Adrenal Gland Flashcards
1
Q
The adrenal gland
A
- derived from the mesoderm
- secretes glucocorticoids, minearlocorticoids, and androgens
- note that mineralocorticoids is secreted by zona glomerulosa while glucocorticoids and androgens were secreted by zona fasciculata and zona reticularis
2
Q
Adrenal medulla
A
- derived from neural crest
- epinephrine, norepinephrine, dopa, and dopamine
- modified post-ganglionic sympathetic nerve cells
- total loss is not life threatening
3
Q
Hormone synthesis in adrenal cortex
A
- common precursor of adrenal cortical hormones is cholesterol, LDL cholesterol or de novo synthesized cholesterol
- except for cytosolic 3beta-hydroxysteroid dehydrogenase, the rest belong to the family of cytochrome P-450 oxidase
- the cholesterol to pregnenolone step is rate limiting (catalyzed by 20,22 desmolase, aka P450 side-chain cleavage enzyme)
4
Q
Aldosterone synthesis in zona glomerulosa
A
- glomerulosa layer lacks 17alpha-hydroxylase but has aldosterone synthase
- secretion of aldosterone by the adrenal is limited by the rate which the glomerulosa cells can synthesize the hormone
- once secreted 37% remains free in the plasma, the rest binds to CBG and albumin
- ma
5
Q
Action of aldoesterone
A
- the major action of aldosterone is to stimulate the kidney to reabsorb sodium and water and enhance potassium secretion. It has similar actions in the colon, salivary glands, and sweat glands
- in the target cells of the renal tubule, aldosterone increases the activity of several key proteins involved in sodium transport. It increases transcription of sodium-potassium pump and expression of apical sodium channels. The net effect of these actions is to increase sodium reabsorption and potassium secretion
6
Q
Effects of aldosterone
A
- increase Na(Cl) reabsorption from distal nephron segments
- increase potassium secretion by distal nephron segments
7
Q
Synthesis of cortisol and androgens
A
-fasciculata and reticularis layers lack aldosterone synthase but have 17-alpha hydroxylase
8
Q
Cortisol transport in plasma
A
- 90% bound to cortisol binding protein (CBP or transcortin)
- 7% bound to albumin
- 3% circulates “free”
9
Q
Androgen synthesis
A
- DHEA and androstenedione are two adrenal androgens. They are far less potent than testosterone or dihydrotestosterone. However, androstenedione can be converted to testosterone in the peripheral tissue
- DHEA reaches peak production in one’s 20s, decline start in early 30s and a 75 year old has 20% of a 25 year old. It is considered to be important for maintenance of sex drive in females after menopause
10
Q
Cortisol mechanisms of action
A
- free cortisol enters target cell by diffusion
- binds to cytoplasmic receptor
- migrates to the nucleus
- modulates gene transcription
- in feedback inhibition loop, cortisol inhibits the expression of CRH receptor and ACTH in the corticotrophs of the anterior pituitary
- cortisol inhibits transcription of POMC gene
11
Q
Metabolic effects of cortisol
A
- stimulates gluconeogenesis in the liver
- enhances protein breakdown in muscle cells to provide amino acid substrate for gluconeogenesis
- stimulates lipolysis in adipose tissue in the peripheral as alternative fuel to glucose. Curiously, some fat is deposited centrally for unknown reasons
- decreases osteoblastic activity in trabecular bone and interferes with Ca2+ absorption from gut
12
Q
Anti-inflammatory effects of cortisol
A
- inhibits production of cytokines
- inhibits production of chemo-attractant molecules
- stabilize lysosomal enzymes
- contributes to vasoconstriction and decreased capillary permeability
13
Q
Immunosuppressive effects of cortisol
A
- decreases lymphocyte production
- inhibits hypersensitivity reactions (especially cell-mediated
- also emotion instability (receptors are expressed in the brain)
14
Q
Glucocorticoid and Mineralocorticoid potency
A
Hydrocortisone- 1, 1 Prednisone- 3.5-5, 0.8 Prednisolone- 4, 0.8 Methylprednisolone- 5-7.5, 0.5 Dexamethasone- 25-80, 0 Triamcinolone- 5, 0 Fludrocortisone acetate- 15, 200 Aldosterone- 0.3, 200-1000
15
Q
Cellular action of ACTH and CRH
A
- ACTH binds with Melanocortin-2 receptor coupled to a G protein
- activate cAMP
- activate PKA
- increase the synthesis of several enzymes and increase activity of P450 scc
- CRH binds to CRH receptor
- activate AC part of G protein and increase cAMP
- activate PKA
- allow Ca2+ to come in
- ACTH vescile fuse
16
Q
Control of cortisol secretion
A
-the synthesis of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland with adrenocorticotropic hormone (ACTH) production of ACTH is in turn stimulated by corticotropin-releasing hormone (CRH), released by the hypothalamus
17
Q
CRH and CRH receptor
A
- CRH is 41 amino acid neuropeptide made in the paraventricular of the hypothalamus
- CRH receptors are G protein coupled receptors on the cell membrane of corticotroph cells
- hormone binding activates signaling through second messengers lead to a rise in intracellular calcium concentration which lead exocytosis of preformed ACTH
- prolonged CRH receptor activation also lead to increased gene transcription and synthesis of the ACTH precursor
18
Q
ACTH and ACTH receptor
A
- ACTH is 39 amino acid peptide hormone secreted by the corticotroph cells of the anterior pituitary
- it is produced by post-translational processing of a large precursor protein (a preprohormone) called POMC
- ACTH receptor is also a G protein coupled receptor called melanocortin-2 receptor
- the resulting increase in cAMP activates PKA, which phosphorylates a variety of proteins
- a rapid effect of ACTH is to stimulate the rate-limiting step in cortisol formation, that is, the conversion of cholesterol to pregenolone
- in addition, prolonged activation of the receptor increase the synthesis of several proteins involved in cortisol synthesis
19
Q
Feedback inhibition of cortisol
A
- circulating cortisol exerts negative feedback control on the release of both ACTH and CRH
- in the anterior pituitary, cortisol inhibits the expression of POMC gene and inhibits the release of presynthesized ACTH stored in vesicles
- in the hypothalamus, cortisol decreases the mRNA and peptide levels of CRH and inhibits the release of presynthesized CRH
20
Q
ACTH processing
A
- corticotrophs synthesize ACTH by complex post-translation processing of a large precursor protein called pro-opiomelanocortin (POMC), a precursor for several peptides hormones
- in the anterior pituitary, processing of POMC gives rise to ACTH, and beta-lipotropin
- during fetal life and pregnancy, the intermediate pituitary lobe processes POMC to yield different hormones including alpha-MSH and beta endorphin
21
Q
Circadiuam rhythm and cortisol secretion
A
- amount of cortisol present in the serum undergoes diurnal variation, with the highest levels present in the early morning and lower levels in the evening
- info about the light/dark cycle is transmitted from the retina to the suprachiasmatic nucleus of the hypothalamus which controls the circadium rhythms of the body
- CRH release from hypothalamus is in pulses which results pulsatile secretion of ACTH
- the greatest ACTH secretory activity occurs in the morning hours and diminishes late in the afternoon and early evening
- rhythmic secretion of ACTH directly controls the diurnal variation of cortisol production
22
Q
Stress and cortisol secretion
A
- physical, psychological and biochemical stresses enhance CRH secretion and thus enhanced ACTH secretion which result in increased secretion of cortisol
- for example, hypoglycemia stimulates the secretion in both CRH and ACTH which leads to increased release of cortisol that tend to raise blood glucose levels
23
Q
21alpha hydroxylase deficiency
A
- genetic mutuation (1:7000) causes decreased production of cortisol and aldosterone
- increased ACTH production (negative feedback gone)
- adrenal hyperplasia, increased androgen production, ambiguous genitalia in females
- elevation of 17-hydroxprogesterone nefore and after ACTH, diagnosis by molecular genetic analysis of CYP21 gene
- glucocorticoids like prednisolone and dexamethsaone provide a substitute for cortisol reducing ACTH levels, reduces stimulus for continued hyperplasia and overproduction of androgens
- mineralocorticoids are replaced in all infants with salt wasting and in most patients with elevated renin levels
- Fludrocortisone is treatment
24
Q
Consequences of 21-alpha hydroxylase deficiency
A
- Decreased aldosterone synthesis
- Loss of salt, hypotension, dehydration
- Decreased cortisol synthesis
- Hypoglycemia, increased size of adrenal gland = hyperplasia
- Increased androgen synthesis
- Virilizing effect in males, ambiguous genitalia in females
25
17-alpha hydroxylase deficiency
- Biochemical consequences:
- reduced cortisol and androgen synthesis
- increased cortisterone (a weak glucocorticoids, which mitigates the adrenal insuffiency) and aldosterone, which causes hypertension and hypokalemia
- reduced estrogen synthesis (in the ovary)
Clinical symptoms: hypertension, hypokalemia, sexual infantilism in genetic females, pseudohermaphorditism and sexual infantilism in genetic males
Hormone replacement therapy:
- hypertension and mineralocorticoid excess os treated with glucocorticoid replacement
- genetic females need estrogen treatment. Genetic males may need surgery or testosterone treatment
26
Consequences of 17-alpha hydroxylase deficiency
- increased aldosterone synthesis
- hypertension, hypokalemia
- decreased cortisol synthesis (but increased corticosterone
- increased size of adrenal gland = hyperplasia
- decreased androgen synthesis
- sexual infantilism in females, pseudohermaphrodistism in males
27
Cushing's syndrome
- hypercortisolism or hyperadrenocorticism
- occurs when the body's tissues are exposed to excessive levels of cortisol for long periods of time
- it is often caused by prolonged use of immunosuppression drugs such as prednisone, adrenal tumors and tumors that increase ACTH such as pituitary adenomas, ectopic ACTH syndromes
- Cushing's syndrome refers to excess cortisol of any etiology
- Cushing's disease refers only to hypercortisolism secondary to excess production of adrenocorticotropin (ACTH) from a pituitary gland adenoma
28
Symptoms of Cushing's syndrome
- moon face, florid complexion (red face), upper body obesity, rounded face, increased fat around the neck, and thinning arms and legs
- change in body fat distribution
- skin thinning and fragility
- osteopenia
- increased frequency and severity of infections
- muscle wasting and weakness
- glucose intolerance
- hypokalemia and hypertension
29
Diagnosis of Cushing's disease
- urinary or salivary cortisol measurement
- Dexamethasone suppression test
- adrenal tumor- high cortisol low ACTH
- ACTH producing tumor- high cortisol and ACTH
-treatment: surgery to remove adrenal adenoma or ACTH producing adenoma. If both adrenals are removed repalcement with hydrocortisone or prednisolone is imperative
30
Addison's Disease
- hypoadrenal function
- failure of the adrenal glands to produce enough cortisol
- in primary adrenal insufficiency (classical Addison's disease) the hormone aldosterone is also deficient
- many symptoms due to hyposecretion of aldosterone leading to hyperkalemia
- adrenaline is also diminished or elimitated
- most addison's disease are due to autoantibodies directed against adrenal cells containing 21-hydrolase
31
Diagnosis and Treatment of Addison's disease
- determine if sufficient levels of cortisol
- ACTH stimulation test- insufficiency is after injection of ACTH is no response in blood and urine cortisol levels
- CRH stimulation test: inject CRH, cortisol and ACTH in the blood are measured before and after. Patients with primary adrenal insufficiency have high ACTHs but do not produce cortisol. Patients with secondary adrenal insuffiency have deficient cortisol responses but absent or delayed ACTH responses
Treatment- replacing missing cortisol, and fludrocortisone as replacements for missing aldosterone
