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Sex Steroid Hormones May Play a Role in the Development of Aggressive Prostate Cancer

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Key Points

  • A case-control study of nearly 400 men was conducted to assess the relationship between estrogen metabolites and the risk of prostate cancer.
  • The investigators found that the risk of aggressive prostate cancer was strongly inversely associated with the estradiol-to-testosterone ratio and positively associated with the ratio of 2-hydroxyestrone to 16α-hydroxyestrone.
  • The estrogen-to-androgen balance warrants further study in relation to prostate cancer endpoints such as asymptomatic, aggressive, and/or fatal disease.

Men with higher estradiol-to-testosterone ratios had a substantially reduced risk of aggressive prostate cancer, whereas men with higher ratios of 2-hydroxyestrone to 16α-hydroxyestrone had an increased risk of such cancer, according to the study findings presented by Black et al in Cancer Epidemiology, Biomarkers & Prevention. Strong estrogenic effects may offer protection against this aggressive type of cancer, and the investigators claim that a better understanding of the estrogen-androgen balance may lead to preventive and therapeutic interventions.

Although sex steroid hormones have been found to play a part in the growth and maintenance of healthy prostate epithelium, evidence of their role in prostate carcinogenesis has been sparse and inconsistent. Attention has turned specifically to the balance between androgens and estrogens and their combined action in the development of prostate cancer.

In the past, accurately measuring low levels of circulating estrogen in men in relation to prostate cancer has proved difficult. However, of late, sensitive and accurate measurement of estrogens has been achieved with liquid chromatography–mass spectrometry methods.

A Glimpse at Study Details

To learn more about estrogen metabolites and their relationship to the risk of prostate cancer, Black and colleagues collected data on younger, non-Hispanic white men who developed aggressive prostate cancers from the randomized, controlled PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer) screening trial. They defined aggressive cancers as stage III or IV and/or a Gleason score ≥ 7. The mean age of patients was 62.8 years at baseline. 

For their analysis, they focused on 195 cases of histologically confirmed aggressive prostate cancer in men younger than age 70 and 195 frequency-matched controls without prostate cancer. The investigators used a liquid chromatography-tandem mass spectrometry assay to measure the levels of serum estrone, estradiol, and 13 estrogen metabolites (in the 2-, 4-, or 16-hydroxylation pathways). Furthermore, not only were the estrogen and estrogen metabolites analyzed individually, they underwent evaluation as groups classified by their metabolic pathway and in ratios of individual hormones and metabolic pathway groups.

Estrogenic Effects Protect Some Men From Prostate Cancer

There seemed to be general similarities in the median concentrations of estrogens, estrogen metabolites, estrogen metabolism pathways, testosterone, and sex hormone–binding globulin between the cases and the controls. In fact, estradiol, estrone, and estrogen metabolites were found to be unrelated to the risk of prostate cancer.

However, there were some clear differences between the groups as well. For instance, there appeared to be an increasing risk of prostate cancer with increasing testosterone levels (odds ratio [OR], 4th quartile vs 1st quartile = 2.96; 95% confidence interval [CI] = 1.25–7.00), which was reported to be consistent with a previous analysis.

In addition, the investigators reported a statistically significant association between the estradiol-to-testosterone ratio and a decreased risk of prostate cancer (OR, 4th quartile vs 1st quartile = 0.27; 95% CI = 0.12–0.59; P trend = .003). They also noted a statistically significant association between the ratio of 2-hydroxyestrone to 16α-hydroxyestrone and an increased risk of aggressive prostate cancer (OR, 4th quartile vs 1st quartile = 2.44; 95% CI: 1.34–4.45; P trend = .001).

Closing Thoughts

This case-control study is alleged to be the first to evaluate prediagnostic serum estrogen metabolites in relation to the risk of aggressive prostate cancer. The authors did acknowledge several limitations of their study.

Although they measured circulating serum hormone levels, it remains unclear the extent to which they may reflect intraprostatic hormone levels. Moreover, nonfasting blood drawn at a single point in time was used to measure hormone levels, and the investigators admitted that this approach may not reflect the cumulative lifetime exposure to such hormones or levels at a time most etiologically relevant.

“It is conceivable that the numerous previous attempts to identify the independent effects of androgens (and estrogens) on prostate cancer risk have provided equivocal and inconclusive results because hormones do not act independently in relation to prostate cancer risk but rather elicit their effects as part of a complex pathway,” the investigators surmised. Thus, the estrogen-androgen balance warrants further study in relation to prostate cancer endpoints such as asymptomatic, aggressive, and/or fatal disease.

Amanda Black, PhD, MPH, of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, is the corresponding author of this article in Cancer Epidemiology, Biomarkers & Prevention.

This study was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, and Leidos Biomedial Research, Inc. The study authors reported no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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