Testosterone breakthrough

[JimJimJimJim]

Jim Marshall (not a doctor) said ...

The reason doctors (not all) measure the testosterone levels while you are on hormone treatment (ADT) is that hormone treatment only works effectively if your testosterone goes down to castrate levels.

A very full account of the various ways of reaching and maintaining castrate testosterone levels is found here:

http://www.ncbi.nlm....les/PMC2725306/

In that account, Dr Gomella says:

The prescribing guidelines for all FDA-approved LHRH agonists and antagonists recommend monitoring testosterone levels to ensure that castrate level is maintained.

But what levels should they be?

• Based on earlier research, the USA FDA set lower than 50 ng/dL some time ago.
  
• Newer research shows that it has to be lower than 32 ng/dL to suppress PSA.
  
• Some doctors recommend it should be less than 20 ng/dl to be safe.
  

When the testosterone rises above these levels, it is called a testosterone breakthrough.

Testosterone breakthrough can lead to PSA rise, and perhaps worse outcomes.

• Some doctors measure testosterone with every PSA test to be sure.
  
• Some doctors measure testosterone only after PSA goes up, to check that castrate levels are really achieved.
  
• Some doctors (in USA) are reported to never measure testosterone of patients on hormone treatment.
  
  • (My guess (I am not a doctor) is that reasons may be that the man is taking more than one hormone treatment at a time (when breakthrough is less likely), or that the doctor considers that some aspects of a man's health mean that increasing the hormone dose, or making treatments more frequent, is inadvisable.
    

... end Jim

There are three defined levels of testosterone in the most common units used in the USA and literature:

• ≥50 ng/dL, representing FDA criterion;
  
• ≥32 ng/dL, which is the level at which PSA fails to be suppressed; and
  
• ≥20 ng/dL, corresponding to the level achieved with orchiectomy.
  

Or translating into Strine:

There are three defined levels of testosterone in the units commonly used in Australia:

• ≥1.7 nmol/L, representing FDA criterion;
  
• ≥1.1 nmol/L, which is the level at which PSA fails to be suppressed; and
  
• ≥0.694 nmol/L, corresponding to the level achieved with orchiectomy.
  

Jim Marshall (not a doctor) said ...

The following paper on testosterone breakthrough quotes other studies (one small) which identified lower survival rates for men with breakthrough. This study, however, found that while PSA indicators were worse for breakthrough men, survival was not reduced.

... end Jim

BJU Int. 2012 May 7. doi: 10.1111/j.1464-410X.2012.11190.x. [Epub ahead of print]

Incomplete testosterone suppression with luteinizing hormone-releasing hormone agonists: does it happen and does it matter?

Pickles T, Hamm J, Morris WJ, Schreiber WE, Tyldesley S.

Source

Radiation Programme, BC Cancer Agency, and Department of Radiotherapy and Developmental Radiotherapeutics, University of British Columbia Cancer Surveillance and Outcomes, BC Cancer Agency Department of Pathology and Laboratory Medicine, Vancouver General Hospital and The University of British Columbia, Vancouver, Canada.

Abstract

Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Previous reports, with small numbers of patients, have described the problem of incomplete testosterone suppression (>1.1 or 1.7 nmol/L) with LHRH agonists. Various predisposing factors have been suggested: different drug agents and patient factors such as age, pretreatment testosterone levels and weight. Such incomplete testosterone suppression has been shown in one small report to be associated with increased PSA failure rates and in another report in those with metastases, with worse survival. This study used testosterone assays that are more accurate at low levels than those used in most previous reports in a large dataset of 2196 men, and confirmed incomplete testosterone suppression (breakthrough) rates >1.7 nmol/L of 3.4% and >1.1 nmol/L of 6.6%. We showed that younger age was strongly associated with the risk of breakthrough, with a minor effect of increasing body mass index. Repeated breakthroughs were more common (16%) in those who had already had one breakthrough. Interim measures of cancer control (PSA kinetics during LHRH therapy) were inferior in those with a breakthrough, and those with breakthroughs between 1.1 and 1.7 nmol/L had worse long-term biochemical control rates.

OBJECTIVES:

•  To describe breakthrough rates above castrate levels of testosterone, in a population-based series of men undergoing adjuvant luteinizing hormone-releasing hormone (LHRH) agonist therapy with curative radiation therapy. •  To explore the predisposing factors for such breakthroughs and their impact on subsequent outcomes.

PATIENTS AND METHODS:

•  All men treated for prostate cancer between 1998 and 2007 with curative radiation in the province of British Columbia, Canada were potentially eligible (n= 11 752). Of these, 2196 fulfilled the eligibility criteria. •  Serial testosterone measurements were obtained during continuous LHRH therapy. •  Breakthrough rates >1.1 nmol/L and >1.7 nmol/L were calculated for each LHRH injection and for each patient course. •  Predisposing factors were identified, and early surrogates of oncological outcome (neoadjuvant nadir and post-treatment nadir) were determined.

RESULTS:

•  The risk of a breakthrough >1.1 nmol/L was 6.6%, and >1.7 nmol/L was 3.4% per patient course and 5.4% and 2.2% per LHRH injection (inclusive ranges). •  Repeated breakthroughs occurred in 16% of patients. •  Younger men were more liable to breakthroughs (P < 0.001). •  Early PSA kinetic surrogates of cancer control were inferior in those with breakthroughs. •  Neither overall biochemical non-evidence of disease (bNED) nor survival were compromised, although subgroup analysis showed inferior 5-year bNED in those with breakthroughs of 1.1-1.7 nmol/L vs those without (58% vs 73%, respectively; P= 0.048).

CONCLUSIONS:

•  Breakthroughs with LHRH agonists occur occasionally per injection, but occur commonly per patient course of treatment, and adversely affect early surrogate measures of outcome. •  The monitoring of testosterone levels during therapy is therefore advised.

© 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.

PMID: 22564197

This extract can be found on http://PubMed.com, and is in the public domain.

On PubMed.com there will be a link to the full paper (often $30, sometimes free).

Any highlighting (except the title) is not by the author, but by Jim Marshall.

Jim is not a doctor.

[John]

John Says

Three Months after a Bilateral Orchidectomy in november last year my PSA dropped again to 0.05

That certainly stopped testosterone production, but not being in a position to measure it I have no idea what level it was before the procedure or after.

Anyone interested in the effects of Orchidectomy, let me know.

[Guest tonybrown]

Thanks for the topic Jim. I did not understand that testosterone was so high for castrate levels - from other sources in the body - adrenal gland etc. Is there any information on how much is necessary to maintain bone density, avoid heart problems diabetes etc. i am assuming they are orders of magnitude higher. What does Snuffy Meyers say about the levels of testosterone required to get to 0.01 psa or less. Is that another benchmark number we need to know?

[Admin]

Tony

We men with the condition may be very happy to hear the lowest numbers that their lab reports - less than 0.01 or less than 0.03.

However, Snuffy Myers is happy to call anything less than 0.05 "undetectable".

If you get that low, I guess that the testosterone levels that achieve this are not important.

Sorry, I can't answer your questions about how much testosterone is necessary for ordinary maintenance.

[Guest tonybrown]

Hi Jim,

And yet I have heard him on a clip talk about ideally psa should be under 0.01 during ADT - leads to less recurrence. Am I missing something or is it that no one has done studies of the optimum testosterone level for zero cancer activity or whether this changes with cancer type or other factors but just (arbitrarily?) assumes every thing is OK if you are at castrate levels. I would have thought these were obvious areas of study given how common ADT is & how prostate cancer seems to get around ADT in a lot of cases. Is the answer simply that testosterone is not being held low enough to stop cancer in a lot of men on ADT?

Also are there more rapid deteriorations of bone density , diabetes etc if testosterone levels are very low ( lower in the castrate range)?

Also I assume oestrogen protects womens bones. I have recently discovered oestrogen is a a break down product of testosterone. Weight lifters who inject testosterone can have problems with breast growth & inflamation from high oestrogen caused by the break down in muscles of testosterone. Is this an answer for bone protection & maybe other functions ( albiet with some significant side effects!)

[JimJimJimJim]

Is the answer simply that testosterone is not being held low enough to stop cancer in a lot of men on ADT?

We only have a partial answer to that question.

"adversely affect early surrogate measures of outcome" quoted above means that the authors did not look at survival, but found that rising psa happened earlier in men with testosterone breakthrough. Though they did quote one other study that did look at survival, and it reported lower survival rates for men with testosterone breakthrough.

Also I assume oestrogen protects womens bones. I have recently discovered oestrogen is a a break down product of testosterone. Weight lifters who inject testosterone can have problems with breast growth & inflamation from high oestrogen caused by the break down in muscles of testosterone. Is this an answer for bone protection & maybe other functions ( albiet with some significant side effects!)

Some clinicians do add oestrogen to their ADT brew. And, for older men it is sometimes used by itself. As you point out, a man has to be psychologically comfortable with the side effects.

Am I missing something or is it that no one has done studies of the optimum testosterone level for zero cancer activity?

I cannot refer you to written information on this. (That is a major deficiency of the video format - it is virtually impossible to refer to it later.)

I do remember some medical oncologists being keen on 'as low as it can go'.

I guess it depends upon how adventurous a doctor is with treatment.

• A doctor can be sure at the FDA level, because most research used this level in their reporting.
  
• The middle PSA failure level seems sensible to use, if we know that PSA sometimes rises above this level.
  
• The lowest level is more a 'commonsense' thing to most of us, and commonsense has often failed in the past when actual research has been done. Some doctors will be recommending this to patients, not based on commonsense or research, but upon the model of how prostate cancer works that they have developed through their clinical experience. They use this personal understanding of the disease to make decisions in cases where the evidence is not yet available, or unclear.
  

For those late in joining the debate:

There are three defined levels of testosterone in the most common units used in the USA and literature:

• 50 ng/dL or lower, representing FDA criterion;
  
• 32 ng/dL or lower, which is the level at which PSA fails to be suppressed; and
  
• 20 ng/dL or lower, corresponding to the level achieved with orchiectomy (surgical removal of the testes or 'balls').
  

Or translating into Strine:

There are three defined levels of testosterone in the units commonly used in Australia:

• 1.7 nmol/L or lower, representing FDA criterion;
  
• 1.1 nmol/L or lower, which is the level at which PSA fails to be suppressed; and
  
• 0.694 nmol/L or lower, corresponding to the level achieved with orchiectomy (surgical removal of the testes or 'balls').