In high concentrations, estrogen may hit and activate which receptors?
What is the main estrogen produced in pre-menopausal and menopausal women?
Estradiol (from the ovaries)
What is the main estrogen produced in post-menopausal women?
Estrone (from adipose tissue - DHEA from adrenals)
In males, where is estrogen produced?
Estrogens from the testes / Estrone/Estradiol from androstenedione and DHEA
What are the estrogens made in fetus/placenta?
Estrone and Estriol from DHEA
What enzyme converts androstenedione to estrone?
What are the steps in estrogen activation in the nucleus?
Estradiol (E2) enters the cell by passive diffusion / E2 binds to ERs (either alpha or beta) / ERs dimerize / Dimer binds to Estrogen Response Element on DNA / Transcriptional Activity Response (either inducer or repressor)
It is longer and is the more important stimulator in most tissues
What is the MOA for progesterone?
Progesterone enters the cell and binds to the PR / PR dimerizes / Dimer interacts with a Co-activator or Co-repressor / Dimer+CoA (R) bind to Progesterone Response Element on DNA and activate/inhibit transcription of mRNA
What neuroendocrine action does progesterone perform?
decreases frequency of GnRH release by the hypothalamus
What reproductive tract activities does progesterone perform?
decreases estrogen-driven endometrial proliferation, causes maturation of the endometrium and suppresses menstruation and uterine contractility
What CNS effects does progesterone perform?
increases basal body temp about 1 degree F at midcycle
What metabolic effects does progesterone perform?
Where is progesterone metabolized?
rapid first-pass metabolism in the liver (hydroxylated metabolites that are then sulfated or gluruonidated)
What are the three classes of progesterone-related compounds?
Pregnanes, Estranes and Gonanes
How are pregnanes absorbed?
poorly absorbed orally (low bioavailability)
What SAR occurs on pregnanes and to what effect?
adding an acyl group to C17 slows liver metabolism (OAc) / Adding CH3 to the C6 decreases metabolism
What SAR occurs on Estranes and to what effect?
Removal of the C19 CH3 (nor) maintains progestin activity and some androgenic effects / adding C17 alkynyl increases progestin activity and decreases metabolism
What SAR occurs on Gonanes and to what effect?
Change of C13 from CH3 to CH2CH3 reduces androgenic effect
What are some therapeutic uses for progesterone and progesterone-like compounds?
Menopausal Hormone Therapy, Regular Oral Contraceptives and Post-Coital Contraception
What two progesterone agents are used in menopausal hormone therapy?
micronized progesterone or medroxyprogesterone (MPA)
What progesterone agent is used as an oral contraceptive?
19-nortestosterone (estrane) or Norgestrel (levonorgetrel) in combo with estrogen (blocks ovulation)
What progesterone agent is used in post-coital contraception?
Levonorgestrel at higher doses (blocks LH surge and ovulation, prevents implantation)
What is the MOA for anti-progestins?
Decidual breakdown of uterine progesterone receptors / Detachment of blastocyst (implanted embryo) / Decreased hCG production and decreased progesterone production by corpus luteum / Increased prostaglandin production in uterus which sensitizes endometrium to contractile actions / Expulsion of blastocyst (embryo)