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Pathophysiology of Adrenal Disorders (Disorders (Cushing's Syndrome…
Pathophysiology of Adrenal Disorders
Hypothalamic-Pituitary-Adrenal axis
Hypothalamus
Located at the base of the brain
Produces:
Vasopressin
Oxytocin
Hormone-releasing factors such as GHRH and Somatostatin
Hormones
CRH: Corticotropin-releasing hormone
TRH: Thyrotropin-releasing hormone
SRIF: Somatotropin Release Inhibiting Factor
GnRH: Gonadotropin-Releasing Hormone
Dopamine
GHRH: Growth hormone releasing hormone
Receives autonomic nervous input from different areas of the body
Regulates:
Limbic functions
Food and water intake
Body temperature
Cardiovascular function
Respiratory function
Diurnal rhythms
Adrenal Pituitary
Contains anterior and posterior lobes
Posterior
Contains nerve terminal of two nuclei from hypothalamus
Hormone release is regulated by direct nervous stimulation
Vasopressin
Antidiuretic hormone; acts on the renal collecting ducts to conserve water
Oxytocin
Contracts the smooth muscles in the breast during lactation
Plays a role in uterine contraction during parturition
Anterior
"Master Gland"
Hypothalamic-hypophyseal portal vessels provide circulation in these areas
Controlled by hypothalamic-releasing and inhibitory hormones
ACTH (Adrenocorticotropic Hormone)
Stimulates synthesis and secretion of adrenocortical hormones
Prolactin
Promotes lactation and inhibits gonadal function
GH (somatotropin)
Stimulates protein synthesis and overall growth in all body tissues
TSH (Thyroid Stimulating Hormone)
Iodine uptake and thyroid hormone synthesis
FSH (Follicle Stimulating Hormone)
Stimulates sperm maturation in testes and follicle growth in ovaries
LH (Luteinizing Hormone)
Stimulates testosterone synthesis in testes and ovulation, corpus luteum formation, and estrogen and progesterone synthesis in ovaries
Function
Regulates 2/3 corticosteroid classes (Glucocorticoids, Adrenal androgens)
Pulsatile release of CRH and ACTH
Negative feedback loop: Cortisol
Cortisol
↑ early AM, peaks in AM, and ↓ in PM
Effects: Physiologic stress response and electrolyte homeostasis
Activates steroids from inactive to active state within the liver
Eliminated via GFR
Half-life 70-120 minutes
Protein binding 95% bound
Renin-Angiotensin-Aldosterone System (RAS)
Function
Regulates 1/3 corticosteroid classes (mineralocorticoids such as aldosterone)
Under NORMAL conditions, hypothalamus release of CRH and pituitary release of ACTH DO NOT impact aldosterone production
Steps
Renin release from juxtaglomerular cells in kidney
Cleavage of angiotensinogen to angiotensin I in liver
Angiotensin Converting Enzyme (ACE) cleaves angiotensin I to angiotensin II
Angiotensin II binds and activates AT1 receptor
↑ adrenal aldosterone production
↑ sodium retention and ↑ potassium excretion (ANTIDIURETIC EFFECT!)
↑ arterial perfusion pressure -> regulating renin release!
Disorders
Cushing's Syndrome (Hypercortisolism)
Epidemiology
More common in women (exception is prepubertal cases predominantly boys)
Only 10% of patients with Cushing's syndrome have a primary, adrenal cause
Most common cause: Glucocorticoid use for immunosuppression or inflammatory disorders
Etiologies
*Iatrogenic (exogenous corticosteroids): Deceased cortisol
Decreased ACTH, Decreased CRH
Cushing’s disease (pituitary adenoma): Increased cortisol , Increased ACTH, Decreased CRH
Adrenal adenoma/carcinoma: Increased cortisol, Decreased ACTH, Decreased CRH
Ectopic ACTH-secreting tumor: Increased cortisol, Decreased ACTH, Decreased CRH
Ectopic CRH-secreting tumor: Increased cortisol, Increased ACTH, IncreasedCRH
Pathophysiology
Hyperglycemia
TD2M
Hyperlipidemia
Central Obesity
"Buffalo Hump"
"Moon Face"
Osteoporosis
Immunosuppression
Muscle atrophy
Skin atrophy
Hypertension
Hypokalemia
Edema
Acne
Menstrual irregularity
Infertility
Mood changes
Depression
Conn's (Primary Hyperaldosteronism)
Aldosterone secreting adrenal adenoma
Presentation
Hypertension
Hypokalemia
Hypervolemia
Addison's Disease (Primary Adrenocortical Insufficiency)
Dysfunction or destruction of Adrenal Cortex
Autoimmune Etiologies
Accounts for ~80% of cases
Autoimmune Polyendocrine Syndrome Type 1 (APS-1) (Rare)
Autoimmune Polyendocrine Syndrome Type 2 (APS-2) (Addison’s disease, Hashimoto’s, thyrotoxicosis, T1DM)
Other Etiologies
Infective (tuberculosis, HIV, parasitic)
Adrenal hemorrhage or infarction
Metastatic cancer
Radiation therapy
Enzyme inhibitors (metyrapone, ketoconazole)
Cytotoxic agents (mitotane)
Congenital effects
Pathophysiology
Hypoglycemia
Fatigue
Weight loss
Hair redistribution
Menstrual irregularities
Hypotension
Hyponatremia
Hyperkalemia
Skin bronzing (due to up-reguoation of ACTH production (only in primary disease)
Secondary Hyperaldosteronism
Increased Renin Production
Pathophysiology
Heart failure
Chronic Kidney Disease
Cirrhosis
Secondary Adrenal Insufficiency
Due to hormonal regulation
Pathophysiology
Hypoglycemia
Fatigue
Weight loss
Hair redistribution
Menstrual irregularities
Hypotension
Hyponatremia
Hyperkalemia
Adrenal Crisis
Cortical hormones below physiology necessary levels
Mineralocorticoid depletion becomes life threatening
Effects
GI symptoms: Abdominal pain, N/V, fever
Postural hypotension --> hypovolemic shock
Stupor/coma