Gonadal hormones Flashcards
Walk through estrogen synthesis from the ovaries.
Pulsatile GnRH stimulates LH and FSH release.
LH stimulates Theca interna cells to produce Desmolase which converts cholesterol to androgens.
FSH stimulates Granulosa cells to stimulates aromatase which takes the androgens that are produced by theca interna cells and converts them to estrogen.
- *ketoconazole inhibits desmolase
- *anastrozole inhibits aomatase
Endogenous estrogens?
Estradiol, Estrone, Estriol
- *estradiol is more potent compared to estrone and estriol
- *50x increase in estradiol and estriol during pregnancy
- *1000x increase in estriol in pregnancy is an indicator of fetal well being
Ethinyl estradiol?
Synthetic Estrogen
MOA - stimulation of estrogen receptors leading to changes in the rates of transcription of estrogen-regulated genes (dimerization in cytosol??)
Clinical uses..
- prevent osteoporosis
- hormone replacement therapy (in post-menopausal women who have undergone ovary removal)
- oral contraceptive therapy
- hypogonadism
- CYP450 metabolism
- Enterohepatic recirculation
AE..
- Moderate toxicity = breakthrough bleeding, nausea, breast tenderness
- Serious toxicity = THROMBOEMBOLISM (estrogens are procoagulants inhibiting protein C and S), gallbladder disease, hypertriglyceridemia, migraine headache, HTN, depression
- breast cancer and endometrial hyperplasia due to unopposed estrogen in postmenopausal women
Mestranol?
Prodrug that is converted to ethinyl estradiol - used in contraceptives
Estrogen esters?
Ex. estradiol cypionate
Long acting estrogens administered IM and used for hypogonadism in young females.
Diethylstilbestrol (DES)?
Non-steroidal estrogen agonist used in pregnancy resulting in female child to infertility and vaginal cancer.
What options are available for hypogonadism in girls/women?
Conjugated estrogens
Ethinyl estradiol
Estradiol esters
What options are available for hormone replacement therapy?
Estrogen component: conjugated estrogens, estradiol, estrone, estriol
Progestin component: progesterone, medroxyprogesterone acetate
What options are available for oral hormonal contraceptives (OC or COC)?
Combined: ethinyl estradiol or mestranol plus a progestin
Progestin only: norethindrone or norgestrel
What options are available for parenteral contraceptives?
-Ethinyl estradiol and norelgestromin as a weekly patch
-Ethinyl estradiol and etonogestrel as a monthly vaginal ring
-L-Norgestrel as an intrauterine device (IUD)
-Etonogestrel as a subcutaneous implant
-Medroxyprogesterone as a depot IM
injection
Options for postcoital contraceptives?
- L-Norgestrel
- Combined oralcontraceptive
Options for Intractable dysmenorrhea or uterine bleeding?
- Conjugated estrogens
- ethinyl estradiol
- oral contraceptive
- depot injection of medroxyprogesterone acetate
- GnRH agonist
Options for infertility?
- Progesterone and other drugs such as clomiphene
- hMG and hCG
- GnRH analogs
- bromocriptine
Options for endometriosis?
- Oral contraceptive
- depot injection of medroxyprogesterone acetate
- GnRH agonist
- danazol
Options for osteoporosis in postmenopausal women?
- Conjugated estrogens
- estradiol (preventive) and raloxifene
Options for hirsuitism?
Combined oral contraceptive
other drugs such as –spironolactone, flutamide, GnRH agonist
What are the sources and physiological functions of progesterone?
Sources of progesterone are: Corpus Luteum, placenta, testes and adrenal cortex
Physiological Functions: Elevation of
progesterone signifies –ovulation
• Stimulates endometrial glandular secretion
• Maintains pregnancy –pro-gestation
• Decrease myometrial contraction and effects
uterine smooth muscle relaxation
• Associated with increase body temperature
• Produce thick cervical mucus that inhibits sperm
access into uterus
• Prevent endometrial hyperplasia and decrease
estrogen receptor expression
Progestins?
Norgestrel
MOA - stimulation of progesterone receptors leading to change in the rates of transcription of progesterone-regulated genes
- CYP450 metabolism
- enterohepatic recirculation
AE - weight gain, reversible decrease in bone mineral density (at high doses), elevated LDL, HTN, lowered HDL
What progestin combinations are availbel for progesteron derivatives, 19-nortestosterone derivatires (old and new) and spirnolactone derivatives?
Progesterone derivatives:
medroxyprogesterone acetate, megestrol acetate
Older 19-nortestosterone derivatives: norethindrone, ethynodiol
Newer 19-nortestosterone derivatives: desogestrel, norelgestromin, norgestimate,
etonogestrel – do not have significant androgenic effects compared to the older preparations
Spironolactone derivative: drospirenone - formerly used as contraceptive that has androgenic effect therefore is commonly used
Tamoxifen?
Selective estrogen receptor modulator
MOA - estrogen ANTAGONIST action in breast tissue and CNS and AGONIST effect on endometrium, liver and bone
Clinical uses … prevention and adjuvant treatment of hormone-responsive breast cancer
Kinetics - oral adminsitration
AE - hot flashes, thromboembolism, endometrial hyperplasi
Toremifene and Raloxifene?
• Toremifene: similar to tamoxifen - same antagonist and agonist effect
• Raloxifene: protect against osteoporosis and
prevention of breast cancer in selected patients; ANTAGONIST effects in breast, CNS, and endometrium and AGONIST effects in the liver & bone
*Raloxifene has agonist effect on bone decreases risk of osteoporosis – increase hip bone density when given to postmenopausal women
Clomiphene?
ER antagonists used to induce ovulation. It effects the pituitary and increases gonadotropin secretion.
AE - ovarian hyper-stimulation leading to enlargement of ovary, multiparity, hot flashes, nausea, vomiting, breast tenderness, weight gain
Fulvestrant?
Estrogen receptor ANTAGONIST in all tissues.
It is used to treat hormone-responsive breast cancer that is resistant to first-line antiestrogen therapy.
*administered via intramuscular administration
AE - hot flashes, headache, injection site reactions
Anastrozole?
Aromatase inhibitor leading to inhibition of estrogen synthesis.
Used to treat hormone-responsive breast cancer and administered orally.
AE - hot flashes, musculoskeletal disorders, reduced bone mineral density, joint symptoms
Letrozole?
Similar to anastrozole
Exemestane?
Irreversible aromatase inhibitor
Leuprolide?
GnRH receptor agonist used for ovarian suppression, ovarian hyperstimulation, central precocious puberty, block endogenous puberty in transgender early pubertal adolescents, tx prostate cancer.
AE - headache, light headedness, nausea, injection site reaction
Gonadorelin?
Synthetic human GnRH
Goserelin, histrelin, nafarelin, triptorelin?
GnRH analogs
Ganirelix?
GnRH receptor antagonist used to prevent premature LH surge during controlled ovulation hyperstimulation.
Administered via subcutaneous injection.
AE - nausea, headache,
Cetrorelix?
Similar to ganirelix - approved for controlled ovarian hyperstimulation
Degarelix?
Approved for advanced prostate cancer
Danazol?
MOA - weak cyp540 inhibitor and partial agonist of progestina nd androgen receptors
Used to tx endometriosis, and fibrocystic breast disease.
oral administration with cyp450 inhibition.
AE - acne, hirsutism, weight gain, menstrual disturbances, hepatic dysfunction
Mifepristone?
Antiprogestine that acts as a progestin and glucocorticoid receptor antagonist. It is used in combination with protaglandin (ex. misprostol) for medical abortion.
Administered orally.
AE - GI disturbances, vaginal bleeding, atypical infection
Endogenous androgens?
Testosterone, androstenedione and DHT (dihydrotestosterone)
*DHT is the most potent
Testosterone - genitalia development (penis, seminal vesicles, sperm, muscle mass, RBC), differentiation of epididymis, vas deferens, seminal vesicles
DHT - early on differentiation of penis, scrotum and prostate with later prostate gland growth, balding, sebaceous gland activity
Testosterone?
Androgen used as androgen receptor agonist in male hypogonadism or weight gain in pts with wasting syndromes.
AE - virilization in females and high doses can cause gynecomastia, testicular shrinkage and infertility in men
Fluocymesterone and methyltestosterone?
Oral androgens
Testosterone esters?
Long acting androgens for parenteral administration?
Anabolic steroids?
(eg., oxandrolone, nandrolone & decanoate): increased ratio of
anabolic-to-androgenic activity in laboratory animals, cholestatic jaundice, liver toxicity
Finasteride?
Anti-androgen, 5a-reductase inhibitor
MOA: Inhibition of 5α-reductase enzyme that
converts testosterone to dihydrotestosterone
Use: Benign prostatic hyperplasia (BPH), malepattern
hair loss
Oral administration
AE: Rarely, impotence, gynecomastia
Dutasteride: Similar to finasteride
Futamide?
MOA: Competitive inhibition of androgen
receptor
Use: Advanced prostate cancer
Oral administration
AE: Gynecomastia, hot flushes, impotence,
hepatoxicity
Bicalutamide, nilutamide: similar to flutamide
but lower risk of hepatotoxicity
Spironolactone?
Spironolactone: mineralocorticoid receptor
antagonist used mainly as a potassium-sparing
diuretic; also has androgen-receptor antagonist
activity, used for the treatment of hirsutism
Cyproterone?
Used in hirsutism and to
↓excessive sexual drive in men.
Ketoconazole
MOA: Inhibition of cytochrome P450 enzymes
involved in androgen synthesis
Use: Advanced prostate cancer that is resistant
to first-line antiandrogen drugs
Oral administration
AE: Interferes with synthesis of other steroids
Many drug interactions due to cytochrome P450
inhibition
**inhibition of desmolase in women?
