What should be done if a woman does not have withdrawal bleeding after a course of medroxyprogesterone (10 mg daily for 5–10 days)?

What to Do If No Withdrawal Bleeding After Progesterone

If a woman does not experience withdrawal bleeding after completing a course of medroxyprogesterone (10 mg daily for 5–10 days), she should have a pregnancy test performed within 3 weeks of completing the progesterone course. 1

Immediate Next Step

• Perform a pregnancy test if no withdrawal bleed occurs within 3 weeks after completing the progesterone course. 1
• This recommendation applies regardless of whether the progesterone was given as emergency contraception or for menstrual regulation. 1

Clinical Interpretation of Absent Withdrawal Bleeding

Absent withdrawal bleeding after progesterone challenge indicates one of three possibilities:

1. Pregnancy

• Pregnancy is the most critical diagnosis to exclude, as progesterone will not induce bleeding in a pregnant woman. 1
• The 3-week timeframe allows sufficient time for hCG levels to become detectable if conception occurred. 1

2. Insufficient Endogenous Estrogen

• Absence of withdrawal bleeding suggests inadequate estrogen priming of the endometrium. 2, 3
• In a landmark 1983 study of 30 asymptomatic postmenopausal women, 25 who had no withdrawal bleeding after progesterone challenge all had non-pathologic histology, confirming that absent bleeding typically reflects low estrogen rather than endometrial pathology. 2
• Endogenous estradiol levels correlate with bleeding response: women with higher baseline estradiol are more likely to bleed after progesterone withdrawal. 3

3. Endometrial Pathology (Less Common)

• In the same 1983 study, 5 of 30 women (17%) who did exhibit withdrawal bleeding had unsuspected adenomatous hyperplasia (p < 0.001), suggesting that the presence of bleeding after progesterone may actually indicate higher risk for endometrial pathology in certain populations. 2
• However, in women with absent bleeding and confirmed non-pregnancy, endometrial pathology is uncommon. 2

Diagnostic Algorithm After Negative Pregnancy Test

Once pregnancy is excluded, the next step depends on the clinical context:

For Women with Polycystic Ovary Syndrome (PCOS) or Chronic Anovulation

• Repeat the progesterone challenge with a higher dose or longer duration: medroxyprogesterone acetate 10 mg daily for 14 days (rather than 10 days). 4
• If still no bleeding, consider adding estrogen priming before progesterone: conjugated estrogens 1.25 mg daily for 21–25 days, followed by medroxyprogesterone 10 mg daily for the last 10–14 days. 5
• The absence of bleeding after adequate estrogen-progesterone priming suggests either Asherman syndrome (intrauterine adhesions) or outflow tract obstruction. 5

For Postmenopausal Women or Those Evaluating Endometrial Status

• Transvaginal ultrasound to measure endometrial thickness: 2
  • Endometrial stripe <4–5 mm suggests atrophy and low estrogen, making hyperplasia or cancer unlikely. 2
  • Endometrial stripe ≥5 mm warrants endometrial sampling (biopsy or aspiration) to exclude hyperplasia or malignancy. 2
• In the 1983 study, all women with absent withdrawal bleeding and non-pathologic histology had thin, atrophic endometrium. 2

For Women of Reproductive Age with Amenorrhea

• Measure serum estradiol: 3
  • Estradiol <50 pg/mL indicates hypogonadotropic hypogonadism or premature ovarian insufficiency; proceed to FSH, LH, prolactin, and TSH. 3
  • Estradiol ≥50 pg/mL suggests adequate estrogen but possible anatomic obstruction (Asherman syndrome) or resistant endometrium; consider hysteroscopy or saline infusion sonography. 3

Dosing Considerations for Progesterone Challenge

The dose and duration of progesterone affect the likelihood of withdrawal bleeding:

• Medroxyprogesterone 300 mg orally for 10 days induces withdrawal bleeding in 90% of women with secondary amenorrhea. 3
• Medroxyprogesterone 200 mg orally for 10 days induces bleeding in only 58% of women. 3
• The standard 10 mg daily dose for 5–10 days (total 50–100 mg) is less effective than higher doses, explaining why many women do not bleed after this regimen. 3
• Endogenous estradiol and achieved progesterone levels have limited predictive value for bleeding response, so empiric dose escalation is reasonable if initial challenge fails. 3

Common Pitfalls to Avoid

• Do not assume absent bleeding means endometrial pathology—in fact, the 1983 study showed that women who did bleed were more likely to have hyperplasia. 2
• Do not repeat progesterone challenge without first excluding pregnancy—this is the single most important step. 1
• Do not use estrogen-progesterone withdrawal bleeding as a pregnancy test—a 1976 randomized trial of 300 women showed no significant difference in bleeding rates between women receiving intramuscular estrogen-progesterone and controls, proving this approach is ineffective for diagnosing pregnancy. 6
• Do not assume the standard 10 mg × 5–10 days dose is adequate—higher doses (200–300 mg total) are more effective at inducing withdrawal bleeding. 3

Summary Algorithm

1. No withdrawal bleeding after medroxyprogesterone 10 mg × 5–10 days → Pregnancy test within 3 weeks. 1
2. Pregnancy test positive → Obstetric management.
3. Pregnancy test negative → Assess clinical context:
   • PCOS/anovulation: Repeat with medroxyprogesterone 10 mg × 14 days or add estrogen priming. 4, 5
   • Postmenopausal/endometrial evaluation: Transvaginal ultrasound; if stripe ≥5 mm, perform endometrial biopsy. 2
   • Reproductive-age amenorrhea: Measure estradiol; if low, check FSH/LH/prolactin/TSH; if normal, consider anatomic evaluation. 3