The Relationship between Serum Levels of Estradiol and Osteoprotegerin in Patients with Anorexia Nervosa

Abstract

Abstract. Osteoporosis is one of the major complications in anorexia nervosa (AN) patients. Receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) have been identified as important regulators of bone turnover. The objective of this study was to clarify the role of RANK-RANKL-OPG system, and their relationship with other regulators for bone metabolism in AN patients. We investigated serum levels of RANKL, OPG, and bone turnover markers of 26 Japanese young female AN patients and 7 age-matched healthy women. We measured serum levels of estradiol (E2), insulin like growth factor-I (IGF-I) and triiodothyronin (T3) from the same samples and studied their relationship with RANKL or OPG. Mean serum levels of E2, IGF-I, T3 and leptin in AN patients were significantly lower than those of controls (p<0.05). Serum levels of OPG in AN patients were significantly higher than those in controls and negatively correlated with body mass index (BMI), E2, IGF-I or leptin. Serum levels of free RANKL could not be detected except for only one healthy control in both groups. These results suggest that serum OPG levels may be increased by a compensatory mechanism for malnutrition and estrogen deficiency which induces an increase in bone resorption. FIFTY percent of new AN outpatients show a decrease in lumbar bone mineral density (BMD) [1][2][3][4][5][6]. We have previously reported that the mechanism of osteoporosis in AN patients is both decreased bone formation and increased bone resorption due to decreased serum levels of insulin like growth factor-I (IGF-I) and estradiol (E2) [4,5]. Receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) have been identified as important regulators of bone turnover [7][8][9]. RANKL is essential for osteoclast differentiation via its receptor located on the surface of osteoclast precursor cells. OPG is a soluble decoy receptor which inhibits osteoclast differentiation through its binding to RANKL. Estrogen negatively regulates osteoclast differentiation and proliferation via RANK-RANKL system, and increases osteoclast apoptosis. Estrogen also inhibits osteocyte apoptosis, maintains osteocyte viability, and stimulates osteoblast-like cells to produce OPG [10][11][12][13]. It is reported that serum levels of RANKL and OPG increased in postmenopausal women [14,15]. AN is accompanied with amenorrhea and demonstrates low serum levels of E2. Serum levels of OPG In AN patients have been already reported [16,17], but the results are controversial. The objective of this study is to clarify the role of RANK-RANKL-OPG system and their relationship with other regulators for bone metabolism in AN patients.

Estrogen Receptor 1 Gene (ESR1) is Associated with Restrictive Anorexia Nervosa

“…Observations between same-sex and opposite-sex twins allowed to find a high AN prevalence in adult life in female compares with male, suggesting an influence of intrauterine exposure level to sex hormone (Procopio and Marriott, 2007). Interestingly, significant deficiency of serum levels for estradiol, the ligand of estrogen receptor, has been described in AN patients compared with controls, and a lower concentration in restrictive subtype rather than the binge eating/purging subtype has been reported (Ohwada et al, 2007). It is tempting to speculate that the association between ESR1 gene and RAN may lead to specific biological effects, such as a modified expression and/or an altered function of the estrogen receptor alpha.…”

“…Thus, our hypothesis is to identify an association between estrogen receptor and AN, especially in RAN subgroup, because a diminution of estradiol level was more important in the restrictive compared with the binging-purging subtype (Ohwada et al, 2007). We more precisely expect to observe an association between AN and ESR1 gene because ovariectomized rat showed an implication of ESR1 but not of ESR2 receptor in food intake, body weight and meal size (Santollo et al, 2007).…”

“…Fourth, the anorexic effect of high estrogen levels was found in animal models (Couse and Korach, 1999;Wade and Gray, 1979). Moreover, estradiol levels were lower in anorexia patients than in controls (Ohwada et al, 2007;Brambilla et al, 2003). Fifth, the ESR1 and ESR2 genes, which code for estrogen alpha and beta receptors and are expressed in nonoverlapping brain regions (Osterlund et al, 2000;Osterlund and Hurd, 2001), colocalize with corticotrophin-releasing factor and modulate its expression (Dagnault and Richard, 1997;Bao et al, 2005).…”

Levels of osteoprotegerin (OPG) and receptor activator for nuclear factor kappa B ligand (RANKL) in serum: Are they of any help?

“…Interestingly, obese perimenopausal women had lower OPG serum levels than controls of normal weight [36]. OPG was inversely related to BMI in patients with anorexia nervosa [37]; in contrast to these findings, in healthy women OPG was positively correlated with the individual waist-hip ratio [27], but again, data in this field are still contradictory.…”

Metabolizm kostny, osteoprotegeryna i ligand receptora aktywatora czynnika jądrowego-kB a wybrane hormony tkanki tłuszczowej u dziewcząt z jadłowstrętem psychicznym

“…Girls with AN suffer from a considerable decrease of bone mass [8][9][10]12 [64], girls with AN exhibited a considerable increase of serum OPG. Misra et al [4] suggested that decreased levels of bone resorption markers in girls with AN might indicate a suppressive effect of elevated serum OPG on osteoclast activity and differentiation.…”