Can a patient use progesterone alone?

Can a Patient Use Progesterone Alone?

Yes, progesterone can be used alone for specific clinical indications including prevention of preterm birth in women with short cervix, treatment of abnormal uterine bleeding, and hormone replacement in certain scenarios, but the appropriateness depends entirely on the clinical context.

For Prevention of Preterm Birth

In women with singleton pregnancies, no prior spontaneous preterm birth, and short transvaginal cervical length ≤20 mm diagnosed before 24 weeks, vaginal progesterone alone (either 90-mg gel or 200-mg suppository) is recommended and associated with reduction in preterm birth and perinatal morbidity and mortality. 1

• The 2024 SMFM guidelines specifically recommend vaginal progesterone as monotherapy for asymptomatic individuals with singleton gestation and transvaginal cervical length ≤20 mm diagnosed before 24 weeks (Grade 1A recommendation). 1

• Importantly, 17-OHPC (17-alpha hydroxyprogesterone caproate) should NOT be used for short cervix, as the 2024 guidelines explicitly recommend against it (Grade 1B). 1 This represents a significant change from older 2012 recommendations, as 17-OHPC has been removed from the market due to lack of efficacy. 2

• For women with prior spontaneous preterm birth, the historical recommendation was 17-OHPC, but this is no longer available or recommended. 1, 2

For Abnormal Uterine Bleeding

Progesterone alone is highly effective for treating abnormal uterine bleeding in reproductive-age and perimenopausal women. 3

• The levonorgestrel intrauterine device (LNG-IUD) is the most effective progesterone-based monotherapy, reducing menstrual blood loss by 71-95%. 3

• Oral micronized progesterone 200 mg daily for 21 days per month effectively reduces menstrual blood loss in women with cyclic heavy bleeding. 3, 4

• Before initiating progesterone monotherapy, rule out pregnancy, structural causes, and malignancy. 3

For Hormone Replacement Therapy

Progesterone should NOT be used alone for hormone replacement in postmenopausal women with an intact uterus—it must be combined with estrogen to prevent endometrial hyperplasia and cancer. 4, 5

• Unopposed estrogen use carries a relative risk of 2.1 to 5.7 for endometrial hyperplasia and adenocarcinoma, requiring progesterone for at least 10-14 days per month for endometrial protection. 4

• In women with premature ovarian insufficiency requiring hormone replacement, 17β-estradiol should be administered continuously with progesterone added either cyclically (12-14 days every 28 days) or continuously. 1

• Oral micronized progesterone 200 mg daily (or vaginal 200 mg daily) for 12-14 days every 28 days is the recommended progestogen when combined with estrogen. 1, 4

For Contraception

Progesterone-only contraceptives can be used as monotherapy and include progestin-only pills, depot medroxyprogesterone acetate (DMPA), and levonorgestrel IUDs. 1

• Self-administered subcutaneous DMPA (DMPA-SC) should be made available as a user-controlled contraceptive method, administered every 3 months (13 weeks). 1

• However, progestin-only contraceptives (pills, injections, implants) may worsen acne, unlike combined oral contraceptives which have anti-androgenic properties. 1

Clinical Scenarios Where Progesterone Alone Should NOT Be Used

Progesterone monotherapy is NOT recommended for: 1

• Multiple gestations for preterm birth prevention (no evidence of benefit) 1
• Preterm labor or preterm premature rupture of membranes 1
• Singleton gestations with no prior preterm birth and unknown cervical length 1
• Women with estrogen-containing hormone replacement therapy and intact uterus (must combine with estrogen) 4

Route of Administration Considerations

The route of administration significantly impacts efficacy and side effects:

• Vaginal progesterone provides preferential uterine uptake through direct vagina-to-uterus transport, allowing lower systemic levels while maintaining endometrial effects. 6

• Oral micronized progesterone undergoes >90% first-pass hepatic metabolism, creating high levels of metabolites that can cause drowsiness and dizziness, best taken at bedtime. 4, 6, 5

• Transdermal progesterone has insufficient evidence for endometrial protection and should not be used to oppose estrogen effects. 7

• Intramuscular progesterone reaches maximum plasma concentrations within 8 hours and maintains levels above baseline for approximately 24 hours. 8

Safety Profile

Natural progesterone has a superior safety profile compared to synthetic progestins: 9, 5

• Meta-analysis of 86,881 postmenopausal women showed natural progesterone associated with significantly lower breast cancer risk compared to synthetic progestins. 9

• Micronized progesterone preserves full progesterone activity without many side effects of synthetic progestins, particularly regarding metabolic effects, breast cancer risk, and venous thromboembolism risk. 5

• The main side effect is mild, transient drowsiness, minimized by bedtime administration. 4, 5