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.
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.
Subscribe by RSS
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
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.
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 ?
Hi Na, that’s in the FAQ
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.
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.
Hi
I have some questions regarding the estrogen that is blocked by the clomid:
Where does it go?
How is it used?
Thx
Andy
Men seem to need some estradiol, for example bone density appears to depend on it.
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?
Doctors interested in learning more about male reproductive medicine might find the 4th edition of Infertility in the Male or An Introduction to Male Reproductive Medicine useful. Both have Kindle editions. (Obvious disclosure: I’m an author of both, which we wrote to serve as resources for physicians.)
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!!!!
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.
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.
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
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.
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.
Doc,
In your experience, what is the highest dose of clomiphene you have given a male with low T?
Thanks,
Kathryn
Hi Kathryn, I typically don’t prescribe doses of clomiphene beyond 100 mg daily.
I have read that Clomiphene can get rid of gynecomastia. Have you seen this in your practice?
Thank you.
Tom
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.
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.
Hi Kevin! Look around these posts and their comments, and you’ll find lots that will answer your questions!
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
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
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 ?
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.
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?
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