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Review
. 2011 Oct 22;346(1-2):4-12.
doi: 10.1016/j.mce.2011.07.012. Epub 2011 Jul 12.

Isolated GnRH deficiency: a disease model serving as a unique prism into the systems biology of the GnRH neuronal network

Ravikumar Balasubramanian  1 , William F Crowley Jr
Affiliations
Review

Isolated GnRH deficiency: a disease model serving as a unique prism into the systems biology of the GnRH neuronal network

Ravikumar Balasubramanian et al. Mol Cell Endocrinol. .
No abstract available

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Figures

Figure 1
Figure 1. Clinical presentations of isolated GnRH deficiency in humans
Pulsatile GnRH secretion is initiated during the late fetal/early neonatal period (“mini-puberty”), followed by quiescence during childhood and reawakening of the pulsatile secretion in mid-childhood. Presence of anosmia signals a developmental defect in GnRH neuronal migration while, microphallus or cryptorchidism signal fetal/neonatal lack of GnRH secretion. Constitutional delay of puberty (CDP) represents a late activation of the HPG axis while KS and nIHH represent partial or complete failure of pulsatile GnRH secretion. Recovery of pulsatile GnRH secretion in KS/nIHH subjects in adulthood is termed “Reversal”, while, AHH (adult-onset hypogonadotropic hypogonadism) refers to the onset of isolated GnRH deficiency during adulthood following a normal mini-puberty and puberty.
Figure 2
Figure 2. GnRH secretory patterns in normal male and males with isolated GnRH deficiency
A. Normal adult male pattern of LH secretion: High amplitude LH pulses at ¬2h interval intervals with normal testosterone levels. B. Apulsatile pattern of LH secretion in a GnRH deficient male subject with frank hypogonadal T levels. C. Developmental arrest or sleep entrained (hatched bar) pattern of LH secretion in a GnRH deficient male. D. Normal frequency but low amplitude pattern of LH secretion in a GnRH deficient male subject.
Figure 3
Figure 3. Genetic causes of isolated GnRH deficiency: A historical perspective
Genetic etiology of isolated GnRH deficiency with relative percentage contribution from each identified gene to the heritability of the syndrome from 1995 – 2011. From only 2 genes that were known in 1995, the number of genes discovered in subjects with isolated GnRH deficiency has steadily increased through 1995–2011. In 2011, the genetic cause of a nearly half of the subjects is known while in the remaining half, the genes are yet to be identified.
Figure 4
Figure 4. GnRH neuronal ontogeny in humans
Specific gene mutations in patients with GnRH deficiency result in failure in GnRH development and migration (KAL1, Kallmann syndrome 1 sequence, MIM: 308700; NELF, nasal embryonic LHRH factor, MIM: 608137) while other gene mutations impair hypothalamic GnRH homeostasis and GnRH secretion (DAX1, dosage-sensitive sex reversal, adrenal hypoplasia congenital critical region on the X chromosome, gene 1, MIM: 300473; PC1, prohormone convertase 1, MIM: 162150; LEPR, leptin receptor, MIM: 601007; LEP, leptin, MIM: 164160; KISS1R, KISS1 receptor, MIM: 604161; TACR3, tachykinin receptor 3, MIM: 162332; TAC3, tachykinin 3, MIM: 162330; GNRH1, gonadotropin-releasing hormone 1, MIM: 152760; GNRHR, GnRH receptor, MIM: 138850). Some gene mutations affect both migration/development as well as neuroendocrine secretion of GnRH (FGFR1, fibroblast growth factor receptor 1, MIM: 136350; FGF8, fibroblast growth factor 8, MIM: 600483; PROKR2, prokineticin receptor 2, MIM: 607123; PROK2, prokineticin 2, MIM: 607002; CHD7, chromodomain helicase DNA binding protein 7, MIM: 608765).
Figure 5
Figure 5. Oligogenicity in isolated GnRH deficiency
(A) Frequency of monoallelic, biallelic, and digenic rare protein-altering variants in 8 genes known to cause isolated GnRH deficiency (B) Number of alleles with rare protein-altering variants in isolated GnRH deficient patients (IHH subjects) and healthy controls.
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