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Role of Testosterone in Prevention of Alzheimer's Disease

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Role of Testosterone in Prevention of Alzheimer's Disease Edith Cowan University Research Online Theses: Doctorates and Masters Theses 2012 Role of testosterone in prevention of Alzheimer's Disease Eka J. Wahjoepramono Edith Cowan University Follow this and additional works at: https://ro.ecu.edu.au/theses Part of the Medicine and Health Sciences Commons Recommended Citation Wahjoepramono, E. J. (2012). Role of testosterone in prevention of Alzheimer's Disease. https://ro.ecu.edu.au/theses/518 This Thesis is posted at Research Online. https://ro.ecu.edu.au/theses/518 Edith Cowan University Copyright Warning You may print or download ONE copy of this document for the purpose of your own research or study. The University does not authorize you to copy, communicate or otherwise make available electronically to any other person any copyright material contained on this site. You are reminded of the following: Copyright owners are entitled to take legal action against persons who infringe their copyright. A reproduction of material that is protected by copyright may be a copyright infringement. Where the reproduction of such material is done without attribution of authorship, with false attribution of authorship or the authorship is treated in a derogatory manner, this may be a breach of the author’s moral rights contained in Part IX of the Copyright Act 1968 (Cth). Courts have the power to impose a wide range of civil and criminal sanctions for infringement of copyright, infringement of moral rights and other offences under the Copyright Act 1968 (Cth). Higher penalties may apply, and higher damages may be awarded, for offences and infringements involving the conversion of material into digital or electronic form. Role of testosterone in prevention of Alzheimer's Disease This thesis is presented for the degree of Doctor of Philosophy Eka Julianta Wahjoepramono School of Medical Sciences Edith Cowan University 2012 CONTENTS Chapter 1 Page 1 The role of testosterone and luteinizing hormone (LH) in subjective memory complainers (SMC) Chapter 2 Page 63 Materials and Methods Chapter 3 Page 91 Reduction of CSF and cerebral Aβ levels by testosterone in castrated guinea pigs Chapter 4 Page 115 CNS administration of human luteinizing hormone increases cerebrospinal fluid and cerebral beta amyloid levels in guinea pigs Chapter 5 Page 140 Peripheral administration of human luteinizing hormone (LH) and leuprolide to the guinea pig impacts on CNS Aβ levels. Chapter 6 Page 173 Effect of testosterone supplementation on plasma biomarkers in men with subjective memory complaints (SMC) Chapter 7 Page 259 Effect of testosterone supplementation on cognitive performance, depression and quality of life in men with subjective memory complaints (SMC) Chapter 8 Page 298 Effects of testosterone treatment on brain metabolite levels and on rates of medial temporal atrophy Chapter 9 Page 344 General Discussion Appendices Page 363 Chapter 1 The role of testosterone and luteinizing hormone (LH) in subjective memory complainers (SMC) 1 1.1 Background Alzheimer’s disease (AD), is the most common cause of dementia in the elderly and is characterized by a progressive memory decline, impairments in language and visual- spatial skills, impairments in behaviour, results in a loss of independence, reduction of quality of life, and ultimately death. Although our knowledge and understanding of the disease continues to grow, currently there are no effective treatments for reversing or even stabilizing the process of the disease. AD remains perhaps the most devastating disease of older people and constitutes a large social and economic burden to both the families and society as a whole. Currently there are 30 million individuals worldwide with dementia (Ferry, C.P et al., 2005) and some predictions indicate as much as a 4 fold increase in the prevalence of AD by 2050 (Brookmeyer et al., 2007). Thus, there is an urgent need for better tools for diagnosis, prevention, and treatment to avoid this upcoming epidemic. Age is the most important known risk factor of AD. As people age, there is a normal decline in the physiological functions of their body, in particular the hormonal deficiency following reproductive senescence known as menopause in women and andropause in men. A number of studies involving postmenopausal women have shown a correlation between decreasing levels of estrogen and increased levels of beta amyloid (A), the major component of the neuritic plaques found in the AD brain. Although the role of testosterone in men has received less attention, it has been shown to share a similar action to that of estrogens on the generation of the Aβ . Therefore, it has been suggested that testosterone may have a similar role to estrogen in the relation to AD. At present, a number of studies in the AD field focus on testosterone levels in men and its effects on the nervous system. While the results are preliminary and the role of androgens in the aged-related cognition is still poorly understood compared to those studies of estrogen, it has been proposed that testosterone therapy may delay the onset of AD in elderly men. Luteinizing hormone (LH), one of the pituitary gonadotropin hormones, is synthesized and secreted under the regulation of gonadotropin-releasing hormone (GnRH), pituitary factors and gonadal hormone feedback which collectively are termed the Hypothalamus-Pituitary-Gonadal (HPG) axis. LH is secreted in a pulsatile manner from 2 pituitary into the peripheral circulation which eventually affect target organs expressing the LH receptor (LHR). In the gonads, LH stimulate gonadal hormone production, such as testosterone, estrogen, progesterone, activin, and inhibin. LHR is highly expressed in the hippocampus; a brain region involved in memory function and which is severely affected in AD (Barron, A.M et al., 2006). Several studies also confirmed that the brain may also be a target organ for LH (Lei, Z et al., 1993; Al-Hader, A.A et al., 1997). However, the regulation of LHR in the brain has been largely unexplored. In aging men, changes of LH levels have been reported with the levels of serum LH shown to be two to three times higher than men in their mid-20s (Neaves, W.B et al., 1984). Recent studies by Short et al., 2001 showed that high levels of LH, are associated with AD. However, whether LH plays a direct role in AD pathogenesis still remains unclear. Recent studies have linked testosterone depletion and perhaps LH elevation with increased risk for the development of AD in men. It is unclear whether the altered actions of both testosterone or LH contribute to the pathogenesis of AD. It is unlikely that any one of the hormones from HPG axis plays a single and predominant role in the reproductive system but rather it may be a combination of hormones acting in concert. This chapter will review the current understanding of the characteristics and pathogenic mechanisms of AD, focussing on the relationship between testosterone, LH and AD. In addition, the review will also discuss the benefits of testosterone and LH suppression in AD. 1.2 Alzheimer’s Disease : Epidemiology and Clinical Characteristics Alzheimer’s disease AD) is the most prevalent form of dementia, accounts for about 50-60% of all dementia cases, compared to other types of dementia, such as vascular dementia (15-20% of the cases), Lewy body dementia (up to 20% of the cases) and fronto-temporal dementia (approximately about 10% which is associated with a younger age of onset) (Schulz, R., Noelker, S Linda., Rockwood, K., Sprott, R, 2006). The number of cases with dementia as well as AD world-wide will increase as the population grows, affecting approximately 4-5 million people in the United States and around 15 million people worldwide (Hebert et al., 2003). Other developed countries 3 such as Australia and Canada will undergo a similar pattern. Although AD is known to be a major problem in developed countries, it already poses a great problem in developing countries, predominantly in Asian countries where the impact of this disease is predicted to be catastrophic if effective prevention measures are not implemented in the near future (Ferri et al., 2005). Moreover, in Indonesia, as a developing country with a high rate of population growth, AD cases are projected to have 295% increment between 1990 and 2030 (Draper and Brian, 2004). The decline in fertility and improvements in life expectancy have contributed to the aging population in Indonesia. As seen in western countries there is a predominance women compared to men in the older age groups which may contribute further to the dementia epidemic. Furthermore there is a greater degree of aging in rural areas and taken together with the large rural population in Indonesia and its associated lower socio-economic status the prevalence of this disease will be considerable. The absolute number of people in Indonesia has increased from 4.9 million in 1950 to 16.3 million in 2000. By 2050, it is estimated that one in four Indonesian would be classified as an elderly person compared to one in ten at present, resulting in 73.6 million in this population group (Fletcher Robert., 2010). Currently there are very few facilities for the treatment and care of people with Alzheimer’s disease and the government is poorly aware of the magnitude of this problem and is thus unprepared to deal with the looming dementia epidemic and no initiatives have yet been taken to develop early diagnostic and prevention programs to combat the consequence of this devastating disease. AD was first described in 1907 by Alois Alzheimer, a German physician who described the neuropathology in the brain of a 51 year old woman named Augusta D. After her death, an autopsy revealed dense deposits outside and around nerve cells in her brain, and twisted strands of fibre inside dead neurons, which were later known as neurofibrillary tangles and neuritic plaques, respectively.
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