Molecular pathophysiology and clinical manifestations of gonadotropin receptor defects

Area of Science:

• Endocrinology
• Reproductive Biology
• Genetics

Background:

• Gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are crucial for reproductive function.
• These hormones bind to specific G protein-coupled receptors, which are susceptible to various mutations.
• Mutations can be activating (gain-of-function) or inactivating (loss-of-function), impacting reproductive health.

Purpose of the Study:

• To review the clinical and genetic implications of gonadotropin receptor mutations.
• To understand the diverse phenotypes associated with activating and inactivating mutations in LH and FSH receptors.
• To highlight the differential effects of these mutations in males and females.

Main Methods:

• Literature review of studies on gonadotropin receptor mutations.
• Classification of mutations into activating and inactivating types.
• Analysis of clinical phenotypes associated with specific mutations in males and females.

Main Results:

• Activating LH receptor mutations cause male-limited pseudoprecocious puberty but typically no phenotype in females.
• Activating FSH receptor mutations are rare, with one case in a fertile hypophysectomized male.
• Inactivating LH receptor mutations lead to amenorrhea in females and hypoandrogenization or infertility in males.
• Inactivating FSH receptor mutations can cause infertility in males, and amenorrhea in females.
• Polymorphic variants of the FSH receptor exist in the general population.

Conclusions:

• Gonadotropin receptor mutations significantly impact human reproduction.
• The clinical presentation of these mutations varies greatly depending on the specific receptor, mutation type, and sex.
• Further research is needed to fully elucidate the effects of constitutive FSH receptor activity.