estrogens progestins pharm Flashcards
estrogen/progesterone metabolism
•degraded rapidly on 1st-pass through liver; analogs that have reduced hepatic degradation have been developed for oral use
- Define the principal estrogens/progestins in humans
Estradiol (E2):most abundant and potent estrogen in menstruating wome. Estrone (E1): 2nd most potent estrogen, the predominant estrogen during menospause. Estriol (E3): weak estrogen
- Define the estrogen-like compounds in our environment.
A. phytoestrogens - occur in plants, fruits, veggies. have estrogenic and antiestrogenic activities: 1) isoflavones are most potent (genistein and diazein in soybeans, chickpeas, lentils) 2) coumestans: split peas, lima beans, 3) lignans (enterolactone and enterodiol found in flaxseed, lentils, grains, fruits, veggies, ). B. bisphenol A- a synthetic compound used in plasticizers; has weak affinity but its bioaccumulation in the environment has raised concerns about potential toxicity
Sites of estrogen synthesis in pre vs post menopausal women (and men)
Premenopausal: ovarian theca and granulosa cells. Men and postmenopausal: adipose tissues (estrone is synthesized from androstenediol secreted by the adrenal cortex) and conversion of test to estradiol via aromatase
compare levels of estrogen in pre vs post menopausal and men
premenopausal: early follicular (40-200 pg/ml); preovulatory (250-500 pg/ml); midluteal (100-150 pg/ml). Post menopausal/ men: <20pg/ml
biosynthetic pathway of estrogen production
cholesterol > pregnenolone > progesterone > androstenedione > estrone (aromatase)> estradiol. OR androstenedione > testosterone > estradiol (aromatase)
two cell theory of estrogen synthesis
the theca cells secrete androgens that diffuse to the granulosa cells to be aromatized to estrogens.
Tissue locations of aromatase
granulosa cells, adipose tissue, muscle and brain
Estrogen feedback regulation
estrogen feeds back primarily at the level of the pituitary to inhibit LH/FSH secretion.
- Describe the mechanism of action of estrogens.
Estrogen (E) binds to ER and facilitates dimerization and interaction with estrogen response element (ERE) sequences in DNA. The ER-DNA complex recruits co-activators SWI/SNF and SRC-1. SRC-1 has histone acetyltransferase activity that alters chromatin structure. This remodeling facilitates the exchange of the recruited proteins such that other co-activators (p300 and TRAP) bind to the gene promoter and recruit proteins that comprise the general transcription apparatus (GTA) resulting in synthesis of mRNA.
Describe MOA of estrogen receptor antagonists
ie. Tamoxifen. Binds ER facilitating dimerization, but recruits co-repressors NcOR. NcOR recruits histone deacetylase I which stabilizes nucleosome and prevents interaction with the general transcription apparatus
The recruitment of factors by the estrogen receptor depends on
The ligand and tissue that the receptor is in
Types of estrogen receptors and which hormones bind to them
ER alpha and beta: 17b-estradiol bind equally to Era and Erb. Estrone has higher affinity for Era. Phytoestrogens genistein and coumestrol have higher affinity for Erb.
tissue distribution of estrogen receptors
ER b: granulosa cells, kidney, intestinal mucosa, lung, bone marrow, brain, prostate. ER a: endometrium, breast cancer cells and ovarian stroma
Therapeutic uses of estrogens
Hypogonadism (plus progestin if uterus intact), menopause, menopause (plus calcium, Vit D and bisphosphanates), contraception (plus progestin to inhibit production of LH/FSH and GnRH), PCOS (plus spironolactone)
Estrogen use in menopause
alleviate vasomotor instability, emotional lability, sleep disturbances, atrophy of estrogen-dependent tissues, and osteoporosis
Modifications to estradiol to increase lipid solubility and decrease degradation by liver
Estradiol is esterified at 17-beta position (R3) to increase lipid solubility. Adding an ethinyl group at position 17 (R2) decreases degradation by the liver.
List the esterified estrogens
estradiol valerate and estradiol cypionate
List the estrogens with ethinyl group added
ethinyl estradiol, mestranol, and quinestrol
compare the routes of estrogen meds and associated risks
Oral estrogen increases hepatic production of thyroxine-binding globulin, corticosteroid-binding globulin, sex hormone-binding globulin, triglycerides, high-density lipoprotein (HDL) cholesterol, and clotting factors, whereas their production is only minimally increased by transdermal estrogen administration. Transdermal has lower risk of venous thromobosis and stroke
List the preparations of 17-B-estradiol, 17-B-estradiol esters, synthetic conjugated estrogens (estrone sulfate), conjugated equine estrogens (Premarin) and ethinyl estradiol
17-B-estradiol: oral (micronized), transdermal, vaginal cream, vaginal ring. 17-B-estradiol esters: oral, IM. Synthetic conjugated estrogens (estrone sulfate): oral. Conjugated equine estrogens (Premarin): oral, HRT. ethinyl estradiol: birth control pill
Risks and side effects of estrogens
Increased risk of cancer (endometrial, lung, vaginal/cervical cancer in offspring), stroke, heart attack, blood clots, gall bladder dz, migraine, nausea, and changes in lipid metabolism
Which cancer risk is increased with progestin
breast cancer
SERMs MOA
display agonistic or antagonistic activities depending on tissue and endpoint.
List the effects of SERM agonists at the breast, endometrium, bone, CV system, CNS and liver
Breast: promotes cancer. Endometrium: promotes cancer. Bone: maintain bone density, anti-resorptive. Cardiovascular system: arterial dilation. CNS: cognitive and neuroprotective. Liver: Stimulates uptake of serum lipoproteins, increases synthesis of coag factors.
“ideal SERM” for hormone replacement
antagonist in endometrium and breast. agonist in bone, cardiovascular system, CNS
Tamoxifen MOA and uses
SERM used in the treatment of breast cancer, act as antagonist at breast but agonist in endometrium ( because of risk of endometrial cancer used for less than 5 years)
Raloxifene MOA and uses
SERM used for osteoporosis, acts as a partial agonist in bone and does not stimulate endometrial proliferation
Toremiphene MOA and uses
SERM used in the treatment of breast cancer, act as antagonist at breast but agonist in endometrium ( because of risk of endometrial cancer used for less than 5 years)
Clomiphene MOA and uses
SERM used for treatment of infertility, induces ovulation by antagonizing inhibitory actions of estrogen at level of pituitary, partial agonist at endometrium and causes hot flashes
Femarelle uses
SERM used for Menopause symptoms and maintaining bone health
List Antiestrogens and uses
Fulvestrant- treatment of breast cancer
List the aromatase inhibitors
anastrozole (arimidex)and letrozole (femara) are non-steroidal, competitive. exemestane (aromasin) and formestane (lentarin) are steroidal, non-competitive
Aromatase inhibitors MOA and uses
Block production of estrogens from androstenediol or testosterone. used for the treatment of breast cancer, primarily in postmenopausal women. Superior to Tamoxifen. No stimulation of endometrium.
Aromatase inhibitors side effects
joint disorders, osteoporosis, hypercholesterolemia
List the principle progestins
Progesterone and 17alpha-hydroxyprogesterone
Sites of progesterone biosynthesis in men and women
Premenopausal women: synthesized mainly by corpus luteum. also in adrenal cortex and placenta. Men and postmenopausal women: Testis and/or adrenal cortex
List the normal concentrations of progesterone in men and women
Premenopausal women: follicular phase (95mg/dl); luteal phase (1000ng/dl). Men and postmenopausal women: 15-90ng/dl
Mechanism of action of progestins
•cytosolic receptor that translocates to nucleus and regulates gene transcription via progesterone response elements.
Progestin receptor forms
A and B. PR receptor is induced by estrogen as well
Therapeutic uses of progestins
- contraception: combo pill (estrogen plus small amount of progestin), progestin only pill (less effective), postcoital contraceptives (high dose intereferes with implantation). 2. HRT: used with estrogens. 3. Ovarian suppression: dysmenorrhea, endometriosis, uterine bleeding
How does progestin work as contraception
Decreases frequency of hypothalamic pulse generator
Progesterone preparations
micronized oral form (Prometrium), injectable oil-based solution, vaginal cream, IUD
Progesterone esters preparations
medroxyprogesterone acetate is given orally (Provera) or IM administration (Depo-Provera)
19-nortestosterone derivatives preparations
norethindrone, norgestrel are given orally with estrogen for contraception. norgestrel is also given as subdermal implant (Norplant). etronorgestrol released with ethinyl estradiol (Nuva ring). norelgestromin and ethinyl estradiol released transdermally (Evra patch); superior compliance to OCP.
Preparation of progesterone that decreases hepatic degradation
Substitution at the 6-position decreases hepatic degradation making MPA orally active. Ethinyl substitution of 19-nortestosterone decreases hepatic degradation making more orally available
List anti-progestins and their uses
Mefipristone (RU 486)- used to terminate pregnancy by acting as competitive antagonist at level of uterus. Can also act as postcoital contraceptive by preventing ovulation via effects on hypothalamus. Given with prostaglandins
