Gonadotropin storage and trafficking.

Abstract

Background: Gonadotropins are synthesized in gonadotropes of the anterior pituitary, and they orchestrate reproductive function in vertebrates. LH and FSH share a common α-subunit that is non-covalently associated with a hormone - and receptor-specific β-subunit. Despite synthesized in the same cell, i.e., gonadotrope the trafficking and secretion patterns of LH and FSH are distinct. FSH is mostly constitutively secreted, whereas LH is stored in dense core granules and is released as a bolus via the regulated pathway in response to gonadotropin-releasing hormone.

Objective: To comparatively review the storage and secretion patterns of gonadotropins in vertebrates.

Materials and methods: Gonadotropin storage patterns are comparatively analyzed in vertebrates starting from primitive fish all the way up to higher mammals. The published work on gonadotropin trafficking/secretion patterns using in vitro and in vivo approaches is critically discussed.

Results: Primitive fish (lampreys and hagfish) express a single gonadotropic hormone. From these early vertebrates, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) have evolved as two distinct hormones. In several species, including teleost fish, monohormonal gonadotropes are present that express either LH or FSH. In higher vertebrates, the majority of the gonadotropes (>90%) are bihormonal and contain both LH and FSH. Both in vitro (cell transfection and expression) and in vivo (transgenic mouse) studies identified that the LHβ caroboxy terminus heptapeptide is a gonadotrope-specific regulated pathway sorting determinant.

Discussion: When FSH is genetically rerouted from the constitutive trafficking mode and is engineered (LHβ heptapeptide fused to FSHβ subunit) to exit via the regulated pathway in gonadotropes of transgenic mice, it resulted in enhanced ovulations due to suppression of atresia and apoptosis and increased pro-survival pathways in ovaries. However, rerouted FSH expressing male mice did not demonstrate any gain of function phenotypes.

Conclusion: Understanding the basic molecular mechanisms of gonadotropin storage/trafficking and secretion may eventually lead to clinical benefits of enhancing female reproductive function and reproductive lifespan.