Isolated hypogonadotropic hypogonadism

Presentation

Congenital hypogonadotropic hypogonadism presents as hypogonadism, e.g., reduced or absent puberty, low libido and infertility, due to an impaired release of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and a resultant lack of sex steroid and peptides production by the gonads.

In Kallmann syndrome, a variable non-reproductive phenotype occurs with anosmia (loss of the sense of smell) including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis.

Causes

IHH is divided into two syndromes: IHH with olfactory alterations or anosmia, Kallmann syndrome and IHH with normal smell (normosmic IHH).

Kallmann syndrome is responsible for approximately 50% of all cases of the condition. It is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROKR2, NELF, CHD7 (which positively regulates GnRH secretion), HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, and WDR11 (gene), genes which are related to defects in neuronal migration.

Gene defects associated with IHH and normal smell include PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11, as in KS, but in addition mutations in KISS1R, TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB. GnRH insensitivity is the second most common cause of IHH, responsible for up to 20% of cases. A minority of less than 5–10% is due to inactivating mutations in genes which positively regulate GnRH secretion such as CHD7, KISS1R, and TACR3.

The causes of about 25% of all IHH cases are still unknown.

References

References

1. Young J. (Mar 2012). "Approach to the male patient with congenital hypogonadotropic hypogonadism". J Clin Endocrinol Metab.
2. Giton F, Trabado S, Maione L. (2015). "Sex steroids, precursors, and metabolite deficiencies in men with isolated hypogonadotropic hypogonadism and panhypopituitarism: a GCMS-based comparative study". J Clin Endocrinol Metab.
3. Trabado S, Maione L, Bry-Gauillard H. (Feb 2014). "Insulin-like peptide 3 (INSL3) in men with congenital hypogonadotropic hypogonadism/Kallmann syndrome and effects of different modalities of hormonal treatment: a single-center study of 281 patients". J Clin Endocrinol Metab.
4. Valdes-Socin Hernan, Rubio Almanza Matilde, Tomé Fernández-Ladreda Mariana. (2014). "Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes". Frontiers in Endocrinology.
5. (July 2025). "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency Overview - GeneReviews™ - NCBI Bookshelf".