Adipokine concentrations in nonobese women: a study of reproductive aging, body mass index, and menstrual cycle effects.

The risk for insulin resistance (IR) increases after menopause and may be related to the decline in estrogen (Carr, 2003). In cycling women, estrogen differentially inhibits lipolysis in adipose tissue and promotes the deposition of fat in the gluteo-femoral region (Pedersen, Kristensen, Hermann, Katzenellenbogen, & Richelsen, 2004). With estrogen suppression at menopause, central fat mass increases, producing a more android pattern of fat distribution (Poehlman, Toth, & Gardner, 1995). The postmenopausal accumulation of intra-abdominal fat is presumed to be disease promoting, as this fat depot is a major predictor of insulin resistance (Cnop et al., 2002) and, in turn, the metabolic syndrome, cardiovascular disease (CVD) and diabetes (Carr et al., 2004; Kannel et al., 1991; Reusch, 2002). However, aging (Guo, Zeller, Chumlea, & Siervogel, 1999) is also believed to accelerate the risk for these conditions. It thus remains uncertain to what extent the decline of estrogen contributes to this risk. The discovery that adipose tissue is an active endocrine organ (Miner, 2004) has provided the opportunity to qualify its role in the pathogenesis of the metabolic syndrome, CVD and diabetes. Adiponectin (AD), the most abundant adipocytokine, improves insulin sensitivity and inhibits inflammatory mediators that adversely affect glucose and lipid metabolism (Ahima, 2006). Inversely related to total and central adiposity (Cnop et al., 2003), low levels of AD are associated with insulin resistance and have been documented in persons with type 2 diabetes, coronary artery disease and the metabolic syndrome (Frystyk et al., 2007; Trujillo & Scherer, 2005; Weyer et al., 2001). AD concentrations are sexually dimorphic, with higher levels in females, implying a role for the sex steroids in its regulation (Nishizawa et al., 2002). However, evidence for a causal relationship between estradiol (E2) and AD has been inconsistent. Increased (Gavrila et al., 2003; Lee et al., 2009), decreased (Chu, Cosper, Orio, Carmina, & Lobo, 2006) and unchanged (Jurimae, Rembel, Jurimae, & Rehand, 2005; Milewicz et al., 2005) AD concentrations have all been observed with menopause. However, nearly half of the existing studies failed to measure serum E2 as a direct marker of menopause status, and only one (Benetti-Pinto et al., in press) tightly controlled for age, a variable directly associated with AD concentrations (Cnop et al., 2003). Moreover, most subjects in existing studies were overweight or obese, a clinical feature closely associated with diminished AD production (Arita et al., 1999). These potential confounders have precluded a direct assessment of the relationship between estrogen status and adiponectin. Leptin, the first adipocytokine to be characterized, influences several metabolic functions (Meier & Gressner, 2004). Leptin levels are directly proportional to body mass index (BMI) and fat mass, with greater expression demonstrated in the subcutaneous fat depots (Van Harmelen et al., 1998). High leptin concentrations are associated with insulin resistance (Margetic, Cazzola, Pegg, & Hill, 2002). As with AD, leptin secretion is sexually dimorphic, with higher levels in women (Zoico et al., 2004). Evidence for a causal relationship between leptin and E2 has also been inconsistent, with increased (Chu et al., 2006), decreased (Hong et al., 2007), and unchanged (Gavrila et al., 2003) leptin concentrations all associated with menopause. Taken together, these discordant findings suggest that multiple factors are likely to mediate changes in adipokine secretion in aging women. Recently, the AD-to-leptin ratio (A/L) has been shown to serve as a novel marker of insulin sensitivity (Inoue, Yano, Yamakado, Maehata, & Suzuki, 2006); however, it has seldom been assessed for changes with menopause. In the United States unparalleled numbers of women are expected to transition to menopause over the next decade (North American Menopause Society, 2007), with an accompanying increased risk for obesity and metabolic disease (Park et al., 2003). As health care professionals distinguished by their attention to health promotion and disease prevention, nurses play a role in the early detection and management of preventable conditions in women. Scientific evidence is necessary to characterize the clinical factors, including menopause, related to metabolic disease risk, such that targeted nursing assessment and management strategies can be developed to preserve women’s health during normal aging. The purpose of this study was to define the influence of reproductive aging, body mass index and the menstrual cycle on adipokine secretion. Using a cross-sectional comparative group design, we examined adiponectin and leptin concentrations and measures of insulin sensitivity in three groups of healthy non-obese women, differing by age (younger cycling vs. older cycling) and reproductive stage (age-matched older cycling vs. early postmenopausal). In a subset of cycling women, we prospectively assessed adiponectin concentrations across the menstrual cycle to determine the effects of ovulation. Archived blood samples from a recently completed parent study of menopause effects on bone health (Lukacs et al., 2006) were used to assess the adipokines and insulin sensitivity parameters. Data on general clinical features (i.e., age, body mass index, sex steroids) of the study sample previously reported as part of the earlier study are presented here as background context for the new study question.