Mineralocorticoids & glucocorticoids

NSB 212: Endocrine, Reproductive and Urinary System

TOPIC : Corticosteroids• GLUCOCORTICOIDS• MINERALOCORTICOIDS

Dr. G.K. Maiyoh

GKM/NSB212/ENDOCRINE,REPRO AND URINARY SYS. 2013

Learning objectives

• Define the endocrine sys, hormones, corticosteriods, glucocoticoids and mineralocorticoids

• Suprarenal gland and hormone production

• Corticosteroid biosynthesis

• Roles of Corticosteroids and mechanism of action

• Renal Biochemistry


Endocrine system (ES)

The ES together with the nervous system, acts as the body´s communication network

- It is composed of various endocrineglands and endocrine cells


Endocrine system- The glands are capable

of synthesizing and releasing special chemical messengers - hormones

• Unlike the nervous system, the endocrine system is anatomically discontinuous.


Hormones • Are substances which are secreted by

specialised cells in very low concentrations and they are able to influence EITHER; secreting cell i tself (autocrine influence), adjacent cells (paracrine influence) or remote cells (hormonal influence)


Corticosteroids• Hormones that are produced from the Adrenal

cortex

• They are synthesized from enzymatic modification of cholesterol

• Two categories;– Glucocoticoids– Mineralocorticoids

– Similar structurally but dramatically different functionally

Cholesterol


Suprarenal Glands• Also called Adrenal glands

• 4grams each

• Divided into two parts;

each with separate functions

– Suprarenal Cortex

– Suprarenal Medulla


The Adrenal Cortex

Figure 25.9aGKM/NSB212/ENDOCRINE,REPR

O AND URINARY SYS. 2013

Glucocorticoids - defined

• Are so referred because they were seen to increase the levels of plasma glucose

• Made in the fasciculata and reticularis layer near cortical medullary junction

• Cortisol is the major glucocorticoid

• Cortisol deficiency can therefore result in hypoglycemia (below normal levels of blood glucose)


Glucocorticoids

Cortisol (Hydrocortisone)

Corticosterone

Cortisone

• Glucocorticoids • Glucocorticoids (naturally

occurring; cortisol -- hydrocortisone)

• · Pharmacokinetics:

• Synthesis:

• § major glucocorticoid: cortisol

• § precursor: cholesterol

Cholesterol

Pregnenolone

Progesterone

Corticosterone

11-Deoxy-corticosterone

18-Hydroxy- corticosterone

ALDOSTERONE

17-α- Hydroxy pregnenolone

11- Deoxy- cortisol

17- Hydroxy progesterone

21,β hydroxylase

CORTISOL

11,β hydroxylase

Dehydro-epi androsterone

Andro-stenedione

Oestrone

Oestriol

TESTOSTERONE OESTRADIOL

ACTH BIOSYNTHESIS17 α-Hydroxylase

17 α-Hydroxylase

DE


Enzymes for Aldosterone synthesis DE Deh. Cholesterol Pregnenolone Progesterone

(21)

Aldosterone (18) corticosterone (11) Deoxy-

corticosterone

DE= debranching enzyme; side chain cleavage enzyme; desmolase

Deh.= 3β-hydroxysteroid dehydrogenase enzyme

21 = 21α hydroxylase

11 = 11 β-hydroxylase

18 = Aldosterone synthase


physiology

Figure 21.15


physiology

• The hypothalamus releases a hormone called corticotropin-releasing-hormone (CRH).

• The CRH then travels directly to the pituitary gland where they cause the release of adrenocorticotropic hormone (ACTH).

physiology

• ACTH is released into the bloodstream.

• Once in the blood, ACTH travels to the adrenal cortex where it effects the release of corticosteroids.

physiology

• However, as well as these excitatory processes, there are also inhibitory influences within the Hypothalamopituitary adrenal (HPA).

• These inhibitory influences act on CRH neurons and also in the pituitary.

• The result of such inhibitions is to reduce the release of ACTH.

Mechanism of Action:

• Glucocorticoid action through glucocorticoid receptors

75% of cortisol bound to plasma proteins

cortisol half-life: about 60-90 minutes

Cortisol metabolism:

--20% converted to cortisone (by renal/other tissues with mineralocorticoid receptors)

• --- Catalyzed by 11-hydroxysteroid dehydrogenase ---Cortisol and cortisone inactivated in the liver by

conversion (3-hydroxysteroid dehydrogenase catalyzed)

Some metabolites ultimately excreted in the urine as 11-oxy, 17-ketosteroids

---Some metabolites undergo hepatic conjugation to form glucuronic acid or sulfate derivatives

Physiological effects of glucocorticoids

Major metabolic effects: due to direct cellular action

• ---Some effects:secondary to homeostatic insulin and glucagon responses

Physiological responses modulated by glucocorticoids ("permissive" effects)

• --- catecholamine vascular/bronchial smooth muscle response:

Metabolic Effects Glucocorticoids: stimulate and are required

for: ---gluconeogenesis (fasted state, diabetes); ---increasing hepatic and renal amino acid

uptake --- increase gluconeogenic enzyme activity Hepatic effects: --- Simulation of glycogen synthase - ---Increase glucose production from protein- --- stimulating insulin release

Metabolic Effects

Adipocytes: —inhibit glucose uptake promoting increased lipolysis — counteracted by enhanced insulin secretion which

stimulates lipogenesis Glucocorticoid effects are most prominent in the fasting

state, through: —stimulation:gluconeogenesis — stimulation: amino acid release from muscle

(catabolism) —inhibition: peripheral glucose uptake — stimulation: lipolysis

promotion of catabolism: —lymphoid tissue — connective tissue — muscle — fat — skin High (supraphysiologic) glucocorticoid levels cause: — decreased muscle mass, weakness Reduced growth in children (not prevented by growth

hormone)

Catabolic Effects

Catabolic effects on bone • ---osteoporosis in Cushing's syndrome • ----major limitation in long-term use • Osteoporosis:

A disease in which the bones become extremely porous, are subject to fracture, and heal slowly

Glucocorticoids, Catecholamines, etc..

Muscle: Net loss of aminoAcids (glucose)

Liver: Deamination of

amino acids, gluconeogenesis

(glucose)

Fat Cells: Free fatty

acid mobilization

Heart rate: Increased

Immune system: altered

Adrenals

Kidney

Posterior Pituitary Gland

Hypothalamus

AnteriorPituitary Gland

ACTH

Stress Circadian

rhythm

CRH

(-)

Glucocorticoids, Catecholamines, etc..

Hypothalamopituitary adrenal (HPA) axis: Negative Feedback


Mineralocorticoids

• Synthesized in the glomerulosa

• Aldosterone is the major mineralocorticoid hormone

• Considered mineralocorticoid because it promotes salt and water retention in the kidneys

• Steriod hormones: Glucocorticoids, mineralocorticoids and sex steroids


Functions of mineralocorticoids• Aldosterone exerts the 90% of the

mineralocorticoid activity. Cortisol also have mineralocorticoid activity, but only 1/400 th that of aldosterone

• Aldosterone increases renal tubular (principal cells) reabsorption of sodium & secretion of potassium

• Excess aldosterone ↑ ECF volume & arterial pressure, but has only a small effect on plasma sodium concentration



Body Fluid Compartments

• In lean adults, body fluids constitute 55% of female and 60% of male total body mass– Intracellular fluid (ICF) inside cells

• About 2/3 of body fluid

– Extracellular fluid (ECF) outside cells• Interstitial fluid between cell is 80% of ECF

• Plasma in blood is 20% of ECF– Also includes lymph, cerebrospinal fluid, synovial fluid,

aqueous humor, vitreous body, endolymph, perilymph, pleural, pericardial, and peritoneal fluids


Body Fluid Compartments

• Excess aldosterone causes hypokalemia & muscle weakness, & too little aldosterone causes hyperkalemia & cardiac toxicity

• Excess aldosterone increases tubular (intercalated cells) hydrogen ion secretion, with resultant mild alkalosis

• Aldosterone stimulates sodium & potassium transport in sweat glands, salivary glands, & intestinal epithelial cells

Functions of mineralocorticoids


Effect of cortisol on protein metabolism

• Reduction of protein storage in all cells except those of liver – ↑ protein catabolism & ↓ protein synthesis

• Cortisol increases liver & plasma proteins

• Mobilizes aminoacids from non hepatic cells, thus increase blood amino acid level.

• ↑ amino acid transport to liver cells & ↓ transport of amino acids into other cells

Functions of glucocorticoids


Mechanisms of action


Corticosteroids are Gene-Active


Effects of Stress and The Adrenal Glands


REGULATION OF CORTISOL SECRETION

INCREASEDBLOOD GLUCOSEBLOOD AABLOOD FATTY ACIDS

HYPOTHALAMUS

CRH

ANTERIOR PITUITARY

ACTH

ADRENAL CORTEX

TARGET ORGANSCORTISOL

STRESSDIURNALRHYTHM

+ +-

- NegativeFeed-back


Renal Biochemistry (Mineralocorticoids role)

Renin-angiotensin-aldosterone axis

Angiotensinogen Renin

Angiotensin I ACE

Angiotensin II

Aldosterone

ACE = Angiotensin converting enzyme

Renin-angiotensin-aldosterone axis

• Principal factor controlling Ang II levels is renin release.

• Decreased circulating volume stimulates renin release via:– Decreased BP

(sensed by JGA).– Decreased [NaCl] at

macula densa (“NaCl sensor”)

– Decreased renal perfusion pressure (“renal” baroreceptor) GKM/NSB212/ENDOCRINE,REPR

O AND URINARY SYS. 2013

Figure 6.12b


• Atrial natriuretic peptide

• Decreased blood pressure stimulates renin secretion


Renin

Aldosterone

Adrenalcortex

Corticosterone

Angiotensinogen

(Lungs)

↓ renal blood flow &/or ↓ Na+

++ Juxtaglomerular apparatus of kidneys(considered volume receptors)

Angiotensin I Convertingenzymes

Angiotensin II(powerful vasoconstrictor)

Angiotensin III(powerful vasoconstrictor)

• Renin-Angiotensin System:

N.B. Aldosterone is the main regulator of Na+ retention.

Renin-Angiotension-Aldosterone System

Disorders of the Adrenal Gland

1. Hypoaldosteronism

results in excess loss of water/Na+

Addison’s disease – low aldosterone & cortisol

2. Hyperaldosteronism

3. Cushing’s syndrome

hypersecretion of cortisol,androgens,aldosterone


Adrenal glands can malfunction

• Cushing syndrome – hypersecretion of glucocorticoids by the adrenal cortex characterized by weight gain in the trunk of the body but not arms and legs1`


Cushing’s Disease• Proximal muscle wasting &

weakness

• Osteoporosis• Glucose intolerance• HTN, hypokalemia

• Thromboembolism• Depression, Psyc• Infection

• Glaucoma


Adrenal glands can malfunction

• Addison’s disease – hyposecretion of glucocorticoids by the adrenal cortex characterized by bronzing of the skin

15.4 Adrenal glands


Mineralocorticoids & glucocorticoids

Health & Medicine

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