Menstrual Cycle I Flashcards
What is the key requirement to maintain the HPG axis?
➝ pulsatile release of both GnRH and gonadotrophins
(Pulsatile GnRH release + Pulsatile/regular gonadotrophin release)
How to calculate the length of the menstrual cycle?
Menstrual cycle length = The number of days between the first day of menstrual bleeding of 1 cycle to the first day of menstrual bleeding of the next cycle
What is the median duration of the MC?
➝ 28 days
How long does menstruation last?
➝ 3-8 days
What is a menstrual cycle of <21 days classed as?
➝ polymenorrheic
What is a menstrual cycle of >35 days classed as?
➝ oligomenorrheic
When is the menstrual cycle most irregular?
➝ during extremes of reproductive life - menarche and menopause
Where does oestrogen production occur and why?
In the granulosa cells of follicles(in ovaries) bc they express aromatase
aromatase converts androgens➝oestrogen
What is the purpose of the intercycle rise in FSH?
Intercycle rise in FSH recruits early antral folls into menstrual cycle
↓ in FSH allows selection of DF (bc rest of the recruited early antral folls die off through follicle atresia, DF survives this fall in FSH bc the foll that is selected to become the DF is the foll w the most FSHr)
Describe the graph
-First rise = intercycle rise in FSH = recruits early antral follicles
-Pink = oestradiol from follicle granulosa cells
-Oestradiol ↑ = exerts neg fb = FSH ↓
-↓ FSH allows for selection of DF
-Red = LH surge
-Increased prog during LP
↑ progesterone from Corpus Luteum
-CL = follicle remnant (leftover of GCs + theca cells) after COC has been ovulated
Which cells are the source of oestradiol?
Granulosa cells of the follicle
-Oestrogen dominates in follicular phase
Which hormone dominates the luteal phase of the cycle?
+ What is the source of this hormone?
Progesterone
CL in luteal phase produces progesterone
Describe the hormones starting from the end of the luteal phase and ending at the formation of the corpus luteum
➝ LP: CL produces prog. ↑ prog = neg fb = ↓ LH,FSH
➝ CL survives 14 days, then dies = prog levels ↓ = removes neg fb = ↑ FSH release = intercycle rise in FSH = recruits early antral follicles.
➝Folls respond to FSH and grow + produce ↑ oestrogen (follicular phase)
➝ ↑ estrogen = neg fb = FSH ↓ = allows selection of DF. (as FSH drops, early antral folls die except the foll w the most FSHr = survives the fall in FSH)
➝DF survives the fall in FSH and exponentially grows, producing lot of oestrogen.
➝sustained elevated oestrogen>200pmol for 48hrs triggers switch from neg->pos fb = ↑ LH = triggers LH surge = triggers ovulation = COC is ovulated out of foll = foll becomes CL (foll remnant, luteinisation)
➝ CL produces prog ………(= neg fb, intercycle rise)
2-cell 2-gonadotropin theory
-LH Rs on theca cell, FSH Rs on granulosa cell - Theca cells and granulosa cells have 2 diff Rs to respond to the gonadotropins
-+ diff enzymes are present in both theca and granulosa for conversion.
➝Theca: enzymes to produce progesterone + androgens
➝Granulosa: Androgens -> Oestrogen. Bc Aromatase is only present in granulosa (not theca)
➝CL has both granulosa and theca cells = produces both androgens + oestrogen. But 1 type of follicle will acquire certain enzymes to make progesterone.
slide 6
What phase in females involves negative feedback?
Luteal phase - progesterone always produces neg fb
Explain the Menstrual Cycle, starting Late Luteal phase
slide 7
All mammals have ……….. ovarian function & the same …………….. to produce ………………….
-cyclical
-reproductive system (HPG axis)
-a mature egg and the necessary sex steroids
What is the menstrual cycle and which species have it?
Menstrual cycle = regular menses (shedding of endometrial lining)
➝ humans + primates (apes, monkeys)
What is the oestrous cycle?
Oestrus cycle = cyclical occurence of sexual behaviour + activity (due to hormone changes).
-During oestrus: heightened sexual activity + receptive to sexual activity
➝ oestrus/heat
➝ no menstruation – endometrium is reabsorbed if fertilization does not occur (endometrial lining not shed)
What is day 0 of the oestrous cycle?
first day of sexual receptivitiy
When does ovulation occur in the oestrous cycle?
➝ early in the cycle
bc high oestrogen stimulates sexual behaviour + exerts pos fb = ovn
What does high estrogen cause in the estrous cycle?
➝ high estrogen stimulates sexual behaviour + exerts pos fb = ovulation
Which species are poly-estrous and what does this mean?
➝ have multiple oestrous cycles/yr - cats, cows, pigs
go into heat + mate + breed several times/yr
Which species are mono-estrous and what does this mean?
Monoestrous animals have only 1 oestrous cycle/yr
➝usually in spring - dogs, foxes, wolves
mate and breed only once/yr
Draw the hypothalamic-pituitary-ovarian axis
How do rabbits ovulate?
induced ovulators - are induced to ovulate by mating (sexual penetration) and can conceive at any arbitrary moment.
What is a seasonal polyoestrus?
Seasonal polyoestrus: Only cycles during a specific season, in response to specific environmental cues e.g. ↑/↓ light hours
-Long day breeders - spring/summer
-Short day breeders - autumn/winter
e.g. sheep, goats, deer
Scientists postulated that other gonadal factor beyond oestrogen/progesterone is involved in fb + regulation of FSH secretion
Inhibin, Activin & Follistatin
Where is inhibin produced?
➝ Sertoli cells (testis)
➝ Granulosa cells (ovary)
What is the structure of inhibin?
➝ protein dimers linked by disulfide bonds; heterodimer
➝2 diff forms of inhibin - Inhibin A + Inhibin B
Inhibin A: Common α subunit + βA subunit
Inhibin B: Common α subunit + βB subunit
Have common α subunit + diff beta subunit(confers specificity)
What do both forms of inhibin do?
Inhibin suppresses FSH secretion by ant pituitary without affecting LH secretion
Inhibin produced by granulosa cells/Sertoli cells + act on ant pit to inhibit FSH secretion
How do we know that inhibin selectively acts on/inhibits FSH and not LH? (experiment)
IMPORTANT KIND OF THING TO THINK ABOUT IN Y3
➝ Experiment done on ovariectomized sheep - to prevent endogenous fb interfering
➝Injected GnRH agonist in presence + absence of inhibin
➝ GnRH agonist alone = stimulated LH production
➝ GnRH agonist + Inhibin = stimulated LH production
➝ GnRH agonist alone = stimulated FSH production
➝ GnRH agonist + Inhibin = did not stimulate FSH production
= Inhibin completely suppresses FSH release - Inhibin is selective for FSH bc no effect on LH (inhibin did not suppress LH)
slide 13
What are the precursor proteins for activins and inhibins?
Biosynthesis of inhibins and activins occurs from 3 genes, makes precursor protein:
➝ α - protein chain - specific for inhibin
➝ βA – protein can form either activin/inhibin
➝ βB – protein can form either activin/inhibin
How many isoforms does inhibin have and what are they?
2 isoforms: Inhibin A and Inhibin B
named after the beta sub chain:
Inhibin A = α chain + βA chain
Inhibin B = α chain + βB chain
How many isoforms does activin have and what do they depend on?
Activin = 3 isoforms, depends on β-chain composition
➝ Activin A (βA - homodimer)
➝Activin B (βB homodimer)
➝ Activin AB (βAβB - heterodimer)
slide 14, slide 15
Activin has no …… chain
alpha
What is the role of activins?
Activins always stimulate FSH
What is the role of inhibins?
Inhibins always inhibit FSH
What superfamily are the inhibin and activin protein subunits a part of?
➝ TGFβ superfamily
What is the function of activin?
Activin stimulates/activates FSH secretion
What do activins correlate with?
➝ an ↑ in FSH in the early follicular phase(intercycle rise in FSH)
What do inhibins correlate with?
➝ a ↓ in FSH in the Late Follicular Phase(after intercycle rise in FSH)
➝inhibins peak in the luteal phase (↓ FSH levels throughout luteal phase)
What are activins and inhibins released by?
➝ granulosa cells
➝ Sertoli cells
What does Follistatin do?
Follistatin indirectly suppresses FSH - binds + inhibits activin
-Binds activin with high affinity
-Neutralizes FSH-stimulating ability of activin
What can follistatin do to activin?
➝ bind to activin and reduce its activity
What is the activity of activins regulated by?
➝ how much follistatin is present in the follicular fluid
What are the levels of activins and inhibins like during antral follicle growth?
➝ Follicle growth in early antral follicle phases = ↑ activin levels; activin gradually declines
➝ Moving towards Selection stages of the antral follicle = ↑ inhibin levels (neg fb on FSH release)
Follicle Stage and Production of Activin/Inhibin:
➝It’s not just activin/inhibin, but the ratio during the cycle during folliculogenesis
➝Produced by granulosa cells, in diff amounts as follicles develop
➝Early follicle = activins dominate
➝Intercycle rise in FSH, recruiting early antral follicles – aided by activin production.
➝As follicles produce oestrogen, neg fb = inhibits FSH – aided by inhibin production (dominates as you move through folliculogenesis)
➝Activin:Inhibin ratio
slide 16
What determines sensitivity to FSH?
➝ the ratio of activin : inhibin
What happens to FSH in the late follicular phase and why?
➝ FSH ↓ in late follicular phase bc recruited early antral folls are producing oestrogen = neg fb = ↓ FSH (aided by inhibins)
➝ ↓ FSH in late follicular phase to allow for selection of DF
What predominates in late follicular phase?
Inhibins
What predominates in early follicular phase?
Activins
How do we know that inhibins help reduce FSH (inhibins inhibit FSH release) in the late follicular phase?
➝Rats in late follicular phase produce inhibin(endogenously).(inhibin A)
➝Inject rats w inhibin antiserum = inhibin Abs bind + inhibin inhibin = FSH ↑
➝ Inject rats w control serum(NRS) = FSH ↓
Shows that in late follicular phase, inhibin production contributes to the ↓ in FSH
[you need both oestrogen(neg fb) + inhibin to inhibit FSH (↓ FSH)]
slide 17
What is the function of inhibin?
➝ contribute to the drop in FSH which is needed to allow for selection of the DF in late follicular phase
What is AMH and what superfamily is it part of?
➝ a glycoprotein
➝ TGF beta superfamily
When is AMH expressed in males?
➝ 7th gestational week
➝ causes regression of Mullerian ducts by a wave of apoptosis
What does AMH do in males?
➝ causes regression of Mullerian ducts by a wave of apoptosis in 7th gestational week
Where is AMH expressed in females and when do the levels peak?
➝ expressed in ovarian granulosa cells
➝ levels peak in selectable follicles (large preantral and small antral) then decreases
➝ AMH highly expressed in (small) early antral folls; Low AMH expression in large preovulatory follicles
Which follicle produces high levels of AMH?
➝ in the small (early) antral follicles and then dies off as the follicle size progresses (through folliculogenesis)
AMH levels peak when you go from large preantral follicles to small antral follicles (selectable follicles)
AMH distribution in follicles
↑ AMH in small early antral follicles
↓ AMH in large preovulatory follicles
slide 19
What are the 2 functions of AMH?
➝ AMH inhibits initiation/activation of primordial folls ->primary follicles
➝ AMH inhibits cyclical recruitment of early antral folls(FSH-dependent) by inhibiting FSHr expression +FSH-stimulated aromatase
(In the normal cycle, AMH prevents over-recruitment of growing follicles)
slide 20
What is the evidence that AMH inhibits the transition from primordial to primary follicles?
Knock out AMH from mice = all resting primordial follicles activated + started to grow (from experimental evidence)
= AMH prevents activation of resting primordial follicles->primary follicles
Where does AMH come from and how does it act?
➝ the surrounding growing follicles (GCs)
➝ it acts in a paracrine way on the primordial follicles
How does AMH work in women?
➝AMH reduces FSHr expression and FSH-stimulated aromatase = reduces follicle sensitivity to FSH
➝(FSH causes follicles to grow)
➝ AMH inhibits FSH-dependent cyclical recruitment of growing follicles
_______________________________________________
➝ AMH inhibits initiation/activation of primordial folls ->primary follicles
➝ AMH inhibits cyclical recruitment of early antral folls(FSH-dependent) by inhibiting FSHr expression +FSH-stimulated aromatase
(In the normal cycle, AMH prevents over-recruitment of growing follicles)
AMH acts to prevent ………….
➝ AMH prevents over-recruitment of growing follicles
➝ you don’t want all the follicles to grow fast or you will deplete the ovarian reserve and enter menopause early
What are the hypothesized mechanisms of action of AMH?
➝ AMH reduces follicle sensitivity to FSH thereby inhibiting aromatase mRNA expression and activity
➝ AMH production surrounding larger follicles(paracrine action) inhibits primordial follicle initiation
__________________________________________
-AMH inhibits initation/activation of primordial folls->primary folls
-AMH inhibits cyclical recruitment of folls (FSH-dependent) by inhibiting FSH-stimulated aromatase + FSHr expression
Removal of which factor allows Resting Primordial Folls to activate to become Primary folls(initiation)?
AMH
What receptors are found in the theca layer?
➝ AMHR2 (but unknown function)
When does preantral growth occur?
What types of follicles need FSH to grow?
➝ antral follicles that have reached 1-2mm
➝ with good vasculature
-FSH plays a key role in antral follicle development
-Primordial folls = FSH-dependent
What follicles respond to the intercyle rise in FSH?
➝ the follicles which have an antrum and good theca vasculature
What do antral follicles produce and what effect does this have?
➝ estrogen
➝ neg fb = FSH ↓
➝ causes selection of the dominant follicle = all the other follicles die
What do the granulosa cells do as the antral follicles are growing and what effect does this have?
➝ the granulosa cells are multiplying and producing activins which further enhance FSH stimulation and will allow the follicles to grow
What is the FSH threshold hypothesis?
➝ Raised FSH (intercycle ↑ in FSH) = a “window” of opportunity
➝ 1 follicle from the group of recruited antral follicles in the ovary is at the right stage at the right time = is selected to become the dominant follicle.
➝ Foll w highest num FSHr is selected to become DF
➝ DF survives the fall in FSH + goes on to ovulate
= SELECTION, can occur in either ovary
What happens after follicle selection?
Dominant follicle produces oestradiol = Estradiol levels rise
↑ oestradiol = neg fb at pituitary = FSH ↓
➝ ↓ FSH prevents further follicle growth
How does the dominant follicle survive the fall in FSH?
➝DF has ↑ FSHr expression = captures the minimal FSH (high sensitivity to FSH)
➝DF increases the number of GCs which doesn’t happen to the other follicles
➝As FSH ↓, LH ↑ (LH surge triggers ovn)
➝Dominant foll increases LHr expression on granulosa cells - gene transcription = DF responds to LH
➝Other follicles do not acquire LHr = lose their stimulant and die
slide 24
What receptors do the granulosa and theca cells have and when do they acquire them?
➝ Granulosa – have FSHr (and GCs of DF acquire LHr from the mid-follicular phase onwards)
➝ Theca – always has LHr, never FSHr
What is the function of FSH and LH in females?
➝ FSH – drives oestrogen production in the follicular phase (FSHr on GC)
➝ LH – drives androgen and progesterone production in luteal phase from theca (LHr on theca cell)
When is inhibin B the highest and when does it decline?
➝ highest in early/mid follicular phase
➝ declines in late follicular phase
➝ zero at luteal phase
inhibin B = follicular phase; inhibin A = luteal phase
As FSH increases(intercycle ↑ in FSH) and follicles mature, GCs multiply = ↑ inhibin B.
When is inhibin A highest and when does it decline?
➝ increases in Late Follicular phase
➝highest in Luteal Phase (produced by CL)
➝ huge decline in inhibin A at the end of the luteal phase
(inhibin B=follicular phase; inhibin A=luteal phase)
Which hormones does CL produce?
Prog + Inhibin A (+ Oestrogen)
Which inhibin does CL produce?
Inhibin A
in Luteal Phase of Menstrual Cycle
Why does inhibin A decline dramatically at the end of the luteal phase?
➝ It allows for increase in FSH (intercycle ↑ in FSH)
➝Death of CL = no longer Inhibin A prod
Describe what is happening in this graph starting from the intercycle rise in FSH
➝ Intercyle rise in FSH recruits follicles which is followed by a drop in FSH because of an increase in negative feedback due to estrogen(produced by folls) and inhibin
➝ the drop in FSH allows for selection of the dominant follicle which produces a lot of estrogen and results in a switch to +ve feedback (prolonged elevated oestrogen >200pmol for >48hrs)
➝ +ve feedback results in LH surge
➝ LH surge triggers ovulation of dominant follicle
➝ Conversion of the follicle to the CL
➝ CL produces prog = neg fb = Both FSH + LH levels ↓
➝ Inhibin A is produced in the luteal phase (Red line)
➝ Antral folls grow = ↑ estrogen prod = reinstates negative feedback and reduces FSH
➝ In follicular phase, inhibin B ↑ and contributes to the increased negative feedback on FSH
Where do changes occur in the reproductive tract during the menstrual cycle?
➝ Endometrium
➝ Uterine tubes
➝ Cervix
➝ Vagina
HPO axis including prog, oestrogen, activin, inhibin
Inhibins and Activins only act at which level?
Pituitary
Window of Opportunity
slide 22
↑ FSH presents a “window of opportunity”
How is the dominant follicle selected?
The foll w the highest num of FSHr is selected to become the DF
Differential release of FSH and LH is due to what?
Differential release of FSH and LH – due to GnRH pulses amplitude(depth)+ frequency(how close they are together)
-Slow GnRH pulse frequencies favour FSH release
-Fast GnRH pulse frequencies favour LH release
Activins are high when ……….. is high
Activins are high when FSH is high
Activins stimulate/promote FSH release from gonadotroph cells of ant pituitary
As oestradiol ↑ , what happens?
Oestradiol ↑ = neg fb = Inhibin B ↑
Oestradiol ↑ in Follicular phase, Inhibin B ↑ in Follicular phase
confused on this - how is it neg fb????**
