A Potential Means of Investigating the Role of Luteinizing Hormone in the Pathogenesis of Alzheimer Disease

Abstract

Editor - I read with great interest the recent review article, “The Contribution of Luteinizing Hormone to Alzheimer Disease Pathogenesis” by Webber et al.1 In this paper and in another article,2 the authors present some intriguing data from various lines of basic, epidemiological and clinical research supporting their hypothesis implicating luteinizing hormone (LH) in the pathogenesis of Alzheimer disease. One might speculate that women who have undergone oophorectomy and men who have undergone orchiectomy might be at increased risk according to this model. Conversely, one would expect that people with lower levels of LH might be less predisposed to Alzheimer disease. If this is true, pharmacological intervention to lower LH levels might potentially decrease this risk. The authors mention Phase II data suggesting stabilization of cognitive function in men with Alzheimer disease from a trial specifically designed to test the potential of leuprolide acetate (leuprolide) (Lupron).3 Leuprolide, along with a similar agent, goserelin acetate (goserelin) (Zoladex), are gonadotropin-releasing hormone (GnRH) agonist analogues that decrease circulating LH levels. GnRH is a hypothalamic hormone that stimulates LH release from the anterior pituitary gonadotrophs when the pituitary is exposed to GnRH in the physiologically normal pulsatile fashion. Although leuprolide and goserelin are agonists at the receptor level, continuous stimulation of the anterior pituitary gonadotrophs by these synthetic analogues paradoxically diminishes LH release. Both agents are commonly used in the treatment of endometriosis, precious puberty and metastatic prostate cancer. Radiation oncologists also frequently use them as adjuvant therapy for locally advanced or high-risk localized prostate cancer. Long-term follow-up has documented improved local control, biochemical control, disease specific survival and overall survival compared to radiotherapy alone for high-risk prostate cancer patients. Given that these studies were prospective, randomized clinical trials, which began in the 1980s, they could perhaps provide additional evidence supporting or refuting the hypothesis. For instance, in the clinical trial RTOG 85–31,4 patients with high-risk prostate cancer were randomized to either indefinite use of goserelin acetate or no treatment following radiation therapy. Thus, a cohort of patients given goserelin (and thus having suppressed LH levels) dating back to 1985 can be compared to a very similar cohort who did not receive such therapy. Definite conclusions, of course, will be limited due to the high percentage of patients who eventually crossed over to the goserelin arm when their disease progressed, the high number of deaths since the trial began, and the possibility that data on Alzheimer disease development over the years was not fully documented. Of note, certain other clinical trials of goserelin or leuprolide and radiation therapy may not be as useful as cohort studies to test the role of LH inAlzheimer disease pathogenesis. A European study5 had an outcome very similar to the RTOG study4 as far as prostate cancer control goes, and many of these men never fully recovered testicular function following withdrawal of the use of adjuvant goserelin for 3 years. Although men in both trials had long-term reductions in testosterone levels and improved prostate cancer control compared to radiotherapy alone, at the completion of the EORTC trial,5 LH levels presumably increased, whereas in the RTOG study4 LH levels remained suppressed. Similarly, although the effect of orchiectomy may be similar to long-term goserelin or leuprolide therapy (i.e. testosterone is decreased to castration levels), the effects on LH will be drastically different with orchiectomy leading to increased LH and “chemical castration” leading to lowered LH. In light of this intriguing hypothesis, it might be interesting and worthwhile to investigate the effects of LH suppression on Alzheimer disease development in these completed, long-term cohorts.