Differential Diagnosis for Secondary Amenorrhea in a 40-Year-Old Woman
The differential diagnosis for secondary amenorrhea in a 40-year-old non-pregnant woman with previously regular menses includes polycystic ovary syndrome (PCOS), functional hypothalamic amenorrhea (FHA), hyperprolactinemia, primary ovarian insufficiency (POI), and thyroid dysfunction—with PCOS and POI being particularly important considerations at this age. 1, 2, 3
Primary Diagnostic Categories
Most Common Etiologies
Polycystic Ovary Syndrome (PCOS) is one of the most common causes of secondary amenorrhea and should be strongly considered, particularly if the patient has obesity, signs of hyperandrogenism (acne, hirsutism), or metabolic dysfunction. 1, 2, 4 An LH/FSH ratio >2 with normal or elevated LH suggests PCOS, and pelvic ultrasound can identify polycystic ovarian morphology. 1
Functional Hypothalamic Amenorrhea (FHA) accounts for 20-35% of secondary amenorrhea cases and results from disruption of the hypothalamic-pituitary-gonadal axis due to stress, excessive exercise, or nutritional deficiencies. 5, 2, 3 This condition is characterized by low estradiol levels and disrupted LH pulsatility. 3
Hyperprolactinemia accounts for approximately 20% of secondary amenorrhea cases and may indicate a pituitary adenoma requiring MRI evaluation. 1, 2, 3 Galactorrhea, headaches, or visual changes are critical red flags. 2
Primary Ovarian Insufficiency (POI) becomes increasingly relevant at age 40 and is characterized by elevated FSH (>40 mIU/mL) and LH levels. 1, 2, 3 Two elevated FSH values measured 4 weeks apart are required for diagnosis. 1 Importantly, patients with POI can maintain unpredictable ovarian function and should not be presumed infertile. 1, 4, 6
Thyroid Dysfunction (both hypothyroidism and hyperthyroidism) is a reversible cause of amenorrhea that must be excluded in all cases by measuring TSH. 1, 2, 3
Less Common but Important Etiologies
Anatomical/Outflow Tract Abnormalities such as Asherman syndrome (intrauterine adhesions) or cervical stenosis can cause secondary amenorrhea, though these are less common than endocrine causes. 4, 7, 6
Other Endocrine Disorders including Cushing syndrome, adrenal insufficiency, and congenital adrenal hyperplasia should be considered if clinical features suggest these diagnoses. 7, 6
Chronic Systemic Disease including advanced liver disease, chronic kidney disease, or poorly controlled diabetes can disrupt the hypothalamic-pituitary axis. 3
Essential Initial Workup
Mandatory First-Line Testing
Pregnancy test is the absolute first step, even in a 40-year-old woman, as pregnancy remains the most common physiological cause of amenorrhea. 2, 4, 8, 6
Hormonal assessment panel should include serum FSH, LH, prolactin, and TSH levels to identify the underlying endocrine dysfunction, which accounts for the vast majority of secondary amenorrhea cases. 1, 2, 4, 6
Interpretation Algorithm Based on Initial Results
If prolactin is elevated (>20 μg/L): Order pituitary MRI immediately to rule out prolactinoma, as delaying imaging can lead to visual field defects requiring urgent intervention. 1
If FSH is elevated (>40 mIU/mL): Diagnose primary ovarian insufficiency and confirm with repeat FSH 4 weeks later (two elevated values required). 1 This is particularly important at age 40, as POI becomes more prevalent in this age group.
If LH/FSH ratio >2 with normal or elevated LH: Suspect PCOS and order pelvic ultrasound to identify polycystic ovarian morphology. 1 Consider measuring testosterone and androstenedione if signs of hyperandrogenism are present. 1
If TSH is abnormal: Treat thyroid dysfunction, as this is a reversible cause of amenorrhea. 1
If all hormones are normal: Consider FHA, particularly if there is history of stress, weight loss, or excessive exercise. 2, 3 A progestin challenge test can determine estrogen status and outflow tract patency. 2, 8
Additional Targeted Testing
Pelvic ultrasound should be performed to evaluate for polycystic ovarian morphology, assess endometrial thickness, and identify uterine abnormalities. 1, 2 Thin endometrium (<5 mm) suggests estrogen deficiency, while thick endometrium (>8 mm) suggests chronic anovulation with unopposed estrogen, increasing endometrial cancer risk. 1
Androgen profile (testosterone, androstenedione) should be measured if PCOS is suspected based on clinical features or LH/FSH ratio. 1, 2
Critical Age-Specific Considerations at Age 40
At age 40, primary ovarian insufficiency becomes a more likely diagnosis compared to younger women, making FSH measurement particularly important. 1 The transition to perimenopause typically begins in the mid-40s, but amenorrhea at age 40 still warrants full evaluation.
Metabolic screening is essential if PCOS is diagnosed, as patients are at risk for glucose intolerance, dyslipidemia, and other aspects of metabolic syndrome. 4, 6
Common Pitfalls to Avoid
Never assume amenorrhea is benign without evaluation, as prolonged hypoestrogenism increases risks of osteoporosis and cardiovascular disease. 1 If amenorrhea extends beyond 6 months despite addressing modifiable factors, consider DXA scan for bone mineral density assessment. 1, 2
Do not overlook eating disorders or excessive exercise, as patients may minimize or deny these behaviors, yet they are common causes of FHA. 2, 4
Do not delay pituitary imaging when prolactin is elevated, as this can lead to visual field defects requiring urgent intervention. 1
Do not presume infertility in patients with POI, as they can maintain unpredictable ovarian function. 1, 4, 6
Assess endometrial thickness on ultrasound, as thick endometrium (>8 mm) in the setting of chronic anovulation indicates unopposed estrogen exposure and increased endometrial cancer risk requiring intervention. 1