Drospirenone for Oral Contraception and Hormone Replacement Therapy Are Its Cardiovascular Risks and Benefits the Same As Other Progestogens?

Drugs 2007; 67 (5): 647-655 CURRENT OPINION 0012-6667/07/0005-0647/$44.95/0

Drospirenone for Oral Contraception and Hormone Replacement Therapy Are its Cardiovascular Risks and Benefits the Same as Other Progestogens?

Apurva Motivala and Bertram Pitt

Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA

Abstract The use of combined estrogen/progesterone has been shown to result in an increased cardiovascular risk in randomised double-blinded trials. However, these studies used oral progestogen (progestin) preparations, which lack anti-mineralocorticoid activity and have suboptimal anti-androgenic activity compared with progesterone. Drospirenone is a unique progestogen that has clinically been shown to have anti-mineralocorticoid/anti-androgenic effects. Drospirenone in combination with estrogen is currently being used for oral contraception and hormone replacement therapy, and has been shown to have favourable effects on a number of cardiovascular risk factors. Our review of the literature suggests that because of its anti-mineralocorticoid effects, drospirenone in conjunction with estrogen may prevent the development of cardiovascular disease in both pre- and post-menopausal women.

Most women become menopausal between the demonstrating a protective effect of estrogen on the ages of 45 and 55 years. Currently, estrogen is the heart and bone. However, the demonstration of in- most effective modality for the relief of post-meno- creased cardiovascular risk with unopposed es- pausal symptoms.[1] Estrogen is usually given short trogen or combined estrogen/progestogen therapy in term for peri-menopausal symptoms (6 months to the Women’s Health Initiative (WHI) has led to a 4–5 years), with the goal of eventually tapering and rapid change in clinical practice patterns. In the US, discontinuing the estrogen (unless there is a compel- annual hormone therapy prescriptions decreased by ling reason to continue it long term). 38% in the year after the first WHI publication in For the past 2–3 decades, long-term estrogen and July 2002.[2] combined estrogen/progestogen (progestin) thera- On the basis of the WHI trial results, and consis- pies have been routinely prescribed for the preven- tent with guidelines as well as updated recommen- tion of coronary heart disease (CHD) and osteo- dations issued by the American Heart Association porosis, based upon extensive observational data (AHA), combined estrogen/progestogen therapy is 648 Motivala & Pitt

no longer recommended for primary or secondary and to cause sodium retention and potassium loss. It prevention of CHD in post-menopausal women.[3] is now recognised that MR are present not only in There is a suggestion, although not compelling evi- the distal renal tubule but in the heart, brain, salivary dence, that the adverse effects of combined es- glands and intestines. It was also thought that angi- trogen/progestogen therapy are due to the proges- otensin II was the principal stimulus for the produc- togen component. tion of aldosterone by the adrenal gland and that Younger women in their reproductive period tak- ACE inhibitors or angiotensin receptor antagonists ing oral estrogen/progestogen supplements for con- (or blockers [ARBs]) were effective in blocking the traception are also at an increased risk of cardiovas- production of aldosterone. However, studies in the cular disease. The use of these agents leads to a angiotensin knockout mouse by Okubo et al.[7] have small but significant blood pressure elevation, an shown that aldosterone can be released from the impaired fasting glucose, a small increase in is- adrenal gland independent of angiotensin II, since chaemic stroke risk, and may be associated with an other stimuli such as potassium may be of equal or increased risk of myocardial infarction. However, greater importance under certain circumstances. this risk has substantially reduced because of the Once released from the adrenal gland, aldosterone reduction in the estrogen dose in these supplements. has been shown to have a number of unfavourable Drospirenone differs from the other currently effects on the cardiovascular system in addition to available progestogens in that it has anti-miner- its effects on sodium and potassium.[8] Patients with alocorticoid activity. Therefore, it has the potential primary aldosteronism have been shown to have an to prevent the development and consequences of increased risk of myocardial infarction, stroke, renal cardiovascular disease in pre- and post-menopausal dysfunction, left ventricular hypertrophy and atrial women, as suggested by recent trials of anti-miner- fibrillation compared with patients with essential alocorticoid agents in patients with severe heart hypertension at equivalent blood pressures. failure and left ventricular dysfunction post-myocar- Plasma aldosterone increases tissue ACE,[9] en- dial infarction.[4,5] dothelin[10] and noradrenaline (norepinephrine),[11] Thus, it is appropriate to review the recent litera- resulting in a number of vicious cycles with a further ture in regard to anti-mineralocorticoid therapy and increase in plasma aldosterone levels. Subsequent drospirenone in particular, to explore its potential to activation of the MR results in pro-inflammatory provide cardioprotection when used as an oral con- effects that are vasculotoxic. We now recognise that traceptive as well as for hormone replacement ther- aldosterone contributes to myocardial and vascular apy in post-menopausal women. stiffness, myocardial and vascular hypertrophy, apoptosis, an increase in myocardial calcium con- 1. Relevant Pathophysiology of tent, hypokalaemia, ventricular arrhythmias, renal Cardiovascular Disease dysfunction and endothelial dysfunction, as well as autonomic and central nervous dysfunction (table [8] 1.1 Role of Aldosterone I).

[6] In 1964, Conn et al. observed a high incidence 1.2 Anti-Inflammatory Effects of of hypertension and cardiovascular pathological Mineralocorticoid Receptor (MR) Blockade changes in patients with hyperaldosteronism. Aldos- terone was originally thought to activate miner- Studies using MR blockade in the salt-fed spon- alocorticoid receptors (MR) in the distal renal tubule taneously hypertensive rat stroke-prone model have

Table I. Effects of mineralocorticoid receptor activation 1.3 Cardiovascular Benefits of Aldosterone Endothelial dysfunction Receptor Inhibition Increased free oxygen radicals Increased cytokine production In the 1970s and 1980s, it was assumed that ACE Inflammation inhibition was sufficient to decrease synthesis of Vascular remodelling and decreased vascular compliance Atherosclerosis serum aldosterone. However, ‘aldosterone escape’ Vasoconstriction (where long-term treatment with ACE inhibitors Thrombosis failed to reduce serum aldosterone levels) was found Essential hypertension to occur even when maximal doses of ACE inhibi- Albuminuria tors or combinations of ACE inhibitors and ARBs Increased perivascular and intersitial fibrosis [16-19] Diastolic dysfunction were used to treat patients with heart failure. Electrical inhomogeneity/prolonged QT dispersion/electrical The mechanism for this escape remains unclear, but remodelling potential mechanisms include (i) aldosterone pro- Left ventricular hypertrophy duction by the heart, brain and blood vessels, which Inhibition of baroreflex sensitivity/heart rate variability [20-22] Myocardial apoptosis are angiotensin independent; (ii) direct stimula- [23] Stroke tion by endothelin; and/or (iii) angiotensin II es- Heart failure cape from ACE inhibitor therapy due to production Sodium retention and potassium loss by chymase.[24] Sudden cardiac death Although direct blockade of the aldosterone receptor (mineralocorticoid receptor) seemed like a demonstrated a reduction in proteinuria and renal logical proposition for the problem of aldosterone microvascular lesions, independent of alterations in escape, only recently have clinical trial data from systemic haemodynamics, leading to a reduced inci- RALES (Randomized Aldactone Evaluation Study) dence of stroke and renal injury.[12,13] Similarly, in and EPHESUS (Epleronone Post-Acute Myocardial double transgenic rats harbouring both the human Infarction Heart Failure Efficacy and Survival renin and angiotensinogen genes (dTGR), a model Study) supported the use of aldosterone inhibitors in associated with angiotensin II excess, and vascular the management of patients with advanced (class and myocardial injury, MR blockade reduced colla- III–IV) heart failure and heart failure post-myocar- gen deposition and inflammation in the myocardi- dial infarction. In RALES, patients treated with low- um, concomitant with the downregulation of the dose spironolactone (mean dose 26mg) had a 30% transcription factors: nuclear factor-kappa β and ac- reduction in all-cause mortality.[4] In EPHESUS, tivator protein-1.[14] The benefits of aldosterone eplerenone (mean dose 42.6mg) reduced all-cause blockade have also been demonstrated in animal mortality by 15% and cardiovascular mortality by models of dietary hyperlipidaemia, in which there 17% (table II).[5] are no elevations of serum aldosterone. In this 1.3.1 Potential Mechanisms for the Cardiovascular model, aldosterone blockade resulted in a significant Benefits of MR Blockade decrease in the reduced form of nicotinamide-ade- Baroreceptor dysfunction and subsequent heart nine dinucleotide/the reduced form of nicotinamide- rate variability along with QT dispersion are impor- adenine dinucleotide phosphate (NADH/NADPH) tant independent predictors of sudden cardiac death. oxidase-dependent free-radical generation within Mineralocorticoids have been shown to increase QT the vascular wall and improved endothelial-depen- dispersion.[29] MR blockade improves heart rate va- dent vasodilatation.[15] riability and reduces QT dispersion.[30-33] These ben-

Table II. Clinical endpoint trials using anti-mineralocorticoid agents Trial Endpoint Using spironolactone/eplerenone RALES (Randomized Aldactone Evaluation Reduction in sudden cardiac death/death from heart failure Study)[4] Improved symptoms and decreased hospitalisation New York Heart Association heart failure class improvement EPHESUS (Epleronone Post-Acute Myocardial Reduction in all-cause mortality and death/hospitalisation from cardiovascular Infarction Heart Failure Efficacy and Survival causes Study)[5] Reduction in sudden cardiac death The 4E-Left Ventricular Hypertrophy Study[25] Significant reduction in left ventricular mass with combined ACE inhibitor/ eplerenone therapy Significant reductions in blood pressure

Using drospirenone Preston et al.[26] Blood pressure reduction No significant increases in hyperkalaemia or its cardiac complications White et al.[27] Significant reduction in daytime systolic and diastolic blood pressures No significant increases in hyperkalemia White et al.[28] Significant reductions in 24h systolic blood pressures Significant reductions in total and low-density lipoprotein cholesterol No significant increases in serum potassium efits may be linked to their effects on nitric oxide (LDL) cholesterol oxidation, platelet activation and availability.[34] MR blockade has also been shown to adhesion, vascular smooth muscle migration and prevent ‘electrical remodelling’ post-myocardial in- activation of metalloproteinases. Thus, MR block- farction with a decrease in myocardial calcium con- ade may have broad applicability as an anti-ather- tent and a decrease in action potential. Additionally, ogenic strategy. the effects of MR blockade on myocardial fibrosis MR blockade has been shown to be effective in and on the renal handling of serum/tissue potassium lowering blood pressure in patients with essential and magnesium may help to explain the decrease in hypertension and is particularly effective in patients sudden cardiac death observed in both RALES and with resistant hypertension.[37,38] MR blockade has EPHESUS. also been shown to reduce left ventricular mass and MR blockade also improves endothelial function, the incidence of microalbuminuria in patients with increases nitric oxide availability, inhibits vascular essential hypertension, effects that may have lead to angiotensin I to II conversion and retards thrombotic the reductions in sudden cardiac death observed in response to injury.[35] Additionally, MR blockade EPHESUS.[25] decreases angiotensin type 1 (AT1) receptor expression, increases AT2 receptor expression, and in- 2. Drospirenone: a Progestogen with creases ACE-2, which would favour the production Mineralocorticoid Antagonism of angiotensin 1–7 and 1–9 and thus vasodilatation. Upregulation of several inflammatory markers may Developing a progestogen with a pharmacologi- be inhibited by spironolactone.[36] As a consequence cal profile similar to progesterone, but with in- of the above, MR blockade has been postulated to creased safety and tolerability, has been a subject of have benefits on a variety of processes in atheroscle- intense research over the last 3 decades.[39,40] The rosis; for example, the expression of adhesion mole- currently available progestogens are structurally re- cules, monocyte activation, adhesion and migration lated to either 19-nortestosterone or 17α-hydropro- into the vascular wall, low-density lipoprotein gesterone. Although some of these have anti-andro-

genic properties, none of them have anti-mineralo- similar to that of progesterone, especially regarding corticoid activity when used in clinically relevant its anti-mineralocorticoid and anti-androgenic activ- dosages.[41,42] ity. These characteristics distinguish drospirenone from any other synthetic progestogens currently Drospirenone (6β,7β,15β,16β-dimethylene-3- used as oral contraceptives and hormone replace- oxo-17α-pregn-4ene-21,17 carbolactone [figure 1]) ment therapy. is a unique progestogen and an analogue of the anti- mineralocorticoid spironolactone, which is The anti-mineralocorticoid activity of drospire- synthesised from androstenolone.[43-45] A compre- none has been examined in animal and human mod- hensive, comparative biochemical characterisation els by studying its influence on electrolyte and water of drospirenone and progesterone examined their balance, weight and blood pressure. Ovariectomised interaction with a series of classical steroid hormone rats fed on a low-sodium diet treated with drospire- receptors.[43] It found that drospirenone and proges- none or spironolactone were evaluated for sodium terone have high relative binding affinities for the and potassium excretion.[46,47] Drospirenone was mineralocorticoid receptor (500% and 1000% for more effective than spironolactone in increasing the the human receptor for drospirenone and progester- Na+/K+ excretion rate and at 10 mg/kg/day showed one, respectively; both 100% for the rat receptor). In a sustained stimulation of this electrolyte excretion separate in vitro studies, it was shown that drospire- ratio.[46] Young women on a moderately low sodium none and progesterone inhibit aldosterone-induced and potassium diet were treated with drospirenone mineralocorticoid activity.[43] These studies demon- 2mg on days 8–13 of their menstrual cycle and strate that the biochemical profile of drospirenone is evaluated for sodium and potassium excretion.[48] Women receiving drospirenone had greater sodium O excretion than those treated with placebo. Also, for O H3C reasons not yet clearly understood, the potassium excretion did not differ between the two groups. H C 3 H H Drospirenone also increased plasma renin activity H H and plasma and urine aldosterone during treatment, H suggesting MR blockade. In contrast to cyproterone H O (a progestogen with no anti-mineralocorticoid activ- H ity), drospirenone induced natriuresis and increased Drospirenone plasma renin activity and aldosterone levels during O the follicular phase of the menstrual cycle. CH3 O Drospirenone has not been shown to have signifi- CH3 cant effects on blood pressure in animal studies. During a 4-week treatment with drospirenone (2 mg/ day), blood pressure did not change significantly in OS spontaneously hypertensive rats, whereas equipo- tent doses of levonorgestrel and cyproterone in- OCH 3 creased blood pressure in these animals.[49] Howev- Spironolactone er, in vivo studies have clearly demonstrated the Fig. 1. Chemical structure of the progestogen drospirenone, which has anti-mineralocorticoid activity, and the aldosterone antagonist anti-mineralocorticoid activity of drospirenone in spironolactone. humans.[45] A group of healthy women received

either drospirenone 3mg with varying doses of to the US market to be used as an oral contraceptive ethinylestradiol (15, 20 or 30µg) or levonorgestrel since April 2006 after its FDA approval in March 150µg with ethinylestradiol 30µg for 6 months on 2006. Over 4 million women worldwide are current- days 1–21 of their respective menstrual cycles. The ly using Yasmin® for oral contraception making it mean bodyweight decreased by 0.8 to 1.7kg in the the most widely used oral contraceptive. Drospire- drospirenone/ethinylestradiol group as opposed to none 2mg/estradiol is currently approved and wide- an increase of 0.7kg in the levonorgestrel/ethinyles- ly used in several European countries for hormone tradiol group, a difference that was statistically sig- replacement therapy in post-menopausal women. nificant at p < 0.05. Moreover, systolic and diastolic blood pressure decreased by 1 to 4mm Hg in the 2.2 Potential Benefits of Using Drospirenone/ drospirenone/ethinylestradiol groups, whereas it in- Estradiol in Post-Menopausal Women creased by 1 to 2mm Hg in the levonorgestrel/ ethinylestradiol groups (all, p < 0.05). Recently, it It has been conclusively established that systolic was demonstrated in a randomised, double-blinded, and diastolic blood pressures have a “strong, contin- placebo-controlled clinical trial that drospirenone uous, graded and aetiologically significant” positive combined with estrogen significantly reduces blood correlation with cardiovascular disease out- pressure in post-menopausal women with hyperten- comes.[50] A significant proportion of post-meno- sion.[28] pausal women have elevated and difficult to control [51,52] [53] Drospirenone, like progesterone, has been shown blood pressures. Vasan et al. estimated the to have anti-androgenic activity. Women adminis- crude cardiovascular event rate at 19.5 per 1000 tered drospirenone 3mg with ethinylestradiol person-years in women aged >65 years with high to (15–30µg) have increases in high-density lipopro- normal blood pressure. Small reductions in blood tein cholesterol (9–23%) and triglyceride levels pressure have recently been shown to significantly (47–73%) above baseline compared with those re- delay the onset of clinical hypertension in this co- [54] ceiving levonorgestrel 150µg and ethinylestradiol hort, thereby potentially delaying/reducing sub- 30µg treatment (12% and unchanged from baseline sequent cardiovascular events. Older post-meno- respectively) [all, p < 0.05]. On the other hand, pausal women with elevated blood pressures, in LDL-cholesterol levels in the drospirenone/ particular, have been shown to develop resistant ethinylestradiol group decreased below baseline hypertension in both the Framingham Heart Study (14–20%) compared with the levonorgestrel/ and ALLHAT (Antihypertensive and Lipid-Lower- [55,56] ethinylestradiol group (no effect).[45] ing Treatment to Prevent Heart Attack Trial). Patients with hypertension and diabetes mellitus are 2.1 Yasmin® and Yaz®: Oral Contraceptives shown to benefit from even relatively short periods [57] Containing Drospirenone of adequate treatment. MR blockade has shown significant additional blood pressure reductions in In 2001, Yasmin® 1 containing drospirenone patients with resistant hypertension.[58] Subsequent- 3mg and ethinylestradiol 30µg was approved by the ly, oral drospirenone/estradiol formulations have FDA to be used as an oral contraceptive in the US. been shown to significantly reduce blood pressure in Yaz®, a compound containing drospirenone 3mg hypertensive post-menopausal women.[26,27,59] This and ethinylestradiol 20µg, has been made available blood pressure reduction was in addition to that

1 The use of trade names is for product identification purposes only and does not imply endorsement.

offered by the use of ACE inhibitors and/or ARBs. the risk of thromboembolism and breast cancer Moreover, oral contraceptives containing drospire- in post-menopausal women and high-risk pre- none were shown to have a favourable metabolic menopausal women, the net effect of drospirenone/ profile with regard to plasma lipids and glucose estradiol should be beneficial. Also, in the trials so tolerance compared with other oral contraceptives in far, hyperkalaemia has not been a problem with the healthy women aged 18–34 years,[45] a finding that use of drospirenone. However, the experience with we believe may also be applicable in older post- this compound is currently limited and the mecha- menopausal women (table II). nisms by which hyperkalaemia is prevented when The existing literature on the cardiovascular risks using it, are unknown. Therefore, caution is advised of post-menopausal hormone replacement therapy when using these agents in patients with impaired has employed traditional oral preparations, which renal function. lack mineralocorticoid activity and have suboptimal The hypothesis that drospirenone will prevent the anti-androgenic activity compared with progester- development of cardiovascular disease in pre- and one. No significant reductions in blood pressure post-menopausal women will require confirmation were observed in post-menopausal women treated by prospective, large-scale, randomised clinical tri- with these traditional estrogen/progestogen prepara- als. However, should this hypothesis prove correct, tions in the WHI.[52] the impact on public health in relation to the morbidity, mortality and costs associated with the cardio- 3. Conclusion vascular prevention and treatment of both pre- and post-menopausal women could be profound. Drospirenone, a unique progestogen, has the potential to improve endothelial dysfunction, the sub- Acknowledgements sequent development of hypertension and atherosclerosis and their consequences, including myocar- No sources of funding were used to assist in the prepara- dial infarction and stroke, decrease the progression tion of this review. Dr Pitt has acted as a consultant for of renal dysfunction, reduce the incidence of sudden Berlex, Pfizer, Novartis and Alteon. Dr Motivala has no cardiac death, and prevent left ventricular modelling conflicts of interest that are directly relevant to the content of this review. post-myocardial infarction and the development of heart failure. Additionally, it has been proven to have favourable effects on the serum lipid profile as References 1. Belchetz PE. Hormonal treatment of postmenopausal women. a result of its anti-androgenic activity. These proper- N Engl J Med 1994; 330: 1062-71 ties of drospirenone/estradiol in contrast to other 2. Hersh AL, Stefanick ML, Stafford RS. National use of postme- available progestogen/estrogen combinations could nopausal hormone therapy: annual trends and response to recent evidence. JAMA 2004; 291: 47-53 offer cardioprotection to post-menopausal women. 3. Mosca L, Collins P, Herrington DM, et al. Hormone replace- However, one might anticipate a similar rate of ment therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. thromboembolic risk and breast cancer with this Circulation 2001; 104: 499-503 combination compared with other currently availa- 4. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone ble progestogen/estrogen combinations. This is be- on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. cause the stimulation of hepatic procoagulant pro- N Engl J Med 1999; 341: 709-17 teins by the estrogenic component is probably the 5. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunc- same with the use of these compounds. However, tion after myocardial infarction. N Engl J Med 2003; 348: since the risk of cardiovascular events far exceeds 1309-21

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