What is the management approach for a 29-year-old female with amenorrhea and inconsistent menstrual cycles, and a negative pregnancy test?

Management of Amenorrhea and Inconsistent Cycles in a 29-Year-Old Female with Negative Pregnancy Test

After confirming pregnancy is excluded, initiate a systematic hormonal evaluation measuring serum prolactin, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) to identify the underlying endocrine cause, then tailor treatment based on the specific diagnosis to prevent long-term complications including osteoporosis, endometrial hyperplasia, and cardiovascular disease. 1, 2, 3

Initial Diagnostic Workup

Essential Laboratory Tests

• Measure serum prolactin levels to evaluate for hyperprolactinemia, which commonly causes amenorrhea and may indicate a pituitary adenoma 4, 1, 5
• Measure TSH to exclude thyroid dysfunction as a reversible cause 4, 2, 3
• Measure FSH and LH levels (ideally between cycle days 3-6 if any bleeding occurs) to differentiate between ovarian failure and hypothalamic-pituitary dysfunction 4, 1, 2
• Measure testosterone and androstenedione if signs of hyperandrogenism are present (hirsutism, acne, male-pattern hair distribution) to evaluate for polycystic ovary syndrome (PCOS) 4, 1

Clinical Assessment Priorities

• Document menstrual history including age at menarche, previous cycle patterns, duration of current amenorrhea (>6 months defines secondary amenorrhea), and any associated symptoms 4, 3
• Assess for galactorrhea by history and examination, as this indicates hyperprolactinemia requiring pituitary imaging 4, 5
• Evaluate for eating disorders, excessive exercise, and psychosocial stressors that suggest functional hypothalamic amenorrhea 2, 3, 5
• Check for signs of hyperandrogenism including hirsutism (using Ferriman-Gallwey scoring if available), acne, and truncal obesity (waist-to-hip ratio >0.9) 4
• Document weight changes and calculate BMI as both weight loss and obesity can cause amenorrhea 4, 3

Diagnostic Algorithm Based on Hormonal Results

If Prolactin is Elevated (>20 μg/L)

• Order pituitary MRI to rule out prolactinoma, as this is the most common pathologic cause of hyperprolactinemia 4, 1
• Review medications that can elevate prolactin (antipsychotics, metoclopramide, some antidepressants) 4
• Rule out hypothyroidism as elevated TSH can cause secondary hyperprolactinemia 4, 5

If FSH is Elevated (>35 IU/L) with Low/Normal LH

• Diagnose primary ovarian insufficiency (premature ovarian failure) 4, 1, 2
• Counsel that unpredictable ovarian function may persist and the patient should not be presumed completely infertile 2, 3
• Initiate hormone replacement therapy to prevent osteoporosis and cardiovascular disease from prolonged hypoestrogenism 6, 5, 7

If LH/FSH Ratio >2 with Normal/Elevated LH

• Suspect PCOS as the most common cause of normogonadotrophic amenorrhea 4, 6, 2
• Order pelvic ultrasound (transvaginal preferred) to identify >10 peripheral cysts (2-8 mm diameter) and thickened ovarian stroma 4, 1
• Screen for metabolic complications including fasting glucose, insulin levels (glucose/insulin ratio >4 suggests insulin resistance), and lipid panel 4, 2, 3

If FSH and LH are Both Low/Normal with Normal Prolactin and TSH

• Diagnose functional hypothalamic amenorrhea as the likely cause 1, 6, 2
• Perform progesterone challenge test (medroxyprogesterone 10 mg daily for 5-10 days) to assess estrogen status and outflow tract patency 5, 7
• If withdrawal bleeding occurs, this confirms adequate estrogen levels and patent outflow tract 5, 7
• If no withdrawal bleeding occurs, consider anatomic abnormalities or severe hypoestrogenism requiring further evaluation 5, 7

Treatment Based on Specific Diagnosis

For Hyperprolactinemia

• Initiate dopamine agonist therapy (bromocriptine or cabergoline) to lower prolactin and restore ovulation 6
• Provide cyclic progestogen (medroxyprogesterone 10 mg for 10-14 days monthly) if fertility is not desired to prevent endometrial hyperplasia 6
• Consider combined oral contraceptives if contraception is needed 6

For Primary Ovarian Insufficiency

• Prescribe hormone replacement therapy with estrogen plus progestogen (sequential or continuous) to prevent osteoporosis and cardiovascular disease 6, 7
• Recommend calcium and vitamin D supplementation (1200-1500 mg calcium, 800-1000 IU vitamin D daily) 5
• Counsel about fertility options including egg donation, as spontaneous pregnancy is rare but possible 2, 3

For PCOS

• Prescribe cyclic progestogen (medroxyprogesterone 10 mg for 10-14 days every 1-3 months) to induce withdrawal bleeding and prevent endometrial hyperplasia from unopposed estrogen 6, 2
• Consider combined oral contraceptives as first-line therapy if contraception is desired, which also improves hirsutism and acne through ovarian androgen suppression 6, 2
• Initiate metformin (500-2000 mg daily) if insulin resistance or glucose intolerance is present 2, 3
• Screen for metabolic syndrome components including hypertension, dyslipidemia, and diabetes annually 2, 3

For Functional Hypothalamic Amenorrhea

• Address underlying causes including stress reduction, nutritional counseling for eating disorders, and modification of excessive exercise 2, 3, 5
• Prescribe sequential estrogen-progestogen therapy or combined oral contraceptives if lifestyle modifications fail and the patient has prolonged hypoestrogenism (>6 months) 6, 5
• Recommend calcium supplementation (1200-1500 mg daily) and weight-bearing exercise to prevent bone loss 5
• Screen for low bone density with DEXA scan if amenorrhea persists >12 months 3

Critical Management Pitfalls to Avoid

Common Errors

• Never assume amenorrhea is benign without evaluation, as prolonged hypoestrogenism increases risks of osteoporosis and cardiovascular disease 2, 3, 7
• Do not delay pituitary imaging if prolactin is elevated, as macroadenomas can cause visual field defects and require urgent intervention 4, 1
• Avoid prescribing estrogen alone without progestogen in women with an intact uterus, as this increases endometrial cancer risk 6, 7
• Do not overlook PCOS patients' endometrial cancer risk from chronic anovulation; ensure regular withdrawal bleeding at least every 3 months 2, 3

Special Considerations

• If pelvic ultrasound shows structural abnormalities (fibroids, polyps, müllerian anomalies), refer to gynecology for further evaluation 4
• If androstenedione is markedly elevated (>10.0 nmol/L), rule out adrenal or ovarian tumor with additional imaging 4
• If patient desires pregnancy, refer to reproductive endocrinology for ovulation induction with clomiphene citrate (PCOS), pulsatile GnRH (hypothalamic dysfunction), or gonadotropins (pituitary failure) 6

Monitoring Requirements

• Reassess in 3-6 months after initiating treatment to confirm restoration of regular cycles or adequate hormone replacement 3, 7
• Monitor bone density in patients with prolonged hypoestrogenism (>12 months) regardless of cause 3, 5
• Screen annually for metabolic complications in PCOS patients including glucose tolerance testing and lipid panels 2, 3