Effects of Dydrogesterone on the Vascular System

Written By: Sam Savage

Published Date: December 14, 2007 Last Edited: December 14, 2007

By Seeger, Harald Mueck, Alfred O

Abstract Estrogens exert beneficial effects on the vascular system, while progestogens generally have a negative impact (e.g. vasoconstrictor effects on the arterial system). In contrast, dydrogesterone appears to be largely neutral in terms of biochemical markers and indirect clinical endpoints, such as blood pressure, that act as surrogate markers for vascular function. Studies on lipid and carbohydrate metabolism, which can also influence vascular function, demonstrate that the addition of dydrogesterone intensifies rather than attenuates beneficial estrogenic effects. Dydrogesterone also has largely neutral effects on hemostasis. Since there are relatively few data available on clinical parameters such as blood flow measurements, especially in women with pre-existing cardiovascular diseases, increased risks cannot be excluded for a combination of estrogen replacement with dydrogesterone. Further studies should focus on this open question since dydrogesterone, with its largely neutral properties, might be a suitable option, including for older women already at increased cardiovascular risk.

Keywords: Dydrogesterone, vascular effects, hemostasis, carbohydrates, lipids, cardiovascular risk, progestogens

Introduction

Epidemiological, experimental and biological evidence supports a cardioprotective effect of estrogens in women. Indeed, women are protected from the development of coronary artery disease until the menopause and lag behind men with regard to the incidence of myocardial infarction and sudden death by 20 years. The reasons for this protection are largely unclear. However, ovarian hormones are implicated since, irrespective of age, postmenopausal women have a higher cardiovascular risk than premenopausal women, and oophorectomized women not taking hormone replacement therapy (HRT) have an incidence of coronary artery disease comparable to that of men of a similar age.

A large body of evidence from observational studies suggests that estrogen replacement therapy (ERT) and, with somewhat more limited evidence, estrogen/ progestogen therapy (EPT) are associated with a significant reduction in cardiovascular mortality and morbidity. This evidence, however, was not supported by recent randomized studies, conducted mainly in elderly women, using conjugated equine estrogens (CEE) alone and combined with medroxyprogesterone acetate (MPA) [1,2]. Nevertheless, in the estrogen-only arm of the Women’s Health Initiative (WHI) study, a trend towards a reduction in coronary heart disease was found in the 50-59-year age group that approached statistical significance [3]. This observation points towards a crucial role for progestogen addition.

Certainly the vascular actions of progestogens are multifactorial, including not only direct vascular effects but also metabolic changes in, for example, lipid profile, carbohydrate metabolism and hemostasis. Such effects are dependent on the different partial glucocorticoid and mineralocorticoid properties of the various progestogens.

All of these effects interact closely within an intermediate metabolic system and can influence vascular function. Thus, metabolic changes in the lipid and carbohydrate systems can initiate atherogenesis. For example, oxidation of low-density lipoprotein (LDL) converts this macromolecule into a highly toxic substance [4]. Enhanced uptake of this oxidized LDL by macrophages changes them to foam cells, which are believed to instigate the atherogenic process [4]. In addition, oxidized LDL can influence vasomotor tone by altering the synthesis of vasoactive agents, such as by reducing nitric oxide, as well as increasing the potential for vasoconstriction in vascular smooth muscle cells [4].

Metabolic effects, as well as direct vascular actions, may be particularly important in the case of long-term changes in vascular function. This review therefore considers both aspects of the action of dydrogesterone.

Why dydrogesterone?

The direct vascular effects of various progestogens were recently comprehensively described [5]. From this review, which included some of our own experimental data, it can be concluded that progestogens show diverse vascular actions. The clinical relevance of the net effect is, however, difficult to assess due to the complexity of the individual effects (which may have partially opposite consequences). Nevertheless, the overall vascular progestogenic effects appear to be mostly negative.

The rationale therefore is to treat with progestogens that have neutral effects on the cardiovascular system, but concomitantly reliably fulfill the most important task of progestogens in hormone therapy, i.e. endometrial protection. The latter criterion will be fulfilled to only a limited extent by natural progesterone since the metabolism of currently available preparations (i.e. oral as well as vaginal application) during ‘first pass’ is individually variable. On the other hand, progesterone is considered to be a special neutral progestogen in terms of the vascular and metabolic system.

Dydrogesterone is classified as a progestogen that structurally most closely resembles progesterone. It is a derivative of retroprogesterone, a stereoisomer of progesterone, with an additional double bond between C6 and C7. The progesterone molecule is almost ‘flat’, while the retroprogesterone molecule is bent by a change of the methyl group at CIO from the beta-position to the alpha-position and the hydrogen at C9 from the alpha- to beta- position. There is also an additional double bond between C6 and C7. Dydrogesterone appears to be a highly selective progestogen which, due to its retro-structure, binds almost exclusively to the progesterone receptor. Its improved bioavailability and the progestogenic nature of its metabolites mean that the equivalence dose with respect to endometrial proliferation is 10 to 20 times lower than that of progesterone, i.e. it has considerably higher endometrial activity than progesterone.

Dydrogesterone is metabolized by reduction at C20 to the 20alpha- hydroxy derivative, and by hydroxylation at the C21 methyl group and the C16 alpha-position. The metabolites maintain the retro-steroid structure and have a similar profile to that of dydrogesterone. Owing to its selectivity, any effects not mediated by the progesterone receptor are minimal or absent [6].

With respect to the longer established partial actions of dydrogesterone, largely neutral effects on the vascular and metabolic system might be expected. It has strong progestogenic and antiestrogenic effects on the endometrium, shows no partial estrogenic effects (in contrast to norethisterone), androgenic effects (in contrast to norethisterone, levonorgestrel and MPA) or partial glucocorticoid effects (in contrast to MPA), but has weak antiandrogenic and antimineralocorticoid effects that are considered beneficial, especially in the metabolic system [6].

Since, on the other hand, dydrogesterone is associated with excellent endometrial protection when used orally, a fact that has been consistently reproduced in clinical studies [7,8], the question arises as to whether negative vascular effects can be avoided by the use of this progestogen, thus making it a highly suitable choice for EPT, especially long-term therapy.

In the following review, the most important vascular properties, including the main metabolic effects, are summarized for this interesting progestogen.

Direct vascular effects

Clinical studies and experimental in vitro investigations indicate that estrogens have direct beneficial effects on the vasculature [9,10]. These actions can be broadly divided into endothelium-dependent and endothelium-independent effects (Figure 1). By modulating the synthesis of nitric oxide, prostacyclin and endothelin, and blocking calcium channels, estrogens beneficially affect the vascular tone. Atherogenesis, which is considered to be an inflammatory, fibro-proliferative process, may be delayed by estrogens via the downregulation of inflammatory markers such as cell adhesion molecules and chemokines. The role of added progestogen, however, has as yet not been fully explored.

Figure 1. Direct vascular effects of estrogens.

To date, few data are available on the effect of dydrogesterone combined with estrogen on the various biochemical markers for vascular tone. In a double-blind, placebo-controlled, cross-over study, no significant difference was found between a combination of estradiol plus dydrogesterone compared with estradiol alone with regard to the reduction of serum endothelin levels after 4 weeks of treatment [11]. Endothelin is one of the most potent vasoconstrictor compounds identified to date. It is synthesized mainly in the vascular endothelial cells and acts abluminally, i.e. it has direct effects on the vascular smooth muscle cells [12].

Nitric oxide may certainly be the most significant compound in terms of vasodilation. It also has anti-aggregatory, antiproliferative, anti-inflammatory and antioxidative effects [13]. Recently it was demonstrated that dydrogesterone and its main metabolite had a neutral effect on the estradiol-induced positive effect on nitric oxide synthase activity and expression [14]. In contrast, MPA had a deleterious effect.

The inflammatory marker C-reactive protein (CRP) has gained increasing attention following a series of clinical investigations indicating that it is an independent marker of impending coronary events [15]. The plasma concentration of CRP is known to increase in inflammatory states, a characteristic that has long been employed for clinical purposes. Induction of CRP in hepatocytes is principally regulated at the transcriptional level by the cytokine interleukin-6, an effect that can be enhanced by interleukin- 1alpha. Recent investigations indicate that CRP may not only be a risk marker for cardiovascular diseases, but also a mediator in atherogenesis [16] as it elicits numerous direct negative effects on the vasculature. The increase in CRP levels observed during hormone therapy appears to be associated with estrogen effects on liver function, especially when using oral preparations. Thus, the effect of progestogen addition seems to be of only secondary importance. In a small cross-over trial, the combination of estradiol and dydrogesterone successfully opposed the estradiol-induced increase in serum CRP levels, while no such effect was seen with an estradiol plus norethisterone combination [17]. Adhesion molecules play a crucial role in the early stages of atherogenesis [18]. They mediate the adhesion, rolling and tethering of leukocytes on endothelial cells and are therefore expressed on the surface of endothelial cells. Recent investigations showed that soluble forms of adhesion molecules can be measured in the serum [19]. Evidence is growing that they emerge from the shedding of membrane-associated adhesion molecules and thus indirectly reflect the expression of adhesion molecules on endothelial cells. A possible pathophysiological role for these soluble forms, however, remains to be determined. Few data are available concerning markers of inflammatory activity, although dydrogesterone has been shown to reduce serum levels of E-selectin after 3 and 15 months of treatment in a controlled, randomized study [20].

Homocysteine is a sulfhydryl-containing amino acid derived from the essential amino acid methionine, which is abundant in animal sources of protein. The metabolic pathway that converts methionine to homocysteine is fundamental for the correct functioning of many biomolecules, including DNA, proteins, phospholipids and neurotransmitters. An increase in homocysteine is associated with arterial and venous thromboembolic disease. Moreover, the measurement of fasting homocysteine has been proposed to help target individuals at greatest risk of various acute cardiovascular events [21]. Of special interest is the suggestion that an association between raised homocysteine concentration and an increased risk of atherothrombosis may be independent of other vascular risk factors. This effect is considered to be strong, dose-related and biologically plausible, although it has not been proven to be causal in any randomized controlled trials [22].

Mijatovic and colleagues showed that dydrogester-one combined with estradiol significantly reduced plasma homocysteine levels after 3 months and that the effect was still observed after 15 months of treatment (Figure 2) [23]. This result was confirmed by Ciantera and associates, who found that dydrogesterone combined with oral or transdermal estradiol showed similar reductions in plasma homocysteine levels [24]. In a recent randomized, placebo- controlled trial, estradiol either with or without dydrogesterone resulted in a lowering of fasting homocysteine levels as assessed by the methionine-loading test [25].

Figure 2. Effect of estradiol (2 mg/day) plus continuous dydrogesterone (10 mg/day) on plasma homocysteine levels during 15 months of treatment [23].

Metabolic effects

As discussed previously, metabolic effects can direcdy influence vascular function. Numerous clinical studies have been conducted to assess the metabolic effects of dydrogesterone.

Carbohydrates

High insulin resistance, impaired glucose tolerance and hyperinsulinemia are possible consequences of postmenopausal estrogen deficiency. ERT can maintain all of these parameters at premenopausal levels, although combination with various progestogens can dose-dependently antagonize these beneficial estrogenic effects. Somewhat differing results can be observed with the same progestogen as the threshold dosages can differ markedly between individuals. However, to our knowledge, no negative effects have been reported with dydrogesterone.

No changes in fasting plasma glucose concentrations have been observed in studies using a combination of estradiol and dydrogesterone (Figure 3) [26]. In particular, insulin sensitivity was found to be improved by dydrogesterone [27-29]. A head-to-head comparison between various progestogens in terms of their effect on insulin sensitivity was recently published by Dansuk and co-workers [29]. Only the combinations of estradiol plus dydrogester-one, or estradiol plus norethisterone acetate, were able to improve insulin sensitivity after 3 months of treatment.

Lipids

The effects of various dosage regimens of estradiol combined with dydrogesterone, either sequentially or continuously, on serum lipid concentrations have been investigated in detail. The results of several clinical studies clearly indicate that treatment with 2 mg estradiol daily sequentially combined with 10 mg dydrogesterone is associated with long-term favorable changes in the serum lipid profile [30-32]. The findings included an increase in high-density lipoprotein-cholesterol and apolipoprotein Al, and a decrease in LDL- cholesterol and total cholesterol. A similar improvement was observed using only 1 mg estradiol daily combined with dydrogesterone.

Figure 3. Mean percentage changes in glucose and insulin concentration during two years of treatment with estradiol (2 mg/ day) sequentially combined with dydrogesterone (10 mg/day) [26].

The observation that the estrogen-induced reduction in serum lipoprotein-(a) (Lp(a)) is not negatively influenced by the addition of dydrogesterone, but rather is enhanced, is of particular significance. Within 12 months of starting treatment, 1-2 mg estradiol sequentially combined with 5-10 mg dydrogesterone triggered a 50% reduction in this marker [33]. Lp(a) is considered a link between lipids and the hemostatic system in intermediate metabolism and is an important marker for blood viscosity [34]. According to epidemiological studies, Lp(a) has been proven as an independent predictor of cardiovascular risk factors, especially for women with high initial Lp(a) levels, a finding that was also reported in the Heart and Estrogen/progestin Study [35].

The lowering of this important marker by HRT is of special significance since, with the exception of a moderate reduction by bezafibrate, lipid-lowering drugs do not show any relevant effects. The effect of estradiol/dydrogesterone on the reduction of serum Lp(a) concentrations appears to be particularly pronounced.

Hemostasis

Estrogen deficiency induces profound changes in parameters that promote coagulation, e.g. an increase in factor VII, fibrinogen and plasminogen-activator inhibitor-1. Van der Mooren and colleagues observed a significant reduction in fibrinogen after 28 cycles of estradiol sequentially combined with dydrogesterone [36]. Another study showed favorable effects on fibrinogen and antithrombin III during 2 years of treatment with dydrogesterone combined with estradiol [37]. Beneficial changes in plasminogen-activator inhibitor-1 (reduction) and plasma plasmin-antiplasmin complex (increase) were also found after 12 months of treatment with estradiol sequentially combined with dydrogesterone [33].

Clinical endpoint trials assessing venous thrombosis risk with the combination of estrogens with the various progestogens are rare. Recently, however, dydrogesterone combined with transdermal estradiol showed a neutral effect (i.e. no increase) on thrombosis risk, in contrast to oral progestogens of the norpregnane type (Scarabin PY, personal communication; 2006).

Indirect clinical endpoints for vascular effects

The most frequently assessed clinical parameters that hint at vascular effects are measurement of blood pressure and blood flow and, with more sophisticated methods, the measurement of vascular reactivity such as flow-mediated dilatation. Following the results of the WHI, control of blood pressure during HRT should be attributed a similarly high significance as has been routine with hormonal contraceptives for many years.

Hypertension is one of the most important risk factors contributing to the incidence of clinical endpoints for vascular effects, such as myocardial infarction and stroke. During estrogen alone, as well as combined HRT, the risk of stroke can be increased up to threefold [38]. In the WHI study, blood pressure increased in both the estrogen-only and the combined HRT arms [3]; the average increase in systolic pressure after 1 year of treatment was not very high (about 1 mmHg), although individual patients will have experienced greater increases. The authors, however, point to a causal connection between minor increases in blood pressure and the observed increase in stroke risk, since it is well known that even a small rise in blood pressure can enhance the risk of stroke and other cardiovascular diseases [39,40].

As we have reviewed elsewhere [41], despite the clear significance of blood pressure changes, only a few studies are available that have assessed the effect of progestogens on blood pressure during HRT using the best method, i.e. 24-h ambulatory blood pressure measurements. One study in particular with dydrogesterone showed that it is necessary to use this method, since continuously measured ambulatory values can differ from the office values. Twenty-four hour ambulatory blood pressure was measured in 29 normotensive (healthy) postmenopausal women receiving either estradiol sequentially combined with dydrogesterone or no treatment (Figure 4) [42]. After 12 months of treatment, a significant decrease in systolic blood pressure of about 5 mmHg was observed with HRT in terms of ambulatory, but not office, blood pressure values. Various clinical studies have demonstrated blood pressure reductions using office measurements, although these appear to be of limited significance. Only very recently a study has been completed on the long-term effects of low-dose estradiol plus dydrogesterone using 24-h ambulatory blood pressure in hypertensive postmenopausal women; as previously discussed, dydrogesterone had a neutral effect [43]. Thus it is conceivable that the cardiovascular risk appears not to be increased by the addition of dydrogesterone, in contrast to the findings of the WHI study regarding progestogen addition. However, as yet, no analogous clinical intervention studies are available.

Figure 4. Twenty-four hour ambulatory systolic blood pressure during 12 months of treatment with estradiol (1 mg/day) sequentially combined with dydrogesterone (10 mg/day) in normotensive women [42].

The use of blood flow measurements for the indirect assessment of vascular effects in clinical studies was introduced by the group of Whitehead in the early 1990s, as the significance of vascular changes, whether independent or in addition to metabolic effects, during HRT was recognized for the first time [44]. Since then, progestogenic effects have been investigated in numerous trials. Only a few data, however, are available as yet for dydrogesterone. In a controlled, randomized study, dydrogesterone combined with estradiol resulted in a significantly lower pulsatility index of the uterine and central retinal arteries compared with untreated controls after 12 months of treatment, with a positive effect being evident after just 3 months [45]. Dydrogesterone had no reversing effect on estradiol-induced vasodilation in postmenopausal women at risk for coronary artery disease [11]. In another double-blind, cross-over study measuring carotid artery pulsatility index, an antagonistic effect of dydrogesterone on the estradiol-induced benefit could not be excluded [46]. It is probable that atherosclerotic damage was already manifest at the start of this study. In addition, in a study measuring systolic cardiac function in postmenopausal women, there was no improvement with estradiol plus sequential dydrogesterone treatment, but dydrogesterone at least did not have negative consequences and showed only neutral effects [47].

Conclusion

Estrogenic vascular effects depend on the stage of vascular function, i.e. the progress of atherosclerotic damage. Generally, progestogens may reduce or abolish beneficial estrogenic effects by, for instance, vasoconstrictory actions on the arterial system. The magnitude of any possible impact may depend on the ability of the vessel to compensate by counter-regulation. Negative progestogenic effects in atherosclerotic vessels, especially during long-term treatment, cannot be excluded but may be reduced by certain progestogens such as dydrogesterone.

The hitherto existing studies investigating biochemical markers acting as surrogates for direct vascular function have demonstrated that dydrogesterone has a mainly neutral effect. These investigations complement studies measuring metabolic changes. In this regard, numerous studies are available on lipid and carbohydrate metabolism showing that the addition of dydrogesterone actually intensities the beneficial estrogenic effects. The effects of dydrogesterone on hemostasis appear to be largely neutral.

Relatively few data are available on clinical parameters such as blood flow measurements. In particular, studies investigating the effects in at-risk patients (i.e. women with pre-existing cardiovascular diseases) are lacking. Increased risks probably therefore cannot be excluded for combination with dydrogesterone. Thus, especially in terms of clinical endpoints for vascular effects, further research on dydrogesterone seems to be necessary and worthwhile as it appears to have a generally neutral profile.

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HARALD SEEGER & ALFRED O. MUECK

Department of Endocrinology and Menopause, University Women’s Hospital, Tuebingen, Germany

(Received 17 May 2007; accepted 5 September 2007)

Correspondence: A. O. Mueck, Department of Endocrinology and Menopause, Centre of Women’s Health, University Women’s Hospital, Calwerstrasse 7, D-72076 Tuebingen, Germany. Tel: 49 7071 298 4801. Fax: 49 7071 29 4801. E-mail: [email protected]

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