Abstract
Hypothalamic gonadotropin releasing hormone (GnRH) is a key player in normal puberty and sexual development and function. Genetic causes of isolated hypogonadotropic hypogonadism (IHH) have been identified during the recent years affecting the synthesis, secretion, or action of GnRH. Developmental defects of GnRH neurons and the olfactory bulb are associated with hyposmia, rarely associated with the clinical phenotypes of synkinesia, cleft palate, ear anomalies, or choanal atresia, and may be due to mutations of KAL1, FGFR1/FGF8, PROKR2/PROK2, or CHD7. Impaired GnRH secretion in normosmic patients with IHH may be caused by deficient hypothalamic GPR54/KISS1, TACR3/TAC3, and leptinR/leptin signalling or mutations within the GNRH1 gene itself. Normosmic IHH is predominantly caused by inactivating mutations in the pituitary GnRH receptor inducing GnRH resistance, while mutations of the β-subunits of LH or FSH are very rare. Inheritance of GnRH deficiency may be oligogenic, explaining variable phenotypes. Future research should identify additional genes involved in the complex network of normal and disturbed puberty and reproduction.
Highlights
Developmental defects of gonadotropin releasing hormone (GnRH) neurons and the olfactory bulb are associated with hyposmia, rarely associated with the clinical phenotypes of synkinesia, cleft palate, ear anomalies, or choanal atresia, and may be due to mutations of KAL1, FGFR1/fibroblast growth factor 8 (FGF8), prokineticin receptor 2 (PROKR2)/prokineticin 2 (PROK2), or chromodomain helicase DNAbinding protein 7 (CHD7)
Impaired GnRH secretion in normosmic patients with isolated hypogonadotropic hypogonadism (IHH) may be caused by deficient hypothalamic GPR54/KISS1, TACR3/TAC3, and leptinR/leptin signalling or mutations within the GNRH1 gene itself
The detailed diagnostic workup of patients with absent or incomplete pubertal development due to gonadotropin deficiency has recently led to the identification of new genetic causes of isolated hypogonadotropic hypogonadism (IHH) [1,2,3,4,5,6,7]
Summary
Normal pubertal development and reproductive function depends on the intact release and action of hypothalamic gonadotropin releasing hormone (GnRH). The detailed diagnostic workup of patients with absent or incomplete pubertal development due to gonadotropin deficiency has recently led to the identification of new genetic causes of isolated hypogonadotropic hypogonadism (IHH) [1,2,3,4,5,6,7] These findings currently improve our understanding of how the onset and course of puberty and reproduction are controlled. The amino- and carboxy-terminal domains of GnRH contribute to receptor binding and activation via extracellular and transmembrane domains inducing conformational changes and signal transduction, thereby inducing synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) These gonadotropins bind to their specific receptors in gonads and stimulate synthesis of estrogens and testosterone resulting in clinical signs of puberty. Disorders of GnRH release have recently been identified as rare causes of GnRH deficiency in patients with normosmic IHH [2, 3, 7], while inactivating mutations of the GnRH receptor are the most frequent cause for normosmic IHH, especially in familial cases [12, 17,18,19,20,21]
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