What is the likely cause and appropriate evaluation for a patient with ~200 days of amenorrhea after initiating continuous progestogen therapy for bleeding?

Evaluation and Management of Prolonged Amenorrhea After Continuous Progestogen Therapy

The most likely cause is progestogen-induced endometrial atrophy, which is an expected and benign consequence of continuous progestogen therapy—this does not require treatment unless the patient desires withdrawal bleeding or underlying pathology is suspected. 1

Understanding the Mechanism

Continuous progestogen administration (without cyclic interruption) causes progressive endometrial suppression leading to:

• Glandular atrophy and stromal decidualization that prevents adequate endometrial proliferation needed for withdrawal bleeding 2
• Endometrial thickness typically reduced to <5mm on imaging, insufficient to generate menstrual flow even after hormone withdrawal 3
• This atrophic state develops over 3-6 months and becomes more pronounced with prolonged use, making amenorrhea increasingly common after the first year 4, 1

The 200-day amenorrhea is consistent with the expected endometrial response to continuous progestogen—100% of women on continuous daily progestin develop an inactive endometrium, and 50% achieve complete amenorrhea 4.

Critical Diagnostic Evaluation Required

Before attributing amenorrhea solely to progestogen therapy, systematically exclude pregnancy and pathology 5, 6:

Mandatory Initial Workup

• Urine pregnancy test immediately—pregnancy complications including ectopic can present with amenorrhea after irregular bleeding 6
• Screen for sexually transmitted infections (chlamydia, gonorrhea) as these cause bleeding pattern changes 5, 6
• Pelvic ultrasound to assess:
  • Endometrial thickness (expect <5mm with progestogen-induced atrophy) 3
  • Rule out structural pathology: fibroids, polyps, or masses 5, 6
• Review medication interactions—enzyme-inducing drugs (anticonvulsants, rifampin, certain antiretrovirals) can alter hormone levels 5, 6

Red Flags Requiring Endometrial Sampling

Any breakthrough bleeding after achieving prolonged amenorrhea mandates endometrial biopsy 7. In one series of women on continuous combined therapy for 8+ years, 6 of 41 who developed bleeding after amenorrhea included 2 with endometrial adenocarcinoma and 2 with polyps 7.

Management Algorithm

If Evaluation is Reassuring (No Pathology Found)

Provide reassurance that amenorrhea is not harmful and represents adequate endometrial suppression 1, 5:

• The atrophic endometrium is protective, not pathologic 1
• All endometrial changes reverse rapidly after discontinuing progestogen 2
• No medical treatment is required for amenorrhea itself 1

If Patient Desires Return of Menses

Switch from continuous to cyclic progestogen regimen 1:

• Administer progestogen for 12-14 days every 28 days (rather than continuously) to allow withdrawal bleeding 1
• Recommended doses: micronized progesterone 200mg daily, or medroxyprogesterone acetate 10mg daily, or dydrogesterone 10mg daily for 12-14 days per cycle 1
• Micronized progesterone is first choice due to superior cardiovascular and thrombotic safety profile 1

Alternatively, consider combined oral contraceptives if contraception is also desired, which provide predictable withdrawal bleeding 1.

If Amenorrhea Persists Despite Cyclic Regimen

This suggests inadequate estrogen priming of the endometrium 3:

• Check serum estradiol levels to confirm adequate estrogenic state
• Consider adding or increasing estrogen component (if using progestogen-only therapy) 1
• One case report documented failure of progesterone withdrawal bleeding despite normal estrogen levels when testosterone was markedly elevated, suggesting androgen interference with endometrial development 3

Common Pitfalls to Avoid

• Never assume amenorrhea is benign without excluding pregnancy first—this is the most critical error 5, 6
• Do not perform endometrial sampling in asymptomatic women with expected progestogen-induced amenorrhea—but any breakthrough bleeding after amenorrhea requires biopsy 7
• Avoid attributing amenorrhea to progestogen therapy in women >40 years without considering premature ovarian insufficiency or perimenopause 1
• Do not continue investigating if patient is reassured and desires amenorrhea—this is a therapeutic goal for many women on continuous regimens 1

When to Refer

• Persistent bleeding despite appropriate management 5
• Suspected structural pathology on imaging requiring procedural intervention 6
• Breakthrough bleeding after prolonged amenorrhea requiring endometrial sampling 7
• Suspected endocrine disorder (thyroid dysfunction, hyperprolactinemia, hyperandrogenism) 6