4/11 Gonadal Hormones and Inhibitors PHARM

Question 1

Possible pharm targets in the HPG axis (both men and women?)

Answer 1

Hypothalamus: GnRH analogs

Pituitary: FSH, LH, hCG

Gonads: Estrogen, Progesterone, Testicular Androgens

Question 2

2 functions of testicles?

Answer 2

• spermatogenesis
• testosterone function

Question 3

in the testes, what do LH and FSH do?

Answer 3

LH –> acts on Leydig cells (testosterone synthesis)

FSH –> regulates Sertoli cells (coordinate spermatogenesis and maturation of spermatocytes)

FSH –> stimulates production and secretion of inhibin by Sertoli cells

Question 4

What type of drug is Goserelin?

Answer 4

GnRH analog.

Bioavailable, stable (more than native GnRH peptide!)

Question 5

What would Goserelin (and other GnRH analogs) be used for clinically? (5 things)

Answer 5

• Suppression of estrogen production in hormone-dependent BC
• Suppression of estrogen production in hormone-dependent prostate cancer
• to delay puberty in cases of precocious puberty
• To delay puberty in trans youth who are too young for hormone replacement therapy
• in cases of hypergonadism

Question 6

Goserelin/GnRH analogs: contraindications?

Answer 6

Pregnancy (Cat D)

Question 7

Goserelin/GnRH analogs: warnings for use in males?

Answer 7

• Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose and for signs/symptoms of CVD during therapy.
• Risk of ureteral obstruction or spinal cord compression (monitor during 1st month of therapy). (unclear why)

Question 8

Goserelin/GnRH analogs: warnings for use in females?

Answer 8

• Use not recommended in nondiagnosed abnormal vaginal bleeding
• Risk factors for decreased bone mineral density (e.g. chronic alcohol, tobacco, anticonvulsants, corticosteroids).
• Premenopausal women: use nonhormonal contraception during and for 12 weeks after therapy or until menses resume.
• Nursing mothers: not recommended.

Question 9

Use of pituitary hormones for management of infertility:

LH/hCG – two source of hCG?

Answer 9

(LH is the same as hCG; LH made by pituitary, hCG made by fertilized egg and placenta)

hCG from mare urine = Pregnyl

hCG from bacteria = Ovidrel

Question 10

FSH: primary use in treatment of infertility?

Answer 10

stimulate ovulation

Question 11

Steroid receptor: if there is no agonist, what are the 2 states a steroid receptor will exist as?

Answer 11

1. in cytoplasm of target cell, associated with multi protein complex (“heat shock complex”)
2. Bound to target genes in nucleus and associated with co-repressor complex with innate histone-deacetylase activity

Question 12

Steroid receptor: in presence of antagonist, what state will receptor exist in?

Answer 12

in presence of an antagonist, receptor is bound to target genes (in nucleus), associated with co-repressor complex with innate histone deactylase activity - may be actively repressing target genes.

Question 13

Steroid receptor: in presence of agonist, what occurs to activate the target gene??

Answer 13

In presence of hormone, the co-repressor complex is bumped off and target gene is activated.

Question 14

Estrogens: clinical uses?

Answer 14

• Contraception
• Hormone replacement therapy
• Oncology (anti-estrogens used more than estrogens)
• M to F transgender promotion

Question 15

Laundry list: effects of estrogens on primary and secondary sex characteristics?

(effects on: ovaries, uterus, vag, cervix, genital dev’t, mammary gland, skin, bone, electrolytes, cholesterol)

Answer 15

• Ovaries : stimulate follicular growth; small doses cause an increase in weight of ovary; large doses cause atrophy
• Uterus: endometrial growth
• Vagina: cornification of epithelial cells with thickening and stratification of epithelium
• Cervix: increase of cervical mucous with a lowered viscosity (favoring sperm access)
• Development and maintenance of internal (fallopian tubes, uterus, vagina), and external genitalia.
• Mammary gland: Promotes ductal outgrowth and branching during puberty and in each mammary regenerative cycle.
• Skin: increase in vascularization, development of soft, textured and smooth skin
• Bone: increase osteoblastic activity
• Electrolytes: retention of Na+, Cl- and water by the kidney
• Cholesterol: hypocholesterolemic effect

(Can lower cholesterol–> protective effect)

Question 16

Estrogens & contraception:

• how do they effect the HPG axis?
• some formulations also include what?

Answer 16

–Ectopic estrogen treatment mimics the negative feedback on the HPG axis resulting in reduced LH and FSH production.

–Many formulations include progesterone which help to offset unwanted side-effects of estrogens.

Question 17

Use of estrogens in breast and endometrial cancer: in past, high-dose estrogens were given. What is used now?

Answer 17

For breast cancer treatment, high-dose estrogen has been replaced by:

• Estrogen receptor antagonists (aka anti-estrogens) or selective estrogen receptor modulators (SERMS)
• P450 Aromatase inhibitors

Question 18

What does tamoxifen do to treat hormone-dependent breast cancer?

Answer 18

• Selectively inhibits of the hormone-binding domain of the estrogen receptor.
• Selective: it has anti-estrogenic activity in certain tissues (e.g. mammary gland) and estrogenic activity in others (e.g. uterus).
• Has been shown to reduce the risk of breast cancer recurrence.

Question 19

Contraindications for Estrogen/Anti-estrogen?

(recall Tamoxifen has each effect… tissue-dependent)

Answer 19

Estrogen C/I:

• Preg, Lactation
• Breast cancer
• Personal or familiial BC history
• If post-menopausal, est can incr ovarian cancer, BC, stroke, dementia, blood clots.

Anti-Estrogen C/I:

• Preg, Lactation
• Uterine Cancer (recall tamoxifen acts as an estrogen here)
• Personal history of uterine cancer

Question 20

Clinical uses of Progestins? (ie Norethindrone, Norgestrel, Medroxyprogesterone)

Answer 20

• Support a preg where there is high risk of miscarriage
• Counteract thickening of uterine lining caused by post-menopausal estrogen

Question 21

Clinical uses of Progestins? (ie Mifepristone aka 5U486)?

Answer 21

• Post-coital contraceptive (interferes with progesterone signaling)
• Abortifacient (at higher doses)

Question 22

Contraindications for progesterone?

Answer 22

• Depression
• Migraines
• Tobacco use
• Clotting disorders
• Seizures
• SLE
• Breast Cancer –Feeds back on est receptor to inc activity
• Ovarian Cancer

Question 23

Contraindications for Mifeprisone (anti-progestin)?

Answer 23

• IUD
• Ectopic Pregnancy
• Adrenal failure –Can suppress adrenal fxn
• Hemorrhagic disorders
• Porphyria
• Prolonged anti-coagulant use
• Prolonged corticosteroid use.

Question 24

Normal physiologic effects of Androgens?

Answer 24

•T and DHT are responsible for most changes associated with male puberty:

–General growth promotion

–Thickening of skin and increases in sebaceous gland activity

–Thickening of vocal cords

–Skeletal growth and epiphysial closure of long bones (analbolic effect)

–Maturation of prostate and seminal vesicles

–Stimulation and maintenance of sexual function

–Increase in lean body mass (anabolic effect)

Question 25

What is Age-Associated Androgen Deficiency (ADAM)?

Answer 25

Circulating levels of free testosterone decline with age. Due to: decreased androgen synthesis, increased levels of Steroid Hormone Binding Globulin -Serum testosterone level drop is a strong predictor of mortality in men!

Question 26

Symptoms of Age-Associated Androgen Deficiency (ADAM)? (aka aging...)

Answer 26

* Low libido (with or without erectile dysfunction) * Decreased strength, energy or stamina * Increased irritability and/decreased enjoyment * Alterations in cognitive function * Osteoporosis/osteopenia (Androgens are metabolized to estrogens in bone, suggesting that bone loss associated with ADAM may be due to local decreases in estrogenic tone) * Loss of muscle mass * Increased visceral adipose * Testicular atrophy * Gynecomastia * Cardiovascular disease (onset and progression)

Question 27

Are there guidelines for the use of androgen replacement therapy (ART)?

Answer 27

No consensus guidelines However the Endocrine Society has proposed that ART be considered when total serum testosterone is \< 200ng/dL (I'm sure the Pharma companies would agree; the dude who gave us the lect on male infertility would think this is total shit)

Question 28

Clinical uses of androgen enhancement in males?

Answer 28

–hypopituitarism and hypogonadism –ADAM (aka andropause) - androgen enhancement can increase lean body mass, decrease bone turnover –Female to male transgender promotion -Delayed puberty in males

Question 29

Clinical uses of androgen enhancement in females?

Answer 29

_Gynecologic Disorders:_ –Post-partum **breast engorgement**: single and small dose of T can help with this (can be painful) –**Endometriosis** –**Chemotherapy** in ER-positive breast tumors in pre-menopausal women -- very rarely used bc high amts needed --\> masculinization/hirsutism

Question 30

why might an aromatise inhibitor like Anastrozole (Arimidex) more successfully treat breast cancer than tamoxifen?

Answer 30

both blocks estrogen production AND enhances androgen levels

Question 31

Contraindications of Androgen enhancement?

Answer 31

Preg/lactation Cardiac disease/MCI Diabetes Prostate cancer of hypertrophy

Question 32

Anti-androgenic pharmacology: the goal is to disrupt androgen synthesis or androgen signaling through the receptor. GnRH agonists (Goserelin) - mechanism?

Answer 32

Disrupts GnRH pulse generator. ## Footnote Chronic administration overrides normal pulsatile secretion of GnRH by hypothalamus --\> signals the pituitary to cease production of LH and FSH. --\> **Loss of LH leads to \>90% reduction in circulating testosterone,** *but only after an initial increase in testosterone (initial increase can be harmful to prostate cancer patients.)*

Question 33

Mechanism of 5a reductase inhibitors? Example medication?

Answer 33

Ex: Finasteride MoA: disrupts conversino of T to DHT. More potent than testosterone.

Question 34

name 2 androgen receptor modulators? MoA?

Answer 34

flutamide, bicalutamide block activation of androgen target genes.

Question 35

finasteride: class? MoA? used for?

Answer 35

5alpha reductase inhibitor Inihbits conversion of T to DHT Used for benign prostatic hyperplasia

Question 36

finasteride: can it be used for prostate cancer treatment? unfortunate SEs of this drug?

Answer 36

No; not really explained, but "does not reduce PSA scores" -Decr libido & impotence

Question 37

Name 2 androgen receptor modulators?

Answer 37

Flutamide Bicalutamide

Question 38

Flutamide: what does it do? MoA? Other stupid stuff on that slide?

Answer 38

**Androgen receptor antagonist for management of prostate cancer** - Non-steroidal. - Orally active and rapidly absorbed - Blocks uptake of T as well as nuclear binding of T and DHT to AR. - Combined with LHRH agonists to suppress output of testosterone.

Question 39

Bicalutamide: MoA? what is it used for?

Answer 39

**Androgen receptor antagonist for management of prostate cancer** Non-steroidal Orally active and rapidly absorbed Competitive AR antagonist Long plasma 1/2-life allows for once-daily dosing. Combined with LHRH agonists to suppress output of testosterone.

Question 40

Adverse effects of Androgen Enhancement?

Answer 40

1. Masculinization of women and pre-pubertal children 2. Endometrial bleeding upon discontinuation 3. Disruption of CNS development in early life 4. Alkyl-substituted Androgens are associated with hepatic dysfunction 5. Associated with increased water-retention and edema 6. Androgenswill increase the expression and activity of the Cyp enzymes, particularly in the liver. This increase the metabolism of other drugs, thereby decreasing their efficacy.