Cardiovascular & Metabolic Complications of Cushing’s Syndrome Presented by: Saeed Behradmanesh, MD Internist, Endocrinologist

Effects of Glucocorticoids Carbohydrate, Protein, and Lipid Metabolism ► In the liver: –cortisol stimulates glycogen deposition –inhibits glycogenolysis –activates gluconeogenesis ► In peripheral tissues (muscle, fat): –inhibits glucose uptake and utilization

► Stimulate adipocyte differentiation & promote adipogenesis. ► Long-term effects upon adipose tissue: –deposition of visceral or central adipose tissue. –catabolic effect on subcutaneous adipose tissue.

► In adipose tissue, lipolysis is activated ═ > release of FFAs into the circulation. ► ↑ Total chol. & ↑ TGs, but ↓ HDL-chol. ► Permissive effect upon other hormones (CCAs & glucagon). ► Insulin resistance & increase in BG. ► Protein and lipid catabolism.

The explanation for the predilection for visceral obesity may relate to the increased expression of both the GR and 11β-HSD1 in omental compared with subcutaneous adipose tissue.

Skin, Muscle, and Connective Tissue ► Catabolic changes in muscle, skin, and connective tissue. ► In the skin and connective tissue: ▬ inhibit epidermal cell division ▬ inhibit DNA synthesis ▬ reduce collagen synthesis and production ► In muscles: ▬ cause atrophy (but not necrosis) ▬ reduce muscle protein synthesis

Bone and Calcium Metabolism ■ Inhibit osteoblast function ■ Cause osteopenia and osteoporosis ■ Osteoporosis affecting 50% of patients treated with GCSts for > 12 months. ■ Cause osteonecrosis (avascular necrosis)

Osteonecrosis (avascular necrosis): Rapid and focal deterioration in bone quality. Primarily affects the femoral head. Leading to pain and ultimately collapse of the bone. It can affect individuals of all ages. May occur with relatively low doses of GCSts (e.g., during replacement therapy for adrenal failure). No explanation for individual susceptibility.

Recent data implicate: –glucocorticoid-induced osteocyte apoptosis in the pathogenesis of the condition, and –the lack of a direct role for an interrupted blood supply.

► Induce negative calcium balance by: ▬ inhibiting intestinal calcium absorption ▬ increasing renal calcium excretion ► PTH secretion is usually increased. ► In children, GCSts suppress growth but the increases in BMI are thought to offset a deleterious effect on BMD.

Salt and Water Homeostasis& BP Control ► GCSts increase BP. ► Mechanisms: effect on the kidney & vasculature. ► In vascular smooth muscle: ▬ Increase sensitivity to pressor agents such as CCAs & ATII ▬ Reduce NO-mediated endothelial dilatation. ► Increase Angiotensinogen synthesis.

On the distal nephron cause Na + retention & K + loss (mediated via the MR). Elsewhere across the nephron increase: –GFR –proximal tubular epithelial Na + transport –free water clearance Antagonism of the action of AVP Dilutional hyponatremia in glucocorticoid deficiency.

Gut ► Long-term but not acute administ. of GCSts ═ ˃ ↑ risk of developing PUD. ► Pancreatitis with fat necrosis. ► The GR is expressed throughout the GI. ► MR is expressed in the distal colon.

Growth and Development ► Stimulate GH gene transcription in vitro. ► In excess, inhibit linear skeletal growth. ► Catabolic effects on connective tissue, muscle, & bone. ► Inhibition of the effects of IGF-1.

► Stimulate lung maturation through the synthesis of surfactant proteins (SP-A, SP-B, SP-C). ► Stimulate phenylethanolamine N- methyltransferase (PNMT): Noradrenaline → Adrenaline