Gonadal hormones & Inhibitors

Question 1

The gonadal hormones include the steroids of the ovary and testis.

Answer 1

Ovary- Estrogens and Progestins.

Testis- Chiefly testosterone.

Question 2

Mixed agonists with estrogenic effects.

Answer 2

Selective Estrogen Receptor Modulators (SERMs)

Question 3

Mixed Agonists

Answer 3

Agonist effects in some tissues and antagonist effects in other tissues.

Question 4

Anabolic definition

Answer 4

Marked by or promoting metabolic activity concerned with the biosynthesis of complex molecules (such as proteins or nucleic acids) : relating to, characterized by, or stimulating anabolism.

Question 5

How is estradiol cypionate, a long-acting ester of etradiol, administered?

Answer 5

Intramuscular Injection (IM)

Question 6

Premarin, a mixture of conjugated estrogen from biologic source, are administered?

Answer 6

Orally, for hormone replacement therapy (HRT)

Question 7

Ethinyl estradiol & Mestranol.

Answer 7

Synthetic estrogens with high bioavailability; used in hormonal contraceptives.

Question 8

Metabolic effects of Estrogen.

Answer 8

1. Modifies serum protein levels.
2. Reduces bone resorption.
3. Enhances the coagulability of blood.
4. Increases plasma triglyceride leves while reducing LDL and increasing HDL.

Question 9

Continuous administration of estrogen, especially in combination with a progestin, _______ the secretion of gonadotropins from anterior pituitary.

Answer 9

Inhibits

Question 10

Clinical use of estrogen.

Answer 10

1. Treatment of hypogonadism in young females.
2. HRT in women with,
   
   1. Estrgogen deficiency resulting from premature ovarian failure, menopause, or surgical removal of ovaries
3. HRT ameliorates hot flushes and atrophic changes in urogenital tract.
4. Prevents bone loss and osteoperosis.
5. Hormonal contraceptives.

Question 11

Estrogen; Toxicity.

Answer 11

1. In hypogonadal girls, the dosage of estrogen must be adjusted carefully to prevent premature closure of the epiphyses of the long bones and short staure.
2. In HRT, estrogen increases the risk of endometrial cancer; prevented by combining the estrogen with a progestin.
3. Can increase the risk of breast cancer and myocardial infarction in post menopausal women.
4. Dose dependent: nausea, breast tenderness, increased risk of migraine headache, thromboembolic events, gall bladder disease, hypertriglyceridemia and hypertension.

Question 12

Diethylstilbestrol (DES)

Answer 12

• Non-steroidal estrogenic compound.
• Associated with infertility, ectopic pregnancy and vaginal adenocarcinoma in the daughters of women who were treated with the drug during pregnancy in a misguided attempt to prevet recurrent spontaneous abortion.

Question 13

Medroxyprogesterone.

Answer 13

• Synthetic progestins have improved oral bioavailability

Question 14

Older and newer progestin drugs examples and comparison.

Answer 14

Older: L-norgestrel and Norethindrone.

Newer: Norgestimate, desogestrel.

Older drugs are more androgenic than the newer progestins.

Question 15

Progestin; Effects.

Answer 15

1. Only progesterone induces secretory changes in the endometrium and is required for the maintenance of pregnancy, other stabilize pregnancy.
2. Progestins do not significantly affect plasma proteins, but affect carbohydrate metabolism and promote deposition of fat.
3. High doses suppress gonadotropin secretion and often cause anovulation in women.

Question 16

Progestins; Clinical use.

Answer 16

1. Contraceptives.
2. To prevent estrogen-induced endometrial cancer in HRT (here, used in combination with estrogen)
3. Used in assisted reproductive technology methods to promote and maintain pregnancy.

Question 17

Progestin; Toxicity.

Answer 17

1. *low toxicity
2. Increase BP.
3. Decrease HDL.
4. Long-term use of high doses in premenopausal women is associated with a reversible decrease in bone density (a secondary effect of ovarian suppression and decreased ovarian production of estrogen)
5. Delayed resumption of ovulation after termination of therapy.

Question 18

Three types of oral contraceptives.

Answer 18

1. Monophasic preparations- Combination estrogen-progestin tablets that are taken in constant dosage throughout the menstrual cycle.
2. Biphasic, triphasic and quadriphasic- Combination preparations in which the progestin or estrogen dosage, or both, changes during the month (To more closely mimc hormonal changes in a mentrual cycle).
3. Progestin only preparations.

Question 19

Postcoital Contraceptives.

Answer 19

1. Emergency contraceptives.
2. Prevents pregnancy if administered within 72h after unprotected intercourse.
3. Oral preparations contaning a progestin (L-norgestrel) alone, estrogen alone or the combination of estrogen and progestin are effective.
4. The progestin-only preparation causes fewer side effects than the estrogen-containing preparations.

Question 20

Contraceptives; major toxicities.

Answer 20

• Thromboembolism
• Breast cancer

Question 21

Selective estrogen receptor modulators (SERMs)

Answer 21

Are mixed estrogen agonists that have estrogen agonist effects in some tissues and act as partial agonists or antagonists of estrogen in other tissues.

Question 22

Tamoxifen

Answer 22

• A SERM
• Effective in treatment of hormone responsive breast cancer.
• Acts as an antagonist to prevent receptor activation by endogenous estrogens.
• Prophylactic use of tamoxifen reduces the incidence of breast cancer in women who are at very high risk.
• Tamoxifen has more agonist than antagonist action on bone and thus prevents osteoporosis in post-menopausal women.

Side effects:

• As an agonist of endometrial receptors, tamoxifen promotes endometrial hyperplasia
• and increases the risk of endometrial cancer.
• The drug also causes hot flushes (an antagonist effect) and increases the risk of venous thrombosis (an agonist effect).

*Toremifene is structurally related to tamoxifen and has similar properties, indications, and toxicity.

Question 23

Raloxifene

Answer 23

• Partial agonist effect on bones; approved for prevention and treatment of osteoporosis in postmenopausal women.
• Antagonist effects in breast tissue and reduces the incidence of breast cancer in women who are at very high risk.
• Adverse effects include hot flushes (an antagonist effect) and an increased risk of venous thrombosis (an agonist effect).

*Bazedoxifene, a newer SERM, is approved for treatment of menopausal symptoms and prophylaxis of postmenopausal osteoporosis in combination with conjugated estrogens.

Question 24

Clomiphene

Answer 24

1. A nonsteroidal compound with tissue-selective actions.
2. Induce ovulation.
3. By selectively blocking estrogen receptors in the pituitary, clomiphene reduces negative feedback and increases FSH and LH output. The increase in gonadotropins stimulates ovulation.

Question 25

Pure Estrogen Receptor Antagonists.

Answer 25

• Fulvestrant
• It is used in the treatment of women with breast cancer that has developed resistance to tamoxifen.

Question 26

Synthesis Inhibitors

Answer 26

1. Aromatase inhibitors-
   
   1. Anastrozole and related compounds (eg, letrozole) are nonsteroidal competitive inhibitors of aromatase, the enzyme required for the last step in estrogen synthesis.
   2. Exemestane is an irreversible aromatase inhibitor.
   • These drugs are used in the treatment of breast cancer.
2. Danazol-
   
   • Danazol inhibits several cytochrome P450 enzymes involved in gonadal steroid synthesis and is a weak partial agonist of progestin, androgen, and glucocorticoid receptors.
   • The drug is sometimes used in the treatment of endometriosis and fibrocystic disease of the breast.

Question 27

GnRH receptor antagonists.

Answer 27

Abarelix and Degareix are approved for prostate cancer.

Question 28

Antiprogestins

Answer 28

• Mifepristone (RU 486) is an orally active steroid antagonist of progesterone and glucocorticoids.
• Its major use is as an abortifacient in early pregnancy (up to 49 days after the last menstrual period).
• The combination of mifepristone and the prostaglandin E analog misoprostol achieves a complete abortion in over 95% of early pregnancies.
• The most common complication is failure to induce a complete abortion.
• Rarely, patients who used mifepristone and misoprostol for medical abortion have experienced serious infection, sepsis, and even death due to unusual infection (eg, Clostridium sordellii).

Question 29

Ganirelix and Cetrorelix

Answer 29

Used in Controlled ovarian hyperstimulation.

Question 30

Testosterone is synthesized from?

Answer 30

Progesterone and Dehydroepiandrosone (DHEA)

Question 31

In plasma, testosterone is partly bound to ?

Answer 31

Sex hormone binding globulin (SHBG), a transport protein.

Question 32

The hormone is converted in several organs to _____, which is the active hormone in those tissues.

Answer 32

Dihydrotestosterone (DHT)

Question 33

Why does testosterone given orally have little efffect?

Answer 33

Because of rapid hepatic effect.

It may be given by injection in the form of long-acting esters or transdermal patch.

Question 34

_______ and ______ are examples of drugs that, in lab tesing have an increased ratio of anabolic-androgenic action.

Answer 34

Oxandrolone and Stanozolol.

However, all so called anabolic steroids have full androgenic agonist effects when used in humans.

Question 35

Testosterone; Effects

Answer 35

1. Testosterone is necessary for normal development of the male fetus and infant and is responsible for the major changes in the male at puberty.
2. The major effect of androgenic hormones, in addition to development and maintenance of normal male characteristics, is an anabolic action that involves increased muscle size and strength and increased red blood cell production.
3. Excretion of urea nitrogen is reduced, and nitrogen balance becomes more positive.
4. Testosterone also helps maintain normal bone density.

Question 36

Testosterone; Clinical use

Answer 36

1. Replacement therapy in hypogonadism.
2. Stimulate RBC production in certain anemias.
3. Weight gain in wasting syndromes like AIDS.

Question 37

Testosterone; Toxicity

Answer 37

• In females, virilization • In men, high doses can cause gynecomastia, testicular shrinkage, infertility.
• In both sexes, high doses of anabolic steroids can cause cholestatic jaundice, elevation of liver enzyme levels, and possibly hepatocellular carcinoma.

Question 38

Antiandrogens; Receptor Inhibitors

Answer 38

1. Flutamide and related drugs bicalutamide, nilutamide, and enzalutamide are nonsteroidal competitive antagonists of androgen receptors. These drugs are used to decrease the action of endogenous androgens in patients with prostate carcinoma.
2. Spironolactone, a drug used principally as a potassium-sparing diuretic, also inhibits androgen receptors and is used in the treatment of hirsutism in women.

Question 39

Antiandrogens; 5-alpha-Reductase Inhibitors.

Answer 39

1. Testosterone is converted to DHT by the enzyme 5α-reductase. Some tissues, most notably prostate cells and hair follicles, depend on DHT rather than testosterone for androgenic stimulation.
2. This enzyme is inhibited by finasteride, a drug used to treat benign prostatic hyperplasia and, at a lower dose, to prevent hair loss in men.
3. Dutasteride is a newer 5α-reductase inhibitor with a much longer half-life than that of finasteride.

Question 40

Gonadotropin-Releasing Hormone Analogs and Antagonists

Answer 40

Suppression of gonadotropin secretion, especially LH, reduces the production of testosterone. This can be effectively accomplished with long-acting depot preparations of leuprolide or similar gonadotropin-releasing hormone (GnRH) agonists. These analogs are used in prostatic carcinoma. During the first week of therapy, an androgen receptor antagonist (eg, flutamide) is added to prevent the tumor flare that can result from the surge in testosterone synthesis caused by the initial agonistic action of the GnRH agonist. Within several weeks, testosterone production falls to low levels.

The GnRH receptor antagonists abarelix and degarelix are approved for advanced prostate cancer.

Question 41

Combined Hormonal Contraceptives

Answer 41

Combined hormonal contraceptives are used in women with androgen-induced hirsutism. The estrogen in the contraceptive acts in the liver to increase the production of sex hormone binding globulin, which in turn reduces the concentration of the free androgen in the blood that is causing the male-pattern hair growth characteristic of hirsutism.

Question 42

Inhibitors of Steroid Synthesis

Answer 42

Ketoconazole, an antifungal drug, inhibits gonadal and adrenal steroid synthesis. The drug has been used to suppress adrenal steroid synthesis in patients with steroid-responsive metastatic prostate cancer.