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Androgel vs. Clomiphene

MY REPLY TO AN EMAIL FROM THE WIFE OF A PATIENT DESIRING SOME ALTERNATIVE TO TESTOSTERONE REPLACEMENT IN HYPOGONDADISM

In response to your questions about Androgel vs. clomiphene directed to both me and Dr. YYYY (he passed his letter to me, suggesting that he wanted me to field this issue).

Well, as my mother used to say, “there’s more than one way to skin a cat.” Yes, there has been interest in using clomiphene to increase gonadotropin (FSH & LH) and subsequent testosterone release. Clomiphene is an antiestrogen that blocks estrogen’s inhibition of FSH & LH.

This therapeutic option has been studied mostly in the area of treating male infertility and results of studies have been mixed—yes, LH, FSH, and testosterone levels rise, but erections, sperm counts, and pregnancy rates don’t consistently improve—in some studies they do and in some (including a well-done study by the World Health Organization in 1992) they don’t. I’ve seen it stated that clomiphene is the most common drug used to stimulate sperm production in infertile men, in spite of the fact that its effectiveness has been questioned ever since 1966. In my personal clinical experience, and in all the lectures I’ve been to, and most of the articles/texts I’ve read on the subject, the preferred treatment to increase sperm production in infertile men is HCG (mimics LH) given as a shot very other day, and often HMG shots (mimicking FSH) are added later. This is far more expensive than clomiphene—but it might be a case of you get what you pay for.

Now, all of that refers the clinical problem of male infertility—that is, the man who walks into his doctor’s office complaining that he can’t get his wife or girlfriend pregnant. That is not the problem that Mr. XXXX walked in the door with. His problem was a low testosterone level, fatigue, poor libido, and impotence—in other words: “hypogonadism.” Hypogonadism might cause infertility of course, but they are not equivalent terms. Their usual treatments, and the goals of those treatments are different.

The goal when we treat infertility is to achieve a pregnancy—period, nothing else. That is a short-term goal—once the couple is pregnant we’re done and stop treatment.

The goal when we treat hypogonadism is to restore testosterone levels to normal for the LONG-TERM purpose of reducing fatigue, increasing muscles mass, strength, and exercise tolerance, decreasing body fat, increasing libido, improving erections and the sexual enjoyment, strengthening bones and preventing osteoporosis, and probably reducing the risk of heart disease. This therapy is likely life-long, not short-term like fertility treatments.

We know from long experience and good research that testosterone replacement in the form of a gel or patch or shot does all of those things in the previous paragraph well, and as far as we know, it is safe for years of use. After all, normal men are exposed to testosterone of their own making for decades presumably without adverse effect. You mention preferring a “natural” therapy. Well what isn’t natural about stimulating the testosterone receptors with testosterone, which is what’s in Androgel? The active ingredient in Androgel is a chemically identical molecule to human testosterone. Clomiphene on the other hand does not to my knowledge exist in nature and certainly not in the normal human—so, I would argue that it is less natural than Androgel. You mention Androgel side effects. Well, no drug is perfect, but the major potential adverse effects of Androgel (prostate enlargement for example) are related to elevated testosterone levels and they would occur no matter how the levels are elevated, including via clomiphene, if they are elevated excessively.

Androgel or other testosterone preparations fix all of the consequences of hypogonadism EXCEPT infertility. Infertility MUST be treated with something (like HCG or clomiphene) that stimulates internal testosterone production, because the only way to get high enough testosterone levels in the testes where sperm is made is to have it made there. Testosterone from the outside doesn’t get into the testes in sufficient concentrations.

So when the clinical problem is infertility from the beginning, or when a hypogonadism patient on testosterone replacement and his partner come in saying they definitely, right-now, want to get pregnant, then we initiate or switch over to SHORT-TERM infertility treatments and once the woman is pregnant, we go back to the LONG-TERM treatment. We don’t give HCG and HMG long term because of cost and the need for frequent injections. We don’t give clomiphene long term, even though it’s cheap and a pill, because safety and effectiveness over years and decades aren’t proven. I for one would wonder what the long-term dangers of blocking estrogen receptors would be in men. I can almost guarantee no one knows the effect of 20 years of clomiphene on bone strength, for example, in men—it’s conceivable it could cause brittleness and fractures.

You state “we want XXXX to keep fertility if he can.” To be blunt, under the modern standard of care for hypogonadism, that is not an achievable goal. It would be ideal of course, but in an ideal world he wouldn’t have ever had to come to me or Dr. YYYY in the first place. Modern, known-to-be-safe-and-effective therapy offers infertility treatment when and only when there is a stated goal that “we want to get pregnant now.” It does not offer restored fertility continuously. Obviously that is a medical advancement we should be working toward but studies and expertise to date don’t establish clomiphene as the answer.

As to Dr. Fisch and his book The Male Biological Clock—I haven’t read it so my comments have to be limited and taken with a grain of salt. I know him to be an expert on infertility, not hypogonadism in general. He has no doubt used and had success with clomiphene in infertility patients and I gather he must have then tried it in older hypogonadal men whose “biological clocks” are running out. Apparently, in his experience and opinion, there was adequate benefit and safety demonstrated in those cases. However one man’s opinion does not establish safety and efficacy and therefore standard care for the rest of us. Though it should of course spark discussion and further research.

Again, I have to be cautious commenting on a book I haven’t read, but it seems to me he’s talking about gradually declining testosterone with age. Estrogen levels increase in older men and might be expected to inhibit LH & FSH, and hence testosterone production. Blocking that estrogen with clomiphene might reverse that process.

Mr. XXXX’s situation is entirely different. He is a young man in whom this problem has come on relatively suddenly. We don’t know why his LH and FSH are low, there could be genetic factors, or head trauma could be to blame. We don’t have any special reason to believe that high estrogen levels are to blame (we could check an estrogen level—I’ve not done that in him) and unless they are, clomiphene won’t work. Also in cases where clomiphene has helped, the increased testosterone is sometimes converted to even more estrogen causing more problems—remember these are men prone to make too much estrogen in the first place, or they wouldn’t need the clomiphene.

I hope that helps. It’s a good question. To put it more simply I will not treat Mr. Crawford with clomiphene because I do not have experience and confidence with it in this situation, nor is it FDA approved for this. I do lots of things that aren’t FDA-approved—all doctors do—but if I’m going to do something off-label (as non-FDA-approved uses are termed) it has to be something I have experience and confidence in. Another doctor might feel different about clomiphene use here, and that’s fine. I consider it bad medicine for me to do things to patients without me having that experience and confidence.

Androgel and the patches both give stable serum levels of testosterone that result in better patient satisfaction. The patches sometimes cause rashes, but we might try them as they avoid the risk of transfer of the gel to women and children. Of course the gel can be used safely if care is taken (store or lock it away like any household poison; cover undried skin with a shirt; wash hands). An every-week-or-two shot is also an alternative—the serum levels fluctuate a lot so that’s why we don’t prefer them, but it would be less expensive. I advise starting the Androgel and see what you think, but let us know and we can try one of these alternatives if you prefer.

Sincerely,

jkr