Progesterone-dependent regulation of female reproductive activity by two distinct progesterone receptor isoforms

doi:10.1016/S0039-128X(03)00126-0

Steroids

Volume 68, Issues 10–13, November 2003, Pages 771-778

https://doi.org/10.1016/S0039-128X(03)00126-0 Get rights and content

Abstract

The steroid hormone, progesterone, is a central coordinator of all aspects of female reproductive activity. The physiological effects of progesterone are mediated by interaction of the hormone with specific intracellular progesterone receptors (PRs) that are expressed from a single gene as two protein isoforms and that are members of the nuclear receptor superfamily of transcription factors. Analysis of the structural and functional relationships of each isoform using in vitro systems has demonstrated that the PR-A and PR-B proteins have different transcription activation properties when liganded to progesterone. More recently, selective ablation of the PR-A and PR-B proteins in mice had facilitated examination of the contribution of the individual PR isoforms to the pleiotropic reproductive activities of progesterone. Analysis of the phenotypic consequences of these mutations on female reproductive function has provided proof of concept that the distinct transcriptional responses to PR-A and PR-B observed in cell-based transactivation assays are reflected in a distinct tissue-selective contribution of the individual isoforms to the reproductive activities of progesterone. In PR-A knock-out mice, in which the expression of the PR-A isoform is selectively ablated (PRAKO), the PR-B isoform functions in a tissue-specific manner to mediate a subset of the reproductive functions of PRs. Ablation of PR-A does not affect response of the mammary gland or thymus to progesterone but results in severe abnormalities in ovarian and uterine function leading to female infertility. More recent studies using PR-B knock-out (PRBKO) mice have shown that ablation of PR-B does not affect either ovarian, uterine or thymic responses to progesterone but results in reduced mammary ductal morphogenesis and alveologenesis during pregnancy. Thus, PR-A is both necessary and sufficient to elicit the progesterone-dependent reproductive responses necessary for female fertility, while the PR-B isoform is required to elicit normal proliferative and differentiative responses of the mammary gland to progesterone. This review will summarize our current understanding of the selective contribution of the two PR isoforms to progesterone action.

Section snippets

PRs are nuclear receptor transcription factors

Progesterone receptors (PRs) are members of a large family of structurally related gene products known as the nuclear receptor superfamily [1], [2], [3], [4]. The family includes receptors for several steroids, thyroid hormone, oxysterols and fat-soluble vitamins in addition to a significant number of ‘orphan’ receptors whose physiological ligand, if any, and function is poorly understood. PRs are composed of two proteins, termed PR-A and PR-B that are expressed from a single gene in rodents

Structural and functional significance of the PR-A and PR-B proteins

PR-A and PR-B differ only in that PR-B contains an additional sequence of amino acids at its amino terminus that is not contained in PR-A. This region encodes a transactivation function (AF3) that is specific to the PR-B protein [20], [21]. Thus, both the PR-A and PR-B are capable of binding P, dimerizing and interacting with P-responsive DNA elements and the transcriptional machinery to regulate gene expression. When expressed in equimolar ratios in cells, the A and B proteins can dimerize and

Physiological role of PRs

Null mutation of the PR gene encoding both isoforms has provided evidence of an essential role of PRs in a variety of female reproductive and non-reproductive activities. Female mice lacking both PRs exhibit impaired sexual behavior, neuroendocrine gonadotrophin regulation, anovulation, uterine dysfunction and impaired ductal branching morphogenesis and lobuloalveolar differentiation of the mammary gland [44], [57], [58], [59]. PRs also play an essential role in regulation thymic involution

Generation of mouse models to examine selective physiological functions of the PR-A and PR-B proteins

The differences in transcriptional activities and coregulator interactions between the PR-A and PR-B observed in vitro predicted that these proteins may mediate different physiological responses to P. In addition, the selective ability of PR-A to inhibit transcriptional responses induced by both PR-B and the estrogen receptors (ER) suggested that PR-A has the capacity to diminish overall P responsiveness in certain tissues as well as contribute to the antiestrogenic activities of P previously

PR and ovarian function

Evidence that ovary derived P may participate in autocrine regulation of ovarian function first emerged with the demonstration that luteinizing hormone (LH), the primary signal for rupture of preovulatory ovarian follicles leading to ovulation, can stimulate transient expression of PR mRNA and protein in granulosa cells isolated form preovulatory follicles [63], [64], [65] and that the antiprogestin, RU486, can inhibit ovulation [66]. Definitive proof that PRs are essential mediators of

PR and uterine development

P plays a critical role in uterine implantation during early pregnancy and is a potent inhibitor of E-induced hyperlasia of the uterine epithelium. The implantation-associated events that are regulated by P include preparation of the uterine epithelium for receptivity to blastocyst implantation and differentiation of endometrial stromal cells to a decidual phenotype that supports development of the implanting embryo. While the molecular signaling pathways that mediate these complex P-dependent

Ovarian steroids in mammary gland development and tumorigenesis

The general mechanisms that underlie both mammary gland development and tumorigenesis are conserved between rodents and humans [76]. The mouse model system, being amenable to genetic manipulation, provides a powerful tool to elucidate the molecular genetic pathways that control these events. With the exception of the emergence of a primitive mammary epithelial rudiment that is established in the midgestational embryo, the bulk of mammary gland development occurs postnatally in two distinct

PRs in mammary gland development

Null mutation of both PR isoforms in PRKO mice has demonstrated that PRs are specifically required for pregnancy-associated ductal proliferation and lobuloalveolar differentiation of the mammary epithelium. The mammary glands of PRKO mice failed to develop the pregnancy-associated side-branching of the ductal epithelium with attendant lobular alveolar differentiation, despite normal postpubertal mammary gland morphogenesis of the virgin mice [57], [89]. Thus, in contrast to its

PR isoform selective contribution to pregnancy associated mammary gland morphogenesis

Both isoforms of PR are expressed in the mammary gland of the virgin mouse [95] and during pregnancy [96], although the levels of PR-A protein exceed those of the PR-B isoform by at least a 2:1 ratio in both cases. To examine the selective contributions of each isoform to the morphogenic responses of the mammary epithelium to P, we analyzed the spatiotemporal expression patterns of the individual isoforms and compared the morphology of mammary glands of ovariectomized wild type, PRAKO and PRBKO

Summary

Analysis of the selective roles of the individual PR isoforms in the female reproductive tract has revealed that the tissue-specific functions of PR-A and PR-B are mostly distinct. These observations may have important clinical implications with regard to the development of improved tissue-selective progestins for reproductive management and hormone replacement therapy. The ability of PR-A to inhibit hyperplasia of the uterine epithelium, together with the reduced proliferative activity of the

Acknowledgements

This work was supported by a grant from NIH, HD32007 to OMC.

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