PHARM: Estrogens and Progestins

Menstrual Cycle

• The ______ Phase is primarily under influence of FSH, while the _______ Phase is primarily under influence of LH.

• The follicular phase secretes ______ while the luteal phase secretes

• What happens in the follicular phase

• What happens in the Luteal Phase

Menstrual Cycle

• The Follicular Phase is primarily under influence of FSH, while the Luteal Phase is primarily under influence of LH.

• The follicular phase secretes estrogen while the luteal phase secretes estrogen&progesterone

• In the follicular phase the follicle matures

• In the Luteal Phase, the corpus luteum forms and ovulation occurs, if not fertilized it degenerates into corpus albicans and the endometrium sheds

What enzyme mediates the conversion of testosterone into estradiol as well as androstenedione into estrone?

Aromatase, which creates an aromatic ring

Genomic Mechanism of action of Estrogens and Progestins

1. Passively diffuse into target cells

2. Bind to nuclear/cytoplasmic PR (A or B) or nuclear ER (alpha or beta)

3. Binding triggers receptor conformation and releases stabilizing/chaperone proteins Hsp90 and Hsp 70

4. Hormone-receptor complex dimerizes into homo/heterodimers

5. Activated dimer enters nucleus

6. Binds ERE or PRE nucleotide sequence and regulates gene transcription

Note: This process alters both transcription and translation → makes it slow acting but long acting

Natural Estradiol Pharmacokinetics

• Physiological effect

• Pharmacokinetics

• Prescription Options

• Clinical use + Combination therapy

• Adverse Effects

• Physiological effect:

  • Normal maturation of female, maintaining reproductive structures

  • Secondary sexual characteristics

  • Develop endometrial lining

    • Continuous exposure can cause abnormal hyperplasia

  • Lack of estrogen leads to osteoporosis

  • Increases plasma triglycerides and HDL, decreases plasma cholesterol and LDL levels

    • decreases risk of heart attack

  • Enhance coagulability of blood, can lead to thrombosis

  • Increase salt and water retention

• Pharmacokinetics: Inactivated by hepatic first-pass metabolism so they have poor oral bioavailability

  • Thus natural is not used for contraception but used for hormone replacement therapy (menopause and 1ry hypogonadism)

  • n circulation binds to SHHG and albumin

  • Doses must be educed in hepatic dysfunction

• Prescription Options of Estradiol by brand name:

  • Natural: well absorbed in all routes, poor oral bioavailability

    • P.o: Estrace

      • Micronized to avoid FPM and are administered p.o

    • IM: Delestrogen and Depo-Estradiol

    • Transdermal patch: Vivelle DOT, Climara, Alora, Minivelle, menostar

      • This route avoids first-pass metabolism and systemic effects such as clotting, strokes, MI

    • Vaginal insets: Estring, Imvexxy, Femring, Vagifem, Divigel

      • Same as transdermal

    • Topical gel: Elestrin and Estrogel

  • Synthetic Estrogens: used as oral contraceptives because they are modified to increase oral bioavailability; highly lipophilic and stored in adipose tissue

    • Steroidal:

      • Ethynyl estradiol

      • Mestranol

    • Non-steroidal:

      • Dinestrol

      • Diethylstilbestrol

• Clinical use + Combination therapy:

  • HRT, Dysmenorrhea, Contraceptives, osteoporosis prophylaxis, hypogonadism, menopause, reduce heart attack risk, increase libido, dysfunctional uterine bleeding,

    • Menopausal Women w/ intact uterus → estrogen + progestin (to prevent cancer from uterine hyperplasia)

      • Prefest (p.o): Estradiol +Norgestimate

      • Activella (p.o and td): Estradiol + Norethindrone

      • Climara Pro (td): Estradiol + Levonorgestrel

      • Angeliq (p.o): Estradiol + Drospirenone

      • Prempro, Premphase): Conjugated estrogens + medroxyprogesterone

    • Hypogonadism and Menopausal women without uterus (add a progestin for intact uterus)

      • Menest (p.o): esterified estrogens (these are from horses and less potent but less side effects) (+ progestin if uterus is intact)

      • Cavaryx, EEMT (p.o): Esterified estrogen + Methyltestosterone (for libido, not progestin)

        • Not indicated for primary hypogonadism

      • Premarin (p.o or vaginal): conjugated equine (also from horse) estrogen mixtures

        • Also for abnormal uterine bleeding and atrophic vaginitis

• Adverse Effects:

  • nausea, vomiting, postmenopausal bleeding, breast tenderness, mastalgia, edema, hypertension, thromboembolism, gallbladder disease, cholestatic jaundice, endometrial hyperplasia, endometrial cancer, migraines, vaginal infections

  • Contraindications: Estrogen-dependent neoplasms, undiagnosed genital bleeding, endometrial hyperplasia, Liver disease, thromboembolic disorders, heavy smokers, pregnancy

Progestins/

• Physiological effect

• Pharmacokinetics

• Prescription Options

• Clinical use

• Adverse Effects

• Physiological effect

  • Produced in ovaries, testes and adrenal gland\

  • Influences alveolar development, prepares uterus to receive the egg

  • In high concentrations inhibits gonadotropin release due to negative feedback

  • Decreases HDL, Increases LDL, increases risk for MI

• Pharmacokinetics: Progesterone has limited oral bioavailability thus micronized form must be used for p.o administration

  • Synthetic progestins are more stable and more durable

• Prescription Options:

  • 1st gen: Medroxyprogesterone

  • 2nd gen Norgestrel, Levonorgestrel (Plan B), Norethindrone

    • Androgenic and metabolic side effects

  • 3rd gen: Norelgestromin, Norgestimate, Etonogestrel, Etonogestrel, Desogestrel, Dienogest

    • Least systemic effects

  • 4th gen: Drospirenone (similar to spironolactone)

    • Used for treating premenstrual dysphoric disorder because of its anti mineralocorticoid activity

  • Combination therapy

• Clinical use of synthetic: Hormonal contraception, HRT, Endometriosis, Endometrial carcinoma, dysfunctional uterine bleeding

• Adverse Effects:

  • Edema, depression

  • Androgenic effects: thromboembolic events, decreased HDL, acne, hirsutism (male pattern hair), weight gain

  • Contraindications: Breast/cervical/uterine or vaginal cancer, history of thromboembolic disease, stroke, MI, thrombophlebitis, hepatic disease, undiagnosed vaginal bleeding

Selective Estrogen Receptor (ER) Modulators (SERMs)

• Physiological effect

• Pharmacokinetics

• Prescription Options

• Clinical use

• Adverse Effects

Tamoxifen: nonsteroidal, p.o

• Physiological effect: ER antagonist in breast tissue and ER agonist in bone → osteoporosis tx and prophy, increases HDL, and decreases risk/treats breast cancer

  • ER agonist in endometrium → Increases endometrial cancer risk

• Pharmacokinetics:

  • HL: 7-14hrs

  • Hepatic clearance, excreted in bile

  • Adverse effects: hot flashes, nausea, vomiting, risk of venous thrombosis and endometrial cancer

Raloxifene: second gen SERM

• Physiological effect: ER antagonist in breast, ER agonist in bone → osteoporosis tx and prophy, increases HDL only PREVENTS breast cancer and DOES NOT cause endometrial cancer!

• Pharmacokinetics: nonsteroidal, p.o

  • HL: >24hr

  • Glucocoronidate in the liver and excreted in bile

  • Adverse effects: venous thrombosis, leg cramps and hot flashes

Anti-Estrogen SERM: Clomiphene: fertility drug

• Physiologic effect: fertility drug that induces ovulation

  • Selectively antagonizes hypothalamic and pituitary ER, thus preventing negative feedback from estrogen → Continued release of FSH and LH

    • Also acts as an antagonist to ER receptors

  • Adverse effects: hot flashes, ovarian cyst formation, ovarian hemorrhage due to enlargement

Anti-Progestin

• Physiological effect

• Pharmacokinetics

• Prescription Options

• Clinical use

• Adverse Effects

Mifepristone: abortifacient drug during first 10 weeks of gestation; contraceptive off-label

• Physiologic effect: PR antagonist and GR antagonist

• Clinical use: induce therapeutic abortion, combined with Misoprostol to induce contractions

• Adverse effects: uterine bleeding, incomplete abortion

Danazol: tx endometriosis

• Physiologic effect: partial agonist that binds to PR, GR and AR but not ER; inhibits gonadal function

• Adverse effects: weight gain, edema, decreased breast size, acne, hirsutism, changes in libido

Aromatase Inhibitors

• Physiological effect

• Clinical use

Anastrazole, letrozole, Exemestane: tx of advanced breast cancer in Tamoxifen-resistant tumors

• Physiologic effect: Inhibits conversion of testosterone into estradiol

Pure Estrogen receptor Antagonist

• Physiological effect

• Clinical use

• Physiological effect: Completely gets rid of estrogen because tamofixen-resistant breast cancer moves ER receptor to membrane and are much more sensitive to small amounts of estrogen to feed themselves

• Clinical use: treats breast cancer in Tamoxifen resistant breast cancer pt