DISEASES OF OVERPRODUCTION & UNDERSECRETION OF GLUCOCORTICOIDS

Glucocorticoid Excess
- Also known as Cushing Syndrome (Corticotropin-dependent or corticotropin-independent) or
Cushing Disease

Glucocorticoid Deficiency
- Also known as Addison Syndrome, which can be the result of autoimmune destruction of the
adrenal gland or inborn errors of steroid hormone synthesis
- Addison Syndrome
- Primary Deficiency: from adrenal dysfunction
- Secondary Disorder: from lack of ACTH stimulation of adrenal glucocorticoid production
Most of the cases involve deficiencies of other pituitary hormones
- Another etiology: chronic disease  chronic treatment (synthetic glucocorticoid)  CTH
& ACTH glucocorticoid deficiency
Sudden discontinuation of treatment using synthetic glucocorticoid (which has higher affinity than
biologic glucocorticoid) can cause acute case of renal insufficiency, a medical emergency.

The Main Targets and Actions of Glucocorticoids and the Consequences of Cushing's Disease and
Addison's Disease.1

TargetSystem Specific Physiologic Cushing's Disease Addison's Disease

Target Function
Intermediary Liver Increased expression Increased hepatic glucose Diminished hepatic
metabolism of gluconeogenic output; together with insulin, glucose output and
enzymes, increased hepatic glycogen stores glycogen stores
phosphoenolpyruvate
kinase, glucose-6-
phosphatase, and
fructose-2,6-
bisphosphatase
Adipose tissue Permissive for Overall effect (together with Decreased adiposity
lipolytic signals insulin): central obesity (truncal and decreased
(catecholamines, obesity, moon facies, and buffalo lipolysis
GH) leading to hump)
elevated plasma FFA
to fuel
gluconeogenesis
Skeletal muscle Degradation of Muscle weakness and wasting Muscle weakness,
fibrillar muscle mainly in proximal muscles; decreased muscle
proteins by increased urinary nitrogen glycogen stores;
activating the excretion (urea from amino decreased urinary
ubiquitin pathway, acids) nitrogen excretion
thereby providing
substrate for
gluconeogenesis
Plasma glucose Maintains plasma Impaired glucose tolerance, Hypoglycemia,
glucose during insulin-resistant diabetes increased insulin
fasting mellitus; increased plasma sensitivity
(antihypoglycemic glucose is due to decreased
action); increases peripheral glucose utilization and
plasma glucose increased hepatic glucose output.
during stress
(hyperglycemic
action)
Calcium Kidney Decreased Hypercalciuria without Retardation of bone
homeostasis reabsorption of hypercalcemia leading to growth mainly
calcium secondary hyperparathyroidism; through decreased
retardation of bone growth and GH; hypercalcemia
bone age by direct action and by possible
decreasing GH; osteoporosis in
adults
 Bone, cartilage Inhibition of collagen
synthesis and bone
deposition
Gastrointestinal Inhibition of calcium,
tract magnesium, and
phosphate
absorption by
antagonizing
calcitriol
Other Hypothalamus, Decreases Scanty menses due to Scanty menses by
endocrine pituitary endogenous opioid suppressed gonadotroph upregulated CRH-
systems production; sensitivity to GnRH; suppressed endogenous opioid
depresses GH secretion by hypothalamic pathway-mediated
gonadotroph action; minimal suppression of suppression of GnRH;
responsiveness to the TRH-TSH axis suppressed GH
GnRH; stimulates GH secretion;
gene expression by hypothyroidism (if
the pituitary; inhibits present) is due to
GH secretion via the direct autoimmune
hypothalamus action
Pancreas Inhibits insulin Absolute hyperinsulinemia with Absolute
secretion by relative hypoinsulinemia (lower hypoinsulinemia with
decreasing the plasma insulin than expected for relative
efficacy of the degree of hyperglycemia) hyperinsulinemia
cytoplasmic Ca2+ on
the exocytotic
process

Adrenal Increases PNMT Increased responses to Decreased responses

medulla expression and sympathoadrenal activation to sympathoadrenal
activity (epinephrine activation
synthesis)
Carrier proteins Decreases all major Decreased in total T4, free T4
(CBG, SHBG, hormone-binding remains normal
TBG) proteins
Immune Thymus, Causes age-related Immunocompromised state; Relative
system lymphocytes involution of the lymphocytopenia lymphocytosis in
thymus. Induces peripheral blood
thymic atrophy.
Monocytes Inhibits monocyte Monocytopenia in peripheral Monocytosis in
proliferation and blood peripheral blood
antigen
presentation;
decreased production
of IL-1, IL-6, and
TNF
Granulocytes Demargination of Peripheral blood: granulocytosis, Peripheral blood:
neutrophils by eosinopenia granulocytopenia,
suppressing the eosinophilia
expression of
adhesion molecules
Inflammatory Inhibition of
response inflammation by
inhibiting PLA2,
thereby inhibiting
production of
leukotrienes and
prostaglandins;
suppresses COX-2
expression

Erythrocytes No significant effect Increased hemoglobin and Anemia is more

hematocrit are due to ACTH-
mediated overproduction of
androgens
Skin and Antiproliferative for Easy bruisability due to dermal
connective fibroblasts and atrophy; striae or sites of
pronounced in women
and is due to loss of
adrenal androgens:
Anemia may be
related to direct
autoimmune targeting
of gastric parietal cells
The darkening of the
skin is due to ACTH-
tissue keratinocytes increased tension, especially sites mediated stimulation
of adipose tissue accumulation; of epidermal
poor wound healing; hirsutism melanocortin 1
and acne are due to ACTH- receptors; vitiligo may
mediated increase of adrenal occur due to direct
androgens; hyperpigmentation is autoimmune
a direct effect of ACTH on destruction of
melanocortin 1 receptors melanocytes in
circumscribed areas
Breast Mammary Mandatory Cushing's disease may be Addison's disease is
epithelium requirement for associated with galactorrhea not associated with
location galactorrhea
Lung Type II Stimulation of
alveolar cell surfactant production
Cardiovascular Heart Increased Hypertension Lower peripheral
system contractility resistance;
hypertension with
further postural
decrease in blood
pressure (orthostatic
hypotension); low-
voltage ECG
Vasculature Increased vascular
reactivity to
vasoconstrictors
(catecholamines,
angiotensin II)
Na+, K+, and Kidney Increased GFR and Hypokalemic alkalosis, increased Hyponatremia,
ECF volume non-physiologic ECF volume due to hyperkalemic acidosis,
actions on mineralocorticoid activity and decreased ECF
mineralocorticoid (increased DOC, saturation of volume are mainly
receptors type 2 11 -hydroxysteroid due to loss of
dehydrogenase by high levels of mineralocorticoid
cortisol). activity.
Posterior Hyponatremia due to SIADH Increased ADH mainly
pituitary via hypovolemia-
related baroreceptor
mechanism
Psychiatric Mood Eucortisolemia Initially, euphoria; long-term, Depression
parameters of maintains emotional depression
CNS function balance
Appetite Increases appetite Hyperphagia Decreased appetite in
spite of improved
taste and smell
Sleep Suppression of REM Sleep disturbances
sleep
Memory Sensitizes Impaired memory, bilateral
hippocampal hippocampal atrophy
glutamate receptors,
induces atrophy of
dendrites
Eye Increasing Cataract formation; increased Decreased intraocular
intraocular pressure intraocular pressure pressure