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New Progestogens

A Review of Their Effects in Perimenopausal and Postmenopausal Women

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Abstract

The progestins have different pharmacological properties depending upon the parent molecule, usually testosterone or progesterone, from which they are derived. Very small structural changes in the parent molecule may induce considerable differences in the activity of the derivative. In postmenopausal women with an intact uterus, progestins are used in combination with estrogen as hormone-replacement therapy (HRT). The development of new generations of progestins with improved selectivity profiles has been a great challenge. Steroidal and nonsteroidal progesterone-receptor (PR) agonists have been synthesised as well, although the latter are still in a very early stage of development. Several new progestins, which have been synthesised in the last 2 decades, may be considered fourth-generation progestins. These include dienogest, drospirenone, Nestorone® (Population Council, New York, NY, USA), nomegestrol acetate and trimegestone. The fourth-generation progestins have been designed to have no androgenic or estrogenic actions and to be closer in activity to the physiological hormone progesterone. Drospirenone differs from the classic progestins as it is derived from spirolactone. It is essentially an antimineralocorticoid steroid with no androgenic effect but a partial antiandrogenic effect. The antiovulatory potency of the different progestins varies. Trimegestone and Nestorone® are the most potent progestins synthesised to date, followed by two of the older progestins, 3-ketodesogestrel and levonorgestrel. The new molecules trimegestone, drospirenone and dienogest also have antiandrogenic activity.

Following the publication of the results of the Women’s Health Initiative study, the role of progestins in HRT became controversial. Unfortunately, this concern has been directed towards progestins as a class, although striking differences exist among the progestins. Natural progesterone and some of its derivatives, such as the 19-norprogesterone molecules, and the new molecules drospirenone and dienogest are not androgenic and, therefore, have no negative effect on the lipid profile. The effects of progestins on breast tissue remain controversial as well. However, depending on the progestin and the duration of application, breast cell differentiation and apoptosis may predominate over proliferation. It is still unclear if the currently available progestins are able to bind specifically to the PR isoforms PR-A or PR-B and whether this is of clinical relevance to breast cell proliferation is also unclear. Although it is likely that the new progestins may have neutral effects on the risk of coronary heart disease or breast cancer in younger postmenopausal women, this hypothesis must be confirmed in large randomised, well controlled clinical trials.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

No sources of funding were used to assist in the preparation of this manuscript. The author thanks Barbara Tokay for editorial assistance. Nestorone® (Population Council, New York, NY, USA), a progestin mentioned in this review, was developed by the Population Council; development of Nestorone® for contraceptive use was funded by grants from the United States Agency for International Development and the National Institute of Child Health and Development. The views of the author do not necessarily reflect those of the Population Council or the funding agencies.

The author has no conflicts of interest that are directly relevant to the content of this review.

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    Régine Sitruk-Ware

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Sitruk-Ware, R. New Progestogens. Drugs Aging 21, 865–883 (2004). https://doi.org/10.2165/00002512-200421130-00004

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