Congenital Hypogonadotropic Hypogonadism in Males: Clinical Features and Pathophysiology

  • Ravikumar Balasubramanian
  • William F. CrowleyJr.
Chapter
First Online:
Part of the Contemporary Endocrinology book series (COE)

Abstract

Ever since the first detailed clinical description by Franz Kallmann, congenital hypogonadotropic hypogonadism has been recognized both clinically and genetically as a heterogeneous disease. There are two broadly recognized clinical forms of CHH: Kallmann syndrome (KS), characterized by CHH and anosmia, represents a syndromic phenotype resulting from joint developmental failure of the GnRH and olfactory systems whereas normosmic CHH (nCHH), i.e., those with a normal sense of smell, indict processes that impair GnRH secretion and/or action without discernible GnRH migratory defects. Reproductive features of CHH depend on the timing of the defect in GnRH deficiency and its severity. In addition, several non-reproductive features are also evident in some patients and relate to the developmental etiology of the condition and the genetic and cellular pathways that are defective. There is considerable phenotypic heterogeneity in the clinical presentation of CHH, and, in addition to the typical KS and nCHH presentations, several variant forms of CHH are recognized including fertile eunuch variant, adult-onset CHH, and, more recently, reversible forms of CHH, wherein CHH recovers in adulthood with the resumption of spontaneous hypothalamo-pituitary gonadal activity. The pathophysiology of CHH, the varied genetic causes of CHH, syndromic forms of CHH, and the clinical evaluation of CHH humans are extensively described in this chapter. Quite remarkably, despite the rarity of CHH, physiologic and genetic studies in CHH patients have begun to reveal several key insights into the regulation of GnRH neurons in humans. First, in keeping with the critical evolutionary role of the reproductive system in species survival, genetic studies of humans with CHH have revealed mutations in several novel genes that represent multi-tiered, overlapping genetic and cellular pathways that govern GnRH neuronal ontogeny. Moreover, in some cases, KS and nCHH occur within a single family sharing a similar genetic milieu suggesting that both variants of CHH represent part of a continuous spectrum of GnRH deficiency. In addition, there is an emerging evidence of oligogenicity, thus explaining the variable expressivity and incomplete penetrance seen within CHH families. Collectively, the phenotypic and genetic features of CHH patients represent a remarkable advancement of our collective understanding of the hypothalamic control of reproduction. However, despite this remarkable progress, the genetic basis of CHH is only known in ~40% of cases and it is clear that several key genes remain to be discovered. With the accelerating advances in next-generation sequencing and reducing costs, further novel genes will be discovered and this chapter will require additional updates.

Keywords

Gonadotropin-releasing hormone (GnRH) Delayed puberty Anosmia Kallmann syndrome 
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Notes

Acknowledgements

This work was supported by NICHD/NIH grants (P50 HD028138, K23 HD077043) as part of the National Centers for Translational Research in Reproduction and Infertility.

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Ravikumar Balasubramanian
    • 1
  • William F. CrowleyJr.
    • 1
  1. 1.Medicine, Reproductive Endocrine Unit, Harvard Medical SchoolMassachusetts General HospitalBostonUSA

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