Synthetic Estrogen MOA - stimulation of estrogen receptors leading to changes in the rates of transcription of estrogen-regulated genes (dimerization in cytosol??) Clinical uses.. 1. prevent osteoporosis 2. hormone replacement therapy (in post-menopausal women who have undergone ovary removal) 3. oral contraceptive therapy 4. 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

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

Gonadal hormones Flashcards by Leslie Rea

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

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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

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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

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Mestranol?

Prodrug that is converted to ethinyl estradiol - used in contraceptives

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Estrogen esters?

Ex. estradiol cypionate

Long acting estrogens administered IM and used for hypogonadism in young females.

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Diethylstilbestrol (DES)?

Non-steroidal estrogen agonist used in pregnancy resulting in female child to infertility and vaginal cancer.

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What options are available for hypogonadism in girls/women?

Conjugated estrogens
Ethinyl estradiol
Estradiol esters

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What options are available for hormone replacement therapy?

Estrogen component: conjugated estrogens, estradiol, estrone, estriol

Progestin component: progesterone, medroxyprogesterone acetate

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What options are available for oral hormonal contraceptives (OC or COC)?

Combined: ethinyl estradiol or mestranol plus a progestin

Progestin only: norethindrone or norgestrel

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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

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Options for postcoital contraceptives?

L-Norgestrel

- Combined oralcontraceptive

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Options for Intractable dysmenorrhea or uterine bleeding?

Conjugated estrogens
ethinyl estradiol
oral contraceptive
depot injection of medroxyprogesterone acetate
GnRH agonist

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Options for infertility?

Progesterone and other drugs such as clomiphene
hMG and hCG
GnRH analogs
bromocriptine

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Options for endometriosis?

Oral contraceptive
depot injection of medroxyprogesterone acetate
GnRH agonist
danazol

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Options for osteoporosis in postmenopausal women?

Conjugated estrogens

- estradiol (preventive) and raloxifene

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Options for hirsuitism?

Combined oral contraceptive

other drugs such as –spironolactone, flutamide, GnRH agonist

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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

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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?