Male Health

As I’ve written before in this blog, clomiphene is an effective if off-label treatment for men with low testosterone who want to preserve their fertility. If used directly, testosterone itself actually decreases the making of testosterone and sperm in a man’s testis. Clomiphene increases testosterone production in the testis by increasing the pituitary hormones that tell the testis to make testosterone.

In the March issue of Fertility and Sterility, a journal that I co-edit with Dr. Antonio Pellicer, Drs. Kim and co-authors review the published medical literature on treating low testosterone with clomiphene and other drugs besides testosterone. They conclude that clomiphene is a safe and effective treatment for men with low testosterone and note that less than one year of treatment with testosterone is usually reversible if a man wants his fertility to return. Unfortunately, we don’t know all that much about longer treatments with testosterone, and many men who have been on testosterone for several years do not have sperm return even with other forms of treatment.

Drs Kim and co-authors give us a nice review that supports the use of clomiphene for men with low testosterone who want to preserve their fertility.

As I’ve written in earlier posts, clomiphene is a medication that a doctor can use to increase a man’s production of testosterone in his own body. (I’ve also written about how doctors can prescribe it. If you think that you’d benefit from this medication, you should see a doctor. I can’t answer personal questions about a man’s health on this blog. Medical care is always done best in person.) But clomiphene is “off-label” for use by men and didn’t go through the rigorous series of studies that the FDA mandates for a drug for a particular use.

One good question is whether clomiphene is safe for long term use by men. John Mulhall, a great doctor in New York, recently published a report in the British Journal of Urology studying the use of clomiphene for up to three years in 46 men diagnosed with low testosterone. Blood testosterone, bone scans, and symptom scores all improved, and men did not report problems with the medication.

There are limitations to this study. It wasn’t controlled, meaning that there wasn’t a group of men treated with a placebo, or sugar pill. 46 isn’t a lot of men, and three years isn’t really a very long time. But this kind of study is what needs to be done with more men and for a longer time to really determine the safety of clomiphene for long term use in men.

Clomid surely has its advantages compared to testosterone for use in men with low testosterone. It’s a pill, and other treatments are either shots or cumbersome skin applications. It also saves sperm, as testosterone itself reduces sperm production. But information about its use is less than that of testosterone, which puts men and their doctors in a kind of Catch-22. Mulhall and colleagues are to be commended for expanding what we know of the safety of this medication.

Google is an amazing place. It seems like almost everything is there. A traditional way for doctors and scientists to search published studies is by using the National Library of Medicine’s PubMed site. I use it a lot, as it contains only peer-reviewed medical studies. Google has a similar resource called “Google Scholar.” I made a Google Scholar profile, and you can see what I’ve written there. Check it out!

May blew by, and I didn’t manage a single new post.  The annual meeting of the American Urological Association and a big burst of research activity in my bioengineering lab did keep me busy, but really, there’s no good excuse, and it’s time to blog again.

One very active area of this blog is How Clomid Works in Men, with over a hundred comments to date.  I’m grateful to Robert for inspiring this post.  His question is, are there medications that decrease estrogen?

To review how the pituitary controls the making of testosterone in the testis, testosterone is converted to the female hormone estrogen, and rising levels of estrogen tell the pituitary to make less luteinizing hormone (“LH”).  The role of LH in a man is to stimulate the testis to make testosterone, and as the pituitary sees more testosterone in the blood through the lens of estrogen, it tells the testis to make less testosterone by reducing LH.  I likened this negative feedback system to a thermostat and a heater: as the room becomes hotter, the thermostat turns down the heater.  Clomiphene binds tightly to the pituitary, (and hypothalamus for you biological sticklers), and tricks the pituitary into thinking less estrogen is bouncing around in the bloodstream.  The pituitary labors to make more LH as a result, and the testis makes more testosterone.  The drug tamoxifen works in a similar way.

But Robert’s question hinted at another way to trick the pituitary: there is a way to decrease estrogen directly so that the pituitary sees less of it and makes more LH.

The enzyme aromatase turns testosterone into estrogen.  Drugs like anastrozole and testolactone block aromatase, causing estrogen to decrease in the blood.  The pituitary makes more LH as a result, and the testis produces more testosterone.  If a man has low testosterone and high estrogen, these drugs can simultaneously increase testosterone and decrease estrogen. In a study published in the Journal of Urology in 2002, doctors Raman and Schlegel report evidence that anastrozole seems to work a little better than testolactone, at least in terms of increasing sperm production.  In that study, the doctors also suggest that these drugs are best used if the ratio of testosterone is less than ten to one.

As I wrote in my post on How Clomid Works in Men, all of these drugs are off-label for use in the male, meaning that the Food and Drug Administration didn’t approve their use in men.  That doesn’t mean that they can’t be used.  It means that doctors need to tell patients what we know about these drugs, allowing for an informed decision on their use.  It also means that many of the questions we have about these drugs don’t have answers.  A good question about aromatase inhibitors in men is whether estrogen plays an important role in some health concerns in men, and if it is decreased for a long period of time, can other health problems occur?  We don’t know.  My current practice for prescribing aromatase inhibitors is mostly to limit their use to male fertility, and to stop the medication as soon as possible.

So there you have the two basic ways that pills can trick the pituitary into telling the testis to make more testosterone.  Thanks, Robert!

Has it really been over three months since my last post?  Between becoming one of the next Co-Editors in Chief of Fertility and Sterility, preparing for a review of our urology training program and finishing my latest book (Thank You, Chapter Authors!) I guess that I’ve let my blogging slip a bit.  Fortunately, thanks to my Italian co-faculty’s discovery of the Saeco Vienna Plus espresso maker at Costco, I’m back at the keyboard.

I turned off the two-week limit for comments, and so far, that’s been a good idea.  People are commenting on older posts (like How Clomid Works in Men) with good questions and thoughtful points.  For new commenters, please read the FAQ.  I can’t answer questions about specific patients.  Those are best left to a live visit with a doctor with an interest in male reproductive medicine.  One great resource is the American Society for Reproductive Medicine’s Society for Male Reproduction and Urology page and the ASRM’s find a doctor search page, (just click on the “Society for Male Reproduction and Urology (SMRU)” button in the “Find Member by Affiliated Society:” section.)  Another excellent way to find a specialist who treats men with reproductive issues is to use the American Urological Association’s Society for the Study of Male Reproduction’s search engine.

This blog post was inspired by several patients who asked after I explained surgical sperm retrieval, if there was somewhere they could go for more information.  I realized that I hadn’t written about such a common issue.

Just as a carpenter has many ways to make a cabinet, a surgeon can tackle a problem in a number of ways.  And just as two cabinets may differ, different surgical problems demand different approaches.  Such is the case in retrieving sperm from the testis.

Most of the time, taking sperm directly from the testis is necessary when a man has azoospermia, where no sperm is found in the ejaculate.  Azoospermia takes two basic forms, obstructive and non-obstructive.  As the name implies, obstructive azoospermia is due to a blockage in the tubes and structures that convey sperm from the testis to the outside world.  In the best case, a surgeon can fix the errant anatomy, allowing a couple to conceive children without further ado.  But because the tubes are so tiny, sometimes the tubes can’t be reconnected with surgery, and the alternative is to take sperm from the testis for it to be used in in-vitro fertilization.

The other form of azoospermia, non-obstructive, arises when the factory making sperm in the testis isn’t working quite right.  Sometimes, the cells starting sperm are missing entirely, a condition known as “Sertoli cell only syndrome”.  Occasionally, sperm may be rolling along their assembly line, a process that takes two to three months to complete, and stop mid-production.  When that happens, it’s called “maturation arrest“.  But frequently, sperm can be found in small amounts in the testis and can be retrieved using surgery.

Because it isn’t mature, sperm from the testis can only be used with in-vitro fertilization and intra-cytoplasmic sperm injection.

How can a surgeon remove sperm?  He or she can take it from the testis itself, or the epididymis, the tiny coiled tube lying on the back of the testis where sperm mature.  The surgeon can insert a needle into the testis or epididymis, he or she may make one or several small incisions into the testis or use microsurgery to retrieve sperm from either the testis or epididymis.  In the case of obstructive azoospermia, it doesn’t seem to matter which technique is used.  There’s plenty of sperm wherever it’s sought, and any method will do to retrieve it.  When a man has obstructive azoospermia, I usually recommend taking a small piece from the testis, as the sperm may be frozen and is good for a number of in-vitro fertilization cycles so that the man doesn’t need to go through a procedure for every cycle, and can be there for his wife during her procedures.

We’ve found that frozen sperm is just as good as fresh.  in fact, the chances for fertilization are the same for fresh and frozen sperm, and the chance for pregnancy may even be a little better for frozen sperm than for fresh.

Frozen sperm should literally last forever.  It’s in liquid nitrogen, which is so cold that the building blocks making sperm don’t decay.  Freezing sperm gives a couple time to plan when in-vitro fertilization is done.

When he has non-obstructive azoospermia, a man’s options are more limited.  A surgeon can use the operating microscope to comb through the testis looking for areas that may contain sperm, a procedure known as “microsurgical testis sperm extraction“.  Other techniques include making several small incisions in the testis or piercing the testis with a needle in a dozen or so different spots.  When a man has non-obstructive azoospermia, I usually recommend microsurgical testis sperm extraction.  More areas of the testis can be examined, and I can see the places that most likely contain sperm.

We’ve observed that prescribing a man with non-obstructive azoospermia clomiphene citrate for a few months before surgical retrieval seems to increase the chance to retrieve sperm.  In many men, sperm appears in the ejaculate and surgery isn’t needed.  If a couple has a few months, taking clomiphene before surgical sperm retrieval might be a good idea.