Antral Folliculogenesis Flashcards
Theca is crucial for preantral to antral follicle transition
- 1970 - radio labelled LH/ hCG injected into adult female rats - LH localized specifically in theca layer of small preantral, antral and preovulatory follicles but NOT PRIMORDIAL FOLLICLES suggesting importance for transition
- evidence comes from Growth Differentiation factor 9 (GD9) K/O in mice (mutation in humans and sheep) fail to develop theca layer and follicles arrest - importance of theca layer in follicle progression
Theca formation
-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 and interstial ovarian tissue
pre-antral to antral follicle transition - antrum formation
200-400 micrometers diameter - surrounded by a vascularized theca and circulating influences (granulosa cell not interacting with surrounding influences, theca does)
-fluid filled spaces appear in between granulosa cells which soon merge together forming a single large fluid filled cavity called the antrum:
-contains fluid formed as exudate of plasma containing secretory products of oocyte and GC
-KL and Cx37 essential for antrum formation in lab animals – as k/o of these genes result in no antral follicle at all
-as the fluid volume increases the follicle continues to grow from 0.2 mm to 20 mm and number of granulosa cell also increase and the fluid starts pushing the oocyte out.
structures of ovarian follicle
1.Theca externa – SMC innervated by autonomic nerves, lymphatic vessels important for ovulation
2.Theca interna – steroid producing cells : contain LHR and insulin R , richly vascularized which is important for the transport of nutrient and oxygen needed for oocyte growth
3. Granulosa – endocrine feedback control – express LHR and FSHR , differentiate into corona radiata after ovulation – mural and cumulus cell lineage
4. Cumulus oophorus – remain in contact with oocyte and interact with oocyte via gap junction – mitotically active – NO LHR
How does Cumulus oocyte complex still respond to rapid LH surge when it has no LH receptors?
still response rapidly to LH surge even with no LH receptors bc GC produce EGF- like ligands that bind LH and allow for secretion of hyaluronan and a complex of hyaluronan cross-linking proteins that cause expansion of COC
Menstrual cycle FSH rise and follicles
inter- cycle rise in FSH crucial for recruitment of AF, into the menstrual cycle
-progression of antral follicles
-selection of dominant follicle
-fate of remaining AF
two - cell, two gonadotrophin concept
The HPG axis acts to control antral follicle growth at this stage
1. Theca – LHR – respond to LH - steroidogenic enzymes – androgen from cholesterol
2. Granulosa – respond to FSH – by upregulating aromatase – to make oestrogen
Role of FSH in antral follicle :
- Increase granulosa cell proliferation
- Increase aromatase and oestrogen
- Oestrogen feedbacks to increase granulosa cell proliferation
- Induces and maintain FSHr
- Induce and maintain LHr
- AMH produced by the granulosa cells inhibit it to avoid too much FSH which would cause multiple follicles growing – and early menopause
Inhibin B
released from follicle
negatively feedbacks to pituitary to reduce FSH levels
Activin
- Stimulates FSH receptor gene – increased FSH synthesis (opposite of inhibin B)
Androgens, FSH and AMH in antral follicles
-Androgens act on granaulosa cells to upregulate AR and FSHR :Androgen k/o mice have reduced FSHR mRNA
- AMH produced by granulosa acts as a brake on FSH recruitment of antral follicles by decreasing FSH – stimulated aromatase expression
This counter balancing effects of AMH , androgens and FSH ensures against premature depletion of PF pool and premature selection of follicles by FSH
FSH threshold and DF selection:
Amount of FSH required to recruit one follicle.
Follicle with the lowest threshold will be recruited
Largest follicle is not always selected
Depends on which follicle is in the right stage at the right time
How does DF survive fall in FSH
- Increased sensitivity to FSH -> increased FSH receptors
- -increased number of granulosa cell
- Acquisition of LH receptors : FSH switches on LH receptor gene through protein kinas A reaction
- Possible involvement of insulin- like growth factors 1 &2 (IGF-2 particularly important
DF and IGFs
-IGF2 enhances FSH effects : IGF binds to both theca and granulosa cells , and stimulates androgen production in the theca and stimulate estrogen in the granulosa
-IGF activity suppressed by IGFBP – IGF binding protein
-IGF is cleaved from IGFBP by pregnancy associated plasma protein (PAPP) = more IGF
-PAPP is seen in high levels in DF = more IGF = more enhanced FSH
-other antral follicles may have less PAPP and high levels of IGFBP to prevent co stimulatory effect of IGF and FSH – shown in cows follicle
- Rest of antral follicles will die off by atresia and only dominant follicle survives
LH importance in folliculogenesis
- Inactivating mutations of LH receptors – normal estradiol in early follicular phase, anovulatory, multiple cysts , morphologically normal antral follicle
- Hypo gonadotrophic women – as long as a little bit of LH FSH treatment is effective – little bit of LH needed to make androgen by LH binding in the theca which is converted to oestrogen by aromatase
- LH K/O mice – antral stage growth blocked
