regard, individuals with higher LH to sex steroid ratios such as
women  and men  with lower endogenous sex steroid
levels (i.e., high LH to estrogen ratio) show higher rates of AD
and would likely benefit from leuprolide acetate treatment more
than women/men with higher endogenous levels of estrogen/
testosterone (lower LH:estrogen ratio), who have lower rates of
AD. Likewise, in men, treatment of leuprolide acetate could be
beneficial albeit masked by the effects of testosterone depletion
, in which case, testosterone replacement could be ideal.
Therefore, and considering that the totality of hormonal
influences cannot be ignored, our study demon strates that
targeting LH with leuprolide acetate, a product already safety-
approved for therapeutic use in prostate cancer, is as effective if
not more effective, as shown by its capacity to both positively
modulate cognition and reduce amyloid-β load, than estrogen
therapy alone. Likewise, the fact that leuprolide acetate was
capable of modulating cognitive behavior and reducing
advanced amyloid-β deposition in aged animals suggests that
this treatment may be an effective treatment strategy even at late
stages of disease. In this regard, a recently completed phase II
clinical trial (http://clinicaltrials.gov/ct/show/NCT00076440?
order=6) indicates that patients treated with high doses of
leuprolide acetate show a stabilization in cognitive decline
(ADAS-Cog, ADCS-CGIC) and activities of daily living
pp. 56–64), therefore our findings are in agreement with
those in human trials.
We would like to thank Dr. Bob Switzer (Neuroscience
Associates Inc.) for his invaluable help with the tissue
preparation and amyloid-β staining and Dr. Nett (Endocrine
Laboratory at ARBL-Colorado State University) for his help
and expert input on serum LH measurements. Work in authors'
laboratories is supported by Voyager Pharmaceutical Corpora-
tion, the Alzheimer's Association (MAS), Philip Morris USA
Inc., and Philip Morris International (GC). Drs. Atwood, Perry
and Smith are consultants to Voyager and own equity.
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