Division of Reprodcutive Sciences, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Fertil Steril. 2023 Feb;119(2):180-183. doi: 10.1016/j.fertnstert.2022.12.005. Epub 2022 Dec 7.
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.
卵泡刺激素（FSH）和黄体生成素（LH）在同一个垂体细胞中合成，即性腺细胞。它们都由一个共同的α亚基组成，该亚基与性腺细胞中的激素特异性β亚基以非共价方式组装。异二聚体通过不同的运输和分泌方式离开性腺细胞。FSH 是持续分泌的，而 LH 则通过涉及致密核心颗粒的受调控途径脉冲式分泌。基于几项体外诱变研究，已鉴定出人 LH-β 亚基羧基末端七肽是性腺细胞分拣决定因素。当七肽基因融合到人 FSH-β 亚基上，并在 Fshb 缺失遗传背景下表达突变基因时，重新定向的 FSH 突变二聚体进入 LH 分泌途径，储存在致密核心颗粒中，在促性腺激素释放激素刺激下与 LH 共同释放，并像持续分泌的野生型 FSH 一样有效地拯救 Fshb 缺失的小鼠。重新定向的 FSH 显著抑制卵泡闭锁，并显著增加每个周期的排卵数，延长雌性生殖寿命。促性腺激素重定向正在成为治疗女性卵巢功能障碍的新范例，它可能解释卵巢周期性的起源，并为理解维持女性整个生殖寿命期间最佳卵巢功能的基因和蛋白质网络提供线索。
