What is the evaluation and treatment approach for amenorrhea (absence of menstruation)?

Evaluation and Treatment of Amenorrhea

Begin by ruling out pregnancy in all cases of amenorrhea, then obtain initial laboratory testing including serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, and thyroid-stimulating hormone (TSH) to guide diagnosis and treatment. 1, 2, 3

Initial Evaluation Algorithm

Primary Amenorrhea (No Menarche by Age 15 or 3 Years Post-Thelarche)

Assess for presence or absence of secondary sexual characteristics: 1, 2, 3

• No signs of puberty by age 13 years: Refer to pediatric endocrinology/gynecology 1
• Primary amenorrhea by age 16 years: Refer to pediatric endocrinology/gynecology 1
• Failure of pubertal progression for ≥12 months: Refer to pediatric endocrinology/gynecology 1

If normal pubertal development is present with a uterus: The most common cause is congenital outflow tract obstruction (transverse vaginal septum or imperforate hymen); rule out obstruction if not already done 1, 4

If abnormal uterine development: Müllerian agenesis is likely; obtain karyotype analysis to confirm 46,XX 4

Secondary Amenorrhea (Cessation of Regular Menses for 3 Months or Irregular Menses for 6 Months)

Obtain pregnancy test first, then measure LH, FSH, prolactin, and TSH: 1, 2, 3

Interpret FSH levels to categorize the cause: 1

• Elevated FSH (menopausal range on two separate occasions ≥4 months apart): Primary ovarian insufficiency 1
• Low or normal FSH with elevated prolactin: Hyperprolactinemia 1
• Low or normal FSH with normal prolactin: Consider functional hypothalamic amenorrhea (FHA) or polycystic ovary syndrome (PCOS) 1

Treatment by Diagnosis

Contraceptive-Induced Amenorrhea

Amenorrhea from hormonal contraceptives (including LNG-IUD, DMPA, etonogestrel implant) requires no medical treatment—provide reassurance only. 1, 5

• Amenorrhea occurs in approximately 22% of etonogestrel implant users and is common after ≥1 year of DMPA use 5
• These bleeding changes are generally not harmful and do not require intervention 1, 5
• If the woman's regular bleeding pattern changes abruptly to amenorrhea, rule out pregnancy 1, 5
• If amenorrhea persists and the woman finds it unacceptable, counsel on alternative contraceptive methods 1, 5

Functional Hypothalamic Amenorrhea (FHA)

Address underlying causes first: stress, nutritional deficiency, excessive exercise, and eating disorders. 1, 5

Optimize energy availability (EA) as first-line treatment—this is the underlying cause, not exercise volume or body composition: 5

• Energy availability below 30 kcal/kg fat-free mass/day suppresses bone formation 5
• It may take more than 6 months for favorable menstrual changes after correcting energy availability 5
• Consult with a registered sports dietitian for comprehensive nutrition assessment 1

For bone protection in FHA, use transdermal β-estradiol patch (100 μg) twice weekly plus cyclic micronized progesterone (200 mg) for 12 days each month: 5

• This approach is preferred over combined oral contraceptive pills (COCPs) for bone mineral density protection 5
• Critical pitfall: Never use COCPs to treat FHA for bone protection—they do not correct the underlying cause and do not protect against bone mineral density loss 5
• Note that transdermal hormones are not contraceptive 5

Add calcium supplementation (1000-1300 mg daily depending on age) and optimize vitamin D (target >50 nmol/L in winter, >75 nmol/L in summer): 5

Obtain bone mineral density (DXA) testing: 1

• For growing children and adolescents: spine and whole body 1
• For adult women: spine and hip 1
• Refer or consult with endocrinology if not experienced in treatment 1

Hyperprolactinemia

Evaluate for prolactin-secreting adenoma with complete pituitary assessment before initiating treatment: 6

If prolactinoma is confirmed, bromocriptine is the primary pharmacologic treatment: 6

• In about 75% of cases, bromocriptine suppresses galactorrhea and reinitiates normal ovulatory menstrual cycles 6
• Menses are usually reinitiated within 6-8 weeks on average, though some patients respond within days and others may take up to 8 months 6

Monitor visual fields in patients with macroprolactinoma for early recognition of secondary field loss due to chiasmal herniation: 6

If pregnancy occurs during bromocriptine treatment, discontinue the medication and monitor closely throughout pregnancy for signs of tumor enlargement: 6

For patients not seeking pregnancy or harboring large adenomas, advise contraceptive measures other than oral contraceptives during bromocriptine treatment: 6

Primary Ovarian Insufficiency (POI)

Defined as absence of menses for ≥4 months and two elevated serum FSH levels in the menopausal range (measured on separate occasions) in women <40 years of age: 1

Refer to gynecology/endocrinology for consideration of sex steroid replacement therapy: 1

Important counseling point: Patients with POI can maintain unpredictable ovarian function and should not be presumed infertile—they may require hormone replacement therapy, contraception, or infertility services. 2, 3

Polycystic Ovary Syndrome (PCOS)

Characterized by hyperandrogenism, hirsutism, follicular arrest, and ovarian acyclicity with hypersecretion of LH and low FSH: 1

Screen for metabolic complications: 2, 3

• Glucose intolerance and diabetes risk 2, 3
• Dyslipidemia 2, 3
• Metabolic syndrome components 2, 3
• Endometrial cancer risk from unopposed estrogen 3, 7

Treatment should address the underlying metabolic dysfunction and provide endometrial protection if anovulatory: 3, 7

DXA Screening Indications for Athletes

Obtain DXA scan if ≥1 high-risk factor is present: 1

• History of DSM-V diagnosed eating disorder 1
• BMI ≤17.5 kg/m², <85% estimated weight, OR recent weight loss ≥10% in 1 month 1
• Menarche ≥16 years of age 1
• Current or history of <6 menses over 12 months 1

Obtain DXA scan if ≥2 moderate-risk factors are present: 1

• Current or history of disordered eating for ≥6 months 1
• BMI between 17.5 and 18.5, <90% estimated weight, OR recent weight loss of 5-10% in 1 month 1
• Menarche between ages 15 and 16 years 1
• Current or history of 6-8 menses over 12 months 1
• One prior stress reaction/fracture 1

Repeat DXA testing every 1-2 years in those with definitive indications to determine ongoing bone loss and evaluate treatment: 1

Critical Pitfalls to Avoid

Do not accept amenorrhea as an inevitable consequence of athletic training—amenorrhea for more than 3 months must be investigated: 5

Oral contraceptives mask clinical signs of menstrual dysfunction and low energy availability in athletes: 5

Never use COCPs to treat functional hypothalamic amenorrhea for bone protection—they do not correct the underlying cause: 5

Do not presume infertility in patients with primary ovarian insufficiency—unpredictable ovarian function can persist: 1, 2, 3

In patients with epilepsy on antiepileptic drugs, be aware that enzyme-inducing medications (carbamazepine, phenobarbital, phenytoin) can cause menstrual disturbances through altered sex hormone metabolism: 1