What is the evaluation and treatment approach for secondary amenorrhea (absence of menstruation) after the first menstrual period?

Evaluation and Management of Secondary Amenorrhea

Secondary amenorrhea requires a systematic diagnostic approach starting with pregnancy exclusion, followed by hormonal assessment (FSH, LH, prolactin, TSH), and targeted treatment based on the underlying etiology—with the most common causes being PCOS, functional hypothalamic amenorrhea (FHA), hyperprolactinemia, and primary ovarian insufficiency. 1

Definition and Prevalence

• Secondary amenorrhea is defined as cessation of previously regular menstruation for >3 months or irregular menstruation for >6 months 2, 1
• Affects approximately 3-4% of women in the general population 2, 1
• The most common etiologies are PCOS, FHA (accounting for 20-35% of cases), hyperprolactinemia (~20% of cases), and primary ovarian insufficiency 2, 1

Initial Diagnostic Workup

Step 1: Exclude Pregnancy

• A pregnancy test is mandatory as the first step in all cases of secondary amenorrhea 1, 3

Step 2: Initial Laboratory Assessment

• Measure serum FSH, LH, prolactin, and TSH levels in all patients 1, 3, 4
• These hormones help categorize the etiology into hypothalamic-pituitary dysfunction, ovarian failure, hyperprolactinemia, or thyroid disorders 1

Step 3: Progestin Challenge Test

• Perform a progestin challenge test to determine estrogen status and outflow tract patency 1, 5
• A positive withdrawal bleed indicates adequate estrogen and patent outflow tract 5
• A negative test suggests hypoestrogenic state or anatomic obstruction 5

Step 4: Additional Testing Based on Initial Results

If prolactin is elevated:

• Order pituitary MRI to rule out prolactinoma 5
• Evaluate for medications causing hyperprolactinemia 3

If TSH is abnormal:

• Treat thyroid dysfunction as the primary cause 1

If FSH is elevated (>40 mIU/mL):

• Indicates primary ovarian insufficiency 3, 4
• Repeat FSH in 1 month to confirm 3
• Consider karyotype analysis if age <30 years 4

If FSH/LH are low or normal with negative progestin challenge:

• Suggests hypothalamic or pituitary dysfunction 5
• Evaluate for FHA by assessing stress, weight loss, excessive exercise, and eating disorders 2, 1, 4

If clinical hyperandrogenism or irregular cycles pre-amenorrhea:

• Order androgen profile (total testosterone, DHEA-S, 17-hydroxyprogesterone) 1
• Perform pelvic ultrasound to evaluate for polycystic ovarian morphology (≥20 follicles per ovary of 2-9mm diameter) 2, 1

Management Based on Etiology

Functional Hypothalamic Amenorrhea (FHA)

• FHA results from chronic stress, excessive exercise, weight loss, or eating disorders causing reduced GnRH pulsatility 2
• Address underlying stressors through counseling about stress management, adequate nutrition, and appropriate activity levels 1
• Screen for eating disorders—patients may minimize or deny disordered eating behaviors 1
• Assess for low bone density risk: order DXA scan if amenorrhea persists >6 months 1, 3
• Consider estrogen replacement therapy to prevent osteoporosis in hypoestrogenic patients 1, 5

Polycystic Ovary Syndrome (PCOS)

• Patients with PCOS require screening for metabolic complications including glucose intolerance, dyslipidemia, and metabolic syndrome 3, 4
• Provide cyclic progestogen to prevent endometrial hyperplasia in anovulatory patients 5
• Address hyperandrogenism and metabolic abnormalities as indicated 1

Hyperprolactinemia

• If pituitary adenoma identified, refer to endocrinology for dopamine agonist therapy 5
• Discontinue causative medications if possible 3

Primary Ovarian Insufficiency

• Patients can maintain unpredictable ovarian function and should not be presumed infertile 3, 4
• Initiate hormone replacement therapy (estrogen with cyclic progestogen) to prevent bone loss and cardiovascular complications 1, 5
• Provide contraception counseling as spontaneous ovulation can occur 4

Contraceptive-Induced Amenorrhea

• For LNG-IUD users: reassure that amenorrhea occurs in ~50% by 2 years and is not harmful 6
• For DMPA users: counsel that amenorrhea is common after ≥1 year of use and is not harmful 6
• If patient desires reversal of DMPA-induced amenorrhea, combined oral contraceptives are more effective than placebo 6
• If amenorrhea occurs abruptly in contraceptive users, rule out pregnancy if clinically indicated 6

Critical Red Flags Requiring Urgent Evaluation

• Galactorrhea suggesting hyperprolactinemia 1
• Headaches or visual changes suggesting pituitary pathology 1
• Signs of eating disorder or significant weight loss 1
• Virilization suggesting androgen-secreting tumor 4

Common Pitfalls to Avoid

• Do not assume all amenorrhea in athletes or stressed patients is benign—other pathology must be excluded 1
• Do not overlook eating disorders in adolescents, as they may minimize symptoms 1
• Do not delay bone density assessment in hypoestrogenic amenorrhea lasting >6 months 1
• Remember that hormone levels and absence of menses are unreliable indicators of menopause during tamoxifen treatment 6