Male Health

Wiki (not sure if that’s his real name) wrote in a comment, “is low Testosterone unusual for young athletic men (under 25) , what will be your minimum level (red line) for Testosterone of men under 25, as i found the minimum level varies according to each lab … mostly skewed based on the middle aged men they usually test.”

Great question! A while ago, many used “age-indexed” testosterone, meaning that lower levels were considered normal in older men. Most in the field have abandoned that approach as it’s like saying, we know that diabetes is more common as people age, so we’ll just use higher blood sugars as normal when they get older. That would be an approach ignorant of the basis of the disease. To make matters worse, to create the age-indexed thresholds of normal testosterone, each lab essentially was required to do that themselves. So you had a lot of labs with different numbers, and that made interpreting those lab results really difficult.

Your question gets to another point, though, which is what is a normal testosterone for an individual man? Testosterone doesn’t work by itself; a whole machine inside the cell uses it. It’s like gas in a car: you can have the same gas, but a Ferrari will drive differently than a Volvo. (No offense to Volvo owners intended.) So one man’s testosterone of 350 ng/dL may be perfectly fine, but for another, that may be low.

That’s why guys need to do evaluation and treatment with their doctors. (If you are trying to figure out a good doctor who knows about hormones in men, check out that part of the FAQ.) A doctor can evaluate the whole man and see other signs of low testosterone, and tailor treatment with different medications (many of which are described elsewhere in this blog.)

Thanks, Wiki, for the great question!

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.

Bob recently asked about using hCG (human chorionic gonadotropin) rather than clomiphene to increase testosterone.  As I explained in How Clomid Works in Men, clomiphene stimulates the pituitary to make luteinizing hormone (LH), which then acts on the Leydig cells in the testis to make testosterone.  So why not use LH directly?

One way to take over the pituitary’s production of its reproductive hormones is to use human chorionic gonadotropin (hCG), which looks like LH to the body.  It effectively stimulates the Leydig cells to make testosterone.  But it’s expensive and must be injected.  So if the pituitary is working, clomiphene may be a better choice to start.  If the pituitary isn’t working, hCG can be tried.  But if the man’s LH is already very high, neither clomiphene or LH will help all that much, as the man’s body is already trying that strategy by itself.

The pituitary also makes follicle stimulating hormone (FSH), which acts on the Sertoli cells around the developing sperm cells.  To help stimulate the making of sperm in the testis, recombinant FSH (rFSH) or human menopausal gonadotropin (hMG) may be used.  Like hCG, these drugs are expensive and must be injected.

Thanks for the question, Bob!

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!