PHRM 825 Lecture 12&13- estrogens

most potent estrogen in humans

produced mostly in ovaries

mostly bound to sex hormone binding globulin

17B- estradiol

explain the regulation of estrogen synthesis

hypothalamus releases GnRH --> triggers anterior pituitary to release FSH and LH --> triggers ovaries to release estrogens and progesterone

what produces estrogen and progesterone in the luteal phase

corpus luteum

early follicular stage

estrogen suppresses the production of FSH

late follicular stage

estrogen stimulates the surge of LH and FSH --> ovulation and formation of corpus luteum

luteal phase

estrogen and progesterone suppresses the production of LH and FSH

how does hCG work during pregnancy

secreted by fertilized egg

acts like LH to stimulate corpus luteum to produce progesterone

explain the production of 17B- estradiol from androstenedione

aromatase turns bottom ring into an aromatic ring with -OH group attached (estrone) --> 17B hydroxysteroid dehydrogenase turns ketone on top into a hydroxy group

what are the natural estrogens

17B estradiol

estrone

estriol

physiological effects of estrogen

-female maturation

-endometrial effects; development of endometrial lining during menstrual cycles

-metabolic and cardiovascular effects (protects bone strength, alteration in composition of plasma lipids

-blood coagulation

-CNS

clinical uses of estrogens

-hormone replacement therapy in postmenopausal women

-osteoporosis

-hormonal contraception

-replacement therapy in patients with primary hypogonadism

how does estrogen help post menopausal women?

relief of CNS disturbances (hot flashes, sweating)

relief of symptoms from urogenital atrophy (vaginal dryness)

relief of psychological effects (mood swings, depression, nervousness)

adverse effects of estrogens

uterine bleeding, endometrial carcinoma, breast cancer, nausea, headache, weight gain

prevents conversion to estrone

enhances oral bioavailability and increases half life

17a alkylated estrogens

what are the 17a alkylated estrogens

ethinyl estradiol

mestranol

quinestrol

decreases solubility and slows the absorption

prolongs action, requires less frequent injections

estrogenic esters

what are the estrogenic esters

estradiol valerate

estradiol cypionate

mixture of estrogens

come from pregnant mares urine

conjugated estrogens

what are the conjugated estrogens

Premarin

50-60% estrone sulfate

20-30% equilin sulfate

what are the non steroidal estrogens

diethylstilbestrol and chlorotrianisene

used in 1940-1970 to prevent miscarriage

increased risk of vaginal adenocarcinoma for women exposed in utero

used in advanced prostate cancer

diethylstilbestrol

postpartum breast engorgment

menopause symptoms

prostate cancer

chlorotrianisene

partial estrogen agonists

has some estrogenic and some antiestrogenic effects

selective estrogen receptor modulators (SERM)

explain the structural basis of SERM activity

when SERM is bound, helix 12 conformation blocks coactivator binding and gene expression is decreased

what are the SERMs

tamoxifen, toremifene, ospemifene, raloxifene, clomiphene

what are the estrogenic and anti estrogen effects of tamoxifen

anti estrogen: treatment of breast cancer, prevents breast cancer

estrogen: estrogen agonist at endometrial cells, prevents osteroporosis, increase the risk of thromboembolic events

used to treat breast cancer

SERM

structurally similar to tamoxifen

toremifene

structurally similar to toremifene

SERM

estrogenic effects on vaginal epithelium

treats dyspareunia in post menopausal women

ospemifene

estrogen and anti estrogen actions of raloxifene

estrogen: prevents osteoporosis in postmenopausal women, decreases LDL levels, increase risk of blood clots

antiestrogen: decrease risk of breast cancer, does not stimulate endometrial cells, cause hot flashes

recently approved analog with similar activities to raloxifene

bazedoxifene

SERM

increases secretion of FSH and LH- stimulate ovulation

treats PCOS

clomiphene

selective estrogen receptor down regulator (SERD)

estrogen antagonist to treat breast cancer

fulvestrant

what are the aromatase inhibitors and what are their effects?

block the biosynthesis of estrogens, used for breast cancer, ovulation induction, and gynecomastia

anastrozole, letrozole, exemestane