In a 32‑year‑old woman with long‑standing irregular menses and hirsutism, currently taking metformin and medroxyprogesterone acetate, who has very low early‑morning cortisol, low estradiol, mildly elevated prolactin, borderline high TSH with normal free T4, elevated ACTH, normal‑size ovaries, thin endometrium, and MRI showing an enlarged sella with near‑complete empty sella, what is the most likely diagnosis and what is the appropriate management?

Most Likely Diagnosis: Primary Empty Sella Syndrome with Secondary Hypopituitarism and Polycystic Ovary Syndrome (PCOS)

This patient has primary empty sella syndrome causing secondary adrenal insufficiency (evidenced by very low morning cortisol 0.80 µg/dL with elevated ACTH 47.9 pg/mL), along with PCOS manifesting as hirsutism, irregular cycles, and enlarged ovaries. The near-complete empty sella on MRI explains the pituitary dysfunction, while the hyperandrogenic features point to concurrent PCOS.

Diagnostic Interpretation

Empty Sella and Hypopituitarism

The MRI finding of near-complete empty sella is clinically significant. Complete empty sella (≥50% CSF filling with pituitary <2 mm) carries substantially higher risk of hypopituitarism than partial empty sella 1. Recent evidence shows that 40-63% of patients with empty sella have at least one pituitary hormone deficiency 2, 3, with secondary adrenal insufficiency and hypogonadism being most common in complete empty sella 1.

The extremely low morning cortisol (0.80 µg/dL) with elevated ACTH (47.9 pg/mL) is paradoxical but diagnostic of secondary adrenal insufficiency. While elevated ACTH typically suggests primary adrenal failure, the very low cortisol with only modestly elevated ACTH (not the markedly elevated levels seen in Addison's disease) indicates inadequate pituitary reserve 4. The later cortisol measurement of 14 µg/dL was likely obtained while on medroxyprogesterone, which can interfere with HPA axis testing 5.

Concurrent PCOS

The 10-year history of irregular cycles, hirsutism, enlarged ovaries (14.3 and 16.5 mL), and borderline TSH (5.094 µIU/mL) with normal free T4 are consistent with PCOS 6. The LH/FSH ratio of 1.17 is not elevated but doesn't exclude PCOS. The mildly elevated prolactin (19.13 ng/mL) likely represents stalk compression from the empty sella rather than a prolactinoma 7.

Appropriate Management Algorithm

Immediate Priority: Glucocorticoid Replacement

Start hydrocortisone 15-20 mg daily immediately (10 mg upon awakening, 5 mg early afternoon) 4. This is life-critical given the morning cortisol of 0.80 µg/dL, which is diagnostic of adrenal insufficiency (cortisol <3 µg/dL confirms AI) 4.

• Provide emergency glucocorticoid card/bracelet and injectable stress-dose kit 4
• Educate on stress-dosing: double or triple dose during illness, injury, or surgery
• Do NOT use fludrocortisone—it is not indicated in secondary adrenal insufficiency 4
• Retest HPA axis only after stopping medroxyprogesterone for ≥24 hours 4

Secondary Priority: Complete Pituitary Function Assessment

Before starting any additional hormone replacement, obtain comprehensive baseline testing 2, 4:

Required tests (off medroxyprogesterone ≥24 hours):

• Repeat 8-9 AM cortisol and ACTH
• IGF-1 and consider GH stimulation testing if low
• Repeat TSH and free T4 (current borderline TSH may represent early central hypothyroidism)
• Repeat FSH, LH, estradiol (current low E2 of 38.24 pg/mL suggests hypogonadism)
• Serum and urine osmolality to exclude diabetes insipidus (no polyuria reported, but screen given complete empty sella)

Central hypothyroidism consideration: The TSH of 5.094 µIU/mL with normal free T4 (1.06 ng/dL) is atypical. In central hypothyroidism, TSH is typically low-normal or mildly elevated with LOW free T4 4. If free T4 drops by ≥20% on repeat testing or symptoms develop, start levothyroxine 4. However, always ensure adequate glucocorticoid replacement before starting thyroid hormone to avoid precipitating adrenal crisis 4.

Tertiary Priority: PCOS Management

Once pituitary function is stabilized:

For hirsutism and hyperandrogenism:

• Discontinue medroxyprogesterone acetate alone—it suppresses gonadotropins but doesn't adequately treat hyperandrogenism 5
• Start combined oral contraceptive (OCP) with antiandrogen properties (e.g., containing cyproterone acetate or drospirenone) as first-line therapy 6, 8
• Continue metformin 500 mg twice daily—it improves insulin resistance and may help menstrual regularity, though it's not first-line for hirsutism 8, 9
• Consider adding spironolactone 50-100 mg daily if hirsutism persists after 6 months on OCP 8

Antiandrogens are significantly more effective than metformin alone for hirsutism (mean difference 3.7 points on hirsutism scores) 8. Metformin shows minimal benefit for hirsutism as monotherapy 8.

For metabolic risk:

• Address elevated LDL (153 mg/dL)—lifestyle modification and consider statin if cardiovascular risk warrants
• Monitor for diabetes development given PCOS and family history risk 6
• Weight management counseling 6

Follow-up Imaging and Monitoring

Repeat MRI sella in 12 months to assess for progression from partial to complete empty sella, which can worsen hypopituitarism 2, 1. However, if pituitary function is intact at baseline, the risk of developing new deficiencies is very low (<2% over 5 years) 10, so annual hormonal reassessment is not mandatory unless symptoms develop.

Critical Pitfalls to Avoid

1. Never start thyroid hormone before glucocorticoid replacement—this can precipitate life-threatening adrenal crisis by increasing cortisol metabolism 4

2. Do not rely on random cortisol measurements—they are unreliable for diagnosing adrenal insufficiency 4. The initial 0.80 µg/dL morning cortisol is diagnostic, but the later 14 µg/dL reading is uninterpretable given medroxyprogesterone use

3. Do not use glucocorticoids to treat PCOS-related hyperandrogenism in this patient. While glucocorticoids suppress adrenal androgens in pure adrenal hyperandrogenism, they show minimal benefit for hirsutism (26% improvement vs. 54% with antiandrogens) and carry risks of glucocorticoid excess 8. This patient needs physiologic glucocorticoid replacement for adrenal insufficiency, not pharmacologic suppression

4. Recognize that elevated ACTH doesn't exclude secondary AI—the combination of very low cortisol with only modestly elevated ACTH (not >100 pg/mL as in primary AI) indicates pituitary dysfunction 4

5. Don't assume mild hyperprolactinemia requires dopamine agonist therapy—prolactin of 19.13 ng/mL without galactorrhea likely represents stalk effect from empty sella and doesn't require treatment 7. Dopamine agonists won't shrink non-prolactinoma incidentalomas 7

Prognosis and Long-term Considerations

Male sex and complete empty sella are independent predictors of hypopituitarism 2, though this patient is female. The complete empty sella places her at higher risk for multiple axis involvement 1. Fortunately, once pituitary function is assessed at diagnosis, progression to new deficiencies is rare (only 2/119 patients developed new deficiencies over 5 years in one cohort) 10.

The combination of PCOS and hypopituitarism requires lifelong monitoring for metabolic complications including diabetes, dyslipidemia, and cardiovascular disease 6. The thin endometrium (4.9-5 mm) will likely normalize with appropriate hormone replacement and cycle regulation.