Which of the following is the most likely cause of the patient's osteoporosis—adrenal carcinoma, chronic inhaled corticosteroid use, excessive alcohol use, nodular adrenal hyperplasia, or pituitary microadenoma—given an ACTH level of 78 pg/mL and serial salivary cortisol levels of 290 nmol/L and 275 nmol/L?

Pituitary Microadenoma (Cushing's Disease)

The most likely cause of this patient's osteoporosis is a pituitary microadenoma causing Cushing's disease, given the elevated ACTH level of 78 pg/mL combined with elevated salivary cortisol levels.

Diagnostic Reasoning Based on ACTH Level

• Any ACTH level >5 pg/mL in the setting of confirmed hypercortisolism definitively indicates ACTH-dependent Cushing's syndrome, immediately excluding adrenal carcinoma, nodular adrenal hyperplasia, chronic inhaled corticosteroid use, and excessive alcohol use—all of which suppress ACTH to undetectable levels 1, 2

• An ACTH level of 78 pg/mL far exceeds the threshold of 29 pg/mL, which has 70% sensitivity and 100% specificity for diagnosing pituitary Cushing's disease specifically 1, 2

• The elevated salivary cortisol levels (290 and 275 nmol/L) confirm loss of normal circadian rhythm and active hypercortisolism, supporting the diagnosis 1

Why Pituitary Microadenoma is Most Likely

• Pituitary adenomas account for 75-80% of all ACTH-dependent Cushing's syndrome cases, making this statistically the overwhelming favorite diagnosis 1, 3, 2

• Microadenomas (≤2 mm) represent 98% of pituitary Cushing's disease cases and are frequently too small to detect on MRI, yet still produce significant ACTH elevation 1, 3

• The combination of elevated ACTH with hypercortisolism creates the classic biochemical signature of pituitary-driven disease 1, 2

Why Other Options Are Excluded

Adrenal Carcinoma and Nodular Adrenal Hyperplasia

• Both conditions cause ACTH-independent Cushing's syndrome with suppressed or undetectable ACTH levels (<5 pg/mL), not elevated ACTH 1, 2
• The patient's ACTH of 78 pg/mL completely rules out any adrenal source 1

Chronic Inhaled Corticosteroid Use

• Exogenous corticosteroids suppress the hypothalamic-pituitary-adrenal axis, resulting in undetectable ACTH levels 2
• The elevated ACTH excludes this diagnosis entirely 2

Excessive Alcohol Use

• While alcoholism can cause false-positive screening tests for Cushing's syndrome (pseudo-Cushing's state), it does not produce sustained ACTH elevation to 78 pg/mL with persistently elevated salivary cortisol 1
• Pseudo-Cushing's states show blunted ACTH responses to stimulation testing, unlike true pituitary disease 1

Osteoporosis Connection

• Cushing's disease causes severe osteoporosis through prolonged glucocorticoid excess, with osteoporosis prevalence of 54.8% in Cushing's syndrome patients 4, 5

• Interestingly, pituitary Cushing's disease actually has lower osteoporosis prevalence (37.8%) compared to adrenal Cushing's (69.6%), likely due to protective effects of concurrent adrenal androgen secretion 4

• Despite this relative protection, osteoporosis remains a major complication requiring monitoring and treatment 5, 6

Next Diagnostic Steps

• Obtain a high-quality pituitary MRI (preferably 3T) with thin slices to identify the adenoma 1

• If MRI shows no lesion or a lesion <6 mm, proceed to bilateral inferior petrosal sinus sampling (BIPSS) to definitively confirm the pituitary source, which has 96-100% sensitivity and near 100% specificity 1, 2

• A central-to-peripheral ACTH ratio ≥2:1 at baseline or ≥3:1 after CRH stimulation confirms pituitary disease 1, 2