Adrenal steroidogenesisAdrenal steroidogenesis

Dr Mohammad Waseem Kausar Dr Mohammad Waseem Kausar

Assistant ProfessorAssistant Professor

IMDC , BiochemistryIMDC , Biochemistry

Adrenocorticotropic Hormone Adrenocorticotropic Hormone (ACTH, corticotropin)(ACTH, corticotropin)

The Adrenal GlandThe Adrenal Gland

Figure 18.16

ADRENAL (SUPRARENAL) GLANDS

Location

Cortex vs. medulla

Cortex = steroids

Medulla = catecholamines

sympathetics

norepinephrine and epinephrine

fight-or-flight

adrenal cortex

adrenal medulla

adrenal gland

kidney

The Adrenal Cortex Has Three The Adrenal Cortex Has Three Distinct LayersDistinct Layers..

Synthesizes many steroids but 3 classes of Synthesizes many steroids but 3 classes of hormoneshormones; glucocorticoids,; glucocorticoids,

mineralocorticoids mineralocorticoids and and androgensandrogens Cortex divided into three layersCortex divided into three layers

Zona glomerulosa (produces mineralocorticoids)Zona glomerulosa (produces mineralocorticoids) Zona fasciculate (produces glucocorticoids)Zona fasciculate (produces glucocorticoids) Zona reticularis (produces androgens)Zona reticularis (produces androgens)

Adrenal cortex Adrenal cortex

ADRENAL CORTEX (ZONA GLOMERULOSA)

Mineralocorticoids (aldosterone)

Electrolyte and fluid balance

Aldosterone secretion in response to either:high blood [K+] (hyperkalemia)

renin-angiotensin system

Actions:

decreased K+ reabsorption by kidneys

Increased Na+ reabsorption by kidneys

ADRENAL CORTEX (ZONA FASCICULATA and reticularis)

Glucocorticoids (cortisol, hydrocortisone, cortisone)

Stress C-RF ACTH glucocorticoids

Actions:

Promote normal metabolism (increased glucose availability)

Resistance to stress (increased alertness, energy, blood pressure)

Anti-inflammatory (membrane stabilization)

ACTHACTH CRH controls its secretion from hypothalamusCRH controls its secretion from hypothalamus Two forms Two forms αα and and ββ ProOpiomelanocortin (POMC, "Big Mama") ant-ProOpiomelanocortin (POMC, "Big Mama") ant-

pitutary.pitutary. Regulates the growth and function of adr-cortexRegulates the growth and function of adr-cortex ACTH stimulates the adrenal cortex. More ACTH stimulates the adrenal cortex. More

specifically, it stimulates secretion of specifically, it stimulates secretion of glucocorticoids such as cortisol glucocorticoids such as cortisol

has little control over secretion of aldosterone, has little control over secretion of aldosterone, the other major steroid hormone from the the other major steroid hormone from the adrenal cortexadrenal cortex

Corticotropin-releasing hormoneCorticotropin-releasing hormone

corticoliberincorticoliberin, a , a polypeptide  hormone  and   and neurotransmitter  

involved in the involved in the stress response.. 41-amino acid peptide derived from a 191-41-amino acid peptide derived from a 191-

amino acid preprohormone. amino acid preprohormone. Marked reduction in CRH has been observed in Marked reduction in CRH has been observed in

association with association with Alzheimer's disease, and , and autosomal recessive hypothalamic corticotropin autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially-fatal deficiency has multiple and potentially-fatal metabolic consequences like hypoglycemia and metabolic consequences like hypoglycemia and hepatitis hepatitis

CRH is produced by (paraventricular nucleus) of CRH is produced by (paraventricular nucleus) of the hypothalamus and is released at the median the hypothalamus and is released at the median eminence from neurosecretory terminals of these eminence from neurosecretory terminals of these neurons into the primary capillary plexus of the neurons into the primary capillary plexus of the hypothalamo-hypophyseal portal systemhypothalamo-hypophyseal portal system

. The portal system carries the CRH to the anterior . The portal system carries the CRH to the anterior lobe of the pituitary, where it lobe of the pituitary, where it stimulates corticotropes to stimulates corticotropes to secrete corticotropin (ACTH) and other biologically secrete corticotropin (ACTH) and other biologically active substances (for example β-endorphin)active substances (for example β-endorphin)

ACTH is a single PP, containing ACTH is a single PP, containing 39 AA39 AA, , ACTIVE COREACTIVE CORE =1 =1stst 23 AA 23 AA from the N terminal while from the N terminal while 24 -39 AA s24 -39 AA stabilizes the molecules and tabilizes the molecules and

varies in composition from species to speciesvaries in composition from species to species

Mechanism of action of ACTHMechanism of action of ACTH

METABOLIC ROLE OF METABOLIC ROLE OF ACTHACTH

act on adrenal cortex & extra adrenal tissuesact on adrenal cortex & extra adrenal tissues affects both basal secretion & under stress affects both basal secretion & under stress

secretion of glucocorticoid.secretion of glucocorticoid. ACTH increases the synthesis & secretion from ACTH increases the synthesis & secretion from

adrenal cortex.adrenal cortex. ACTH has a profound changes in ACTH has a profound changes in

1 adrenal structure1 adrenal structure

2 chemical composition2 chemical composition

3 enzymatic activity3 enzymatic activity

Specific receptors on fascicularisSpecific receptors on fascicularis It stimulates the It stimulates the synthesissynthesis & & secretionsecretion of of

GlucocorticoidGlucocorticoid11,, increases the transfer of cholesterol from increases the transfer of cholesterol from plasma lipoprotein into cellsplasma lipoprotein into cells22, cAMP, phosphorylation & activation of , cAMP, phosphorylation & activation of cholesterol esterase thus free choles.cholesterol esterase thus free choles.33, it promotes the binding of cholesterol to mito- , it promotes the binding of cholesterol to mito- cyt- P450, which is required for hydroxylation.cyt- P450, which is required for hydroxylation.44, it activates dehydrogenase of HMP to increase , it activates dehydrogenase of HMP to increase the concentration of NADPH for hydroxylationthe concentration of NADPH for hydroxylation55 it activates the hormone sensitive lipase it activates the hormone sensitive lipase lipolysis FFA lipolysis FFA

Feed back control of ACTH Feed back control of ACTH

Basic structureBasic structure

Cholesterol side chain cleavage and basic steroid Cholesterol side chain cleavage and basic steroid hormone structurehormone structure

Synthesis of three major classes of adr- steroidSynthesis of three major classes of adr- steroid

MINERALOCORTICOIDSMINERALOCORTICOIDS Are C21 steroidsAre C21 steroids Influences the metabolism of Na & KInfluences the metabolism of Na & K Chief is Aldosterone, others are Chief is Aldosterone, others are

CortocosteroneCortocosterone 11- deoxycortisol11- deoxycortisol 11- deoxycorticosterone11- deoxycorticosterone

Metabolic roles of Metabolic roles of ALDOSTERONEALDOSTERONE

1, Na reabsorption1, Na reabsorption From DCT, CT and loopFrom DCT, CT and loop

2, chloride ions reabsorption2, chloride ions reabsorption secondarily to Nasecondarily to Na

3, K excreation3, K excreation

(hypokalemia--- muscle paralysis)(hypokalemia--- muscle paralysis)

4, effect on acid base balance(alkalosis)4, effect on acid base balance(alkalosis)

5, effect on blood volume5, effect on blood volume

Metabolic role of theGlucocorticoids

Generally Anti-insulin Catabolic to peripheral tissues Anabolic to liver

EFFECT ON CHO Hyperglycemia Decreased glucose uptake by muscles, adipocites and lymphoid

tissues by inhibiting membrane transport Rate of gluconeogenesis as much as 6- to 10-fold in liver.

• induces key enzymes of gluconeogenesis• Increasing protein catabolism in extrahepatic tissues by synthesis of

amino acid catabolic enzymes like transaminases• Decreasing amino acids incorporation in proteins

.

Cont-Cont- effect on lipid metabolismeffect on lipid metabolism• Net effectNet effect increase FFA and GLYCEROL increase FFA and GLYCEROL• Lipolysis by activating hormone sensitive TG lipaseLipolysis by activating hormone sensitive TG lipase effect on protein metabolismeffect on protein metabolism In extrahepatic tissues it is catabolic to proteinsIn extrahepatic tissues it is catabolic to proteins In liver it is anabolic byIn liver it is anabolic by

1, inc- A A uptake1, inc- A A uptake2, inc- incorporation of A A into ribosomal proteins2, inc- incorporation of A A into ribosomal proteins3, inc- m-RNA , inc- plasma proteins3, inc- m-RNA , inc- plasma proteins4, inc- urea synthesis by inc- necessary enzymes4, inc- urea synthesis by inc- necessary enzymes

ACTH pathophysiologyACTH pathophysiology Weak MSH like activity ----- hyper pigmentation Weak MSH like activity ----- hyper pigmentation Excessive production by pituitary or by tumor Excessive production by pituitary or by tumor

results in results in Cushing’s syndromeCushing’s syndrome. Manifestation are . Manifestation are due to excessive adrenal steroids includes due to excessive adrenal steroids includes

1,negative nitrogen, K1,negative nitrogen, K+ + and Phosphorus balanceand Phosphorus balance

2,sodium retention------- hypertention, oedema2,sodium retention------- hypertention, oedema

3,diabetes mellitus3,diabetes mellitus

4,inc- FFA4,inc- FFA

5,dec- lymp.5,dec- lymp.

Muscular atrophy, truncal obesityMuscular atrophy, truncal obesity

Enzymatic deficiencyEnzymatic deficiency Congenital defect ; dec- cortisol secretion Congenital defect ; dec- cortisol secretion

and and CAHCAH

1, Gene defect for protein in gonads and 1, Gene defect for protein in gonads and adrenals, for movement of cholesterol into adrenals, for movement of cholesterol into mitoc-.(cause of sever CAH)mitoc-.(cause of sever CAH)

2,. Cholesterol desmolase def-.2,. Cholesterol desmolase def-.

fatal in utero b/c placenta can not synthesis fatal in utero b/c placenta can not synthesis progesteroneprogesterone

Common defects areCommon defects are

21 21 ββ hydroxylase hydroxylase def-.def-.

90–95 % cases of CAH.90–95 % cases of CAH.Virilization( ACTH)Virilization( ACTH)Enough gluco & minera-Enough gluco & minera-Sustain lifeSustain lifeIn sever casesIn sever casesMasculinizationMasculinizationFemale pseudohermo-.Female pseudohermo-.Salt loosing Salt loosing

11 11 ββ hydroxylase def- hydroxylase def-1% of cases1% of casesvirilization ( ACTH)+virilization ( ACTH)+Excess sec- of 11- Excess sec- of 11-

deoxy cortisol &11- deoxy cortisol &11- deoxy corticosterone deoxy corticosterone

salt & water retentionsalt & water retention hypertensivehypertensive