Estrogens Flashcards
E1
Estrone
18 Carbon Steroid
Medium Potency
E2
Estradiol
E3
Estriol
Premenopausal women have…
E2 (estradiol) released by the granulosa cells in the ovaries
In pregnant, the estrogen produced is…
Estriol (E3) by the placenta’s syncytiotrophoblasts - fetal liver
In post-menopausal women, what produces estrogen?
Adipose stroma cells
- E1 (estrone)
In men, what produces estrogens?
The testes
E1 (estrone)
E2 (estradiol)
ER alpha receptor
Expressed in endometrium
70% of breast cancer pts have overexpression
ER beta
Expressed in the:
Kidney
Brain
E2 (estradiol) binds what receptors?
Both receptors (alpha and beta)
E1 prefers to bind to which receptor?
ER alpha
E3 prefers to bind to what receptor
ER beta
Estrogen does ___ to bones.
Increases bone formation!
Increases HT, decreases muscle mass
Estrogen does ____ to HDL and ____ to VDL.
Increases HDL, VLDL, TG
Decreases LDL, total cholesterol
Increases metabolism of fat!
Estrogen ___ coagulation factors.
Increases coagulation factors.
Increases platelet adhesiveness.
Estrogen ___ to cortisol binding globulin (CBG), thyroxine binding globulin (TBG), and sex hormone binding globulin (SHBG).
Increases CBG, TBG, SHBG
What does estrogen do to GI functioning?
Decreases GI functioning
Increases cholesterol in the bile
Increases risk of gallstone formation
Progesterone (P4) is a …
Precursor of other steroids
P5 (Pregnenolone) is converted to P4
Progesterone is involved in…
Menstrual cycle, pregnancy and embryogenesis
Where does progesterone come from in non-pregnant vs. pregnant individuals?
Non-preg:
- corpus luteum, granulosa lutein cells, stimulated by LH
Pregnant:
- corpus luteum but stimulated by hCG
During the 2nd and 3rd month of pregnancy, what does the placenta secrete?
Estriol (E3) and progesterone
Two types of progesterone receptors include:
PR-B = stimulates epithelial cell proliferation
PR-A = opposes estrogen-induced proliferation
What induces PR expression in the endometrium?
Estrogen level rising!
What are the metabolic effects of progesterone?
Increases insulin levels
Increases LDL
Progesterone ______GnRH frequency.
Decreases GnRH frequency
Increases the amplitude of LH
In the CNS, what does progesterone do?
Increases depressant and hypnotic actions
What effect does progesterone have on the reproductive tract?
Increases the endometrium!
Decreases the action of E2
Half life of progesterone?
5 minutes
What are the types of hormonal contraceptives?
Progestin-only pill (aka the mini pill)
Progestin-Estrogen Pill
Northindrone
Progestin-only pill
Norethindrone or norgestrel are…
Less effective than combo pill.
Must be taken at same time, every day.
Used during pregnancy as estrogen reduces breast milk production.
What are the Long Term Reversible Method options for Progestin-Only BC?
Implants: Etonogestrel
Injection: MPA (wt gain and bone loss)
IUS: Levonorgestrel (Minera) 5 years
Etonogestrel (Implanon)
3 year implant
LT Reversible Method
Medrooxyprogesterone Acetate (MPA)
3 months
Injection
Causes wt gain, bone loss
Levonorgestrel (Minera)
5 yers
IUD,
At very LOW doses, what does the progestin pill do?
Inhibits ovulation in half of cycles
Thickens the cervical mucus (reduces sperm viability and penetration)
At medium doses, what does the progestin pill do?
Inhibits ovulation in 97% of the cycles
Thickens the cervical mucus
At high doses, what does the Progestin-Only pill do?
Completely inhibits ovulation
Thickens the cervical mucus
Anovulatory cycles causes by progestin-only pill causes…
Interference with implantation of the blastocyst
Ethinyl Estradiol (EE) = combo pill
Mestranol
Mestranol is Metabolized into EE
Side effects of Combo BC:
Irregular menstrual bleeding
Amenorrhea
Headaches
Bloating
Low Dose Combo Pill
Contain as little as 20 mcg of EE nd 100 mcg of progestin
Continuous Pills of CBC
Seasonique (30 EE and 150 levonorgestrel - progestin) cuts cycle to one every 3 mo
EE and Mestranol
Mestranol is converted to 17-alpha-EE in the liver
This conversion increases the oral effectiveness of these estrogens.
The modifications to EE increase the ORAL BIOAVAILABILITY.
The 17alpha ethinyl group on mestranol inhibits…
Hydroxylation and glucuronization in metabolism
The 3 methyl Group in mestranol inhibits..
Sulfation
High levels of progestin = Levonorgestrel aka PLAN B
70-80% effective
Side effects: Nausea Abdominal pain Fatigue, headache Vomiting, menstrual changes Deterioration in glucose tolerance, increases in plasma insulin
Combo pill used as emergency contraceptive
Side effects worse than plan B
PREVEN, YUZPE
Copper T IUD
Highly effective and for ongoing contraceptive
Ulipristal Acetate (Ella)
Alternative to levonorgestrel
Take one dose within 5 days
selective PR modulator (SPRM)
Mifipristone
Effective within 5 days
An anti-progestin
Disrupts follicular maturation, mid-cycle LH surge, alters the endometrium
Hormone replacement therapy:
To make up for decline in estrogen-progestin after menopause
Relieving symptoms postmenopausally
- vasomotor problems, hot flashes, night sweats
- vaginal atrophy
- osteoporosis
Women who want to take it..do it for lowest dose and shortest period!
Estrogen Alone HRT: Estrones
Estropipate
Conjugated Equine Estrogens (CEE)
Estradiol (E2) Estrogen-alone HRT
Naturally present in premenopausal women
Estriol (E3) Estrogen-Alone HRT
A weak natural estrogen elevated during pregnancy
Estriol (E3) HRT
Does not increase risk of breast or endometrial cancers, asa it is not converted into estrone
Estrogen and Progestin HRT
Prempo = CEE plus MPA
Indicated for women with a uterus and postmenopausal symptoms
Why is progestin added to HRT COMBO?
Progestin is added to prevent endometrial hyperplasia from unopposed estrogen
What are risks associated with Estrogen-Progestin HRT?
Venous thromboembolism
Coronary event
Pulmonary embolism
Should not be initiated or continued in postmenopausal women from prevention of CV disease
SERM : Selective Estrogen Receptor Modulator
Acts as agonist and antagonist
Tamoxifen
SERM
Nonsteroidal
Antagonist on BREAST
Agonist on UTERINE AND BONE
Treatment of ER+ breast cancer
Hepatic metabolism of Tamoxifen (SERM), produces…
Produces highly active 4-hydroxytamoxifen
Tamoxifen effects:
Decreases total cholesterol, LDL, lipoproteins
Does not increase HDL and TG
Side effects: HOT FLASHES ENDOMETRIAL CARCIMONA DVT PULM EMBOLISM
Toremifene
Structurally similar to tamoxifen, similar properties/indications/toxicities
Raloxifene
Nonsteroidal
Partial agonist on bone
Antagonist on uterus and breast
What is raloxifene used for?
Prevention and treatment of osteoporosis in postmenopausal women and breast cancer
Does not increase LDL, like tamoxifen
Does not simulate endometrium, therefore less uterine cancer risk
Effects are diminished by:
Estrogens
Cholesterol lowering drug (decreases absorption)
Clomiphene
Older partial agonist
Used as ovulation-inducing agent
Bazedoxifere
Approved as HRT and for osteoporosis
Used in combo with conjugated estrogens
Fulvestrant
Analog of estradiol (estrogen antagonist)
- no known estrogenic activity
Indicated for ER pos breast cancer, if resistant to tamoxifen
Side effects of fulvestrant
More potent than tamoxifen, degrades the ER alpha receptor
May cross placenta and cause abnormalities
Side effects include GI symptoms, headache, hot flashes, pharyngitis
Mifipristone
A PR and GR antagonist
Luteolytic properites
USED FOR MEDICAL ABORTIONS 7 weeks into pregnancy, effective emergency contraceptive
Misoprostol
Prostaglandin E1
- added to induce uterine contractions
Mechanism of Mifepristone
Blocks uterine PR
- decrease hCG
- decrease progesterone secretion from corpus luteum
- further decidual breakdown
- increase prostaglandins from uterus, leads to expulsion of detached blastocyst
Side effects of Mifepristone
Prolonged bleeding
Aromatase Inhibitors (AI) TYPE 1
Irreversible, steroidal
Exemestane - similar to androstenedione
Exemestane
Type I - aromatase inhibitor
Exemestane is used for
Postmenopausal women with ER pos early breast cancer
More effective than tamoxifen
Irreversible binds to aromatase (converts testosterone -> estradiol)
Formestane
Similar to exemestane (Type I AI)
- weak androgen
- mild AI
- poor bioavailability
Type II Aromatase Inhibitor
Reversible, non-steroidal
Anastrozole
For ER+ breast cancer as first line treatment following tamoxifen
Tamoxifen resistant cancer rarely responds to anastrozole
Causes hot flashes
Letrozole
Type II AI
Reversible, Nonsteriodal
ER+ breast cancer
Blocks estrogen production, increase FSH, stimulates follicle growth
SERMs
Tamoxifen
Raloxifene
Bazedoxifene
Clomiphene
Anti-estrogen
Fulvestrant
Aromatase Inhibitor
Anastrozole
Letrozole
Exemestane
Formestane
Aromatase Inhibitor
Anti-Progestin
Mifepristone (misoprostol)
Progestin
Norethindrone
Levonorgestrel
Medroxyprogesterone Acetate (MPA)
SPRM
Ulipristal
Estrogens
Ethinyl Estraadiol (EE)
Mestranol
Conjugated Equine Estrogens (CEE)
