What are the considerations for Hormone Replacement Therapy (HRT) in women with an intact uterus?

From the Guidelines

For women with an intact uterus, a combined estrogen-progestogen regimen is the recommended approach for hormone replacement therapy (HRT) to prevent endometrial cancer. The use of estrogen without progestin is generally restricted to women who have had a hysterectomy, as unopposed estrogen use increases the risk for endometrial cancer in women with an intact uterus 1. The standard approach involves daily oral estrogen plus either cyclic progestogen or continuous progestogen.

Key Considerations

• The progestogen component is crucial as it prevents endometrial hyperplasia and reduces the risk of endometrial cancer that can occur with unopposed estrogen.
• Cyclic regimens typically cause monthly withdrawal bleeding, while continuous combined therapy may cause irregular bleeding initially but often leads to amenorrhea after 6-12 months.
• Treatment should start at the lowest effective dose and be individualized based on symptom relief and side effects.

Risks and Benefits

• The use of estrogen and progestin therapy is associated with a small increased risk for deep venous thrombosis (DVT) and pulmonary embolism, as well as a small increase in the risk for stroke, dementia, gallbladder disease, and urinary incontinence 1.
• There is convincing evidence that estrogen and progestin therapy does not have a beneficial effect on coronary heart disease (CHD) and probably increases the risk for its occurrence 1.
• The benefits of HRT, including relief of menopausal symptoms and prevention of osteoporosis, must be weighed against the potential risks.

Monitoring and Follow-up

• Regular follow-up appointments are important to assess effectiveness, adjust dosing if needed, and monitor for adverse effects.
• HRT should be used for the shortest duration necessary to control menopausal symptoms, with annual reassessment of risks and benefits.

From the FDA Drug Label

When estrogen therapy is prescribed for a postmenopausal woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.

• Hormone Replacement Therapy (HRT) for women with an intact uterus should include progestin in addition to estrogen to reduce the risk of endometrial cancer.
• The treatment should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman 2.

From the Research

HRT for Women with an Intact Uterus

• Women with an intact uterus require a progestogen for endometrial protection when choosing estrogens for menopausal symptom relief 3.
• The addition of progestogen reduces the risk of endometrial hyperplasia and carcinoma associated with unopposed estrogen therapy 4, 5, 6.
• Unopposed estrogen therapy is associated with increased risk of endometrial hyperplasia at all doses and durations of therapy between one and three years 4.
• Combined continuous estrogen-progestogen therapy and sequential estrogen-progestogen therapy with a minimum of 1 mg norethisterone acetate (NETA) or 1.5 mg medroxyprogesterone acetate (MPA) are not significantly different from placebo in terms of endometrial hyperplasia risk 4.
• The use of natural micronized progesterone in lieu of synthetic progestins can alleviate uncomfortable side effects and reversal of some cardiovascular and metabolic benefits of estrogen 7.

Progestogen Regimens

• Most progestogens are only available as oral formulations, but some are available as transdermal formulations 3.
• Continuous combined estrogen-progestogen therapy and sequential estrogen-progestogen therapy are effective in reducing the risk of endometrial hyperplasia 4, 5, 6.
• Long cycle sequential therapy (progestogen given every three months) has a higher incidence of hyperplasia compared to monthly sequential therapy (progestogen given every month) 5, 6.
• Natural micronized progesterone administered on days 1-25 of a cyclic combined regimen has been shown to provide endometrial safety and a high rate of tolerability 7.

Endometrial Hyperplasia Risks

• Unopposed moderate or high dose estrogen therapy is associated with a significant increase in rates of endometrial hyperplasia with increasing rates at longer duration of treatment and follow up 4, 5, 6.
• Atypical complex hyperplasia is the most likely to progress to carcinoma 7.
• The addition of progestogen reduces the risk of endometrial hyperplasia, but may cause uncomfortable symptoms, bleeding, and spotting 4, 5, 6.