Introduction Ovulation, fertilization, and implantation are complex processes that depend on the exquisitely coordinated interaction of neurons in the hypothalamus, gonadotroph cells in the anterior pituitary, and target cells in the ovary. These three participants form the gonad/pituitary/hypothalamic axis. Abnormalities in the regulation of this axis can result in infertility and miscarriage (1-3). Peptide-releasing factors produced in the hypothalamus stimulate gonadotroph cells to release

more »

... e glycoprotein hormones follitropin (FSH) and lutropin (LH) into the circulation. FSH directs follicular development and oocyte maturation, whereas LH is responsible for the rupture of antral follicles to release the ovum and for the conversion of postovulatory follicles into corpora lutea (4). The precisely controlled production of estrogen and progesterone, initially by developing follicles and subsequently by corpora lutea, is essential for differentiation of the uterus into a receptive state for the fertilized egg and for implantation (5-9). LH characteristically demonstrates an episodic rise and fall in the circulation that is critical for the biologic activity of LH in vivo. Gonadotropin-releasing hormonestimulated release of LH from dense core granules in pituitary gonadotrophs generates these pulses at specific intervals. The amplitude and frequency of LH pulses produced in the circulation are in turn regulated by progesterone and estrogen levels (10-14). The pulsatile rise and fall in circulating LH levels results in the episod-ic stimulation of the LH receptor, a G protein-coupled receptor (15). Episodic stimulation may be critical because the activated form of the LH receptor is recognized by β-arrestin, resulting in uncoupling from adenylyl cyclase and internalization of the occupied receptor (16). Replenishment at the cell surface with unoccupied LH receptor requires periods between pulses when the cells are not exposed to the hormone. The episodic rise and fall in LH levels also requires that LH have a short half-life in the circulation. The circulatory half-life of LH, but not FSH, is precisely controlled by the Man/GalNAc-4-SO 4 receptor that we have identified in hepatic endothelial cells (17, 18) . We initially demonstrated that LH bears unique oligosaccharide structures that terminate with β1,4-linked GalNAc-4-SO 4 whereas FSH bears structures that terminate with sialic acid linked to galactose (19) (20) (21) . We have shown that it is the cysteine-rich domain located at the aminoterminus of the Man/GalNAc-4-SO 4 receptor, expressed at high levels in hepatic endothelial cells, that specifically binds terminal β1,4-linked GalNAc-4-SO 4 located on the N-linked oligosaccharides of LH (22) (23) (24) . This binding mediates the rapid clearance of LH from the circulation. The Man/GalNAc-4-SO 4 receptor expressed by hepatic endothelial cells is present in the form of a dimer that must simultaneously bind to two terminal GalNAc-4-SO 4 moieties on LH to achieve the apparent K d of 1.6 × 10 -7 M we have observed with isolated cells (25). The bound hormone is internalized and rapidly trans-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.