When is progesterone (P4) therapy without estrogen considered in clinical practice?

Progesterone Therapy Without Estrogen: Clinical Indications

Progesterone therapy without estrogen is primarily indicated for prevention of preterm birth in high-risk pregnant women, treatment of secondary amenorrhea, and as part of hormone replacement therapy for endometrial protection in specific clinical scenarios. 1, 2

Prevention of Preterm Birth

Progesterone therapy without estrogen is strongly recommended in the following obstetric scenarios:

Singleton Pregnancies with Prior Spontaneous Preterm Birth (SPTB)

• 17-alpha-hydroxyprogesterone caproate (17P) 250 mg IM weekly starting at 16-20 weeks until 36 weeks is the recommended treatment for women with singleton gestations and prior SPTB at 20-36 6/7 weeks 1
• This regimen has been shown to reduce the incidences of preterm birth <37 weeks (RR, 0.66; 95% CI, 0.54–0.81) and <32 weeks, as well as reducing neonatal complications including supplemental oxygen need and intraventricular hemorrhage 1

Singleton Pregnancies with Short Cervical Length (CL)

• For women with singleton gestations without prior SPTB but with short cervical length ≤20 mm at ≤24 weeks, vaginal progesterone (90-mg gel or 200-mg suppository daily) is recommended from diagnosis until 36 weeks 1
• Vaginal progesterone in this population has been associated with a 45% reduction in preterm birth and 43% reduction in composite neonatal morbidity and mortality 1

Important Considerations for Preterm Birth Prevention

• Progesterone therapy is not effective for multiple gestations (twins, triplets) regardless of prior preterm birth history or cervical length 1
• There is insufficient evidence to recommend progesterone for preterm labor tocolysis or for preterm premature rupture of membranes (PPROM) 1
• If a woman on 17P for prior preterm birth develops cervical shortening <25 mm, it is reasonable to continue 17P rather than switching to another progesterone formulation 1

Gynecologic Indications

Secondary Amenorrhea

• Oral progesterone 400 mg daily at bedtime for 10 days is indicated for women with secondary amenorrhea (absence of menstrual periods in women who previously had periods) 2
• In clinical studies, this regimen resulted in withdrawal bleeding within 7 days in 80% of women with secondary amenorrhea for at least 90 days 2
• Oral micronized progesterone is preferred over synthetic progestins due to fewer metabolic and vascular side effects 3, 4

Endometrial Protection in Special Circumstances

• While progesterone is typically used with estrogen for endometrial protection in hormone replacement therapy, there are specific scenarios where progesterone alone may be considered:
  • For women with a history of endometrial cancer who require management of menopausal symptoms but in whom estrogen is contraindicated 1
  • For women with severe vasomotor symptoms who cannot tolerate estrogen or have contraindications to estrogen therapy 4, 5

Administration Routes and Formulations

Oral Micronized Progesterone

• Advantages: Convenient administration, better bioavailability than non-micronized natural progesterone 3, 4
• Dosing: 400 mg daily for secondary amenorrhea; 200 mg daily for 12 continuous days per 28-day cycle for endometrial protection 2
• Side effects: Mild and transient drowsiness (take at bedtime to minimize this effect) 3, 5

Vaginal Progesterone

• Advantages: Higher uterine bioavailability due to first-pass uterine effect, fewer systemic side effects 5
• Formulations: 90-mg gel or 200-mg suppository daily 1
• Particularly useful for preterm birth prevention in women with short cervical length 1

Injectable Progesterone (17P)

• Primary indication: Prevention of preterm birth in women with prior spontaneous preterm birth 1
• Dosing: 250 mg IM weekly from 16-20 weeks until 36 weeks gestation 1

Potential Adverse Effects

• Drowsiness and dizziness (particularly with oral formulations) 2, 4
• Risk to fetus if used during early pregnancy (cleft palate, congenital heart defects) 2
• Possible risk of abnormal blood clotting 2
• Less metabolic and vascular side effects compared to synthetic progestins 3, 4

Clinical Pitfalls to Avoid

• Avoid using progesterone for preterm birth prevention in multiple gestations as it has not shown benefit 1
• Do not use progesterone for primary tocolysis in active preterm labor as evidence is insufficient 1
• Be aware that oral progesterone has significant first-pass metabolism, which may limit efficacy for some indications 5
• Remember that progesterone alone does not provide adequate protection against endometrial hyperplasia in women receiving estrogen therapy - specific dosing regimens are required 2, 6