Pharm Unit 5 - Estrogens and Androgens

Estrogen and Androgen Therapeutic Use

-replacement, contraception, and management of menopausal symptoms

-antagonists effective in cancer chemotherapy

Estradiol (17 B-estradiol)

-most potent estrogen produced, secreted by the ovary

-principle estrogen in pre-menopausal women

Estrone

-metabolite of estradiol with 1/3 estrogenic potency of estradiol

-principle estrogen after menopause

Estriol

-metabolite of estradiol

-present in significant amounts during pregnancy

-produced by the placenta

Conjugated Estrogens

-estrone and equilin

-obtained from pregnant mare's urine

-used for hormone replacement

Ethinyl Estradiol

-synthetic estrogen

-undergoes less 1st pass metabolism

-effective at lower doses than naturally occurring estrogens

Estrogen MOA

-after dissociation from binding sites on sex hormone - binding globulin or albumin in the plasma, diffuse across cell membranes and bind with high affinity to specific nuclear-receptor proteins

-alpha and beta subtypes

Estrogen Uses

-contraception

-post menopausal hormone replacement therapy

-primary hypogonadism

Post-menopausal HRT

-estrogen helps with vasomotor instability and vaginal atrophy

-helps with maintenance of bone mass

-lower doses for HRT

-must be combined w/ progesterone if patient has not had a hysterectomy

Primary Hypogonadism

-estrogen therapy used to mimic natural cyclic pattern (used in conjunction with progesterone)

-stimulates the development of secondary sexual characteristics

Naturally occuring Estrogens

-absorbed through GI tract, skin, and mucus membranes

-Estradiol: PO is rapidly metabolized and partially inactivated by the liver

Synthetic Estrogen analogs

-ethinyl estradiol

-well-absorbed when taken PO or from topical admin (transdermal patch, topical gel, intravaginally, injection)

Estrogen Pk

-high 1st pass effect

-multiple mechanisms (hydroxylated, then glucuronidated or sulfated)

-Excreted into bile and reabsorbed into enterohepatic circulation

-urinary excretion of inactive metabolites

Estrogen ADE

-m/c: nausea and breast tenderness

-other: thromboembolic events, MI, peripheral edema, HTN, HA, increased risk of breast and endometrial cancer

progesterone

the risk of endometrial cancer with estrogen therapy can be offset by including what?

Estrogens - HRT

-lowest effective dose and for shortest possible time

-may be used an extended time for women where benefits outweigh risks

-not used for prevention of osteoporosis

estrogen - osteoporosis

-estrogen decreases resorption of bone, but has no effect on bone formation

-estrogen decreases frequency of hip fracture

-estrogen replacement is not preferred therapy for prevention of osteoporosis

estrogen - vasomotor

-estrogen treatment reestablishes feedback on hypothalamic control of NE secretion

-leads to decreased frequency of hot flashes

Estrogen - Urogenital Tract

-estrogen treatment reverses postmenopausal atrophy of the vulva, vagina, urethra, and trigone of the bladder

Tamoxifen

-SERM

-competes with estrogen for receptors in breast tissue

-Palliative treatment of metastatic breast cancer and adjuvant therapy after mastectomy or radiation

Tamoxifen ADE

-hot flashes, nausea, menstrual irregularities, vaginal bleeding

-endometrial hyperplasia/malignancies, DVT/PE

Tamoxifen Pk

-orally active

-extensively metabolized by CYP450

-excreted through bile into feces

Raloxifene

MOA: exhibits antagonism of the estrogen receptors in breast tissue; increases bone density by decreasing resorption of bone and decreasing bone turnover

-prophylaxis of breast cancer in high-risk women, prevention and tx of osteoporosis in postmenopausal women

Raloxifene ADE

-hot flashes

-leg cramps

-DVT/PE

Raloxifene Pk

-orally active

-converted to glucuronide conjugates through first-pass metabolism

-highly plasma protein bound and excreted through bile into feces

Clomiphene

-MOA: acts as a partial estrogen agonist and interferes with the negative feedback loop of estrogen on hypothalamus,

stimulates ovulation

-Treatment of infertility associated with anovulatory ccycles

Clomiphene Pk

-undergoes enterohepatic cycling

-excreted through bile into feces

Clomiphene ADE

-headache, nausea, vasomotor flushes, visual disturbances, ovarian enlargement, multiple births

Natural Progesterone

-produced in response to LH

-promotes development of a secretory endometrium to accommodate implantation of embryo

-if conception occurs, progesterone continues secretion

-if conception does not occur, menstruation is stimulated

Progesterone MOA

-increase in hepatic glycogen

-decrease Na+ reabsorption in the kidney due to competition with aldosterone at the mineralocorticoid receptor

-increase in body temp

-decrease in some plasma amino acids

-increase in excretion of urinary nitrogen

Progesterone Uses

-treatment of hormonal deficiency and contraception

-dysfunctional uterine bleeding

-dysmenorrhea

-management of endometriosis and infertility

Progestins ADE

-headache

-depression

-weight gain

-changes in libido

Progestin Pk

-active orally, IM, Subq

-Natural: short t1/2, excreted by the kidney

-Synthetic: less rapidly metabolized

medroxyprogesterone

-synthetic progestin

-t1/2 = 12-17 hr orally

-t1/2 = 40-50 days if IM or subq

Mifepristone

-progesterone antagonist with partial partial agonist activity

-used for abortion in early pregnancy

-followed by a dose of misoprostol

-combination increases the change of termination of pregnancy

uterine bleeding, incomplete abortion

what are the ADE for mifepristone?

Contraceptives

-mechanism to decrease fertility

-prevention of ovulation

-impairment of gametogenesis, disruption of gamete maturation

-interference with gestation

Combined OCPs

-synthetic estrogen + synthetic progestin

-highly effective at preventing conception

-more predictable cycles, less pain and blood loss associated with cycles

-most commonly used type of contraception

monophasic combined OCP

-same tablet taken every day

-same strength of estrogen/progestin in each tablet

triphasic combo OCP

tablets alter the strength of progestin to more closely mimic the natural hormone cycle

Combo OCP regimen

-typical: 21 days of active tablets, 7 days of inactive tablets

-extended cycle: 84 days of active, 7 days inactive

Combo OCPs Benefits

-decreased risk of endometrial cancer, ovarian cancer, benign breast disease, pelvic infections, ectopic pregnancies, iron deficiency anemia

-menstrual periods are predictable, shorter, and less painful

Combo OCPs Warnings

-thromboembolic disease, CAD, cerebral vascular disease

-smokers >35 y/o

-liver dysfunction or hepatic disorders

-breast cancer

-undiagnosed abn vaginal bleeding

-pregnancy

Combo OCP Cautions

-HTN

-DM

-Gallbladder disease

-epilepsy

Combo OCPs DI

-antibiotics

-barbiturates

-benzodiazepines

-phenytoin

-sulfonamides

-may affect anticoagulants and hypoglycemics

Transdermal Patch

-alternative to OCPs

-patch applied weekly x 3 weeks, week 4 is patch free

-total estrogen exposure is greater than OCPs

-may not be as effective in patients >90 kg

-may increase risk of thromboembolism

Vaginal Ring

-inserted into vagina and left in place for 3 weeks, 4th week is ring-free

-continual absorption of estrogen/progestin

-has efficacy, adverse effects, and CI similar to OCP

-ring may occasionally slip or be expelled accidentally

Progestin Only Mini Pill

-norethindrone or drospirenone

-low continuous dose of progestin

-less effective than combo OCPs

POPs MOA

-inhibit ovulation by suppressing LH surge

-thickening of cervical mucus

-alter fallopian tube peristalsis

Progestins

-contraceptive

-use: contraindications to estrogen, breastfeeding

-vary in progestin, estrogen/antiestrogen, and androgenic activity, so SE profile varies greatly

-orally, injectible IM

Nexplanon

-progestin implant

-subdermal implant in upper arm

-slowly releases progestin over 3 years

-nearly as reliable as sterilization, but is reversible upon removal

-SE: HA and irregular menstrual bleeding

Progestin IUD

-intrauterine device with progestin

-provides contraception through release of progestin and by IUD mechanism for up to 5 years

-reversible upon removal

Postcoital Contraception

-emergency

-reduces probability of pregnancy to 0.2-3%

-uses high doses of progestin, estrogen + progestin, and mifepristone

-should be administered within 72 hr or sooner

progestin-only

___________ formulations of postcoital contraception are generally better tolerated than combos

Androgens

steroidal compounds with anabolic (or masculinizing) effects in males and females

Testosterone

-synthesized by leydig cells of testes in males

-thecal cells in ovaries in females

-adrenal gland in males and females

5a-dihydrotestosterone

-active metabolite of testosterone

-inhibits testosterone production through a negative feedback loop

Androgen Functions

-normal maturation in males

-sperm production

-increased muscle and hemoglobin synthesis

-decreased bone resorption

Synthetic Androgens

-modified to create hormones with longer half-lives

-separation of anabolic and androgenic effects

Androgen MOA

-testosterone binds to a specific receptor in the target cell

-most be metabolized to be active

-testosterone is converted DHT by 5a-reductase

-may also be converted to estradiol

Androgens Uses

-androgenic effects

-anabolic effects

-endometriosis

-increased lean body mass, muscle strength, and endurance

Testosterone Pk

-ineffective orally

-IM injection, transdermal patches, topical gel, buccal tablets

-some synthetic testosterone derivatives can be given orally

-rapidly absorbed and metabolized

-urine excretion

masculization effects

what are the adverse effects of androgens in women?

Males Androgens ADE

-priapism or impotence

-decreased spermatogenesis

-gynecomastia

-growth of prostate

-cosmetic changes

Children Androgens ADE

-abnormal sex maturation

-growth disturbances

Androgens ADE

-increased LDL, decreased HDL

-fluid retention

5a-reductase inhibitor

-anti-androgen

-used for BPH

-finasteride

Androgen-Receptor Blockers

-antiandrogen

-used in carcinoma of prostate

-flutamide