Androgens Flashcards
What are the Major categories of natural sex steroids:
- Estradiol (Estrogens)
- Progesterone
- Androgens
tx for 17a-hydroxylase def.
Estrogens, anti-HTN
tx. for 21-hydroxylase def
fluids + salt repletion and administer cortisol to lower ACTH.
tx. for 11B-hydroxylase def
estrogens and anti-HTN
What type of drugs are antiestrogens
Receptor antagonists - selective estrogen receptor antagonists - Full antagonists (Fulvestrant) aromatase inhibitors GnRH agonists
Estrogens
PK
“EEEEDMC”
- Ethinyl estradiol
- Conjugated estrogen
- Mestranol
- Diethylstilbestrol
- Estradiol
- Estrone
- Estriol
•Available for oral, intramuscular, transdermal and topical administration.
Estrogens
PD
•Metabolism of estrogens relies on cytochrome P-450 system; they have enterohepatic circulation. Combination with P-450 inducers can lead to failure of contraceptive effectiveness.
•Diethylstilbestrol (DES) AE
–a nonsteroidal estrogen agonist used in pregnancy results in female child to infertility, vaginal cancer.
Absolute contraindications of estrogen use
- History of thromboembolism
- Breast & endometrial cancer
- Pregnancy
- Liver disease
Selective Estrogen Receptors Modulators –SERMs
•Mixed mechanism of actions: They exhibit agonistic action in some tissue and antagonists in other tissues.
•Tamoxifen: E-receptor antagonist effect on breast tissue but agonistic effect on liver, bone and partial agonist endometrium.
•Used in treatment of breast cancer & prophylaxis for high risk patients.
•Adverse effects:
–Hot flushes (Antagonist) and thrombosis (Agonistic)
–Risk of endometrial cancers
SERMs
•Toremifene (SERM): approved for treatment of breast cancer and prevention of breast cancer in high-risk women
•Raloxifene: E-receptor antagonist at breast and but agonist at bone. No estrogenic effect on endometrium
•No increased risk of endometrial cancer
•Uses:
–Prophylaxis against breast cancers (in high risk patients)
–Prevention of postmenopausal osteoporosis
Estrogen receptor antagonist in all tissues
•Fulvestrant: I.M.
AE
- Used in the treatment breast cancer in tamoxifen resistant patients.
- A.E: Hot flushes, injection site reactions & headache
Aromatase inhibitors
Administration
AE
•Inhibits conversion of androgens to estrogen
Letrozole
Anastrozole
Exemestane –an irreversible aromatase inhibitor
•Used in treatment of breast cancer (estrogen dependent) as 2nd line drugs following tamoxifen resistant.
•Oral administration
•A.E: hot flushes, decreased bone mineral density.
What is clomiphene
MOA
A fertility drug
Acts as estrogen antagonist in hypothalamus and anterior pituitary
•Used in treatment of anovulatory infertility
Clomiphene
Side effects
–Ovarian hyper-stimulation leading to enlargement of ovary.
–Multiple pregnancy 10%
–Hot flushes, nausea, vomiting, breast tenderness and weight gain.
Progestins
admin:
"N3P D2M" •Progesterone •Medroxyprogesterone •Norgestrel •Norethindrone •Norgestimate •Desogestrel •Drospirenone
ADMINISTRATION: Oral or I.M. injection
ANTINPROGESTIN
admin
MOA
AE
MIFEPRISTONE - therapeutic abortificient
oral
•Competitive inhibitor of progesterone & glucocorticoid receptors.
•Controversial “morning after” drug used as an abortifacient.
•It is given concomitantly with PG-E or PG-F to increase myometrial contraction.
•Adverse effects: Excessive bleeding, gastrointestinal effects as nausea, vomiting, anorexia and abdominal pain.
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PROGESTERONE –Preps
Medroxyprogesterone, Norgestrel, Norethindrone, Norgestimate, Desogestrel –newer preps lacking of androgenic and antiestrogenic effects.
Drospirenone –a spironolactone derivative used as O.C. antagonize aldosterone effects useful in acne in females.
Progestins AE
Long term use may result in
- Weight gain
- Glucose intolerance
- Androgenic –hirsutism & acne
- Anti-estrogenic (blocks lipid changes)
- Depression,
- Edema, acne
- increase HDL, decrease LDL & hypertension
Synthetic androgens –17alkyl derivatives with increased anabolic effects:
"Oxan, Stan, Nan, Dan, are hairy MOFs" •Oxandrolone •Methyltestosterone •Stanozolol •Fluoxymesterone •Nandrolone •Oxymetholone •Danazol
Antiandrogens
Receptor antagonist - Flutamide
5a-reductase inhibitor - Finasteride
Synthesis inhibitors - Ketoconazole
GnRH Agonists
Androgens clinical uses
- Substitution therapy in hypogonadism;
- Increases bone density (prevent osteoporosis), could be used in increasing muscle mass (+ve nitrogen balance)
- Some cases of aplastic anemia.
- Administration: Transdermal, buccal, subcutaneous implant and I.M.
Androgens AE
•Adverse effects:
–Over-masculinization
–In women could lead to hirsutism, suppression of menses, acne, and clitoral enlargement.
–hepatic adenomas & prostatic hypertrophy
–Cholestatic jaundice (elevated serum transaminations)
–Aggression & dependency
–Premature closure of epiphysis
–Illicit use in athletics
•Over-dosage of androgen can result in feminization (gynecomastia, testicular shrinkage, infertility, azoospermia) as a result of feedback inhibition (HPG axis) & conversion of exogenous testosterone into estrogen.
Danazol MOA
AE
- Danazol is an inhibitor of P450 in gonadal steroid synthesis.
- It an androgen derivative, a partial agonist of progestin, and glucocorticoid receptors.
- Used in endometriosis and fibrocystic disease of breast.
•AE: hepatitis –abnormal liver function tests and drug interaction due to P-450 inhibition.
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It is a modified testosterone shows some signs of musculinising effects – acne, hirsutism, menstrual disturbances.
•Androgen Receptor Antagonists:
- Flutamide
- Bicalutamide
- Nilutamide
- Cyproterone
- Spironolactone
- Ketoconazole
Androgen receptor blockers –used for androgen-receptor-positive cancers.
Flutamide –a substituted anilide.
Bicalutamide
Nilutamide
•Primarily used in conjunction with GnRH analogs e.g., leuprolide (to ↓initial tumor flare-ups of prostate carcinoma).
Other drugs with antiandrogen action
- Spiranolactone: blocks aldosterone and competes androgen receptors. It is used in hirsutism.
- Cyproterone: it has progesteronal effect suppresses LH & FSH. Used in hirsutism and to ↓excessive sexual drive in men
Ketoconazole
admin
use
AE
oral administration
•Adrenal and gonadal steroid synthesis inhibitor
•Use: in prostate cancer but not 1st line drug.
•AE: May have drug interactions with other steroids due to P-450↓
5-α reductase inhibitor Drug Admin USE AE
- Finasteride (PROPECIA):
- Oral administration
- Inhibit conversion of testosterone to dihydrotestosterone.
- Use: BPH and promotes hair growth.
- AE: gynecomastia, teratogenicity and impotence
