Is progesterone beneficial in women without a uterus (womb)?

Progesterone Benefits in Women Without a Uterus

Progesterone therapy offers no clear benefit for women without a uterus and is not recommended as part of hormone therapy in this population. In women with an intact uterus, progesterone is necessary to prevent endometrial hyperplasia and cancer when using estrogen therapy, but this protective effect is irrelevant after hysterectomy.

Evidence on Progesterone Use After Hysterectomy

Current Guidelines and Recommendations

The American College of Physicians specifically recommends estrogen-only therapy for women who have undergone hysterectomy, while reserving combined estrogen-progestin regimens only for women with an intact uterus 1. This recommendation is based on the understanding that:

• The primary purpose of progesterone in menopausal hormone therapy is to protect the endometrium from estrogen-stimulated hyperplasia and potential cancer
• Without a uterus, this protective effect becomes unnecessary

Risks vs. Benefits Analysis

Potential Benefits

While some research has explored progesterone-only therapy for menopausal symptoms, the evidence for its use in women without a uterus is limited:

• In a systematic review of progestin-only treatment, only three of seven randomized controlled trials showed improvement in vasomotor symptoms, with inconsistent results across studies 2
• The largest study using oral micronized progesterone (300 mg) showed a 58.9% improvement in vasomotor symptoms compared to 23.5% in the placebo group, but this was not specific to women without a uterus 2
• No studies have demonstrated mood symptom improvement with progesterone-only therapy 2

Potential Risks

Adding progesterone when not necessary may introduce additional risks:

• Side effects such as headaches and vaginal bleeding were significant in five of seven RCTs of progestin-only therapy 2
• These side effects led to treatment discontinuation in 6% to 21% of patients 2
• Some progestins may negatively impact cardiovascular risk profiles, though micronized progesterone appears to have a more favorable profile than synthetic progestins 3

Clinical Decision-Making Algorithm

1. For women without a uterus requiring hormone therapy:

   • Prescribe estrogen-only therapy as first-line treatment for menopausal symptoms
   • Avoid adding progesterone as it provides no endometrial protection benefit and may introduce unnecessary risks

2. If considering hormone therapy for specific symptoms:

   • For vasomotor symptoms (hot flashes): Estrogen alone is the most effective treatment
   • For sleep disturbances: Consider that while progesterone may improve sleep 4, estrogen alone is sufficient for women without a uterus
   • For genitourinary symptoms: Vaginal estrogen or ospemifene may be more appropriate than systemic therapy 5

3. If estrogen is contraindicated:

   • Consider non-hormonal alternatives like low-dose paroxetine, venlafaxine, or gabapentin for vasomotor symptoms 5
   • For vaginal symptoms, non-hormonal vaginal moisturizers may be beneficial 5

Important Caveats and Considerations

• The FDA withdrew approval of 17-alpha hydroxyprogesterone caproate in 2023, highlighting evolving understanding of progestin safety and efficacy 6
• Hormone therapy decisions should prioritize morbidity, mortality, and quality of life outcomes
• The U.S. Preventive Services Task Force concludes that the benefits of hormone therapy for chronic disease prevention are unlikely to outweigh harms for most postmenopausal women 1
• If a patient reports significant sleep benefits from progesterone, the risks versus benefits should be carefully weighed, as this would be an off-label use without strong supporting evidence

In conclusion, while progesterone plays a crucial role in hormone therapy for women with an intact uterus, there is no established benefit to adding progesterone for women who have undergone hysterectomy. Estrogen-only therapy remains the standard of care for this population when hormone therapy is indicated.