Examples of Hormone Replacement Therapy (HRT)
For women with an intact uterus, combined estrogen-progestogen therapy is required, with options including conjugated equine estrogens (CEE) or estradiol paired with progestogens such as medroxyprogesterone acetate (MPA), norethisterone acetate (NETA), micronized progesterone, or dydrogesterone; for women without a uterus, estrogen-only therapy with CEE or estradiol is appropriate 1.
Estrogen-Only Regimens (For Women Without a Uterus)
Women who have undergone hysterectomy can safely use estrogen monotherapy without progestogen 1. Available options include:
Oral formulations:
- Conjugated equine estrogens (CEE): Standard doses range from 0.3-0.625 mg daily
- Micronized estradiol: 0.5-2 mg daily
- Esterified estrogens: 0.3-1.25 mg daily
Transdermal formulations:
- Estradiol patches: 0.025-0.1 mg (changed weekly or twice weekly depending on product)
- Estradiol gel or spray: Applied daily
The lowest effective dose should be used—for example, 0.3 mg CEE or 0.025 mcg transdermal estradiol patch are FDA-approved for osteoporosis prevention and often sufficient for symptom control 2.
Combined Estrogen-Progestogen Regimens (For Women With a Uterus)
Progestogen must be added to estrogen therapy in women with an intact uterus to prevent endometrial hyperplasia and cancer 1, 3. Unopposed estrogen increases endometrial cancer risk at all doses and durations 3.
Continuous Combined Regimens
These provide daily estrogen plus daily progestogen, designed to minimize bleeding:
Oral combinations:
- CEE 0.3-0.625 mg + MPA 1.5-2.5 mg daily
- Estradiol 1 mg + norethisterone acetate (NETA) 0.5 mg daily
- Estradiol + drospirenone combinations
- Estradiol + bazedoxifene (a SERM alternative to progestogen) 1, 4
Transdermal combinations:
The minimum effective progestogen doses for endometrial protection are 1 mg NETA or 1.5 mg MPA when combined with low-dose estrogen 3.
Sequential (Cyclic) Regimens
These provide continuous estrogen with progestogen added for 10-14 days per month (or every 3-4 months with very low-dose estrogen):
- Estrogen daily + progestogen for 12-14 days monthly
- Results in predictable withdrawal bleeding
- May use lower progestogen exposure overall 2
Common progestogens include MPA 5-10 mg, micronized progesterone 200 mg, or NETA 1 mg for the cyclic portion.
Route-Specific Considerations
Transdermal estrogen is preferred over oral in certain populations 1:
- Women at increased VTE risk (obesity, thrombophilia, prior VTE from reversible causes)
- Women with diabetes or hypertriglyceridemia
- Women with active gallbladder disease
When using transdermal estrogen, a separate oral progestogen must be prescribed (micronized progesterone 100-200 mg or dydrogesterone are preferred as they are neutral on coagulation parameters) 1, 6.
Emerging Trends in Clinical Practice
Recent data from Japan shows increasing preference for transdermal estradiol over oral CEE, and increasing use of dydrogesterone and transdermal NETA while MPA use declines 7. However, a concerning finding is that approximately 30% of women with a uterus receiving estrogen for ≥180 days did not receive concurrent progestogen—a practice that violates safety guidelines 7.
Critical Safety Point
A common and dangerous pitfall is prescribing estrogen without progestogen to women with an intact uterus 7. Always verify hysterectomy status before prescribing estrogen-only therapy. Any woman with a uterus requires either combined estrogen-progestogen therapy or estrogen plus bazedoxifene to prevent endometrial hyperplasia 1, 3, 4.