenotypic diversity, molecular genetic mechanisms, and recent discoveries. Endocr Rev 2019; 40 (05) 1285-1317
  • 77 Howard SR. The genetic basis of delayed puberty. Front Endocrinol (Lausanne) 2019; 10: 423
  • 78 Rohayem J, Nieschlag E, Kliesch S, Zitzmann M. Inhibin B, AMH, but not INSL3, IGF1 or DHEAS support differentiation between constitutional delay of growth and puberty and hypogonadotropic hypogonadism. Andrology 2015; 3 (05) 882-887
  • 79 Zhu J, Choa RE, Guo MH. et al. A shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2015; 100 (04) E646-E654
  • 80 Lewkowitz-Shpuntoff HM, Hughes VA, Plummer L. et al. Olfactory phenotypic spectrum in idiopathic hypogonadotropic hypogonadism: pathophysiological and genetic implications. J Clin Endocrinol Metab 2012; 97 (01) E136-E144
  • 81 McCormack SE, Li D, Kim YJ. et al. Digenic inheritance of PROKR2 and WDR11 mutations in pituitary stalk interruption syndrome. J Clin Endocrinol Metab 2017; 102 (07) 2501-2507
  • 82 Parks JS, Brown MR, Hurley DL, Phelps CJ, Wajnrajch MP. Heritable disorders of pituitary development. J Clin Endocrinol Metab 1999; 84 (12) 4362-4370
  • 83 Daubenbüchel AM, Müller HL. Neuroendocrine disorders in pediatric craniopharyngioma patients. J Clin Med 2015; 4 (03) 389-413
  • 84 Kanber D, Giltay J, Wieczorek D. et al. A paternal deletion of MKRN3, MAGEL2 and NDN does not result in Prader-Willi syndrome. Eur J Hum Genet 2009; 17 (05) 582-590
  • 85 Gross-Tsur V, Hirsch HJ, Benarroch F, Eldar-Geva T. The FSH-inhibin axis in Prader-Willi syndrome: heterogeneity of gonadal dysfunction. Reprod Biol Endocrinol 2012; 10: 39
  • 86 Seppä S, Kuiri-Hänninen T, Holopainen E, Voutilainen R. Management of Endocrine Disease: diagnosis and management of primary amenorrhea and female delayed puberty. Eur J Endocrinol 2021; 184 (06) R225-R242
  • 87 Petersenn S. Biochemical diagnosis in prolactinomas: some caveats. Pituitary 2020; 23 (01) 9-15
  • 88 Reindollar RH, Byrd JR, McDonough PG. Delayed sexual development: a study of 252 patients. Am J Obstet Gynecol 1981; 140 (04) 371-380
  • 89 Mikhael S, Dugar S, Morton M. et al. Genetics of agenesis/hypoplasia of the uterus and vagina: narrowing down the number of candidate genes for Mayer-Rokitansky-Küster-Hauser syndrome. Hum Genet 2021; 140 (04) 667-680
  • 90 Howard SR, Guasti L, Poliandri A. et al. Contributions of function-altering variants in genes implicated in pubertal timing and body mass for self-limited delayed puberty. J Clin Endocrinol Metab 2018; 103 (02) 649-659
  • 91 Plant TM. Neuroendocrine control of the onset of puberty. Front Neuroendocrinol 2015; 38: 73-88
  • 92 Farooqi IS. Leptin and the onset of puberty: insights from rodent and human genetics. Semin Reprod Med 2002; 20 (02) 139-144
  • 93 Roberts AC, McClure RD, Weiner RI, Brooks GA. Overtraining affects male reproductive status. Fertil Steril 1993; 60 (04) 686-692
  • 94 Savage MO, Beattie RM, Camacho-Hübner C, Walker-Smith JA, Sanderson IR. Growth in Crohn's disease. Acta Paediatr Suppl 1999; 88 (428) 89-92
  • 95 Haffner D, Zivicnjak M. Pubertal development in children with chronic kidney disease. Pediatr Nephrol 2017; 32 (06) 949-964
  • 96 Caronia LM, Martin C, Welt CK. et al. A genetic basis for functional hypothalamic amenorrhea. N Engl J Med 2011; 364 (03) 215-225
  • 97 Ladjouze A, Donaldson M. Primary gonadal failure. Best Pract Res Clin Endocrinol Metab 2019; 33 (03) 101295
  • 98 King TF, Conway GS. Swyer syndrome. Curr Opin Endocrinol Diabetes Obes 2014; 21 (06) 504-510
  • 99 Zieliñska D, Zajaczek S, Rzepka-Górska I. Tumors of dysgenetic gonads in Swyer syndrome. J Pediatr Surg 2007; 42 (10) 1721-1724
  • 100 Tam YH, Wong YS, Pang KK. et al. Tumor risk of children with 45,X/46,XY gonadal dysgenesis in relation to their clinical presentations: further insights into the gonadal management. J Pediatr Surg 2016; 51 (09) 1462-1466
  • 101 Rossetti R, Ferrari I, Bonomi M, Persani L. Genetics of primary ovarian insufficiency. Clin Genet 2017; 91 (02) 183-198
  • 102 Szeliga A, Calik-Ksepka A, Maciejewska-Jeske M. et al. Autoimmune diseases in patients with premature ovarian insufficiency-our current state of knowledge. Int J Mol Sci 2021; 22 (05) DOI: 10.3390/ijms22052594.
  • 103 Nahata L, Woodruff TK, Quinn GP. et al. Ovarian tissue cryopreservation as standard of care: what does this mean for pediatric populations?. J Assist Reprod Genet 2020; 37 (06) 1323-1326
  • 104 Hinkle K, Orwig KE, Valli-Pulaski H. et al. Cryopreservation of ovarian tissue for pediatric fertility. Biopreserv Biobank 2021; 19 (02) 130-135
  • 105 Chan YM, Lippincott MF, Sales Barroso P. et al. Using kisspeptin to predict pubertal outcomes for youth with pubertal delay. J Clin Endocrinol Metab 2020; 105 (08) dgaa162
  • 106 Sullivan SD, Sarrel PM, Nelson LM. Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause. Fertil Steril 2016; 106 (07) 1588-1599
  • 107 Crofton PM, Evans N, Bath LE. et al. Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover. Clin Endocrinol (Oxf) 2010; 73 (06) 707-714
  • 108 Klein KO, Phillips SA. Review of hormone replacement therapy in girls and adolescents with hypogonadism. J Pediatr Adolesc Gynecol 2019; 32 (05) 460-468
  • 109 Kim EY, Lee MI. Psychosocial aspects in girls with idiopathic precocious puberty. Psychiatry Investig 2012; 9 (01) 25-28