MENOPAUSE ANDROPAUSE Pharmacology of Estrogens and Gestagens 33 PHARMACOLOGY OF ESTROGENS AND GESTAGENS H. KUHL Replacement therapy with estrogens for osteoporosis prevention, and it does and gestagens serves the purpose of not have any effect on the lipid meta­ avoiding the unfavorable consequences bolism. In order to assess the advan­ of the loss of endogenous estradiol and tages and disadvantages of the various progesterone production. It is not of therapy regimens, it is important to primary importance to restore the know the pharmacokinetics and physiological conditions of an ovula­ metabolism of the preparation used. tory cycle, but much rather to realize Thereby it must be noted that there are the intended purpose of the treatment great inter-individual differences in ab­ in an optimal way. Various prepara­ sorption and metabolism that account tions are available for this purpose, for the individual variations in serum allowing the individual situation to be level, effects and side effects. Attention taken into account to a large extent. to the time-related differences in estro­ The choice of estrogen depends on gen levels after administration and their whether only certain complaints (e.g. accumulation or decrease during long­ atrophic symptoms) are to be treated, term application are a prerequisite for or whether the entire therapeutic and correct interpretation of the hormone preventive potential of hormone replace­ analysis, should these be considered ment therapy (HRT) is to be exploited, necessary in certain cases for monitor­ on whether bleeding will be tolerated, ing or prevention. and which side effects are acceptable. With regard to the risk of serious com­ plications, ethinyl estradiol is consid­ ered unsuitable for HRT, since the available natural estrogens estradiol, EFFECTIVENESS OF ESTROGENS estrone sulfate and estriol are suffi­ ciently effective preparations for which there are hardly any contraindications There are numerous natural and syn­ today. These preparations are supple­ thetic estrogens, all of which vary quite mented by the equine conjugated considerably in terms of their effective­ estrogens, which have a stronger effect ness (Fig. 1). The prerequisite for a strong on the hepatic metabolism than estrogenous effect is a strong binding estradiol. In the case of certain health with the estrogen receptor (Table 1), limitations (e.g. liver disorders, gastro­ whereby the resulting complex must intestinal complaints, hypertriglycerid­ have the “correct” steric configuration emia), the various alternative methods in order to remain bound to the steroid­ of application help to choose the opti­ sensitive element on the DNA for a mal therapy. Estriol, which does not sufficiently long time and to trigger the have any hepatic effects, is unsuitable biological effect. 34 Pharmacology of Estrogens and Gestagens Estradiol Estradiol valerate Estrone Estriol Equilin Dihydroequilin Equilenin Dihydroequilenin Figure 1. Structural formulas of the estrogens used in HRT Table 1. Relative binding affinities (RBA) of ent effects in the individual tissues. A some estrogens to the estrogen receptors ERα high affinity alone does not necessarily β and ER (from Kuiper et al. [1]). Since they mean a strong estrogen effect, as the depend on the incubation conditions, they are not consistent. They are not a measure of bio­ example of the anti-estrogens shows. logical effect. Moreover, the application must lead to sufficiently high concentrations in the Estrogen RBA to RBA to target cell, which depends primarily α β ER ER on the serum levels and local meta­ Estradiol-17β 100 100 bolization in the cell. Estradiol-17α 58 11 Of the physiological estrogens, Estrone 60 37 Estriol 14 21 estradiol has the strongest effect, whilst 4-hydroxyestradiol 13 7 estrone has only a slight effect due to its 2-hydroxyestradiol 7 11 low binding affinity. The significance Estrone sulfate < 1 < 1 Tamoxifen 7 6 of estrone lies in the fact that it is a 4-hydroxytamoxifen 178 339 metabolite and precursor of estradiol at Diethylstilbestrol 468 295 the same time (Fig. 2). It is conjugated Coumestrol 94 185 Genistein 5 36 into estrone sulfate, which circulates in high concentrations, and into estrone glucuronide, most of which is elimi­ Meanwhile, it has been demonstrated nated. that there are two different estrogen Estriol is a weak estrogen, which, at receptors, ERα and ERβ, which occur the normal dose, has only a low prolif­ in different concentrations in the various erative effect on the endometrium. This organs and tissues. The so-called organ­ is due to the fact that estriol is an specific effects of certain estrogens or estrogen with a short-term effect, and anti-estrogens (e.g. estriol, tamoxifene, although it is bound by the receptor raloxifene) can be explained by the fact with the same association rate as that the relevant estrogen-estrogen estradiol, it only remains bound for 1 to receptor complexes can induce differ- 4 hours due to the rapid dissociation. Pharmacology of Estrogens and Gestagens 35 As a result, the biological effects that the value of an estradiol determination rely on binding of the estrogen receptor to monitor the therapy success is doubt­ complex to the DNA for 8 to 12 hours ful. Similarly, the effectiveness of the cannot be triggered. Estriol is an end various estrogens can only be under­ product of metabolization that cannot stood as an average estimate with be transformed back into estradiol considerable individual deviations. and is also eliminated as a conjugate. Thereby, it must be noted that the ef­ Although the serum levels of the fects of the estrogens depend on the estrogens and their metabolites corre­ relevant organ or test system, so that late with the dose administered, the in­ e.g. the effect on the karyopyknotic dividual effects – like the serum levels index does not necessarily correlate on administration of the same dose – with bone density, hot flushes or he­ are very different, even if the measured patic angiotensinogen synthesis [2]. estrogen levels are identical. Accord­ In terms of their clinical effect, the ingly, the question of an optimal dose of 1 to 2 mg estradiol or estradiol estradiol level cannot be answered and valerate corresponds with a dose of 0.6 to 1.25 mg equine conjugated estrogens, which is generally consid­ ered to be the minimum effective dose 2 mg estradiol valerate for the therapy and prevention of com­ plaints and disorders caused by an Estradiol Estradiol sulfate estrogen deficiency. It is roughly com­ Day 1: 0.2 nmol/l Day 1: 0.6 nmol/l parable with a transdermal treatment Day 21: 0.3 nmol/l Day 21: 1.0 nmol/l with 100 µg estradiol [2]. By contrast, estradiol and the conju­ gated estrogens differ considerably in their effect on the hepatic metabolism Estrone Estrone sulfate (Table 2). Equine conjugated estrogens, Day 1: 1.0 nmol/l Day 1: 44 nmol/l Day 21: 1.5 nmol/l Day 21: 54 nmol/l a mixture of various estrogen conju­ gates, have a considerably stronger Figure 2. Mutual transformation of estradiol, stimulating effect on the synthesis of estrone, estrone sulfate and estradiol sulfate many proteins (e.g. angiotensinogen, during treatment with estradiol and estrone SHBG) than estradiol, which is prima­ sulfate (after Aedo et al. [4]) rily due to the equilins. In addition, oral Table 2. Relative effectiveness of certain estrogens with regard to various clinical and metabolic parameters (from Kuhl [3]). Estrogen Hot FSH HDL-CH CBG SHBG Angio­ flushes tensinogen Estradiol-17β 100 100 100 100 100 100 Estriol 30 30 20 Estrone sulfate 90 50 70 90 150 Conjugated estrogens 120 110 150 150 300 500 Equilin sulfate 600 600 750 750 Ethinyl estradiol 12,000 12,000 40,000 60,000 50,000 35,000 36 Pharmacology of Estrogens and Gestagens treatment has a stronger effect than creases, although to a far lesser degree parenteral administration due to the than estrone sulfate. The half-life of high local concentrations in the liver estradiol in the serum is around 35, that during the first passage [2]. Accordingly, of estrone around 20, that of estradiol transdermal estradiol therapy is prefer­ sulfate around 20 and that of estrone able to oral therapy in patients suffering sulfate around 12 hours [4]. Compared from severe liver function disorders or with micronized estradiol, slightly disorders of the hepatic metabolism, lower estrone levels are found after and equine conjugated estrogens administration of the same dose of should not be administered. Estriol, on estradiol valerate, although the estra­ the other hand, has no effect on the diol concentrations are similar [5]. This liver at the recommended doses. means that valerate slows down the intestinal metabolization of estradiol. In the further course of treatment with estradiol valerate, estradiol and its ESTRADIOL AND metabolites accumulate in the serum, so that on day 21 of treatment the se­ ESTRADIOL ESTER rum levels of estradiol and estrone are about 50%, that of estrone sulfate 25% and that of estradiol sulfate 65% higher Oral Administration than on day 1 (Fig. 3) [4]. In contrast to ethinyl estradiol or When administered orally, the micro­ estriol, where a rapid increase to a nized estradiol is metabolized into maximum and a similarly rapid de­ estrone, estrone sulfate and estradiol crease in serum levels is observed after sulfate to a large part in the duodenum administration, estradiol has a special and jejunum, as well as in the liver. status with regard to pharmacokinetics. Due to the large surface of the The maximum estradiol concentration microcrystals, however, a sufficient is not reached until after about 5 hours, quantity of estradiol is absorbed rap­ and the decrease is also gradual, so that idly and thus escapes metabolization. an increased estradiol level can be Similar conditions are found in treat­ found for several hours (Fig.