Pharmacology of Estrogens and Progestins Flashcards
Use of pharmacologic vs physiologic doses of estrogens/progestins
Pharmacologic: suppress hyp/pit/ov axis via neg feedback (contraception)
Ex: ethinyl estradiol 20-35 mcg
Physiologic doses: menopausal hormone therapy (MHT) for their actions on target tissues (esp urogenital, bone, and vasculature).
-Ex: ethinyl estradiol 5-10 mcg
Receptors for estrogen agonists
ER alpha
ER beta
Estrogens diffuse through plasma membrane, enter nucleus, bind to estrogen receptor, dimerization, bind to estrogen response elements of target genes.
Physiologic effects of estrogen
- normal maturation and ovulatory cycle
- metabolic effects: maintenance of normal structure of skin and blood vessels, decrease resorption of bone (antagonize PTH effect), alter liver metabolism
- enhance coagulability of blood (increase II, VII, IX, X, decrease antithrombin III)
- increase HDL and decrease LDL (cardioprotective)
- increased incidence of gallstones (increased cholesterol saturation)
- influence libido
Symptomatic treatment in menopause (Menopausal hormone therapy)
- Systemic estrogen for moderate to severe menopausal vasomotor symptoms (hot flashes, night sweats) and vulvovaginal and urogenital complaints (vaginal dryness, pruritus, post-coital bleeding)
- Should use vaginal estrogen alone for vulvovaginal complaints.
- use lowest effective dose for shortest duration possible
- risk of endometrial cancer reduced if use estrogen then progesterone or continuous combined estrogen/progesterone.
Ospemifene
SERM for painful sexual intercourse.
Non-hormonal therapy for menopause
-hot flashes in women who can’t or won’t take estrogen:
antidepressants (venlafaxine, fluoxetine, paroxetine), clonidine, and gabapentin
-OTC: Vit E, soy (variable response: convert isoflavone daidzein to equol), black cohosh (only mildly better than placebo)
SERMs and prevention of osteoporosis
Selective estrogen receptor modulators
- Ex.: Raloxifene
- agonist (estrogen-like) activity on bone receptors (increase bone mineral density) and liver (decrease LDL, increase HDL), lack agonist activity in uterine and breast tissue
- risk of thromboembolic disorders
-only for those with significant risk of osteoporosis (thin, inactive, low Ca intake, Caucasian, etc)
Prevention of cardiovascular disease
Estrogen is NO LONGER APPROVED for hear disease prevention. (No CV benefits, serious side effects: increased risk of MI, stroke)
Contraindications to MHT
- undiagnosed vaginal bleeding
- acute liver disease
- active thrombosis
- recent breast cancer
- recent endometrial cancer
Side effects of MHT
- Postmenopausal bleeding (estrogens are major cause)
- Nausea, breast tenderness common; anorexia, vomiting, diarrhea
- Hypertension (1-5%, reversible); increased migraine headache frequency; gallstones
Physiologic effects of estrogen on bone
-decrease number and activity of osteoclasts (increased OB production of osteoprotegerin “decoy” that prevents OC activation
Tamoxifen
SERM:
Treatment and prevention of breast cancer (ER+)
-palliation in metastatic disease
-increases risk of endometrial cancer 5x (partial agonist)
-risk for: hot flashes (antag), venous thromboembolism
Raloxifene
SERM:
Prevention of breast cancer (ER+)
-ER agonist in bone (osteoporosis prevention)
-risk for: hot flashes, venous thromboembolism (less than tamoxifen)
How can you minimize estrogen hepatic effects?
use non-oral routes
-topical, transdermal, parenteral
Physiologic Effects of Progestins
- large increase in secretion during luteal phase
- Stimulates LPL activity favoring fat deposition
- Increases insulin levels and insulin response to glucose; promotes liver glycogen storage and ketogenesis
- Prolonged high levels impair glucose tolerance (pregnancy)
- High doses: compensatory increases in aldosterone secretion by adrenal cortex (pregnancy)
- Increases body temperature (1deg F at ovulation)
- Increases ventilatory response to CO2
- Anti-estrogen action on endometrial proliferation
