Adrenal glands
(glandula suprarenalis)
Bi1100en Hormones – Cellular and Molecular Mechanisms
▪ paired endocrine gland (triangular and crescent-shaped; human approx. 8 g)
▪ upper pole of the kidneys, common fat sheath (right kidney is lower)
▪ blood vessels directed through cortex to medulla (glucocorticoids > NA > A)
▪ fibrous capsula > septa + parenchyma:
1. Cortex - mesoderm
- steroid production
2. Medulla – neuroectoderm, neural crest
- catecholamine production
Adrenal glands
▪ up to 70 % of adrenal volume; rich blood supply:
zona glomerulosa (15 %) - oval groups of cylindrical cells, many capillaries
zona fasciculata (75 %) - polyhedral cells arranged radially
zona reticularis (10 %) - smaller cells with lipofuscin in the cytoplasm
Adrenal glands - structure of the cortex
▪ irregularly shaped cells grouped around blood vessels (sinusoids)
▪ chromaffin cells – granules stained with chromium and silver salts
▪ A-cells producing epinephrine / adrenaline
▪ NA-cells producing norepinephrine / noradrenaline
Adrenal glands - structure of the medulla
▪ cholesterol
converted to
pregnenolone
▪ stored only in small
quantities (de novo
synthesis)
▪ ACTH receptor
▪ enzymes:
21-hydroxylase
(mineralocorticoids)
17-hydroxylase
(glucocorticoids)
11-hydroxylase
Synthesis of steroid hormones in the adrenal glands
▪ deficiency of cholesterol or transport protein StAR (transfers cholesterol to the
mitochondria
▪ defects of enzymes catalyzing specific steps of biosynthesis (most often lack of
21-hydroxylase)
▪ a disorder of the partial step of synthesis usually leads to a reduction in the
production of hormones in the pathway behind the defect, but also to an increase
in the concentration of precursor steroids, including their hormonal activity
▪ there may be a loss of feedback; e.g. when the production of glucocorticoids is
impaired, the CRH-ACTH axis is not attenuated, it stimulates the adrenal glands,
where glucocorticoid precursors accumulate to a greater extent, but
glucocorticoids themselves are still missing
Disorders of steroid hormone synthesis in the adrenal
glands
Regulation of hormone production in the adrenal
glands
▪ endocrine (ACTH) >
StAR and steroidogenic
enzymes > cortical
hormones > negative
feedback loop
▪ renin-angiotensinaldosterone
system
(K+, Na+ concentration)
▪ sympathetic >
medullary hormones
▪ preferentially regulated
at the level of synthesis
and degradation; stored
minimally
Adrenal hormones
▪ mineralocorticoids
(aldosterone)
▪ glucocorticoids
(cortisol)
▪ androgens
▪ catecholamines
(adrenaline,
noradrenaline)
▪ adrenal cortex - zona glomerulosa
▪ aldosterone, corticosterone, 11-deoxycorticosterone
▪ most of aldosterone is transported freely in plasma (0.17 nmol/l) + low
amount is bound to protein transporters
▪ short half-life (20 min)
▪ cortisol also binds to aldosterone receptors (ineffective at normal
concentrations because it is converted to cortisone in target cells)
Regulation:
▪ ACTH stimulation, renin-angiotensin system (when blood volume and blood
pressure decrease)
▪ released at hyperkalemia
▪ inhibition by atrial natriuretic hormone / peptide (ANP)
Degradation:
▪ conjugated to glucuronic acid in the liver
▪ bile / fecal excretion, kidney
Mineralocorticoids:
aldosterone
▪ binding to nuclear receptors
(mineralocorticoid receptor)
and affecting gene expression
Effects:
▪ Na+ uptake in renal tubules >
water resorption through
osmotic gradient (synergy
with ADH x ANP antagonist)
▪ K+ and H+ excretion in kidneys
▪ Na+ uptake and K+ excretion
in the large intestine
▪ also targets sweat and
salivary glands, gallbladder
▪ increase the number of
Na+/K+ ATPases in cells
Increase in blood pressure
due to retention of Na+ in the
body.
Mineralocorticoids:
activity and action
Mineralocorticoids:
activity and action
▪ genomic (mineralcorticoid receptor) and non-genomic effect (EGFR, ERK1/2)
▪ epithelial Na+ channels (ENaC)
ENaC
Abundance
▪ most often due to increased renin release (see renin-angiotensin-aldosterone
system), such as kidney problems or dehydration
▪ adrenal tumors producing aldosterone (Conn‘s syndrome)
▪ adrenal defects (mineralocorticosteroid effects of high cortisol concentrations)
▪ due to increased hypervolemia hypertension occurs (in combination with the
effects of glucocorticoids abundance may lead to atherosclerosis)
▪ reduction in potassium concentration (hypokalaemia) leads to increased
neuromuscular excitability, cardiac disorders
Deficiency
▪ genetic defects, autoimmune inflammation, tumors, after operations, etc.
▪ hypokalaemia or malfunction of renin-angiotensin system
▪ high losses of Na+ in kidneys, retention of Mg2+ and H+ > hypotonic
dehydration, hypovolemia and decreased blood pressure
▪ high concentration of K+, H+ and Mg2+ and leads to a reduced neuromuscular
irritability and defects in neural conduction
▪ restricted renal flow causes increased production of renin and angiotensin
Mineralocorticoids: abundance (Cushing disease)
deficiency (Addison‘s disease)
▪ adrenal cortex – mainly zona fasciculata
▪ cortisol (hydrocortisone), smaller amount of cortisone
▪ regulated by CRH-ACTH axis
▪ negative feedback (cortisol) x stimulation by CRH and adrenaline
▪ cortisol secretion at 2-3 hour intervals + day/night rhythm (maximum in the
morning; opposite to melatonin) + response to stress and low blood glucose
▪ mostly binding and transport by globulin transcortin; small part free in plasma
and biologically active
▪ receptors in almost every tissue > diverse action
Glucocorticoids:
cortisol and corticosterol
140-700 nmol/l
▪ binding to nuclear receptors and changing gene expression
▪ mediates the adaptation of metabolism, blood circulation, immune system and
other tissues to stress
▪ catabolic effect in muscles, bones and adipose tissue x anabolic effect in liver
▪ increases blood glucose level
▪ stimulates protein degradation in liver and lipolysis of adipose tissue
(gluconeogenesis)
▪ glycogen storage (glycogenesis) in liver
▪ slows down development and growth of bones and muscles (catabolism and
decreased protein synthesis, e.g. collagen)
▪ enhancing the effect of catecholamines > stronger cardiac contraction and
vasoconstriction
▪ suppresses production of lymphokines (IL-12, IFN-α, IFN-γ, TNF-α), reduces
leukocyte counts, inhibits histamine release and stabilizes lysosomes > antiinflammatory
and anti-allergic effects (immunosuppressive effect)
▪ weakens the protection of the gastric mucosa (stress)
Glucocorticoids: activity and action
▪ most commonly the therapeutic administration of glucocorticoids to induce
immunosuppression
▪ tumors
▪ excessive stimulation of the adrenal glands by the CRH-ACTH axis
▪ cortisol increases the concentration of glucose in the blood, in extreme cases it
causes steroid diabetes associated with increased insulin production
▪ adipose tissue is redistributed by glucocorticoids and insulin > characteristic
obesity (moon face, buffalo neck)
▪ loss of muscles, osteoporosis, subcutaneous tissue breakdown (stretch
marks), increased vascular damage (purpura), impaired wound healing
▪ polyglobulinemia and increased blood clotting, higher risk of infection due to
immunosuppression
▪ hypertension, increased risk of atherosclerosis, thrombosis and clogging of
blood vessels
▪ inhibition of mucus production in stomach and increased secretion of
hydrochloric acid and pepsin > gastric and duodenal ulcers
Glucocorticoids: abundance (Cushing disease)
Glucocorticoids: abundance (Cushing disease)
moon face
purpuric
striae
▪ causes are the same as for mineralocorticoids, except for renin-angiotensin
stimulation
▪ decreased gluconeogenesis and increased glycolysis lead to hypoglycemia
▪ as a result of hypoglycemia, the sympathetic nervous system is activated and
adrenaline increases lipolysis, protein breakdown, cardiac activity and sweat
production > muscle weakness, tachycardia, sweating
▪ stomach and intestinal infections due to lower production of hydrochloric acid,
diarrhea and vomiting
▪ weakening of hematopoiesis (anemia)
▪ cortisol deficiency causes failure of negative feedback loop, so that a larger
amount of ACTH, including its precursor proopiomelanocortin (POMC), is
formed in the pituitary gland > production of α-melanotropin (α-MSH) >
increased skin pigmentation (Addison‘s disease is also referred to as
"bronzing")
Glucocorticoids: deficiency (Addison‘s disease)
▪ adrenal cortex - zona reticularis; furthermore, testicles and ovaries
▪ dehydroepiandrosterone and its sulphate, androstenedione and more
▪ low production > do not play a significant role in the organism
▪ in the adrenal glands, mainly precursors for the production of sex
hormones in the gonads are formed
▪ androgens transported from arenal glands to other organs (gonads)
Dehydroepiandrosterone
▪ mild masculinisation (in women) and anabolic effects
▪ premature puberty
Androgens
▪ adrenaline/epinephrine (A), noradrenaline/norep. (NA) derived from tyrosine
▪ hydroxylation and decarboxylation of tyrosine
▪ phenylethanolamine-N-methyltransferase (PNMT) methylates NA to form A
▪ NA converted to A in the cytoplasm
▪ NA and A stored in vesicles (chromaffin granules) > impulse > exocytosis
as peptide hormones
▪ adrenal medullary cells release endocrine A (95 %) and NA (5 %)
Catecholamines:
adrenaline (A) and noradrenaline (NA)
▪ sympathetic nerves stimulate production of hydroxylases in medulla:
stress situation > sympathetic signalling > acetylcholine release in synapses >
receptor signal > depolarization > Ca2+ influx through voltage-gated channels >
exocytosis of chromaffin granules > release of NA into the blood > reaction of
cells without direct sympathetic innervation
▪ stimulated by ACTH and cortisol (expression of PNMT)
▪ reuptake into nerve endings, diffusion from the synaptic cleft,
▪ half-life app. 2 min: enzymatic degradation, reuptake into synapses, diffusion
from synaptic cleft
▪ adrenaline is not regulated by negative feedback!
▪ NA suppresses dopamine production (negative feedback)
Catecholamines: regulation
adrenaline and noradrenaline
Catecholamines: activity and action
G protein-coupled
receptors in the
membrane of target cells
(adrenoreceptors)
intracellular pathway
hormone effect
▪ water-soluble hormone (A) and neurotransmitter (NA)
▪ four main types of adrenergic receptors for NA/A: α1, α2, β1, β2 (differences in
sensitivity) + β3 (lipolysis and oxidation of fatty acids)
▪ A it binds to all receptors, NA doesn't bind to β2
▪ all receptors act through G proteins
α1-adrenergic receptors:
▪ via PLC > IP3 > ↑Ca2+ and DAG > PKC
▪ ↑ sympathetic activity in the CNS, ↑ secretion in the salivary glands,
↑ glycogenolysis in the liver, ↑ smooth muscle contraction
▪ hyperpolarization in intestinal ducts > inhibition of gastrointestinal motility
α2-adrenergic receptors:
▪ inhibits adenylate cyclase and production of cAMP
▪ supports opening of voltage-dependent K+ channels (hyperpolarization)
▪ inhibition of exocytosis and secretion (e.g. salivery glands)
Catecholamines: activity and action
β1-adrenergic receptors:
▪ adenylate cyclase > production of cAMP > PKA > protein phosphorylation
▪ increase in blood pressure
▪ opening Ca2+ channels in heart muscle > ↑ heart rate transmission; ↑ renin
release in the kidneys
β2-adrenergic receptors:
▪ adenylate cyclase > cAMP > decrease of Ca2+ concentration (mechanism not
yet fully understood)
▪ dilatation of bronchioles and blood vessels in muscles, gastrointestinal
relaxation
Stress reaction (A):
▪ energy mobilization (lipolysis, glycogenolysis), ↑ glucose uptake in skeletal
muscle, increase in cardiac output and blood flow to organs other than the
digestive tract, support of the release of hormones controlling the recovery of
energy reserves (ACTH)
Catecholamines: activity and action
Kidneys (nephros)
▪ erythropoietin synthesis
▪ calcitriol synthesis (Ca2+ resorption in intestine and kidneys)
▪ eicosanoids production (prostaglandins)
▪ renin-angiotensin-aldosterone system
Erythropoietin:
▪ glycoprotein (34 kDa)
▪ half-life 5 hours
▪ produced in the kidneys and liver
▪ released in response to hypoxia
▪ receptors associated with tyrosine kinase
acitivity > phosphorylation of target proteins
▪ stimulation of erythropoiesis in bone marrow
Renal endocrine function
▪ peptidase renin (juxtaglomerular cells) secreted when the mean blood
pressure in the kidneys falls below 90 mmHg (renal baroreceptors) >
increase of plasma concentration
▪ angiotensinogen (453 AA) from liver converted to angiotensin (10 AA)
▪ angiotensin I converted to angiotensin II by cleaving 2 AA (ACE =
angiotensin-converting enzyme from lungs and endothelial cells)
▪ stimulates the production of aldosterone in the adrenal glands
Renin-angiotensin-aldosterone system (RAAS)
▪ stimulation of aldosterone synthesis in the adrenal glands
Renin-angiotensin-aldosterone system (RAAS)
Regulation:
▪ stimulated by acute decrease in plasma volume and blood pressure
▪ activated by α1-adrenoreceptors > higher mean blood pressure required for
renin secretion x β1-adrenoreceptors > lower mean blood pressure is
sufficient for renin secretion
▪ prostaglandin-stimulated renin secretion (PGI2, PGE2)
▪ negative feedback (angiotensin II and aldosterone)
Action:
▪ aldosterone reduces Na+ and water losses
▪ angiontensin II is strongly vasoactive (vasoconstriction)
▪ constriction in the renal blood vessels
▪ hypothalamus > thirst and taste for salty
▪ angiotensin II increases secretion of aldosterone, vasopressin (ADH) and
adrenaline
Renin-angiotensin-aldosterone system (RAAS)
Renin-angiotensin-aldosterone system (RAAS)
ACE = angiotensin-converting enzyme
Summary of the response to stress:
mobilization of energy stores and vasoconstriction