Background: Leptin deficiency leads to midluteal-phase defect or reduced testicular volume in adults, despite normal gonadotropin levels. All children documented to date with leptin deficiency were prepubertal with physiologically low gonadotropins prior to therapy. A direct effect of leptin on pubertal development in a leptin-naive adolescent has not yet been shown. Methods: In 2010, we reported the first connatal leptin-deficient adolescent girl with clinically and chemically proven hypogonadotropic hypogonadism. In this study, we evaluated the effect of recombinant methionyl human leptin substitution. Results: Initially, the patient had prepubertal basal and stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, low growth hormone and insulin-like growth factor 1 (IGF1) levels and no pulsatile secretion of LH and FSH. After 11 weeks of therapy, basal and stimulated LH and FSH levels rose to pubertal values and nocturnal pulsatility was initiated. After 76 weeks of therapy, menstruation occurred at the age of 16.3 years. Pulsatile nocturnal growth hormone secretion, stimulated growth hormone secretion and IGF1 values also normalized. Conclusion: We describe here the first adolescent with hypogonadotropic hypogonadism due to connatal leptin deficiency. Leptin substitution led to a rapid induction of gonadotropin secretion and menarche. These data are further proof of the concept that leptin is needed for a timely maturation of the hypothalamic/pituitary/gonadal axis.

Keywords:
Leptin, Puberty, Obesity, Hypogonadotropic hypogonadism
1.
Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O’Rahilly S: Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903–908.
2.
Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD: A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998;18:213–215.
3.
Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna V, Jebb SA, Perna F, Fontana S, Lechler RI, DePaoli AM, O’Rahilly S: Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 2002;110:1093–1103.
4.
Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O’Rahilly S, Trussell RA: Congenital leptin deficiency due to homozygosity for the delta133g mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 2004;89:4821–4826.
5.
Ozata M, Ozdemir IC, Licinio J: Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 1999;84:3686–3695.
6.
Paz-Filho GJ, Babikian T, Asarnow R, Esposito K, Erol HK, Wong ML, Licinio J: Leptin replacement improves cognitive development. PLoS ONE 2008;3:e3098.
7.
Mazen I, El-Gammal M, Abdel-Hamid M, Amr K: A novel homozygous missense mutation of the leptin gene (n103k) in an obese Egyptian patient. Mol Genet Metab 2009;97:305–308.
8.
Farooqi IS: Monogenic human obesity. Front Horm Res 2008;36:1–11.
9.
Fischer-Posovszky P, von Schnurbein J, Moepps B, Lahr G, Strauss G, Barth TF, Kassubek J, Muhleder H, Moller P, Debatin KM, Gierschik P, Wabitsch M: A new missense mutation in the leptin gene causes mild obesity and hypogonadism without affecting T cell responsiveness. J Clin Endocrinol Metab 2010;95:2836–2840.
10.
Ingalls AM, Dickie MM, Snell GD: Obese, a new mutation in the house mouse. J Hered 1950;41:317–318.
11.
Swerdloff RS, Batt RA, Bray GA: Reproductive hormonal function in the genetically obese (ob/ob) mouse. Endocrinology 1976;98:1359–1364.
12.
Chehab FF, Lim ME, Lu R: Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet 1996;12:318–320.
13.
Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O’Rahilly S: Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999;341:879–884.
14.
Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O’Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML: Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA 2004;101:4531–4536.
15.
Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, Lank E, Bottomley B, Lopez-Fernandez J, Ferraz-Amaro I, Dattani MT, Ercan O, Myhre AG, Retterstol L, Stanhope R, Edge JA, McKenzie S, Lessan N, Ghodsi M, De Rosa V, Perna F, Fontana S, Barroso I, Undlien DE, O’Rahilly S: Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 2007;356:237–247.
16.
Bray GA, York DA: Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiol Rev 1979;59:719–809.
17.
Tannenbaum GS, Lapointe M, Gurd W, Finkelstein JA: Mechanisms of impaired growth hormone secretion in genetically obese Zucker rats: roles of growth hormone-releasing factor and somatostatin. Endocrinology 1990;127:3087–3095.
18.
Carro E, Senaris R, Considine RV, Casanueva FF, Dieguez C: Regulation of in vivo growth hormone secretion by leptin. Endocrinology 1997;138:2203–2206.
19.
Ozata M, Dieguez C, Casanueva FF: The inhibition of growth hormone secretion presented in obesity is not mediated by the high leptin levels: a study in human leptin deficiency patients. J Clin Endocrinol Metab 2003;88:312–316.
20.
Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B: A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998;392:398–401.
21.
Dubuc PU: Thyroid hormone responses to feeding in ob/ob mice. Horm Metab Res 1989;21:546–549.
22.
Herter LD, Golendziner E, Flores JA, Becker E Jr, Spritzer PM: Ovarian and uterine sonography in healthy girls between 1 and 13 years old: correlation of findings with age and pubertal status. AJR Am J Roentgenol 2002;178:1531–1536.
23.
Prader A, Largo RH, Molinari L, Issler C: Physical growth of Swiss children from birth to 20 years of age. First Zurich longitudinal study of growth and development. Helv Paediatr Acta Suppl 1989;52:1–125.
24.
Musso C, Cochran E, Javor E, Young J, Depaoli AM, Gorden P: The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism 2005;54:255–263.
25.
Andreelli F, Hanaire-Broutin H, Laville M, Tauber JP, Riou JP, Thivolet C: Normal reproductive function in leptin-deficient patients with lipoatropic diabetes. J Clin Endocrinol Metab 2000;85:715–719.
26.
Bayley N, Pinneau SR: Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standards. J Pediatr 1952;40:423–441.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.