E2 L3/4: Estrogens

Question 1

Describe the change in estrogen levels during the menstrual cycle:

Answer 1

Early Follicular phase:
Estrogen suppresses the production of FSH
Late follicular phase:
Estrogen stimulates the surge of LH and FSH = ovulation and formation of corpus luteum
Luteal phase=
Estrogen suppresses the production of LH and FSH

Question 2

Describe the change in progesterone levels during the menstrual cycle

Answer 2

Luteal Phase:
Progesterone suppresses the production of LH and FSH

Question 3

Explain the regulation of estrogen and progesterone synthesis during the menstrual cycle: if pregnancy occurs

Answer 3

Fertilized egg/embryo secretes human chorionic gonadotropin (hCG)
hCG acts like LH to simulate corpus luteum to produce progesterone during the first trimester
Higher progesterone levels support maintenance of endometrium
Chromatographic immunoassays of hCG in the urine are used as pregnancy tests

Question 4

Explain the regulation of estrogen and progesterone synthesis during the menstrual cycle: if pregnancy does NOT occur

Answer 4

Corpus luteum degenerates
Production of estrogen and progesterone by corpus luteum declines - menstruation

Question 5

List the physiological effects of estrogens: Female maturation

Answer 5

Development of the vagina, uterus and uterine tubes
Stromal development and ductal growth in the breast
Accelerated growth phase and the epiphyseal closure
Growth of axillary and pubic hair
Alteration in the distribution of body fat to produce female body contours
Pigmentation in the skin (nipples, areolae, and genital region

Question 6

List the physiological effects of estrogens: Endometrial effects

Answer 6

Development of endometrial lining during menstrual cycles
Prolonged exposure leads to hyperplasia of the endometrium and abnormal bleeding

Question 7

List the physiological effects of estrogens: Metabolic and cardiovascular effects:

Answer 7

Decrease in the rate of resorption of bone - estrogen deficiency can lead to osteoporosis
Stimulation of synthesis of transcortin and SHBG
Alteration in the composition of plasma lipids - increase in HDL, decrease in LDL

Question 8

List the physiological effects of estrogens: blood coagulation and CNS:

Answer 8

Coagulation - enhancement of the coagulability of blood
CNS - Mood

Question 9

Describe the consequence of the enterohepatic circulation in estrogen metabolism:

Answer 9

Conjugated estrogens in the bile can be hydrolyzed in the intestine and reabsorbed (enterohepatic circulation)
Orally admin. estrogens have a high ratio of hepatic to peripheral effects; can be avoided by using routes that avoid first-pass liver exposure
Prolonged use = delayed final elimination of steroids from the body

Question 10

List the clinical uses of estrogens:

Answer 10

Hormone replacement therapy in postmenopausal women
Osteoporosis
Hormonal contraception
Replacement therapy in patients with primary hypogonadism

Question 11

Clinical use: Hormone replacement therapy in postmenopausal women

Answer 11

Relief to CNS disturbances - hot flashes, sweating, flushing
Relief of symptoms resulting from urogenital atrophy - vaginal dryness, nervousness

Question 12

Clinical use: Osteoporosis

Answer 12

For post-menopausal osteoporosis only
Estrogens decrease the rate of bone resorption

Question 13

Clinical use: Replacement therapy in patients with primary hypogonadism

Answer 13

Failure of development of the ovaries
Chromosomal disorders - Turner syndrome - absence of one or all sex chromosomes
Castration (oophorectomy)

Question 14

Recognize the structural characteristics responsible for variance in drug properties in steroidal and non-steroidal estrogens

Answer 14

Aromaticity in ring A is REQUIRED
Hydroxyl can be masked as ether
Hydroxyl can be masked as ether derivative; ether is hydrolyzed in vivo
Hydroxyl at the 3 position is ESSENTIAL for activity
Unsaturation in B ring is tolerated
16-OH decreases activity
17a-ethynyl substituent blocks metabolism and allows for oral activity
17B OH group REQUIRED for activity; can be temporarily blocked by ester for drug delivery

Question 15

SERM meaning

Answer 15

Selective Estrogen Receptor Modulators

Question 16

Explain the mechanism of action of SERMS and estrogen antagonists:

Answer 16

“Designer estrogens”
Partial estrogen agonists - Block the action of stronger estrogens
Estrogenic in some tissues and antiestrogenic in others
Mostly nonsteroidal estrogens
Hold promise as the alternative for estrogen replacement therapy
Extra arm is IMPORTANT -rest binds to pocket
with extra arm: pushes out, H12 cannot bind properly, hormone cannot bind, estrogen in this case? antagonist
IMPORTANT POINT: Tissue specificity

Question 17

SERMs examples

Answer 17

Tamoxifen
Toremifene and ospemifene
Raloxifene
Clomiphene

Question 18

SERD example:

Answer 18

Fulvestrant (selective estrogen receptor downregulator)

Question 19

Describe the pharmacological uses of aromatase inhibitors

Answer 19

Aromatase inhibitors block the biosynthesis of estrogens
Effective in some patients whose breast cancer has become resistant to tamoxifen
Ovulation induction (off-label use)
Gynecomastia-develop female like breasts (treated with aromatase inhibitor)

Question 20

Name the aromatase inhibitors

Answer 20

Anastrozole
Letrozole
Exemestane