1. Adrenocorticosteroids
Adrenocortical Insufficiency
Addison’s disease (primary)
Abrupt stoppage of long term steroid use (secondary)
Adrenocortical Hyperactivity
Congenital adrenal hyperplasia
Cushing’s syndrome
Conn’s syndrome (primary aldosteronism)

2. Adrenal steroids
Corticosteroids are the hormones produced by the adrenal cortex.
Glucocorticoids have effect on intermediary metabolism, immune response and inflammation.
Mineralocorticoids have salt retaining activity.
Dehydroepiandrosterone have androgenic activity.
Adrenal androgens is responsible for androgenic action in females and constitutes the major endogenous precursors of estrogens in women after menopause.
ZONA FASCICULATA SYNTHESIZE CORTISOL because 11 beta hydroxylase is expressed in it.
POMC , a precursor polypeptide is cleaved into ACTH, MSH, lipoprotein and beta endorphin.
Because of the similarities between ACTH and MSH, high concentration of ACTH can stimulate MSH receptors, which is seen in primary hypoadrenalism, in which increased ACTH results in increased skin pigmentation.
Addisons disease is primary adrenal insufficiency in which adrenal cortex is selectively destroyed by T cells.
SECONDARY ADRENAL FAILURE IS CAUSED BY HYPOTHALAMIC OR PITUITARY DISORDERS OR BY PROLONGED EXOGENOUS GLUCOCORTICOIDS, IN WHICH THERE IS DECREASE IN ACTH WHICH CAUSES DECREASE IN SEX STEROIDS AND CORTISOL BUT DO NOT ALTER LEVELS OF ALDOSTERONE SYNTHESIS.
ALDOSTERONE PRODUCING ZONA GLOMERULOSA CONTINUE TO FUNCTION IN THE ABSENCE OF ACTH, BECAUSE ANGIOTENSIN AND POTASSIUM MAINTAIN PRODUCTION OF ALDOSTERONE

3. Adrenal cortex steroids
The adrenal cortex contains three anatomically and functionally distinct compartments. The major functional compartments of the adrenal cortex are shown, along with the steroidogenic enzymes that determine the unique profiles of corticosteroid products. Also shown are the predominant physiological regulators of steroid production: angiotensin II (Ang II) and K+ for the zona glomerulosa and ACTH for the zona fasciculata. The physiological regulator(s) of dehydroepiandrosterone (DHEA) production by the zona reticularis are not known, although ACTH acutely increases DHEA biosynthesis.
As with pituitary gland, adrenal gland consists of two organ fused during embryonic development.
The outer cortex originates from mesoderm and inner medulla is derived from neural crest cells.
DHEA is not regulated by FDA and used over the counter. DHEA is considered as prohormone. Exogenous DHEA can be converted to testosterone by liver but also has risk of CV disease and cancer.
The adrenal medulla is important though not essential for maintaining sympathetic tone by secretion of epinephrine.

4. Corticosteroids
Physical and metal stress are powerful stimulators of CRH which in turn increases ACTH and cortisol.
Initial feedback suppression of pituitary ACTH occurs in minutes and too rapid to be explained on the basis of protein synthesis.
Secretion of adrenocortical steroids is controlled by the physical and mental stress and also pituitary release of ACTH
Secretion of the aldosterone is chiefly under the influence of renin angiotensin system and partly under ACTH.

5. Pituitary hormones ACTH
Proopiomelanocortin (POMC) is the precursor for ACTH and MSH.
ACTH mainly stimulates the zona faciculata and zona reticularis to produce the cortisol and adrenal androgens.
Aldosterone secretion from zona glomerulosa is mainly dependent on angiotensin and plasma potassium.
HIGH CONC OF ACTH CAN STIMULATE MSH RECEPTORS AS SEEN IN PRIMARY HYPOADRENALISM-ADDISON’S DISEASE.
THE INCREASED ACTH IN ADDISON’S DISEASE STIMULATES GLUCOCORTICOIDS, ANDROGENS AND EVEN ALDOSTERONE SYNTHESIS AND SECRETION BY THEIR RESPECTIVE ZONES BUT THE EFFECT OF ACTH ON MINERALOCORTICOID SECRETION IS TRANSIENT AND IS CALLED “ACTH ESCAPE”.
The aldosterone is regulated mainly by plasma angiotensin II, or potassium levels.

6. Pituitary hormones ACTH analogs: Cosyntropin – synthetic ACTH
It is used in treatment of infantile spasms
It is employed in diagnostic tests.
To diagnose congenital adrenal hyperplasia.
To diagnose adrenal insufficiency in a test that measures cortisol before and after cosyntropin injection.
Corticotropin - porcine ACTH.
Adrenal insufficiency can be caused by diseases affecting the adrenal cortex (primary), the pituitary gland and the secretion of adrenocorticotropic hormone (ACTH) (secondary), or the hypothalamus and the secretion of corticotropic-releasing hormone (CRH) (tertiary).
Cortisol Secretion: The diagnosis of adrenal insufficiency depends upon the demonstration of inappropriately low cortisol secretion. Serum cortisol concentrations are normally highest in the early morning hours (04:00h - 08:00h) and increase further with stress. Serum cortisol concentrations determined at 08:00h of less than 3 µg/dL (80 nmol/L) are strongly suggestive of adrenal insufficiency (25), while values below 10 µg/dL (275 nmol/L) make the diagnosis likely.
Basal urinary cortisol and 17-hydroxycorticosteroid excretion is low in patients with severe adrenal insufficiency, but may be low-normal in patients with partial adrenal insufficiency.
ACTH Secretion: Inappropriately low serum cortisol concentrations in association with increased plasma ACTH concentrations determined simultaneously are suggestive of primary adrenal insufficiency. On the other hand, inappropriately low baseline morning cortisol and ACTH concentrations indicate secondary or tertiary disease.
CRH Stimulation Test: This test is used to differentiate between secondary and tertiary adrenal insufficiency. In both conditions cortisol levels are low at baseline and remain low after CRH. In patients with secondary adrenal insufficiency, there is little or no ACTH response, whereas in patients with tertiary disease there is an exaggerated and prolonged response of ACTH to CRH stimulation, which is not followed by an appropriate cortisol response.

7. ACTH ACTH used in diagnosis of Congenital adrenal hyperplasia
In patients suspected of adrenal insufficiency, to test for a response
In patients suspected of CAH, to identify 21-hydroxylase deficiency, 11- hydroxylase deficiency and 3-beta hydroxylase dehydrogenase deficiency, based on steroid that accumulate in response to ACTH stimulation
Approximately 95% of cases of CAH are due to 21-hydroxylase deficiency.
Treatment of all forms of CAH may include any of:
supplying enough glucocorticoid to reduce hyperplasia and overproduction of androgens or mineralocorticoids
providing replacement mineralocorticoid and extra salt if the person is deficient
providing replacement testosterone or estrogen at puberty if the person is deficient
additional treatments to optimize growth by delaying puberty or delaying bone maturation
genital reconstructive surgery to correct problems produced by abnormal genital structure.
Screening for CAH due to 21-hydroxylase deficiency is by fluorometric assay to measure the 17 hydroxy (OH) progesterone level.
Measurement of serum 17-OH progesterone level and serum electrolytes is also recommended.
ACTH STIMULATION TEST (detecting adrenal insufficiency)
This important test monitors the response of the adrenal cortex to a dose of exogenous ACTH. These are several variations.
One rapid test to screen for Addison's disease requires synthetic ACTH ("cosyntropin" 250 mcg I.M. or IV), with plasma cortisol
measured just before and one hour after.
A serum cortisol peak over 415 nmol/L rules out Addisonism.
In full-blown Addison's disease, there is little or no response. You may then confirm this with a prolonged infusion test.
One prolonged infusion test requires synthetic ACTH 500 mcg to be given over 8 hrs each day for one to five days, with plasma
cortisol measured before, during, and after each infusion, and urinary hormones measured daily.
In a healthy person, this will result in an increase in hormone production of 3-5 fold on the first day. (If the test is repeated the
next day, the response is likely to be still greater.)
In a patient with primary adrenal insufficiency, there is little or no response on the first day. There may be a slight response on the
second and third days, but this is likely to taper off on the fourth and fifth days. (Why?)
In a patient with adrenal insufficiency secondary to pituitary insufficiency (low ACTH), adrenal atrophy will usually prevent a normal
response. There will be a greater response on each successive day the test is run ("staircase"). (Remember to check these patients
for deficiencies in other anterior pituitary hormones!)
OTHER CAUSES OF CAH:
Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency
Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency
Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency
Sermorelin is approved for diagnostic evaluation of pituitary function and also for increasing growth in children.
Off label usage may include acute or age-related growth hormone insufficiency.
The corticorelin stimulation test helps to differentiate between the etiologies of ACTH-dependent hypercortisolism as follows:
High basal plasma ACTH plus high basal plasma cortisol ( mcg/dL). Test Methodology:    To evaluate the status of the
pituitary-adrenal axis in the differentiation of a pituitary source from an ectopic source of excessive ACTH secretion.
ACTHREL (corticorelin for injection) injection (1 mcg/kg) results in: a. Increased plasma ACTH levels b. Increased plasma cortisol levels      Diagnosis: Cushing's disease (ACTH of pituitary origin)
High basal plasma ACTH (may be very high) plus high basal plasma cortisol ( mcg/dL). ACTHREL injection (1 mcg/kg) results in:
a. Little or no response of plasma ACTH levels b. Little or no response of plasma cortisol levels      Diagnosis: Ectopic ACTH syndrome
CRH Stimulation Test: This test is used to differentiate between secondary and tertiary adrenal insufficiency. In both conditions cortisol levels are low at baseline and remain low after CRH. In patients with secondary adrenal insufficiency, there is little or no ACTH response, whereas in patients with tertiary disease there is an exaggerated and prolonged response of ACTH to CRH stimulation, which is not followed by an appropriate cortisol response
Cosyntropin is preferred because of fewer allergic reactions.
Cortisol response to cosyntropin varies considerably among healthy persons. The cosyntropin test performs well in patients with primary adrenal insufficiency, but the lower sensitivity in patients with secondary adrenal insufficiency necessitates use of tests involving stimulation of the hypothalamus if the pretest probability is sufficiently high.
Protirelin stimulates release of a hormone called thyroid-stimulating hormone or TSH from the anterior pituitary gland.
TSH then stimulates the thyroid gland.
By measuring the amount of TSH in the blood after protirelin is given, one can determine
how well the anterior pituitary is working.
ACTH used in diagnosis of Congenital adrenal hyperplasia

8. Steroids – normal circadian rhythm and mechanism of action
A model of the interaction of a steroid, S (eg, cortisol), and its receptor, R, and the subsequent events in a target cell. The steroid is present in the blood in bound form on the corticosteroid-binding globulin (CBG) but enters the cell as the free molecule. The intracellular receptor is bound to stabilizing proteins, including two molecules of heat-shock protein 90 (hsp90) and several others, denoted as "X" in the figure. This receptor complex is incapable of activating transcription. When the complex binds a molecule of cortisol, an unstable complex is created and the hsp90 and associated molecules are released. The steroid-receptor complex is now able to dimerize, enter the nucleus, bind to a glucocorticoid response element (GRE) on the regulatory region of the gene, and regulate transcription by RNA polymerase II and associated transcription factors. A variety of regulatory factors (not shown) may participate in facilitating (coactivators) or inhibiting (corepressors) the steroid response. The resulting mRNA is edited and exported to the cytoplasm for the production of protein that brings about the final hormone response. An alternative to the steroid-receptor complex interaction with a GRE is an interaction with and altering the function of other transcription factors, such as NF-B in the nucleus of cells.
Intracellular mechanism of action of the glucocorticoid receptor.The figure shows the molecular pathway by which cortisol (labeled S) enters cells and interacts with the glucocorticoid receptor (GR) to change GR conformation (indicated by the change in shape of the GR), induce GR nuclear translocation, and activate transcription of target genes. The example shown is one in which glucocorticoids activate expression of target genes; the expression of certain genes, including pro-opiomelanocortin (POMC) expression by corticotropes, is inhibited by glucocorticoid treatment. CBG, corticosteroid-binding globulin; GR, glucocorticoid receptor; S, steroid hormone; HSP90, the 90-kd heat-shock protein; HSP70, the 70-kd heat-shock protein; IP, the 56-kd immunophilin; GRE, glucocorticoid-response elements in the DNA that are bound by GR, thus providing specificity to induction of gene transcription by glucocorticoids. Within the gene are introns (gray) and exons (red); transcription and mRNA processing leads to splicing and removal of introns and assembly of exons into mRNA.
The glucocorticoid receptor has high affinity for cortisol but low affinity for aldosterone, whereas the mineralocorticoid receptor has high affinity for aldosterone and cortisol.

9. Adrenal steroids Glucocorticoids stimulate gluconeogenesis.
It inhibits the uptake of glucose by the muscle and adipose tissue.
Muscle protein is catabolized.
Redistribution of body fat with an increase fat deposition in face and shoulder and lipolysis in periphery.
Most effects are due to direct actions. Many of the effects of steroids are dose related.
Some effects are called permissive – In the absence of which many normal functions becomes deficient.
For eg., the response of vascular and bronchial smooth muscle to catecholamines are diminished in the absence of glucocorticoids. The lipolytic responses of fat cells to catecholamines and ACTH are attenuated in the absence of glucocorticoids.

10. Glucocorticoids
HYDROCORTISONE IS SYNTHETIC CORTISOL.

11. Anti-inflammatory actions of glucocorticoids
Immuno-suppressive actions of glucocorticoids
Inhibition of prostaglandin synthesis by inhibiting phospholipase A2.
Glucocorticoids suppress T lymphocytes and production of cytokines.
After single dose - neutrophil concentration in circulation increase and while lymphocyte, eosinophils and basophils decrease.
These also suppress B lymphocytes – dampen humoral immunity.
It prevents the mast cell, basophil and eosinophil from degranulation.
These are lymphotoxic in nature.
Dexamethasone, a glucocorticoid with a low degree of protein binding is given to the pregnant women in premature labor to hasten maturation of the lungs.

12. Anti-inflammatory actions of glucocorticoids
Typical Effects of Cortisol on the White and Red Blood Cell Counts in Humans (Cells/microL).
Cell
Normal
Cortisol-Treated
White blood cells 
Total
9000
10,000
PMNs
5760
8330
Lymphocytes
2370
1080
Eosinophils
270 20
Basophils 60 30
Monocytes
450
540
Red blood cells 
5 million
5.2 million
Ganong's Review of Medical Physiology, 24e > Chapter 20. The Adrenal Medulla & Adrenal Cortex > Physiologic Effects of Glucocorticoids > Effects on the Blood Cells & Lymphatic Organs >
Dexamethasone, a glucocorticoid with a low degree of protein binding is given to the pregnant women in premature labor to hasten maturation of the lungs.

13. GLUCOCORTICOIDS
Dexamethasone, a glucocorticoid with a low degree of protein binding, is given to the pregnant women in premature labor to hasten maturation of the lungs.

14. Adrenal steroids
GLUCOCORTICOIDS :
It antagonize the effect of vitamin-D on calcium absorption.
Catabolic effect on the bone is responsible for osteoporosis.
Stimulates the gastric acid and pepsin production.
Dexamethasone, a glucocorticoid with a low degree of protein binding, is given to the pregnant women in premature labor to hasten maturation of the lungs.

15. Adrenal steroids
GLUCOCORTICOIDS :
Glucocorticoids increase the production of surfactant in the fetal lung and also help in the development of fetal lung.
Dexamethasone / Betamethasone is used for fetal lung maturation.
Dexamethasone, a glucocorticoid with a low degree of protein binding, is given to the pregnant women in premature labor to hasten maturation of the lungs.
IN PREGNANCY PREDNISONE CAN BE ADMINISTERED TO MOTHERS WITHOUT FETAL SIDE EFFECTS AS FETAL LIVER DO NOT FUCTION AND CAN NOT ACTIVATE PREDNISONE TO PREDNISOLONE, THEREFORE, PREDNISONE IS SAFE TO FETUS.
DEXAMETHASONE IS PRESENT IN ACTIVE FORM IN THE FETUS AND CAN BE USED IN FETUS LUNG MATURATION.

16. CORTISOL (Hydrocortisone)
ANTIINFLAMMATORY ACTIVITY
DURATION
GLUCOCORTICOIDS
SALT RETAINING ACTIVITY 1
8-12 hrs
CORTISOL (Hydrocortisone) 4
12-36hrs
PREDNISONE
0.8 5
TRIAMCINOLONE 25
24-72hrs
BETAMETHASONE DEXAMETHASONE
Primary adrenal insufficiency (Addison's disease) is due to adrenocortical disease, while secondary and tertiary adrenal insufficiency are due to disorders of the pituitary gland (ACTH secretion) or the hypothalamus (corticotropic-releasing hormone secretion), respectively. Primary adrenal insufficiency is associated with both cortisol and mineralocorticoid deficiency. In contrast, secondary and tertiary adrenal insufficiency are associated with cortisol, but not mineralocorticoid deficiency, because aldosterone is regulated primarily by the renin-angiotensin system, which is independent of the hypothalamus and pituitary. This distinction accounts for the different clinical presentation and management of these disorders.
ACTH stimulation of aldosterone secretion is not sustained for more than few days in normal individuals. Aldosterone can participate in suppressing ACTH, the quantities of aldosterone produced by adrenal cortex is insufficient for any significant feedback control of ACTH.
Deoxycorticosterone serves as a precursor of aldosterone
Fludrocortisone is an orally active, potent, commonly used mineralocorticoid.
MINERALOCORTICOIDS PREPARATIONS
SALT RETAINING ACTIVITY
FLUDROCORTISONE
125

17. Glucocorticoids - effects
Dexamethasone, a glucocorticoid with a low degree of protein binding is given to the pregnant women in premature labor to hasten maturation of the lungs.

18. Adrenal steroids GLUCOCORTICOIDS : Toxicity
Adrenal suppression may occur, when corticosteroids are used for more than 2 weeks.
Cushingoid syndrome features like moon faces, muscle wasting, thinning of skin and hyperglycemia.
Osteoporosis
It may take 2-12 months for the HPA axis to function properly after suppression.

19. Adrenal steroids USES : Glucocorticoids :
Primary adrenal failure (Addison’s disease) – hydrocortisone / fludrocortisone.
Secondary adrenal failure - Glucocorticoids
Stimulation of the maturation of the fetus lung.
Inflammation, allergy and autoimmune diseases – Bronchial asthma, Myasthenia gravis
Cancer – lymphoma.
Organ graft rejection reactions.
Psoriasis and hypercalcemia.
Adrenal insufficiency
A disease state caused by insufficient circulating glucocorticoid and/or mineralocorticoid hormones
May be caused by abnormalities at each level of the hypothalamic-pituitary-adrenal axis
Primary adrenal insufficiency
Inadequate production of glucocorticoids and mineralocorticoids caused by adrenal gland destruction or dysfunction Addison’s disease, an autoimmune disorder, is the most common cause.
The dexamethasone suppression test is designed to diagnose and differentiate among the various types of Cushing's syndrome and other hypercortisol states.
Dexamethasone is an exogenous steroid that provides negative feedback to the pituitary to suppress the secretion of ACTH. This steroid is unable to pass the blood brain barrier which allows this test to assess a specific part of the Hypothalamic-pituitary-adrenal axis. Specifically, dexamethasone binds to glucocorticoid receptors in the basal medial hypothalamus, which lies outside the blood brain barrier, resulting in regulatory modulation.
The test is given at low and high doses of dexamethasone and the levels of cortisol are measured to obtain the results.
A normal result is decrease in cortisol levels upon administration of low-dose dexamethasone.
Results indicative of Cushing's disease involve no change in cortisol on low-dose dexamethasone, but inhibition of cortisol on high-dose dexamethasone.
If the cortisol levels are unchanged by low and high-dose dexamethasone then a cortisol secreting adrenocortical tumor is suspected or an ectopic ACTH syndrome.
Secondary adrenal insufficiency
Inadequate secretion of glucocorticoids caused by pituitary insufficiency
Tertiary adrenal insufficiency
Inadequate secretion of glucocorticoids caused by hypothalamic disease.
Congenital hyperplasia of adrenal gland is characterized by defects in the synthesis of cortisol (due to defects in 21-hydroxylase enzyme deficiency in 90% and 11-hydroxylase in 9% of cases ). It would lead to compensatory increase in ACTH, which makes the gland hyperplastic and produces large amounts of precursors like 17-hydroxyprogesterone that can be diverted to androgen pathway leading to virilization. In these conditions, administration of a potent synthetic glucocorticoid suppresses ACTH secretion sufficiently to reduce the synthesis of abnormal steroids.
ACTH secreting pituitary adenoma is cushing’s disease.
Dexamethasone Suppression Test
This test helps to distinguish patients with excess production of ACTH due to pituitary adenomas from those with ectopic ACTH-producing tumors.
Patients are given dexamethasone, a synthetic glucocorticoid, by mouth every 6 hours for 4 days. For the first 2 days, low doses of dexamethasone are given, and for the last 2 days, higher doses are given. Twenty-four hour urine collections are made before dexamethasone is administered and on each day of the test. Since cortisol and other glucocorticoids signal the pituitary to lower secretion of ACTH, the normal response after taking dexamethasone is a drop in blood and urine cortisol levels.
Different responses of cortisol to dexamethasone are obtained depending on whether the cause of Cushing's syndrome is a pituitary adenoma or an ectopic ACTH-producing tumor.
The test is given at low (usually 1-2 mg) and high (8 mg) doses of dexamethasone and the levels of cortisol are measured to obtain the results.

20. Treatment of Adrenocortical Insufficiency
Treatment of Primary adrenocortical insufficiency (Addison’s Disease)
hypo secretion of both cortisol & aldosterone
hypersecretion of ACTH – pigmentation (loss of negative feedback)
glucocorticoid insufficiency : weakness, fatigue
treated by hydrocortisone or prednisone
mineralocorticoid insufficiency : sodium loss, potassium retention
treated by hydrocortisone or fludrocortisone
Treatment of Secondary adrenocortical insufficiency
hypo secretion of cortisol
TREATMENT REQUIRES GLUCOCORTICOIDS ONLY

21. Adrenal steroids USES : Glucocorticoids :
Acute adrenal crisis: Weakness, fever, abdominal pain, confusion, vomiting.
Hypotension, dehydration, skin pigmentation may be increased.
Causes: Sudden withdrawal of long-term corticosteroid therapy and stress.
Treatment is intravenous hydrocortisone and fluids.
Adrenal insufficiency
A disease state caused by insufficient circulating glucocorticoid and/or mineralocorticoid hormones
May be caused by abnormalities at each level of the hypothalamic-pituitary-adrenal axis
Serum potassium high and sodium low.
Primary adrenal insufficiency
Inadequate production of glucocorticoids and mineralocorticoids caused by adrenal gland destruction or dysfunction Addison’s disease, an autoimmune disorder, is the most common cause.
The dexamethasone suppression test is designed to diagnose and differentiate among the various types of Cushing's syndrome and other hypercortisol states.
Dexamethasone is an exogenous steroid that provides negative feedback to the pituitary to suppress the secretion of ACTH. This steroid is unable to pass the blood brain barrier which allows this test to assess a specific part of the Hypothalamic-pituitary-adrenal axis. Specifically, dexamethasone binds to glucocorticoid receptors in the basal medial hypothalamus, which lies outside the blood brain barrier, resulting in regulatory modulation.
The test is given at low and high doses of dexamethasone and the levels of cortisol are measured to obtain the results.
A normal result is decrease in cortisol levels upon administration of low-dose dexamethasone.
Results indicative of Cushing's disease involve no change in cortisol on low-dose dexamethasone, but inhibition of cortisol on high-dose dexamethasone.
If the cortisol levels are unchanged by low and high-dose dexamethasone then a cortisol secreting adrenocortical tumor is suspected or an ectopic ACTH syndrome.
Secondary adrenal insufficiency
Inadequate secretion of glucocorticoids caused by pituitary insufficiency
Tertiary adrenal insufficiency
Inadequate secretion of glucocorticoids caused by hypothalamic disease.
Congenital hyperplasia of adrenal gland is characterized by defects in the synthesis of cortisol (due to defects in 21-hydroxylase enzyme deficiency in 90% and 11-hydroxylase in 9% of cases ). It would lead to compensatory increase in ACTH, which makes the gland hyperplastic and produces large amounts of precursors like 17-hydroxyprogesterone that can be diverted to androgen pathway leading to virilization. In these conditions, administration of a potent synthetic glucocorticoid suppresses ACTH secretion sufficiently to reduce the synthesis of abnormal steroids.
ACTH secreting pituitary adenoma is cushing’s disease.
Dexamethasone Suppression Test
This test helps to distinguish patients with excess production of ACTH due to pituitary adenomas from those with ectopic ACTH-producing tumors.
Patients are given dexamethasone, a synthetic glucocorticoid, by mouth every 6 hours for 4 days. For the first 2 days, low doses of dexamethasone are given, and for the last 2 days, higher doses are given. Twenty-four hour urine collections are made before dexamethasone is administered and on each day of the test. Since cortisol and other glucocorticoids signal the pituitary to lower secretion of ACTH, the normal response after taking dexamethasone is a drop in blood and urine cortisol levels.
Different responses of cortisol to dexamethasone are obtained depending on whether the cause of Cushing's syndrome is a pituitary adenoma or an ectopic ACTH-producing tumor.
The test is given at low (usually 1-2 mg) and high (8 mg) doses of dexamethasone and the levels of cortisol are measured to obtain the results.

22. Congenital Adrenal Hyperplasia
primary defect in cortisol biosynthetic enzymes
21-B hydroxylase defect – no cortisol and aldosterone
shunts precursors into androgen pathway
compensatory increase in ACTH (loss of negative feedback)
mineralocorticoid deficiency
glucocorticoid deficiency
adrenal hypertrophy
virilization of physical features
fludrocortisone as mineralocorticoid replacement in salt wasters
hydrocortisone/dexamethasone as
replacement therapy and also to suppress ACTH
Figure illustrates adrenal steroidogenesis: Five enzymatic steps necessary for cortisol production are shown in numbers. 1= 20, 22 desmolase, 2= 17 hydroxylase (17-OH), 3=3ß-hydroxysteroid dehydrogenase (3ß HSD), 4=21 hydroxylase (21-OHD), 5=11ß hydroxylase (11-OH) In the first step of adrenal stereoidgeneis, cholesterol enters mitochondria via a carrier protein called StAR. ACTH stimulates cholesterol cleavage, the rate limiting step of adrenal steroidogenesis.
The clinical symptoms of the five different forms of CAH result from the particular hormones that are deficient and those that are produced in excess as outlined in fugure .
In the most common form 21 OHD-CAH, the function of 21-hydroxylating cytochrome 450 is inadequate, creating a block in cortisol production pathway. This leads to an accumulation of 17-hydroxyprogesterone (17-OHP), a precursor adjacent to the 21-hydroxylation step. Excess 17-OHP is then shunted into the intact androgen pathway, where the 17,20-lyase enzyme converts the 17-OHP to 4-androstenedione, which is converted into androgens. Mineralocorticoid deficiency is a feature of the most severe form of the disease called salt wasting CAH. The enzyme defect in the non-classical form of 21-OHD CAH is only partial and salt wasting in this mild form of the disease is not evident. The analogy of all other enzyme deficiencies in terms of precursor retention and product deficiencies are shown
The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones. It is primarily present in steroid-producing cells, including theca cells and luteal cells in the ovary, Leydig cells in the testis and cell types in the adrenal cortex.
Cholesterol needs to be transferred from the outer mitochondrial membrane to the inner membrane where cytochrome P450scc enzyme cleaves the cholesterol side chain, which is the first enzymatic step in all steroid synthesis.

23. Congenital Adrenal Hyperplasia
primary defect in cortisol biosynthetic enzymes
11-B hydroxylase defect – no cortisol
shunts precursors into androgen pathway
Compensatory increase in ACTH (loss of negative feedback)
Deoxycorticosterone
Deoxycorticosterone has mild salt retaining properties - hypertension
Glucocorticoid deficiency
Adrenal hypertrophy
Virilization of physical features
Hydrocortisone/dexamethasone as
replacement therapy and also to suppress ACTH
Figure illustrates adrenal steroidogenesis: Five enzymatic steps necessary for cortisol production are shown in numbers. 1= 20, 22 desmolase, 2= 17 hydroxylase (17-OH), 3=3ß-hydroxysteroid dehydrogenase (3ß HSD), 4=21 hydroxylase (21-OHD), 5=11ß hydroxylase (11-OH) In the first step of adrenal stereoidgeneis, cholesterol enters mitochondria via a carrier protein called StAR. ACTH stimulates cholesterol cleavage, the rate limiting step of adrenal steroidogenesis.
The clinical symptoms of the five different forms of CAH result from the particular hormones that are deficient and those that are produced in excess as outlined in fugure .
In the most common form 21 OHD-CAH, the function of 21-hydroxylating cytochrome 450 is inadequate, creating a block in cortisol production pathway. This leads to an accumulation of 17-hydroxyprogesterone (17-OHP), a precursor adjacent to the 21-hydroxylation step. Excess 17-OHP is then shunted into the intact androgen pathway, where the 17,20-lyase enzyme converts the 17-OHP to 4-androstenedione, which is converted into androgens. Mineralocorticoid deficiency is a feature of the most severe form of the disease called salt wasting CAH. The enzyme defect in the non-classical form of 21-OHD CAH is only partial and salt wasting in this mild form of the disease is not evident. The analogy of all other enzyme deficiencies in terms of precursor retention and product deficiencies are shown
The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones. It is primarily present in steroid-producing cells, including theca cells and luteal cells in the ovary, Leydig cells in the testis and cell types in the adrenal cortex.
Cholesterol needs to be transferred from the outer mitochondrial membrane to the inner membrane where cytochrome P450scc enzyme cleaves the cholesterol side chain, which is the first enzymatic step in all steroid synthesis.

24. Glucocorticoids in bronchial asthma
INHALED GLUCOCORTICOIDS : Beclomethasone, Budesonide, Fluticasone
Dexamethasone, a glucocorticoid with a low degree of protein binding, is given to the pregnant women in premature labor to hasten maturation of the lungs.   
Dexamethasone suppression test measures the response of the adrenal glands to ACTH.
How the Test is Performed   
During this test, you will receive dexamethasone and the health care provider will measure your cortisol levels.
There are two different types of dexamethasone suppression tests: the low-dose test and the high-dose test. Each type can either be done in an overnight or standard (3-day) way.
Low-dose overnight method -- you will get 1 mg of dexamethasone at 11 p.m., and a health care provider will draw your blood at 8 a.m. for a cortisol measurement.
Standard low-dose method -- urine is collected over 3 days (stored in 24-hour collection containers) to measure cortisol. On day 2, you will get a low dose (0.5 mg) of dexamethasone by mouth every 6 hours for 48 hours.
High-dose overnight method -- the health care provider will measure your cortisol on the morning of the test. Then you will receive 8 mg of dexamethasone at 11 p.m. Your blood is drawn at 8 a.m. for a cortisol measurement.
Standard high-dose test -- urine is collected over 3 days (stored in 24-hour collection containers) for measurement of cortisol. On day 2, you will receive a high dose (2 mg) of dexamethasone by mouth every 6 hours for 48 hours.
This test is performed when the health care provider suspects that your body is producing too much cortisol.
The low-dose test can help tell whether your body is producing too much cortisol. The high-dose test can help determine whether the problem is in the pituitary gland (Cushing's Disease).
The level of cortisol in the blood normally regulates the release of ACTH from the pituitary gland. As blood cortisol levels increase, ACTH release decreases. As cortisol levels decrease, ACTH increases.
Dexamethasone is a man-made (synthetic) steroid that is similar to cortisol. It reduces ACTH release in normal people. Therefore, taking dexamethasone should reduce ACTH levels and lead to decreased cortisol levels.
If your pituitary gland produces too much ACTH, you will have an abnormal response to the low-dose test, but a normal response to the high-dose test.
Normal Results   
Cortisol levels should decrease after you receive dexamethasone.
Low dose:
Overnight: 8 a.m. plasma cortisol < 1.8 mcg/dl
Standard: Urinary free cortisol on day 3 < 10 mcg/day
High dose:
Overnight: > 50 % reduction in plasma cortisol
Standard: > 90% reduction in urinary free cortisol
Normal value ranges may vary slightly among different laboratories. Talk to your doctor about the meaning of your specific test results.

25. Prednisone (prednisolone)
PREFERRED GLUCOCORTICOIDS
Uses
Hydrocortisone (cortisol)
Replacement in both primary and secondary adrenocortical deficiency states and CAH
Fludrocortisone
Primary adrenocortical deficiency states and salt wasting CAH
Prednisone (prednisolone)
Autoimmune diseases, Organ transplantation, Lymphoma/leukemia, Bronchial asthma
Triamcinolone
Autoimmune diseases
Betamethasone Dexamethasone
Antenatally in premature labor to improve lung function
Other uses of glucocorticoids
Temporal arteritis, Hypercalcemia
Most effects are due to direct actions. Many of the effects of steroids are dose related.
Some effects are called permissive – In the absence of which many normal functions becomes deficient.
For eg., the response of vascular and bronchial smooth muscle to catecholamines are diminished in the absence of glucocorticoids. The lipolytic responses of fat cells to catecholamines and ACTH are attenuated in the absence of glucocorticoids.
Potassium loading increase the aldosterone synthesis independent of renin activity. ACTH plays only a minor role in physiological synthesis of aldosterone.
Aldosterone do not negatively regulate ACTH secretion.
CAH and polycystic ovarian disease are related to increased adrenal androgen production. CAH treatment is aimed at glucocorticoid replacement which suppress excessive hypothalamic and pituitary release of CRH and ACTH resulting in decreased androgen production.

26. Worsening of diabetes mellitus Peptic ulceration, perforation
GLUCOCORTICOIDS
ACTIONS
Unwanted Effects
Immunosuppression
Infections
Muscle protein breakdown is increased
Proximal myopathy
Increased vascular reactivity and mineralocorticoid activity
Hypertension
Glucocorticoids stimulate gluconeogenesis and decreased glucose utilization
Worsening of diabetes mellitus
Stimulates the gastric acid and pepsin production.
Peptic ulceration, perforation
Both lipogenesis and lipolysis are stimulated with net increase in fat deposition in face and shoulder
Central Obesity, Buffalo hump
Catabolic effect on the bone and it antagonize the effect of vitamin-D on calcium absorption.
Osteoporosis leading hip fractures
Avascular necrosis of bone
Most effects are due to direct actions. Many of the effects of steroids are dose related.
Some effects are called permissive – In the absence of which many normal functions becomes deficient.
For eg., the response of vascular and bronchial smooth muscle to catecholamines are diminished in the absence of glucocorticoids. The lipolytic responses of fat cells to catecholamines and ACTH are attenuated in the absence of glucocorticoids.
Potassium loading increase the aldosterone synthesis independent of renin activity. ACTH plays only a minor role in physiological synthesis of aldosterone.
Aldosterone do not negatively regulate ACTH secretion.
CAH and polycystic ovarian disease are related to increased adrenal androgen production. CAH treatment is aimed at glucocorticoid replacement which suppress excessive hypothalamic and pituitary release of CRH and ACTH resulting in decreased androgen production.

27. ADRENAL STEROID SYNTHESIS INHIBITORS
TRILOSTANE: inhibitor of 3 beta hydroxysteroid dehydrogenase.

29. ADRENAL ADENOMA HIGH CORTISOL CHECK ACTH High Low
HIGH DOSE DEXAMETHASONE SUPPRESSION TEST
THE RELATIONSHIP BETWEEN HYPOTHALAMIC HORMONES AND PITUITARY IS NOT ALWAYS 1:1 AND NOT ALWAYS STIMULATORY.
TRH NOT ONLY STIMULATES TSH SECRETION BUT ALSO CAUSE RELEASE OF PROLACTIN.
THUS THERE IS OVERLAP BETWEEN THE HORMONES.
ADENO AND NEURO HYPOPHYSIS DENOTES …. BUCCAL AND NEURAL ECTODERM ORIGIN.
Oxytocin and ADH hormones are synthesized by the supraoptic and paraventricular nucleus of the hypothalamus and transported to posterior pituitary for release.
GH and prolactin act on JAK / STAT superfamily (janus kinase/ signal transduction and activators transcription).
FSH, TSH and LH have common alpha sub unit and differ in beta sub unit.
These three hormones act on G protein receptors. ACTH also act on G protein coupled receptor.
ADRENAL ADENOMA
SUPPRESS
CORTISOL
> 50%
NO SUPPRESS
CORTISOL
PITUITARY ADENOMA
ECTOPIC ORIGIN

30. Adrenal steroid synthesis inhibitors
Metyrapone : is a selective inhibitor of glucocorticoid synthesis.
It mainly inhibits 11-β hydroxylation, the final step in glucocorticoid pathway.
Used in the diagnosis of pituitary ACTH reserve and treatment of cushing’s syndrome.
Major adverse effects are salt and water retention and hirsutism.
Metyrapone blocks cortisol synthesis by inhibiting steroid 11β-hydroxylase. This stimulates ACTH secretion, which in turn increases plasma 11-deoxycortisol levels. When excess ACTH secretion is the cause of hypercortisolism, the metyrapone test helps clarify if the source of the ACTH is pituitary or ectopic (non-pituitary). Those with pituitary dependent cushing’s syndrome exhibit a normal response and those with ectopic ACTH secretion exhibit no change in ACTH or 11-decoxycortisol levels.
METAPYRONE CAUSE DISINHIBITION OF ACTH SECRETION BY BLOCKING FEED BACK INHIBITION OF CORTISOL AND CAN BE USED AS TEST OF ACTH RESERVE .
Major adverse effects are salt and water retention and hirsutism resulting from diversion of 11-deoxycortisol precursor to DOC and androgens.
GENERAL PRINCIPLES :
Metyrapone blocks the conversion of 11-deoxycortisol to cortisol by CYP11B1 (11-beta-hydroxylase, P-450c11), the last step in the synthesis of cortisol, and induces a rapid fall of cortisol and an increase of 11-deoxycortisol in serum.
Because it is essentially devoid of glucocorticoid activity, 11-deoxycortisol does not inhibit ACTH secretion. Thus, in healthy individuals, the fall in serum cortisol concentrations leads sequentially to increases in ACTH secretion, adrenal steroidogenesis, and the secretion of cortisol precursors, in particular, 11-deoxycortisol, the substrate of CYP11B1, which can be measured by radioimmunoassay, HPLC, or in urine as a 17-hydroxycorticosteroid (17-OHCS) .
The increase in serum 11-deoxycortisol concentrations or in urinary 17-OHCS excretion provides an index of the increase in ACTH release; a failure of these values to rise can indicate either ACTH deficiency or primary adrenal disease.

31. Adrenal steroid synthesis inhibitors
Aminoglutethimide :
It blocks the conversion of cholesterol to pregnenolone, an early and rate limiting enzyme (SCC) in steroid synthesis.
It also inhibits aromatase which converts androgens to estrogen (low dose).
It is used in the treatment of breast cancer and cushing’s syndrome.
Aminoglutethimide is also an inhibitor of aromatase activity. Intravenous etomidate is the most potent adrenostatic drug available and is probably the treatment of choice to rapidly control severe life-threatening hypercortisolism.
Aminoglutethimide is abused by body builders and other steriod users to lower circulating levels of cortisol in the body and prevent muscle loss. Cortisol is catabolic to protein in muscle and effective blockade of P450scc by aminogluthethimide at high doses prevents muscle loss.

32. Adrenal steroid synthesis inhibitors
Ketoconazole :
It inhibits primarily CYP17 (17α-hydroxylase) required for the adrenal and gonadal androgen synthesis at doses higher than those employed for antifungal therapy.
At even higher doses, it inhibits CYP11A1 (SCC), effectively blocking steroidogenesis.
It is well tolerated and used in the treatment of hypercortisolism.
Doses higher than that used in antifungal therapy is required in Cushing's syndrome.
Low dose decrease the adrenal androgens ( blocking 17alpha hydroxylase)
High dose decrease the synthesis of all adrenal steroids ( blocking CYP 11 A 1, also known as desmolase)
The sensitivity of the ketoconazole to the inhibition of cytpP450 enzymes is low and seen at high doses.

33. Antagonist of Adrenal steroids
Mifepristone : Progesterone antagonist
Anti-progesterone activity by blocking the receptor.
High doses exerts anti-glucocorticoid activity.
It is used mainly to induce early abortion upto 49 days (along with misoprostol, PGE-1).
Black box warning for vaginal bleeding and infections

34. Mineralocorticoid antagonists
Spironolactone :
It competes with aldosterone binding site and decrease its effect.
It is used in the treatment of primary and secondary hyperaldosteronism
It is also an androgen antagonist and used in hirsutism.
Eplerenone is used in hypertension as it blocks aldosterone binding sites but has the advantage that it does not block androgen receptors.
it is named after Dr Jerome W. Conn ( ), the American endocrinologist who first described the condition at the University of Michigan in 1955.

35. Mineralocorticoid antagonists
Eplerenone is an aldosterone antagonist used as an adjunct in the management of chronic heart failure.
It is similar to spironolactone, more specific for the mineralocorticoid receptor.
It does not block androgen receptors.
Eplerenone is used in hypertension as it blocks aldosterone binding sites but has the advantage that it does not block androgen receptors.