Download PDF
Exp Clin Endocrinol Diabetes 2019; 127(04): 234-239
DOI: 10.1055/s-0043-125067
Article
© Georg Thieme Verlag KG Stuttgart · New York

LHCGR Gene Analysis in Girls with Non-Classic Central Precocious Puberty

Hwal Rim Jeong
1   Department of Pediatrics Hallym University, School of Medicine, Chuncheon, Korea
,
Hae Sang Lee
2   Department of Pediatrics Ajou University, School of Medicine, Suwon, Korea
,
Jin Soon Hwang
2   Department of Pediatrics Ajou University, School of Medicine, Suwon, Korea
› Author Affiliations
Further Information

Publication History

received 01 October 2017
revised 07 December 2017

accepted 18 December 2017

Publication Date:
05 March 2018 (online)

Also available at
    Permissions and Reprints

Abstract

Background Luteinizing hormone (LH) is a useful parameter in diagnosing precocious puberty. The pubertal response of serum LH to a GnRH stimulation test is varied, and clinical symptoms of precocious puberty are sometimes disproportionate with serum LH concentrations. Many patients present in a state of precocious puberty that advances rapidly, but the post-GnRH peak LH remains prepubertal. LH receptor mutations are suspected of involvement in the non-classic type of central precocious puberty (CPP).

Objective To examine the association between LHCGR polymorphism and non-classic CPP in subjects exhibiting a peak LH<5 IU/L on a GnRH stimulation test. Methods: In total, 102 girls with non-classic CPP and 100 normal adult women were enrolled. All subjects underwent LHCGR gene analysis by the Sanger method, and patients and controls were compared. Auxological data and gonadotropin concentrations were analyzed in the 102 patients. Of these patients, 75 completed GnRH agonist treatment, and the treatment outcomes were analyzed.

Results A total of seven variants were identified, including two missense mutations (g.48698754 G/A and g.48688613 G/A) that were found in the patient group (no patients contained both mutations). In silico analysis of these missense mutations suggested the possibility of damaging the LHCGR. However, no significant association was found between the identified LHCGR variants and non-classic CPP. GnRH agonist treatment decreased bone age advancement and increased predicted adult height.

Conclusions LHCGR gene polymorphisms do not appear to be a major causative factor for the relatively low concentration of LH in patients with non-classic CPP. GnRH agonist treatment improved clinical parameters in these patients.

Key words

LHCGR gene - precocious puberty - GnRH agonist
 

  • References

  • 1 Carel JC, Leger J. Clinical practice. Precocious puberty. The New England journal of medicine 2008; 358: 2366-2377
    CrossrefPubMedGoogle Scholar
  • 2 Resende EA, Lara BH, Reis JD. et al. Assessment of basal and gonadotropin-releasing hormone-stimulated gonadotropins by immunochemiluminometric and immunofluorometric assays in normal children. The Journal of clinical endocrinology and metabolism 2007; 92: 1424-1429
    CrossrefPubMedGoogle Scholar
  • 3 Rousseau-Merck MF, Misrahi M, Atger M. et al. Localization of the human luteinizing hormone/choriogonadotropin receptor gene (LHCGR) to chromosome 2p21. Cytogenetics and cell genetics 1990; 54: 77-79
    CrossrefPubMedGoogle Scholar
  • 4 Ascoli M, Fanelli F, Segaloff DL. The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocrine reviews 2002; 23: 141-174
    CrossrefPubMedGoogle Scholar
  • 5 Arnhold IJ, Lofrano-Porto A, Latronico AC. Inactivating mutations of luteinizing hormone beta-subunit or luteinizing hormone receptor cause oligo-amenorrhea and infertility in women. Hormone research 2009; 71: 75-82
    PubMedGoogle Scholar
  • 6 Rosenthal SM, Grumbach MM, Kaplan SL. Gonadotropin-independent familial sexual precocity with premature Leydig and germinal cell maturation (familial testotoxicosis): effects of a potent luteinizing hormone-releasing factor agonist and medroxyprogesterone acetate therapy in four cases. The Journal of clinical endocrinology and metabolism 1983; 57: 571-579
    CrossrefPubMedGoogle Scholar
  • 7 Schedewie HK, Reiter EO, Beitins IZ. et al. Testicular leydig cell hyperplasia as a cause of familial sexual precocity. The Journal of clinical endocrinology and metabolism 1981; 52: 271-278
    CrossrefPubMedGoogle Scholar
  • 8 Laue L, Chan WY, Hsueh AJ. et al. Genetic heterogeneity of constitutively activating mutations of the human luteinizing hormone receptor in familial male-limited precocious puberty. Proceedings of the National Academy of Sciences of the United States of America. 1995; 92: 1906-1910
    CrossrefPubMedGoogle Scholar
  • 9 Jeha GS, Lowenthal ED, Chan WY. et al. Variable presentation of precocious puberty associated with the D564G mutation of the LHCGR gene in children with testotoxicosis. The Journal of pediatrics 2006; 149: 271-274
    CrossrefPubMedGoogle Scholar
  • 10 Moon JS, Lee SY, Nam CM. et al. 2007; Korean National Growth Charts: review of developmental process and an outlook. Korean J Pediatr DE - 2008-01-01 KUID - 0052KJP/20085111 2008;51 1-25
    PubMedGoogle Scholar
  • 11 Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of disease in childhood 1969; 44: 291-303
    CrossrefPubMedGoogle Scholar
  • 12 Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. The American Journal of the Medical Sciences 1959; 238: 393
    PubMedGoogle Scholar
  • 13 Bayley N, Pinneau SR. Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standards. The Journal of pediatrics 1952; 40: 423-441
    CrossrefPubMedGoogle Scholar
  • 14 Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Current protocols in human genetics 2013; Chapter 7: Unit7.20
    PubMedGoogle Scholar
  • 15 Thathapudi S, Kodati V, Erukkambattu J. et al. Association of luteinizing hormone chorionic gonadotropin receptor gene polymorphism (rs2293275) with polycystic ovarian syndrome. Genetic testing and molecular biomarkers 2015; 19: 128-132
    CrossrefPubMedGoogle Scholar
  • 16 Valkenburg O, Uitterlinden AG, Piersma D. et al. Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome. Human reproduction (Oxford, England) 2009; 24: 2014-2022
    CrossrefPubMedGoogle Scholar
  • 17 Ozcabi B, Tahmiscioglu Bucak F, Ceylaner S. et al. Testotoxicosis: Report of Two Cases, One with a Novel Mutation in LHCGR Gene. Journal of clinical research in pediatric endocrinology 2015; 7: 242-248
    CrossrefPubMedGoogle Scholar
  • 18 Shenker A, Laue L, Kosugi S. et al. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 1993; 365: 652-654
    CrossrefPubMedGoogle Scholar
  • 19 Latronico AC, Segaloff DL. Naturally occurring mutations of the luteinizing-hormone receptor: lessons learned about reproductive physiology and G protein-coupled receptors. American journal of human genetics 1999; 65: 949-958
    CrossrefPubMedGoogle Scholar
  • 20 Siviero-Miachon AA, Kizys MM, Ribeiro MM. et al. Cosegregation of a novel mutation in the sixth transmembrane segment of the luteinizing/choriogonadotropin hormone receptor with two Brazilian siblings with severe testotoxicosis. Endocrine research 2017; 42: 117-124
    CrossrefPubMedGoogle Scholar
  • 21 Rosenfield RL, Bordini B, Yu C. Comparison of detection of normal puberty in girls by a hormonal sleep test and a gonadotropin-releasing hormone agonist test. The Journal of clinical endocrinology and metabolism 2013; 98: 1591-1601
    CrossrefPubMedGoogle Scholar
  • 22 Dickerman Z, Prager-Lewis R, Laron Z. Response of plasma LH and FSH to synthetic LH-RH in children at various pubertal stages. American journal of diseases of children (1960) 1976; 130: 634-638
    PubMedGoogle Scholar
  • 23 Sperling MA. Pediatric Endocrinology E-Book: Elsevier Health Sciences 2014
    PubMed
  • 24 Houk CP, Kunselman AR, Lee PA. Adequacy of a single unstimulated luteinizing hormone level to diagnose central precocious puberty in girls. Pediatrics 2009; 123: e1059-e1063
    CrossrefPubMedGoogle Scholar
  • 25 Brito VN, Batista MC, Borges MF. et al. Diagnostic value of fluorometric assays in the evaluation of precocious puberty. The Journal of clinical endocrinology and metabolism 1999; 84: 3539-3544
    PubMedGoogle Scholar
  • 26 Rosenfield RL. Selection of children with precocious puberty for treatment with gonadotropin releasing hormone analogs. The Journal of pediatrics 1994; 124: 989-991
    CrossrefPubMedGoogle Scholar
  • 27 Jung MK, Song KC, Kwon AR. et al. Adult height in girls with central precocious puberty treated with gonadotropin-releasing hormone agonist with or without growth hormone. Annals of pediatric endocrinology & metabolism 2014; 19: 214-219
    CrossrefPubMedGoogle Scholar
  • 28 Pasquino AM, Pucarelli I, Accardo F. et al. Long-term observation of 87 girls with idiopathic central precocious puberty treated with gonadotropin-releasing hormone analogs: impact on adult height, body mass index, bone mineral content, and reproductive function. The Journal of clinical endocrinology and metabolism 2008; 93: 190-195
    CrossrefPubMedGoogle Scholar
  • 29 Heger S, Partsch CJ, Sippell WG. Long-term outcome after depot gonadotropin-releasing hormone agonist treatment of central precocious puberty: final height, body proportions, body composition, bone mineral density, and reproductive function. The Journal of clinical endocrinology and metabolism 1999; 84: 4583-4590
    PubMedGoogle Scholar
  • 30 Baek JW, Nam HK, Jin D. et al. Age of menarche and near adult height after long-term gonadotropin-releasing hormone agonist treatment in girls with central precocious puberty. Annals of pediatric endocrinology & metabolism 2014; 19: 27-31
    CrossrefPubMedGoogle Scholar
  • 31 Erickson GF, Wang C, Hsueh AJ. FSH induction of functional LH receptors in granulosa cells cultured in a chemically defined medium. Nature 1979; 279: 336-338
    CrossrefPubMedGoogle Scholar
  • 32 Law NC, Weck J, Kyriss B. et al. Lhcgr expression in granulosa cells: roles for PKA-phosphorylated beta-catenin, TCF3, and FOXO1. Molecular endocrinology (Baltimore, Md) 2013; 27: 1295-1310
    CrossrefPubMedGoogle Scholar
  • 33 El-Hayek S, Demeestere I, Clarke HJ. Follicle-stimulating hormone regulates expression and activity of epidermal growth factor receptor in the murine ovarian follicle. Proceedings of the National Academy of Sciences of the United States of America. 2014; 111: 16778-16783
    CrossrefPubMedGoogle Scholar