Men Treated For Prostate Cancer Have A Decreased Incidence of Dementia

1
Men Treated For Prostate Cancer Have A Decreased
Incidence of Dementia
Richard L. Bowen1, Heather Beaird2, Craig S.
Atwood3, Mark A. Smith2, Alfred A. Rimm2
1Voyager Pharmaceutical Corp., Raleigh, NC, USA
2Case Western Reserve University, Cleveland, OH,
USA 3University of Wisconsin, Madison, WI, USA.
Probability of Developing Dementia (Patients Aged
67 to 69 at Time of Procedure)
ABSTRACT A serendipitous encounter with a patient
has led us to examine the possibility that
hormones of the hypothalamic-pituitary-gonadal
axis other than the sex steroids may directly
contribute to the pathogenesis of Alzheimers
disease. After he patient received the
gonadotropin releasing hormone (GnRH) agonist
leuprolide acetate a common hormonal treatment
for prostate cancer, his wife noticed an
improvement in his cognitive function which
subsequently remained stable for more than five
years. To ascertain whether treatment with GnRH
agonists such as leuprolide has a beneficial
effect in Alzheimers disease, an epidemiological
study was performed. The study was designed to
determine the incidence of dementia in men who
underwent prostatectomy for prostate cancer and
would have likely received a GnRH agonist (it is
estimated that approximately 40 of prostatectomy
patients will experience disease recurrence and
undergo GnRH agonist therapy). All in-patient
Medicare hospitalization claims for men aged 67
to 75 during the years 1984 through 1997 were
analyzed and the incidence of dementia in men who
underwent prostatectomy for prostate cancer
(n139,414) was compared to three control groups
who would not have received GnRH agonist therapy.
The control groups included men with gallbladder
disease who underwent cholecystectomy
(n255,493), inguinal hernia who underwent
herniorrhaphy (n162,115), and benign prostatic
hyperplasia who underwent transurethral
prostatectomy (n635,615). The cohorts were
separated into three groups based on their age at
the time of the procedure A) 67-69, B) 70-72,
and C) 73-75. The prostate cancer group was
designated the reference group with a risk of
developing dementia of 1.0 At five years
post-procedure, the relative risk of dementia for
men with BPH was 2.2, 2.1, and 2.8 for age groups
A, B, and C respectively. For men with
gallbladder surgery the risk was 1.8, 1.8, 2.0
and for the hernia group it was 2.4, 2.2, and
2.9. Along with our other findings, these results
lend further support to the premise that
gonadotropins promote the development of AD and
that GnRH agonists are a potential therapeutic
agent for its treatment. Clinical trials using
leuprolide acetate in the treatment of mild
to moderate Alzheimers disease are currently
underway.
5 Year Relative Risk of Dementia
Prostatectomy Group Exclusions
Herniorrhaphy Group Exclusions
Prostate Cancer Gall-bladder Enlarged Prostate Inguinal Hernia
Age 67-69 1.0 1.8 2.2 2.4
Age 70-72 1.0 1.8 2.1 2.2
Age 73-75 1.0 2.0 2.8 2.9
Transurethral prostatectomy
Herniorrhaphy
Cholecystectomy Prostatectomy
Probability of Dementia

DISCUSSION
This study provides convincing evidence that,
regarding hormones, it is the age-related
increase in gonadotropins rather than the loss of
sex steroids that contributes to the pathogenesis
of Alzheimers disease. This statement is based
on the fact that more than 10 prospective studies
have failed to demonstrate a statistically
significant association between circulating
levels of androgens and prostate cancer risk. In
other words, since there is a clearly an inverse
relationship between prostate cancer and
dementia, but no relationship between prostate
cancer and testosterone, it is unlikely
testosterone is playing a direct role in the
pathogenesis of Alzheimers disease. The most
common treatment, GnRH agonists, suppresses both
gonadotropins and sex steroids. If the
difference in the rate of dementia seen in this
study is due to the GnRH agonist, its effect
would be exceptional. For example, among the 73
to 75 year age group, if it is assumed that the
59 of patients in the prostatectomy group (whose
risk is shown to be 0.062) really has a risk of
developing D/AD equivalent to that of say, the
cholecystectomy group (0.095). Then the 41 of
patients believed to have received a GnRH agonist
would actually have an exceptionally decreased
risk of 0.015 for dementia.
Years
Probability of Developing Dementia (Patients Aged
70 to 72 at Time of Procedure)
Probability of Dementia
Transurethral Prostatectomy Group Exclusions
Cholecystectomy Group Exclusions
Hypothalamic-Pituitary-Gonadal Axis
Years
Probability of Developing Dementia (Patients Aged
73 to 75 at Time of Procedure)
CONCLUSION
At five years, men who underwent surgical
prostatectomy for prostate cancer have
approximately half the risk of developing
dementia as men who undergo other common surgical
procedures. Further research is needed to
determine if this difference is due to GnRH
agonist therapy. Phase II clinical trials using
the GnRH agonist leuprolide to treat patients
with Alzheimers disease are currently underway
and should provide important information as to
its effect.
Probability of Dementia
Years

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Cell Cycle Inhibition CYP51 encodes for an
enzyme that is responsible for production of
mitosis activating factor in animals. Inhibiting
CPY51 inhibits reproductive function. By the
theory would be expected to extend
longevity EcR The same mechanism may be
responsible for a similar phenotype exhibited by
Drosophila melanogaster that possess a
heterozygous mutation of the EcR gene which codes
for a sex steroid receptor (Simon et al., 2003).