More Pills and Testosterone

June 7th, 2011 § 38 comments

May blew by, and I didn’t manage a single new post.  The annual meeting of the American Urological Association and a big burst of research activity in my bioengineering lab did keep me busy, but really, there’s no good excuse, and it’s time to blog again.

One very active area of this blog is How Clomid Works in Men, with over a hundred comments to date.  I’m grateful to Robert for inspiring this post.  His question is, are there medications that decrease estrogen?

To review how the pituitary controls the making of testosterone in the testis, testosterone is converted to the female hormone estrogen, and rising levels of estrogen tell the pituitary to make less luteinizing hormone (“LH”).  The role of LH in a man is to stimulate the testis to make testosterone, and as the pituitary sees more testosterone in the blood through the lens of estrogen, it tells the testis to make less testosterone by reducing LH.  I likened this negative feedback system to a thermostat and a heater: as the room becomes hotter, the thermostat turns down the heater.  Clomiphene binds tightly to the pituitary, (and hypothalamus for you biological sticklers), and tricks the pituitary into thinking less estrogen is bouncing around in the bloodstream.  The pituitary labors to make more LH as a result, and the testis makes more testosterone.  The drug tamoxifen works in a similar way.

But Robert’s question hinted at another way to trick the pituitary: there is a way to decrease estrogen directly so that the pituitary sees less of it and makes more LH.

The enzyme aromatase turns testosterone into estrogen.  Drugs like anastrozole and testolactone block aromatase, causing estrogen to decrease in the blood.  The pituitary makes more LH as a result, and the testis produces more testosterone.  If a man has low testosterone and high estrogen, these drugs can simultaneously increase testosterone and decrease estrogen. In a study published in the Journal of Urology in 2002, doctors Raman and Schlegel report evidence that anastrozole seems to work a little better than testolactone, at least in terms of increasing sperm production.  In that study, the doctors also suggest that these drugs are best used if the ratio of testosterone is less than ten to one.

As I wrote in my post on How Clomid Works in Men, all of these drugs are off-label for use in the male, meaning that the Food and Drug Administration didn’t approve their use in men.  That doesn’t mean that they can’t be used.  It means that doctors need to tell patients what we know about these drugs, allowing for an informed decision on their use.  It also means that many of the questions we have about these drugs don’t have answers.  A good question about aromatase inhibitors in men is whether estrogen plays an important role in some health concerns in men, and if it is decreased for a long period of time, can other health problems occur?  We don’t know.  My current practice for prescribing aromatase inhibitors is mostly to limit their use to male fertility, and to stop the medication as soon as possible.

So there you have the two basic ways that pills can trick the pituitary into telling the testis to make more testosterone.  Thanks, Robert!

Tagged , , , , , , , , , , , , ,

§ 38 Responses to More Pills and Testosterone"

  • Ettore Caroppo says:

    I currently use antiestrogens in selected infertile males (chiefly those showing integrity of the HPG axis), and the results are promising. However my numbers are too insignificant to draw a firm conclusion about it. I think that it’s time to draw a multicenter study on clomiphene/tamoxifen employment in male infertility. What do you think about it?

    • maledoc says:

      The best of course would be a placebo, double blind trial with appropriate endpoints. The question is, as always, who will fund it?

  • nebula says:

    Hi Doc,

    Thanks for this wonderful post. I am curious to know what effect clomid and anastrozole have on viscosity of the semen analysis.

    I have been on clomid therapy for about 3 mos now and recent semen analysis showed dramatic improvement except the viscocity became “severe” from “normal”.

    Have you seen this in your experience/practice ? I am meeting my urologist this week about the same but would like to get your point of view.


  • Don says:

    Is is possible to be on TRT and maintain fertility?

    I’ve been “low normal” my entire adult life in terms of T and sperm parameters, went on TRT at age 41 (am 46 now), feel better but my sperm count goes to “zero” on T, even with HcG. When I go off, and my sperm count creeps back up to low-normal after about 6 months, but I feel awful. My urologist basically shrugs when I ask if I can have TRT and fertility at the same time.

    Surely this is possible…what is the latest best practice to raise T without shutting down the sperm factory?
    Is there a protocol for TRT which maintains fertility?

  • Carl Weber says:

    How long after using Androgel does sperm production rebound? Does it matter if 50 yrs. with past fertility? Does HCG shots and/or Arimidex help to jumpstart testosterone level for sperm production? Secondary infertility related to prescribed anabolic steroids for low testosterone.

  • Christa says:

    Can a woman still be fertile if menstrual cycles continued during and after chemotherapy treatments?

  • David says:

    If in cases secondary hypogonadism without elevated baseline serum estradiol treated with clomiphene successfully normalizes testosterone levels, but elevates serum estradiol to above normal values (where [testosterone]:[estradiol] is <10:1), could an anti-aromatase, such as anastrozole be used in combination with clomiphene?

    • maledoc says:

      Hi David, please read the FAQ.

      • David says:

        Hi Dr. Niederberger, I am not sure that the entry in the FAQ really answers my question. You discuss therapeutic combinations of clomiphene and testosterone, but not clomiphene and anastrozole.

        • maledoc says:

          You have a point–it doesn’t specifically address that combination. But the general idea is the same: you have two drugs acting at different points in the male endocrine system, so controlling what you intend is like trying to make stew by throwing ice cubes into it while it’s on the stove. If you want to cool it down, just take it off the stove. If you want to heat it up, don’t put in the ice cubes. In nearly all cases, using only one drug or the other achieves the desired effect.

          • David says:

            Thank you for your response, Dr. Niederberger. Just to clarify: clomiphene be a first-line treatment for secondary hypogonadism unless labs return abnormal after treatment with clomiphene alone (e.g. estradiol:testosterone = <10:1), where anastrozole (alone) would then become the preferred treatment?

          • maledoc says:

            I wouldn’t say that. I described the drugs and what they do. Choosing, dosing and ordering (which comes first) depends on the patient under the care of his doctor.

  • Kari says:

    You say that your current practice is to stop the use of an aromatase inhibitor as soon as possible. Are there any long-term solutions for low testosterone that would not compromise a man’s future fertility?

    • maledoc says:

      A sensible strategy is to use an aromatase inhibitor until a man has the family that he desires, and after that fertility is not the primary concern.

  • Dr. Harris says:

    How do you dose anastrozole? any difference in dosing if you use anastrozole along with clomid?


  • Jim says:

    I heard that clomid has agonist and antagonist properties. What does that mean?
    Also is clomid better than tamoxifen ? What’s the difference?

  • Rico says:

    Hey doc, In the FAQ you mention that you shouldn’t take clomid and testosterone at the same time. What about taking arimidex and testosterone together if your estrogen levels are to high?

  • Jose says:

    Hi doctor thanks for all the good info this blog provides. I know that either clomid or anastrazole can both raise testosterone levels. Do you know if one works better than the other at improving fertility? Are there any studies on this?

  • fefe says:

    Hello doc,

    I read somewhere that taking tamoxifen could reduce your libido due to the disturbed testosterone/estrogen ratio causing the body (pituitary?) to down regulate your testosterone levels to get the body in equilibrium again?

    Wouldn’t this be kind of contradictory if you’re a male aiming for an increased testosterone production?

  • Bill says:

    G’day from Australia doc, I know there are several blog posts on meds to increase testosterone and sperm count, but wondering if you could add some comments on effective ways to increase and sustain testosterone levels without meds. I know strength training can increase it, but to what extent? Perhaps a new blog post idea here? Cheers!

    • maledoc says:

      Hi Bill, working out probably doesn’t directly increase testosterone, but indirectly by improving overall health. Similarly, anything that improves general health may increase testosterone levels.

  • Scott says:

    Hi Doc,

    Do you prescribe Clomid for secondary hypogonadism even if E2 levels are high to begin with or go straight to anastrozole?

    • maledoc says:

      It depends on the man, his clinical picture, and his labs including LH, FSH, testosterone, bioavailable testosterone, and estradiol. It’s different for every man.

      • Scott says:

        If LH levels are low and estradiol levels are high, it seems to me that clomid would exacerbate the estrogen problem.

        • maledoc says:

          That group of men has highly variable response to clomiphene. Nature only partially responds to logic. That’s why there are doctors 🙂

  • Tom Mitchels says:

    Great post doc! Thanks for all the useful tips and facts! Found everything to be very useful. Cheers!

  • wiki says:

    is low Testosterone unusual for young athletic men (under 25) , what will be your minimum level (red line) for Testosterone of men under 25, as i found the minimum level varies according to each lab … mostly skewed based on the middle aged men they usually test.

  • maledoc says:

    It’s been many years, and I’ve finally turned off comments for this WordPress blog. Why? Although it’s the first question in the FAQ, I still get comments (a bunch a day!) asking personal medical questions that I can’t answer. That’s sad and frustrating for me, because as a doctor, I really like to help patients. But this WordPress site was never meant to deliver personal medical care, and the University lawyers tell me that doing so would run afoul of State and Federal laws.

    If you have specific questions about your own personal care, I urge you as outlined in the FAQ to use the American Urological Association’s Society for the Study of Male Reproduction’s search engine

    I also urge you to read through all of and especially the comments. For the five or so years that it was active, A lot of excellent questions were asked, including by other healthcare providers. Chances are, if you have a general question, it’s been answered here and more than once.