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Clomid Doesn't Work for Every "Low-T" Patient

I was contacted via email by a gentleman providing very little information other than he has a low testosterone level, and that he wanted to try Clomid, and did not want testosterone replacement. Going on, he wrote: “Who can get that done for me…Need a doctor that will make it happen. Can’t find any.” And that was it—a man of few words.

Clomid is a drug usually used as a female fertility treatment. In certain cases it can raise testosterone levels in men by blocking estrogen receptors that inhibit release of LH, the pituitary hormone that drive testosterone production by the gonads. In part here is my reply to my emailer:

(1) I realize physicians tend to be a pretty conservative lot--by that I mean it can be difficult to find one willing to color outside the lines of standard care and evidence-based medicine (what's proven to work and be safe by published mainstream research), even in cases where common sense might make such an unproven therapy seem like a good idea. There are legitimately reasons for that, but it can frustrate patients. In my own case, I have a lot of knowledge and experience with difficult hypothyroidism cases. Based on that, I'm sometimes willing to handle things differently than the average doctor. In areas where my knowledge and experience is average compared to my peers, however, I'm as conservative (read: stubborn?) as the next guy.

(2) Clomid use in men is non-standard. There is increasing interest in it as a male fertility therapy, and I have used it that way a couple of times. Fertility treatment though is always short term—once pregnancy occurs, treatment stops. Use of Clomid as a long-term treatment for permanent hypogonadism (low testosterone, or "Low-T") presents different issues. I doubt anyone knows whether it's safe for men to take it for a long time. In fact, as an estrogen blocker, there is real concern that it weakens bones, causing fractures. Remember, estrogen strengthens women's bones—same with men. With that in mind it may well be that no good physician would agree to what you're asking. I wouldn't, not without there having been quality research proving long-term safety. Now, were there reason to believe this might be short-term therapy, Clomid might be a consideration, but you've given no details to suggest that's the case. The right therapy for anything is highly dependent on details.

(3) Which leads to my last point: Just because you want something does not make that something medically appropriate—always a primary concern of a good physician. And no good physician ought to promise a certain therapy without seeing and evaluating you. The only doctor who would promise to "make it happen" would most likely be a quack.

The simple fact is, there are causes of "low T"—most causes perhaps—where Clomid would not work. These include any serious defect in the testes interfering with testosterone production, and any serious damage to the pituitary gland's ability to make LH, which tells the testes to make testosterone. All Clomid does is block estrogen-caused inhibition of LH production, but after that the pituitary still has to be able to make LH and the testes still have to be able to make T. Sometimes it's obvious from a complete set of labs what the situation is, other times not.

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Androgel vs. Clomiphene


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.


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Should Women Take Testosterone Replacement or Have Testosterone Pellets Implanted?


I have reviewed the Endocrine Society’s clinical practice guidelines from 2006 for androgen (testosterone) therapy in women. These guidelines—as I told you—advised against diagnosing and treating testosterone deficiency in women. Their basis for that position was a lack of understanding of what the normal ranges of testosterone levels are for women at different points in their lives, known inaccuracies in available testosterone blood tests, and a lack of studies demonstrating safety over many years. That is, what might be safe for a week or a month or a year, might not be safe for 5 years or 10 years or 20 years.

The accuracy of testing is important—what we’re saying is that the testosterone blood tests physicians use everyday aren’t accurate enough, especially at the lower levels that are normal in women, to be trusted for identifying women who need treatment and monitoring that therapy once started to be sure enough but not too much is given. I don’t know about what testing XXXX, for example, has add, but many of these types of clinics (that prescribe testosterone and other hormones outside the recommendations of mainstream endocrinology—HRC Medical would be an example) use saliva testing. There is even less confidence among physicians as to the accuracy and usefulness of saliva testing than blood testing.

The following summarizes the Endocrine Society’s safety concerns that need further study before testosterone therapy is recommended in women:

(1) Endometrium (uterine lining)—endometrial hyperplasia, which can led to uterine cancer, SEEMS UNLIKELY in women taking testosterone, but the endometrium should be monitored in adequate long-term research studies to be sure.

(2) Breast—too much testosterone has been shown to cause breast atrophy (shrinkage); testosterone does not directly promote breast cancer, but some breast pre-cancerous lesions have the enzyme aromatase that converts testosterone to estrogen (estrogen does promote breast cancer); therefore the possibility exists that aromatization of exogenous (outside) testosterone and other androgens “could contribute to breast cancer risk for women taking them.” Actual research done in this area is as yet inconclusive and of limited quality.

(3) Cardiovascular and metabolic function—the guidelines essentially state that research is needed as to the safety of testosterone treatment in women with respect to cholesterol issues, diabetes risk, and heart disease and stroke risk.

(4) Skin and voice—it is well established that testosterone can cause facial and body hair growth in women, acne, baldness, and a deepening of the voice. No studies have been done looking at these effects in women taking testosterone in doses that maintain “normal” levels for greater than 1 year.

I think I need to emphasize that there is a very different philosophy with which I and these guidelines approach this issue, compared to you and XXXX and your friends and colleagues. I emphasize this, to point out the potential weaknesses of our assertions—namely, I and the guidelines, and most physicians follow a Hippocratic philosophy that states that we will “first do no harm.” That is, we will not give any therapy that has not been proven effective AND safe. By safe, I mean that the benefits clearly outweigh the risks—because there are ALWAYS risks. Anything that is strong enough to help is strong enough to hurt. Furthermore we need to establish exactly who should be treated, and how that treatment should be monitored for effectiveness and safety.

I and these guidelines are not saying that there might not be some benefit to testosterone supplementation in some women. I am certainly not saying that XXXX, for example, doesn’t feel better when she takes testosterone. What I am saying is that it has not been established to our satisfaction who needs this therapy to avoid real medical harm, how much should be given and how it should be monitored, and that it doesn’t do more harm than good over years and years.

I know nothing about the provider prescribing to XXXX—I will be so bold, however, as to say that there are practices that are more concerned about billing people who understandably want to feel better than they are about safety and the other issues I have discussed.

I hope this helps. I am trying to emphasize that there are no absolute right answers here. There a lot of uncertainties, and the differences are in the way we deal with the uncertainties—ignore them, or be scared off by them—truthfully the “right answer” is probably somewhere in the middle. You might take another look at The Thyroid Paradox because it talks about many of the same issues regarding the use of thyroid hormone. In the case of thyroid hormone I do treat more often than most first-do-no-harm physicians do. I do that based on many years of experience and contemplation, which I have not applied to the testosterone-in-women question, so I am ethically obligated to go along with what the mainstream guidelines say. See?

All real medicine boils down to managing uncertainty. That is, accepting the possibility of error. Malpractice lawyers fail to grasp that—but that’s another story. With regard to testosterone therapy in women—especially otherwise healthy young women—I am counseling that we should err on the side of safety, and not do it, despite the possibility of denying the patient something that might help them feel better, and enjoy other benefits. XXXX and her provider, on the other hand, are erring on the side of feeling better. Just remember: cocaine makes people feel good, but most of us don’t advocate its use for that purpose.


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