Progestins

list the progestin facts

• the term progestins denote a number of related hormones and not a single molecule

• can be used alone for birth control and for hormone replacement therapy or in conjunction with estrogen in combination oral contraceptive

• used to treat endometriosis and pain associated with it

• used to treat breast, uterus, and kidney cancer by changing the cell’s ability to use other hormones

• progesterone is secreted during the second half (luteal phase) in preparation for pregnancy

• stimulate angiogenesis in the endometrium when egg is fertilized and implanted

steps in the synthesis of endogenous progestins

cholesterol → pregnenolone (3-beta HSD) → progesterone (17-alpha hydroxylase) → 17-hydroxyprogesterone

location for endogenous progestin synthesis

corpus luteum

natural progestin

progesterone = released from ovary and important in maintaining pregnancy by suppressing menstruation and uterine contractility (switch from proliferative to secretory state)

synthetic progestins

lab made

uses = contraception (with or without estrogen) menopause symptoms (with estrogen) endometriosis, dysfunctional uterine bleeding

important carbon ring positions for modifications

Carbons 3-6 and 17-20

types of synthetic progestins

progesterone derivatives

19-nortestosterone derivatives (estranes and gonanes)

general pathway for hormone binding and response

hormone binds to NR and heat-shock protein dissociates → dimerization between two NR-ligand → translocation to nucleus → NR dimer binds to HRE of DNA → recruitment of coactivators and proteins for transcription to mRNA → new protein to modify cell function

what happens if PR-A is expressed alone

acts as repressor

what happens if PR-B is expressed alone

acts as an initiator/stimulator

what happens if both PR-A and PR-B are expressed

PR-A suppresses PR-B mediated transcription and represses estrogen, androgen, glucocorticoid and mineralocorticoid receptor activities

physiological response if progestin is used as contraceptive

prevents LH surge and ovulation, thickens cervical mucus, thins lining of uterus making implantation less likely

physiological response if progestin is used to treat endometriosis

stimulates atrophy or regression of endometrial lesions

physiological response if progestin is used for HRT

added with estrogen to reduce risk of uterine cancer in women who still have a uterus; inhibits estrogen induced proliferation of endometrium

progestin only use side effects

• episodes of irregular/unpredictable spotting and break thru bleeding

• acne (androgenic effect)

• headache

• mood changes

• weight gain

• decrease bone density

contraindications for progestins

• thromboembolic or CVD

• MI or CAD

• congenital hyperlipidemia

• carcinoma of the breast or female reproductive tract

• impaired liver function

• hypertension

• diabetes

• pregnancy

• gallbladder disease

what structural modifications may be present that differ from endogenous progestin

synthetic progestins may contain: -CH3 on C6; -ene on C6-7; substitutions at C17 or C20

what are the available dosage forms for progestins

• vaginal gel

• vaginal insert

• IM injection

• oral capsules

PK parameters for progestins

• oral bioavailability = low (<10%) and variable

• extensively metabolized

• highly protein bound (>95%)

• large Vd

SARs for progesterone derivatives

• pregnane (required)

• 3-keto and 4,5 double bond (required)

• 20-keto

• 17-hydroxyl ester (acetate) to increase activity

• 6-methyl (increase oral stability)

SARs for 19-norprogestins

• estrane nucleus

• 3-keto and 4,5 double bond

• 17-beta OH

• 17-alpha ethinyl group

• 18-ethyl (in place of methyl)

• 11-exocyclic double bond