Estrogens: 13 and 14

Question 1

What are some main functions of estrogens?

Answer 1

Develop and and maintain female reproductive tissues EX: ovaries, uterus, breast and vagina

Regulate CNS (temperature and mood)
-temperature fluctuations causes mood changes

Effects in peripheral tissues (bone, CV and liver)

Question 2

What are some main functions of progesterone?

Answer 2

Develop and and maintain female reproductive tissues EX: uterus and breast

Maintain pregnancy “progestation”

Effects in other tissues - brain

Question 3

What is important about 17B-estradiol?

Answer 3

Most potent estrogen in human but not most abundant.

Produced mostly in ovaries in premenopausal women.
-made in placenta during pregnancy

Plasma levels: 5-85 ng/dL
-varies during menstruation

Mostly bound to SHBG and albumin. 2% available like testosterone.

Question 4

How is estrogen synthesis regulated?

Answer 4

There is negative and positive feedback unlike testosterone. Only theories for how it switches between the two.

Same hormones released from hypothalamus and anterior pituitary.

FSH and LH will stimulate the ovaries to produce estrogen and progesterone.

Question 5

How does the follicular phase of the menstrual cycle work?

Answer 5

If there is no pregnancy, days 1-5 will be the menstrual phase where corpus luteum degenerates and estrogen and progesterone production by corpus luteum declines (menstruation)

Early follicular phase:
First FSH peak will stimulate growth of follicle.
Shortly after estrogen is released and will suppress the production of FSH
Estrogen promotes endometrial growth.

Late follicular phase:
Estrogen surge stimulates a FSH and LH surge leading to ovulation and formation of corpus luteum.

On day 14, ovulation happens where the graafian follicle ruptures releasing the oocyte.

Question 6

How does the luteal phase of the menstrual cycle work?

Answer 6

Endometrium continues to mature.

Estrogen and progesterone are produced and suppress the function of LH and FSH.

Question 7

What happens if pregnancy occurs?

Answer 7

Fertilized egg/embryo will secrete hCG (human chorionic gonadotropin).

hCG acts like LH to stimulate corpus luteum to produce progesterone in first trimester. High progesterone levels support maintenance of endometrium.

Chromatographic immunoassays (like covid test) of hCG in urine are used as pregnancy test.

Question 8

How are estrone and estriol produced?

Answer 8

Made in liver and peripheral tissues.

Once at androstenedione aromatase can act and create aromatic ring 1 and remove carbon 19 to make estrone.
-add 2 hydroxyls to carbons 16 and 17 to make estriol.

Question 9

What does the enzyme 17B hydroxysteroid dehydrogenase do?

Answer 9

It will convert the ketone group on carbon 17 to a beta hydroxyl.

Conversion of androstenedione to testosterone.

Conversion of estrone to 17B-estradiol.

Question 10

What are the natural estrogens?

Answer 10

Estradiol-most potent
Estrone-less potent
Estriol-less potent (dominant during pregnancy made by placenta)

Question 11

What are the synthetic estrogens?

Answer 11

Drugs with estrogenic activities

come as steroidal and non steroidal

Question 12

What are phytoestrogens?

Answer 12

Estrogen-mimetic compounds in plants (flavonoids)

Question 13

What are environmental estrogens?

Answer 13

Compounds used in manufacturing of plastics.

Bisphenols, alkylphenols, phthalate phenols.

Can cause problems in pregnant women -avoid

Question 14

How are estrogens metabolized and excreted?

Answer 14

Metabolism: happens in liver.
-conjugated estrogens in bile can be hydrolyzed in intestine and reabsorbed (enterohepatic circulation)

Excretion: to the bile and urine

Question 15

What is the problem with orally administered estrogens?

Answer 15

The have a high ratio of hepatic to peripheral effects.

This is avoided by using routes that avoid first-pass liver exposure.

Question 16

What are some of the physiological effects of estrogen related to female maturation?

Answer 16

Female maturation:
-Organ development (vagina, breast, uterus and uterine tubes)
-Stromal development and ductal growth in breast
-Accelerated growth phase +epiphyseal closure
-Growth of axillary and pubic hair
-17B estradiol causes alteration in body fat distribution
-Pigmentation of skin (nipples, areolae and genital region)

Question 17

What are some of the physiological effects of estrogen related to endometrial effects?

Answer 17

Endometrial effects:
-develop endometrial lining during menstrual cycles
-prolonged exposure leads to hyperplasia of endometrium and abnormal bleeding.

Question 18

What are some of the physiological effects of estrogen related to metabolic and CV effects?

Answer 18

Metabolic and cardiovascular effects:
-decrease in rate of reabsorbed bone (protects bones; estrogen deficiency can lead to osteoporosis)
-stimulation of synthesis of transcortin and SHBG
-Plasma lipids (increase in HDL and decrease in LDL)
-Enhanced blood coagulation
-CNS and mood

Question 19

What are the clinical uses of estrogens?

Answer 19

Hormone replacement therapy in Postmenopausal women.
-Relief of CNS hot flashes, sweating and flushing
-Relief of symptoms from urogenital atrophy (vaginal dryness and increase risk of infections)
-Relief of psychological effects - mood swings, insomnia, depression and nervousness

Hormone replacement therapy in patients with hypogonadism.
-failure to develop ovaries
-chromosomal disorders (turner syndrome absence of one or all sex chromosomes)
-Oophorectomy

Osteoporosis
-For Postmenopausal osteoporosis only

Hormonal contraception

Question 20

What are the adverse effects of estrogen?

Answer 20

Uterine bleeding
-can be prevented with administration of a progestin in each cycle

Endometrial carcinoma
-using progestin can reduce the risk

Breast cancer
-due to long term use
-adding progestin doesn’t protect against

Nausea, headache, fluid retention and weight gain

Question 21

What are the 3 requirements on estrogen for SAR activity?

Answer 21

Aromaticity in ring A

Hydroxyl on carbon 3

17B hydroxyl

Question 22

What is happens with the 17a-alkylated estrogen modification?

Answer 22

PRODRUG: It will block metabolism to estrone. This enhances oral bioavailability and increases half life.

Ex: ethinyl estradiol

An alkylated addition on carbon 3 as an ether is quick dealkylated in vivo

Ex: mestranol + quinestrol

Question 23

What happens when the ester is added on 17B-hydroxy as an estrogen modification?

Answer 23

Esterification decreases solubility and slows absorption. Ideal for inject of the estrogen due to slow absorption at injection site.

Ex: estradiol valerate + estradiol cypionate

Question 24

What happens when the sulfate is added on carbon 3 as an estrogen modification?

Answer 24

These are called conjugated estrogens as they also have a ketone at carbon 17.

Collected from bear (mares’) urine.

Mixture of estrogens (orally ava.)

Ex: estrone sulfate (50-60%) + equilin sulfate (20-30%)

Question 25

What is the requirement on nonsteroidal estrogens for SAR activity?

Answer 25

OH group should be 10-12 angstroms from the other OH group for agonist activity.

Planar just like estrogen with a rigid core.

Amine substituted side chain= blocks helix 12 and causes antagonist/SERM activity

Question 26

What are the nonsteroidal estrogen examples

Answer 26

Diethylstilbestrol (DES): used in advanced prostate cancer as a full agonist.
-was used from 1940-1970 to prevent miscarriage but created an increased risk for vaginal adenocarcinoma
(not used for that anymore).

Chlorotrianisene (Tace): postpartum breast engorgement, menopause symptoms and prostate cancer.

Question 27

What are the basic of SERMS

Answer 27

Designed estrogens called selective estrogen receptor modulators.

PARTIAL AGONIST AND PARTIAL ANTAGONIST. -blocks stronger estrogens

Promising as an alternative to estrogen replacement therapy.

Question 28

What is the structural basis of SERM activity.

Answer 28

For an agonist (DES), helix 12 conformation allows for coactivator to bind. INCREASE gene expression

For SERM (tamoxifen), helix 12 conformation blocks coactivator binding. DECREASE gene expression

Question 29

What does tamoxifen do (SERM)?

Answer 29

Prodrug with both agonist and antagonist activities.

Antiestrogen action:
-treat breast cancer
-prevent breast cancer in high risk women

Estrogenic actions:
-weak agonist at endometrial cells (bleeding)
-increases risk for blood coagulation
-prevents osteoporosis

Question 30

What do toremifene and ospemifene do (SERM)?

Answer 30

Toremifene:
-Structurally similar to tamoxifen
-used for advanced breast cancer

Ospemifene:
-structurally similar to toremifene
-Estrogen effects on vaginal epithelium (PMS women vaginal dryness)
-Treats dyspareunia (painful intercourse dry vagina) in PMS women.

Question 31

What does raloxifene do (SERM)?

Answer 31

Tissue specific activities

Anti Estrogen actions:
-decrease risk for breast cancer
-doesn’t stimulate endometrial cells
-may cause hot flashes

Estrogen actions:
-prevent osteoporosis in PMS women
-Decrease LDL levels
-Increase risk for blood clots

Bazedoxifene is recently approved and looks similar and have similar activities.

Question 32

What does Clomiphene do (SERM)?

Answer 32

Increase secretion of FSH and LH by inhibiting negative estradiol feedback.

Stimulates ovulation in women with irregular menstruation or PCOS.

PCOS: gonadotropin-dependent ovarian hyperandrogenism (too much test. production in ovary)

Molecule is identical to toremifene but has shorted Chlorine bond.

Question 33

What does Fulvestrant do (SERD)?

Answer 33

Selective estrogen receptor DOWN REGULATOR.

Pure antagonist for treatment of breast cancer.

More effect than SERM in patients with resistance to tamoxifen.

Molecule has long HC chain with 5 fluorine atoms on end.

Question 34

What are aromatase inhibitors?

Answer 34

Block synthesis of estrogen.

Effective to patients with breast cancer resistant to tamoxifen.

Off label: ovulation induction

can lead to gyno

Ex: anastrozole, letrozole and exemestane