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PMCOL 343 > Estrogens and Antiestrogens > Flashcards

Estrogens and Antiestrogens Flashcards

1
Q

Describe the HPG axis

A
  • GnRH from hypothalamus (+) FSH and LH from anterior pituitary
  • LH binds to theca/Leydig cells to increase expression of StAR
  • sex hormones synthesized and released from ovaries/testicles (negative feedback at hypothalamus, anterior pituitary, ovaries/testicles)
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2
Q

Which estrogen is the main secretory product of the ovary?

A

estradiol (E2)

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3
Q

Which estrogens are formed in liver or peripheral tissue?

A
  • estrone (E1)
  • estriol (E3)
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4
Q

Which estrogen is produced exclusively by fetal liver?

A

esterol (E4)

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5
Q

What is progesterone secreted by in nonpregnant women?

A

corpus luteum

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6
Q

What is progesterone secreted by in pregnant women?

A
  • until 10 weeks: corpus luteum
  • from 10 weeks on: placenta
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7
Q

What is the pathway of extraovarian steroidogenesis? Which enzymes are involved?

A

1) androstenedione (A) converted to E1 by aromatase
2) E1 converted to E2 by 17-beta-HSD

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8
Q

What peptide hormones are produced by the ovary? What are their functions? where are they produced?

A
  • inhibin: suppress FSH; granulosa cells
  • activin: enhance FSH; granulosa cells and pituitary gonadotrophs
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9
Q

What is the role of GnRH in the ovarian cycle?

A

main positive stimulator of FSH and LH release from ant pit (i.e. acts on ant pit)

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10
Q

What triggers ovulation? What are the phases of the ovarian cycle?

A
  • ovulation triggered by surge in LH
  • early follicular phase
  • late follicular phase
  • luteal phase
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11
Q

Describe the events of the early follicular phase.

A
  • granulosa cells secrete activin
  • activin stimulates FSH production by ant pit
  • increase FSH receptors on granulosa cells
  • decrease androgen production by theca cells
  • high FHS stimulate follicle growth
  • mature follicle develops and switches from activin to inhibin
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12
Q

Describe the events of the late follicular phase.

A
  • granulosa cells on mature/dominant follicle secrete inhibin
  • decrease FSH production by ant pit
  • increased LH leads to production of androgens by theca cells
  • androgens converted to estrogens
  • increase estrogens leads to: increase FSH receptors on follicles, neg feedback on pit to reduce FSH production, increase LH receptors on granulosa cells
  • LH SURGE
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13
Q

Describe the events of the luteal phase.

A
  • surge in LH stimulates conversion to corpus luteum
  • corpus luteum secretes progesterone and estrogen
  • negative feedback on hypothalamus and hypophysis
  • decrease GnRH, FSH, LH
  • IMPLANTATION: hCG maintains corpus luteum, increase progesterone, endometrium maintained
  • NO IMPLANTATION: degenerate corpus luteum, decrease progesterone, GnRH/FSH/LH reinitiate cycle
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14
Q

what are the phases of the uterine cycle and how do they correspond to the ovarian cycle?

A
  • menses = first part of follicular phase
  • proliferative phase = second part of follicular phase
  • secretory phase = luteal phase
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15
Q

why does menses occur? (Hint: what is the main hormone involved?)

A

sharp decline in PROGESTERONE

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16
Q

Describe the events of the proliferative phase. (Hint: what is the main hormone involved?)

A
  • endometrium adds cell layers due to the action of ESTROGENS
  • estrogen makes mucus thinner (allows for penetration by sperm)
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17
Q

Describe the secretory phase. (Hint: what is the main hormone involved?)

A

corpus luteum produces PROGESTERONE which:

  • limits endometrial growth
  • increases endometrial secretion
  • makes mucus thick (impedes sperm penetration)
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18
Q

Arrange the following in order of earliest to latest in the ovarian cycle:

  • primary follicle
  • primordial follicle
  • Graafian follicle
  • tertiary follicle
  • corpus albicans
  • secondary follicle
  • corpus luteum
A
  • 1) primordial follicle
  • 2) primary follicle
  • 3) secondary follicle
  • 4) tertiary follicle
  • 5) Graafian follicle
  • 6) corpus luteum
  • 7) corpus albicans
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19
Q

At which developmental follicular stage is the ovarian follicle considered mature?

A

tertiary follicle

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20
Q

Describe the primordial follicle.

A
  • single layer of granulosa cells
  • single immature oocyte arrested in the first meiotic division
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21
Q

Describe the primary follicle.

A
  • multilayered granulosa cells
  • zona pellucida between oocyte and granulosa layer
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22
Q

Describe the secondary follicle.

A
  • theca interna (adjacent to basal lamina)
  • theca externa (merge with surrounding stroma)
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23
Q

Describe the tertiary follicle.

A
  • hypertrophy of theca
  • antrum (fluid-filed space among granulosa cells)
24
Q

Describe the Graafian follicle.

A
  • increase in size due to gonadotropins
  • antral fluid increases in volume
  • oocyte in eccentric position within follicle
  • ready to release ovum
25
Q

Describe the corpus luteum.

A
  • formed from granulosa and theca cells that remain after ovulation
  • transitory endocrine gland
26
Q

Describe the corpus albicans.

A
  • ovarian scar that forms after the corpus luteum degenerates (luteolysis)
  • made of collagen
27
Q

Effect of estrogens on brain?

A

neuroprotective

28
Q

effect of estrogens on heart?

A

cardioprotective

29
Q

effect of estrogens on vasculature?

A

vasodilation

30
Q

effect of estrogens on adipose tissue?

A

influence adipogenesis and adipose tissue metabolism

31
Q

effect of estrogens on bones?

A
  • regulate bone turnover and growth
  • prevent osteoporosis
32
Q

effect of estrogen on skeletal muscle?

A

reduce skeletal muscle damage and inflammation

33
Q

Which binding proteins do estrogens affect? How do they affect the binding protein levels

A
  • corticosteroid-binding globulin (CBG)
  • sex hormone-binding globulin (SHBG)
  • thyroxine-binding globulin (TBG)
  • INCREASE LEVELS
34
Q

effect of estrogen on HDL and LDL?

A

increase HDL, decrease LDL

35
Q

effect of estrogens in kidney?

A

salt and water retention

36
Q

What are the 2 genomic mechanisms of action of estrogens?

A
  • classical genomic signaling
    -ligand-independent genomic actions
37
Q

explain classical genomic signaling

A
  • estrogen binds to ERs in cytoplasm
  • complex dimerizes and translocate to nucleus
  • transactivation/transrepression
  • ER-alpha homodimer > ER-alpha/beta heterodimer > ER-beta homodimer
38
Q

.Explain ligand-independent genomic actions

A
  • growth factors activate protein-kinase cascades
  • cause phosphorylation and activation of nuclear ERs at EREs
39
Q

what are the 2 non-genomic mechanisms of action of estrogens?

A
  • ER-independent signaling
  • plasma membrane ER signaling
40
Q

Explain ER-independent signaling.

A

E2 exerts antioxidant effects without ER

41
Q

explain plasma membrane ER signaling.

A
  • ligand binds to membrane ERs
  • activate second messenger systems
  • E2 interacts with GPER1 on endoplasmic reticulum
  • activates effectors
42
Q

phytoestrogens

A

exogenous; plant-derived

43
Q

xenoestrogens

A

exogenous; synthetic in bottles, cans, etc.; potent endocrine disruptor

44
Q

pharmacological use of estrogens?

A
  • contraception
  • menopausal hormonal therapy
  • primary hypogonadism (hypo-ovarian)
  • vaginitis
  • prostate cancer
45
Q

pharmacological use of antiestrogens?

A
  • hormone-responsive breast cancer
  • osteoporosis
  • infertility
  • polycystic ovary syndrome
46
Q

pharmacological uses of SERMs and SERDs?

A
  • breast cancer
  • osteoporosis
47
Q

adverse effects of estrogens?

A
  • cancer risk
  • thrombosis
  • weight gain
  • liver toxicity
  • breast hypertrophy, gynecomastia (in men), galactorrhea
  • nausea and vomiting
  • depressive moods
48
Q

List the following for clomiphene:
- class of drug
- MOA
- uses
- adverse effects

A
  • class: antiestrogen
  • MOA: block ER in pituitary and hypothalamus (ER antagonist)
  • uses: induce ovulation in women with a functional HPO axis (i.e. treat infertility, amenorrhea, PCOS)
  • adverse effects: ovarian enlargement, ovarian cysts, hot flashes, blurred vision, multiple births
49
Q

List the following for aromatase inhibitors:
- class of drug
- MOA
- uses
- adverse effects

A
  • class: antiestrogen
  • MOA: inhibit aromatase –> inhibit estrogen synthesis
  • uses: first-line treatment of breast cancer
  • NO increase in risk of uterine cancer or blood clots
50
Q

Mechanism of action of selective estrogen receptor modulators (SERMs)? agonist vs antagonist?

A
  • selective agonist/antagonist effects on various estrogen target tissues
  • pure agonist = enable interaction of ER with CoA (activator)
  • pure antagonist = allow ER to interact only with CoR (repressor)
51
Q

List the following for tamoxifen:
- class of drug
- antagonistic effect
- agonistic effect
- MOA
- uses
- adverse effects

A
  • class: SERM
  • antagonistic effect: breast tissue
  • agonistic effect: uterus/bone/heart
  • MOA: PRODRUG converted to ENDOXIFEN by Cyp450; modulation of signaling proteins and activation of apoptosis
  • uses: breast cancer, osteoporosis
  • adverse effects: uterine cancer, blood clots
52
Q

List the following for raloxifene:
- class of drug
- antagonistic effect
- agonistic effect
- MOA
- uses
- adverse effects

A
  • class: SERM
  • antagonistic effect: breast tissue proliferation
  • agonistic effect: N/A
  • MOA: modulation of signaling proteins and activation of apoptosis?
  • uses: breast cancer; osteoporosis
  • adverse effects: NO increased endometrial cancer risk; increase blood clot risk
53
Q

What is the mechanism of action of selective estrogen receptor degraders?

A

bind to ER and induce its degradation

54
Q

List the following for fulvestrant:
- class of drug
- MOA
- uses
- adverse effects

A
  • class: SERD
  • MOA: bind to ER in monomeric form –> prevent dimerization of ER –> increase ER degradation through ubiquitin-proteasome pathway
  • uses: inhibit growth of tamoxifen-resistant tumors in breast cancer
  • adverse effects: N/A
55
Q

List the following for PROTAC:
- full name
- class of drug
- target receptor?
- MOA
- uses
- adverse effects

A
  • name: proteolysis-targeting chimeras
  • class: SERD
    -target: ER-alpha
  • MOA: bind to ER –> ubiquitination –> degradation of the protein by proteasome (
56
Q

List the following for PROTAC:
- full name
- class of drug
- target receptor?
- MOA
- uses
- adverse effects

A
  • name: proteolysis-targeting chimeras
  • class: SERD
    -target: ER-alpha
  • MOA: bind to ER –> ubiquitination –> degradation of the protein by proteasome
  • uses: breast cancer
  • adverse effects: N/a
57
Q

Which enzyme is required to catalyze ubiquitylation in ER degradation?

A

E3 ligases

PMCOL 343 (27 decks)

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