Progestogen therapies: differences in clinical effects?

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Progestogen therapies: differences in clinical effects? Inka Wiegratz and Herbert Kuhl Department of Obstetrics and Gynecology, J. W. Goethe University Frankfurt, Frankfurt am Main, Germany

A large number of estrogen/progestogen preparations are available for the treatment of estrogen-deficiency symptoms. These preparations differ in the route of administration, the type and dose of both the estrogen and progestogen. The only indication for the addition of a progestogen is endometrial protection, but, depending on its chemical structure, a progestogen can either enhance (e.g. hot flushes, gonadotropin release, breastepithelial proliferation and bone mineral density) or antagonize (e.g. endometrium, arterial wall, lipid metabolism, hepatic protein synthesis and mood) the effects of the estrogen component. Available progestogens differ largely in their hormonal pattern and, in addition to their progestogenic and antiestrogenic action on the endometrium, they can exert androgenic, antiandrogenic, glucocorticoid and/or antimineralocorticoid effects. There are no comprehensive trials comparing directly the modulating effects of the various progestogens, and clinical and epidemiological data do not allow a definite conclusion on the clinical relevance of differences between progestogens. Estrogen-replacement therapy is an effective tool to treat climacteric symptoms and prevent postmenopausal osteoporosis. The regular addition of a progestogen is mandatory to protect the endometrium against the development of estrogen-induced hyperplasia. The generalization of the results of randomized studies on the increase in the risk of breast cancer and cardiovascular disease during the continuous use of a combination of conjugated equine estrogens and medroxyprogesterone acetate (CEE/MPA) (see Glossary) has led to controversial debates about whether this is a class effect or a compoundspecific phenomenon. There are many estrogen/synthetic progestogen (progestin) formulations, which can be administered orally, transdermally, subcutaneously, intramuscularily, vaginally and intranasally. Because of the pharmacokinetic differences associated with the route of administration, the effects on surrogate parameters (e.g. hepatic factors), clinical symptoms and health risks might vary. Moreover, several estrogens are available (estradiol, estradiol esters, CEEs, estrogen conjugates and estriol), which differ in their interaction with the estrogen receptor a (ERa) and ERb, their tissue-specific effects and hormonal potency [1–4]. Corresponding author: Herbert Kuhl ([email protected]). Available online 4 July 2004

Therefore, the assessment of agonist and antagonist effects of a progestogen must take into account these variations, but systematic, comparative trials are lacking. The issue is complicated profoundly because available progestogens differ in their chemical structure, hormonal potency and hormonal pattern. Some compounds are prodrugs that are converted after administration to hormonally active metabolites, and some are metabolites of active progestogens which are hormonally active [5]. Whether the variations in tissue-specific actions of progestogens are clinically relevant remains a challenge for future clinical and epidemiological research.

Differences in the hormonal pattern of progestogens Progestogens are defined as compounds that cause a secretory transformation of an estrogen-primed endometrium and inhibit further proliferation. Only progesterone, not synthetic progestins, can maintain human pregnancy. The progestogenic effect is dependent on the existence of a keto group at C3 and a double bond between C4 and C5 of the steroid molecule. ‘Progestins’ without this structure are prodrugs that are converted rapidly to active hormones after oral administration (Figure 1). Progestins can exert many other effects, which differ according to the chemical structure. Because of a structural relationship between progesterone, androgen, glucocorticoid and mineralocorticoid receptors, some progestins can bind to one or more of these transcriptional Glossary CEE: conjugated equine estrogens CEE/MPA: 0.625 mg CEE plus 2.5 mg MPA CHD: coronary heart disease CPA: cyproterone acetate CVD: cardiovascular disease DG: desogestrel DNG: dienogest DSR: drospirenone EE: ethinylestradiol GSD: gestodene HER: Heart and Estrogen/Progestin Replacement HRT: hormone replacement therapy LNG: levonorgestrel MPA: medroxyprogesterone acetate NET: norethisterone NETA: norethisterone acetate NYD: norethynodrel Aromatase cytochrome P450: a transcript of the CYP19 gene RR: relative risk TIB: tibolone T-R: thrombin receptor WHI: Women’s Health Initiative

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19-Nortestosterone derivatives

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Progesterone derivatives and 19-Norpregnane derivatives CH3

OH

OH

OH CH2

CH2 CN

CH3

CH3

C O

O

C

O

C

O

CH

C C5H11 O

O

O

O

19-Nortestosterone

O

Dienogest

O

Levonorgestrel O

OH

O

OH C

C

CH

CH

O

Progesterone

Hydroxyprogesterone caproate

CH3

C

CH3

C

C O O

CH

Dydrogesterone

CH3

C2H5

C O

C

CH3

C C5H11

O CH3

O O

O

O

O

HO N

Norethynodrel

Norgestimate

O CH3

Cl

Norethisteron

Chlormadinone acetate

Medrogestone

Promegestone OH

CH3

O O

C

CH3

C

CH

OH

H2C

H2C C

OH C

CH

O

CH2

CH

HC CH3

CH3

C O

C

C O

C CH3

C C5H11

O

O

O CH3

O O O

O

Norethisteron acetate

Desogestrel

OH

C C

C

OH C

O

C O C CH3

O

Trimegestone CH3 C O

C CH3

O

O CH3

Nomegestrol acetate

Megestrol acetate

CH3 C

O C

CH

CH

C

CH3 O

C

CH3

O

O O C CH3 CH2

O

O

Gestodene

CH3

Tibolone (7a-Methyl-norethynodrel)

O

O

Drospirenone

C CH3 O

CH3

Medroxyprogesterone acetate

OH

OH

O

O

CH3

Norelgestromine (Levonorgestrel-oxime

Ethynodiol diacetate

CH3

C O

O

HO N

O

Lynestrenol

CH

Gestonorone caproate

CH3 O

CH

CH

H3C C O

O

CH3

O

Cyproterone acetate

O O

O

Cl

Etonogestrel (3-Keto-desogestrel)

O

O

Demegestone

Nesterone TRENDS in Endocrinology & Metabolism

Figure 1. Structural formula of progestogens. Except for drospirenone, the compounds are derivatives of either 19-nortestosterone or progesterone and 19-norpregnane (19-nor indicates that the C19-methyl group is lacking). The changes in the steroid molecules of 19-nortestosterone or progesterone slow the rate of inactivation and the compounds, except nestorone, can be used orally at relatively low doses. The changes also alter the hormonal pattern of the compounds because they modulate the affinities of binding to the androgen, glucocorticoid and mineralocorticoid receptors. The structural prerequisite for a progestogenic activity is the D4–3-keto group (keto group at C3 and a double bond between C4 and C5). Compounds without this structure (such as desogestrel and tibolone) are prodrugs that become hormonally active after metabolic conversion.

regulators with either agonistic or antagonistic effects (Table 1 and Table 2) [5–16]. Irrespective of the existence of receptor isomers and nongenomic interactions with membrane receptors, the binding affinities of the respective cytosolic and nuclear steroid receptors (Table 2) do not reflect the biological efficacy, because the results of binding experiments in vitro depend largely on the incubation conditions and the biological material used. Moreover, binding to a distinct receptor might be associated with agonist, antagonist or no hormonal activity. Although the hormonal activity of a compound depends on binding to the receptor and compounds that lack binding affinity do not interact with a receptor, hormonal activity is also dependent on the local concentration of the steroid. The only natural progestogen is progesterone, which is rapidly inactivated after oral administration. Therefore, progestins with an enhanced hormonal potency have been developed. Progestins are derived chemically from 19-nortestosterone, progesterone, 19-norpregnane and spirolactone (Figure 1). The term 19-nor indicates that the C19-methyl group between rings A and B is lacking. www.sciencedirect.com

MPA and 19-nortestosterone derivatives, except dienogest (DNG), exert some androgenic actions, whereas some progesterone derivatives and 19-norpregnane derivatives, as well as DNG and the spirolactone derivitive drospirenone (DSR), have antiandrogenic properties (Table 1). The weak glucocorticoid activity of some progestogens might be relevant clinically in the vessel wall. Progestogens do not bind to estrogen receptors and, therefore, have no estrogenic effects. The weak estrogenic effect of norethisterone (NET) and its prodrugs lynestrenol, ethynodiol diacetate and norethynodrel (NYD) is caused by the rapid aromatization of a small proportion of the dose in the liver yielding ethinylestradiol (EE) [17,18]. The prodrug tibolone (TIB, 7a-methyl-NYD) is transformed rapidly to the progestin 7a-methyl-NET (D4-TIB), whereas a small proportion of the dose is aromatized to the potent estrogen 7a-methyl-EE [19]. The latter findings have been called into question by experiments in vitro in which human recombinant aromatase aromatized neither TIB nor NET [20]. By contrast, both NET and TIB were aromatized after oral administration to women [18,19], and NET was aromatized during incubation with primary

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Table 1. Spectrum of hormonal activities of progestogensa Progestogen Progesterone Chlormadinone acetate Cyproterone acetate Medroxyprogesterone acetate Medrogestone Dydrogesterone Norethisterone Levonorgestrel Gestodene Etonogestrel (3-keto-desogestrel) Norgestimate Dienogest Tibolone metabolites Drospirenone Trimegestone Promegestone Nomegestrol acetate

AEb C C C C C C C C C C C C C C C C C

c

EST

AND

AA

GLU

AM

K K K K K K C K K K K K C K K K K

K K K (C) K K C C C C C K CC K K K K

(C) C C K K K K K K K K C K C (C) K C

C C C C ? ? K K (C) (C) ? K K ? K C K

C K K K K (C) K K C K ? K K C (C) K K

a

Data are based mainly on animal experiments [1,5–9,13,15–17]. The clinical effects of the progestogens are dependent on their tissue concentrations. Abbreviations: AE, antiestrogenic; EST, estrogenic; AND, androgenic; AA, antiandrogenic: GLU, glucocorticoid; AM, antimineralocorticoid activity. CC, strongly effective; C, effective; (C) weakly effective; K, ineffective; ?, unknown.

b c

hepatocytes and homogenates of healthy human adult liver (Table 3) [21,22]. Because NET does not inhibit human recombinant aromatase [20] but does inhibit irreversibly the aromatization of androstenedione by microsomes from human placenta [23], it might be assumed that cytochrome P450 enzymes other than AROMATASE CYTOCHROME P450 are involved in the aromatization of nortestosterone derivatives. The use of high doses of progestogens with weak glucocorticoid activity could alter pituitary–adrenal function and decrease insulin sensitivity. Treating cancer patients with 400 mg MPA daily leads to the development of Cushingoid symptoms, whereas therapy of hirsutism with 100 mg cyproterone acetate (CPA) daily for six months reduces cortisol secretion [24,25]. In vitro and animal experiments demonstrated glucocorticoid activity of MPA at low doses in the arterial wall, resulting in an upregulation of the thrombin receptor and an increase in thrombin-induced production of tissue-factor and procoagulatory activity [16]. Progesterone

and DSR have marked, and gestodene (GSD) weak, antimineralocorticoid activity, which is compensated for by an increase in the serum aldosterone level [26]. Effect on the endometrium There are large interindividual variations in the endometrial response to progestins. In postmenopausal women treated with CEE, either 5 mg or 10 mg MPA daily for 12 days per cycle causes a full secretory transformation in only 65% and 72%, of patients, respectively [27]. By contrast, the effective dose of norethisterone acetate (NETA) is 0.5 mg daily, or less, and in women treated transdermally with 50 mg estradiol, the sequential addition of 0.5–1.0 mg NETA for 12 days per cycle prevents endometrial hyperplasia [28]. However, the purpose of combining estrogen therapy with a progestin is not the secretory transformation of a proliferated endometrium, but the prevention of hyperplasia.

Table 2. Relative binding affinities of steroid receptors and serum binding globulinsa Progestogen

PRb

AR

ER

GR

MR

Progesterone Chlormadinone acetate Cyproterone acetate Medroxyprogesterone acetate Dydrogesterone Norethisterone Levonorgestrel Gestodene Etonogestrel (3-keto-desogestrel) Norgestimate Dienogest D-4-Tibolone (7a-methyl-norethisterone) Drospirenone Trimegestone Promegestone Nomegestrol acetate

50 67 90 115 75 75 150 90 150 15 5 90 35 330 100 125

0 5 6 5

0 0 0 0

10 8 6 29

100 0 8 160

0 0 0 0

36 0 0 0

15 45 85 20 0 10 35 65 1 0 6

0 0 0 0 0 0 1 0 0 0 0

0 1 27 14 1 1 0 6 9 5 6

0 75 290 0 0 0 2 230 120 53 0

16 50 40 15 0 0 1 0

0 0 0 0 0 0 0 0

0 0

0 0

a

SHBG

CBG

Values compiled by cross-comparison of the literature [1,5,10–12,14]. Because the results of the various in vitro experiments depend largely on the incubation conditions and biological materials used, the published values are inconsistent. They do not reflect the biological effectiveness. Abbreviations: AR, androgen receptor (metribolone R1881, 100%); CBG, corticoid-binding globulin (cortisol, 100%); ER, estrogen receptor (estradiol-17b, 100%); GR, glucocorticoid receptor (dexamethasone, 100%); MR, mineralocorticoid receptor (aldosterone, 100%); PR, progesterone receptor (promegestone, 100%); SHBG, sex hormone-binding globulin (dihydrotestosterone, 100%).

b

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Table 3. Aromatization of norethisterone to ethinylestradiol by adult human liver tissuea Liver tissue

Formation of EE (fmol.100 mg proteinK1)

Male, 48 years, cirrhosis Male, 54 years, cancer Male, 54 years, healthy Female, 48 years, cancer Female, 40 years, cirrhosis Female, 69 years, cirrhosis Female, 48 years, cancer Male, 38 years, healthy Male, 51 years, healthy

157 24 169 54 1121 699 414 302 604

a 3

[H]-labeled norethisterone was incubated with homogenates of healthy, cirrhotic and cancerous liver for 2 h at 37 8C. After extraction and isolation by column chromatography and thin-layer chromatography, 3[H]-labeled ethinylestradiol (EE) that originated from norethisterone was cocristallized with ethinylestradiol to constant radioactivity, which was measured. (ethinylestradiol: 100 fmolZ30 pg). Data from Yamamoto et al. (1986) [21].

Treatment of postmenopausal women with estrogens that are unopposed by a progestin increases the rate of endometrial hyperplasia, dose and time-dependently [29]. Therefore, the regular addition of a progestin is mandatory to reduce the risk. However, because the effect depends primarily on the duration of treatment, at least 12 days per cycle are necessary to achieve sufficient protection [30]. Because the composition of a hormonereplacement therapy (HRT) preparation is chosen according to the requirement that the incidence of endometrial hyperplasia is !2% within 1–2 years of treatment, it is nearly impossible to find differences between progestins with regard to their protective effectiveness (Table 1). The appropriate doses that are used for either sequential or continuous combined therapy differ in the estrogen dose, the route of administration, the potency of the respective progestin and the duration of the progestin addition. Moreover, the dose is also chosen with respect to the cycle control or rate of irregular bleeding [31,32]. In continuous combined preparations, a lower dose of progestin (e.g. MPA and dydrogesterone) might be sufficient for endometrial protection compared with sequential formulations. The available epidemiological data on the risk of endometrial cancer are not conclusive because a high proportion of patients have been treated sequentially with progestins for !12 days per cycle [33]. However, the

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results indicate that long-term, continuous, combined use of estrogen/progestin preparations reduces the risk of endometrial cancer. Nortestosterone derivatives seem to be more effective than progesterone derivatives with regard to endometrial protection, but this remains to be proved [34,35]. Effect on the breast It is now generally accepted that treating postmenopausal women with HRT for R5 years increases the relative risk (RR) of breast cancer by w35%. However, the RR returns to baseline within 5 years of discontinuing therapy [36]. In this large reanalysis, no significant influence of the progestin components was discernible owing to insufficient data. In both Heart and Estrogen/Progestin Replacement (HER) and Women’s Health Initiative (WHI) studies, continuous combined therapy for w5 years with CEE/MPA was associated with an increased RR of invasive breast cancer of 24–27% [37–39]. This risk elevation concerned exclusively women who were pretreated with hormones before the start of the study. Because this seemed to be associated with a considerably lower rate of breast cancer in the placebo group, a selection bias cannot be excluded [39]. A decreased rather than an increased breast cancer risk was observed in the WHI study arm with CEE only [37]. Several case-control studies and reviews confirm the suggestion that the additional progestin plays a major role in the development of breast cancer (Table 4) [40–49]. The studies do not distinguish between different brands. One Swedish study has reported a higher risk for users of estrogens combined with nortestosterone derivatives than with progesterone derivatives. However, this was not significant and was lower than that in users of estrogenonly preparations [50]. In the Million Women Study, the risk increase with estrogen/progestin combinations was observed during the first year of use, which contradicts the results of the Collaborative reanalysis and randomized prospective studies [36–38]. There was no significant difference between different preparations, and the elevation in breast cancer risk by TIB was in the same range (Table 5) [51]. Concerning the various regimens of HRT (i.e. sequential or continuous treatment, oral or transdermal route, and the dose of progestins), no clearcut conclusions can be drawn because of inconsistent results and insufficient data [52].

Table 4. Relative risk of breast cancer in postmenopausal women treated with estrogens only or estrogen/progestin preparationsa

a

Year

Groupb

Estrogen RR (95% CI)

Estrogen/progestin: RR (95% CI)

Refs

1999 2000 2000 2000 2002 2002 2002 2002 2002 2002 2002 2003

Ever Current Per 5 years; ever 10 years, ever Current 5.2 years; current 6.8 years; current R10 years; ever R5 years; current R5 years; current R5 years; ever; lobular cancer Ever

1.94 (1.47–2.55) 1.10 (1.00–1.30) 1.06 (0.97–1.15) 1.23 (1.06–1.42) 1.17 (0.85–1.60) no effect

1.63 1.40 1.24 1.67 1.49 1.26 1.27 3.48 1.76 1.37 2.00 1.80

[50] [40] [41] [43] [44] [31] [38] [45] [46] [47] [48] [49]

1.74 0.99 0.81 1.30 1.00

(0.93–3.24) (0.65–1.53) (0.63–1.04) (0.8–2.2) (0.6–1.4)

Abbreviations: CI, confidence interval; E, estrogen only; E/P, estrogen and progestin; RR, relative risk. Ever, ever users of E or E/P; current, current users of E or E/P at the time of diagnosis.

b

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(1.37–1.94) (1.10–1.90) (1.07–1.45) (1.18–2.36) (1.04–2.12) (1.00–1.59) (0.84–1.94) (1.00–12.11) (1.29–2.39) (1.06–1.77) (1.3–3.2) (1.3–2.5)

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Table 5. ’Million Women Study’: Effect on breast-cancer risk of treatment of postmenopausal women with estrogens only, tibolone and different estrogen/progestin combinationsa

a

Hormone preparation

Relative risk

95% Confidence interval

Estrogens only Tibolone EstrogenCnorethisterone EstrogenCmedroxyprogesterone acetate EstrogenCnorgestrel/levonorgestrel

1.30 1.45 1.53 1.60 1.97

1.22–1.38 1.25–1.67 1.35–1.75 1.33–1.93 1.74–2.33

Data from [51].

From the reduced risk of breast cancer in anovulatory women and the elevated risk in women with early menarche and late menopause, it can be deduced that natural sex steroids play an etiological role that is similar to that of synthetic estrogens and progestins [36,53,54]. These findings, as well as the increase in the RR of breast cancer within a few years of HRT and the decrease after cessation of treatment, indicate an association with the proliferative effect rather than a mutagenic/carcinogenic action of estrogen/progestin preparations. The highest mitotic activity in healthy breast epithelium and in primary invasive breast cancers is found during the luteal phase [55,56]. Continuous combined treatment of postmenopausal women with either CEE or CEE/MPA reveals a slight increase in the proliferation rate of breast epithelium with estrogen only and a pronounced enhancement with CEE/MPA, which was comparable with that during the luteal phase in premenopausal women [57]. Although treatment with TIB did not increase mammary epithelial proliferation, the results of trials with HRT preparations that contain estrogens and either NET or levonorgestrel (LNG) are inconsistent [58,59]. Similar results have been obtained in ovarectomized, nonhuman primates [60–62]. Long-term treatment of premenopausal women with benign mastopathia with either 8–10 mg NET or NET prodrugs daily reduced the risk of breast cancer by 50%, whereas progesterone derivatives did not [63]. It remains to be clarified whether a reduction in the mammary blood flow observed during treatment with 5–10 mg NETA [64] contributes to the lower incidence of breast cancer. Cardiovascular disease Coronary heart disease The Framingham study showed a dramatic increase in the incidence and severity of coronary heart disease (CHD) after the menopause, which was associated with an accelerated development of atherosclerosis [65,66]. Observational studies, animal experiments and investigations in vitro demonstrate that treating postmenopausal women with estrogens prevents atherosclerosis, improves endothelial function and reduces the risk of CHD. The available data indicate that some progestins might counteract the direct favourable effects of estrogens on the vessel wall. Experiments with cynomolgus monkeys and clinical data demonstrate that effective prevention of atherosclerosis by estrogen therapy is possible, provided that it is www.sciencedirect.com

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initiated early after menopause and the arterial lesions are not too pronounced [67,68]. In a double-blind, placebocontrolled, randomized study, treatment of hypercholesterolemic postmenopausal women with 1 mg estradiol (without additional progestin) prevented the progression of atherosclerosis as effectively as statins, which indicates that primary prevention of CHD might be possible [68]. Because the effects of estrogens on the vessel wall are dependent on a functional endothelium, and atherosclerosis is associated with a reduced estrogen receptor expression, long-term estrogen deficiency will have deleterious consequences and prevent secondary prevention of CHD. Among older postmenopausal women, favorable effects of estrogens might be limited to those who have not yet developed atherosclerotic vascular disease [69,70]. Recently, the public was informed by the media that in the estrogen-only arm of the WHI study there was no harmful effect concerning cardiovascular disease (CVD), except an elevated risk of stroke. By contrast, the WHI primary-prevention study and the HER secondary prevention-study revealed a transitory increase in the RR of CHD during the first year of treatment with CEE/MPA [71,72]. The question arises as to whether this was caused by the addition of the progestin. The hormone-induced elevation in the CHD risk in the WHI primary-prevention study was not significant, and was associated, partially at least, with the high age of the women and the high prevalence of risk factors. This was confirmed by a recent subanalysis, which clearly shows an outcome similar to that of the HER study, which indicates that the study design was unsuitable for assessing primary prevention (Table 6). Although age has no influence, a clear association with the duration of estrogen deficiency was found: in the CEE/MPA group, the RR was reduced (nonsignificantly) in women who were !10 years postmenopausal, and increased with the number of years since the menopause [71]. Like the HER study, the RR of CVD was elevated significantly only in the first year of treatment (Table 6) [71,72]. There are no comparative trials on the effects of the various progestins on estrogen-dependent prevention of atherosclerosis. In the monkey model, combinations of EE and nortestosterone derivatives (e.g. LNG and NET prodrugs) protect against the accumulation of low density lipoprotein in the intima, particularly in animals with stress-related high risk and high cortisol levels [73]. Although progesterone did not counteract the direct effect of estradiol on the arterial wall, the addition of MPA caused atherosclerosis and vasoconstriction [74,75]. In postmenopausal women, estradiol was shown to prevent the development of atherosclerosis even in combination with 0.15 mg LNG [76]. The underlying mechanisms are not clear. There might be an association with the effect of some progestins on the expression of the thrombin receptor (T-R), which is located on thrombocytes, vascular epithelial and smooth muscle cells. The activation of the T-R by thrombin stimulates the extrinsic coagulation cascade, and is involved in the development of atherosclerosis. The T-R is upregulated by low concentrations of glucocorticoids and progestins with glucocorticoid activity (Table 7) [1,16]. Treatment with

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Table 6. Risk of coronary heart disease in the WHI study for primary prevention of CHD [71] and the HER study for secondary prevention of CHDa,b

a

Subgroup

n (CEE/MPA)

n (placebo)

Hazard ratio

Nominal 95% CI

WHI study for primary prevention of CHD Total CHD events !10 years since menopause 10–19 years since menopause R20 years since menopause Total CHD events, 1st year Non-fatal myocardial infarction CHD death Angina

188 31 63 74 42 151 39 106

147 34 51 44 23 114 34 126

1.24 0.89 1.22 1.71 1.81 1.28 1.10 0.82

1.00–1.54 0.53–1.44 0.83–1.79 1.17–2.46 1.09–3.01 1.00–1.63 0.70–1.75 0.63–1.06

HER study for secondary prevention of CHD Total CHD events Total CHD events, 1st year Non-fatal myocardial infarction CHD death Angina

179 57 122 70 109

182 38 134 59 120

0.99 1.52 0.92 1.20 0.91

0.84–1.17 1.01–2.29 0.72–1.17 0.85–1.69 0.70–1.18

Abbreviations: CEE/MPA 0.625 mg conjugated estrogens and 2.5 mg medroxyprogesterone acetate; CHD, coronary heart disease; CI, confidence interval. Data from [72].

b

progestins with glucocorticoid activity might, therefore, stimulate thrombin-induced expression of the tissuefactor and upregulate the procoagulatory and vasoconstrictory activity of lesioned arterial walls [16]. It has been suggested that the glucocorticoid effect, of progestins rather than the androgenic effect could be involved in the development of CVD. Venous thromboembolic disease There is no doubt that HRT increases the risk of thromboembolic disease, particularly during the first years of treatment [37,72,77,78]. However, there is insufficient data on the role of the progestin component in this phenomenon. It is not clear whether there are parallels to the elevated risk of venous thromboses during the use of oral contraceptives, which is higher with oral contraceptives that contain either GSD or desogestrel (DG) than those that contain LNG and NET, even though this has been disputed [79]. In addition to stimulating the expression of the T-R, tissue factor and extrinsic coagulatory activity, the increased formation of thrombin by some progestins can downregulate fibrinolytic activity via enhanced production of the thrombin-activatable fibrinolysis inhibitor. Table 7. Relative binding affinity of steroid hormones to the glucocorticoid receptor and their in vitro effect on the expression of the thrombin receptor in vascular smooth muscle cellsa,b

a

Steroid hormone

Thrombin receptor upregulationa

Relative binding affinity

Dexamethasone Medroxyprogesterone acetate Gestodene 3-Keto-desogestrel Progesterone Levonorgestrel Norgestimate Norethisterone Ethinylestradiol

CC C C C C K K K K

100% 29% 27% 14% 10% 1% 1% 0% 0%

CC, strong effect; C, pronounced effect; K, no significant effect. Data from [1,16].

b

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This effect is more pronounced in women treated with DG-containing oral contraceptives than with preparations with LNG [80]. Progestins might also modify the estrogeninduced increase in serum procoagulatory activity, mediated by their effect on the hepatic production of coagulation factors. With regard to this, progestins with androgenic properties, such as LNG and NET, appear to be more favourable [81]. Moreover, the reversible estrogen-induced resistance to activated protein C is antagonized dose-dependently by LNG but not by GSD and DG, probably because of the androgenic activity of LNG [82]. Effect on hot flushes In general, additional progestins enhance rather than impair the beneficial effect on hot flushes. There are no comparative trials that allow the evaluation of differences in the effects of various progestins. In women with contraindication for estrogens, progestins only might be used because they have been shown to relieve hot flushes at higher doses [83]. Effect on bone TIB and high-dose NETA are the only two compounds demonstrated to prevent bone resorption in postmenopausal women without additional estrogen [84,85]. The role of estrogenic metabolites of NET (EE) and TIB (7a-methyl-EE, 3a-hydroxy-TIB and 3b-hydroxy-TIB) is unclear [18,19]. High doses of MPA cause only a partial reduction of bone resorption [86] and other progestins have no or only a small effect in addition to that of the estrogen. Effect on skin and hair Both aging and estrogen deficiency are involved in the development of skin and hair changes observed in postmenopausal women. There are no systematic and controlled studies on the effect of additional progestins on the estrogen-induced increase in the collagen content or other properties of the skin. Estrogen deficiency might be associated with a diffuse loss of scalp hair and the predominance of endogenous androgen activity in

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Box 1. Synopsis of the physiological effects of progestins used in hormone therapy and contraception Endometrium Prevention of endometrial hyperplasia is dependent on the dose of estrogen and the duration of additional use of progestins. The dose of progestin is adapted according to endometrial protection so there is no evidence for differences between progestins.

Breast Additional progestins enhance the breast-cancer risk that is associated with estrogen, probably by enhancing estrogen-dependent proliferation. It is possible that progestins with androgenic activity have a less pronounced proliferative effect.

Coronary heart disease Synthetic progestins might counteract the estrogen-dependent prevention of atherosclerosis, probably according to type, dose and the duration of treatment. This is possibly more pronounced using progestins that have glucocorticoid activity such as MPA. Additional progestins might cause a transient increase in the risk of coronary heart disease in patients with severe arterial lesions.

estrogen-induced resistance to activated Protein C. The risk of venous thrombosis appears to be slightly higher using oral contraceptives with GSD and DG than with LNG and NET.

Hot flushes At higher doses progestins reduce hot flushes, and at lower doses they enhance estrogen effects. No comparative data is available.

Skin and hair Androgenic disorders are improved by estrogen/progestin preparations. In severe cases, progestins with antiandrogenic activity (CPA, DNG, DSR and chlormadinone acetate) are probably more effective.

Bone NET and TIB prevent postmenopausal bone resorption without additional estrogen. Other progestins are either less effective or ineffective.

Mood Thrombosis Progestins with glucocorticoid activity (MPA, DG and GSD) enhance extrinsic procoagulatory activity. Progestins with androgenic activity reduce estrogen-induced change of hemostasis factors and

postmenopausal women might contribute to hirsutism and androgenetic alopecia. Preparations that contain an estrogen and an antiandrogenic progestin such as CPA, chlormadinone acetate, DNG and DSR are recommended for treatment of androgenic hair disorders, but there are no studies comparing the various preparations. Effect on mood It has been suggested that estrogen deficiency might cause depressive states in predisposed women, whereas estrogen replacement might have a beneficial effect. There is, however, insufficient evidence from controlled studies. In a randomized, placebo-controlled study CEE increased mood scores dose-dependently and MPA had an antagonistic action [87], but there are no studies comparing the effect of different progestins on mood. Provided that estrogens improve mood in postmenopausal women, the unfavorable effect of additional progestins might be due to their estrogen-antagonistic effect, which also affects the CNS. However, progesterone differs from synthetic progestins because progesterone metabolites (pregnanolones) modulate GABAA receptor activity and, consequently, mood, emotions and behavior [88]. The data on the effects of TIB, which is metabolized to a progestin with a strong androgenic activity and a potent EE derivative [15], on mood, are not consistent [85]. Conclusions The only indication for the addition of progestins to estrogen-replacement therapy is endometrial protection. Epidemiological and clinical data sugest that the additional progestins are involved in the development of breast cancer, CVD and other disorders. Because progestins can either enhance or counteract the effects of the estrogen component (Box 1), the choice of the most suitable progestogen component is important for the tolerability and acceptance of HRT. Considering the risk www.sciencedirect.com

In predisposed women, the antiestrogenic activity of progestins can impair the beneficial effects of estrogen. In addition, oral progesterone might exert sedative and anxiolytic effects after conversion to pregnanolones.

of CVD, progestins with glucocorticoid rather than androgenic activity seem to play a role in the development of the disease. However, lack of sufficient, consistent data makes it difficult to identify progestins with the least unfavourable effects. Because the use of surrogate parameters, such as serum levels of lipoproteins and hemostatic factors, is unsuitable for the prediction of clinical outcomes, either standardized tests in women or primate models should be developed to evaluate, for example, the proliferative effect on breast tissue and the antiatherosclerotic actions of new preparations. In the future, the development of selective progesterone receptor modulators the action of which is restricted to the endometrium, might be a promising approach. References 1 Kuhl, H. (1990) Pharmacokinetics of oestrogens and progestogens. Maturitas 12, 171–197 2 Bhavnani, B.R. (2000) Pharmacology of estrogens. Basic aspects. Menopause Rev. 5, 9–22 3 Kuhl, H. (2000) Pharmacology of estradiol and estriol. Menopause Rev. 5, 23–44 4 Bhavnani, B.R. (2000) Pharmacology of conjugated equine estrogens. Menopause Rev. 5, 45–68 5 Kuhl, H. (2001) Pharmacology of progestogens. Basic aspects progesterone derivatives. Menopause Rev. 6, 9–16 6 Rozenbaum, H. (2001) Pharmacology of progesterone and related compounds: dydrogesterone and norpregnane derivatives. Menopause Rev. 6, 17–28 7 Golbs, S. et al. (2001) Pharmacology of nortestosterone derivatives. Menopause Rev. 6, 29–44 8 Beier, S. et al. (1983) Toxicology of hormonal fertility-regulating agents. In Endocrine Mechanisms in Fertility Regulation (Benagiano, G. and Diczfalusy, E., eds), pp. 261–346, Raven Press 9 Fotherby, K. and Caldwell, A.D.S. (1994) New progestogens in oral contraception. Contraception 49, 1–32 10 Ojasoo, T. (1995) Multivariate preclinical evaluation of progestins. Menopause 2, 97–107 11 Pollow, K. et al. (1992) Dihydrospirorenone (ZK30595): a novel synthetic progestagen – characterization of binding to different receptor proteins. Contraception 46, 561–574

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