Conceptualizing the role of estrogens and serotonin in the development and maintenance of bulimia nervosa

Abstract

Serotonergic dysregulation is thought to underlie much of the pathology in bulimia nervosa (BN). The purpose of this review is to expand the serotonergic model by incorporating specific and nonspecific contributions of estrogens to the development and maintenance of bulimic pathology in order to guide research from molecular genetics to novel therapeutics for BN. Special emphasis is given to the organizing theory of general brain arousal which allows for integration of specific and nonspecific effects of these systems on behavioral endpoints such as binge eating or purging as well as arousal states such as fear, novelty seeking, or sex. Regulation of the serotonergic system by estrogens is explored, and genetic, epigenetic, and environmental estrogen effects on bulimic pathology and risk factors are discussed. Genetic and neuroscientific research support this two-system conceptualization of BN with both contributions to the developmental and maintenance of the disorder. Implications of an estrogenic-serotonergic model of BN are discussed as well as guidelines and suggestions for future research and novel therapeutic targets.

Figure 1

Panels A and B present a simplified model of the binge—compensatory behavior cycle. In panel A, trait based anxiety and harm avoidance place an individual in a perpetual state of concern about overeating. This concern makes them more alert and sensitive to environmental cues relevant to eating (e.g., diet commercials, food adds, etc.), more susceptible to stress responses, and more emotionally driven. The increased pressure from these triggers leads to an increased likelihood of overeating, which is reinforced through reduction of anxious or stressful state associated with eating. Similarly, compensatory behaviors (e.g., exercise, vomiting, etc.) serve to temporarily reduce the anxious or stressful state associated with having overeaten. In panel B, the paradigm is similar except the individual is particularly vulnerable to hedonic or metabolic motivational states. Overeating and compensatory behaviors serve to be temporarily pleasurable and satiating. We note that these deficits and their basic reinforcement patterns are not mutually exclusive and often co-occur in the same individual. There is also feedback from the dietary control (via deprivation in nutrition or thinking about dieting) to increase stress and the drive for reward and eating.

Figure 2

The figure above highlights an escalating series of pressures on the estrogenic and serotonergic systems in a developing female. Genetic polymorphisms from birth can limit the efficacy of the serotonergic system. Prenatal exposure to estrogens further organizes the brain for later estrogenic effects. After birth, specific forms of stress brought about by parenting style my further compromise serotonergic genes. Simultaneously, the individual is exposed to environmental estrogens which further predispose the individual for weight gain and increased subcutaneous fat deposition. The consequence of these pressures may include increased attempts at dieting. Puberty brings phasic shifts in estrogens and subsequent regulatory power over the serotonergic system. Social pressures to be thin increase and a challenged estrogen-serotonin system leaves the individual vulnerable to dysphoric mood, behavioral disinhibition, and ultimately a pattern of dieting, binging, and purging. These symptoms further reduce estrogens, exacerbating serotonergic dysfunction. The pattern persists until the individual is able to stabilize their pattern of eating and exercise.

Figure 3

Simplified schematic of general arousal and its relationship to specific behaviors. Equation 1 (adopted from Garey, et al., 2003) at the top, puts mathematical form to the concept where general arousal contributes to system specific behavioral states. A = arousal. Ag = generalized arousal. K = constant. s = specific system such as fear, eating, etc. This mathematical form also allows for K and A to vary by individual, suggesting different thresholds and dependency on general arousal for each person and for each behavior. As general arousal increases, the specific system transitions into a coordinated increase in behavior followed by a lagged inhibition of this behavior. Both processes occur simultaneously, but the balance between the specific behavioral system dictates which behavior is expressed. When the behavior terminates, it decreases general arousal, temporarily reducing the likelihood for the wide range of behaviors and relevant arousal states. The above model also allows for specific system dysregulation. For instance, 5-HT1a receptor dysregulation in the hypothalamus may reduce the eating specific system's negative feedback loop making it particularly difficult to stop eating once initiated.

Figure 4

Estrogens influence serotonergic transmission in a number of specific ways summarized above. (A) Estrogens bind to nuclear ER α or β which activate transcription factors for a number of proteins via EREs. Transcription results in increased SERT and TPH and decreased MAO-A. (B) The net result of these changes is increased intracellular 5-HT and decreased clearance of 5-HT from the synaptic cleft. TPH degrades tryptophan into 5-hydroxytryptophan whereas MAO-A degrades 5-HT into the inactive 5-HTIAA metabolite. SERT recovers synaptic 5-HT from the cleft, conserving it and functionally terminating the neural transmission. (C) Activation of the mERs deactivates 5-HT1a receptors by uncoupling G proteins. The 5-HT1a receptor is an autoreceptor that inhibits neural firing, so deactivating of the receptor functionally reduces the inhibitory effects of 5-HT1a. (D) Post-synaptic 5-HT2a receptors are excitatory neurons which increase neuronal firing. Estrogens working through nuclear receptors increase 5-HT2a mRNA and functionally increase the neuronal sensitivity to presynaptic 5-HT release. ER = estrogen receptor. ERE = estrogen response element. mER = membrane estrogen receptor. E = estrogen. SERT = serotonin reuptake transporter. MAO = monoamine oxidase. TPH = tryptophan hydroxylase.