Hypogonadotropic Hypogonadism

Leticia F. G. Silveira; Gavin S. MacColl; Pierre M. G. Bouloux

doi:10.1055/s-2002-36707

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2002; 20(4): 327-338
DOI: 10.1055/s-2002-36707

Hypogonadotropic Hypogonadism

Leticia F.G. Silveira, Gavin S. MacColl, Pierre M.G. Bouloux

Department of Medicine, Neuroendocrine Unit, Royal Free and University College Medical School, London, United Kingdom

Abstract

ABSTRACT

Hypogonadotropic hypogonadism is characterized by failure of gonadal function secondary to deficient gonadotropin secretion, resulting from either a pituitary or hypothalamic defect, and is commonly seen in association with structural lesions or functional defects affecting this region. Although the genetic basis for idiopathic hypogonadotropic hypogonadism is largely unknown, mutations in several genes involved in the hypothalamo-pituitary-gonadal axis development and function have recently been implicated in the pathogenesis of this condition. Genes currently recognized to be involved include KAL-1 (associated with X-linked Kallmann Syndrome), gonadotropin-releasing hormone (GnRH) receptor, gonadotropins, pituitary transcription factors (HESX1, LHX3, and PROP-1), orphan nuclear receptors (DAX-1, associated with X-linked adrenal hypoplasia congenital, and SF-1), and three genes also associated with obesity (leptin, leptin receptor, and prohormone convertase 1 [PC1]). Study of these mutations provides an important contribution in the understanding of the different stages of the reproductive axis development and physiology. Treatment options currently available for puberty induction, maintenance replacement therapy, and fertility induction are considered here. Gametogenesis can be induced with either exogenous gonadotropin or pulsatile GnRH therapy, depending on the etiology.

KEYWORD

Hypogonadotropic hypogonadism - etiology - genetics - treatment

Full Text

References

REFERENCES

1 Seeburg P H, Adelman J P. Characterization of cDNA for precursor of human luteinizing hormone releasing hormone. Nature . 1984; 1311 666-668
2 Themmen A PN, Huhtaniemi I T. Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocr Rev . 2000; 21 551-583
3 Terasawa E, Fernandez D L. Neurobiological mechanisms of the onset of puberty in primates. Endocr Rev . 2001; 22 111-151
4 Seminara S B, Hayes F J, Crowley Jr F W. Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): pathophysiological and genetic considerations. Endocr Rev . 1998; 19 521-539
5 Winter J S, Faiman C, Hobson W C, Prasad A V, Reyes F I. Pituitary-gonadal relations in infancy I: patterns of serum gonadotropin concentrations from birth to four years of age in man and chimpanzee. J Clin Endocrinol Metab . 1975; 40 545-551
6 Wu F C, Butler G E, Kelnar C J, Stirling H F, Huhtaniemi I. Patterns of pulsatile luteinizing hormone and follicle-stimulating hormone secretion in prepubertal (midchildhood) boys and girls and patients with idiopathic hypogonadotropic hypogonadism (Kallmann's syndrome): a study using an ultrasensitive time-resolved immunofluorometric assay. J Clin Endocrinol Metab . 1991; 72 1229-1237
7 Mitamura R, Yano K, Suzuki N, Ito Y, Makita Y, Okuno A. Diurnal rhythms of luteinizing hormone, follicle-stimulating hormone, and testosterone secretion before the onset of male puberty. J Clin Endocrinol Metab . 1999; 84 29-37
8 Grumbach M M, Styne D M. Puberty: ontogeny, neuroendocrinology, physiology, and disorders. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams' Textbook of Endocrinology Philadelphia: W.B. Saunders 1998: 1509-1625
9 MacColl G, Quinton R, Bouloux P M. GnRH neuronal development: insights into hypogonadotrophic hypogonadism. Trends Endocrinol Metab . 2002; 13 112-118
10 Quinton R, Duke V M, Robertson A. Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization. Clin Endocrinol (Oxf) . 2001; 55 163-174
11 Quinton R, Duke V M, de Zoysa A P. The neuroradiology of Kallmann's syndrome: a genotypic and phenotypic analysis. J Clin Endocrinol Metab . 1996; 81 3010-3017
12 Silveira L FG, MacColl G S, Stewart P, Thomas M, Bouloux P MG. Novel homozygous splice site GnRH receptor mutation associated with severe familial hypogonadotropic hypogonadism. Proceedings of the 83nd annual meeting of The Endocrine Society, Denver, 2001
13 Perkins R B, Hall J E, Martin K A. Aetiology, previous menstrual function and patterns of neuro-endocrine disturbance as prognostic indicators in hypothalamic amenorrhoea. Hum Reprod . 2001; 16 2198-2205
14 Laughlin G A, Yen S SC. Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea. J Clin Endocrinol Metab . 1997; 82 318-321
15 Miller K K, Parulekar M S, Schoenfeld E. Decreased leptin levels in normal weight women with hypothalamic amenorrhea: the effects of body composition and nutritional intake. J Clin Endocrinol Metab . 1998; 83 2309-2312
16 Nachtigall L B, Boepple P A, Pralong F P, Crowley Jr F W. Adult-onset idiopathic hypogonadotropic hypogonadism: a treatable form of male infertility. N Engl J Med . 1997; 336 410-415
17 Sauder S E, Frager M, Case G D, Kelch R P, Marshall J C. Abnormal patterns of pulsatile luteinizing hormone secretion in women with hyperprolactinemia and amenorrhea: responses to bromocriptine. J Clin Endocrinol Metab . 1984; 59 941-948
18 Cook C B, Nippoldt T B, Kletter G B, Kelch R P, Marshall J C. Naloxone increases the frequency of pulsatile luteinizing hormone secretion in women with hyperprolactinemia. J Clin Endocrinol Metab . 1991; 73 1099-1105
19 Cohen P G. The hypogonadal-obesity cycle: role of aromatase in modulating the testosterone-estradiol shunt: a major factor in the genesis of morbid obesity. Med Hypotheses . 1999; 52 49-51
20 Zumoff B. Hormonal abnormalities in obesity. Acta Med Scand Suppl . 1988; 723 153-160
21 Mayston M J, Harrison L M, Quinton R, Stephens J A, Krams M, Bouloux P M. Mirror movements in X-linked Kallmann's syndrome: a neurophysiological study. Brain . 1997; 120 1199-1216
22 Oliveira L M, Seminara S B, Beranova M. The importance of autosomal genes in Kallmann's syndrome: genotype-phenotype correlations and neuroendocrine characteristics. J Clin Endocrinol Metab . 2001; 86 1532-1538
23 Schwanzel-Fukuda M. Origin and migration of luteinizing hormone-releasing hormone neurons in mammals. Microsc Res Tech . 1999; 44 2-10
24 Hardelin J P. Kallmann syndrome: towards molecular pathogenesis. Mol Cell Endocrinol . 2001; 179 75-81
25 Hardelin J P, Julliard A K, Moniot B. Anosmin-1 is a regionally restricted component of basement membranes and interstitial matrices during organogenesis: implications for the developmental anomalies of X chromosome-linked Kallmann syndrome. Dev Dyn . 1999; 215 26-44
26 Robertson A, MacColl G S, Nash J A, Boehm M K, Perkins S J, Bouloux P M. Molecular modelling and experimental studies of mutation and cell-adhesion sites in the fibronectin type III and whey acidic protein domains of human anosmin-1. Biochem J . 2001; 357 647-659
27 Mason A J, Hayflick J S, Zoeller R T. A deletion truncating the gonadotropin-releasing hormone gene is responsible for hypogonadism in the hpg mouse. Science . 1986; 234 1366-1371
28 Beranova M, Oliveira L BM, Bedecarrats G Y. Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab . 2001; 86 1580-1588
29 Kakar S S, Musgrove L C, Devor D C, Sellers J C, Neill J D. Cloning, sequencing, and expression of human gonadotropin-releasing hormone (GnRH) receptor. Biochem Biophys Res Commun . 1992; 189 289-295
30 Chi L, Zhou W, Prikhozhan A. Cloning and characterization of the human GnRH receptor. Mol Cell Endocrinol . 1993; 9 R1-R6
31 Pitteloud N, Boepple P, DeCruz S, Valkenburgh S B, Crowley Jr F W, Hayes F J. The Fertile Eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab . 2001; 86 2470-2475
32 Pralong F P, Gomez F, Castillo E. Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab . 1999; 84 3811-3816
33 Kottler M L, Chauvin S, Lahlou N. A new compound heterozygous mutation of the gonadotropin-releasing hormone receptor (L314X, Q106R) in a woman with complete hypogonadotropic hypogonadism: chronic estrogen administration amplifies the gonadotropin defect. J Clin Endocrinol Metab . 2000; 85 3002-3008
34 Soderlund D, Canto P, de la Chesnaye E, Ulloa-Aguirre A, Mendez J P. A novel homozygous mutation in the second transmembrane domain of the gonadotropin releasing hormone receptor gene. Clin Endocrinol . 2001; 54 493-498
35 Costa E MF, Bedecarrats G Y, Mendonca B B, Arnhold I JP, Kaiser U B, Latronico A C. Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction. J Clin Endocrinol Metab . 2001; 86 2680-2686
36 De Roux N, Young J, Brailly-Tabard S. The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred. J Clin Endocrinol Metab . 1999; 84 567-572
37 Weiss J, Axelrod L, Whitcomb R W, Harris P E, Crowley W F, Jameson J L. Hypogonadism caused by a single amino acid substitution in the beta subunit of luteinizing hormone. N Engl J Med . 1992; 326 179-183
38 Matthews C H, Borgato S, Beck-Peccoz P. Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone. Nat Genet . 1993; 5 83-86
39 Layman L C. Mutations in the follicle-stimulating hormone-beta (FSH beta) and FSH receptor genes in mice and humans. Semin Reprod Med . 2000; 18 5-10
40 Hermesz E, Mackem S, Mahon K A. Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke's pouch of the mouse embryo. Development . 1996; 122 41-52
41 Dattani M T, Robinson I C. The molecular basis for developmental disorders of the pituitary gland in man. Clin Genet . 2000; 57 337-346
42 Dattani M T, Martinez-Barbera J P, Thomas P Q. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet . 1998; 19 125-133
43 Thomas P Q, Dattani M T, Brickman J M. Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet . 2001; 10 39-45
44 Bridwell J L, Price J R, Parker G E, McCutchan Schiller A, Sloop K W, Rhodes S J. Role of the LIM domains in DNA recognition by the Lhx3 neuroendocrine transcription factor. Gene . 2001; 277 239-250
45 Sheng H Z, Zhadanov A B, Mosinger Jr B. Specification of pituitary cell lineages by the LIM homeobox gene Lhx3. Science . 1996; 272 1004-1007
46 Netchine I, Sobrier M L, Krude H. Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet . 2000; 25 182-186
47 Sloop K W, Dwyer C J, Rhodes S J. An isoform-specific inhibitory domain regulates the LHX3 LIM homeodomain factor holoprotein and the production of a functional alternate translation form. J Biol Chem . 2001; 276 36311-36319
48 Sornson M W, Wu W, Dasen J S. Pituitary lineage determination by the prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature . 1996; 384 327-333
49 Deladoey J, Fluck C, Buyukgebiz A. "Hot spot" in the PROP1 gene responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab . 1999; 84 1645-1650
50 Wu W, Cogan J D, Pfaffle R W. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet . 1998; 18 147-149
51 Fluck C, Deladoey J, Rutishauser K. Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg → Cys at codon 120 (R120C). J Clin Endocrinol Metab . 1998; 83 3727-3734
52 Parker K L, Schimmer B P. Steroidogenic factor 1: a key determinant of endocrine development and function. Endocr Rev . 1997; 18 361-377
53 Bakke M, Zhao L, Parker K L. Approaches to define the role of SF-1 at different levels of the hypothalamic-pituitary-steroidogenic organ axis. Mol Cell Endocrinol . 2001; 179 33-37
54 Achermann J C, Ito M, Ito M, Hindmarsh P C, Jameson J L. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet . 1999; 22 125-126
55 Muscatelli F, Strom T M, Walker A P. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature . 1994; 372 672-676
56 Zanaria E, Muscatelli F, Bardoni B. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature . 1994; 372 635-641
57 Zhang Y H, Guo W, Wagner R L, Huang B L. DAX1 mutations provide insight into structure-function relationships in steroidogenic tissue development. Am J Hum Genet . 1998; 62 855-864
58 Achermann J C, Jameson J L. Advances in the molecular genetics of hypogonadotropic hypogonadism. J Pediatr Endocrinol Metab . 2001; 14 3-15
59 Reutens A T, Achermann J C, Ito M. Clinical and functional effects of mutations in the DAX-1 gene in patients with adrenal hypoplasia congenita. J Clin Endocrinol Metab . 1999; 84 504-511
60 Ito M, Yu R, Jameson J L. DAX-1 inhibits SF-1-mediated transactivation via a carboxy-terminal domain that is deleted in adrenal hypoplasia congenita. Mol Cell Endocrinol . 1997; 17 1476-1483
61 Achermann J C, Weiss J, Lee E J, Jameson J L. Inherited disorders of the gonadotropin hormones. Mol Cell Endocrinol . 2001; 179 89-96
62 Takahashi T, Shoji Y, Shoji Y, Haraguchi N, Takahashi I, Takada G. Active hypothalamic-pituitary-gonadal axis in an infant with X-linked adrenal hypoplasia congenital. J Pediatr . 1997; 130 485-488
63 Habiby R L, Boepple P, Nachtigall L, Sluss P M, Crowley Jr F W, Jameson J L. Adrenal hypoplasia congenita with hypogonadotropic hypogonadism: evidence that DAX-1 mutations lead to combined hypothalmic and pituitary defects in gonadotropin production. J Clin Invest . 1996; 98 1055-1062
64 Seminara S B, Achermann J C, Genel M, Jameson J L, Crowley Jr F W. X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females. J Clin Endocrinol Metab . 1999; 84 4501-4509
65 Chehab F F, Lim M E, 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
66 Montague C T, Farooqi I S, Whitehead J P. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature . 1997; 387 903-908
67 Strobel A, Issad T, Camoin L, Ozata M, Strosberg A D. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet . 1998; 18 213-215
68 Wauters M, Considine R V, Van Gaal F L. Human leptin: from an adipocyte hormone to an endocrine mediator. Eur J Endocrinol . 2000; 143 293-311
69 Clement K, Vaisse C, Lahlou N. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature . 1998; 392 398-401
70 Jackson R S, Creemers J W, Ohagi S. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet . 1997; 16 303-306
71 Hayes F J, Seminara S B, Crowley Jr F W. Hypogonadotropic hypogonadism. Endocrinol Metab Clin North Am . 1998; 27 739-763
72 Buchter D, Behre H M, Kliesch S, Nieschlag E. Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur J Endocrinol . 1998; 139 298-303
73 Liu P Y, Turner L, Rushford D. Efficacy and safety of recombinant human follicle stimulating hormone (Gonal-F) with urinary human chorionic gonadotrophin for induction of spermatogenesis and fertility in gonadotrophin-deficient men. Hum Reprod . 1999; 14 1540-1545
74 Jones T H, Darne J F. Self-administered subcutaneous human menopausal gonadotrophin for the stimulation of testicular growth and the initiation of spermatogenesis in hypogonadotrophic hypogonadism. Clin Endocrinol (Oxf) . 1993; 38 203-208
75 Schopohl J. Pulsatile gonadotrophin releasing hormone versus gonadotrophin treatment of hypothalamic hypogonadism in males. Hum Reprod . 1993; 8 (suppl 2) 175-179
76 Kirk J M, Savage M O, Grant D B, Bouloux P M, Besser G M. Gonadal function and response to human chorionic and menopausal gonadotrophin therapy in male patients with idiopathic hypogonadotrophic hypogonadism. Clin Endocrinol (Oxf) . 1994; 41 57-63
77 Ginsburg J, Hardiman P. Ovulation induction with human menopausal gonadotropins: a changing scene. Gynecol Endocrinol . 1991; 5 57-78
78 Seminara S B, Beranova M, Oliveira L M, Martin K A, Crowley Jr F W, Hall J E. Successful use of pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction and pregnancy in a patient with GnRH receptor mutations. J Clin Endocrinol Metab . 2000; 85 556-562
79 Martin K A, Hall J E, Adams J M, Crowley Jr F W. Comparison of exogenous gonadotropins and pulsatile gonadotropin-releasing hormone for induction of ovulation in hypogonadotropic amenorrhea. J Clin Endocrinol Metab . 1993; 77 125-129