Gwen V. Childs, Ph.D.
The following objectives (in bold) now have answers included.
1. Understand the basic science principles behind Mrs. Kelso’s infertility. It has significance to each part of her reproductive system, which is why I used it. Work through her treatment and it will help you understand the structure and function of the cells and hormones as well as the reproductive system events.
What led to her blocked uterine tube? (oviduct)
Pelvic inflammatory disease left scar tissue that blocked the tube. This reduced her chances to get pregnant (all things being equal) 50%, because every other month, the sperm could not reach the oocyte.
Why she might have ovulated, but not had gotten pregnant (endometrial defect)?
She had glandular developmental arrest. In other words, her day 24 endometrium still had expression of cyclin E. This indicated that the endometrium was not maturing properly. Perhaps this came from poorly functioning follicles or a corpus luteum that was not functioning well. It indicates that her serum progesterone and / or estrogen may not be adequate to support full development of the uterine glands.
How the corpus luteum affected her basal body temperature (what is the function of the cells).
The corpus luteum produces progesterone which elevates basal body temperature. As long as the temperature is high, this suggests that the corpus luteum is secreting progesterone and that it is alive..
How aging and stress affected her follicles and uterine endometrium.
While we don’t know exactly how this happens, it appears that aging reduces the quality of the oocytes and follicles which will also reduce the quality of the corpus luteum. We do know that aging reduces the number of follicles. If the quality of the follicles is lower (and their numbers) the uterine endometrium may not develop properly and may be arrested in an immature state. They see this by late expression of cyclin E.
We know even less about how stress affects the system, however the one example given in class (see slide show) showed that stress will cause glandular developmental arrest (GDA) which can be seen as a day 24 expression of cyclin E. We also saw that after the woman got a new job (another case described in the slide show), she relaxed and her glandular endometrium returned to normal. This problem can be superimposed on the problem of aging.
The significance of a Day 24 expression of cylin E in her endometrium.
Cyclin E is used in the proliferative phase of the menstrual cycle. It drives the cells to S phase. It should not be expressed in the secretory phase of the endometrial cycle…that phase should be characterized by differentiation (expression of p27 and no expression of cyclin E).
The significance of the presence of antral follicles (seen by ultrasound) in the first few days of her cycle.
This suggested that she was having a fairly normal follicular phase, with the rise in FSH needed to stimulate the Antral follicles. Also, it meant that her previous cycle may have been normal, allowing the late rise in FSH seen as the corpus luteum dies and progestrone and estrogen are lowered (hence the negative feedback is less). This FSH rise is vital for the stimulation of the next crop of Antral follicles.
Why she was treated with FSH for a number of days.
FSH stimulates Antral follicles and they continued to treat her daily with FSH to mature as many follicles as they could. Because this was by injection, a steady dose allowed maturation of more follicles than in a normal cycle. Note: they had shut down her endogenous hormones by injections of a potent GnRH agonist which down regulated GnRH receptors and prevented gonadotropes from being stimulated. Thus, they could control the stimulation of the follicles more readily.
Why she was treated with one dose of hCG before retrieval.
hCG is biologically identical to LH and this would be identical to the LH surge in a normal cycle. Thus one injection of hCG will stimulate all of the events needed to get the Graaffian follicles to ovulate. They will retrieve the oocytes before ovulation, however.
Why she was treated with progesterone after retrieval.
To help maintain the uterine lining, in case the corpora lutea formed by the ovulated follicles were not functioning well.
Why her embryos were co-cultured with her endometrial cells.
To provide nutrition normally available to the embryos in vivo.
The significance of the transfer of “hatched blastocysts” to the uterus.
Blastocysts have to hatch out of the zona pellucida before they can implant. This may happen spontaneously, or the zona pellucida may have to be removed.
2. Understand the significance of the expression of cyclin E and p27 by the uterine endometrium and the importance of timing. Why is this a better way of detecting endometrial defects than histological dating (presence of the glycogen vacuole)?
See handout and slide show. Cyclin E drives cells to the S phase of the cell cycle. It is inhibited by p27. Cyclin E is therefore expressed most abundantly in the proliferative phase. It should not be expressed in the secretory phase. If it is found on day 24, for example, this indicates that the endometrium is immature…not fully developed and able to support a pregnancy. Often patients present with a normal histological appearance (normal droplet of glycogen in the cytoplasm), but they have an abnormal expression of cyclin E. Thus, the normal histology is not detecting the underlying abnormality in the glands (their lack of maturity). This is called glandular developmental arrest.
3. Understand the value and use of basal body temperature for predicting fertility.
The BBT is low and goes down slightly just before ovulation. Then, it rises 0.5-0.6 degrees and remains high as long as the corpus luteum is alive. Thus, it predicts ovulation and the life of the corpus luteum, which should be 14-16 days. The temperature drops when progesterone drops (because the corpus luteum has undergone atresia) and the menstrual phase begins.
4. In the lecture, I traced the route to and from maternal to fetal blood several times, at every stage of development. Be sure and do this yourself and understand how the layers change and how the embryo and fetus is nourished. This is critical to understanding how the uterus and placenta respond to the growing fetus. Check out the cartoons in Langman!
Laboratory:
For the laboratory, be able to identify all of the functional cells and their developmental stages, if any, in the ovary, uterus, oviduct (uterine tube), cervix, vagina, and placenta. The different cell types are named in my study guide. Look at LM’s and EM’s in your text book as well as Histology Time. Use images to distinguish stages of the cycle or stages of development. I suggest you make a list of landmarks for each cell or structure (e.g., vagina has no muscularis mucosa) and learn these landmarks. Be able to visually put a pin in a structure and tell us about the layers penetrated (e.g., layers across which the oocyte must pass to ovulate; layers of the mucosa of the vagina, etc). Understand the correct sequence of developmental events and be able to place a cell in the appropriate stage.
Please understand that a lecture-type question can be linked to a lab-type image and vice versa. This is the time to integrate information and it is important to do that as you are studying either lab or lecture material. Use images to tell us what stimulates a given cell or the function of that cell. This will be true for the Endocrine system as well.