Elsevier

Maturitas

Volume 47, Issue 4, 15 April 2004, Pages 277-283
Maturitas

Pharmacological profile of progestins

https://doi.org/10.1016/j.maturitas.2004.01.001Get rights and content

Abstract

The synthetic progestins used so far for contraception and menopausal hormone therapy are derived either from testosterone (19-nortestosterone derivatives) or from progesterone (17-OH progesterone derivatives and 19-norprogesterone derivatives). Among the 19-nortestosterone derivatives, the estrane group include norethisterone (NET) and its metabolites, and the gonane group include levonorgestrel (LNG) and its derivatives. The later, including desogestrel (DSG) and its derivative etonogestrel, gestodene (GES) and norgestimate (norelgestromin), have been referred to as third-generation progestins. Several new progestins have been synthesized in the last decade and may be considered as a fourth-generation of progestins. Dienogest is referred to as a hybrid progestin being derived from the estrane group with a 17α-cyanomethyl group, and drospirenone derives from spirolactone. These two progestins have no androgenic effect but a partial antiandrogenic effect. The later exerts anti-mineralocorticoid effects. This property leads to a decreased salt and water retention and a lowering in blood pressure in users of pills containing this progestin. The 19-norprogesterone derivatives appear more specifically progestational and do not possess any androgenic, estrogenic or glucocorticoid activity. They are referred to as “pure” progestational molecules as they bind almost exclusively to the progesterone receptor (PR) and do not interfere with the other steroid receptor. This category includes, trimegestone, nomegestrol acetate and Nestorone® is not active orally but proved to be a potent anti-ovulatory agent when given in implants, vaginal rings or percutaneous gel. Non-androgenic progestins would appear neutral on metabolic factors and on the vessels and would have the advantage of avoiding acnea. Progestins with antiandrogenic properties may also be used for the treatment of women with preexisting androgen related conditions. The progestins available for therapy exhibit profound differences according to their structure or metabolites and it is inappropriate to consider the various effects of the old and new molecules as class-effects.

Introduction

Progesterone (P) and synthetic progestins interact not only with the progesterone receptor (PR), but also with other steroid receptors. Depending on the derivative molecule (either P or testosterone, T) some progestins bind to androgen receptors (AR) as well, inducing either androgenic or anti-androgenic effects. Molecules similar to the native hormone P may exert a competitive inhibition to the mineralocorticoid receptor and some derivatives of 17-hydroxy progesterone or testosterone may exert glucocorticoid-like effects.

When considering the comparative potency of progestins, it is necessary to note their specific actions: i.e. whether (1) the progestin has progestational activity with the ability to maintain pregnancy and transform the endometrium into the secretory phase; (2) the progestin is anti-estrogenic with the ability to down regulate the estrogen receptors and to decrease the thickness of the estrogen-primed endometrium; or (3) the progestin has anti-androgenic activity, i.e., it opposes androgen-induced prostate growth, as observed in animal experiments or counteracts the effects of endogenous androgen in humans.

The effects of progestins relate to their interactions with receptors: AR (e.g., acnea, lipid effects); glucocorticoid receptors (GR) (e.g., salt and water retention, bloating); or mineralocorticoid receptors (e.g., decreased water retention and weight). Anti-androgenic progestins may act in several ways. They can exert competitive inhibition of the AR, or bind to the enzyme 5-alpha reductase and hence interact with the conversion of testosterone into dihydrotestosterone (its active metabolite). When combined with estrogen the non-androgenic progestins do not oppose the estrogen-dependent increase in SHBG. The later effect results in more binding of the circulating androgens and less free T available for action at the receptor level. Thus, anti-androgenic progestins may have beneficial effects (e.g., controlling endogenous androgen and decreasing acnea or hirsutism).

The synthetic progestins used in clinical practice are derived either from T (19-nortestosterone derivatives) or from P (17-OH progesterone derivatives and 19-norprogesterone derivatives) [1].

Among the 19-nortestosterone derivatives is the first generation progestin, norethynodrel (the first progestin synthesized) [1]. The second generation is categorized into two groups: the estrane group includes norethisterone (NET) and its metabolites, and the gonane group includes levonorgestrel (LNG) and its derivatives. Norethynodrel, lynestrenol and ethynodiol acetate are prodrugs of NET and convert into NET for exerting their action. The third generation of progestins, derived from the latter group are: desogestrel (DSG) with its active metabolite 3-keto-desogestrel also named etonogestrel, gestodene (GES) and norgestimate (and its active 17-deacetylated metabolite, norelgestromin). These testosterone-derived molecules have been used in most of the contraceptives available to date and some have androgenic activity.

Section snippets

Specific activities of new progestins

Several new progestins have been synthesized in the last decade [2]. Dienogest, referred to as a hybrid progestin, is derived from the estrane group with a 17α-cyanomethyl radical [3]. However it is considered to be close to the pregnane group as it does not exert the androgenic effects of the testosterone derivastives. In contrast it has a significant anti-androgenic activity. Drospirenone is derived from spirolactone [4]. The 19-nor derivatives of progesterone are referred to as ‘pure’

Pharmacokinetic differences between gestagens

Other important considerations in evaluating progestagen action are pharmacokinetic properties and binding of progestins to serum proteins. A comparison of radioactivity recovered in urine and feces after oral and IV administration of a labelled compound indicates the absolute bioavailability of that compound and determines its absorption via the oral route. The compounds with the highest oral bioavailability are gestodene, desogestrel and cyproterone acetate (CPA) [12], [13]. The new

New progestins used in contraception and HRT

Drospirenone, which has pharmacodynamic properties very similar to progesterone [14], [15], has been developed as an oral contraceptive in pills containing 3 mg of the progestin and 30 μg of ethynylestradiol (EE) (Yasmin®) [4], [18] and also for HRT in a combination containing oral estradiol (Angeliq®). Drospirenone has anti-mineralocorticoid and progestogenic properties not found in most synthetic progestins. The main feature of this combination resides in the ability of the progestin to

Progestins and cardiovascular disease

Many of the progestins used in contraception, as well as HRT, are derived from T, and their main side effects are related to androgenic properties or to their glucocorticoid effects. Improvement of OCs has been attempted by decreasing the androgenic potency of the steroids. However, the third generation progestins, having fewer androgenic effects than the second generation, have lost some of the ability to oppose the effects of the ethinyl estradiol component of the OCs. Whether this property

Acknowledgements

The author wishes to express her gratitude to Ms. Margaret Small for her excellent contribution and help in the editing of the manuscript.

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