When is progesterone alone versus combined estrogen and progesterone (hormone replacement therapy, HRT) recommended for patients?

Determining Progesterone Alone vs. Combined Estrogen-Progesterone Therapy

The decision to use progesterone alone versus combined estrogen-progesterone therapy depends entirely on whether the patient has a uterus: women with an intact uterus require combined therapy (estrogen plus progesterone) to protect the endometrium, while women who have had a hysterectomy should receive estrogen-only therapy. 1, 2

Primary Decision Point: Uterine Status

Women WITH an Intact Uterus

• Must receive progestogen combined with estrogen therapy to prevent endometrial hyperplasia and carcinoma 1, 2
• Unopposed estrogen increases endometrial hyperplasia risk dramatically, with rates reaching 62% at 36 months compared to 2% with placebo 3, 4
• The protective effect is dose and duration dependent—progestogen must be given for at least 10-14 days per month 5, 4
• Progesterone alone provides no therapeutic advantage for menopausal symptom management or chronic disease prevention in women with intact uteri 6

Women WITHOUT a Uterus (Post-Hysterectomy)

• Should receive estrogen-only therapy as the standard approach 6
• There is no therapeutic advantage in prescribing progestins to hysterectomized women since there is no endometrium requiring protection 6
• Estrogen alone in hysterectomized women reduces fractures and breast cancer risk, though it increases stroke and thromboembolic events 6

Progestogen Regimen Selection (For Women with Intact Uterus)

Cyclical vs. Continuous Regimens

• Cyclical progesterone (12-14 days per month) is preferred over continuous regimens, particularly for women with premature ovarian insufficiency and those in perimenopause 7
• Cyclical regimens allow earlier recognition of potential pregnancy, important since 20-25% of women with premature ovarian insufficiency may spontaneously ovulate 7
• Continuous combined therapy provides better endometrial protection at longer durations (>2 years) compared to sequential therapy 4, 8
• During the first year, irregular bleeding is more common with continuous therapy, but by the second year, sequential regimens have higher bleeding rates 4

Progestogen Type and Dosing

• Micronized natural progesterone (100-200 mg/day for 12-14 days) is recommended due to favorable cardiovascular and thrombotic risk profiles 1, 7
• Medroxyprogesterone acetate has the strongest evidence for endometrial protection but may negatively impact cardiovascular risk 1
• Minimum effective doses: 1 mg norethisterone acetate or 1.5 mg medroxyprogesterone acetate when continuously combined with low-dose estrogen 8
• Dydrogesterone (5-10 mg/day) is another option with less negative effects on lipid metabolism 1

Special Clinical Scenarios

Premature Ovarian Insufficiency

• Begin cyclical progestogens after at least 2 years of estrogen therapy or when breakthrough bleeding occurs 1, 7
• This delayed approach allows for adequate estrogen exposure for bone health and pubertal development in younger patients 1

Adolescents with Turner Syndrome

• Start low-dose estrogen at age 12-13 years if no spontaneous development and FSH is elevated 1
• Begin cyclical progesterone after 2 years of estrogen or when breakthrough bleeding occurs 1, 7

Endometriosis After Oophorectomy

• Combined estrogen/progestogen therapy is effective for vasomotor symptoms and may reduce risk of disease reactivation 1
• Progesterone alone may be prescribed to postmenopausal women with residual intra-peritoneal endometriosis 6

Breast Cancer Considerations

• HRT is generally contraindicated in breast cancer survivors 1
• Hormone receptor-positive breast cancer is a contraindication to all progesterone therapy, including micronized progesterone 5
• HRT is an option for women carrying BRCA1/2 mutations without personal history of breast cancer after prophylactic bilateral salpingo-oophorectomy 1

Critical Pitfalls to Avoid

• Never prescribe unopposed estrogen to women with an intact uterus—this increases endometrial hyperplasia risk with odds ratios ranging from 5.4 at 6 months to 15.0 at 36 months 4
• Do not use long-cycle sequential therapy (progestogen every 3 months) as it has higher hyperplasia incidence compared to monthly sequential therapy 4
• Avoid prescribing progestogen to hysterectomized women unless there is residual endometriosis, as it provides no benefit and may increase risks 6
• For women with severe peanut allergies, use vaginal progesterone gel formulations instead of oral micronized progesterone capsules containing peanut oil 5
• Do not discontinue HRT prematurely in women with premature ovarian insufficiency—therapy should continue until at least the age of natural menopause 7

Monitoring Requirements

• Annual clinical review once established on therapy, with particular attention to compliance 1
• No routine monitoring tests required but may be prompted by specific symptoms or concerns 1
• For undiagnosed persistent or recurring abnormal vaginal bleeding, undertake adequate diagnostic measures including endometrial sampling 2
• Reevaluate periodically (every 3-6 months) to determine if treatment is still necessary 2