Clinical Note

Progesterone and Body Temperature

Progesterone has a mild thermogenic effect and may increase basal body temperature by as much as 1°F. Because the appearance of progesterone indicates the presence of a corpus luteum, a woman can readily determine when ovulation has occurred, and hence the time of maximum fertility, by monitoring her temperature daily. This simple, noninvasive procedure has been helpful for couples seeking to conceive a child or who are practicing the "rhythm method'' of contraception.

More recently evidence has been brought forth that estrogens may protect cognitive functions.

Progesterone also acts on the central nervous system, and, in addition to its effects on regulation of gonado-tropin secretion (see below), it may produce changes in behavior or mood. It is curious that more dramatic effects may result from withdrawal of progesterone than from administering it. Thus, withdrawal of progesterone may trigger menstruation, lactation, parturition, and the post-partum psychic depression experienced by many women.

Mechanism of Action

Estrogens and progesterone, like other steroid hormones, readily penetrate cell membranes and bind to receptors that are members of the nuclear receptor superfamily of transcription factors (see Chapter 2). In addition, various nongenomic effects of both hormones have been reported but the molecular processes involved in these actions are incompletely understood. Two separate estrogen receptors, designated ERa and ER^, are products of different genes and are expressed in many different cells in both reproductive and nonreproductive tissues of both men and women. Their DNA binding domains are almost identical. While some differences are present in their ligand binding domains, ERa and ER^ differ mainly in the amino acid sequences of their activation function (AF) domains; therefore, they interact with different transcriptional coactivator and other nuclear regulatory proteins to control expression of different sets of genes. Upon binding ligand, ERa and ERy8 may form homo- or heterodimers before binding to DNA in estrogen-sensitive genes. The resulting synthesis of new messenger RNA is followed, in turn, by the formation of a variety of proteins that modify cellular activity. Both receptors can also be activated by phos-phorylation in the absence of ligand, and both receptors can modulate the transcription-activating properties of other nuclear regulatory proteins without directly binding to DNA. Finally, estrogen receptors have the interesting property of assuming different conforma-tional changes depending upon the particular ligand that is bound. Because the conformation of the liganded receptor profoundly affects its ability to interact with other transcription regulators for which expression is cell type specific, some compounds produced in plants (phytoestrogens) or pharmaceutically manufactured "antiestrogens" may block the effects of estrogen in some tissues while acting as estrogen agonists in other tissues. Additionally, some compounds may bind to activate ERa but antagonize actions of ER^. These properties have given rise to a very important category of drugs called selective estrogen receptor modulators (SERMS), which, for example, may block the undesirable proliferative or neoplastic actions of estrogens on the breast and uterus while mimicking desirable effects on maintenance of bone density in postmenopausal women. One of these compounds, tamoxifen, is routinely used in treatment of breast cancer.

Two isoforms of the progesterone receptor, PRA and PRB, are expressed by progesterone-responsive cells. They are products of the same gene whose mRNA transcript contains two alternate translation start sites. PRA and PRB differ by the presence of an additional sequence of amino acids at the amino terminus of PRB that provides an additional region for interacting with nuclear regulatory proteins. Liganded PRs bind to the DNA of target genes as homodimers or heterodimers and in different combinations may activate different subsets of genes. When expressed together in some cells, liganded PRA can repress the activity of PRB. Both PRA and PRB expression are induced by prior exposure of cells to estrogens and can repress the activity or expression of ERa. Studies under way in mice in which expression of specific progesterone or estrogen receptors is disrupted by genetic manipulation are determining which particular responses to ovarian steroid hormones are mediated by each receptor.

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