Volume 14, Number 2, 2005
Mary Ann Liebert, Inc.

The Effect of Hormone Replacement Therapy and EFTIHIA SBAROUNI, M.D., ZENON S. KYRIAKIDES, M.D., ABSTRACT
Background: Homocysteine may be an independent risk factor for coronary artery disease
(CAD), and the risk is at least as strong for women as for men. Homocysteine levels are lower
in women compared with men, and homocysteine is lower during pregnancy and higher dur-
ing menopause.

Purpose: To investigate the effects of hormone replacement therapy (HRT), simvastatin, and
their combination on plasma homocysteine levels, we treated 16 postmenopausal, hypercho-
lesterolemic women with CAD with HRT (0.625 mg conjugated equine estrogens [CEE] com-
bined continuously with 2.5 mg medroxyprogesterone), 20 mg simvastatin, and their combi-
nation in a randomized, placebo-controlled study. Each treatment period was 8 weeks long,
with a 4-week washout interval. Plasma homocysteine levels were evaluated at the end of
each treatment period.

Results: Only HRT, alone and in combination with simvastatin, significantly reduced ho-
mocysteine levels compared with placebo (11.82 ؎ 0.74 and 12.22 ؎ 0.71 vs 13.58 ؎ 0.83
mol/L, respectively, p Ͻ 0.05). Simvastatin had no effect (13.02 ؎ 0.94 mol/L), and the com-
bination therapy was not better that monotherapy with HRT.

Conclusions: Oral HRT reduces homocysteine plasma levels, whereas simvastatin has no
effect. If confirmed by randomized, prospective studies with clinical end points, HRT may
be considered for women with mild hypercholesterolemia and high homocysteine levels.

addition, homocysteine levels decrease after es-trogen and antiandrogen administration to male PLASMA HOMOCYSTEINE MAY BE an independent (transsexual) subjects and increase after androgen
risk factor for atherosclerotic vascular dis- administration to female (transsexual) subjects.9 ease.1,2 Homocysteine levels are lower in pre- Lipid-lowering drugs have divergent effects on homocysteine plasma levels. Bile acid resins, matched men.3,4 Similarly, homocysteine levels niacin, and fibrates seem to increase homocys- are reduced during pregnancy4 and increased af- teine,10–15 fish oil may decrease it,16 and statins ter menopause,5 and estrogen replacement ther- do not modify it.12,13,15 Statin therapy is the apy (ERT) significantly decreases homocysteine first-line therapy for women with hypercholes- compared with placebo in healthy postmeno- terolemia and coronary artery disease (CAD).17 pausal women in most6,7 but not all studies.8 In We and others have shown previously that hor- 2nd Department of Cardiology, Onassis Cardiac Surgery Center, Athens, Greece.
mone replacement therapy (HRT) decreases total minated the study early, because of significant re- and low-density lipoprotein (LDL) cholesterol sults, at a prescheduled interim analysis when 16 but not to the degree achieved by a statin, and women had completed the protocol. Of note, the only HRT lowers lipoprotein(a) (Lp(a)).18,19 No HRT regimen is the one used in the HERS and previous study, however, has compared the ef- the ERA trials. Each treatment period was 8 fect of these therapies on homocysteine plasma weeks long, and the washout period between levels. We examined the effect of HRT, simvas- them was a 4-week interval. All patients contin- tatin, and their combination compared with ued the same diet during all treatment arms, and placebo on homocysteine in postmenopausal wo- their antihypertensive-antianginal medications men with hypercholesterolemia. We focused on remained unchanged throughout the study pe- women with CAD, as these may benefit most riod. Blood samples were taken at the end of each from homocysteine reduction. Most previous studies included healthy women only.
Fasting total plasma homocysteine levels were evaluated with a fluoresence polarization im-munoassay (FPIA) method, the AXSYM homo-cysteine assay. The results obtained by this MATERIALS AND METHODS
method are highly correlated with those obtainedby high-performance liquid chromatography at least 12 months of amenorrhea, who were hy- One-way analysis of variance (ANOVA) with percholesterolemic, with fasting total cholesterol repeated measures and post hoc analysis with the 200 mg/dl and LDL cholesterol Ͼ130 mg/dl, Tukey test was applied for comparison.
and with angiographically documented CAD,that is, at least Ͼ80% diameter stenosis of an epi-cardial vessel. Women with a contraindication toHRT—history or family history of breast or en- dometrial cancer, previous thromboembolism, orliver disorders—were excluded from the study.
We treated 16 women, 66 Ϯ 4 years of age All patients had a normal mammogram and a (range 59–72). Thirteen of these had already un- normal cervical smear within the last year, as well dergone revascularization procedures; 7 had per- as normal liver and thyroid function tests. All pa- cutaneous transluminal coronary angioplasty, 5 tients were clinically stable, and those with my- had coronary artery bypass grafting, and 1 had ocardial infarction (MI) or unstable angina within both. The remaining 3 patients were on medical the last 3 months were excluded from the study.
therapy. All treatments were well tolerated. Nine Other exclusion criteria were uncontrolled hy- patients reported mastalgia while on HRT, but pertension, previous stroke, and need for antico- only 1 of the 15 women who had an intact uterus agulation therapy. Patients with conditions asso- suffered vaginal bleeding, immediately after ces- ciated with high homocysteine levels, such as renal failure, hypothyroidism, systemic lupus Results are expressed as mean Ϯ SE. Baseline erythematosus (SLE), and various drug therapies, values of lipids and homocysteine are shown in such as theophylline, methotrexate, and L-dopa, Table 1, and the effects of the four treatments are were also excluded from the study. The study shown in Table 2. Only therapies including HRT protocol was approved by the Ethics Committee significantly decreased homocysteine plasma lev- els compared with placebo. The combination of This was a randomized, placebo-controlled, HRT and the statin was not better than HRT crossover study. All patients were randomly as- alone; simvastatin had no effect on homocysteine.
signed to placebo, HRT (conjugated equine es- The changes induced by each treatment com- trogens [CEE] 0.625 mg daily combined continu- pared with baseline values are 1%, 5%, 14%, and ously with medroxyprogesterone acetate [MPA] 11%, respectively, for placebo, simvastatin, HRT, 2.5 mg daily), simvastatin (20 mg daily), and the and the combination therapy. HRT uniquely de- combination of HRT and simvastatin in all 24 pos- creased homocysteine as well as Lp(a). However, sible orders (Latin square). We had to enroll 24 total and LDL cholesterol were significantly patients according to the study design, but we ter- lower on simvastatin compared with HRT.18 SBAROUNI ET AL.
higher methionine transamination induced by es-trogen are possible mechanisms.28 High levels of homocysteine promote endothelial cell injury by producing reactive oxygen species,29 and estra- diol prevents endothelial damage by increasing the intracellular content of glutathione in vitro.30 Various epidemiological studies have identi- fied a continuous positive association betweenblood homocysteine levels and the risk of vascu- aValues are expressed as mean Ϯ SD for lipids and mea- lar disease,31,32 and this risk is at least as strong sured in milligrams per deciliter. Homocysteine values in women as in men.33,34 This association exists are expressed as mean Ϯ SE and measured in mol/L.
across a broad range of usual homocysteine lev-els; even a 1 mol/L-prolonged lower level of DISCUSSION
blood homocysteine is associated with a 10%lower risk of vascular disease.32 At present, the We have observed a significant decrease in upper limit of the reference range for homocys- homocysteine plasma levels on oral HRT, either teine is Ͻ15 mol/. It seems, however, that car- alone or in combination with simvastatin—13% diovascular risk increases even at lower homo- and 10%, respectively. Previous studies on the cysteine concentrations for both stable coronaryrelation between HRT and homocysteine also patients and acute coronary syndrome patients,35 found a decrease in homocysteine levels in wo- and some authors propose that the desirable men receiving HRT. Some studies showed treat- homocysteine concentration should be Ͻ10 ment effects similar to the effect we found, be- tween 9% and 13%;21–23 other studies observed a Estrogen exert favorable effects on various bi- 7% reduction obtained by HRT.6,7 The addition ological parameters (lipids, fibrinolysis, endothe- of a progestin does not seem to have an unfa- lium, oxidative stress). This, however, has not vorable effect on homocysteine metabolism.23,24 been translated to improvement in clinical out- The effect of transdermal estrogen on homocys- comes, possibly due to proinflammatory and teine levels is controversial.25,26 Simvastatin ther- procoagulant the effects. Both Women’s Health apy had no effect in our study, and this is in Initiative (WHI), in primary prevention, and mul- agreement with three previous reports that eval- tiple randomized, placebo-controlled, secondary uated atorvastatin 10 mg and simvastatin 20 mg, prevention trials have shown no overall benefit respectively.12,13,15 It is, however, possible that higher doses of a statin may be effective in low-ering plasma concentrations of homocysteine.
Such an effect has been reported with 80 mg of CONCLUSIONS
simvastatin.27 No other study has examined theeffect of the combination therapy on homocys- Statins are first-line therapy in patients with teine metabolism, and our results suggest that the CAD and hypercholesterolemia. In addition, their addition of a statin to HRT has no effect.
pleiotropic effects, other than lipid lowering, ren- The mechanisms involved in homocysteine re- der them an effective therapy even in patients duction by estrogen are unknown, but increased with normal cholesterol levels. Current indica- methionine synthase activity in the kidney and tions for HRT are hot flushes and osteoporosis.37 TABLE 2. EFFECT OF HRT AND SIMVASTATIN ON HOMOCYSTEINE LEVELS (MOL/L) aResults are expressed as mean Ϯ SE.
*p Ͻ 0.05 vs. placebo.
Increased plasma homocysteine levels seem to in- lipid lowering agents. A comparison between ator- crease the risk of cardiovascular disease, but it re- vastatin and fenofibrate in patients with mixed hy- mains unclear if lowering homocysteine levels perlipidemia. Atherosclerosis 2001;154:421.
will reduce this risk.38 If this is confirmed by ran- 14. Dierkes J, Westphal S, Kunstmann S, et al. Vitamin supplementation can markedly reduce the homocys- domized, prospective studies with clinical end teine elevation induced by fenofibrate. Atherosclero- points, women with mild hypercholesterolemia and high homocysteine plasma levels may be 15. Melenovsky V, Malik J, Wichterle D, et al. Compari- son of the effects of atorvastatin or fenofibrate on non-lipid biochemical risk factors and the LDL particlesize in subjects with combined hyperlipidemia. AmHeart J 2002;144:E6.
16. Olszewski AJ, McCully KS. Fish oil decreases serum homocysteine in hyperlipidemic men. Cor Artery Dis 1. Ridker PM, Manson JE, Buring JE, et al. Homocys- teine and risk of cardiovascular disease among post- 17. Mosca L, Collins P, Herrington DM, et al. Hormone menopausal women. JAMA 1999;281:1817.
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of hormone replacement therapy alone and in com- 3. Nygard O, Vollset SE, Refsum H, et al. Total plasma bination with simvastatin on plasma lipids of hyper- homocysteine and cardiovascular risk profile. The cholesterolemic postmenopausal women with coro- Hordaland Homocysteine Study. JAMA 1995;274: nary artery disease. J Am Coll Cardiol 1998;32:1244.
19. Herrington DM, Werbel BL, Riley WA, et al. Individ- 4. Morris MS, Jacques PF, Selhub J, et al. Total homo- ual and combined effects of estrogen/progestin ther- cysteine and estrogen status indicators in the third apy and lovostatin on lipids and flow-mediated va- National Health and Nutrition Examination Survey.
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5. Hak AE, Polderman KH, Westendrop ICD, et al. In- 20. Wilcken D, Wang X, Adachi T, et al. Relationship be- creased plasma homocysteine after menopause. Ath- tween homocysteine and superoxide dismutase in ho- mocysteinuria: Possible relevance to cardiovascular 6. Walsh BW, Paul S, Wild RA, et al. The effects of hor- risk. Arterioscler Thromb Vasc Biol 2000;20:1199.
mone replacement therapy and raloxifene on C-reac- 21. Mijatovic V, Kenemans P, Jakobs C, et al. A random- tive protein and homocysteine in healthy postmeno- ized controlled study of the effect of 17beta-estradiol- pausal women: A randomized, controlled trial. J Clin dydrogesterone on plasma homocysteine in post- menopausal women. Obstet Gynecol 1998;91:432.
7. Hak AE, Bak AA, Lindemans J, et al. The effect of hor- 22. Mijatovic V, Netelendos C, van der Mooren MJ, et al.
mone replacement therapy on serum homocysteine Randomized, double-blind, placebo-controlled study levels in perimenopausal women: A randomized con- of the effects of raloxifene and conjugated equine trolled trial. Atherosclerosis 2001;158:437.
estrogen on plasma homocysteine levels in healthy 8. Lacut K, Oger E, Abalain JH, Moineau MP, Mottier postmenopausal women. Fertil Steril 1998;70:1085.
D, on behalf of the SARAH investigators. Effects of 23. van Baal WM, Smolders RG, van der Mooren MJ, et oral and transdermal 17 beta-estradiol combined with al. Hormone replacement therapy and plasma homo- progesterone on homocysteine metabolism in post- cysteine levels. Obstet Gynecol 1999;94:485.
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of long-term hormone replacement therapy on 9. Giltay EJ, Hoogeveen EK, Elbers JM, et al. Effects of plasma homocysteine in postmenopausal women: A sex steroids on plasma total homocysteine levels: A randomized controlled study. Am J Obstet Gynecol study in transsexual males and females. J Clin En- 25. Chiantera V, Sarti CD, Fornaro F, et al. Long-term ef- 10. Blankenhorn DH, Malinow MR, Mack WJ. Colestopil fects of oral and transdermal hormone replacement plus niacin therapy elevates plasma homocysteine therapy on plasma homocysteine levels. Menopause 11. Dierkes J, Westphal S, Luley C. Serum homocysteine 26. Smolders RG, van der Mooren MJ, Teerlink T, et al. A increases after therapy with fenofibrate or bezafibrate.
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27. Luftjohann D, Sigit JI, Locatelli S, et al. High-dose sim- 13. Giral P, Bruckert E, Jacob N, et al. Homocysteine and vastatin decreases plasma concentrations of total SBAROUNI ET AL.
homocysteine in patients with hypercholesterolemia.
Risk in Communities (ARIC) study. Circulation 28. Blom HJ, Boers GH, van den Elzen, JP, et al. Differ- 35. Stubbs PJ, Al-Obaidi MK, Conroy RM, et al. Effect of ences between premenopausal women and young plasma homocysteine concentration on early and late women in the transamination pathway of methionine events in patients with acute coronary syndromes.
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33. Verhoef P, Meleady R, Daly LE, et al. Homocysteine, vitamin status and risk of vascular disease: Effects of gender and menopausal status. Eur Heart J 1999; 34. Folsom AR, Nieto FJ, McGovern PG, et al. Prospec- tive study of coronary heart disease incidence in re- lation to fasting total homocysteine, related geneticpolymorphisms, and B vitamins: The Atherosclerosis

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