Estrogens and Antiestrogens Flashcards
Describe the HPG axis
- 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)
Which estrogen is the main secretory product of the ovary?
estradiol (E2)
Which estrogens are formed in liver or peripheral tissue?
- estrone (E1)
- estriol (E3)
Which estrogen is produced exclusively by fetal liver?
esterol (E4)
What is progesterone secreted by in nonpregnant women?
corpus luteum
What is progesterone secreted by in pregnant women?
- until 10 weeks: corpus luteum
- from 10 weeks on: placenta
What is the pathway of extraovarian steroidogenesis? Which enzymes are involved?
1) androstenedione (A) converted to E1 by aromatase
2) E1 converted to E2 by 17-beta-HSD
What peptide hormones are produced by the ovary? What are their functions? where are they produced?
- inhibin: suppress FSH; granulosa cells
- activin: enhance FSH; granulosa cells and pituitary gonadotrophs
What is the role of GnRH in the ovarian cycle?
main positive stimulator of FSH and LH release from ant pit (i.e. acts on ant pit)
What triggers ovulation? What are the phases of the ovarian cycle?
- ovulation triggered by surge in LH
- early follicular phase
- late follicular phase
- luteal phase
Describe the events of the early follicular phase.
- 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
Describe the events of the late follicular phase.
- 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
Describe the events of the luteal phase.
- 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
what are the phases of the uterine cycle and how do they correspond to the ovarian cycle?
- menses = first part of follicular phase
- proliferative phase = second part of follicular phase
- secretory phase = luteal phase
why does menses occur? (Hint: what is the main hormone involved?)
sharp decline in PROGESTERONE
Describe the events of the proliferative phase. (Hint: what is the main hormone involved?)
- endometrium adds cell layers due to the action of ESTROGENS
- estrogen makes mucus thinner (allows for penetration by sperm)
Describe the secretory phase. (Hint: what is the main hormone involved?)
corpus luteum produces PROGESTERONE which:
- limits endometrial growth
- increases endometrial secretion
- makes mucus thick (impedes sperm penetration)
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
- 1) primordial follicle
- 2) primary follicle
- 3) secondary follicle
- 4) tertiary follicle
- 5) Graafian follicle
- 6) corpus luteum
- 7) corpus albicans
At which developmental follicular stage is the ovarian follicle considered mature?
tertiary follicle
Describe the primordial follicle.
- single layer of granulosa cells
- single immature oocyte arrested in the first meiotic division
Describe the primary follicle.
- multilayered granulosa cells
- zona pellucida between oocyte and granulosa layer
Describe the secondary follicle.
- theca interna (adjacent to basal lamina)
- theca externa (merge with surrounding stroma)
Describe the tertiary follicle.
- hypertrophy of theca
- antrum (fluid-filed space among granulosa cells)
Describe the Graafian follicle.
- increase in size due to gonadotropins
- antral fluid increases in volume
- oocyte in eccentric position within follicle
- ready to release ovum
Describe the corpus luteum.
- formed from granulosa and theca cells that remain after ovulation
- transitory endocrine gland
Describe the corpus albicans.
- ovarian scar that forms after the corpus luteum degenerates (luteolysis)
- made of collagen
Effect of estrogens on brain?
neuroprotective
effect of estrogens on heart?
cardioprotective
effect of estrogens on vasculature?
vasodilation
effect of estrogens on adipose tissue?
influence adipogenesis and adipose tissue metabolism
effect of estrogens on bones?
- regulate bone turnover and growth
- prevent osteoporosis
effect of estrogen on skeletal muscle?
reduce skeletal muscle damage and inflammation
Which binding proteins do estrogens affect? How do they affect the binding protein levels
- corticosteroid-binding globulin (CBG)
- sex hormone-binding globulin (SHBG)
- thyroxine-binding globulin (TBG)
- INCREASE LEVELS
effect of estrogen on HDL and LDL?
increase HDL, decrease LDL
effect of estrogens in kidney?
salt and water retention
What are the 2 genomic mechanisms of action of estrogens?
- classical genomic signaling
-ligand-independent genomic actions
explain classical genomic signaling
- estrogen binds to ERs in cytoplasm
- complex dimerizes and translocate to nucleus
- transactivation/transrepression
- ER-alpha homodimer > ER-alpha/beta heterodimer > ER-beta homodimer
.Explain ligand-independent genomic actions
- growth factors activate protein-kinase cascades
- cause phosphorylation and activation of nuclear ERs at EREs
what are the 2 non-genomic mechanisms of action of estrogens?
- ER-independent signaling
- plasma membrane ER signaling
Explain ER-independent signaling.
E2 exerts antioxidant effects without ER
explain plasma membrane ER signaling.
- ligand binds to membrane ERs
- activate second messenger systems
- E2 interacts with GPER1 on endoplasmic reticulum
- activates effectors
phytoestrogens
exogenous; plant-derived
xenoestrogens
exogenous; synthetic in bottles, cans, etc.; potent endocrine disruptor
pharmacological use of estrogens?
- contraception
- menopausal hormonal therapy
- primary hypogonadism (hypo-ovarian)
- vaginitis
- prostate cancer
pharmacological use of antiestrogens?
- hormone-responsive breast cancer
- osteoporosis
- infertility
- polycystic ovary syndrome
pharmacological uses of SERMs and SERDs?
- breast cancer
- osteoporosis
adverse effects of estrogens?
- cancer risk
- thrombosis
- weight gain
- liver toxicity
- breast hypertrophy, gynecomastia (in men), galactorrhea
- nausea and vomiting
- depressive moods
List the following for clomiphene:
- class of drug
- MOA
- uses
- adverse effects
- 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
List the following for aromatase inhibitors:
- class of drug
- MOA
- uses
- adverse effects
- 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
Mechanism of action of selective estrogen receptor modulators (SERMs)? agonist vs antagonist?
- 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)
List the following for tamoxifen:
- class of drug
- antagonistic effect
- agonistic effect
- MOA
- uses
- adverse effects
- 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
List the following for raloxifene:
- class of drug
- antagonistic effect
- agonistic effect
- MOA
- uses
- adverse effects
- 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
What is the mechanism of action of selective estrogen receptor degraders?
bind to ER and induce its degradation
List the following for fulvestrant:
- class of drug
- MOA
- uses
- adverse effects
- 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
List the following for PROTAC:
- full name
- class of drug
- target receptor?
- MOA
- uses
- adverse effects
- name: proteolysis-targeting chimeras
- class: SERD
-target: ER-alpha - MOA: bind to ER –> ubiquitination –> degradation of the protein by proteasome (
List the following for PROTAC:
- full name
- class of drug
- target receptor?
- MOA
- uses
- adverse effects
- 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
Which enzyme is required to catalyze ubiquitylation in ER degradation?
E3 ligases
