Putative Gonadotropin-Releasing Hormone Agonist Therapy and Dementia: An Application of Medicare Hospitalization Claims Data

Article type: Research Article

Authors: Smith, Mark A.^{a; 1} | Bowen, Richard L.^b | Nguyen, Richard Q.^c | Perry, George^{c; *} | Atwood, Craig S.^{d; *} | Rimm, Alfred A.^e

Affiliations: [a] Department of Pathology, Case Western Reserve University, Cleveland, OH, USA | [b] Sozo Pharma, Inc., Charleston, SC, USA | [c] Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA | [d] Department of Medicine, University of Wisconsin, Madison, WI, USA | [e] Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

Correspondence: [*] Correspondence to: Craig S. Atwood, PhD, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Veterans Administrative Hosp., 2500 Overlook Terrace, Madison, WI 53705-2254. USA. Tel.: +1 608 256 1901; E-mail: csa@medicine.wisc.edu and George Perry, PhD, Department of Biology, College of Sciences, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA. Tel.: +1 210 458 4450; Email: george.perry@utsa.edu.

Note: [1] Deceased.

Abstract: Background:Estrogen and hormone replacement therapies to reduce Alzheimer’s disease (AD) have yielded conflicting results. However, this study proposes that the well-characterized increase in serum gonadotropins following menopause or andropause are accountable for the increased risk of developing AD among the elderly population. Objective:To determine the role of gonadotropins in the development of AD and investigate gonadotropin-releasing hormone (GnRH) agonist therapy as a potential preventative and/or disease-modifying approach to AD management. Methods:Male Medicare beneficiaries aged 67 to 75 and hospitalized with prostate cancer (n = 115,789) were compared to three control groups: men of the same demographics undergoing a cholecystectomy (n = 97,267), herniorrhaphy (n = 68,778), or transurethral prostatectomy (n = 267,691). A proportion of the patients hospitalized with prostate cancer were assumed to have low concentrations of serum gonadotropins and sex steroids as a result of GnRH agonist therapy, while those in the control groups were assumed to have elevated gonadotropin but lowered sex steroid levels that are associated with andropause in this age group. Results:The rates of development of select diagnoses of dementia, including AD, over a twelve-year follow-up period following surgery. When compared to control patients, men hospitalized with prostate cancer have a protection against dementia after twelve years of follow-up, with relative risks ranging from 0.48 to 0.83. Conclusion:Patients with prostate cancer are treated with the GnRH analogue leuprolide acetate, our data suggest that leuprolide acetate may be therapeutic for AD via its downregulation of serum gonadotropins.

Keywords: Alzheimer’s disease, cancer, castration, epidemiology, gonadotropin receptors, hormone replacement therapy, leuprolide, Medicare Part A, testosterone

DOI: 10.3233/JAD-170847

Journal: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1269-1277, 2018