[Hypogonadism due to LH deficiency]

Area of Science:

• Endocrinology
• Human Genetics
• Reproductive Biology

Background:

• Luteinizing hormone (LH) is essential for male sexual maturation and fertility.
• Deficiencies in LH can cause hypogonadism, characterized by delayed puberty and infertility.
• Genetic defects in the LHbeta gene are a rare cause of LH deficiency.

Observation:

• Two male patients presented with delayed puberty and infertility due to absent circulating LH.
• Genetic analysis identified distinct mutations in the LHbeta gene in both patients: a missense mutation (G36D) and a 3-base pair deletion.
• The G36D mutation disrupted the LHbeta protein's cystine knot motif, impairing heterodimerization and secretion.

Findings:

• The missense mutation (G36D) resulted in complete LH deficiency, leading to hypogonadism.
• The 3-base pair deletion also caused a loss of function, resulting in similar clinical manifestations.
• Hormone replacement therapy with hCG normalized testosterone levels and improved sperm production in the first patient.
• Assisted reproductive technology enabled the first patient to father a child who was a carrier of the G36D mutation.

Implications:

• These cases highlight the critical role of LH in male reproductive health and development.
• Understanding these genetic mutations provides insights into the molecular mechanisms of LH synthesis and function.
• Targeted hormone therapy and assisted reproduction offer viable solutions for individuals with LH deficiency-related infertility.