Why do some men get worse/more hot flashes than others?

A newly published study in the Journal of Urology has suggested that men with certain genetic polymorphisms, of younger age, and of lower body mass index are at greater risk for hot flashes than control subjects when being treated with androgen deprivation therapy (ADT).

This new paper by Gonzalez et al. appears to be the first published report of a prospective investigation into the effects of hot flash interference in men under treatment with ADT is a relatively small one, and so the results should be seen as “hypothesis generating” as opposed to a “proven” hypothesis. However, with that caution, here is a summary what Gonzalez et al. are reporting:

  • They enrolled 249 men divided into one of three very different groups:
    • Group A comprised 60 men recruited before or within 21 days after starting ADT for treatment of prostate cancer.
    • Group B comprised 83 men with prostate cancer treated by radical prostatectomy who were matched, by age and education, to the men in Group A.
    • Group C comprised 86 men with no history of prostate cancer who were matched, by age and education, to the men in Group A.
  • All study participants were required to
  • Men in Group A (unsurprisingly) reported greatly increased hot flash interference with time relative to men in Groups B and C (p < 0.001), with significant group differences apparent at both 6 and 12 months (all p <0.001).
  • Several specific genetic polymorphisms appear to predict greater increases in hot flash interference (all p <0.01).
  • Such polymorphisms involved genes associated with vasoconstriction, immune function, neurotransmission, and circadian rhythms.
  • Patients treated with ADT who were younger and had a lower BMI at baseline also showed greater increases in hot flash interference with time (all p ≤ 0.01).

The full text of this paper is available on line, so interested readers can explore this study for themselves. For example, Figure 2 in the paper clearly shows the differences in incidence of hot flashes correlated to the presence of a series of selected gene mutations.

Now we should also be clear that this study has a lot of limitations. It is a small study. It does not compare necessarily “like” patients to other “like” patients. And it lasted for only 12 months. Participants’ serum testosterone (T) and serum dihydrotestosterone (DHT) levels were not being measured during the study (although it may be possible for the authors to use the blood samples to go back and measure levels of T and DHT). However, the idea that certain very specific genetic and biological characteristics may place some men at at greater risk for hot flashes when treated with ADT is very interesting.

A way to further examine this effect would be to randomize a series of hormone-naive men with prostate cancer who are eligible for initiation of treatment with ADT (but who may not actually need it) to treatment with an LHRH agonist or a placebo for a year and monitor the frequency and intensity of hot flashes along with a variety of biological parameters (including PSA, serum T, and serum DHT levels) in these men. Any patient whose PSA starts to rise at a predefined PSA doubling time of less than (say) 12 months could be immediately switched on to ADT, and such patients would not be eligible for inclusion in the trial.

Of course finding the money to conduct such a trial these days might be challenging, but this is the type of study that would be needed to confirm the hypothesis being put forward by Gonzalez et al.  Patients enrolled in this study could be stratified by age, by body mass index, and perhaps by the presence of absence of the most interesting genetic polymorphisms as a way to explore the relevance of these issues in pre-specified subgroup analyses.

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