Elsevier

Steroids

Volume 68, Issues 10–13, November 2003, Pages 879-890
Steroids

All progestins are not created equal

https://doi.org/10.1016/j.steroids.2003.08.003Get rights and content

Abstract

A variety of progestins are available for therapeutic use. It is convenient to classify them into those related in chemical structure to progesterone or testosterone. Progestins related to progesterone can be subdivided into pregnanes and 19-norpregnanes, whereas those related to testosterone can be subdivided into those with and without a 17-ethinyl group. 17-Ethinylated progestins consist of the families of norethindrone (estranes) and levonorgestrel (13-ethylgonanes). Progestins administered orally undergo extensive hepatic first pass metabolism primarily by reduction and conjugation, and in most instances, relatively high progestin doses are required for therapeutic use. There are limited reliable data on the pharmacokinetics of most progestins. Some progestins are prodrugs, requiring transformation prior to exhibiting progestational activity. Qualitative and quantitative tests utilizing either human or animal species have been used to establish progestin potency. However, profound differences in progestational activity are often observed between human and animal tissues. Also, there is a misconception about androgenicity of progestins due largely to extrapolation of data from rat studies to the human. Progestins differ widely in their chemical structures, structure–function relationships, metabolism, pharmacokinetics, and potencies; they are not created equal.

Introduction

A variety of progestins are used in combination with estrogen for hormone replacement therapy (HRT) in postmenopausal women. Progestins are compounds that transform proliferative to secretory endometrium in estrogen-primed uteri. They are administered either continuously combined, sequentially or intermittently during estrogen replacement therapy (ERT) to prevent endometrial hyperplasia. Alternate names for progestin include progestogen, progestagen, gestogen, and gestagen [1].

Progestins differ widely in their chemical structure, pharmacokinetics, and potency. It is important that physicians understand these differences in order to prescribe the optimum type and dose of progestin for HRT.

The objectives of the present review are: (a) to show which progestins are available for therapeutic use and how they differ in chemical structure; (b) to summarize what is known about the metabolism, pharmacokinetics, and potency of progestins; (c) to show that all progestins are not created equal.

Section snippets

Classification of progestins

To understand the pharmacokinetics and potency of progestins, it is helpful to know their chemical structures and how they differ from each other. Table 1 shows a classification scheme for progestins, most of which are used for HRT; their chemical structures are depicted in Fig. 1, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7. Progestins can be divided into natural and synthetic types. There is only one natural progestin and that is progesterone (Fig. 1). Use of the term “natural” here implies that

Metabolism of progestins

The metabolism of progestins is poorly understood. This is due to the fact that relatively few studies on the metabolism of the different progestins have been carried out.

Steroids administered orally undergo hepatic first pass metabolism. The extent to which this occurs varies and depends on the chemical structure of the progestin. Progestins are first subjected to metabolism by bacterial enzymes in the intestine. The metabolized and unmetabolized progestins are then absorbed and enter the

Pharmacokinetics of progestins

Following oral administration of a drug and measurement of the drug or its active metabolite(s) in serum or plasma over a 24-h period, a profile of the administered compound or its metabolite, showing absorption, distribution, and elimination, can be graphed as shown in Fig. 8, Fig. 9, Fig. 10, Fig. 11. These progestin concentrations can be used to calculate a variety of pharmacokinetic parameters; they include maximum concentration (Cmax), the time to reach Cmax, area under the curve (AUC),

Progestin potency

The term “potency” in relation to a drug is controversial and can be confusing. Here, the term is defined as an estimate of a specific effect of a drug. In general, tests of potency can be divided into three types: in vitro receptor binding assays, bioassays, and clinical evaluations. A number of variables are associated with potency tests. However, probably the most important variable is the extrapolation of potency estimates from animals to humans. As an example, Table 6 shows a comparison of

Androgenicity of progestins

In addition to the characteristic progestational activity of progestins, they may also possess anti-estrogenic, androgenic, anti-androgenic, and/or anti-mineralocorticoid activities. The most controversial and confusing of these activities is the androgenicity of certain progestins.

What is an androgenic progestin? It is often defined as a progestin that exhibits androgen-like effects. The two most notable androgenic progestins are levonorgestrel and norethindrone. Primary evidence for their

Conclusion

It is obvious from the present review that progestins differ widely in their chemical structures, structure–function relationships, metabolism, pharmacokinetics, and potency. We can therefore conclude that all progestins are not created equal.

References (39)

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