What is the difference between cyclical progesterone (Progesterone) and continuous progesterone in hormone replacement therapy (HRT) for women with an intact uterus?

Cyclical vs Continuous Progesterone in Hormone Replacement Therapy

For women with an intact uterus, cyclical progesterone regimens are preferred over continuous regimens in hormone replacement therapy due to better endometrial protection and allowing earlier recognition of potential pregnancy. 1

Differences Between Cyclical and Continuous Progesterone Regimens

Cyclical Progesterone

• Progesterone is administered for 12-14 days of the month in combination with estrogen 1, 2
• Causes regular withdrawal bleeding similar to menstrual periods 1
• Allows earlier recognition of potential pregnancy, which is important as women with premature ovarian insufficiency may spontaneously ovulate (20-25% incidence) 1, 2
• Provides adequate endometrial protection when used appropriately 1
• Recommended for women with premature ovarian insufficiency and those in perimenopause 1

Continuous Progesterone

• Progesterone is administered daily alongside estrogen 1
• Prevents withdrawal bleeding, which some women may prefer 1
• May provide better endometrial protection than sequential regimens during long-term therapy 3
• Associated with more irregular bleeding and spotting during the first year of therapy compared to sequential regimens 3
• May be preferred for postmenopausal women who want to avoid monthly bleeding 2

Endometrial Protection Considerations

• The primary purpose of adding progesterone to estrogen therapy is to prevent endometrial hyperplasia and cancer in women with an intact uterus 4, 3
• Continuous combined therapy shows better protection against endometrial hyperplasia during long-term treatment compared to sequential therapy 3, 5
• Continuous combined therapy is associated with a reduced risk of endometrial cancer (relative risk 0.71) compared to never users of HRT 6
• Cyclic combined therapy shows no significant alteration in endometrial cancer risk (relative risk 1.05) compared to never users 6
• Long-cycle sequential therapy (progesterone every three months) has a higher incidence of hyperplasia compared to monthly sequential therapy 3

Bleeding Patterns

• During the first year of therapy, irregular bleeding and spotting are more common with continuous combined therapy than with sequential therapy 3
• During the second year, bleeding and spotting become more likely with sequential regimens 3
• Continuous regimens eventually lead to amenorrhea in most women 1
• Withdrawal bleeding with cyclical regimens is predictable and mimics normal menstrual cycles 1

Progesterone Types and Dosing

• Micronized natural progesterone (100-200 mg/day) is recommended due to its favorable cardiovascular and thrombotic risk profile 1, 2
• Dydrogesterone (5-10 mg/day) is another option listed in ESHRE guidelines 1
• Medroxyprogesterone acetate has the strongest evidence for endometrial protection but may negatively impact cardiovascular risk 1
• The dose of progesterone should be based on the concurrent dose of estrogen administered 1

Special Considerations

• For women with premature ovarian insufficiency, ESHRE guidelines recommend beginning cyclical progestogens after at least 2 years of estrogen or when breakthrough bleeding occurs 1
• For adolescents with Turner Syndrome, cyclical progesterone is recommended to be started after 2 years of estrogen therapy or when breakthrough bleeding occurs 1
• Body mass index affects the efficacy of progesterone regimens, with the beneficial effects of combined HRT being greatest in obese women 6
• Women seeking contraception should consider combined oral contraceptives rather than HRT 1

Common Pitfalls to Avoid

• Using inadequate doses of progesterone that don't provide sufficient endometrial protection 2, 5
• Failing to add progesterone in women with an intact uterus, which significantly increases risk of endometrial hyperplasia and cancer 3, 5
• Using long-cycle sequential therapy (every 3 months) instead of monthly sequential therapy, as this provides less endometrial protection 3
• Discontinuing HRT prematurely (before age of natural menopause) 2

In conclusion, while both regimens provide endometrial protection when used appropriately, cyclical progesterone is generally preferred for women with premature ovarian insufficiency and those in perimenopause, while continuous regimens may be more suitable for postmenopausal women who wish to avoid monthly bleeding.