Steroidal Hormones

steroid nucleus

• 17 carbon nucleus

• 4 fused ring systems

cholestane nucleus

• animal steroid

• 27 carbons

• cholesterol

• 8 carbon aliphatic tail on C17

Pregane nucleus

• 21 carbons

• progesterone and corticosteroids

• ethyl on C17

Estrane nucleus

• 18 carbons

• estradiol

• C18 methyl

Androstane nucleus

• 19 carbons

• testosterone

• C18 and C19 methyl

What are the 2 major steroidal homrones?

1. corticosteroids

2. sex hormones

What are the 2 subclasses of corticosteroids?

1. mineralocorticoids (MC)

2. glucocorticoids (GC)

Glucocorticoids and mineralocorticoids are both synthesized from the precursor ______.

corticosterone

Corticosterone

• pregnane nucleus (21 C)

• 2 ketone groups @ C3 and C20

• double bond between C4 and C5

• 2 hydroxyl groups @ C11 and C21

• 2 angular methyl groups @ C18 and C19

T/F: Corticosterone has a cholestane nucleus.

FALSE → pregnane nucleus

Describe how mineralocorticoids and glucocorticoids differ.

OXIDATION STATUS @ C17 and C18

• MC:

  • C18 methyl → oxidation → aldehyde

• GC:

  • C17 hydrogen → oxidation → OH

Aldosterone

• mineralocorticoid

• C18 methyl oxidation of corticosterone → aldehyde

• increases BP by promoting Na + H2O retention

• 100:1 activity (MC:GC)

• only used in adrenal insufficiency (Addison’s)

hydrocortisone

• starting point for all glucocorticoids

• C17 hydrogen oxidation of corticosterone → hydroxyl

Cortisone

• GC

• HC with C11 oxidized into ketone

• slightly more lipophilic than HC

• no difference in activity

Fludrocortisone

• GC

• HC with fluorine at C9

• increased lipophilicity → better absorption

• 10x more glucocorticoid effect

• 300x more mineralocorticoid effect

• better drug for adrenal insufficiency vs aldosterone

T/F: Fludrocortisone has more glucocorticoid activity than mineralocorticoid activity.

FALSE

• 300x more MC activity

Prednisolone

• GC

• HC with additional double bond @C1-C2

• 10:1 GC to MC activity

  • may lead to elevated BB

prednisone

• GC

• ketone

  • OH of prednisolone oxidized

• no difference in activity

Triamcinolone

• GC

• HC with 3 modifications:

  • C1-C2 double bond

  • fluoro @ C9

  • additional OH @ C-16

• highly polar molecule → poor bioavailability

What is the significance of the additional OH at C-16?

• eliminated all MC effects but still maintained very high GC effects

• makes drug highly polar (4 OHs)

What are the advantages of eliminating all MC effects but maintaining high GC effects?

decreases in:

• H2O retention

• edema

• BP elevations

What is the disadvantage of triamcinolone?

highly polar → poor bioavailability

Triamcinolone Acetonide

• GC

• acetonide group

  • formed from interactions w/ C16 and C17 OH groups + acetone

• increased lipophilicity → enhanced absorption

How does the structure of triamcinolone acetonide allow for enhanced absorption?

eliminates 2 polar groups by forming acetonide + increasing # of Carbons

→

increases lipophilicity

Dexamethasone

• GC

  • bioisoteric replacement of C16 OH of triamcinolone → methyl

• C16 methyl → increases lipophilicity

  • alpha orientation

Betamethasone

• GC

  • exactly like dexamethasone BUT methyl group in Beta orientation

• no difference in activity

T/F: Dexamethasone has a methyl in the beta position, while Betamethasone has a methyl in the alpha position.

FALSE

• dexmethasone → alpha

• betamethasone → beta

Beclomethasone dipropionate

• GC

• Cl substitution @ C9 (instead of fluoro)

  • increases lipophilicity

• 2 ester groups

  • volatile material → used for asthma

Fluocinolone Acetonide

• 2 fluoro groups @ C6 and C9

• acetonide

• increased lipophilicity

Clobetasol

• fluoro @ C9

• Cl @ C21

  • bioisotere w/ OH

• mono propionate ester @C17

  • increased lipophilicity → increased penetration thru skin

Mometasone

• C9 chloro

• C21 chloro

• C17 furoate ester (furoate + 2 COOHs)

• used as aerosol for asthma

Disodium hydrocortisone phosphate

• water soluble injection

  • ester made from C21 OH + acidic proton of phosphoric acid

  • other protons of phosphoric acid → sodium salts

sodium hydrocortisone succinate

• water soluble injection

  • ester made from C21 OH + acidic proton of succinate

  • other protons of succinate → sodium salts

What are the 4 subclasses of reproductive hormones?

1. estrogens

2. progestins

3. androgens

4. anabolic steroids

What are estrogens?

• female sex hormones

  • promotes development + maintenance of female sex characteristics in puberty

  • promotes conversion of follicles into ovum post puberty

  • essential for bone growth

• used in OCs

  • treats uterine cancer

  • prevents osteoporosis

Describe the biosynthesis of estrogens in the HPA axis.

1. hypothalamus

   1. FSH releasing factor

2. pituitary

   1. FSH

3. ovaries

   1. estrogen

4. follicle conversion to ovum

T/F: the parent nucleus for estrogens is estrane.

TRUE

What are the key structural features of estrogens?

estrane (18 carbon nucleus) + aromatic ring A w/ phenolic OH @ C3

Estradiol

• estrane nucleus

• OH @ C3 and C17 (diol)

• Dose: 0.1 mg

  • if PO → 1.2 mg x 10

How will this drug be metabolized?

estradiol

• oxidation of OH @ C17 → ketone → estrone

  • much less active than estradiol

• phase 2 conjugation w/ sulfate group of OH @ C3

Estrone

• minor female hormone

• less active than estradiol

• ketone

  • product of oxidation of C17 OH on estradiol

Estriol

• minor female hormone

• inactive product produced by hydration of estrone