13: Pharmacology of Reproduction

Question 1

Menstrual cycle phases

Day 1 – 13, follicular phase controlled by _____, follicle matures & estrogen is released & stimulates endometrium lining

Day 14 = ovulatory phase, _____ of ovum (LH surge stimulates ovulation)

Day 15 - 28, luteal phase, corus luteum stilulated by _____ secretes estrogen and progesterone. If no fertilization then corpus luteum degenerates corpus albicans–which cannot secrete hormones, and menses occurs.

Answer 1

Menstrual cycle phases

Day 1 – 13, follicular phase controlled by FSH, follicle matures & estrogen is released & stimulates endometrium lining

Day 14 = ovulatory phase, ovulation of ovum (LH surge stimulates ovulation)

Day 15 - 28, luteal phase, corus luteum stilulated by LH secretes estrogen and progesterone. If no fertilization then corpus luteum degenerates corpus albicans–which cannot secrete hormones, and menses occurs.

Question 2

Low estrogen and progesterone triggers _____ release & LH & FSH which stimulates _____ to make estrogen and progesterone & when estrogen and progesterone are high they negativley feed back on GnRH

Answer 2

Low estrogen and progesterone triggers GnRH release & LH & FSH which stimulates ovary to make estrogen and progesterone & when estrogen and progesterone are high they negativley feed back on GnRH

Question 3

Estradiol can be converted can be converted to estrone and estriol in _____.

Estrogens can also be produced in other tissues, such as adipose tissue and _____ gland in men and post-menopausal women. During pregnancy, large quantities of estriol are produced by the _____.

The major circulating estrogen in premenopausal women is _____; for men and postmenopausal women it is _____.

Answer 3

Estradiol can be converted can be converted to estrone and estriol in liver.

Estrogens can also be produced in other tissues, such as adipose tissue and adrenal gland in men and post-menopausal women. During pregnancy, large quantities of estriol are produced by the placenta.

The major circulating estrogen in premenopausal women is estradiol; for men and postmenopausal women it is estrone.

Question 4

_____ is converted by aromatase into Estrone

_____ is converted to estriol by aromatase

Answer 4

Androstenedione is converted by aromatase into Estrone

Testosterone is converted to estriol by aromatase

Aromatase is involved in the production of estrogen. It converts testosterone to estradiol and androstenedione to estrone. This enzyme is expressed by estrogen producing cells of the ovaries, placenta, adrenal gland, adipose tissue, testicles and brain. It is important for estrogen biosynthesis.

Question 5

_____ estrogens are used more than nonsteroidal estrogens in the clinic.

Diethylstilbestrol (DES-a Nonsteroidal synthetic estrogen) was reported to increase the risk of _____ cell adenocarcinoma in the vagina and cervix.

Answer 5

Steroidal estrogens are used more than nonsteroidal estrogens in the clinic.

Diethylstilbestrol (DES-a Nonsteroidal synthetic estrogen) was reported to increase the risk of clear cell adenocarcinoma in the vagina and cervix.

Question 6

Estrogen binds to sex hormone binding _____.

Estrogen is hydrophobic so it crosses bilayer and binds to estrogen receptor in _____

Which then binds to estrogen response element in the _____, ERE

Answer 6

Estrogen binds to sex hormone binding globulin.

Estrogen is hydrophobic so it crosses bilayer and binds to estrogen receptor in cytoplasm

Which then binds to estrogen response element in the nucleus, ERE

Question 7

Estrogens used in therapy are absorbed through _____, _____ membranes, and the _____ tract.

You can put estrogens up the vagina!

Estrogens are widely distributed in the body. In circulation, estradiol binds strongly to sex hormone-_____ _____ (SHBG). It also binds to albumin with lower affinity.

Answer 7

Estrogens used in therapy are absorbed through skin, mucous membranes, and the gastrointestinal tract.

You can put estrogens up the vagina!

Estrogens are widely distributed in the body. In circulation, estradiol binds strongly to sex hormone-binding globulin (SHBG). It also binds to albumin with lower affinity.

Question 8

Estradiol (E2) is mainly metabolized in the _____ to estrone (E1).

Estradiol is not used orally frequently clinically due to the extensive _____ pass effect. Micronization _____ the half-life of estradiol and reduces its destruction in the GI tract.

If a patient has liver issues we do _____ give them estrogen.

Microlization = make estrogen into smaller particle which makes it more stable and _____ the first pass effect and _____ half-life

Answer 8

Estradiol (E2) is mainly metabolized in the liver to estrone (E1).

Estradiol is not used orally frequently clinically due to the extensive first pass effect. Micronization increases the half-life of estradiol and reduces its destruction in the GI tract.

If a patient has liver issues we do not give them estrogen.

Microlization = make estrogen into smaller particle which makes it more stable and lessens the first pass effect and lengthens half-life

Question 9

Estrogen has positive feedback right before ovulation @ end of follicular phase. That is, estrogen has positive feedback on FSH release, but also LH surge. In contraception we give estrogen at a constant level before surge @ levels _____ between negative feedback and the positive feedback levels at the LH surge.

Answer 9

Estrogen has positive feedback right before ovulation @ end of follicular phase. That is, estrogen has positive feedback on FSH release, but also LH surge. In contraception we give estrogen at a constant level before surge @ levels intermediate between negative feedback and the positive feedback levels at the LH surge.

Question 10

We do not give estrogen if the patient already has _____tension since _____tension is a side effect of estrogen administration.

Answer 10

We do not give estrogen if the patient already has hypertension since hypertension is a side effect of estrogen administration.

Question 11

Estogen given with _____ supresses the risk of cervical and endometrial cancers as cervical and endometrial cancers. We do _____ give estrogen alone.

Answer 11

Estogen given with progestin supresses the risk of cervical and endometrial cancers as cervical and endometrial cancers. We do not give estrogen alone.

Question 12

Estrogen administration is strongly _____ in patients with breast or endometrial cancer, endometriosis and undiagnosed vaginal bleeding.

Generally _____ in patients with pregnancy, thromboembolic disease, hypertension, hepatic disease or with family history of breast or uterine cancer.

Answer 12

Estrogen administration is strongly contraindicated in patients with breast or endometrial cancer, endometriosis and undiagnosed vaginal bleeding.

Generally contraindicated in patients with pregnancy, thromboembolic disease, hypertension, hepatic disease or with family history of breast or uterine cancer.

Question 13

Tamoxifen and Clomiphene are estrogen _____ competitive antagonists (or partial agonists in some setting).

Answer 13

Tamoxifen and Clomiphene are estrogen receptor competitive antagonists (or partial agonists in some setting).

Question 14

Tamoxifen is a _____ steroidal agent which has a strong _____ estrogenic effect on mammary epithelium & _____ estrogenic effect on uterine endometrium and bone.

Tamoxifen works as a partial estrogen competitive antagonist in the breast. It blocks estrogen from _____ to estrogen receptors (ER) and is commonly used for the treatment of ER-_____ advanced breast cancers.

Answer 14

Tamoxifen is a nonsteroidal agent which has a strong antiestrogenic effect on mammary epithelium & pro-estrogenic effect on uterine endometrium and bone.

Tamoxifen works as a partial estrogen competitive antagonist in the breast. It blocks estrogen from binding to estrogen receptors (ER) and is commonly used for the treatment of ER-positive advanced breast cancers.

Question 15

Estrogen has much _____ binding affinity for its receptor than that of Tamoxifen. Tamoxifen must be used in a concentration much _____ than estrogen to maintain inhibition of breast cancer cells.

Prolonged use of Tamoxifen (for prevention of breast cancer) increases incidence of _____ carcinoma.

Answer 15

Estrogen has much higher binding affinity for its receptor than that of Tamoxifen (about 100-1,000 times higher). Tamoxifen must be used in a concentration much higher than estrogen to maintain inhibition of breast cancer cells.

Prolonged use of Tamoxifen (for prevention of breast cancer) increases incidence of endometrial carcinoma.

Question 16

Clomiphene citrate is a nonsteroidal agent. It has two isomers, cis-chlomiphene (zuclomiphene) and trans-chlomiphene (enclomiphene).

cis-clomiphene (~30%) is a weak estrogen _____.

trans- clomiphene (~70%) is a potent _____.

Clomiphene _____ estrogen binding to its receptors in the hypothalamus and inhibits estradiol’s negative feedback on the gonadotropins -> _____ in the secretion of gonadotropins and LH -> leads to _____. GNRH gets high & you get LH & FSH _____ since estrogen is not sensed.

Answer 16

Clomiphene citrate is a nonsteroidal agent. It has two isomers, cis-chlomiphene (zuclomiphene) and trans-chlomiphene (enclomiphene).

cis-clomiphene (~30%) is a weak estrogen agonist.

trans- clomiphene (~70%) is a potent antagonist.

Clomiphene blocks estrogen binding to its receptors in the hypothalamus and inhibits estradiol’s negative feedback on the gonadotropins -> increases in the secretion of gonadotropins and LH -> leads to ovulation. GNRH gets high & you get LH & FSH surge since estrogen is not sensed.

Question 17

Clomiphene used for stimulating _____ in patients with disorders of ovulation who wish to become pregnant.

Clomiphene side effects include symptoms of menopause (_____ flashes) & _____ pregnancy.

Answer 17

Clomiphene used for stimulating ovulation in patients with disorders of ovulation who wish to become pregnant.

Clomiphene side effects include symptoms of menopause (hot flashes) & multiple pregnancy.

Question 18

Progesterone is secreted in females by the corpus _____ in the ovary. During pregnancy, high levels of progesterone are produced and secreted by the _____. In males synthesized in the _____. Also produced by the adrenal _____ in both sexes.

Production is stimulated by _____ hormone and gonadotropin. Progestin is considered as Synthetic Progesterone. Progesterone = natural form.

Answer 18

Progesterone is secreted in females by the corpus luteum in the ovary. During pregnancy, high levels of progesterone are produced and secreted by the placenta. In males synthesized in the testis. Also produced by the adrenal cortex in both sexes.

Production is stimulated by luteinizing hormone and gonadotropin. Progestin is considered as _____ Progesterone. Progesterone = _____ form.

Question 19

Studies show progesterone has a growth _____ effect on endometrial cancers. Long-term use of progesterone has atrophic effect on endometrium. We use this to _____ endometrial cancer.

High levels of progesterone trigger a negative feedback
on the hypothalamus to stop releasing gonadotropin,
thus _____ ovulation.

Answer 19

Studies show progesterone has a growth suppressing effect on endometrial cancers. Long-term use of progesterone has atrophic effect on endometrium. We use this to reduce endometrial cancer.

High levels of progesterone trigger a negative feedback
on the hypothalamus to stop releasing gonadotropin,
thus suppressing ovulation.

Question 20

Contraception = _____ only method or progestin + estrogen method

Progesterone hormone replacement therapy is used in postmenopausal women. Progesterone counters the endometrial stimulatory effects of _____ and _____ the risk of endometrial cancer.

Answer 20

Contraception = progestin only method or progestin + estrogen method

Progesterone hormone replacement therapy is used in postmenopausal women. Progesterone counters the endometrial stimulatory effects of estrogen and reduces the risk of endometrial cancer.

Question 21

_____ progesterone (e.g. PROMETRIM). Natural progesterone has a _____ half life. _____ progesterone increases the half-life of progesterone, decreases first-pass metabolism and enhances the dissolution of progesterone. Orally active.

Answer 21

Micronized progesterone (e.g. PROMETRIM). Natural progesterone has a short half life (few minutes). Micronized progesterone increases the half-life of progesterone, decreases first-pass metabolism and enhances the dissolution of progesterone. Orally active. (Micronized progesterone: Natural progesterone is processed to reduce the diameter of the particle size).

Question 22

Trans _____ progesterone (e.g. CRINONE). Delivered through non-oral route (vaginal _____). Intravaginal administration produces uterine effects with minimal systemic side effects (avoid first pass metabolism and IM injections).

Answer 22

Transvaginal progesterone (e.g. CRINONE). Delivered through non-oral route (vaginal gel). Intravaginal administration produces uterine effects with minimal systemic side effects (avoid first pass metabolism and IM injections).

Question 23

Synthetic _____ Medroxyprogesterone, Norethindrone, Norgestrel, Megestrol can be taken _____. Considered to have strong androgenic activity and can cause _____ (excessive growth of hair) and acne.

Answer 23

Synthetic progestins Medroxyprogesterone, Norethindrone, Norgestrel, Megestrol can be taken orally. Considered to have strong androgenic activity and can cause hirsutism (excessive growth of hair) and acne.

Question 24

Synthetic Progestins have _____ side effects than natural progestins (almost none in natural).

Major side effect of progestins is Increases risks of thrombosis & pulmonary _____ or _____ disease.

Answer 24

Synthetic Progestins have more side effects than natural progestins (almost none in natural).

Major side effect of progestins is Increases risks of thrombosis & pulmonary embolism or liver disease.

**Do not give progesterone to women with history of embolism or thrombosis

Question 25

Contraceptive Estrogen only agent:

Constant levels of estrogen suppress _____ secretion thus prevents follicle maturation. Constant levels of estrogen can also suppress _____ surge. The estrogenic component significantly contributes to COC’s efficacy.

Answer 25

Contraceptive Estrogen only agent:

Constant levels of estrogen suppress follicle-stimulating hormone (FSH) secretion thus prevents follicle maturation. Constant levels of estrogen can also suppress luteinizing hormone surge. The estrogenic component significantly contributes to COC’s efficacy.

Question 26

Estrogen-Progestin Combination Contraceptives

Also known as the Pill, OCs, BCs, BC tablets, or birth control pills, also as combined oral contraceptives (COCs)

The most _____ form of contraception available.

Reversible contraceptives.

If use properly, _____% effective in preventing pregnancy.

3-8% failure rates due to poor patient _____.

Answer 26

Estrogen-Progestin Combination Contraceptives

Also known as the Pill, OCs, BCs, BC tablets, or birth control pills, also as combined oral contraceptives (COCs)

The most effective form of contraception available.

Reversible contraceptives.

If use properly, 99.9% effective in preventing pregnancy.

3-8% failure rates due to poor patient compliance.

Question 27

Contraceptive Progestational agent:

Progestin primarily suppresses _____ hormone secretion and thus prevent ovulation.

_____ cervical mucus and makes it impenetrable to sperm.

Develops endometrial _____; making endometrium unreceptive to implantation.

Answer 27

Contraceptive Progestational agent:

Progestin primarily suppresses luteining hormone (LH) secretion and thus prevent ovulation.

Thickens cervical mucus and makes it impenetrable to sperm.

Develops endometrial atrophy; making endometrium unreceptive to implantation.

Question 28

Progestin-only Oral Contraceptives (Mini pills) Micronor & Ovrette are less effective than combination (with estrogen) preparations.

Useful when estrogens are _____ indicated.

Studies show progesterone has a growth _____ effect on endometrial cancers. It is a preferred contraceptive for patient has family history of endometrial cancer.

_____ women are good candidates for this contraceptive method (estrogen in combined OC reduces milk production).

More likely to produce _____ menstrual cycle than the combination products (estrogen in combined OC provides stability to the endometrium to minimize irregular endomedrium shedding).

Answer 28

Progestin-only Oral Contraceptives (Mini pills) Micronor & Ovrette are less effective than combination (with estrogen) preparations.

Useful when estrogens are contraindicated.

Studies show progesterone has a growth suppressing effect on endometrial cancers. It is a preferred contraceptive for patient has family history of endometrial cancer.

Lactating women are good candidates for this contraceptive method (estrogen in combined OC reduces milk production).

More likely to produce irregular menstrual cycle than the combination products (estrogen in combined OC provides stability to the endometrium to minimize irregular endomedrium shedding).

Question 29

Postcoital contraceptive (emergency contraception), morning after pill or plan B.

Needs to be taken within _____ hours of coitus.

Likely works by interfering with _____ and inhibiting or delaying _____.

Answer 29

Postcoital contraceptive (emergency contraception), morning after pill or plan B.

Needs to be taken within 72 hours of coitus.

Likely works by interfering with implantation and inhibiting or delaying ovulation.

Question 30

RU-486 (Mifepristone)–“The Abortion Pill”

Considered as an antiprogestin

It is a progestin _____ that competitively binds to progesterone _____ and blocks progesterone binding to its receptor.

Progesterone stimulates development of the uterine lining. RU-486 by blocking progesterone’s effect on uterus causes breakdown of uterine lining thus leading to _____ of embryo or fetus.

Answer 30

RU-486 (Mifepristone)–“The Abortion Pill”

Considered as an antiprogestin

It is a progestin antagonist that competitively binds to progesterone receptor and blocks progesterone binding to its receptor.

Progesterone stimulates development of the uterine lining. RU-486 by blocking progesterone’s effect on uterus causes breakdown of uterine lining thus leading to detachment of embryo or fetus.

Question 31

Drugs for the treatment of Erectile Dysfunction (ED):

Three oral drugs have been approved by the FDA: Cialis, Levitra, and Viagra–They are all phosphodiesterase type 5
inhibitors (PDE5i).

Phosphodiesterase type 5 (PDE5) is an enzyme which expresses predominantly in the corpus _____ and the _____.

PDE5 inhibitor acts to decrease cGMP -> 5’ _____ formation to favor the erectile pathway by maintaining concentration of cGMP.

Answer 31

Drugs for the treatment of Erectile Dysfunction (ED):

Three oral drugs have been approved by the FDA: Cialis, Levitra, and Viagra–They are all phosphodiesterase type 5
inhibitors (PDE5i).

Phosphodiesterase type 5 (PDE5) is an enzyme which expresses predominantly in the corpus cavernosum and the retina (eye side effects).

PDE5 inhibitor acts to decrease cGMP -> 5’ GMP formation to favor the erectile pathway by maintaining concentration of cGMP.

Question 32

PDE5 inhibitors bind to the _____ site of PDE5 to inhibit its enzymatic activity.

PDE5 inhibitors do not trigger an automatic erection but improve the response to _____ stimulation.

Major side effects of PDE5 inhibitors:

Flushing and change in _____

PDE5 inhibitors can cause sudden blood pressure _____ to unsafe level when taken with other drugs such as nitrates and alpha-blockers.

Avoid using the combination of PDE5 inhibitors with _____ and _____-blockers (causes unsafe reduction in blood pressure).

Answer 32

PDE5 inhibitors bind to the catalytic site of PDE5 to inhibit its enzymatic activity.

PDE5 inhibitors do not trigger an automatic erection but improve the response to sexual stimulation.

Major side effects of PDE5 inhibitors:

Flushing and change in vision

PDE5 inhibitors can cause sudden blood pressure drop to unsafe level when taken with other drugs such as nitrates and alpha-blockers.

Avoid using the combination of PDE5 inhibitors with nitrates and alpha-blockers (causes unsafe reduction in blood pressure).