How damaged is your genetic sheet metal?

Imaging parking your car at home after work and all the nicks and scratches are removed while you sleep, before heading to work the next day. All shiny and new, polished even, while you sleep. Believe it or not, this is normally what happens to your genes and chromosomes on a minute-to-minute basis. DNA mismatch repair is a constant and vigilant process, occurring in all cells of the body. Why the biologic vigilance?  Well, It keeps us whole, healthy and cancer free.

About 11 years ago, we published a paper showing for the first time that infertile men can’t repair the errors normally encountered in their DNA as well as normal men. This was startling news in part because it implied that infertile men may be more likely to develop other problems later in life, including cancer. Why cancer? Because the development of cancer has been associated with the inability to normally repair the frequent daily errors that occur to one’s DNA as the body’s cells divide and renew.

Today, however, we know much more. We know that testis cancer is 3-fold more likely to occur in previously infertile men than in fertile men as they age. And our latest research has shown that prostate cancer, thought to be a disease exclusive to older men, occurs more seriously and more commonly in previously infertile men.

So what does this mean? Is male infertility the first sign of a larger problem in our species? It is the ultimate medical problem of a species trying to reproduce?  Well, honestly it isn’t entirely clear. However, to me it indicates that male infertility should certainly be considered an insurable and real medical condition that should be taken as seriously as a heart attack. Even more worrisome is the issue of whether the use of sperm from severely infertile men is putting their offspring at even higher risk of medical issues than that experienced by their fathers.

So do not ignore the infertility issue when it strikes and get that male partner evaluated by a specialist. Teach him to perform testicular self-examination, a simple maneuver performed once monthly in the shower that has far more potential to extend his life than even exercising or weight control. Educate him about prostate cancer so that he does not ignore the powerful screening tools available to find it early. The age of innocence is over. The warning signs are now clear; get men the care that they deserve.

Can we be DNA barcoded like a soup can in a grocery store?

How many of you would take a blood test to learn exactly how long you will live? How about whether or not you will become demented? Since the Human Genome Project ended, the genes and mutations associated with a vast array of diseases are being discovered daily and it is pretty easy to just put them on “chip” and make them available to the public.

Don’t get me wrong; gene testing already has already improved our lives. Such tests can clarify a diagnosis and better direct care, while others allow families to avoid having children with life-threatening or disabling conditions. They can be used to prevent disease before it happens, as with monitoring and removal of colon growths among those who have a gene for familial polyposis, and can diagnose common iron-storage diseases early enough to treat them and prevent them from becoming fatal. They can also help to positively identify murderers two decades after the crime.

One real problem is that many commercialized gene tests are targeted to healthy people who might be at high risk because of a strong family medical history for a disorder. Unfortunately, because of how complex we are as biological organisms, the tests give only a “probability” for developing the disorder. That means that some people who carry a mutation may never develop the disease. Another limitation is the possibility of laboratory errors. What this means is that the tests are not perfect and could be wrong.

And what happens to your job prospects and health (or life) insurance rates when it is learned through genetic testing that you might develop a significant disease? Well…nothing. Because of the federal GINA Law (Genetic Information Nondiscrimination Act) passed in May 2008, insurance companies and employers cannot discriminate on the basis of information derived from genetic tests. So, genetics has now been added to the list of characteristics first embodied by the Civil Rights Act of 1964, that states that U.S. employers cannot discriminate according to race, color, national origin, sex, or religion. And this is good.

So, go ahead and take the “23 and Me” “DeCode” or “Navigenics” genomic screens if you so desire. Get to know your DNA barcode. Maybe you will get an idea of what may be around the corner for you. And maybe, just maybe, you will take better care of yourself knowing more about your genes. Just understand that many in the medical community feel that uncertainties surrounding test results, the current lack of available treatment options, the tests’ potential for provoking anxiety and social stigmatization could outweigh the benefits of testing. You know the saying: “Too much information…”

Do you agree with the Ancients on the good of the hood?

To circumcise or not. A loaded subject to be sure. The practice of male circumcision is ancient, likely far older than the biblical account of Abraham in Genesis. The Jewish faith, but not that of the Greeks or Romans, routinely recommended circumcision of newborn males. In the past century, it became “medicalized” as a preventative procedure only to be debunked in the last decade. Well, it may be now a procedure on the rise once again.

Circumcision is the removal of some or all of the foreskin or prepuce from the penis. The august American Academy of Pediatrics continues to recommend that circumcision is medically unnecessary, that it lacks any proven benefit, and that it should not be performed routinely in neonates. Maybe that is why the incidence of neonatal circumcision in the U.S. has continued to decline, from 80% in the 1960’s to 60% in 1996, to 55% of boys in 2001.

Why should circumcision be avoided? Issues of neonatal pain, behavioral changes and the potential for loss of sexual sensitivity from removal of the prepuce are age-old arguments for its discontinuation. However, a military study showing that there is a higher rate of urinary tract infections (UTIs) in non-circumcised boys and the fact that penile cancer tends to occur almost exclusively in uncircumcised men has kept the procedure alive and well.

In a somewhat radical departure from earlier recommendations, public health officials are now arguing that circumcision of men is a key weapon in the fight against human immunodeficiency virus (HIV) in Africa. Three recent, large, controlled studies have shown that circumcision reduces infection rates by 50 to 60% among heterosexual African. These studies stem from 3 different parts of the continent: South Africa, Uganda, and Kenya. In fact, two of the three clinical trials were stopped early because of overwhelmingly positive results. Experts now estimate that more than 3 million lives could be saved in sub-Saharan Africa alone if the procedure becomes widely used. And there is more recent data showing that the incidence of Herpes virus and HPV (Human Papilloma Virus) may also be reduced in circumcised men.

How circumcision prevents HIV transmission is not completely understood, but it is believed that the foreskin acts as a reservoir for HIV-containing secretions, increasing the contact time between the virus and target cells in the foreskin.

The problem with HIV and circumcision is that it is much more than a simple “behavior-based” intervention and this may ultimately be its biggest obstacle to wide acceptance. Changing social mores and behavior is one thing, but the “cold, hard steel” aspect of this public health initiative may not survive in the long run. If you don’t live in Africa, a clean penis and a clean life may be all that’s needed to replace the knife.

Throwing a wrench in the machinery of sperm production...

I have to admit, the testis “mapping” procedure that I developed some years ago has truly been a workhorse technique for my male infertility practice. And for the practices of other male reproductive specialists around the world as well. Creating fertility from sterility. I bring it up again because it is gathering more attention in the press as this week we recently published another paper that highlights its utility—this time in cancer survivors.

In a related study from 2002, we published that the majority of men who had been exposed to chemotherapy for cancerous or non-cancerous disease and who were “sterile” afterwards have sperm in the testis that can be safely used for fatherhood with assisted reproduction. Fine needle aspiration (FNA) mapping was employed in this study and its potential to help cancer survivors to conceive was convincingly demonstrated. The recent paper expands that group of men to include those who received not only chemotherapy and radiation therapy but also a relatively extreme treatment for certain cancers termed bone marrow transplantation.

Let’s back up a minute for a biology lesson. How does chemotherapy affect a man’s fertility? Well, the basis of its effectiveness in curing cancer is that chemotherapy preferentially kills rapidly dividing cells more than slowly dividing cells. In general, cancer cells divide more rapidly than do normal body cells. The term for this difference in cell susceptibility is “therapeutic index”. Unfortunately, sperm are also produced very rapidly (about 1200 sperm are made every heartbeat) and therefore sperm precursor cells are also very sensitive to the effects of chemotherapy. Think of sperm production as a rapidly turning set of gears and chemotherapy as a wrench being thrown into them. Ka-chunk! Machine comes to a loud and crashing halt. Sperm production is over, or tremendously slowed down. The same action is true for radiation therapy treatment.

Now, imagine not just one small wrench being thrown into the gears, but a huge wrench (or many wrenches) being suddenly thrown into the machine of sperm production. The result? More damage to the sperm-making machinery and a much higher chance of sterility. This is the essential difference between the patients from the 2002 paper on mapping and the most recent one. The cancer survivors in this week’s paper got blasted with the heaviest doses of chemotherapy imaginable, and topped off with a dollop of radiation therapy just to be sure. Hard to believe, but they also had usable pockets of sperm in their testicles. And normal babies as a result.

So, with techniques like FNA sperm mapping, there continues to be hope and good news about fertility after the storm of cancer treatment has passed.

Heirlooms for the species.

As a living, breathing being on this good earth, we tend to take things for granted. The ability to have offspring can be one of them. That is, until the day that a serious medical condition like cancer rears it ugly head and puts childbearing at risk. In addition to the sterilizing effect of cancer treatments, the mad rush to treat the disease often marginalizes efforts to preserve fertility. Fire all the canons and check for collateral damage later.

Fertility preservation seeks to protect men, adolescents and children from a common, serious and impactful side effect of cancer treatment: infertility. The goal of fertility restoration is to empower patients who are cured and potentially infertile to bear children. These related fields have burgeoned recently because medical care is now shifting from curing cancer to improving the quality of life among survivors. And without a doubt, for many, fertility is a key quality of life issue at some point. Thankfully, exciting new methods of restoring fertility have already been developed and even newer technologies are under study.

Classic techniques for fertility preservation in men include gonadal shielding and sperm banking. Gonadal shielding uses lead-based devices to protect the testicles from being struck directly by sterilizing radiation treatment. Sperm banking is the process of freezing healthy sperm before cancer treatment begins for later use to conceive. But there is more. For patients who are too young to bank sperm, for those who have precious little time to bank sperm, or for those who have no ejaculated sperm to bank, testis sperm retrieval by biopsy (TESE) or needle aspiration (TESA) for banking is now possible before cancer treatment. In fact, in some cases of testis cancer, it is possible to remove only the cancerous nodule instead of the whole testis, or to freeze sperm from the testicle after it is surgically removed. These are now routine ways to preserve fertility in men.

Fertility restoration for men has also seen real advances lately. Sperm “mapping” is an innovation that I developed for men who survive cancer treatment but have no sperm in the ejaculate. It non-invasively and non-surgically deciphers whether there are small numbers of mature sperm in the testis, too few to get into the ejaculate, but usable nonetheless. In men who sustain nerve injury from cancer surgery and who are unable to ejaculate, a special medical instrument can produce an ejaculate for fertility purposes in a process termed electroejaculation. Techniques such as these are valuable tools to help men deemed “sterile” after cancer treatment to become fathers.

One of the most exciting areas of fertility restoration involves stem cell technology. Yes, the “promise” that we have all heard about stem cells curing disease will likely find its way into the fertility field as well. In pre-pubertal boys with cancer, ejaculated sperm is not present. Despite this, it may be possible to freeze the early stem cells from the testicles of boys before sterilizing treatment. After thawing, these “adult” stem cells may later be used to create sperm after further growth in a Petri dish or after transplantation back into the same individual. Also on the horizon is our ability to take skin cells from a sterile man, convert them into an embryonic-like stem cells and then “drive” these cells to become mature sperm in a dish–a true “artificial testicle.” So, with the belief that hope can cure misery, the world of science has taken fertility research from science fiction to reality. Not convinced? Stay tuned!