Normosmic idiopathic hypogonadotropic hypogonadism: update on the genetic background and future challenges

Abstract

The neuroendocrine control of reproduction in all mammals is governed by a hypothalamic neural network of approximately 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that control the activity of the reproductive axis across life. Recently, the syndrome of human GnRH deficiency, either with anosmia, termed Kallmann syndrome, or with a normal sense of smell, termed normosmic idiopathic hypogonadotropic hypogonadism, has proven to be important disease models that have revealed much about the abnormalities that can befall the GnRH neurons as they differentiate, migrate, form networks, mature and senesce. Mutations in several genes responsible for these highly coordinated developmental processes have thus been unearthed by the study of this prismatic disease model. These genetic studies have opened up a new chapter in the physiology and the pharmacology of the gonadotropic axis.

Central Hypogonadotropic Hypogonadism: Genetic Complexity of a Complex Disease

“…Isolated GnRH deficiency, caused by defects in the secretion or action of hypothalamic GnRH, is one of the rare genetic diseases originally thought to be strictly monogenic but the numerous studies about this disorder led to the discovery of several new loci [34] (Table 1), with key roles for the developmental and neuroendocrine control of human reproduction [1, 12, 14]. So far, twenty-four genes have been identified (Table 1).…”

“…The proteins, encoded by the genes involved so far in this pathology, have been grouped, according to their function, in three functional categories: development and migration of GnRH neurons, regulation of GnRH secretion, and GnRH and gonadotropins action [1, 11, 12, 35] (Figure 1). However, the function of some genes, recently identified, is not fully clear.…”

“…The amino acid sequence of the final active peptide is encoded by exon 5 only [81]. So far, three causative mutations, a splicing variant (c.209-1G>C) [12, 79], a frame-shift variant (G20fsX39) [76] and a missense variant (M90T) [78], were detected in CHH patients (Table 2). All these mutations (Table 2) occurred in homozygous state, suggesting an autosomic recessive inheritance.…”

“…The identified mutations, either synonymous, or nonsynonymous or affecting physiologic splicing, are widely distributed along the gene, covering all main domains [12, 15, 76–78, 82] (Table 2). …”

“…The disease associated with a normal sense of smell, occurring in 40–45% of CHH patients [13], is called normosmic Idiopathic Central hypogonadism (nICH) or normosmic hypogonadotropic hypogonadism (nHH). When a defective sense of smell, hyposmia or anosmia, is associated with hypogonadotropic hypogonadism, in 60% of patients [13], the disease is called Kallmann syndrome (KS), explained by the common embryonic origins and developmental pathways of GnRH and olfactory neurons [1, 11, 12, 14]. CHH is either congenital or acquired, and it can be isolated or combined with other pituitary hormone defects [1].…”