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