Progestogens in Obstetrics and Gynecology 2015th Ed.

2. Pharmacology of Progestogens

Adolf E. Schindler¹

(1)

Institute for Medical Research and Education, University Clinic Essen, SHH1, Hufelandstrasse 55, D-45122 Essen, Germany

Adolf E. Schindler

Email: adolf.schindler@uni-due.de

Keywords

ProgesteronePharmacologyPharmacokineticsProgestogensProgestins

1 Introduction

Progesterone is the only natural progestogen, synthesized, produced and released by the corpus luteum of the ovary during the luteal phase. Its unique features include, an increase in the basal body temperature, secretory changes in the endometrium in preparation for fertilisation and ovum implantation. In addition to these basic biological effects, the progestogens may, to differing degrees, suppress the hypothalamic pituitary axis, an effect which mainly accounts for the contraceptive effect of some progestogens. Progestogens may also affect abnormal endometrial tissue such as hyperplastic endometrium and endometriosis which have been chronically and excessively stimulated by endogenous or exogenous estrogens.

In 1934 progesterone was isolated from animal corpora lutea and structurally identified [1]. The structure of progesterone is shown in Fig. 2.1. In the 1940s the manufacture of progesterone was made possible, by synthesis from the plant sterol “diosgenin” [1]. However, it was soon realized that progesterone could not be properly absorbed by the gut. Progress in pharmacological development led to the development of “micronization” of progesterone, which improves oral as well as parenteral absorption [2]. However, bioavailability is low (approximately 5 %). Other progestogens, have different absorbative properties and different bioavailabilities. Dydrogesterone for example, a retroprogesterone, derived from progesterone by ultra violet light exposure is readily absorbed orally and has been calculated to have 28 % bioavailability.

Fig. 2.1

Structure of progesterone

The broad variety of progestogens available with different progestogenic potencies, as well as a whole array of partial effects, warrants a detailed presentation and description of the progestogens.

2 Classification of Progestogens

Progestogens are all steroid compounds with progestogenic activity of different intensity regarding progestogenic action per molecule. Some of the compounds used therapeutically act as prodrugs, which need to be metabolized in the body before the respective function is obtained (see Table 2.1). Progestogens not only have different structures, but each progestogen expresses a different pattern of partial effects. This partial effect pattern is responsible for the different clinical effects and side effects seen for each progestogen.

Table 2.1

Progestogens as prodrugs

Progesterone and all the other synthetic progestogens are called progestogens. If progesterone is excluded the term “progestin” is used. An overview of the various types of progestogens is shown in Table 2.2[3, 4]. The development of the classification of the progestogens started in the 1950s. Removal of the C19-Methyl-group increased progestogenic activity and oral resorption but decreased androgenic action. The introduction of a 17α-Ethyl-group produced ethisterone, which had a much higher binding affinity to the progesterone receptor. Both processes together produced the progestogen norethisterone (norethindrone in the United States), which is highly active, well tolerated and has been clinically available since 1957 [5]. In 1951 Norethisterone acetate (NETA) was synthesized by Schering and Norethinodrel by Searle. In the 1960s, the prodrugs norethisterone (NET), lynestrenol, ethinylethinodiol acetate, norethinodrel and DL-norgestrel appeared on the market. The first progesterone derivative 17-acetoxyprogesterone was developed by Schering in 1954 followed by medroxyprogesterone acetate in 1957. This was followed by medrogestone acetate and chlormadinone acetate in 1959. The retroprogesterone dydrogesterone was formed from progesterone by UV light exposure [6]. Dydrogesterone is still the only retroprogesterone presently available on the market. In 1961 cyproterone acetate became clinically available, followed by desogestrel in 1972 (Organon). Thereafter gestodene, dienogest and the spirolactone derivative drospirenone followed [7].

Table 2.2

Classification of progestogens, and partial effect pattern modified from [3, 4]

++, strongly positive; +, positive; ±, weakly positive; −, negative

3 Pharmacokinetics and Pharmacology of Progestogens

Pharmacokinetics such as absorption, distribution and excretion determine how much of the progestogen is available to the tissues, by measuring the blood levels and the amount that enters the cell is regulated by the extent to which the progestogen is bound to carrier proteins. Carrier proteins cannot cross the cell membranes. The pattern of distribution of the progestogens is mainly regulated by binding to transport proteins and steroid receptors in the tissues.

Generally, all progestogens are bound in the blood with low affinity and high capacity to albumin. However, some of the progestogens derived from 19-Nortestosterone, such as norethisterone (norethindrone) are also bound with high affinity but low capacity to sex hormone binding globulin (SHBG), while others, such as progesterone itself can be bound to the corticosteroid-binding globulin (CBG). The binding of progestogens to transport proteins is reversible, so that a change in binding protein concentration may contribute to the variation or variability of a progestogen. The non-protein-bound (unbound or free fraction) of a steroid is available for metabolism in steroid metabolising cells or binds to a receptor in target cells.

Progestogens given orally reach a maximum concentration within 1–3 h. Information on bioavailability and half-life has been derived from frequent blood sampling during the first 24 h after oral administration. Bioavailability represents the amount of the progestogen that is found in the circulation (area under the curve). The half-life is the time in hours in which the progestogen has been absorbed to one half of its highest level. The longest half life is found with drospirenone (31–32 h), whereas norethisterone has the shortest half life (8 h). Details are summarized in Fig. 2.2.

Fig. 2.2

Dose, bioavailability and half-life of progestogens modified from [3, 4]. *Dydrogesterone 17 h with metabolites

Among progestogens there are great differences in bioavailability. Progesterone itself has a bioavailability of less than 5 %, dydrogestrone has a bioavailability of 28 % and nomegestrol of 60 % [4]. The bioavailability of progestogens derived from 19-nortestosterone can reach more than 90 %. The distribution of some progestogens bound to SHBG, CBG, albumin and free fraction is shown in Table 2.3.

Table 2.3

Relative binding affinities of progestogens to steroid receptors and serum binding proteins modified from [3, 7]

PR progesterone receptor (promegestone = 100 %), AR androgen receptor (metribolone = 100 %), ER estrogen receptor (estradiol-17β = 100 %), GR glucocorticoid receptor (dexamethason = 100 %), MRmineralocorticoid receptor (aldosterone = 100 %), SHBG sex hormone binding globulin (dihydrotestosterone = 100 %), CBG corticosteroid-binding globulin (cortisol = 100 %), ND not determined

The clinical effects of the progestogens is not only dose dependent but also influenced by the different partial effect pattern of each progestogen, as summarized in Table 2.2. Each progestogen has a different partial effect pattern, which can modify the final biological effect of each progestogen. Acquaintance with the partial effect pattern will enable the clinician to choose the optimal progestogen.

Progestogens also differ according to the affinity for various steroid receptors such as the progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), mineralocorticoid receptor (MR) or glucocorticoid receptor (GR). Affinity for the different receptors is summarised in Table 2.3. Affinity for different receptors is influenced by specific receptor binding proteins (Table 2.3). The clinical consequences of receptor binding are shown in Table 2.4.

Table 2.4

Comparison of partial effects and metabolic effects of dydrogesterone, medroxyprogesterone acetate and norethisterone

A most recent area of interest and controversies is the influence of the various progestogens on thromboembolic risk [8].

4 Conclusions

Progestogens are different: in structure and in action profile. Besides the common progestogenic effect, each progestogen has a particular partial effect pattern, which has utmost relevance when clinically used. Effects and possible side effects can be influenced or determined by this.

References

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8.

Schindler AE. Progestogens and thromboembolic risk. Front Gynecol Endocrinol. 3: 2014 (in press)