Ablation of GalNAc-4-sulfotransferase-1 enhances reproduction by altering the carbohydrate structures of luteinizing hormone in mice

Luteinizing hormone (LH), produced in the anterior lobe of the pituitary, is a member of the hypothalamic-pituitary-gonad axis that is required for production of the sex hormones estradiol, progesterone, and testosterone. Perturbations in levels of hormones associated with this axis can result in defects in sexual development and maturity. LH bears unique N-linked carbohydrate units that terminate with a sulfated N-acetylgalactosamine structure (GalNAc-4-SO(4)) that mediates its clearance from the blood. To determine the significance of this terminal structure, we ablated the gene encoding the sulfotransferase responsible for sulfate addition to GalNAc on LH, GalNAc-4-sulfotransferase-1 (GalNAc-4-ST1) in mice. Mice lacking GalNAc-4-ST1 exhibited increased levels of circulating LH. In male mice, this resulted in elevated levels of testosterone and precocious maturation of testis and seminal vesicles. Female mice lacking GalNAc-4-ST1 demonstrated elevated estrogen levels and exhibited precocious sexual maturation and increased fecundity. Female mice remained in estrus for prolonged periods and produced almost 50% more litters per mouse than wild-type mice over the same period of time. Thus, sulfate modification of the terminal glycosylation of LH plays a central role in regulating the hypothalamic-pituitary-gonad axis in vivo

Regulation of lutropin circulatory half-life by the mannose/N-acetylgalactosamine-4-SO(4) receptor is critical for implantation in vivo

Lutropin (LH) directs ovulation and implantation by regulating the production of estrogen and progesterone. We have shown that the circulatory half-life of LH is controlled by the Man/GalNAc-4-SO(4) receptor, which binds GalNAc-4-SO(4) on LH oligosaccharides. The short half-life in conjunction with episodic release of LH from the pituitary accounts for the pulsatile rise and fall in circulating LH. Complete genetic ablation of the Man/GalNAc-4-SO(4) receptor results in death in utero. Heterozygous female mice clear LH from the circulation more slowly and have smaller litters due to a reduction in the rate of implantation. This reduction is fully correctable by exogenous progesterone and estrogen, indicating that the rate of LH clearance is critical for the production of sufficient progesterone and estrogen for implantation. Thus, the Man/GalNAc-4-SO(4) receptor regulates the endocrinological status of the female and is essential for an early event in embryonic development