What is the role of hormone replacement therapy (HRT) in perimenopausal women?

From the Guidelines

Hormone replacement therapy (HRT) should be prescribed at the lowest effective dose and for the shortest duration of use consistent with treatment goals and risks for the individual perimenopausal woman. This approach is based on the U.S. Preventive Services Task Force recommendation statement, which highlights the importance of weighing the benefits and harms of HRT in postmenopausal women 1. The benefits of HRT include the prevention of fractures (about 56 fractures of any type prevented per 10 000 person-years) and a small reduction in the risk for invasive breast cancer (about 8 fewer cases per 10 000 person-years) and for dying of the disease (about 2 fewer deaths per 10 000 person-years) 1. However, HRT is also associated with important harms, such as an increased likelihood of stroke, deep vein thrombosis (DVT), and gallbladder disease.

Key Considerations

• The U.S. Food and Drug Administration (FDA)–approved indications for hormone therapy in postmenopausal women are limited to the treatment of menopausal symptoms and the prevention of osteoporosis 1.
• The timing of initiation of hormone therapy relative to menopause onset has not been prospectively evaluated in randomized trials, but post hoc subgroup analyses suggest an increased probability of harm with increasing age at initiation and longer duration of use 1.
• Women with a history of breast cancer, coronary heart disease, previous venous thromboembolism, or stroke should not be prescribed HRT due to increased risks in these populations.

Treatment Regimen

The most common regimen includes estrogen (such as oral estradiol 0.5-1mg daily, transdermal estradiol patch 0.025-0.05mg/day, or estradiol gel 0.25-0.5mg daily) combined with progesterone (such as micronized progesterone 100-200mg daily or medroxyprogesterone acetate 2.5-5mg daily) for women with an intact uterus to prevent endometrial hyperplasia. Women who have had a hysterectomy can take estrogen alone. Treatment should be initiated at the lowest effective dose and typically continues for 2-5 years or until symptoms resolve, with annual reassessment of benefits and risks.

Additional Benefits and Risks

Beyond symptom relief, HRT may provide additional benefits including prevention of bone loss and improvement in mood and cognitive function. However, HRT is also associated with an increased incidence of stress, mixed, or any urinary incontinence in previously asymptomatic women after 1 year 1. Therefore, it is essential to carefully weigh the benefits and risks of HRT for each individual perimenopausal woman and to monitor for potential adverse effects.

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 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.

Hormone Replacement Therapy (HRT) in Perimenopausal Women:

• The use of estrogen-alone and estrogen plus progestin therapy has been associated with an increased risk of breast cancer, ovarian cancer, and other health risks.
• The decision to use HRT should be made after careful consideration of the individual woman's risk factors and medical history.
• HRT should be prescribed at the lowest effective dose and for the shortest duration necessary to achieve treatment goals.
• Women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations.
• Mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results 2, 3.
• The exact duration of hormone therapy use associated with an increased risk of ovarian cancer is unknown 2.
• The risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to the risk with estrogen-alone therapy 2.

From the Research

Hormone Replacement Therapy in Perimenopausal Women

• Hormone replacement therapy (HRT) is an effective treatment for symptoms associated with perimenopause and menopause, including hot flashes, night sweats, and vaginal dryness 4, 5, 6.
• Unopposed estrogen therapy can increase the risk of endometrial hyperplasia and carcinoma in women with an intact uterus, while the addition of progestogen can reduce this risk 4, 5, 7.
• The risk of endometrial hyperplasia with HRT can be minimized by using low-dose estrogen and adding progestogen, with a minimum of 1 mg norethisterone acetate (NETA) or 1.5 mg medroxyprogesterone acetate (MPA) 5.
• Continuous combined estrogen-progestogen therapy can be more effective than sequential therapy in reducing the risk of endometrial hyperplasia, especially at longer durations of treatment 4, 7.
• However, sequential therapy may be associated with less irregular bleeding and spotting during the first year of treatment, while continuous therapy may be more protective against endometrial hyperplasia over the long term 4, 7.

Considerations for Perimenopausal Women

• Perimenopausal women may experience a range of symptoms, including irregular menstrual bleeding, hot flashes, and mood changes 8, 6.
• Hormonal contraceptives can provide non-contraceptive benefits for perimenopausal women, including treatment of abnormal uterine bleeding, relief from vasomotor symptoms, and endometrial protection 8.
• Individualized medical therapy and a multidisciplinary approach, considering lifestyle and food habits, are essential for managing perimenopause and menopause symptoms 8, 6.

Current Recommendations

• HRT is currently recommended for the management of menopausal symptoms, with the benefits and risks carefully weighed for each individual woman 6.
• The use of HRT should be tailored to the individual woman's needs, with consideration of her medical history, risk factors, and preferences 6.
• Further research is needed to fully understand the effects of HRT on perimenopausal and menopausal women, including the potential risks and benefits of different treatment regimens 4, 5, 7, 6.