Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women
Corresponding Author
S. R. Salpeter
Stanford University School of Medicine, Stanford, CA, USA
Santa Clara Valley Medical Center, San Jose, CA, USA
Shelley R. Salpeter, MD, Santa Clara Valley Medical Center, 751 S. Bascom Ave, San Jose, CA 95128, USA.E-mail:[email protected]Search for more papers by this authorJ. M. E. Walsh
University of California, San Francisco, CA, USA
Search for more papers by this authorT. M. Ormiston
Santa Clara Valley Medical Center, San Jose, CA, USA
Search for more papers by this authorE. Greyber
Santa Clara Valley Medical Center, San Jose, CA, USA
Search for more papers by this authorCorresponding Author
S. R. Salpeter
Stanford University School of Medicine, Stanford, CA, USA
Santa Clara Valley Medical Center, San Jose, CA, USA
Shelley R. Salpeter, MD, Santa Clara Valley Medical Center, 751 S. Bascom Ave, San Jose, CA 95128, USA.E-mail:[email protected]Search for more papers by this authorJ. M. E. Walsh
University of California, San Francisco, CA, USA
Search for more papers by this authorT. M. Ormiston
Santa Clara Valley Medical Center, San Jose, CA, USA
Search for more papers by this authorE. Greyber
Santa Clara Valley Medical Center, San Jose, CA, USA
Search for more papers by this authorAbstract
Aim: To quantify the effects of hormone-replacement therapy (HRT) on components of the metabolic syndrome in postmenopausal women.
Methods: Comprehensive searches of electronic databases were performed from April 1966 to October 2004. We included randomized controlled trials that were of at least 8 weeks duration and evaluated the effect of HRT on metabolic, inflammatory or thrombotic components. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). Subgroup analysis evaluated the effects for transdermal and oral treatment and for diabetic and non-diabetic women.
Results: Pooled results of 107 trials showed that HRT reduced abdominal fat [−6.8% (CI, −11.8 to −1.9%)], HOMA-IR [−12.9% (CI, −17.1 to −8.6%)] and new-onset diabetes [relative risk 0.7 (CI, 0.6–0.9)] in women without diabetes. In women with diabetes, HRT reduced fasting glucose [−11.5% (CI, −18.0 to −5.1%)] and HOMA-IR [−35.8% (CI, −51.7 to −19.8%)]. HRT also reduced low-density lipoprotein/high-density lipoprotein cholesterol ratio [−15.7% (CI, −18.0 to −13.5%)], lipoprotein(a) [Lp(a)] [−25.0% [CI, −32.9 to −17.1%)], mean blood pressure [−1.7% (CI, −2.9 to −0.5%)], E-selectin [−17.3% (CI, −22.4 to −12.1%)], fibrinogen [−5.5% (CI, −7.8 to −3.2%)] and plasminogen activator inhibitor-1 [−25.1% (CI, −33.6 to −15.5%)]. Oral agents produced larger beneficial effects than transdermal agents, but increased C-reactive protein (CRP) [37.6% (CI, 17.4–61.3%)] and decreased protein S [−8.6% CI, −13.1 to −4.1%)], while transdermal agents had no effect.
Conclusions: HRT reduces abdominal obesity, insulin resistance, new-onset diabetes, lipids, blood pressure, adhesion molecules and procoagulant factors in women without diabetes and reduced insulin resistance and fasting glucose in women with diabetes. Oral agents adversely affected CRP and protein S, while transdermal agents had no effects.
References
- 1
Kannel WB.
Metabolic risk factors for coronary heart disease in women: perspective from the Framingham Study.
Am Heart J
1987; 114: 413–419.
- 2
Grundy SM,
Brewer HB Jr,
Cleeman JI,
Smith SC Jr,
Lenfant C.
Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition.
Arterioscler Thromb Vasc Biol
2004; 24: e13–e18.
- 3
Reilly MP,
Wolfe ML,
Rhodes T,
Girman C,
Mehta N,
Radar DJ.
Measures of insulin resistance add incremental value to the clinical diagnosis of metabolic syndrome in association with coronary atherosclerosis.
Circulation
2004; 110: 803–809.
- 4
Haffner SM,
Lehto S,
Ronnemass T,
Pyorala K,
Laakso M.
Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
N Engl J Med
1998; 339: 229–234.
- 5
Kanaya AM,
Vittinghoff E,
Shlipak MG et al. Association of total and central obesity with mortality in postmenopausal women with coronary heart disease.
Am J Epidemiol
2003; 158: 1161–1170.
- 6
Ross R.
Atherosclerosis—an inflammatory disease.
N Engl J Med
1999; 340: 115–126.
- 7
Stevenson JC.
The metabolic basis for the effects of HRT on coronary heart disease.
Endocrine
2004; 24: 239–244.
- 8
Seed M,
Knopp RH.
Estrogens, lipoproteins, and cardiovascular risk factors: an update following the randomized placebo-controlled trials of hormone-replacement therapy.
Curr Opin Lipidol
2004; 15: 459–467.
- 9
Kanaya AM,
Herrington D,
Vittinghoff E et al. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/Progestin Replacement Study. A randomized, double-blind, placebo-controlled trial.
Ann Intern Med
2003; 138: 1–9.
- 10
Margolis K,
Bonds DE,
Rodabough RJ et al. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial.
Diabetologia
2004; 47: 1175–1187.
- 11
Espeland MA,
Hogan PE,
Fineberg SE et al. Effect of postmenopausal hormone therapy on glucose and insulin concentrations. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions.
Diabetes Care
1998; 21: 1589–1595.
- 12
Lobo RA,
Bush T,
Carr BR,
Pickar JH.
Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism.
Fertil Steril
2001; 76: 13–24.
- 13
Matthews DR,
Hosker JP,
Rudenski AS,
Naylor BA,
Treacher DF,
Turner RC.
Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
Diabetologia
1985; 28: 412–419.
- 14
Bonora E,
Tarcher G,
Alberiche M et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity.
Diabetes Care
2000; 23: 57–63.
- 15
Miura K,
Soyama Y,
Morikawa Y et al. Comparison of four blood pressure indexes for the prediction of 10-year stroke risk in middle-aged and older Asians.
Hypertension
2004; 44: 715–720.
- 16
DerSimonian R,
Laird N.
Meta-analysis in clinical trials.
Control Clin Trials
1986; 7: 177–188.
- 17
Stratton IM,
Adler AI,
Neil AW et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.
BMJ
2000; 321: 405–412.
- 18
Bonora E,
Formentini G,
Calcaterra F et al. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects.
Diabetes Care
2002; 25: 1135–1141.
- 19
Altman DG,
Bland JM.
Interaction revisited: the difference between two estimates.
BMJ
2003; 326: 219.
- 20
Carr MC.
The emergence of the metabolic syndrome with menopause.
J Clin Endocrinol Metab
2003; 88: 2404–2411.
- 21
Isomaa B,
Almgren P,
Tuomi T et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome.
Diabetes Care
2001; 24: 683–689.
- 22
Salomaa V,
Stinson V,
Kark JD,
Folsom AR,
Davis CE,
Wu KK.
Association of fibrinolytic parameters with early atherosclerosis. The ARIC Study. Atherosclerosis Risk Communities Study.
Circulation
1995; 91: 284–290.
- 23
Juhan-Vague I,
Pyke SD,
Alessi MC,
Jespersen J,
Haverkate F,
Thompson SG.
Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities.
Circulation
1996; 94: 2057–2063.
- 24
Ridker PM,
Brown NJ,
Vaughan DE,
Harrison DG,
Mehta JL.
Established and emerging plasma biomarkers in the prediction of first atherothrombotic events.
Circulation
2004; 109: IV6–IV19.
- 25
Despres JP,
Lemieux I,
Dagenais GR,
Cantin B,
Lamarche B.
HDL-cholesterol as a marker of coronary heart disease risk: the Quebec cardiovascular study.
Atherosclerosis
2000; 153: 263–272.
- 26
Danesh J,
Collins R,
Peto R.
Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies.
Circulation
2000; 102: 1082–1085.
- 27
Carey DG,
Jenkins AB,
Campbell LV,
Freund J,
Chisholm DJ.
Abdominal fat and insulin resistance in normal and overweight women: direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM.
Diabetes
1996; 45: 633–638.
- 28
Salpeter SR,
Walsh JM,
Greyber E,
Ormiston TM,
Salpeter EE.
Mortality associated with hormone replacement therapy in younger and older women: a meta- analysis.
J Gen Intern Med
2004; 19: 791–804.
- 29
Grodstein F,
Manson JE,
Colditz GA,
Willett WC,
Speizer FE,
Stampfer MJ.
A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease.
Ann Intern Med
2000; 133: 933–941.
- 30
Hulley S,
Grady D,
Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart Estrogen/Progestin Replacement Study (HERS) Res Group.
JAMA
1998; 280: 605–613.
- 31
Anderson GL,
Limacher M,
Assaf AR et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial.
JAMA
2004; 291: 1701–1712.
- 32
Rossouw JE,
Anderson GL,
Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.
JAMA
2002; 288: 321–333.
- 33
Grodstein F,
Manson JE,
Stampfer MJ.
Postmenopausal hormone use and secondary prevention of coronary events in the nurses’ health study: a prospective, observational study.
Ann Intern Med
2001; 135: 1–8.
- 34
Danesh J,
Whincup P,
Walker M et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses.
BMJ
2000; 321: 199–204.
- 35
Berk BC,
Weintraub WS,
Alexander RW.
Elevation of C-reactive protein in ‘active’ coronary artery disease.
Am J Cardiol
1990; 65: 168–172.
- 36
Alvarez Garcia B,
Ruiz C,
Chacon P,
Sabin JA,
Matas M.
High-sensitivity C-reactive protein in high-grade carotid stenosis: risk marker for unstable carotid plaque.
J Vasc Surg
2003; 38: 1018–1024.
- 37
Redberg RF,
Rifai N,
Gee L,
Ridker PM.
Lack of association of C-reactive protein and coronary calcium by electron beam computed tomography in postmenopausal women: implications for coronary artery disease screening.
J Am Coll Cardiol
2000; 36: 39–43.
- 38
Ferreiros ER,
Boissonnet CP,
Pizarro R et al. Independent prognostic value of elevated C-reactive protein in unstable angina.
Circulation
1999; 100: 1958–1963.
- 39
Burke AP,
Tracy RP,
Kolodgie F et al. Elevated C-reactive protein values and atherosclerosis in sudden coronary death: association with different pathologies.
Circulation
2002; 105: 2019–2023.
- 40
Stauffer BL,
Hoetzer GL,
Smith DT,
DeSouza CA.
Plasma C-reactive protein is not elevated in physically active postmenopausal women taking hormone replacement therapy.
J Appl Physiol
2004; 96: 143–148.
- 41
Sbarouni E,
Kyriakides ZS,
Kremastinos DT.
Effect of simvastatin on serum C-reactive protein during hormone replacement therapy.
Am J Cardiol
2004; 93: 217–218.
- 42
Koh KK,
Schenke WH,
Waclawiw MA,
Csako G,
Cannon RO III.
Statin attenuates increase in C-reactive protein during estrogen replacement therapy in postmenopausal women.
Circulation
2002; 105: 1531–1533.
- 43
Ridker PM,
Cushman M,
Stampfer MJ,
Tracy RP,
Hennekens CH.
Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men.
N Engl J Med
1997; 336: 973–979.
- 44
Assmann G,
Schulte H,
Von Eckardstein A.
Hypertriglyceridemia and elevated lipoprotein(a) are risk factors for major coronary events in middle-aged men.
Am J Cardiol
1996; 77: 1179–1184.
- 45
Lamarche B,
Tchernof A,
Mauriege P et al. Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease.
JAMA
1998; 279: 1955–1961.
- 46
Daly E,
Vessey MP,
Hawkins MM,
Carson JL,
Gough P,
Marsh S.
Risk of venous thromboembolism in users of hormone replacement therapy.
Lancet
1996; 348: 977–980.
- 47
Oger E,
Alhenc-Gelas M,
Lacut K et al. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial.
Arterioscler Thromb Vasc Biol
2003; 23: 1671–1676.
- 48
Post MS,
Rosing J,
Van Der Mooren MJ et al. Increased resistance to activated protein C after short-term oral hormone replacement therapy in healthy post-menopausal women.
Br J Haematol
2002; 119: 1017–1023.
- 49
Swiatkiewicz A,
Jurkowski P,
Kotschy M,
Ciecierski M,
Jawien A.
Level of antithrombin III, protein C, protein S and other selected parameters of coagulation and fibrinolysis in the blood of the patients with recurrent deep venous thrombosis.
Med Sci Monit
2002; 8: CR263–CR268.
- 50
Espeland MA,
Applegate W,
Furberg CD,
Lefkowitz D,
Rice L,
Hunninghake D.
Estrogen replacement therapy and progression of intimal-medial thickness in the carotid arteries of postmenopausal women. ACAPS Investigators. Asymptomatic Carotid Atherosclerosis Progression Study.
Am J Epidemiol
1995; 142: 1011–1019.
- 51
Stevenson JC,
Oladipo A,
Manassiev N,
Whitehead MI,
Guilford S,
Proudler AJ.
Randomized trial of effect of transdermal continuous combined hormone replacement therapy on cardiovascular risk markers.
Br J Haematol
2004; 124: 802–808.
- 52
Abbas A,
Fadel P,
Wang Z,
Arbique D,
Jialal I,
Vongpatanasin W.
Contrasting effects of oral versus transdermal estrogen on serum amyloid A (SAA) and high-density lipoprotein-SAA in postmenopausal women.
Arterioscler Thromb Vasc Biol
2004; 24: e164–e167.
- 53
Wakatsuki A,
Okatani Y,
Ikenoue N,
Fukaya T.
Different effects of oral conjugated equine estrogen and transdermal estrogen replacement therapy on size and oxidative susceptibility of low-density lipoprotein particles in postmenopausal women.
Circulation
2002; 106: 1771–1776.
- 54
Tangney CC,
Mosca LJ,
Otvos JD,
Rosenson RS.
Oral 17beta-estradiol and medroxyprogesterone acetate therapy in postmenopausal women increases HDL particle size.
Atherosclerosis
2001; 155: 425–430.
References
- 1
Adami S,
Rossini M,
Zamberlan N,
Bertoldo F,
Dorizzi R,
Lo Cascio V.
Long-term effects of transdermal and oral estrogens on serum lipids and lipoproteins in postmenopausal women.
Maturitas
1993; 17 (3): 191–196.
- 2
Affinito P,
Palomba S,
Bonifacio M et al. Effects of hormonal replacement therapy in postmenopausal hypertensive patients.
Maturitas
2001; 40 (1): 75–83.
- 3
Alecrin IN,
Aldrighi JM,
Caldas MA,
Gebara OC,
Lopes NH,
Ramires JA.
Acute and chronic effects of oestradiol on left ventricular diastolic function in hypertensive postmenopausal women with left ventricular diastolic dysfunction.
Heart
2004; 90 (7): 777–781.
- 4
Aloia JF,
Vaswani A,
Russo L,
Sheehan M,
Flaster E.
The influence of menopause and hormonal replacement therapy on body cell mass and body fat mass.
Am J Obstet Gynecol
1995; 172 (3): 896–900.
- 5
Andersson B,
Mattsson LA,
Hahn L et al. Estrogen replacement therapy decreases hyperandrogenicity and improves glucose homeostasis and plasma lipids in postmenopausal women with noninsulin-dependent diabetes mellitus.
J Clin Endocrinol Metab
1997; 82 (2): 638–643.
- 6
Stork S,
Von Schacky C,
Angerer P.
The effect of 17beta-estradiol on endothelial and inflammatory markers in postmenopausal women: a randomised, controlled trial.
Atherosclerosis
2002; 165: 301–307.
- 7
Binder EF,
Williams DB,
Schechtman KB,
Jeffe DB,
Kohrt WM.
Effects of hormone replacement therapy on serum lipids in elderly women. a randomized, placebo- controlled trial.
Ann Intern Med
2001; 134 (9 Pt 1): 754–760.
- 8
Bjarnason NH,
Byrjalsen I,
Hassager C,
Haarbo J,
Christiansen C.
Low doses of estradiol in combination with gestodene to prevent early postmenopausal bone loss.
Am J Obstet Gynecol
2000; 183 (3): 550–560.
- 9
Bladbjerg EM,
Madsen JS,
Kristensen SR et al. Effect of long-term hormone replacement therapy on tissue factor pathway inhibitor and thrombin activatable fibrinolysis inhibitor in healthy postmenopausal women: a randomized controlled study.
J Thromb Haemost
2003; 1 (6): 1208–1214.
- 10
Brito-Zurita OR,
Posadas-Romero C,
Hermosillo AG et al. Estrogen effect on heart rate variability in hypertensive postmenopausal women.
Maturitas
2003; 44 (1): 39–48.
- 11
Bunyavejchevin S,
Limpaphayom KK.
The metabolic and bone density effects of continuous combined 17-beta estradiol and noresthisterone acetate treatments in Thai postmenopausal women: a double-blind placebo-controlled trial.
J Med Assoc Thai
2001; 84 (1): 45–53.
- 12
Cagnacci A,
Rovati L,
Zanni A,
Malmusi S,
Facchinetti F,
Volpe A.
Physiological doses of estradiol decrease nocturnal blood pressure in normotensive postmenopausal women.
Am J Physiol
1999; 276 (4 Pt 2): H1355–H1360.
- 13
Cheng GJ,
Liu JL,
Zhang Q,
Ye HF,
Wang ZQ,
Pan HP.
Prospective double-blind study of CEE3 in peri- and postmenopausal women: effects on bone loss and lipoprotein lipids.
Chin Med J (Engl)
1992; 105 (11): 929–933.
- 14
Christiansen C,
Christensen MS,
Hagen C,
Stocklund KE,
Transbol I.
Effects of natural estrogen/gestagen and thiazide on coronary risk factors in normal postmenopausal women. A 2-year double-blind placebo study.
Acta Obstet Gynecol Scand
1981; 60 (4): 407–412.
- 15
Colacurci N,
Zarcone R,
Mollo A et al. Effects of hormone replacement therapy on glucose metabolism.
Panminerva Med
1998; 40 (1): 18–21.
- 16
Conard J,
Basdevant A,
Thomas JL et al. Cardiovascular risk factors and combined estrogen-progestin replacement therapy: a placebo-controlled study with nomegestrol acetate and estradiol.
Fertil Steril
1995; 64 (5): 957–962.
- 17
Conard J,
Gompel A,
Pelissier C,
Mirabel C,
Basdevant A.
Fibrinogen and plasminogen modifications during oral estradiol replacement therapy.
Fertil Steril
1997; 68 (3): 449–453.
- 18
Cornu C,
Mercier C,
Ffrench P et al. Postmenopause hormone treatment in women with NIDDM or impaired glucose tolerance: the MEDIA randomized clinical trial.
Maturitas
2000; 37 (2): 95–104.
- 19
Darko DA,
Dornhorst A,
Kennedy G,
Mandeno RC,
Seed M.
Glycaemic control and plasma lipoproteins in menopausal women with Type 2 diabetes treated with oral and transdermal combined hormone replacement therapy.
Diabetes Res Clin Pract
2001; 54 (3): 157–164.
- 20
Davidson MH,
Maki KC,
Marx P et al. Effects of continuous estrogen and estrogen-progestin replacement regimens on cardiovascular risk markers in postmenopausal women.
Arch Intern Med
2000; 160 (21): 3315–3325.
- 21
De Valk-de Roo GW,
Stehouwer CD,
Meijer P et al. Both raloxifene and estrogen reduce major cardiovascular risk factors in healthy postmenopausal women: a 2-year, placebo-controlled study.
Arterioscler Thromb Vasc Biol
1999; 19 (12): 2993–3000.
- 22
Demirol A,
Baykal C,
Kirazli S,
Ayhan A.
Effects of hormone replacement on hemostasis in spontaneous menopause.
Menopause
2001; 8 (2): 135–140.
- 23
Estradiol Clotting Factors Study Writing Group (ECFS).
Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a 1-year, double-blind, placebo-controlled study. The writing group for the Estradiol Clotting Factors Study.
Thromb Haemost
1996; 75 (3): 476–480.
- 24
Farag NH,
Nelesen RA,
Parry BL,
Loredo JS,
Dimsdale JE,
Mills PJ.
Autonomic and cardiovascular function in postmenopausal women: the effects of estrogen versus combination therapy.
Am J Obstet Gynecol
2002; 186 (5): 954–961.
- 25
Friday KE,
Dong C,
Fontenot RU.
Conjugated equine estrogen improves glycemic control and blood lipoproteins in postmenopausal women with type 2 diabetes.
J Clin Endocrinol Metab
2001; 86 (1): 48–52.
- 26
Genant HK,
Lucas J,
Weiss S et al. Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group.
Arch Intern Med
1997; 157 (22): 2609–2615.
- 27
Girdler SS,
Hinderliter AL,
West SG,
Grewen K,
Steege J,
Light KC.
Postmenopausal smokers show reduced hemodynamic benefit from oral hormone replacement.
Am J Cardiol
2000; 86 (5): 590–592, A510.
- 28
Girdler SS,
Hinderliter AL,
Wells EC,
Sherwood A,
Grewen KM,
Light KC.
Transdermal versus oral estrogen therapy in postmenopausal smokers: hemodynamic and endothelial effects.
Obstet Gynecol
2004; 103 (1): 169–180.
- 29
Gottsater A,
Rendell M,
Hulthen UL,
Berntorp E,
Mattiasson I.
Hormone replacement therapy in healthy postmenopausal women: a randomized, placebo-controlled study of effects on coagulation and fibrinolytic factors.
J Intern Med
2001; 249 (3): 237–246.
- 30
Guzic-Salobir B,
Keber I,
Vrabic L.
A randomized, placebo-controlled trial of the effects of continuous combined hormone replacement therapy on coagulation and fibrinolytic systems in healthy postmenopausal women.
Fertil Steril
2002; 78 (6): 1178–1183.
- 31
Haarbo J,
Hassager C,
Jensen SB,
Riis BJ,
Christiansen C.
Serum lipids, lipoproteins, and apolipoproteins during postmenopausal estrogen replacement therapy combined with either 19-nortestosterone derivatives or 17-hydroxyprogesterone derivatives.
Am J Med
1991; 90 (5): 584–589.
- 32
Haarbo J,
Christiansen C.
Treatment-induced cyclic variations in serum lipids, lipoproteins, and apolipoproteins after 2 years of combined hormone replacement therapy: exaggerated cyclic variations in smokers.
Obstet Gynecol
1992; 80 (4): 639–644.
- 33
Haines C,
Chung T,
Chang A,
Masarei J,
Tomlinson B,
Wong E.
Effect of oral estradiol on Lp(a) and other lipoproteins in postmenopausal women. A randomized, double-blind, placebo-controlled, crossover study.
Arch Intern Med
1996; 156 (8): 866–872.
- 34
Hartmann B,
Kirchengast S,
Albrecht A,
Laml T,
Bikas D,
Huber J.
Effects of hormone replacement therapy on growth hormone secretion patterns in correlation to somatometric parameters in healthy postmenopausal women.
Maturitas
1995; 22 (3): 239–246.
- 35
Hassager C,
Christiansen C.
Estrogen/gestagen therapy changes soft tissue body composition in postmenopausal women.
Metabolism
1989; 38 (7): 662–665.
- 36
Hayashi T,
Ito I,
Kano H,
Endo H,
Iguchi A.
Estriol (E3) replacement improves endothelial function and bone mineral density in very elderly women.
J Gerontol A Biol Sci Med Sci
2000; 55 (4): B183–B190.
- 37
Herrington DM,
Reboussin DM,
Brosnihan KB et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis.
N Engl J Med
2000; 343 (8): 522–529.
- 38
Hodis HN,
Mack WJ,
Lobo RA et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial.
Ann Intern Med
2001; 135 (11): 939–953.
- 39
Hodis HN,
Mack WJ,
Azen SP et al. Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women.
N Engl J Med
2003; 349 (6): 535–545.
- 40
Howard BV,
Hsia J,
Ouyang P et al. Postmenopausal hormone therapy is associated with atherosclerosis progression in women with abnormal glucose tolerance.
Circulation
2004; 110 (2): 201–206.
- 41
Hughes TA,
Pace DT,
Ke RW,
Tolley EA,
Qureshi N,
Stentz F.
Lipoprotein compositional changes with combination hormone therapy (conjugated estrogen and medroxyprogesterone) in African American women.
Endocr Pract
2004; 10 (3): 179–186.
- 42
Hulley S,
Grady D,
Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.
JAMA
1998; 280 (7): 605–613.
- 43
Jensen J,
Christiansen C,
Rodbro P.
Oestrogen-progestogen replacement therapy changes body composition in early post-menopausal women.
Maturitas
1986; 8 (3): 209–216.
- 44
Jhund PS,
Dawson N,
Davie AP et al. Attenuation of endothelin-1 induced vasoconstriction by 17beta estradiol is not sustained during long-term therapy in postmenopausal women with coronary heart disease.
J Am Coll Cardiol
2001; 37 (5): 1367–1373.
- 45
Jirapinyo M,
Theppisai U,
Manonai J,
Suchartwatnachai C,
Jorgensen LN.
Effect of combined oral estrogen/progestogen preparation (Kliogest) on bone mineral density, plasma lipids and postmenopausal symptoms in HRT-naive Thai women.
Acta Obstet Gynecol Scand
2003; 82 (9): 857–866.
- 46
Kanaya AM,
Herrington D,
Vittinghoff E et al. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial.
Ann Intern Med
2003; 138 (1): 1–9.
- 47
Kennedy G,
McLaren M,
Belch JJ,
Seed M.
Elevated levels of sE-selectin in post-menopausal females are decreased by hormone replacement therapy to levels observed in pre-menopausal females.
Thromb Haemost
1999; 82 (5): 1433–1436.
- 48
Kimmerle R,
Heinemann L,
Heise T et al. Influence of continuous combined estradiol-norethisterone acetate preparations on insulin sensitivity in postmenopausal nondiabetic women.
Menopause
1999; 6 (1): 36–42.
- 49
Kornhauser C,
Malacara JM,
Garay ME,
Perez-Luque EL.
The effect of hormone replacement therapy on blood pressure and cardiovascular risk factors in menopausal women with moderate hypertension.
J Hum Hypertens
1997; 11 (7): 405–411.
- 50
Lacut K,
Oger E,
Le Gal G et al. Differential effects of oral and transdermal postmenopausal estrogen replacement therapies on C-reactive protein.
Thromb Haemost
2003; 90 (1): 124–131.
- 51
Lamon-Fava S,
Posfai B,
Asztalos BF,
Horvath KV,
Dallal GE,
Schaefer EJ.
Effects of estrogen and medroxyprogesterone acetate on subpopulations of triglyceride-rich lipoproteins and high-density lipoproteins.
Metabolism
2003; 52 (10): 1330–1336.
- 52
Lee CC,
Kasa-Vubu JZ,
Supiano MA.
Differential effects of raloxifene and estrogen on insulin sensitivity in postmenopausal women.
J Am Geriatr Soc
2003; 51 (5): 683–688.
- 53
Lewis-Barned NJ,
Sutherland WH,
Walker RJ et al. Plasma cholesterol esterification and transfer, the menopause, and hormone replacement therapy in women.
J Clin Endocrinol Metab
1999; 84 (10): 3534–3538.
- 54
Li C,
Samsioe G,
Borgfeldt C,
Bendahl PO,
Wilawan K,
Aberg A.
Low-dose hormone therapy and carbohydrate metabolism.
Fertil Steril
2003; 79 (3): 550–555.
- 55
Light KC,
Hinderliter AL,
West SG et al. Hormone replacement improves hemodynamic profile and left ventricular geometry in hypertensive and normotensive postmenopausal women.
J Hypertens
2001; 19 (2): 269–278.
- 56
Lindheim SR,
Notelovitz M,
Feldman EB,
Larsen S,
Khan FY,
Lobo RA.
The independent effects of exercise and estrogen on lipids and lipoproteins in postmenopausal women.
Obstet Gynecol
1994; 83 (2): 167–172.
- 57
Lobo RA,
Bush T,
Carr BR,
Pickar JH.
Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism.
Fertil Steril
2001; 76 (1): 13–24.
- 58
Luyer MD,
Khosla S,
Owen WG,
Miller VM.
Prospective randomized study of effects of unopposed estrogen replacement therapy on markers of coagulation and inflammation in postmenopausal women.
J Clin Endocrinol Metab
2001; 86 (8): 3629–3634.
- 59
Manning PJ,
Allum A,
Jones S,
Sutherland WH,
Williams SM.
The effect of hormone replacement therapy on cardiovascular risk factors in type 2 diabetes: a randomized controlled trial.
Arch Intern Med
2001; 161 (14): 1772–1776.
- 60
Manson JE,
Hsia J,
Johnson KC et al. Estrogen plus progestin and the risk of coronary heart disease.
N Engl J Med
2003; 349 (6): 523–534. Information on diabetes in the WHI trial provided by: Margolis K, Bonds DE, Rodabough RJ
et al. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial.
Diabetologia
2004; 46: 1175–1187.
- 61
McKenzie J,
Jaap AJ,
Gallacher S et al. Metabolic, inflammatory and haemostatic effects of a low-dose continuous combined HRT in women with type 2 diabetes: potentially safer with respect to vascular risk?
Clin Endocrinol (Oxf)
2003; 59 (6): 682–689.
- 62
Mills PJ,
Farag NH,
Matthews S,
Nelesen RA,
Berry CC,
Dimsdale JE.
Hormone replacement therapy does not affect 24-h ambulatory blood pressure in healthy non-smoking postmenopausal women.
Blood Press Monit
2003; 8 (2): 57–61.
- 63
Modena MG,
Molinari R,
Muia N Jr,
Castelli A,
Pala F,
Rossi R.
Double-blind randomized placebo-controlled study of transdermal estrogen replacement therapy on hypertensive postmenopausal women.
Am J Hypertens
1999; 12 (10 Pt 1): 1000–1008.
- 64
Munk-Jensen N,
Ulrich LG,
Obel EB,
Nielsen SP,
Edwards D,
Meinertz H.
Continuous combined and sequential estradiol and norethindrone acetate treatment of postmenopausal women: effect of plasma lipoproteins in a two-year placebo-controlled trial.
Am J Obstet Gynecol
1994; 171 (1): 132–138.
- 65
Naessen T,
Rodriguez-Macias K,
Lithell H.
Serum lipid profile improved by ultra-low doses of 17 beta-estradiol in elderly women.
J Clin Endocrinol Metab
2001; 86 (6): 2757–2762.
- 66
Nanda S,
Gupta N,
Mehta HC,
Sangwan K.
Effect of oestrogen replacement therapy on serum lipid profile.
Aust N Z J Obstet Gynaecol
2003; 43 (3): 213–216.
- 67
Ory SJ,
Field CS,
Herrmann RR,
Zinsmeister AR,
Riggs BL.
Effects of long-term transdermal administration of estradiol on serum lipids.
Mayo Clin Proc
1998; 73 (8): 735–738.
- 68
Ossewaarde ME,
Bots ML,
Bak AA et al. Effect of hormone replacement therapy on lipids in perimenopausal and early postmenopausal women.
Maturitas
2001; 39 (3): 209–216.
- 69
Ossewaarde ME,
Dallinga-Thie GM,
Bots ML et al. Treatment with hormone replacement therapy lowers remnant lipoprotein particles in healthy postmenopausal women: results from a randomized trial.
Eur J Clin Invest
2003; 33 (5): 376–382.
- 70
Park JS,
Jung HH,
Yang WS,
Kim SB,
Min WK,
Chi HS.
Effects of hormonal replacement therapy on lipid and haemostatic factors in post-menopausal ESRD patients.
Nephrol Dial Transplant
2000; 15 (11): 1835–1840.
- 71
Espeland MA,
Marcovina SM,
Miller V et al. Effect of postmenopausal hormone therapy on lipoprotein (a) concentration. PEPI investigators.
Circulation
1998; 97: 979–986.
- 72
Perera M,
Sattar N,
Petrie JR et al. The effects of transdermal estradiol in combination with oral norethisterone on lipoproteins, coagulation, and endothelial markers in postmenopausal women with type 2 diabetes: a randomized, placebo-controlled study.
J Clin Endocrinol Metab
2001; 86 (3): 1140–1143.
- 73
Perrone G,
Stefanutti C,
Galoppi P et al. Effect of oral and transdermal hormone replacement therapy on lipid profile and Lp(a) level in menopausal women with hypercholesterolemia.
Int J Fertil Menopausal Stud
1996; 41 (6): 509–515.
- 74
Post MS,
Van Der Mooren MJ,
Stehouwer CD et al. Effects of transdermal and oral oestrogen replacement therapy on C-reactive protein levels in postmenopausal women: a randomised, placebo-controlled trial.
Thromb Haemost
2002; 88 (4): 605–610.
- 75
Saitta A,
Altavilla D,
Cucinotta D et al. Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma no concentrations, endothelin-1 levels, and endothelium-dependent vasodilation in postmenopausal women.
Arterioscler Thromb Vasc Biol
2001; 21 (9): 1512–1519.
- 76
Samaras K,
Hayward CS,
Sullivan D,
Kelly RP,
Campbell LV.
Effects of postmenopausal hormone replacement therapy on central abdominal fat, glycemic control, lipid metabolism, and vascular factors in type 2 diabetes: a prospective study.
Diabetes Care
1999; 22 (9): 1401–1407.
- 77
Samsioe G,
Li C,
Borgfeldt C,
Wilawan K,
Aberg A,
Larsen S.
Changes in lipid and lipoprotein profile in postmenopausal women receiving low-dose combinations of 17beta-estradiol and norethisterone acetate.
Menopause
2002; 9 (5): 335–342.
- 78
Sattar N,
Perera M,
Small M,
Lumsden MA.
Hormone replacement therapy and sensitive C-reactive protein concentrations in women with type-2 diabetes.
Lancet
1999; 354 (9177): 487–488.
- 79
Sbarouni E,
Kyriakides ZS,
Kremastinos D.
The effect of hormone replacement therapy alone and in combination with simvastatin on plasma lipids of hypercholesterolemic postmenopausal women with coronary artery disease.
J Am Coll Cardiol
1998; 32 (5): 1244–1250.
- 80
Scarabin PY,
Alhenc-Gelas M,
Plu-Bureau G,
Taisne P,
Agher R,
Aiach M.
Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial.
Arterioscler Thromb Vasc Biol
1997; 17 (11): 3071–3078.
- 81
Scott AR,
Dhindsa P,
Forsyth J,
Mansell P.
Effect of hormone replacement therapy on cardiovascular risk factors in postmenopausal women with diabetes.
Diabetes Obes Metab
2004; 6 (1): 16–22.
- 82
Seed M,
Sands RH,
McLaren M,
Kirk G,
Darko D.
The effect of hormone replacement therapy and route of administration on selected cardiovascular risk factors in post-menopausal women.
Fam Pract
2000; 17 (6): 497–507.
- 83
Skouby SO,
Gram J,
Andersen LF,
Sidelmann J,
Petersen KR,
Jespersen J.
Hormone replacement therapy: estrogen and progestin effects on plasma C-reactive protein concentrations.
Am J Obstet Gynecol
2002; 186 (5): 969–977.
- 84
Sipila S,
Taaffe DR,
Cheng S,
Puolakka J,
Toivanen J,
Suominen H.
Effects of hormone replacement therapy and high-impact physical exercise on skeletal muscle in post-menopausal women: a randomized placebo-controlled study.
Clin Sci (Lond)
2001; 101 (2): 147–157.
- 85
Soma MR,
Osnago-Gadda I,
Paoletti R et al. The lowering of lipoprotein[a] induced by estrogen plus progesterone replacement therapy in postmenopausal women.
Arch Intern Med
1993; 153 (12): 1462–1468.
- 86
Sorensen MB,
Rasmussen V,
Jensen G,
Ottesen B.
Temporal changes in clinic and ambulatory blood pressure during cyclic post-menopausal hormone replacement therapy.
J Hypertens
2000; 18 (10): 1387–1391.
- 87
Soranna L,
Cucinelli F,
Perri C et al. Individual effect of E2 and dydrogesterone on insulin sensitivity in post-menopausal women.
J Endocrinol Invest
2002; 25 (6): 547–550.
- 88
Stevenson JC,
Oladipo A,
Manassiev N,
Whitehead MI,
Guilford S,
Proudler AJ.
Randomized trial of effect of transdermal continuous combined hormone replacement therapy on cardiovascular risk markers.
Br J Haematol
2004; 124 (6): 802–808.
- 89
Tangney CC,
Mosca LJ,
Otvos JD,
Rosenson RS.
Oral 17beta-estradiol and medroxyprogesterone acetate therapy in postmenopausal women increases HDL particle size.
Atherosclerosis
2001; 155 (2): 425–430.
- 90
Taskin O,
Muderrisoglu H,
Akar M,
Simsek M,
Mendilcioglu I,
Kursun S.
Comparison of the effects of tibolone and estrogen replacement therapy on echocardiographic basic cardiac functions in post-menopausal women: a randomized placebo controlled study.
Maturitas
2004; 48 (4): 354–359.
- 91
Teede HJ,
Liang YL,
Kotsopoulos D,
Zoungas S,
Cravent R,
McGrath BP.
A placebo-controlled trial of long-term oral combined continuous hormone replacement therapy in postmenopausal women: effects on arterial compliance and endothelial function.
Clin Endocrinol (Oxf)
2001; 55 (5): 673–682.
- 92
Teede HJ,
Liang YL,
Kotsopoulos D,
Zoungas S,
Craven R,
McGrath BP.
Placebo-controlled trial of transdermal estrogen therapy alone in postmenopausal women: effects on arterial compliance and endothelial function.
Climacteric
2002; 5 (2): 160–169.
- 93
Tonstad S,
Ose L,
Gorbitz C,
Djoseland O,
Bard JM,
Fruchart JC.
Efficacy of sequential hormone replacement therapy in the treatment of hypercholesterolaemia among postmenopausal women.
J Intern Med
1995; 238 (1): 39–47.
- 94
Tsuda K,
Kinoshita-Shimamoto Y,
Mabuchi Y,
Nishio I.
Hormone replacement therapy improves membrane fluidity of erythrocytes in postmenopausal women: an electron paramagnetic resonance investigation.
Am J Hypertens
2003; 16 (6): 502–507.
- 95
Tuppurainen M,
Heikkinen AM,
Penttila I,
Saarikoski S.
Does vitamin D3 have negative effects on serum levels of lipids? A follow-up study with a sequential combination of estradiol valerate and cyproterone acetate and/or vitamin D3.
Maturitas
1995; 22 (1): 55–61.
- 96
Ulloa N,
Arteaga E,
Bustos P et al. Sequential estrogen-progestin replacement therapy in healthy postmenopausal women: effects on cholesterol efflux capacity and key proteins regulating high-density lipoprotein levels.
Metabolism
2002; 51 (11): 1410–1417.
- 97
Van Baal WM,
Kenemans P,
Van Der Mooren MJ,
Kessel H,
Emeis JJ,
Stehouwer CD.
Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women.
Thromb Haemost
1999; 81 (6): 925–928.
- 98
Van Ittersum FJ,
Van Baal WM,
Kenemans P et al. Ambulatory—not office—blood pressures decline during hormone replacement therapy in healthy postmenopausal women.
Am J Hypertens
1998; 11 (10): 1147–1152.
- 99
Vehkavaara S,
Westerbacka J,
Hakala-Ala-Pietila T,
Virkamaki A,
Hovatta O,
Yki-Jarvinen H.
Effect of estrogen replacement therapy on insulin sensitivity of glucose metabolism and preresistance and resistance vessel function in healthy postmenopausal women.
J Clin Endocrinol Metab
2000; 85 (12): 4663–4670.
- 100
Ventura P,
Cagnacci A,
Malmusi S et al. Continuous combined hormone replacement therapy with oral 17beta-estradiol and norethisterone acetate improves homocysteine metabolism in postmenopausal women.
Menopause
2001; 8 (4): 252–258.
- 101
Vigna GB,
Donega P,
Zanca R et al. Simvastatin, transdermal patch, and oral estrogen-progestogen preparation in early-postmenopausal hypercholesterolemic women: a randomized, placebo-controlled clinical trial.
Metabolism
2002; 51 (11): 1463–1470.
- 102
Vihma V,
Vehkavaara S,
Yki-Jarvinen H,
Hohtari H,
Tikkanen MJ.
Differential effects of oral and transdermal estradiol treatment on circulating estradiol fatty acid ester concentrations in postmenopausal women.
J Clin Endocrinol Metab
2003; 88 (2): 588–593.
- 103
Wakatsuki A,
Ikenoue N,
Shinohara K,
Watanabe K,
Fukaya T.
Effect of lower dosage of oral conjugated equine estrogen on inflammatory markers and endothelial function in healthy postmenopausal women.
Arterioscler Thromb Vasc Biol
2004; 24 (3): 571–576.
- 104
Walker RJ,
Lewis-Barned NJ,
Sutherland WH et al. The effects of sequential combined oral 17beta-estradiol norethisterone acetate on insulin sensitivity and body composition in healthy postmenopausal women: a randomized single blind placebo-controlled study.
Menopause
2001; 8 (1): 27–32.
- 105
Walsh BW,
Kuller LH,
Wild RA et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women.
JAMA
1998; 279 (18): 1445–1451.
- 106
Wang Y,
Xing S,
Dong X.
Effect of hormone replacement therapy on hemorheology in postmenopausal women.
Zhonghua Fu Chan Ke Za Zhi
2001; 36 (8): 476–478.
- 107
Ye Y,
Gao P,
Guo X.
Effect of hormone replacement therapy on coagulation function in postmenopausal women.
Zhonghua Fu Chan Ke Za Zhi
2000; 35 (5): 285–287.