What are the specific risks and likelihood of complications associated with Hormone Replacement Therapy (HRT)?

From the Guidelines

Hormone Replacement Therapy (HRT) carries specific risks, including a small increased chance of breast cancer, cardiovascular events, and venous thromboembolism, which must be weighed against the benefits of symptom relief and disease prevention. The most significant risks associated with HRT include breast cancer, with approximately 8 additional cases per 10,000 women per year, as reported in the Women's Health Initiative (WHI) study 1. Cardiovascular risks include a slightly increased risk of stroke and venous thromboembolism, particularly in the first year of treatment and with oral formulations, with a relative risk of 2.14 for venous thromboembolism 1. Other potential complications include gallbladder disease and, rarely, endometrial cancer if progestogen is not included for women with an intact uterus. Key factors influencing the risk-benefit profile of HRT include the type of therapy, duration of use, age at initiation, and individual health factors. Some key points to consider when evaluating the risks and benefits of HRT include:

• The timing of HRT initiation, with starting within 10 years of menopause or before age 60 offering the most favorable risk-benefit profile.
• The use of the lowest effective dose for the shortest duration needed to minimize risks.
• The consideration of alternative treatments for menopausal symptoms and disease prevention.
• The importance of individualized decision-making, taking into account a woman's personal preferences, medical history, and risk factors. Overall, the decision to use HRT should be based on a careful evaluation of the potential benefits and risks, with consideration of individual factors and alternative treatment options.

From the FDA Drug Label

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12- fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose Most studies show no significant increased risk associated with use of estrogens for less than one year The greatest risk appears associated with prolonged use with increased risks of 15- to 24-fold for five to ten years or more and this risk persists for 8 to over 15 years after estrogen therapy is discontinued The WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation An increased risk of ovarian cancer has been reported with the use of hormonal therapy for menopausal symptoms The relative risks associated with current use of hormonal therapy was 1.58 (95 percent CI, 0.77 to 3.24) Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE) In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women years) In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years) In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE plus MPA compared to women receiving placebo (35 versus 17 per 10,000 women-years)

The specific risks of Hormone Replacement Therapy (HRT) include:

• Endometrial cancer: 2- to 12-fold increased risk with unopposed estrogen use, dependent on duration and dose of treatment 2
• Breast cancer: increased risk with estrogen plus progestin therapy, with a relative risk of 1.24 and absolute risk of 41 vs 33 cases per 10,000 women-years 2
• Ovarian cancer: increased risk with hormonal therapy for menopausal symptoms, with a relative risk of 1.58 (95% CI, 0.77 to 3.24) 2
• Cardiovascular events: increased risk of myocardial infarction, stroke, and venous thromboembolism with estrogen and estrogen/progestin therapy 2
• Venous thromboembolism (VTE): 2-fold increased risk with estrogen plus progestin therapy, with a rate of 35 vs 17 per 10,000 women-years 3 The likelihood of these complications varies depending on the specific type and dose of HRT, as well as individual patient factors such as age, medical history, and risk factors. Key points:
• HRT is associated with an increased risk of endometrial, breast, and ovarian cancer
• HRT is also associated with an increased risk of cardiovascular events and VTE
• The risk of these complications varies depending on the specific type and dose of HRT, as well as individual patient factors.

From the Research

Specific Risks of HRT

The specific risks associated with Hormone Replacement Therapy (HRT) include:

• Risk of stroke 4
• Cardiovascular disease 4
• Breast cancer 4, 5, 6, 7
• Venous thromboembolism 4, 8

Likelihood of Complications

The likelihood of complications associated with HRT varies depending on the type of HRT used. For example:

• Combined estrogen-progesterone regimens increase the risk of breast cancer more than estrogen alone 5, 7
• The risk of breast cancer is higher for estrogen receptor-positive cancers than for estrogen receptor-negative cancers, and for low-grade cancers compared with high-grade cancers 6
• The use of dydrogesterone in HRT may minimize the risks of breast cancer, stroke, and venous thromboembolism 8

Factors Affecting Risk

Several factors can affect the risk of complications associated with HRT, including:

• Initiation of hormone use immediately after menopause 6
• Lean body mass 6
• High mammographic breast density 6
• Type of HRT used (e.g. estrogen alone vs. combined estrogen-progesterone) 7
• Duration of HRT use 4, 6, 7