Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer's disease

Abstract

We examined the relationships between normal aging, Alzheimer's disease (AD), and brain levels of sex steroid hormones in men and women. In postmortem brain tissue from neuropathologically normal, postmenopausal women, we found no age-related changes in brain levels of either androgens or estrogens. In comparing women with and without AD at different ages, brain levels of estrogens and androgens were lower in AD cases aged 80 years and older but not significantly different in the 60–79 year age range. In male brains, we observed that normal aging was associated with significant decreases in androgens but not estrogens. Further, in men aged 60–79 years, brain levels of testosterone but not estrogens were lower in cases with mild neuropathological changes as well as those with advanced AD neuropathology. In male cases over age 80, brain levels hormones did not significantly vary by neuropathological status. To begin investigating the relationships between hormone levels and indices of AD neuropathology, we measured brain levels of soluble β-amyloid (Aβ). In male cases with mild neuropathological changes, we found an inverse relationship between brain levels of testosterone and soluble Aβ. Collectively, these findings demonstrate sex-specific relationships between normal, age-related depletion of androgens and estrogens in men and women, which may be relevant to development of AD.

Introduction

Advancing age is the most significant risk factor for the development of Alzheimer's disease (AD) (Evans et al., 1989, Jorm et al., 1987, Rocca et al., 1986). One age-related change all women experience is the almost complete loss of their primary sex steroid hormone, the estrogen 17β-estradiol (E₂) at menopause. Men also experience a robust age-related decrease in circulating levels of their primary sex steroid hormone testosterone (T), however this effect is much more gradual and typically less severe than E₂ depletion in women (Morley et al., 1997, Vermeulen et al., 1996). The loss of sex steroid hormones during normal aging increases the risk of disease and dysfunction in hormone-responsive tissues (Baumgartner et al., 1999, Burger et al., 1998, Kleerekoper and Sullivan, 1995, Morley, 2001, Stampfer et al., 1990). Since the brain is a hormone-responsive tissue, age-related hormone depletion presumably results in diminished neuroprotective actions of hormones and an increased risk to neurodegenerative diseases such as AD (Pike et al., 2006, Rosario and Pike, 2008). In fact, epidemiological evidence has linked estrogen loss during menopause with an increased risk for the development of AD in women (Cholerton et al., 2002, Henderson, 2006). However, studies comparing E₂ levels in women with and without AD have yielded conflicting results (Cunningham et al., 2001, Manly et al., 2000, Twist et al., 2000), as have studies evaluating the efficacy of hormone therapy in the prevention and treatment of AD (Espeland et al., 2004, Kawas et al., 1997, Rapp et al., 2003, Shumaker et al., 2004, Shumaker et al., 2003, Zandi and Breitner, 2003, Zandi et al., 2002).

In men, low circulating levels of total and free T have been associated with an increased risk for the development of AD (Hogervorst et al., 2003a, Hogervorst et al., 2003b, Hogervorst et al., 2004, Hogervorst et al., 2001, Paoletti et al., 2004, Watanabe et al., 2004). While these studies established a relationship between androgens and AD, they did not distinguish whether low T levels are contributing to or resulting from the disease process. However, a longitudinal study found that the relationship between low T and AD precedes clinical diagnosis by several years (Moffat et al., 2004). Further, we previously reported that T levels in male brain are significantly reduced not only in cases of severe AD but also in cases with mild neuropathological changes, supporting the idea that low androgen levels are a risk factor for development of AD (Rosario et al., 2004).

In this study, we expanded our previous investigation into the relationship between brain levels of sex steroid hormones and AD neuropathological diagnosis. Specifically, we analyzed brain levels of testosterone (T), its active metabolite dihydrotestosterone (DHT), the weak estrogen estrone (E₁), and its active metabolite the potent estrogen E₂. We compared levels in postmortem brain samples from men and women both across normal aging and by AD neuropathological diagnosis. For male cases, we were also able to obtain sufficient cases with mild neuropathological changes consistent with very early stages of AD to evaluate hormone changes in transitional stages of AD pathogenesis. We report sex-specific relationships in levels of estrogens and androgens with both aging and AD.