The hypothalamus-pituitary-ovarian axis as a model system for the study of SERM effects: An overview of experimental and clinical studies

Abstract

Ovarian hormones control female reproductive function by acting at different levels of the hypothalamus-pituitary-gonadal axis throughout the synergistic activation of several receptor subtypes. In most mammalian species, including the human, the activity of this highly coordinated system is aimed at maintaining reproductive cycles, leading to eventual pregnancy, and at promoting body adaptations to maternal metabolism. In the case of women, given the beneficial effects of sex steroid hormones on a variety of reproductive and nonreproductive tissues, the development of specific molecules capable of reproducing steroid hormone action after cessation of ovarian function with aging has been a main objective of modern pharmacology. As described in different parts of this book, SERMs are compounds that may act either as estrogen agonists or antagonists in a tissue- or cell-specificmanner and therefore have the capacity to influence hypothalamus-pituitary function in a complex manner. In this chapter, we have analyzed the available evidence from both experimental and clinical studies in order to understand the impact of SERM treatment on gonadotropin secretion. Recent findings indicate that particular SERMs may interact with several ER-dependent pathways within the same cell, thereby inducing a variety of responses that are highly dependent on estrogen and progesterone status. This fact partially explains why treatment with different SERMs in human subjects frequently gives conflicting results depending on dose, age, gender, reproductive status, duration of treatment, and coadjuvant medication. Therefore, the use of newer SERMs in whole animal and cell studies not only will provide basic investigators with tools to dissect the biology of classical and alternative ERs but also will surely help to design specific and selective approaches in hormone therapy. In addition, the analysis of clinical trials with steroid hormone analogs from the consideration of integrated estrogen and progesterone molecular interactions will provide critical insight for drug development in this promising field. © 2006 Springer-Verlag Berlin Heidelberg.