Estrogens and Progestins Flashcards
Steroidogenesis in the ovary
-what cell types and what do they produce and do?
1) theca cell:
- Stimulated by LH to produce testosterone and androstenedione from cholesterol
2) Granulosa cell
- stimulated by FSH to convert testosterone and androstenedione to estrenone and estradiol by aromatase
Hypothalamic-Pituitary gonadal axis - feedback regulation:
- what hormones
- how?
-estrogen and progesterone have both pos and neg effect
Menstrual cycle:
- phases?
- which hormonses involved?
1) Follicular phase
- high frequency, low amplitude LH secretion
- ESTROGEN rises-controls endometrial proliferation
2) Ovulation (day 14)
- estrogen induced gonaotropin surge (Surge of FSH and LH due to high estrogen) LH IS REQUIRED FOR OVULATION
3) Luteal Phase
- FSH AND LH DROP
- INHIBIN A and B RISE
- rise in estrogens and progesterone
* *-endometrial differentiation under control of progesterone**
4) No implantation-steroidogenesis is not maintained and endometrial lining is shed
Rise in body temp due to what hormone?
progesterone
Steroid-Estrogen MOA?
-endogenous steroid bind intracellular receptors and modulate transcriptional activity
Estrogen vs progesterone:
-effect on endometrium?
E=proliferation
P=differentiation/prepare for implantation, decrease uterine contractions
Estrogen vs progesterone:
Metabolic effects:
E=LIPIDS- dec LDL, Inc HDL inc triglyc (CARDIO PROTECTIVE); BONE-antiresorptive (MAINTAIN BONE DENSITY); LIVER-inc plasma proteins; BLOOD-inc coa factor, dec antithrombin
P=LIPIDS-inc LDL, in fat deposition; GLUCOSE-inc fasting glucose levels
Estrogen vs progesterone:
development:
E&P=ovaries, fall tubes, uterus, vagina, breasts
Estrogen vs progesterone:
menstrual cycle-
E=key regulator during follicular phase
P=key regulator during luteal chase
Estrogen vs progesterone:
uterus smooth muscle
E=NONE
P=dec uterine contractions, dec prostaglandin production, maintina relaxin secretion
Estrogen vs progesterone:
cervical glands
E=NONE
P=inc cervical mucous viscosity
Which hormone appears to be cardio protective?
estrogen
Inc in blood glucose with which hormone?
progesterone
Which hormone decreases prostaglandin production? What does this mean for the uterus?
- Progesterone
- Prostaglandins CONTRACT muscle so by dec levels we are relaxing the uterus muscles
steroidal naturals:
- estradiol
- estrone
- estriol
steroidal synthetics:
- ethinyl estradiol
- mestranol
Nonsteroidal synthetic:
diethylstilbestrol
benefit of steroidal synthetics compared to naturals?
naturals have t.5 of minutes while the synthetics have t.5 of 13-27 hrs.
sturctural alteration = SIGNIFICANTLY LESS LIVER METABOLISM
Conjugated equine estrogen
- type?
- solubility?
- benefit to use?
- estrogen prep
- natural water-soluble estrogen sulfates
- need mcuh LESS equine than ethinyl estradiol
Ethinyl estradiol
- type?
- -use?
- synthetic steroid estrogen
- contraception
- need much less of these synthetics than the naturals
Mestranol
- type?
- use?
- synthetic steroid estrogen
- contraception
- need much less of these synthetics than the naturals
Diethylstilbestrol (DES)
- type
- use?
- first synthetic non-steroidal estrogen
- not used much
Uses of estrogen:
1) hypogonadism-promote dev of female sex organs
2) hormone replacement therapy (HRT) - maintain bone density, suppress hot flashes, suppress urogenital atrophy (NEGATIVE FEEDBACK ON PIT AND HYPOTHAL
3) contraception - negative feedback on HPG axis = prevent LH surge = inh ovulation
4) Acne treatment-suppress steroidogenesis which cause acne produced by theca cells - so we are blocking LH hormone which stimuates theca cells; INC sex hormone binding globulin (SHBG) production by the liver=less free testosterone concentrations
*Key results of womens health initiative studies (estrogen + progestin)?
1) INC risk of coronary heart disease
2) INC risk of stroke
3) INC risk of pulmonary embolism
4) INC risk of invasive breast cancer
5) DEC risk of colorectal cancer
6) DEC risk of hip fracture
Key physiological effects of estrogens:
- breast tenderness
- endometrial hyperplasia
- inc blood coagulation
- nausea
- cholestasis-changes in cholesterol secretion into bile, bile canaliculi function
- migraine-sign of altered blood coag
- cancer- beast or endometrial
- bloating-loss of intravascular fluid
Adverse effects of HRT combo therapy:
1) inc risk of invasive breast cancer
2) likely due to progestin not estrogen
Adverse effects of HRT estrogen monotherapy:
1) inc risk for endometrial cancer
Adverse effects of contrceptive therapy;
1) reduced risk of ovarian and endometrial cancer
2) breast cancer (dose has changed so its hard to tell- low dose seems to show no risk but high dose shows risk)
Estrogen and cancer MOA
1) trophic effects of hormones
2) reactive oxygen species production during metabolism
When can you give estrogen therapy monotherapy?
-ONLY if woman has had a total hysterectomy
Progestins
-what is the parent steroid and what progestin is made from it?
- Progesterone–> medroxyprogesterone acetate (MPA)
- 19-nortestosterone –> nerethindrone
Medryoxyprogesterone (MPA)
- what type?
- how used?
- used for what purpose?
- progesterone family
- combined with estrogen for HRT
- long acting contraceptive
Norethindrone
- what type?
- how used?
- used for what purpose?
- 19-nortestosterone deriv
- combined OR progestin only horomone contraceptive
Norgestrel
- what type?
- how used?
- used for what purpose?
- 19-nortestosterone deriv
- combo or progestin only hormone contraceptive
What is the problem with 19-nor compounds?
-they also have affinity for androgen receptors
Uses of progestins
1) contraceptive - ALONE or combo with estrogen (inh ovulation and inc cervical mucous viscosisty)
2) Hormone replacement therapy - dec risk of endometrial hyperplasia caused by estrogens
3) Dysmenorrhea -
- dec endometrial mass
- dec prostaglandin production
4) endometriosis
- dec endometrial proliferation by regulating ER expression and stimulaing differentiation of endometrial cells
why dont we usually give progestins alone for contraception even though we could?
-progestins alone have a lower success rate of preventing contraception compared to progestins +estrogens
Adverse effects of progestins:
- breakthrough bleeding-changes in endometrial vasculature
- impaired glucose tolerance (hyperglycemia)
- changes in lipid metabolism (atherosclerosis)
Important AE of 19-Nor compounds:
Acne
hirsutism
Oral pill birth control
- which hormones?
- treatment duration?
- MOA?
1) -estrogens & progesterone
- progestins alone
2) Monthly, quarterly, yearly
3) -suppress LH and FSH surge
- alter cervical mucus
- alter endometrium
Injectable birth control
- which hormones?
- treatment duration?
- MOA?
1) -estrogens & progesterone
- progestins alone
2) monthly or quarterly
3) -suppress LH and FSH surge
- alter cervical mucus
- alter endometrium
Implantable birth control
- which hormones?
- treatment duration?
- MOA?
1) progestins alone
2) 5 years or 3 years
3) -suppress LH and FSH surge
- alter cervical mucus
- alter endometrium
Intrauterine device (IUD) birth control
- which hormones?
- treatment duration?
- MOA?
1) Progestins alone
- COPPER
2) 5 years
3) -suppress LH and FSH surge
- alter cervical mucus
- alter endometrium
transdermal birth control
- which hormones?
- treatment duration?
- MOA?
1) Estrogens & progestins
2) monthly
3) -suppress LH and FSH surge
- alter cervical mucus
- alter endometrium
Vaginal ring birth control
- which hormones?
- treatment duration?
- MOA?
1) estrogens and progestins
2) monthyl
3) -suppress LH and FSH surge
- alter cervical mucus
- alter endometrium
What drug is depo-provera?
medroxyprogesterone - IM injection
Oral contraceptives are what drugs?
-combo estrogen and progestin
OR
-progestin only
Injectable contraceptives are what drugs?
-progestin only
What is the key to success with emergency contraceptives?
HIGH DOSE but MOA is unknown
Hormone contraceptive- MILD adverse effects:
- nausea
- mastalgia
- breakthrough bleeding (estrogen)
- edema
- headache
- withdrawal bleed failure
- serum protein changes
Hormone contraceptive- MODERATE adverse effects:
- breakthrough bleeding (Progestin) - fragile vasculature
- weight gain
- inc skin pigmentation
- acne
- hirsutism (19-nor effects)
- vaginal infections
- amenorrhea
Hormone contraceptive- SEVERE adverse effects:
- thromboembolic disease
- MI
- cerebrovascular disease
- GI disorders (cholestasis)
- depression
- cancer (high dose issue)
Non-contraceptive benefits to using hormone birth control:
1) reduced risk of ovarian and endometrial cancer
2) reduction in dysmenorrhea, endometriosis
3) dec incidence of ectopic pregnancy
4) dec incidence of benign breast disease
5) inc hemoglobin concentrations
6) suppress acne and hirsutism
Contraindications of estrogen containing contraceptives:
1) known or suspected breast cancer or cancer of reproductive tract
2) thromboembolic disorders
3) liver disease
4) Hx of MI, CAD, hyperlipidemia (CV disease)
5) smokers 35 yr old +
Interactions of birth control:
1) inc metabolism=
- HIV agents -
- anticonvulsants
- St johns wort
2) antibiotics lower contraceptive effectiveness-knock out gut flora=inc estrogen excretion
Clomiphene
- type?
- MOA?
- use?
- AE?
- estrogen receptor partial agonist (reduce inhibitor effects of estrogen with partial agonist)
- fertility drug - if its due to low levels of FSH and LH -used 5 days prior to day 14 ovulation
- multiple births
- hot flashes
- ovary enlargement
- blurred vision
SERMS-selective estrogen receptor modulators
-Actions in tissues?
depends on the tissue- either agonist (inc estrogenic transcription), partial agonist, or antagonist (complete transcriptional block of estrogen)
SERMS - effect on bone?
-agonist activity = suppress resorption
SERMS - effect on endometrium?
-partial agonist - proliferation but not to same extent as estrogen would
SERMS - effect on Pituitary and breast?
- antagonist -
- pit=hot flashes
- breast=inh proliferation
SERMS - name the drugs:
- tamoxifen
- raloxifene
Tamoxifen
1) MOA?
2) USE?
3) AE?
1) -agonist- bone
- partial agonist - endometrium
- antagonist-breast/ HPG axis
2) Estrogen Receptor positive BREAST CA
3) -hot flashes
- endometrial CA
- nausea
- vomting
Raloxifene
1) MOA?
2) USE?
3) AE?
1) -agonist- bone
- partial agonist - none really (lower risk for endometrial cancer)
- antagonist-breast/uterus/HPG axis
2) -CA
- postmenopausal bone loss
3) -Hot flashes
- nausea
- vomit
Which SERMS drug has lower risk for endometrial cancer?
Raloxifene lower risk
Tamoxifen has more risk
Which SERMS drug is good for postmenopausal bone loss?
raloxifene
Danazol
- type?
- MOA?
- uses?
- AE?
1&2) inhibition of estrogen - inh gonadal function (displacing steroids from plasma proteins = inc clearance)
3) -endometriosis
- breast fibrocystic disease
4) -WG
- edema
- oily skin
- acne
- hirsutism
- hot flashes
Anastrozole and letrozole
1) type
2) mOA?
3) use?
4) AE?s
1) inh of estrogen
2) aromatase inh
3) breast cancer
4) -GI disturbances
- hot flashes
- lethargy
Anti-progesterone drugs:
- abortifacient - Mifepristone
- emergency contraceptive - Ulipristal
Mifepristone
1) type?
2) MOA?
3) Dosing?
1) ant-progesterone or progesterone receptor modulators or abortifacient
2) Antagonist
3) less than 7 weeks= 1 dose and dose of misoprostol 48hrs later
Ulipristal
1) type?
2) MOA?
3) Dosing?
1) ant-progesterone or progesterone receptor modulators or emergency contraceptive
2) Partial agonist
3) longer acting up to 5 days after sex
Anti-progesterone MOA?
1) inh progesterone receptors
2) induce uterine contractions
3) shed lining of uterus
4) open cervix
Anti-progesterone other uses:
- contraceptive=distrupt ovulation
- anticancer - breast or endometrial
- induce delivery after fetal death
- induce labor at end of 3rd trimester
