Cushing’s syndrome — or hyperadrenocorticism (HAC) — is one of the most commonly diagnosed endocrine disorders in dogs. Yet the condition is frequently misunderstood, in part because its signs and symptoms are diffuse and develop gradually. To truly understand what’s happening in a dog with Cushing’s, you have to start at the source: a disruption in the hypothalamic-pituitary-adrenal (HPA) axis.
The Normal HPA Axis
Under normal physiological conditions, cortisol production is tightly regulated through a feedback loop involving three structures:
- The hypothalamus releases corticotropin-releasing hormone (CRH) in response to stress, low cortisol, or circadian signals.
- The anterior pituitary gland responds to CRH by secreting adrenocorticotropic hormone (ACTH).
- The adrenal cortex responds to ACTH by synthesizing and releasing cortisol and other hormones from the outer layers of the adrenal gland.
Once cortisol levels rise appropriately, the hormone feeds back negatively to both the hypothalamus and pituitary, suppressing further CRH and ACTH secretion. This self-correcting loop maintains cortisol within a narrow physiological range — essential for immune function, glucose metabolism, blood pressure regulation, and stress response.
In a healthy dog, this system operates continuously and precisely. In a dog with Cushing’s, it doesn’t.
Where the Axis Fails
Canine HAC occurs in two primary forms, each representing a different point of failure in the HPA axis.
Pituitary-Dependent Hyperadrenocorticism (PDH) accounts for approximately 80–85% of cases. In PDH, a functional adenoma — most often a microadenoma, though macroadenomas occur — develops on the pituitary gland. This tumor produces ACTH autonomously, independent of normal regulatory signals. Because it does not respond appropriately to negative feedback from rising cortisol levels, ACTH secretion continues unchecked. The adrenal glands, chronically overstimulated, enlarge bilaterally and produce sustained excess cortisol.
Adrenal-Dependent Hyperadrenocorticism (ADH) accounts for the remaining 15–20% of cases. Here, a tumor of the adrenal cortex itself — either an adenoma or, in roughly 50% of adrenal cases, a carcinoma — produces cortisol autonomously. Because cortisol levels are already elevated, endogenous (pituitary-produced) ACTH is suppressed via negative feedback. The contralateral (unaffected) adrenal gland typically atrophies from disuse.
The distinction between PDH and ADH has significant clinical implications for both diagnosis and treatment, which we cover in how vets tell pituitary Cushing’s from adrenal Cushing’s.
Both of those forms are driven by a tumor. A third is not: prolonged glucocorticoid medication can suppress the axis from the outside and produce the same clinical picture, which is why steroid-induced (iatrogenic) Cushing’s is the one type that is often reversible.
The Systemic Consequences of Chronic Cortisol Excess
Cortisol is a glucocorticoid with wide-ranging effects across virtually every organ system. In physiological amounts, it is essential. In chronic excess, it is profoundly destructive.
Musculoskeletal: Cortisol accelerates protein catabolism and inhibits protein synthesis. Over time, this leads to muscle wasting, weakness, and the characteristic pot-bellied appearance caused by redistribution of fat to the abdomen combined with weakened abdominal musculature. Owners often notice their dog struggling to jump, climb stairs, or rise from a lying position.
Dermatological: The skin thins as collagen synthesis is inhibited. Bilaterally symmetric alopecia — hair loss that spares the head and extremities — is a hallmark sign. Calcinosis cutis, the deposition of calcium salts in the skin, occurs in a subset of cases and presents as firm, white or yellowish plaques, often in the groin and dorsal midline.
Renal and fluid balance: Cortisol reduces sensitivity to antidiuretic hormone (ADH/vasopressin) and increases glomerular filtration rate, resulting in obligatory polyuria. Compensatory polydipsia follows. Daily water intake in affected dogs commonly exceeds 100 ml/kg — a diagnostic threshold worth noting.
Metabolic: Cortisol promotes gluconeogenesis and induces peripheral insulin resistance. This significantly elevates the risk of concurrent diabetes mellitus, which occurs in an estimated 10% of Cushing’s cases. Hepatomegaly is nearly universal, driven by cortisol-induced hepatic glycogen accumulation.
Immunological: Chronic glucocorticoid excess suppresses both cell-mediated and humoral immune responses. Dogs with uncontrolled Cushing’s are substantially more susceptible to bacterial infections — particularly urinary tract infections — and may show poor wound healing. Skin infections (pyoderma) are common.
Cardiovascular and thromboembolic: Hypertension is present in an estimated 30–85% of dogs with Cushing’s. Cortisol excess also promotes a hypercoagulable state, increasing the risk of pulmonary thromboembolism — a serious and potentially fatal complication.
Diagnostic Evaluation
No single test confirms Cushing’s with absolute certainty; diagnosis typically requires combining clinical signs with one or more endocrine screening tests.
Urine cortisol:creatinine ratio (UCCR): A first-morning urine sample collected at home (to minimize stress-related cortisol elevation) and analyzed for the cortisol:creatinine ratio. A normal result effectively rules out HAC; an elevated result warrants further testing. (A depressed result may indicate the opposite of Cushing’s — Addison’s disease, in which cortisol levels are chronically too low.)
ACTH stimulation test: Measures cortisol before and one hour after administration of synthetic ACTH (cosyntropin). ACTH should produce a predictable rise in cortisol levels in normal dogs. However, an exaggerated post-stimulation cortisol response supports a diagnosis of HAC. This test is also the standard for monitoring response to mitotane or trilostane therapy (and for ruling out Addison’s disease).
Low-dose dexamethasone suppression test (LDDST): A low dose of dexamethasone is administered, and cortisol is measured at 4 and 8 hours. Normal dogs suppress cortisol to below 1.0 µg/dL at 8 hours. Failure to suppress is consistent with HAC. Dexamethasone is a synthetic hormone that gets “read” by the pituitary as cortisol and suppresses ACTH production through negative feedback. Thus, failure to lower cortisol indicates either that the pituitary is functioning normally but the adrenal gland is not (ADH) or that the pituitary is insensitive to the elevated cortisol and therefore not responding to normal feedback (PDH). Administration of a subsequent higher dose of dexamethasone (high-dose dexamethasone suppression test) can help determine which is correct.
Differentiation tests: Once HAC is confirmed, distinguishing PDH from ADH requires additional workup — endogenous ACTH measurement, high-dose dexamethasone suppression testing, and abdominal ultrasound are the primary tools.
Why the Mechanism Matters
Understanding the HPA axis isn’t just academic. It directly informs how Cushing’s is treated, how treatment response is monitored, and why certain supportive interventions — including lignans and melatonin — may exert a measurable effect on cortisol regulation in some dogs.
In upcoming posts, we’ll examine the diagnostic criteria in greater detail, explore breed-specific predisposition data, and review the peer-reviewed evidence for both conventional and natural treatment approaches.
If you’re exploring natural options alongside or in place of pharmaceutical treatment, our sponsors at lignans.com offer a straightforward introduction to the evidence behind SDG lignans and melatonin for dogs with Cushing’s.
The information on this site is educational and not a substitute for veterinary diagnosis or treatment. Always work with a licensed veterinarian for your dog’s care.
Sources
- Merck Veterinary Manual — Cushing Disease (Pituitary-Dependent Hyperadrenocorticism)
- Patterns of the low-dose dexamethasone suppression test in canine hyperadrenocorticism revisited
- García San José et al., “Prevalence and risk factors associated with systemic hypertension in dogs with spontaneous hyperadrenocorticism,” J Vet Intern Med, 2020
- Concurrent hyperadrenocorticism and diabetes mellitus in dogs
- Iowa Veterinary Specialties — Canine Hyperadrenocorticism overview
- Retrospective evaluation of urinary tract infection in 42 dogs with hyperadrenocorticism or diabetes mellitus or both
