Listen and listen hard...

This week, I refused to perform a vasectomy on a patient of mine. That is, until he saw a doctor about his sky-high blood pressure. Thirty years old and a father of three, he is a productive, hardworking member of society who just happened to never have seen a doctor as an adult. Unusual? Not at all.

Why does this happen? Is it because, in the words of Andy Rooney, that “death is a distant rumor to the young?”  What is it about being young and male that instills this concept of immortality? For one thing, men do not have a monthly biological reminder of their health, similar to the female menstrual cycle. Second, the culture of men is imbibed with the “breadwinner” mentality that tends to equate illness with weakness. Lastly, men are terrible goaltenders of their own health. It is simply not on the radar of most men to think about their health unless something a) hurts, or b) is life threatening.

Lets delve into the last of these a bit as there is an interesting corollary to back this up. It is clear from many studies over the last century that married men uniformly outlive their single counterparts. In some studies, the difference in lifespan approached 10 years. Viewed another way, divorce affects a man’s health about the same as picking up a pack-a-day cigarette habit. So, it is clear that one of the best strategies to a longer life is to marry and stay married. If it is in your personality to gain immortality by this approach then so be it.

But that may not be the case of my patient, who in fact came back one week later for his vasectomy, feeling empowered, and with his blood pressure under perfect control. “And I thought the headaches that I had been getting were due to the stress I have been feeling.” He was a changed man, in control of his health for the first time in his life. He also understood the concept that life-threatening illnesses may be subtler than a broken bone.

After 17 years of caring for young men, it is clear to me that they are an incredibly underserved population. In fact, this is one the key points that I will make as an invited speaker to the Centers For Disease Control (CDC) upcoming summit on “Advancing Men’s Reproductive Health in the US” to be held in Atlanta next months. In my practice, I assume that men need help understanding how to take better care of themselves. I know that they would like to find out more about what health issues they may have inherited that can harm them, but they have trouble asking and knowing where to turn. Hence my practice motto: “The way to take great care of men is simple: just listen to them.” And listen quietly, as their voices are soft. Trust me, this hardly ever happens in the standard, 12-minute office visit that is currently de rigueur in this country.

Just say no.

Most couples in most countries will conceive within a year of trying. Families in the Ukraine take an average of 2.5 years, according to a new U.S. publication. Why? Radiation discharged from the ill-fated nuclear explosion at nearby Chernobyl in 1986 is the likely culprit. Male infertility is the consequence.

We know that sperm production is exquisitely sensitive to radiation, and we actually know how sensitive it is to this exposure. Believe it or not, this was demonstrated in a series of never-to-be-repeated experiments conducted in the 1960’s right here in America. Recall that this was the time of the Cuban Missile Crisis and extreme Cold War tension. The Walla Walla experiments in Washington state involved irradiation of 64 prisoners with various dose levels at Washington State Penitentiary to find the dose that would sterilize them. A similar, second set of prisoner experiments were also conducted at Oregon State Penitentiary during the same period. These studies on “volunteers” demonstrated two things: 1) prisoners do not have the free will to be considered for scientific experiments and 2) the testis is very sensitive to radiation.

How sensitive? Let’s use a chest X-ray for comparison (0.1 mSV). When 15 mSV (150 chest X-ray equivalents) of radiation was aimed at the testis, sperm counts fell. When 50 mSV (500 chest X-rays) were used, it caused temporary sterility. And after 500 mSV (5000 chest X-rays) of radiation, permanent sterility resulted.

So, it is not surprising that a nuclear explosion in the Ukraine occurring 24 years ago over a fallout area 1/3 as large as Iceland’s recent Eyjafjallajokull volcano (19,000+ square miles) might have an effect on human fertility in the surrounding area. Those exposed to radiation as children are now grown, have survived their thyroid cancers, and are trying to reproduce.

As a scientist and doctor, teacher, humanitarian and ethicist, I find this world an often frightfully complex place, mainly because of a failure to learn and grow from our mistakes. Haven’t we realized that good planets are hard to find? In the case of Chernobyl, and in the words of Alan Eddison:

Modern technology

Owes ecology

An apology

Estrogens and the manly man.

There must be something in the air… or water. The Bolivian President Evo Morales recently asserted publicly that hormones found in mass-produced foods are “feminizing” men. Speaking about chicken in Bolivia, which he believes are “loaded with feminine hormones,” he suggested that when men eat chicken “they are diverted from their nature as men.” So, is this how metrosexuals came to be?

But wait, the Vatican commented on this issue a year earlier, although they blamed female hormones from birth control pills for the increased estrogens in ground water. Pedro Castellvi, writing in the Vatican newspaper L’Osservatore Romano in 2009, stated: “we have sufficient data to affirm that one of the reasons for the not insignificant rise in male infertility in the west, is the environmental contamination caused by the pill.” Actually, it’s not the birth control pill itself but the urine from women taking the pill.

In fact, to date, the urine of women taking birth control pills has been blamed for worsening sperm counts in men, the growth of female sex organs in male fish, breast growth in young men and the early onset of puberty in young girls. What next?

Can I add a little balance to this discussion? First of all, exactly what is happening to men in Bolivia such that the President is not happy with them? Are they more civilized and less disruptive? Second, male infertility is not necessarily increasing in the western world; it may even be true that men have lower sperm counts now than a generation ago not because they are less fertile but because women are more fertile. Third, estrogens are found everywhere in the environment including in many plants (phytoestrogens) such as soy and legumes, and are not produced exclusively from the urine of women. Fourth, the intersex conditions that have been reported in many animal species tend to be caused by a very specific exposure at a very specific time point during fetal development and have been linked to pesticides, bisphenol A, dioxins and other environmental contaminants (xenoestrogens). Fifth, did we somehow forget about the worldwide obesity epidemic in humans and the fact that fat converts male hormones to female hormones? Lastly, there is little evidence that substantially increasing a man’s estrogen levels as an adult will dramatically alter anything, except maybe waist size and color preferences. Where the truth lies in all of this is currently unknown, but it is hard for me as a urologist to see how women’s urine could be blamed for so much.

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.

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.

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!

Stem cells, like wine grapes, need tender nuturing to reach their potential.

Last week, I mentioned that I was a believer, that I have seen things happen in stem cell research that others haven’t. Collaborating with Renee Reijo Pera, PhD at Stanford, we have been developing adult stem cells that would not involve embryos, or viruses, and that would not be rejected from the body. It all started when we put our heads together and thought hard about how sperm are made and how stem cells are grown. From this line of thinking, we concluded that the adult human testicle would be a great place to create a stem cell. Why? Because the first thing a developing embryo does as it begins to grow is to set aside cells and designate them as “germ” or reproductive cells. Much later on in fetal life, other tissues develop. So, germ cells are special and very closely related to embryonic stem cells; that is, they are very “stem like.”

The next problem, and a big one at that, was how to take adult stem cells and “reprogram” them to become embryonic-like stem cells. This took the better part of four years to figure out. And, like your grandmother’s great apple pie, the secret is in the recipe. Indeed, we found that just the right combination of feeder layers (a layer of cells in a petri dish which help the stem cells to develop) and bathing solutions were instrumental in nurturing these rare testis stem cells to become embryonic-like in a laboratory dish. I developed a lot of respect and a certain fondness for these rare and special cells through this process of discovery. The care lavished on them reminds me of winemakers and their finicky pinot noir vines, which require the right conditions and care to produce their transcendent fruit. Both require a delicate touch.

So, slowly, with persistence, we were able to generate a very “stem like” adult germ cell in a dish starting from a testicle. We showed that, like a real embryonic stem cell, this cell could begin to form the different layers of the body, including nerve, in a dish. What is still not clear from all of this work is exactly what kinds of body tissues can be made from this cell. Can we make an entire heart? How about a clavicle? Or can we just make sperm? This is what the next four years of research are for. In any case, this discovery may help to bypass the whole moral debate surrounding embryonic stem cells. There would also be no viruses to worry about, nor tissue rejection issues to dodge, because your body would simply be rebuilding itself.

Understand that this research is still in its infancy, but it’s a whole new world of medicine, where whole organs may be regrown, and sight and fertility restored. With more time, this kind of research may be as earthshaking as the discovery of antibiotics a century ago. Stem cell research is likely to be even more transformative than this. May the wonder and awe from scientific discovery never end.

The genetic complexity of sperm and precursor cells when the chromosomes are painted is similar to that of constellations of planets and stars, and look very similar.

So what did we find?

The study showed that men who are infertile have a much higher risk (3 times) of developing testis cancer later in life than the average citizen. And this was based on some serious number crunching. We worked from a huge database of over 51,000 infertile couples who sought care over a 22 year period in California.  The male partners were cross referenced with a California cancer registry to figure out who among them developed testis cancer as they got older. Among infertile couples in whom the male partner was not the reason for infertility, the future risk of testis cancer was the same as in the general population. However, among infertile men who were themselves the cause of the infertility, the risk of future testis cancer was 3 times higher.

So what does this really mean? Well, first of all, it confirms studies from Europe that have suggested the same thing is happening there. This confirmation in a U.S. based study is important, because the rate of testis cancer in many European countries is much higher than it is in the U.S. It also implies that there may be a connection of some kind between male infertility and testis cancer.

But what kind of connection could exist between male infertility and testis cancer? Well, environmental exposures might link these two conditions. However, the kinds of substances that could do this are still unclear. Estrogenic compounds such as bisphenol A, phthalates and pesticides have garnered much press lately as they alter sexual development in animals, but have not been definitively linked either to testis cancer or human infertility.

The connect, I think, may be even more basic: it probably involves genes and gene mutations. About 10 years ago, we and others reported that severely infertile men have more trouble than other men in properly repairing the daily breaks and kinks that occur in everyone’s DNA with daily use. Because faulty DNA repair is clearly associated with cancer in humans, this led us to surmise back then that infertile men with faulty DNA repair might have a higher risk of cancer later in life.  And voila! The results from the recent research appear to support this idea. 

For the time being, the risk holds only for testis cancer, but who know what future research will show? Based on this, I recommend that all infertile men certainly be evaluated by a urologist with a good history and physical examination. They should also be taught testicular self examination as a screening tool to detect testis cancer.

Infertility as a window into men’s health?  As a shift in thinking, it certainly does shine a new light on the problem.

But the common wisdom has been that male infertility is a benign condition.  It is something that occurs in otherwise healthy men, making it harder for them to have a baby, but has no other real health implications. 

What we are taught often causes us to look something and see it in only one dimension, when in fact if it were turned slightly differently we would see that there is a completely other side to it.  In medicine, breaking out from what is taught, from what is ‘common wisdom,’ is particularly hard because we are a consensus-driven fraternity where the truth can take years to uncover and even then is often inconclusively viewed.  You don’t – at least I can’t – just one day see something and suddenly shift the paradigm in your head.

So it took some time for the light bulb to finally go on for me.  But when it did, it was an “aha” moment.  What if, instead of being a benign condition, infertility was a “window” into men’s health?  What if we could look at it as a signal that other conditions could occur or might happen, that are just as important, later in life?  If that were the case, could we use it as an early-warning tool to help prevent future disease? 

That insight became the hypothesis for a series of studies that I and several of my colleagues at UCSF Medical Center – Thomas J. Walsh, Mary  Croughan, Michael Schembri, June M. Chan (a really incredible team that any researcher would be proud to share a challenge with) – put together to understand the link between male infertility and other diseases.  The team was meticulous in the design and implementation of the study, and the results were nothing short of astounding. 

The results will take some time to explain, so I’ll save them for my next posting.