5 - Estrogens/Progestins

What is the role of LH in estrogen synthesis?

increases cholesterol transport in cells → increases androgen precursors

What is the role of FSH in estrogen synthesis?

stimulates aromatase activity

What 3 estrogens are produced by aromatase activity?

• estrone

• estradiol

• estriol

What is the primary structure responsible for selective, high affinity binding to estrogen receptors?

phenolic A ring

Where is estrogen synthesized & secreted in premenopausal women?

ovary

Where is estrogen synthesized & secreted in postmenopausal women?

adipose tissue, DHEA → estrogen

Where is estrogen synthesized & secreted in men?

adipose tissue, androgen precursors & testosterone → estrogens

Where is estrogen synthesized & secreted in gestation?

fetal adrenal → androgen precursor → placenta aromatizes to estriol (large amounts)

Where are estrogen receptors located?

located as monomers in the nucleus

• stabilized by heat shock

What are the subtypes of estrogen receptors?

1. ER⍺

2. ERβ

Where is ER⍺ expressed?

• female reproductive tract

• hypothalamus

• endothelial cells

• vascular smooth muscle

Where is ERβ expressed?

• prostate & ovaries (high expression)

• lung, brain, bone, vasculature (lower expression)

What are the effects of estrogen in female development?

• changes at puberty

• growth/development of vagina, uterus, fallopian tubes

• enlargement & differentiation of breast tissue

• libido

• menstrual cycle changes to organs

What is the effect of estrogen on the bone?

• increased bone mineral density

• closes epiphyses

• increases osteoblasts, decreases osteoclasts

What are the effects of estrogen on the cardiovascular system?

• generally beneficial on blood lipids

• vasodilation

• enhanced blood coagulation

• sodium/water retention

What are the effects of estrogen on the CNS?

• stimulates CRH

• SNS (promotes sense of wellbeing)

What are the therapeutic uses of estrogen?

• primary - female hypogonadism

• contraception

• endometriosis & dysmenorrhea

• menopause & hormone replacement

What is menopause?

cessation of menstrual cycle & decline in estradiol levels

• typically 45-60 years of age

What are the s/s of menopause?

• hot flasshes

• sweating

• irritability, sleep disturbances

• atrophy of estrogen dependent tissue

• increased risk of osteoporosis, cardiovascular risk

• memory loss, cognitive difficulties

What are the goals of therapy of postmenopause hormone replacement?

• reduce vasomotor symptoms

• amerliorate atrophy of estrogen-dependent tissue

• bone loss prevention

What is the first line therapy for postmenopausal bone loss?

• bisphosphonates

• adequate Ca2+ & vitamin D

What are the PK of estrogen preparations?

• readily absorbed from all sites

• topical application sufficient to produce systemic effects

• 1st pass metabolism can be significant

What are the estrogenic agents?

• estradiol

• mestranol

• estradiol cypionate

• estropipate

• conjugated estrogens

• quinestrol

What are the ADE of estrogen?

• large doses cause nausea, GI effects

• large doses may cause fluid retention

• increase risk for deep vein thrombosis & pulmonary embolism

• uterine bleeding

What are the carcinogenic concerns of estrogenic agents?

• use by postmenopausal women w/ intact uterus increases endometrial cancer risk

  • use with progestin

• estrogen dependent cancers

• pregnancy

What are the therapeutic uses of anti-estrogens & selective estrogen receptor modulators (SERM)?

• breast cancer

• osteoporosis

• infertility

What is the MOA of selective estrogen receptor modulators (SERMs)?

• selective beneficial estrogenic actions in bone, brain, & liver

• selective anti-estrogenic actions in breast, maybe endometrium

What agents are SERMs?

• tamoxifen

• toremifene

• raloxifene

What are the effects of tamoxifen & toremifene?

• reduces breast tumor size & number

• stimulates endometrial cell proliferation (increases risk of endometrial carcinoma)

• blocks bone resorption

• decreases TC & LDL

• increases risk of DVT & PE

What are the PK characteristics of tamoxifen & toremifene?

• orally bioavailable

• long half-life (requires 3-4wk to reach steady state)

• metabolized by CYP2D6

What is the primary use of tamoxifen & toremifene?

breast cancer

What are the effects of raloxifene?

• activates ER in bone, blocking bone resorption

• decreases TC & LDL

• reduces proliferation in ER+ breast cancer

• increases risk of DVT & PE

• increases hot flashes & leg cramps

What are the PK characteristics of raloxifene?

• rapid absorption after oral admin

• metabolized by liver, eliminated in feces

What is the primary use of raloxifene?

post-menopausal osteoporosis

What agents are estrogen receptor antagonists?

• fulvestrant

• clomiphene

What is the MOA of fulvestrant?

• binds ER with greater affinity than estradiol

• represses gene transcription

• increases ER⍺ degradation

What is the primary use of fulvestrant?

tamoxifen-resistant breast cancer

What is the dosage form of fulvestrant?

monthly IM injections

What are the ADE of fulvestrant?

menopausal symptoms

What agents are aromatase inhibitors?

• exemestane

• anastrozole

• letrozole

What is the primary use of aromatase inhibitors?

primarily used to treat breast cancer, 1st or 2nd line after tamoxifen

How do aromatase inhibitors compare to tamoxifen?

• no increase in endometrial/uterine cancer

• no increase in DVT/PE

• increased hot flashes

• no beneficial effect on bone density

Where is progestin synthesized and secreted in premenopausal women?

ovary → corpus luteum

Where is progestin synthesized and secreted in postmenopausal women?

adrenal cortex via DHEA

Where is progestin synthesized and secreted in men?

testes & adrenal cortex

Where is progestin synthesized and secreted in gestation?

fetal adrenal → androgen precursor → placenta synthesized progesterone in large quantities

What are the receptor subtypes of progesterone?

• PR-B

• PR-A

What is the function of PR-B?

stimulatory activities of progesterone

What is the function of PR-A?

• strong inhibition of PR-B

• inhibits transcription of other steroid receptors

What are the physiological effects of progesterone on female reproduction?

• breast development

• maturation & secretory changes in endometrium following ovulation

• maintains pregnancy

  • suppresses menstruation/uterine contraction

What are the physiological effects of progesterone on carbohydrate metabolism?

• increased basal insulin & insulin response to glucose

• promotes glycogen storage

What are the physiological effects of progesterone on cardiovascular/renal systems?

• competes w/ aldosterone for mineralocorticoid receptor

• increases LDL

What are the physiological effects of progesterone on CNS?

• increased body temp during ovulation (hypothalamus)

• alters regulatory centers to increase CO2 ventilation

• depressant & hypnotic effects

What are the therapeutic uses of progesterone?

• hormone replacement therapy

• contraception

What are the semi-synthetic progestin agents?

• hydroxyprogesterone

• medroxyprogesterone

• dimethisterone

• norethindrone

• desogestrel

What progestin agents are pregnanes (similar to progesterone)?

• hydroxyprogesterone caproate

• medroxyprogesterone acetate

• megestrol acetate

What progestin agents are estranes?

• norethynodrel

• norethindrone

• norethindrone acetate

What progestin agents are gonanes?

• desogestrel

• L-norgestrel

• norgestimate

Which progestin agent category has much less androgenic activity than the others?

gonanes

What are the PK characteristics of progestins?

• well absorbed

• very short t1/2 (~5 minutes)

• metabolized in liver

What are the ADE of progestins?

• depressant, hypnotic

• dysmenorrhea

• weight gain

• mood changes

• decreased bone mineral density, HDL

• increased LDL

What are the androgenic ADE of progestins?

• acne

• hirsutism