Dr. Saidunnisa

Dr. Saidunnisa Professor of Biochemistry

Adrenal cortical hormones

Adrenal CortexHormones produced by the adrenal cortex are referred to as corticosteroids. These comprise mineralocorticoids, glucocorticoids and androgens.The cortex is divided into three regions:zona glomerulosa zona fasciculata zona reticularisAdrenal cortical hormones Outermost zone Zona Glomerulosa secretes mineralocorticoids involved in regulation of electrolytes in ECF. Naturally synthesized mineralocorticoid of most importance is aldosterone.Middle zone Zona Fasciculata secretes glucocorticoids involved in increasing of blood glucose levels. The naturally synthesized glucocorticoids of most importance is cortisol.

Zona ReticularisInnermost zone between the fasciculata and medullaPrimary secretion is androgens.Androgenic hormones exhibit approximately the same effects as the male sex hormone testosterone.

Synthesis of steroid hormonesCholesterol is acted upon by the enzyme system that catalyzes the Six carbon unit cleavage reaction by a P450-linked side chain cleaving enzyme (P450ssc) or 20,22-desmolase. Which is found in the mitochondria of steroid-producing cells.This is a common precursor for all steroid hormones. This is a rate limiting step.ACTH stimulates this step.

Aldosterone synthesisPregnenolone is converted into Progesterone in two steps: -hydroxyl group is converted to a keto group. Shift of a double bond from c5 to c4Progesterone is further converted into mineralocorticoids, glucocorticoids, and sex steroids.All these are hydroxylation reaction specific Monoxygenases which are NADPH dependent.

The major mineralocorticoid is aldosterone.

Aldosterone has OH group at C11 and aldehyde group at C18Aldosterone synthesisProgesterone is hydroxylated by 21 hydroxylase to form 11-deoxy-corticosterone (DOC).11DOC is hydroxylated by 11- hydroxylase to form corticosterone.Corticosterone is converted by 18 hydroxylase and 18hydroxy dehydrogenase to form aldosterone.

50% bound to plasma proteins50% free

circulating half-life 15 minAll steroid hormones are metabolized and inactivated in the liver by reduction and conjugation.

Transport of aldosterone in the blood

Regulation of aldosterone secretionRenin-Angiotension-Aldosterone System

Angiotensisn II can raise blood pressure by: vasoconstrictor effects.stimulating aldosterone secretion.Effects of AldosteroneRenal effects : ECF volume regulationsodium and potassium ECF concentrationsPromotes reabsorption of sodium from the ducts of sweat and salivary glands during excessive sweat/saliva loss.Enhances absorption of sodium from the intestine esp. colon. absence leads to diarrhea.

Effects of Aldosterone Increase rate of tubular reabsorption of sodium.

Increase rate of tubular reabsorption of chloride.

Increase loss of k+ in urine resulting in hypokalemia

Metabolic alkalosis.Plasma volume increases ECF increases

Synthesis of cortisolProgesterone is converted to 17 hydroxy progesterone this is further converted into 11deoxy cortisol and this is further converted into cortisol all by specific hydroxylases.Urinary steroids are referred to as 17-hydroxy steroids(derived from adrenal) and 17-ketosteroids (derived from adrenal and gonads).

70% bound to CBP (corticosteroid binding protein = cortisol binding globulin = transcortin)20% bound to albumin20% free which is biologically active Half-life 120 minutes. Steroid hormones are metabolized in the liver and inactivated by the liver by conjugation and excreted in urine.

Transport of cortisol in the blood

Mechanism of action All the steroid hormones exert their action by passing through the plasma membrane and binding to intracellular receptors.Regulation of Cortisol Release

Cortisol release is regulated by ACTH

release follows a daily pattern circadiansecretion maximum at 8-10 h (morning)secretion minimum at 23 h (nights).

Negative feedback by cortisol inhibits the secretion of ACTH and CRH

Enhanced release can be caused by:physical trauma infection extreme heat and cold exercise to the point of exhaustion extreme mental anxiety

17Effects of CortisolCarbohydrates metabolism : Promotes gluconeogenesis.Decreased glycolysis and glucose utilization by the peripheral cells all lead to hyperglycemia.

Lipid metabolism : Increase lipid mobilization and facilitate fat breakdown (lipolysis)

Protein metabolism :Promotes Increased catabolism of proteins of skeletal muscle and nucleic acids.

Effects of CortisolFluid and electrolyte: increases water excretion by increasing GFR and inhibiting ADH secretion.Bone and calcium: decrease serum calcium by inhibiting osteoblastic activity leading to osteoporosis.Secretory action: stimulate secretion of gastric acid and induces acid peptic disease.Connective tissue: impaired collagen formation, poor wound healing.Immune system: immunosuppressant and anti-inflammatory and antiallergic.

Anti-inflammatory Effects of Cortisol

Suppresses lymphoid tissue systemically therefore decrease in T cell and antibody production thereby decreasing immunity.Decrease immunity could be fatal in diseases such as tuberculosisDecrease immunity effect of cortisol is useful during transplant operations in reducing organ rejection.reduces fever suppresses allergic reactions wide spread therapeutic use

Assessment of Glucocorticoid secretion Basal level of cortisol: Plasma cortisol measured by RIA or ELISA or CLIA. (Normal range: 5-25micrograms/dl at 9AM : 2-5 micrograms/dl at 10PM)

Estimation of urinary free cortisol: which is biologically active fraction, high levels are seen in hyper function and low levels in hypo function.

Plasma ACTH: decreased levels are seen in hyperadrenalism and high levels in hypoadrenalism and Cushing's disease.

CRH: This test is of importance in establishing the cause of adrenal hyperfunction (primary, secondary or tertiary).Excess of hormones of adrenal cortexGlucocorticoids Cushings syndrome defect in adrenal gland.Cushing's disease is due to excessive production of ACTH from pituitary (tumors)

HypertensionAdrenal diabetesHyper secretion of cortisol results in increase blood glucose levels, up to 2 x normal (200mg/dl)Prolonged over secretion of insulin burns out the beta cells of the pancreas resulting in life long diabetes mellitus

decreased protein synthesis immune system - infectionsosteoporosis

22Hyper-AdrenalismPrimarily the Glucocorticoids

CushingsSyndromeBuffalo torso Redistribution of fat from lower parts of the body to the thoracic and upper abdominal areas

Cushings Syndromestriaemoon face

Moon FaceEdematous appearance of faceAcne & hirsutism( excess growth of facial hair)Collagen fibers in subcutaneous tissue tear forming striaeExcess of hormones of adrenal cortexMineralocorticoids Conns syndrome due to aldosterone secreting tumor.Diagnosed by: Elevated Plasma aldosterone levelsPlasma renin activity decreasedHypernatremia and Hypokalemia muscle weaknessPlasma pH is increased -(hypokalemic alkalosis) increased neuromuscular excitabilityOsmolality increased- (hypertonic contraction) Hypervolemia hypertension

Excess of hormones of adrenal cortexAndrogenic hormonesin childhood in boys pseudopubertas praecox: rapid development of male sexual organsin adulthood in men non-visiblein childhood in girls and in adulthood in womenMasculinizing effect (virilizing): growth of clitoris, growth of beard, deeper voice, masculine distribution of hairLack of hormones of adrenal cortexAdrenal hypofunctionGlucocorticoides and mineralocorticoides Addisons diseaseconsequences of lack of aldosterone:decreased Na+ reabsorption, decreased ECF volumeHypercalcemia, mild acidosis rise of hematocrit decrease of cardiac outputconsequences of lack of cortisol:depressed gluconeogenesis reduced fat and protein metabolismhigh level of ACTH - pigmentation Addisonian crisis - during stress (trauma, surgical operations) extra need for glucocorticoidsHyperpigmentation due to increased ACTH levels on MSH activity.Hyponatremia : plasma sodium decreases and may lead to circulatory collapse.TirednessDehydration

Hypoadrenalism: Addisons DiseaseMelanin PigmentationCharacteristic of Addisons disease is uneven distribution of melanin deposition in thin skin eg. Mucous membranes, lips, thin skin of the nipples.Feedback and effect on MSHTreatmentTotal destruction, if untreated, could lead to death with a few days.Treatment small quantities of mineralocorticoids and glucocorticoids daily.

Zona ReticularisInnermost zone between the fasciculata and medullaPrimary secretion is androgens.Androgenic hormones exhibit approximately the same effects as the male sex hormone testosterone.

Synthesis of adrenal androgens

Inborn errors of metabolismThese are autosomal recessive disorders.All the 5 enzymes involved in the synthesis can be deficient resulting in CAH.

Adrenal tumorPituitary Involvement???General Masculinization

Adrenogenital SyndromeAndrogenital syndrome Congenital deficiency of steroid hydroxylases leading to deficient secretion of cortisol.The major feed back effect is not present ACTH secretion continues leading to CAH.

21-hydroxylase deficiencyDepending on the enzyme defect the manifestations vary.21-hydroxylase deficiency: common type production of cortisol is absent totally.Lack of feed back leads to increased androgen synthesis.This leads to virilization of female children who develop ambiguous genitilia. Precocious puberty in male children

11 alpha hydroxylase 11 alpha hydroxylase the symptoms are more serious.Manifests with hypertension. Prognosis is bad.

Classic Sex Hormones: Gonad and AdrenalEstrogenProgesteroneDihydrotestosteroneTestosterone

Sex Hormones