Table 1.

The effects of the use of sex hormones on cardiovascular diseases in menopausal women

	Trial (publication year) [reference]	Age*	Formulations, doses and duration of sex hormones’ use	Duration* of follow-up	CV outcomes**
Primary prevention	The Postmenopausal Estrogen/Progestin Interventions Trial (1995) [24]	45–64	oCEE, 0.625 mg/day; oCEE, 0.625 mg/day, plus cyclic oMPA, 10 mg/day, for 12 days/month; oCEE, 0.625 mg/day, plus consecutive oMPA, 2.5 mg/day; or oCEE, 0.625 mg/day, plus cyclic micronized progesterone, 200 mg/day for 12 days/month	3	Oestrogen alone or in combination with a progestin improves lipoproteins and lowers fibrinogen levels without detectable effects on post-challenge insulin or blood pressure. Unopposed oestrogen is the optimal regimen for elevation of HDL, but the high rate of endometrial hyperplasia restricts use to women without a uterus. In women with a uterus, oCEE with cyclic micronized progesterone has the most favourable effect on HDL and no excess risk of endometrial hyperplasia.
	The Estrogen in the Prevention of Atherosclerosis Trial (2001) [25]	60.9 (6.7)	Unopposed micronized 17 β-oestradiol, 1 mg/day	2	Overall, the average rate of progression of subclinical atherosclerosis was slower in healthy postmenopausal women taking 17 β-oestradiol than in women taking placebo. Reduction in the progression of subclinical atherosclerosis was seen in women who did not take lipid-lowering medication but not in those who took these medications.
	The Women’s Health Initiative Randomized Controlled Trial of Estrogen plus Progestin (2002) [2]	63.2 (7.1)	oCEE, 0.625 mg/day, plus oMPA, 2.5 mg/day	5.2	Overall health risks exceeded benefits from use of combined oestrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for prevention of CHD.
	The Kronos Early Estrogen Prevention Study (2014) [6]	42–58	oCEE (Premarin, 0.45 mg/day) plus oral progesterone (Prometrium; micronized progesterone, 200 mg/day) for 12 days/month; tE2 (Climera, 50 μg/day) plus oral progesterone (Prometrium; micronized progesterone, 200 mg/day) for 12 days/month	4	Four years of early MHT did not affect progression of atherosclerosis as measured by changes in CIMT despite improving some markers of CV disease risk.
	The Early versus Late Intervention Trial with Estradiol (2015) [35]	55.4, median time since menopause was 3.5 ‘Early’ 65.4, median time since menopause was 14.3 ‘Late’	Oral micronized 17 β-oestradiol, 1 mg/day, with 4% vaginal micronized progesterone gel, 45 mg/day, for 10 days/month for women with intact uterus oral micronized 17 β-oestradiol, 1 mg/day, alone for women without intact uterus	16 ‘10 of randomized treatment and 6 post-intervention’	Reduced incidence of CHD and total mortality in young postmenopausal women ‘younger than 60 years’ who initiate MHT near menopause ‘<10 years since menopause’.
Secondary prevention	The Heart and Estrogen/progestin Replacement Study (1998) [38]	67	oCEE, 0.625 mg/day, plus oMPA, 2.5 mg/day	4.1	During an average follow-up of 4.1 years, treatment with oCEE plus oMPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall CV benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favourable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue.
	The Estrogen Replacement and Atherosclerosis Trial (2000) [39]	65.8	oCEE, 0.625 mg/day, alone; oCEE, 0.625 mg/day, plus oMPA, 2.5 mg/day	3.2	Neither oCEE alone nor oCEE plus oMPA affected the progression of coronary atherosclerosis in women with established CV disease. These results suggest that such women should not use oestrogen replacement with an expectation of CV benefit.
	The Coumadin Aspirin Reinfarction Study (2001) [40]	67 (60–73), never users of MHT 59 (52–66), prior/current users of MHT 58 (51–65), new users of MHT	Different MHT were used by prior/current users and new users	1	Postmenopausal women who initiated MHT after a recent MI had an increased risk of CV events largely due to excess unstable angina during follow-up.
	The Women’s Angiographic Vitamin and Estrogen Trial (2002) [41]	65, MHT group	oCEE, 0.625 mg/day, alone; oCEE, 0.625 mg/day, plus oMPA, 2.5 mg/day	2.8	In postmenopausal women with coronary disease, neither MHT nor antioxidant vitamin supplements provide CV benefit. Instead, a potential for harm was suggested with each treatment.
	EStrogen therapy for Prevention of ReInfarction Trial (2002) [42]	50–69	Oral oestradiol valerate, 2 mg/day	2	Oestradiol valerate does not reduce the overall risk of further cardiac events in postmenopausal women who have survived a MI.

A comparison between main studies that evaluated the effects of the use of sex hormones for primary and secondary prevention of cardiovascular diseases in menopausal women.

^*Reported in years – except if otherwise mentioned – as mean with or without range or S.D., or median with or without interquartile range [IQR], or range, or average.

^**Published conclusions of each study.