Female Sex Hormones Flashcards
1) Learn what the female sex hormones ARE and what they DO 2) Understand pathways of their biosynthesis and receptor mediated action 3) Understand targets for drug action 4) Appreciate risks/benefits of replacement TX 5) Understand MOA of SERMS 6) Understand MOA of estrogen synthesis inhibitors
What are 3 natural steroidal estrogens to know?
Estrone - E1
Estradiol - E2
Estriol - E3
Have different # of hydroxy groups
What is a naturally occurring estrogenic compounds to be aware of?
Flavinoids in soybeans / palmetto. Might be bad for hormone-dependent cancers. Unclear.
Synthetic estrogenic compounds (non-pharmaceutical) to be aware of?
Bisphenols, alkylphenols, phthalates… in plastics. CAN bind to Estrogen Receptors.
What the major product of ovarian steroidogenesis?
Estradiol (E2)
Where are E1 and E3 made? What are they made from?
In liver, from E2.
In periphery, from androstenedione.
What’s a druggable enzyme in the female sex hormone synthesis pathway? What does it do? (She emphasized this….)
Aromatase: Converts T -> E2, and androstenedione -> E1.
Other than female sex organs and female secondary sex characteristics, what are 3 physiological effects of estrogen on female maturation?
1) Closure of epiphyses of long bones. (for males, too- determinant for final height someone achieves)
2) Areolar and genital skin pigmentation.
3) Fat redistribution (pear shaped!)
Review: 2 Effects of estrogens on endometrium?
1) Proliferation during follicular/proliferative phase.
2) Hyperplasia, if too much–> can result in endometrial cancer (unopposed estrogen)
CV / hemotologic effects of estrogen? Name 3.
1) Increased coagulability.
2) Increased HDL-C and triglycerides.
3) Contributes to normal vascular structure and function…..
So basically… we are confused… conflicting data….
Nitty gritty: How does estrogen increase coagulability (2 ways)?
Increases factors II, VII, IX, X (extrinsic, tissue factor pathway).
Decreases antithrombin III.
How do we know that estrogen has protective effects on CV health? *Do we?
Epidemiology. Can’t really predict that from are knowledge of its physiological effects.
*Data from later slides seems to suggest that ERT increases risk of CV disease…..
Metabolic effects of estrogen? (name 2)
1) Increases production of leptin. (inhibits appetite)
2) Increased serum proteins such as fibrinogen, SHBG, transferrin (carries iron)… others.
What’s estrogen got to do with bone? (She emphasized this)
Estrogen promotes the apoptosis of osteoclasts -> maintenance of bone density. (there’s probably more too it than that)
- Why in post menopause women lose lots of bone density
Relevance of progesterone to labor?
Progesterone makes the uterus insensitive to oxytocin until labor.
(why some medical abortion drugs (not methotrexate!) that inhibit progesterone signaling can be used to induce labor)
What allows a full agonist to work? (in the context of steroid receptor ligands) Where do these “molecules” exist?
Recruitment of a co-activator.
- Co activators exist in uterus, breast, myocardium, vasculature… everywhere estrogen has an effect
What’s a Type I antagonist? (when talking about steroid receptors)
Drug binds to receptor, preventing it from binding to the HRE (the DNA where it normally binds).
What’s a Type II antagonist? (when talking about steroid receptors)
Drug binds receptor, causing it to recruit a co-repressor.
What does a partial agonist/antagonist for steroid receptors do (Type III-IV antagonist) ? Key example of this? (She emphasized this…)
In some tissues, causes receptor to recruit a co-activator. In other tissues, causes receptor to recruit a co-repressor.
Some tissues-may have an absence of receptors.
Tamoxifen: Estrogen repressor in breast, activator in endometrium, bone, maybe CV
- Need to monitor if women are PRE menopausal and have an intact uterus
Are there non-genomic responses to sex hormones?
Yes estrogen can act paracrine/autocrine in nature… can cause increased uterine blood flow without transcriptional changes (estrogen binds to ER on vasculature and causes vasodilation)
4 ways to modulate estrogen signaling pathways? (example of a drug for each?)
Agonize (estrogens)
Antagonize (mifepristone)
Modulate receptor (Selective ER modulator - SERM… confusing name, but tamoxifen fits in this class)
Inhibit synthesis (aromatase inhibitors)
3 uses for estrogen agonism as therapy?
Hypogonadism (primary or secondary) -> for more normal puberty and bone density.
Suppression of ovulation (Note: progestins are way more important for this).
Post-menopausal hormone-replacement therapy.
Does estrogen work to help prevent osteoporosis?
Yes.
(In study- group that exercised and took estrogen was only one that improved bone density–> lead to use of HRT.. which then was stopped)
2 specific beneficial effects seen in estrogen replacement therapy?
Reduced incidence of colorectal cancer.
Reduced incidence of hip fractures.
Also good for symptoms like hot-flashes and vaginal atrophy/dryness.
4 cardioprotective effects of estrogen replacement therapy (ERT)?
Increases HDL, decreases LDL.
Delays intimal thickening (but makes arteries thicker).
Decreases angiotensin II.
Reverse ACh-induced vasoconstriction of carotid arteries.
4 bad things about ERT?
May increase risk for coronary artery disease, stroke, PE, and invasive breast cancer.
What would be a feature of an ideal anti-estrogen drug for treatment of hormone-sensitive breast / uterine etc. cancer?
Selectivity such that it did not affect bone.
What’s raloxifene? What does it do? (She emphasized this…)
Reloxifene is a SERM that blocks E2 signaling in both breast and uterus - used for hormone-sensitive cancer.
It’s an agonist in bone and CV system.
(seems like a pretty cool drug - big downside is strokes and DVTs)
What are aromatase inhibitors used for? What are 2 examples?
ER-positive cancers (breast and uterine)
Anastrozole (Arimidex)
Exemestane (Aromasin)
4 uses of progestins?
1) Replacement therapy (to mitigate hazards of giving estrogen).
2) Contraception / IVF.
3) Endometriosis.
4) Dysfunctional Uterine Bleeding (DUB) -recall: is often caused by anovulation -> lack of progesterone.
What is RU486/ mifepristone MoA?
Recruits co-repressor, blocks progestrone activity.
2 estrogens used for hypogonadism and contraception?
Ethinyl estradiol (EE) and mestranol.
Estrogen notes as being used for ERT?
Estradiol cypionate. (longer duration than unmodified E2)
What was the aromatase inhibitor listed in the chart?
Letrozole.
anastrozole and exemestane were mentioned earlier in the lecture…
Progestin example listed in the chart?
Norethindrone.
REVIEW: Where are estrogens made in 1st part of menstrual cycle? After ovulation? During pregnancy? During menopause
- During proliferative phase: Theca and granulosa cells of Graafian follicle
- After ovulation: Made by corpus luteum
- During pregnancy: Made by feto-placental unit
- During menopause: Estrogen mostly comes from adrenal gland- with hepatic conversion of estrogen precursors (ovaries have stopped functioning)
What are the 4 MAIN female sex hormones? (Objective #1)
1) Progesterone
2) Estrone
3) Estradiol
4) Estriol
REVIEW: What produces progesterone in non pregnant state? During pregnancy?
- Non pregnant state: Corpus Luteum
- In pregnancy: Placenta (in HUGE quantities)- maintains endometrium to hold on to the fetus
What is a “genomic” response? Why may this be a potential drug target?
Ex: When estrogen binds to endometrium/ breast tissue receptor- changes TF’s
- Different tissues have marked differences in how they respond to estrogen- may be able to leverage for personalized medicine (genome specific)
