Estrogen Progesterone and Androgen Receptors

The steroid and corticosteroid hormone receptors are responsible for controlling a number of reproductive and homeostatic systems, respectively. The sex steroid receptors ER, PR, and AR direct transcription of genes involved in sexual development, differentiation, and specification (Tables 3.4, 3.5). As a result of their growth-promoting activities in these processes, these receptors are pharmacologically targeted in a number of neoplastic reproductive tissues. Receptors ERa and ERjS are predominantly expressed in reproductive tissues, as well as in vasculature, cardiac muscle, and bone. Their activity is subject to estradiol availability, which is regulated by hormonal cascades generated from the ovary and other steroidogenic tissues. Confirmation of the role of ERs in the regulation of the reproductive tract was achieved by targeted deletion of ERa and ERjS alleles in transgenic mice, which develop normally but are infertile or suffer ovarian dysfunction, respectively.296,297 In addition to reproductive maintenance, specialized roles for ERs include regulation of bone density and involvement in vascular function. Apparently, ERa also plays a physiological role in spermatogenesis since both male and female mice are infertile. In addition to infertility, ERa knockout mice have diminished bone density, as expected from the causal relationship between the loss of estrogen production following menopause and the occurrence of osteoporosis. Analy sis of gene expression in ERa knockouts also demonstrates loss of induction of suspected target genes (PR, lactoferrin, prolactin) and further reveals a role for ERs in the negative regulation of gonadotropin gene expression in the hypo-thalamic-pituitary axis.286,289 The reproductive phenotype of ERjS knockout mice is considerably less severe than that of ERa-deficient animals. Although ERa and ERjS share overlapping expression patterns and functional roles, they are not completely redundant since ERjS cannot rescue the reproductive phenotype of the ERa knockout. Compound knockouts display pheno-types similar to individual receptor knockouts, with one exception: although the reproductive tract of compound mutants develops normally, ovarian tissues transdifferentiate to form cells and structures characteristic of testes, suggesting that loss of both receptors may result in sex reversal.285 Conversely, these receptors are also apparently not required for survival since compound knockouts are viable. Because ERa and ERjS are capable of heterodimerization, it is possible that the spectrum of phenotypes observed in these animals reflects partially penetrant phe-notypes due to loss of one functional subunit in the heterodimer.30 Future studies may resolve this isoform specificity, as well as address the ER activity in regulating CNS function and behav

Table 3.4 Summary of Class I Steroid Hormone Receptor Proposed Functions and Representative Target Genes

Receptor

Binding Site

Principal Functions

Target Genes

References

ERa,ß

IR-3 (AGGTCA)

Reproductive regulation

Myc, lactoferrin, oxytocin, PR, cathepsin, EB1, vitellogenin, PRL, ovalbumin, pS2

282, 289

Pregnancy Guide

Pregnancy Guide

A Beginner's Guide to Healthy Pregnancy. If you suspect, or know, that you are pregnant, we ho pe you have already visited your doctor. Presuming that you have confirmed your suspicions and that this is your first child, or that you wish to take better care of yourself d uring pregnancy than you did during your other pregnancies; you have come to the right place.

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