Gonadal Hormones Flashcards
Mestranol
Mestranol is a prodrug is converted into Ethinyl estradiol, present in some contraceptives. ↑bio-availability, ↑half-life and ↓FSH & LH via feed-back.
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.
Clinical uses of estrogens
- I.M. Long acting estrogen preparations are used in females with Hypogonadism.
- Oral contraceptives in combination with progestins – Suppress FSH & LH secretion and inhibit ovulation.
- Postmenopausal hormonere placement therapy (HRT) – HRT help and reduce hot flashes, prevent bone loss & fractures, ↓incidence of colon cancer, ↓urogenital atrophy & ↑feeling of well-being.
- Used in dysmenorrhea, uterine bleeding, prostate cancer and acne.
Adverse effects
Increased incidence of thromboembolism.
Increased incidence of breast, Endometrial hyperplasia & cancers (unless progestin is added).
Migraine, Cholestasis, and mood changes.
Nausea,breast tenderness and bloating
Diethylstilbestrol (DES)–anonsteroidalestrogen agonist use in pregnancy result in female child to infertility, vaginal cancer.
Absolute contraindications of estrogen use
History of thromboembolism
Breast & endometrial cancer
Pregnancy
Liver disease
Tamoxifen
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 flashes (Antagonist) and thrombosis (Agonistic) – Risk of endometrial cancers
Toremifene
Toremifene (SERM): approved for treatment of breast cancer, breast cancer that has metastasized and prevention of breast cancer in high-risk women.
Raloxifene
Raloxifene: E-receptor antagonist at breast 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
Fulvestrant
Estrogen receptor antagonist in all tissues
Fulvestrant: I.M.
Used in the treatment breast cancer in tamoxifen resistant patients.
A.E: Hot flushes, injection site reactions & headache
Letrozole
Aromatase inhibitors
• Inhibits conversion of androgens to estrogen
Anastrozole
Aromatase inhibitors
• Inhibits conversion of androgens to estrogen
Exemestane
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 flashes, decreased bone mineral density.
Clomiphene
Clomiphene – fertility drug
Acts as estrogen antagonist in hypothalamus and anterior pituitary. Estrogen Antagonist prevents feedback inhibition of GnRH release by hypothalamus. Continued release of GnRH from hypothalamus. Increased LH and FSH from the pituitary leads to increased ovulation.
Taken orally, half-life is 5-7days, has significant protein binding and enterohepatic circulation.
Used in treatment of anovulatory infertility.
Side effects:
– Ovarian hyper-stimulation leading to enlargement of ovary.
– Multiple pregnancy 10%
– Hot flashes, nausea, vomiting, breast tenderness and weight gain.
Norgestrel
PROGESTERONE –Preps
Norethindrone
PROGESTERONE –Preps
Desogestrel
PROGESTERONE –Preps
Norgestimate
PROGESTERONE –Preps
PROGESTERONE –Preps
PROGESTERONE –Preps
Medroxyprogesterone, Norgestrel, Norethindrone, Norgestimate, Desogestrel –newer preps lacking of androgenic and antiestrogenic effects.
Therapeutic uses of progestins
Used alone or with estradiol for contraception.
In combination with estrogen they are used in hormone replacement therapy (HRT).
↓incidence of endometrial hyperplasia & carcinoma caused by unopposed action of estrogens –in this settings pts may have irregular bleeding (DUB).
Used in ovarian suppression –in the treatment of dysmenorrhea and endometriosis.
They are used to diagnose estrogen secretion & for responsiveness of endometrium. Menstruation occurs after progesterone administration in patient with amenorrhea –this occurs after 5-7 days.
ADMINISTRATION: Oral or I.M. injection
Progestins –Adverse effects
Long term use may result in:
Weight gain
Glucose intolerance
Androgenic –hirsutism & acne
Anti-estrogenic (blocks lipid changes)
Depression, Edema, acne
Increased HDL, decreased LDL & hypertension
Drospirenone
Drospirenone – a spironolactone derivative used as O.C. to antagonize aldosterone effects useful in acne in females.
Mifepristone
Antiprogestins
RU 486 or Mifepristone – oral administration
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.
Oxandrolone
Synthetic androgens –17alkyl derivatives with
increased anabolic effects
Stanozolol
Synthetic androgens –17alkyl derivatives with
increased anabolic effects
Fluoxymesterone
Synthetic androgens –17alkyl derivatives with
increased anabolic effects
Nandrolone
Synthetic androgens –17alkyl derivatives with
increased anabolic effects
Oxymetholone
Synthetic androgens –17alkyl derivatives with
increased anabolic effects
Danazol
Synthetic androgens –17alkyl derivatives with
increased anabolic effects
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.
It is a modified testosterone shows some signs of musculinising effects – acne, hirsutism, menstrual disturbances.
Methyltestosterone
Synthetic androgens –17alkyl derivatives with
increased anabolic effects
Clinical uses: along with all the other ones
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.
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.
Antiandrogens
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).
Spiranolactone
Spiranolactone: blocks aldosterone and competes androgen receptors. It is used in hirsutism.
Cyproterone
Cyproterone: it has progesteronal effect suppresses LH & FSH. Used in hirsutism and to ↓excessive sexual drive in men.
Ketoconazole
Ketoconazole – 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↓
Finasteride
5-α reductase inhibitor
Finasteride (PROPECIA):
Oral administration
Inhibit conversion of testosterone to dihydrotestosterone.
Use: BPH and promotes hair growth.
AE: gynecomastia, teratogenicity and impotence
