9. Oestrogen And Anti-Oestrogens Flashcards
Describe the structure of the breast
- adipose tissue surrounds duct/lobule systems.
- lobule contains alveoli
- alveoli is made up of a milk-containing lumen, rounded by epithelial cells.
- myoepithelial cells line the ductules.
- capillaries surround alveoli
- ampulla carries milk from ducts out the nipple (lactiferous duct)
What hormones in the menstural cycle does the pituitary gland secrete?
FSH / LH
Which hormone increases womb wall lining?
Progesterone
What is the predominant intracellular oestrogen?
17b-estradiol (E2)
What cells secrete E2 during the menstrual cycle?
Granulosa cells in the ovary
What does the hypothalamic pituitary-ovarian (HPO) axis regulate?
The ovarian production of oestrogen
Which enzyme mediates oestrogen biosynthesis in post menopausal women?
What tissues is this enzyme found in?
Aromatase, found in adipose tissue mainly, also in liver & adrenal glands
At what points of the menstrual cycle do these hormones peak:
- progesterone
- estrogen
- testosterone
- P: slightly during follicular, highly mid-luteal
- E: highly just before ovulation/end of follicular, and during luteal. It is very low during menstruation
- T: during ovulation
Describe the changes in hormones during the menstrual cycle
- E2 production rises 8-10 fold during ovulation
- LH and FSH are released in response to GnRH at the end of follicular phase, ~day 13
- LH stimulates androgen production. FSH upregulates aromatase, converting androgen to estrogen.
- High levels of oestrogen act via negative feedback to dampen oestrogen production, inhibiting GnRH, LH, and FSH
- Cycle continues
When is swelling/tenderness of the breast most and least prominent during the menstrual cycle?
- Most: during the second half
- Least: 7-10 days after the beginning of the menses
How do oestrogen and progesterone affect breast changes during the menstrual cycle?
- Oestrogen: mammary ducts enlarge and proliferate during luteal phase (stimulate duct growth)
- Progesterone: growth of lobules and alveoli, breasts increase in size, tenderness, and retain more fluid (stimulate secretory alveoli formation)
Describe the breast pathology during phase 1-4 of the menstrual cycle
-1: distinction between epithelial/myoepithelial is not clear
-2: increase in distinction
-3: larger lobules with increased number of terminal duct units
-4: extensive vacuolation within lobules (fluid collection/retention)
What does GnRH stand for?
Gonadotropin-Releasing Hormone
What is another name for aromatase?
What enzyme family does it belong to?
CYP19A1
Cytochrome P450 family
What stimulates the conversion of androgens to estrogen in:
- premenopausal women
- postmenopausal women
- Premenopausal: Gonadotropins (LH & FSH) stimulate ovary to produce estrogen from androgens via aromatase enzyme
- Postmenopausal: Adrenocorticotropic hormon (ACTH) stimulates adrenal gland to produce estrogen from androgens via aromatase
How does oestrogen cause the synthesis of ER associated proteins?
Oestrogen binds to ER
Homodimers bind to DNA
Activate ER regulated genes
Synthesis of ER associated proteins that can change cell behaviour
What are the 2 was to activate estrogen?
- Through estradiol direct binding to ERa
- Through dimeristation of Her2/3, IGFR, EGFR, causing phosphorylation of ERa
T or F: 70% of breast tumours show high expression of ER
true
What kind of prognosis is high expression of ER associated with?
- Negative nodal status (no spread)
- Low tumour grade
- Correlates with improved overall survival and disease-free survival
- Well differentiated
What are the 2 types of endocrine therapy against oestrogen?
A) anti-oestrogen: competitive binding, blocks estradiol signalling
B) oestrogen deprivation: aromatase inhibitors block conversion of androgen to estrogen
What % of ER+ tumours respond to endocrine treatment?
60%
What does SERM stand for?
Selective estrogen-receptor modulator
Describe the mechanism of tamoxifen
- Binds to ER, leads to dimerisation
- Conformational change in the activating function-2 (AF2) domain of ER and binding to oestrogen-response elements (EREs)
- Leads to persistent bye less efficient transcription of oestrogen-dependent genes
T or F: tamoxifen induces a conformational change of ER that switches off transcription of ER-dependent genes
F: the conformational change of tamoxifen is different from E2
Leads to less efficient transcription of genes, doesn’t completely switch off
