Gonadal Hormones

Question 1

Mestranol

Answer 1

Mestranol is a prodrug is converted into Ethinyl estradiol, present in some contraceptives. ↑bio-availability, ↑half-life and ↓FSH & LH via feed-back.

Metabolism of estrogens relies on cytochrome P-450 system; they have enterohepatic circulation. Combination with P-450 inducers can lead to failure of contraceptive effectiveness.

Clinical uses of estrogens

• I.M. Long acting estrogen preparations are used in females with Hypogonadism.
• Oral contraceptives in combination with progestins – Suppress FSH & LH secretion and inhibit ovulation.
• Postmenopausal hormonere placement therapy (HRT) – HRT help and reduce hot flashes, prevent bone loss & fractures, ↓incidence of colon cancer, ↓urogenital atrophy & ↑feeling of well-being.
• Used in dysmenorrhea, uterine bleeding, prostate cancer and acne.

Adverse effects

Increased incidence of thromboembolism.

Increased incidence of breast, Endometrial hyperplasia & cancers (unless progestin is added).

Migraine, Cholestasis, and mood changes.

Nausea,breast tenderness and bloating

Diethylstilbestrol (DES)–anonsteroidalestrogen agonist use in pregnancy result in female child to infertility, vaginal cancer.

Absolute contraindications of estrogen use

History of thromboembolism

Breast & endometrial cancer

Pregnancy

Liver disease

Question 2

Tamoxifen

Answer 2

Tamoxifen: E-receptor antagonist effect on breast tissue but agonistic effect on liver, bone and partial agonist endometrium.

Used in treatment of breast cancer & prophylaxis for high risk patients.

• Adverse effects:
– Hot flashes (Antagonist) and thrombosis (Agonistic) – Risk of endometrial cancers

Question 3

Toremifene

Answer 3

Toremifene (SERM): approved for treatment of breast cancer, breast cancer that has metastasized and prevention of breast cancer in high-risk women.

Question 4

Raloxifene

Answer 4

Raloxifene: E-receptor antagonist at breast but agonist at bone. No estrogenic effect on endometrium.

• No increased risk of endometrial cancer

• Uses:

– Prophylaxis against breast cancers (in high risk patients)

– Prevention of postmenopausal osteoporosis

Question 5

Fulvestrant

Answer 5

Estrogen receptor antagonist in all tissues

Fulvestrant: I.M.

Used in the treatment breast cancer in tamoxifen resistant patients.

A.E: Hot flushes, injection site reactions & headache

Question 6

Letrozole

Answer 6

Aromatase inhibitors

• Inhibits conversion of androgens to estrogen

Question 7

Anastrozole

Answer 7

Aromatase inhibitors

• Inhibits conversion of androgens to estrogen

Question 8

Exemestane

Answer 8

Exemestane –an irreversible aromatase inhibitor

Used in treatment of breast cancer (estrogen dependent) as 2nd line drugs following tamoxifen resistant.

Oral administration
• A.E: hot flashes, decreased bone mineral density.

Question 9

Clomiphene

Answer 9

Clomiphene – fertility drug

Acts as estrogen antagonist in hypothalamus and anterior pituitary. Estrogen Antagonist prevents feedback inhibition of GnRH release by hypothalamus. Continued release of GnRH from hypothalamus. Increased LH and FSH from the pituitary leads to increased ovulation.

Taken orally, half-life is 5-7days, has significant protein binding and enterohepatic circulation.

Used in treatment of anovulatory infertility.

Side effects:
– Ovarian hyper-stimulation leading to enlargement of ovary.

– Multiple pregnancy 10%

– Hot flashes, nausea, vomiting, breast tenderness and weight gain.

Question 10

Norgestrel

Answer 10

PROGESTERONE –Preps

Question 11

Norethindrone

Answer 11

PROGESTERONE –Preps

Question 12

Desogestrel

Answer 12

PROGESTERONE –Preps

Question 13

Norgestimate

Answer 13

PROGESTERONE –Preps

Question 14

PROGESTERONE –Preps

Answer 14

PROGESTERONE –Preps

Medroxyprogesterone, Norgestrel, Norethindrone, Norgestimate, Desogestrel –newer preps lacking of androgenic and antiestrogenic effects.

Therapeutic uses of progestins

Used alone or with estradiol for contraception.

In combination with estrogen they are used in hormone replacement therapy (HRT).

↓incidence of endometrial hyperplasia & carcinoma caused by unopposed action of estrogens –in this settings pts may have irregular bleeding (DUB).

Used in ovarian suppression –in the treatment of dysmenorrhea and endometriosis.

They are used to diagnose estrogen secretion & for responsiveness of endometrium. Menstruation occurs after progesterone administration in patient with amenorrhea –this occurs after 5-7 days.

ADMINISTRATION: Oral or I.M. injection

Progestins –Adverse effects

Long term use may result in:

Weight gain

Glucose intolerance

Androgenic –hirsutism & acne

Anti-estrogenic (blocks lipid changes)

Depression, Edema, acne

Increased HDL, decreased LDL & hypertension

Question 15

Drospirenone

Answer 15

Drospirenone – a spironolactone derivative used as O.C. to antagonize aldosterone effects useful in acne in females.

Question 16

Mifepristone

Answer 16

Antiprogestins

RU 486 or Mifepristone – oral administration

Competitive inhibitor of progesterone & glucocorticoid receptors.

Controversial “morning after” drug used as an abortifacient.

It is given concomitantly with PG-E or PG-F to increase myometrial contraction.

Adverse effects: Excessive bleeding, gastrointestinal effects as nausea, vomiting, anorexia and abdominal pain.

Question 17

Oxandrolone

Answer 17

Synthetic androgens –17alkyl derivatives with

increased anabolic effects

Question 18

Stanozolol

Answer 18

Synthetic androgens –17alkyl derivatives with

increased anabolic effects

Question 19

Fluoxymesterone

Answer 19

Synthetic androgens –17alkyl derivatives with

increased anabolic effects

Question 20

Nandrolone

Answer 20

Synthetic androgens –17alkyl derivatives with

increased anabolic effects

Question 21

Oxymetholone

Answer 21

Synthetic androgens –17alkyl derivatives with

increased anabolic effects

Question 22

Danazol

Answer 22

Synthetic androgens –17alkyl derivatives with

increased anabolic effects

Danazol is an inhibitor of P450 in gonadal steroid synthesis.

It an androgen derivative, a partial agonist of progestin, and glucocorticoid receptors.

Used in endometriosis and fibrocystic disease of breast.

• AE: hepatitis– abnormal liver function tests and drug interaction due to P-450 inhibition.

It is a modified testosterone shows some signs of musculinising effects – acne, hirsutism, menstrual disturbances.

Question 23

Methyltestosterone

Answer 23

Synthetic androgens –17alkyl derivatives with

increased anabolic effects

Clinical uses: along with all the other ones

Substitution therapy in hypogonadism;

Increases bone density (prevent osteoporosis), could be used in increasing muscle mass (+ve nitrogen balance)

Some cases of aplastic anemia.

Administration: Transdermal, buccal, subcutaneous implant and I.M.

Adverse effects:

– Over-masculinization

– In women could lead to hirsutism, suppression of menses, acne, and clitoral enlargement.

– hepatic adenomas & prostatic hypertrophy

– Cholestatic jaundice (elevated serum

transaminations)

– Aggression & dependency

– Premature closure of epiphysis

– Illicit use in athletics

• Over-dosage of androgen can result in feminization (gynecomastia, testicular shrinkage, infertility, azoospermia) as a result of feedback inhibition (HPG axis) & conversion of exogenous testosterone into estrogen.

Question 24

Antiandrogens

Answer 24

Androgen receptor blockers –used for androgen- receptor-positive cancers.

Flutamide –a substituted anilide.

Bicalutamide

Nilutamide

• Primarily used in conjunction with GnRH analogs e.g., leuprolide (to ↓initial tumor flare-ups of prostate carcinoma).

Question 25

Spiranolactone

Answer 25

Spiranolactone: blocks aldosterone and competes androgen receptors. It is used in hirsutism.

Question 26

Cyproterone

Answer 26

Cyproterone: it has progesteronal effect suppresses LH & FSH. Used in hirsutism and to ↓excessive sexual drive in men.

Question 27

Ketoconazole

Answer 27

Ketoconazole – oral administration
• Adrenal and gonadal steroid synthesis inhibitor

• Use: in prostate cancer but not 1st line drug.
• AE: May have drug interactions with other steroids due to P-450↓

Question 28

Finasteride

Answer 28

5-α reductase inhibitor

Finasteride (PROPECIA):

Oral administration

Inhibit conversion of testosterone to dihydrotestosterone.

Use: BPH and promotes hair growth.

AE: gynecomastia, teratogenicity and impotence