Adrenal cortical Hormones – Glucocorticoids/Cortisole Lecture NO: - 2nd MBBS Dr Muhammad Ramzan

Adrenal/supra renal Gland It Is an endocrine gland situated at the upper pole of both kidneys - Right and left Is semi lunar in shape consisting of 2 distinct parts: the adrenal medulla and Cortex Its cortex secretes steroid hormones . Major 3 : Aldosterone, Cortisole, and Androgens Adrenal medulla secretes epinephrine and nor epinephrine

Adrenal Cortex – the histology Adrenal cortex comprises of 3 zones going from outside to inside and produce: Zona Glomeruloza = Minerolocorticoid - Aldosterone Zona Fasciculata = Glucorticoids - Cortisole Zona Reticularis = Androgens - Testosterone

Adrenal gland- Histology

Cortisole – the definition Cortisole is a steroid hormone secreted by the Zona Fasciculata of the adrenal cortex A Glucocoticoid that derives its name from its association with glucose metabolism 1 Its secretion from the adrenal cortex and 2 Steroidal nature 3

Cortisole – the background Regulates blood glucose level and metabolism Controls the salt water balance and BP Excess promotes weight gain in face, chest and abdomen Slender arms, legs and central obesity Cortisole is Known to suppress; Immunity, autoimmune diseases and Inflammation Acts as a stress hormone

Properties of Cortisole CH is the precursor for all steroid hormones Cortisole is Water soluble and exists in free and bound form Bound form are transported in the blood in combination with the plasma proteins – Albumen and Globulin Albumen is the common plasma protein carrier Globulin is the specific carrier protein for Cortisole

Cortisole - Biosynthesis CH is the primary precursor for the synthesis of Cortisole and takes place in the SER of Zona Fasciculata CH is converted to Pregnenolone and Progesterone and further to 17 α Hydroxy progesterone and Deoxycortisole Deoxycortisole is altered to Cortisole Major enzyme involved is the Cytochrome 450

Cortisole Biosynthesis

Target organs for Cortisole Target organs are the ones with Cortisole receptors. Are different from other steroids (GCR- GPCR) All the animal cells have Cortisole receptors Major ones are the : Liver; Adipose tissues, muscles CNS : Hypothalamus and anterior pituitary gland CVS: Cardiac and vascular smooth muscles Immune system; B,T lymphocytes and Plasma cells

Cortisole – the Regulation Cortisole is regulated through – negative feed back It is achieved by 2 pathways 1. Neuroendocrine/Long loop/Indirect pathway Short loop/direct pathway

Neuroendocrine/long loop pathway Hypothalamic – Pituitary – Adrenal- axis This is the interaction B/W circulating level of Cortisole and Corticotrophin Releasing hormone (CRH) from the hypothalamus The deficiency of Cortisole ↑the hypothalamic CRH leading to the ↑ the ACTH from Pituitary to ↑Cortisole from Adrenal Cortex Opposite is true when Cortisole is high

Short loop / Direct pathway Pituitary – Adrenal- Cortisole axis This is the interaction B/w circulating level of Cortisole and ACTH from anterior pituitary gland Deficiency of Cortisole leads to ↑ the ACTH from the Pituitary and Cortisole from Adrenal cortex Opposite is true when Cortisole is high

Regulation of Cortisone

Cortisole - Mechanism of action activation of genes Cortisole is a steroid and its mechanism of action is similar to the rest of the steroids (activation of genes) Cortisole binds with the Cytoplasmic receptors to form HRC that is translocated to the Acceptor site at Nucleus to form HRE - the gene Transcription of mRNA leads to the expression of Protein/Enzymes that carry out Cortisole action

Mechanism of action of Cortisole

Metabolic effects of Glucorticoids Cortisole affect all the body cells as most of them have steroid receptors Major metabolic effects of Cortisole are on : Protein metabolism Lipid metabolism Carbohydrate metabolism Immune system and development of lungs

Effects on protein metabolism Cortisole promotes Proteolysis to divert amino acids for hepatic Gluconeogenesis AAs are mobilized from the breakdown of extra hepatic tissues like Skeletal muscles to ↑ AAs level Free AAs are prevented from their entry into the cell and inhibits Proteogenesis

Metabolic effects on lipid metabolism Cortisole stimulates the break down of fats/lipolysis in adipose tissue and Releases: Glycerol, free fatty acids and elevates their level in blood and satisfies energy needs of the body Glycerol is used for Gluneogenesis

Effects on carbohydrate metabolism Cortisole inhibits glucose uptake by extra hepatic tissues like : the muscles and adipose tissues Inhibits Glycolysis,↑ blood glucose level – is hyperglycemic Cortisole ↑ Gluconeogenesis by ↑ the enzymes involved The AAS are released by the Proteolysis of the skeletal muscles of the body

Effects on Immune system Cortisole has potent anti-inflammatory and immuno- -suppressive properties. This is particularly evident when they are administered at pharmacologic doses Consequently, Cortisole is widely used as : drugs for the treatment of allergies; hypersensitivity and Auto Immune diseases like Rheumatic fever/ arthritis, Glomerunephritis and graft rejection

Effects on immune systems- the mechanism Cortisole suppresses the immune system by: Muting the white blood cells 1 Reduces the their production from the bone marrow Inhibits IgA secretion in serum Reduces Collagen fiber synthesis and wound repair

Effects on the development of Lungs Cortisole is essential for the maturation and function of the lungs especially in premature infants This is due to the synthesis of Surfactant , a molecule essential to prevent the collapse of the lungs Also called as Respiratory distress syndrome Cortisole is given to the expectant mothers to prevent the deficiency of surfactant in premature infants

Abnormalities of Cortisole production It is the ability of adrenal gland to produce its hormones that are either too high or too low for the body requirements Cortisole is secreted either in excess or there may be deficiency of Cortisole Excess of Cortisole is called Cushing's syndrome Deficiency is referred to Addison disease

Excess – Cushing's Syndrome is a metabolic disorder caused by the excess of the Cortisole from the adrenal cortex It is associated with obesity, DM and hypertension Causes are : Exogenous and endogenous Exogenous : Long term use of oral Cortisole Endogenous: Pituitary/Adrenal adenomas/ectopic tumours www.medicineplus.gov

Features of Cushing's syndrome It is common in adults and women Obesity, hypertension and diabetes mellitus Buffalo hump – A fatty mass B/W the shoulders Slender legs and arms Rounded moon like faces Purple/Pink stretch marks over the abdomen; chest thighs and arms. Skin is thin and easily bruise able www.mayoclinic.org

Diagnosis of Cushing syndrome Comparison of old and fresh photographs 24 hour urine collection for the Cortisole estimation Low dose (1mg) Dexamethasone suppression test: 1mg Dexamethasone, dose at 11PM and blood Cortisole estimation at 8AM of the following morning Low level of Cortisole suggestive of Cushing disease www.Pituitary Network Association

Cushing's syndrome – Central obesity

Moon like face with Facial plethora

Buffalo hump

SKIN stretches

Deficiency of Cortisole - Addison's' disease A British physician It is an endocrine disorder in which adrenal glands produce less steroids than body requirements Major cause is the auto immune disease of the adrenals May be associated with Aldosterone deficiency Characterized by the weight loss; muscle wasting, hypotension Hypoglycemia, Abdominal pain and vomiting

Diagnosis of Addison disease blood examination reveals : Low sodium, Cortisole and ACTH Elevated Potassium and www.addison.org

Feature of Addison's disease

Addison's disease – John F. Kennedy

Addison disease

Hyper pigmentation in Addison disease