Steroid Hormones: Estrogens, Progestins and Androgens Flashcards
Estradiol
Most active of the natural estrogens | rapidly metabolized and has low oral bioavailability (esterification of 17-beta-hydroxy increases bioavailability)
Estrone
Estriol
DHEA
Converted from 17alpha-hydroxypregnenolone by 17,20 lyase
Converted to androstenedione by 3beta-HSD
Androstenedione
Testosterone
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
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)
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
Dienestrol
OH-OH spacing maintained to retain estrogenic effects
Available as cream for atrophic vaginitis
Resveratrol
Phenolic constituent of grapes and wines
10-fold greater affinity for estrogen receptor beta (compared with alpha)
R = H (Daidzein); R = OH (Genistein)
Soy isoflavins
Being investigated as an alternative for HRT
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
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
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
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
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
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
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
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
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
Formestane
Irreversible aromatase inhibitor (IC50 = 30 nM in breast cancer cells)
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
Testolactone
weak, irreversible aromatase inhibitor
Limited use in breast cancer due to frequent dosing and more effective alternatives
19-nor-17-alpha-ethynyltestosterone
17-alpha-ethynyl group enhances progestational activity and metabolic stability in testosterone
Norethynodrel
Converted to norethisterone by HCl (or gastric juice)
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
5-beta-pregnane-3-alpha, 20S-diol
Product of progesterone metabolism:
green (20-alpha-HSD), blue (3-alpha-HSD), yellow (5-beta-reductase)
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
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
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
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
Etonogestrel | Synthetic progestin
Active metabolite of desogestrel
Progestin component of implant and nuvaring
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)
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)
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
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
Mifepristone | Synthetic progestin
Progesterone receptor antagonist
Used as abortion agent in first few months of pregnancy
In smaller doses, used for EC
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
Nandrolone | Anabolic androgenic steroid
Available in 17-beta-esters
Has been used for treatment of certain anemias | replaced by EPO
Fluoxymesterone | Anabolic androgenic steroid
9-alpha-F; 11-OH; 17-alpha-methyl (increased metabolic stability)
Highly potent, orally active androgen
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
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
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
2-hydroxymethyl ethisterone (major danazol metabolite)
Flutamide | Androgen receptor antagonist
Hepatotoxic
Dose 3 x 250 mg/day (t1/2 = 6 hours)
Hydroxyflutamide
More potent AR antagonist (contributing significantly to overally drug action)
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)
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
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
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
