Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Premature Adrenarche and its Association with Cardiovascular Risk in Females

Author(s): Sarantis Livadas*, Christina Bothou and Djuro Macut

Volume 26 , Issue 43 , 2020

Page: [5609 - 5616] Pages: 8

DOI: 10.2174/1381612826666201012164726

Price: $65


Early activation of the adrenal zona reticularis, leading to adrenal androgen secretion, mainly dehydroepiandrosterone sulfate (DHEAS), is called premature adrenarche (PA). The fact that adrenal hyperandrogenism in females has been linked to a cluster of cardiovascular (CV) risk factors, even in prepubertal children, warrants investigation. Controversial results have been obtained in this field, probably due to genetic, constitutional, and environmental factors or differences in the characteristics of participants. In an attempt to understand, in depth, the impact of PA as a potential activator of CV risk, we critically present available data stratified according to pubertal status. It seems that prepubertally, CV risk is increased in these girls, but is somewhat attenuated during their second decade of life. Furthermore, different entities associated with PA, such as polycystic ovary syndrome, non-classical congenital adrenal hyperplasia, heterozygosity of CYP21A2 mutations, and the impact of DHEAS on CV risk, are reviewed. At present, firm and definitive conclusions cannot be drawn. However, it may be speculated that girls with a history of PA display a hyperandrogenic hormonal milieu that may lead to increased CV risk. Accordingly, appropriate long-term follow-up and early intervention employing a patient-oriented approach are recommended.

Keywords: Adrenarche, pubarche, PCOS, insulin, metabolic syndrome, CYP21A2, DHEAS.

Bird IM. In the zone: understanding zona reticularis function and its transformation by adrenarche. J Endocrinol 2012; 214(2): 109-11.
[] [PMID: 22700191]
Campbell B. Adrenarche in comparative perspective. Am J Hum Biol 2011; 23(1): 44-52.
[] [PMID: 21140467]
Auchus RJ, Rainey WE. Adrenarche - physiology, biochemistry and human disease. Clin Endocrinol (Oxf) 2004; 60(3): 288-96.
[] [PMID: 15008992]
Parker CR Jr. Dehydroepiandrosterone and dehydroepiandrosterone sulfate production in the human adrenal during development and aging. Steroids 1999; 64(9): 640-7.
[] [PMID: 10503722]
Dorn LD, Rotenstein D. Early puberty in girls: the case of premature adrenarche. Womens Health Issues 2004; 14(6): 177-83.
[] [PMID: 15589767]
Mäntyselkä A, Jääskeläinen J, Lindi V, et al. The presentation of adrenarche is sexually dimorphic and modified by body adiposity. J Clin Endocrinol Metab 2014; 99(10): 3889-94.
[] [PMID: 25029425]
Corvalán C, Uauy R, Mericq V. Obesity is positively associated with dehydroepiandrosterone sulfate concentrations at 7 y in Chilean children of normal birth weight. Am J Clin Nutr 2013; 97(2): 318-25.
[] [PMID: 23283497]
Ibáñez L, Dimartino-Nardi J, Potau N, Saenger P. Premature adrenarche--normal variant or forerunner of adult disease? Endocr Rev 2000; 21(6): 671-96.
[] [PMID: 11133068]
Idkowiak J, Lavery GG, Dhir V, et al. Premature adrenarche: novel lessons from early onset androgen excess. Eur J Endocrinol 2011; 165(2): 189-207.
[] [PMID: 21622478]
Liimatta J, Utriainen P, Voutilainen R, Jääskeläinen J. Girls with a History of Premature Adrenarche Have Advanced Growth and Pubertal Development at the Age of 12 Years. Front Endocrinol (Lausanne) 2017; 8: 291-8.
[] [PMID: 29163361]
Remer T, Manz F. Role of nutritional status in the regulation of adrenarche. J Clin Endocrinol Metab 1999; 84(11): 3936-44.
[] [PMID: 10566631]
Charkaluk ML, Trivin C, Brauner R. Premature pubarche as an indicator of how body weight influences the onset of adrenarche. Eur J Pediatr 2004; 163(2): 89-93.
[] [PMID: 14689304]
Utriainen P, Jääskeläinen J, Romppanen J, Voutilainen R. Childhood metabolic syndrome and its components in premature adrenarche. J Clin Endocrinol Metab 2007; 92(11): 4282-5.
[] [PMID: 17698912]
Neville KA, Walker JL. Precocious pubarche is associated with SGA, prematurity, weight gain, and obesity. Arch Dis Child 2005; 90(3): 258-61.
[] [PMID: 15723910]
Paterson WF, Ahmed SF, Bath L, et al. Exaggerated adrenarche in a cohort of Scottish children: clinical features and biochemistry. Clin Endocrinol (Oxf) 2010; 72(4): 496-501.
[PMID: 19863577]
de Ferran K, Paiva IA, Garcia LdosS, Gama MdeP, Guimarães MM. Isolated premature pubarche: report of anthropometric and metabolic profile of a Brazilian cohort of girls. Horm Res Paediatr 2011; 75(5): 367-73.
[] [PMID: 21464553]
Cebeci AN, Taş A. Higher body fat and lower fat-free mass in girls with premature adrenarche. J Clin Res Pediatr Endocrinol 2015; 7(1): 45-8.
[] [PMID: 25800475]
Kaya G, Yavas Abali Z, Bas F, Poyrazoglu S, Darendeliler F. Body mass index at the presentation of premature adrenarche is associated with components of metabolic syndrome at puberty. Eur J Pediatr 2018; 177(11): 1593-601.
[] [PMID: 30056577]
Oron T, Lebenthal Y, de Vries L, Yackobovitch-Gavan M, Phillip M, Lazar L. Interrelationship of extent of precocious adrenarche in appropriate for gestational age girls with clinical outcome. J Pediatr 2012; 160(2): 308-13.
[] [PMID: 21907353]
Liimatta J, Utriainen P, Voutilainen R, Jääskeläinen J. Trajectories of Growth and Serum DHEAS and IGF-1 Concentrations in Girls With a History of Premature Adrenarche: Attenuation of the Phenotype by Adulthood. Front Endocrinol (Lausanne) 2018; 9: 375-83.
[] [PMID: 30042733]
Ribeiro FA, Resende EAMR, Silva APD, Tomé JM, Palhares HMDC, Borges MF. Metabolic and hormonal assessment of adolescent and young adult women with prior premature adrenarche. Clinics (São Paulo) 2019; 74: e836.
[] [PMID: 31241662]
DiSilvestro D, Petrosino J, Aldoori A, Melgar-Bermudez E, Wells A, Ziouzenkova O. Enzymatic intracrine regulation of white adipose tissue. Horm Mol Biol Clin Investig 2014; 19(1): 39-55.
[] [PMID: 25390015]
Schiffer L, Arlt W, O’Reilly MW. Understanding the Role of Androgen Action in Female Adipose Tissue. Front Horm Res 2019; 53: 33-49.
[] [PMID: 31499495]
Potau N, Riqué S, Eduardo I, Marcos V, Ibañez L. Molecular defects of the CYP21 gene in Spanish girls with isolated precocious pubarche. Eur J Endocrinol 2002; 147(4): 485-8.
[] [PMID: 12370110]
Ibáñez L, Ong K, de Zegher F, Marcos MV, del Rio L, Dunger DB. Fat distribution in non-obese girls with and without precocious pubarche: central adiposity related to insulinaemia and androgenaemia from prepuberty to postmenarche. Clin Endocrinol (Oxf) 2003; 58(3): 372-9.
[] [PMID: 12608944]
Liimatta J, Utriainen P, Laitinen T, Voutilainen R, Jääskeläinen J. Cardiometabolic Risk Profile Among Young Adult Females With a History of Premature Adrenarche. J Endocr Soc 2019; 3(10): 1771-83.
[] [PMID: 31528825]
Neeland IJ, Poirier P, Després JP. Cardiovascular and Metabolic Heterogeneity of Obesity: Clinical Challenges and Implications for Management. Circulation 2018; 137(13): 1391-406.
[] [PMID: 29581366]
Fernández-Veledo S, Nieto-Vazquez I, Vila-Bedmar R, Garcia-Guerra L, Alonso-Chamorro M, Lorenzo M. Molecular mechanisms involved in obesity-associated insulin resistance: therapeutical approach. Arch Physiol Biochem 2009; 115(4): 227-39.
[] [PMID: 19673658]
Wallace IR, McKinley MC, Bell PM, Hunter SJ. Sex hormone binding globulin and insulin resistance. Clin Endocrinol (Oxf) 2013; 78(3): 321-9.
[] [PMID: 23121642]
Larqué E, Gil-Campos M, Villada I, Ramírez-Tortosa MC, Cañete R, Gil A. Postprandial plasma adiponectin response is reduced in prepubertal premature pubarche girls. Metabolism 2010; 59(9): 1319-26.
[] [PMID: 20096425]
Uçar A, Saka N, Baş F, Hatipoğlu N, Bundak R, Darendeliler F. Reduced atherogenic indices in prepubertal girls with precocious adrenarche born appropriate for gestational age in relation to the conundrum of DHEAS. Endocr Connect 2012; 2(1): 1-10.
[] [PMID: 23781312]
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(7): 2283-8.
[] [PMID: 9215308]
Jean AM, Hassoun A, Hughes J, et al. Utility of early insulin response and proinsulin to assess insulin resistance. J Pediatr 2009; 155(6): 893-9.
[] [PMID: 19643436]
Zukauskaite S, Lasiene D, Lasas L, Urbonaite B, Hindmarsh P. Onset of breast and pubic hair development in 1231 preadolescent Lithuanian schoolgirls. Arch Dis Child 2005; 90(9): 932-6.
[] [PMID: 15855182]
Çelik N, Alp H, Çamtosun E, Alp E, Çelik S, Berk E. The Association between Premature Adrenarche and Cardiovascular Risk May Be Greater than Expected. Horm Res Paediatr 2017; 87(1): 7-14.
[] [PMID: 27871080]
Silfen ME, Manibo AM, Ferin M, McMahon DJ, Levine LS, Oberfield SE. Elevated free IGF-I levels in prepubertal Hispanic girls with premature adrenarche: relationship with hyperandrogenism and insulin sensitivity. J Clin Endocrinol Metab 2002; 87(1): 398-403.
[] [PMID: 11788683]
Ibáñez L, Potau N, Chacon P, Pascual C, Carrascosa A. Hyperinsulinaemia, dyslipaemia and cardiovascular risk in girls with a history of premature pubarche. Diabetologia 1998; 41(9): 1057-63.
[] [PMID: 9754824]
Güven A, Cinaz P, Bideci A. Is premature adrenarche a risk factor for atherogenesis? Pediatr Int 2005; 47(1): 20-5.
[] [PMID: 15693861]
Vuguin P, Linder B, Rosenfeld RG, Saenger P, DiMartino-Nardi J. The roles of insulin sensitivity, insulin-like growth factor I (IGF-I), and IGF-binding protein-1 and -3 in the hyperandrogenism of African-American and Caribbean Hispanic girls with premature adrenarche. J Clin Endocrinol Metab 1999; 84(6): 2037-42.
[PMID: 10372707]
Teixeira RJ, Ginzbarg D, Rodrigues Freitas J, Fucks G, Silva CM, Bordallo MA. Serum leptin levels in premature pubarche and prepubertal girls with and without obesity. J Pediatr Endocrinol Metab 2004; 17(10): 1393-8.
[] [PMID: 15526717]
Livadas S, Dracopoulou M, Lazaropoulou C, et al. A favorable metabolic and antiatherogenic profile in carriers of CYP21A2 gene mutations supports the theory of a survival advantage in this population. Horm Res 2009; 72(6): 337-43.
[PMID: 19844122]
Meas T, Chevenne D, Thibaud E, et al. Endocrine consequences of premature pubarche in post-pubertal Caucasian girls. Clin Endocrinol (Oxf) 2002; 57(1): 101-6.
[] [PMID: 12100077]
Mathew RP, Byrne DW, Linton MF, Vaughan DE, Fazio S, Russell WE. Evidence of metabolic syndrome in lean children with premature pubarche at diagnosis. Metabolism 2008; 57(6): 733-40.
[] [PMID: 18502254]
Williams KM, Oberfield SE, Zhang C, McMahon DJ, Sopher AB. The Relationship of Metabolic Syndrome and Body Composition in Children with Premature Adrenarche: Is It Age Related? Horm Res Paediatr 2015; 84(6): 401-7.
[] [PMID: 26513727]
Utriainen P, Jääskeläinen J, Gröhn O, Kuusisto J, Pulkki K, Voutilainen R. Circulating TNF-Alpha and IL-6 Concentrations and TNF-Alpha -308 G > A Polymorphism in Children with Premature Adrenarche. Front Endocrinol (Lausanne) 2010; 1: 6-12.
[PMID: 22654787]
Andiran N, Yordam N, Kirazli S. Global fibrinolytic capacity is decreased in girls with premature adrenarche: a new pathological finding? J Pediatr Endocrinol Metab 2005; 18(12): 1373-81.
[PMID: 16459463]
Christen T, Trompet S, Rensen PCN, et al. The role of inflammation in the association between overall and visceral adiposity and subclinical atherosclerosis. Nutr Metab Cardiovasc Dis 2019; 29(7): 728-35.
[PMID: 31138500]
Iacobellis G. Local and systemic effects of the multifaceted epicardial adipose tissue depot. Nat Rev Endocrinol 2015; 11(6): 363-71.
[] [PMID: 25850659]
Wu Y, Zhang A, Hamilton DJ, Deng T. Epicardial Fat in the Maintenance of Cardiovascular Health. Methodist DeBakey Cardiovasc J 2017; 13(1): 20-4.
[] [PMID: 28413578]
Mathew RP, Hernanz-Schulman M, Wang W, Saville B, Bremer A. Changes in carotid artery sonogram in premature adrenarche. J Pediatr Endocrinol Metab 2012; 25(1-2): 139-45.
[] [PMID: 22570963]
Falhammar H, Frisén L, Hirschberg AL, et al. Increased Cardiovascular and Metabolic Morbidity in Patients With 21-Hydroxylase Deficiency: A Swedish Population-Based National Cohort Study. J Clin Endocrinol Metab 2015; 100(9): 3520-8.
[] [PMID: 26126207]
Livadas S, Bothou C, Kanaka-Gantenbein C, et al. Unfavorable Hormonal and Psychologic Profile in Adult Women with a History of Premature Adrenarche and Pubarche, Compared to Women with Polycystic Ovary Syndrome. Horm Metab Res 2020; 52(3): 179-85.
[] [PMID: 32074632]
Conway G, Dewailly D, Diamanti-Kandarakis E, et al. ESE PCOS Special Interest Group. The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur J Endocrinol 2014; 171(4): 1-29.
[] [PMID: 24849517]
Nader S. Adrenarche and polycystic ovary syndrome: a tale of two hypotheses. J Pediatr Adolesc Gynecol 2007; 20(6): 353-60.
[] [PMID: 18082857]
Battaglia C, Regnani G, Mancini F, et al. Isolated premature pubarche: ultrasonographic and color Doppler analysis--a longitudinal study. J Clin Endocrinol Metab 2002; 87(7): 3148-54.
[PMID: 12107215]
Ibañez L, Potau N, Virdis R, et al. Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism. J Clin Endocrinol Metab 1993; 76(6): 1599-603.
[] [PMID: 8501168]
Ibáñez L, Potau N, Marcos MV, de Zegher F. Exaggerated adrenarche and hyperinsulinism in adolescent girls born small for gestational age. J Clin Endocrinol Metab 1999; 84(12): 4739-41.
[] [PMID: 10599744]
Ibáñez L, Potau N, Carrascosa A. Insulin resistance, premature adrenarche, and a risk of the Polycystic Ovary Syndrome (PCOS). Trends Endocrinol Metab 1998; 9(2): 72-7.
[] [PMID: 18406245]
Diamanti-Kandarakis E, Christakou C, Palioura E, Kandaraki E, Livadas S. Does polycystic ovary syndrome start in childhood? Pediatr Endocrinol Rev 2008; 5(4): 904-11.
[PMID: 18552753]
Livadas S, Dracopoulou M, Dastamani A, et al. The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene. Clin Endocrinol (Oxf) 2015; 82(4): 543-9.
[] [PMID: 25041270]
Livadas S, Bothou C. Management of the Female With Non-classical Congenital Adrenal Hyperplasia (NCCAH): A Patient-Oriented Approach. Front Endocrinol (Lausanne) 2019; 10: 366-75.
[] [PMID: 31244776]
Improda N, Barbieri F, Ciccarelli GP, Capalbo D, Salerno M. Cardiovascular Health in Children and Adolescents With Congenital Adrenal Hyperplasia Due to 21-Hydroxilase Deficiency. Front Endocrinol (Lausanne) 2019; 10: 212-8.
[PMID: 31031703]
Macut D, Zdravković V, Bjekić-Macut J, Mastorakos G, Pignatelli D. Metabolic Perspectives for Non-classical Congenital Adrenal Hyperplasia With Relation to the Classical Form of the Disease. Front Endocrinol (Lausanne) 2019; 10: 681-97.
[] [PMID: 31632355]
de Vries L, Lebenthal Y, Phillip M, Shalitin S, Tenenbaum A, Bello R. Obesity and Cardiometabolic Risk Factors in Children and Young Adults With Non-classical 21-Hydroxylase Deficiency. Front Endocrinol (Lausanne) 2019; 10: 698-704.
[] [PMID: 31681171]
Krysiak R, Kowalcze K, Marek B, Okopień B. Cardiometabolic risk factors in women with non-classic congenital adrenal hyperplasia. Acta Cardiol 2019; 4: 1-6.
[] [PMID: 31538536]
Dacou-Voutetakis C, Dracopoulou M. High incidence of molecular defects of the CYP21 gene in patients with premature adrenarche. J Clin Endocrinol Metab 1999; 84(5): 1570-4.
[] [PMID: 10323382]
Admoni O, Israel S, Lavi I, Gur M, Tenenbaum-Rakover Y. Hyperandrogenism in carriers of CYP21 mutations: the role of genotype. Clin Endocrinol (Oxf) 2006; 64(6): 645-51.
[] [PMID: 16712666]
Witchel SF, Lee PA, Suda-Hartman M, Trucco M, Hoffman EP. Evidence for a heterozygote advantage in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 1997; 82(7): 2097-101.
[] [PMID: 9215278]
Charmandari E, Merke DP, Negro PJ, et al. Endocrinologic and psychologic evaluation of 21-hydroxylase deficiency carriers and matched normal subjects: evidence for physical and/or psychologic vulnerability to stress. J Clin Endocrinol Metab 2004; 89(5): 2228-36.
[] [PMID: 15126546]
Nordenström A, Svensson J, Lajic S, et al. Carriers of a Classic CYP21A2 Mutation Have Reduced Mortality: A Population-Based National Cohort Study. J Clin Endocrinol Metab 2019; 104(12): 6148-54.
[] [PMID: 31393570]
Prough RA, Clark BJ, Klinge CM. Novel mechanisms for DHEA action. J Mol Endocrinol 2016; 56(3): R139-55.
[] [PMID: 26908835]
Akyürek N, Atabek ME, Eklioglu BS, Alp H. Is there a relationship between cardiovascular risk factors and dehydroepiandrosterone sulfate levels in childhood obesity? J Pediatr Endocrinol Metab 2015; 28(5-6): 545-50.
[] [PMID: 25381943]
Mäntyselkä A, Lindi V, Viitasalo A, et al. Associations of Dehydroepiandrosterone Sulfate With Cardiometabolic Risk Factors in Prepubertal Children. J Clin Endocrinol Metab 2018; 103(7): 2592-600.
[] [PMID: 29757399]
Wu TT, Gao Y, Zheng YY, Ma YT, Xie X. Association of endogenous DHEA/DHEAS with coronary heart disease: A systematic review and meta-analysis. Clin Exp Pharmacol Physiol 2019; 46(11): 984-94.
[] [PMID: 31347187]
Ng MK, Nakhla S, Baoutina A, Jessup W, Handelsman DJ, Celermajer DS. Dehydroepiandrosterone, an adrenal androgen, increases human foam cell formation: a potentially pro-atherogenic effect. J Am Coll Cardiol 2003; 42(11): 1967-74.
[] [PMID: 14662261]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy