Rerouting of follicle-stimulating hormone secretion and gonadal function

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are synthesized in the same pituitary cell, i.e., gonadotrope. They both consist of a common α-subunit that is noncovalently assembled with a hormone-specific β-subunit in gonadotropes. The heterodimers exit gonadotropes through distinct modes of trafficking and secretion. The FSH is constitutively secreted, whereas LH is secreted in pulses through the regulated pathway that involves dense core granules. Based on several in vitro mutagenesis studies, the carboxy terminus heptapeptide of human LH-β subunit is identified as a gonadotrope sorting determinant. When heptapeptide is genetically fused to human FSH-β subunit and the mutant transgene expressed on a Fshb null genetic background, the rerouted FSH mutant dimer enters the LH secretory pathway, stored in dense core granules, coreleased with LH on gonadotropin releasing hormone stimulation and rescues Fshb null mice as efficiently as the constitutively secreted wild-type FSH. The rerouted FSH markedly suppresses follicle atresia and significantly enhances ovulations per cycle and prolongs the female reproductive life span. Gonadotropin rerouting is emerging as a novel paradigm to treat ovarian dysfunction in women, and may explain the origins of ovarian cyclicity as well as provide clues to understand gene and protein networks that maintain optimal ovarian function throughout the female reproductive life span.