51 Adrenal Gland Physiology (W) Flashcards
Identify and describe adrenal anatomy, its substructures (zones) and their role in adrenal hormone synthesis.
- Adrenal cortex made up of 3 functional zones:
- Zona glomerulosa – cells have angiotensin II receptors and contain aldosterone synthase. Regulated by angiotensin and K+
- Zona fasciculata – responsible for production of cortisol - Zona reticularis – responsible for production of adrenal androgens (DHEA and androstenedione)
- Adrenal Medulla: innervated by sympathetic system and produces norepinephrine/epinephrine
Zona Glomerulosa – mineralcorticoid: aldosterone
Zona Fasciculata – glucocorticoids: cortisol and corticosterone
Zona Reticularis – androgens: dehydroepiandrosterone (DHEA) and androstenedione
Recognize and describe the biosynthetic pathways and metabolism of the adrenal steroids.
- ACTH promotes uptake of cholesterol and activation of side-chain cleavage enzyme complex. ACTH has its primary affects on the inner 2 zones of the adrenal cortex. An increase in ACTH will transiently increase mineralcorticoid (aldosterone) production, but will eventually revet back to normal after a short period (ACTH Escape). Chronic deficiency of ACTH only mildl affects zona glomerulosa. There is a picture of the pathways in his handout…but I’m more willing to lose a point then learn them.
- ACTH results in aldosterone, cortisol, and androstenedione…and estradiol
Identify the key metabolic enzymes in the synthesis of the adrenal hormones and the sequelae of a
deficiency in each.
All are derived from cholesterol. Cholesterol is moved into the mitochondria via the steroid acute regulatory (STAR) protein. Cholesterol then converted to pregnenolone by p450cc (is rate limiting step limited by ACTH).
Just need to know enzymes, intermediates are board-relevant though.
Mineralcorticoids – pregnenolone converted to progesterone by 3beta-hydroxysteroid dehydrogenase. Progesterone converted to DOC by 21-hydroxylase. DOC converted to corticosterone by 11beta-hydroxylase. Aldosterone synthase then turns corticosterone into Aldosterone.
Glucocorticoids – pregnenolone is converted to 17-OH pregnenolone by 17alpha-hydroxylase and 17, 20 lyase. 17-OH pregnenolone converted to 17-OH progesterone by 3beta-hydroxysteroid dehydrogenase. 17-OH progesterone converted to 11-Deoxycortisol by 21 hydroxylase. 11-deoxycortisol then converted to cortisol by 11beta-hydroxylase.
Adrenal Androgens – pregnenolone converted to 17-OH pregnenolone by 17alpha hydroxylase and 17, 20 lyase. 17-OH pregnenolone converted to DHEA again by 17alpha hydroxylase and 17, 20 lyase. 17-OH progesterone can be converted to androstenedione by 17alpha hydroxylase and 17, 20 lyase also.
Recognize and describe the mechanisms, regulation of production and actions of the
glucocorticoids. (cortisol)
- Carbohydrate metabolism: increased gluconeogenesis (due to not being able to use insulin very well…need a place for all of the glucose to go), decrease glucose utilization, increase glycogen formation. Increased glucose leads to increased insulin release.
- Protein metabolism: increased beakdown, decrease synthesis
- lipid metabolism: increase free FA, increase lipid breakdown
- diminished immune system
- anti-inflammatory by inhibiting phospholipase A2 diminished vascular permeability
- Promotes bone resorption
- lung maturation in the fetus
Recognize and describe the mechanisms, regulation of production and actions of the
mineralcorticoids. (Aldosterone)
- Stimulated by Angiotensin II and K+
- Intracellular receptors bind cortisoland aldosteron. 11beta dehydrogenase leads to specificity of aldosterone due to the enzyme changing cortisol cortisone (which doesn’t bind the receptor)
- Aldosterone promotes Na reabsorption water reabsorption. This is at the expense of K+ by way of Na/K/H exchange
- Decreased K+ will hinder aldosterone production and vice-versa
- Recognize and describe the mechanisms, regulation of production and actions of the adrenal
androgens.
- Easily converted to TESTOSTERONE or ESTROGEN by tissue aromatase
- Males: in adolescense an excess early puberty. Also could get peripheral conversion to estrogen causing some feminization of males.
- Females: important in maintaining normal pubic/axillary hair. Good source of estradiol for Post-menopause. Excess androgens can lead to hirsuitism/masculinization
Recognize and describe the pathological consequences of excess and deficiency of the adrenal
hormones.
- Addison’s Disease: adrenocortical steroid production is low due to insufficiency but ACTH levels are high (no neg feedback). Causes pigmentation due to alphaMSH
- Cushing’s syndrome: cortisol excess by disease or prolonged drugs. Osteoporosis, increased susceptibility to infection common side effects.
- Conn’s Disease: Adrenal mineralcorticoid excess. Low renin and high aldosterone (lots of diseases can cause this and is obvious in the name) or elevated renin and high aldosterone.
- Pheochromocytoma: high levels of catecholamines, most secrete norepinephrine. Sustained/episodic hypertension, sweating, palpitaitons, hyperglcemia, glycosuira.
Describe the control mechanisms of the hypothalamus-pituitary-adrenal (HPA) axis
The hypothalamus receives signals of stress, diurnal signals, and signals from stressors like fever etc. It releases CRH which binds to a receptor on the ant. pit. corticotroph cells. Leads to exocytosis of ACTH which binds to Melanocortin 2 receptor (MC2R) on the plasma memb. of the adrenal cortex. Leads to elevated cholesterol into steroidogenesis pathway. Results in increase of serum cortisol levels. ACTH released in a pulsatile fashion, also follows circadian rhythm where there is a greatest release of cortisol just before and after waking. Very low cortisol around midnight.
Cortisol exerts neg feedback on HPA axis by binding to glucocorticoid receptors on the ant. pit. and hypothalamus. Inhibits synth of CRH and ACTH.
Demonstrate knowledge of the function of 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, 21-hydroxylase,
and 11β-hydroxylase by determining how a deficiency of each of these enzymes would affects levels of aldosterone, cortisol, and adrenal androgens.
see picture in notes
Describe the physiological effects of cortisol and aldosterone
Cortisol – increased blood glucose, inhibits immune system, decreases fibroblast proliferation (leads to decreased connective tissue), increased bone matrix reabsorption and calcium excretion. Increased glycogen deposition in liver by increased glycogen synthase and decreased glycogen phosphorylase. Increased expression of receptors for epinephrine and norepinephrine -> increased cardiac output. Increased expression of enzyme which converts norepinephrine to epinephrine.
Aldosterone – Increases blood vol. and pressure. Increases Na and H2O reabsorption and decreases K reabsorption.
Describe the mechanisms by which cortisol increase plasma glucose levels.
In liver, Increased gluconeogenesis and glycogenesis. In skel. muscle decreased gluc uptake and increased glycogenesis and protein catabolism. In adipose, decreased gluc uptake and increase lipolysis.
Describe the mechanism by which aldosterone increases water and sodium reabsorption.
Binds to and activates mineralocorticoid receptors (MR) in distal convoluted tubule and collecting ducts cytoplasm. MR translocates to nucleus to increase gene transcription of ENaC and Na/K pumps. ENaC transports Na into cell and Na/K ATPase transports it out to blood. Water follows Na.
Identify the catecholamines released by the adrenal medulla.
Epinephrine and Norepinephrine.
Identify the mechanisms by which cortisol facilitates the effects of norepinephrine and epinephrine.
Cortisol induces expression of receptors for norep and ep.
Identify and describe the causes, symptoms, and pathophysiology of Cushing’s syndrome.
Pituitary hypersecretion of ACTH – leads to over secretion of cortisol (called Cushing’s disease)
Adrenal Adenoma – hypersecretion of cortisol and neg feedback on pit so low ACTH
Ectopic ACTH Production – occurs in lung cancer.
Iatrogenic Cushing’s syndrome – prescribed cortisol can cause this
