, Volume 10, Issue 4, pp 381–391 | Cite as

Genetic insights into human isolated gonadotropin deficiency

  • Ericka Barbosa Trarbach
  • Leticia Gontijo Silveira
  • Ana Claudia Latronico


The identification of naturally occurring genetic mutations has provided unique insight into the current knowledge of the human hypothalamic-pituitary-gonadal axis. In the past decade, several monogenic causes have been reported in patients with isolated gonadotropin deficiency. Kallmann Syndrome is a clinically and genetically heterogeneous disorder, characterized by isolated hypogonadotropic hypogonadism and anosmia or hyposmia. To date, loss-of-function mutations in the genes encoding anosmin-1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1) have been described in the X-linked and autosomal dominant forms of this syndrome, respectively. More recently, several heterozygous, homozygous or compound heterozygous mutations in the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2) were described in Kallmann syndrome. In addition, complex genetic transmission (digenic inheritance) was recently demonstrated in this condition. Regarding isolated hypogonadotropic hypogonadism without olfactory abnormalities, loss-of-function mutations in the Gonadotropin-releasing hormone (GnRH) receptor (GnRH-R) or the G-protein coupled receptor 54 (GPR54) genes, both encoding transmembrane receptors, have been described, as well as FGFR1 mutations. Finally, mutations of the beta sub-units of LH and FSH have been described in patients with selective gonadotropin deficiency. We review the role of these distinct genetic factors in human isolated hypogonadotropic hypogonadism.


Hypogonadotropin hypogonadism Kallman syndrome Gonadotropin deficiency Gonadotropin-releasing hormone 



This work was supported in part by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo—FAPESP (to ACL, process number: 05/04726-0) and Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq (to ACL, process number: 300469/2005-5)


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Ericka Barbosa Trarbach
    • 1
  • Leticia Gontijo Silveira
    • 1
  • Ana Claudia Latronico
    • 1
    • 2
  1. 1.Developmental Endocrinology Unit, Hormone and Molecular Genetic Laboratory LIM/42Clinical Hospital, São Paulo University Medical SchoolSao PauloBrazil
  2. 2.Disciplina de Endocrinologia e MetabologiaHospital das Clínicas, Faculdade de Medicina da Universidade de São PauloSao PauloBrazil

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