When should progesterone be started in a woman with a uterus who is receiving estrogen therapy or requires luteal‑phase support after ovulation or embryo transfer?

When to Start Progesterone

The timing of progesterone initiation depends critically on the clinical context: for women with a uterus receiving estrogen therapy (HRT), start progesterone after at least 2 years of estrogen or when breakthrough bleeding occurs; for frozen embryo transfer in artificial cycles, start progesterone after 12-14 days of estrogen priming once adequate endometrial preparation is confirmed; for natural/stimulated cycles, begin progesterone after ovulation or luteinization; and for preterm birth prevention, start 17-hydroxyprogesterone caproate at 16-20 weeks gestation. 1, 2, 3

Hormone Replacement Therapy (HRT) Context

For Women with Premature Ovarian Insufficiency or Menopause

• Begin cyclical progestogens after at least 2 years of estrogen therapy or when breakthrough bleeding occurs. 1
• This delayed initiation allows for adequate breast development and bone maturation in younger women before introducing cyclical bleeding. 1
• For adolescents with premature ovarian insufficiency (ages 14-16 years), initiate cyclic progestogen after 2 years of estrogen or when breakthrough bleeding occurs, using oral micronized progesterone 100-200 mg/day or dydrogesterone 5-10 mg/day for 12-14 days per month. 1

Endometrial Protection Considerations

• The strongest evidence for endometrial protection comes from oral cyclical combined treatment, though patient preference for route and method must be considered. 1
• For prolonged treatment, progesterone, dydrogesterone, or medroxyprogesterone are preferred over other progestogens due to less negative effects on lipid metabolism and fewer androgenic effects. 1

Assisted Reproductive Technology (ART) Context

Frozen Embryo Transfer (FET) - Artificial/Programmed Cycles

• Start progesterone supplementation on the day of endometrial transformation, which occurs after 12-14 days of estrogen priming. 2, 3
• Critical pitfall to avoid: Do not start progesterone on a fixed cycle day (like day 9) without confirming adequate endometrial preparation via ultrasound—most patients require 12-14 days of estrogen priming before endometrial transformation. 3
• Confirm endometrial thickness ≥7-8 mm with trilaminar pattern on transvaginal ultrasound before initiating progesterone. 3
• Blastocyst transfer should occur 117-120 hours (approximately 5 full days) after initiating progesterone supplementation. 3

Natural or Ovarian Stimulation Cycles

• Begin routine progesterone supplementation after ovulation or after luteinization. 2
• In natural cycles, progesterone administration should start 36 hours after the onset of the LH surge (when measured in morning serum) or 36 hours after HCG administration for triggering final follicular maturation. 4
• Blastocyst transfer should be performed after 5 full days of progesterone supplementation. 4

Duration of Luteal Support in ART

• Continue luteal support for 1-3 weeks after ultrasound confirmation of viable intrauterine pregnancy (approximately 4 weeks post-transfer) in natural/stimulation cycles. 2
• In artificial cycles, continue estrogen and progesterone at original doses for 3-4 weeks after pregnancy confirmation, then gradually taper over 2 weeks. 2

Preterm Birth Prevention Context

Women with Prior Spontaneous Preterm Birth

• Start 17-alpha-hydroxyprogesterone caproate (17P) 250 mg intramuscularly weekly at 16-20 weeks gestation and continue until 36 weeks. 1, 5
• This represents a 34% reduction in recurrent preterm birth at <37 weeks gestation. 1
• Critical distinction: Do not substitute vaginal progesterone for 17P in this population—these formulations have different evidence bases and are not interchangeable. 2, 5

Women with Short Cervical Length (≤20 mm at 18-24 weeks)

• Vaginal progesterone (90-mg gel or 200-mg suppository daily) is preferred over oral progesterone 400 mg daily, though both can be used. 5
• This applies to singleton pregnancies without prior preterm birth. 5

Functional Uterine Bleeding (Non-ART Context)

• For functional uterine bleeding, progesterone 5-10 mg intramuscularly is given daily for six doses, with bleeding expected to cease within six days. 6
• When estrogen is given concurrently, progesterone administration begins after two weeks of estrogen therapy. 6

Key Clinical Distinctions by Formulation

Progesterone formulations are not interchangeable across clinical indications. 2 Injectable 17-hydroxyprogesterone caproate (17P) is specifically indicated for preterm birth prevention in women with prior spontaneous preterm birth, not for luteal phase support in conception attempts. 2 Vaginal progesterone is the standard for ART luteal support and short cervix management. 2, 5