James K. Rone, MD, FACP, FACE

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

May 17, 2014

Tags: Testosterone, Hypogonadism in Men

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.

Dr. Rone

Comments

  1. September 25, 2015 4:43 PM EDT
    First off, I agree that Doctor 'shopping' for a self diagnosed condition isn't a good thing. However, as someone who is currently being prescribed Clomid for my Low-T, I also take exception to your statement that no 'good' physician would agree to prescribe this long term. My doctor is very good. Actually he was my doctor when I was participating in Repros phase III trials for encolomiphene citrate. (I bought Repros stock after the study because of my strong positive results on the trial medication). I was monitored on this drug trial for just over a full year. It worked wonders and I was really distraught that I would lose the benefit of it when my study trial ended. The enclomiphene citrate molecule is very similar to the Clomid molecule. It is the single isomer version of Clomid. After my study ended my doctor transitioned me over to Clomid until enclomiphene citrate gets FDA approval (fingers crossed). There is no guarantee it will get approval, so you could describe my current use as 'long term'. My doctor had a year's worth of my study statistics as well as continues a full bloodwork battery every 6 months. Again I take issue with the 'no good' physician comment. My physician is very good. Has a wealth of information on me, and continues to montitor me.
    - Chris Sansom
  2. November 5, 2016 1:04 AM EDT
    This is some great information. I'm curious what would
    be the next drug to try for someone with low t? Arimidex, Letrozole or something else? Thanks Doctor!
    - Mike Strip
  3. January 28, 2017 8:25 PM EST
    Chris, I deeply apologize for somehow overlooking your comment of over a year ago, until I noted it when checking out Mike’s more recent, but nonetheless also unacknowledged-for-far-too-long contribution to the same blog post. It is no excuse, but I have been distracted from the blog by more pressing issues in my practice. Regardless, I trust the information I have previously posted remains helpful to those interested.

    Mike, let me answer you first, and that will segue into Chris’s comment.

    You ask “what would be the next drug to try for someone with low T?” Then you mention 2 aromatase inhibitors, drugs which, as you probably know, block conversion of testosterone to estrogen. Rational drug prescribing absolutely requires knowing what condition is being treated. You state “low T,” which I am going to more precisely define as “male hypogonadism,” a condition wherein testosterone production from the testes is either absent or inadequate to meet the man’s physiological needs. This may result from either a disorder of the testes or a failure of the pituitary gland to make LH, the hormone that stimulates the testes to make testosterone.

    Now, a different condition that requires a different approach to treatment, but which often accompanies male hypogonadism is “male infertility.” Infertility only needs treatment, however, if the patient and his female partner have made a definite decision to get pregnant. Otherwise the man who has hypogonadism and infertility only needs to have his low testosterone levels (hypogonadism) corrected, not his low sperm counts (infertility). And since the drug therapies for those two conditions are different, with different goals: this is why I emphasize the importance of knowing what we’re treating.

    You specify “low-T,” as did Chris, in other words hypogonadism. Assuming it has been properly and definitively diagnosed, lifelong testosterone replacement is typically needed to correct or protect against the consequences of the sex-steroid lack—symptoms such as fatigue, depression, sexual dysfunction; increased fat mass, loss of muscle mass, heart disease, and osteoporosis. As I say, this would typically be lifelong, or at least long term and open-ended, with testosterone given as an intramuscular injection, or by various patch produces, various testosterone gels, or buccal (inside the cheek) adhesive tablets. There are implantable pellets as well. My experience is limited to the shots, patches and some but not all of the gels.

    For male infertility, on the other hand, testosterone cannot be used. Reason: very high intra-testicular testosterone levels are needed for sperm production and you can only get that from internal production, not from any exogenous (taken in somehow from outside the body) testosterone product; moreover, that internal production requires the pituitary hormone LH, and pharmacological testosterone shuts LH off. Testosterone replacement is effectively a contraceptive, the opposite of what we want in infertility. So, say a man with hypogonadism, who is only partially deficient, is eking out enough endogenous (internally produced) testosterone to make some sperm—and even if sperm counts are low, it only takes one—is prescribed testosterone replacement for some symptom like poor libido or impotence. That prescription is likely to eradicate whatever sperm counts he’s managing. Testosterone replacement cannot therefore be given to any hypogonadal male when pregnancy is desired.

    Consequently, for infertility patients, there are a host of fairly standard drugs for supporting the internal production of testosterone, and hence, sperm. These include HCG (mimics LH) shots, often with add-on HMG (FSH) shots (HCG w/ or w/o HMG is the first-line treatment for male infertility; however it is expensive and requires every other day or so shots), and drugs in pill form like clomiphene and the aromatase inhibitors, probably in that order of frequency and effectiveness. Now, all of these therapies require some intact physiology: HCG requires that the testes are healthy and capable of making sperm, i.e., the problem has to be a pituitary problem. Clomiphene, a SERM (selective estrogen receptor modulator), requires some intact pituitary function, as it works by reducing estrogen inhibition on LH release. If LH can’t be produced, because of serious pituitary damage, then all the clomiphene in the world won’t help. AI’s (aromatase inhibitors) block testosterone conversion to estrogen, preventing a disappearance of testosterone, transmuted into estrogen, and an increase in the antagonistic (i.e., female) hormone, estrogen. But AI’s bring no benefit if there is no testosterone—there must be intact testicular function.

    The key difference in infertility treatment and hypogonadism treatment is duration. Whatever we see fit to give for infertility is only necessary until pregnancy is achieved. That does not mean the same drugs are acceptable—even if they do work—for the longer-term, even possibly lifelong, treatment of hypogonadism in general. Clomiphene and AI’s have in common a reduction of estrogen effect and estrogen effect is key to male and female bone health, fracture prevention. It might take 20 years of these drugs to see an increase in hip and spine fractures—I don’t know that to be true, but I don’t know it not to be, and there is a plausible physiological reason that it might be true. And unless I am greatly uninformed there is no study that tells us definitively (or otherwise) that these drugs are safe for 10 or 20 years. Chris took me to task for the phrase “good physician”—well I’ll use it here. Good physicians are usually highly reluctant to prescribe treatments without there being some reasonable evidence of safety, or at least benefit being greater that risk.

    We may be working towards that—the study Chris participated in being an example. We appreciate his commitment to medical advancement. But even if Androxal (enclomiphene) is eventually approved—and my brief internet search does not suggest that is likely, it suggests the FDA effectively rejected it in Dec. 2015—I would not assume such approval would guarantee the long-term safety that I’m talking about. No drug submitted for FDA approval can demonstrate 20 years of safety data. If we required that we’d get nothing helpful released in the US. FDA approval can be helped or hindered by many factors, which might or might not be medically relevant. But if the FDA hasn’t approved a drug for something, then I can’t use it legally and ethically for anything in the US. If they do approve it for something then I can use it for anything I can medically justify. Which is why I can use clomiphene “off-label” for hypogonadism if I wish, but not enclomiphene—as sorry as I am for Chris’s investment.

    After that long preamble, to answer, sort of, your question, Mike: What would be the next drug to try? From context of the blog post, I assume you mean 1) for hypogonadism, and 2) next after Clomid/clomiphene.

    The rub is, for hypogonadism, I can honestly say I have never been to an endocrinology continuing medical education conference, or read a major textbook, in close to 30 years of doing this, where ANYTHING other than some form of testosterone was talked about. Meaning that alternatives are nonstandard. That mindset was the basis of my original post, and remains true.

    However, since then, and in researching this reply, I am seeing reports of SERM’s (clomiphene) or AI’s (specifically anastrozole) being used in hypogonadism as an alternative to testosterone. So, I will change my tune a little bit and say that you and Chris aren’t off base, but just getting into areas that most of clinical medicine, including endocrinology, haven’t embraced yet as standard therapy. I feel it important to emphasize that just because something can be done, and is being done by some doctors in or out of research setting, and some patients have experienced benefit and believe strongly in it—does not necessarily mean that the therapy is yet or ever will become standard practice, which is what mostly shows up in textbooks and in CME conferences. I see tons of research out there in the medical journals for things that might never make it out of the laboratory or clinical trial setting, into mainstream accepted practice. It depends on demonstrating significant benefit, for a significant number of people given the therapy, with a reasonable margin of safety. Anything strong enough to help is strong enough to hurt.

    To the extent that there is or might be an expanding role for SERM’s and AI’s in hypogonadism, I would also remind you that for either of these to work there must be some intact pituitary and testicular function. It either of those is missing, then these drugs will not work. In other words, some hypogonadal men might be treatable with a SERM or AI, while others will require testosterone.

    As for your specific comments Chris, your doctor’s participation in a formal new drug trial gives him immunity from any negative suggestions I might have made, at least with respect to the study drug. As for transitioning you to clomiphene, as I say, I do see it is being done, and it may become standard therapy at some point, but it isn’t there yet. Your doctor sounds like he is highly expert in this particular sub-sub-specialty area, i.e., gonadal disorders in men; we all color outside the lines, for the benefit of our patients, in areas where we have greater knowledge and experience than average. I don’t disagree with doing that—much of what I have written in my many blog posts on this site involves coloring outside the lines, in areas in which I consider myself highly expert. I don’t include hypogonadism in that assessment of myself. I am knowledge about it, and can manage patients with it, but it is not a focus of my practice. Which means “coloring outside the lines” in this particular matter, is not something I feel qualified to recommend, as a conscientious healthcare provider. I gather you’re getting good results with clomiphene, Chris. I would just ask you to remember the adage I quoted above—if it is strong enough to help it is strong enough to hurt—and just make sure the benefits you’re getting outweigh the risks or the uncertainties, which your doctor should be willing to, and probably has, discussed with you. Best wishes, and thanks for sparking further discussion.

    Back to Mike’s query about other options: there are two additional points I’d like to make.

    Interestingly, and this was news to me when I was researching the SERM/AI issue, it turns out that PDE5 inhibitors (these are the Viagra’s of the world), increases the ratio of testosterone to estrogen, like AI’s, and it is felt that with chronic use, the PDE5I’s in fact inhibit aromatase and that might be part of their benefit in erectile dysfunction.

    Latly—so far we have been talking about hypogonadism caused by some irreversible damage to the pituitary or testes preventing adequate testosterone production. There is however a not-too-uncommon cause of male hypogonadism that must always be looked for and ruled out—because there is a specific, effective therapy that often restored normal gonadal function, and because of the other consequences of missing this underlying diagnosis. I am talking about the most common hormone-producing pituitary tumor, a “prolactinoma.” This is a usually benign tumor of the pituitary gland that makes prolactin, a hormone that in excess will shut off LH, FSH, and testosterone production directly at their sources. Sometimes surgery is needed for these tumors, but often a once or twice weekly, well-tolerated pill, called cabergoline will shrink the tumor and restore Prolactin to normal, and the hypogonadism resolves, permanently. On the other hand, missing this diagnosis can have serious consequences. The tumor might grow and invade part of the brain and compress the optic nerves leading to partial blindness. This tumor tends to be easier to catch early in women, but in men the only early clue might be hypogonadism. So, every affected man should get a prolactin level drawn, and make sure that is normal before going down the road of testosterone or a SERM or whatever.

    Dr. Rone
    - James Rone
  4. April 9, 2017 11:32 AM EDT
    This is a terrible response. You are minimizing the patient's authority over their own treatment and possibly forcing them to lie to get what they want for themselves. As a man with low T, I can tell you it is very frustrating to have to go through months of ineffective treatment in the name of being conservative. Nothing wrong with education, it just sounds like you need to put your patients in higher regard.
    - Scott
  5. April 12, 2017 11:05 AM EDT
    I am not minimizing a patient’s authority over their own treatment, I am rejecting it. A patient certainly has a complete right to accept or reject any healthcare practitioner’s advice or prescriptive orders, a complete right to stop seeing one physician, and seek a more compatible and effective therapeutic relationship with another. However, a licensed physician is ethically bound (and held to a medicolegal standard) to offer only treatments that are known to be both reasonably effective and reasonably safe, on the basis of that physician’s knowledge and experience. To follow Hippocrates’s oft quoted admonition, “primum non nocere,” or “first, do no harm.” I am very much a proponent of open-mindedness amongst physicians when considering treatments not meeting a current paradigm, and I do believe the medical profession tends to be overly dogmatic. If I am going to be coloring outside the lines, though, my professional ethical obligation to my patient is to be confident that what I am offering is likely to help and reasonably unlikely to hurt—and to the extent that there are risks (there are risks with all treatments, standard and nonstandard) that I understand those risks completely and share them with the patient ahead of time. The atypical therapies discussed in this string don’t meet that standard for my personal practice; if they do for another physician’s, that’s fine, and that doesn’t make either of us wrong.
    - James Rone
  6. April 13, 2017 11:26 AM EDT
    Permit me to enhance and modify my last comment slightly. Scott, was concerned I was “minimizing a patient’s authority over their own treatment.” I said bluntly that, no, I was rejecting it, and went on to cite ways in which it would be perfectly appropriate for a patient to exercise their “rights” with respect to their care. Here I am very carefully distinguishing patient “rights” from “authority.” A patient certainly has natural and proper civil and human rights in my office as elsewhere to reject or refuse anything I say or advise. I often tell patients when counseling them about options they seem a little wary of: “nobody’s going to hog tie you and make you have that procedure [or whatever].”

    My point to Scott is, no patient has authority to demand from me a treatment I disagree with. “Disagree,” in this context, meaning that I do not personally feel that it is adequately proven both safe and effective for the problem at hand. To take any other position would be tantamount to saying there is no value in seeking a physician’s expertise, based upon robust training and experience, and no value to all the laws and regulations regarding drug prescribing, and even the existence of the FDA. I’m not saying every physician (myself included), law, or FDA action is correct—but the alternative, therapeutic anarchy, rampant snake-oils-manship, would be far worse.

    Now, it is not uncommon that I counsel a patient about 2 or 3 acceptable therapeutic or diagnostic alternatives, explaining the pros and cons of each. Once I’ve done that, the patient is free—has the “authority”—to chose any of the 2 or 3 options, even if I have perhaps recommended one over the other(s). But the authority to demand anything, regardless of my professional option about acceptability: No.
    - Dr. Rone
  7. August 2, 2018 11:27 AM EDT
    I am 64 and have had green light laser 8 years ago for BPH we thinking was due to testosterone replacement for the past 15-17 years. I just had my second procedure yesterday - Button Photovaprization. My surgeon saw me in the preop yesterday and we disucsse the possibily of Clomid to try to boost the testosteron produce and do away with the topical "T". I have tried all the forms of "t" replacement. He said he was going to investigate the use of Clomid as he is not a great believer in "t" replacement, did not find out the cause initially even though I had a pituitary MRI before we started and have monitored all of the hormone levels. My Prolactin level shot up ????? But is back down. Do you have any comments and is clomid safe for my age. I certainly want to follow my surgeon's recommendations in any even.
    - R. Straight
  8. August 11, 2018 5:49 PM EDT
    The average age of the patients in the one study I have at my fingertips supporting the use on clomiphene for male hypogonadism was 44.3; there were 2 patients in their 60s (67 and 68) and they reportedly had a good short-term clinical response. They do reference another study where the average age was 62, and there was an impressive doubling of testosterone levels. They conclude the drug is more effective in younger healthier men, but it doesn't seem obvious to me that your age contraindicates using Clomid. Just remember, Clomid only works if testicular function is intact and the problem relates in some way to the brain and pituitary's control of the testes. Fifteen to 17 years of testosterone replacement will have thoroughly suppressed your testosterone producing system at every level--brain, pituitary, and testes. So, regardless of what the original problem was, everything is probably worse now, and your internal testosterone production, off testosterone replacement may or may not ever wake up. Clomid might help it wake up??
    Bottom line--it's probably worth trying as long as your doctor is willing to use it off-label, and is comfortable with and briefs you on potential safety issues, which all drugs have. I think you have to be prepared for the possibility of it not working under the circumstances, however.
    I hope that helps.
    Good luck!
    Dr. Rone
    - James Rone
  9. August 22, 2018 10:24 AM EDT
    My husband is suffering from low testosterone and we are trying to conceive. He is going to have a semen analysis done this week. I have heard if men taking clomid while doing testosterone therapy but I had Never heard of men taking clomid without testosterone. I have a little more faith in the ability to have a child after reading this. We have had successful pregnancies and also unsuccessful pregnancies as of recently. In this post you talk about short term use of clomid, if clomid were to work, how long does it take post starting it to up the sperm count? I know with women it is 5 days a month for ovulation but I’m wondering if it would be a consistent for my husband of does it start to work quickly and could be used strictly during our fertile period? Thank you for this wealth of information.
    - BD
  10. August 22, 2018 6:49 PM EDT
    Finally! An easy question!
    If I recall correctly, it takes 120 days for 1 spermatocyte to grow to maturity. Meaning, to whatever extent Clomid will help your husband produce sperm, it absolutely must be used continuously--for a BARE minimum of 4 months (if I'm remembering that 120-day figure correctly--even if I'm wrong, it's close to that).
    For men, when I say short-term treatment I mean months to a few years. Long-term would be…a decade, maybe for life…
    This use of Clomid is absolutely not analogous to the female menstrual cycle situation.
    I wish you and your husband well, and good luck!
    Dr. Rone
    - James Rone
  11. November 15, 2018 8:27 AM EST
    Hi Dr. I lucked upon this topic after doing a google search following my visit to my endo doctor last week. I'm a 36YO male with pan hypopituitism. In addition to medication for thyroid, HGH and cortisone replacement, the doctor has prescribed Clomid instead of testosterone as we still wish to have children. He said there have been recent studies in the US, Australia and the UK that support its use for hypopituitsm where fertility is still desired. I'm really hoping that it works!
    - Anonymous

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