genetics and fertility

Understanding How Genetics Play a Major Part in Fertility & Reproduction

Understanding how genetics plays a major part in fertility and reproduction is very important. Many couples are completely unaware that their fertility issues and inability to conceive may in fact be from genetic, or hereditary issues that have not been screened for.

When it comes to fertility and being able to conceive more and more couples are now struggling. Some of this is due to increased stress levels, poor diet and lifestyle, increase alcohol consumption, lack of preconception care and many other factors. However, one key area that is not often talked about, or even known to many is genetic factors, chromosomal factors and DNA issues passed on through our sperm and eggs.

Fertility and reproduction is one of the hardest areas of medicine to understand. I am sure many people think that they understand it, but even with years of study and clinical experience, some questions just cannot be answered at this present time. No amount of “Dr Google” searching is going to bring answers for many couples and this is something that needs to be discussed more. Unless you have done years of study and clinical research into fertility and reproduction, you cannot understand the finer details and intricacies of conception. Even then, some answers are just not available to anyone at this present time.

The Reality of Fertility and Reproduction

The reality of fertility and reproduction is that just because an egg and sperm are put together, it does not mean that an embryo will be formed. Even if an embryo is formed, it does not mean that it will become a baby. Even if an embryo meets scientific grading categories (grade 1-4 etc), it still does not mean that the inner make up of that embryo is chromosomally viable. Even if the embryo is tested to be chromosomally viable (via PGD/PGS testing), it still does not mean that the embryo will go on to become a baby. This is the hardest thing for people to get their heads around and why we need to discuss this more. Quite simply, something that is supposed to seem easy really isn’t that easy at all. Reproduction and having babies is not as easy as many have led us to believe.

Chromosomal Errors

One of the biggest factors in embryos not developing, or IVF cycles failing, or even natural conception not working is chromosomal errors at the embryo stage. Even if both parents have normal karyoptype (46XX and 46XY) it does not mean that they cannot produce random chromosomal and genetic errors in their sperm and eggs. The thing is, the older we get, the more these errors occur and the harder it is to fall pregnant. An abnormal embryo with and abnormal number is cells is called aneuploidy. When an embryo has the correct number of cells it is called euploidy. Unfortunately, many couples are producing high numbers of aneuploidy embryos and this is why they are struggling to conceive. As mentioned before, just because the outer features of the embryo look fine, it does not mean the inner workings (chromosomes and DNA) are fine.

The Important of Genetic Screening

Speaking about chromosomal and genetics, when couples are struggling with fertility and being able to conceive, one of the biggest factors I see is that couples are not being screened properly. This is screening on all aspects, not just the standard blood tests and fertility investigations. Many couples that come to see me for help for fertility often believe that they have had everything done, yet most times I am finding that they have only had the basics done. Many couples have not even had basic genetic screening for karyoptype and genetic issues such as cystic fibrosis.

Understanding the Coding on DNA

Understanding the coding on the DNA is now having a profound practical impact on the practice of medicine today. This is particularly important in the area of infertility. There is increasing knowledge that there is frequently a major genetic component both from nuclear and mitochondrial DNA in couples with infertility or subfertility.

Significant examples include:

  • The demonstration of microdeletions on the Y chromosome in men with low sperm count (oligozoospermia)
  • The identifications of mutations in the Cystic Fibriosis gene in those with congenital bilateral absence of the vas deferens
  • The high rate of aneuploidy in normally dividing embryos after fertilisation in older infertile couples
  • The presence of an expanded triplet repeat in the androgen receptor in some men with low sperm counts.

Without seeing someone who has all this  knowledge of the molecular and genetic basis  of fertility many couples will continually have troubles trying to fall pregnant and may possible end up with repeated failed cycles in IVF too. There is so much to genetics and it is often overlooked in all areas of fertility these days. No amount of “Dr Google” is going to give you this information, nor will it give you understanding, unless you have a degree in reproductive medicine, or genetics. I do understand that people get desperate for answers, but unfortunately, sometimes these answers cannot be found by an internet search.

Other Genetic Factors Affecting Fertility

There are also other genetic conditions and chromosomal errors such as balanced translocations, reciprocal translocations, Robertsonian translocations, Turner’s syndrome, Kleinfelter’s syndrome, fragile X syndrome and many more. Again, many who are struggling with fertility issues and struggling to have a baby may not have even had some of these genetic screening done.

When I see couples, I also recommend advanced genetic carrier screening which tests for several hundred more genetically inherited mutations. Many fertility clinics do not recommend couples to do advanced carrier screening. Given that 1 in 22 couples are at risk of a hereditary gene mutation, it is really important to screen couples properly and not just do the basics.

Mutations in Genes

A mutation is a change in the information encoded in the DNA sequence. Such a change may result in the production of an abnormal protein, produce a truncated protein, reduce the levels of that protein, or cause it not to be made at all.

A single gene genetic disorder is one where an alteration in the DNA sequence of only one of the genomes 40,000 genes has resulted in significant pathology and disorders that affect the human body.

Such disorders include cystic fibrosis, Duchenne muscular dystrophy, Huntington disease and familial breast cancer. Although individually these disorders are rare, as a group, they are numerous and therefore important.

Cystic fibrosis, one of the most common autosomal recessive conditions affecting people of Northern European decent has a population incidence of 1 in 2,500.

To date up to 6,000 single gene disorders have been characterized and it is estimated that 14 per 1,000 people suffer from one of these conditions. A person who inherits a mutation in a single gene will carry that mutation in every cell of their body.

Mutations occur when a cell is dividing. The task of correctly copying 6 billion “bits” of information, the number of base pairs in the human genome, is huge and mistakes do occur. It has been established experimentally that these mistakes occur and are uncorrected in one in one billion base-pairs copied (or about 6 errors per cell division).

When a mutation occurs in the coding DNA sequence of a gene it may be a polymorphism with no effect or it may significantly impair the gene function. All mutations are thereafter inherited. Inherited or germ line mutations must be present in the egg or sperm. They are twice as common in sperm as eggs.

 Male Sperm Quality is a Big Part of Fertility Issues

Before everyone jumps to the conclusion that all failed cycles are related to women’s egg quality, I need to make it absolutely clear that men are half of the fertility equation. They are not exempt when conception does not take place, or an IVF cycle fails. As mentioned above many genetic mutations are twice more likely to be present in sperm than eggs. Up to 85% of miscarriage and chromosomally defective embryos are related to chromosomal errors that men have passed through their sperm.

Women’s eggs do have more errors as they get older, and eggs are not as viable as they get older, but men’s sperm are exactly the same. If men are not having their sperm quality managed while trying to fall pregnant, there is half your problem then and there. This is why all men are treated and managed on all levels of their health when doing my fertility program.

Sperm quality is variable and each time a man ejaculates the quality of that sperm can vary by as much as 20% at a given time. This is why men need to be continually looking after their health and sperm health while trying to conceive. Men are actually the bigger part of conception not taking place and we need to talk about this more. Men are not exempt when it comes to making babies.

Creating Life

Life does not begin with conception, but is simply a continuum from living cell to living cell with genetic information being transmitted through the genome from one generation to the next. A failure to achieve this is recognised as infertility.

At conception we are a single fertilized cell resulting from the fertilization of the egg by the sperm. The sperm contributes one copy of nuclear DNA, the egg the other copy and the mitochondrial DNA. That cell proceeds to divide, and over the course of 9 months (32 cell divisions) billions of cells are created, with specialized functions, forming complex tissues and organs that constitute the working human body. That first cell therefore must contain all the information necessary for embryological development, growth from fetus and then growth through to adult life. Without all the right coding and necessary information, life does not get created. This is also the answer to why so many couples are having problems trying to conceive.

The Importance of Seeing a Reproductive Medicine Expert

There are many factors to fertility and reproduction and why it is important that couples see someone who is a fertility expert. The fertility profession is largely unregulated and many who are now practicing in that profession are not experts at all. Many actually do not have further training and qualifications in reproductive medicine and are some of the reason why people are struggling to fall pregnant.

Final Word

Lastly, while we cannot change our chromosomes, or change genetic mutations, we can do things to change and improve our cellular DNA. This is why proper preconception care and preconception programs are so important. Everything we do, we ingest, we think etc, can be passed on to our future offspring via sperm and eggs. Health parents produce healthy sperm and eggs, thus producing healthy babies.

If you need help with being able to conceive, give my friendly staff a call and find out how my fertility program may be able to assist you. I use a ‘No Stone Left Unturned’ approach to assisting couples with fertility issues and will look at every aspect of a couples lives, including genetic and hereditary issues, to help them have the best chance of having a baby.

Regards

Andrew Orr

-No Stone Left Unturned

-Master of Reproductive Medicine

-The International Fertility Experts

IVF cover image

Let’s Talk About Why IVF Cycles Fail

Let’s talk about why IVF cycles fail because it is a very common question that is asked when a cycle fails. Often there will be no conclusive answer and often when I am asked this, I have to say the old saying “How long is piece of string?”

The reason I say this is that there are so many factors involved with a cycle failing. It could be from following

  • poor egg quality
  • poor sperm quality
  • age of the couple
  • genetic factors (diagnosed, or undiagnosed)
  • hereditary issues
  • DNA and chromosomal issues
  • a non-receptive endometrium
  • dietary and lifestyle factors
  • weight factors (excess or too little weight)
  • emotional factors, or mood disorders
  • stress
  • incorrect hormone therapy
  • medications
  • human error
  • lab errors
  • many other factors in the IVF process.

I wish it was as easy as putting a sperm and an egg together and it just happening. I know many couples do look at it this way, but there is so much more to the whole process of conception. I know it is often hard to understand, but no google search is going to tell you all of this and you would need years of study to completely understand the whole process. Plus IVF is still only a young form of medicine and it still evolving.

This is why IVFsuccess rates are still relatively low. We just do not have the technology yet to tell us which embryo will go on to become a baby. If we had that, then there would be a much higher, if not near 100% success rate. The reality is that type of technology may never be available, or would be many many years off. We can only hope.

The other thing I explain to couple is that sometimes it is literally the IVF process hindering a couples chances of success, by not having the right protocol, or right team helping them.  I could go on and on because there are so many factors that could affect a cycle and someones chances of conceiving. This is why I use the term “How long is a piece of string?”

This is why I do what I do and explain all of this and more to all my patients as part of my fertility program. I am literally there to hold their hands every step of the way and explain everything in detail each step of the way as well. I will always make sure everything is done properly and even go into bat for them and step on toes if I have too. My patient’s come first always.

What is required for a successful pregnancy?

At least three things are required for a successful pregnancy during in an vitro fertilization (IVF) cycle:

  • a healthy embryo
  • a receptive endometrium
  • careful transfer at the proper time in the cycle

There are things other things such as the right diet and right nutrients and right emotional state for the couples and proper preconception care, but for now I am just talking about a successful embryo transfer on a medical level. Firstly I will discuss the IVF process.

IVF has improved significantly in its almost 40-year history. Different types of hormone and fertility drugs have been developed that are easier to administer and are associated with an improved safety profile. In addition, numerous stimulation protocols are available that allow us to individually tailor treatments. For example, ultrasound-guided embryo transfer using soft catheters and embryo glue (enzyme to assist implantation) has also helped with ensuring better placement of the embryo, without trauma to the endometrium, but very few clinics are actually doing this. Tests can also be used to evaluate the receptivity of the endometrium in order to determine the best time to schedule the transfer.

Despite all these improvements, however, implantation and pregnancy rates with IVF only slowly increase year after year.

Achieving Implantation-The hardest step

The rate-limiting step of IVF is implantation. It requires the proper interaction of a healthy embryo and a receptive endometrium. It often fails due to problems with the embryos. The genetic health of the embryo depends on both its inherited genetic material and on the errors and repairs during the cell divisions.

A chromosomally abnormal (anuploidy) embryo is unlikely to implant, and when it does it is likely to be lost early on. Many embryos that are transferred have chromosomal abnormalities, even if they look fine on the outside, or are classified as being the best grade prior to transfer. We need people to understand that just because and embryo has reached Blastocyst, or Morella stage and it looks like a good quality embryo from the outside, it does not mean that the inside and the chromosomes inside the embryo are OK. Not every fertilised egg will result in a genetically sound embryo that will go on to become a baby.

DNA & Chromosomal When Sperm and Egg Combine

We also need people to realise that an embryo is made up the genetic material of two people and that requires the sperm to be healthy both outwardly, but also chromosomally, and this can change with each batch of sperm ejaculated. Sperm quality and the viability of sperm changes and just because something was “OK” last cycle, or two years ago, or last month, or last week, does not mean that it is OK now.

Unfortunately people need to face the reality of what happens with the body and reproduction. The health of the sperm is also reflected in the health and lifestyle and age of the male too. Unhealthy males produce unhealthy sperm and higher levels or sperm with chromosomal abnormalities and damage to the DNA. Unless you are testing every batch of sperm for DNA and chromosomal abnormalities, you aren’t going to see this and even then, testing can only see so much.

A healthy embryo (Euploidy embryo) also requires a female to be healthy and her eggs to be health chromosomally and on a DNA level. It also requires a healthy male for his sperm quality to be healthy on a DNA levels as well. Egg and sperm quality is also related to age, diet, lifestyle, environment, and exposure to environmental disruptors, weight, body fat, stress and so many other factors.

We need people to be aware of this. Then when you put two unhealthy people’s genetic and reproductive material together, there is a high likelihood that it will produce higher numbers of abnormal embryos, and sometimes it can be all of them. It all depends on the health of the sperm and health of the eggs at time of fertilisation. Even then we can still have random errors in chromosomes and DNA and this then produces faulty embryos. Again this is a hard process to explain and again Dr Google isn’t going to tell you this.

Pre-implantation Genetic Diagnosis/Screening (PGD/PGS)

Various methods of genetic testing of embryos have been evaluated in past decades. During the early days of PGD/PGD many embryos were lost in this form of screening. Today it is more routine and more perfected.  One can test the chromosome content of the polar bodies, but a cleavage-stage embryo (day 3 of development) or a blastocyst-stage embryo can be evaluated as well. In addition, various techniques  are available for assessing the chromosomes.  There are also new testing and new technologies that have addressed the shortcomings of these earlier tests.

The authors of a recent systematic review concluded that comprehensive genetic screening of embryos using day 5 blastocyst biopsy is associated with increased implantation and pregnancy rates. In addition, this technology appears to be a good tool to limit the number of embryos transferred. But embryos can still be tested early on in their development, with good results, too.

Most experts recommend genetic testing of embryos in women with advanced reproductive age, recurrent implantation failure, recurrent pregnancy loss, or severe male factor infertility/DNA issues. This then gives a greater probability of transferring a chromosomally normal embryo and having a higher chance of implantation and pregnancy occurring. But even a chromosomally normal embryos doesn’t ensure a pregnancy. This is often the hardest thing for people to get their heads around. To be honest, much of this comes down to luck and is really in the hands of the gods. Again this is often not told to people and no google search is going to tell you this either.

Preconception care increases chances of conceiving

But what you can do to ensure healthy egg quality, healthy sperm quality, healthy embryo quality, healthy uterine lining, decreases stress levels, optimal health at time of transfer etc, is doing proper preconception care as part of proper fertility program.  There is now growing evidence that the health of both parents before and at the time of conception influences the chances of conceiving and the short and long term health of the future offspring. (9,10,11,12,13,14,15)

This is why I offer couples a program to go over everything they need to know and everything the need to do prior to trying to conceive or trying to embark on the next IVF cycle. It is about getting the couple as healthy as possible and their bodies as ready as possible to give them the best chances of success. I always explain to people that preparing for an IVF cycle is like preparing for a marathon. If you do the work and get the body ready, it gives you a better chance of making it to the finish line.

If you are having trouble falling pregnant, or are having failed IVF cycle, then give my clinic a call and find out more about how my fertility program may be able to assist you achieving success of having a baby. So far my program has helped over 12,500 plus babies into the world and counting. It doesn’t matter if you are starting the journey, or well on your way into the journey or trying to have a baby. You can also do a meet and greet appointment to find out more about the fertility program before you commit to the whole program.

Take care

Regards

Andrew Orr

-No Stone Left Unturned

-Master of Reproductive Medicine and Women’s Health Medicine

-Women’s and Men’s Health Advocate

01 Dr Andrew Orr 1

References

  1. Mains L, Van Voorhis BJ. Optimizing the technique of embryo transfer. Fertil Steril. 2010;94:785-790. Abstract
  2. Society for Assisted Reproductive Technology. Clinic Summary Report. https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0Accessed April 27, 2015.
  3. Staessen C, Platteau P, Van Assche E, et al. Comparison of blastocyst transfer with or without preimplantation genetic diagnosis for aneuploidy screening in couples with advanced maternal age: a prospective randomized controlled trial. Hum Reprod. 2004;19:2849-2858. Abstract
  4. Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357:9-17. Abstract
  5. Yang Z, Liu J, Collins GS, et al. Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Mol Cytogenet. 2012;5:24.
  6. Scott RT Jr, Upham KM, Forman EJ, et al. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertil Steril. 2013;100:697-703. Abstract
  7. Forman EJ, Tao X, Ferry KM, et al. Single embryo transfer with comprehensive chromosome screening results in improved ongoing pregnancy rates and decreased miscarriage rates. Hum Reprod. 2012;27:1217-1222. Abstract
  8. Scott RT Jr, Upham KM, Forman EJ, et al. Cleavage-stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not: a randomized and paired clinical trial. Fertil Steril. 2013;100:624-630. Abstract
  9. Buck Louis, G. M., et al. (2016). Lifestyle and pregnancy loss in a contemporary cohort of women recruited before conception: The LIFE Study. Fertility and Sterility, 106(1), 180-188. doi: 10.1016/j.fertnstert.2016.03.009
  10. Chiu, Y.-H., Chavarro, J. E., & Souter, I. (2018). Diet and female fertility: doctor, what should I eat? Fertility and Sterility, 110(4), 560-569. https://doi.org/10.1016/j.fertnstert.2018.05.027
  11. Day, J., et al. (2016). Influence of paternal preconception exposures on their offspring: through epigenetics to phenotype. American Journal of Stem Cells, 5(1), 11-18
  12. Homan, G. F., Davies, M. J., & Norman, R. J. (2007). The impact of lifestyle factors on reproductive performance in the general population and those undergoing infertility treatment: a review. Human Reproduction Update, 13(3), 209-223.
  13. Nassan, F. L., et al. (2018). Diet and men’s fertility: does diet affect sperm quality? Fertility and Sterility, 110(4), 570-577. https://doi.org/10.1016/j.fertnstert.2018.05.025
  14. Salas-Huetos, A., et al. (2017). Dietary patterns, foods and nutrients in male fertility parameters and fecundability: a systematic review of observational studies. Human Reproduction Update, 23(4), 371-389. doi: 10.1093/humupd/dmx006
  15. Sharma, R., et al. (2013). Lifestyle factors and reproductive health: taking control of your fertility. [Review]. Reprod Biol Endocrinol, 11(66), 1477-7827.