The link between Cystic Fibrosis and infertility

November 14, 2012Carole 2 Comments »

Andrologists performing semen analysis sometimes encounter  patients with no sperm in their ejaculate. There can be many reasons for “shooting blanks” ; the sperm factory could be closed (spermatogenesis failure) or the plumbing could be blocked (previous scarring from infection or a vasectomy) or the plumbing could actually be missing. The tubing that connects each testicle to the penis is called the vas deferens and some men are missing this sperm conduit at birth. This condition, called Congenital Bilateral Absence of the Vas Deferens (CBAVD)  is associated with a mutation in the CFTR  gene.  But most people are probably more familiar with mutations in the CFTR gene as the cause of a genetic disease called cystic fibrosis (CF).

The CFTR gene encodes for a protein called the cystic fibrosis transmembrane conductance regulator. The CFTR protein product is a chloride channel protein that is found in cell membranes of cells lining the lungs, liver, reproductive tract, pancreas, intestines and skin.  This protein is responsible for chloride ion transport across the cell membrane. If the CFTR gene is mutated, it creates an abnormal protein which can not move chloride ions across the cell membrane,  upsetting the normal balance between sodium and chloride ions, resulting in a variety of symptoms, depending on which cell type is affected. In the lungs, mutations in the CFTR gene are responsible for the production of a very thick mucous that is difficult to clear causing both breathing problems and increased susceptibility to infections.

In the US, about 30,000 children and adults have cystic fibrosis. Some common symptoms of CF  (copied from the Cystic Fibrosis Foundation website) include:

  • salty-tasting skin
  • Persistent phlegmy coughing
  • Increased occurrence of pneumonia or bronchitis
  • Trouble breathing as evidenced by wheezing or shortness of breath
  • Stunted growth even with adequate nutrition
  • Gastrointestinal symptoms such as frequent greasy, bulky stools or difficult evacuating bowels
  • Nasal growths called nasal polyps

Although the average life expectancy for people suffering from CF is only in the mid-thirties, this average life expectancy can vary considerably among individuals due to variability  in the number and type of mutations in the gene. There is no cure for CF at the present time. Treatments are aimed at thinning the mucous, keeping airways as clear as possible, reducing inflammation and preventing infections like pneumonia. Patients sometimes need to take pancreatic enzymes with meals so that they can more easily extract the nutrients they need from the food they eat. As with cancer treatments, as treatments become more effective and life expectancy increases, patients suffering from CF start to think about treating infertility issues and having children of their own.

A far greater number–ten million people–are carriers of the defective gene who don’t actually suffer from the disease and don’t usually know they carry the CF gene mutation. One normal copy of the gene (we get one copy from each parent) is sufficient to prevent symptoms of CF. Interestingly, although these carriers of the CFTR gene mutation do not have CF per se, some of these carriers have reduced fertility or are infertile.

Mutations in the CFTR gene are implicated in causing infertility in both male and females.

  • MALE infertility in patients with CF or carriers is often linked to CBAVD- the absence of both vas deferens; In fact, approximately 98% of men who suffer from cyctic fibrosis disease are infertile due to the absence of their vas deferens. Carriers of one copy of the genetic mutation are usually healthy but may also be infertile due to undiagnosed CBAVD.
  • FEMALE infertility in patients who have CF disease is likely to be a consequence of thickened cervical mucous. Thickened cervical mucous can cause infertility via intercourse and is treated with intrauterine insemination (IUI) to bypass the cervical mucous by depositing sperm directly into the uterus. The link between other causes of female infertility and CFTR mutations is less clear, but CF patients may complain of irregular periods and anovulation which are common causes of female infertility. Women with  CFTR mutations who have fertility problems can also benefit from routine IVF to treat their anovulation and  irregular cycle issues. The link between CF and female infertility is not as clear since many women with CF disease have normal fertility.

As there are more than a thousand possible mutations in the CFTR gene, some of these mutations may affect fertility, while others have no effect. Other factors like environment and underlying genetic factors can also determine how severe CF symptoms are and perhaps also whether fertility is affected.

Interestingly, a rare mutation of the CFTR gene (a DNA variant in the 5T allele) has been found in otherwise healthy male carriers who present with infertility problems. This deletion is often detected when azoospermia (no sperm in the ejaculate) is diagnosed in otherwise healthy patients. Upon referral to a urologist and more testing, CF carriers of this deletion have no sperm in their ejaculate because they are missing both vas deferens (CBAVD), so here is a clear link between a specific CFTR mutation and a specific infertility cause.

Male infertility due to CBAVD is “treated” by recovering sperm surgically from either the testicles (TESE) or from the epididymis (MESE or PESA). Sperm recovered surgically is frequently either non-motile (can not swim) or only weakly motile. Sperm acquire full motility as they move through the various regions of the epididymis, the smaller storage/maturation organ that lies on top of the testicle.  Sperm injection (ICSI) is necessary to fertilize the egg if TESE/MESE or PESA sperm are used. More about the epididymis  can be found at this previous post.

Genetic implications of fertility treatment. Although fertility is restored with IVF/ICSI, the patient still has the risk of passing on their mutated gene copy to their child.  If a man presents for fertility treatment with azoospermia and CBAVD is suspected, both he and his female partner are typically referred for genetic screening to see if they are carriers of the CFTR gene mutation. If both of them are carriers, they have a 50% chance of having a child who is also a carrier and a 25% chance that their child will receive both copies of the mutated gene and develop cystic fibrosis, or alternatively a 25% chance that their child will be lucky enough to receive only the normal gene copies.

Fortunately, carrier couples can avoid relying on a genetic roll of the dice if they use IVF with pre-implantation genetic diagnosis (PGD) on their embryos to find out which embryos are unaffected (two normal genes ), carriers (one abnormal gene) or will be affected by cystic fibrosis (two abnormal genes). With this information, embryos that are either normal for the gene or only have one mutated copy can be transferred so that a healthy child will be born.

Want to support the Cystic Foundation’s efforts to educate the public and improve treatments for cystic fibrosis?

If you want to know more about Cystic Fibrosis, check out the Cystic Fibrosis Foundation website.  There are more than 75 local chapters all over the US so you probably can find local events to support your local chapter. My local CF chapter in Raleigh is the beneficiary of multiple fund raising events in the area in the coming months.

Zygote Science, LLC. is one of the local sponsors supporting a Women in Bio Chapter hosted First Annual 5K walk/run to support the Cystic Fibrosis Foundation (CFF) of Raleigh, NC. The 5K walk/run is happening on December 1, 2012. The walk/run is mostly on paved wooded trails on the Research Triangle Park grounds near the North Carolina Biotech Center. If you are are Raleigh-area reader, check it out. More information on the race can be found here.



© 2012, Carole. All rights reserved.

2 Responses to this entry

  • Heidi Says:

    What do you think about Ovascience and their proposed clinical trial using mitochondria?

  • Carole Says:

    Hi Heidi,
    I think the Ovascience company has some really interesting basic research behind it. This earlier post talks a little bit about stem cell technologies This older post talks about reawakening ovarian stem cells to make higher quality “new” eggs. But the comments below the post link to the work Ovascience is doing on Augment- a mitochondrial infusion of sorts. Ovascience is working on clinical research to first, harvest ovarian stem cells from patients, amplifying the number of stem cells by culturing them, and harvesting mitochondria from the amplified in-vitro stem cells–mitochondria which are then returned to the same patient’s own eggs at the time of ICSI with the injected sperm. What do I think about the clinical trial? I think that we know that mitochondrial injections do increase the pregnancy rate for some patients who are older or have diminished ovarian reserve. The practice of injecting mitochondria from donor eggs into a patients own eggs was successful and performed by a few clinics but was stopped by the FDA because essentially the resulting embryos contained DNA from three individuals because mitochondria contain mitochondrial DNA. The Augment approach uses the patient’s own stem cells and mitochondria so the problem of three sources of DNA is not an issue. Will mitochondrial injections cause other problems in the egg and embryo or child much further down the road? I don’t know. I would be interested in seeing the consent forms for the clinical trial to see exactly what is known, unknown and where they think the major risks are. But it is very exciting work and if successful and safe, could be a game changer for older infertile women. Carole

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