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130 Cards in this Set
- Front
- Back
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Steroid hormones are derived from what?
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Cholesterol
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Name 3 groups of steroids and their own receptors:
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1. Glucocorticoid
2. Mineralocorticoid 3. Progestagen 4. Androgens 5. Estrogens |
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Major sex steroid in females:
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1. Estrogen
2. Progesterone (ovaries) |
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Minor sex steroid in females:
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1. Testosterone (ovaries)
2. Other androgens (adrenals) |
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Major sex steroid in males:
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1. Testosterone (testes)
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Minor male sex steroid:
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1. Estrogen (From testosterone by aromatase)
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Function of aromatase enzyme
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Convert Testosterone --> Estrogen
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Synthesis of sex hormones under control of:
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Hypothalamus and Pituitary
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Hypothalamus secretes:
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GnRH (Gonadotropin Releasing Hormone)
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Pituitary (AP) produces:
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FSH (granulosa cell and Sertoli cell)
LH (Thecal cell and Leydig cell) |
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Negative feedback control of sex steroid production via
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1. Hypothalamic negative feedback
2. Anterior pituitary negative feedback |
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Physiologic action of FSH in males
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Stimulate seminiferous tubules (Spermatogenesis)
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Physiologic action of FSH in females
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Stimulate follicular growth and estrogen production
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Physiologic action of LH in males
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Stimulate androgen secretion
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Physiologic action of LH in females
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Stimulate ovulation and luteinization; corpus luteum produces both estrogen and progesterone
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Products of corpus luteum
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Estrogen AND progesterone
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Mechanism of action of FSH and LH
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Specific receptors coupled to adenylate cyclase
Increased cAMP causes increased synthesis of sex steroids in gonads and luteinization |
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Estrogen and progesterone mediates negative/positive feeback on gonadotropic hormone secretion (FSH/LH)?
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Negative feedback
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What happens at critical point in female cyce with negative feedback action of estrogen?
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Switches to exert positive feedback on secretion of gonadotropic hormones (FSH and LH)
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Action of FSH in female
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Stimulate development and growth of (usually) single follicle and associated ovum
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Follicle secretes:
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Estradiol
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Principle endogenous estrogen in humans is:
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Estradiol
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Estrogen initially exhibits (+/-) feedback of GnRH?
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Negative feedback
Limits secretion of FSH and LH by the pituitary |
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Action of estradiol on endometrium in uterus
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Endometrial proliferation and thickening
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When does rising level of estrogen (being produced by follicle) reach critical point?
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Mid cycle
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What happens mid cycle of female?
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LH Surge
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Consequence of LH surge:
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Triggers ovulation
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Ruptured follicle after LH surge and ovulation now becomes:
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Corpus luteum
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Corpus luteum secretes what hormone?
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Progesterone
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Action of progesterone
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Acts on thickened endometrium (uterus) to maintain it
Promotes transformation of endometrium into highly vascular "secretory endometrium" = good environment for fertilized ovum to implant |
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What happens to corpus luteum if no pregnancy occurs?
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Corpus luteum atrophies
Progesterone levels fall |
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What happens when progesterone levels fall (such as in case of no pregnancy?)
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No progesterone to maintain endometrial lining --> endometrial lining breaks down and sloughs off at about day 28
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When does endometrial lining break down and slough off?
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Day 28
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What does corpus luteum become if pregnant?
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Blastocyst
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What does implanted blastocyst prodcue?
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HCG
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HCG has activity similar to what hormone?
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LH
Has LH-like activity |
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Action of HCG
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Prevents atrophy of corpus luteum
Allows corpus luteum to continue producing progesterone to maintain thick secretory endometrium |
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Clomiphene
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Anti-estrogen used to treat ovarian failure
"Fertility drug" Blocks estrogen mediated inhibition of FSH/LH release |
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How can clomiphene cause multiple pregnancies?
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Overstimulation of ovaries
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Menotropin (Pergonal)
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FSH and LH recovered from urine of menopausal women
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Urofollitropin
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Purified FSH
Produces follicular stimulation |
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Fillitropin
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Recombinant FSH
Produces follicular stimulation |
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Human chorionic gonadotropin
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Collected from urine of pregnant women
Action similar to LH |
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When to use HCG in fertility treatment?
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After priming with Pergonal (Menotropin), inject hCG to induce ovulation (Mimic's LH surge)
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Danazol
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Tx of endometriosis
Synthetic androgen used to inhibit output of FSH/LH in endometriosis Removes hormonal stimulation |
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Clomiphene is an antagonist of ER in what pathway of the HPA?
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Negative feedback loop
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Excessive estrogenic feedback inhibition of GnRH in hypothalamus can cause
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Female infertility
FSH levels are too low to "get things started" |
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Estrogen receptor antagonist in negative feedback loop
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Clomiphene
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If Clomiphene works too well --> can cause:
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Development of more than 1 follicle = multiple births!
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Menotropin + hCG
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Induction of ovulation
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What treatment to use if pituitary fails to produce FSH and LH
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Menotropin + hCG
Menotropin = purified FSH from urine of post-menopausal women (Pergonal) hCG = LH like activity |
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Schedule of menotropin (pergonal) + hCG
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Give menotropin for first 14 days
Follow with single injection of hCG to mimic LH surge |
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What if menotropin + hCG works too well?
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Multiple births
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Menotropin + hCG
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Induction of ovulation
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What treatment to use if pituitary fails to produce FSH and LH
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Menotropin + hCG
Menotropin = purified FSH from urine of post-menopausal women (Pergonal) hCG = LH like activity |
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Schedule of menotropin (pergonal) + hCG
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Give menotropin for first 14 days
Follow with single injection of hCG to mimic LH surge |
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What if menotropin + hCG works too well?
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Multiple births
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Synthetic androgen to inhibit output of FSH/LH
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Danazol
Removes hormonal stimulation |
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Treatment of endometriosis
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Danazol
Removes hormonal stimulation |
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Any sex steroid can inhibit the secretion of FSH/LH in either sex (T/F)
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True
Danazol (synthetic androgen) inhibits excessive FSH/LH production in endometriosis |
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Leuprolide
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GnRH analog
Used in fertility and CA chemotherapy |
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Nafarelin
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GnRH analog
Used in fertility and CA chemotherapy |
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Goserelin
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GnRH analog
Used in fertility and CA chemotherapy |
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Ganirelix
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GnRH antagonist
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Abarelix
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GnRH antagonist
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What happens to GnRH receptors if overstimulated
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Receptor desensitization
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Treatment of hypothalamic amenorrhea
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GnRH analogue:
Leuprolide, Nafarelin, Goserelin Results in sustained release of FSH/LH = ovulation |
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More frequent administration of GnRH analog (Leuprolide, Nafarelin, Goserelin) results in?
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Contraceptive effect
Due to desensitization of GnRH receptors on AP gonadotrophs Leads to suppression of FSH and LH |
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Result of less frequent administration of GnRH analog:
Result of more frequent administration of GnRH analog: |
1. Ovulation (treatment of infertility)
2. Contraception (prevent pregnancy) |
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Rationale for GnRH use as contraception instead of treating infertility
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Overstimulation causes GnRH receptor desensitization
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Aside from infertility and use as contraceptive, GnRH analogs can be used in what particular cancer therapy?
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Prostate Cancer
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Why are GnRH analogs used in prostate cancer treatment?
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80% of prostate cancer are androgen-dependent
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Most important use of GnRH analog is in treatment of what disease
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Cancer (Prostate Cancer)
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Hormonal Control Therapy
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Treatment of cancers influenced by hormones (like prostate CA - 80% are androgen-dependent)
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Name a GnRH superagonist
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Leuprolide (Lupron)
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Name 3 GnRH superagonists
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1. Leuprolide
2. Nafarelin 3. Goserelin |
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Mechanism of leuprolide in prostate CA treatment:
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Reduce androgenic stimulation by stimulating and desensitizing GnRH receptors on pituitary gonadotrophs.
Prevents release of FSH and LH = reduce circulating testosterone levels |
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Medical Castration drug
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Leuprolide
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Pure GnRH antagonist
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Ganirelix (Antagon)
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Effect of Ganirelix (Antagon) on FSH/LH release
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Inhibits FSH/LH release without initial increase
Use in management of infertility, especially in IVF |
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What drug prevents premature LH surge?
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Ganirelix (Antagon)
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2 GnRH antagonists:
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1. Ganirelix (Antagon)
2. Abarelix |
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What molecular group do conjugated estrogens have?
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Sulfate
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Why are estrogens conjugated with sulfate?
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To allow hydrolysis by enzymes in lower gut to allow absorption of estrogens
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Premarin
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Conjugated estrogen derived from urine of pregnant mares
Used in HRT |
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Steroidal estrogens are hydrophilic or lipophilic?
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Lipophilic
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Lipophilicity of estrogens allows what mode of drug delivery to be possible?
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Transdermal patch
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Estrogens are/are not extensively bound to plasma proteins?
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Extensively bound to plasma proteins (>90%)
Binds to SSBG |
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Metabolism of estrogens
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Hepatic metabolism
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Clinical findings in male patient with hepatic dysfunction
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Feminization due to inability to metabolize estrogens
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Estradiol is/is not effective orally?
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Not effective orally:
1. First pass effect 2. Rapid T1/2 |
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Ethinyl estradiol
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Slower T1/2 (12-24 hours) than estradiol
Therefore orally effective |
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Mestranol
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Prodrug
Orally effective Quickly demethylated in body to ethinyl estradiol |
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Esterified (conjugated) estrogens, ethinyl estrogen, mestranol are drugs or prodrugs?
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Prodrugs
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What physiologic factor prolongs the T1/2 of ethinyl estradiol and all other estrogen prodrugs?
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Enterohepatic circulation
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Giving estrogens orally will have what effect on the liver?
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Intensify effects on liver
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Estrogen enters the cell and binds to what, where?
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Binds to Estrogen Receptor in nucleus of the cell
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Dimerized nuclear ER binds to what?
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Estrogen response element (ERE)
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Estrogen-ER unit is a "skeleton" for functional transcriptional unit. What else is needed?
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Cofactors
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What determines the nature of the functional estrogen transcription unit and enhances or inhibition?
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Estrogen-ER + Cofactors
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Estrogen receptors are found on many/single tissues?
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Many tissues:
Bone, heart, liver, CNS, vascular endothelium |
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Estrogen has positive/negative effects on bone mass and density?
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Positive effects (Decrease resorption)
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Estrogen effects on serum lipids
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Increased HDL and Decreased LDL (Good!)
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Estrogen effects on blood vessels
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Vasodilation and reduction of atherosclerosis
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Estrogen effects on fluid retention
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Increases fluid retention
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Estrogen effects on biliary function
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Increased cholesterol production + decreased bile acid secretion = increased gallstone formation risk
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Estrogen effect on amount of plasma hormone binding proteins:
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Increased plasma hormone binding proteins
(CBG, TBG, SSBG) |
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Estrogen effect on thrombosis
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Facilitate clot formation
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Estrogen effect on endometrium and what disease can result?
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Endometrial Cancer when given in post-menopausal women without a progestin
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If a fetus is exposed to estrogen in utero what two cancers are they at increased risk?
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1. Clear cell vaginal
2. Cervical adenocarcinoma |
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Diethylstilbestrol (DES)
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Orally active synthetic nonsteroidal estrogen
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Estrogen and breast cancer
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Increased incidence of breast cancer
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Can you give estrogens in pregnancy?
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No, never give estrogens in pregnancy.
Cause fetal abnormalities Increased risk of clear cell vaginal and cervical adenocarcinoma |
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Increased risk of thromboembolic disorders with estrogen (T/F)?
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True!
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Mechanism of increased gall bladder disease with estrogen use
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Estrogens increase cholesterol and decrease bile acids = promote gallstones
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Major endogenous estrogen in humans
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17beta-estradiol
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Mestranol (Premarin, Equilin)
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Precursor of ethinyl estradiol
Demethylated to become ethinyl estradiol From urine of pregnant mares |
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Ethinyl estradiol
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Longer T1/2 than estradiol (12-24 hours)
Orally active |
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Treatment regimen for post-menopausal hormone replacement therapy
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Estrogen + progestin to reduce endometrial hyperplasia and risk of endometrial carcinoma
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Treatment regimen for post-menopausal HRT in patient with hx of hysterectomy
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Estrogen alone
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HRT appears to increase/decrease risk of CV disease
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Increase risk of CV disease
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FDA recommendation for women using HRT
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At lowest effectve dose for shortest time necessary
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Phytoestrogens
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Non-steroidal compounds from plants with estrogen-like structure
Can have estrogenic or anti-estrogenic activity Not FDA regulated or approved |
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Clomiphene
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Competitive estrogen receptor antagonist
Treatment of breast cancer, prosatic, and endometrial cancer |
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Raloxifene
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Competitive estrogen receptor antagonist
Treatment of breast cancer, prosatic, and endometrial cancer |
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Tamoxifen
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Competitive estrogen receptor antagonist
Treatment of breast cancer, prosatic, and endometrial cancer |
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Drug of choice in treatment of breast cancer
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Tamoxifen
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Tamoxifen effects on bone density
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Increase bone density in post-menopausal women
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Adverse effects of tamoxifen
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Nausea
Vomiting Hot flashes |
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Estrogenic effects on cholesterol levels
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Lower LDL by inhibiting cholesterol synthesis
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