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Home , Biotransformation, Conjugated estrogens, Coumestrol, Cyclodextrin, Cyproterone, Diethylstilbestrol

ANDROPAUSE of and Gestagens 33

PHARMACOLOGY OF ESTROGENS AND GESTAGENS

H. KUHL

Replacement therapy with estrogens for prevention, and it does and gestagens serves the purpose of not have any effect on the meta­ avoiding the unfavorable consequences bolism. In order to assess the advan­ of the loss of endogenous and tages and disadvantages of the various production. It is not of therapy regimens, it is important to primary importance to restore the know the and physiological conditions of an ovula­ 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 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 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 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 and 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 (Table 1), limitations (e.g. 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 ­ 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 Estrone Estriol

Equilin Dihydroequilin 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 , 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 < 1 < 1 Tamoxifen 7 6 of estrone lies in the fact that it is a 4-hydroxytamoxifen 178 339 and precursor of estradiol at 468 295 the same time (Fig. 2). It is conjugated 94 185 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 . 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 ) 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 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 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 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 , 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 estrogen deficiency. It is roughly com­ Day 1: 0.2 nmol/l Day 1: 0.6 nmol/l parable with a 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 (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 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 rum levels of estradiol and estrone are about 50%, that of estrone sulfate 25% and that of estradiol sulfate 65% higher 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 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. 3) [4]. ment with estradiol valerate, which is Accordingly, the terminal half-life time split rapidly after administration, (t1/2β) of estradiol is fairly long at 35 whereby estradiol is released. Within a hours. The reason for this lies in the fact short time of administration of e.g. that estrone, estrone sulfate and 2 mg estradiol valerate, the estrogen estradiol sulfate must be regarded not serum concentration rises to a maxi­ only as metabolites but also as precur­ mum of about 40 pg/ml on average on sors of estradiol, and they can be trans­ the first day, and up to 80 to 100 pg/ml formed back into estradiol (Fig. 2). after daily administration. The serum These relationships become clear when levels of estrone reach values that are the concentrations of estradiol, estrone about four to six times as high as those and estrone sulfate after administration of estradiol, whilst estrone sulfate, of estradiol valerate are compared with which is produced in large quantities, those after administration of estrone reaches concentrations that are 30 to sulfate (Fig. 3). Since estrone and 40 times as high as those of estrone estrone sulfate circulate in considerably (Fig. 3) [4]. Estradiol sulfate also in­ higher concentrations, they represent a Pharmacology of Estrogens and Gestagens 37

2 mg estradiol valerate

Estrone day 21 Estrone sulfate day 21

Estrone day 1

Estrone sulfate day 1

Estradiol day 21

Estradiol day 1

2.5 mg estrone sulfate

Estrone day 21 Estrone sulfate day 21

Estrone day 1 Estrone sulfate day 1

Estradiol day 21

Estradiol day 1

Figure 3. Average serum concentration curve for estradiol, estrone and estrone sulfate following oral administration of 2 mg estradiol valerate (above) or 2.5 mg estrone sulfate (below). Modified from Aedo et al. [4]. 38 Pharmacology of Estrogens and Gestagens large, hormonally inactive reservoir lower, but the steady state is already that is responsible for the estradiol level reached with the second patch. With still being raised 24 hours after admini­ the 25 µg patch, the estradiol levels are stration. The ratio of estrone to estradiol, 30–40 pg/ml, and with the 100 µg patch which is often used as a criterion for they are between 60 and 110 pg/ml. a “more physiological” or “more un­ With transdermal treatment, there are physiological” therapy and which is also strong intra-individual fluctuations 5:1 in oral therapy, 1:1 in transdermal of the estradiol level, ranging from 30 therapy, 1:2 in young women and 2:1 to 65 pg/ml with the 50 µg patch and in postmenopausal women, is without from 60 to 100 pg/ml with the 100 µg any clinical relevance. patch. Usually, a strong decrease in estradiol is observed on the third day, Transdermal Administration since becomes weaker with the disappearance of the . In Transdermal treatment avoids the strong about 30% of the women, the values metabolization in the intestinal tract are fairly low due to poor . and during the first passage through the In the matrix patch, the estradiol is liver. It is particularly suitable for distributed in the adhesion layer con­ women suffering from gastrointestinal sisting of an acryl or vinyl poly­ or liver disorders. There are two types mer, and it diffuses into the when of patches containing estradiol, namely the matrix is applied, whereby various the reservoir patch and the matrix absorption enhancers (fatty acids, fatty patch. acid , lecithin) facilitate the pene­ The reservoir patch contains an al­ tration. The diffusion rate of the matrix coholic with 2, 4 or 6 mg estradiol. system is fairly constant, so that the After application, the estradiol dis­ estradiol levels are still around 50% of solved in alcohol diffuses through the the maximum value after 4 days (Fig. 4) membrane into the horny layer and [6]. Therefore, the matrix patch lasts reaches the in the dermis. seven days, even though some manu­ The diffusion depends on the concen­ facturers recommend changing it twice tration gradient between the reservoir a week. Once the matrix patch has and the capillaries, whereby the alco­ been applied, the maximum estradiol hol not only facilitates diffusion but level is reached after only 12 hours, also reduces metabolization of the whereby the values are 30–45 pg/ml estradiol in the skin. The system is only efficient as long as the patch sticks and the alcohol is present. The res­ Matrix patch ervoir patch is available with different Reservoir patch doses, whereby release rates of 25, 50 or 100 µg per day are indicated. After the application of a 50 µg patch, the estradiol levels increase rapidly and reach a maximum of 40–60 pg/ml after days 30 hours. Then they decrease again, Figure 4. Schematic illustration of the serum reaching a level of 30 pg/ml after 48 concentration curve for estradiol following single hours and the baseline value after 72 administration of a matrix patch and after two hours (Fig. 4) [6, 7]. When the first administrations of a reservoir patch (after Baracat patch is applied, the levels are slightly et al. [6]) Pharmacology of Estrogens and Gestagens 39 with the 25 µg patch, 40–80 pg/ml with every day. Therefore, the estradiol lev­ the 50 µg patch, and 90–140 pg/ml els do not correlate with the treated with the 100 µg patch. In addition, skin surface. there are matrix patches with a release rate of 37.5 µg and 75 µg per day. The Subcutaneous Administration observation that the estradiol level is higher in the evening than in the morn­ In England and in the USA, pellets of ing, possibly due to circadian fluctua­ crystalline estradiol are available for tions in the circulation of the skin, is subcutaneous implantation, which re­ interesting [8]. lease the hormone in fairly equal rates The administration of an alcohol­ over a period of several months. With a gel containing estradiol, which pellet of 100 mg estradiol, estradiol is applied to a certain area of the ab­ levels of between 150 and 250 pg/ml domen or upper arm, follows a differ­ are reached, which decrease only ent principle. The hormone penetrates slowly and are still at about 50 pg/ml very rapidly, until the gel has dried after 12 months. Therefore, an accu­ (within 2 minutes). Thereby, the horny mulation of estradiol must be expected layer acts as a store from which the after repeated implantation. There have estradiol gradually diffuses into the been reports on estrogen deficiency capillaries of the dermis and reaches syndromes that occurred between 3 the circulation. and 16 weeks after the implantation of There are two different types of such 50 or 100 mg estradiol, although the preparations. One of them contains a estradiol levels were within a range dose of 1.5 mg estradiol in 2.5 g gel from 400 to 1000 pg/ml [11]. It is pos­ (0.06% estradiol) and is always applied sible that extremely high estradiol con­ to the same area of skin. As a result, the centrations cause desensitization, so horny layer is saturated with estradiol, that even the start of a decrease in and the estradiol level correlates with estradiol level may lead to the recur­ the surface of the treated skin. Conse­ rence of hot flushes. quently, an increase in estradiol level is observed during the first four or five Intramuscular Administration days, until the steady state is reached. When 1.5 mg estradiol is applied to The intramuscular of an 400 cm² skin surface daily, serum lev­ estradiol ester produces a microcrystal­ els of 70 to 90 pg/ml are reached [9]. line primary deposit at the injection site The other preparation contains 0.1% or a secondary deposit in the fatty tis­ estradiol hemi-hydrate (crystal water), sue, from which the ester is released and it is applied to different areas of gradually and broken down into skin. After application of 1.5 g gel with estradiol in the liver. The deposit effect 1.5 mg estradiol, the estradiol level in­ is all the more marked, the more lipo­ creases to a peak value of about 30 pg/ philic the contained is. After ml within 6 hours [10]. After repeated the injection of 4 mg estradiol valerate, daily administration, a steady state with a maximum estradiol level of about a maximum estradiol level of 80 pg/ml 400 pg/ml is reached within two days, is reached after 4 hours. Here, too, the which decreases again gradually and horny layer serves as a store, but the reaches a level of about 150 pg/ml after skin is not saturated with estradiol 10 days. If, on the other hand, the more since the area of application is changed lipophilic estradiol cipionate (estradiol 40 Pharmacology of Estrogens and Gestagens cyclopentyl propionate) is used, the can even be avoided with a vaginal peak estradiol level of 340 pg/ml is ring that contains 2 mg estradiol in its lower, but the increase and decrease hollow core and releases only 7.4 µg last much longer than after an injection estradiol per day. The ring lasts for an with estradiol valerate [12]. application period of 85 days [16].

Vaginal Administration Intranasal Administration

After the vaginal administration of Intranasal administration of estradiol 0.5 mg estradiol, the good absorption with the help of an aqueous spray con­ and fairly low metabolization rate lead taining estradiol – conjugated with to estradiol levels of about 900 mg, i.e. methylated β-cyclodextrin – results in a 10 to 20 times as high as after oral significantly raised estradiol level for a administration, but which drop again short time within 10–30 minutes due to rapidly. With regard to the serum con­ rapid absorption in the strongly vascu­ centrations of estrone, estrone sulfate larized nasal mucosa, followed by an and estradiol sulfate, however, there equally rapid decrease to about 10% are no differences between vaginal and of the peak value after 2 hours [17]. oral administration [13]. Accordingly, With a daily dose of 300 µg estradiol, topical administration of estrogen at a which is adequately effective in 80% sufficient dose is not only a strong local of women, a peak serum estradiol level therapy but also a systemic therapy of 1150 pg/ml is reached, that drops to with much higher effectiveness than 150 pg/ml again within 2 hours. The that of oral administration of the same therapeutic effectiveness of this method dose. When a is used, is proof that even large daily fluctua­ which contains 4% estradiol in a tions in estradiol level do not necessar­ matrix of silicon elastomer, a gradual ily have to exert unfavorable effects, release of 100–200 µg per day is and that an even distribution of the achieved, resulting in systemic estra­ estradiol concentration does not have diol levels of between 60 and 150 pg/ any particular benefits. ml. At a release rate of 140 µg per day, an estradiol level of 85 pg/ml is Sublingual Administration reached [13]. Limitation to a purely topical effect Due to the rapid absorption and low on the vaginal is only possi­ metabolization rate, very high bolus­ ble if the applied estradiol dose is very like estradiol levels are observed after low. After vaginal application of 25 µg sublingual administration of estradiol. tablets, there is a slight rise in estradiol A maximum estradiol level of about level to 50 pg/ml on the first day only, 300 pg/ml and an estrone level of 60 but after 14 days of treatment a sys­ pg/ml is reached within one hour of temic effect is no longer to be expected sublingual administration of a [14]. This is presumably due to the fact containing 0.25 mg micronized estra­ that at the beginning of local therapy diol. This is followed by a rapid de­ the atrophic has vir­ crease in estrogen level. After sublin­ tually no metabolic capacity, but with gual administration of 1 mg estradiol, increasing proliferation and normaliza­ an estradiol peak of 450 pg/ml is tion it inactivates a large part of the reached [18]. absorbed estradiol [15]. Systemic effects Pharmacology of Estrogens and Gestagens 41

Within 5 hours of administration of CONJUGATED ESTROGENS 2.5 mg estrone sulfate, the estrone level increases to about 250 pg/ml, and with continued daily administration it The and increases to over 400 pg/ml (Fig. 3). esters of the estrogens, which are water­ The estrone sulfate concentration is 30 soluble and circulating in high concen­ to 40 times as high as the estrone con­ trations – especially the –, are centration [4]. The estradiol serum generally referred to as conjugated level increases only slowly on the first estrogens or estrogen conjugates. They day of treatment, reaching a value of are particularly important for the meta­ about 50 pg/ml after 12 hours. In the bolism and elimination of endogenous further course of treatment, an increase . It is less well known that steroid in estradiol to an average of 100 pg/ml conjugates occupy numerous can be observed [4]. Part of the estrone systems directly, i.e. without prior sulfate is converted directly into , as a substrate, and can thus estradiol sulfate, which reaches serum influence the steroid synthesis. However, levels that are 3 to 4 times as high as since they only have a mild affinity to those of estradiol [4, 20]. About 3 the receptor, they do not have any hours after the administration of 10 hormonal effect until after being split mg conjugated equine estrogens, a into the free steroid. maximum equilin serum level of about The conjugated estrogens that are 530 pg/ml and a maximum estrone used for substitution therapy are the level of 1400 pg/ml is observed [21]. sulfates of various estrogens that are It may be assumed that daily adminis­ available as . In the USA, tration of equilin and equilin sulfate the sodium may be replaced by pipera­ will also result in an accumulation in zine, a strong organic base. The most the serum. important conjugates used in therapy The conjugated estrogens do not are estrone sulfate and equilin sulfate have a hormonal effect until after (Fig. 1). Equine conjugated estrogens hydrolysis of the sulfuric acid and con­ are a mixture of 9 different conjugates, version into the active substances. whereby the total dose consists of Thereby, hydrolysis of the sulfates about 50% estrone sulfate, 25% equi­ takes place not only in the liver, which lin sulfate, and 15% 17α-dihydro- they pass through largely without equilin sulfate (Table 3). Mainly the modification, but also in the peripheral estradiol produced from the estrone [20]. As with the conversion of sulfate and the 17β-dihydroequilin estrone into 17β-estradiol, the forma­ produced from the equilin sulfate are tion of 17β-dihydroequilin and 17β- responsible for the estrogen effect. dihydroequilenin from equilin and 17α-dihydroequilin, on the other hand, equilenin is an important factor for has hardly any hormonal effect, their effectiveness (Fig. 1). Due to the although it is bound by the estrogen fairly strong binding to albumin, the receptor with a fairly high affinity half-life of equilin sulfate in the (Table 1) [19]. is considerably longer than that of After administration of the conju­ equilin [2]. However, both equilin and gated estrogens, a large part of the equilin sulfate are eliminated much estrone sulfate and the other conju­ faster than estrone and estradiol or gates is absorbed without modification. estrone sulfate [23]. 42 Pharmacology of Estrogens and Gestagens

Table 3. Composition of conjugated estrogens, extend the retention of estriol in the and relative estrogen effectiveness and relative target cell and interaction with the binding affinity to the estrogen receptor (RBA) receptor, proliferation of the endo­ of the individual components [3, 19, 22]. The substances are contained in the preparation as metrium in the long term cannot be the sodium salt of the relevant sulfuric acid excluded. The same holds true for very conjugate (sulfate). The relative effectiveness is high estriol doses or for dividing the with reference to growth of the rat [19, daily dose into two or three applica­ 22]. tions. Therefore, the entire estriol dose should be taken at one time, preferably Substance Share Relative Relative in the evening. (%) effective­ binding ness (%) affinity (%) Oral (estriol-16,17- dihemisuccinate) is absorbed almost Total preparation 100 100 32 Estrone 49.1 32 41 without modification and much more Equilin 22.8 80 40 slowly than estriol, since the intestinal Dihydroequilin 13.5 2.6 6 8,9-dehydro estrone 3.9 mucosa hardly hydrolyses the ester. In Estradiol-17α 3.7 3.5 32 the liver, however, the substance is Equilenin 2.8 11.4 7 Dihydroequilenin-17α 1.6 1.3 18 splitted much faster and then metabo­ Dihydroequilin-17β 1.5 200 47 lized further [25]. After the first admin­ Dihydroequilenin-17β 0.7 9.4 46 Estradiol-17β 0.5 246.2 100 istration of 8 mg, the estriol level reaches a maximum of 40 pg/ml only after 12 hours, but with daily admini­ stration it rises to 80 pg/ml within 5 days [26]. ESTRIOL

10 mg estriol oral Oral Administration

Following oral administration, most of the estriol is metabolized rapidly within the intestinal tract, so that only 1–2% of the dose reaches the circula­ tion without modification [2]. Within 1 to 4 hours of administration of 4 mg, a peak serum level of 35 pg/ml is reached, followed by a fairly rapid 0.5 mg estriol vaginal decrease. The greater part of the ad­ ministered estriol circulates in the form of glucuronides and sulfates with con­ centrations that are 500 times as high as those of unconjugated estriol. Daily administration leads to an accumula­ tion, however, and the estriol serum levels rise up to 130 pg/ml [24]. Since estriol is subject to a marked entero­ Figure 5. Average serum concentration curve for hepatic circulation, a second peak estriol following oral administration of 10 mg serum level may be reached within one estriol (above) or vaginal administration of 0.5 mg hour after eating [2]. Since this may estriol (below). Pharmacology of Estrogens and Gestagens 43

Vaginal Administration 0.5 mg, and doubling the dose does not lead to any significant improvement. Since the strong intestinal meta­ During long-term local treatment – in bolization is bypassed, vaginal admini­ contrast to oral administration – there is stration results in estriol levels that are a continuous decrease in estriol levels, 10 to 20 times higher than after oral ad­ which are 30–50% lower than on the ministration of the same dose [2]. This first day of treatment after 4 weeks [27]. means that similar estriol levels and This is presumably due to normaliza­ similar systemic effects are achieved tion of the vaginal epithelium, which with local therapy with e.g. 0.5 mg has a metabolic activity similar to that estriol as with oral treatment with 10 of the endometrium [15]. Since in this mg estriol (Fig. 5). Following vaginal the production administration of 0.5 mg estriol, a of estriol conjugates is very low com­ maximum serum level of 100 to 160 pared with oral administration, the pg/ml is reached after 1 to 2 hours. If enterohepatic circulation of estriol the vaginal dose is doubled, the estriol does not play a role. The same applies level only increases by 10%, however. to the vaginal administration of estriol Accordingly, the maximum effect of succinate, which is hydrolyzed in the vaginal estriol therapy is achieved with liver after absorption, as for estriol.

Progesterone derivatives Nortestosterone derivatives

Progesterone 19-norestosterone

Medroxyprogesterone acetate acetate

Levonorgestrel acetate

Tibolone 7α-methyl norethisterone

Figure 6. Structural formulas of the gestagens used in HRT 44 Pharmacology of Estrogens and Gestagens

gesterone and the progesterone deriva­ STRUCTURE AND HORMONAL tives have a weak effect that may be of importance in associa­ PATTERN OF GESTAGENS tion with the cardiovascular risk. The most important effect of the gestagens The only indication for the use of a is their strong anti-estrogenic and dif­ gestagen in HRT is to reduce the ferentiating effect on the endometrium, risk of endometrial carcinoma, so that which inhibits estrogen-induced pro­ gestagen addition is not necessary for liferation. The anti-estrogenic effect can women after . Exceptions also be observed in the cervical are benign disorders, the and vaginal epithelium, whilst it tends Raynaud syndrome, (former) cycle­ to enhance the proliferative effect of related , and osteoporosis, in estrogens in the tissue. which cases the addition of gestagen With the exception of dydrogesterone, may have beneficial effects. With the gestagens have a central effect, they regard to the effect on bone, however, reduce and norethisterone is the only gestagen for raise the basal temperature. The vary­ which a significant effect has been ing hormonal pattern of the gestagens shown. In patients for whom estrogens is based on their binding ability to the are contraindicated, hot flushes can , glucocorticoid and mineral often be improved with sufficient doses corticoid receptor, whereby there are of progesterone derivatives. The gesta­ considerable differences with regard to gens also include , a nortesto­ the binding affinity and the resulting sterone derivative that is effective for effects (Table 4). climacteric complaints and suitable for the prevention of osteoporosis. Since the natural gestagen progester­ one is inactivated very rapidly by re­ PROGESTERONE duction of the carbonyl groups on C3 and C20 and the double bond between C4 and C5, synthetic gestagens have In the , progesterone reaches been developed that are metabolized serum concentrations of between 10 much more slowly and can therefore and 25 ng/ml. It is an effective aldoster­ be administered orally at fairly low one antagonist, but this effect is com­ doses. We distinguish between the pensated by an increase in progesterone derivatives and the level. Progesterone is also available in nortestosterone derivatives (Fig. 6). micronized form for oral administra­ Due to their origin, the two gestagen tion, and it is particularly suitable for types have different hormonal action high risk patients (e.g. with severe liver patterns. With the exception of disorders). With regard to its use in dienogest, the nortestosterone deriva­ women with cardiovascular disorders, tives have weak androgenic properties, however, a number of issues is still un­ but in combination with an effective answered. estrogen these are without clinical In the circulation, 17% of progester­ relevance. They also have a stronger one is bound to CBG and 80% to albu­ effect on the various hepatic para­ min. Due to the strong metabolism, the meters, some of which are considered half-life of 6 (t1/2α) and 42 (t1/2β) minutes beneficial, others less beneficial. Pro­ is very short. Therefore, in oral and Pharmacology of Estrogens and Gestagens 45 vaginal administration daily doses of Vaginal Administration 200–300 mg are required. With regard to the produced metabolites and their In vaginal treatment with progesterone, serum concentrations, there are con­ administration in the evening is recom­ siderable individual differences. The mended for practical reasons. Within 5 most important inactive metabolite of hours of vaginal administration of 400 progesterone is , which is mg, a maximum progesterone level of eliminated mainly as a conjugate. about 16 ng/ml is reached, whilst the various metabolites are produced in Oral Administration small quantities only. After administra­ tion of 45 and 90 mg gel with 4% or In oral therapy with progesterone, meta­ 8% progesterone, the natural gestagen bolites with a sedative effect may be is released quite evenly and with delay, produced. Therefore, administration in so that administration twice a week is the evening is recommended. Follow­ sufficient. Thereby, it seems to be a direct ing the administration of 200 mg, a connection between vaginal tissue and maximum progesterone level of 10–20 endometrium (uterine first-pass effect). ng/ml is reached after 3–4 hours. In some women the sedative, ring A-re­ duced metabolites 5α- and 5β-pregna- nolone may reach serum concentrations PROGESTERONE DERIVATIVES of 35 and 20 ng/ml [28]. Other major metabolites are 20α-dihydroprogester- one, which accounts 25–50% of the In the progesterone derivatives, the gestagen effect of progesterone, and steroid frame has been modified by 11-deoxycorticosterone (DOC), which introducing a methyl or chlorio substi­ is a strong mineral corticoid that can tute at C6 and a methyl or acetyl group partly compensate the anti-aldosterone at C17α, so that the reduction reactions effect of progesterone. Due to the are strongly inhibited and the effective­ considerable inter-individual variations, ness is thus enhanced considerably. only a part of the patients are affected The progesterone derivatives are usu­ by these side effects. ally administered orally, but depot

Table 4. Relative binding affinities of gestagens to the steroid receptors. The values are compiled from literature, are not consistent and correlate only in part with the biological effects. PR = ( = 100), AR = ( = 100), ER = estrogen receptor (estradiol = 100), GR = ( = 100), MR = mineral corticoid receptor (aldosterone = 100).

Gestagen PR AR ER GR MR Progesterone 50 0 0 10 100 acetate 115 5 0 29 160 Chloromadinone acetate 67 3 0 8 0 90 6 0 6 8 Medrogestone Dydrogesterone 75 Dienogest 5 10 0 1 0 Norethisterone 75 15 0 0 0 150 45 0 2 70 ∆ 4-tibolone 90 35 1 2 46 Pharmacology of Estrogens and Gestagens preparations with medroxyprogester­ reactions. 3β-hydroxychlormadinone one acetate or hydroxyprogesterone acetate has 70% of the anti-androgenic caproate for effect of . are also available. The progesterone derivatives are less suitable for trans­ Cyproterone Acetate dermal therapy. When administered orally at a dose of Medroxyprogesterone Acetate 1 to 2 mg, cyproterone acetate has a of almost 100%. It has Medroxyprogesterone acetate is ad­ fairly strong anti-androgenic and mild ministered orally at doses of 5 or 10 mg glucocorticoid effects. For the treat­ daily, or as microcrystalline depot ment of androgenic symptoms, higher preparation (injection of 150 mg every dosages are often necessary. Following three months). The gestagen has weak the administration of 2 mg, the cypro­ androgenic properties and low gluco­ terone acetate serum concentration corticoid effects. The bioavailability is increases to about 11 ng/ml, whereby 100%, and a maximum medroxy­ 93% are bound to albumin. It is stored progesterone acetate serum level of in the fatty tissue and eliminated very 4–5 ng/ml is reached 1–2 hours after slowly, with a half-life of 2–8 (t1/2α) and administration of a dose of 5 mg [5]. In 60 (t1/2β) hours. Daily administration of the serum, it is bound only to albumin. higher doses may therefore lead to The half-life is 2.2 (t1/2α) and 33 (t1/2β) accumulation and a depot effect. The hours. The most important inactivation most important metabolic steps are steps are reactions on hydroxylation reactions and de-acetyli­ C6β and C21. zation, whilst the C4 double bond is maintained. Of the metabolites, 15β- Chlormadinone Acetate hydroxycyproterone acetate has a simi­ lar anti-androgenic effectiveness, but At a dosage of 1 or 2 mg, chlorma­ only 10% of the gestagen effect of dinone acetate has a bioavailability of cyproterone acetate. almost 100%. A maximum chlor­ madinone acetate serum level of about Medrogestone 4 ng/ml is reached between 1 and 2 hours after administration of 4 mg. In Medrogestone differs from the other the serum, it binds only to albumin, with progesterone derivatives in that it has a weak affinity. Chlormadinone acetate methyl group instead of an acetyl has mild anti-androgenic properties group at C17α. The bioavailability is that correspond to about 30% with about 100%, and following the admini­ those of cyproterone acetate. In view of stration of 10 mg medrogestone serum­ the fairly low concentrations and low concentrations of 10–15 ng/ml are binding affinity, however, the clinical reached. The half-life is 4 (t1/2α) and 36 relevance is doubtful. The substance is (t1/2β) hours. In the serum, it is bound stored in the fatty tissue and eliminated mainly to albumin. The most important very slowly, with a half-life of 2.4 (t1/2α) metabolic steps are hydroxylation reac­ and 89 (t1/2β) hours. The most important tions. Data on its binding to the various inactivation steps are reduction of the steroid receptors are not available, 3-oxo group, whereby the double therefore possible side effects cannot bond is maintained, and hydroxylation be estimated (Table 4). Pharmacology of Estrogens and Gestagens 47

Dydrogesterone intestinal tract and in the liver soon after administration, the pharmacokinetics Dydrogesterone is a so-called retro­ and of the two sub­ progesterone where rings A and B do stances are quite similar. Norethisterone not lie on the same plane as rings C and does not have any glucocorticoid or D, and the steric configuration differs anti- effects, and the from that of the other steroids. This is mild androgenic properties are not presumably the reason why there are effective at a dose of 0.5 mg or 1 mg, if virtually no central effects, i.e. no go­ the substance is combined with an nadotropin-inhibiting, thermo-genetic estrogen. When administered orally, the and sedating properties. Due to the bioavailability is between 50 and 77%. unusual steric structure, the 3-carbonyl Following the administration of 1 mg, group and the C4 double bond are not norethisterone levels of 5–10 ng/ml are reduced. Even so, the half-life is short, measured. In the serum, 36% of the so that doses of 10–20 mg are required. norethisterone binds to SHBG and 61% The most important metabolization to albumin. The half-life is 2.5 (t1/2α) and steps are reduction of the 20-carbonyl 8 (t1/2β) hours. The most important meta­ group and hydroxylation reactions. bolic step is reduction of the 3-oxo Apart from the binding affinity to the group and the double bond in ring A. A progesterone receptor, no data are small part of the norethisterone (0.35%) available on the binding to other is aromatized in the fatty tissue, but the steroid receptors (Table 4). ethinyl estradiol levels produced after administration of 1 mg norethisterone are usually close to or below the detec­ tion limit and – in the presence of high NORTESTOSTERONE DERIVATIVES estradiol levels – without clinical relevance [29]. At higher dosages, e.g. 5 mg or 10 mg, ethinyl estradiol con­ The mild androgenic properties of the centrations similar to those after ad­ nortestosterone derivatives, which are ministration of inhibitors can derived from 19-nortestosterone (nan­ be found [30]. drolone), are normally without clinical After transdermal administration of significance, since the gestagens are 0.25 mg norethisterone acetate, the applied at a fairly low dosage and in norethisterone concentration increases combination with estrogens. As with to 0.5–1 ng/ml within 2 days, and then the anabolic agent , reduc­ decreases to about half this level when tion of the C4 double bond decreases the next change of patch is due (every rather than enhancing the androgenic 3.5 days). effect – as is seen with dihydrotesto­ sterone. A patch with norethisterone Levonorgestrel and DL- acetate is available for transdermal substitution. DL-norgestrel is a racemate and con­ sists of equal parts of the strong gesta­ Norethisterone and gen levonorgestrel and the hormonally Norethisterone Acetate ineffective dextronorgestrel. Therefore, only 0.25 mg levonorgestrel are effec­ Since norethisterone acetate is hydro­ tive when 0.5 mg DL-norgestrel are lized to norethisterone in the gastro­ administered. Because of the mild 48 Pharmacology of Estrogens and Gestagens androgenic properties, levonorgestrel group. Dienogest is also aromatized to should be administered at the lowest a very minor extent. possible dose. The bioavailability is almost 100%. Following the adminis­ Tibolone tration of 0.125 mg levonorgestrel, a levonorgestrel level of about 3.5 ng/ml Tibolone is the 7α-methyl derivative of is reached. In the serum, 48% of the the old gestagen norethynodrel and, like levonorgestrel is bound to SHBG and this substance, a . Whilst nor­ 50% to albumin. The half-life is 1 (t1/2α) ethynodrel is converted into norethis­ and 24 (t1/2β) hours. The most important terone after administration, tibolone is metabolic step is reduction of the converted into 7α-methyl norethis­ 3-oxo group and of the C4 double terone (Fig. 6). Like norethynodrel, bond. tibolone has a mild androgenic and When an con­ marked estrogenic effect. The estrogenic taining levonorgestrel is administered, effects are thought by the manufacturer 20 µg levonorgestrel are released daily. to be due to the metabolites 3α- and 3β- High local concentrations of gestagen hydroxy tibolone, which have a low in the endometrium occur, which binding affinity to the estrogen cause of the endometrium receptor. Since the serum levels of the even during estrogen treatment. Since two metabolites are unknown and it the levonorgestrel serum levels remain must be assumed that they are largely very low at 0.1–0.2 ng/ml, systemic present as ineffective conjugates, their effects are hardly noticeable. clinical significance is doubtful. Since both norethynodrel and norethisterone Dienogest are aromatized to a minor degree, it cannot be excluded that tibolone and Dienogest differs from the other nor­ the resulting 7α-methyl norethisterone derivatives in that it has a are also converted into an effective cyanomethyl group at C17α instead of estrogen. Tibolone has no glucocorti­ an ethinyl group (Fig. 6). It has an anti­ coid or anti-mineralocorticoid effects, androgenic effect rather than an andro­ and no or very little proliferative effect genic effect, equivalent to about 40% on the endometrium. Following the ad­ of the effect of cyproterone acetate. In ministration of 2.5 mg, the unmodified the serum, it does not bind to SHBG or tibolone reaches a maximum serum CBG; 90% are bound to albumin. Even level of about 1 ng/ml. In the serum, so, the dienogest serum levels follow­ tibolone and its metabolites are bound ing administration of 2 mg reach very mainly to albumin only. The terminal high values of about 50 ng/ml, which half-life (t1/2β) is 45 hours. Inactivation is decrease again with a fairly short half­ caused primarily by hydroxylation re­ α life of 9 hours (t1/2β). The most impor­ actions. Although the 7 -methyl group tant metabolic steps are reduction of blocks reduction of the double bond on the 3-oxo group, hydroxylation reac­ C4, it does not block – as tions, and conversion of the cyano was shown in the example of 7α-methyl group into a hydroxy or carbonic acid nortestosterone [31]. Pharmacology of Estrogens and Gestagens 49

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