What's the best approach for a patient presenting with two months of amenorrhea (absence of menstruation) and low Follicle-Stimulating Hormone (FSH) levels?

Approach to Two Months of Amenorrhea with Low FSH

This patient has hypogonadotropic hypogonadism (low FSH with amenorrhea), most likely functional hypothalamic amenorrhea (FHA), and requires immediate assessment of underlying stressors—particularly nutritional deficiency, excessive exercise, or psychological stress—with hormonal replacement therapy considered if amenorrhea persists beyond 6 months to prevent irreversible bone loss. 1, 2

Immediate Diagnostic Steps

Exclude pregnancy first with a urine or serum pregnancy test, as this is mandatory before any further hormonal evaluation 3, 1, 2.

Essential Laboratory Panel

Draw the following hormones (can be done at any time given amenorrhea):

• Prolactin: Elevated levels (>20 μg/L) indicate hyperprolactinemia, which accounts for ~20% of amenorrhea cases and presents with galactorrhea 4, 3, 1
• TSH: To exclude thyroid dysfunction as a reversible cause 1, 2
• LH: Calculate LH/FSH ratio—a ratio <1 is seen in 82% of FHA cases, while ratio >2 suggests PCOS (though less likely with low FSH) 1
• Estradiol: Low levels (<30 pg/mL) confirm hypoestrogenism and support FHA diagnosis 1, 2

Critical Clinical Assessment

Document the following to identify FHA triggers:

• Weight history: Calculate BMI and assess for recent weight loss or BMI <18.5 kg/m² 2
• Exercise patterns: Document hours per week and intensity—>10 hours/week of intense training warrants concern 2
• Nutritional intake: Calculate energy availability (goal >30 kcal/kg fat-free mass/day) 4, 2
• Psychological stressors: Screen for eating disorders, anxiety, depression 3, 2
• Medication review: Antipsychotics, antiepileptics, and hormonal contraceptives can cause amenorrhea 1

Imaging Studies

• Pelvic ultrasound: Assess endometrial thickness—thin endometrium (<5 mm) indicates estrogen deficiency supporting FHA, while thick endometrium (>8 mm) suggests chronic anovulation 1, 2
• Brain MRI: Only if prolactin is elevated or if headaches/visual changes suggest pituitary pathology 4, 2

Differential Diagnosis Based on Low FSH

Most Likely: Functional Hypothalamic Amenorrhea (FHA)

Clinical profile: Low FSH, low LH, low estradiol, LH/FSH ratio <1, thin endometrium, history of weight loss/excessive exercise/stress 1, 2

Alternative: Hyperprolactinemia

Clinical profile: Elevated prolactin (>20 μg/L), galactorrhea, low FSH/LH secondary to prolactin suppression of GnRH 4, 3, 1

Less Common: Hypothalamic Hypothyroidism

Clinical profile: Low TSH with low T4, though amenorrhea may persist even after thyroid replacement if hypothalamic dysfunction affects GnRH 5

Rare: Pituitary Failure

Clinical profile: Both FSH and LH suppressed, multiple pituitary hormone deficiencies, requires MRI 2

Treatment Algorithm

Step 1: Address Underlying Causes (First-Line for FHA)

Increase caloric intake to achieve >30 kcal/kg fat-free mass/day 2

Reduce exercise volume and intensity if excessive (>10 hours/week intense training) 2

Nutritional counseling by a sports dietitian experienced with energy availability assessment 2

Weight restoration to BMI ≥18.5 kg/m² is essential before considering fertility treatment 2

Note: Recovery of menstrual function may take >6 months despite addressing energy deficits 2

Step 2: Hormonal Replacement Therapy (If Amenorrhea Persists >6 Months)

Preferred regimen for bone health:

• Transdermal estradiol 100 μg patch twice weekly
• PLUS cyclic micronized progesterone 200 mg for 12 days/month 2

Critical pitfall to avoid: Do NOT prescribe oral contraceptives as first-line therapy—they mask the problem without addressing underlying energy deficit, provide false reassurance, and do not protect bone mineral density as effectively as physiologic estrogen replacement 2

Step 3: Bone Density Assessment

Obtain DXA scan if amenorrhea extends beyond 6 months, regardless of age, as prolonged hypoestrogenic states significantly increase osteoporosis risk 2

Rationale: 90% of peak bone mass is attained by age 18, making it critical to address amenorrhea early to prevent long-term bone loss 2. FHA is associated with 2-fold increased fracture risk 2.

Step 4: Treatment for Hyperprolactinemia (If Identified)

If prolactin >20 μg/L:

• Cabergoline 0.25 mg twice weekly initially, may increase by 0.25 mg twice weekly every 4 weeks up to 1 mg twice weekly based on prolactin levels 6
• Perform cardiovascular evaluation and consider echocardiography before initiating treatment 6
• Recheck prolactin levels and adjust dose accordingly 6
• After normal prolactin maintained for 6 months, may discontinue with periodic monitoring 6

Fertility Considerations (If Pregnancy Desired)

For FHA patients desiring pregnancy:

• Ensure BMI ≥18.5 kg/m² and spontaneous menstrual cycles have resumed before offering ovulation induction 2
• Pulsatile GnRH therapy is the most effective treatment for hypothalamic dysfunction, with ovulation rates of 80.8% and ongoing pregnancy rates of 70% 2
• Avoid clomiphene citrate as first-line for FHA due to uncertain efficacy 2

Critical point: Patients with primary ovarian insufficiency can maintain unpredictable ovarian function and should not be presumed infertile 1, 7, 8

Red Flags Requiring Urgent Evaluation or Referral

• Significant weight loss or signs of eating disorder: Requires multidisciplinary eating disorder team 2
• Headaches or visual changes: Suggests pituitary pathology, requires immediate MRI 2
• Galactorrhea with elevated prolactin: May indicate pituitary adenoma 4, 2
• Hirsutism or acne: May indicate PCOS or late-onset congenital adrenal hyperplasia despite initial low FSH 2
• Persistently abnormal hormone levels despite treatment: Refer to endocrinology or gynecology 2

Common Pitfalls to Avoid

Do not assume amenorrhea in athletes or stressed patients is benign—other pathology must be excluded even when clinical picture suggests FHA 2

Do not overlook eating disorders—adolescents frequently minimize symptoms; direct questioning about specific behaviors is necessary 2

Do not delay bone density assessment—DXA scanning is indicated regardless of age if amenorrhea extends beyond 6 months 2

Do not prescribe oral contraceptives as first-line therapy—this masks the problem without addressing underlying energy deficit 2