How should I manage a reproductive‑age woman with amenorrhea using a high‑dose progesterone challenge (norethisterone 5 mg twice daily for 5 days), and what are the next steps if no withdrawal bleed occurs?

Progesterone Challenge Test with Norethisterone 5mg BD for 5 Days in Amenorrhea

Norethisterone 5 mg twice daily for 5 days is an appropriate high-dose progesterone challenge test to assess endogenous estrogen production in women with amenorrhea; withdrawal bleeding within 2–7 days after completing the course indicates adequate estrogen priming and an intact, responsive endometrium, whereas absence of bleeding suggests either insufficient estrogen or an anatomic/endometrial defect requiring further investigation. 1, 2

Rationale for the Progesterone Challenge Test

• The progesterone challenge test differentiates between anovulation with adequate estrogen (which will produce withdrawal bleeding) and hypogonadotropic or hypergonadotropic states with insufficient estrogen (which will not produce bleeding). 1, 2

• A positive withdrawal bleed (occurring within 2–7 days after the last norethisterone dose) confirms that the endometrium has been adequately primed by endogenous estrogen and that the outflow tract is patent. 3

• Norethisterone 5 mg twice daily for 5 days provides sufficient progestational stimulus to induce secretory transformation of an estrogen-primed endometrium, mimicking the luteal phase. 1, 2

Interpreting the Results

If Withdrawal Bleeding Occurs (Positive Test)

• Withdrawal bleeding within 2–7 days indicates:

  • Adequate endogenous estrogen production (typically estradiol >40 pg/mL)
  • Functional, responsive endometrium
  • Patent outflow tract (no Asherman syndrome or cervical stenosis)
  • The cause of amenorrhea is likely anovulation (e.g., polycystic ovary syndrome, hypothalamic amenorrhea with partial estrogen production, or early ovarian insufficiency with intermittent function). 1, 2, 3

• Next steps after positive withdrawal bleed:

  • Measure serum FSH, LH, prolactin, and TSH to identify the specific cause of anovulation
  • Consider androgen levels (total testosterone, DHEA-S) if clinical signs of hyperandrogenism are present
  • Pelvic ultrasound to assess ovarian morphology (polycystic ovaries vs. normal)
  • If FSH is elevated (>25–40 IU/L on two occasions 4 weeks apart), diagnose premature ovarian insufficiency and initiate hormone replacement therapy until age 51. 1, 4

If No Withdrawal Bleeding Occurs (Negative Test)

• Absence of bleeding indicates:

  • Insufficient endogenous estrogen to prime the endometrium (estradiol typically <40 pg/mL)
  • Possible anatomic defect (Asherman syndrome, cervical stenosis)
  • Endometrial unresponsiveness (rare). 1, 2

• Next steps after negative withdrawal bleed:

  • Proceed to an estrogen-progesterone sequential challenge to distinguish between inadequate estrogen and outflow tract obstruction:

    • Administer conjugated equine estrogen 0.625 mg daily (or transdermal estradiol 50 µg daily) for 21 days
    • Add norethisterone 5 mg twice daily (or medroxyprogesterone acetate 10 mg daily) for the last 10–14 days
    • If withdrawal bleeding occurs after this combined regimen, the diagnosis is hypoestrogenic amenorrhea (e.g., hypothalamic amenorrhea, premature ovarian insufficiency, pituitary dysfunction). 1, 4, 2
    • If no bleeding occurs despite estrogen-progesterone priming, suspect outflow tract obstruction (Asherman syndrome, cervical stenosis) and perform hysteroscopy or saline infusion sonography. 1

  • Measure serum FSH, LH, prolactin, TSH, and estradiol to determine the etiology:

    • Elevated FSH (>25–40 IU/L) → premature ovarian insufficiency
    • Low or normal FSH with low estradiol → hypothalamic or pituitary dysfunction (functional hypothalamic amenorrhea, hyperprolactinemia, pituitary adenoma)
    • Elevated prolactin → prolactinoma or medication-induced hyperprolactinemia. 1, 4

Dosing and Administration Details

• Norethisterone acetate 5 mg orally twice daily (total 10 mg/day) for 5 consecutive days is the standard high-dose progesterone challenge regimen. 1, 2, 5

• The 5-day duration is sufficient to induce secretory transformation in an estrogen-primed endometrium; shorter durations (<5 days) may be inadequate. 1, 2

• Withdrawal bleeding typically occurs 2–7 days after the last norethisterone dose; if no bleeding occurs by day 10, the test is considered negative. 3

Safety and Contraindications

• Norethisterone 5 mg BD for 5 days is safe for short-term diagnostic use in reproductive-age women with amenorrhea. 1, 2

• Absolute contraindications to norethisterone include:

  • Known or suspected pregnancy (always perform a pregnancy test before initiating the challenge)
  • Active liver disease
  • History of venous thromboembolism or stroke
  • Known or suspected breast cancer or other hormone-sensitive malignancy. 1, 4, 2

• Relative contraindications include:

  • Undiagnosed vaginal bleeding (the progesterone challenge is contraindicated until malignancy is excluded)
  • Severe cardiovascular disease
  • Migraine with aura. 1, 4

Common Pitfalls to Avoid

• Do not skip the pregnancy test before administering norethisterone; pregnancy is the most common cause of secondary amenorrhea in reproductive-age women, and progesterone exposure in early pregnancy can complicate interpretation. 1, 4

• Do not interpret light spotting as a positive withdrawal bleed; only moderate-to-heavy flow lasting ≥2 days should be considered a positive result. 1, 2

• Do not assume a negative progesterone challenge definitively rules out ovarian function; some women with premature ovarian insufficiency have intermittent estrogen production and may occasionally have a positive withdrawal bleed. Confirm the diagnosis with two FSH measurements ≥25–40 IU/L taken 4 weeks apart. 1, 4

• Do not use the progesterone challenge as a therapeutic intervention; it is purely diagnostic. Women with anovulatory amenorrhea and adequate estrogen require cyclic progestin therapy (e.g., medroxyprogesterone acetate 10 mg for 10–14 days every 1–3 months) to prevent endometrial hyperplasia, not just a single 5-day course. 1, 2, 3

Alternative Progesterone Challenge Regimens

• Medroxyprogesterone acetate 10 mg daily for 5–10 days is an alternative to norethisterone and is more widely available in some regions. 1, 2, 3

• Micronized progesterone 200 mg daily for 10 days is another option, though it is less commonly used for diagnostic challenges due to variable oral bioavailability. 1, 2

• The 5-day norethisterone regimen (10 mg/day total) is preferred for its reliability and shorter duration compared with 10-day regimens. 1, 2, 5

Long-Term Management After Diagnosis

• If the progesterone challenge is positive (anovulation with adequate estrogen):

  • For women desiring pregnancy: ovulation induction with clomiphene citrate or letrozole
  • For women not desiring pregnancy: cyclic progestin therapy (medroxyprogesterone acetate 10 mg for 10–14 days every 1–3 months) or combined oral contraceptives to prevent endometrial hyperplasia. 1, 2, 3

• If the progesterone challenge is negative (hypoestrogenic amenorrhea):

  • For premature ovarian insufficiency: initiate hormone replacement therapy with transdermal estradiol 50–100 µg daily plus micronized progesterone 200 mg nightly for 12–14 days per month (or continuously) until age 51, then reassess. 1, 4, 2
  • For hypothalamic amenorrhea: address underlying causes (weight restoration, stress reduction, treatment of eating disorders) and consider short-term hormone replacement if bone density is compromised. 1, 4