]>MAT1245S0378-5122(98)00056-510.1016/S0378-5122(98)00056-5Elsevier Science Ireland LtdFig. 1Reductions in lipoprotein(a) during hormone replacement therapy.Table 1Reduction in homocysteine during hormone replacement therapyHRT regimen*Reduction (%)AuthorReferenceOestradiol–dydrogesterone (sc)10.9Van der MoorenEur J Clin Invest 1994;24:733–736Conj. oestrogen–medrogestone (sc)6.8Van der MoorenFertil Steril 1997;67:67–73Oestradiol–dydrogesterone (cc)13.5MijatovicFertil Steril 1998;69:876–882Oestradiol–dydrogesterone (sc)12.6MijatovicObstet Gynecol 1998;91:432–436*Oral HRT regimen; sc, sequentially combined; cc, continuously combined.Hormone replacement therapy in postmenopausal women with specific risk factors for coronary artery diseaseMarius Jvan der Mooren*VeljaMijatovicWMarchien van BaalCoen D.AStehouwerProject ‘Ageing Women’, Departments of Obstetrics and Gynaecology and Internal Medicine, University Hospital-Vrije Universiteit, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands*Corresponding author. Tel: +31 20 4443244; fax: +31 20 4444422; e-mail: mj.vandermooren@azvu.nlAbstractHormone replacement therapy (HRT) in postmenopausal women is associated with a reduction in the risk of developing coronary artery disease (CAD) of about 50%. Women with an elevated risk for CAD appear to benefit most by HRT. The HRT-associated cardiovascular protection may be related to favourable changes in several important cardiovascular risk estimators, such as circulating blood concentrations of cholesterol, lipoprotein(a) (Lp(a)) and homocysteine. This paper reviews the literature presently available on the effects of HRT on cholesterol, Lp(a) and homocysteine concentrations, and special attention will be given to the effects on their elevated concentrations. The effect of HRT in women with hypertension is reviewed as well. From this overview it can be concluded that risk factors such as cholesterol, Lp(a), and homocysteine can be favourably modulated by HRT, and especially, that the strongest reductions can be achieved in those women with the highest concentrations. Although clinical trials still need to demonstrate the impact of lowering concentrations of Lp(a) and homocysteine, HRT appears to be a promising risk reduction strategy in this respect.KeywordsCoronary artery diseaseOestrogensHormone replacement therapyRisk factorsCholesterolLipoprotein(a)HomocysteineHypertension1IntroductionIn industrialised countries coronary artery disease (CAD) is the major cause of death in women. The mortality rate from CAD is about 3–4 fold that related to cancer. The risk of developing atherothrombotic CAD is associated with various factors. Modulation of these factors is a potential tool for the primary and secondary prevention of CAD, and may therefore be of great importance for the cardiovascular health in the individual, but it may also have a substantial socio-economic impact.In women as compared to men, the incidence of CAD is low before the age of 50. In contrast, in women older than 50, CAD risk strongly increases, indicating that the postmenopausal oestrogen deficiency state is a major risk factor in the development of CAD. Moreover, young ovariectomised women also suffer from an increased risk of dying from CAD [1], which supports the hypothesis that loss of ovarian function increases CAD risk.Accumulating evidence supports the suggested cardiovascular protective role of postmenopausal hormone replacement therapy (HRT) [2, 3]. Many epidemiological studies and several meta-analyses have reported a 50% lower incidence of CAD in oestrogen users compared with non-users [4], and comparable data have recently been published for combined oestrogen–progestogen users [5]. In addition, experimental studies in monkeys [6], in rabbits and rats have demonstrated that hormone administration reduces the arterial cholesterol accumulation.The cardiovascular protective influence of HRT appears to be of special benefit in women at high risk for CAD [7–12]. In the Lipid Research Clinic study, Bush et al. [7]reported a stronger reduction in CAD mortality in oestrogen-using hyperlipidaemic women compared with oestrogen-using normo-lipidaemic women. Ross et al. [8]demonstrated, in oestrogen-using women, that CAD mortality was relatively more reduced in heavy smokers when compared with non-smoking women. Ten-year mortality in oestrogen-using versus non-using women with angiographically proven CAD was more reduced in women with severe coronary stenosis than in women with normal angiography [9].2Risk factorsAn increasing number of factors have been identified which influence the risk of developing CAD. For many years, most attention was given to the impact on CAD risk due to changes in serum lipids and lipoproteins, and it was demonstrated that postmenopausal women have a more atherogenic lipid profile when compared with premenopausal women. Furthermore, HRT was found to have favourable effects on the lipid profile reflected by a reduction in the atherogenic LDL-cholesterol and an increase in the anti-atherogenic HDL-cholesterol.However, the alterations in lipids and lipoproteins appear to explain only 30–50% of the cardiovascular benefit of HRT [7]. Many other cardiovascular risk factors (haemostatic and fibrinolytic factors, parameters of endothelial function and parameters of vascular and cardiac function) have recently been reported to be modulated by sex steroids, and therefore may contribute to the cardiovascular protection mediated by postmenopausal HRT [3, 13, 14]. Recent reports have demonstrated that plasma concentrations of lipoprotein(a) (Lp(a)) and homocysteine are independent cardiovascular risk factors that play a role in the modulating influence of sex steroids on CAD risk.The next paragraphs will review the literature presently available on the effects of HRT in women with increased cardiovascular risk based on specific risk factors, namely hypercholesterolaemia, high Lp(a), hyperhomocysteinaemia, and hypertension. Although HRT has been reported to beneficially influence the fibrinolytic potential without disturbing coagulation, and to reduce postmenopausal insulin resistance, most of these studies were done in healthy women [14, 15]. However, in postmenopausal women with non-insulin-dependent diabetes mellitus short-term treatment with 17β-oestradiol results in an improvement of insulin sensitivity in the liver, glycaemic control, the lipoprotein profile and fibrinolysis [16, 17]. Until now no data were available on the effects of HRT in women with risk factors such as a high fibrinogen level or a disturbed coagulation-fibrinolysis balance, heavy smoking, and obesity, and therefore these risk factors will not be reviewed here.2.1CholesterolThe effects of HRT on conventional lipids and lipoproteins, such as total cholesterol, LDL- and HDL-cholesterol, triglycerides and apolipoproteins, have been thoroughly investigated and published in numerous reports [15, 18–20]. In general it can be concluded that during oral HRT, plasma concentrations of total and LDL-cholesterol decrease by about 10–15% and HDL-cholesterol increases by about 10–15%, all changes that favour cardiovascular health. Triglyceride concentrations however increase during oral HRT, the clinical relevance of which is unknown. The effects of transdermal HRT on lipids and lipoproteins are generally less marked, but do not show an increase in triglycerides.2.2HRT and hypercholesterolaemiaIn hypercholesterolaemic women, HRT, both oral and transdermal, is effective in improving the lipid and lipoprotein profile [21–27].Slowinska-Srzednicka et al. [23]observed an increase of 62% in HDL2-cholesterol and a decrease of 10% in total cholesterol during treatment of 11 postmenopausal non-obese hypercholesterolaemic women with transdermal 17β-oestradiol (100 μg/day), sequentially combined with oral chlormadinone acetate (2 mg/day).Tonstad et al. [24]demonstrated reductions of 14 and 19% in total cholesterol and in LDL-cholesterol, respectively, during treatment of hypercholesterolaemic women with oral sequentially combined 17β-oestradiol plus norethisterone acetate, in addition to a lipid-lowering diet. The reduction in LDL-cholesterol correlated positively with its initial level, indicating stronger reductions in women with high LDL-cholesterol.Denke [25]reported continuous combined conjugated oestrogens (0.625 mg/day) plus medroxyprogesterone acetate (2.5 mg/day) to be very effective in addition to a lipid-lowering diet in 32 hypercholesterolaemic women. Total cholesterol was reduced by 17%, and in 62% of women the high LDL-cholesterol concentrations were normalised.Recent studies [26, 27]have demonstrated that treatment with statins, when compared with HRT, are more potent in reducing total cholesterol and LDL-cholesterol in hypercholesterolaemic postmenopausal women, and do also reduce triglyceride levels, whereas oestrogen replacement increases HDL-cholesterol and triglycerides. Treatment with conjugated oestrogens plus pravastatin resulted in the combined favourable effects of both individual treatments [27].It can be concluded that, from the data available so far, HRT, oral as well as transdermal, appears to provide an effective approach in the management of hypercholesterolaemia in postmenopausal women.2.3Lipoprotein(a)Lp(a) is an independent risk factor for atherothrombotic cardiovascular disease [28–30]. The Lp(a) particle structurally greatly resembles low density lipoprotein. However, in Lp(a), the protein moiety consisting of apoprotein B-100 is covalently linked to the glycoprotein Apo(a). Due to the similarity of Apo(a) to plasminogen, Lp(a) competes for the binding of plasminogen in the fibrinolytic cascade. Furthermore, Lp(a) may accumulate in the arterial wall and contribute to the formation of atherosclerotic plaques. Therefore, Lp(a) has both thrombogenic and atherogenic properties.Genetic constitution strongly determines circulating levels of Lp(a). Unlike other lipoproteins, Lp(a) concentrations have been demonstrated to be moderately reduced by only a few drugs [31].After natural and surgical menopause, Lp(a) concentrations increase [32–34], indicating that the postmenopausal elevation in CAD risk may be mediated, at least in part, by changes in Lp(a) concentrations. During the last decade, several studies have reported that Lp(a) can be reduced by postmenopausal HRT [34–49].2.4HRT and high lipoprotein(a)The Lp(a)-lowering effects of HRT are reported to vary widely from 10 to 50% [34–49](Fig. 1), and some of these are already demonstrable after 2 months of intervention [38]. This probably is related to the diversity of HRT regimens studied, and it has been suggested that androgenic progestogens induce the largest fall in Lp(a). Crook et al. [50]reported a mean reduction of 79% in premenopausal women treated for endometriosis with the anabolic steroid danazol. Some of the studies have demonstrated a correlation between the reduction in Lp(a) and its level before intervention.Soma et al. [35]were the first to report a 51% fall in mean Lp(a) after 12 months of treatment with sequentially combined oral conjugated oestrogen (1.25 mg/day)-medroxyprogesterone acetate (10 mg/day). They later reported a significant correlation between absolute decrease in Lp(a) and baseline concentrations (r=0.59; P<0.001) in the same trial [36, 37].Farish et al. [38]observed a 47% reduction in Lp(a) after 2 months of treatment with oral norethisterone (10 mg/d). Their data indicated a larger fall in the women (n=2) with the highest pretreatment value.Lobo et al. [39]found marginally significant reductions of 31.7 and 26.9%, respectively, during 6 months of treatment with oral conjugated oestrogen (0.625 mg/d) only whether or not combined with excercise. They also observed a non-significant reduction of 10.6% during 6 months treatment with transdermal oestradiol (50 μg/day). In contrast to others [36–38, 41, 45, 48, 49], the authors found the largest fall (38%) in women with low Lp(a) values compared with a fall of 8% in women with ‘high’ values. However, they chose a threshold value of only 100 mg/l, which is rather low.Van der Mooren et al. [40]demonstrated a significant reduction of 17.5% after 6 months of treatment with sequentially combined oral oestradiol (2 mg/day)-dydrogesterone (10 mg/day), and in their 2-years’ report they showed this reduction to persist for 24 months, and also to be present in women with Lp(a) concentrations higher than 300 mg/l, a threshold level that appears to confer a significant higher risk of atherothrombotic disease [51].Marsh et al. [41]reported a decrease of 17.6% after 12 months treatment with continuously combined oral oestradiol (1 mg/d)-desogestrel (0.15 mg/d), and found a significant correlation between absolute change in Lp(a) and the pretreatment value (r=0.66; P<0.001).Taskinen et al. [45]observed mean decreases in Lp(a) of 31 and 16% after 12 months of treatment with, respectively, continuous combined oral oestradiol (2 mg/day)-norethisterone (1 mg/day) therapy and sequentially combined transdermal oestradiol (50 μg/day)-oral medroxyprogesterone acetate (10 mg/day) regimen. The decrement in Lp(a) was significantly correlated with the baseline Lp(a) levels (r=0.96 and 0.88, respectively; P<0.001). The authors observed a larger reduction in subjects with high baseline Lp(a) values during both HRT regimens.Mijatovic et al. [48]reported a mean decrease of 13.0% after 6 months’ treatment with a continuous combined oral oestradiol (2 mg/d)-dydrogesterone (2.5–15 mg/day) regimen. The reduction in Lp(a) correlated significantly with baseline Lp(a) (r=0.65; P<0.001), and women with high pretreatment values (>250 mg/l) performed better (P=0.055) than women with with normal baseline values.Tuck et al. [49]found a mean decrease of 23% (P=0.0002) after 4 weeks treatment with oral conjugated oestrogen (0.625 mg/d), and in their study the absolute amount of Lp(a) lowering correlated with the initial Lp(a) level (r=0.6; P=0.018) although they could not detect a difference between women with Lp(a) levels>40 mg/dl compared with subject with Lp(a) levels<30 mg/dl.How HRT interacts with Lp(a) metabolism still needs to be elucidated. Possibly LDL-receptor-mediated degradation of Lp(a) increases as the LDL-receptor is upregulated by oestrogens [52–54]. Alternatively, increased oestrogen-induced VLDL-synthesis in the liver may hamper the production of Lp(a) and be responsible for lower Lp(a) levels during oestrogen administration [55, 56].2.5HomocysteineHomocysteine is the demethylated derivative of the essential amino acid methionine. Mildly elevated plasma concentrations of homocysteine (hyperhomocysteinaemia) are an independent risk factor for vascular occlusive disease [57–65]. In addition, there is increasing evidence that homocysteine may affect the coagulation system and the resistance of the endothelium to thrombosis [66], and that it may interfere with the vasodilator and anti-thrombotic functions of nitric oxide [67].Plasma levels of homocysteine are, in part, genetically determined [65, 68], but acquired states such as folic acid and vitamin B deficiences as well as renal and liver failure may increase homocysteine levels too [59]. Homocysteine concentrations have also been reported to be higher in postmenopausal women compared to premenopausal women [69, 70], indicating that the low CAD risk before menopause may be related, in part, to favourable effects of oestrogens and/or progestogens on homocysteine metabolism. On the other hand, HRT reduces homocysteine concentrations in postmenopausal women [71–75].2.6HRT and hyperhomocysteinaemiaOnly few studies have been published on the relation between HRT and homocysteine metabolism [71–75](Table 1). The first report by Van der Mooren et al. [71]demonstrated a significant reduction of 10.9% in fasting serum homocysteine concentrations after 6 months of treatment with sequentially combined oestradiol (2 mg/day)-dydrogesterone (10 mg/day) therapy in 21 healthy postmenopausal women. Most of the demonstrated reduction could be attributed to the decrease of 17% observed in the women with elevated baseline homocysteine concentrations (higher than 13.8 μmol/l). The observed decrease was maintained during 24 months of treatment.Another observation from the same group was done in women treated with transdermal oestradiol in two dosages, 50 and 80 μg/day [72]. Although the decreases in homocysteine levels were modest, again reductions (about 10%) were observed especially in women with elevated homocysteine values at baseline.Furthermore, a significant decrease of 6.8% in fasting plasma homocysteine concentrations was demonstrated after 6 months of treatment with 3-monthly sequentially combined conjugated oestrogen (0.625 mg/day)-medrogestone (10 mg/day) therapy in 23 healthy postmenopausal women [73]. In this study, the decrease was also found especially in the hyperhomocysteinaemic women in whom a significant 12% reduction was observed. However, in this study the reduction in homocysteine was temporary and after 12 months of treatment no significant changes versus baseline were found. A large uncontrolled study by Mijatovic et al. [74]in 135 healthy postmenopausal women treated with continuously combined oestradiol (2 mg/day)-dydrogesterone (2.5–15 mg/day) therapy demonstrated a significant reduction in homocysteine levels of 13.5% after six months of treatment. They also observed the largest reduction in the women with the highest baseline homocysteine concentrations. The abolute decrease in homocysteine significantly correlated with the pretreatment concentration (r=0.42; P<0.001) indicating a larger reduction in women with high homocysteine levels. However, all these studies were uncontrolled, and three of them consisted of relatively small numbers. They remained therefore inconclusive.Very recently, our group demonstrated, for the first time in a controlled study, that HRT, given as sequentially combined oestradiol (1 mg/day)-dydrogesterone (5–10 mg/day) therapy during 15 months, reduced homocysteine concentrations with 12.6% versus baseline, whereas no changes were observed in a control group [75].The mechanisms underlying the observed decrease in plasma homocysteine by HRT are still unknown. It may be related to an increase in kidney methionine synthase activity [76]and to changes in the transamination of methionine [77], but it may also result from anabolic/catabolic effects [78].From the data currently available we can conclude that homocysteine concentrations can be reduced by postmenopausal HRT and that women with elevated levels demonstrate the largest reduction. Although the clinical relevance of lowering homocysteine concentrations still has to be elucidated, indirect data based on B-vitamin (folate, vitamin B6 and B12) administration (which are potent homocysteine-lowering agents) induced reduction in atherosclerotic plaque formation [79]and reduction in non-fatal myocardial infarction and fatal coronary heart disease [80]are very promising. Future prospective randomised clinical trials on cardiovascular outcome in hyperhomocysteinaemic women are needed before HRT can indeed be recommended as risk reduction strategy in hyperhomocysteinaemic women.3Blood pressureThe effects of HRT on blood pressure have scarcely been investigated. Most studies have reported no change or a small decrease in systolic and diastolic blood pressures [13, 81–91]. Proposed mechanisms to explain these observations are vasodilation [92], possibly related to calcium antagonistic effects of oestrogens [93], and inhibition of the angiotensin-converting-enzyme [94].3.1HRT and hypertensionIn an open prospective study Lip et al. [85]reported no changes in systolic and diastolic blood pressures in 75 hypertensive women on HRT for 8–32 months.Although Pines et al. [86]observed no changes in blood pressure after 6–9 months of oral conjugated oestrogens (0.625 mg/day) or oestradiol (2 mg/day) in 14 postmenopausal women with borderline to mild hypertension, they demonstrated a significant improvement in several parameters of cardiac function as measured by echocardiography at rest and during exercise.Van der Mooren [90]reported significant reductions of respectively 6.8 and 8.6 mmHg in systolic and diastolic blood pressures of 99 postmenopausal women with baseline diastolic blood pressure of 90 mmHg or more, and treated for 6 months with sequentially combined oral 17β-oestradiol (2 mg/day) plus dydrogesterone (5–20 mg/day).In a double-blind, randomised, placebo-controlled trial Kornhauser et al. [91]observed no changes in blood pressure after 90 days treatment with two HRT regimen in hypertensive postmenopausal women who had interrupted their antihypertensive medication.It can be concluded from the data available so far that HRT has no unfavourable effects in (mildly) hypertensive postmenopausal women. Taking into account all the other reported cardiovascular benefits of HRT, together with the possible slight reduction in both systolic and diastolic blood pressures, this population at risk should not be denied HRT.4ConclusionsBased on the literature presently available, there is strong evidence that cholesterol, Lp(a) and homocysteine, as important predictors for occlusive arterial disease, can be favourably modulated by HRT, and that the strongest reductions can be achieved in women with the highest concentrations.Although clinical trials still need to demonstrate the impact of lowering concentrations of homocysteine and Lp(a), HRT appears to be a promising risk reduction strategy in this respect.References1MJStampferGAColditzWCWillettMenopause and heart disease: a reviewAnn NY Acad Sci59219901932032PGCrosignaniPKenemansRPaolettiMRSomaFPWoodfordHormone replacement and the menopause: a European position paperEur J Obstet Gynecol Reprod Biol74199767723APinesVMijatovicMJVan der MoorenPKenemansHormone replacement therapy and cardioprotection: basic concepts and clinical considerationsEur J Obstet Gynecol Reprod Biol7119971931974FGrodsteinMJStampferThe epidemiology of coronary heart disease and estrogen replacement in postmenoausal womenProg Cardiol Dis3819951992105FGrodsteinMJStampferJEMansonPostmenopausal estrogen and progestin use and the risk of cardiovascular diseaseNew Engl J Med33519964534616JKWilliamsMSAnthonyEKHonoreRegression of atherosclerosis in female monkeysArterioscler Thromb Vasc Biol1519958278367TLBushEBarrett-ConnorLDCowanCardiovascular mortality and noncontraceptive use of estrogen in women: results from the lipid research clinics program follow-up studyCirculation751987110211098RKRossAPaganini-HillTMMackMArthurBEHendersonMenopausal oestrogen therapy and protection from death from ischaemic heart diseaseLanceti19815555609JMSullivanRVan der ZwaagJPHughesEstrogen replacement and coronary artery disease: effects on survival in postmenopausal womenArch Intern Med15019902557256210JHO’KeefeSCKimRRHallVCCochranSLLawhornBDMcCallisterEstrogen replacement therapy after coronary angioplasty in womenJ Am Coll Cardiol2919971511GMCRosanoPMSarrelPAPoole-WilsonPCollinsBeneficial effect of estrogen on exercise-induced myocardial ischaemia in women with coronary artery diseaseLancet342199313313612KMNewtonAZLaCroixBMcKnightEstrogen replacement therapy and prognosis after first myocardial infarctionAm J Epidemiol145199726927713Postmenopausal Estrogen/Progestin Intervention Trial Writing GroupEffects of estrogen/progestin regimen in heart disease risk factors in postmenopausal womenJ Am Med Assoc273199519920814VMijatovicAPinesCDAStehouwerMJVan der MoorenPKenemansThe effects of oestrogens on vessel wall and cardiac function, haemostasis and homocysteine metabolismEur Menopause J33199620921815MJVan der MoorenVMijatovicAPinesThe cardiovascular risk profile: influence of menopausal status and postmenopausal HRTGynaecology Forum131996121816HEBrussaardJAGevers LeuvenMFrolichCKluftHMKransShort-term oestrogen replacement therapy improves resistance, lipids and fibrinolysis in postmenopausal women with NIDDMDiabetologica40199784384917HEBrussaardJAGevers LeuvenCKluftEffect of 17β-estradiol on plasma lipids and LDL oxidation in postmenopausal women with type II diabetes mellitusArterioscler Thromb Vasc Biol17199732433018AHMRijpkemaAAVan der SandenAHCRuijsEffects of post-menopausal oestrogen-progestogen replacement therapy on serum lipids and lipoproteins: a reviewMaturitas12199025928519RALoboEffects of hormonal replacement on lipids and lipoproteins in postmenopausal womenJ Clin Endocrinol Metab73199192593020GSamsioeLipid profiles in estrogen usersRSitruk-WareWUtianThe Menopause and Hormonal Replacement Therapy1991Marcel DekkerNew York18120021GSamsioeGBalsellAÅbergKSandinTransdermal oestradiol plus medroxyprogesteron acetate lowers cholesterol in moderately hypercholesterolemic womenMaturitas27 Suppl196665 (abstract)22MJTikkanenEANikkiläEVariainenNatural oestrogen as an effective treatment for type-II hyperlipoproteinaemia in postmenopausal womenLancetii197849049223JSlowinska-SrzednickaSZgliczynskiEChotkowskaEffects of transdermal 17β-oestradiol combined with oral progestogen on lipids and lipoproteins in hypercholesterolaemic postmenopausal womenJ Int Med234199344745124Tonstad S, Ose L, Görbitz C, Djoseland, Bard JM, Fruchart JC. Efficacy of sequential hormone replacement therapy in the treatment of hypercholesterolaemia among postmenopausal women. J Int Med 1995;238:39–47.25MADenkeEffects of continuous combined hormone-replacement therapy on lipid levels in hypercholesterolemic postmenopausal womenAm J Med991995293526GMDarlingJAJohnsPIMcCloudSRDavisEstrogen and progestin compared with simvastatin for hypercholesterolemia in postmenopausal womenNew Engl J Med337199759560127MHDavidsonLMTestolinKCMakiSvon DuvillardKBDrennanA comparison of estrogen replacement, pravastatin, and combined treatment for the management of hypercholesterolemia in postmenopausal womenArch Int Med15719971186119228GHoeflerFHarnoncourtEPaschkeWMitrlKHPfeifferGMKostnerLipoprotein(a): a risk factor for myocardial infarctionArteriosclerosis8198839840129AMScanuRMLawnKBergLipoprotein(a) and atherosclerosisAnn Intern Med115199120921830VMGMaherBGBrownLipoprotein(a) and coronary heart diseaseCurr Opin Lipidol6199522923531LBerglundDiet and drug therapy for lipoprotein(a)Curr Opin Lipidol61995485632JHeinrichMSandkampRKokottHSchulteGAssmanRelationship of lipoprotein(a) to variables of coagulation and fibrinolysis in a healthy populationClin Chem3719911950195433CJKimWSRyuJWKwakCTParkUHRyooChanges in Lp(a) lipoprotein and lipid levels after cessation of female sex hormone production and estrogen replacement therapyArch Intern Med156199650050434FBruschiMMeschiaMSomaDPerottiRPaolettiPGCrosignaniLipoprotein(a) and other lipids after oophorectomy and estrogen replacement therapyObstet Gynecol88199695095435MRSomaRFumagalliRPaolettiEffect of oestrogen and progestin on plasma Lp(a) levels in postmenopausal womenLancet3371199161236MRSomaIOsnago-GaddaRPaolettiThe lowering of lipoprotein(a) induced by estrogen plus progesterone replacement therapy in postmenopausal womenArch Intern Med15319931462146837MRSomaMMeschiaFBruschiHormonal agents used in lowering lipoprotein(a)Chem Phys Lipids67/68199434535038EFarishHARoltonJFBarnesDMHartLipoprotein(a) concentrations in postmenopausal women taking norethisteroneBr Med J303199169439RALoboMNotelovitzLBernsteinFYKhanRKRossLPWellingtonLp(a) lipoprotein: relationship to cardiovascular disease risk factors, excercise, and estrogenAm J Obstet Gynecol16619921182119040MJVan der MoorenPNMDemackerCMGThomasGFBormRRollandA 2-year study on the beneficial effects of 17β-oestradiol-dydrogesterone therapy on serum lipoproteins and Lp(a) in postmenopausal women: no additional unfavourable effects of dydrogesteroneEur J Obstet Gynecol Reprod Biol52199311712341MSMarshDCrookSIJWhitcroftMWorthingtonMIWhiteheadJCStevensonEffect of continuous combined estrogen and desogestrel hormone replacement therapy on serum lipids and lipoproteinsObstet Gynecol831994192342JRymerDCrookMSidhuMChapmanJCStevensonEffects of tibolone on serum concentrations of lipoprotein(a) in postmenopausal womenActa Endocrinol (Cph)128199325926243SMendozaEVelazquesAOsonaTHamerCJGlueckPostmenopausal cyclic estrogen-progestin therapy lowers lipoprotein(a)J Lab Clin Med123199483784144CJKimHCJangDHChoYKMinEffect of hormone replacement therapy on lipoprotein(a) and lipids in postmenopausal womenArterioscler Thromb14199427528145MRTaskinenJPuolakkaTPyoralaHormone replacement therapy lowers plasma Lp(a) concentrations. Comparison of cyclic transdermal and continuous estrogen–progestin regimensArterioscler Thromb Vasc Biol1619961215122146CHainesTChungAChangJMasareiBTomlinsonEffect of oral estradiol on Lp(a) and other lipoproteins in postmenopausal women. A randomised, double-blind, placebo-controlled, crossover studyArch Intern Med156199686687247MMGelfandPFugereFBissonnetteConjugated estrogens combined with sequential dydrogesterone or medroxyprogesterone acetate in postmenopausal women: effects on lipoproteins, glucose tolerance, endometrial histology, and bleedingMenopause41997101848VMijatovicPKenemansJCNetelenbosERAPeters-MullerGJVan KampGAVoetbergPHMVan de WeijerMJVan der MoorenOral 17β-oestradiol continuously combined with dydrogesterone lowers serum lipoprotein(a) in healthy postmenopausal womenJ Clin Endocrinol Metab8219973543354749CHTuckSHolleranLBerglundHormonal regulation of lipoprotein(a) levels: effects of estrogen replacement therapy on lipoprotein(a) and acute phase reactants in postmenopausal womenArterioscler Thromb Vasc Biol1719971822182950DCrookMSidhuMSeedMO’DonnellJCStevensonLipoprotein(a) levels are reduced by danazol, an anabolic steroidAtherosclerosis921992414751AMScanuGMFlessLipoprotein(a): heterogeneity and biological relevanceJ Clin Invest8519901709171552MLSnyderRVHayPFWhitingtonAMScanuGMFlessBinding and degradation of lipoprotein(a) and LDL by primary cultures of human hepatocytesArterioscler Thromb14199477077953SLHofmanDLEatonMSBrownWJMcConathyJLGoldsteinREHammerOverexpression of human low density lipoprotein receptors leads to accelerated catabolism of Lp(a) lipoprotein in transgenic miceJ Clin Invest8519901542154754EWindlerPTKovanenYSChaoMLBrownRJHavelJLGoldsteinThe estradiol stimulated lipoprotein receptor of rat liverJ Biol Chem25519801964197155DJRaderWCainKIkewakiThe inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rateJ Clin Invest9319942758276356WJMcConathyVNTrierEKorenCSWangCCCorderTriglyceride-rich lipoprotein interactions with Lp(a)Chem Phys Lipids67–68199410511457PMUelandHRefsumLBrattströmPlasma homocysteine and cardiovascular diseaseRBFrancisAtherosclerotic Cardiovascular Disease, Hemostasis and Endothelial Function1992Marcel DekkerNew York18323658MJStampferMRMalinowWCWillettA prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physiciansJ Am Med Assoc268199287788159LDalyKRobinsonKSTanIMGrahamHyperhomocysteinaemia: a metabolic risk factor for coronary heart disease determined by both genetic and environmental influencesQ J Med86199368568960KRobinsonELMayerDPMillerHyperhomocysteinemia and low pyrodixal phosphate. Common and independent reversible risk factors for coronary artery diseaseCirculation9219952825283061CJBousheySAABeresfordGSOmennAGMotulskyA quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakesJ Am Med Assoc27419951049105762GAlfthanAAroKFGreyPlasma homocysteine and cardiovascular disease mortalityLancet349199739763IMGrahamLEDalyHMRefsumPlasma homocysteine as a risk factor for vascular disease–the European concerted action projectJ Am Med Assoc2772219971775178164ONygardJENordrehaugHRefsumPMUelandMFarstadSEVollstePlasma homocysteine levels and mortality in patients with coronary diseaseNew Eng J Med337199723023665HJBlomMJVan der MoorenHyperhomocysteinemia: a risk factor for cardiovascular disease-Influence of sex hormones on homocysteine metabolismGynecol Endocrinol10Suppl 21996757966MRMalinowHomocyst(e)ine and arterial occlusive diseasesJ Intern Med236199460361767JSStamlerASlivkaBiological chemistry of thiols in the vasculature and in vascular-related diseaseNutr Rev54199613068SHMuddFSkovbyHLevyThe natural history of homocystinuria due to cystathionine β-synthase deficiencyAm J Hum Genet37198513169GHJBoersAGHSmalsJMFTrijbelsAILeermakersPWKloppenborgUnique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive yearsJ Clin Invest7219831971197670MGAJWoutersMThECMoorreesMJVan der MoorenHJBlomGHJBoersLASchellekensCMGThomasTKABEskesPlasma homocysteine and menopausal statusEur J Clin Invest25199580180571MJVan der MoorenMGAJWoutersHJBlomLASchellekensTKABEskesRRollandHormone replacement therapy may reduce high serum homocysteine in postmenopausal womenEur J Clin Invest24199473373672Van der Mooren MJ, Wouters MGAJ, Blom HJ, Schellekens LA, Eskes TKAB, Rolland R. Homocysteine: a new cardiovascular risk factor. Influences of menopause and hormone replacement. Abstract FC-2; abstract book, 11th Congress of European Association of Gynaecologists and Obstetricians, Budapest, Hungary, June 1996.73MJVan der MoorenPNMDemackerHJBlomYBDe RijkeRRollandThe effects of sequential three-monthly hormone replacement therapy on several cardiovascular risk estimators in postmenopausal womenFertil Steril671997677374VMijatovicPKenemansJCNetelenbosCJacobsCPopp-SnijdersERAPeters-MullerMJVan der MoorenPostmenopausal oral 17β-oestradiol continuously combined with dydrogesterone reduces fasting serum homocysteine levelsFertil Steril69199887688275VMijatovicPKenemansCJacobsWMVan BaalERAPeters-MullerMJVan der MoorenA randomized controlled study of the effects of 17β-oestradiol-dydrogesterone on plasma homocysteine in postmenopausal womenObstet Gynecol91199843243676JFinkelsteinMethionine metabolism in mammals. Effect of age, diet, and hormones on three enzymes of the pathway in rat tissuesArch Biochem Biophys122197258359077HJBlomGHJBoersJPAMElzenJJMVan RoesselJMFTrijbelsATangermanDifference between premenopausal women and young men in the transamination pathway of methionine catabolism and the protection against vascular diseaseEur J Clin Invest18198863363878EJGiltayEKHoogeveenJMElbersLJGoorenHAsschemanCDStehouwerEffects of sex steroids on plasma total homocysteine levels: a study in transsexual males and femalesJ Clin Endocrinol Metab83199855055379JCPetersonJDSpenceVitamins and progression of atherosclerosis in hyper-homocyst(e)inaemiaLancet351199826380EBRimmWCWillettFBHuFolate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among womenJAMA279199835936481NMKaplanEstrogen replacement therapy. Effect on blood pressure and other cardiovascular risk factorsJ Reprod Med30198580280482CAMaschakRALoboEstrogen replacement therapy and hypertensionJ Reprod Med30198580581083CHassagerBJRiisVStromTTGuyeneCChristiansenThe long term effect of oral and percutaneous estradiol on plasma renin substrate and blood pressureCirculation76198775375884Foidart JM. Effects of estraderm-TTS 50 plus medroxyprogesterone acetate on blood pressure in hypertensive postmenopausal women. In: Samsioe G, editor. Cardiovascular Disease and HRT. Parthenon Publ Group, 1992, 41–44.85GYLipMBeeversDChurchillDGBeeversHormone replacement therapy and blood pressure in hypertensive womenJ Hum Hypertens8199449149486APinesEZFismanIShapiraExercise echocardiography in postmenopausal hormone users with mild systemic hypertensionAm J Cardiol7819961385138987RALoboEstrogen replacement therapy and hypertensionPostgrad Med141997485488AAAkkadAWFHalliganKAbramsFAl-AzzawiDiffering responses in blood pressure over 24 hours in normotensive women receiving oral or transdermal estrogen replacement therapyObstet Gynecol8919979710389Van Ittersum FJ, Van Baal WM, Kenemans P, Mijatovic V, Donkers AJM, Van der Mooren MJ, Stehouwer CDA. Ambulatory-not office-blood pressures decline during hormone replacement therapy in postmenopausal women. Am J Hypertens, (in press).90Van der Mooren MJ. Reduced blood pressure in hypertensive women on combined oestradiol/dydrogesterone therapy. Acta Obstet Gynecol Scand 1997;76 Suppl 167:5;60 (abstract).91CKornhauserJMMalacaraMEGarayELPerex-LuqueThe effect of hormone replacement therapy on blood pressure and cardiovascular risk factors in postmenopausal women with moderate hypertensionJ Hum Hypertens11199740541192PCollinsCMCRosanoPMSarrel17β-Estradiol attenuates acetylcholine-induced coronary arterial consriction in women but not in men with coronary heart diseaseCirculation921995243093PCollinsGMRosanoCJiangCardiovascular protection by oestrogen—a calcium antagonist effect?Lancet34119931264126594AJProudlerAIHasib AhmedDCrookHormone replacement therapy and serum angiotensin-converting-enzyme activity in postmenopausal womenLancet34619958990