Pharmacology of Estrogens and Progestins Flashcards
1
Q
Principal estrogens in humans
A
- Estradiol (E2) > Estrone (E1) > Estriol (E3)
- Most –> least potent
- Estradiol: most abundant and potent estrogen in menstruating women
- Estrone: predominant estrogen during menopause
- Estriol: made by placenta
2
Q
Estrogen-like compounds in humans
A
- Phytoestrogens
- Estrogenic and anti-estrogenic activities
- Nonsteroidal compounds that occur naturally in many plants, fruits, and vegetables
- 3 primary types:
- Ligans: flaxseed, lentils, grains, fruits, veggies
- Isoflavones (most potent of phytoestrogens): Genistein, Daidzein, soybeans, chickpeas, lentils
- Coumetans: split peas, lima beans, pinto beans
- Alternative to HRT, perception of improved safety
- Bisphenol A
- Synthetic compound found in plasticizers
- Weak affinity but potential toxicity due to bioaccumulation in environment
3
Q
Cell types in which estrogens are made
A
- Premenopausal women:
- Ovarian granulosa cells with thecal androgen contribution
- Postmenopausal women, men:
- Adipose tissue (estrone synthesized from adrostenediol secreted by adrenal cortex)
- Conversion of testosterone to estradiol via aromatase
4
Q
Site of progesterone biosynthesis
A
- Premenopausal women:
- Corpus luteum
- Adrenal cortex
- Placenta
- Postmenopausal women, men:
- Testis and/or adrenal cortex
5
Q
Steps of estradiol synthesis
A
- LH stimulates theca cell (adenylyl cyclase pathway) –> increases synthesis of LDL receptors and side-chain-cleavage enzyme
- Theca cells increase synthesis of androstenedione
- Androstenedione freely diffuses to granulosa cells
- FSH (through adenylyl cyclase pathway) –> stimulates granulosa cell to produce aromatase
- Aromatase converts converts androstenedione to estrone
- 17b-HSD converts estrone to estradiol OR 17b-HSD can convert androstenedione to testosterone, then to estradiol via aromatase
- Estradiol diffuses into blood vessels
6
Q
Negative feedback in estrogen biosynthesis
A
- Synthesis of estrogen and progesterone by ovary - under control of hypothalamic-pituitary axis
- Estrogen synthesis regulated by negative feedback system
- Estrogen feeds back primarily at level of pituitary to inhibit LH/FSH secretion
- Progesterone acts at both pituitary and hypothalamic levels
- Prior to puberty: GnRH pulse generator in arcuate nucleus of hypothalamus does not function
- GnRH is shut down –> no menstrual cycles
7
Q
MOA of estrogens
A
- Unliganded estrogen receptor (ER) exists as monomer within nucleus
- Agonists (estrogen):
- Bind to ER, cause conformational change to facilitate dimerization & interaction with specific estrogen response element sequences in DNA
- Proteins: co-activators SWI/SNF, SRC-1, p300, TRAP
- Antagonists (tamoxifen):
- Also bind to ER but produce different receptor conformation
- Antagonist-induced conformation facilitates dimerization and interaction with DNA
- Proteins: co-repressors NcoR, HDAC1
8
Q
MOA of progestins
A
- Cystolic receptor (A or B, induced by estrogen) translocates to nucleus, regulates gene transcription via progesterone response elements
9
Q
Use of estrogen/progestin agonists and antagonists in clinic: primary, secondary, tertiary defects
A
- Primary level: ovarian defect
- Congenital: Turner’s syndrome
- Acquired: Autoimmune, chemotherapy, radiation
- Labs: High GnRH, high LH/FSH
- Secondary level: pituitary defect
- Pituitary tumors: prolactinomas
- Labs: Normal GnRH, low LH/FSH
- Tertiary level: hypothalamic defect
- Congenital: Kallman’s syndrome
- Acquired: Illness, stress, excessive exercise, anorexia
- Labs: Low GnRH, low LH/FSH
10
Q
Other clinical indications for estrogen/progestin agonists & antagonists
A
- Menopause
- Administer estrogens in conjunction with calcium, vitamin D, and bisphosphonates
- Estrogen therapy alleviates vasomotor instability, emotional lability, sleep disturbances, atrophy of estrogen-dependent tissues, and osteoporosis
- Lack of estrogen precipitates most menopausal symptoms
- Primary ovarian deficiency
- Estrogen levels 1/8 of normal, progesterone levels 1/3 of normal, elevated LH/FSH
- Contraception
- Estrogens used in conjunction with progestin to inhibit production of LH/FSH and GnRH; prevent ovulation
- PCOS
- Tx with contraceptives to block androgen production in combination with anti-androgen (e.g. spironolactone)
- HRT
- Progestins used with estrogens when uterus is intact
- Ovarian suppression –> progestin
- Dysmenorrhea
- Endometriosis
- Uterine bleeding
11
Q
Estrogen preparations
A
- 17-b-estradiol (E2)
- Oral (micronized), transdermal patches, vaginal cream, and vaginal ring
- Esters of 17-b-estradiol (EE)
- Oral, IM
- Synthetic conjugated estrogens (estrone sulfate)
- Oral
- Conjugated equine estrogens (CEE) (Premarin)
- Oral (~0.625 mg/day); HRT
- Ethinyl estradiol
- Oral (20-35 ug/day); birth control pill
12
Q
Progestin preparations
A
- Progesterone
- Micronized oral form (Prometrium), injectable oil-based solution, vaginal cream, IUD
- Esters of progesterone
- Medroxyprogesterone acetate - orally (Provera) or IM administration (Depo-Provera)
- 19-nortestosterone derivatives
- Norethindrone, norgestrel - oral with estrogen for contraception
- Norgestrel also given as subdermal implant (Norplant)
- Estronorgestrol released with ethinyl estradiol (Nuvaring)
- Norelgestromin and ethinyl estradiol released transdermally (Evra patch); superior compliance to OCPs
13
Q
Estrogen/progestins pharmacology
A
- Adding ester group increases lipid solubility and half-life
- Adding ethinyl group dereases hepatic degradation
- Differ in potency, but very little in efficacy
- Oral route impacts liver, increasing hepatic production of thyroxine-binding globulin, corticosteroid-binding globulin, sex hormone binding globulin, triglycerides, HDL cholesterol, and clotting factors
- Transdermal estrogen administration only minimally increases hepatic-produced entities
- Prevention of bone density loss
- Treatment of menopausal symptoms
- Lower risk of venous thrombosis and stroke
- Less effect on serum lipid concentrations
14
Q
Aromatase inhibitors
A
- Anastrozole (arimidex) and letrozole (femara)
- Non-steroidal, competitive
- Exemestane (aromasin) and formestane (lentarin)
- Steroidal, non-competitive
- Block production of estrogens from androstenediol or testosterone
15
Q
Clinical uses of aromatase inhibitors
A
- Treatment of breast cancer, primarily in postmenopausal women
- Benefits:
- Highly efficacious (superior to tamoxifen)
- No stimulation of endometrium
- Side effects:
- Joint disorders
- Osteoporosis
- Hypercholesterolemia
