Lecture 6: Menstrual Cycle Flashcards
(107 cards)
1
Q
What axis controls the menstrual cycle?
A
- HPO axis (Hypothalamic-Pituitary-Ovarian)
2
Q
What are the key requirements to maintain the HPO axis?
A
Pulsatile release of both:
- GnRH
- Gonadotrophins
3
Q
What are the gonadotrophins?
A
- LH
- FSH
(-hCG)
4
Q
Describe the HPO axis
A
5
Q
What determines the length of a menstrual cycle?
A
- number of days between first day of menstrual bleeding of one cycle to the onset of menses of the next cycle
6
Q
What are the characteristics of the normal menstrual cycle (MC)
A
- Median duration of MC is 28 days with most cycles between 25-30 days
- Menstruation lasts 3-8 days, written as 7/28 or 5-6/27-32
7
Q
What is the term when the MC is less than a certain number of days?
A
- MC<21 days
- polymenorrheic
8
Q
What is the term when the MC is greater than a certain number of days?
A
- MC>35 days
- oligomenorrheic
9
Q
When is MC most irregular typically?
A
- around extremes of reproductive life
- i.e menarche and menopause
10
Q
Describe/Draw the levels of steroids and gonadotrophin during a normal MC
A
11
Q
Describe the follicle and its size during a normal MC
A
12
Q
What is the corpus luteum?
A
Mass of cells (leftovers of the follicle), secreting mainly P and some E2:
- Granulosa cells
- Theca cells
13
Q
An increase in E2 levels leads to a …
A
- decrease in FSH levels
- negative feedback
14
Q
Where do we get the Progesterone in MC?
A
- Corpus luteum
15
Q
Where do we get the E2 from in the MC?
A
- Granulosa cells
16
Q
What causes recruitment of early antral follicles?
A
- intercycle rise of FSH
17
Q
What is the 2 cell 2 gonadotrophin theory?
A
Different enzymes in different cellular compartments
- Theca: enzymes predominately responsible for P & Androgen families
- Granulosa: production of E2
- LHR only - Theca
- FSHR (& LHR) - Granulosa
18
Q
Where and what drives androgen & progesterone production?
A
- Theca cells
- LH
19
Q
Where is E produced?
A
- Granulosa cells
20
Q
When is E produced?
A
- Follicular phase
21
Q
What drives E production?
A
- FSH
22
Q
Which steroids are made where?
A
23
Q
When is LHR acquired in the granulosa cell?
A
- From mid-follicular phase onwards in DF only
- After selection of dominant follicle; allows Dominant follicle to make P
24
Q
What is the function of the LHR in the granulosa cell?
A
- To produce Progesterone only
- after MF phase, will drive P and E production as well
25
Between Theca and GC, where is aromatase only found?
- Granulosa
26
What happens during the LL and EF phase of the MC?
- P declines
-> Selectively raises FSH (break from HPO axis is released due to decline in P)
= Inter-cycle rise in FSH
27
Why does P decline in the LL and EF phase?
- CL dies if no pregnancy thus decline in P
28
What is the significance of the inter-cycle rise in FSH?
- recruitment of the antral-follicles into the MC
29
What happens during the MF phase of the MC?
- E2 increases
-> Negative Feedback
= FSH falls -> Selection of dominant follicle
30
What causes the increase in E2?
- Antral follicles grow (i.e. GC grow) -> release E2 -> E2 levels increase -> exerts negative feedback -> FSH levels decrease
31
When does the LH surge occur?
- Mid-cycle
32
What requirements need to be fulfilled for the LH surge to occur?
- 2 days of E2; >300 pmol
33
What does 2 days of E2 > 300 pmol cause?
- Positive Feedback
- Thus LH surge
34
What causes the high E2 levels mid cycle?
- Dominant follicle
- As it grows quickly and expansively it pumps out E2
35
What does the LH surge cause?
- Ovulation
- Formation of CL
36
What happens to the antral follicles when FSH decreases?
- Die
- EXCEPT for dominant follicle
37
What occurs during the ML phase?
- High P due to High LH (LH surge)
-> Negative feedback
- P overcomes E2 (P always dominates of E2)
=Low FSH/LH
38
What is the cause of the high P in the ML stage?
- CL
39
What is the Follicular Phase?
- growth of follicles up to ovulation
- dominated by E2 production from follicles
40
What is the luteal phase?
- formation of CL from the empty follicle
- dominated by P production from CL
41
Which phase has a set number of days?
- Luteal phase
- 14 days
- Dominated by CL
42
What feedback occurs during Follicular Phase?
- VARIES
1. Release of -ive feedback from CL
2. -ive feedback then reinstated, then
3. Switch from -ive to +ive feedback
43
What feedback occurs during Luteal phase?
- Negative feedback
-> Progesterone
44
When does ovulation occur?
- end of Follicular phase
45
What becomes of the reminent of the follicle after ovulation?
- Becomes CL
46
What occurs at the end of Luteal Phase if no pregnancy?
- CL dies
-> Increase in FSH & MC restarts
47
What happens during the rise and fall of FSH during the follicular phase?
Rise:
- "window of opportunity": Recruitment of the growing follicles into the follicular stage
Fall:
- Increase in E2 -> Selection of one of these follicles (others die) -> DOMINANT FOLLICLE -> PREOVULATORY FOLLICLE -> OVULATES
48
Do all animals have the MC?
No, only:
- Humans
- Primates (apes and monkeys)
49
What do all mammals have in common?
- cyclical ovarian function
- Same reproductive system when it comes to HPG axis
- Produce mature egg and necessary sex steroids
50
What is the oestrus cycle?
- cyclic appearance of behavioural sexual activity (heat or oestrus)
51
Do animals that undergo oestrus menstruate?
No - endometrium reabsorbed if no fertilisation
52
What is day 0 of the oestrus cycle?
- First day of sexual receptivity
53
When does ovulation occur in animals that undergo oestrus?
- Early in cycle
- High E2 levels = stimulation of sexual behaviour & +ive feedback
54
Do all species that undergo oestrus have the same cycle length?
- No
55
What is poly-oestrus?
- In heat several times/year
- cats, cows, pigs
56
What is di-oestrus?
- Twice/year
57
What is mono-oestrus?
- One breeding season/year
- usually in spring (daylight)
- Bears, foxes, wolves
58
Which animal has no oestrus cycle?
- Rabbits
- Induced ovulates
- Induced to ovulate by mating & can conceive at any moment
59
HPO axis
60
What gonadal protein inhibits FSH directly? Where is it produced?
- Inhibin
- Sertoli cells in testes
- Granulosa cells in ovary
61
What is the structure of inhibin?
- Disulphide-linked protein dimers
- Common α-subunit with different β-subunits giving two forms of Inhibin
- Both forms suppress FSH secretion by pituitary
- Not affecting LH secretion
62
What gonadal protein stimulates FSH secretion?
- Activins
- Isolated from follicular fluid
63
What gonadal protein indirectly suppresses FSH secretion?
- Follistatin
- FSH-suppressing protein
- From follicular fluid
64
How does Follistatin work?
- binds activin with high affinity » neutralizes FSH-stimulating ability of activin
65
How do we know inhibin only works on FSH and not LH?
- Experiment: Using ovariectomized (ovx) sheep, GnRH agonist was injected in the presence and absence of inhibin
66
Why did they use ovx sheep?
- Mono-ovulators
- similar to humans
- Sheep are a good model for reproduction
- otherwise mice due to limitations when it comes to sheep (expense/storage etc.)
67
What does overiectomised (ovx) mean?
- Removal of ovaries
68
Why were ovx sheep used?
- Prevent the endogenous feedback effects interfering
69
Why did the experiment inject GnRH agonist?
- stimulate gonadotrophin production
70
Biosynthesis of inhibins and activins occurs from how many genes?
- 3
71
What are the TGFβ- superfamily of precursor proteins involved in?
3 genes encoding for:
- α- protein (specific for inhibin)
- βA- protein,
- βB- protein,
These alpha and beta subunits are all members of TGF-beta superfamily of proteins.
72
The genes encode for larger precursor proteins which are then processed... (activin/inhibin genes)
proteolytically
73
What are the isoforms of inhibin?
- Inhibin A
- Inhibin B
74
What are the isoforms of activin?
- Activin A (βA-homodimer),
- Activin B (βB-homodimer)
- Activin AB (βAβB-heterodimer)
75
How are inhibin and activin produced?
- The gene products are the sub-units which will combine at the time of release from the cell.
76
How is the amount of activin and inhibin determined during MC and folliculogenesis?
- Ratio of Activin:Inhibin
77
Where is inhibin and activin produced in females?
- Granulosa cells
78
When do activins dominate in the MC?
- EFP
- Correlates with high FSH
79
When do inhibins dominate in the MC?
- LFP
- Correlates with decreased FSH
80
Which hormone aids the inter-cycle rise in FSH?
- Activin
81
What does the inter-cycle rise in FSH cause?
- recruits early antral follicles
82
What is the significance of inhibin on the MC?
- Rise in E2
- Fall in FSH
83
What happens to the levels of activin and inhibin as we go through folliculogenesis?
- Inhibin production increases
- Activin produced decreases
84
Describe the experimental procedure that questioned what happens when inhibin is blocked?
- (Red) Inject rats in the late antral phase with Inhibin anti-serum
- = blocks inhibin from working as it has antibodies that bind to and prevent it from working
- Red = increase in FSH
- (Green) Inject with normal serum = no peak of FSH (as you’d expect at this stage of MC)
= thus showed that in Late Antral phase, inhibin needed for fall in FSH; NOT ONLY E2!!
85
? + ? = Fall in FSH
E2 + Inhibin = Fall in FSH
86
What are the main hormones in the TGFBeta superfamily?
- Inhibin
- Activin
- AMH
87
What is AMH?
- Anti-Mullerian Hormone
- glycoprotein
- member of TGFBeta superfamily
88
What is the importance of AMH in males?
- expressed from week 8 of development
- causes regression of Müllerian ducts by a wave of apoptosis.
89
Do females express AMH?
Yes
90
Where is AMH expressed in females?
- ovarian granulosa cells
91
Do AMH levels peak in females, and if so, where?
- levels peaking in selectable follicles (large preantral & small antral follicles)
--> then decreases
92
Has AMH been detected elsewhere? (other than preantral and small antral follicles)
Yes
- Prenatal follicles
- However variable and may be species variable
93
What is the role of AMH in the MC?
- regulator of normal follicle growth and development
94
What is the function of AMH?
- Inhibits transition from primordial to primary follicles
- Inhibits FSH-dependent cyclical recruitment of follicles
-> by inhibiting FSH-stimulated aromatase & FSHr expression → in normal MC, prevents over-recruitment of growing follicles
95
What is the function of FSH?
- To drive follicle growth
- Recruiment of antral follicles into MC
- stimulates aromatase
96
What does AMH inhibit?
- The function of FSH
97
What does AMH prevent in the normal MC?
- over-recruitment of growing follicles
= AMH maintains a balance
98
What is the problem with over-recruitment of follicles?
- Depletion of follicles quicker
-> early menopause
99
Where do inhibins and alctivins act on?
- Anterior Pituitary ONLY
100
Where to E2 and P act on?
- Hypothalamus
- A. Pituitary
101
What is the 'window of opportunity' & follicle selection?
- Raised FSH present a “window” of opportunity
- FSH threshold hypothesis
- One follicle from the group of antral follicles in ovary is just at the right stage at the right time….
- Becomes DOMINANT follicle -> survives fall in FSH & goes onto ovulate
- Known as “selection”
- Can be in either ovary
- E2 levels rise reinstating -ive feedback at pituitary -> FSH levels fall = prevents further follicle growth
102
How does the dominant follicle survive the fall in FSH?
- As FSH falls, LH increases.
- Dominant follicle acquires LH receptors on granulosa cells.
- Other follicles do not, so they loose their stimulant and die.
103
How are the gonadotrophin receptors distributed in follicles? Thus, what steroids are produced?
Granulosa:
- FSHr
- LHr from mid-follicular phase onwards in DF
- FSH drives E2 production in FP; LH drives P ONLY (no androgens) in LP
Theca:
- LHr ONLY
- P and androgen production
104
- Inhibin B: highest in early-mid FP (ratio of activin: inhibin) and declines in LFP (small peak at LH surge), zero in luteal phase.
- decline in Inhibin A at end of L phase allows for increase in FSH.
Inhibin A: increases in late FP with highest levels in L phase (being made by CL) – contributes to inhibition of FSH in this phase.
- Decline in Inhibin A at end of L phase allows for increase in FSH.
- Activin High = FSH High
- E2 rises via -ive feedback = inhibit B which contrinbutes to this -ive feedback
105
Are E2 and P the only factors affecting the HPO axis?
No!!
106
Are the gonadal steroid hormones only acting on the follicles?
NO!!
- Acting elsewhere in the female reproductive tract - everything has to be ready for both transport of fertilised egg and sperm!
107
Other than the follicles, what else are the steroid hormones acting on?
E2, P and (Androgens?) are acting on:
- Endometrium
- Oviduct/Fallopian tubes
- Cervix
- Vagina - changes in vaginal epithelial cells
