steroidal hormones

describe the parent nucleus of steroidal hormones

• 17 carbon nucleus w/ 4 fused ring systems

C21: the nucleus is called ______. IT is the parent nucleus of …

• pregnane nucleus

  • progesterone and corticosteroids

C19: the nucleus is called ______. IT is the parent nucleus of …

is called ______

• androstane nucleus

  • androgens (ex. testosterone)

C18: the nucleus is called ______. IT is the parent nucleus of …

• estrane nucleus

  • estrogens (ex. estradiol)

steroidal hormones include 2 major bio-molecules …

• corticosteroids

• reproductive hormones

both types of corticosteroids are biosynthesized from the same precursor known as …

• corticosterone

describe the features of corticosterone

• pregnane nucleus (21 C)

• 2 ketone groups at C3 + C20

• double bond between 4-5

• 2 hydroxyl groups at C11 + C21

• methyl groups (C-18 + C-19)

how do mineralocorticoids and glucocorticoids differ in structure?

• mineralo = C18 methyl oxidation → aldehyde

• gluco = C17 oxidation → OH

what is the role of aldosterone?

• regulates BP by promoting Na+ ion retention (and water retention) → increased BP

Aldosterone is useful for the treatment of….

• adrenal insufficiency (Addison’s disease)

what is the primary glucocorticoid biologically synthesized?

• hydrocortisone

what is the purpose of the structural modifications to corticosterone?

• to suppress mineralocorticoid activities for safer use of treatment of inflammation

T/F: hydrocortisone has no mineralocorticoid activity

• false

  • has considerable mineralocorticoid activity

difference between hydrocortisone and cortisone

• cortisone = C11 = ketone (oxidation)

• hydrocortisone = C11 = OH

is hydrocortisone or cortisone more lipophilic?

• cortisone

  • OH → ketone

what is the difference between hydrocortisone and fludrocortisone

• fludrocortisone = added a fluorine at position 9

  • hydrocortisone = H

describe the effects of fludrocortisone. what is it useful for?

• more mineralocorticoid effect than glucocorticoid effect

  • 300x versus 10x

• better drug for adrenal insufficiency (Addison’s disease)

prednisolone structure vs hydrocortisone

• prednisolone = additional double bond at C1-C2

prednisolone vs prednisone

• prednisone = ketone (C11) equivalent of prednisolone

  • NO difference in activity between each other

describe the effects of prednisolone / prednisone

• high ratio of gluco:Mineralo activity (10:1)

  • still considerable minero activity

  • may lead to elevated BB (?)

describe the structure of triamcinolone

• fludrocortisone w/ an additional OH at C-16

what is the role of the additional C-16 OH In triamcinolone?

• almost 0 mineralocorticoid effects w/ high glucocorticoid activity

what are the modifications to get triamcinolone from HC ?

• C-1-2 double bond

• C9 fluoro

• C16 OH

what is the issue with triamcinolone?

• a lot of polar groups (4 OH Groups) → bioavailability issue

dexamethasone structure changes compared to HC

• bio-isosteroic replacement of C16 OH → Methyl

  • increased lipophilicity

• double bond C1-2

• C9 = fluoro

betamethasone structure description

• same as dexamethasone but has C16 methyl in beta position

  • different stereochemistry

betamethasone structure changes compared to HC

• C16 methyl (beta)

• C9 Fluoro

• C1-2 double bond

dexamethasone = ____ - methyl

betamethasone = ___ - methyl

• dexamethasone = alpha

• betamethasone = beta

is triamcinolone or dexamethasone better?

• dexamethasone

  • increased lipophilicity = decreased bioavailability issues

is triamcinolone or betamethasone better?

• betamethasone

  • increased lipophilicity = decreased bioavailability issues

T/F: dexamethasone and betamethasone have no difference in activity/properties

• true

beclomethasone dipropionate structure changes compared to HC

• C-9 chloro substitution

• C-21 + C17 = ester formations instead of OH

• C1-2 double bond

• C16 methyl

what is the benefit of the ester formations in beclomethasone dipropionate

• volatile material = very suitable for asthma

fluocinolone acetonide structure changes compared to HC

• C6 +C9 fluoro

• C16-17 OH → acetonide structure

• 1-2 double bond

Clobetasol structure differences compared to HC

• C9 = F

• C21 = Cl

  • bioisostere

• C17 = mono propionate ester at C17

• C1-2 double bond

• C16 methyl

mometasone structural changes compared to HC

• C9 + C21 = chloro

• C17 = furoate ester

• C16 methyl

• C1-2 double bond

which glucocorticoids have esters?

• clobetasol

• mometasone

• beclomethasone dipropionate

which glucocorticoids are prodrugs?

• dexamethasone

• betamethasone

• beclomethasone dipropionate

which of the following drugs has a furoate ester?

a) beclomethasone dipropionate

b) mometasone

c) clobetasol

d) dexamethasone

b) mometasone

which of the following drugs does NOT have C1-2 double bond?

a) prednisolone

b) mometasone

c) triamcinolone

d) fludrocortisone

d) fludrocortisone

SATA: which of the following drugs have C9 Cl instead of fluoro?

a) fluocinolone acetonide

b) mometasone

c) beclomethasone dipropionate

d) dexamethasone

b) mometasone

c) beclomethasone dipropionate

which of the following drugs has an acetonide?

a) fluocinolone acetonide

b) mometasone

c) beclomethasone dipropionate

d) dexamethasone

a) fluocinolone acetonide

which ring in estrogens is the only aromatic ring in the structure?

a) A

b) B
c) C

d) D

• a) A

what is the parent nucleus for estrogens?

• 18 carbon steroidal nucleus (estrane)

  • ring A = aromatic

  • phenolic OH at C3

what are estrogens clinically used for?

• oral contraceptives

• treatment of uterine cancer

• prevent osteoporosis

describe the structure of estradiol

• estrane nucleus

• OH groups at C3 + C17

  • “diol”

how is estradiol metabolized?

• C17 OH → ketone

  • liver makes estrone

what is the issue with estradiol?

• needs a higher dose because of very fast first-pass metabolism by CYP

  • oral dose

describe the structural differences between estrone and estradiol

• estradiol is metabolized → estrone

  • estradiol = C17 OH

  • estrone = C17 ketone

is estradiol or estrone more active?

• estradiol

estriol structure comparison to estrone and estradiol

• estriol = C17 OH + C16 OH + C3OH

• estradiol = C17 OH + C3 OH

• estrone = C17 ketone + C3 OH

what functional group is added to estrogens for oral use? what does it do?

• ethinyl group added to C17 (makes tertiary OH)

  • no FPM but same activity as estradiol

what is added to estrogens to make them for IM use?

• add a fatty acid w/ esters to C17

  • makes it an oily product → dissolves into muscles for IM injection

T/F: ethinylestradiol is a prodrug

• false

  • not a prodrug

what is the advantage of converting secondary OH to tertiary OH in estrogen

• no FPM

how is ethinylestradiol metabolized?

• goes to phase 2 metabolism from C3 OH

what functional group change in mestranol helps resist phase II-metabolism?

• C3 OH → ether

  • resists phase II metabolism

Mestranol metabolism

• needs to be metabolized back to ethinylestradiol by O-demethylation

what is Estropipate

• sulfate conjugate of estrone stabilizes as piperazine salt

• water soluble product given both IV or oral

Estrogens designed for use as IM depot preparation are ALL ______

• prodrugs

which of the following is not a prodrug?

a) Estradiol Valerate

b) Estradiol Enanthate

c) Ethinylestradiol

d) Estradiol Cypionate

c) Ethinylestradiol

what is the structure of Diethylstilbestrol (DES)

• 2 phenyl rings around a double bond

how to make an estrogen/corticosteroid for emergency IV use?

• OH → ester w/ phosphoric acid

  • need to be made into esters → water-soluble → use IV

why was Diethylstilbestrol (DES) not on the market anymore?

• association with ovarian and endometrium cancers

what are the functions of SERMs

• treatment of breast cancer

• preventing osteoporosis

how are SERMs given?

• orally

what type of drug is Chlortriansene

• SERM

what is the general structure of SERMs? what is the purpose of the specific parts?

• 3 phenyl groups around double bond

  • additional aromatic ring = increases lipophilicity = increases affinity = estrogen antagonist activity

Are SERMs good as contraceptives?

• no

how do SERMs help in the treatment of breast cancer?

• block estradiol receptors in the breast area

how do SERMs help in preventing osteoporosis

• stimulate synthesis of estrogenic receptors in bones + enhancing its sensitivity to estradiol

what type of drug is Tamoxifen?

• SERM

what type of drug is Raloxifene?

• SERM

which of the following is NOT a SERM?

a) Mifepristone

b) Chlortriansene

c) Tamoxifen

d) Raloxifene

a) Mifepristone

which SERM is mainly used for breast cancer?

a) Raloxifene

b) Chlortriansene

c) Tamoxifen

c) Tamoxifen

which SERM is mainly used for osteoporosis?

a) Raloxifene

b) Chlortriansene

c) Tamoxifen

a) Raloxifene

what are the 2 main uses of Progestins?

1. contraceptives

2. fix pregnancy (habitual abortion)

function of progesterone with fertilized ovum vs non fertilized ovum

• fertilized ovum = enhances/maintains pregnancy

• non fertilized = shed uterus wall / menses / period

T/F: Progesterone and estradiol are BOTH controlled through HPA axis

• true

how is Progesterone metabolized?

• liver metabolism → hydroxyprogesterone (active metabolite)

• C20 ketone enolyzes → inactive metabolite

what functional group in hydroxyprogesterone acetate makes it advantageous?

• C17 OH → ester (non-fatty/oily)

  • used orally

what is the benefit of the C17 OH added in hydroxyprogesterone

• no more H+ because of substitution = no enoylation = no deactivation

• equally active to progesterone w/ no FPM

which of the following progesterone is used IM?

a) Progesterone

b) hydroxyprogesterone

c) hydroxyprogesterone acetate

d) hydroxyprogesterone caproate

d) hydroxyprogesterone caproate

• has long fatty acid ester

what is ethisterone?

• orally stable derivative of hydroxyprogesterone

what is the drawback with ethisterone?

• similar backbone to testosterone (C19)

which of the following has androgenic properties for females?

a) norethindrone

b) norethisterone acetate

c) ethisterone

d) hydroxyprogesterone acetate

c) ethisterone

how to remove the androgenic effects from ethisterone to make norethindrone (or also known as norethisterone)?

• removal of C10 methyl

what is the preferred progestin used for oral contraceptives?

• norethindrone

T/F: Ethisterone is preferred over norethindrone

• false

what is the indication for mifepristone?

• induce abortion

what part of mifepristone helps it act as an antagonist?

• C11 phenyl group substitution = increased lipophilicity

  • NOT aromatic ring A

what type of drug is mifepristone?

• antiprogesterone (antagonist)

which of the following is anti-progesterone?

a) norethindrone

b) fluoxymestrone

c) tamoxifen

d) mifepristone

d) mifepristone

what are the 2 major functions of testosterone?

1. androgenic (puberty + spermatogenesis)

2. anabolic (protein/muscle buildup)

how is testosterone metabolized?

• FPM = oxidation at C17 OH → ketone

• or saturation of the C4-5 double bond → dihydrotestosterone (DHT)

how to get dihydrotestosterone (DHT) from testosterone?

• dihydrotestosterone reductase

  • saturates C4-C5 double bond

activity of DHT (dihydrotestosterone)

• active metabolite with more androgenic properties

where is dihydrotestosterone reductase found?

• only at androgenic receptors

how to suppress FPM of testosterone?

• ORAL: add methyl group to C17 OH

  • NOT ethinyl group

• IM: add fatty acid ester