Repro: 2:00 - 3:00Scribe: Caitlin Cox

Friday, November 6, 2009Proof: Marjorie O’Neil

Dr. CotlinThe Female Reproductive SystemPage1 of 7

Introduction [S1]:
The male system is always producing lots of sperm. Every spermatogonium is going to give rise to 4 spermatids. This is always going on from puberty on, generating and sloughing off sperm.
This is very different in the female. We are going to see that all oogonia happen just in utero, and then it is a very slow process over the course of a woman’s life.
The Female Reproductive System [S2]:
Internal Organs:
Ovaries, considered endocrine, are usually in a pair.
Oviducts are going to conduct eggs from an ovary to thesingle uterus, which is where implantation will occur.
Cervix is the opening of the uterus to the vagina.
Vagina is the canal.
External genitalia and mammary glands - not really part but related.
The Female Reproductive System [S3]:
Men’s cycles in terms ofsperm production are going to cycle through LH and FSH, but on a very different cycle than a female.Both will start at puberty, but the female has a cyclical monthly cycle.
The term menarche is the initiation of menstrual cycles. It can occur anywhere between 9-14 years of age; it just depends on the individual.
Menopause is the point at which you stop maturing eggs and having menstrual cycles. The norm for most menstrual cycles is 28-30 days, and all the charts are based on a 28 day cycle.
Internal organs of the female reproductive system [S4]:
She pointed out the:
Ovaries where the follicles and eggs are developing.
Uterine/Fallopian tubes (a pair of them), which are not attached to the ovary. This is where fertilization takes place, usually in the ampulla region.
Fimbriae, which are fingerlike projections that catch the egg as it is ovulated and released from the ovary.
Once the egg gets to the uterus, it can no longer be fertilized.
The whole thing is encased in the broad ligament, which is in close contact with the ovaries and oviducts.
Uterus and Adnexa [S5]:
This is a posterior view. She pointed out the oviducts and uterus.
The uterus is a huge smooth muscular organ (myometrium) with a very unique epithelium. These smooth muscle cells can proliferate; undergo hypertrophy and hyperplasia in a pregnant woman.
Function of the Ovaries [S6]:
Two primary functions:`
Oogenesis, which is the production of gametes. (Compare this to spermatogenesis.)
Developing gametes are going to be oocytes.
Mature gametes are ova (egg). Oogonia are the stem cells.
Production of steroids.
Estrogens and progestogens are going to be produced in the ovaries at different times in the cycle.
So the two primary functions areproduction of gametes and production of steroids.
The Ovaries[S7]:
Paired, almond shaped, 3 by 2 cm.
It is covered with what is called germinal epithelium. It is more like a mesothelium, which is why books are beginning to drop the terminology of germinal epithelium because it has nothing to do with giving rise to germ cells. In the testes, that germinal epithelium is a true epithelium and it gives rise to sperm. If you see germinal epithelium in ovaries, it is just a covering.
Ovaries can be divided into:
Medulla- the inner region; it is basically blood vessels, nerves and lymphatics.
Cortex-the outer region. All of your developing follicles/oocytes will be found in the cortex
Structure of the Ovary [S8]:
The mesothelium on this slide is the same thing as the cortex. This is the layer that is sometimes referred to as germinal epithelium.
Ovarian Follicles[S9]:
There are 5 classes of follicles. To produce a mature ovum that is going to be ovulated, it goes through these 5 cycles.
Primordialfollicle, which make up the bulk of the oocyte in the cortex.
Primary follicle (unilamilar)
Late primary follicle,when it has multiple layers. She pointed out a primordial follicle. It starts to bulk up these cells; it’s got one layer of follicle cells around it, and then multiple layers.
Secondary follicleis when we start to see some of the fluid buildup.
Graafian follicleis a mature follicle; it is the one that is going to be ovulated.
Development of primordial follicle [S10]:
Primordial germ cells are called oogonia. All of them development in utero.
A couple of months after fertilization, all of the oogonia are going to start going through mitosis, starting to populate, regenerating themselves. This is going to go on until about the 5th or 6th month.
Each ovary might have about 5-7 million oogonia.
About 1 million oogonia will become surrounded by follicular cells. These are the ones that will survive; the remaining oogonia will degenerate and die.
So at birth, a female has about 1 million oogonia. Oogonia are those stem cells that are going through mitosis.
Folliculogenesis [S11]:
About 1 million oogonia survive and will be called primordial follicles. The same terminology applies; we had spermatogonia, primary spermatocytes, secondary spermatocytes, and spermatids. Here we have oogonia, primary oocyte, secondary oocyte, and mature ova. In this case, all surviving oogonia at birth are going to enter that first stage of meiosis and arrest in prophase of meiosis 1. So every egg cell in an ovary in an adult is arrested in prophase meiosis 1. When she discusses primordial, secondary, mature follicles in a minute, that is the designation of the maturation of the follicle. Regardless, the egg at ALL points is arrested in primary oocyte stage. All of your eggs at this point and all of these follicles are primary oocytes.
At menarche, the average female has only about 400,000 primordial follicles left. The rest become atretic, they disintegrate and will be dissolved.
At menarche, ovulation will occur about every 28 days for the next 30-40 years. Each month about 12 follicles will to develop, and usually only one is ovulated. In the case of fraternal twins, two are ovulated. This whole maturation takes about 2-3 months, so it is usually on a cycle so that one month an egg is ovulated from one ovary and the other ovary the next month. The ovaries are on different developmental cycles where they are going back and forth in their production of mature follicles.
Of all these primordial follicles, how do they determine which ones will develop? Some of the primordial follicles will produce receptors for FSH. FSH is responsible for maturation. If there is a limited amount of FSH, then the ones that respond first will be the ones that mature. The others will have to wait until the next cycle.
Meiosis in the Female [S12]:
All oocytes in the ovary are arrested in the primary oocyte stage.
Upon ovulation, those cells are stimulated to complete the first meiotic division. This is where it is also different from a male. A primary oocyte is going to divide into two. Here is our complement of 4 sets of chromosomes: two will go into what is going to become asecondary oocyte and two are going to go into the first polar body. From 1 primary oocyte, you will only get 1 mature ovum. So in a sense, 3 sets of that chromosomal material arelost. Occasionally, this first polar body will split, but the body is going to degrade this.
She pointed out a primary oocyte arrested at prophase 1. At ovulation, it isgoing to complete meiosis 1, and then it is going to arrest at meiosis 2. Only upon fertilization is it going to complete meiosis 2 and give off a second polar body.
She pointed out a mature ovum that is capable of fertilization.
So, you complete meiosis 1 at ovulation, complete meiosis 2 only upon fertilization.
Again, out of those 4 complements, only 1 is going to be retained.
Histology [S13]:
This is a section of an ovary. She pointed the cortex and medulla with all the vasculature and nerves. She wants you to notice the assortment of follicles with different sizes and at different stages of development. The smallest cells are the primordial follicles. They gradually start to bulk up. The cells around them (the follicular cells) bulk up and mature. She pointed out a large, almost mature graafian follicle.
Cross section of an ovary[S14]:
At any given time, a dozen or so are going through this maturation process. Usually, only one is ovulated; the others are atretic (will dissolve). And again, there is cycling between the two ovaries.
Primordial Follicle [S15]:
These are the most primitive. The number you have at birth is the number you will have for the rest of your life.
It is surrounded by a single layer of follicular cells.
The cell itself is a primary oocyte, which is going to be the cell all throughout.
The follicular cells are usually very squamous and completely surround the oocyte. So at no point is an oocyte ever exposed or bare; it is always surrounded by follicular cells. Those follicular cells are attached by desmosomes and tight junctions in order to really protect that egg.

Primordial Follicle diagram [S16]:
Here you see oocyte and follicular cells. She pointed out a basement membrane on the outside of the follicular cells. Follicular cells put out a basement membrane that surrounds the follicular cells and the egg. The follicular cells are encased in the basement membrane itself.
Cortical region of an ovary [S17]:
See the germinal epithelium; remember this is not really a germinal epithelium, but a mesothelium. She pointed out the follicular cells, the oocytes, and the thin layer of cells around them. You cannot always see all the follicular cells, but every egg has them.
Unilaminar Primary Follicle [S18]:
The next stage is the unilaminar primary follicle. Of those primordials, a fraction of them in any given month will start to develop into primary follicles. These will become very large cells.
Zona pellucida will start to form: It is an enriched layer of proteins: glycosaminoglycans and glycoproteins. It will develop between the follicular cells and the egg itself. ***Go to S19 for a minute then come back here.
Sometimes you will see these follicular cells start to be called granulosa cells. The follicular cells that are starting to divide and bulk up—those are at some point going to be called granulosa cells.
Early Primary Follicle (unilaminar) [S19]:
She pointed out the egg and the follicular cells. They are really starting to bulk up relative to what they were in the primordial stage. You have the basement membrane, follicular cells, and the egg. Between the egg (oocyte) and the follicular cells, that is where we see this zona pellucida start to form.
Primary Follicle Histology [S20]:
Here is a primary follicle. She pointed out an egg with a nice zona pellucida and the single layer of follicular cells.
Late Primary Follicle (multilaminar) [S21-22]: *She switched back and forth between these two slides, so the script is simply in order of what she said.
Those follicular cells will start proliferating. In the primordial follicle, they are small and squamous. They are going to bulk up to become these follicular cells in a primary follicle. Then they are going to start dividing. At this point they are usually called granulosa cells. They are going to proliferate. Then we are going to have a primary follicle that has multiple layers of granulosa cells surrounding it.
Zona pellucida is very prominent at this point.
She pointed out the oocyte, zona pellucida, and the multiple layers of granulosa cells.
The oocyte and granulosa cells are going to communicate by gap junctions; across the zona pellucida they are going to be in contact. These granulosa cells and this oocyte are extending filopodia and microvilli into that zona pellucida space to make contact with one another.
She pointed out the basement membrane surrounding the granulosa cells that are surrounding the oocyte.
The cells outside of the basement membrane start to take form as well. These are called theca layers. There is usually a designation of a theca interna and a theca externa layer. These cells are going to be important for producing hormones after ovulation. So when Dr. Galin talks about the theca cells, those are going to be the cells that are immediately outside of a developing follicle. After the egg is ovulated, the goal is fertilization, so that egg will need nutrients as it goes on its path. The theca cells in the ovary are going to persist and produce hormone until or unless fertilization occurs.
Multilaminar Primary Follicle Histology [S23]:
You canthe granulosa cells, zona pellucida, and theca cells. The theca cells are starting to orient around the follicle.
Secondary (Antral) Follicles [S24]:
The designation between a primary multilayer and a secondary (antral) follicle is the presence of fluid buildup.
Secondary FollicleDiagram [S25]:
You are going to see the granulosa cells start to produce a liquid, called liquor folliculi. This starts to accumulate. The granulosa cells are going to keep dividing, but at some point, they will start producing the fluid that is going to produce a vacuole within the follicle.
She pointed out the basement membrane, granulosa cells, and zona pellucida. The granulosa cells are producing so much fluid, the vacuole will form.
Sometimes they will have multiple vacuoles; eventually, they will all come together to make one single antrum.
Secondary Follicle Histology [S26]:
The antrum is that vacuole that you see.
Graafian (Mature) Follicle [S27]:
The Graafian follicle is the mature one.
Usually, one out of about a dozen follicles that are developing will become the primary.
This is the follicle that is going to go through ovulation.

Graafian (Mature) Follicle[S28]:
There is always a layer of cells directly surrounding the oocyte. The egg is never exposed. At least one layer of cells is going to stay in close contact; this layer of cells is called the corona radiata. These cells will be physically ovulated with the oocyte. When the egg is ovulated, it will be dispelled from the ovary, and it is still going to be surrounded with granulosa cells. Those cells that are going to be ovulated along with the oocyte are called granulosa cells.
Usually, there is a little spot called the cumulus oophorus. The egg is not free floating; it is going to be embedded to one side.
Graafian (Mature) Follicle[S29]:
Here is a nice picture of a graafian follicle. The dark line represents the basement membrane surrounding the entire follicle, granulosa cells included. She pointed out the basement membrane, granulosa cells, cumulus oophorus (nesting bed for the oocyte), oocyte, antrum (fluid-filled), and theca layer.
Mature (Graafian) Follicle [S30]:
She pointed out the corona radiata and oophorus. The corona radiata are the ones that are always in very close contact and are going to be ovulated as well.
EM of oocyte and follicular cells [S31]:
This EM shows how the egg puts out processes. The follicular cells do too. This creates a meshwork with physical attachments surrounding the zona pellucida. Some of the follicular cells have pulled away.
Again, she pointed out the oocyte, zona pellucida, granulosa cells, and the outer basement membrane. ***She pointed these out over and over again, so probably will be a TQ.
An atresic secondary follicle [S32]:
Sometimes we see follicles like this. Not all of these are going to be ovulated. Determining which one gets ovulated might be a simple survival-of-the-fittest. The ones that respond to the hormone first are going to be the ones that develop first.
A free oocyte is most likely an atretic one. It is very normal to always see follicles that are degenerating.
Hormonal control of ovarian functions [S33]:
What controls this is: FSH and LH.
FSH will be instrumental in the maturation process just described. All of those cells will have receptors for FSH and that will guide the maturation process.
LH is going to be instrumental in the process of ovulation and the maintenance of the corpus luteum. Once the oocyte is ovulated, the corona radiata cells are going to leave with the egg. All of the other granulosa cells and the cumulus oophorus will stay and form the corpus luteum. This will continue to provide nutrients and hormones until the next menstrual cycle.
FSH controls the follicular phase. LH controls the luteal phase.
The Menstrual Cycle[S34]:
Here is what is happening on the follicle level. We have all these primordial and primary follicles, and at some point, their activation really ramps up. This represents the dozen or so that are going to mature.
Day one of the menstrual cycle is always the first day of bleeding.
The proliferative (or follicular) phase is named for the fact that the granulosa cells in the follicle are proliferating.
The first half is the proliferative phase—proliferation of the follicles. Then there is the secretory (luteal) phase, which is going to be the second half.
In the luteal phase, there will be a marked proliferation of the uterine lining to get ready for implantation.
FSH is high in the proliferative phase; LH surge happens right at ovulation.
Ovulation predictor kits are testing the level of LH because high LH will be responsible for ovulation.
This is given as a 28 day cycle.