Sex Steroids I - Pharmacology II

Exam V

How do the Hypothalamus and the Anterior Pituitary drive ovulation?

Hypothalamus releases GnRH

GnRH stimulates the anterior pituitary to release LH and FSH

Why shouldn’t someone at risk of cancer be put on estrogen?

Estrogen is proliferative

Describe the roles of FSH and LH in Ovulation

FSH will act on the ovarian follicles to stimulate development of the follicle.

LH causes ovulation.

What is our Contraception Hypothesis?

• Inhibiting GnRH, LH, and FSH will reduce follicular development and ovulation and thus provide contraceptive effects

• Estradiol and Progesterone Inhibit these signals

• Estradiol receptors and Progesterone receptors are druggable targets

What does C17 Substitution do to Estradiol and Progesterone?

Turns into Ethinyl Estradiol and Norethindrone; extends their Half-Lives!

• From MINUTES to 8 hours and 30 hours respectfully

Where does Estrogen act in the body?

Estrogen Receptors:

• Brain

• Brests

• Endometrium

• Metabolic effect (cholesterol)

• Blood

• Bone

• Bladder, skin, lung

Estradiol Causes…

• Dizziness, headaches, migraines, nausea

• Breast tenderness

• Stimulates cervical mucus

• Increases coagulation factors II, VII, IX, X, fibrinogen, renin substrate, & decreases anti-thrombin

Where does progesterone act in the body?

Progesterone Receptors:

• Brain

• Breasts

• Endometrium

• Stomach

• Fluid Retention

• Immune

• Skin and Muscles

Progestin Causes:

• Headache, depression, fatigue, drowsiness, or insomnia

• Breast tenderness and swelling

• Irregular bleeding

• Stomach upset, changes in appetite, weight gain

• Fluid retention and edema

• Allergic skin rashes, hives, fever

• Thrombosis (increased distensibility and capacitance resulting in decreased blood flow and increased risk)

• Androgenic activity (masculinization, hirsutism, acne)

Describe the first Combined oral Contraceptive, Loestrin Fe

Norethindrone 1.5mg & Ethinyl Estradiol 0.03mg

List additional Benefits of Estrogen

• Decreased ovarian cycts/cancer and endometriosis

• Decreased endometrial cancer (E+P)

• Reduced probability of osteoporosis and rheumatoid arthritis

• Reduced dysmenorrhea and acne

• Increased HDL and lowered LDL

• Increased circulating levels of proteins:

  • Sex hormone binding globulin (antiadrogenic)

  • Thyroxine-binding globulin

  • Transferrin

How many generations of progestins are there?

4

List ROAs for Combined drugs (E+P)

• Oral (mono, bi, tri, quadri-phasic cycles)

• Transdermal patches

• Vaginal rings

List Progestin only ROAs

• Oral

• Injectable (IM or SQ)

• Implants

• IUDs

• Post-coital contraception

Describe the 1st Generation Progestins

Norethindrone (Oral) & Medroxyprogesterone Acetate (IM)

• Low risk of thrombosis

• Mildly androgenic (acne, fluid retention, hirsutism, muscle mass)

• Dosing — Monophasic

  • Norethindrone 1.5mg; Ethinyl Estradiol 0.03mg

Describe the 2nd Generation Progestin

Levonorgestrel (Oral, IUD, Postcoital)

• 0.5x greater risk of thrombosis

• More androgenic activity (attenuated when combined with estrogen)

• Less N/V

• Prolonged t½ — 323% binding affinity

• Dosing — extended continuous (Lybrel)

  • 84 days on, 7 days off

  • Levonorgestrel 0.15mg; Ethinyl Estradiol 0.03mg

Describe the 4th Generation Progestin

Drospirenone (Oral)

• Greatest risk of thrombosis

• Less androgenic [also an androgen receptor antagonist]

• Decreases BP [also mineralocorticoid receptor antagonist]

• Risk of Hyperkalemia b/c of diuretic action

• Dosing — 21/7 (Yaz/Yasmin)

  • Drospirenone 3mg; Ethinyl Estradiol 0.02mg

  • Lawsuits over causing heart problems

Compare Oral, Patch, and IUD/Ring Bioavailability

Oral: 50%

Patch: Peak=25% lower than oral; AUC 60% higher than oral

IUD/Ring: 100%

Describe the 3rd Generation Alternate Products (E+P): Norelgestromin

Patch

• 2-3x greater risk for thrombosis

• Less androgenic

• Prolonged t½

• Dosing:

  • Norelgestromin 6mg; Ethinyl Estradiol 0.075mg

  • Weekly patch

Describe the 3rd Generation Alternate Products (E+P): Etonogestrel

Ring, Rod

• 2-3x greater risk of thrombosis (Venous thromboembolism, especially desogestrel)

• Less androgenic

• Prolonged t½

• Dosing:

  • Etonogestrel 0.12; Ethinyl Estradiol 0.15mg

  • 3wk on, 1 wk off

Describe the 1st Gen Progestin only Product: Norethindrone

Oral

• Low risk of thrombosis

• Mildly androgenic (acne, fluid retention, hirsutism, muscle mass)

• Dosing:

  • Norethindrone 0.35mg

  • Daily, same time every day

• Good for Nursing Mothers

Describe the 1st Gen Progestin only Product: Medroxypprogesterone

IM

• Low risk of thrombosis

• Mildly androgenic (acne, fluid retention, hirsutism, muscle mass)

• Dosing:

  • Medroxyprogesterone 150mg

  • Q 3 months

Describe the 2nd Gen Progestin only Product: Levonorgestrel

As an IUD (only dosing changed)…

• 0.5x greater risk of thrombosis

• More androgenic activity (attenuated when combined with estrogen)

• Less N/V

• Prolonged t½ — 323% binding affinity

• Dosing:

  • Levonorgestrel (58mg; 20µg/d)

  • Copper spermicide

• Examples:

  • Mirena — 5yrs

  • ParaGuard — 10yrs

Describe the 3rd Gen Progestin only Product: Etonogestrel

Rod (Only dosing changed)

• 2-3x greater risk of thrombosis (Venous thromboembolism, especially desogestrel)

• Less androgenic

• Prolonged t½

• Dosing:

  • Etonogestrel 68mg

  • Every 3 yrs

How long does it take for Contraceptives to take affect?

For combo orals or progestin only:

• Considered immediate inf administered/implanted during first 1-5 days of menstruation

• If administered any other time, full protection will occur ~7 days

What is a big AE of Progestin-only Drugs?

Decreased HDL, increased LDL

Describe Post-Coital Contraception

Levonorgestrel (1.7mg) Pill

• Within 72hrs → 89% protection

Describe DDIs with Oral Preps

• CYP450 inducers will reduce contraceptive effects

• Contraceptives can inhibit hepatic metabolism of drugs tricyclic antidepressants or diazepam

• Antibiotics such as rifampin may reduce contraceptive effects due to the disruption in the gut flora

Describe DDIs with Estrogen containing preps

Warfarin may be less effective b/c of potential clotting

What are some patient considerations for Contraceptives?

• Pregnant or nursing mothers — estrogen reduces milk production initially, and crosses into breast milk

• Risk for or having blood clots

• Uncontrolled high BP

• Serious heart conditions (heart attack, stroke, angina, history of heart disease, vascular disease, ischemia)

• Breast or ovarian cancer

• Smoker and over 35yo

  • Myocardial infarction and stroke risk is already high in this population high b/c blood clots and narrowing and hardening of arteries

How does Clomiphene Increase Fertility?

Block Negative Feedback

• MOA: SERM—inhibits endogenous estrogen’s negative feedback in the hypothalamus, thus increasing gonadotropin

• Most common, less expensive, long half life, ~30% success

• SEs: Longterm use can have bad effects on uterine lining

How does Letrozole Increase Fertility?

Block Negative Feedback

• MOA: Aromatase Inhibitor. Less estrogen production = less negative feedback

• More expensive, shorter t½ life (48hrs), higher success rate (~30%)

• Less long-term SEs

• Some women are clomiphene resistant

How does Gonadotropins Increase Fertility?

Drive Ovulation

• Injectable FSH, LH

• Injections are uncomfortable, mulitple pregnancies are more common

• ~30% success rate

Describe Finasteride

BLOCKS Dihydrotestosterone, which proliferates prostate cells and inhibits hair growth

• Anti-Adrogen

• MOA: inhibits 5𝛼-reductase

• Used to treat benign prostate hyperplasia

• Used to treat androgenic alopecia

Describe Flutamide

Androgen Receptor Inhibitor

• MOA: androgen receptor antagonist

• Used to treat prostate carcinoma (castration is alternative therapy)