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Steroidal Drugs 1-Estrogens
Terms in this set (53)
Estrogens: Physiological Role
-Promote development & function of reproductive organs
-promote development of secondary sex characteristics
-exert cyclical control over menstruation
-affect sexual behavior:
Organizational actions (circuitry of female brain): permanent sexual differentiation
Activational effects: increase in sexual activity in adult
Menstrual cycle what stages
Gonadarche stage (ovaries start to function at puberty)
Menarche stage -onset of menstrual cycle (uterus—periodic bleeding)
end of reproductive life?
Trigger: pulsatile release of GnRH from hypothalamus
End of reproductive life ovaries no longer producing estrogen, hypothalamus will restore estrogen levels, cause inc in LH and FSH and GnRH-neg feedback
There are 3 sets of changes associated with the menstrual cycle:
-The ovarian cycle
-The endometrial cycle-changes in lining of uterus
-The secretion pattern of 4 hormones:
FSH, LH, estrogen, progesterone
prior to puberty release____?
onset of puberty?
reproductive years over,
extrogen excreted how?
-FSH & LH is low
-cyclical changes in LH & FSH, peaks of estrogen at onset of puberty
-ovaries no longer put out estrogen, so there is rise in FSH & LH. Rise provides potential source of fertility drugs for women who can't get pregnant.
-Estrogen excreted in urine.
when does it begin? in response to what hormone?
what 2 phases?
-begins when 20+ vesicular follicles enlarge in response to FSH
-follicular & luteal
what happens first 2 weeks
what triggers ovulation
After 5-6 days, one follicle outgrows the others to become the dominant follicle & begins secreting E (follicular phase)-first 2 weeks.
The other vesicular follicles undergo atresia (regression).
The dominant follicle is surrounded by theca & granulosa cells that develop a fluid-filled chamber known as the antrum.
The mid-cycle surge of LH & FSH triggers ovulation = release of a mature ovum onto the Fallopian tubes, fertilized if encounter sperm cells, implanted onto uterus
how does corpus luteum form
if no pregnancy?
The remaining theca & granulosa cells proliferate to become the corpus luteum which produces E & P for the remainder of the cycle
If no pregnancy, corpus luteum degenerates to become corpus albicans.
what triggers menstruation
if pregnancy occurs?
E & P fall rapidly, but sudden ↓ in P triggers menstruation
If pregnancy occurs, corpus luteum continues to secrete E & P
what happens prior to ovulation?
-Corpus luteum-source of estrogen & P, prior to ovulation there is inc in E levels, after ovulation come down, achieve 2nd peak lower than 1st peak occurs midway between ovulation and menstruation
-P levels are low from 14 days of cycle, after ovulation, corpus luteum secrete P and there is peak developing. Not sustained bc corpus luteum becomes corpur albicans-white, no longer releasing E & P, estradiol levels go down & P levels go down
first 2 weeks prior to ovulation known as?
First two weeks prior to ovulation is known as the proliferative stage
Is estrogen dependent
Increase in estradiol promote Re-epithelialization of the uterine wall-thickness of endometrium
last 2 weeks after ovulation?
what happens when corpus luteum stops secreting E & esp P?
Is progesterone dependent-triggers secretory phase
Increased secretory capacity of the endometrial wall-mucus
Provides initial support for implantation of a fertilized egg.
When corpus luteum stops secreting E & especially P, it triggers sloughing off of endometrial wall with loss of small amount of blood & serous fluid.
2 peaks in estradiol when?
peak prior to ovulation
peak achieved mid luteal phase
P begins to rise when?
P peak achieved when?
mid luteal phase
spike in LH and FSH =?
trigger for onset of ovulation-release of mature ovum onto fallopian tube
what happens to ovaries?
low circulating E results in ?
Defined as cessation of menstruation (uterine bleeding)
Occurs at mean age of 52 in US
The ovaries cease secrete E's & P's
Low circulating E results in loss of trophic influence of E's on bone & increase risk of osteoporosis (weaker bones)-not seen until E is absent
low circulating levels of E& P=?
results in the continuous & uninhibited release of FSH & LH due to loss of negative feedback actions at level of hypothalamus & anterior pituitary
Consequently, the urine of post-menopausal women has been an important source for gonadotropins to treat infertility disorders in women & men
sources of estrogens what 3 are naturally occuring?
estriol E3-short acting
most___ of ___
major product of ovary (premenopausal)
most potent endogenous estrogen
produced by granulosa cells stimulated by FSH from androgen precursors made by theca cells (LH stimulated)-provide substrates for granulosa cells to secrete estradiol
LH-> theca cells->androgen precursor->FSH->granulosa->E2
principal estrogen in____
synthesized? secreted by?
principal estrogen in post-menopausal women and in men
synthesized in adipose tissue stroma cells from DHEA secreted by adrenal cortex; ADRENAL CORTEX-->DHEA-->ADIPOSE TISSUE STROMA
Bc estrone synthesized by fat cells, the fatter you are, the more estrogen produced-most noticeable in men bc start to develop gynecomastia
E1 interconvertible to E2 in the liver
what is key enzyme in synthesis of estrogens
6 sites of production of endogenous estrogens
ovaries-E2-theca & granulosa cells
placenta-E1 & E3
fat tissues-both sexes
adrenal cortex-both sexes
testes-(E receptors in testes) knock out mice, males are infertile
Endogenous Estrogens: Target Tissues (4)
Uterus--stimulates overall development & cyclical growth & secretory activity of endometrial cells
Fallopian tubes, cervix & vagina-produce mucus
Breasts--increase stromal tissue & duct development
Hypothalamus--negative feedback receptors (membrane bound) control GnRH & FSH secretion
3 physiological Actions
Growth & development of sexual organs in females
Promote endometrial growth during follicular (proliferative) phase and increases no. of progesterone receptors during secretory phase-cause augmentation of response to progesterone
Promote feminization (secondary sex characteristics)
Metabolic Effects of Estrogens-1
preserve____ through _____
Direct and/or indirect
Preservation of bone mass--decrease resorbtion by osteoclasts (decrease no. of osteoclast & activity); osteoclast are bone disassemblers
lipid metabolic effect?
slight increase of serum triglycerides & slightly dec serum cholesterol
increase HDL & decrease LDL and lipoprotein A
increase cholesterol secretion & decrease bile acid secretion by gall bladder (risk of gallstones development
protein metabolic effect?
increase many serum proteins produced by liver (1st pass effect)-stim protein synthesis by the liver
CBG-corticotropin binding globulin (transcortin), TBG-thyrotropin binding globulin, SSBG-sex steroid binding globulin, transferrin, renin substrate
Also increasing circulating levels of thyroxine, estrogen, testosterone, iron, copper
Also increase multiple clotting factors & renin substrate
orally admin estrogens?
inc risk of ___disease?
hepatic effects minimized by?
Undergo extensive first pass metabolism
High ratio of hepatic to peripheral effects
Promote coagulation & thromboembolic events
Increase risk of thromboembolic disease
avoid first pass by vaginal, transdermal, injection routes
Estrogenic Agents & Dosage Forms
how for oral?
what kind of dosage forms? what effects if use these forms compared to oral?
extensive first pass effect-not widely used orally, low bioavailability
micronized for oral (Estrace)—still low bioavailability, variability in blood levels are higher
multiple dosage forms: p.o., s.c., I.M., topical creams, transdermal patch (less lipoprotein effects except p.o.)
esters of estradiol used for?
oil for IM-slow release
used in many____bc___
approved by FDA for?
improved oral bioavailability
E component in most oral O.C's bc good oral bioavail
Financed by catholic priest in MA
Approved by FDA for menstrual disorders-code for contraceptive
Estrogenic Agents & Dosage Forms (cont):
name of an OC that releases ethinyl estradiol?
Mestranol-O.C.'s, release Ethinyl estradiol
mostly used in HRT-combination hormonal contraceptive (E & P), ERT is estrogen only
synthetic conjugated estrogens?
Original source: pregnant equine urine (Premarin)-1938-from urine of horse
mix of sulfate esters of estrone, equilin, 17-α-dihydroequilin; not purified
Synthetic conjugated estrogens:
Cenestin—(generic: conjugated estrogens A)-1999
derived from yam & soy plants; 9 synthetic E's produced
Enjuvia—(generic: conjugated estrogens B)-2004
derived from plants; includes delta-8,9-dihydroestrone sulfate
The 3 products are not considered to be bioequivalent.
No evidence synthetic E's are more or less efficacious or safe at equiestrogenic doses.
Estrogenic Agents & Dosage Forms (cont)
estropipate-what is it made of
3 other synthetic estrogens?
Estropipate (Ogen tabs or cream--1977)
-estrone solubilized as sulfate, stabilized with piperazine
-enzymes in gut remove sulfate groups
Quinestrol, chlorotrianesene, methallenestriol-synthetic estrogen
what are SERMS?
what kind are they?
actions at different tissues?
selective estrogen receptor modulators
Competitive partial agonist-antagonist at E receptors
Block E receptors in reproductive tissues (breast, endometrium) only; Agonistic action for bone & lipids-favorable
drugs that are SERMS?
what is it
hormonal replacement therapy HRT, Evokes menopausal symptoms, prevents bone loss, prevents breast cancer
antag at where? ag at where?
active metabolite: 5-hydroxytamoxifen-prodrug); antag in breast, ag in endometrium-treat breast cancer
approved ___to treat____
risk of ____but less than ___
Approved 2013 to tx menopausal women experiencing dyspareunia (pain during sexual intercourse due to vaginal & vulvar atrophy)
Box warning: can stimulate endometrial thickening can → endometrial cancer.
Also risk for thrombotic or hemorrhagic strokes and DVT but less than for HRT with a full estrogen
why are tissues capable of diff responses with diff estrogens? 5 reasons
2 Versions of estrogen receptor 1 & 2: distribution of 1 and 2 is not the same
Estrogen receptor is a dimer, homodimer (alpha & alpha or beta & beta), if tissues have both subtypes=3 total: homodimer and heterodimer that is produced
Diff estrogens produce diff conformational changes-diff conformational change than other agents= diff tissue response
How estrogen is in DNA-direct or tethered binding
Cofactors in diff tissues-coactivating factors (agonist effect) and corepressor factors (repressing)
Estrogens: Potential Carcinogenicity
What is DES, inc risk of? What happens if take during pregnancy?
Tumors in lab animals
most potent non-steroidal estrogen in 1930s
↑'d risk of vaginal & cervical adenocarcinoma in offsprings of mothers exposed (0.01-0.1% incidence)
also non-malignant genital abnormalities in offspring exposed during pregnancy=contraindication of estrogens during pregnancy
unopposed use in ERT not HRT:
___fold inc risk of? how is it prevented?
what other cancer? percentage risk? frequency of disease? risk factor?
15-fold increase risk of endometrial cancer in 5 yrs (reversible with discontinuation)
-Preventable-Add progestin in hormone replacement therapy to give HRT
breast cancer—occurs in 10% of women
-frequency of disease 1 in 8 in women over 85
-50% of women have no identifiable risk factor
-Risk factor = 1.25
Estrogens: Potential Carcinogenicity
no AE in what kind of therapy?
WHI (women's health initiative) & MWS (million women study)
short term E therapy
WHI (women's health initiative) & MWS (million women study)
2 large randomized clinical studies
Establishes a small but increased risk of breast cancer (↑25%)
-Progestin appears to play a major role to increase breast cancer risk: Medroxyprogesterone has been implicated
-excess risk of breast cancer appears to abate 5 years after discontinuation post menopausal hormone replacement therapy
HRT for __years or less is often prescribed to ____
mitigate hot flashes with minimal risk of breast cancer.
Start immediately with menopausal symptoms bc effects may not be same if ppl take later on after menopause
Estrogens: Undesirable Effects
Metabolic & Cardiovascular Issues: 4
2 to 3 fold increase in gallbladder disease
3-fold increase risk of venous thrombosis in healthy women
1.35 factor increase risk of stroke
some women may develop hypertension
Estrogens: Undesirable Effects
-Nausea & vomiting-tolerance may develop
take with food-post absorptive peak is lower, or at bedtime
-Fullness & tenderness of breasts/edema
-Severe migraine in some-cause to stop drug
-Reactivation or aggravation of endometriosis (uterus overstim by too much E, endometrium is appearing in fallopian tubes) & related pain
-Hyperpigmentation (chloasma, melasma)
-Increased frequency of monilia infection-yeast infection
Estrogen dependent cancers
undiagnosed vaginal bleeding but cause in unknown, vaginal bleeding is first sign of cancer
liver disease/gallbladder disease-liver to metabolize
history of thromboembolic-clotting disorders-inc of protein synthesis of coagulating factors
why E contraindicate in pregnancy?
how does E & P work in pregnancy?
estrogens and progestins have opp effects of uterine muscle-E promote uterine contraction; progestin promote uterine relaxation, pregnancy-E levels go up, progestin levels go up, P levels so high, drown out E; just prior to birth production of goes down, production of E rise=contractions
E Drug interactions
blocks effects of bromocriptine
***cigarette smoking increases risk of serious cardiac adverse reactions
inhibits metabolism of cyclosporin
Estrogens: Therapeutic Uses
Post-menopausal Hormone Replacement Therapy
-conjugated estrogens most commonly used
-lower dose than OC's/less side effects
Prevention of osteoporosis & related bone fractures
Treatment of vasomotor symptoms of menopause
hot flashes, alternating chills, inappropriate sweating, parasthesias in fingers
Estrogens: therapeutic uses (cont)
Reversal of urogenital atrophy
effective to treat vaginal dryness & itching (topical for vagina), pain during intercourse, genital swelling, pain on urination, sudden unexpected urinary incontinence
previously thought to slow development of Alzheimer's disease
benefits not confirmed & harm uncovered in recent prospective study
WHI study: increased risk of dementia
treatment of primary hypogonadism
percent inc/dec in health problems among women taking hormones vs placebo
national study showed that although risks for indiv women taking hormone therapy was small, overall risks outweighed benefits
blood clots 111%
breast cancer -26%
colorectal cancer (-37%)
hip fracture (-34%)
total fractures (-24%)
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