An hormonal storm in a set of Italian pre-surgical teacups

An article available online in Cancer makes the rather surprising suggestion that high serum levels of 17β-estradiol (E2) may be better indicators of risk for high-grade prostate cancer than high serum levels of testosterone.

Salonia et al., working at the University Vita-Salute San Raffaele, in Milan, Italy, set out to assess the association between pre-surgical levels of E2, total testosterone (T), and sex hormone-binding globulin (SHBG) in serum at the time of radical prostatectomy and the risk for pathologically evident high-grade prostate cancer.

Serum samples were taken from the patients between 8:00 and 10:00 am local time on the morning before surgery. The patients then underwent radical retropubic prostatectomy.

Here are the key findings reported by Salonia and her colleagues:

  • The total cohort comprised 655 consecutive Caucasian-European patients who underwent radical prostatectomy at the authors’ institution and for whom all relevant data was available (out of a complete series of 673 patients).
  • High-grade prostate cancer (Gleason score 4 + 3 = 7) was identified pathologically and post-surgery in 156/655 patients (23.8 percent).
  • The patients with high-grade prostate cancer had significantly higher pre-surgical PSA levels, clinical stages, and biopsy Gleason sums compared with those who were found to have cancers of pathologic Gleason score 3 + 4 = 7 and lower (all P < 0.001).
  • No other significant differences were observed between the groups of patients.
  • On univariate analysis
    • Continuously coded E2 levels were not significantly associated with the presence of high-grade prostate cancer (odds ratio [OR] = 1.009; P = 0.25).
    • Men with E2 levels ≥ 50 pg/ml had a 3.24-fold increase in risk for high-grade prostate cancer (P < 0.001).
  • On multivariate analysis
    • Continuously coded E2 levels were significantly associated with the presence of high-grade prostate cancer (OR = 1.02; P = 0.04).
    • The E2 level was a categorical predictor of risk for high-grade prostate cancer (OR = 3.94; P < 0.001) after accounting for other variables.
    • Serum levels of total T and SHBG were not significantly associated with risk for high-grade prostate cancer.

An editorial by Morgentaler will be published in the same issue of Cancer (and is already available free as a full text article).

The authors and Morgantaler come to very different conclusions about what these data mean!

Salonia et al. conclude that preoperative levels of total circulating T in serum (considered to be low if they were < 300 ng/dl) can not be used a a predictor of high-grade prostate cancer, but that serum levels of E2 may be able to be used to predict such risk. In contrast, Morgentaler argues that their data show the complete opposite:

  • That low-levels of circulating T in serum increased risk for high-grade disease by 50 percent compared to normal circulating serum T levels.
  • That severely low levels of circulating T in serum increased risk for high-grade disease by 200 percent compared to normal circulating serum T levels.

Now we don’t pretend to be able to resolve these two conflicting interpretations of the same data. But here is what we do know:

  • It would likely have been better if Salonia and her colleagues had measured the levels of free (as opposed to total) circulating serum T.
  • Morgentaler is clearly using his interpretation of these data to support his long-standing hypothesis that normalizing the level of serum T in men with low serum T levels may reduce risk for prostate cancer in general (and for high-grade prostate cancer in particular).
  • It is going to take further study to resolve this question … but this may not be difficult to do.

Could circulating estrogen levels have predictive value in assessment of risk for higher-grade forms of prostate cancer at time of diagnosis? Are low and very low serum T levels potential indicators for high-grade prostate cancer? Could “normalizing” serum T levels in carefully selected men prevent prostate cancer? Are we all barking up the wrong trees?

At present the answer to all of these questions is a an absolute and definitive, “Maybe!”

It is interesting in interpreting the two very different viewpoints to read Morgentaler’s statement of the objective of the study by Salonia et al., which reads as follows:

In this issue of Cancer, Salonia et al. explore … whether low T may be associated with high-risk [prostate cancer].

But if you read the objective of the study as written by Salonia and her colleagues, it says something very different:

The objective of this study was to assess the association between preoperative circulating levels of 17β-estradiol (E2) and high-grade prostate cancer … at the time patients underwent radical retropubic prostatectomy.

Perchance the differences in opinion simply reflect the differences in point of view, and there is a whole other interpretation of the results of this study (which may take wiser heads to decipher).

One Response

  1. Mike,

    Morgentaler has been playing the same record for some time while recommending TRT for those with low T (and treating them). This in spite of the fact that numerous studies cannot find a significant difference in testosterone levels among men diagnosed with prostate cancer. In simpler words, testosterone doesn’t seem to be the cause of prostate cancer either when high or low in men diagnosed with prostate cancer.

    Since estradiol (E2) is a metabolic product of testosterone by aromatization, the higher the E2, the lower the T level by conversion. Therefore is low testosterone a cause of more aggressive prostate cancer or just a consequence of this hormonal change and E2 is the real culprit as Salonia claims? Who knows for sure …?

    For any man to be treated for low T with TRT, it makes sense to inhibit the creation of E2. For that reason it makes sense to add an inhibitor such as Arimidex or Femara just in case. … BTW, as far as I know Morgentaler does not inhibit E2 while treating men with TRT.

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