Pharmacology of Estrogens and Progestins Flashcards Preview

Life Cycles Unit 1 > Pharmacology of Estrogens and Progestins > Flashcards

Flashcards in Pharmacology of Estrogens and Progestins Deck (31):
1

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

2

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.

3

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

4

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.

5

Ospemifene

SERM for painful sexual intercourse.

6

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)

7

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)

8

Prevention of cardiovascular disease

Estrogen is NO LONGER APPROVED for hear disease prevention. (No CV benefits, serious side effects: increased risk of MI, stroke)

9

Contraindications to MHT

-undiagnosed vaginal bleeding
-acute liver disease
-active thrombosis
-recent breast cancer
-recent endometrial cancer

10

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

11

Physiologic effects of estrogen on bone

-decrease number and activity of osteoclasts (increased OB production of osteoprotegerin "decoy" that prevents OC activation

12

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

13

Raloxifene

SERM:
Prevention of breast cancer (ER+)
-ER agonist in bone (osteoporosis prevention)
-risk for: hot flashes, venous thromboembolism (less than tamoxifen)

14

How can you minimize estrogen hepatic effects?

use non-oral routes
-topical, transdermal, parenteral

15

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

16

Medroxyprogesterone, megestrol

-progesterone derivatives with little effect on gonadotropin release from pituitary, mainly peripheral actions (endometrial tissue)

17

Norethindrone

-progestin in OC
-1st gen (lower activity than 2nd gen)-- higher risk of bleeding/spotting

18

Levonorgestrel

-progestin in OC
-2nd gen (increased activity and longer half life)
-decreased VTE risk
-increased androgenic actions

19

Desogestrel
norethynodrel
norgestimate

3rd generation
lower androgenic activity
slightly higher VTE risk

20

Drospirenone

4th gen
-spironolactone analog
-antimineralocorticoid and antiandrogenic activity
increased VTE risk
-antag of aldosterone action may result in temporary weight loss

21

Progestins in OCs contain

19-nortestosterone analogs:
-androgenic and anabolic effects

22

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)

23

Side effects of progesterone

• CNS: mental depression, somnolence, headache
• Breast enlargement, tenderness; nausea, elevated blood pressure; edema, weight gain

24

Hormonal contraception

either estrogen plus progestin (COC)
or progestin alone

25

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

26

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)

27

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%)

28

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

29

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

30

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

31

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