Adrenal Gland Disorders and Hormones

Adrenal Gland Disorders

• Adrenal gland disorders include Cushing syndrome/disease, IHA/Conn's disease, and Addison disease.
• The study of adrenal gland disorders involves recognizing the pathophysiology, understanding the clinical manifestations and their mechanisms, and relating laboratory test results to the diagnosis.

Adrenal Cortex Hormones

• The adrenal cortex is divided into three zones: zona glomerulosa, zona fasciculata, and zona reticularis.
• The zona glomerulosa produces mineralocorticoids, mainly aldosterone.
• The zona fasciculata primarily produces glucocorticoids, mainly cortisol.
• The zona reticularis produces sex steroids, including androgens.
• Renin-angiotensin system influences the secretion of mineralocorticoids where aldosterone increases Na+ reabsorption and K+ and H+ secretion.
• ACTH influences the secretion of glucocorticoids (Cortisol) which increase glucose, fat, and protein.
• The secretion of Androgens is also influenced by ACTH.

Cushing Syndrome- Classification

• Cushing Syndrome is classified as ACTH-Dependent or ACTH-Independent.
• ACTH-Dependent Cushing Syndrome includes Cushing disease(pituitary adenoma; rarely CRH) at 70% relative frequency and a ratio of females to males being 3.5:1.
• Ectopic corticotropin syndrome (ACTH) occurs at 10% relative frequency and a ratio of females to males being 1:1.
• ACTH-Independent Cushing Syndrome includes Adrenal adenoma at 10% relative frequency and a ratio of females to males being 4:1.
• ACTH-Independent Cushing Syndrome includes Adrenal carcinoma at 5% relative frequency and a ratio of females to males being 1:1.
• ACTH-Independent Cushing Syndrome includes Macronodular hyperplasia (ectopic expression of hormone receptors, including GIPR, LHR, vasopressin and serotonin receptors at <2 relative frequency and a ratio of females to males being 1:1.
• ACTH-Independent Cushing Syndrome includes Primary pigmented nodular adrenal disease (PRKARIA and PDE11 mutations) at<2 relative frequency and a ratio of females to males being 1:1.
• ACTH-Independent Cushing Syndrome includes McCune-Albright syndrome (GNAS mutations) <2 relative frequency and a ratio of females to males being 1:1.

Endogenous Cushing Syndrome

• In Cushing Disease (ACTH-dependent), elevated levels of ACTH lead to excess cortisol and androgen production.
• ACTH-dependent Cushing Syndrome caused by ACTH-secreting pituitary adenoma accounts for 70% of all endogenous cases of Cushing syndrome.
• Cushing disease particularly affects women, occurring four times more frequently than in men and typically in young adults.
• ACTH-dependent Cushing Syndrome may also arise from ACTH-secreting nonpituitary/ectopic tumors, accounting for 10% of cases.
• Small-cell carcinoma of the lung and carcinoid tumors are associated with ectopic tumors.
• Adrenal glands show bilateral cortical hyperplasia in ACTH-dependent Cushing Syndrome due to elevated ACTH levels, leading to hypercortisolism.
• ACTH-independent Cushing Syndrome is caused by an adrenal adenoma; 10% of cases.
• Low ACTH are caused by an adrenal adenoma; 10% of cases.
• ACTH-independent Cushing Syndrome bilateral adrenal cortical atrophy.

Exogenous Cushing Syndrome

• Exogenous Cushing syndrome results from the administration of exogenous glucocorticoids.
• Exogenous glucocorticoids suppress the ACTH-anterior pituitary-CRH-hypothalamus axis, leading to low ACTH levels.
• A lack of ACTH-mediated stimulation causes adrenal cortex atrophy over time, similar to ACTH-independent Cushing syndrome.

Clinical Manifestation

• Cushing syndrome develops gradually, with early symptoms including hypertension and weight gain.
• Elevated glucocorticoid levels lead to gluconeogenesis, lipolysis, and protein catabolism.
• Excess glucocorticoid secretion overwhelms the kidneys' ability to inactivate cortisol, causing it to exert mineralocorticoid actions.
• Excessive glucocorticoids suppress gonadotropin production, leading to hypogonadism and amenorrhea, and affect the AP-H-TSH axis.
• Clinical manifestations associated with metabolic alterations are caused by Cortisol:
  • Stimulation of gluconeogenesis
  • Glucose intolerance
  • Decreased glucose utilization
  • Diabetes ("adrenal diabetes")
  • Increased mobilization of amino acids from muscles with further conversion into glucose.
  • Lipolysis
  • Dyslipidemia

Cushing Syndrome and Body Fat Distribution

• Clinical manifestations of Cushing's syndrome affect body fat, leading to obesity.
• Central pattern of adipose tissue deposition (truncal obesity).
• Accumulation of fat in the face (moon face).
• Accumulation of fat in the posterior neck and back (buffalo hump).
• Suggested mechanism of fat distribution: increased stimulation of food intake

Cushing Syndrome and Muscle, Skin, and Bone

• Clinical manifestations of Cushing syndrome affect muscle, skin, and bone systems due to Cortisol's effect on protein include:
  • decreased synthesis
  • increased catabolism
  • increased mobilization of amino acids.
• Clinical symptoms include:
• Weakness and decreased proximal muscle mass due to atrophy of gluteal and upper leg muscles.
• Skin: loss of collagen, cutaneous, purple striae in the abdominal area (skin easy to tear apart), fragile skin (thin, easy to bruise)
• Osteoporosis (bone resorption) associated with backache and increased risk of fractures.

Cushing Syndrome & Blood and Immune Systems

• Clinical Manifestations of Cushing syndrome affect blood and immune systems due to Cortisol's effect on immune system, including:
• Blocks early stages of inflammation.
• Causes rapid resolution of ongoing inflammatory process.
• Decreases the permeability of capillaries.
• Decreases migration of white blood cells to the inflamed area.
• Suppresses T lymphocytes.
• Reduces IL-1 release from white leukocytes.
• Increased risk for infections

Cushing Syndrome & Cardiovascular System

• Clinical Manifestations of Cushing syndrome affect the cardiovascular system because of:
• Mineralocorticoid effect of cortisol excess.
• Excess of glucocorticoids secretion overcomes the ability of kidney to rapidly inactivate cortisol, thereby exerting mineralocorticoid actions.
• It causes:
• Hypokalemia (weakness, paresthesia).
• Hypertension
• Edema
• Atherosclerosis

Cushing Syndrome Clinical Manifestations for CNS

• Clinical manifestations of Cushing of syndrome affect the CNS, leading to mental and emotional disturbances:
• Irritability
• Emotional Lability
• Depression
• Sometimes cognitive defects
• In severe cases, paranoid psychosis

Addison Disease

• Addison Disease primarily involves lack of aldosterone, cortisol, and androgen production, leading to adrenal insufficiency.
• Chronic primary adrenocortical insufficiency is Addison Disease.
• More than 90% of it is caused by:
• Autoimmune adrenalitis (60-70% of all cases)
• tuberculosis
• AIDS
• Metastatic cancer

Addison Disease Associated with Autoimmune Disorders

• A hallmark of APS associated adrenal insufficiency is the presence of autoantibodies against 21- or 17-hydroxylase due to defect in central tolerance to the peripheral antigens.
• Autoimmune adrenalitis involves autoimmune destruction of steroidogenic cells, and autoantibodies to key several steroidogenic enzymes.
• Autoimmune adrenalitis are much more common in whites and in women.
• Autoimmune adrenalitis can occur in one of the two clinical settings:
  • Autoimmune polyendocrine syndrome (APS1) is characterized by mucocutaneous candidiasis, abnormalities of skin, dental enamel, and nails in conjunction with organ-specific autoimmune disorder (autoimmune adrenalitis, autoimmune hypoparathyroidism, idiopathic hypogonadism, pernicious anemia).
  • It is caused by mutation in AIRE [Autoimmune Regulator] gene, which leads to lack of central T-cell tolerance to the peripheral antigens.
  • Autoimmune polyendocrine syndrome type 2(APS2) starts in early adulthood and is a combination of adrenal insufficiency, autoimmune thyroiditis, or less commonly T1DM.
• It has polygenic inheritance with confirmed association with HLA-DR3 region and CTLA4, PTPN22 genes.

Symptoms caused by Mineralocorticoid Deficiency

• Salt craving due to decreased renal Na+ reabsorption (hyponatremia).
• The loss of Na+ and H2O in urine leads to low BV and BP/hypotension, dizziness.
• Increased serum creatinine (due to volume depletion)
• Myalgia, joint pain due to K+ retention (hyperkalemia).
• Death within 4 days-2 weeks.
• If untreated it causes rapid progression.

Symptoms caused by Glucocorticoid Deficiency

• Hypoglycemia, especially between meals due to problems with gluconeogenesis.
• Progressive weakness, fatigue, anorexia, and weight loss.
• Fever
• Patients are susceptible to any kind of stress, which can easily lead to acute adrenal crisis or death after a mild infection.

Addison Disease Clinical Manifestations

• Sex steroid deficiency leads to lack of energy, dry and itchy skin and libido loss..

Other Addison Disease Symptoms Include:

• Hyperpigmentation of the skin of sun-exposed areas, areas with increased friction (palmar creases), and around pressure points. Hyperpigmenation occurs due to increased POMC (pro-opiomelanocortin) synthesis, which is a precursor of MSH and ACTH. MSH

Primary Hyperaldosteronism

• Primary hyperaldosteronism includes Idiopathic hyperaldosteronism (IHA) and Conn's Disease.
• Hyperaldosteronism is a group of disorders caused by chronic excess of aldosterone.
• Primary hyperaldosteronism stems from autonomous production of aldosterone with resultant suppression of the RA and decreased plasma renin activity.
• Causes:
• Idiopathic hyperaldosteronism (IHA).
• Adrenocortical neoplasm (adenoma, Conn's Disease)
• Glucocorticoid-remediable.

###IHA and Conn's Disease

• IHA is characterized by bilateral nodular hyperplasia of the adrenal glands and is the most common cause of the primary hyperaldosteronism (60% of all cases).
• Affected individuals are older and have less severe hypertension, the pathogenesis remains unclear.
• Adrenocortical neoplasm (aldosterone producing adenoma or rarely carcinoma) underlies about 35% of cases; typically, it presents as a solitary adenoma in middle-aged individuals.
• Women are affected more often than men, with a 2:1 ratio.
• Glucocorticoid-remediable hyperaldosteronism is rare but very interesting in term of its pathogenesis andstems from rearrangement involving chromosome 8 that places CYP11B2 gene under control of the ACTH responsive CYP11B1 gene promoter.
• In this case, ACTH stimulates the production of aldosterone synthase because the production of aldosterone is under control of ACTH, it can be suppressed by glucocorticoids.

Conn's Disease Manifestations

• Hypertension occurs in 5-10% of nonselected hypertensive patients or 20% of treatment-resistant hypertension patients.
• Aldosterone (via mineralocorticoid receptor) increases Na reabsorption, which results in water reabsorption/fluid retention, leading to edema and increased extracellular volume, increasing cardiac output.
• Hypernatremia or normal serum sodium levels (due to expansion of extracellular and plasma volumes).
• Hypertension leading to:
• Cardiovascular compromise
• Left ventricular hypertrophy
• Atherosclerosis
• Stroke
• Myocardial infarction
• Hypokalemia resulting from renal potassium wasting cause: Neuromuscular manifestations
• Weakness
• Paresthesia
• Visual disturbances
• Frank tetany