Is transdermal estrogen given continuously without a break with progesterone for 10-12 days per month for Hormone Replacement Therapy (HRT) in premature menopause?

Transdermal Estrogen and Progesterone Administration for HRT in Premature Menopause

For hormone replacement therapy (HRT) in premature menopause, transdermal estrogen should be administered continuously without breaks, with progesterone added for 12-14 days per month in women with an intact uterus. 1, 2

Recommended Regimen

• Transdermal 17β-estradiol should be administered continuously throughout the month without interruption 1
• Progesterone should be added for endometrial protection in women with an intact uterus 1, 2
• The standard recommendation is to administer progesterone for 12-14 days every 28-day cycle in a sequential regimen 2, 3
• This cyclical administration of progesterone with continuous estrogen is considered the standard approach for premature ovarian insufficiency (POI) 1

Progesterone Options and Dosing

• Micronized progesterone is the preferred choice due to its lower risk of cardiovascular disease and venous thromboembolism when taken cyclically 2, 4
• Standard dosing for sequential regimens includes:
  • 200 mg of oral or vaginal micronized progesterone for 12-14 days per month 2, 3
  • Alternative options include 10 mg of medroxyprogesterone acetate or 10 mg of dydrogesterone for 12-14 days per month 2, 4
• Clinical trials have demonstrated that 200 mg of progesterone administered for 12 days per 28-day cycle provides effective endometrial protection when combined with estrogen therapy 3, 5

Transdermal Estrogen Benefits

• Transdermal estradiol is the preferred method of delivery, especially in women with hypertension 1
• 17β-estradiol is preferred to ethinylestradiol or conjugated equine estrogens for estrogen replacement 1
• Transdermal administration avoids first-pass liver metabolism, resulting in more stable hormone levels and fewer side effects 6, 7
• This route of administration is associated with a lower risk of venous thromboembolism compared to oral estrogen 6

Sequential vs. Continuous Combined Regimens

• Sequential regimen (recommended for most women with POI):
  • Continuous transdermal estrogen with progesterone for 12-14 days per month 2, 4
  • Results in monthly withdrawal bleeding, which some women prefer as reassurance 1, 2
• Continuous combined regimen (alternative option):
  • Both estrogen and progesterone administered daily without interruption 2, 8
  • May be preferred by women who wish to avoid monthly bleeding 2
  • Standard doses for continuous regimens include 1 mg of oral norethisterone, 2.5 mg of oral medroxyprogesterone acetate, or 5 mg of oral dydrogesterone daily 1

Duration of Therapy

• HRT should be continued at least until the average age of natural menopause (approximately 51 years) 1
• This approach helps control future risk of cardiovascular disease and bone loss 1
• Annual monitoring is recommended, paying particular attention to compliance 1
• No routine monitoring tests are required but may be prompted by specific symptoms or concerns 1

Important Considerations

• Patient preference for route and method of administration should be considered when prescribing, as should contraceptive needs 1
• Women with POI should be informed that HRT has not been found to increase the risk of breast cancer before the age of natural menopause 1
• FDA-approved clinical trials have shown that progesterone administered for 12 days per 28-day cycle provides significant protection against endometrial hyperplasia compared to estrogen alone (6% vs. 64% hyperplasia rate) 3, 5
• Common side effects of progesterone therapy, such as mood changes and breast tenderness, typically resolve within the first 3 months of treatment 2

Special Populations

• For women with POI and hypertension, transdermal estradiol is strongly preferred 1
• HRT is a treatment option for women carrying BRCA1/2 mutations without personal history of breast cancer after prophylactic bilateral salpingo-oophorectomy 1
• HRT is generally contraindicated in breast cancer survivors 1