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
Medroxyprogesterone, megestrol
-progesterone derivatives with little effect on gonadotropin release from pituitary, mainly peripheral actions (endometrial tissue)
Norethindrone
- progestin in OC
- 1st gen (lower activity than 2nd gen)– higher risk of bleeding/spotting
Levonorgestrel
- progestin in OC
- 2nd gen (increased activity and longer half life)
- decreased VTE risk
- increased androgenic actions
Desogestrel
norethynodrel
norgestimate
3rd generation
lower androgenic activity
slightly higher VTE risk
Drospirenone
4th gen
-spironolactone analog
-antimineralocorticoid and antiandrogenic activity
increased VTE risk
-antag of aldosterone action may result in temporary weight loss
Progestins in OCs contain
19-nortestosterone analogs:
-androgenic and anabolic effects
Clinical uses of progesterone
- Oral (+/- estrogen component) and implant contraception
- Menopausal hormone therapy - must be added to estrogen in women with intact uterus
- Long-term ovarian suppression (anovulation and amenorrhea with large parenteral doses) for treatment of dysmenorrhea (NSAIDs preferred), endometriosis, bleeding disorders (if estrogens contraindicated), and hirsutism. Dosage of progestins and timing of administration is critical in these indications
- Anorexia / weight loss of AIDS (megestrol)
Side effects of progesterone
- CNS: mental depression, somnolence, headache
* Breast enlargement, tenderness; nausea, elevated blood pressure; edema, weight gain
Hormonal contraception
either estrogen plus progestin (COC)
or progestin alone
OCs and mortality
OCs reduce mortality (relative to childbirth) in women less than 35 who don’t smoke, but show 2-4 fold increase in mortality for those greater than 35 who do smoke
Mech of Action for hormonal contraceptives
inhibit ovulation via:
- suppression of FSH and follicle development (estrogen)
- prevention of ovulatory surge of LH (progestin)
- Progestin alone decreases the frequency of GnRH pulses, but less reliable LH suppression
- Cervical mucus, uterine endometrium, motility-secretion in fallopian tubes leads to decreased likelihood of implantation (estrogen + progestin)
- monophasic (single dose of progestin) or multiphasic (varying dose of one or both hormones during cycle)
COC adverse effects
- thromboembolic disorders (estrogen), but minimal effect in healthy non smokers
- increased, but small risk of breast cancer
- increased risk of cervical cancer (long term: greater than five years and with persistent HPV)
- reduced risk of endometrial and ovarian cancer
- decreased risk of colorectal cancer
- cholestatic jaundice
- depression (6%)
COC contraindications
Smokers over 35 years old
Women with uncontrolled hypertension
Diabetes with end organ damage
Migraines with focal neurological deficits (aura)
History of breast cancer, VTE, or liver disease
Adolescents with incomplete epiphyseal closure
COC drug interactions
- drugs that induce or enhance estrogen metabolism, leading to reduction in contraceptive effect
- **Rifampin (CYP450 inducer– clearance of COCs increased), anticonvulsants (phenytoin, carbamazepine, phenobarbital), griseofulvin
Benefits of OCP use
Younger Women: Decreased incidence of dysmenorrhea, iron deficiency, anemia, acne
Older Women: Decreased incidence of endometrial / ovarian cancer, salpingitis, ectopic pregnancy, benign breast disease, osteoporosis
Emergency contraception
Levonorgestrel (Plan B)
Ulipristal (Ella)
1-2 doses given 12 hours apart within 72 hrs of unprotected intercourse
85-90% efficacy with plan B
nausea is often SE
