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Science of Reproduction -Year 3 > Antral Folliculogenesis > Flashcards

Antral Folliculogenesis Flashcards

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1
Q

What is a crucial step for the transition of preantral to antral follicle ?

A

This is the formation of a theca.

A study was carried out where radio-labelled LH and hCG where injected into adult female rats.

These localised to the theca layer of small pre-antral ,antral and ovulatory follicles.
(not the primordial follicles)

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2
Q

What does the theca of a follicle contain and what does it differentiate into?

A

Theca of follicle is envelope of connective tissue-differentiates into theca interna and externa containing vascular tissue, immune cells and matrix factors

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3
Q

What is the importance of the theca to the follicle?

A

The theca is critical for maintaining the structural integrity of follicle and delivering nutrients to avascular GC layer .

The theca cell is vascularised , has ability for neo-angiogenesis (formation of new blood vessels )will allow follicle interaction with systemic endocrine factors.

Theca cells are also steroidogenic.

The substrate for aromatase which is found in the granulosa cells are androgens from the theca cells

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4
Q

Why is the theca extremely important for preantral to antral progression?

A

This is because in knock out gene mice :

GDF9 k/o and GDF9 mutations in humans and sheep,

It was found that they failed to develop theca layer and follicles arrest.

This is because they didn’t have the oocyte derived GDF9 (this is being secreted from the oocyte and oing into the granulosa cells) which regulates formation of theca cell layer.

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5
Q

How are the theca cells formed ?What are they derived from

A

The theca is made up of interna and externa

The theca cells are derived from 2 different sources in the embryonic gonad :

Mesenchymal (from mesonephros) cells become steroidogenic cell

Stromal cells surrounding the follicle (indigenous to medullary region) become fibroblasts ,perivascular smooth muscle cells and interstitial ovarian tissue

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6
Q

How does antrum formation take place ?

When does this occour?

A

When the follicle has reached a diameter of around 200 to 400 micrometre surrounded by a vascularised theca.

Fluid filled spaces appear between the granulosa cells which soon combine to form a single large fluid filled caviry or antrum

-Contains fluid formed as exudate of plasma containing secretory products of oocyte and granulosa cell.

Known as folliclular fluid

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7
Q

What genes have been found to be important for antrum formation?

A

KL and Cx37 as in k/o models there was no antral follicles

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8
Q

Outline the different parts of the structure of an ovarian follicle

A

Theca externa -Concentrically arranged smooth muscle cells which are innervated by autonomic nerves ,lymphatic vessels which are important for ovulation

Concentrically having a common centre, such that two or more spheres, circles, or segments of circles are within one another.

Theca interna -This consists of steroid-producing cells which contain LH-r and Insulin-r, richly vascularised.

Granulosa cells will differentiate into 2 mature cell lineages :
Mural and cumulus cells.
Mural -found around the edge adjacent to basal lamina
Cumulus -found around the oocyte

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9
Q

What is the function of mural granulosa cells ?

A

The mural granulosa cells are involved in endocrine feedback control via production of oestrogen ;express FSHr ,p450aromatase which makes the oestrogen and LHr in the dominant follicle

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10
Q

What do cumulus oophorus cells do ?

A

Granulosa cells found surrounding the oocyte :
These remain in contact with the oocye and interact with the oocyte via gap junctions

These cells are mitotically active and do not contain LHr (even if it becomes selected to be the dominant follicle )

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11
Q

How do the cumulus oocyte complex respond rapidly to the LH surge if there are no LH receptors present ?

A

Granulosa cells produce EGF-like ligands which will bind to LH and allow for the secretion of hyaluronan and a complex of hyaluronan cross-linking proteins which will cause the expansion of the COC.

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12
Q

What happens to the antral follicles when there is an intercycle rise in FSH ?

A

There will be the recruitment of antral follicles into the menstrual cycle.

It is involved in the porgression of antral follicles , the selection of dominant follicles and the fate of the remaining antral follicles.

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13
Q

Describe and outline the two cell , two gonadotrophin concept.

A

The HPG axis will act to control antral follicle growth at this stage :

In response to LH ,theca expressed key steroidogenic enzymes to make androgens from cholesterol.

The androgens produced in the theca will then diffuse to the granulosa cell where
FSH will stimulate the aromatase.

This will form Estrone which is the converted Oestradiol and this diffuses into the blood and circulate round back to the hypothalamus

Granulosa cells respond to FSH by up-regulating aromatase (CyP19A1) and 17-beta-HSD to make oestrogens.

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14
Q

What is the role of FSH in antral follicles ?

A

FSH increases:

  • granulosa cell proliferation (increases the mitotic potential allowing the cells to increase in numbers )
  • aromatase (converts androgens in theca to oestrogen )
  • induces and maintains FSHr (allows the receptor to bind FSH)
  • induces and maintains the LHr
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15
Q

What can activin do to FSH ?

A

It can act on FSHr and increase their binding to FSH as well as acting on the pituitary to stimulate FSH

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16
Q

Describe the FSHr.What type of receptor is it and what signalling takes place ?

A

It is a G-coupled receptor.
When the FSH ligand binds to the receptor there is a cascade which produces cAMP which activates PKA and this leads to differentiation of granulosa cells.

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17
Q

What is the effects of androgens on granulosa cells?

A

Androgens will act on granulosa cells (paracrine interaction) to upregulate AR (androgen receptor )and FSHR (FSH receptor)

AR k/o mice have reduced FSHR mRNA

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18
Q

What is the effect of AMH on FSH recruitment ?

A

AMH is produced by Granulosa cells of the small antral follicles.

It will act as a brake on FSH recruitment of antral follicles by:

decreasing FSH sensitivity
decreasing FSH-stimulated aromatase expression

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19
Q

What is the effect of AMH on FSH recruitment ?

A

AMH is produced by Granulosa cells of the small antral follicles.

It will act as a brake on FSH recruitment of antral follicles by:

decreasing FSH sensitivity
decreasing FSH-stimulated aromatase expression

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20
Q

What is the aim of AMH androgens and FSH working together ?

A

This ensure to protect against premature depletion of PF pool and premature selection of follicles by FSH

As both these reasons could cause early menopause

21
Q

Relating to FSH which follicle will be selected as the DF?

A

The amount of FSH recquired to recruit one follicle is the FSH threshold.

The follicle with the lowest threshold will be the one recruited within a micro-environment.

It is not necessarily the largest follicle

22
Q

How are FSH thresholds lowered in the DF ?

A
  1. Increased number of receptors
  2. Coupled more effectively to down stream signalling can exert the actions of FSH more effectively.

These actions include:
Increased cell division of GC
Increase of size
Increased aromatase =200x more E2 than the other follicles

23
Q

How does increased theca vasculature area aid the DF?

A

This is because it is more open to circulating influences such as insulin, gonadotrophin and growth factors.

24
Q

Describe the process of FSH acquisition of LHR in GC of the selected DF.

A

FSH will activate the LHR by activating the LHR gene ,.

25
Q

Provide a summary of how a dominant follicle will survive a fall in FSH

A

Dominant follicle survives fall in FSH by:
increased sensitivity to FSH  increased FSH receptors
increased numbers of granulosa cells
acquisition of LH receptors
the LHR gene is switched on by FSH
possible involvement of insulin-like growth factors 1&2 (IGF-2 particularly important in humans)

26
Q

How do IGFS enhance the DF selection?

A

IGFs in particular IGF-2 will enhance the effects of FSH .
This will stimulate androgen output and hence oestrogen

IGF-activity can be suppressed by IGFBP (IGF binding protein )

IGF cleaved from IGFBP by PAPP-A (pregnancy -associated plasma protein A )

27
Q

How can the effects of IGF activity be suppressed ?How can we stop this suppression ?

A

IGF-activity can be suppressed by IGFBP (IGF binding protein ), it will bind to it and prevent it from acting.

This can be stopped by cleaving IGF from IGFBP using PAPP A (pregnancy associated plasma protein A ).

28
Q

What are the differences in normal follicles and the dominant follicle in terms of IGF ?

A

The dominant follicle is thought to have higher PAPP-A expression compared to the DF.

The AF in cohort may have higher levels of IGFBP hence preventing co-stimulatory effect of IGF and FSH.

29
Q

How has the importance of LH been observed in women?

A

In woman who have inactivating mutations of LH receptor, it was found that there early folliclular phase E2 was normal.
However they are annovulatory, multiple cysts and morphological normal antral follicles

hypogonadotrophic women
FSH treatment effective as long as some LH present
E2 is significantly reduced but detectable, why?
can some A be accessed from adrenal?
LH k/o mice
Antral stage growth blocked

30
Q

What is the role of LH in the antral follicles ?

A

LH will act on both theca and granulosa cells .
It will start acting on granulosa cell once the follicle has been selected to be the dominant follicle.

Increase theca function of CYP11a,CYP17 and this causes the growth and steroidogenesis in dominant follicle.

There is also a withdrawal of gap junctions between gc and oocyte +resumption of meiosis

31
Q

What is the role of LH in the antral follicles ?

A

LH will act on both theca and granulosa cells .
It will start acting on granulosa cell once the follicle has been selected to be the dominant follicle.

Increase theca function of CYP11a,CYP17 and this causes the growth and steroidogenesis in dominant follicle.

There is also a withdrawal of gap junctions between gc and oocyte +resumption of meiosis

Expands the COC

Ovulation and luteinisation (theca and gc)

Will also induce progesterone receptor in granulosa cells

32
Q

Outline what typpe of receptor LH will bind to as well as the nature of signalling

A

The LHr is a g-protein coupled receptor and it leads to production of cAMP which activates PKA.
This leads to formation of steroids from cholesterol precursor.

LH activates the enzymes which catalyse the reactions

33
Q

What are the effects of insulin of LH signalling ?

A

It was found that insulin can augment the actions of LH (intensify).
Important to consider this in woman who can develop insulin resistance

34
Q

If LH and FSH both have the same second messenger how can the cell distinguish between them ?

A

The second messenger in both is cAMP.
This is distinguished because FSH produces low cAMP and LH produces high cAMP levels.

Second theory is that LHr are more dense

35
Q

What is the role of cAMP?

A

It provides energy for biosynthetic activity

Mediates effects of FSH and LH on protein production e.g aromatase , SCC, LHr and proteolytic enzymes

36
Q

What is ovarian angiogenesis and what is its important ?

A

This is the creation of new blood vessels .

It is important for growth of follicle through ovarian tissue, angiogenesis of CL ,tissue repair

36
Q

What is ovarian angiogenesis and what is its important ?

A

This is the creation of new blood vessels .

It is important for growth of follicle through ovarian tissue, angiogenesis of CL ,tissue repair

37
Q

What are some important factors required for ovarian angiogenesis?

A

Angiogenic factors stimulated by primarily by androgens but also oestrogens – theca, gc, stroma all involved
Basic fibroblast growth factor (bFGF)
endothelial cell mitogen, most potent angiogenic factor
Vascular endothelial growth factor (VEGF)
endothelial cell mitogen, enhances vascular permeability
Ovarian lymphatic vessels recruited to theca and stroma layers around growing follicle, under control of VEGF-

38
Q

What is the accepted model for how androgens affect endothelial cells?

A

Liganded AR induces HIF-1 expression which is a transcription factor for VEGF.

Androgen binds to AR (a nuclear receptor) , translocated and will bind to ARE in nucleus.

This causes HIF-1 expression via target genes.

This will bind to the HRE on VEGF genes and cause production of VEGF which will bind to receptor on endothelial cells which causes proliferation

39
Q

What will the serum AMH show ?

A

AMH secretion is maximal during small antral follicle stage and decreases to undetectable levels after this.

Therefore the serum AMH will reflect small growing antral follicles.

The number of antral follicles in the early follicular phase will correlate with number of growing follicles only.

The change in AMH is observable earlier than the rise in FSH serum levels

40
Q

What can low numbers of antral follicles indicate ?

A

This can indicate ovarian ageing.

41
Q

Why was FSH used traditionally as the mark of early menopause ?

A

This is because FSH levels are controlled by feedback from the antral follicles from oestrogen produced.

As the numbers of follicles decrease , the oestrogen levels will decrease therefore FSH levels will rise.

42
Q

What markers can we analyse to tell the functional ovarian reserve ?

A

AFC ,serum markers FSH,AMH and E2 and Inhibin B are all used to determine the reserve but these do not show the amount of PF you are born with.

43
Q

What markers can we analyse to tell the functional ovarian reserve ?

A

AFC ,serum markers FSH,AMH and E2 and Inhibin B are all used to determine the reserve but these do not show the amount of PF you are born with.

The PF are difficult to determine as there are no markers released by them as they are in a rested state

44
Q

What is POI? What can it cause

A

This is premature ovarian failure /primary ovarian insufficicency

It affects 1% of women and is defined as ovarian dysfunction.
Oligomenorrhoea or amenorrhoea

The main feature will be infertility which results from accelerated depletion or reduced follicle reserve

45
Q

What are some reasons why POI is thought to cause depletion of follicle reserve?

A

Environmental genotoxins induce DNA damage e.g chemo/radio therapy for cancer treatment

Mutations in genes e.g. BRCA1 and BRCA2 which repair DNA double strand breaks which results in diminished ovarian reserve.
(Mitotic and meiotic breaks can occur )

Altered hormonal signalling
Chromosomal defects e.g. Turners syndrome (XO) have streak ovaries

Autoimmune diseases including thyroiditis and Addison disease

46
Q

How were 3D culture systems developed ?

A

Hydrogel matrix to support follicle so that contact can be mainatined between oocyte and granulosa cell.

Also needs to be permeable to media

Modifiable in terms of rigidity.

Because as the follicle increases in size it will require space to grow.

Types:
Collagen
Aliginate (from seaweed)

47
Q

How have 3D printed ovaries been developed ?

A

3D printer makes ovary from microporous hydrogel scaffolds.

Follicles seeded throughout to create mouse bio-prosthetic ovary

Scaffold will provide 3D support to follicles and this allows for vascularisation and ovulation

Science of Reproduction -Year 3 (30 decks)

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