How should a missed period (amenorrhea) be evaluated and managed?

Evaluation and Management of Missed Period (Amenorrhea)

Rule out pregnancy first with a urine pregnancy test, then proceed with a systematic hormonal evaluation measuring FSH, LH, prolactin, and TSH to categorize the cause and guide treatment. 1, 2

Initial Assessment

Immediate First Step

• Perform a urine pregnancy test before any other evaluation, as pregnancy is the most common cause of amenorrhea and must be excluded before proceeding 1, 2, 3
• Modern home pregnancy tests (particularly First Response brand) can detect 97% of pregnancies on the day of missed menses with sensitivity of 5.5 mIU/mL 4

Critical History Elements

• Document menstrual history: age of menarche, previous cycle regularity, duration of amenorrhea, and last menstrual period 1, 2
• Assess for functional hypothalamic amenorrhea triggers: weight loss >5% in past 6 months, current BMI, exercise patterns (>10 hours/week intense training warrants evaluation), eating behaviors, and psychosocial stressors 2, 5
• Screen for hyperandrogenism: hirsutism, acne, androgenetic alopecia 1, 2
• Evaluate for hyperprolactinemia: galactorrhea, headaches, visual changes 1, 2
• Review medications: hormonal contraceptives, antipsychotics, antiepileptics, antiretrovirals 6, 5

Physical Examination Priorities

• Calculate BMI: obesity (>25 kg/m²) suggests PCOS; low BMI (<18.5 kg/m²) suggests functional hypothalamic amenorrhea 2, 5
• Assess Tanner staging in adolescents to determine pubertal development 2
• Examine for hyperandrogenism: male-pattern hair distribution, acne, truncal obesity 2, 5
• Perform nipple expression to detect occult galactorrhea 2

Mandatory Laboratory Testing

First-Line Hormonal Panel

Draw the following labs on any amenorrheic patient after pregnancy is excluded:

• FSH and LH (draw days 3-6 if cycles present, anytime if amenorrheic): differentiates ovarian failure from hypothalamic/pituitary dysfunction 1, 2, 5
• Prolactin (single morning resting sample; avoid post-exercise, post-stress, or post-ictal collection): levels >20 μg/L indicate hyperprolactinemia 1, 2, 5
• TSH: identifies reversible thyroid dysfunction 1, 2, 5
• Estradiol: levels <30 pg/mL confirm hypoestrogenism characteristic of functional hypothalamic amenorrhea 2, 5

Interpretation Algorithm by FSH Level

Elevated FSH (>35-40 mIU/mL):

• Indicates primary ovarian insufficiency 1, 2
• Confirm with repeat FSH 4 weeks later (two elevated values required for diagnosis) 2
• Order karyotype if age <40 years to detect Turner syndrome or chromosomal abnormalities 2, 5
• Initiate hormone replacement therapy to prevent osteoporosis and cardiovascular disease 2, 7

Low FSH with Low LH:

• Indicates hypothalamic or pituitary dysfunction 1, 2
• LH/FSH ratio <1 seen in 82% of functional hypothalamic amenorrhea cases 2, 5
• Low estradiol (<30 pg/mL) confirms hypoestrogenism 2, 5
• Address underlying causes: weight restoration to BMI ≥18.5 kg/m², reduce excessive exercise, nutritional counseling 2

Normal FSH with Elevated LH:

• LH/FSH ratio >2 strongly suggests PCOS 1, 2, 5
• Proceed with androgen testing and pelvic ultrasound 1, 2

Additional Testing When Indicated

If hyperandrogenism present (hirsutism, acne):

• Total testosterone (draw days 3-6): >2.5 nmol/L suggests PCOS; >5 nmol/L warrants tumor evaluation 2, 5
• Androstenedione: >10.0 nmol/L requires investigation for adrenal/ovarian neoplasm 5
• DHEA-S: age-adjusted thresholds screen for non-classical congenital adrenal hyperplasia 5

If prolactin elevated:

• First exclude hypothyroidism by checking TSH 2
• Order pituitary MRI if prolactin remains elevated or >100 μg/L, or if headaches/visual changes present 2, 5

Imaging Studies

Pelvic Ultrasound Indications

• LH/FSH ratio >2 (evaluate for polycystic ovarian morphology) 2, 5
• Clinical features suggesting ovarian pathology 1, 5
• Assess endometrial thickness: thin (<5 mm) indicates estrogen deficiency; thick (>8 mm) suggests chronic anovulation with unopposed estrogen 2
• Use transvaginal approach when possible for superior visualization 1, 5

Pituitary MRI Indications

• Persistent hyperprolactinemia after excluding thyroid disease 2, 5
• Prolactin >100 μg/L 5
• Headaches or visual field deficits 2, 5

Management by Etiology

Functional Hypothalamic Amenorrhea

Primary treatment addresses underlying causes:

• Increase caloric intake to achieve >30 kcal/kg fat-free mass/day 2
• Reduce exercise volume if >10 hours/week intense training 2
• Nutritional counseling by sports dietitian 2
• Recovery may take >6 months despite addressing energy deficits 2

If amenorrhea persists >6 months:

• Obtain DXA scan for bone mineral density assessment (critical in adolescents as 90% of peak bone mass attained by age 18) 2
• Initiate transdermal estradiol 100 μg patch twice weekly with cyclic micronized progesterone 200 mg for 12 days/month 2
• Avoid oral contraceptives as first-line: they mask the problem without addressing energy deficit and don't protect bone density as effectively as physiologic estrogen replacement 2

Polycystic Ovary Syndrome

• Cyclic progestogen (e.g., medroxyprogesterone 10 mg for 10-14 days monthly) to induce withdrawal bleeding and prevent endometrial hyperplasia 7, 8
• Combined oral contraceptives for patients desiring contraception or with acne/hirsutism 6, 7
• Screen for metabolic complications: fasting glucose, lipid panel 8

Hyperprolactinemia

• Prolactin-lowering drugs (dopamine agonists) for cycle restoration and fertility 7
• Cyclic progestogen or hormone replacement therapy for cycle disturbance 7
• Contraceptive pill if contraception needed 7

Primary Ovarian Insufficiency

• Hormone replacement therapy with estrogen to prevent osteoporosis and cardiovascular disease 2, 7, 8
• Counsel that unpredictable ovarian function can persist; patients should not be presumed infertile 2, 8

Referral Criteria

Urgent Referral Required

• No signs of puberty by age 13 years with elevated FSH 2
• No menarche by age 16 years despite secondary sexual characteristics 2
• Failure to progress through puberty for ≥12 months 2
• Prolactin >100 μg/L or any elevation with headaches/visual disturbances 5
• Testosterone >5 nmol/L or rapid virilization (suggests tumor) 5

Routine Referral Indications

• Confirmed amenorrhea >6 months 1
• Abnormal hormone levels suggesting specific pathology 1
• Signs of hyperandrogenism with menstrual irregularity 1
• Suspected structural abnormalities on imaging 1
• Signs of eating disorder or Female Athlete Triad 5

Critical Pitfalls to Avoid

• Never draw prolactin immediately after seizure, stress, breast examination, or sexual activity; wait 24 hours and obtain morning resting sample 2, 5
• Do not assume amenorrhea in athletes is benign; exclude other pathology even when clinical picture suggests functional hypothalamic amenorrhea 2
• Do not prescribe oral contraceptives as first-line for functional hypothalamic amenorrhea; this masks the problem without addressing underlying energy deficit 2
• Do not overlook eating disorders; adolescents frequently minimize symptoms, requiring direct questioning about specific behaviors 2
• Do not delay bone density assessment; DXA scanning indicated if amenorrhea extends beyond 6 months regardless of age 2
• Do not misdiagnose functional hypothalamic amenorrhea with polycystic ovarian morphology as PCOS; check LH/FSH ratio and estradiol (FHA has ratio <1, low estradiol, thin endometrium despite ovarian appearance) 2, 5