What is the recommended treatment approach for peri-menopausal women considering estrogen plus medroxyprogesterone (Provera) therapy?

From the Guidelines

For peri-menopausal women considering estrogen plus medroxyprogesterone therapy, the treatment approach should prioritize the lowest effective dose for the shortest duration needed to manage symptoms, due to the associated risks of breast cancer, venous thromboembolism, and stroke. The standard regimen for those with an intact uterus includes estrogen plus medroxyprogesterone acetate (Provera) to protect against endometrial hyperplasia, with typical dosing including conjugated equine estrogens 0.3-0.625 mg daily or estradiol 0.5-1 mg daily, combined with medroxyprogesterone acetate 2.5-5 mg daily in a continuous regimen, or 5-10 mg for 12-14 days per month in a cyclic regimen 1. Key considerations for treatment include:

• Symptom severity and impact on quality of life
• Medical history, including risk factors for breast cancer, coronary heart disease, and venous thromboembolism
• Regular follow-up appointments with clinical breast exams, mammograms, and endometrial monitoring to minimize risks
• Contraindications, such as history of breast cancer, coronary heart disease, previous venous thromboembolism, stroke, active liver disease, or unexplained vaginal bleeding. Hormone therapy effectively treats vasomotor symptoms, vaginal dryness, and may help with mood fluctuations and sleep disturbances, but the benefits must be weighed against the potential harms, including an increased risk for stroke, dementia, gallbladder disease, and urinary incontinence, as well as a small increase in the incidence of invasive breast cancer and breast cancer deaths 1.

From the FDA Drug Label

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA FOR ESTROGEN PLUS PROGESTIN THERAPY Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2. 5 mg], relative to placebo. The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2. 5 mg), relative to placebo. Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.

The recommended treatment approach for peri-menopausal women considering estrogen plus medroxyprogesterone therapy is to use the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman 2. Key considerations include:

• Cardiovascular risks: Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia.
• Breast cancer risk: The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.
• Dementia risk: The WHI Memory Study reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older. It is essential to re-evaluate patients periodically (for example, 3 to 6 month intervals) to determine if treatment is still necessary 2.

From the Research

Estrogen and Medroxyprogesterone Therapy in Peri-Menopausal Women

Overview of Therapy

The use of estrogen plus medroxyprogesterone (Provera) therapy in peri-menopausal women is a common practice for managing menopausal symptoms. However, the safety and efficacy of this therapy have been debated due to potential risks associated with breast cancer and cardiovascular disease.

Side Effects and Risks

• The Women's Health Initiative (WHI) study and its reanalysis have shown a higher risk of breast cancer and cardiovascular disease in women taking conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) compared to those taking CEE alone 3.
• Medroxyprogesterone acetate has been associated with an increased risk of breast cancer and cardiovascular disease, particularly in older women 4.
• Short-term use of MPA with an estrogen for less than 5 years may not be associated with an increased risk of these disorders 4.
• Progestin-only therapy, including medroxyprogesterone acetate, has been shown to improve vasomotor symptoms in some studies, but may also be associated with side effects such as headaches and vaginal bleeding 5.

Alternative Therapies

• Selective estrogen receptor modulators (SERMs) and tissue-selective estrogen complexes (TSECs) have been developed as alternative therapies for menopausal symptoms, with potentially improved safety profiles compared to traditional hormone therapy 6, 7.
• Conjugated estrogens/bazedoxifene (CE/BZA) is a TSEC that has been shown to reduce hot flush frequency and severity, prevent bone loss, and improve quality of life, without increasing the risk of endometrial hyperplasia or breast cancer 7.

Considerations for Therapy

• The choice of hormone therapy should be individualized, taking into account the risk/benefit profile and tolerability of therapy, as well as patient preferences 7.
• Women should be informed about the potential risks and benefits of estrogen plus medroxyprogesterone therapy and alternative therapies, and should be closely monitored for any adverse effects.