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Science of Repro > Antral Folliculogenesis > Flashcards

Antral Folliculogenesis Flashcards

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1
Q

What is formed for the Preantral to Antral Follicle Transition? (3)

A

Theca:

Theca of follicle is envelope of connective tissue → differentiates
into theca interna &
externa containing vascular tissue, immune cell + matrix factors

  • critical for main. structural integrity of follicle + delivering nutrient to avascular GC layer
  • Form. and differ. of theca extremely important for
    preantral to antral progression.
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2
Q

Theca formation (3)

A

Theca cells derived from 2 different sources in the
embryonic gonad:

− Mesenchymal (from mesonephros) cells
become steroidogenic cell

− Stromal cells (indigenous to medullary region) become fibroblasts, perivascular smooth muscle cells + interstitial ovarian tissue

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3
Q

Antrum formation (3)

A

follicle reaches a diameter of 200-400μm,
surrounded by a vascularized theca, hence subject to circulating influences.

Fluid-filled spaces appear b/w GC
which soon coalesce together to form a single, large, fluid-filled cavity or “antrum”

  • As the fluid volume increases the follicle continues to
    expand greatly in size
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4
Q

Antrum (2)

A

– Contains fluid formed as exudate of plasma containing secretory
products of oocyte & GC

Known as FOLLICULAR FLUID

images

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5
Q

Change in GC & FF volume

A

As the fluid volume increases, the follicle continues to expand greatly in size.

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6
Q

Ovarian Follicle elements (4)

A

Theca externa
Theca Interna
GC
Cumulus Oophorus

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7
Q

Theca externa

A

Concentrically arranged smooth muscle cells; innervated by autonomic nerves; lymphatic vessels;
important during ovulation

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8
Q

Theca interna(3)

A

Steroid-producing cells;
contain LH-r & Insulin-r;
richly vascularized

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9
Q

GC (3)

A

Mural Granulosa – involved in endocrine feedback control; express FSHr, P450arom, LHr

Remain in contact with oocyte & interact with oocyte via gap junctions; mitotically active; no LHr

GC differentiate into 2 mature cell lineages: mural and cumulus cells

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10
Q

Cumulus Oophorus

A

Remain in contact with oocyte & interact with oocyte via gap junctions; mitotically active; no LHr

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11
Q

How do COC respond so rapidly after LH surge if no LH receptors on cumulus gc?

A

GC produce EGF-like ligands that bind LH and allow for secretion of hyaluronan + a complex of hyaluronan cross-linking proteins that cause expansion of COC

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12
Q

Why in the FSH inter-cycle rise important? (4)

A

crucial for recruitment
of AF into MC

Progression of antral follicles
* Selection of dominant follicle
* Fate of remaining AF

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13
Q

Two-cell, Two-Gonadotrophin Concept (3)

A
  • HPG axis acts to control antral follicle growth at this stage

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

-GC respond to FSH by up-regulating aromatase
(CYP19A1) and 17β-HSD to make oestrogens

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14
Q

What determines survival of follicles?

A

FSH:

↑ granulosa cell proliferation
↑ aromatase
↑ induce and maintain FSHr
↑ induce and maintain LHr
Interact with paracrine factors

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15
Q

Autocrine Control of FSHR Expression

A

image

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16
Q

Androgens + antral Follicles (2)

A

Androgens act on granulosa cells (paracrine interaction)
to upreg.AR & FSHR

– AR k/o mice have reduced FSHR mRNA

17
Q

AMH + antral Follicles (4)

A

(produced by GC of small antral follicles)

acts as a brake on FSH recruitment of antral follicles by:
– decreasing FSH sensitivity
– decreasing FSH-stimulated aromatase expression

18
Q

Counter-balancing effect of AMH, Androgens and FSH to ensure against.., (2)

A

– premature depletion of PF pool and/or
– premature selection of follicles by FSH

19
Q

FSH threshold & DF selection (9)

A

amount of FSH required to recruit one follicle

»follicle w/ the lowest threshold will be recruited

» largest follicle is not always selected

»FSH receptors
– Increased no,’s
– Coupled more effectively to down-stream signalling

»Growth and Oestradiol production
– increased cell division (2-5 million GC in EFP and 50-100 million at ovulation)

– Size ~5.5-8.2mm in EFP and 18-20mm in LFP
– increased aromatase (200x more E2 than other follicles)

»Androgens & Oestrogens

»Intra-follicular cAMP

»Increased area of theca vasculature

20
Q

Dominant follicle (5)

A

Dominant follicle survives fall in FSH by:

»increased sensitivity to FSH = increased FSHr

»increased no. of GC

»acquisition of LHr
‒ the LHR gene is switched on by FSH

»possible involvement of insulin-like growth factors 1&2 (IGF-2 particularly important in humans)

21
Q

DF & IGFs (bovine)

A

» IGF-2 enhances FSH effects; stimulates androgen output and
hence oestrogen

» IGF activity suppressed by IGFBP (IGF-binding protein)

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

» PAPP-A expression high in DF

» Thought that other AF in cohort may have higher levels of IGFBP
hence preventing co-stimulatory effect of IGF & FSH

22
Q

Importance of LH in folliculogenesis (6)

A

»inactivating mutations of LH receptor = normal *EFP E2 , anovulatory, multiple cysts, morphologically normal antral follicles

»hypogonadotrophic women:
- FSH treatment effective as long as some LH
present
- E2 is sig.reduced but detectable, why?
* can some A be accessed from adrenal?

»LH k/o mice
* Antral stage growth blocked

23
Q

Role of LH in Antral Follicles

A

diagram

24
Q

LH signalling in theca interna

A

diagram

25
Q

one message, 2 signals - cAMP

A

LH and FSH have same 2nd messenger - cAMP

FSH produces low cAMP LH produces high cAMP

Difference in density of FSHr & LHr (LHr>FSHr or LHr more effectively coupled to cAMP generation)

provides energy for biosynthetic activity

  • mediates effects of FSH and LH on protein production eg. aromatase, SCC, LHr, proteolytic enzymes
26
Q

Why do we need ovarian angiogenesis?

A

Constant re-modelling to allow for growth of follicle (2-20mm) through the ovarian tissue, angiogenesis of CL, tissue repair etc.

27
Q

Ovarian angiogenesis (4)

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

*VEGF
– endothelial cell mitogen, enhances vascular permeability

  • Ovarian lymphatic vessels recruited to theca and stroma layers around growing follicle, under control of VEGF-R3
28
Q

Androgens & VEGF (2)

A

image
Working model for
androgen action on
endothelial cells:

liganded AR induces
HIF-1 expression
which is transcription
factor for VEGF

29
Q

AMH, Antral Follicle Count (AFC) & Ovulatory Potential (7)

A

AMH sec. =maximal during small
antral follicle stage (≤4mm) and
dec. to undetectable levels later

  • = serum AMH reflect small AFs
  • no. of antral follicles (AFC) in the EF phase correlates w/numbers of growing follicles only
  • Use ultrasound to count number of 2-8mm follicles at start of cycle &
    correlate ≈ AMH serum levels
  • Low numbers of antral follicles are a sign of ovarian ageing
  • Observable earlier than a rise in FSH serum level
  • right ovary has been shown to be larger +
    have higher AFC than left ovary → thought to be due to larger PF pool in right ovary formed in fetal life
30
Q

Fertility & Follicle Reserve

A

AFC & serum markers FSH, AMH, E2 and
Inhibin B used to determine “functional
ovarian reserve”, but does not indicate
true PF reserve
ie what you are born with

31
Q

Premature Ovarian Failure/Primary
Ovarian Insufficiency (POI)

A

term for premature ovarian failure

  • Affects 1% of women worldwide
  • Defined as ovarian dysfunction <40yrs → oligomenorrhoea
    or amenorrhoea
  • Overarching feature is infertility resulting from
    accelerated depletion or reduced follicle reserve.
  • Aetiology is poorly understood:
32
Q

Causes of POF/POI (5)

A

– Environmental genotoxins induce DNA damage eg chemo/radio-
therapy for cancer treatment

– Mutations in genes e.g. BRCA1 and BRCA2that repair DNA double-
stand breaks, resulting in diminished ovarian reserve

– Altered hormonal signalling

– Chromosomal defects e.g. Turner’s syndrome (XO) → have streak
ovaries

– Autoimmune diseases including thyroiditis & Addison disease

Science of Repro (32 decks)

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