Sperm DNA Fragmentation
Intracytoplasmic sperm injection (ICSI), a procedure where a single sperm is injected into an egg, went into widespread use in the US in the early 1990's. With it came the view that as long as a man had any sperm, he could father a child. In many ways ICSI was a remarkable procedure, allowing thousands of infertile males to have children. And ICSI worked even when the sperm didn't swim well, had poor morphology or were surgically recovered from the epididymis or testicle. It appeared as though there was no physical obstacle to fertilization as long as a live sperm was available for injection.
Now, with over 10 years experience with this procedure, and regardless of sperm or egg quality, we understand that on average 70-80% of all eggs will fertilize following ICSI. If we physically place the sperm inside the egg, fertilization happens most of the time. However, fertilization is not a very reliable measure of sperm quality, or even egg quality, and the rate at which your eggs fertilize has little bearing on whether or not your embryos will implant after transfer. Eggs recovered from women aged 40 and older, where we know that egg quality is poor, will fertilize at the same rate as younger eggs. Similarly, sperm with poor morphology will fertilize eggs at the same rate as sperm with normal morphology.
After fertilization, if embryo quality is poor, or if embryos fail to implant after transfer, we tend to implicate the eggs as the likely source of the problem. It is very hard to pin the blame on the sperm and we usually have very little evidence that would implicate the male partner in the failure. After all, much time and effort was needed to get the eggs, the egg is mostly responsible for preimplantation development, and the developing embryo was placed safely in the uterus. The tiny sperm brought only the male's genetic material or DNA, and we saw that that was safely inside the egg at fertilization.
Even when we start to worry about the DNA, eggs are much better known for genetic problems than sperm. Down syndrome is the classic example, as it is well known that the incidence increases with increasing maternal age. Genetic problems in children due to paternal age are less well known and in fact less than 10% of Down Syndrome cases arise as a result of a genetic error in the sperm.
In trying to visualize what DNA looks like, you have to think of a ladder. DNA is a double strand that is held together by the rungs, and the ladder is twisted and coiled. In sperm or eggs the DNA is organized on 23 distinct structures called chromosomes. Each chromosome is simply a very long twisted and coiled ladder.
When we count chromosomes in sperm and eggs, sperm have the right number about 90% of the time and for eggs this varies according to maternal age. For women over age 40, we would expect at least 50% of their eggs to have an incorrect number of chromosomes. These abnormalities don't appear to stop eggs from fertilizing, but the majority of the resulting embryos either won't implant or will miscarry early in pregnancy.
Because we know that sperm don't carry a lot of chromosomal abnormalities, we have to dig deeper to find problems that may cause infertility. The sperm chromatin structure assay (SCSA) is a test developed to look at the integrity of the DNA. Basically it looks at the structure of the ladder and determines if the strands are coming apart due to broken rungs. The more severe the DNA fragmentation is, the less likely that the sperm can establish a viable pregnancy.
To have the test performed, we ship a frozen semen sample to Donald Evenson, PhD, in Brookings, South Dakota www.scsadiagnostics.com. There the sperm are assessed and any sample with less than 15% DNA fragmentation is considered normal. Levels of fragmentation up to 30% may cause reduced fertility, and men with greater than 30% fragmentation are considered to have significantly reduced potential to father a child.
Environmental stresses such as smoking, exposure to other chemicals or toxins, or any other chemical or physical stresses that the sperm may be subjected to may cause or contribute to high levels of sperm DNA fragmentation. In the testes it takes over 70 days to make each sperm, so the potential for exposure to stress is high. Consequently, it's important for men to look after their health in the months leading up to their attempts to conceive. As always it's good to eat well, exercise, avoid illnesses, hot tubs and exposure to toxins and take your vitamins. We particularly recommend vitamins C and E, beta-carotene and anti-oxidants for sperm health. We don't routinely recommend the SCSA for our male patients since sperm fragmentation is likely to affect a very small number of men. The significance of a high fragmentation index is still under debate as there are reports in scientific literature of pregnancy successes despite a bad test result. Further, it is unclear what the prognosis is for men that succeed in reducing their fragmentation score by taking their vitamins and living healthier lives. An alternative solution for men with high fragmentation is to use donor sperm, however most couples choose to use their own sperm despite high fragmentation. - Joe Conaghan, PhD
Joe Conaghan, PhD, HCLD, PFC's ART Laboratory Director, is internationally recognized for his work with human embryos. His background in research includes involvement in the first PGD on human embryos. His high standards, excellent patient care and extensive experience brings national recognition to our laboratory. In addition, he trains fellow embryologists for licensure and is an inspector for CAP, the licensing body for IVF laboratories in the United States.
Sperm DNA Fragmentation Index
In graph A (pregnant) DNA fragmentation index is nice and low at 7.5%. You can see clearly that there are very few sperm (7.5%) with moderate or high fragmentation and that most of the sperm are bunched tightly together with very little fragmentation. These healthy sperm were able to establish and maintain a pregnancy.
In graph B (not pregnant), the sperm DNA is much more unstable and there is a fairly even spread of low, moderate and high fragmentation. The DNA fragmentation index is 65% and these sperm were unable to establish a viable pregnancy.
From Us to You
New FDA Regulations
On May 25, 2005 new FDA regulations go into effect that will drastically change certain areas of Assisted Reproductive Technology. At PFC, we feel it is important for our patients to understand the implications of these regulations and the effect they may have on their fertility care. We have created an in-house task force to not only ensure that PFC is in compliance with these new regulations, but also to provide patients with as much information as possible. While these new FDA laws will require more time and expense on the part of patients and clinics, federal law mandates that we adhere to them.
These new FDA requirements will affect the infectious disease screening of egg and sperm donors and individuals using gestational carriers. The law as currently written also will affect couples that may wish to donate their frozen embryos to another individual at some time in the future. The source of the eggs or sperm must be screened in accordance with the new rules if the eggs are retrieved or sperm collected on or after May 25, 2005 at any IVF clinic or sperm bank in the United States.
In compliance with California State laws PFC currently performs infectious disease testing on all individuals involved in IVF as well as sperm donors for intrauterine insemination (IUI). The FDA regulations apply to any situation in which eggs or sperm (or the resultant embryos) from an individual are being placed into another person with whom the source is not sexually intimate. The FDA requires screening for some diseases such as Jacob-Creutzfeldt disease and cytomegalovirus that California does not. Screening involves review of medical records, an interview, physical examination and testing.
The most difficult of the federal requirements is that testing must be performed within seven days of collecting the sperm or eggs. This means predicting the exact day that an egg retrieval or IUI will take place and relying upon sometimes slow outside reference laboratories to send test results back quickly.
The embryo transfer or IUI CANNOT OCCUR until the results are received and the donor(s) determined to be eligible. If results are not available by the day of scheduled embryo transfer, transfer may be postponed up to day 5 (blastocyst transfer) or ultimately cancelled. The embryos would be frozen for transfer at a later date. IUI's with donor sperm would have to be cancelled if results are not available.
In an effort to minimize the likelihood that a retrieval or IUI will be cancelled and to maintain compliance with FDA and California regulations, PFC will continue to perform infectious disease testing on ALL IVF patients, egg donors and sperm sources (IVF & IUI) prior to cycle commencement. Individuals subject to FDA screening will complete the infectious disease questionnaire and physical examination. Within seven days of the anticipated egg retrieval or IUI, a second set of infectious disease tests will be done. Sperm sources will be requested to freeze a sperm sample within seven days of the initial screening as backup in case the second set of tests are not available on the day of retrieval or IUI. For couples wishing to maintain the option of donating their embryos in the future, the egg and sperm sources will need to be retested six or more months after the egg retrieval.
PFC staff are working to identify outside reference laboratories that meet the FDA criteria and that will provide quick turn around time at reasonable cost to our patients. Your clinical coordinator in conjunction with the PFC FDA Task Force will address any concerns you may have on this issue.
- PFC FDA Task Force
Ask the Experts
My friend was tested with a high FSH of 10 and she still got pregnant, naturally! Now I'm confused – I have a low FSH of 7 and have not been able to conceive, even with IVF.
It is true that the follicle stimulating hormone (FSH) test can be a useful indicator of a woman's ovarian reserve (egg quality/quantity) but it is by no means a perfect screening for egg quality and/or quantity.
FSH, a hormone produced by the pituitary gland in the brain, is released into the bloodstream and travels to the ovary where it stimulates immature follicles containing microscopic oocytes to eventually develop a mature oocyte (egg). Early in the menstrual cycle, if the blood level of FSH is high, it indicates that the pituitary is working hard to stimulate the ovaries, therefore, the number and perhaps quality of the remaining eggs is decreased.
FSH is tested on day 2 or 3 of your cycle to provide a baseline measurement. An elevated FSH level above 8 might suggest that a woman is starting to experience the loss of her ovarian reserve. Menopausal women show FSH levels that are above 40. However, there are several variables, and as with many issues surrounding infertility, it has much to do with age.
Proper interpretation of FSH levels requires a simultaneous measurement of blood estrogen (estradiol) levels. Estradiol is made by the ovary, enters the blood stream and travels back to the brain (pituitary) to help regulate FSH release. Early in the cycle, day 2 or 3, it should be less than 60. A high level of estradiol, above 80, indicates that estradiol is suppressing the pituitary and providing an inaccurate FSH reading.
Several studies have set out to determine whether women with elevated basal FSH levels should be excluded from fertility treatment. A comprehensive study in the United Kingdom analyzed over 2000 patients for four years undergoing IVF treatment. Although it found no significant correlation between FSH levels and fertilization rates or miscarriage rates, the pregnancy rates and live birth rates were lower among women with higher FSH levels. Elevated FSH levels were also associated with more frequent cycle cancellation, need for larger amounts of stimulation medication, and lower numbers of eggs and embryos with fewer embryos transferred. However younger women, even with high FSH levels, had significantly greater live birth rates compared to older women with normal FSH levels. Again, age matters, despite a normal FSH value.
A normal FSH reading, although reassuring, may be indicative of egg quantity but not necessarily quality. The follicles may be producing mature eggs, however, the quality of those eggs may not be adequate. This is especially true for women over 40 years old.
Another caveat is that most women have variable FSH readings from one cycle to another. The best indicator of treatment response, however, is typically the highest FSH reading. There is no benefit, therefore, in repeated testing of FSH over several cycles and choosing to undergo an IVF cycle when the FSH is normal. - Carl M. Herbert, MD
PFC Spot Light
"The Nice Woman at the Front Desk..."
Patients repeatedly commend our friendly staff members at PFC but frequently do not know their names. Laurie, whose story follows, is often referred to as “The nice woman at the front desk with blonde hair.” We at PFC thought our readers would enjoy being able to put a name with that face and even better, the story behind the face.
From the time I was very young, I imagined myself being a nurse. I enjoyed helping people and have always wanted to work where I was able to help people in a way that mattered.
I chose to train as a medical assistant to get my foot in the door of the medical field. Unfortunately, I found that while I was good at drawing blood, seeing blood in any other fashion made me woozy. After a while I came to realize that being a member of a support staff could also be helpful and rewarding work, so I decided to explore that option.
I have now been working in medical settings for 18 years. This summer will mark my 13th year with Pacific Fertility Center. My husband and I believe 13 is a lucky number and I feel fortunate to have a job where I can make a difference, not only by helping PFC patients, but also by being a contributing member of the front desk team.
As much as I enjoy my work, I relish my time away from the office. Each summer my husband and I go to the Kenai Peninsula in Alaska for one month. We camp on our small lot, roughing it and enjoying every moment of each 22-hour day.
Our stories of the world-class salmon fishing and the meals of delicious salmon (smoked to perfection by my husband) have often tempted our friends to come for a visit. We enjoy taking them for a ride on our boat up and down the Kenai River and sharing our love of the amazing beauty of Alaska.
Once I return home to Novato, I revert to being a homebody in the 21st century: reading, gardening and designing our “someday” house.
Although I am naturally an upbeat, happy person, there are times when I can't help but be affected by a patient's difficult situation. In fact all of us at the front desk silently root for patients; we may shed a tear at news of a failed cycle and or share the joy of a positive pregnancy test.
Though we may not always be able to communicate our sentiments, we care about our patients and want every one to find success here at PFC. - Laurie
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-- Best regards from all of us at Pacific Fertility Center.
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