Week 2: estrogens and progesterones

Question 1

Estrogen -route of administration

Answer 1

1. Oral
   - goes through first pass metabolism and first pass hepatic effect
   - high conc. of estrogens in liver induces synthesis of proteins with adverse (TE, HTN, gallstone) and beneficial effects (lipoproteins)
2. Non oral: transdermal, vaginal, intramuscular route
   - diluted in systemic circulation
   - bound to protein

Question 2

Transport of estrogens in body

Answer 2

• Estradiol has high affinity to sex hormone binding globulin (SHBG) and low affinity for albumin
• estrogen conjugates and ethinyl estradiol have high affinity for albumin
• free estrogen is physiologically active

Question 3

Metabolism of estrogens

Answer 3

• hydroxylated by microsomal enzymes in liver to derivatives that are glucuronidated or sulfated
• inactive products excreted in urine
• conjugated metabolites also subjected to enterohepatic recirculation: excreted in bile, converted to free estrogens by intestinal bacteria, reabsorbed into circulation

Question 4

Natural estrogens

Answer 4

1. Estradiol: not used orally because of first pass hepatic metabolism
   -miconized (small particle) prep: can be used orally, but in high doses because of low bioavailability
2. Transdermal estradiol: releases over 1 week
   Uses: ERT for post menopausal women. Rarely used.

Question 5

Conjugated esters

Answer 5

1. Conjugated equine estrogen (Premarin)
   - contains at least 10 components, mostly estrone and equilin
   - most common used estrogen for ERT
2. Estrone esters (synthetic)
   - easily hydrolyzed in gut and absorbed. Low first pass metabolism.

Question 6

Ethinyl estradiol

Answer 6

• synthetic steroid estrogen, with ethanol group at C17. Reduces metabolism
• half life is ~2- hrs
• useful as contraceptive
• not regulated by SHBG. While induces SHBG (like natural estradiol), EE doesn’t bind to SHBG. EE can regulated SHBG, E2, and androgen levels.
• natural estrogen self regulates since it induces SHBG, and binds to it

Question 7

side effects of estrogen

Answer 7

1. minor: few for ERT. As OCP, breast tenderness, edema, nausea
2. Major
   - Endometrial cancer: unopposed estrogen. The addition of progestogen reduces risk.
   - breast cancer
   - HTN: Angiotensinogen synthesis stimulated. majority of women will reduce renin. However, some won’t due to genetics, and have HTN.
   - Thromboembolism: increased synthesis of clotting factors in liver. Minimized with transdermal delivery
   - Gallstone formation: estrogen increases cholesterol excretion in bile
   - CV disease: controversial

Question 8

Contraindications of estrogen therapy

Answer 8

• pregnancy: high doses teratogenic but not low doses (as in OCPs)
• breast and endometrial cancers
• hepatic disease
• undiagnosed genital bleeding
• thromboembolic diseases

Question 9

ERT applications for post menopausal conditions

Answer 9

1. vasomotor symptoms
   - premarin widely used
   - if have breast cancer taking tamoxifen, treat with clonidine, gabapentine, SNRI
2. Genitourinary atrophy
   - vaginally administered estrogen cream
3. osteoporosis
   - hysterectemized women: ERT
   - intact uterus: low dose ERT, or HRT

Question 10

Raloxifene

Answer 10

• SERM: selective estrogen receptor modulator
• undergoes extensive glucuronidation
• used for osteoporosis and breast cancer prevention
• adverse: DVT, PE, hot flashes, cramps
• agonist in: bone
• antagonist: breast, uterus, vasomotor symptoms

Question 11

Clomiphene

Answer 11

• related to tamoxifen.
• acts as anti estrogen and estrogen (SERM)
• oral
• used to treat anovulatory infertility and infertility related to PCOD. Antagonists estrogen receptors in hypothalamus and pit (blocks negative feedback), increases GnRH and FSH/LH- thereby inducing follicular dev. and ovulation
• adverse: multiple births

Question 12

Progestogens

Answer 12

1. C21 -derivative of progesterone
   - medroxyprogesterone acetate: long half life. oral or IM. Used for HRT, Depo-provera.
2. C19: derivative of testosterone.
   - estranes: norethinedrone
   - gonanes: levonorgestrel, norgestimate