Drospirenone for Oral Contraception and Hormone Replacement Therapy Are Its Cardiovascular Risks and Benefits the Same As Other Progestogens?
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Drugs 2007; 67 (5): 647-655 CURRENT OPINION 0012-6667/07/0005-0647/$44.95/0 © 2007 Adis Data Information BV. All rights reserved. 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-mineralo- corticoid 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 © 2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (5) Cardiovascular Risks and Benefits of Drospirenone 649 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 re- ceptor (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