The Adrenal Glands

The Adrenal Glands - Structure

Adrenal cortexDerived from same embryological tissue that gave rise to gonads

(mineralocorticoids)

(glucocorticoids)

(gonadocortocoids)

Synthesis

孕烯醇酮

17羟孕酮 雄烯二酮

Develops from ectoderm, the same embryological tissue that gives rise to the nervous system; 2 hormones - epinephrine and norepinephrine; Stimulated directly by sympathetic division of nervous system

• Epinephrine (E): 80%

• Norepinephrine (NE): 20%

• Adrenomedullin 肾上腺髓质素

Synthesis of Catecholamines (DA, NE, E)

Functions of E and NE

Cardiovascular effects

Metabolic effects– ↑ Glucose production– ↑ BMR（基础代谢率）

Stress response

The Adrenal cortex

Steroid Representative Effects

Mineralocorticoids AldosteroneNa+, K+ and water

homeostasis

Glucocorticoids CortisolGlucose homeostasis

and many others

Sex steroid Androgens

Synthesis of the different steroids is not uniformly distributed through the cortex.

The outermost group of cells (zona glomerulosa) synthesizes aldosterone, but essentially no cortisol nor androgens, because those cells do not express the enzyme 17-alpha-hydroxylase which is necessary for synthesis of 17-hydroxypregnenolone and 17-hydroxyprogesterone.

That enzyme is however present in cells of the inner zones of the cortex (zonae fasiculata and reticularis), which are the major sites of cortisol production.

17羟孕烯醇酮

孕烯醇酮

The Adrenal Glands - Production of Hormones

Mineralocorticoids

• Aldosterone: the most common mineralocorticoid, accounts for about 90% of all mineralocorticoid activity

• About 60% are bound to plasma proteins, half life is about 20 min

• Aldosterone increases Na+ retention in kidney, sweat glands, and salivary glands, which also increases water retention

• Increases K+ and H+ secretion in kidney

• Save Na+, lose K+: Renal reabsorption of Na+ in the principal cells of the collecting tubules, the distal tubules and collecting ducts; excretion of K+ and hydrogen ions in the distal tubules and collecting ducts

Regulation of aldosterone secretion

Increased K; Increased activity of Renin-angiotensin system; Increased sodium – through renin; ACTH

血管紧张素转换酶

The Adrenal Glands - Cortisol

CRH

Glucocorticoids

Cortisol (hydrocortisone) : the most common glucocorticoid, 95% of all glucocorticoid activity,

involved with glucose metabolism,

protects against low blood glucose levels, or hypoglycemia;

Others: Cortisone (synthetic, as potent as cortisol); Dexamethasone (synthetic, 30 times as potent as cortisol)

Glucocorticoids

Metabolism: catabolic hormone causing the breakdown of complex molecules to be used for energy

– Proteins: increases protein breakdown, releasing amino acids into blood

– Lipids: mobilizes fatty acids from adipose tissue

– Carbohydrates: increases blood glucose levels and gluconeogenesis

Large amounts of cortisol decreases inflammation, suppresses immune system, slows healing

The Adrenal Glands---Cortisol

Effects on blood cells

↑RBC, neutrophils, monocytes and platelets

↓Lymphocytes, eosinophils and basophils

Effects on Vascular System

Permissive action through inhibition of enzyme (e.g. COMT) that degrades norepinephrine at sympathetic nerve endings- optimize vascular responses to catecholamines- cortisol is needed for maintaining blood pressure

Helps to maintain blood volume by decreasing the permeability of the vascular endothelium

Effect on bone formation-inhibition

– reduce the synthesis of type I collagen (the fundamental component of bone matrix)

– decreases absorption of calcium from the viscera

– ↑calcium excretion via ↑glomerular filtration rate in the kidney

– ↑the rate of bone resorption (excess cortisol → osteoporosis)

↑ Excitability of CNS - alters mood and behavior, insomnia, strikingly depress or elevate moods

Effects on nervous system

Anti-inflammatory effects

Suppress the immune response (stabilizing lysosomes)

Widely used in therapy:

- to reduce the inflammatory destruction of rheumatoid arthritis and other autoimmune diseases

- to prevent the rejection of transplanted organs

- to control asthma

Effects on digestive system

↑ Digestive secretions

Mechanism of actionBinds to cytosolic receptor - Cortisol-receptor complex migrates to nucleus and transferred to nuclear binding site - interacts with DNA -Increase RNA synthesis

Regulation of cortisol secretion – the HPA axis

ACTH (corticotropin, adrenocorticotropin)

↑ Cortisol secretion

Cause hypertrophy or proliferation of the adrenocortical cells

Secretion with MSH

Diurnal rhythm

Transport of Adrenocorticosteroids

– 75% of cortisol bound to corticosteroid-binding globulins (CBG, transcortin)

– 15% of cortisol bound to Albumin

– 10% free

Abnormalities of adrenocortical secretion

Hypoadrenalism, Also called Addison’s disease

Clinical features

excessive urinary loss of Na and Cl ions (dehydration)

Hypoglycaemia

Muscle weakness

Skin pigmentation (due to ↑ACTH)

Hypotension

Inability to withstand stress

Autoimmune disease

Cannot use lipid reserves for ATP production,

K+ buildup, acidosis, etc.

Hyperadrenalism– Cushing’s syndrome

Fat deposits in cheeks - “moon face”, plethora (reddish face & neck), trunk obesity

Purple abdominal striae (loss of collagen in subcutaneous tissue and increases tearing), thin skin, resulting in easy bruisability

Skin pigmentation (due to ↑ACTH)

Poor wound healing

Hypertension (mineral effects of cortisol)

Hyperglycaemia

Osteoporosis (loss of protein in bone)

Muscular weakness

Mental abnormalities

Hirsutism (due to adrenal androgens)

The amount of androgen secreted by adrenal cortex is too low to have much effect under normal circumstances

Stress Response and the HPA axis

Stress can be productive (for example, appropriate levels of short term stress can help you respond to a crisis) or non-productive (for example, long term stress due to a job you hate can suppress the immune system)

• Alarm phase– Fight or flight, adrenal medulla, E and NE

• Resistance phase– Glucocorticoids mobilize energy reserves, but saves

glucose for nervous system

• Exhaustion phase – Mineralocorticoids - gastritis, ulcers, irritable bowel

syndrome, depression, etc.

Stress and the HPA axisStress overrides negative feed-back i.e. cortisol secretion is stimulated even though cortisol level is high, but gradually it is diminished

Virtually any type of physical or mental stress results in elevation of cortisol concentrations in blood due to enhanced secretion of CRH in the hypothalamus

Result of stress

Start of stress

Schematic representation of the interactions between the HPAl axis and the reproductive and growth axes.

Chronic hyperactivation of the stress system may lead to osteoporosis and metabolic syndrome.

SmC: somatomedin C.

Activation is represented by solid green lines and inhibition by dashed red lines.

Schematic representation of the interactions between the HPA axis and the thyroid and immune function.

Schematic representation of the detrimental effects of chronic stress on adipose tissue, bone and muscle metabolism.

Schematic representation of the effects of stress on gastrointestinal function.

LC: locus ceruleus.

Schematic representation of the interactions between the HPA axis, the adipose tissue and the hypothalamic appetite-satiety centers.

ARC: arcuate nucleus, PVN: paraventricular nucleus, LHA: lateral hypothalamic area, NPY: neuropeptide Y AgRP: agouti related peptide, Y1: neuropeptide Y receptor type 1, MC4R: melanocortin receptor type 4, MCH: melanin concentrating hormone.