the primordial germ cells in the female fetus are the cells which are going to give rise to the gamete the oocyte these primordial germ cells migrate from the oat sac into the fetal ovary and when they get to the fetal ovary they actually undergo a lot of proliferation they undergo mitosis but the final stage of mitosis which is the division of cytoplasm cytokinesis is often incomplete so they actually form these interconnected cells where they are joined by bridges of cytoplasm therefore sometimes you see them referred to as germ cell cysts or germ cell nests within the fecal ovary many of these actually undergo apoptosis and quite a lot of them are lost at this stage through apoptosis but others go on to start meiosis and they begin meiosis to form primary oocyte but the primary oocyte only ever gets as far as prophase one of meiosis one and it gets arrested at prophase and it stays in that arrested state unless it is ovulated and it will only ever complete meiosis one if it is ovulated and so we'll talk about what controls meiotic arrest a little later anyway as the oocytes go into meiosis one there is breakdown of these intercellular bridges and that results in the enclosure of the oocyte within a single layer of somatic cells which are known as granulosa cells to give the primordial follicle and the female is born with about a million primordial follicles in her rosy ovary and it's thought that this development of the primordial follicle is regulated by factors within the oocyte itself however through observations of wildlife and also laboratory animal experiments it's been shown that environmental contaminants can modulate the formation of primordial follicles resulting in primordial follicles which have more than one oocyte and then these get selected for depredation because clearly if they were to go on to be fertilized that would result in a developmentally compromised embryo so they got rid of which then means that the individual could be born with a fewer number of follicles and then of course would have a smaller oocyte reserve which would ultimately affect their reproductive lifespan so there's quite a lot of interest in how these contaminants might be regulating this process here's a histological section of human ovary and here you can see some primordial follicles so as you know they just consist of the oocyte in the middle which is arrested in prophase one and this single layer of granulosa cells around the outside and these primordial follicles then go on to become the primary follicle and the primary follicle has still got its oocyte it's still got granulosa cells but now the granulosa cells have undergone proliferation so there's more than one layer and also they've changed shape they're much more cuboidal instead of being flat but the new feature of the primary follicle is the appearance of the zona pellucida this blue layer here and that's a glycoprotein layer which the sperm are going to have to penetrate in order to actually access the oocytes and to fertilize the oocytes and you'll hear more about that from mark and other colleagues in this lecture series the primary follicle then goes on to form the secondary follicle where you can see the appearance of these additional cell layers called the thecal cells and you can see that this secondary follicle is much bigger but there's still the oocyte still the zone pellucida still all these granulosa cells but now you've also got these thicker cells the thicker internal cells and the thicker external cells so the thicker in turn cells are the ones that are closest to the granulosa cells and the thicker externa are the ones on the outside of the follicle and are responsible for giving the follicle of structural support now this development from primordial follicle through to secondary follicle does not depend on the gonadotrophins it is gonadotrophin independent and it is occurring all of the time in the ovary through factors from within the follicles themselves and as we were saying before there is cooperation between the components of the follicle so the oocyte produces factors which are known as oocyte secreted factors or osfs and these are members of the tgfb super family and the important ones are gdf9 and bmp15 and i've coded these in green because they're important in promoting follicle development but the granulosa cells also contribute to the development of the follicle and the particularly important factors are kit ligand and also amh which is anti-malaria hormone so again i've put kit ligand in green because that promotes follicle development but it's thought that amh might restrain follicle development and so you might have heard of amh as the hormone that some people suggest can be used to determine a woman's ovarian reserve and how long a reproductive lifespan she might have so the idea is that amh normally keeps the follicle development in check so you don't have too many follicles developing each month but if your amh level is low that suggests you've not got such a good check on development and so too many follicles might activate too soon and therefore you reduce your follicle reserve and therefore go into menopause earlier than say somebody who has a higher amh level so there's quite a lot of interest at the moment in measuring amh as a mean of determining a woman's reproductive lifespan but it's quite controversial some people think it's a good thing and others don't so i think that's something that's going to continue to develop over the coming years anyway in order to get from primordial follicle through to the secondary follicle you need a balance of factors produced by the follicle and itself but to go any further that's when you need the input from the brain from the hypothalamus and anterior pituitary and the gonadotrophins so development from this secondary follicle into a tertiary follicle is fsh dependent so we've got a picture of a tertiary follicle here it's still got the oocyte and which is still arrested in prophase one it's still got the zona pellucida and it's still got the fecal cells the thicker interna and the thicker externa and we still got the granulosa cells but you can probably see that the granulosa cells are looking a bit different now we've had differentiation of the granulosa cells so now we've got the cumulus ground loads of cells the ones that are immediately around the oocytes and also the neural glandulosa cells which you can see here and these granulosa cells secrete a fluid which accumulates between cells to give rise to this cavity which is called the antral cavity and we know that fsh is very important for this development because if you knock out the beta subunit of fsh then you never get formation of tertiary follicles and formation of the anterior cavity and in some books you might see these follicles the primordial through to the um secondary follicles being referred to as pre-anterior follicles whereas the tertiary follicle referred is referred to as the antral follicle because of the presence of this cavity and the other really key feature of a tertiary follicle is it now starts to produce sex steroids so all of these follicles don't produce any sex steroids only the tertiary follicle produces sex steroids