And you thought this was old...

What do you own that is 600 million years old? Your old suit? That little league baseball glove? Your cologne? In fact, every man possesses something that old, and believe it or not, it’s a gene. Not the clothing kind, but the kind you keep in your genome, in your chromosomes. We’ve talked about the Y chromosome in this space but lets take a moment to focus on a single tiny gene.

Tucked away in every cell of your body is a gene called Boule, a piece of DNA critical for sperm production. A colleague of mine just announced that the Boule gene is present in every organism from insects like fruit flies, to sea urchins, roosters, fish and man. It is in invertebrates and vertebrates alike. That is, this tiny bit of DNA has remained essential for making sperm through 600 million years of evolution. Surely the oldest treasure you own.

But what’s really impressive about the Boule gene is that is has not changed over time. And change is the rule with every other known gene involved with reproduction in every species. In fact, evolution of reproductive traits is how a species diverges from other species. It gives each species its identity. And this change can be very rapid: in some fish, reproductive traits are observed to change in fewer than a dozen generations. So why would this one gene stay the same?

We think that the Boule gene has remained true over 600 million years because it is essential for reproduction. Boule is a “quality control” gene that ensures all goes well as sperm are made. Just as you would want your new car to be well inspected so it is safe to drive when you buy it, you want your sperm to be reproductively fit. In fact, if the Boule gene is removed, sperm production stops entirely. Not a single sperm is made in its absence. Now that’s control.

What’s also impressive about the Boule gene is that since it is linked to sperm production, it means that sperm are very, very ancient cells. Seems that nature sticks with what is tried and true and feels no need to experiment with magic potions or fairy dust to get the job done. Reminds me of what Einstein once said while reflecting on relativity and physics: “God does not play dice.” When it comes to reproduction, the Boule gene phenomenon suggests that he may take even fewer chances.

This Da Vinci fetus is way past the critical window of exposure.

A relatively alarming study was published a couple of years ago that suggested that a pregnant woman’s behavior can determine the fertility of her unborn son. Sperm quality from 387 men was compared to beef consumption their mothers reported while pregnant with them. They found that the sons of “high beef consumers” (>7 beef meals/week) had sperm counts that were 24% lower than in men whose mothers ate less beef. Interestingly, sperm counts in the sons were not related to mother’s consumption of other meat or to the son’s consumption of meat. In essence, the author’s thought that estrogens in beef consumed by women may alter the testis development of their unborn sons and may adversely affect the son’s fertility. Similarly impressive decreases in semen quality have been described in the sons of women who smoked during pregnancy.

Sounds almost biblical, doesn’t it? I bring this up because of a point that I made in last week’s blog. In “The Curse of Women’s Urine,” I mentioned how xenoestrogens or environmental estrogens have been shown in animals to act at a very precise point in the developing male fetus and result in intersex conditions at birth or infertility as adults. Well, as the study of mothers’ beef intake reveals, the same issues may also exist in humans. As Aristotle once said: “At his best, man is the noblest of all animals; separated from law and justice he is the worst.”

Time for a quick lesson in biology. When do testicles develop in humans? Believe it or not, when male fetus in just 4 weeks old, the location where the future testis will be is organized (the urogenital ridge). Two weeks later, the primitive germ cells (sperm precursor cells) migrate to the urogenital ridge and set up what is to later become the testis. About 1-2 weeks after that, “sex cords” develop in the primitive testis, setting up the architecture of the mature organ. So, by 8-12 weeks of pregnancy, the human testis is virtually a complete organ, holding within it all of the potential it will ever have.

So the “critical window” of exposure for the human testis, that period in which even a potentially small exposure could wreak significant developmental and long lasting havoc, is about the time when women actually just realize that they are pregnant. The time of morning sickness and painful breasts.

So, does male infertility begin in the womb? Still not clear, really, as all studies have flaws. For example, in the study of beef eating pregnant women, the cohort of son’s whose sperm counts were so thoroughly examined were ALL fertile. That’s right, their wives were all pregnant. Oscar Wilde couldn’t have said it better when he said: “The pure and simple truth is rarely pure and never simple.”

Did Warhol know about the "cola limit?"

How much coffee or tea do you consume everyday? Since many of us buy Slurpee sized cups of coffee in the morning, you should break those down into units of 8 ounce cups. How about cans of soda and in particular colas? Might be a good idea to keep track of this for a moment, as a recent study of 2,554 young Danish man has suggested that excessive cola intake could lead to lower sperm counts.

For comparison, the average young Danish military recruit consumes about 1 cup of coffee and 1 can of soda daily. This is in addition to about a half of cup of tea and 2 small chocolate bars (why not, Danish chocolate is yummy). This intake was associated with normal semen quality. However, the semen quality of young Danish men who consume more than 2 liters (2.1 quarts) of fizzy colas daily had a 30% less ejaculated sperm than men who drank no colas.

Interestingly, although colas are a weak source of caffeine (ounce for ounce, colas have 65% of the caffeine in coffee) there were no strong correlations between any amount of caffeine intake (even up to 7 cups of coffee a day!) and semen quality in these men. So, it is not likely that caffeine is the issue.

So what is the issue among those men who drink colas in excess? Well, the same issue as those who drink almost anything in excess—they have unhealthier lifestyles than those who consume in moderation. More burgers, more smoking, more alcohol, and fatter.

So, does drinking cola make men infertile? I doubt it, as the average sperm counts in men from all different levels of cola intake in the study were all normal by established fertility standards. Plus, fertility was not actually studied in these men, only a single semen sample. And even a good man can have a bad day.

There is a deeper truth running through this though. And you have heard this from me before. To be the best that you can be reproductively (and in life), do all things in moderation and treat your body like a temple.

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.

How about being happy and hopeful as well as healthy?

The couple had been trying to conceive for 5 years unsuccessfully. The tension and anxiety in the relationship was palpable and strained. They had spent well into the 5 digits to have a child with test tube baby technology (IVF) and yet were still not pregnant. His vasectomy reversal had also failed them. And they were going to try one more time, just once, with me, before calling it quits.

When he came to me for care, he was frankly depressed. Out of money and full of debt, close to losing his job in this economy and in a strained relationship hanging on by a thread, he sat across from me. He looked terrible. “Can you help?” he asked me.

Well I did help. I reversed his vasectomy again and it worked. Fast-forward 9 months and a birth announcement arrives in the office from the couple with a long personal note of thanks on the back. But one line really struck me:

”Looking at her, sleeping quietly, I see her future as an astronaut, the President, a doctor, a lawyer or anything else that she wants to be. She can be or do anything!”

Absolutely unbridled hope and enthusiasm was infusing a mind once filled with almost unfathomable despair. All this change, nine months and one baby ago. Wow!

Talk about a biological drive. Reproduction easily ranks up there with breathing and eating. Not for everyone of course, but for many. I am quite sure that if you surveyed infertile couples about their quality of life with infertility, as has been done in patients with cancer, you would find these diagnoses equally impactful. I have no doubt many of my patients would give up five healthy years of their life to have a child. Maybe even 10. Just because it cannot be assessed by a blood pressure cuff, a blood test, or a scar does not make infertility any less important an affliction.

And yet, despite its profound impact, its ability to tear apart relationships, crush self-esteem and slow down an otherwise productive couple to a grinding halt, infertility is not really considered a disease in many societies, including ours.

Want a more productive and healthier society? Cure infertility. And what about something else that this world could use a lot more of, as expressed by my patient: the resurrection of those elemental feelings that lead us to live good lives and to make the world a better place for those who will follow us.

The best medicine for man is man...and good government

A couple sees a reproductive specialist for infertility. She gets a complete evaluation and he gets a semen analysis checked. It looks like his semen quality is low and they are recommended to pursue in vitro fertilization  (IVF) and intracytoplasmic sperm injection (ICSI) to conceive, the highest level of what is termed “assisted reproduction.” They try this at significant expense and it fails. They try again and it fails again. At this point, the man sees a urologist and, after a proper physical examination, he is told that he has a testis mass and is diagnosed with testis cancer.

The point: Male infertility can be a symptom of another medical condition.

The question: What would have happened to this man if they had successfully conceived with IVF-ICSI?

This scenario is not all that uncommon in our field. And it is why I gladly accepted the invitation to go Washington D.C. and consult with the National Institute of Health (NIH) last fall regarding where government research monies should be spent in the future in the field of male reproductive health. At that meeting, I suggested that we start calling infertility a medical disease, just like any other, and get men the medical care that they deserve. I expect several great grant initiatives to stem from this gathering and was honored to have participated in it.

This scenario is also why I am excited to have been more recently invited to join the Medical Advisory Board of the Cooperative Reproductive Medicine Network at the National Institute for Child Health and Diseases (NICHD) at the NIH. The RMN, established in 1989, is a cooperative effort of seven universities and the government and is charged with conducting and publishing high quality clinical research studies in reproductive medicine.  Thankfully, one of the areas of focus is on male infertility. So, I will be taking my “infertility as a disease” mantra to Washington quite a bit this year as I believe scenarios like the case outlined above should never happen in modern medicine.

Cellular metabolites: woven together like a rug

Call me a nerd, but I have to admit that I am pretty excited about metabolomic technology. Uh, what? Metabolomics is the study of the chemical fingerprints that cells leave behind. It does not look at genes, DNA, RNA or proteins, but is a peek into the products or metabolites that result from all this genetic orchestration. It is a “physiological snapshot” of a living cell.

This past week, we published a study that applies metabolomics to male infertility. If you have been reading this column, you are well aware of my interest in helping sterile men become fathers. Over the last decade, it has become clear that many men with azoospermia (no ejaculated sperm) may have small pockets of sperm in the testicle. The question is how to safely find that sperm without causing undo harm to the testicle. Current methods for evaluating whether sperm are present include somewhat invasive techniques such as testicular biopsy and microdissection and less invasive ones such as FNA Sperm Mapping that I invented 13 years ago. However, as I always say, there is always room for improvement.

Wouldn’t it be nice to find the “pockets” of sperm in the testis through a simple scan and avoid a biopsy? Maybe even a scan that involves no radiation exposure, like an MRI? Well, that is precisely what we have developed in this study.

We showed that magnetic resonance (MR) spectroscopy can measure metabolic activity in the testis. And given that most metabolic activity in the testis is concentrated on building sperm (remember, normally men produce 1200 sperm/heartbeat!), metabolic measurements in the testis generally reflect sperm production. The study showed that the metabolomic scanning is as accurate as a more invasive testis biopsy in reading several abnormal patterns of sperm production typically associated with infertility. It also showed that testes that contain sperm carry a distinct chemical “signature” that can be distinguished by MR Spectroscopy.

How does it work? Essentially, the scan looks for chemicals in the testis that are the building blocks for sperm production. The theory is if you see a pile of bricks in the yard, then there is a good chance that a house is being built. In the study, phosphocholine was observed as one of the building-block chemicals in the testis. The more there is, the more likely sperm are being made.

Not only that, MR Spectroscopy can evaluate for sperm in as many as 100-200 areas within the testis, significantly increasing the ability to sample for sperm well beyond any of the more invasive techniques commonly used today.

Are we ready to replace a testis biopsy with an MRI scan? Not yet, but give me some time to tweak the system a bit and perform clinical trials comparing it to current approaches. My motivation runs deep, as I know that men would rather have their picture taken than have a surgical procedure to understand whether they can be fathers.

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.

Bacchus is no longer a role model...

What you weigh affects how your sperm play. And your fertility. Overweight men tend to have lower semen volumes, less sperm and more oddly shaped sperm. The same is also true for men who are too thin. So, along with the many other health hazards associated with obesity, add poor semen quality to the list.

Obesity in both sexes is known to be associated with heart disease, diabetes, hypertension, and metabolic syndrome among other nasty conditions that can shorten your life. Typically, obesity is measured with BMI or body mass index, which looks at weight in relation to height. Not a perfect measure, but reasonably accurate. Using this tool, the ideal BMI for men (and women) is considered to be 20-25. A Danish study of 1600 men showed that overweight men with a BMI > 25 had a 22% lower sperm concentration compared with healthy weight men. Interestingly, a BMI of <20 was also associated with poor semen quality. For optimal sperm production, then, it helps to be not too fat and not too thin.

But what about fertility? Is it also affected by obesity? Yup. Another recent study showed that for every 20-pound increase in a man’s weight, there is a 10% increase in the chance of infertility. And this remained true when other factors that might influence the results were accounted for, including obesity status of the women, the man’s age, cigarette smoking, alcohol intake, and solvent and pesticide exposure. In addition, obesity was associated with infertility in both older and younger men.

So what is it about weight that influences men’s sperm production and fertility? One theory is that sex hormone metabolism is altered by changes in weight. Sex hormones are the “fuel” for the engine (testis) to make sperm. Obesity increases fat stores and fat converts male hormones (testosterone) into female hormones (estrogens). Too much estrogen in men is bad for sperm production. Another theory posits that normal 2-degree difference in testis temperature relative to the body is lost with obesity, as excessive fat provides too much insulation and results in overheating. On the other hand, when a man is too thin, he may take on a “catabolic” metabolic state. With a body in “starvation mode,” fertility is not the first thing on its mind and sperm production and fertility suffer.

So, is the epidemic of obesity the reason why sperm counts have been falling in Western countries over the last 50 years? Maybe. But this problem is unique in that it is utterly and entirely preventable. Eat well and in moderation, sleep well and treat your body like a temple. You used to it for your own health; now do it for the health of your future family.

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!