Congenital hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is a rare endocrine disorder characterized by a deficiency in gonadotropin-releasing hormone (GnRH) secretion or action that is present from birth. This results in low levels of the pituitary gonadotropins — luteinizing hormone (LH) and follicle-stimulating hormone (FSH) — which in turn leads to impaired sexual development and reduced or absent puberty. When CHH is accompanied by an impaired sense of smell (anosmia or hyposmia), the condition is known as Kallmann syndrome. When the sense of smell is normal, it is referred to as normosmic congenital hypogonadotropic hypogonadism (nCHH). Other synonyms include isolated gonadotropin deficiency and idiopathic hypogonadotropic hypogonadism (IHH). The condition primarily affects the reproductive and endocrine systems. In males, key features include micropenis and cryptorchidism (undescended testes) at birth, absent or incomplete puberty, lack of secondary sexual characteristics (such as facial hair and deepening of the voice), small testes, and infertility. In females, the condition manifests as absent or incomplete breast development, primary amenorrhea (absence of menstruation), and infertility. Both sexes may experience reduced bone mineral density and decreased libido. Additional non-reproductive features can include synkinesia (mirror movements), renal agenesis, cleft lip or palate, dental agenesis, hearing loss, and skeletal anomalies, depending on the underlying genetic cause. CHH can be caused by mutations in numerous genes, including KAL1 (ANOS1), FGFR1, FGF8, PROKR2, PROK2, CHD7, GNRHR, GNRH1, KISS1R, KISS1, TAC3, TACR3, and many others. Inheritance patterns vary depending on the gene involved and can be X-linked recessive, autosomal dominant, autosomal recessive, or oligogenic. Treatment focuses on hormone replacement therapy to induce and maintain secondary sexual characteristics, using testosterone in males and estrogen-progesterone combinations in females. When fertility is desired, pulsatile GnRH therapy or gonadotropin injections (LH/FSH) can be used to stimulate gonadal function and enable conception. Early diagnosis and treatment are important for optimizing bone health, sexual development, and psychosocial well-being.

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