Posts Tagged ‘azoospermia’

Your Oldest Treasure

Sunday, July 18th, 2010
And you thought this was old...

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.

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Does Male Infertility Begin in the Womb?

Sunday, May 2nd, 2010
This Da Vinci fetus is way past the critical window of exposure.

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.”

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Handling The Truth

Sunday, March 28th, 2010
Patients can handle the truth...try them.

Patients can handle the truth...try them.

How would you react to a doctor who, instead of explaining the entirety of your medical options, simply said “trust me, this is the right choice.” Maybe that style of “care” worked a generation or two back, but today’s patients have access to any piece of medical information that their doctors do. Patients want to know as much as they can so they can make the best choices for themselves or their loved ones.

Why do I bring this up? Well, because I got a call the other day from a patient who was seeking for more information about his options for fatherhood after vasectomy. He had an older vasectomy, 25 years or so, and a wife who was 40 years old. He met with two doctors in other cities and asked them about vasectomy reversal and sperm retrieval with assisted reproduction. Both of these are options for vasectomized men. Both urologists said, “forget it!” The patient was stunned. He just wanted information to help him decide how he was going to approach the family building issue. Instead, he received no information, and, without asking, he was told what he should do. Forget it.

Two things are still true after visiting these two doctors:

1. He still wants a family.

2. He knows no more than he did before about how to achieve this goal.

Now what is wrong with this picture? Patients do not necessarily depend on doctors for information; they can get that almost anywhere on the Web. However, they do depend on doctors for wisdom and knowledge–the interpretation of information as it applies to the patient. I believe that life is a journey, one that involves many forks in many roads. Some are chosen and others are not. In the end, there is a story, a memory, of the path that was taken. Making decisions about medical care is also part of the journey that we all take. As doctors, we are obliged to use our experience and wisdom to help patients face decisions and choices that affect their health, their budgets and often their very lives. A patient’s “trust” is earned and is not gifted to doctors. Be their trusted consultant, someone who they can rely on for good solid information and wisdom. Unlike what Col. Nathan R. Jessep says in A Few Good Men, patients can handle the truth.

In my discussion with this patient, I gave him the facts about each choice. Older vasectomies are less successful at being reversed than younger ones, but the results are still very respectable in the right hands. His wife’s age could influence his decision either way, especially if she has limited time left to have children. Pregnancies after reversals of older vasectomies occur later than those after younger vasectomies. Sperm retrieval and assisted reproduction

can be a faster, albeit more expensive, way to conceive. If more than one child is desired, then assisted reproduction can get very expensive compared to vasectomy reversal. No value judgments, just the facts. There are lots of ways to build families and patients armed with good informaton can decide which way is best for them.

It has always been my philosophy as a physician and surgeon to walk the walk with the patient. Even stepping into their shoes and taking the journey with them. This makes good sense in situations in which outcomes cannot be guaranteed. Sure, I will offer an opinion if they ask, “what would you do?” However, in my brief stay on this good earth, I have found that the educated consumer always makes the best choices.

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Adding Hope to Health

Sunday, March 7th, 2010
How about being happy and hopeful as well as healthy?

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.

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Metabolomics: The Picture of Fatherhood

Sunday, February 7th, 2010
Cellular metabolites: woven together like a rug

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.

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The Quiet After the The Storm of Cancer

Sunday, January 17th, 2010
Throwing a wrench in the machinery of sperm production...

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.

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