1) Adrenal Gland & their drugs

What are the roles played by estrogens and androgens?

• conception

• embryonic maturation

• development of 1er & 2er sexual characteristics at puberty

List the main therapeutic uses of Estrogens and Androgens.

• Contraception

• HRT

• Manage menopause sx

What is Estradiol?

→ most potent estrogen

• principal estrogen in premenopausal women

What is Estriol?

→ metabolite of estradiol that’s significantly less potent

• present in significant amounts during pregnancy b/c it’s synthesized by the placenta

What is ethinyl estradiol and its advantage over naturally occurring estrogens?

→ synthetic estrogen

(+) undergoes less first-pass metabolism than naturally occurring hormones → effective at lower oral doses

What are the main menopausal sx?

• vasomotor instability ("hot flashes")

• vaginal atrophy

Identify 2 estrone-based oral preparations for postmenopausal HT.

1. Esterified estrogens

2. Estropipate

How does estrogen minimizes the risk of osteoporosis and hot flashes?

🦴 Osteoporosis — by ↓ bone resorption

🥵 Hot flashes — by reestablishing feedback on hypothalamic control of NE secretion → ↓ flashes freq

Why are bisphosphonates preferred over estrogens for treatment of osteoporosis?

b/c estrogen therapy is assoc with risks (e.g., cardiovascular events & breast cancer)

What is the advantage of adding a progestogen with estrogen?

↓ endometrial carcinoma risk that’s assoc with unopposed estrogen therapy

What are the advantages of synthetic estrogens over natural estrogens?

• well absorbed orally

• fat-soluble (allowing storage in adipose tissue and slow release)

• prolonged action

• higher potency

Identify 5 major side effects of estrogens.

1. Breast tenderness

2. Thromboembolism

3. HTN

4. Fluid retention

5. MI

What are the adverse effects of Tamoxifen?

• hot flashes

• nausea

• endometrial malignancies

When are progestogens released and where it synthesized?

→ released in response to LH

• Synthesized by: ovaries (females), testes (males), & adrenal cortex (both sexes)

What is the main role of progestogens?

promote a secretory endometrium for embryo implantation

How does conception influence progesterone levels?

→ progesterone levels continue to be secreted to maintain the endometrium and ↓ uterine contractions

• ↓ progesterone → menstruation

Name 4 synthetic progestogens and 1 injectable form of progestogen.

Synthetic

1. Levonorgestrel

2. Norgestrel

3. Norethindrone

4. Norethindrone acetate

.

Injectable form

1. Medroxyprogesterone acetate

What are the complications of administering mifepristone?

• abdominal pain

• uterine bleeding

• incomplete abortion

Name some common estrogens and progestins included in oral contraceptives.

Estrogens - Ethinyl estradiol

Progestins - norgestimate, norethindrone, norethindrone acetate, levonorgestrel

What does the transdermal patch for contraception contain? How is it used?

→ contains ethinyl estradiol & norelgestromin

• applying one patch weekly for 3 weeks, followed by one week with no patch

Name the progestin included in IUD. In what category of patients is it contraindicated?

→ contains levonorgestrel

• Contraindicated in: pt with pelvic inflammatory disease or ectopic pregnancy hx

What are the 2 main effects of androgens? How is testosterone release regulated?

→ have anabolic and/or masculinizing effects

• Hypothalamus releases GnRH

• GnRH travels to anterior pituitary stimulates FSH & LH secretion

• LH produces testosterone

• Testosterone or its active metabolite (DHT) provides (-) feedback to inhibit these hormones

How is DHT formed?

Testosterone → DHT by 5α-reductase in target cells (prostate, seminal vesicles, epididymis, skin)

What are Androgenic steroids used for?

males with 1er or 2er hypogonadism

What is the role of DHEA and Danazol?

DHEA: androgen secreted in small amounts by the testes

Danazol: weak androgen used to treat endometriosis & fibrocystic breast disease

What are the routes by which testosterone can be administered?

• oral (derivatives)

• intramuscular (esters)

• transdermal patch/gel

• buccal tablet

• implantable pellet

Why is Testosterone ineffective orally?

due to inactivation by first-pass metabolism

Provide 2 examples of orally administered testosterone derivatives.

1. Methyltestosterone

2. Fluoxymesterone

Why should testosterone not be used by pregnant women?

causes virilization of a female fetus

What are the risk factors associated with testosterone replacement therapy?

• ↑ MI & stroke risk

• Edema

• ↑ serum LDL

• ↓ serum HDL

What are the hormones coming out of 3 zones of adrenal cortex? Give their role.

1. Outer zona glomerulosa: produces mineralocorticoids (e.g., aldosterone) to regulate salt and water metabolism

2. Middle zona fasciculata: produces glucocorticoids (e.g., cortisol) for metabolism and stress response

3. Inner zona reticularis: secretes adrenal androgens

How is the release of ACTH and CRH regulated?

1. Hypothalamus releases CRH to stimulate the pituitary to release ACTH

2. Glucocorticoids inhibit ACTH and CRH secretion via (-) feedback

   

How does cortisol release vary?

→ diurnal release

1. Cortisol peak (early morning)

2. Decline

3. 2^nd smaller cortisol peak (late afternoon)

What is the influence of glucocorticoids on intermediary metabolism?

Provide glucose for energy via:

• stimulate gluconeogenesis

• mobilize AA

• stimulate lipolysis

How do glucocorticoids help combat stress?

provide energy by ↑ [glucose]_plasma

What role do Glucocorticoids play in anti-inflammatory action?

inhibit phospholipase A2 → blocks arachidonic acid release

What are the main effects of aldosterone?

• Na⁺, HCO₃^-, H₂O reabsorption

• K⁺, H+ excretion in urine

List 3 consequences of elevated Aldosterone levels.

1. Alkalosis & hypokalemia

2. Na⁺ & H₂O retention

3. ↑ BV & BP

What drug treats Hyperaldosteronism (↑ aldosterone levels)?

Spironolactone

What is the main cause of Cushing’s syndrome? How is it diagnosed?

→ hypersecretion of glucocorticoids due to ACTH excess, adrenal tumors, or chronic high-dose glucocorticoid treatment

• diagnosed using Dexamethasone (this suppresses cortisol in normal pt but not in Cushing’s pt)

How is hydrocortisone dosed to match normal diurnal variation of cortisol?

2/3 dose given in morning

1/3 dose given in afternoon

What is CAH (Congenital adrenal hyperplasia)? How is it treated?

→ enzyme defect in steroid synthesis that can cause virilization in females

• Treatment: corticosteroids to suppress CRH/ACTH & normalize hormone levels

What is the role of fetal cortisol in development?

Fetal cortisol regulates lung maturation

How can respiratory distress syndrome in fetus be minimized?

administering betamethasone or dexamethasone intramuscularly to the mother 48 hours before premature deliver

What are the common routes by which corticosteroids are administered?

• Oral

• IV

• IM

• Intra-articular

• Intranasal

• Inhalation*

• Topical*

What effect do topical and inhaled glucocorticoids have on the HPA axis?

suppress HPA axis b/c its absorbed systemically

When does suppression of HPA axis occur? How is it prevented?

→ occurs when large doses are required for more than 2 weeks

• can be prevented by alternate-day administration

How do glucocorticoids induce osteoporosis?

• suppress intestinal Ca²⁺ absorption

• inhibit bone formation

• ↓ sex hormone synthesis

How glucocorticoids induced Osteoporosis is it treated?

• Ca²⁺/vitamin D supplements

• bisphosphonates

Identify the key adverse effects of corticosteroids.

• osteoporosis

• Cushing-like syndrome (fat redistribution, puffy face)

• cataracts

• hyperglycemia/diabetes

• impaired wound healing

Why is sudden discontinuation of steroids dangerous? How can it be prevented?

→ causes fatal acute adrenal insufficiency if the HPA axis is suppressed

• prevented by tapering the dose slowly

Name the drugs useful for inhibition of adrenocorticoid synthesis.

1. Ketoconazole

2. Spironolactone

3. Eplerenone

Give the 3 main adverse effects of spironolactone.

• Hyperkalemia

• Gynecomastia

• Menstrual irregularities & skin rashes

What is the advantage of using eplerenone in place of spironolactone?

highly specific for the mineralocorticoid receptor → avoids the gynecomastia associated with spironolactone