Progestins: 15 Flashcards
What is important about progesterone?
Most important progestin.
Functions as hormone and precursor to estrogens, androgens and corticosteroids.
Made in ovary, testis and adrenal glands.
How is progesterone metabolized?
Rapid absorption following any administration (half life 5 minutes)
Almost fully metabolized in one pass through liver.
Converted to pregnanediol and conjugated with glucuronic acid and then excreted in the urine.
What are the physiological effects of progestins?
Maturity and secretory changes in endometrium following ovulation.
Increases basal insulin levels and insulin response to glucose.
-promotes glycogen storage in liver
Competes with aldosterone for mineralocorticoid receptor.
-causes decrease in Na+ reabsorption causing increase in aldosterone secretion by adrenal cortex (in pregnancy)
Depressant and hypnotic effects on brain
What are progestins clinically used for?
Hormonal contraception
Hormone replacement therapy in combo with estrogens.
-prevents AE of estrogen like uterine bleeding and endometrial carcinoma
Growth of endometrial cells outside of uterine cavity
-progestins suppress the growth of endometrial cells and reduce pain and inflammation
Dysmenorrhea -menstrual cramps
Bleeding disorders
What SAR is required for progestin activity?
C-18 methyl or ethyl group required for activity.
Ketone at carbon 3 (can be introduced by in vivo oxidation)
What are the 19-nor, 17-ethynyl steroids (oral contraceptives)?
1st generation progestins
17-ethynyl group increase oral BioAVA.
-replace acetyl with OH increase oral BioAVA
19-methyl group replace with H enhances activity
Ex: Norethindrone + Ethynodiol diacetate
What is important to know about levonorgestrel and norgestimate?
Levonorgestrel is an isomer of norgestrel which is a racemic mixture.
ONLY levo form is active
High oral BIOAVA.
Used in IUDs and Mirena
NORgestimate is a prodrug.
-converted to levonorgestrel oxime and then to levonorgestrel in vivo.
What is important to know about desogestrel and etonogestrel?
Desogestrel is a prodrug.
-rapidly metabolized to etonogestrel
-High oral BIOAVA.
-STRUCTURE: loss of carbon 3 carbonyl
Etonogestrel is the active form of desogestrel.
-structurally analogous to levonorgestrel (difference is an methene group on carbon 11)
-used in subdermal implant (nexplanon) or vaginal ring (NuvaRing)
What is important to know about drospirenone and medroxyprogesterone acetate?
Drospirenone is weak progestogenic activity (10% of levonorgestrel)
-Antimineralocorticoid activity
-Negative side effects of ethinyl estradiol in combo therapy
-STRUCTURE: 2 epoxide rings
Medroxyprogesterone acetate
-IM injectection (Depo-provera) as long acting progesterone only contraceptive
-STRUCTURE: Carbon 6 alpha methyl
What is the breakdown of progestin activities?
Progestin activity:
-Norethindrone (+)
-Levonorgestrel (+++)
-Norgestimate (+++)
-Desogestrel (+++)
Androgen activity:
-Norethindrone (++)
-Levonorgestrel (+++)
-Desogestrel (-/+)
Anti Estrogen activity:
-Norethindrone (+)
-Levonorgestrel (++)
-Norgestimate (+++)
-Desogestrel (+++)
What are the different types of hormonal contraception?
Combo estrogens (ethinyl estradiol or mestranol) and progestins
-21 days on active compounds, 7 days on sugar placebo (withdrawal bleeding)
-continuous progestin therapy without estrogen (minipill AKA norethindrone)
What are the different way hormonal contraception is delivered?
Mostly oral administration.
-adherence to schedule more important for progestin-only therapies
Implantable (etonogestrel), IUD (levonorgestrel), or depot injection (medroxyprogesterone acetate)
What are the pharmacological effects of oral contraceptives?
Inhibition of ovulation
-combo estrogens and progestins selectively inhibit pituitary function (progestin only do not always inhibit ovulation)
Suppress ovarian function
-after stopping, most patients return to normal cycle in 1-2 months
Change in cervical mucus and uterine endometrium (decrease in chance of conception and implantation)
Combo only stimulate breast enlargement due to estrogen
-suppresses lactation as well
What are adverse effects of oral contraceptives?
Mild
-nausea, HTN, edema, breast fullness - estrogens
-increased appetite, fatigue breast regression - due to progestins
Moderate
-irregularities in menstruation - more common in progestin-only contraceptives
-weight gain, acne, hirsutism - common with combos containing androgen-like progestins
Severe
-venous thromboembolic disease -estrogens
-MI - due to androgenic activity of progestins
-dangerous to women over 35 who smoke
What are the drug interactions of progestins?
ORAL contraceptives may increase blood levels of other steroids by interfering their metabolism.
Anticonvulsants like phenytoin decrease the effectiveness of ORAL contraceptives.
Antibiotics like rifampin increase the rate of metabolism of other drugs.
-tetracycline suppress gut flora that participate in enterohepatic recycling.
