Follicle stimulating hormone (FSH) and luteinizing hormone (LH) are glycoprotein hormones, each comprised of two dissimilar subunits alpha and beta, encoded for the separate genes on different chromosomes. Although much is known concerning the regulation of the biosynthesis of the subunits. The recent availability of cDNA probes for the rat FSH(beta), LH(beta, and alpha subunits now permits and examination of the differential regulation of FSH and LH gene expression at the pretranslational level in different physiologic states and following various endocrine manipulations. There are 3 major objectives: 1) First, to define the normal physiology of gonadotropin subunit gene expression in the female by examining the ontogeny of gonadotropin synthesis: during gestation, in infancy and across sexual development, during the estrous cycle and with aging in the retired breeder. Then with this normative data as a backdrop, the role of gonadal steroids and hypothalamic factors in the pretranslational control of FSH and LH will be delineated. 2) The second aim of this proposal is to examine the differential regulation of gonadotropin mRNA levels by sex steroid hormones in the female rat. In vivo studies will examine the effects of (a) the type of sex steroid replacement (estrogen vs. progestin vs. androgen), (b) the dosage of steroid administration (subphysiologic to supraphysiologic), (c) the impact of the time interval following ovariectomy before replacement, and (d) the duration of steroid replacement of FSH(beta), LH(beta), and alpha subunit mRNA levels. Additionally, intact animals will receive steroid hormone antagonists as an alternative approach to defining the role of gonadal steroids in the regulation of gonadotropin subunit mRNAs. Concurrent in vitro rat pituitary cell culture studies will explore similar paradigms to dissect the locus of steroid action--either directly at the gonadotrope and/or indirectly via effects on hypothalamic factors. The changes in subunit mRNA levels in pregnancy will also be examined as a model of excessive endogenous steroid milieu. 3) Third, the differential dependence of gonadotropin subunit synthesis upon gonadotropin-releasing hormone (GnRH) will be delineated. A potent GnRH gonadotropin secretion. In this model of relative GnRH deficiency, the variable changes in FSH(beta), CH(beta), in this GnRH-deficient model, specific sex steroids and/or gonadal peptides will be reintroduced to determine their effects on the biosynthesis and secretion of the gonadotropin subunits. These proposed studies will expand our understanding of the normal physiology of the reproductive axis in the female. Additionally, they will impact on the design of future fertility and contraceptive agents and potential therapeutic interventions for reproductive disorders and hormone responsive malignancies.
