Endoc- Gonadal hormones and Inhibitors Flashcards
Sex Steroids
Estrogens Progestins Androgens Antiestrogens Antiprogestins Antiandrogens
Estrogens
Diethylstilbestrol (DES)
Estradiol
Estriol
Estrone
Ethinyl estradiol
Antiestrogens Selective Estrogen Receptor Modulators (SERMs)
Clomiphene Tamoxifen Raloxifene
Estrogens: Indications For Use
1) Replacement in estrogen deficiency
Female hypogonadal or postmenopausal
Prevention & treatment of osteoporosis
2) Oral contraceptive therapy (combined with progestins)
3) Hirsutism
4) Amenorrhea
5) Dysmenorrhea
Physiologic effects of estrogens
Physiologic effects of estrogens
1) Normal female maturation
-secondary sex characteristics
-stimulates stromal and ductal growth of the breast
2) Accelerated growth phase at puberty, closing of long bone epiphyseal plate
3) Antagonizes the effect of PTH on bone resorption - increases bone density
4) Promotes growth of endometrium - prolonged unopposed exposure causes hyperplasia
5) Maintains skin & blood vessel integrity
6) Alters liver metabolism - primarily when given orally
Increases production of plasma proteins (Transport proteins, Proteins related to hemostasis)
Alters plasma lipid/lipoprotein profile
Increases: HDL and TG
Decreases: cholesterol and LDL
7) Enhances blood coagulability
8) Alters vascular reactivity - affects vascular smooth muscle cells and endothelial cells
Decreases: endothelin-1, TXA2 receptor number, angiotensin II receptor number, decreases or scavenges free radicals
Increases: expression of nitric oxide synthase (NOS), NOS activity
9) Facilitates movement of fluid into extravascular space (decrease in plasma volume) with compensatory sodium and water retention.
10) Others - increases angiotensinogen
Pharmacokinetics of estrogens
Strongly bound to sex hormone binding globulin (SHBG) and with lower affinity to albumin
Estradiol is metabolized to estrone in peripheral tissue.
Estradiol is metabolized to estriol, estrone and 2-hydroxyestrone in the liver.
The hydroxylated derivative is conjugated (with glucuronic acid or sulfate) and secreted in the bile.
Conjugated metabolites may undergo enterohepatic circulation. Thus, more effects are seen on the liver when estrogens are administered orally than by other routes
Estrogens: Adverse effect
s Nausea, vomiting
Breast tenderness
Postmenopausal uterine bleedin
g Endometrial hyperplasia, cancer
Edema (sodium, water retention), hypertension
Weight gain
Hypertriglyceridemia
Cholestasis, gallbladder disease
Migraine headaches
Estrogen-progestin combinations: Adverse effects
Increased risk for breast cancer
Slight increase in coronary artery disease
Increased risk for thromboembolic episodes (e.g., stroke, pulmonary embolism, deep vein thromboses)
_________ - most active endogenous estrogen, and has highest affinity for estrogen receptor. Metabolites estrone and estriol have weak uterine effects.
Estradiol
” Dikit”
- more effect on levels of CBG, SHBG, and other liver proteins (e.g., angiotensinogen) than transdermal preparations.
Oral preparations
l Associated with cervical & vaginal carcinoma in daughters of women who took the drug during pregnancy
Diethylstilbestrol
Selective Estrogen Receptor Modulators (SERMs)
Nonhormonal pharmacological agents that bind to the estrogen receptors
Tamoxifen
Raloxifene
Clomiphene
” CaRT”
partial estrogen agonist in breast, full agonist in bone & endometrium
Tamoxifen
” thats why in CA patient taking hormonal therapy has an adverse result of endometrial ca”:
_____________ – estrogenic activity in bone, antagonist in both breast and endometrial tissue
Raloxifene
Used in treatment of breast cance
r Increased incidence of endometrial cancer
SERMs: Tamoxifen
____________
Used in prevention and treatment of osteoporosis
Prophylaxis of breast cancer in women at risk
SERMs: Raloxifene
Good effects of Raloxifene
- Lowers LDL
- Prevents breast ca
- prevents uterine CA
- Strengthens the bones
What are the bad effects of Raloxifene?
Increases blod clot risk
**No relief for hot flashes **
Progestins
Progesterone
Hydroxyprogesterone
Medroxyprogesterone
Megestrol
Norethindrone
Norgestrel
Antiprogestins
l Mifepristone
Indications for the use of progesterone/progestins Progestins are synthetic progesterone-like compounds
1) Primary use in contraceptive therapy
2) With estrogen for replacement therapy
3) May be used in treatment of dysfunctional uterine bleeding (DUB), dysmenorrhea, endometriosis
4) May delay premature labor
Physiologic effects of progesterone
1) Stimulates lipoprotein lipase & favors fat deposition
2) Increases basal insulin levels & increases insulin response to glucose
3) Competes with aldosterone at the renal tubule therefore antagonizes aldosterone-mediated Na+ & water retention
4) Increases ventilatory response to CO2
5) Responsible for alveolobular development of secretory apparatus in the breast
6) Relaxes smooth muscle - including inhibition of uterine contraction
7) Participates in preovulatory LH surge and causes maturation, secretory changes in the endometrium that are seen following ovulation
8) depressant and hypnotic effects on the brain
Contraception
Contraception
Combination Oral (Estrogen and Progestin combination)
Monophasic
Multiphasic
Progestin only
1) An oral combination of estrogen and progestin is given at a ___________________
Withdrawal bleeding occurs during “off” period.
constant dose for 21 days followed by 7 days without hormone.
Monophasic
each of the 21 pills per month have the same amount and proportion of estrogen and progestin
Progestin dose is_______________, i.e. estrogen dominance early in the cycle and progestin dominance later.
varied over the 21 days (“on”) to more closely mimic menstrual cycle
Contraception: Mechanism of action
_______________ – Negative feedback on the hypothalamus and anterior pituitary to inhibit the surge of LH and thus inhibit ovulation
Primary Secondary
_________- - Estrogen and progesterone suppresses FSH - blocking follicular development
- Progestin causes thickening of cervical mucus - interfering with sperm migration
- Progestins (out of sequence) cause disturbances in endometrium making it unsuitable for implantation
- Progestins may impair tubal transport of ovum (due to relaxant effect of progestin on smooth muscle in fallopian tube)
- Effectiveness: 2 to 3 pregnancies per 100 women years (theoretical 0.1/100 women yrs)
SECONDARY
2______________ - ora
l Used when estrogen is contraindicated
Mechanisms of action
Thickening of cervical mucus
. Inhibition of ovulation
As listed above for progestin component of combination OC.
Effectiveness: 3 pregnancies per 100 women years
) Progestin only minipill
Oral Contraceptives: Beneficial effects
Reduced risk for:
Ovarian cysts
Ovarian & endometrial cancer
Benign breast disease
Ectopic pregnancy
Fe deficiency
Rheumatoid arthritis
Oral Contraceptives:
Other uses Amelioration of:
Premenstrual symptoms Dysmenorrhea Endometriosis Acne Hirsutism
Contraceptives: CONTRAINDICATIONS
Thrombophlebitis/thromboembolic disorders
Cerebral vascular or coronary artery disease
Uncontrolled hypertension
Known or suspected estrogen-dependent neoplasm (e.g., breast, endometrium)
Cholestatic jaundice or history with prior pill use
Hepatic adenomas, carcinomas, benign liver tumors
l Markedly impaired liver function
l Severe hypertriglyceridemia
l Known or suspected pregnancy
Contraceptives: RELATIVE CONTRAINDICATIONS
Migraine or vascular headache
Cardiac or renal dysfunction
Hypertension
Psychic depression
Varicose veins
History of worsening of a chronic condition during pregnancy (e.g. cholestatic jaundice)
Over age 35 and a cigarette smoker or over age 45
Progestins: ADVERSE REACTIONS
Hypertension Reduce plasma HDL, hirsutism, acne (especially androgenic progestins) Slightly increases breast cancer risk in combination with estrogen Irregular uterine bleeding Depression
