Estrogens, Progestins, & Their Antagonist Flashcards
Estrogens
- critical for sexual development and 2nd characteristics
- stimulate growth of uterine muscle & endometrial lining
3 human nature estrogens
E1: estrone
E2: estradiol
E3: estriol
Strongest most potent estrogen
E2 (80x) > E1 (8x) > E3 (1x)
Metabolic & Cardiovascular Effects of Estrogen
Blood, Lipid, Bone
(good) Bone: increase formation, decrease resorption, increase height, decrease muscle mass
(good) Lipid: increase HDL, VLDL, TG; decrease LDL, total cholesterol, fat deposition; increase fat metabolism
(bad) Blood: increase coagulation factors, increase coagulability of blood, increase risk of blood clots
Estrogen Receptors
ERa ERb
made from two different genes
ERa: endometrium
ERb: kidney, brain
E2 binds both receptors; E1 prefers ERa; E3 prefers ERb
Estrogen is expressed mainly in
bone, heart, breast
ERa
endometrium; over expressed in breast cancer
Estrogen Mechanism of Action
- estrogen cross cell membrane and bind ERa/b
- conformational change
- interacts with coregulators
- coregulators may affect tissue-specific effects of selective estrogen receptor modulators (SERM)
ERb vs ERa
ERb has its own separate action, and may have a dominant negative effect on ERa
ERa/b are made from
two different genes
Biosynthesis of Estrogens
Premenopausal
producing mainly E2 upon FSH stimulation
Biosynthesis of Estrogens
Postmenopausal
producing mainly E1
Biosynthesis of Estrogens
Pregnancy
producing mainly E3
Biosynthesis of Estrogens
Men
producing small amounts of E1 & E2
Main target for drug therapy
Aromatase
Ethinyl Estradiol EE
Synthetic Estrogen
Diethylstilbestrol DES
no longer used; hurt babies
Commonly used Estrogens
Ethinyl Estradiol Micronized estradiol Estradiol cypionate Estradiol valerate Estropipate
ESTRADIOL & ESTROPIPATE
17a-ethinylestradiol
as active as E2
Mestranol
- converted into 17aEE by liver
- chemical alterations increase oral bioavailability
Estrogen modifications
delay metabolism, increasing oral bioavailability
Clinical Uses of Estrogens
Primary Hypogonadism
- replacement therapy in estrogen-deficient patients
- attempts to mimic the physiology of puberty
- chronic maintenance therapy consists of both estrogens and progestins
Clinical Uses of Estrogens
HRT
Postmenopausal Hormone Therapy
- use estrogen/progestin to make up for declines after menopause
relieving symptoms including:
- hot flashes
- drying itchiness
- sleep disturbances
USE SHOREST AND LOWEST POSSIBLE because potential risks
Estrogens for HRT
E1, E2, E3
Estrogens for HRT
E1
- estropipate
- CCE, PREMARIN (conjugated equine estrogens)
Estrogens for HRT
E2
- attached to acetate, valerate, and cypionate groups that are hydrolyzed away in the body to produce estradiol
Estrogens for HRT
E3
- weak natural estrogen elevated during pregnancy
- ISNT converted into estrone; DOESNT INCREASE RISK OF BREAST OR ENDOMETRIAL CANCERS; higher dosage needed
ERa cancer
over expressed in breast cancer
Estrogen + Progestin for HRT
NEVER USE PROGESTIN ALONE; can use estrogen alone
- CEE + MPA (medroxyprogesteron acetate)
- indicated in women with a uterus
- progesterone added to prevent endometrial hyperplasia from estrogen
- added risks
Progestins
- need lots during pregnancy
Progesterone
- natural progestin in human
- controls menstrual cycle, pregnancy
- C21 steroid; precursor to other steroids
Name the Active Progesterone
P4
Biosynthesis of Progesterone
Non-pregnant women
- by granulosa lutein cells in corpus luteum
- LH stimulation
Biosynthesis of Progesterone
Pregnant women
- from corpus luteum
- hCG stimulation
Biosynthesis of Progesterone
2nd month of pregnancy
- placenta secretes estriol and progesterone under delivery
- peaks third trimester
Progesterone Receptor A&B made by
ONE gene; different due to splicing
Need estrogen and progestin or
nada will happen (pregnancy wise)
MPA
Medroxyprogesterone Acetate
mixed with CEE estrogen for HRT
6 Progestational Agents
- progesterone
- hydroxyprogesterone
- medroxyprogesterone
- dimethisterone
- norethindrone
- desogestrel
Most Important use of Progestins
Hormonal Contraception
- can use just progestin but usually with estrogen
Therapeutic Applications of Progestins
- HRT (w/ estrogen, never alone)
- Long-term ovarian suppression
- diagnostic uses: test estrogen secretion
- hormonal contraception
Norgestrel
aka Norethindrone
Progestin-ONLY Pills
- taken daily
ectopic pregnancy risk
- less effective than combination pills
Levonorgestrel
Plan B
- ONLY progestin
- use within 3 days; sooner = better
Ulipristal Acetate
SPRM
Selective PR modulator
Emergency Contraceptive
Mechanism of Hormonal Contraceptives
1) suppress ovulation
2) affects viscosity of mucus fluid and mobility and secretion of the uterine tubes (sperm can’t reach egg)
3) interfere with implantation
Tamoxifen
Selective Estrogen Receptor Modulator (SERM)
- nonsteroidal, antagoinst on the breast, and partial agonist on uterine and bone
- palliative care for ER+ breast cancer
- decreases total cholesterol
- – does not increase HDL and triglyceride
Rolaxifene
Selective Estrogen Receptor Modulator
- nonsteroidal partial agonist on bone and antagonist on uterus and breast
- ** same as tamoxifen EXCEPT less uterine cancer risk ***
Fulvestrant
Anti-estrogen
- estrogen receptor
- analog of estradiol with no known estrogenic activity
- indicated for ER-positive metastatic breast cancer when resistant to Tamoxifen
- degrades ERa receptor
- affects fetus
Mifepristone
Anti-progestin
- progestin receptor
- PR and GR antagonist with luteolytic properties
- medical abortion
Selective Estrogen Receptor Modulator
SERM
- tissue-selective estrogenic actions
- Agonist: bone & CVS
- Antagoinst: Breast & uterus
Toremifene
similar to Tamoxifen
Aromatase Inhibitors
Type 1
- Irreversible
- Steroidal
Exemestane
Aromatase Type I Inhibitor
- binds irreversibly to aromatase
- for postmenopausal women with ER+ early breast cancer
- MORE EFFECTIVE than tamoxifen
Aromatase
Type 2
- reversible
- nonsteroidal
Anastrozole
Aromatase Type II Inhibitor
- for ER+ breast cancer; first line treatment or following tamoxifen
- sometimes helps ER-
- NO RISK OF UTERINE CANCER OR DVT
Letrozole
Aromatase Type II Inhibitor
- ER+ breast cancer
- block estrogen production, increase FSH, stimulate follicle growth
Formestane
Aromatase Type I Inhibitor
- irreversible
- steroidal
- similar to exemestane
- weak androgen, mild AI; poor oral availability; no longer popular
Bazedoxifene
SERM
- in combination with conjugated estrogens, approved as HRT and osteoporosis
Clomiphene
SERM
- older partial agonist
- ovulation-inducing agent
Progestins without androgenic activity include
- desogestrel
- norgestimate
- gestodene
