What is the appropriate evaluation and initial management for a teenage girl with primary amenorrhea (no menses by age 15 with secondary sexual characteristics or by age 13 without)?

Primary Amenorrhea: Evaluation and Management

Initial Definition and Diagnostic Thresholds

Primary amenorrhea requires evaluation when there is no menarche by age 15 years in girls with secondary sexual characteristics, or by age 13 years in girls without any signs of pubertal development. 1, 2

Additionally, evaluation should begin if there is no menarche 3 years after breast development starts, or if there is failure to progress through puberty for ≥12 months. 1

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Algorithmic Approach Based on Presence of Secondary Sexual Characteristics

Scenario 1: No Breast Development by Age 13 (Delayed Puberty)

This represents hypogonadotropic or hypergonadotropic hypogonadism and requires earlier intervention. 1, 2

Initial workup:

• Perform Tanner staging to document absence of breast development 1
• Order FSH, LH, estradiol, prolactin, and TSH 1
• Obtain karyotype analysis 3

Interpretation:

• Elevated FSH (menopausal range): Indicates primary ovarian insufficiency or gonadal dysgenesis (e.g., Turner syndrome); refer urgently to pediatric endocrinology and gynecology 1
• Low FSH and LH with low estradiol: Indicates hypogonadotropic hypogonadism from hypothalamic or pituitary dysfunction 1
• Elevated prolactin: Check TSH first; if normal, obtain pituitary MRI to evaluate for adenoma 1

Critical red flag: Absence of pubic and axillary hair despite some breast development distinguishes androgen insensitivity syndrome from constitutional delay. 1

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Scenario 2: Normal Breast Development but No Menarche by Age 15-16

This suggests either outflow tract obstruction or eugonadal amenorrhea. 4

Initial workup:

• Document Tanner stage (should be ≥3-4 for breast development) 1
• Order FSH, LH, prolactin, TSH 1
• Pelvic ultrasound is mandatory to assess uterine and ovarian anatomy 1

Interpretation:

• Normal hormones + absent uterus on ultrasound: Suspect Müllerian agenesis; confirm with karyotype (should be 46,XX) 4
• Normal hormones + normal uterus + normal breast development: Pelvic ultrasound must exclude outflow tract obstruction (imperforate hymen, transverse vaginal septum) 1, 4
• Abnormal hormones: Follow algorithm in Scenario 1 based on FSH/LH pattern 1

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Detailed History and Physical Examination Elements

Growth and development patterns to assess:

• Document height velocity and compare to growth charts 1
• Calculate BMI: low BMI (<18.5 kg/m²) suggests functional hypothalamic amenorrhea from energy deficit 1
• Ask specifically about weight loss >5% in past 6 months 1

Nutritional and exercise assessment:

• Calculate energy availability: consuming >30 kcal/kg fat-free mass/day is adequate 1
• Document hours per week of intense exercise; >10 hours/week warrants evaluation for Relative Energy Deficiency in Sport (RED-S) 1
• Screen directly for restrictive eating behaviors, as adolescents frequently minimize or deny disordered eating 1

Psychological stressors:

• Assess for significant life stressors, anxiety, or depression that can disrupt the hypothalamic-pituitary-gonadal axis 1

Physical examination specifics:

• Perform complete Tanner staging of breast and pubic hair development 1
• Examine for galactorrhea by nipple expression 1
• Look for signs of hyperandrogenism: hirsutism, acne, male-pattern hair distribution 1
• Check for headaches or visual field defects suggesting pituitary pathology 1

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Laboratory Testing Algorithm

First-line tests for all patients:

• Pregnancy test (even if patient denies sexual activity) 1
• FSH, LH, prolactin, TSH 1
• Estradiol level 1

Interpretation and next steps:

If FSH elevated (menopausal range):

• Indicates primary ovarian insufficiency 1
• Obtain karyotype to evaluate for Turner syndrome or variants 1, 3
• Refer urgently to pediatric endocrinology 1

If FSH/LH low with low estradiol (<30 pg/mL):

• Indicates hypogonadotropic hypogonadism 1
• LH/FSH ratio <1 seen in 82% of functional hypothalamic amenorrhea cases 1
• Assess endometrial thickness on ultrasound: <5 mm confirms estrogen deficiency 1

If prolactin elevated:

• First exclude hypothyroidism by checking TSH 1
• If TSH normal and prolactin remains elevated, obtain pituitary MRI 1
• Ensure sample not drawn post-exercise, post-stress, or post-seizure to avoid false positives 1

If LH/FSH ratio >2:

• Strongly suggests PCOS 1
• Proceed with pelvic ultrasound for polycystic ovarian morphology 1
• Consider androgen profile (testosterone, DHEA-S) if clinical hyperandrogenism present 1

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Imaging Studies

Pelvic ultrasound indications:

• All cases of primary amenorrhea to assess uterine and ovarian anatomy 1
• Mandatory to exclude outflow tract obstruction or Müllerian agenesis in patients with normal hormones and normal breast development 1
• When LH/FSH ratio >2 to evaluate for polycystic ovarian morphology 1

Pituitary MRI indications:

• Persistent hyperprolactinemia after excluding thyroid disease 1
• Headaches or visual field deficits 1

Bone density assessment (DXA scan):

• Obtain if amenorrhea extends beyond 6 months, regardless of age 1
• Critical because 90% of peak bone mass is attained by age 18, making adolescent bone loss particularly concerning 1

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Management Based on Etiology

Functional Hypothalamic Amenorrhea (FHA)

Primary treatment strategy (address underlying causes first):

• Increase caloric intake to achieve >30 kcal/kg fat-free mass/day 1
• Reduce exercise volume and intensity if excessive 1
• Provide nutritional counseling by sports dietitian experienced with energy availability assessment 1
• Address psychological stressors through counseling about stress management 1
• Screen for and treat eating disorders with multidisciplinary team if present 1

Important caveat: Recovery of menstrual function may take >6 months despite addressing energy deficits, so patience is required. 1

Hormonal replacement therapy (if amenorrhea persists >6 months despite lifestyle modifications):

• Use transdermal estradiol 100 μg patch twice weekly with cyclic micronized progesterone 200 mg for 12 days/month 1
• This regimen protects bone mineral density more effectively than oral contraceptives 1
• Do not prescribe oral contraceptives as first-line therapy because they mask the problem without addressing underlying energy deficit and provide false reassurance 1

Hypogonadotropic Hypogonadism (Low FSH/LH)

Hormonal replacement:

• Initiate estrogen replacement therapy with cyclic progestogen to induce menstrual cycles and prevent bone loss 1
• Use low-dose transdermal estradiol 100 μg patch twice weekly preferred over oral formulations 1

If fertility desired in future:

• Ensure BMI ≥18.5 kg/m² and weight restoration before considering ovulation induction 1
• Pulsatile GnRH therapy is most effective for hypothalamic dysfunction, with ovulation rates of 80.8% 1
• Avoid clomiphene citrate as first-line due to uncertain efficacy in FHA 1

Primary Ovarian Insufficiency (Elevated FSH)

Management:

• Hormonal replacement therapy is indicated to reduce risk of osteoporosis, cardiovascular disease, and urogenital atrophy 1
• Multidisciplinary team including gynecologists, pediatricians, endocrinologists, dietitians, and psychologists 1
• Important: Patients can maintain unpredictable ovarian function and should not be presumed infertile 5

Structural Abnormalities (Müllerian Agenesis, Outflow Obstruction)

Management:

• Surgical correction for outflow tract obstruction (imperforate hymen, transverse vaginal septum) 4
• For Müllerian agenesis, provide hormonal support if needed and refer to specialized gynecology for fertility counseling 4

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Urgent Referral Criteria

Refer immediately to pediatric endocrinology and/or gynecology if:

• No signs of puberty by age 13 years AND elevated FSH 1
• No menarche by age 16 years despite secondary sexual characteristics 1
• Failure to progress through puberty for ≥12 months 1
• Signs of eating disorder or significant weight loss 1
• Galactorrhea suggesting hyperprolactinemia 1, 6
• Headaches or visual changes suggesting pituitary pathology 1
• Severe hirsutism or virilization (testosterone >2.5 nmol/L warrants evaluation for androgen-secreting tumor) 1

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Critical Pitfalls to Avoid

Do not assume amenorrhea in athletes or stressed adolescents is benign – other pathology must be excluded even when clinical picture suggests FHA. 1

Do not overlook eating disorders – adolescents frequently minimize symptoms; direct questioning about specific behaviors is necessary. 1

Do not prescribe oral contraceptives as first-line therapy for FHA – this masks the problem without addressing underlying energy deficit. 1

Do not delay bone density assessment – DXA scanning is indicated regardless of age if amenorrhea extends beyond 6 months. 1

Do not assume patients with primary ovarian insufficiency are infertile – they can maintain unpredictable ovarian function. 5

Do not draw prolactin post-exercise, post-stress, or post-seizure – this causes false-positive elevations. 1