Review
Anorexia nervosa and estrogen: Current status of the hypothesis

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Abstract

Anorexia nervosa occurs predominantly in young women. Also, recent data suggest that a heritable, genetic defect may contribute to this feeding disorder. These observations support the hypothesis that an inherited, abnormal response of the brain to rising levels of estrogens at puberty may contribute to the symptoms of weight loss in anorexia. To evaluate the merits of this hypothesis, the current literature on feeding depression by estrogens in anorexic patients and possible genetic or developmental mechanisms that could alter brain responsiveness to estrogens are reviewed. It is concluded that a number of specific biochemical or developmental pathways—abnormalities in the classical or membrane-bound forms of estrogen receptors, in co-activators for estrogen, in thyroxine receptors, in steroid metabolizing enzymes, in quantitative trait loci, in perinatal androgenization, and in processes of puberty—could converge to produce an abnormal response to estrogen and the onset of anorexia nervosa.

Section snippets

Evidence for abnormal effects of steroids in feeding disorders

Direct evidence that an abnormal response to estrogens may be present in AN is sparse and mainly comes from clinical studies that could be criticized as anecdotal in nature. Most of these clinical studies describe a sub-population of anorexics who also have Turner's syndrome of gonadal dysgenesis. Such patients show signs of sexual immaturity and are consequently treated with sex steroids to induce the secondary sexual characteristics of puberty. The sudden introduction of sex steroids to

Anorexic effects of estrogen

The ability of estrogens to depress feeding in ovariectomized rodents is well known and has been summarized in a number of excellent reviews (Asarian and Geary, 2006, Butera, 2010). Similar effects in humans have been suggested by a decreased caloric intake (by about 10%) that occurs during the days of the menstrual cycle when levels of estrogen are elevated (Asarian and Geary, 2006). The subjective explanation for this decline in caloric intake has not been clarified: it is not known whether

Molecular mechanisms of estrogen action

For many years it has been thought that estrogens affect cell function mainly by binding to one of two forms of estrogen receptor protein (ERs), the ERα and the ERβ, which have steroid-binding domains and DNA-binding domains. Thus, estrogen-induced regulation of transcription (genomic mechanism) has received the most attention. An initial study suggested that the ERβ might be important for feeding regulation, however, later studies have contradicted this conclusion and have shown that the ERα

Developmental events that affect responsiveness to estrogen

If a hypersensitivity to estrogens is present in AN, then any event that depresses responsiveness to estrogens should have a protective influence upon the development of AN. One such event is exposure to androgens during embryonic or neonatal periods, which reduces the ability of estrogens to reduce feeding later in adulthood (at least in rodents) (Asarian and Geary, 2006, Young et al., 1979). How can this influence be examined in humans?

One approach, adopted by Klump et al., has been to

Conclusions

All of the above data show that the existence of an abnormal response to estrogen is a plausible explanation for the sex difference in incidence of AN. Varied, multiple mechanisms—abnormalities in the classical or membrane-bound forms of estrogen receptors, in co-activators for estrogen, in thyroxine receptors, in steroid metabolizing enzymes, in quantitative trait loci, in perinatal androgenization, and in processes of puberty—could all conceivably result in a common endpoint, namely, an

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