By Genazzani, A R; Mannella, P; Simoncini, T
Key words: ALDOSTERONE, ANTIALDOSTERONE, CARDIOVASCULAR, DROSPIRENONE, PROGESTERONE, PROGESTIN
Drospirenone is a unique progestogen derived from 17α- spirolactone, with a pharmacologic profile very similar to that of endogenous progesterone. In contrast with other available progestins, drospirenone is a progestogen with aldosterone receptor antagonism (PARA) through its affinity for the mineralocorticoid receptor. It is thus able to act on the renin-angiotensin- aldosterone system (RAAS), which prevents excessive sodium loss and regulates blood pressure. Estrogen acts on the RAAS to stimulate the synthesis of angiotensinogen, which increases aldosterone levels and promotes sodium and water retention. When these effects are unopposed, for example during estrogen replacement therapy, they can lead to increases in weight and blood pressure. The antialdosterone properties exhibited by drospirenone promote sodium excretion and prevent water retention, conferring potential blood pressure benefits. In addition to its effects on the kidney, aldosterone has effects on the vasculature, myocardium and central nervous system, which may elicit a variety of pathophysiologic processes associated with cardiovascular disease. The antialdosterone properties of drospirenone may therefore confer additional cardiovascular benefits beyond the RAAS system. The combined actions of drospirenone on sodium and water retention and cardiovascular parameters make it a more attractive therapeutic option as a component of hormone replacement therapy than other synthetic progestins.
Drospirenone (DRSP: 6β,7β,15β, 16β- dimethylen-3-oxo-17α-pregn-4-ene-21,17-carbo-lactone) is a novel progestogen, which demonstrates a pharmacologie profile very similar to that of endogenous progesterone1-3. Like progesterone, drospirenone has both antialdosterone and antiandrogenic properties, but is devoid of any androgenic or glucocorticoid activity1-6. Whereas most other progestogens originate from 17α- hydroxyprogesterone or 19-nortestosterone, drospirenone is derived from 17α-spirolactone (Figure 1). In a rat model, drospirenone was shown to have eight times the antialdosterone potency of spironolactone4. The aldosterone receptor antagonism exhibited by drospirenone is a result of its affinity for the mineralocorticoid receptor. Table 1 compares the properties of drospirenone with other progestins, none of which have clinically evident antialdosterone activity. The pharmacologie profile of drospirenone more closely resembles endogenous progesterone than any other available synthetic progestin.
Figure 1 The structures of progesterone, medroxyprogesterone acetate and drospirenone
Table 1 Pharmacodynamic properties of progesterone, drospirenone and other progestins6,7. Adapted from Rbig A. Drospirenone: a new cardiovascular-active progestin with antialdosterone and antiandrogenic properties. Climacteric 2003;6(Suppl 3):49-54 with permission from Taylor & Francis (http://www.tandf.co.uk/journals)
DROSPIRENONE AND THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
Because of its antialdosterone activity, drospirenone can mimic the effects of endogenous progesterone on the renin-angiotensin- aldosterone system (RAAS). The most important functions of the RAAS are to prevent excessive sodium loss and regulate blood pressure8. Activation of the RAAS ultimately leads to the production of aldosterone by the adrenal cortex. Renin, produced in the kidney, converts angiotensinogen into angiotensin I. Angiotensin-converting enzyme catalyzes the transformation of angiotensin I into angiotensin II, and angiotensin II stimulates aldosterone secretion. Aldosterone acts in the kidney to promote sodium and water retention, with concomitant potassium and magnesium loss.
Estrogen stimulates the synthesis of angiotensinogen9, leading to increased aldosterone production and consequently promoting sodium and water retention, which can result in increased blood pressure. In the normal menstrual cycle, aldosterone is prevented from interacting with mineralocorticoid receptors in the kidney by progesterone secreted during the luteal phase, thus preventing sodium retention. Conventional synthetic progestogens used in continuous combined hormone replacement therapy (HRT) do not exhibit the antialdosterone activity of natural progesterone6,9; therefore the RAAS system can be stimulated in postmenopausal women taking conventional combined HRT preparations, leading to sodium and water retention, which may in turn lead to increased blood pressure10. Unlike other synthetic progestins, drospirenone mimics endogenous progesterone through its antialdosterone properties, promoting sodium excretion and preventing water retention. Consequently, women who receive drospirenone may maintain, or even lose, weight. There may also be potential blood pressure benefits.
Clinical data have confirmed the benefits of drospirenone acting via the RAAS. In a study reported by Oelkers and colleagues11, 12 women received a diet containing 100 mmol sodium per day during days 3-13 of their normal menstrual cycles. Between days 8 and 13 of their cycles, the women were given either 2 mg drospirenone (n = 6) or placebo (n = 6). Mean sodium excretion rose from 79.6 to 98.6 mmol/day for women receiving drospirenone, whereas placebo had no effect. Mean weight loss in women receiving drospirenone was 0.6 kg over the treatment period, compared with 0.4 kg for women taking placebo.
Figure 2 The effects of drospirenone (DRSP) on body weight. Adapted from Archer et al. Long-term safety of drospirenone- estradiol for hormone therapy: a randomized, double-blind, multicenter trial. Menopause 2005;12:716-27, with permission from Lippincott Williams & Wilkins. E2, 17β-estradiol
Weight loss associated with drospirenone treatment has also been observed in a multicenter, double-blind, randomized, parallel-group study assessing the long-term safety of drospirenone/ 17β- estradiol (E2) as HRT12. The study involved a total of 1142 postmenopausal women, each of whom received thirteen 28-day cycles of treatment. A total of 226 women received 1.0 mg E2 alone and 227 were given 1.0 mg E2 plus 2.0 mg DRSP (Angeliq, Schering AG, Berlin, Germany). The mean body weight for both groups was comparable at baseline (71.2 kg in the 1.0 mg E2 group and 72.7 kg in the 1.0 mg E2/2.0 mg DRSP group). However, during the treatment period, a statistically significant weight decrease (p = 0.001 compared with baseline) was apparent in the 1.0 mg E2/2.0 mg DRSP group (Figure 2), whereas women receiving E2 monotherapy reported weight gain.
In women with normal blood pressure, no statistically significant changes in blood pressure were recorded in either treatment group. However, a post hoc subgroup analysis of a subset of women with elevated blood pressure at baseline (systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg) found statistically significant decreases from baseline in both mean systolic and mean diastolic blood pressures in the 1.0 mg E2/2.0 mg DRSP subgroup (n = 15; p = 0.011 for systolic and p
ALDOSTERONE AND CARDIOVASCULAR DISEASE
In addition to its effects on the kidney, aldosterone acts on mineralocorticoid receptors in the vasculature and myocardium to elicit a variety of other pathophysiologic processes associated with cardiovascular disease (Figure 3). Aldosterone can also act via the central nervous system. The effects of aldosterone include myocardial and vascular fibrosis13,14, direct vascular damage15, endothelial dysfunction16, and reduced arterial compliance17. Furthermore, as well as promoting sympathetic activation18, aldosterone can reduce parasympathetic activity and baroreflex sensitivity19.
Aldosterone antagonists have well-documented clinical benefits with regard to cardiovascular disease. The Randomized Aldactone Evaluation Study (RALES), performed in patients with moderate to severe heart failure who were already receiving angiotensin- converting enzyme inhibitor treatment, showed aldosterone blockade with spironolactone to provide significant morbidity and mortality benefits20. In addition, eplerenone, a more recently developed aldosterone receptor antagonist21, has been shown to reduce morbidity and mortality in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure22.
Figure 3 The effects of aldosterone in cardiovascular disease. PARA, progestogen with aldosterone receptor antagonism
PROGESTINS AND CORONARY HEART DISEASE
Possibly as a result of the antiatherogenic effects of normal ovarian function, women tend not to develop clinically significant coronary heart dis ease (CHD) until after the menopause23. Although the favorable cardioprotective effects of E2 are well documented24, recent findings raise questions about the cardioprotective effects of HRT25.
The Women’s Health Initiative (WHI) investigated the major health benefits and risks of the most commonly used comb\ined hormone preparation in the United States26. In this study (n = 8506), women receiving conjugated equine estrogens (CEE, 0.625 mg/day) together with medroxyprogesterone acetate (MPA, 2.5 mg/day) had a 24% higher risk of coronary heart disease versus those receiving placebo (hazard ratio 1.24; nominal 95% confidence interval 1.00-1.54; 95% confidence interval with adjustment for sequential monitoring 0.97- 1.6O)27. The absolute rates of CHD were 39 and 33 cases, respectively, per 10 000 person-years. However, analysis of hazard ratios by number of years since menopause suggested that CHD risk increased with the time following menopause: 0.89, 1.22, and 1.71, respectively, for women in whom the menopause had begun
Progesterone and MPA: effects on the development of atherosclerosis
Studies in monkeys show that the addition of progesterone or a synthetic progestin to estrogen treatment can have different effects on atherosclerosis development. In experiments studying diet- induced coronary artery atherosclerosis in ovariectomized monkeys, Adams and colleagues30 reported that the progression of atherosclerosis was inhibited by continuously administered E2, both with and without cyclically administered progesterone. Register and colleagues31 have also studied arterial responses in ovariectomized monkeys. After 24 months on an atherogenic diet, monkeys were switched to a plasma lipid-lowering diet. One group received the diet alone (control group), another was treated with CEE alone, and a third group received CEE together with continuous MPA. It was found that the abdominal aortas of the monkeys underwent chemical remodeling after receiving a lipid-lowering diet. Data suggested that treatment with CEE inhibited the detrimental changes in connective tissue accompanying lesion regression, but MPA antagonized these beneficial effects.
Progesterone and MPA: experimental models
Atherosclerotic degeneration can give rise to dysfunctional endothelial cells with impaired synthesis of molecules such as nitric oxide (NO). NO makes an important contribution to vascular function, acting as a potent vasodilator and thaving anti- inflammatory properties32. Estrogen can stimulate the activity of endothelial nitric oxide synthase (eNOS)33, which ultimately increases levels of NO and has a positive effect on vascular biology.
Experiments using isolated human endothelial cells have shown progesterone to significantly increase the synthesis of NO, whereas MPA does not34. In addition, the beneficial effects of physiologic concentrations of E2 on NO were potentiated by progesterone but impaired by MPA. In further experiments involving ovariectomized rats, oral administration of E2 was shown to induce the expression of eNOS in the abdominal aorta to levels comparable with those found in fertile animals34. Co-administration of E2 and progesterone also produced eNOS levels similar to those of fertile animals. However, when MPA was administered together with E2, there was a significant reduction in eNOS level compared with fertile rats.
The results can be explained in terms of progesterone and MPA triggering different signaling events34. Progesterone stimulates the synthesis of NO as a result of increased enzymatic activity of eNOS, and can exert its effects via both transcriptional and non- transcriptional mechanisms. MPA does not induce these effects.
Progesterone, MPA and drospirenone: effects on eNOS induction
In vitro experiments performed using cultured human endothelial cells in a system similar to that previously described by Simoncini and colleagues34 have demonstrated differential induction of eNOS by progesterone, drospirenone and MPA. Progesterone and drospirenone significantly increased eNOS activity, whereas MPA had no effect (Table 2). When drospirenone was incubated with RU486, a progesterone receptor antagonist, the effects on eNOS activity were blocked. Western blot analysis, performed to visualize the eNOS protein, confirmed the differential induction. eNOS induction by drospirenone was also found to be dose- and time-dependent. Further experiments have shown differential induction of eNOS by progesterone, drospirenone and MPA in the presence of E2 (Table 2). E2 increases eNOS activity, and this effect remains when E2 is administered in combination with either progesterone or drospirenone. MPA partially antagonizes the effect of E2. As RU486 is an antagonist of the progesterone receptor, adding this to the E2 and drospirenone combination does not significantly reduce eNOS activity. Western blot analysis of the eNOS protein confirmed the differential induction.
Table 2 Differential induction of endothelial nitric oxide synthase (eNOS) by progesterone (PRG), drospirenone (DRSP) and medroxyprogesterone acetate (MPA) either alone or in the presence of 17β-estradiol (E2). DRSP and PRG alone increased eNOS activity and expression, whereas MPA had no effect. The addition of the mixed progesterone receptor/glucocorticoid receptor antagonist RU486 completely blocked the effects of DRSP on eNOS induction. Co- treatment of E2 plus PRG or DRSP did not inhibit the substantial increase in eNOS activity induced by E2 alone, whereas the addition of MPA significantly interfered with the effects of E2. The addition of RU486 to E2 plus DRSP had no significant effect on eNOS regulation (T. Simoncini and A. R. Genazzani, data unpublished)
In addition, in the presence of aldosterone, eNOS is differentially induced by progesterone, drospirenone and MPA (Simoncini and Genazzani, data unpublished). Compared with controls, progesterone and drospirenone increase eNOS activity, whereas MPA has no effect. Aldosterone reduces eNOS activity. Co-administration of ZK 91587, an inhibitor of the aldosterone receptor, does not affect progesterone or drospirenone, as these are acting via the progesterone receptor. The negative effect of aldosterone on eNOS activity is, however, abolished under these conditions. Coadministration of aldosterone partially reduces the effect of progesterone, significantly reduces eNOS production by MPA, but does not affect drospirenone, due to its antagonistic effect on aldosterone (Simoncini and Genazzani, data unpublished).
Drospirenone may confer benefit with regard to eNOS activity via both progesterone and mineralocorticoid receptors. Drospirenone can increase the activity of eNOS by binding to the progesterone receptor and it may also prevent the aldosterone-induced inhibition of eNOS activity by binding to the aldosterone receptor.
Drospirenone is a novel progestogen with a unique profile that closely mimics that of natural progesterone. The antialdosterone properties of drospirenone counteract the salt and water retention elicited by estrogen. Therefore administration of drospirenone as part of HRT contributes to the maintenance of stable body weight, and has potential blood pressure benefits. The antialdosterone properties of drospirenone may also confer additional metabolic benefits.
Natural progesterone, MPA and drospirenone have different effects on human endothelial cell eNOS production in culture, suggesting that specific progestins have substantially different effects on human vascular cells in vivo. Such differences may be relevant to vascular function and disease. Due to its NO-enhancing action, and interference with mineralocorticoid receptor signaling, drospirenone is likely to have cardiovascular benefits, in contrast to MPA.
The authors express their appreciation to the Molecular and Cellular Gynecological Endocrinology Laboratory, which conducted the in vitro experiments.
Conflicts of interest Nil.
Source of funding This work was supported by funding from the University of Pisa and Schering AG.
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A. R. Genazzani, P. Mannella and T. Simoncini
Department of Obstetrics and Gynecology, University of Pisa, Pisa, Italy
Correspondence: Professor A. R. Genazzani, Department of Obstetrics and Gynecology, University of Pisa, Via Roma 56, Pisa 56127, Italy
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