GHRH excess and blockade in X-LAG syndrome

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• X-linked acrogigantism (X-LAG) syndrome is a rare genetic disorder causing pituitary gigantism, linked to microduplications of the GPR101 gene on chromosome Xq26.3.
• Patients typically present with early-onset growth acceleration and markedly elevated growth hormone (GH) and prolactin levels, often from mixed pituitary adenomas or hyperplasia.

Observation:

• This study investigated a sporadic X-LAG patient, revealing consistently elevated GHRH levels alongside GH and prolactin hypersecretion.
• In vitro studies using pituitary tumor cultures demonstrated that GHRH directly stimulates GH and prolactin release.
• GH secretion showed a paradoxical increase after TRH administration and was inhibited by a GHRH receptor antagonist and pasireotide, but not octreotide.

Findings:

• GHRH hypersecretion is identified as a potential contributing factor to the pituitary abnormalities in X-LAG syndrome.
• The findings support the hypothesis that hypothalamic GPR101 dysregulation leads to elevated GHRH secretion.
• Specific GHRH receptor antagonists and pasireotide effectively inhibited GH secretion in vitro.

Implications:

• Targeting GHRH secretion therapeutically may offer a novel treatment strategy for X-LAG syndrome.
• Understanding the role of GHRH in X-LAG could lead to improved management of pituitary gigantism.
• Further research into hypothalamic GPR101 function is warranted to elucidate its role in growth regulation.