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Follicular Development


There are about 7 million follicles in a fetus. At birth, only 2 million of those are left. Follicles start out as primordial follicles, which contain an immature oocyte (egg). The oocyte is less than 25 micrometers in diameter and it is arrested in meiotic prophase. A single layer of granulosa cells surrounds the oocyte. Granulosa cells produce estrogen (discussed later). Granulosa cells are surrounded by a basement membrane, which functions as a separation barrier between the follicle and the adjacent ovarian stroma. During prepubertal years, some of the follicles undergo growth but most undergo artesia (die out). Only about 400,000 follicles are left by puberty and out of these, only 400 follicles ovulate. The next stage of follicular development is the primary follicle. The difference between a primordial follicle and a primary follicle is that the primary follicle develops another gelatinous membrane called zona pellucida, which surrounds a mature oocyte. The oocyte is now 80-100 micrometers in diameter and the granulosa cells start to quickly proliferate. As the follicle enlarges, fluid accumulates between the granulosa cells forming small patches. The follicle develops into a secondary follicle when another layer of granulosa cells rests on the outside of the basement membrane. These cells are called thecal cells, which develop into two distinct layers in tertiary follicles. The fluid filled patches enlarge in secondary follicles and form a cavity called antrum. In tertiary follicles the oocyte and some granulosa cells migrate to one side of the follicular cavity. The inner thecal layer is called theca interna, and the outer layer is called theca externa. Theca externa is composed of smooth muscle cells, which aid in ovulation. The functions of theca interna will be discussed later. All of the processes above are hormone independent. That is, they do not require LH or FSH production by the anterior pituitary gland. The development of a tertiary follicle from a primordial follicle takes about one year. After puberty, a single follicle is selected for further development every month. The oocyte in this follicle is pushed out of the ovaries into the fallopian tubes, by a process called ovulation. This oocyte is ready for fertilization. The selection process is hormone dependent. It requires FSH and takes about 20 days. A few follicles are selected each month, but only one of them ovulates and the rest undergo artesia. The way a follicle is selected is by decreasing FSH production and release around day 6 of the ovarian cycle. The follicle with the largest antrum will contain high concentrations of FSH and will not be effected by the lowered FSH concentration in the blood. However, the few follicles that have smaller antrum cannot develop without FSH and will undergo artesia. The final stage of a follicle is the Graafian follicle or preovulatory follicle. It has a diameter of about 5 millimeters and contains lots of fluid in its antrum. Also, the innermost layer of granulosa cells becomes firmly attached to the zona pellucida. This layer of cells is called corona radiata and they contain gap junctions, which will be important later. The oocyte is now a primary oocyte and is located in the middle of the antrum and it is connected to the granulosa cells by a stalk called cumulus oophorus. Ovulation is triggered by LH, FSH surge. LH stimulates the granulosa cells to produce two types of prostaglandins, PGE2 and PGF2a. PGE2 attracts lysosomes to the basement membrane of the follicle. The lysosomal enzymes degrade a region of the basement membrane. PGF2a stimulates smooth muscle cells in theca externa to contract. FSH stimulates the granulosa cells to produce plasminogen activating factor (PAF) which converts plasminogen, which is inactive, to plasmin, the active form of the protein. Plasmin is a protease and it also helps to break down a region of the basement membrane, forming a hole called stigma. Another effect of FSH on granulosa cells is the expansion of the cumulus. All of these effects lead to the ejection of the oocyte out of the ovary and into the fallopian tube. The rest of the follicle collapses and becomes the corpus luteum, which plays a major role during the latter half of the ovarian cycle. Ovulation also triggers the completion of meiosis I. Before ovulation, the oocyte is not allowed to complete meiosis I, because the granulosa cells of the corona radiata are stimulated by FSH to increase cytosolic cAMP concentration, which inhibits meiosis I. For this reason, cAMP is known as oocyte maturation inhibitor or OMI. The mechanism of FSH stimulated cAMP increase is mediated by Gs proteins. Recall that the granulosa cells of the corona radiata have gap junctions, which is how cAMP finds its way into the oocyte and inhibits meiosis I. During the FSH surge (around ovulation), the increased FSH down regulates/desensitizes FSH receptors on the granulosa cells. This leads to a decrease in cAMP, and the oocyte is allowed to complete meiosis I.

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