 Human Egg
In the fifth week of pregnancy, a female fetus will develop a small structure called the genital
ridge (which will evolve into the ovaries), colonized by special cells called primordial germ cells.
Multiplying rapidly, these early cells eventually become eggs. About half way through the pregnancy there are about 7 million of these so-called primitive eggs. Their frenetic multiplication tapers off and actually declines down to 2-3 million eggs by the time of birth, the point at which scientists have assumed that a female has developed all the eggs that she will ever have.
Strangely, in competition with this process of germ cell multiplication, there is a remarkable course of cell death, which begins at about 16 weeks into gestation and continues unrelentingly until all the eggs are gone (typically when a woman is in her early 50's). From the many millions of eggs at the time of birth, the reserve reduces to about 400,000 by puberty. During her lifetime, a woman will ovulate between three and four hundred eggs total. The rest die and are reabsorbed by the ovaries.
The reasons behind this early cell death have remained a mystery. But the facts are staggering. Before a girl even ovulates her first egg (at puberty), she has lost an average of 340 eggs per day since birth. After puberty, the rate averages out at about 25 per day. The rate of depletion then doubles at about age 37, ensuring that the egg supply is exhausted by the early 50’s. Evolutionary biologists have assumed that this is nature's way of stopping a woman from having more babies than she can raise.
Now this entire foundation of knowledge regarding female egg production and depletion is in question. A recent paper by Johnson et al., (Nature, March11th 2004, Vol. 428, pp. 145-150) has opened up new doors for a drastic revision of the biological theory behind female egg production, and thus her fertility.
The research comes from the laboratory of Jonathan Tilly, an established and highly respected developmental biologist at Harvard Medical School. By studying mice, the researchers determined that germ cells persist after birth; and such stem cells give rise to new eggs throughout a mouse's life. In a remarkably simple experiment, researchers quantified the rate of egg depletion in the mouse ovaries, and determined that the rate should have exhausted the egg supply much earlier. Yet an unidentified replenishment was taking place. Mice are normally fertile for about a year, but Tilly found that their egg supply would be exhausted in just 2 weeks if it were not somehow being replenished.
Tilly is confident that these same results will be found with human ovaries, despite significant differences in egg biology between the two species. If he is correct, many new therapies could evolve to preserve fertility and stave off menopause in omen. The germ cells for example, might be easier to preserve (freeze) than eggs, and women under-going ovarian irradiation as part of cancer treatment, which destroys eggs, could have their ovaries repopulated. Also, since the ovary creates estrogen-producing granulosa cells to surround each new egg, germ cell
transplants could reverse the hormone withdrawal effects of menopause.
A tremendous amount of research will have to take place over many years before any of this conjecture starts to take shape. Meanwhile, one has to be cautious in assuming that human eggs behave like those of mice, because significant differences exist. Mouse eggs, for example, do not display the same age-related problems, such as increased rate of genetic abnormalities and decreased embryo implantation, which are evident in the eggs of older women. But the prospect of a replenishing egg supply is very exciting and provides hope for those of us trying to preserve fertility.
- Joe Conaghan, PhD, HCCLD
 Dr. Joe Conaghan, PFC's ART Laboratory Director, teaches human reproduction, trains fellow embryologists for licensure and is an inspector for CAP, the licensing body for IVF Laboratories in the United States. His background in research includes involvement in the first PGD on human embryos. He directs PFC's team of all board certified embryologists. His high standards, excellent patient care and extensive experience brings national recognition to our laboratory.
My husband and I were married for 6 years before we started trying to have a baby, and essentially got pregnant on the first attempt. Unfortunately, I miscarried in the second month. Our doctor told us not to worry; we tried again, got pregnant again, and miscarried early again. We still weren't particularly worried, but had some tests performed and nothing in particular seemed to be inhibiting fertility. Over the next 5 years we went through phases of trying and not trying as we moved twice to accommodate dual careers, worked with 3 different fertility specialists in 2 states, negotiated a variety of insurance policies, endured the gamut of fertility tests, and suffered 3 more early miscarriages. Along the way I also struggled with mild depression, and guilt that perhaps the stress and travel associated with my job was the culprit, but we generally remained optimistic that we would someday have a baby.
Gradually we attempted more intense treatments, from Clomid to ovulation induction injections to intrauterine insemination (IUI). When our second IUI attempt failed last spring, our hopes really started to fade. I was 36, and while my husband and I are blessed with the resources to try several assisted fertility cycles, there were limits to what we could withstand financially and emotionally. Although I liked my doctor (a specialist at a teaching hospital), the support staff seemed to be in flux, the office environment had a high chaos factor, and I didn't feel as though my particular case was significant to them.
On the recommendation of my primary care physician, I set up a consultation with Pacific Fertility
Center and met with Dr. Ryan. I was immediately encouraged by the thorough review of my history and finally felt that someone was really listening to me, unfortunately this is not a given with all practices. After discussing a range of options it was crystal clear to me that we should try IVF with PGD, in order to screen the embryos (since we had experienced so many early miscarriages). We figured even if PGD told us that none of the embryos were viable, at least we would have valuable information about our next steps.
We embarked on a cycle of IVF this past winter, and with each successful step of the cycle, were amazed and encouraged. When the results of PGD came in we found that the majority of our embryos had a chromosomal abnormality, but several also appeared perfectly normal. We transferred 3 embryos, and I'm delighted to report that I'm now in the 5th month of my pregnancy (one baby, a boy, due in August). So 6 years after we began our quest for a baby we see the proverbial light at the end of the tunnel, and it is an amazing feeling. We can't thank PFC enough for their combination of expertise and compassion. They restored our confidence and hope.
- Name withheld upon request
Q:
Can I collect my sperm at home and store it in my freezer? I have heard there is a kit that allows me to do this?
A:
There are collection and storage kits that allow you to initially collect and freeze your sperm specimen at home, but are not intended for storage in your kitchen freezer. The necessary temperature for maintaining sperm viability is far colder than a home freezer maintains. Specialized kits sold by only a few andrology clinics are designed to let you manage the collection process in the comfort of your own home. They can be purchased and shipped to you for about $350. (Please go to www.nwcryobank.com). These kits maintain the necessary frigid temperature for up to about a week, providing plenty of time to store several specimens for return to the andrology clinic. The kits include the necessary sterile implements for collection.
Naturally, home sperm collection is preferable over visiting a clinic, but freezing sperm is rather involved, and requires a great deal of attention to detail. Be sure to carefully follow the clinic's instructions.
If you decide this process is for you, here's what to expect:
The kits usually contain several vials for collecting multiple specimens over several days, thus ensuring back-ups. The specimen must be collected through masturbation using no lubricants, to avoid contamination. Once collected, the sample needs to sit at room temperature for 30 minutes while enzymes in the seminal fluid allow the initially thick sample to become more liquid.
Then the sample needs to be mixed with cryoprotectant, or antifreeze, which should be prepackaged inside the vials included in the sperm collection kit. The antifreeze must be separated from the sperm before insemination.
Do not attempt to freeze and thaw the sperm on your own for home insemination. Only an andrology lab can perform the critical step of extracting the sperm from the antifreeze upon thawing.
Also, even if you know that the sperm is of good quality, it is important to know how well it tolerates freezing and thawing. Your infertility clinic or a sperm bank can provide you with valuable information on the quality of the sperm and its capacity to withstand freezing. Results can be extremely variable. Northwest Andrology reports that on average, healthy normal sperm in one out of ten men simply do not hold up to cryopreservation. Poor sperm survival rates can greatly impact the outcome of IUI, which requires more sperm than other procedures like IVF and IVF with ICSI.
Unfortunately, there is no "in between" process that allows for short term home freezing in one's freezer for out-of-town moments, or other reasons. And timing fresh sperm for home insemination also requires a certain degree of precision. If the sperm provider cannot be there at the exact time he is needed, the sperm will die in the seminal fluid fairly quickly. If fresh sperm are to be used, it is necessary to do the insemination within an hour or two of collecting the sample.
--- Joe Conaghan, PhD
Couples who are at risk of passing on an inherited disease are probably familiar with genetic counselors. However, those who have decided to undergo IVF with Preimplantation Genetic Diagnosis (PGD) will need to see a genetic counselor who is specialized in the procedure of PGD itself. It is important to make sure that the mutation in question can be diagnosed by PGD since not all heritable diseases have DNA probes. And sometimes there are other means of using PGD to determine mutation likelihood.
In cases where there is concern about chromosomal abnormalities rather than single gene defects, Preimplantation Genetic Screening (PGS) is another option that requires a genetic counseling session. The genetic counselor can help patients understand the basics of chromosomes, how they affect the health of embryos and what this testing conveys about the embryos.
Some of the common reasons why patients undergo PGS include:
1. Age (eggs of women >35 years old have a higher risk for chromosome abnormalities),
2. Unexplained recurrent pregnancy loss,
3. Gender selection for genetic disease,
4. History of unexplained unsuccessful IVF cycles.
Who Are Genetic Counselors?
Genetic counselors are health care professionals with graduate degree training in genetics and counseling, and certified by the American Board of Genetic Counseling. Genetic counselors practice in several subspecialty areas of genetics including assisted reproduction technologies, infertility genetics, and prenatal diagnosis. Because your genetic counselor can see you to discuss PGD or PGS, as well as prenatal testing options once you are pregnant, you will receive continuity of care. He/she will help you understand the complex information involved in your PGS cycle, and encourage your own decision making according to your needs. He/she will also serve as a liaison between you, your fertility doctors, and the PGD/PGS laboratory.
What Happens During A Genetic Counseling Visit?
There are two main objectives:
1. Family History Review: Your genetic counselor will take a three generation family tree (pedigree) to identify any additional genetic risks. This process ensures that the type of screening being offered is correct, and to identify any additional testing needed. Medical records may be requested for review.
2. Informed Consent: Informed consent includes an in depth discussion of the PGD/PGS process, from beginning to end, and a review of the information in the consent form, which is designed to inform and protect patients. Important information contained in the consent form includes risks and limitations of PGD/PGS, as well as the purpose of the procedure and the diagnostic technique. Your genetic counselor is available to answer questions regarding its content and to help you thoroughly understand it before signing. For those who have already gone through IVF, the beginning of the IVF with PGD/PGS cycle will be familiar. However, as complex as IVF is, embryo testing adds yet another layer of complexity. Additional steps include biopsy procedures, screening of a single cell for specific chromosome abnormalities or DNA mutations, and reviewing the results prior to embryo transfer. Only a genetic counselor is especially trained to mentally guide you through this process before you are actually in cycle so that, hopefully, there are no unanticipated outcomes.
How Can I Find Out More?
Please contact the Certified Genetic Counselor working with Pacific Fertility Center: Lauri Black at (415) 600-6371.
--- Carolyn Givens, MD and Lauri Black, MS, CGC
Preimplantation genetic diagnosis (PGD) is a technique used to identify many inherited diseases. PGD uses DNA amplification to identify embryos with specific mutations of single genes, which may have been acquired from the mother, or father or both.
What PGD can do:
1. PGD can diagnose embryos at risk for some specific genetic diseases if the parent(s) are known to be carriers, and the molecular genetic basis of that disease is known.
2. PGD identification enables elimination of those embryos carrying the genetic mutation that causes the disease in question. It cannot repair those mutations.
What PGD cannot do:
1. PGD cannot guarantee that the baby will be free of all diseases or birth defects because the genetic basis for many defects is unknown. At this time, it is impractical or impossible to screen for most diseases, such as diabetes and cancer, or birth defects such as cleft lip and palate.
2. PGD cannot diagnose all diseases, even if the genetic basis is known, because some of the rarer diseases do not yet have available DNA probes.
3. PGD cannot determine traits, such as eye color, height, intellectual or athletic abilities.
4. PGD is not perfect, despite how sophisticated it is. Errors in diagnosis can occur, albeit at a very low rate. Confirmation of the correct diagnosis should be done by chorionic villus sampling (CVS) or amniocentesis, once the pregnancy is established.
The second type of genetic analysis is what we like to call Preimplantation Genetic Screening (PGS) to look for abnormalities in entire chromosomes missing or extra chromosomes or multiple complex abnormalities in chromosome numbers.
What PGS can do:
1. PGS can screen for abnormalities in 9 out of the 23 chromosome pairs. Currently it is not technically possible to screen for abnormalities in the other 14 chromosome pairs.
2. PGS can help to reduce the risks of miscarriage, commonly due to Monosomy X (one X chromosome) or Trisomy 16 (three of chromosome 16).
3. PGS can help to significantly decrease the risk of Down Syndrome (Trisomy 21) and Trisomy 18, as well as abnormalities in numbers of sex chromosomes (X and Y) (These are among the few abnormalities in fetuses that can survive to the time of amniocentesis and birth).
4. PGS can reduce the number of embryos one must transfer to find the embryos most likely to succeed.
5. PGS may help couples experiencing multiple IVF failures to determine if the failed implantations may be due to aneuploidy (chromosomal abnormalities).
6. PGS can determine the gender of the embryo.
What PGS cannot do:
1. PGS cannot screen for specific genetic diseases couples at risk need PGD.
2. PGS cannot guarantee that the baby will be free of all diseases or birth defects.
3. PGS is not perfect. The detection rate is between 90-93% for the chromosomes analyzed, which is why we still recommend CVS or amnio as a confirmation of PGS findings.
--- Carolyn Givens, MD
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Genetic Counseling is a prerequisite