Castrate serum T levels and prostate cancer-specific mortality

A few weeks ago, a Letter to the Editor in the New England Journal of Medicine focused on the significance of castrate levels of serum testosterone (serum T) in men being treated with LHRH agonists for advanced forms of prostate cancer.

The “right” level of serum T in men being treated with androgen deprivation therapy (ADT) has never been categorically established. As Crawford and Rove note in their letter:

  • The target serum T level for men being treated with LHRH agonists and LHRH antagonists — as defined by the U.S. Food & Drug Administration — is < 50 ng/dl, which is equivalent to 50 μg/ml or 1.7 nmol/l. However, …
  • The typical serrum T level in men after an orchiectomy is 14 ng/dl, which is equivalent to 14 μg/ml or 0.5 nmol/l.

Over the years, there have been many specialists who have argued that the appropriate serum T level for a man who is being well-controlled on ADT should, in fact, be < 20 ng/dl (0.7 nmol/l).

The other key points made by Crawford and Rove in their letter are that:

  • About 85 percent of physicians who treat advanced prostate cancer with ADT do not routinely measure serum T levels at all.
  • Morote et al. have shown that 25 percent of men receiving continuous ADT with an LHRH agonist have a serum T level > 50 ng/dl
  • 44 percent of the same group of men studied by Morote et al. had a serum T level that was consistently < 20 ng/dl (0.7 nmol per liter).
  • Also, in the same group of men, Morote et al. demonstrated a direct correlation between serum T levels and time to development of castration-resistant prostate cancer (CRPC) .
  • Perachino et al. have also reported a significant association between serum T levels 6 months after initiation of ADT and overall survival.

With the rapid evolution of a wide series of new and development-stage drugs for the treatment of advanced prostate cancer, it seems to The “New” Prostate Cancer InfoLink that regular monitoring of serum T levels is now probably obligatory for men receiving continuous ADT. At the same time, we need prospective (as opposed to retrospective) clinical data on the association between serum T levels and prostate cancer-specific mortality. Such data should not be difficult to collect, given the large number of ongoing and upcoming trials on the management of late stage prostate cancer.

If the progression-free, disease-specific, or overall survival of men with advanced prostate cancer who are being treated with ADT is affected by their serum T level while they are on therapy, we need to know this. We also need to appreciate what this implies for men who are on intermittent ADT. Do these men need a serum T of < 20 ng/dl while they are on ADT to allow for their rising serum T while they are off therapy?

3 Responses

  1. Interestingly, I just posted a reply to a patient who had the same questions. I have found in exchanges with many men prescribed ADT that only their PSA level is periodically checked, but rarely their testosterone. Stephen Strum has repeatedly remarked how ridiculous this is, since the idea of prescribing an LHRH agonist is to significantly reduce testosterone (T) level with the consequence also of bringing down PSA level. So if your intent is to bring down the T level, why would you not determine that this is, in fact occurring?

    I certainly agree with the considerations identified by the webmaster. My recommendations today to the patient who had radiation therapy (RT) and seeking information as to length of time following RT to be on ADT were as follows:

    “The downside of androgen deprivation therapy (ADT) during and following radiation treatment is that you have no idea how well the radiation worked, since the ADT medications are (or should be) keeping your PSA level likely down into the ultrasensitive range well below 0.1 ng/ml. Though some physicians encourage two years and sometimes longer ADT, in my opinion the importance is how well the ADT medications are working in the first 12 months. If your PSA has dropped down to or below 0.05 ng/ml and your testosterone down to near or below 20 ng/dl and stays steady at those levels for an entire 12 months, a break from the LHRH agonist and the antiandrogen could be considered to permit a return of testosterone to improve your general well being. However, also in my opinion, is that during that time off from the LHRH agonist and antiandrogen, it is important to then ‘maintain’ with a 5-alpha reductase (5AR) inhibitor, my choice being dutasteride/Avodart, to inhibit that returning testosterone from converting to the more powerful stimulant to PC cell growth, dihydrotestosterone (DHT), when that returning testosterone would otherwise come in contact with 5AR isoenzymes that would bring about that conversion.

    “In my personal case, I did not ‘maintain’ with a 5AR inhibitor the first time I went of the LHRH agonist and antiandrogen and my ‘time off’ was short-lived to two years before I had to return to those medications because of rising PSA. With my second ‘time off,’ and this time maintaining with the 5AR inhibitor dutasteride/Avodart, I was able to remain ‘off’ the other medications for two months short of six years before my PSA had reached 2.0 ng/ml, the point at which I had determined I would return to the other ADT medications.

    “I hope this provides you a PSA/testosterone level guideline for consideration when to go off the LHRH agonist and antiandrogen and then maintaining with dutasteride/Avodart. Important, too, with that ‘time off,’ would be the determination of whether or not your prior radiation therapy had actually eradicated your cancer.”

  2. I’m confused. My husband had radical prostate removal, non-nerve sparing, and his PSA went up from 25 to 33 after surgery. He was put on Casodex for 1 week, then Lupron. He is now also in the fourth week of radiation therapy. His first PSA level, after 1 month on Lupron, was 0.5; now, almost 3 months later, it is 0.0, but his testosterone level is 50 … Is this too high? The urology nurse said 20 ng/dl for “castrate level” is outdated, and it is now 50 or below.

  3. Dear Lynda:

    I can understand your confusion.

    First, for a man who is taking Lupron (leuprolide acetate), the formally approved level of serum testosterone (T) should be less than 50 ng/dl. However, many prostate cancer experts believe that it is better if the T level is lower than that, at less than 20 ng/dl. So this idea that a castrate serum T level of 20 ng/dl or less is “outdated” is puzzling to me too. It is still very much a matter over which there is no absolute agreement between the experts.

    Second, the good news is that your husband’s PSA level has, appropriately dropped to zero.

    So … If your husband’s PSA stays at zero and his serum T level is stable at less than 50 ng/dl, this is good. It might well be better if his serum T level was lower than 20 ng/dl, but this is more a matter of strong opinion than established fact. he important thing is that his T level stays down at 50 ng/dl or lower.

    The next time that you and your husband meet with the urologist, you should ask him specifically about whether he believes that a lower serum T level would be a good idea. The addition of a drug called Avodart (dutasteride) to the Lupron would likely further help to block the conversion of testosterone to dihydrotestosterone (DHT), which would further limit the likelihood of stimulus of the growth of any currently remaining prostate cancer cells, and you could also ask your doctor about this.

    I hope this helps.

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