What are the indications for hydroxyprogesterone (hydroxyprogesterone caproate)?

Hydroxyprogesterone Caproate Indications

Primary FDA-Approved Indications

Hydroxyprogesterone caproate is FDA-approved for non-pregnant women only, specifically for advanced adenocarcinoma of the uterine corpus (Stage III or IV), management of amenorrhea, abnormal uterine bleeding due to hormonal imbalance, and as a test for endogenous estrogen production. 1

However, the clinical reality differs substantially from the FDA label, as the medication has been extensively used off-label in obstetrics.

Off-Label Obstetric Use (Historical)

Prevention of Recurrent Preterm Birth in Singleton Pregnancies

For women with singleton pregnancies and a history of spontaneous preterm birth at 20-36 6/7 weeks, 17-alpha-hydroxyprogesterone caproate 250 mg intramuscularly weekly, starting at 16-20 weeks until 36 weeks, was the recommended first-line treatment. 2, 3, 4

• This indication was based on evidence showing a 34% reduction in recurrent preterm birth at <37 weeks gestation 5
• The American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine previously endorsed this as the preferred progestogen for this specific population 5
• Treatment should ideally begin between 16-20 weeks for maximum effectiveness 3, 4

Important Caveat: Market Withdrawal

Note that 17-hydroxyprogesterone caproate has been subject to regulatory scrutiny and market withdrawal discussions, though the evidence documents reference its historical endorsement by ACOG and SMFM. 5 The current availability and regulatory status should be verified before prescribing.

Non-Indications (Where Hydroxyprogesterone is NOT Effective)

Multiple Gestations

• Hydroxyprogesterone caproate is not recommended for women with twin, triplet, or higher-order multiple gestations 2, 3, 4
• Multiple trials in twins and triplets showed no effect on preterm birth rates or perinatal outcomes 2

Active Preterm Labor

• Hydroxyprogesterone is not effective as a tocolytic agent once active preterm labor has begun 2, 3, 4
• It should not be used for primary or adjunctive tocolysis 2

Preterm Premature Rupture of Membranes (PPROM)

• There is no evidence of effectiveness in women with PPROM 2, 3, 4

Short Cervical Length Without Prior Preterm Birth

• For women with short cervical length (≤20 mm at ≤24 weeks) but no prior preterm birth, vaginal progesterone (90-mg gel or 200-mg suppository) is preferred over 17-hydroxyprogesterone caproate 2, 3, 4

Clinical Algorithm for Obstetric Use (Historical)

Step 1: Confirm singleton pregnancy 2

Step 2: Document history of spontaneous preterm birth between 20-36 6/7 weeks 2, 4

Step 3: If both criteria met, initiate 17-hydroxyprogesterone caproate 250 mg IM weekly at 16-20 weeks 2, 3

Step 4: Continue weekly injections until 36 weeks or delivery 2, 3

Step 5: If cervical length shortens to ≤25 mm at ≤24 weeks despite treatment, consider cervical cerclage rather than switching progesterone formulations 2

Dosing for Non-Obstetric Indications

Advanced Uterine Adenocarcinoma

• 1,000 mg or more intramuscularly, repeated 1 or more times weekly (1-7 g per week) 1
• Continue until relapse or after 12 weeks with no objective response 1

Amenorrhea and Abnormal Uterine Bleeding

• 375 mg intramuscularly as a single dose for "medical D&C" 1
• For cyclic therapy: 375 mg followed by cyclic regimen with estradiol valerate 1

Test for Endogenous Estrogen Production

• 250 mg intramuscularly, with bleeding 7-14 days after injection indicating endogenous estrogen in non-pregnant patients 1

Safety Considerations

• No long-term adverse effects have been identified in children exposed to progesterone in utero 4
• No detectable teratogenic risk in offspring of mothers treated during early pregnancy 6
• Care should be taken to inject deeply into the upper outer quadrant of the gluteal muscle 1