What is the main therapeutic use of Progesterones?
Contraceptives, like the estrogens
What is interesting about the Progesterone Receptor?
Steroid nucleus structures in the estrane, adrostane, and pregnane class all can activate the progesterone receptor
What should the ideal progestin have?
1) High potency at the progesterone receptor. 2) Antiestrogenic actions on endometrium. 3) No activity on the other steroid receptors (AR, GR, ER)
What is the nomenclature for Progesterones?
Progestogen: a molecule with progesterone-like activity (including progesterone); Progestin: a synthetic progestogen
What are the SARs for Progestogens?
1) Requires an intact nucleus (blue bonds), C4=C5. Most other features are not required. 2) C20,21 promote binding, but other double bonds can compensate. 3) Forms lacking C3 keto can be active (prodrugs). 4) Does not require C19 side chain (methyl, having methyl is antagonistic)
What can be done to catabolically block progestogens?
OR blocks catabolism of the required C17 Beta side chain. Adding a C6 side chain and/or C6=C7 can block as well
What can be done to easily increase the Progestin activity 5-10 fold?
Removal of the C19 methyl (demethyl progestins). C17 beta configuration required for high activity (high activity at the progesterone receptor, low activity at other steroid receptors)
What are Androstane-Based Progestins?
The two carbons in the C17 alpha side chain play a dual role: they block catabolism, they provide activation of the progesterone receptor, dimethisterone contains a second catabolic blocking group at C6, and has increased activity. Both compound are orally active
Info on Demethyl, Androstane Progestins?
Orally active, used therapeutically. Moving the double bond decreases activity by 10 fold. Removal of the C3 keto doesn't further compromise activity
What are some other things that can be done to Demythl, Androstane Progestins?
Adding an additional methyl to C18 increases receptor binding, creates Norgestrel. Other modifications to norgestrel are also active and used (as a class, these are termed "GONANES"). Desogestrel and Norgestimate have decreased androgenic side effects
What happens to transactivation activity when Testosterone is made into Ethisterone?
What happens to transactivation activity when Testosterone is made into 19-nor-Testosterone?
How do Ethisterone and 19-nor Testosterone compare in activity?
Relatively the same
How does Progesterone activity compare to Ethisterone and 19-nor Testosterone?
Much higher in lower concentrations
What happens when Ethisterone is made into Norethindrone?
Much higher activity
How do Norethindrone and Progesterone compare?
C19 nor is better than progesterone
What happens when Norethindrone is made into Levonorgestrel?
Much higher activity at lower concentrations, at higher concentrations they become similar
What is Drospirenone?
Highly modified Androstane-based Progestin. Synthetic progestin, analog of spironolactone. Activity profile close to progesterone and dienogest. Component of Yasmin and Yaz
Why are Anti-Progesterones used as contraceptives?
Progesterone activity is required for implantation following conception. Anti-progesterones are competitive antagonists, bind strongly, but don't activate the receptor. These are the morning after pills
What is the pharmacologic effect of Progestins as Contraceptives?
Inhibit ovulation by suppressing function of the hypothalamic-pituitary-ovarian axis. Modify midcycle surges of LH and FSH. Diminish ovarian hormone production. Produce endometrial changes unfavorable for ovum implantation. Thicken cervical mucus to impede sperm transit. Inhibit sperm action