Endocrine System: Function and Disease

• Endocrine glands synthesize, store, and release hormones into the bloodstream, influencing activity within target tissues.
• Clinical signs of endocrine diseases commonly stem from altered hormone levels, either excessive or diminished, affecting tissues distant from the endocrine organ.
• Less frequently, clinical signs arise from physical effects of endocrine gland lesions, often related to neoplastic diseases within the gland.

Increased Functional Effects of Hormones

• Hyperfunction involves excess hormone production by an endocrine gland, increasing circulating hormone levels.
• A new source of hormone, other than the endocrine gland, can also increase hormone levels.

Hyperfunction Types

• Primary hyperfunction is intrinsic to the gland, involving a pathological change resulting in autonomous hormone secretion, independent of a stimulus. This can include functional hyperplastic or neoplastic disease that is less sensitive to negative feedback mechanisms.
• Secondary hyperfunction is extrinsic to the gland, with a stimulus outside the gland causing excess hormone production.

Secondary Hyperfunction

• Hormone is released by a different endocrine gland with a functional lesion, which produces excess stimulatory hormone that then stimulates another endocrine gland to produce excess hormone.
• Non-hormonal signals, like electrolytes (e.g., calcium), can stimulate endocrine glands. Primary diseases causing persistently elevated blood calcium levels result in excess stimulation and hormone production.

Increased Hormonal Function

• Exogenous sources, such as drug administration, can increase hormonal function.
• Endogenous sources, such as tumour production (e.g., anal sac apocrine gland carcinoma producing parathyroid hormone-related peptide in dogs), can increase hormonal function.

Differentiating Endocrine Lesions

• Differentiating between hyperplastic lesions, benign tumours, and malignant tumours can be difficult based on microscopic appearance.
• Tumours are generally larger than hyperplastic nodules, and carcinomas are often larger than adenomas.
• Capsules may help differentiate (nodular hyperplasia is non-capsulated; adenomas may have a capsule).
• Local tissue invasion or metastases indicate malignancy.
• Species differences exist in neoplastic lesion incidence and behaviour. For example, parathyroid carcinomas in dogs have a low incidence of metastasis, while adrenocortical carcinomas have a moderate to high incidence.

Decreased Functional Effects of Hormones

• Hypofunction of an endocrine gland results in insufficient hormone production.
• Lack of response to a hormone is less common, but involves circulating hormone with no target tissue response.

Primary Hypofunction

• Results from conditions affecting endocrine glands, leading to insufficient circulating functional hormones due to insufficient production or synthesis.

Primary Hypofunction - Congenital

• Genetic mutations can cause biochemical defects in hormone synthesis or activation pathways.
• Developmental anomalies can lead to insufficiently functional tissue to produce enough hormone (e.g., severe hypoplasia or complete lack of development).

Primary Hypofunction - Acquired

• Acquired causes involve the destruction of functional cells, leading to loss of functional capacity and insufficient hormone secretion. This could be from infections, immune-mediated disease, neoplastic disease, vascular disease (e.g., infarctions), or treatments (e.g., surgical excision, radiotherapy, drugs).

Secondary Hypofunction

• Results from factors outside the endocrine gland that lead to a lack of stimulation of the gland or impair its ability to synthesize, store, and release hormones.

Secondary Hypofunction - Other

• Other causes can include a lack of substrate for hormone synthesis (e.g., primary nutritional deficiency or intestinal disease that decreases nutrient absorption).

Lack of Hormone Response

• Sufficient circulating hormone levels exist; however, the target tissue fails to respond due to primary disease (e.g., genetic abnormal receptor) or dysfunction secondary to another disease.

Hyperadrenocorticism (HAC) (Cushing’s syndrome)

• Clinical manifestations are caused by excess cortisol.
• Hyperfunction of the adrenal cortex is the most common endocrine condition.

Hyperadrenocorticism - Normal Function

• ACTH is produced by cells in the pituitary (adenohypophysis), stimulating the adrenal gland to produce cortisol.

Primary Hyperadrenocorticism

• Results from a functional tumour in the adrenal cortex, causing autonomous cortisol production.
• Cortisol produced exerts negative feedback on the hypothalamus and pituitary, reducing CRH and ACTH.
• Excessive cortisol production continues autonomously, independent of ACTH stimulation, leading to atrophy of the adrenal cortices.

Adrenal Cortical Tumours

• Most common in older dogs.
• May be functional or non-functional. Some animals have tumours in both adrenal glands.
• Adenomas are more common than carcinomas.
• Carcinomas are larger than adenomas, can obliterate the affected adrenal gland, invade local tissues (e.g., caudal vena cava), and metastasize to distant organs (e.g., liver, kidneys, lungs, mesenteric LNs).

Adrenal Cortical Nodular Hyperplasia

• Is a common, incidental finding in older dogs, cats, and horses.
• It doesn't cause signs of hyperadrenocorticism and is of no clinical significance.

Secondary Hyperadrenocorticism (Pituitary-Dependent)

• Caused by a functional ACTH-producing tumour within the pituitary, which leads to secondary hyperfunction of the adrenal glands.
• Excess cortisol exerts negative feedback on the hypothalamus, reducing corticotropic releasing hormone; however, the tumour is insensitive to this feedback and continues to produce ACTH.

Iatrogenic Hyperadrenocorticism

• Caused by the prolonged administration of glucocorticoids, which leads to negative feedback on the hypothalamus and pituitary.
• This leads to bilateral atrophy of the adrenal cortices and can cause problems if glucocorticoids are withdrawn rapidly.

Hypoadrenocorticism (Adrenocortical Insufficiency) (Addison’s Disease)

• Primary hypoadrenocorticism involves bilateral adrenocortical atrophy or destruction in significant proportions.
• Causes include idiopathic (likely immune-mediated destruction of cortical cells), adrenal inflammation (adrenalitis), vascular disease (e.g., adrenal gland infarction, haemorrhage, and necrosis), and metastatic tumour spread to the adrenals.
• Most commonly seen in dogs, often as severe bilateral idiopathic atrophy.

Primary Hypoadrenocorticism - Clinical Signs

• Can result from deficiencies of all steroids produced by the adrenal cortex (mineralocorticoids, glucocorticoids, and sex steroids).

Secondary Hypoadrenocorticism

• Uncommon and caused by pituitary disease leading to reduced ACTH production and secretion.
• Causes include pituitary infection and neoplasm.
• Lack of ACTH leads to atrophy of adrenal cortices, primarily affecting glucocorticoid (cortisol) production but not significantly affecting mineralocorticoid production in the zona glomerulosa.

Iatrogenic Secondary Hypoadrenocorticism

• Follows the withdrawal of glucocorticoid therapy, it also spares the zona glomerulosa.
• Rapid withdrawal of glucocorticoids leads to hypoadrenocorticism because the atrophied cortices cannot respond to the rapid cortisol demand increase.

Adrenal Medulla - Pheochromocytoma

• Uncommon and can be benign or malignant, with malignant tumours invading local structures and metastasizing.
• Arise from catecholamine-secreting cells.
• May be functional, releasing adrenaline/noradrenaline.
• Occurs in dogs or cattle.

Diabetes Mellitus (“Sugar Diabetes”)

• Can result in chronic hyperglycaemia.
• Glucose in the blood comes from liver production (main source when fasting) and absorption from the gut.
• Insulin is released by pancreatic beta-cells in response to high circulating blood glucose, suppressing glucose production by the liver and enhancing glucose uptake by peripheral tissues.
• Loss of insulin action causes loss of regulatory control of blood glucose levels, resulting in persistent hyperglycaemia due to overproduction by the liver and reduced disposal of blood glucose by skeletal muscle and adipose tissues.

Diabetes Mellitus - Mechanisms

• Pancreatic beta-cell hypofunction results in insufficient insulin production.
• Insulin resistance involves reduced response to insulin by target cells or antagonism of insulin.

Diabetes Mellitus - Classification (Human-Based)

• Type 1: Deficiency of insulin due to primary immune-mediated or idiopathic loss of beta-cells.
• Type 2: Complex multifactorial disease with inadequate insulin production and resistance to insulin in peripheral tissues.
• Other causes (Type S): Destruction of beta-cells by exocrine pancreatic disease or antagonism of insulin by other hormones or drugs.

Diabetes Mellitus In Dogs

• Beta-cell destruction is a more common cause resulting from exocrine pancreatic disease (e.g., pancreatitis, pancreatic necrosis).
• Immune-mediated destruction of beta-cells is seen in adults rather than juveniles and is common in certain breeds.
• Insulin antagonism (insulin resistance) can be caused by progesterone, growth hormone, cortisol and exogenous glucocorticoids and progestogens.

Diabetes Mellitus In Cats

• Usually Type 2 diabetes (reduced insulin production and insulin resistance).
• Accumulation of amyloid within the pancreatic islands.
• Risk factors include: age >10 years, obesity, male sex and certain breed.

Beta cell destruction causing Diabetes Mellitus In Cats

• Can occur due to pancreatitis.
• Insulin antagonism (insulin resistance) can occur due to growth hormone and cortisol production.

Beta-Cell Exhaustion and Glucotoxicity

• Insulin resistance and hyperglycaemia can result in persistent stimulation of the beta-cells to produce insulin.
• Injury to beta cells is reversible in early stages but becomes irreversible over time if hyperglycaemia is not controlled.

Beta Cell Hyperfunction

• Excess insulin production, which results in hypoglycaemia.
• An insulin-secreting beta-cell tumour is called an insulinoma.
• These are frequently malignant (~90% of cases in dogs) with a high risk of metastasis (~50% at diagnosis), leading to a poor prognosis.
• Can metastasize widely throughout the liver and spread to local lymph nodes.

Explore the intricacies of endocrine diseases in animals, focusing on clinical signs and underlying mechanisms. This includes primary and secondary endocrine hyperfunction, as well as the impact of neoplastic lesions. The content also covers the meaning of 'functional' cells in the context of endocrine disease.