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Genetics and Infertility

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By Daniel A. Potter, M.D., F.A.C.O.G.

an egg and spermmen

It is estimated that up to 20% of couples experience infertility as defined as not achieving or maintaining a pregnancy after one year of unprotected intercourse. 

Family history can be a factor in determining your fertility potential.  One rule of thumb is that your effective fertility will end approximately ten years earlier than your mother underwent menopause.  So, if your mother had her last period at age 52 years, you would be looking at your effective fertility being over at 42 years of age.  There are also factors in the man’s family history that can predict fertility difficulties.  This brief article will look at some of these factors.  Forewarned is forearmed!

Women are born with all the eggs they will ever have.  A woman will have 1-2 million eggs at birth but by the time she goes through puberty, only 400,000 or so eggs remain.  The eggs are then lost at the rate of about 1,000 per month and each month just one of these 1,000 are available for fertilization.  The age at which a woman reaches menopause is essentially determined by how many eggs they start out with and how fast they lose them.  While the number of eggs that a woman starts out with results from a random process, the rate at which they are lost appears to have a genetic component.   A woman’s fertility is effectively over several years before the last egg is released (menopause). 

During this period of ovulatory infertility, women are releasing eggs with very poor fertility potential.  Several factors that have not yet been fully defined are at work.  One of these factors is likely to be micro-deletions on the X chromosome.   Turner’s syndrome, in which only one X chromosome is present, results in rapid loss of eggs.  Small deletions of the X chromosome likely results in significantly accelerated egg loss.  At this time there is no genetic test for this condition but a family history of a mother or sister that had premature menopause is considered to be a marker. 

If you have a family history suggestive of pre-mature menopause, the first thing you should do is have your ovarian reserve tested.  The ovarian reserve is a measure of how many eggs a woman has left.  As the ovarian reserve dwindles, so does the woman’s fertility.  Testing the ovarian reserve can be accomplished several different ways.  The measurement of the hormones follicle stimulating hormone (FSH) and estradiol on the third day of menses is the most basic.  More advanced tests include the clomiphene citrate challenge test (CCCT), day three antral follicle count ultrasound and measuring the hormone anti-mullerian hormone (AMH) at any point in the cycle. 

A diminished ovarian reserve is a call to action and pursuit of the most aggressive possible fertility treatments is recommended in most cases.   If you have a family history suggestive of early menopause and still have good ovarian reserve, get pregnant soon or consider freezing your eggs for use later when you are ready to have a baby.

Endometriosis is a condition widely associated with infertility and it can run in families.  Despite a tremendous amount of research, we still do not know why some women develop endometriosis and others do not.  What we do know is that there is at least a six-fold increase in endometriosis among first-degree relatives in the maternal line of women who have been diagnosed surgically with endometriosis.  Endometriosis is a condition that can have no symptoms at all, or that can cause painful menses, painful intercourse or painful bowel movements.    Women with endometriosis have menstrual tissue that, instead of being expelled in the menstrual fluid, tracks by through the tubes and implants in the pelvis.  This tissue continues to menstruate in the pelvis, causing inflammation, scarring and pain.  The resulting change in the pelvic environment and distortion of the pelvis anatomy results in reduced fertility.  Women with symptoms of endometriosis, particularly those that also have a family history of endometriosis, should seek the advice of a fertility specialist.  Possible treatments include fertility treatment, continuous birth control pills and/or surgery. 

A final and rare cause of heritable infertility is abnormalities of the female reproductive tract.  An excellent review by Lawrence S Amesse, MD, PhD can be found here (http://emedicine.medscape.com/article/273534-overview).  Abnormalities of the female reproductive system have been shown to occur on family clusters.  Symptoms can include lack of menses, recurrent pregnancy loss and breech presentation at birth.  Treatment is often surgical but can also include using a gestational carrier (surrogate mother). 

A final cause of poor reproductive performance with a genetic basis is chromosomal translocations.  Chromosomal translocations can occur de novo or be inherited.  Translocations occur when material from one chromosome breaks off from its origin and attaches to a different chromosome.  This results in a certain percentage of the off spring from an individual having an “unbalanced’ translocation which will result in recurrent miscarriage.  Translocations can be diagnosed with a blood karyotype of the parents.

Men can also have translocations or other chromosomal abnormalities that lead to poor reproductive performance.  Translocations will often result in recurrent miscarriages as they do in females.  Other genetic causes of male infertility are possible.  These include micro-deletions of the long arm of the Y chromosome.  The small size of the Y chromosome has resulted in these abnormalities being the earliest such defined.  Deletions of the long arm of the Y chromosome, called Yq deletions, result in very low sperm counts.  The sperm count is usually below 5 million per milliliter and often less than one million per milliliter.  This condition is usually successfully treated with in vitro fertilization (IVF) and intracytoplamic sperm injection (ICSI).  Male offspring from this procedure will also bear the same deletion and therefore also require IVF-ICSI in the future.  There are no other problems associated with this condition.   Klinefelter’s Syndrome (a male that is XXY instead of XY) can also be the cause of low sperm counts.  This condition can sometimes be treated with IVF-ICSI but often requires donor sperm.  A final genetic condition that results in male infertility is carriers status for cystic fibrosis.  Cystic fibrosis is often a fatal condition for the affected individuals (who have two copies of the abnormal gene).  Males that carry only a single abnormal copy of the gene usually enjoy normal health but can have congenital absence of the vas deferens, the tube that connects the testicle to the ejaculatory duct system.  This condition results in no sperm being found in the ejaculate.  This condition can be easily treated with IVF-ICSI with sperm being obtained from percutaneous epididymal sperm aspiration (PESA).  The prognosis is excellent but the female partner needs to be screened for cystic fibrosis as well to prevent an affected offspring.  Cystic fibrosis has a carrier rate of 1/22 in the Caucasian population but fortunately most cystic fibrosis mutations do not result in infertility.

Family history can be an important factor in determining fertility potential and should not be overlooked in the initial evaluation of infertile couples.  Individuals should also be aware of these familial associations and seek expert help if they feel that they are at risk.

Daniel A. Potter, MD, FACOG is the Medical Director, HRC Fertility and the Laboratory Director of Natera, Inc.  He is also Chair, Medical Advisory Board, for The American Fertility Association

 

 

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