Control Of Terminal Follicle Development Flashcards
Describe the FSH threshold hypothesis of terminal follicle development.
The hypothesis is that there is a clinical threshold of FSH that allows the follicle to a large antral preovulatory size.
In super ovulation in assisted conception we give a women FSH to stimulate all the gonadotrophic responsive follicles available to be released into the ovulatory pool.
Describe the gonadotrophic dependence of the antral follicle.
We usually get this switch from dependence on FSH to dependence on LH as development progresses.
15mm follicles are mostly LH responsive.
During this transition we are getting progressive development of LH receptors.
The follicle that has developed LH receptors will survive the depression in FSH by using LH as a surrogate. The rest of the cohort that haven’t developed LH receptors will die. This is the basis of follicle selection.
The follicles become dependent on LH.
Give a summary of gonadotrophic control of terminal follicle development.
FSH provides support for gonadotrophic dependent follicles above a critical threshold concentration.
As LH receptors develop on granulosa cells follicles can transfer dependence from FSH to LH and this is part of the selection mechanism and dominance.
However, there is a problem with the threshold hypothesis. How does selection of the follicle that is to go on to develop LH receptors occur? Surely all follicles are being exposed to the same stimulus?
There is a problem with the threshold hypothesis. How does selection of the follicle that is to go on to develop LH receptors occur? Surely all follicles are being exposed to the same stimulus?
We think that our gonadotrophic signals are being modulated by local factors that are secreted by the oocyte, granulosa cells and Theca cells. These have the effect of either attenuating or amplifying the gonadotrophic signal which affects the switch from proliferation to differentiation.
The fate of individual follicles depends on balance between intra follicular action augmentors or attenuators of gonadotrophic actions.
For example, more IGF, insulin, Inhibin A, BMP-6 may lead to rapid growth and differentiation due to the enhancement of the gonadotrophic signal. In contrast, AMH, BMP-15 and GDF-9 act to inhibit gonadotrophic signals and lead to slower growth and atresia.
The selection mechanism therefore operates according to the factors present. The follicle with the best concentration of enhancers and the lowest concentration of attenuators will be the one that is selected to go on to become the dominant follicle.
If you have higher levels of FSH you will recruit the next best follicle and so on (graduated response). In this way if you have a high enough dose of FSH you will recruit the whole cohort no matter what the concentration of enhancers or attenuators. It is a matter of sensitivity to FSH stimulation.
What are the local modulators of gonadotrophin signal response?
They include local paracrine and autocrine factors:
Enhancers - IGF-II, Inhibin A, BMP-6.
Attenuators - IGF-BP, EGF/TGF-alpha, AMH, BMP-15, GDF-4
Secondary endocrine factors:
Enhancers - IGF-I, Insulin, Growth Hormone
Attenuators - Prolactin, IGF-BP, Leptin
What local and paracrine factors act as enhancers of the gonadotropin signal response in the late follicles?
Enhancers - IGF-II, Inhibin A, BMP-6.
What local paracrine and autocrine factors act as attenuators of the gonadotrophin signal response in late follicular development?
Attenuators - IGF-BP, EGF/TGF-alpha, AMH, BMP-15, GDF-4
What secondary endocrine factors act as attenuators of the gonadotrophin signal response in late follicular development?
Attenuators - Prolactin, IGF-BP, Leptin
What secondary endocrine factors act as enhancers of the gonadotrophin signal response in late follicular development?
Enhancers - IGF-I, Insulin, Growth Hormone
Describe the Insulin-like growth factor system and its importance in terminal follicle development.
The IGF system consists of 2 ligands (IGF I and II), 2 receptors (I and II) and at least 6 binding proteins (IGF-BP I-VI).
IGFBP2 is not expressed in follicles more than 8mm. This is the stage at which follicles start to develop LH receptors. Therefore, this depression of IGFBP2 could be one of the mechanisms by which the follicle becomes more responsive to gonadotrophins.
We may suggest that IGFII and IGFI coming in through the blood can act on both the Theca cells to enhance the androgen production, but also on the granulosa cells to enhance their response to FSH and hence produce oestrodiol.
IGFBP2 which is expressed by the granulosa cells inhibits that process, but as we move to the preovulatory follicles the levels of IGFBP2 decrease which will act to enhance the levels of local factors and oestrodiol which is the primary characteristic of a preovulatory follicle. This oestrodiol then suppresses the FSH which causes the other follicles to die.
IGFBP2 modulates the actions that IGFI and II have on the cells. Only when it is suppressed can IGFI and II enhance the cells response to FSH.
Describe Inhibin and its role in terminal follicle development.
Inhibin is composed of a common alpha subunit combined with either a beta a or beta b subunit.
In most species cell follicles secrete Inhibin A. In humans and other primates the small follicles secrete Inhibin B and the large antral follicles express Inhibin A.
Having high levels of Inhibin is probably a positive association in terms of the development of our oestrogenic follicles.
When culturing Theca cells in vitro we see increasing concentrations of oestrodiol when dosed with increasing Inhibin A in both small and larger follicles.
We can propose that Inhibin that is produced by granulosa cells is having both paracrine and autocrine actions. It’s paracrine action is crossing the basement membrane and stimulating the production of androgen in response. Inhibin also stimulates the production of oestrodiol under the influence of FSH.
Inhibin has a double whammy effect on the production of oestrogen.
Describe how BMP-6 acts to enhance terminal follicle development.
BMP-6 is an oocyte secreted factor.
BMP-6 stimulates oestrodiol production on granulosa cells. It also has an inhibitory effect on progesterone production in the same cells. This suggests that a lot of the progesterone produced is being converted into oestrodiol in response to BMP-6 accumulation.
What local factors to granulosa cells need to be responsive to FSH?
Granulosa cells need IGF-I and BMP-6 to be responsive FSH.
Get an increase in oestrodiol production proportional to FSH stimulation on the addition of IGFI and BMP-6 to the media individually and an additive response when both are added. There is no response to FSH when neither is present.
What is the effect of BMP-6 on Theca cells?
The effect of BMP-6 on the Theca cells seems to be inhibiting follicular differentiation via the suppression of androgen production. However, at very low doses of BMP-6 it seems to follicular differentiation which is probably what is happening in vivo.
How does AMH act as an attenuators of gonadotrophic actions?
There is an inverse relationship between AMH and aromatase in membrane granulosa cells in sheep as follicle size increases.
There is a massive decline in AMH expression in gonadotrophin-dependent follicles and a converse induction of aromatase expression.
This privides good circumstantial evidence that AMH may be inhibitive of differentiation actions.
In vitro physiological AMH doses appear to inhibit oestrodiol production in granulosa cells.
In Theca cells AMH appears similarly to inhibit androgen production.
