Elsevier

NeuroImage

Volume 59, Issue 2, 16 January 2012, Pages 1123-1131
NeuroImage

Genetic influences on hippocampal volume differ as a function of testosterone level in middle-aged men

https://doi.org/10.1016/j.neuroimage.2011.09.044Get rights and content

Abstract

The hippocampus expresses a large number of androgen receptors; therefore, in men it is potentially vulnerable to the gradual age-related decline of testosterone levels. In the present study we sought to elucidate the nature of the relationship between testosterone and hippocampal volume in a sample of middle-aged male twins (average age 55.8 years). We found no evidence for a correlation between testosterone level and hippocampal volume, as well as no indication of shared genetic influences. However, a significant moderating effect of testosterone on the genetic and environmental determinants of hippocampal volume was observed. Genetic influences on hippocampal volume increased substantially as a function of increasing testosterone level, while environmental influences either decreased or remained stable. These findings provide evidence for an apparent gene-by-hormone interaction on hippocampal volume. To the best of our knowledge, this is the first study to demonstrate that the heritability of a brain structure in adults may be modified by an endogenous biological factor.

Highlights

► The brain is highly responsive to androgens such as testosterone. ► In men, the hippocampus is vulnerable to age-related changes in testosterone. ► We found no significant correlation between testosterone and hippocampal volume. ► The heritability of hippocampal volume increases as a function of testosterone. ► Testosterone level is likely a valuable biomarker for brain aging in men.

Introduction

As early as the fourth decade of life, testosterone levels in men begin to decline at a steady rate (Feldman et al., 2002, Ferrini and Barrett-Connor, 1998, Harman et al., 2001, Muller et al., 2003). This decline is especially pronounced for bioavailable or free testosterone, which is not bound to the sex hormone binding globulin and therefore is physiologically active (Feldman et al., 2002, Ferrini and Barrett-Connor, 1998, Harman et al., 2001, Muller et al., 2003). The gradual loss of testosterone leads to functional changes in androgen responsive tissue, those areas of the body in which androgen receptors (AR) are abundant (Morley, 2001, Vermeulen, 2000). In addition to the prostate (Cunha et al., 1987), heart (Marsh et al., 1998), skin (Blauer et al., 1991), and musculoskeletal tissue (Sheffield-Moore and Urban, 2004), the brain is highly responsive to androgens such as testosterone, with the hippocampus being one of the most strongly influenced regions (Beyenburg et al., 2000, Kerr et al., 1995, Simerly et al., 1990). Indeed, the level of AR expression in the hippocampus, as measured by AR mRNA concentration, has been shown to be of the same order of magnitude as expression in the prostate (Beyenburg et al., 2000). Thus, although testosterone is frequently associated with sexually dimorphic physical characteristics, as well as behavioral traits such as aggression, the gradual decrease in the availability of testosterone for hippocampal tissue is likely a key component of the processes underlying brain aging in men (Pike et al., 2006, Veiga et al., 2004).

Animal studies have demonstrated a significant positive association between testosterone and hippocampal volume (Galea et al., 1999), as well as effects of the hormone on hippocampal neural plasticity (Harley et al., 2000, MacLusky et al., 2006), synaptic density (Leranth et al., 2003, Parducz et al., 2006), and neurogenesis (Galea, 2008, Galea et al., 2006). In humans, testosterone level has been found to correlate positively with hippocampal volume during adolescence (Neufang et al., 2009). On a more global scale, levels of bioavailable testosterone from midlife (roughly age 60) have been shown to predict total cranial volume as well as frontal and parietal lobe volumes 10 to 16 years later (Lessov-Schlaggar et al., 2005). We are aware of no studies in adult humans that have established a direct relationship between testosterone and hippocampal volume; however, higher testosterone levels have been linked to increased regional cerebral blood flow within the human hippocampus (Moffat and Resnick, 2007). While there has been minimal investigation of the relationship between testosterone and the hippocampus in humans, numerous studies have found a positive correlation between testosterone and hippocampally-mediated cognitive processes (e.g., episodic memory and visual–spatial ability) in middle-aged and older adults (Barrett-Connor et al., 1999, Martin et al., 2008, Matousek and Sherwin, 2010, Yaffe et al., 2002).

In addition to associations with the hippocampus and cognition, low testosterone levels have been shown to be predictive of Alzheimer's disease (AD) in men (Hogervorst et al., 2004, Moffat et al., 2004), as well as amnestic mild cognitive impairment (Chu et al., 2008). Evidence indicates that testosterone regulates the accumulation of β-amyloid in the brain, potentially abating the neuropathology underlying AD (Gouras et al., 2000, Rosario et al., 2006). Interactions between testosterone and the apolipoprotein-E (APOE) ε4 allele have also been observed for measures of cognitive functioning and hippocampal volume (Raber, 2008, Panizzon et al., 2010), as well as for the risk of AD itself (Hogervorst et al., 2002). Findings such as these have promoted the hypothesis that androgens like testosterone are neuro-protective, sparking interest into hormone replacement as a possible therapeutic intervention (Hammond et al., 2001, Pike et al., 2009, Veiga et al., 2004). It should be noted, however, that the actual risks and benefits of such hormone replacement treatment remain largely undetermined.

The aim of the present study was to elucidate the nature of the relationship between testosterone and hippocampal volume in adult men. Using data from a cohort of middle-aged male twins we examined two potential mechanisms. First, given that multiple animal studies have shown a relationship between testosterone and structural aspects of the hippocampus (Galea et al., 1999, Galea et al., 2006, Leranth et al., 2003, MacLusky et al., 2006), as well as some evidence for a direct relationship in humans (Moffat and Resnick, 2007, Neufang et al., 2009), we examined whether testosterone level and hippocampal volume were significantly correlated with one another, and the extent to which any observed correlation was driven by shared genetic or environmental factors. Second, we tested whether testosterone modifies the degree to which hippocampal volume is influenced by genetic and environmental factors. In any type of tissue, testosterone primarily exerts its influence by binding with the AR (Li and Al-Azzawi, 2009). As a transcriptional activator the AR modulates the expression of numerous downstream genes by regulating the conversion (i.e., transcription) of DNA into RNA (Dalton and Gao, 2010, Li and Al-Azzawi, 2009). Thus, the function of the AR provides a mechanism by which testosterone may alter the degree to which a phenotype like hippocampal volume is influenced by genetic factors. Along these lines, a number of studies have to date shown that testosterone can alter the expression of specific genes within the hippocampus and other brain regions (Chowen-Breed et al., 1989, Kerr et al., 1996, Tirassa et al., 1997, Zhang et al., 1999). We therefore tested whether the heritability of hippocampal volume (i.e., the proportion of variance contributed by genetic factors) would vary as a function of testosterone level. Put another way, we examined whether the level of testosterone alters the balance of latent genetic and environmental factors that contribute to individual differences in hippocampal volume.

Section snippets

Participants

Data were obtained as part of the Vietnam Era Twin Study of Aging (VETSA), a longitudinal study of cognitive and brain aging with baseline in midlife (Kremen et al., 2006). Participants in the VETSA were sampled from the Vietnam Era Twin (VET) Registry, a nationally distributed sample of male–male twin pairs who served in the United States military at some point between 1965 and 1975 (Goldberg et al., 2002). Detailed descriptions of the VET Registry's composition and method of ascertainment

Results

Prior to statistical adjustment, the average testosterone level was 98.4 pg/ml (SD = 29.3), and a small but significant correlation was observed between the hormone level and age, r = −.13 (p = .01). The unadjusted, average left and right hippocampal volumes were 3974.7 mm3 (SD = 393.7) and 4198.0 mm3 (SD = 426.1), respectively. These volumes are consistent with those reported for similarly aged samples that were collected utilizing nearly identical imaging and post-processing methods (Walhovd et al., 2011

No correlation between testosterone and hippocampal volume

In the present study, there was no evidence for either a phenotypic or genetic correlation between testosterone level and hippocampal volume. In other words, hippocampal volumes did not increase or decrease as a function of testosterone levels, and there was no evidence of shared genetic variance between the hormone and the brain structure. A small but significant unique environmental correlation was observed between testosterone level and right hippocampal volume; however, the magnitude of

Disclosure statement

Dr. Anders M. Dale is a founder and holds equity in CorTechs Laboratories, Inc., and also serves on the Scientific Advisory Board. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. All other authors state that there are no actual or potential conflicts of interest.

Acknowledgments

The VETSA project is supported by National Institutes of Health/National Institute on Aging (NIH/NIA) Grants , , , . The U.S. Department of Veterans Affairs has provided support for the development and maintenance of the Vietnam Era Twin Registry. Numerous organizations have provided invaluable assistance, including VA Cooperative Studies Program; Department of Defense; National Personnel Records Center, National Archives and Records Administration; the Internal Revenue Service; National

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