1. Professor of Biochemistry Adrenal cortical hormones
Dr. Saidunnisa
Professor of Biochemistry
Adrenal cortical hormones

3. Adrenal Cortex
Hormones 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 reticularis

4. Adrenal 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.

5. Zona Reticularis Innermost zone – between the fasciculata and medulla
Primary secretion is androgens.
Androgenic hormones exhibit approximately the same effects as the male sex hormone – testosterone.

6. Synthesis of steroid hormones
Cholesterol 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.

7. Aldosterone synthesis
Pregnenolone is converted into Progesterone in two steps:
β -hydroxyl group is converted to a keto group.
Shift of a double bond from c5 to c4
Progesterone 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 C18

8. Aldosterone synthesis
Progesterone is hydroxylated by 21 hydroxylase to form 11-deoxy-corticosterone (DOC).
11DOC is hydroxylated by 11β- hydroxylase to form corticosterone.
Corticosterone is converted by 18 hydroxylase and 18hydroxy dehydrogenase to form aldosterone.

9. Transport of aldosterone in the blood
50% bound to plasma proteins
50% free
circulating half-life 15 min
All steroid hormones are metabolized and inactivated in the liver by reduction and conjugation.

11. Regulation of aldosterone secretion Renin-Angiotension-Aldosterone System
Angiotensisn II can raise blood pressure by:
vasoconstrictor effects.
stimulating aldosterone secretion.

12. Effects of Aldosterone
Renal effects :
ECF volume regulation
sodium and potassium ECF concentrations
Promotes 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.

13. 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

14. Synthesis of cortisol
Progesterone 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).

15. Transport of cortisol in the blood
70% bound to CBP (corticosteroid binding protein = cortisol binding globulin = transcortin)
20% bound to albumin
20% 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.

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

17. Regulation of Cortisol Release
Cortisol release is regulated by ACTH
release follows a daily pattern – circadian
secretion 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

18. Effects of Cortisol Carbohydrates 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.

19. Effects of Cortisol
Fluid 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.

20. 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 tuberculosis
Decrease immunity effect of cortisol is useful during transplant operations in reducing organ rejection.
reduces fever
suppresses allergic reactions
wide spread therapeutic use

21. 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).

22. Excess of hormones of adrenal cortex
Glucocorticoids – Cushing’s syndrome defect in adrenal gland.
Cushing's disease is due to excessive production of ACTH from pituitary (tumors)
Hypertension
“Adrenal diabetes”
Hyper 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 - infections
osteoporosis

23. Cushing’s Syndrome Hyper-Adrenalism Primarily the Glucocorticoids
Buffalo torso
Redistribution of fat from lower parts of the body to the thoracic and upper abdominal areas

24. Cushing’s Syndrome
Collagen fibers in subcutaneous tissue tear forming striae
“moon face”
Moon Face
Edematous appearance of face
Acne & hirsutism( excess growth of facial hair)
striae

25. Excess of hormones of adrenal cortex
Mineralocorticoids – Conn’s syndrome due to aldosterone secreting tumor.
Diagnosed by:
Elevated Plasma aldosterone levels
Plasma renin activity decreased
Hypernatremia and Hypokalemia – muscle weakness
Plasma pH is increased -(hypokalemic alkalosis) – increased neuromuscular excitability
Osmolality increased- (hypertonic contraction)
Hypervolemia – hypertension

26. Excess of hormones of adrenal cortex
Androgenic hormones
in childhood in boys
pseudopubertas praecox: rapid development of male sexual organs
in adulthood in men – non-visible
in childhood in girls and in adulthood in women
Masculinizing effect (virilizing): growth of clitoris, growth of beard, deeper voice, masculine distribution of hair

27. Lack of hormones of adrenal cortex
Adrenal hypofunction
Glucocorticoides and mineralocorticoides – Addison’s disease
consequences of lack of aldosterone:
decreased Na+ reabsorption, decreased ECF volume
Hypercalcemia, mild acidosis
rise of hematocrit – decrease of cardiac output
consequences of lack of cortisol:
depressed gluconeogenesis
reduced fat and protein metabolism
high level of ACTH - pigmentation
Addisonian crisis - during stress (trauma, surgical operations) – extra need for glucocorticoids

28. Hypoadrenalism: Addison’s Disease
Hyperpigmentation due to increased ACTH levels on MSH activity.
Hyponatremia : plasma sodium decreases and may lead to circulatory collapse.
Tiredness
Dehydration

29. Melanin Pigmentation
Characteristic of Addison’s disease is uneven distribution of melanin deposition in thin skin eg. Mucous membranes, lips, thin skin of the nipples.
Feedback and effect on MSH

30. Treatment
Total destruction, if untreated, could lead to death with a few days.
Treatment – small quantities of mineralocorticoids and glucocorticoids daily.

31. Zona Reticularis Innermost zone – between the fasciculata and medulla
Primary secretion is androgens.
Androgenic hormones exhibit approximately the same effects as the male sex hormone – testosterone.

32. Synthesis of adrenal androgens

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

34. Adrenogenital Syndrome Adrenal tumor Pituitary Involvement???
General Masculinization

35. Androgenital 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.

36. 21-hydroxylase deficiency
Depending 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

37. 11 alpha hydroxylase
11 alpha hydroxylase the symptoms are more serious.
Manifests with hypertension.
Prognosis is bad.

38. Sex Hormones Classic Sex Hormones: Gonad and Adrenal Estrogen
Progesterone
Dihydrotestosterone
Testosterone