Oral Hormone Replacement Therapy Options for Women
For women with an intact uterus, the recommended oral regimen is conjugated equine estrogens (CEE) 0.625 mg daily combined with micronized progesterone 200 mg at bedtime, or alternatively, oral 17β-estradiol 1-2 mg daily with the same progestin. 1, 2 For women who have had a hysterectomy, estrogen-alone therapy (CEE 0.625 mg or oral estradiol 1-2 mg daily) is appropriate and does not require progestin. 1, 3
Primary Oral Estrogen Options
Conjugated Equine Estrogens (CEE):
- Standard dose: 0.625 mg daily 4
- Lower doses available: 0.45 mg and 0.3 mg daily 4
- Most extensively studied in WHI trials with established risk-benefit data 5, 1
- Demonstrated 75% reduction in vasomotor symptoms and 22-27% reduction in fracture risk 1
Oral 17β-Estradiol:
- Preferred over CEE by European guidelines due to more physiologic hormone profile 5, 1
- Standard doses: 1-2 mg daily 1
- Ultra-low dose option: 0.5 mg daily for minimal effective dosing 1
- Estradiol valerate 2 mg daily is another bioequivalent option 1
Mandatory Progestin for Women with Intact Uterus
You must add progestin to any estrogen regimen in women with a uterus—unopposed estrogen increases endometrial cancer risk 10- to 30-fold after 5 years of use. 1, 2
Micronized Progesterone (Preferred):
- Dose: 200 mg orally at bedtime 1, 2
- Superior breast safety profile compared to synthetic progestins 1, 2
- Can be given continuously (daily) or sequentially (12-14 days per month) 1
- Reduces endometrial cancer risk by approximately 90% when combined with estrogen 1, 2
Medroxyprogesterone Acetate (MPA) (Alternative):
- Continuous regimen: 2.5 mg daily (as in Prempro) 1, 4
- Sequential regimen: 10 mg daily for 12-14 days per month 5, 1
- More extensive safety data from WHI trials but higher breast cancer risk than micronized progesterone 1
Dydrogesterone (Alternative):
Critical Prescribing Principles
Use the lowest effective dose for the shortest duration necessary—risks including stroke, venous thromboembolism, and breast cancer increase with both dose and duration. 5, 1, 2
- For every 10,000 women taking combined estrogen-progestin for 1 year: 8 additional breast cancers, 8 additional strokes, 8 additional pulmonary emboli, 7 additional coronary events 5, 1
- Benefits include: 6 fewer colorectal cancers, 5 fewer hip fractures, 75% reduction in hot flashes 5, 1
- Breast cancer risk does not appear until after 4-5 years of combined therapy 1
- Estrogen-alone therapy (post-hysterectomy) shows no increased breast cancer risk and may be protective (RR 0.80) 1, 4
Important Clinical Caveats
Never prescribe estrogen-alone to women with an intact uterus—this dramatically increases endometrial cancer risk (RR 2.3-9.5). 1, 2
Absolute contraindications to oral HRT include: 1, 2
- Personal history of breast cancer or hormone-sensitive malignancies
- Active or history of venous thromboembolism or stroke
- Coronary heart disease or myocardial infarction
- Active liver disease
- Antiphospholipid syndrome
Consider transdermal over oral routes in women with: 1, 2
- Hypertension
- Elevated triglycerides
- Obesity or metabolic syndrome
- History of gallbladder disease
- Coagulation concerns
The oral route produces hepatic first-pass metabolism that increases coagulation factors and triglycerides more than transdermal administration, though it may provide greater LDL reduction. 6, 7
Monitoring and Duration
- Annual clinical review focusing on symptom control and compliance 5, 1
- No routine laboratory monitoring (estradiol or FSH levels) required—management is symptom-based 1
- Attempt dose reduction or discontinuation at 3-6 month intervals once symptoms are controlled 2
- Most favorable risk-benefit profile exists for women under 60 or within 10 years of menopause 1, 2
- At age 65, reassess necessity and attempt discontinuation—do not initiate HRT after age 65 for chronic disease prevention 1