Postmenopausal Hormone Replacement Therapy and Cardiovascular Disease: HORMONE REPLACEMENT THERAPY

27 Jun

The administration of HRT has been shown to counteract many of these negative effects of menopause that increase the risk of CHD. However, the combination of hormones, dosage, and route of administration can affect the outcomes (Table 1).

Although oral estrogen monotherapy has the most favorable effect on serum lipoproteins, resulting in decreased total and LDL-cholesterol and increased HDL-cholesterol levels, it can result in increased triglyceride levels. This regimen should be used only in postmenopausal women who have undergone a partial or complete hysterectomy because of the increased risk of endometrial cancer associated with unopposed estrogen ther­apy. It is recommended that women who have an intact uterus use combined estrogen and progestin therapy either in a continuous regimen (progestin administered daily) or in a cyclic regimen (progestin administered at established intervals). The addition of a progestin increases the activity of hepatic lipases and results in decreased HDL-cholesterol concentrations. Thus, the addition of a progestin sometimes attenuates the effect of estrogen on serum HDL-cholesterol. This effect does vary among progestins, depending on the chemical structure, androgenic activity, and the dose of the progestin. The addition of a pro-gestin can also result in a beneficial lowering of serum triglyc-eride concentrations. In addition to progestins, androgens (such as methyltestosterone) can be added to the HRT regimen in order to improve energy, mood, and libido. Androgens have a negative effect on serum lipoproteins and may increase total and LDL-cholesterol and decrease HDL-cholesterol, reducing the favorable effects of estrogen supplementation.

Table 1 Effects of Hormone Replacement Therapy on Serum Lipoproteins

LDL-C      HDL-C       Lp(a)   Triglycerides
CEEs11         TT         1         TT
CEEs + MP11         T1T
CEEs + MPA11         T1T

Transdermal administration of HRT results in different effects on lipoproteins because hepatic metabolism is bypassed with this modality. Estrogen monotherapy and estrogen-plus-progestin combination patches are available. This mode of delivery can bring about modest reductions in total cholesterol and LDL-cholesterol, but it neither increases HDL-cholesterol levels nor affects triglyceride levels.

HRT also affects another lipoprotein called lipoprotein (a) [Lp(a]), which is composed of LDL-cholesterol and apo A (plas-minogen). The LDL-cholesterol portion of this molecule contributes to atherosclerosis, whereas the apo A segment is associated with thrombosis. Lp(a) may provide the link between atherosclerosis and thrombosis seen with CHD, making it an independent risk factor for this disorder. Estrogen therapy, with or without progestins, consistently produces a persistent decrease in Lp(a) concentrations.

HRT is also associated with non-lipoprotein effects. Estrogen monotherapy has a favorable effect on carbohydrate metabolism, body fat distribution, and endothelial relaxation. The consequence of adding progestins or androgens is unclear. canada drugs online

Another option for HRT is the selective estrogen receptor modulators (SERMs). Raloxifene (Evista®, Eli Lilly) is the primary agent in this class and is used for osteoporosis prevention. In addition to its favorable effects on bone, raloxifene has been shown to decrease LDL-cholesterol, Lp(a), and fibrinogen. How­ever, it does not have any of the favorable effects on HDL-choles-terol or plasminogen that are observed with traditional HRT.

Table 2 Summary of Prospective, Experimental Trials

Trial (Yr)InterventionsSample/ DurationEndpointsSummary of Results
PEPI (1995)21 •  Effect on Lipoproteins•    Placebo•CEEs 0.625 mg q.d.

•CEEs 0.625 mg + MPA 2.5 mg q.d.

•    CEEs 0.625 mg q.d. + MPA 10 mg

q.d. for 12 days/mo •CEEs 0.625 mg q.d. + MP 200 mg q.d. for 12 days/mo

n = 875 3 yrHDL-C SBP Insulin Fibrinogen•     HDL-C was increased and fibrinogen was decreased in all HRT groups•       MPA blunted the increase in HDL-C more than MP

•       HRT did not affect SBP or carbohydrate metabolism

HERS (1998)22 • Secondary CHD Prevention• Placebo•CEEs 0.625 mg + MPA 2.5 mgn = 2,763 4.1 yrNF-AMICHD Death•    HRT did not reduce the rate of CHD in women with established CAD•    HRT increased the incidence of DVT/PE events and gallbladder disease

•       No difference in cancer or fracture rates between groups

HERS II (2002)24 • Secondary CHD Prevention• Placebo•CEEs 0.625 mg + MPA 2.5 mgn = 2,3212.7 yrNF-AMICHD Death•     HRT did not reduce the rate of CHD in women with established CAD•       The trend in decreased risk over time did not continue

•     Correcting data for confounders, including statin use, did not change results

WHI (2002)25 •  Primary CHD Prevention• Placebo•CEEs 0.625 mg + MPA 2.5 mgn = 16,608 5.2 yrNF-AMICHD Death•    HRT did not reduce the rate of CHD among young, healthy women•    HRT increased the incidence of DVT/PE and gallbladder disease

•    HRT decreased the risk and osteoporotic fracture

•    There was an increased but nonsignificant increase in breast cancer

•    Risks of HRT outweighed observed benefit for primary CHD prevention

MORE (2002)26• SERM, CHD

Secondary Outcome

•    Placebo•    RAL 60 mg QD

•    RAL 120 mg QD

n = 7,7055 yrAMI, Angina CVA, TIA•       No difference in overall CHD risk between groups•     Decreased CHD risk in women at high CHD risk at baseline


Over the years, many observational studies evaluating the effects of HRT on cardiovascular risk in postmenopausal women have reported a potential benefit. Because of the limitations of an observational study design, however, questions remain concerning whether HRT is truly beneficial in preventing CHD among postmenopausal women. As a result of the self-selection of the women enrolled in these studies, these subjects are often younger, healthier, and proactive concerning their health care. These characteristics may make the results less applicable to all postmenopausal women. In response to the lingering questions, prospective, experimental studies were designed to address these concerns (Table 2).