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 (metrorrhagia) results from both structural causes—including polyps, adenomyosis, leiomyomas, and malignancy—and non-structural causes such as coagulopathy, ovulatory dysfunction, endometrial disorders, and iatrogenic factors, with the PALM-COEIN classification system providing the diagnostic framework. 1

Structural Causes (PALM)

Polyps, adenomyosis, leiomyomas, and malignancy/hyperplasia represent the structural etiologies of intermenstrual bleeding 1, 2:

• Uterine 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, 3
• Endometrial polyps are particularly common in women over 40 years of age and can cause irregular bleeding patterns 4
• Adenomyosis frequently coexists with fibroids, presenting with heavy menstrual bleeding, dysmenorrhea, and dyspareunia, most commonly affecting women in their 40s 1, 2
• Endometrial hyperplasia and malignancy must be excluded, particularly in postmenopausal women where endometrial cancer is the most serious etiology 1

Non-Structural Causes (COEIN)

Coagulopathy, ovulatory dysfunction, endometrial disorders, iatrogenic causes, and not yet classified conditions comprise the non-structural etiologies 1, 2:

Coagulopathy

• Von Willebrand disease is the most common coagulation defect causing menorrhagia 5
• Women on anticoagulation, particularly NOACs like rivaroxaban, have significantly increased risk of abnormal uterine bleeding (27% vs 8.3% with warfarin) 1

Ovulatory Dysfunction

• Polycystic ovary syndrome (PCOS) is a common cause of irregular periods, affecting 4-6% of women in the general population, characterized by hyperandrogenic chronic anovulation with low mid-luteal phase progesterone levels 6
• Hypothalamic amenorrhea (hypogonadotropic hypogonadism) causes oligomenorrhea and infertility without signs of hyperandrogenemia, associated with disturbed pituitary gonadotropin secretion 6
• Thyroid dysfunction can cause menstrual irregularities and should be evaluated with TSH levels 6, 2, 5
• Hyperprolactinemia may result from pituitary adenomas, hypothyroidism, or medications (antipsychotics, antiepileptics), requiring prolactin level measurement 6, 5

Endometrial Disorders

• Dysfunctional uterine bleeding occurs when no structural, coagulation, or endocrine pathology is identified, accounting for approximately 50% of menorrhagia cases 7, 8
• Abnormal levels of prostaglandins or dysregulation of the fibrinolytic system in the endometrium have been implicated 8

Iatrogenic Causes

• 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 6
• Antiepileptic drugs (carbamazepine, phenobarbital, phenytoin) induce hepatic cytochrome P450-dependent steroid hormone breakdown, reducing biologically active sex hormone concentrations and potentially causing menstrual disturbances 6

Special Considerations in Women with Endocrine Conditions

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 6. In women with epilepsy, PCOS prevalence increases to 10-25% even without antiepileptic drug use 6.

Thyroid disorders require evaluation with TSH measurement, as both hypothyroidism and hyperthyroidism can cause abnormal bleeding patterns 6, 2, 5.

Critical Diagnostic Pitfall

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 6. Pregnancy must be ruled out in all reproductive-age women before proceeding with evaluation 2. Women 35 years or older with recurrent anovulation, those younger than 35 with endometrial cancer risk factors, and those with bleeding unresponsive to medical therapy require endometrial biopsy 5.