What is the appropriate evaluation and treatment for a patient with amenorrhea and normal breast development?

Evaluation and Management of Amenorrhea with Normal Breast Development

A patient with amenorrhea and normal breast development most likely has either an outflow tract obstruction (if primary amenorrhea) or hypothalamic/pituitary dysfunction, PCOS, or primary ovarian insufficiency (if secondary amenorrhea), and should undergo immediate pregnancy testing followed by measurement of FSH, LH, prolactin, and TSH levels to guide further evaluation. 1, 2

Initial Diagnostic Approach

Rule Out Pregnancy First

• Pregnancy must be excluded in all cases before proceeding with any further evaluation, as it is the most common cause of amenorrhea in reproductive-age women 2, 3, 4

Determine Type of Amenorrhea

• Primary amenorrhea is defined as no menarche by age 15 years, or by age 13 years in the absence of secondary sexual characteristics 1
• Secondary amenorrhea is defined as cessation of regular menses for 3 months or irregular menses for 6 months 1, 3, 5
• The presence of normal breast development indicates adequate estrogen exposure, suggesting either Tanner stage 2 or beyond has been achieved 6

Essential Laboratory Testing

First-Line Hormone Panel

Obtain the following tests in all patients after excluding pregnancy 1, 2:

• FSH and LH levels: Differentiates between hypothalamic/pituitary causes (low/normal) versus ovarian failure (elevated) 1, 2, 3
• Prolactin level: Identifies hyperprolactinemia, which may indicate pituitary adenoma 2, 3, 4
• TSH level: Assesses thyroid function, as thyroid disorders commonly cause menstrual irregularities 1, 2, 3
• Estradiol level: Helps assess ovarian function and estrogen status 2

Interpretation of Results

Elevated FSH (>40 mIU/mL in menopausal range):

• Indicates primary ovarian insufficiency (POI), defined as ovarian failure before age 40 with amenorrhea ≥4 months and two elevated FSH levels 6
• Requires karyotype analysis to identify chromosomal abnormalities like Turner syndrome 3, 7
• Note that patients with POI can maintain unpredictable ovarian function and should not be presumed infertile 3, 5

Low or Normal FSH with Normal Prolactin and TSH:

• Suggests hypothalamic amenorrhea or polycystic ovary syndrome (PCOS) 2, 3
• Measure total and free testosterone levels to evaluate for PCOS 2
• Perform progesterone withdrawal test: administer progesterone 200-400 mg daily for 10 days 8
  • Withdrawal bleeding indicates adequate estrogen and patent outflow tract (consistent with PCOS or hypothalamic dysfunction) 4
  • No bleeding suggests either inadequate estrogen or outflow tract obstruction 4

Elevated Prolactin (>25 ng/mL):

• Obtain brain MRI to evaluate for pituitary adenoma 3, 4
• Review medications that may elevate prolactin 2

Imaging Studies

Pelvic Ultrasound

Perform pelvic ultrasound to 1:

• Assess uterine and ovarian anatomy
• Identify structural abnormalities (particularly important in primary amenorrhea with normal breast development, suggesting possible outflow obstruction like transverse vaginal septum or imperforate hymen) 7
• Evaluate for polycystic ovarian morphology (≥20 follicles of 2-9mm per ovary or ovarian volume >10mL) 1
• Assess endometrial thickness 1

Bone Density Assessment

Order DXA scan for patients with 1, 2:

• Amenorrhea lasting >6 months
• BMI <18.5 kg/m²
• History of eating disorders or excessive exercise
• Menarche ≥16 years of age

Specific Diagnostic Considerations

For Primary Amenorrhea with Normal Breast Development

The most likely causes are 7:

• Outflow tract obstruction (transverse vaginal septum, imperforate hymen): Most common when uterus is present
• Müllerian agenesis: Absent uterus with 46,XX karyotype
• Complete androgen insensitivity syndrome: 46,XY karyotype with absent uterus

For Secondary Amenorrhea with Normal Breast Development

The most common causes are 3, 5:

• Polycystic ovary syndrome (PCOS): Most frequent cause
• Functional hypothalamic amenorrhea: Associated with weight loss, stress, or excessive exercise
• Hyperprolactinemia: Often from pituitary adenoma or medications
• Primary ovarian insufficiency: Premature ovarian failure

Special Populations

Athletes

• Evaluate for Female Athlete Triad or Relative Energy Deficiency in Sport (RED-S) 1, 2
• Calculate energy availability (energy intake minus exercise energy expenditure) 2
• Assess for eating disorders, as hypothalamic amenorrhea is frequently associated with nutritional deficiency 1, 3

Cancer Survivors

• Young adult cancer survivors treated with alkylating agents or pelvic radiation are at high risk for POI 6
• POI in this population is defined as amenorrhea ≥4 months with two FSH levels in menopausal range 6

Treatment Based on Etiology

Functional Hypothalamic Amenorrhea

• Address underlying energy deficiency through nutritional counseling 2
• Modify excessive exercise habits 2
• Provide psychological support for stress management 5
• Consider hormone replacement therapy if hypoestrogenic to prevent bone loss 4, 5

Primary Ovarian Insufficiency

• Initiate hormone replacement therapy to prevent complications of hypoestrogenism including osteoporosis and cardiovascular disease 2, 9
• Counsel that unpredictable ovarian function may persist and fertility is possible 3, 5
• Provide calcium and vitamin D supplementation 6

Polycystic Ovary Syndrome

• For cycle regulation: cyclic progestogen (progesterone 200-400 mg daily for 10-14 days per month) 8, 9
• For contraception and hyperandrogenism: combined oral contraceptives 9
• Screen for metabolic syndrome components (glucose intolerance, dyslipidemia) 3, 5
• Counsel about increased endometrial cancer risk and need for regular withdrawal bleeding 5

Hyperprolactinemia

• Dopamine agonists for prolactin-lowering if pituitary adenoma present 9
• Discontinue causative medications if possible 2

Common Pitfalls to Avoid

• Failing to rule out pregnancy: This is the most common and critical error 2, 4
• Misdiagnosing functional hypothalamic amenorrhea with polycystic ovarian morphology as PCOS: These are distinct entities requiring different management 2
• Assuming chemotherapy-induced amenorrhea equals menopause: Cessation of menses does not necessarily denote absence of ovarian function, and premenopausal estradiol levels can be found in patients with transient chemotherapy-induced amenorrhea 6
• Neglecting bone health assessment: Patients with prolonged amenorrhea (>6 months) require DXA scanning 1, 2
• Using aromatase inhibitors without adequate ovarian suppression: In premenopausal women, aromatase inhibitors can stimulate ovarian function and are contraindicated without concurrent ovarian function suppression 6
• Failing to monitor estradiol levels in patients on ovarian suppression: Estradiol should be checked to confirm adequate suppression, particularly in women under age 45 receiving GnRH agonists 6

Monitoring During Treatment

For Patients on Ovarian Function Suppression

If using GnRH agonists (goserelin 3.6 mg SC every 4 weeks or leuprolide 3.75-7.5 mg IM every 4 weeks) 6:

• Monitor estradiol and FSH/LH levels prior to next dose, particularly in women under age 45 6
• Frequency of testing should be individualized but is especially important if breakthrough bleeding occurs 6
• If vaginal bleeding occurs while on aromatase inhibitor, contact physician immediately as this may indicate inadequate ovarian suppression 6

Definition of Adequate Menopausal Status

For women under age 60 with amenorrhea, confirm postmenopausal status with 6:

• Amenorrhea ≥12 months prior to initiation of therapy (in absence of chemotherapy, tamoxifen, or ovarian suppression)
• FSH and estradiol in postmenopausal range measured prior to any systemic therapy
• Note that hormone levels are unreliable during tamoxifen treatment 6