What are the risks associated with Hormone Replacement Therapy (HRT) for menopause?

From the Guidelines

Hormone Replacement Therapy (HRT) for menopause carries significant risks, including an increased chance of breast cancer, blood clots, stroke, and heart disease, which must be carefully weighed against its benefits. The main risks associated with HRT include an increased chance of breast cancer, particularly with combined estrogen-progestin therapy used for longer than 3-5 years 1. Women taking HRT also face higher risks of blood clots, stroke, and heart disease, especially if they start therapy more than 10 years after menopause or have pre-existing cardiovascular risk factors. Specific medications like conjugated equine estrogens (Premarin) combined with medroxyprogesterone acetate (Provera) have shown higher risk profiles than transdermal estradiol with micronized progesterone 1. Other potential side effects include gallbladder disease, urinary incontinence, and possibly an increased risk of ovarian and endometrial cancers with certain formulations. Some key points to consider when evaluating the risks of HRT include:

• The type of HRT used, with combined estrogen-progestin therapy generally carrying a higher risk profile than estrogen-only therapy 1
• The duration of HRT use, with longer-term use associated with a higher risk of breast cancer and other adverse effects 1
• The individual woman's risk factors, including her age, time since menopause, personal medical history, and family history 1
• The specific benefits of HRT for the individual woman, including relief from hot flashes, night sweats, vaginal dryness, and protection against osteoporosis 1 Given the potential risks and benefits of HRT, the most appropriate approach is to use the lowest effective dose for the shortest possible time, typically less than 5 years, to minimize the risk of adverse effects while still providing relief from menopausal symptoms 1.

From the FDA Drug Label

In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and pulmonary embolism [PE]) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose The relative risk of invasive breast cancer was 1.24 (95 percent nCI, 1.01-1. 54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo.

The risks with HRT for menopause include:

• Venous Thromboembolism (VTE): a 2-fold greater rate of VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), compared to placebo 2
• Endometrial Cancer: an increased risk of endometrial cancer with unopposed estrogen therapy, dependent on duration of treatment and estrogen dose 2
• Breast Cancer: an increased risk of invasive breast cancer with estrogen plus progestin therapy, with a relative risk of 1.24 and an absolute risk of 41 versus 33 cases per 10,000 women-years compared to placebo 2
• Coronary Heart Disease: no cardiovascular benefit with estrogen plus progestin therapy in postmenopausal women with established coronary heart disease 3
• Probable Dementia: no conclusion can be drawn due to limited information 2

From the Research

Risks Associated with HRT for Menopause

The following are some of the risks associated with Hormone Replacement Therapy (HRT) for menopause:

• Increased risk of coronary heart disease, particularly in older women and those a number of years beyond menopause 4
• Increased risk of breast cancer with extended use of HRT 4
• Increased risk of endometrial hyperplasia and carcinoma with unopposed estrogen therapy 5, 6
• Irregular bleeding and spotting, which can affect adherence to therapy 5, 6
• Increased risk of venous thromboembolism (VTE) and cardiovascular outcomes 7
• Potential risks associated with the use of progestins, such as synthetic progestogens, compared to progesterone 7

Factors Influencing Risks

The risks associated with HRT can be influenced by several factors, including:

• Duration of use: Risks increase with increasing duration of use 4, 5, 6
• Dose: Higher doses of estrogen are associated with increased risks 5, 6
• Type of estrogen and progestogen used: E2 and progesterone may have a better safety profile compared to CEE and progestins 7
• Individual characteristics: Women with a history of breast or endometrial cancer, cardiovascular disease, or thromboembolic disorders may be at increased risk 4

Recommendations

Current recommendations for HRT use in menopausal women emphasize the importance of individualized care, taking into account a woman's medical history, needs, and preferences 4, 8. The benefits and risks of HRT should be carefully weighed, and the lowest effective dose should be used for the shortest duration necessary 4.