What are the causes of intermenstrual (metrorrhagia) bleeding in women of reproductive age, particularly in those with a history of polycystic ovary syndrome (PCOS), thyroid disorders, or other endocrine conditions?

Causes of Intermenstrual Bleeding

Intermenstrual bleeding stems from both structural abnormalities (polyps, adenomyosis, fibroids, malignancy) and non-structural causes (coagulopathy, ovulatory dysfunction, endocrine disorders, iatrogenic factors), with PCOS and thyroid dysfunction being particularly important endocrine contributors in reproductive-age women. 1

Structural Causes (PALM)

Uterine pathology:

• Fibroids (leiomyomas) are among the three most common structural causes in premenopausal women, typically presenting with heavy or prolonged menstrual bleeding and an enlarged, irregular uterus on palpation 1
• Adenomyosis frequently coexists with fibroids, presenting with heavy menstrual bleeding, dysmenorrhea, and dyspareunia, most commonly affecting women in their 40s 1
• Endometrial polyps are particularly common above 40 years of age and require imaging beyond standard ultrasound for reliable diagnosis 2
• Endometrial hyperplasia and malignancy must be excluded, particularly in women with risk factors for endometrial cancer 1

Non-Structural Causes (COEIN)

Endocrine Disorders (Critical in PCOS/Thyroid Patients)

Polycystic Ovary Syndrome (PCOS):

• PCOS affects 4-6% of women and is a common cause of irregular periods, characterized by hyperandrogenic chronic anovulation with low mid-luteal phase progesterone levels 1
• Women with PCOS have elevated prevalence of menstrual irregularities due to hyperandrogenism, insulin resistance, and anovulation, manifested as hypersecretion of luteinising hormone and ovarian dysfunction 1
• Chronic anovulation leads to prolonged unopposed estrogen stimulation of the endometrium, increasing risk of endometrial cancer 3

Thyroid Dysfunction:

• Both hypothyroidism and hyperthyroidism can cause menstrual irregularities and abnormal bleeding patterns, requiring TSH evaluation 1, 3
• Thyroid dysfunction should be evaluated with TSH levels in all women presenting with intermenstrual bleeding 1

Hyperprolactinemia:

• May result from pituitary adenomas, hypothyroidism, or medications (antipsychotics, antiepileptics), requiring prolactin level measurement 1

Hypothalamic amenorrhea:

• Causes oligomenorrhea and infertility without signs of hyperandrogenemia, associated with disturbed pituitary gonadotropin secretion 1

Coagulopathy

• Von Willebrand disease is the most common coagulation defect causing ovulatory abnormal uterine bleeding 3
• Women on anticoagulation, particularly NOACs like rivaroxaban, have significantly increased risk of abnormal uterine bleeding (27% vs 8.3% with warfarin) 1

Iatrogenic Causes

Hormonal contraceptives:

• Progestin-only contraceptives (pills, DMPA, implants) frequently induce irregular bleeding patterns, especially during the first 3-6 months, though this may persist longer with implants 1

Antiepileptic drugs:

• Carbamazepine, phenobarbital, and phenytoin induce hepatic cytochrome P450-dependent steroid hormone breakdown, reducing biologically active sex hormone concentrations and potentially causing menstrual disturbances 1

Critical Diagnostic Pitfalls

Mandatory exclusions before treatment:

• Pregnancy must be ruled out in all reproductive-age women before proceeding with evaluation 1, 4
• Unexplained vaginal bleeding suspicious for serious conditions requires evaluation before initiating treatment, as progestin-only contraceptives might mask symptoms of underlying pathology including pelvic malignancy 1

Age-specific considerations:

• Women 35 years or older with recurrent anovulation, women younger than 35 years with risk factors for endometrial cancer, and women with excessive bleeding unresponsive to medical therapy should undergo endometrial biopsy 3

Diagnostic Approach

Initial workup should include:

• Pregnancy test (mandatory) 4
• TSH and prolactin levels 1, 4
• Complete blood count with platelets 4
• Transvaginal ultrasound with Doppler if structural etiology suspected or symptoms persist 4

Advanced imaging when indicated:

• Saline infusion sonohysterography has high sensitivity and negative predictive value for assessing intracavitary pathology 4
• Hysteroscopy allows visualization of endometrial cavity and endocervix, diagnosing focal lesions possibly missed by endometrial sampling 4