What is the diagnosis and management for a patient with hypothalamic or pituitary dysfunction, suppressed LH and FSH, low estradiol, low-normal free testosterone, mildly elevated PTH, and iron deficiency, not pregnant?

Diagnosis: Functional Hypothalamic Amenorrhea (FHA)

This patient has functional hypothalamic amenorrhea characterized by suppressed gonadotropins (LH <0.1, FSH <0.3), low estradiol (<30 pmol/L), and evidence of estrogen deficiency, requiring immediate assessment for underlying causes and hormone replacement therapy to prevent long-term complications of hypoestrogenism. 1

Diagnostic Confirmation

The hormonal profile definitively establishes hypothalamic-pituitary dysfunction:

• Suppressed LH and FSH with low estradiol confirms hypogonadotropic hypogonadism, indicating hypothalamic dysfunction rather than primary ovarian failure 1
• Elevated SHBG (186 nmol/L) is consistent with estrogen deficiency, as low estrogen states increase hepatic SHBG production 1
• Low-normal free testosterone (4 pmol/L) reflects the suppressed gonadotropin drive to the ovaries 2
• Negative β-hCG excludes pregnancy as a cause of amenorrhea 1

Identify Underlying Etiology

Immediately assess for the three classic FHA triggers before proceeding with treatment 1:

• Energy deficit/caloric restriction: Obtain detailed dietary history, calculate BMI, and assess for eating disorders 1
• Excessive exercise: Quantify exercise volume (hours/week and intensity) 1
• Psychological stress: Screen for major life stressors, anxiety, or depression 1

Additional metabolic concerns in this patient:

• Iron deficiency (ferritin 24 µg/L) requires oral iron supplementation, as this can contribute to fatigue and may worsen with hypoestrogenism 1
• Mildly elevated PTH (70 ng/L) suggests secondary hyperparathyroidism, likely from vitamin D deficiency or early bone loss from estrogen deficiency; check 25-OH vitamin D levels 3

Management Algorithm

Step 1: Address Reversible Causes First

If BMI <18.5 kg/m², weight restoration is mandatory before any ovulation induction therapy 1:

• Nutritional counseling with target weight gain of 2-4 kg
• Multidisciplinary approach including psychology if eating disorder suspected 1

If excessive exercise identified, reduce training volume by 10-20% and increase caloric intake 1

Step 2: Hormone Replacement Therapy

Initiate estrogen-progestin therapy immediately to prevent the deleterious effects of hypoestrogenism 1:

• Combined oral contraceptives or transdermal estradiol with cyclic progestin are first-line options 1
• Critical: Start physiologic glucocorticoid replacement BEFORE thyroid hormone if concurrent adrenal insufficiency is suspected (though AM cortisol 741 nmol/L argues against this) 1, 2
• Estrogen therapy prevents bone loss, improves cardiovascular risk, and addresses symptoms of hypoestrogenism 1

Step 3: Correct Nutritional Deficiencies

• Iron supplementation: Oral ferrous sulfate 325 mg daily for ferritin <30 µg/L 1
• Vitamin D supplementation: Check level and supplement if low (likely given elevated PTH) 3
• Calcium intake: Ensure 1200-1500 mg daily from diet or supplements given estrogen deficiency 1

Monitoring Strategy

Initial follow-up at 3 months 1:

• Assess for return of spontaneous menses if lifestyle modifications implemented
• Repeat ferritin, PTH, and vitamin D levels
• Evaluate adherence to hormone replacement therapy
• Screen for bone density with DEXA scan if amenorrhea >6-12 months 1

Long-term monitoring every 6-12 months 1:

• Continue hormone replacement until spontaneous cycles resume or until age-appropriate menopause
• Serial DEXA scans every 1-2 years if bone loss documented 1
• Reassess underlying triggers (weight, exercise, stress) at each visit 1

Critical Pitfalls to Avoid

Do NOT use clomiphene citrate for ovulation induction in FHA - it is ineffective because the hypothalamic-pituitary axis is suppressed, not resistant to estrogen feedback 1

Do NOT delay estrogen replacement - the majority of patients with FHA require lifelong or prolonged hormone replacement, and bone loss from hypoestrogenism is often irreversible 1

Do NOT assume PCOS based on any single finding - while this patient has elevated SHBG (opposite of PCOS), if polycystic ovarian morphology were present on ultrasound, the suppressed LH/FSH ratio <1 and clear estrogen deficiency confirm FHA, not PCOS 1

Do NOT overlook the possibility of evolving panhypopituitarism - while isolated gonadotropin deficiency is most common, monitor for development of other pituitary hormone deficiencies, especially given the mildly elevated PTH suggesting possible broader hypothalamic-pituitary dysfunction 1, 2, 4

Fertility Considerations (If Applicable)

If pregnancy desired in the future 1:

• Spontaneous conception should be attempted first after lifestyle modifications and weight restoration (BMI ≥18.5) 1
• If spontaneous cycles do not resume, pulsatile GnRH therapy is the treatment of choice for FHA, as it directly stimulates the pituitary 2
• Alternatively, gonadotropin therapy (FSH/LH or hCG) can induce ovulation when GnRH is unavailable 5, 2