DNA binding Zn Zn

Hormone binding

Dimerization -

Transactivation Nuclear localization —

FIGURE 13-14 Schematic diagram of the genomic organization, domain structure, and functional characteristics of the estrogen receptor. The ER gene spans over 140 kb of DNA. Note that the exon structure does not correlate with the domains of the ER (see Figure 1-26). The DNA-binding domain C is composed of two zinc fingers (see Figure 1-42). Two dimerization domains on the ER have been detected in domains C and E. The hinge domain D codes for a nuclear localization signal. Two transactivation domains in the A/B and E/F regions have also been described; they act independently and confer on the ER both promoter and target organ specificity. Modified with permission from Pfeffer, E. U., Fecarotta, E., Arena, G., Forlani, A., and Vidali, G. (1996). Alternative splicing of the estrogen receptor primary transcript normally occurs in estrogen receptor positive tissues and cell lines. J. Steroid Biochem. Mol. Biol. 56, 99-105.

ley, and colleagues as well as R. Palmiter and R. Schimke have carried out detailed biochemical analyses of estrogen- and progesterone-mediated induction of ovalbumin, conalbumin, and other egg white proteins in the chick oviduct. Figure 13-17 presents a schematic diagram of the hormone-mediated events in the immature chick oviduct. As shown here, estrogen plays a key role in priming the immature oviduct to be responsive to subsequent treatment with either estrogen or progesterone. Then, secondary stimulation with either progesterone or estrogen leads to rapid biosynthesis of ovalbumin and other egg white proteins.

The synthesis of DNA complementary to ovalbumin messenger RNA (cDNA probes) has permitted a detailed study of gene expression in the chick oviduct system. By employing this cDNA probe to analyze the consequences of primary estrogen treatment or secondary estrogen or progesterone treatment, extensive data have been accumulated that strongly support the primary hypothesis that steroid hormones act by gene activation.

C. Hormonal Effects on Ovulation and the Menstrual Cycle

1. Steroid Receptors

The mammalian uterus structure and function are determined in large part as a consequence of its exquisite sensitivity to progesterone and estrogen. In gen eral, progesterone and estradiol exert opposing effects on the estrogen and progesterone receptor systems. The presence of estradiol increases, via protein synthesis pathways, the concentration of receptors for both progesterone and estradiol, while progesterone generally leads to the down-regulation of receptor-binding sites for these steroids. An additional regulatory component relates to the blood levels of the steroid hormones.

In the golden hamster there is ample evidence of a positive relationship between the increase in estrogen secretion occurring during the follicular phase of the estrous cycle and the elevation of the uterine estrogen and progesterone receptors (see Figure 13-18). The details of the biochemical changes contributing to receptor changes during ovulation are not clear. The ovulatory surge of gonadotropin probably stimulates a transitory rise in serum estradiol; however, the occupied estrogen receptor fails to accumulate due to sup-

TABLE 13-6 Biological Actions of Progesterone

Thermogenesis (in woman)

Regulation of egg movement through fallopian tubes

Preparation of the uterus to receive the blastocyst

Alteration of electrical activity in the brain

Control of uterine contraction (at parturition)

Generation of the secretory system of breasts (during pregnancy)

13. Estrogens and Progestins

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