Fertility and fragrance: another cause of Kallmann syndrome
Shlomo Melmed
Shlomo Melmed
Published May 18, 2015
Citation Information: J Clin Invest. 2015;125(6):2275-2278. https://doi.org/10.1172/JCI82061.
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Commentary

Fertility and fragrance: another cause of Kallmann syndrome

Abstract

Kallmann syndrome is an inherited deficiency of gonadotropin-releasing hormone (GnRH) that is characterized by hypogonadism with delayed or absent puberty and dysfunctional olfaction. While Kallmann syndrome–associated mutations have been identified in some sets of patients, for many of these individuals, the underlying cause remains unknown. In this issue of the JCI, Cariboni and colleagues identify mutations in semaphorin 3E (SEMA3E) in two brothers with Kallmann syndrome. In animal models, loss of SEMA3E signaling recapitulated phenotypes of the probands and resulted in enhanced GnRH neuron death during development. The results of this study offer important insight into the development of Kallmann syndrome and provide tools for elucidating mutations that underlie complex hormonal phenotypes.

Authors

Shlomo Melmed

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Figure 1

The cascade of reproductive axis signal amplification initiated by GnRH and culminating in gonadal function confers fertility and secondary sex characteristics.

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The cascade of reproductive axis signal amplification initiated by GnRH ...
Central molecules, including KAL1, FGF8/FGFR1, PROK2/PROK2R, NELF, SEMA3A/PLXND1, HS6ST1, CHD7, and WDR11, determine GnRH neuron development in the olfactory region (27) and migration to the hypothalamus. Multiple intrahypothalamic, nutritional, and hormonal signals, such as KISS1/KISS1R, TAC3/TAC3R, and PCSK1, determine the generation of age- and time-determined GnRH pulses, which traverse the hypophyseal portal circulation to signal through the pituitary gonadotroph GnRHR. Transcription factors, including NR5A1, NROB5, SF1, DAX1, and PROP1, also determine cell-specific gonadotropin hormone (FSH and LH) expression. Unique pulsatile FSH and LH release patterns induce gonadal hormones and determine germ cell function. Hypogonadotrophic hypogonadism can be caused by disruptions at each of the depicted CNS/hypothalamic/pituitary levels. Heterogenous oligogenic patterns of inheritance may be associated with a similar clinical phenotype of gonadal failure in the presence of inappropriately low gonadotropin hormone levels. Acquired causes of hypogonadotrophic hypogonadism include neoplastic, inflammatory, or iatrogenic (surgery, radiation) hypothalamic-pituitary damage.