Pharm: estrogens and progestogens

Question 1

Steroid hormone levels in postmenopausal women

Answer 1

• Drastically lower E2, androgens reduced by 50%, P not detectable
• Complications of low E2 levels: vasomotor Sx (hot flashes), genitourinary atrophy, osteoporosis, decrease in mental function
• Natural estrogens: E2, estrone, conjugated equine estrogens (premarin)
• Synthetic estrogens: ethinyl estradiol (steroidal), diethylstilbestrol (non-steroidal)

Question 2

General properties of estrogen replacement Rx: route of administration

Answer 2

• Oral 17-B E2 subject to extensive first pass metabolism and hepatic effect (using skin patch drastically lowers first pass metabolism and hepatic effect)
• Hepatic effect: high concentrations of estrogens in liver induces synthesis of some proteins that lead to negative effects (thromboembolism, HTN, gallstone formation) and positive effects (changes in lipoproteins)
• Oral equine estrogen, or oral/skin patch ethinyl estradiol will cause hepatic effect, due to reduced metabolism by, and thus accumulation in, the liver
• Equine estrogen can also be administered IM, or vaginal and estrogens given via IM, vaginal or transdermal routes have minimal hepatic effects
• Equine estrogen is most commonly used ERT, and ethinyl estradiol is used as contraceptive

Question 3

General properties of estrogen replacement Rx: transport and metabolism

Answer 3

• E2 binds to SHBG and induces SHBG synthesis by liver
• Ethinyl estradiol does not bind SHBG but does induce its synthesis
• Estrogens are metabolized by CYP and then glucuronidated or sulfated
• Glucuronidated metabolites are subjected to enterohepatic circulation (synthetics have longer T1/2)

Question 4

Side effects of estrogen replacement Rx: minor side effects, CA, and HTN

Answer 4

• Minor side effects: HA, edema, N/V, breast tenderness
• Uterine CA: unopposed estrogen increases risk of endometrial CA (E2 causes uterus proliferation), but when using HRT (E+P) the risk of endometrial CA is reduced
• Endometrial CA risk high when high dose and long duration of ERT
• Breast CA: Estrogen alone is protective against breast CA, but HRT increases breast CA risk 1.2 fold over 5 yrs
• HTN: seen in 5% of pts taking ethinyl estradiol contraceptives (not seen in ERT/HRT)
• Due to increased synthesis of angiotensiogen by liver and thus increased RAS

Question 5

Side effects of estrogen replacement Rx: thromboembolism, gallstones, and CVD

Answer 5

• Thromboembolism: part of hepatic effect, seen in all forms of ERT/HRT that are oral
• Due to increased synthesis of clotting factors (VII and X) in liver
• Gallstones: part of hepatic effect, estrogens increase cholesterol saturation in bile promoting gallstones
• CVD: ERT alone leads to a reduction in CVD risk, probably due to decrease in LDL and increase in HDL
• Adding progestins (HRT) may reverse this beneficial effect in older women
• HRT increases CVD in women >60yo, but decreases CVD in women <60yo

Question 6

Contraindications to estrogens

Answer 6

• Pregnancy: teratogenic, but low dose contraceptives are not
• Breast and/or endometrial CA
• Hepatic disease
• Undiagnosed genital bleeding
• Thromboembolic d/os
• Uncontrolled HTN

Question 7

Mechanism of ERT and indications based on Sxs 1

Answer 7

• Vasomotor (hot flashes): estrogen withdrawal -> increases hypothalamic NE-> increases GnRH release and causes downward resetting of central thermoregulatory center (body wants to cool off)
• This causes heat dissipation thru vasodilation and perspiration
• Onset may be due to hot liquids, alcohol, increased environmental temp
• Rx: equine estrogen (lowest dose that controls Sxs), no need for progestin
• Alternative: E2 skin patch
• If estrogen is contraindicated (breast/uterine CA): clonidine, gabapentine, SNRI

Question 8

Mechanism of ERT and indications based on Sxs 2

Answer 8

• Genitourinary atrophy: may be atrophic vaginitis and/or urethral syndrome (atrophy of urethra/bladder)
• Rx: vaginal premarin (lowest dose) for 3 mo (no progestin)
• Alternative: vaginal ring releasing estradiol
• Osteoporosis: estrogen decreases bone resorption and thus replacing estrogen will reduce osteoporosis
• Rx for hysterectomized women: unopposed estrogen Rx (ERT) w/o progestins
• Rx for women w/ intact uterus: HRT w/ low dose progestin
• Alternative to HRT (if CVD risk is high): raloxifene or alendronate (bisphosphonate)

Question 9

Selective estrogen receptor modulators (SERMs): raloxifene

Answer 9

• SERMs: goal is to produce beneficial estrogenic effects (agonist) in bone and brain, and have antagonistic estrogenic effects in breast and uterus
• Raloxifene: used to prevent and Rx osteoporosis, also reduces breast CA risk
• It has enterohepatic circulation (due to glucuronidation), T1/2 is 30 min
• Agonist in bone (decreases vertebral fractures but not hip fractures), antagonist in breast/uterus, and antagonist in hypothalamus (causes hot flashes)
• Raloxifene also increases risk of DVT, PE, and leg cramps

Question 10

Clomiphene (antiestrogen)

Answer 10

• Clomiphene: used to Rx anovulatory infertility (including infertility due to polycystic ovary disease)
• Only effects anovulation due to hypothal dysfxn and not anovulation due to pit/ovary dysfxn
• Mech: antagoniszes estrogen receptors in hypothal and pit to increase secretion of GnRH, LH, and FHS, thereby inducing follicle development and ovulation
• Clomiphene does not prevent estrogen-induced positive feedback in pit mid cycle that leads to LH surge
• Adverse effects: multiple births, and thinning of endometrium (use minimum dose to prevent this)
• T1/2 is 5 days due to protein binding and enterohepatic circulation

Question 11

Tamoxifen (SERM)

Answer 11

• Used for adjuvant Rx for ER+ breast CA, and breast CA prevention
• Agonist in bone and uterus: decreases vertebral fractures, increases risk for endometrial CA
• Antagonist in breast and hypothalamus: decreases breast CA risk and causes hot flashes