Female Sex Hormones

Question 1

What are 3 natural steroidal estrogens to know?

Answer 1

Estrone - E1
Estradiol - E2
Estriol - E3

Have different # of hydroxy groups

Question 2

What is a naturally occurring estrogenic compounds to be aware of?

Answer 2

Flavinoids in soybeans / palmetto. Might be bad for hormone-dependent cancers. Unclear.

Question 3

Synthetic estrogenic compounds (non-pharmaceutical) to be aware of?

Answer 3

Bisphenols, alkylphenols, phthalates… in plastics. CAN bind to Estrogen Receptors.

Question 4

What the major product of ovarian steroidogenesis?

Answer 4

Estradiol (E2)

Question 5

Where are E1 and E3 made? What are they made from?

Answer 5

In liver, from E2.

In periphery, from androstenedione.

Question 6

What’s a druggable enzyme in the female sex hormone synthesis pathway? What does it do? (She emphasized this….)

Answer 6

Aromatase: Converts T -> E2, and androstenedione -> E1.

Question 7

Other than female sex organs and female secondary sex characteristics, what are 3 physiological effects of estrogen on female maturation?

Answer 7

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!)

Question 8

Review: 2 Effects of estrogens on endometrium?

Answer 8

1) Proliferation during follicular/proliferative phase.

2) Hyperplasia, if too much–> can result in endometrial cancer (unopposed estrogen)

Question 9

CV / hemotologic effects of estrogen? Name 3.

Answer 9

1) Increased coagulability.
2) Increased HDL-C and triglycerides.
3) Contributes to normal vascular structure and function…..

So basically… we are confused… conflicting data….

Question 10

Nitty gritty: How does estrogen increase coagulability (2 ways)?

Answer 10

Increases factors II, VII, IX, X (extrinsic, tissue factor pathway).
Decreases antithrombin III.

Question 11

How do we know that estrogen has protective effects on CV health? *Do we?

Answer 11

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…..

Question 12

Metabolic effects of estrogen? (name 2)

Answer 12

1) Increases production of leptin. (inhibits appetite)

2) Increased serum proteins such as fibrinogen, SHBG, transferrin (carries iron)… others.

Question 13

What’s estrogen got to do with bone? (She emphasized this)

Answer 13

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

Question 14

Relevance of progesterone to labor?

Answer 14

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)

Question 15

What allows a full agonist to work? (in the context of steroid receptor ligands) Where do these “molecules” exist?

Answer 15

Recruitment of a co-activator.

- Co activators exist in uterus, breast, myocardium, vasculature… everywhere estrogen has an effect

Question 16

What’s a Type I antagonist? (when talking about steroid receptors)

Answer 16

Drug binds to receptor, preventing it from binding to the HRE (the DNA where it normally binds).

Question 17

What’s a Type II antagonist? (when talking about steroid receptors)

Answer 17

Drug binds receptor, causing it to recruit a co-repressor.

Question 18

What does a partial agonist/antagonist for steroid receptors do (Type III-IV antagonist) ? Key example of this? (She emphasized this…)

Answer 18

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

Question 19

Are there non-genomic responses to sex hormones?

Answer 19

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)

Question 20

4 ways to modulate estrogen signaling pathways? (example of a drug for each?)

Answer 20

Agonize (estrogens)
Antagonize (mifepristone)
Modulate receptor (Selective ER modulator - SERM… confusing name, but tamoxifen fits in this class)
Inhibit synthesis (aromatase inhibitors)

Question 21

3 uses for estrogen agonism as therapy?

Answer 21

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.

Question 22

Does estrogen work to help prevent osteoporosis?

Answer 22

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)

Question 23

2 specific beneficial effects seen in estrogen replacement therapy?

Answer 23

Reduced incidence of colorectal cancer.
Reduced incidence of hip fractures.
Also good for symptoms like hot-flashes and vaginal atrophy/dryness.

Question 24

4 cardioprotective effects of estrogen replacement therapy (ERT)?

Answer 24

Increases HDL, decreases LDL.
Delays intimal thickening (but makes arteries thicker).
Decreases angiotensin II.
Reverse ACh-induced vasoconstriction of carotid arteries.

Question 25

4 bad things about ERT?

Answer 25

May increase risk for coronary artery disease, stroke, PE, and invasive breast cancer.

Question 26

What would be a feature of an ideal anti-estrogen drug for treatment of hormone-sensitive breast / uterine etc. cancer?

Answer 26

Selectivity such that it did not affect bone.

Question 27

What’s raloxifene? What does it do? (She emphasized this…)

Answer 27

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)

Question 28

What are aromatase inhibitors used for? What are 2 examples?

Answer 28

ER-positive cancers (breast and uterine)
Anastrozole (Arimidex)
Exemestane (Aromasin)

Question 29

4 uses of progestins?

Answer 29

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.

Question 30

What is RU486/ mifepristone MoA?

Answer 30

Recruits co-repressor, blocks progestrone activity.

Question 31

2 estrogens used for hypogonadism and contraception?

Answer 31

Ethinyl estradiol (EE) and mestranol.

Question 32

Estrogen notes as being used for ERT?

Answer 32

Estradiol cypionate. (longer duration than unmodified E2)

Question 33

What was the aromatase inhibitor listed in the chart?

Answer 33

Letrozole.

anastrozole and exemestane were mentioned earlier in the lecture…

Question 34

Progestin example listed in the chart?

Answer 34

Norethindrone.

Question 35

REVIEW: Where are estrogens made in 1st part of menstrual cycle? After ovulation? During pregnancy? During menopause

Answer 35

• 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)

Question 36

What are the 4 MAIN female sex hormones? (Objective #1)

Answer 36

1) Progesterone
2) Estrone
3) Estradiol
4) Estriol

Question 37

REVIEW: What produces progesterone in non pregnant state? During pregnancy?

Answer 37

• Non pregnant state: Corpus Luteum

- In pregnancy: Placenta (in HUGE quantities)- maintains endometrium to hold on to the fetus

Question 38

What is a “genomic” response? Why may this be a potential drug target?

Answer 38

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)