Steroid Hormones: Estrogens, Progestins and Androgens Flashcards Preview

Pharmacy School 2016-17 > Steroid Hormones: Estrogens, Progestins and Androgens > Flashcards

Flashcards in Steroid Hormones: Estrogens, Progestins and Androgens Deck (51):
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Estradiol

Most active of the natural estrogens | rapidly metabolized and has low oral bioavailability (esterification of 17-beta-hydroxy increases bioavailability)

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Estrone

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Estriol

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DHEA

Converted from 17alpha-hydroxypregnenolone by 17,20 lyase

Converted to androstenedione by 3beta-HSD

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Androstenedione

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Testosterone

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R = H (Ethinyl Estradiol); R = CH3 (Mestranol)

Metabolized by CYP3A4 to 2-OH steroid, resulting catechol degraded by COMT | Mestranol methyl must be removed by 2C9 (prodrug)

17-alpha-ethinyl helps prevent enzymatic oxidation of 17-beta-hydroxy

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Equilin

Conjugated estrogens USP (mixture isolated from pregnany mare urine, PREMARIN) | Premarin also contains 17-alpha-sulfate of estradiol and is most commonly used as HRT in post-menopausal women

Cenestin is a mixture of 9 estrogens synthesized from soy sterols (ergosterol; approved for treatment of vaginal atrophy with menopause)

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Diethylstilbestrol (DES)

Trans isome 10x more potent than cis

Teratogenic (DES daughters; high risk of vaginal, cervical and uterine abnormalities) | Increased risk for breast cancer | CV toxicity (DVT and MI)

Diphosphate form is used IV for prostate cancer

Used to be used as a growth stimulant in cattle feed

PROTECT FROM LIGHT

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Dienestrol

OH-OH spacing maintained to retain estrogenic effects

Available as cream for atrophic vaginitis

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Resveratrol

Phenolic constituent of grapes and wines

10-fold greater affinity for estrogen receptor beta (compared with alpha)

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R = H (Daidzein); R = OH (Genistein)

Soy isoflavins

Being investigated as an alternative for HRT

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8-prenylnaringenin

Most potent phytoestrogen | isolated from hops

Used in MENOHOP, a belgian product for treatment of hot-flashes (no safety established)

Recently discovered to be a potent aromitase inhibitor

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Tamoxifen

Used in breast cancer and prophylactically for prevention of breast cancer in at-risk individuals

Requires activation (to 4-OH) by CYP2D6 | those with polymorphism 4*/4* have higher risk of relapse

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Raloxifene

ER antagonist in breast and endometrium, agonist in bone and CV system (approval from treatment of osteoporosis in post-menopausal women)

Removal of nitrogen from ring will convert from antagonist to full agonist

 

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Fulvestrant

Pure antagonist at alpha and beta estrogen receptors (alkyl chain induces conformational change in receptor)

Used to treat breast cancer when tamoxifen is not effective | considered an alternative to aromatase inhibitors

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Clomiphene

Mix of Z and E isomers (Z is weak agonist in all tissues; E is antagonist in uterine but agonist in bone)

Ovulation stimulant

10% have multiple births | birth defects in live newborns in 2-3%

If abdominal discomfort, alert physician immediately

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Ospemifene

Treatment for dyspareunia (painful intercourse), a symptom of vulvar and vaginal atrophy due to menopause

Increases thickness of vaginal tissue better than raloxifene

Side effects include hot flashes | black box warning for endometrial cancer

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Aminoglutethimide

Weak aromatase inhibitor (IC50 in breasts cancer cells is 20,000 nm)

Lack of selectivity = toxicity (no longer recommended)

Has been used to treat Cushings

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Letrozole

Aromatase inhibitor | 2nM IC50 in breast cancer cells

Reduces estrogen levels by up to 95% within 2-3 days

Specificity = no significant effects on corticosteroid biosynthesis

CYP3A4/2A6 metabolism | carbinol is major metabolite and is inactive due to loss of triazole | interaction with tamoxifen

Abused by athletes to prevent gynecomastia secondary to anabolic steroid use

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Anastrozole

Aromatase inhibitor | 8nM IC50 in breast cancer cells

First specific inhibitor | first choice if tamoxifen is not sufficient in monotherapy

Estrogen levels reduced by 80% in 14 days (t1/2 = 50 hours)

Inactive metabolites from N-dealkylation and glucuronidation of carbinol

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Formestane

Irreversible aromatase inhibitor (IC50 = 30 nM in breast cancer cells)

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Exemestane

Approved for breast cancer

Irreversible aromatase inhibitor | reduces plasma estrogen levels by 90% within 2-3 days | IC50 = 15 nM

Does not inhibit major CYPs and no interaction with steroid receptors | excellent safety profile, well tolerated

SEs include hot flashes, fatigue and nausea

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Testolactone

weak, irreversible aromatase inhibitor

Limited use in breast cancer due to frequent dosing and more effective alternatives

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19-nor-17-alpha-ethynyltestosterone

17-alpha-ethynyl group enhances progestational activity and metabolic stability in testosterone

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Norethynodrel

Converted to norethisterone by HCl (or gastric juice)

 

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Progesterone

Pharmaceutical uses include: inhibition of ovulation, reduction of risk of endometrial cancer in HRT, treatment of amenorrhea caused by hormone deficiency or imbalance, for pallative treatment of breast or endometrial cancer, PMS

 

Not orally active due to poor absorption and extensive first pass metabolism (t1/2 = 5 minutes) | better absorption with micronized progesterone (PROMETRIUM) | IM and vaginal cream also available

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5-beta-pregnane-3-alpha, 20S-diol

Product of progesterone metabolism:

green (20-alpha-HSD), blue (3-alpha-HSD), yellow (5-beta-reductase)

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Medroxyprogesteron Acetate | Progesterone derivative

6-alpha-methyl inhibits metabolic reduction of 4-ene-3-one system | 17-alpha-acetate inihibits metabolic reduction of 20-oxo

Orally active | long duration of action, not suitable for menstrual disorders | used pallatively for breast and endometrial cancer

Is component of some birth control

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R = CH3 (Ethisterone); R = H (Norethisterone) | Synthetic progestin

Nor has 5-10x greater progestational activity

17-alpha-ethenyl group helps metabolic stability and progestational activity

component of many oral contraceptives, some andronergic side effects

Metabolism by hydroxylation at C6 and C16 groups, followed by conjugation

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Norgestrel, Levonorgestrel | Synthetic progestin

Ethyl group at C13 = steric interaction with androgen receptor = less androgenic side effects

Norgestrel is racemic mixture (- active) | Norgestrel only used in oral contraceptives

Levenorgestrel used in oral contraceptives and implants

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Desogestrel | Synthetic progestin

Orally active but must be converted to 3-oxo derivative (by 2C9 and 2C19)

11-vinyl is bio-isosteric with 11-oxo, seen in corticosteroids

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Etonogestrel | Synthetic progestin

Active metabolite of desogestrel

Progestin component of implant and nuvaring

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Drosperinone | Synthetic progestin

Progestational and anti-mineralocorticoid activity (structurally similar to spironolactone)

Some anti-androgenic effects due to cyclo-propyl groups Progestin component of new oral contraceptive (Yasmin)

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Tibolone | Synthetic progestin

Estrogenic, progestogenic and weak androgenic properties

Not approved in US | Osteoporosis in Europe

Estrogenic effects due to 3-alpha/beta-OH-T metabolites (significant hot-flash reduction, decrease bone turnover, increase bone density)

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Delta-4-Tibolone | Synthetic progestin

Metabolite of tibolone | formed in endometrium by 3-beta-HSD isomerase

No estrogenic but has progestagenic activity (no endometrial stimulation)

Androgenic effects include reduced HDL and libido stimulation

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Ulipristal Acetate | Synthetic progestin

Synthetic steroid derived from 19-norprogesterone | potent progesterone receptor antagonist

Orally administered drug indicated for EC up to 120 hours after intercourse (30 mg)

>98% bound to plasma protein | extensively metabolized by 3A4

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Mifepristone | Synthetic progestin

Progesterone receptor antagonist

Used as abortion agent in first few months of pregnancy

In smaller doses, used for EC

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Testosterone

Rapidly metabolized, not orally active

Available in patch, gel and implants | 17-beta esters for long-acting, depot formulation | 17-alpha-methyl less active than testosterone IM but more orally active

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Nandrolone | Anabolic androgenic steroid

Available in 17-beta-esters

Has been used for treatment of certain anemias | replaced by EPO

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Fluoxymesterone | Anabolic androgenic steroid

9-alpha-F; 11-OH; 17-alpha-methyl (increased metabolic stability)

Highly potent, orally active androgen

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Stanozolol | Anabolic androgenic steroid

Used prophylactically in hereditary angioedema | abused by olympic athletes in the past

Metabolism by 3 and 16-beta hydroxylation | glucuronides and sulfates found in urine

 

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Oxandrolone | Anabolic androgenic steroid

Used anabolically for weight loss following surgery and to offset protein catabolism in long-term corticosteroid use

Used to relieve bone pain from osteoporosis

Mainly excreted as glucuronide | lactone hydrolysis is minor

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Danazol | Anabolic androgenic steroid

Weak androgen, estrogen and progestin

Binds to sex-hormone binding globulin, decreasing its hepatic synthesis (free T increases, inhibiting LH and FSH production)

Causes endometrial atrophy so has use in endometriosis

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2-hydroxymethyl ethisterone (major danazol metabolite)

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Flutamide | Androgen receptor antagonist

Hepatotoxic

Dose 3 x 250 mg/day (t1/2 = 6  hours)

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Hydroxyflutamide

More potent AR antagonist (contributing significantly to overally drug action)

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Bicalutamide | Androgen receptor antagonist

More potent than flutamide with longer half life (6 days) | dose 1 x 50 mg/day

Used in treatment of advaned prostate cancer

Sold as racemate (R has higher affinity for AR receptor)

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Nilutamide | Androgen receptor antagonist

Used for treatment of metastatic prostate cancer in combo with surgical castration

t1/2 = 40 hours

SEs are visual disturbances, alcohol intolerance, allergic pneumonitis

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Finasteride

Sucicide inhibitor of 5-alpha reductase (release of complex is slow, taking around 30 days)

Relatively selective for Type 2 5-alpha-reductase (in the prostate)

Used in treatment of benign prostatic hyperplasia and for male pattern baldness

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Dutasteride

Approved for BPH

Inhibits type 1 and type 2 isoforms of 5-alpha reductase (may broaden therapeutic use)

Under investigation for treatment of male pattern baldness