What is the increased risk of Hormone Replacement Therapy (HRT) in women over 60 years of age?

From the Guidelines

Hormone Replacement Therapy (HRT) after age 60 significantly increases health risks, particularly for cardiovascular events and breast cancer, with a 26% increased incidence of breast cancer observed in the treatment group, as demonstrated by the Women's Health Initiative (WHI) study 1. Women starting HRT after 60 face approximately a 30% increased risk of coronary heart disease, stroke, and venous thromboembolism compared to non-users. Breast cancer risk increases by about 20-30% with combined estrogen-progestin therapy, with risk rising with longer duration of use. These risks are substantially higher than when HRT is initiated during the "window of opportunity" near menopause (before age 60 or within 10 years of menopause onset). The most recent guidelines from the American Heart Association, published in 2024, recommend assessing for contraindications to menopausal hormone therapy use, including history of breast cancer, liver disease, and thrombophilic disorders 1. Key points to consider when evaluating the risks and benefits of HRT in women over 60 include:

• The increased risk of breast cancer, particularly with combined estrogen-progestin therapy
• The increased risk of cardiovascular events, including coronary heart disease, stroke, and venous thromboembolism
• The potential benefits of HRT in preventing osteoporosis and reducing the risk of colorectal cancer
• The importance of individualized decision-making, taking into account a woman's medical history, risk factors, and personal preferences. If HRT is deemed necessary after 60, the lowest effective dose should be used for the shortest duration possible, with regular risk assessments. Transdermal estrogen may offer a slightly lower thrombosis risk than oral formulations, as suggested by the 2024 guideline for the primary prevention of stroke 1. These age-related risk differences occur because older women's blood vessels and tissues have already undergone more significant changes that HRT can exacerbate rather than prevent.

From the FDA Drug Label

The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years).

The FDA drug label does not provide a direct answer to the question of how much HRT increases the risk over age 60. However, based on the available information, it can be inferred that:

• HRT increases the risk of stroke in postmenopausal women, with a statistically significant increased risk reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone or CE (0.625 mg) plus MPA (2.5 mg) compared to placebo.
• HRT increases the risk of dementia in postmenopausal women 65 years of age or older.
• The risk of cardiovascular events, including myocardial infarction, stroke, and venous thromboembolism, is increased in postmenopausal women receiving HRT. It is essential to note that the FDA drug label recommends that estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman 2, 2, 3.

From the Research

Risk of HRT in Women Over 60

The risk of Hormone Replacement Therapy (HRT) in women over 60 is a topic of ongoing debate.

• Studies have shown that the risk-benefit balance of HRT varies depending on the age of initiation and the type of HRT used 4.
• In women over 60, the risk of HRT may be higher due to the increased risk of cardiovascular disease and breast cancer 5, 4.
• However, some studies suggest that HRT may still be beneficial for women over 60 who are experiencing severe menopausal symptoms, as it can improve quality of life and reduce the risk of osteoporotic fractures 4, 6.

Specific Risks Associated with HRT in Women Over 60

Some specific risks associated with HRT in women over 60 include:

• Increased risk of cardiovascular disease, including coronary heart disease and stroke 5, 4.
• Increased risk of breast cancer, although this risk may be lower with certain types of HRT, such as conjugated estrogens/bazedoxifene 7.
• Increased risk of endometrial cancer and endometrial hyperplasia, although this risk may be lower with certain types of HRT, such as estrogen/progestin combination therapy 7.
• Increased risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism 8, 5.

Factors to Consider When Prescribing HRT to Women Over 60

When prescribing HRT to women over 60, healthcare providers should consider the following factors:

• The individual woman's risk factors for cardiovascular disease, breast cancer, and other health conditions 4, 6.
• The type and dose of HRT used, as well as the route of administration 5, 6.
• The woman's symptoms and quality of life, as well as her preferences and values regarding HRT 4, 6.
• The potential benefits and risks of HRT, as well as alternative treatment options 4, 6.