How Clomid Works in Men

April 28th, 2010 § 811 comments

With the suspension of Cincinnati Reds pitcher Edinson Volquez for performance enhancing drug use and a swirl of rumors that the agent involved was clomiphene (also known as Clomid,) I thought it timely to write about how clomiphene works and how it’s used. From what I read on the internets, there is an enormous amount of misinformation floating around out there.

To understand how clomiphene works, you need to know how the pituitary controls the making of testosterone in the testis. Testosterone is made by Leydig cells in the testis, which I explained in my last post. The pituitary releases a hormone called luteinizing hormone (“LH”) that stimulates the Leydig cells to make testosterone. Testosterone is converted to the female hormone estrogen, (which I also explained in my last post,) and estrogen tells the pituitary to stop making more LH. This kind of negative feedback system is common when it comes to how hormones work. It’s just like a thermostat and heater. As the room gets warmer, the thermostat sends less electricity to the heater. When the room gets colder, the thermostat sends more electricity to the heater.

LH testosterone.png

Clomiphene works by blocking estrogen at the pituitary. The pituitary sees less estrogen, and makes more LH. More LH means that the Leydig cells in the testis make more testosterone.

As I explained in my last post, giving testosterone to a man does just the opposite. The pituitary thinks that the testis is making plenty of testosterone, and LH falls. As a result, the testis stops making testosterone, and the usually high levels of testosterone in the testis fall to the lower level in the blood.

So clomiphene is a way to increase testosterone in the blood and the testis at the same time. It preserves testis size and function while increasing blood testosterone.

Unfortunately, clomiphene is not FDA approved for use in the male. Like most of the medications that we use to treat male fertility, the pharmaceutical company that originally sought approval by the FDA did it for women. Clomiphene is now generic, and it’s unlikely that anyone will pony up the hundreds of millions of dollars necessary to get it approved for the male. That’s the bad news. The good news is that it means that this medication is fairly inexpensive, cheaper than most forms of prescription testosterone. Can a doctor prescribe clomiphene for a man? Yes. It’s “off label”, meaning that it’s not FDA approved for use in men.

As a medication, clomiphene is usually well tolerated by men. In my experience, most patients don’t feel anything as their testosterone rises. Those that do feel an increase in energy, sex drive, and muscle mass, especially if they work out. Very rarely I’ve had patients report that they feel too aggressive, or too angry. Very very rarely (twice in the last 20 years) I’ve had patients report visual changes. That’s worrisome, as the pituitary is near the optic nerve in the brain, and visual changes suggests that the pituitary may be changing in size. Because the skull is a closed space, it’s alarming if anything in the brain changes in size. In the last twenty years, I’ve also had two patients who had breast enlargement (called “gynecomastia”) while using clomiphene. Needless to say, for any of these problematic side effects, the clomiphene is discontinued.

So that’s the story with clomiphene. It can be used in the male, either for fertility or low testosterone levels. It’s an off label prescription drug. It works, and is usually well tolerated by men who take it.

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§ 811 Responses to How Clomid Works in Men"

  • Frank says:

    Hey Doc,

    This blog is great. I have had trouble finding info this thorough elsewhere. If a 34 y.o. man were receiving Testosterone replacement therapy for 2.5 years and then prescribed Clomid for fertility would the time on he spent on T replacement potentially have harmed his ability to produce sperm?

    Thanks agian

    • maledoc says:

      Thanks! I’m sorry, that’s close enough of a personal question that I can’t answer it. If you live in the US, the FAQ has some good resources on finding doctors.

  • Na says:

    What happens when a man stops taking clomid after a course of clomid.
    do testosterone levels stay up high or will they fall back to pre-clomid levels ?

  • George says:

    So for twenty years, the worst side effects have been the two visual problems and the two gynecomastia incidents for your patients? Or is there anything else? The longest study was only 3 years and I’m looking for what might be expected when a young male begins using beyond 6mos to a year.

    Also, it seems alot of doctors/patients seem to miss or ignore aromatase when the testosterone levels start dropping and the estradiol rises. Do you think an aromatase inhibitor would curb this problem (I have not looked into the medications cost or side effects whether its worth it or not)? I’m thinking that at least the known herbal and food aromatase inhibitors might help some.

    • maledoc says:

      To the first, yes :) But as I wrote, we don’t have formal long term studies. To the second, a specialist familiar with aromatase inhibition in the male would be a good doctor to see for a man who was interested in it.

  • andy says:

    Hi
    I have some questions regarding the estrogen that is blocked by the clomid:
    Where does it go?
    How is it used?

    Thx

    Andy

    • maledoc says:

      Men seem to need some estradiol, for example bone density appears to depend on it.

      • Will says:

        Hello Dr … great blog! I’d appreciate a little more elaboration on your answer to Andy’s question since I have the same concern. It seems that Clomid treatment would block my brain from recognizing the actual estrogen levels. In response, the testes kick out more testosterone which eventually results in elevated estrogen floating around.

        Cutting to the chase, I don’t want to develop breasts or get all emotional from this potential imbalance. is this something you’ve ever noted as a side effect?

        • maledoc says:

          Hi Will, unfortunately I can’t answer personal questions about your own health. Please read the FAQ.

          • Will says:

            I must have phrased the question wrong if you thought I was seeking personal information. In your professional opinion, what goes on in the male body when the brain is unable to detect elevated levels of estrogen which would seem to be a side effect of Clomid treatment?

          • maledoc says:

            Men have differing internal workings when it comes to responding to medication. That’s why each needs to be under a doctor’s care if he’s taking it.

      • Korey Smith says:

        You mentioned that maintaining “Bone Density” relies on some Estrogen, however, I thought that was the purpose of Testosterone? Do they both work together in males on Testosterone Replacement Therapy to achieve the same purpose (maintaining bone density?), especially when there is some Testosterone to Estrogen conversion taking place?

        Korey

        • maledoc says:

          Your reading was right, Korey: although scientists aren’t certain, it looks like estrogen is more important than testosterone in the male for bone density. Estrogen is a natural product of testosterone in the male body and is made by the enzyme aromatase. Read the other posts in this blog and especially the comments: you’ll find a lot of interesting information.

  • rob says:

    If my doctor is not familiar the topic, are there any medical articles that address use the medical uses of Clomid for men (e.g. dosage, counter-indications, etc) to which I can refer him?

  • sunny says:

    could clomid be used for treatment of klinefelters syndrome if no other treatment for the same was done in past… and is it safe????
    are the side effects lesser or more than hormone replacement treatment!!!!

    • maledoc says:

      Men with Klinefelter syndrome have an extra X chromosome and often experience low testosterone. Clomiphene may be useful in some. Any man with Klinefelter syndrome who has low testosterone and is interested in treating it should see a physician experienced in working with men with Klinefelter syndrome.

  • BB Gregory says:

    Hi Dr. Niederberger;

    I read several resources that indicate Clomid works on the estrogen receptors in the Anterior Hypothalamus and the Anterior Hypophysis, blocking them and causing increase production of GnRH, which then acts on the Pituitary causing increased LH and FSH production. Is this in addition to its direct action on the Pituitary, or is the Hypothalamus not part of the mechanism of action of Clomid?

    Thank you, trying to understand what is happening in my body when I take Clomid as a treatment for hypogonadism.

    • maledoc says:

      It’s an interesting and open question, BB. The estrogen receptor has been identified in both the hypothalamus and pituitary, and clomiphene may affect both. LH and FSH both increase after treatment, suggesting a hypothalamic effect, but to variable degrees, suggesting a pituitary effect. There is much in science that we don’t fully understand, and your question is one :)

  • Danielle says:

    Do you have any actual studies of men who had been on testosterone previously and went on clomid to help boost fertility, of it actually working? I can’t seem to find that anywhere no matter how hard I look.

    • maledoc says:

      It’s really common to switch medications, and it works well, but it’s different for every man. Thant’s why a man should see his own doctor for treatment and monitoring.

  • Kathryn says:

    Doc,

    In your experience, what is the highest dose of clomiphene you have given a male with low T?

    Thanks,
    Kathryn

  • Tom Trebes says:

    I have read that Clomiphene can get rid of gynecomastia. Have you seen this in your practice?

    Thank you.
    Tom

    • maledoc says:

      Clomiphene typically increases both testosterone and estradiol. While the increase in estradiol may cause gynecomastia, which is why estradiol needs to be monitored by a doctor while a man is taking the medication, I haven’t observed anybody to have less gynecomastia while prescribed clomiphene, and it doesn’t make biological sense why that would happen.

  • Kevin Hastings says:

    Hello,

    I have read where testosterone supplements may cause several side effects. When prescribing clomiphene citrate have any of your patients experience short or long term hair loss?

    Thank you.

  • Ari says:

    Dear Dr.Niederberger,

    I am an athletic and active professional with 10% body fat ( 6’1/ 210 lbs). I recently discovered my sperm count was 2million/ per ml. My testosterone level was 91!! I have been placed on 50mg clomid for 2 week with repeat Testosterone levels at that time.
    ( FSH of .9).
    1. Question: Can taking one month of steroids 8 years ago have caused this?
    2. Question: I have no symptoms of low testosterone ( No fatigue, no depression, No decrease in Sex drive etc): Is this possible?

    Thanks much

    • maledoc says:

      I’m sorry, Ari, but I can’t answer personal questions about your own health. Please read the FAQ. The doctor that is prescribing clomiphene should answer your questions; that’s his or her job :)

  • joe says:

    Hi Doc,

    How do you advise your patients to come off Clomid. Do they taper off slowly or do they just stop taking the medicine ?

    • maledoc says:

      That’s a great question, Joe. If someone is prescribed steroids, typically there’s a tapering of the medication when it is discontinued to allow the body to catch up in making its own steroid hormones. It’s as if the pituitary goes to sleep and needs a little time to wake up. I haven’t seen such a need with clomiphene therapy, which acts to increase testosterone production rather than decrease it such as an external steroid would.

  • Jim says:

    Dr. Niederberger

    My question is this, do you know of any protocols to use both testosterone and Clomid? Where the Clomid is used to prevent “shrinkage”? versus replacing testosterone with Clomid. For instance, I have read of people using HCG a couple of times a week for this purpose, but not Clomid. In your opinion, could this be done safely?

    • maledoc says:

      Hi Jim, check out the FAQ where I talk about the pitfalls of using two different medications. Part of the problem is that every man comes with his own cookbook :)

  • Debbie says:

    Hi Dr. Craig,
    Refering to your article on “How Clomid Works in Men”, can I say that if a patient’s pituitary is damaged / partially damaged by a brain tumor, Clomiphene will not work for him as a Testosterone Replacement Therapy, since his pituitary may not produce LH in the first place? What is the way to find out? Can we measure LH level in the blood?

    If Clomiphene does not work in this case, is there any other alternative Testosterone Replacement Therapy that do not reduce sperm count? (I understand that testosterone replacement, eg., Nebido, does reduce sperm count).

    Thanks so much,
    Debbie.

  • Jake says:

    Hi doc. Is it true that sperm motility determines whether you have a boy or a girl? I heard that if motility is high, then your more likely to have a boy. Is this just a myth?

  • ritch says:

    Dr. I’ve heard of guys boosting T levels by combining clomid and stinging nettle root. What are your thoughts on that? I have ” text book” normal levels but have all the symptoms.

    • maledoc says:

      Hi Ritch, I’m unaware of controlled clinical trails of stinging nettle root for low testosterone in men. (They may be there: if they are, I’m unaware of them.) But I don’t typically recommend two different medications at the same time. For an explanation, read my FAQ :)

  • Tom says:

    Hi, Dr. Craig Niederberger. Thanks for creating and continuing to participate in this informative blog.

    Does clomiphene act as an estrogen agonist (active estrogen) in the liver?

    If it does, would the estrogen promote the production of sex hormone binding globulin which then binds to testosterone hormones and render them inactive?

    Would this result in a person having higher total testosterone levels but with actual bioactive testosterone being not so high? If this is the case, does it explain why most men taking clomiphene don’t feel an increase in well-being aspects that are associated with increased testosterone?

    On a similar note, if clomiphene is an estrogen agonist in the liver, would this result in IGF-1 being reduced?

    • maledoc says:

      Hi Tom, as the liver breaks down drugs, there are a lot of studies about clomiphene, how it’s broken down in the liver, and its byproducts. There aren’t a lot of studies about clomiphene action in the liver. For most men, sex hormone binding globulin levels stay the same while taking the medication, but for a few, they rise. (A man’s doctor will monitor his blood chemistry while prescribed clomiphene.) Bioavailable testosterone typically increases with the medication. I wouldn’t say that “most men taking clomiphene don’t feel an increase in well-being” with clomiphene compared to testosterone. Some men prefer clomiphene for how they feel, and some prefer testosterone.

  • joe says:

    Hi Doc,

    This is Joe again with another question that I don’t think has been asked.

    Does Clomid increase the levels of Prolactin in men ?

  • joe says:

    Hi Doc,

    A follow up on your response about prolactin.

    Could it be that long term use of Clomid causes the pituitary to grow and produce more prolactin ?

    Cheers,
    Joe

  • CJ says:

    Hi Doc,

    You replied to Kathryn that you generally don’t prescribe above 100mg daily. What would be the potential benefits/side effects of going higher. Maybe 150mg or even 200mg daily?

    • maledoc says:

      Hi CJ, I’ve found that if someone doesn’t respond at that high of a dose, going higher doesn’t work. It means that the pituitary isn’t responding to the medication, and it’s time to try something else if possible.

  • Alvin says:

    I read that if the clomid didn’t raise the T levels than it could be primary hypogonadsm where the testes don’t produce for whatever reasons? All hypothetical of course!

  • Peter says:

    Hi! If I’ve understood things correctly clomiphene is also given to men despite normal & good testosterone levels who are having problems with their sperm. Does clomid, in those cases, raise testosterone just as it does when used treating hypogonadism? I’ve looked around for studies but I’m having trouble narrowing down the search.

    Thank you for your time!

  • joe says:

    Hi Doc,

    Great blog, chock full of good stuff.

    May I ask you to write a column called “How Armidex works in men”. I think that would be very interesting

    thanks

  • Mark says:

    Androgel can sometimes lead to higher levels of hemoglobin. Have you seen any impact of clomiphene on hemoglobin levels?

    • maledoc says:

      I haven’t seen it, but I rarely see increased hemoglobin even with testosterone therapy. It likely has to do with my location at sea level in Chicago. We still monitor it for all therapies that increase testosterone, including clomiphene.

  • Ted says:

    Hello Dr. Niederberger. Are there any problems with taking Clomid every other week in a pulse fashion?. How long does it take for the testosterone level to stabilize when taking 25mg daily? How fast does the Testosterone level drop when the treatment is stopped? Are there any negative or positive effects on the pituitary with pulse dosing?

    • maledoc says:

      Hi Ted, I wrote a bit about how sperm production works: read those posts and comments. It doesn’t make biological sense to prescribe clomiphene in that kind of pulse fashion. Usually by two weeks, the testosterone level is constant. I’ve written about what happens when clomiphene is discontinued: read through the comments, and you’ll find some really great questions that people have asked and their answers.

  • Rob says:

    What is the mechanism for male hot flushes with Clomid and what can be given to prevent it.

    • maledoc says:

      Hi Rob, it’s really important for the physician prescribing clomiphene to know what the testosterone level is, as if it is in good range, hot flashes are infrequent and usually self limited.

  • Barry says:

    Great information. Can you tell me exactly which tissues clomid acts as an estrogen agonist and which tissues it acts as an estrogen antagonist? I can find this Info anywhere.
    I know it is antagonist in pituitary and hypothalamus but what about other tissues with estrogen receptors like bone, skin, hair, muscle, fat etc.

    • maledoc says:

      Hi Barry, here’s a nice article that discusses a bit of how clomiphene may work in both agonistic and antagonistic ways. You can get the article for free. Practically speaking, the conversion of testosterone to estrogen by aromatase is probably more meaningful in terms of estrogenic effects of the medication, which is why a prescribing physician might want to see what happens to estradiol for a man prescribed the medication.

  • Robert says:

    Hi, I have posted general questions here asking about clomid use in men. Your level of knowledge on the subject always makes for good learning.

    I have been doing research lately on 5 alpha reductase inhibiters. I came across the website propeciahelp.com. This website has over 3000 members who all claim they have taken a 5 alpha reductase inhibiter and have experienced long term negative sexual side effects. All of the men on this website believe that the 5 alpha reductase inhibiter that they took caused these long term side effects. Several members on this website only took the medication for a short period of time such as one month or less.

    Seeing that you obviously have a level of understanding as to how men’s endocrine systems work that goes beyond what most doctors have I was thinking that maybe I could pick your brain on this issue to see what you think.

    In your opinion if a man was to take a 5 alpha reductase drug such as propecia or avodart and experience long term negative sexual side effects such as decreased ability to achieve and maintain an erection, decreased libido, decreased semen, watery semen and loss of sensation in the penis do you think that a possible explanation as to why this might be is that the 5 alpha reductase type 2 enzyme in the prostate (and in other areas of the body) might be turned off because of the taking the 5 alpha reductase medication?

    In order words if a man was really sensitive to this type of a drug is it possible that inhibiting this function could have some type of long term effect on some men?

    Also if you feel that some type of long term 5 alpha reductase type 2 effect has taken place is it possible to reverse it or in other words turn this function back on, possible by using DHT in an attempt to increase 5 alpha reductase activity?

    • maledoc says:

      Hi Robert, there may be a small number of men whose fertility are affected by 5 alpha reductase inhibitors, but the risk is likely to be very small, around one in 200 if it exists. (See this paper.) The only way to know would be to discontinue the medication, wait three months, test sperm, (as it may not be purely a hormonal effect,) start the medication again, wait three months, and retest sperm. Even then, without a comparison group of men who are taking a sugar pill, you can’t be certain that the results wouldn’t be chance. At this point, I would say that an infrequent effect of this kind of medication has been raised for male fertility, and we should think about larger studies in the future to learn if it’s real.

  • Robert says:

    Also in your opinion is it possible to measure a man’s body’s ability to convert testosterone to DHT via the 5 alpha reductase type 2 enzyme? I ask this questions because if a problem with this enzyme is to blame for long term side effects after taking a DHT inhibiter I am assuming that the first step in fixing this problem would be to find a way to measure it to know if this is actually what’s causing the problem or not

    I have been doing research and if I understand what I am reading correctly it seems as if you can’t measure men’s ability to convert testosterone to DHT based off of checking DHT blood levels alone because it’s possible for a man to have normal levels of DHT floating around in the blood because their 5 alpha reductase type 1 enzyme in the skin and liver is working properly. (which is far as I know has no or little effect on sexual function) In other words just because a man has normal levels of DHT in the blood, it does not mean that the 5 alpha reductase type 2 enzyme function’s are working normally. Is this correct?

    If this is correct do you know of a way to measure/test for the 5 alpha reductase type 2 enzyme function specifically?

    Do you think testing for Androstanediol Glucuronide (3a-diol G) is helpful in judging 5 alpha reductase type 2 activity? Do you know if 3a-diol G is a metabolite of DHT?

    How about THF/5-a-THF? have you heard of that being a way to test for it?

    Was also wondering if you are aware of the study that’s going on at Brigham and Women’s hospital in Boston? Supposedly it’s a study involving men who have taken 5 alpha reductase type 2 inhibiters and who suffer from long term sexual side effects.

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