The Gonadotropic Hormones

LH and FSH are members of the glycoprotein family of hormones, which also includes thyroid-stimulating hormone (TSH) and human chorionic gonadotropin (hCG). These heterodimers are composed of a common a-subunit and unique P-sub-units. The subunits have oligosaccharide chains that are associated with asparagine residues. Each subunit is encoded by a unique gene that is found on a separate chromosome: the human a-subunit gene is on 6p21.1-23, LH-P is on 19q13.3, and FSH-P is on 11p13 (see Chapter 6).

LH and FSH production is directly influenced by the level of the gonadotropin subunit mRNAs. This relationship is especially strong for FSH-P mRNA and FSH secretion. Each of the gonadotropin subunit mRNAs is increased by GnRH, and stimulation of the P-subunit genes by GnRH is primarily transcriptional. Complexes of transcription factors, including SF-1, EGR-1, and SP1, are activators of the LHP-sub-unit gene (23), whereas the AP1 proteins fos/jun are important for upregulation of FSH-P transcription by GnRH (24). GnRH stimulation must be pulsatile for LH-P and FSH-P mRNA levels to increase. Transcriptional regulatory proteins that control a-subunit expression include cAMP response element-binding protein (CREB), MAP kinase/ERK1, and GATA-binding proteins (25). a-Subunit gene expression is increased robustly by both pulsatile and continuous GnRH, and GnRH not only stimulates a-subunit transcription but also prolongs the half-life of the a-subunit mRNA (26). Thus, the requirements for a-subunit mRNA upregulation by GnRH are less stringent than those for the P-subunit genes. These factors partly explain why a-sub-unit is synthesized in excess of P-subunits and why P-subunits are rate limiting for gonadotropin synthesis.

Proteins that are destined for secretion are synthesized on ribosomes that are bound to the endoplasmic reticulum. During the translational process, preformed oligosaccharide chains are linked to the side chain amino group of asparagines on the gonadotropin subunits. As translation continues, sugar moieties are trimmed and the subunits change configuration, allowing for their combination. A region of the P-subunit, termed the "seatbelt," wraps around the a-subunit loop 2 (27). Dimeric LH and FSH are segregated in the endoplasmic reticulum (er) and transferred to the Golgi, where they are concentrated in secretory granules. These protein-rich vesicles subsequently fuse with the plasma membrane after GnRH stimulation. This process is termed "exocytosis." There is evidence that FSH-containing granules are also exported directly to the plasma membrane, independent of GnRH pulsatile stimulation. This mode of secretion allows for FSH secretion between pulses. Gonadotrophs also secrete uncombined a-subunit, both in pulsatile fashion and continuously.

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