We demonstrated decreased oxytocin levels in women with anorexia nervosa compared to healthy controls. Furthermore, we found that mean overnight serum oxytocin levels were associated with bone mineral density, fat mass and leptin levels. These relationships were independent of levels of estradiol, a key regulator of oxytocin secretion.
Oxytocin, a nine amino acid peptide hormone produced in the hypothalamus and released into the peripheral circulation via the posterior pituitary, is widely known for its important role in parturition and milk letdown. Studies in animal models suggest that oxytocin also plays a role in the regulation of food intake. Intracerebroventricular and intraperitoneal administration of oxytocin to fasting rats resulted in dose-dependent decreased food intake and an increase in the time before eating1, 13
. When an oxytocin antagonist was given prior to administration of intracerebroventricular oxytocin, these effects were reversed1
. Oxytocin is thought to be involved in leptin signaling. The leptin receptor has been identified on oxytocinergic cells in the supraoptic and paraventricular nuclei of the hypothalamus14
. In fasting mice, oxytocin mRNA levels were reduced and administration of leptin increased oxytocin mRNA transcripts15
. An oxytocin antagonist reversed the anorexigenic effects of intraventricular leptin administration in rats16
. In contrast to this line of evidence, several studies of rats have shown increases in food intake, weight and fat with subcutaneous or central administration of oxytocin2, 3, 17
. Furthermore, increased food intake has been reported after intraventricular administration of oxytocin to oxytocin and oxytocin receptor knockout mice4
. Therefore, although oxytocin appears to be an important modulator of appetite in animals, the specific effects are unclear.
There are some data in the literature which have primarily focused on cerebrospinal fluid (CSF) levels of oxytocin that raise the possibility of an “oxytocin-deficient state” in anorexia nervosa. In a study of 5 women with restrictive anorexia nervosa, cerebrospinal fluid (CSF) oxytocin levels were lower than healthy controls18
. In contrast, CSF oxytocin levels in women with bulimic subtype anorexia nervosa did not differ from the controls in this study. Frank et al. demonstrated that CSF oxytocin levels were comparable in 10 recovered women with bulimic subtype anorexia nervosa and controls. However, women with active anorexia nervosa and those with restrictive subtype were not studied19
. Chiodera et al. investigated the plasma oxytocin response to stimulation in 7 women with anorexia nervosa and controls. They found that stimulation was suppressed at the time of hospitalization, improved with partial weight recovery, and normalized with full weight recovery20
. No published study has looked at oxytocin secretion in a well-defined cohort with active disease. Although oxytocin is produced in the hypothalamus, it is secreted into the periphery via the posterior pituitary and can be measured in the blood. Our study averages 36 serum samples over 12 hours for an integrated measure of oxytocin in a much larger patient sample than previously studied. We demonstrated lower levels of mean 12 hour serum oxytocin levels in women with anorexia nervosa compared to healthy controls, confirming that there is a state of relative oxytocin deficiency in anorexia nervosa compared to young healthy women. It is unclear whether oxytocin deficiency is an adaptive response to the energy deficit associated with chronic starvation, or if oxytocin dysregulation is an etiologic factor in the development of anorexia nervosa. Low oxytocin levels may contribute to symptoms of anorexia nervosa through effects on appetite and food intake. In addition, oxytocin has been implicated in prosocial behavior21
, and a relative oxytocin deficiency in anorexia nervosa may contribute to associated deficits in social functioning, which in turn predict poor outcome22, 23
Anorexia nervosa is characterized by central hypogonadism and decreased bone mineral density. The severity of bone loss is increased compared to women with normal-weight hypothalamic amenorrhea24
, and prospective studies have found no benefit of estrogen replacement25–27
. Additional hormonal abnormalities, including hypercortisolemia and growth hormone resistance have been implicated in the pathogenesis of anorexia nervosa-induced bone loss28
. There is a growing body of evidence indicating that oxytocin is an important hormone in bone remodeling. The oxytocin receptor has been found on human osteoclasts29
and osteoblasts4, 30
. In a study of human osteoblast-like cells from an osteosarcoma cell line, oxytocin increased cell proliferation and protein synthesis. Administration of an oxytocin antagonist blocked the proliferative effects of oxytocin31
. Similarly in human osteoclast and preosteoclast cell cultures, oxytocin administration increases preosteoclast proliferation29
. Cultured human bone marrow stem cells preferentially differentiate into osteoblasts over adipocytes when exposed to oxytocin7
. In rats, oxytocin treatment increases osteoblast proliferation and bone turnover, promoting net bone formation32
. Oxytocin and oxytocin receptor knockout mice display marked osteoporosis. Peripheral administration of oxytocin to animal models of osteoporosis, including knockout mice or estrogen-deficient ovariectomized mice, increases osteoblast and osteoclast formation and microarchitecture while decreasing bone marrow adipocyte number4, 7
. A study by Elabd et al. investigated fasting morning oxytocin levels in postmenopausal women, and found that levels were 55% lower in the 20 subjects with osteoporosis than the 16 without osteoporosis7
. There was no correlation with age, BMI or weight. To the best of our knowledge, no other studies have examined the relationship between oxytocin levels and bone density in humans. Consistent with the concept that oxytocin regulates bone remodeling, our study showed a significant association between peripheral oxytocin levels and bone mineral density. This, along with lower levels of oxytocin in women with anorexia nervosa compared to controls, supports the hypothesis that oxytocin contributes to bone loss in AN. It is also possible that this relationship simply reflects a decrease in both oxytocin and bone mineral density due to low weight. Further studies are needed to establish causality.
Anorexia nervosa is characterized by low body fat and severe bone loss with increased bone marrow fat. Inverse correlations between bone marrow fat and bone mineral density, and bone marrow fat and subcutaneous and total abdominal fat have been described33
. Given these relationships and the fact that adipocytes and osteoblasts develop from the same mesenchymal precursor cells in bone marrow, shunting of pluripotent marrow cells from osteogenic to lipogenic pathways in chronically starved patients with AN has been hypothesized33
. We demonstrated an association between oxytocin and fat mass as well as leptin levels. Further investigation would be useful to determine the relationship between oxytocin and marrow fat. Previous studies suggest that leptin signaling may involve activation of oxytocin neurons14–16
, and that oxytocin may be involved in the regulation of leptin secretion34
. It is possible that fat, leptin, and oxytocin share a common signaling pathway, or may independently indicate energy availability. In the case of women with anorexia nervosa, oxytocin deficiency may signal an energy deficit and lack of resources for bone formation. This is a cross-sectional study and causality cannot be determined.
In summary, we showed that oxytocin levels are decreased in women with AN compared to healthy controls and that these levels were positively associated with bone mineral density, fat mass and leptin levels. Further investigation will be important to determine whether oxytocin deficiency resolves with recovery in anorexia or contributes to the pathophysiology of the disease.