female endocrine disorders - estrogen

FSH and LH

-regulate ovarian production of estrogen and progesterone

LH: ovulation

-at mid-cycel, estrogen triggers a surge of LH release

-followed by release of an egg from ovary

follicular phase

-first part of menstrual cycle

-estrogens produced in ovarian follicle

luteal phase

-post ovulation

-estrogens/progesterones synthesized by luteinized ovarian cells

luteinized ovarian cells aka

-corpus luteum

three major forms of estrogen

-estradiol (E2)

-estrone (E1)

-estriol (E3)

formation of E1 and E3

-mostly formed in the liver from E2

-or peripheral tissues from androgens

E2 secretion

-secreted in large quantities by ovaries

also secreted by

-adrenal cortex

-placenta during pregnancy

-testes in males

E2 metabolism

-rapid oxidation of E2 in liver to estrone (E1)

E2 enterohepatic cycling

-50% not excreted un urine

-metabolite reabsorded from intestine into blood and recycled

-prolongs half-life

estrogens moa

-bind to nuclear receptors in cytosol

-receptor complex dimerizes and translocates to nucleus

-complex binds to ERE to alter gene expression

-transcription/translation = cell response

pharmaco(physio)logical effects of estrogens

-secondary gender characteristics

-anabolic effects

-endometrial proliferation

-plasma lipid effects

-increased synthesis of clotting factors

-increased cholesterol in bile (less gallbladder emptying)

-retention of salt and water

anabolic effects of estrogen

-bone growth and epiphyseal closure

plasma lipid effects of estrogens

-hypolipidemic

-increases HDL and decrases LDL

synthetic estrogens examples

-ethinyl estradiol (EE)

-mestranol

EE vs natural estrogen

-500 times mores potent

mestranol vs estrogens

-a prodrug

-activated in liver to EE

clinical use of synthetic estrogens

-oral contraceptives

estrogens clinical uses

-hormone replacement

-contraception

estrogen as hormone replacement

-primary hypogonadism

-peri and post-menopausal replacement therapy

estrogens as contraceptives

-cannot be used alone (in combination with progestin)

-only synthetics used orally

menopause

-permanent cessation of menses following loss of ovarian follicular activity

post-menopausal symptoms (estrogen deficiency)

-vasomotor symptoms

-GSM

-osteoporosis

-CVD

vasomotor symptoms (post-menopausal)

-hot flashes and night sweats

GSM

-genitourinary syndrome of menopause

-vaginal atrophy/dryness

-burning

-dyspareunia

-recurrent UTIs

-urinary urgency

-dysuria

systemic menopausal hormone therapy (MHT)

-oral estrogen preparations

-TD estrogen preparations

types of oral estrogen preparations

-conjugated equine estrogens or CEE

-synthetic conjugated estrogens

-micronized 17B-estradiol

conjugated equine estrogens (CEE) examples

-from urine of pregnant horses

-Premarin

-Enjuvia

synthetic conjugated estrogens examples

-chemically modified estrogen from plants

-Cenestin

micronized 17B-estradiol examples

-Estrace

-better oral absorption

TD estrogen preparations examples

-Estraderm

-Vivelle

-Alora

-Climara

advantaged of TD over oral preparations

-higher bioavailability

-lower risk of thrombosis, stroke, and CVD

MHT: topical and intra-vaginal estrogen preparations

17B-estradiol

-topical emulsion

-topical gel

-topical spray

-vaginal tablets

-vaginal ring

-vaginal cream

CEE

-vaginal cream

example of 17B-estradiol topical emulsion

-Estrasorb

example of 17B-estradiol topical gel

-EstroGel

-Elestrin

-Divigel

example of 17B-estradiol topical spray

-Evamist

example of 17B-estradiol vaginal tablets

-Estrace

-Vagifem

example of 17B-estradiol vaginal ring

-Estring

example of 17B-estradiol vaginal cream

-Estrace

example of CEE vaginal cream

-Premarin

local estrogen therapy reserved for

-those exclusively experiencing mod-severe GSM

clinical applications of systemic MHT

-mod to severe vasomotor symptoms with/without GSM

-after a hysterectomy

-estrogen given daily, but progestin dose varies with regimen

to who must systemic estrogen always be given with progestin

-women with an intact uterus

-decrease risk of endometrial hyperplasia and cancer

combined hormonal therapy regimens

-continuous cyclic

-continuous combined

continuous cyclic

-mimics normal menstrual cycle

-daily estrogen + co-administration of progestin with estrogen for last 12-14 days of 28 day cycle

ADE of continuous cyclic regimen

-withdrawal bleeding (hormonal period)

continuous combined regimen

-more acceptable than cyclic

-daily estrogen + progestin without a break

ADE of continuous combined regimen

-endometrial atrophy

-breakthrough bleeding

advantage of continuous combined regimen

-offers best protection against endometrial hyperplasia and cancer

benefits of MHT in post-menopausal women

-estrogen has favorable effect in lipid profile

-estrogen decreases risk of osteoporosis

-estrogen decreases risk of colon cancer

s/e and risks of estrogen replacement

-nausea

-migraines

-gallstones

-high BP

-clots/DVT

-endometrial cancer

-breast cancer

cause of high BP with estrogen replacement

-estrogen increases angiotensin production and water retention

cause of DVT/increased clotting with estrogen replacement

-estrogen increases vitamin K dependent clotting factors

findings of E along and E+P in post-menopausal women

-decreased risk of fractutres

-decreased risk of colorectal cancer

-increased incidence of CAD, DVT, stroke

-increased incidence of breast cancer

recommendations from WHI on estrogen replacement

-HRT not recommended for decreasing CVD, cognitive impairment, dementia

-use smallest effective dose for shortest duration

-systemic estrogen must be given with progestin in those with intact uterus

goal of selective estrogen receptor modulators (SERMs)

-increase estrogen benefits and decrease risks

SERMs (need)

-agonist actions on bone and lipids

-antagonist or no actions on uterine and breast tissue

what are SERMs

-non steroidal agents

-exhibit tissue-selective actions (estrogenic in bone/liver and antagonistic in breast/brain/uterus)

1st gen SERMs

-tamoxifen

2nd gen SERM

-raloxifene

3rd gen SERM

-bazedoxifene

clinical uses of SERMs

-treat breast cancer and post-menopausal osteoporosis

ADEs of SERMs

-hot flashes

-leg cramps

-VTE

-stroke

tamoxifen clinical use

-antagonist in breast (treat breast cancer)

-agonist in bone and uterus (uterince cancer)

-NOT used in post-menopausal women

raloxifene clincal use

-antagonist in breast and uterus (treat breast cancer)

-agonist in bone (treat osteoporosis)

bazedoxifene clinical use

-antagonist in uterus

-agonist in bone

-used on combination with conjugated estrogens

SERMs: ospemifene

-no effect on breast and uterus

-agonistic effects on vagina

ospemifene clinical uses

-treatment of dysparaeunia and vaginal dryness

ospemifene ADEs

-similar to other SERMs

ospemifene boxed warning

-increased risk of endometrial hyperplasia/cancer

SERMS: clomiphene moa

-partial agonist at estrogen receptors (competitive inhibitor of endogenous estrogen)

clomiphene clinical uses

-to induce ovulation and treat infertility

clomiphene ADEs

-ovarian enlargement

-hot flashes