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151

ANTI-INFLAMMATORY and IMMUNOSUPPRESSIVE ACTIONS of Cortisol

- ↓ production of proinflammatory cytokines
- ↑ production of anti-inflammatory cytokines
- Stabilizes lysozomal membranes ↓ release of proteolytic enzymes that augment local swelling
- Inhibit leucocyte migration to site of injury

152

ANTI-INFLAMMATORY and IMMUNOSUPPRESSIVE ACTIONS of Cortisol

- Inhibit phagocytic activity of neutrophils
- At high levels:
↓ circulating T-lymphocytes (esp. helper T cells)
↓ ability of T-lymphocytes to migrate to site of antigenic stimulation
- Promote atrophy of thymus and other lymphoid tissue
- Inhibit cell-mediated immunity

153

- has an almost global effect in reducing all aspects of inflammatory process
- does not impair antibody production by B-lymphocytes

Cortisol

154

ACTIONS ON REPRODUCTIVE SYSTEM of Cortisol

- depress reproductive behavior and function
↓ the function of the reproductive axis at the hypothalamic, pituitary and gonadal levels

155

ACTIONS ON BONE METABOLISM of CORTISOL

- ↑ bone resorption
- Inhibit osteoblast bone-forming functions

156

How does Cortisol increase bone resorption?

- ↓intestinal Ca+2 absorption
- ↓ renal Ca+2 reabsorption
- As a result: Lower serum Ca+2 ↑ PTH secretion

157

ACTIONS ON THE KIDNEYS of CORTISOL

- Inhibit secretion and action of ADH (thus ADH antagonist)
- ↑ GFR by increasing cardiac output and acting directly on the kidney (Vasodilation of the afferent arteriole)

158

CORTISOL: EFFECTS ON THE CNS

Glucocorticoid receptor in the limbic system
1. Decreases REM sleep
2. Increases slow-wave sleep
3. Increases awake time

159

CORTISOL: ACTIONS ON FETAL DEVELOPMENT

- Required for normal development of CNS, retina, skin, GI tract and lungs
- In the lungs, induces differentiation and maturation of type II alveolar cells

160

How does Cortisol affect the Connective tissue?

Inhibit fibroblast proliferation and collagen formation

161

Action of Cortisol in Gastrointestinal tract?

1. Trophic effect on GI mucosa
2. Stimulates appetite
3. Stimulates gastric acid and pepsin secretion

162

Cortisol: Regulation of secretion

1. Regulated by hypothalamus-pituitary-adrenal axis
Hypothalamus: corticotropin-releasing hormone/factor (CRH)
Pituitary gland: adrenocorticotropic hormone
2. Almost entirely controlled by ACTH from anterior pituitary
3. Norigenic and systemic stress
4. strong diurnal rhythmic regulation from suprachiasmatic nucleus
5. CRH chronically increases proopiomelanocortin (POMC) gene expression

163

- surges early predawn and morning hours then decline continually throughout the day and night

Cortisol

164

is the precursor of ACTH and other peptides such as melanocyte-stimulating hormone (MSH)

proopiomelanocortin (POMC)

165

Immediate of Acute effects when ACTH binds to melanocortin 2 receptor (MC2R) of the zona fasciculata

1. Cholesterol is rapidly mobilized from lipid droplets
- activation of cholesterol ester hydrolase
2. Cholesterol is rapidly transported to mitochondrial membrane - Rapidly increases StAR protein gene expression and activates StAR protein
3. Ultimately increase pregnenolone

166

Chronic effects when ACTH binds to melanocortin 2 receptor (MC2R) of the zona fasciculata

1. ↑ gene transcription of steroidogenic enzymes and their coenzymes
2. ↑ expression of LDL and HDL receptors

167

Long term effects when ACTH binds to melanocortin 2 receptor (MC2R) of the zona fasciculata

Trophic actions on zona fasciculata and reticular
- ↑ size and functional complexity of organelles
- ↑ size and number of cells

168

- Produces dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione

- Only small amounts of potent androgens are normally produced by adrenal cortex

- In females, adrenal androgens are major androgens
For pubic and axillary hair
For libido

Adrenal androgens

169

- main product adrenal androgen
- Become detectable at ~6 years old: adrenarche
- Continually increase, peak during mid-twenties and progressively decline with age (DHEA exhibit same pattern)
- Most abundant circulating hormone in young adults

DHEAS

170

Formation of DHEA and DHEAS

1. Zona reticularis expresses cofactors or conditions that enhance the 17,20-lyase function of CYP17, generating DHEA from 17-hydroxypregnenolone

2. expresses DHEA sulfotransferase (SULT2A1 gene), which converts DHEA into DHEAS

3. 3β-HSD is expressed at much lower levels
-androstenedione is a minor product compared to DHEAS and DHEA

171

Metabolism and fate of DHEAS and DHEA

1. DHEAS can be converted back to DHEA by peripheral sulfatases

2. DHEA and androstenedione can be converted to active androgens (testosterone and dihydrotestosterone) peripherally in both sexes

3. DHEA binds to albumin and other globulins in blood with low affinity so efficiently excreted by the kidney
half-life: 15-30 mins

4. DHEAS binds to albumin with high affinity
half-life: 7-10 hours

172

Contribution of adrenal androgens to active androgens

Men: negligible
Women: for the growth of axillary and pubic hair and for libido

173

Regulation of secretion of DHEAS and DHEA

1. ACTH: primary regulator
zona reticularis shows the same atrophic changes as the zona fasciculata in conditions with little or no ACTH

2. DHEA and androstenedione display same diurnal pattern as cortisol

174

Other unknown factors regulate zona reticular function (DHEAS and DHEA)

1. Adrenarche occurs in the face of constant ACTH and cortisol levels

2. Rise and decline of DHEAS is not associated with a similar pattern of ACTH and cortisol production

175

The adrenal cortex secretes an entirely different group of hormones, called __

corticosteroids

176

21-B-Hydroxylase

Aldosterone: Decreased
Cortisol: Decreased
Androgens: Increased
ACTH: Increased
Blood Pressure: Decreased
Accumulating substrate: 17-hydroxyprogesterone

177

11-B-Hydroxylase

Aldosterone: Decreased
Cortisol: Decreased
Androgens: Increased
ACTH: Increased
Blood Pressure: Increased
Accumulating substrate: 11-deoxycorticosterone

178

17-alpha-Hydroxylase

Aldosterone: Increased
Cortisol: Decreased
Androgens: Decreased
ACTH: Increased
Blood Pressure: Increased
Accumulating substrate: Pregnenolone

179

- One of the largest endocrine glands
- Located below the larynx on each side of the trachea
- Weighs 15 to 20g in adults

Thyroid Gland

180

(Thyroid Gland)
secrete hormones, cuboidal (inactive) to columnar (active)

Follicular Cells