What are the effects of daily progesterone administration with hormone replacement therapy (HRT)?

From the Guidelines

Daily progesterone should be included in hormone replacement therapy (HRT) for women with an intact uterus to protect against endometrial cancer, with a preferred regimen of continuous daily progesterone. The use of progesterone in HRT is supported by the need to balance the benefits and harms of hormone therapy, as outlined in the study by the USPSTF 1. According to this study, the harms of estrogen-progestin therapy may outweigh the benefits for most women, but individual risk factors and preferences should be considered in selecting effective interventions.

When considering daily progesterone with HRT, common options include micronized progesterone (100-200mg daily) or synthetic progestins like medroxyprogesterone acetate (2.5-5mg daily). The choice of progesterone regimen should be based on individual patient needs and preferences, with consideration of potential side effects such as breast tenderness, mood changes, and bloating.

Key points to consider when prescribing daily progesterone with HRT include:

• The importance of protecting against endometrial cancer in women with an intact uterus
• The need for individualized decision-making, taking into account patient risk factors and preferences
• The potential benefits and harms of hormone therapy, as outlined in the USPSTF study 1
• The preferred regimen of continuous daily progesterone for optimal endometrial protection and elimination of monthly withdrawal bleeding.

From the FDA Drug Label

A comparison of the progesterone capsules plus conjugated estrogens treatment group to the conjugated estrogens only group showed a significantly lower rate of hyperplasia (6 percent combination product versus 64 percent estrogen alone) in the progesterone capsules plus conjugated estrogens treatment group throughout 36 months of treatment. The use of daily progesterone with hormone replacement therapy (HRT), specifically with conjugated estrogens, is supported by the drug label as it shows a significantly lower rate of endometrial hyperplasia compared to estrogen-only therapy.

• The study found that the combination of progesterone capsules and conjugated estrogens resulted in a lower rate of hyperplasia (6%) compared to conjugated estrogens alone (64%) over 36 months of treatment 2.
• This suggests that daily progesterone can be used with HRT to reduce the risk of endometrial hyperplasia.
• However, the label also mentions the Women's Health Initiative (WHI) studies, which found an increased risk of breast cancer and cardiovascular events with the use of estrogen plus progestin therapy 2.

From the Research

Daily Progesterone with Hormone Replacement Therapy

• The use of daily progesterone with hormone replacement therapy (HRT) is a common practice to reduce the risk of endometrial hyperplasia and carcinoma in postmenopausal women 3, 4, 5, 6, 7.
• Studies have shown that unopposed estrogen therapy can increase the risk of endometrial hyperplasia, while the addition of progestogen can reduce this risk 3, 4, 6, 7.
• The type and dosage of progestogen used can affect the risk of endometrial hyperplasia, with some studies suggesting that natural micronized progesterone may be a safer option than synthetic progestins 5.
• The timing and duration of progestogen therapy can also impact the risk of endometrial hyperplasia, with continuous combined therapy being more effective than sequential therapy in reducing the risk of hyperplasia at longer durations of treatment 3, 4.

Benefits and Risks of Daily Progesterone with HRT

• Benefits of daily progesterone with HRT include:
  • Reduced risk of endometrial hyperplasia and carcinoma
  • Improved adherence to therapy
  • Relief of menopausal symptoms
• Risks of daily progesterone with HRT include:
  • Irregular bleeding and spotting
  • Uncomfortable side effects
  • Reversal of some of the cardiovascular and metabolic benefits of estrogen

Recommended Regimens

• The recommended regimen for daily progesterone with HRT varies depending on the individual woman's needs and medical history 6.
• A common regimen is the use of low-dose estrogen continuously combined with a minimum of 1 mg norethisterone acetate (NETA) or 1.5 mg medroxyprogesterone acetate (MPA) 6.
• Natural micronized progesterone may be a safer option than synthetic progestins, and can be used in a cyclic combined regimen comprising estrogen and 100 mg micronized progesterone administered on days 1-25 5.