[Genes of pituitary gonadotropin hormones and their regulation]

LH and FSH are produced in the pituitary gonadotropes; each contains two subunits, a common alpha and a unique LH beta- or FSH beta-subunit. All 3 subunits are synthesized as precursors, encoded by separate genes. Gonadotropin subunit messenger RNAs from different species have been isolated and characterized, their nucleotide sequence has been determined after synthesis and cloning of the complementary DNA. In this way, the primary structure of corresponding precursors has been obtained. The post-translational processing of the precursors which results in the formation of native glycosylated subunits has been studied in situ. Finally the gonadotropin subunit genes have been isolated and their structure elucidated, confirming the hypothesis that they evolved from a common ancestral gene. The different approaches used to study gonadotropin synthesis has allowed the demonstration of the hormonal regulation of the expression of the gonadotropin subunit genes. Hormones that affect gonadotropin release, such as gonadal steroids, GnRH, inhibin and thyroid hormones, also influence subunit gene expression, in a complex and varied manner, the mechanisms of which are still unclear. For example, at least part of the in vivo effects of oestradiol (inhibitory) or thyroid hormones (stimulatory at low doses) result from an indirect action via the hypothalamus, which probably affects GnRH secretion. It is now well established that GnRH stimulates gene expression and the synthesis of gonadotropin subunits. These effects are reproduced by direct activation of protein kinases A and C, in a manner which suggests a coordinate control of both synthesis and release of gonadotropins, through the mediation of intracellular signalling pathways (cyclic AMP, and phosphatidyl inositol hydrolysis). Gene transfer studies have demonstrated the presence of regulatory elements in the 5'-flanking regions of the (human) alpha gene that confer sensitivity to different factors including tri-iodothyronine, glucocorticoids, and cyclic AMP. The identification of regulatory domains of the genes in conjunction with studies using gonadotrope cells will help deepen our understanding or the cellular and molecular mechanisms involved in the multihormonal control of gonadotropin subunit synthesis.