Wednesday, January 22, 2014

"When Good Eggs Go Bad": Mechanisms of Female Infertility

By Becca Yeamans

There are many ways by which a woman can be infertile, however, most of the time, the problems center around the formation and maturation of the egg (oogenesis).   Age at pregnancy is one of those factors that are often cited when discussing fertility rates among women, however, it still is debated exactly how maternal age plays into the fertility story and what can and does go wrong when a woman gets to be of a certain age while pregnant. 

In addition to age, external stimuli, such as estrogen-like compounds like BPA and other EDCs found in the environment as a result of the various plastics and processed materials in our lives which are designed to make life “easier”.

In 2008, two researchers from Washington State University in Pullman, WA put together a very comprehensive review paper illustrating the different ways in which human female infertility can occur, specifically focusing on the egg itself and the processes it must go through between formation and maturation that can run into problems and cause infertility.  This paper provides excellent framework for the mechanisms behind female infertility related to problems with egg development, which I will summarize briefly for you in this post and draw from periodically when making possible connections to endocrine disruptors in future posts.



On average, the age at which women in the United States experience their first pregnancy is 3.6 years later than it has been in previous decades, a trend which is seen in many other parts of the world as well.  It is also known that pregnancies occurring in older women tend to experience higher risks, including genetic disorders caused by age-related problems with the “egg development machinery” such as Trisomy disorders and increased infertility related to chromosomal abnormalities of the egg. 
The review paper by researchers at Washington State University found three different times during the development of the egg that are solidly linked to increased trisomies or other chromosomal abnormalities, including the stage of meiotic prophase, formation of the follicle, and egg growth and final maturation.  These times include: during the recombination stage of meiotic prophase in the developing fetus, follicle formation in the developing fetus, and the maturation stage of oogenesis (i.e. egg development) in the adult ovaries.

Fetal Meiotic Prophase

During the prophase segment of meiosis, the chromosomes experience a variety of changes, most importantly the breaking and recombining of chromosomes to create a completely unique individual egg that is unlike any other egg with the ultimate goal of spreading genetic diversity among the population.  After this stage, the developing egg goes into a resting phase where it sits and waits patiently for the next step in development.  It is also during this phase where the egg goes through a checkpoint—the body’s way of making sure there were no errors in recombination and that it’s safe to move forward with the development. 

There are a few different mutations that can occur during prophase that when found at the checkpoint during prophase in the male (development of sperm), the process is abandoned and that cell reabsorbed by the body.  However, in the female, this checkpoint may not be as effective; thereby some of the developing eggs with chromosomal mutations are allowed to continue developing and if fertilized, could result in significant health problems or even death for the fetus.  Since recombination involves the breaking of and recombining of sections of chromosomes, studies have found that the sheer number and position of the recombination crossover on the chromosome can have a significant effect on recombination and segmentation errors.  Think about it---if your chromosome is programed to break up and recombine in a lot of places, the chance they might not reconnect properly or even break up properly to begin with increases.  If your chromosome is only programed to break up and recombine in one spot, the chance for error is slim.  The more chances your chromosomes have to break up, cross over, and recombine, the greater the chance of there being some sort of error, leading to trisomies or other chromosomal abnormalities that result in infertility or severely disabled offspring.

Development of the Follicle in the Fetus

Simply put, the follicle is a “community” of cells, including the oocytes (developing eggs), and granulosa cells.  It is within the follicle that the developing egg undergoes intensive hormone-driven growth and the place which provides a safe environment for the egg to continue on its maturation path.  The follicle itself forms in the fetus during the second trimester of pregnancy, which is triggered by what some researchers think is a sudden drop in estrogen levels, though the consensus is not all uniform. 

In order to form a follicle, you need the breakdown of connections between lumped together immature oocytes, as well as the encasing of the now-individual oocytes in somatic cells (granulosa cell precursors).  If errors occur and the connections between lumped together immature oocytes are not broken down, then there is a significantly increased risk of “multi-oocyte follicles”, which is basically a death sentence for the embryo.  If a woman continually has this problem of multi-oocyte follicles, then her fertile egg pool will be significantly diminished and she will likely experience an early end to her reproductive potential and also possibility an overall decrease in the quality of eggs produced, potentially leading to miscarriage or health problems for the offspring.

Oocyte Growth and Maturation in the Adult Female

Many fertility issues can be linked to how the oocytes develop in the fetus, though there are also some fertility problems that can arise in a woman’s prime reproductive years.  Specifically, when meiosis starts up again in the adult after lying dormant for many years, the oocyte continues to grow until ovulation occurs (85 days in humans).  In order for the follicles and oocytes to grow, several hormones play roles in developing a healthy egg that is viable and fertilization-worthy.  These hormones include pituitary gonadotropin, estrogen, and hormones in the TGF-β superfamily. 
As a woman ages, problems in the meiotic maturation of her remaining oocytes can continue to increase until she is no longer fertile.  Though the mechanism behind which is not currently agreed upon, FSH hormone levels are shown to rise with age and possibly by environmental factors.  Researchers have also found that increased FSH levels in women may be related to increase reproductive failure.  Similarly along those lines, with age come more potential difficulties or errors in spindle and microtubule formation during meisos, which could lead to errors in chromosome division and allocation into individual developing egg cells.  In other words, as a woman ages, and as she is exposed to certain environmental toxins, it becomes much more difficult to produce and healthy, viable egg, thus leading to trisomies, other chromosomal disorders, miscarriage, or early menopause.

Summary

This review paper, pulled together by researchers from Washington State University in Pullman, WA, illustrated just when and where problems can occur during the maturation of the eggs not only as an adult, but also when in utero as well.  It is important to understand these mechanisms, as it will give us an opportunity to understand just exactly how some of these situations where you have a “good egg gone bad” have connections to environment toxins, such as BPA or other endocrine disruptors.
What does this information tell us about endocrine disruptor function and fertility in women?  Stayed tuned for a follow up to this post delving into this side of things!

Source:

Hunt, P.A., and Hassold, T.J. 2008. Human female meiosis: what makes a good egg go bad? Trends in Genetics 24(2): 86-93.



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