What causes the uterus to not respond to hormones, leading to bleeding?

Causes of Uterine Unresponsiveness to Hormones Leading to Bleeding

The primary causes of uterine unresponsiveness to hormones that lead to bleeding include structural abnormalities, endocrine disorders, and pathologic conditions of the endometrium itself. 1

Structural and Pathologic Causes

• Structural abnormalities (PALM components of PALM-COEIN classification):

  • Polyps
  • Adenomyosis
  • Leiomyomas (fibroids), especially submucosal
  • Malignancy and hyperplasia

• Endometrial pathology:

  • Altered prostaglandin metabolism in the endometrium 2
  • Endometrial inflammation or infection
  • Endometrial hyperplasia
  • Endometrial cancer

Hormonal and Systemic Causes

• Ovulatory dysfunction causes (O component of PALM-COEIN):

  • Adolescence (immature hypothalamic-pituitary-ovarian axis)
  • Perimenopause (declining ovarian function)
  • Hyperandrogenic conditions (PCOS)
  • Hypothalamic dysfunction (stress, extreme weight changes, exercise)
  • Hyperprolactinemia
  • Thyroid disease (hypo/hyperthyroidism)
  • Primary pituitary disease
  • Premature ovarian failure 1

• Iatrogenic causes:

  • Hormonal contraceptive use (especially during first 3-6 months) 1
  • Medications that affect hormone metabolism
  • Anticoagulants

• Systemic conditions:

  • Coagulopathies
  • Liver disease (affecting hormone metabolism)
  • Chronic kidney disease

Diagnostic Approach

When evaluating uterine unresponsiveness to hormones:

1. Rule out pregnancy with beta-hCG testing
2. Assess endocrine function:
   • Thyroid-stimulating hormone
   • Prolactin levels
3. Evaluate structural causes:
   • Transvaginal ultrasonography
   • Saline infusion sonohysterography (96-100% sensitivity)
   • Hysteroscopy for direct visualization 1
4. Consider endometrial sampling:
   • Endometrial biopsy (preferred over D&C for hyperplasia/cancer detection)
   • Note: sensitivity may be affected by lesion type, size, and location 1

Management Algorithm

1. For hormonal contraceptive users with bleeding:

   • If within first 3-6 months: Counsel and reassure as this is common and typically resolves 1, 3
   • If persistent beyond 3 months:
     • Consider supplemental estrogen and/or NSAIDs
     • Change to higher estrogen content OCP or different progestin formulation 3

2. For anovulatory bleeding (estrogen breakthrough):

   • First-line: Progestin therapy 4
   • Avoid estrogen therapy except in cases of profuse bleeding unresponsive to progestin 4

3. For ovulatory dysfunctional bleeding:

   • NSAIDs (target prostaglandin metabolism)
   • Oral contraceptives
   • Cyclic progestins 2
   • Consider levonorgestrel IUD for menorrhagia 5

4. When medical management fails:

   • Further investigation with imaging and hysteroscopy
   • Consider surgical options:
     • Endometrial ablation
     • Hysterectomy (when other options have failed) 1, 6

Common Pitfalls and Caveats

• Misdiagnosis: Dysfunctional uterine bleeding is a diagnosis of exclusion after ruling out structural, systemic, and iatrogenic causes 6

• Inappropriate estrogen use: Estrogen therapy alone is contraindicated in anovulatory bleeding as it increases risk of endometrial hyperplasia and cancer 4

• Premature surgical intervention: Surgery should only be considered when hormonal and other medical therapies have failed 6

• Incomplete evaluation: Failure to perform appropriate imaging or endometrial sampling in high-risk patients may miss underlying pathology 1, 5

• Overlooking medication effects: Many cases of abnormal bleeding with hormonal contraception are due to inconsistent use or drug interactions 1, 3