Steroids Part 1

Steroid Structure

• ring system of androgens, progestins, and adrenocorticoids

  • 17 carbons

• estrogen ring system

  • 17 carbons

• A ring of estrogen is aromatic

Steroid Nomenclature

Cholestane

• 27 carbons

• rings trans fused

• up → beta

• down → alpha

Adrostane

• 19 carbons

• no carbon sub at C-17

• androgens

Pregnane

• 21 carbon

• 2 carbon side chain at C-17

• progestins and adrenocorticoids

Estrane

• 18 carbons

• no methyl at C10, no side chain at c-17

• estrogens

Female sex steroids

estrogens

progestins

male sex steroids

androgens

adrenocorticoids

minerocorticoids

glucocorticoids

Estrogens

Progestins

minerocorticoids

glucocorticoids

Androgens

Production of sex steroids

• FSH promotes the development of ovarian follicles which secretes estradiol.

• corpus luteum produces progesterone

• LH stimulates testosterone production by the Leydig cells in the testes.

Physiological effect of estrogen

• female secondary sex characteristics

• development of reproductive tract

Physiological effect of Progesterone

• primary effect on uterus

• placenta produces large amounts during pregnancy ; sends neg feedback signal to hypothalamus to stop FSH and LH production

Physiological effect of androgens

• male secondary sex characteristics

• differentiation and growth of male reproductive organs

Estrogen main three

17B estradiol, estrone, estriol

potency in that order as well

estrogen produced greatest amount in body? In plasma? in Urine?

17B estradiol greatest in body → rapid oxidation to estrone which has largest conc in plasma

estiol greates in urine

estrogens cleared from plasma?

• insouble in water and highly bound to plasma proteins

• cleared as water soluble glucuronide and sulfate conjugates

General Therapeutic Uses of Estrogens

• estradiol available in oral, transdermal, vaginal formulation

• Use in prepubertal females to treat

  • Gonadal* dysgenesis

  • excessive height

  • genital infections.

• Use during the reproductive years

  • To treat various conditions related to

    • menstrual disorders (amenorrhea, menorrhagia, dysmenorrhea);

    • infertility (poor cervical mucus and anovulation)

    • pregnancy (abortion, lactation suppression)

    • dermatological disorders (acne vulgaris, hirsutism)

    • Endometriosis

  • For contraception - combined estrogen/progestogen** therapy

• Use dyring postmenopausal years, to treat

  • post-menopausal syndrome

  • Hormone-dependent breast cancer

  • Osteoporosis

    • estrogen promotes the activity of osteoblasts

• In men, to treat

  • prostactic cancer

  • sexual dysfunction

Estrogenic drugs

Estradiol

• Formulations:

  • oral tablet, transdermal patch, vaginal ring formulations

• Most potent natural estrogen

• Poor OBA

  • conjugated in the intestine and eliminated

  • absorbed is rapidly oxidized in the liver.

• Indication

  • To treat post-menopausal conditions

    • Vasomotor symptoms associated with menopause

    • Vulvar/Vaginal atrophy associated with menopause (topical only)

Estrogenic Drug

Estradiol cypionate

• prodrug of estradiol

• Indication

  • Hypogonadism; moderate to severe vasomotor symptoms associated with the menopause.

• Formulation

  • IM injection at monthly intervals

  • slow release forms also available

• Black box warning: Estrogens have been reported to increase the risk of endometrial carcinoma in postmenopausal women

Estrogenic Drug

Ethinyl estradiol (EE)

• synthetic estrogen

• more stable metabolically than estradiol

  • C17 ethynyl group prevents oxidation

• more potent than estradiol

• formulation

  • oral, transdermal, vaginal

  • rapidly and complete absorb after oral admin

• first pass metabolism

• Indication

  • Hypogonadism; moderate to severe vasomotor symptoms associated with the menopause.

Estrogenic Drug

Mestranol

• prodrug

• oral admin → rapid metabolized via hepatic oxidative o-demethylation

• formulation

  • oral, injectable, topical

• use

  • primarily oral contraceptive combo formulation

  • treat hypogonadism

Estrogenic Drug

Quinestrol

• prodrug of ethinlestradiol

• dealkylated in vivo

• once weekly oral dosing

• use

  • oral contraception

  • hypogonadism

• two unique estrogenic compounds excreted in the urine of pregnant mares

  • Equilenin and equilin, as sodium sulfate conjugates.

• These conjugated metabolites also are used in estrogen preparations, often combined with estrone sodium sulfate

• Premarin®*

  • combination of sodium estrone sulfate (52.5% to 61.5%) and sodium equilin sulfate (22.5% to 30.5%), sodium equilenin sulfate

  • oral, IV, IM formulations.

  • Poor oral bioavailability

  • treat uterine bleeding

• Boxed warning: Can cause endometrial cancer, breast cancer, and CV disorders

Diethylstilbestrol (DES)

• non steroidal estrogen

• as active as estrone

• z isomer only 10% as active as E-DES

• discontinued to pregnant women b/c birth defects and rare tumors

SERMs

estrogenic drugs that can act as estrogen agonist or antagonist depending on the target organ and duration of treatment.

Tamoxifen

• A selective estrogen receptor modulator (SERM).

• MoAc

  • in breast tissue- estrogen receptor antagonist (a non-steroidal antiestrogen)

• Indication

  • to treat estrogen-dependent breast cancer in women.

• Oral drug

• N-desmethyl tamoxifen = major metabolite

  • It is less active than tamoxifen.

• minor metabolite, 4- hydroxy-N-methyltamoxifen (endoxifen) = more potent than the parent.

• Tamoxifen resistance:

  • On prolonged treatment the agonist property takes over and tamoxifen effectively “feeds” the tumor.

Toremifene

• A selective estrogen receptor modulator (SERM)

• treatment of breast cancer.

• Oral drug

• MoAc

  • in breast tissue- estrogen receptor antagonist (a non-steroidal antiestrogen).

• N-desmethyl toremifene is an active metabolite

• Carries black box warning for QTc prolongation

Clomiphene

• a 1:1 mixture of enclomiphene and zuclomiphene)

• enclomiphene and zuclomiphene = Geometric isomers

• Zuclomiphene has estrogenic activity; enclomiphene has anti-estrogenic activity.

• Blocks the feedback inhibition of estrogen receptors at the pituitary, thereby stimulating FSH release → ovulation

• Use

  • mainly as an ovulation stimulant (most commonly used fertility drug).

  • treat polycystic ovary syndrome.

• Oral drug

• Clomiphene is considered a SERM because the drug mixture has estrogenic and anti-estrogenic activity.

Raloxifene

• A selective estrogen receptor modulator (SERM)

• Acts as an estrogen agonist on receptors in osteoblasts and osteoclasts but as an antagonist at breast and uterine estrogen receptors.

• Indications

  • For the treatment and prevention of osteoporosis in postmenopausal women

  • For the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis or high risk of breast cancer

• Does not increase the risk of endometrial or breast cancer because of low resistance.

• as effective as tamoxifen in reducing the incidence of breast cancer in certain high risk groups of females

• Low OBA (2%) due to rapid phase-II metabolism.

• Undergoes enterohepatic circulation

• Glucuronidated in the intestine

Aromatase Inhibitors

block production of estrogen from testosterone by inhibition of aromatase (CYP19)

Anastrazole

• non-steroidal aromatase inhibitors

• competitive inhibitors that bind to the heme portion of the enzyme (via the triazole)

• Indication

  • hormone receptor-positive* breast cancer as first-line treatment and for relapse following tamoxifen therapy

  • Overall more effective than tamoxifen in treating breast cancer

• Advantage over tamoxifen!

  • Tamoxifen therapy is limited to 5 years

  • this can be used without this limitation and for relapses occurring subsequent to tamoxifen therapy

• Orally bioavailable

Letrozole

• non-steroidal aromatase inhibitors

• competitive inhibitors that bind to the heme portion of the enzyme (via the triazole)

• Indication

  • hormone receptor-positive* breast cancer as first-line treatment and for relapse following tamoxifen therapy

  • Overall more effective than tamoxifen in treating breast cancer

• Advantage over tamoxifen!

  • Tamoxifen therapy is limited to 5 years

  • this can be used without this limitation and for relapses occurring subsequent to tamoxifen therapy

• Orally bioavailable

Exemestane

• steroidal!

• Irreversible aromatase inhibitor (“suicide inhibitor”)

• Formulation

  • Oral

• Indication

  • Estrogen positive breast cancer in post menopausal women

  • Risk reduction for invasive breast cancer in postmenopausal women