The impact of chronic estrogen deprivation on immunologic parameters in the ovariectomized rhesus monkey (Macaca mulatta) model of menopause

Abstract

A large clinical literature suggests that estradiol (E₂) plays a critical role in immune function. To further explore the relationship between E₂ and immune function, we examined a variety of immunological parameters in a rhesus monkey model of menopause and hormone replacement therapy. Rhesus monkeys (Age, 13.7±2.6 years) were ovariectomized and received either sham (n=10) or estradiol (n=10) replacement implants. Nine months post-ovariectomy, a variety of immunologic parameters were measured. E₂-deprivation reduced natural killer cell activity and increased serum soluble gp130 levels. There was a trend for an increased proportion of CD8⁺ (P=0.12) and HLA-DR⁺CD3⁺ cells (P=0.15) and decreased proportion of eosinophils (P=0.11) in the E₂-deprived monkeys. There was no difference in leukocyte distribution, CD28, CD56, CD4, CD8/CD45, colony forming units-granulocyte/monocytes formation, peripheral blood mononuclear cell apoptotic rate, or serum TNF, TNF-R1, TNF-R2, IL-6, soluble IL-6R, and IL-1 between the groups. These data demonstrate that E₂-deprivation affects several aspects of immune function. These findings may have implications for menopause-associated changes of immune function that occur in women.

Introduction

A large clinical literature suggests that estradiol (E₂) plays a critical role in immune function (Cutolo et al., 1995). Specifically, women are more susceptible to autoimmune diseases than men (Ansar Ahmed and Talal, 1989, Jansson and Holmdahl, 1998) and hormone replacement therapy of menopause modulates immune parameters (Brunelli et al., 1996). A variety of mechanisms for this phenomenon have been postulated including E₂'s ability to regulate cytokine production (Deshpande et al., 1997, Hunt et al., 1997) and inhibit apoptosis of peripheral blood mononuclear cells (Evans et al., 1997, Hofmann-Lehmann et al., 1998). However, these studies are often inconsistent due to differences in subject selection (e.g. differences in menopausal status or time since onset of menopause) and environmental factors (e.g. nutrition or alcohol intake, etc.).

Female rhesus monkeys (Macaca mulatta) have reproductive parameters similar to women. For example, they have 28-day menstrual cycles (Bosu et al., 1973) and undergo menopause in the latter third of life (Roberts et al., 1997, Kaack et al., 1998). In addition to the similarities of normal reproductive endocrinology, monkeys respond similarly as women to several hormone-based interventions, such as surgically induced menopause and E₂ replacement therapy (Jayo et al., 1990, Keller et al., 2000). Therefore, rhesus monkeys may serve as an appropriate animal model to explore the effect of menopause on the immune system. This is an important area of exploration because of the impact that hormones have on autoimmune disease and the increasing interest in hormone replacement therapy. Accordingly, the goal of the current study was to explore the effect of long-term E₂ deprivation on various immune parameters in rhesus monkeys.