Discussion
The focus of most previous studies was on evaluation of the correlation
between breast cancer and melatonin levels while there is quite limited
number of studies examining the correlation between melatonin and
prostate cancer. A cross-sectional study carried out by Bartsch et al.
revealed that there were lower melatonin levels among the men who had
prostate cancer than that in men with BPH21. In a
case-cohort study in the Icelandic population, it was found that
subjects whose first morning urinary 6-sulfatoxymelatonin (aMT6s) levels
were below the median level were exposed to a 4-fold higher risk than
the subjects with aMT6s levels above the median level (hazard ratio =
4.04; 95% CI = 1.26-12.98)22. On the contrary, in the
present study, no significant correlation was found between morning
urinary aMT6 levels and total risk of prostate cancer. In fact, in our
study, there was a statistically significant negative correlation
between the melatonin/cortisol (M/C) ratio and first-morning urinary
melatonin-sulfate levels and the risk of advanced (end-stage) prostate
cancer and general prostate cancer. In our study, we strongly believe
that our results will contribute to the literature on prostate cancer
risk and the circadian hormones. Melatonin had the protective effect on
risk of cancer due to inhibiting growth of cancer cell, which protects
cells against damage of DNA, and promotes DNA repair after it
occurs1,23,24. Blask et al. recently used both steroid
receptor-negative and receptor-positive human breast cancer xenografts
in rats to perform a series of experiments and to discover an inverse
correlation between tumor activity and melatonin level25. Similar results with prostate cancer xenografts
were reported in similar research group 26. In other
studies, a decrease in the malignant prostate tumor cells growth has
been reported with the administration of both pharmacological and
physiological doses of melatonin27.
In our study, we further measured another important circadian hormone
i.e. cortisol, secreted by the adrenal cortex. Cortisol has been found
to regulate both inflammation and immunity. This hormone deficiency can
disrupt the immune system, and immune reactions may be suppressed by
excessive hormone 28. Furthermore, there has been
association between the chronic irregularity of rhythm of the circadian
cortisol and increasing inflammation which is highly effective in
carcinogenesis28,29. Mirick et al. found the effect of
circadian disruption on the pattern of cortisol secretion release,
increasing the risk of cancer30. Even though the
present study found no significant correlation between prostate cancer
and spot morning urinary cortisol level, we found an inverse correlation
between advanced (end-stage) prostate cancer and prostate cancer and the
M/C ratio. In the previous studies, the M/C ratio was related to the
depression severity and different types of depression31,32. However, as far as we know, our study is one of
the few studies evaluating the correlation between prostate cancer and
the M/C ratio.
Whether to undergo an invasive prostate biopsy for subjects with
abnormal PSA levels can be clinically determined with difficulty. The
results of our study which support the conclusion that combined low M/C
ratios and PSA levels exceeding 10 ng/mL indicates that a person is
exposed to advanced (end-stage) prostate cancer and prostate cancer,
suggesting that the M/C ratio should be considered a biomarker. The
urine M/C ratio will be additionally used to decide if a prostate biopsy
is necessary with increasing PSA levels. More studies are needed in
order to examine the clinical utility of evaluation by combining PSA and
M/C ratio for detecting the prostate cancer and the disease stage.
In our study, the male control group also had a high PSA level exceeding
10 ng/mL. The serum of patients with prostate cancer and BPH was
expected to have higher concentrations of PSA 33. An
estimated 50% of 50-year-old men, 75% of 80-year-olds, and 90% of
85-year-old men have histological evidence of BPH34.
Men aged above 50 had about 99% of prostate cancer35. This is particularly problematic in older men with
more prevalent BPH due to increase of glandular volume with BPH so that
the PSA level and the sampling errors number related to prostate biopsy
is enhanced34. While prostate cancer detection rates
in Caucasian men can be as high as 40% for men whose PSA is 4-10 ng/mL,
prostate cancer is observed in only 20% of Chinese men with the same
level of PSA36. In our control group, the inclusion
criteria include either remarkable or unremarkable digital rectal exams
but with BPH confirmed histologically. For this reason, some male
patients with undiagnosed prostate cancer may have been included in our
control group. However, the inclusion of such patients in the control
group would only lead to an underestimation of the correlation that is
happening.
One of the strengths of our study is that we evaluated the most
important risk factors of prostate cancer in our analyses, including PSA
level and clinical stage. Furthermore, two important circadian
biomarkers were evaluated and then the M/C ratio was discovered to be
more relevant for prostate cancer. There are some limitations in the
present study. The first limitation is its cross-sectional and
case-control nature. For this reason, a precise causal relationship
cannot be inferred. If sleep interruption or circadian disruption after
diagnosis of a cancer causes melatonin levels to drop, there is a
possibility of inverse causation between prostate cancer and circadian
hormones. A further limitation is our use of one spot morning urine
biomarkers single measurement not representing long-term exposure
levels. Even though we have extensive knowledge of various covariates
and can easily control possible confounders, we still did not know about
factors such as the presence of sleep disorders or drug use. As a
consequence, the related exposures and risks were gathered with a
questionnaire, leading to some recall bias.