Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects

Abstract

The safety of progestogens as a class has come under increased scrutiny after the publication of data from the Women's Health Initiative trial, particularly with respect to breast cancer and cardiovascular disease risk, despite the fact that only one progestogen, medroxyprogesterone acetate, was used in this study. Inconsistency in nomenclature has also caused confusion between synthetic progestogens, defined here by the term progestin, and natural progesterone. Although all progestogens by definition have progestational activity, they also have a divergent range of other properties that can translate to very different clinical effects. Endometrial protection is the primary reason for prescribing a progestogen concomitantly with postmenopausal estrogen therapy in women with a uterus, but several progestogens are known to have a range of other potentially beneficial effects, for example on the nervous and cardiovascular systems. Because women remain suspicious of the progestogen component of postmenopausal hormone therapy in the light of the Women's Health Initiative trial, practitioners should not ignore the potential benefits to their patients of some progestogens by considering them to be a single pharmacological class. There is a lack of understanding of the differences between progestins and progesterone and between individual progestins differing in their effects on the cardiovascular and nervous systems, the breast, and bone. This review elucidates the differences between the substantial number of individual progestogens employed in postmenopausal hormone therapy, including both progestins and progesterone. We conclude that these differences in chemical structure, metabolism, pharmacokinetics, affinity, potency, and efficacy via steroid receptors, intracellular action, and biological and clinical effects confirm the absence of a class effect of progestogens.

Figure 1.

A, Chemical structure of the natural progestogen, progesterone; B, chemical structure of testosterone.

Figure 2.

Progestins structurally related to progesterone: pregnane derivatives, acetylated and nonacetylated.

Figure 3.

Progestins structurally related to progesterone: 19-norpregnane derivatives, acetylated and nonacetylated.

Figure 4.

Progestins structurally related to testosterone: ethinylated derivatives, estranes.

Figure 5.

Progestins structurally related to testosterone: ethinylated derivatives, 13-ethylgonanes.

Figure 6.

Progestins structurally related to testosterone: nonethinylated derivatives.

Figure 7.

Schematic diagram to illustrate differential genomic (nuclear) and nongenomic (extranuclear, cytoplasmic) actions of progestogens and endogenous steroid hormones. The two progestins, MPA and norethindrone, were chosen to illustrate the concept of differential actions compared with each other and progesterone. In genomic actions, all progestogens bind to the PR and act as agonists. MPA is a partial to full agonist for the GR and AR but has no significant activity via the MR or ER. However, norethindrone is a partial to full agonist for the AR but has no significant activity via the GR, MR, or ER. Progesterone is a weak agonist for the GR and AR, has no significant activity via the ER, and is a full antagonist for the MR. The two best-characterized genomic mechanisms for steroid receptors are illustrated. The first is transactivation by steroid receptor dimers binding directly to SREs in the promoters of target genes, followed by recruitment of coactivators and increased transcription. The second is transrepression via tethering of a steroid receptor monomer to other positively acting transcription factors, followed by recruitment of a corepressor and inhibition of transcription. Other complexes and higher-order effects on chromatin structure as discussed in the text are not depicted for simplicity. The depicted nongenomic or cytoplasmic actions include activation of various cytoplasmic targets by the classical nuclear steroid receptors or by membrane steroid receptors. Progesterone is a full agonist for the mPR, whereas MPA and norethindrone have no significant activity via mPR. Note that cytoplasmic actions can also lead to genomic actions by targeting of nuclear proteins such as transcription factors, cofactors, and chromatin proteins or even steroid receptors. Also depicted is the cross talk between the classical PR and other plasma membrane receptors (R) such as the epidermal growth factor receptor, as discussed in the text. Note that actions of progesterone as a weak GR or AR agonist are not depicted. ALD, aldosterone; CORT, cortisol; E₂, estradiol; mER, membrane ER; NET, norethindrone; PROG, progesterone; SR, steroid receptor; TEST, testosterone; TF, transcription factor.