S P E C I A L

F E A T U R E R e v i e w

Endocrine Manifestations of Eating Disorders

Michelle P. Warren
Columbia University College of Physicians and Surgeons, New York, New York 10032 Context: The endocrinopathies associated with eating disorders involve multiple systems and mechanisms designed to preserve energy and protect essential organs. Those systems that are most affected are in need of significant energy, such as the reproductive and skeletal systems. The changes in neuropeptides and in the hypothalamic axis that mediate these changes also receive input from neuroendocrine signals sensitive to satiety and food intake and in turn may be poised to provide significant energy conservation. These adaptive changes are described, including the thyroid, GH, and cortisol axes, as well as the gastrointestinal tract. Evidence Acquisition: Articles were found via PubMed search for both original articles and reviews summarizing current understanding of the endocrine changes of eating disorders based on peer review publications on the topic between 1974 and 2009. Conclusion: The signals that control weight and food intake are complex and probably involve multiple pathways that appear to have as a central control the hypothalamus, in particular the medial central area. The hypothalamic dysfunction of eating disorders provides a reversible experiment of nature that gives insight into understanding the role of various neuropeptides signaling nutritional status, feeding behavior, skeletal repair, and reproductive function. (J Clin Endocrinol Metab 96: 333343, 2011)

he endocrinopathies seen with eating disorders have fascinated scientists for decades. They present strong evidence for diffuse hypothalamic dysfunction and provide a reversible experiment of nature that gives insight into understanding the role of various neuropeptides signaling nutritional status. In turn, these central signals of nutritional status may be important mediators in the maintenance of normal reproduction and skeletal integrity. Eating disorders include the syndrome of anorexia nervosa, which is characterized by a classic triad of amenorrhea, weight loss, and psychiatric disturbance (13). Bulimia nervosa is often related to previous anorectic behavior and is characterized by gorging followed by periods of severe food restriction. Unusual methods are employed to lose weight, including vomiting and abuse of diuretics or laxatives. Some eating disorders are classified as an eating disorder not otherwise specified or EDNOS and may be associated with excessive exercise (4). All of these conditions are more common in women when thin-

ness is advantageous, such as professional dance and certain competitive athletics including gymnastics and longdistance running (5).

Anorexia Nervosa
Hormonal changes The most extensively studied eating disorder is anorexia nervosa. Typically, hypothalamic amenorrhea is accompanied by low levels of gonadotropins and a profound estrogen deficiency. Amenorrhea may be absent, however, and there is presently considerable debate as to the appropriateness of the criteria for anorexia nervosa due to the presence of multiple endocrine and metabolic abnormalities in some patients without amenorrhea (6). Some of the lowest levels of LH seen in secondary amenorrhea have been observed in this syndrome (7), although the LH level may be higher if there are other endocrinopathies present such as an underlying polycystic ovarian
Abbreviations: BMD, Bone mineral density; BMI, body mass index; CRH, corticotropinreleasing hormone; EDNOS, eating disorder(s) not otherwise specified; HPA, hypothalamicpituitary-adrenal; PCOS, polycystic ovarian syndrome; POMC, proopiomelanocortin; PYY, peptide YY; TRH, thyrotropin-releasing hormone.

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright 2011 by The Endocrine Society doi: 10.1210/jc.2009-2304 Received October 29, 2009. Accepted November 5, 2010. First Published Online December 15, 2010

J Clin Endocrinol Metab, February 2011, 96(2):333343

jcem.endojournals.org

333

334

Warren

Endocrine Manifestations of Eating Disorders

J Clin Endocrinol Metab, February 2011, 96(2):333343

TABLE 1.

Changes in hormonal mediators in anorexia nervosa, bulimia, and EDNOS

Anorexia nervosa 2(slight) 2 2 2 2 1 1/2 1 2 1 1 1 1 ? 1 2 ? 1 1 Bulimia nervosa ? ? 2 ? ? ? ? 1 2 ? 2 ? 2 ? ? EDNOS ? ?

Hormone TSH T4 Estradiol Testosterone IGF-I GH Insulin sensitivity Cortisol Leptin Adiponectin Ghrelin PYY

1, Increase; 2, decrease; ?, undetermined.

syndrome (PCOS), an association that has recently been reported (8). Twenty-four-hour studies of gonadotropin secretion, which reflect GnRH secretion, reveal persistent low levels throughout the day and night with the absence of the normal pulsatile peaks of LH every 60 90 min (9). With recovery (weight gain), sleep-associated episodic secretion of LH occurs similar to the peripubertal child, and with full recovery the normal pulsatile activity occurs without sleep-associated spikes (9). However, as the GnRH pulse generator recovers, a variety of LH patterns may occur (9). Additional hormone changes of the eating disorders are summarized in Table 1. Low leptin levels have been reported (10, 11). Leptin is a small anorexigenic polypeptide made by many tissues including fat cells and is thought to be a signal to the brain of nutritional status. It also changes rapidly with food restriction. Its administration in nutritionally restricted animals will cause the return of LH pulsatility, and administration of recombinant leptin has led to return of LH pulsatility and ovulation in some patients with hypothalamic amenorrhea (12). Leptin also has a diurnal pattern of secretion, with rising levels during the day and falling at night. Fasting will delay this rise (13, 14). Low basal and pulsatile secretion of leptin has been reported in anorexia nervosa and hypothalamic amenorrhea, and weight gain appears to result in a surge of secretion leading to higher than normal levels (15, 16). However, there is a large variability in levels with overlap with normal. Other neuropeptides Ghrelin, in contrast to leptin, is an orexigenic peptide secreted from the oxyntic cells of the stomach that causes decreased gonadotropin pulsatility in animals and humans (17). It has been found to be elevated in women with disordered eating and amenorrhea (18) and may be a better discriminator of immediate energy availability than leptin (19), which was found to be normal in anorexia whereas ghrelin was elevated.

Peptide YY (PYY), like leptin, is an anorexigenic peptide that is secreted in response to caloric intake and is derived from the gut. It is thought to act at the level of the hypothalamus by binding to the Y2 receptor, causing presynaptic inhibition of neuropeptide Y neurons with resultant stimulation of proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. PYY is low in obesity, and its administration in the rodent decreases food intake (20). Patients with anorexia nervosa have been found to have elevated levels. This may predispose patients with this syndrome to reduce food intake (15). Thus, these neuropeptides secreted by the fat cells, the stomach, and gut, respectively, are most likely interacting signals reflecting nutritional homeostasis as reflected in fat composition and the sum of energy available and in turn appropriateness for reproduction. The neuropeptides are also most likely involved in the regulation of signals reaching the medial central hypothalamus from the arcuate nucleus, the center responsible for the important episodic stimulation of GnRH. This interaction intimately ties metabolic status to reproduction. Both leptin and ghrelin interact with POMC and agouti-related peptide/neuropeptide Y, key peptides in the arcuate nucleus, and appear to modulate food intake. Both POMC and agouti-related peptide send projections into other areas of the hypothalamus, including the lateral hypothalamus and the periventricular nucleus. Thus, there are multiple integrated signals that may be affected with nutritional restriction and may affect other systems such as the skeleton and the reproductive system (21, 22) (Fig. 1). The adrenal axis The suppressed gonadotropin secretion in anorexia is accompanied by low T3, low IGF-I, and high cortisol levels, the latter finding differentiating anorexia nervosa from pituitary insufficiency. Diurnal variation of cortisol is preserved, but at a higher set point as shown in 24-h

J Clin Endocrinol Metab, February 2011, 96(2):333343

jcem.endojournals.org

335

FIG. 1. Adipose tissue- and gut-derived hormones and reproduction. [Reproduced with permission from Budak et al.: Fertil Steril 85:15631581, 2006 (21).] CART, Cocaine and amphetamine-regulated transcript; NPY, neuropeptide Y; AgRP, Agouti-related protein.

studies of cortisol secretion. Elevated cortisol is found in multiple sites including the serum, urine, and saliva (23), and corticotropin-releasing factor (CRH) is elevated in cerebral spinal fluid (24), suggesting a centrally driven mechanism causing the elevated cortisol. However, the ACTH response is inappropriately low and suggests feedback at the pituitary level, whereas failure of dexamethasone to fully suppress cortisol suggests impairment in feedback or an altered set point. Increased secretory bursts and half-life of cortisol have been found and appear to account for the elevated levels (23). At the present time, the balance of evidence suggests that an altered set point occurs with a diurnal variation maintained at a higher level (25). Recent studies suggesting an absence of diurnal variation have infrequent sampling of cortisol (26, 27) and thus may not be accurate. Chronic elevation of cortisol would be expected to be associated with Cushingoid-like features, but this is not the case. However, the weight gain associated with recovery in anorexia is marked by an accumulation of fat in a central (truncal) pattern denoting accumulation of visceral fat and documented by magnetic resonance imaging and dual-energy x-ray absorptiometry (28, 29). In one study, cortisol predicted increases in body fat (30), and cortisol levels may be instrumental in this pattern of fat distribution. Insulin levels are usually normal, but sensitivity may be increased (31, 32).

The GH axis Increased GH levels accompanied by decreased IGF-I suggest an acquired resistance to GH that reverses with refeeding (3335) as well as a reduction in the bioactivity of IGF-I (36). In the starved state, GH shows increased basal secretory rates as well as increased secretory pulses. This appears to be an adaptation to starvation because IGF-I secretion is blocked by the liver and negative feedback is attenuated (33, 34). GH levels are also negatively correlated with markers of nutritional status including body mass index (BMI), fat mass, and leptin (37). The thyroid axis Also typical in anorexia are changes seen with the euthyroid sick syndrome (37). T3 levels are low, whereas rT3 is elevated. In some patients, T4 is also decreased (37, 38). TSH levels are normal or occasionally slightly reduced, suggesting a hypothalamic origin of the suppressed thyroid function. With weight gain, T3 levels rise and rT3 levels fall, and one study showed a correlation with rising metabolic rate suggesting that T3 is involved in controlling metabolic rate (37, 39). Interestingly, anorexia presents with many clinical features of hypothyroidism (bradycardia, hypothermia, delayed ankle reflexes), features that conserve energy. Treatment with thyroid hormone is inappropriate and leads to undesirable weight loss and loss

336

Warren

Endocrine Manifestations of Eating Disorders

J Clin Endocrinol Metab, February 2011, 96(2):333343

of muscle mass (37). It should be noted that in starving patients, a lowered metabolic rate, an increase in cortisol (which stimulates gluconeogenesis and decreases peripheral glucose utilization), and a decrease in gonadotropins (with a loss of fertility) are all appropriate adaptations. The gonadal axis The primary changes in this axis are described under hormonal changes. Secretion of androgens including in particular testosterone is deficient in this syndrome, suggesting that gonadal sources are compromised (40). Although smaller longitudinal studies suggest compromise with improvement in recovery (41), adrenal precursors appear to be normal in large cross-sectional studies (40, 42). Low estradiol levels are also seen in anorexia due to a lack of ovarian stimulation. However, estrogen metabolism is also altered. Estradiol, which normally undergoes 16 -hydroxylation, is channeled to 2-hydroxylation and the formation of a catechol estrogen (2-hydroxyestrone) in the undernourished state (43). This compound has no intrinsic biological activity and acts as an antiestrogen. Thus, the very low estrogen levels seen in anorexia are compounded by an endogenously produced antiestrogen. The lack of adipose tissue may also contribute to the hypoestrogenic state by limiting the extraovarian sources of estrogen because fat converts androstenedione to estrone and testosterone to estradiol. Adipose tissue Most studies have also noted increased levels of adiponectin in anorexia nervosa (44), which appears to be inversely related to BMI. The increase in this adipokine may be related to the increased insulin sensitivity seen in anorexia. Although some studies report normal or increased insulin sensitivity and some report normal insulin

sensitivity, they may be explained by different methodologies. For example, when homeostasis model of assessment for insulin resistance is examined under basal conditions, increased insulin sensitivity (31, 45) is demonstrated, whereas use of the euglycemic hyperinsulinemic clamp technique shows decreased (46) or normal insulin sensitivity (32, 47). SHBG is high, perhaps related to the insulin sensitivity, and appears to be a marker of nutritional recovery (48, 49). Another adipokine affecting fuel homeostasis and insulin action is resistin, which is decreased in some studies on anorexia (32) although its role in fuel homeostasis is unclear. Bone Osteoporosis is a leading and severe complication of anorexia nervosa. Most of the endocrinopathies described above likely contribute to the bone loss including low T3, estradiol, testosterone, IGF-I, high cortisol, and various neuropeptides. In addition, it has recently been recognized that bone is a highly metabolically active tissue requiring energy (50), and the process of forming new bone is appropriately suppressed in situations where nutritional status is compromised. Mechanisms that link bone formation to the adipose cells have recently been recognized and open new vistas to the understanding and treatment of bone loss. In addition, the skeleton itself interacts with body weight, has feedback from energy expenditure, and is involved in glucose homeostasis. In summary, the etiology of the low bone mass in anorexia nervosa is multifactorial (51), reflecting endocrine dysfunction in several areas (52) (Fig. 2). Osteopenia, or low bone mass, and osteoporosis are among the most severe and common complications of anorexia nervosa (5355) and are associated with fragility fractures, even in the young population where this condi-

FIG. 2. Hormonal adaptation in anorexia nervosa. [Reproduced with permission from Jayasinghe et al.: BJOG 115:304 315, 2008 (52).] FLI, Free leptin index; sOB-r soluble leptin receptor; IGFBP1&2, IGF-binding protein 1 and 2.

J Clin Endocrinol Metab, February 2011, 96(2):333343

jcem.endojournals.org

337

PTH levels are also generally normal, suggesting that the impressive bone loss seen in anorexia is not due to deficiencies in vitamin D and a secondary hyperparathyroidism (71, 72). Androgens, which also have an anabolic effect on bone, are also known to be depressed in anorexia nervosa. However, a 1-yr randomized study of oral dehydroepiandrosterone did not demonstrate significant effect of treatment (73). A 3-wk study with testosterone administration also did not have FIG. 3. Mean ( SD) changes in osteocalcin and urine N- telopeptide (NTX) concentrations consistent effects on bone, but mood from admission for treatment of anorexia nervosa until recovery of 90% of ideal body weight was improved (74). (IBW) for subjects who regained menses and subjects who remained amenorrheic. Bold lines represent 2 SD values from the mean osteocalcin (a marker of formation) value of 6.20 Cortisol excess may also affect bone 1.90 ng/ml and mean NTX (a marker of resorption) value of 37.00 6.00 nmol/mmol loss by inhibiting bone formation. Markcreatinine (Cr) for reference control subjects. (reference controls; L. Audi, personal ers of bone formation are inversely corcommunication, 23 November 2004). [Adapted from J. Dominguez et al.: Am J Clin Nutr 86: 9299, 2007 (8).] related with cortisol levels as well as spine bone mineral density (BMD) (23). tion generally surfaces (56). The cumulative risk of fracRecently, it has been suggested that a bone-adipose axis ture is 57% for a follow-up of 40 yr after diagnosis (57), exists and that various adipokines such as leptin, adiand microarchitecture is abnormal (58). Bone mass may ponectin, and resistin may be involved in bone physiology not fully return to normal levels even with weight gain, (51, 75). In addition, the skeleton itself may have effects on calcium supplementation, and hormonal therapy. Young body weight control and glucose homeostasis and is a regpatients most likely never reach their optimal peak bone ulator of energy balance (50, 75). Leptin, which is found mass, which puts them at risk for severe osteoporosis later in adipose tissue, is low in anorexia (17, 37) and has been in life (59). Severe complications such as collapse of the found to have contradictory effects on bone (37, 50, 76 femoral head and hip fracture and other fractures have 78). However, in a study of patients with hypothalamic been reported at a young age (60 65). amenorrhea given recombinant leptin, an increase in osConsiderable confusion in the pathogenesis of bone teocalcin (a marker of bone formation) was seen (12). loss in anorexia nervosa has led to the widespread belief that estrogen replacement will prevent bone loss. Multiple Adiponectin (which is elevated in anorexia) is thought to randomized studies have shown, however, that neither indirectly affect induction of osteoclast formation via reestrogen replacement nor oral contraceptive therapy is ef- ceptor activator for nuclear factor B ligand stimulation fective and, in fact, bone loss and fractures may continue and inhibition of osteoprotegerin production in osteoblasts, although human studies are very preliminary (32). in treated women (66, 67). These observations would suggest that estrogen defi- Resistin, which is low in anorexia (32), is thought to stimciency alone cannot explain the skeletal findings in an- ulate osteoclasts and osteoblastic proliferation, although orexia nervosa. In the pure hypoestrogenic model, both its effect in humans is unclear. The role of leptin in regulation of bone mass is unclear formation and resorption of bone increase. In contrast, anbut probably involves peripheral secretion signaling hyorexia has been associated with an uncoupling of markers of bone turnover and with a suppression of bone formation that pothalamic neurons and ultimately a hypothalamic relay reverses with refeeding. This appears to be the dominant involving the sympathetic nervous system, which suggests mechanism (68). Bone resorption on the other hand is in- that feedback systems exist that are sensitive to energy creased and does not normalize until menses return, associ- demands (50, 51, 76). In this system, leptin stimulates the 2-adrenegic receptor in bone, decreasing osteoblast proated with endogenous estrogen secretion (8) (Fig. 3). However, it is possible that the restoration of menses is associated liferation and bone formation (76). Another possible role with improvement in the secretion of other important neu- of leptin is mediated through activation of cocaine amphetamine-regulated transcript neurons expressed in the ropeptides that may positively affect bone mass. Vitamin D levels in anorexia are generally normal, as is hypothalamus, which appear to inhibit bone loss (79, 80). the vitamin D binding protein (69), although the serum Thus, several systems may be involved in the cross-regubinding capacity was diminished in a small study (70). lation of bone and energy, and because the data are highly

338

Warren

Endocrine Manifestations of Eating Disorders

J Clin Endocrinol Metab, February 2011, 96(2):333343

preliminary, the exact dysfunction in anorexia nervosa is not understood. In addition to the bone-adipose tissue connection is a gut-skeleton connection with serotonin as an important mediator (81). The fact that energy requirements involving neuropeptides are key regulators in both the skeleton and the gut suggests that these systems may be interconnected. Gastrointestinal peptides The gut appears to be an important source of neuropeptide signals. The cells that secrete these signals include the L cells in the small intestine and colon that secrete peptides such as glucagon-like peptide 1 and PYY, which has been associated with low bone density in anorexia (20, 44, 82). Ghrelin, which is elevated in anorexia, is secreted from the stomach, which at present has no known effect on the skeleton (50). Noteworthy is that these peptides travel to the brain to control metabolism and food intake, suggesting that the brain uses these peripheral signals to measure nutritional status, energy intake, and energy needs. Receptors for these peptides are present in the hypothalamus and the hindbrain, and the arcuate nucleus appears to behave as a control center. The signals for normal GnRH pulsatility also emanate from the arcuate nucleus, integrating nutrition and reproduction. Treatment In terms of treatment, the most significant predictor of recovery as measured by return of menses is the BMI (22). For underweight subjects, nutritional counseling is paramount with psychological or psychiatric therapy if eating disorders are present. Increases in BMI are accompanied by increases in bone density (12, 58). Thus, reestablishing a normal weight is the first aim in recovery, although normalization of BMD may not occur. With refeeding, parameters of bone turnover return rapidly to normal. The effects of weight gain are robust and to date no pharmacological intervention has approached the improvement seen with refeeding (83). In a controlled hospital environment, increases of 3 to 4% in BMD have been seen in as little as 3 months (8). Numerous pharmacological interventions have been tried. Some have shown a small effect. In some cases, intervention has been questioned because of the possible suppression of bone formation. Interventions have included dehydroepiandrosterone (73) and testosterone replacement (74), oral contraceptives (84), bisphosphonates (85, 86), and IGF-I (87). The bisphosphonates are relatively contraindicated because of their long half-life in the bone but may be used with caution in compassionate situations when low bone mass is associated with fragility fractures and refeeding is not feasible. These compounds are labeled category C be-

cause of toxic effects in pregnant rats (88, 89). Young women may eventually recover their reproductive potential and become pregnant and may put a developing fetus at risk if these compounds leach from bone. The GH resistance noted in anorexia may have direct or indirect effects (via IGF-I) on bone. In a randomized study of women with anorexia nervosa, the administration of recombinant IGF-I had a small bone-sparing effect, and the within-group change was positive only in combination with an oral contraceptive (87). Nutritional restriction, particularly protein restriction, may be minimizing the powerful anabolic effects of IGF-I on bone (90). Animals deprived of protein show a rapid fall in IGF-I, which is accompanied by a decrease in osteocalcin. This effect is not reversed by the exogenous administration of IGF-I/IGF binding protein 3, indicating resistance in the face of protein deficiency (91). In fact, with presently available pharmacological interventions, the literature suggests that fractures and bone loss may continue in the face of weight loss or poor nutrition (56, 62, 67, 84, 92, 93).

Bulimia
Bulimia, or bulimia nervosa, is an eating disorder marked by recurrent episodes of binge eating that may be followed by restrictive eating and inappropriate behavior to prevent weight gain (self-induced vomiting, laxatives, diuretics, and/or excessive exercise). This syndrome is also marked by a lack of impulse control, impulsive behavior, alcohol or drug use, promiscuity, and stealing or shoplifting. Anorectic behavior often precedes bulimia and may determine the presence of endocrine findings. The prevalence of bulimia is 11.5% of the population. Bulimia is more common in men than anorexia, but like anorexia the majority of patients are women with an incidence of 2% in community-based samples and 4 13% in college-aged groups (3). Patients tend to be older than those with anorexia nervosa, usually between 17 and 25 yr of age. Patients with bulimia nervosa are sometimes classified as having the purging or nonpurging type, with the latter being less severe and the former having more psychiatric comorbidity, more metabolic disturbances, and lower weight. Depression is also common. Often the bulimic behavior evolves from the completely restricting anorexia nervosa. Weight fluctuates but is generally not at low levels, but metabolic issues cause serious health problems. Bulimics have a wide variety of medical problems including tooth decay, parotid enlargement, carpopedal spasm, stomach rupture, metabolic alkalosis, hypercarotenemia, hypokalemia, and pancreatitis. Bulimia has not been studied as extensively as anorexia and because the weight may remain within a reasonable

J Clin Endocrinol Metab, February 2011, 96(2):333343

jcem.endojournals.org

339

range, this type of problem is often difficult to diagnose. Multiple neuroendocrine abnormalities exist but are less pronounced than in anorexia. Bulimic patients may present with menstrual irregularity, but the incidence is highly variable (94 97), ranging from 37 to 64%, with amenorrhea occurring in 5 40% (94, 95, 98). This variability may be due to the fact that patients have adequate estrogen secretion and present with an anovulatory syndrome and irregular bleeding. With a preceding history of anorexia, however, the incidence of amenorrhea is much higher (77%) (98). The menstrual disorder and amenorrhea may also develop when weight is within a reasonable range. Because bulimic behavior is often secretive, patients will often not admit to this behavior, even when questioned directly (94). Eventually the protein calorie malnutrition and the metabolic problems may make the diagnosis obvious. However, laboratory values may remain normal, and these should not be relied upon to make a diagnosis. Risk factors for the development of menstrual dysfunction include the lowest reported BMI, a history of anorexia, or weight loss. More subtle associations include low calorie and dietary fat intake, frequent vomiting or binge eating, increased exercise, and low T4 levels (95, 9799). The menstrual irregularity may persist with fluctuations in body weight, depression, and smoking suggesting a metabolic stress on the hypothalamic-pituitary-ovarian axis (96). Low LH and FSH levels along with low estradiol levels have been found in normal-weight women with bulimia nervosa as well as reduced LH patterns over a 24-h period (100). Another interesting observation is the association of an abnormal polycystic ovarian morphology and bulimia, which is seen with high frequency (76 100%) (97). Criteria for polycystic ovarian morphology in these studies have used the Adams criteria (more than 10 follicles measuring 2 6 cm) (101), which is more liberal than the Rotterdam criteria (12 follicles measuring 29 mm and an ovarian volume of 10 ml) (102). Patients with PCOS may also have a high frequency of bulimia (6%) (103106), although standard criteria for PCOS were not used and further work is needed. In a 9-yr follow-up of eight patients with bulimia, polycystic ovary morphology was seen at baseline in seven of nine patients. Five patients who were still bulimic continued to show polycystic ovary morphology by the Adams criteria, whereas three who had resolution of their bulimia had normal ovarian morphology (107). This is the first report of resolution of this morphology. It also suggests that binge eating may lead to abnormal insulin secretion and ovarian morphology (105). Hyperinsulinemia has been described in controlled experiments in normal women submitted to binge eating (108). PCOS may also lead in turn to bulimia by increasing insulin levels (97). Other axes besides the hypothalamic-pituitary-ovarian have been found to be affected. The hypothalamic-pitu-

itary-thyroidal axis is also abnormal. Bulimia nervosa has been associated with a decreased resting metabolic rate, which has been attributed to lower T3 levels. There is a delayed peak and blunted response of thyrotropin-releasing hormone (TRH) to TSH. However, the data are conflicting, and others have noted normal thyroid indices and responses to TRH (109). One carefully done study examined bulimics at baseline and after 3 wk of abstinence from bulimic behavior. T3 levels were normal at baseline but were significantly lower than matched controls. After abstinence, there was a decline in T3 and T4 levels and an increase in TSH. This suggests that the metabolic rate may be higher during bingeing episodes due to the higher thyroid indices and the indices fall when bingeing is absent, perhaps due to the low caloric intake of bulimics when not bingeing. Other studies have shown a lower resting metabolic rate and T3 levels after abstinence. Interestingly, low T4 levels have been associated with poor outcome in bulimics (110). The hypothalamic-pituitary-adrenal (HPA) axis also shows dysregulation, and because satiety appears to be abnormal, the neurotransmitters involved in food intake and satiety have been the focus of research. In particular, the limbic-HPA axis appears to play an important role in hunger and satiety signaling. Both normal and increased circadian secretion of cortisol has been reported in bulimia nervosa. A recent study of eight bulimics with 3 wk of abstinence from purging or overeating showed decreased HPA activity with lower cortisol levels between 0600 and 1400 h and hyperreactivity to CRH (111). The heterogeneous results published in the literature may relate in part to whether the subjects are studied during an active bingeing interval or after a significant time of abstinence from this behavior. Morphological changes have also been reported, including increased visceral fat and adrenal gland volume (112). Bulimia is associated with decreased leptin (113). In normal subjects, binge eating drastically alters the diurnal secretion of leptin, leading to a progressive and lower than normal fall in leptin during the day and a delay in the nocturnal rise in leptin after the evening meal. Associated with this change in leptin dynamics is an exaggerated insulin secretion and an increase in fasting glucose (108). As would be expected when leptin levels are decreased, ghrelin is increased in bulimia nervosa, with responses to ghrelin injection being fairly normal (114). Unlike anorexia nervosa where ghrelin injection causes a decrease in GH, bulimia is marked by a normal increase in GH, prolactin, ACTH, cortisol, and glucose, with a decrease in insulin and increases in appetite and food intake. Bone density is also altered in bulimia, but this appears to be determined primarily by the presence of previous anorexia (115).

340

Warren

Endocrine Manifestations of Eating Disorders

J Clin Endocrinol Metab, February 2011, 96(2):333343

Eating Disorders Not Otherwise Specified (EDNOS)

EDNOS have not been extensively studied but may appear more frequently in females with menstrual dysfunction than realized (116 118). This group includes those patients whose weight has not fallen to less than 85% of ideal body weight, women with a short interval of amenorrhea (less than 3 months), patients who purge regularly without bingeing or vice versa, and some patients who present the female athletic triad (disordered eating, amenorrhea, and osteoporosis). In particular, athletic women without eating disorders are often noted to report abnormal eating behavior that cannot be categorized as anorexia or bulimia but may have characteristics of both. Patients with all of the characteristics of anorexia nervosa and normal menses may also fall into this category. Disciplines where it is advantageous to be thin present particular risk, and some endocrine changes seen in anorexia are reported. A hypoestrogenic hypothalamic amenorrhea may develop with normal to low gonadotropins. Twenty-four-hour secretion of gonadotropins is altered with decreased pulses of LH and FSH. The underlying etiology is a chronic negative caloric balance. Findings specific to women with the female athletic triad include low T3 levels and an increase in reverse T3. IGF-I levels may be low. Cortisol levels are higher than matched controls, and leptin is low whereas ghrelin is high, although there is much overlap (17, 19, 116, 119, 120). PYY elevation has also been associated with amenorrhea (121). Bone density may also be affected and show lower than normal levels. Fractures, particularly stress fractures, are a significant problem (122). Some reversal of the bone loss occurs with return of menses, but similar to anorexia nervosa, the use of hormone replacement does not guarantee a bone-sparing effect and may mask an important indicator of recovery. Although the use of oral contraceptives or hormones is commonly prescribed, the emerging evidence indicates that fractures may continue, and the problem is not due to hypoestrogenism but is mainly a nutritional issue (8, 93, 123126). In fact, normal women put on an experimental protocol of exercise and food restriction were found to have rapid effects on indices of bone formation (within 5 d) and, if the restriction is severe enough, on bone resorption (127). These experiments show that the skeleton is exquisitely sensitive to nutritional restriction. Eating disorders present with extensive hormonal dysfunctions that appear to give an unusual insight on the bodys metabolic adjustments to food restriction and negative energy balance. In the case of bulimia, they also suggest that prolonged abnormal eating patterns may induce metabolic alterations possibly associated with chronically

induced hyperinsulinemia. These syndromes are unfortunate, but unique metabolic aberrations associated with eating disorders may provide keys to understanding the neuroendocrine control of weight loss, reproduction, and nutritionally induced osteoporosis. At present, the most effective treatment to prevent bone loss and fractures is nutritional rehabilitation and normalization of aberrant eating patterns.

Acknowledgments
Address all correspondence and requests for reprints to: Michelle P. Warren, M.D., 622 West 168th Street, PH 16-128, New York, New York 10032. E-mail: mpw1@columbia.edu. Disclosure Summary: M.P.W. received honorarium, consultancy fee, educational grant, and research support from Wyeth, and Wyeth activities include Advisory Board, speaker, and research; received consultancy fee from Pfizer; received speaker honorarium from Merck and Amgen; received consultancy fee from Depomed; received consultancy fee and consulted for Barr Laboratories; received consultancy fee and consulted for Bradley Pharmaceuticals; received speaker honorarium and clinical trial support from Novartis; received speaker honorarium from Novo Nordisk; received clinical trial support from Solvay Pharmaceuticals; received speaker honorarium from Upsher Smith; received speaker honorarium, consultancy fee, and consulted for Warner Chilcott; received consultancy fee and consulted for QuatRx; received consultancy fee and consulted for Council on Menopause Management; received royalty from Wolters Kluwer; received clinical trial support from Ferring Pharmaceuticals; received consultancy fee from and is member of Advisory Board for Yoplait; received consultancy fee and gave expert review for Medical Malpractice Insurance Pool.

References
1. Warren MP 1985 Anorexia nervosa and related eating disorders. Clin Obstet Gynecol 28:588 597 2. Klein DA, Walsh BT 2003 Eating disorders. Int Rev Psychiatry 15:205216 3. Warren MP 1993 Anorexia and bulimia. In: Sciarra JJ, ed. Gynecology and obstetrics. Philadelphia: Lippincott; 115 4. Psychiatric AA 2000 Diagnostic and statistical manual of mental disorders, text revision (DSM-IV-TR). 4th ed. Washington, DC: American Psychiatric Association 5. Warren MP 1999 Health issues for women athletes: exercise-induced amenorrhea. J Clin Endocrinol Metab 84:18921896 6. Attia E, Roberto CA 2009 Should amenorrhea be a diagnostic criterion for anorexia nervosa? Int J Eat Disord 42:581589 7. Golden NH, Jacobson MS, Schebendach J, Solanto MV, Hertz SM, Shenker IR 1997 Resumption of menses in anorexia nervosa. Arch Pediatr Adolesc Med 151:16 21 8. Dominguez J, Goodman L, Sen Gupta S, Mayer L, Etu SF, Walsh BT, Wang J, Pierson R, Warren MP 2007 Treatment of anorexia nervosa is associated with increases in bone mineral density, and recovery is a biphasic process involving both nutrition and return of menses. Am J Clin Nutr 86:9299

J Clin Endocrinol Metab, February 2011, 96(2):333343

jcem.endojournals.org

341

9. Boyar RM, Katz J, Finkelstein JW, Kapen S, Weiner H, Weitzman ED, Hellman L 1974 Anorexia nervosa. Immaturity of the 24-hour luteinizing hormone secretory pattern. N Engl J Med 291:861 865 10. Kopp W, Blum WF, von Prittwitz S, Ziegler A, Lubbert H, Emons G, Herzog W, Herpertz S, Deter HC, Remschmidt H, Hebebrand J 1997 Low leptin levels predict amenorrhea in underweight and eating disordered females. Mol Psychiatry 2:335340 11. Hebebrand J, Muller TD, Holtkamp K, Herpertz-Dahlmann B 2007 The role of leptin in anorexia nervosa: clinical implications. Mol Psychiatry 12:2335 12. Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS 2004 Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 351:987997 13. Elimam A, Marcus C 2002 Meal timing, fasting and glucocorticoids interplay in serum leptin concentrations and diurnal profile. Eur J Endocrinol 147:181188 14. Schoeller DA, Cella LK, Sinha MK, Caro JF 1997 Entrainment of the diurnal rhythm of plasma leptin to meal timing. J Clin Invest 100:18821887 15. Hebebrand J, Blum WF, Barth N, Coners H, Englaro P, Juul A, Ziegler A, Warnke A, Rascher W, Remschmidt H 1997 Leptin levels in patients with anorexia nervosa are reduced in the acute stage and elevated upon short-term weight restoration. Mol Psychiatry 2:330 334 16. Misra M, Miller KK, Kuo K, Griffin K, Stewart V, Hunter E, Herzog DB, Klibanski A 2005 Secretory dynamics of leptin in adolescent girls with anorexia nervosa and healthy adolescents. Am J Physiol Endocrinol Metab 289:E373E381 17. Christo K, Cord J, Mendes N, Miller KK, Goldstein MA, Klibanski A, Misra M 2008 Acylated ghrelin and leptin in adolescent athletes with amenorrhea, eumenorrheic athletes and controls: a cross-sectional study. Clin Endocrinol (Oxf) 69:628 633 18. Misra M, Miller KK, Kuo K, Griffin K, Stewart V, Hunter E, Herzog DB, Klibanski A 2005 Secretory dynamics of ghrelin in adolescent girls with anorexia nervosa and healthy adolescents. Am J Physiol Endocrinol Metab 289:E347E356 19. Schneider LF, Warren MP 2006 Functional hypothalamic amenorrhea is associated with elevated ghrelin and disordered eating. Fertil Steril 86:1744 1749 20. Misra M, Miller KK, Tsai P, Gallagher K, Lin A, Lee N, Herzog DB, Klibanski A 2006 Elevated peptide YY levels in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab 91:10271033 21. Budak E, Fernandez Sanchez M, Bellver J, Cervero A, Simon C, Pellicer A 2006 Interactions of the hormones leptin, ghrelin, adiponectin, resistin, and PYY336 with the reproductive system. Fertil Steril 85:15631581 22. Badman MK, Flier JS 2007 The adipocyte as an active participant in energy balance and metabolism. Gastroenterology 132:2103 2115 23. Misra M, Miller KK, Almazan C, Ramaswamy K, Lapcharoensap W, Worley M, Neubauer G, Herzog DB, Klibanski A 2004 Alterations in cortisol secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab 89:4972 4980 24. Hotta M, Shibasaki T, Masuda A, Imaki T, Demura H, Ling N, Shizume K 1986 The responses of plasma adrenocorticotropin and cortisol to corticotropin-releasing hormone (CRH) and cerebrospinal fluid immunoreactive CRH in anorexia nervosa patients. J Clin Endocrinol Metab 62:319 324 25. Boyar RM, Hellman LD, Roffwarg H, Katz J, Zumoff B, OConnor J, Bradlow HL, Fukushima DK 1977 Cortisol secretion and metabolism in anorexia nervosa. N Engl J Med 296:190 193 26. dos Santos E, dos Santos JE, Ribeiro RP, Rosa E Silva AC, Moreira AC, Silva de Sa MF 2007 Absence of circadian salivary cortisol rhythm in women with anorexia nervosa. J Pediatr Adolesc Gynecol 20:1318 27. Putignano P, Dubini A, Toja P, Invitti C, Bonfanti S, Redaelli G, Zappulli D, Cavagnini F 2001 Salivary cortisol measurement in

28.

29.

30.

31.

32.

33.

34.

35.

36.

37. 38.

39.

40.

41.

42.

43. 44.

45.

normal-weight, obese and anorexic women: comparison with plasma cortisol. Eur J Endocrinol 145:165171 Mayer L, Walsh BT, Pierson Jr RN, Heymsfield SB, Gallagher D, Wang J, Parides MK, Leibel RL, Warren MP, Killory E, Glasofer D 2005 Body fat redistribution after weight gain in women with anorexia nervosa. Am J Clin Nutr 81:1286 1291 Misra M, Soyka LA, Miller KK, Grinspoon S, Levitsky LL, Klibanski A 2003 Regional body composition in adolescents with anorexia nervosa and changes with weight recovery. Am J Clin Nutr 77:13611367 Misra M, Prabhakaran R, Miller KK, Tsai P, Lin A, Lee N, Herzog DB, Klibanski A 2006 Role of cortisol in menstrual recovery in adolescent girls with anorexia nervosa. Pediatr Res 59:598 603 Karczewska-Kupczewska M, Straczkowski M, Adamska A, Nikoajuk A, Otziomek E, Gorska M, Kowalska I 2010 Insulin sensitivity, metabolic flexibility, and serum adiponectin concentration in women with anorexia nervosa. Metabolism 59:473 477 Dostalova I, Smitka K, Papezova H, Kvasnickova H, Nedvdkova J 2007 Increased insulin sensitivity in patients with anorexia nervosa: the role of adipocytokines. Physiol Res 56:587594 Misra M, Miller KK, Bjornson J, Hackman A, Aggarwal A, Chung J, Ott M, Herzog DB, Johnson ML, Klibanski A 2003 Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab 88:56155623 Stving RK, Veldhuis JD, Flyvbjerg A, Vinten J, Hangaard J, Koldkjaer OG, Kristiansen J, Hagen C 1999 Jointly amplified basal and pulsatile growth hormone (GH) secretion and increased process irregularity in women with anorexia nervosa: indirect evidence for disruption of feedback regulation within the GH-insulin-like growth factor I axis. J Clin Endocrinol Metab 84:2056 2063 Golden NH, Kreitzer P, Jacobson MS, Chasalow FI, Schebendach J, Freedman SM, Shenker IR 1994 Disturbances in growth hormone secretion and action in adolescents with anorexia nervosa. J Pediatr 125:655 660 Stving RK, Chen JW, Glintborg D, Brixen K, Flyvbjerg A, Hrder K, Frystyk J 2007 Bioactive insulin-like growth factor (IGF) I and IGF-binding protein-1 in anorexia nervosa. J Clin Endocrinol Metab 92:23232329 Lawson EA, Klibanski A 2008 Endocrine abnormalities in anorexia nervosa. Nat Clin Pract Endocrinol Metab 4:407 414 Croxson MS, Ibbertson HK 1977 Low serum triiodothyronine (T3) and hypothyroidism in anorexia nervosa. J Clin Endocrinol Metab 44:167174 Leslie RD, Isaacs AJ, Gomez J, Raggatt PR, Bayliss R 1978 Hypothalamo-pituitary-thyroid function in anorexia nervosa: influence of weight gain. Br Med J 2:526 528 Miller KK, Lawson EA, Mathur V, Wexler TL, Meenaghan E, Misra M, Herzog DB, Klibanski A 2007 Androgens in women with anorexia nervosa and normal-weight women with hypothalamic amenorrhea. J Clin Endocrinol Metab 92:1334 1339 Zumoff B, Walsh BT, Katz JL, Levin J, Rosenfeld RS, Kream J, Weiner H 1983 Subnormal plasma dehydroisoandrosterone to cortisol ratio in anorexia nervosa: a second hormonal parameter of ontogenic regression. J Clin Endocrinol Metab 56:668 672 Estour B, Germain N, Diconne E, Frere D, Cottet-Emard JM, Carrot G, Lang F, Galusca B 2010 Hormonal profile heterogeneity and short-term physical risk in restrictive anorexia nervosa. J Clin Endocrinol Metab 95:22032210 Warren MP 1983 Effects of undernutrition on reproductive function in the human. Endocr Rev 4:363377 Rosen CJ, Klibanski A 2009 Bone, fat, and body composition: evolving concepts in the pathogenesis of osteoporosis. Am J Med 122:409 414 Fukushima M, Nakai Y, Taniguchi A, Imura H, Nagata I, Tokuyama K 1993 Insulin sensitivity, insulin secretion, and glucose effectiveness in anorexia nervosa: a minimal model analysis. Metabolism 42:1164 1168

342

Warren

Endocrine Manifestations of Eating Disorders

J Clin Endocrinol Metab, February 2011, 96(2):333343

46. Pannacciulli N, Vettor R, Milan G, Granzotto M, Catucci A, Federspil G, De Giacomo P, Giorgino R, De Pergola G 2003 Anorexia nervosa is characterized by increased adiponectin plasma levels and reduced nonoxidative glucose metabolism. J Clin Endocrinol Metab 88:1748 1752 47. Castillo M, Scheen A, Lefebvre PJ, Luyckx AS 1985 Insulin-stimulated glucose disposal is not increased in anorexia nervosa. J Clin Endocrinol Metab 60:311314 48. Estour B, Pugeat M, Lang F, Dechaud H, Pellet J, Rousset H 1986 Sex hormone binding globulin in women with anorexia nervosa. Clin Endocrinol (Oxf) 24:571576 49. Barbe P, Bennet A, Stebenet M, Perret B, Louvet JP 1993 Sexhormone-binding globulin and protein-energy malnutrition indexes as indicators of nutritional status in women with anorexia nervosa. Am J Clin Nutr 57:319 322 50. Confavreux CB, Levine RL, Karsenty G 2009 A paradigm of integrative physiology, the crosstalk between bone and energy metabolisms. Mol Cell Endocrinol 310:2129 51. Gomez-Ambrosi J, Rodrguez A, Catalan V, Fruhbeck G 2008 The bone-adipose axis in obesity and weight loss. Obes Surg 18:1134 1143 52. Jayasinghe Y, Grover SR, Zacharin M 2008 Current concepts in bone and reproductive health in adolescents with anorexia nervosa. BJOG 115:304 315 53. Miller KK, Grinspoon SK, Ciampa J, Hier J, Herzog D, Klibanski A 2005 Medical findings in outpatients with anorexia nervosa. Arch Intern Med 165:561566 54. Miller KK, Lee EE, Lawson EA, Misra M, Minihan J, Grinspoon SK, Gleysteen S, Mickley D, Herzog D, Klibanski A 2006 Determinants of skeletal loss and recovery in anorexia nervosa. J Clin Endocrinol Metab 91:29312937 55. Grinspoon S, Miller K, Coyle C, Krempin J, Armstrong C, Pitts S, Herzog D, Klibanski A 1999 Severity of osteopenia in estrogendeficient women with anorexia nervosa and hypothalamic amenorrhea. J Clin Endocrinol Metab 84:2049 2055 56. Cohen A, Fleischer J, Freeby MJ, McMahon DJ, Irani D, Shane E 2009 Clinical characteristics and medication use among premenopausal women with osteoporosis and low BMD: the experience of an osteoporosis referral center. J Womens Health (Larchmt) 18:79 84 57. Lucas AR, Melton 3rd LJ, Crowson CS, OFallon WM 1999 Longterm fracture risk among women with anorexia nervosa: a population-based cohort study. Mayo Clin Proc 74:972977 58. Lawson EA, Miller KK, Bredella MA, Phan C, Misra M, Meenaghan E, Rosenblum L, Donoho D, Gupta R, Klibanski A 2010 Hormone predictors of abnormal bone microarchitecture in women with anorexia nervosa. Bone 46:458 463 59. Soyka LA, Misra M, Frenchman A, Miller KK, Grinspoon S, Schoenfeld DA, Klibanski A 2002 Abnormal bone mineral accrual in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab 87:4177 4185 60. Raymond CA 1987 Long-term sequelae pondered in anorexia nervosa. JAMA 257:3324 3325 61. Vestergaard P, Emborg C, Stving RK, Hagen C, Mosekilde L, Brixen K 2002 Fractures in patients with anorexia nervosa, bulimia nervosa, and other eating disordersa nationwide register study. Int J Eat Disord 32:301308 62. Warren MP, Shane E, Lee MJ, Lindsay R, Dempster DW, Warren LF, Hamilton WG 1990 Femoral head collapse associated with anorexia nervosa in a 20-year-old ballet dancer. Clin Orthop Relat Res 251:171176 63. Rigotti NA, Neer RM, Skates SJ, Herzog DB, Nussbaum SR 1991 The clinical course of osteoporosis in anorexia nervosa. A longitudinal study of cortical bone mass. JAMA 265:11331138 64. Kaplan FS, Pertschuk M, Fallon M, Haddad J 1986 Osteoporosis and hip fracture in a young woman with anorexia nervosa. Clin Orthop Relat Res 212:250 254 65. Hay PJ, Hall A, Delahunt JW, Harper G, Mitchell AW, Salmond C

66. 67.

68.

69.

70.

71. 72. 73.

74.

75. 76. 77. 78.

79.

80.

81. 82.

83.

84.

85.

86.

1989 Investigation of osteopaenia in anorexia nervosa. Aust N Z J Psychiatry 23:261268 Levine RL 2002 Endocrine aspects of eating disorders in adolescents. Adolesc Med 13:129 143, vii Sim LA, McGovern L, Elamin MB, Swiglo BA, Erwin PJ, Montori VM 2010 Effect on bone health of estrogen preparations in premenopausal women with anorexia nervosa: a systematic review and meta-analyses. Int J Eat Disord 43:218 225 Hotta M, Fukuda I, Sato K, Hizuka N, Shibasaki T, Takano K 2000 The relationship between bone turnover and body weight, serum insulin-like growth factor (IGF) I, and serum IGF-binding protein levels in patients with anorexia nervosa. J Clin Endocrinol Metab 85:200 206 Haagensen AL, Feldman HA, Ringelheim J, Gordon CM 2008 Low prevalence of vitamin D deficiency among adolescents with anorexia nervosa. Osteoporos Int 19:289 294 Olmos JM, Riancho JA, Amado JA, Freijanes J, Menendez-Arango J, Gonzalez-Macas J 1991 Vitamin D metabolism and serum bind ing proteins in anorexia nervosa. Bone 12:43 46 Rigotti NA, Nussbaum SR, Herzog DB, Neer RM 1984 Osteoporosis in women with anorexia nervosa. N Engl J Med 311:16011606 Carmichael KA, Carmichael DH 1995 Bone metabolism and osteopenia in eating disorders. Medicine (Baltimore) 74:254 267 Gordon CM, Grace E, Emans SJ, Feldman HA, Goodman E, Becker KA, Rosen CJ, Gundberg CM, LeBoff MS 2002 Effects of oral dehydroepiandrosterone on bone density in young women with anorexia nervosa: a randomized trial. J Clin Endocrinol Metab 87:4935 4941 Miller KK, Grieco KA, Klibanski A 2005 Testosterone administration in women with anorexia nervosa. J Clin Endocrinol Metab 90:1428 1433 Karsenty G 2006 Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab 4:341348 Wolf G 2008 Energy regulation by the skeleton. Nutr Rev 66:229 233 Lee NK, Karsenty G 2008 Reciprocal regulation of bone and energy metabolism. Trends Endocrinol Metab 19:161166 Cirmanova V, Bayer M, Starka L, Zajckova K 2008 The effect of leptin on bone: an evolving concept of action. Physiol Res 57(Suppl 1):S143S151 Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M, Clement K, Vaisse C, Karsenty G 2005 Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434:514 520 Singh MK, Elefteriou F, Karsenty G 2008 Cocaine and amphetamine-regulated transcript may regulate bone remodeling as a circulating molecule. Endocrinology 149:39333941 Oury F, Karsenty G 2009 [Intestinal serotonin and regulation of bone mass]. Med Sci (Paris) 25:445 446 Utz AL, Lawson EA, Misra M, Mickley D, Gleysteen S, Herzog DB, Klibanski A, Miller KK 2008 Peptide YY (PYY) levels and bone mineral density (BMD) in women with anorexia nervosa. Bone 43:135139 Hotta M, Shibasaki T, Sato K, Demura H 1998 The importance of body weight history in the occurrence and recovery of osteoporosis in patients with anorexia nervosa: evaluation by dual x-ray absorptiometry and bone metabolic markers. Eur J Endocrinol 139: 276 283 Liu SL, Lebrun CM 2006 Effect of oral contraceptives and hormone replacement therapy on bone mineral density in premenopausal and perimenopausal women: a systematic review. Br J Sports Med 40:1124 Miller KK, Grieco KA, Mulder J, Grinspoon S, Mickley D, Yehezkel R, Herzog DB, Klibanski A 2004 Effects of risedronate on bone density in anorexia nervosa. J Clin Endocrinol Metab 89:39033906 Golden NH, Iglesias EA, Jacobson MS, Carey D, Meyer W, Schebendach J, Hertz S, Shenker IR 2005 Alendronate for the treatment of osteopenia in anorexia nervosa: a randomized, double-

J Clin Endocrinol Metab, February 2011, 96(2):333343

jcem.endojournals.org

343

87.

88.

89.

90. 91.

92.

93.

94.

95. 96.

97. 98.

99.

100.

101.

102.

103. 104. 105.

106. 107.

blind, placebo-controlled trial. J Clin Endocrinol Metab 90:3179 3185 Grinspoon S, Thomas L, Miller K, Herzog D, Klibanski A 2002 Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa. J Clin Endocrinol Metab 87:28832891 Patlas N, Golomb G, Yaffe P, Pinto T, Breuer E, Ornoy A 1999 Transplacental effects of bisphosphonates on fetal skeletal ossification and mineralization in rats. Teratology 60:68 73 Minsker DH, Manson JM, Peter CP 1993 Effects of the bisphosphonate, alendronate, on parturition in the rat. Toxicol Appl Pharmacol 121:217223 Bonjour JP 2005 Dietary protein: an essential nutrient for bone health. J Am Coll Nutr 24:526S536S Bourrin S, Ammann P, Bonjour JP, Rizzoli R 2000 Dietary protein restriction lowers plasma insulin-like growth factor I (IGF-I), impairs cortical bone formation, and induces osteoblastic resistance to IGF-I in adult female rats. Endocrinology 141:3149 3155 Golden NH, Lanzkowsky L, Schebendach J, Palestro CJ, Jacobson MS, Shenker IR 2002 The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa. J Pediatr Adolesc Gynecol 15:135143 Golden NH 2007 Eating disorders in adolescence: what is the role of hormone replacement therapy? Curr Opin Obstet Gynecol 19: 434 439 Pirke KM, Fichter MM, Chlond C, Schweiger U, Laessle RG, Schwingenschloegel M, Hoehl C 1987 Disturbances of the menstrual cycle in bulimia nervosa. Clin Endocrinol (Oxf) 27:245251 Cantopher T, Evans C, Lacey JH, Pearce JM 1988 Menstrual and ovulatory disturbance in bulimia. BMJ 297:836 837 Gendall KA, Bulik CM, Joyce PR, McIntosh VV, Carter FA 2000 Menstrual cycle irregularity in bulimia nervosa. Associated factors and changes with treatment. J Psychosom Res 49:409 415 Vyver E, Steinegger C, Katzman DK 2008 Eating disorders and menstrual dysfunction in adolescents. Ann NY Acad Sci 1135:253264 Poyastro Pinheiro A, Thornton LM, Plotonicov KH, Tozzi F, Klump KL, Berrettini WH, Brandt H, Crawford S, Crow S, Fichter MM, Goldman D, Halmi KA, Johnson C, Kaplan AS, Keel P, LaVia M, Mitchell J, Rotondo A, Strober M, Treasure J, Woodside DB, Von Holle A, Hamer R, Kaye WH, Bulik CM 2007 Patterns of menstrual disturbance in eating disorders. Int J Eat Disord 40:424 434 Schweiger U, Pirke KM, Laessle RG, Fichter MM 1992 Gonadotropin secretion in bulimia nervosa. J Clin Endocrinol Metab 74: 11221127 Pirke KM, Dogs M, Fichter MM, Tuschl RJ 1988 Gonadotrophins, oestradiol and progesterone during the menstrual cycle in bulimia nervosa. Clin Endocrinol (Oxf) 29:265270 Adams J, Franks S, Polson DW, Mason HD, Abdulwahid N, Tucker M, Morris DV, Price J, Jacobs HS 1985 Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone. Lancet 2:13751379 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2004 Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome. Fertil Steril 81:19 25 McCluskey S, Evans C, Lacey JH, Pearce JM, Jacobs H 1991 Polycystic ovary syndrome and bulimia. Fertil Steril 55:287291 McCluskey SE, Lacey JH, Pearce JM 1992 Binge-eating and polycystic ovaries. Lancet 340:723 Raphael FJ, Rodin DA, Peattie A, Bano G, Kent A, Nussey SS, Lacey JH 1995 Ovarian morphology and insulin sensitivity in women with bulimia nervosa. Clin Endocrinol (Oxf) 43:451 455 Jahanfar S, Eden JA, Nguyent TV 1995 Bulimia nervosa and polycystic ovary syndrome. Gynecol Endocrinol 9:113117 Morgan JF, McCluskey SE, Brunton JN, Hubert Lacey J 2002 Polycystic ovarian morphology and bulimia nervosa: a 9-year follow-up study. Fertil Steril 77:928 931

108. Taylor AE, Hubbard J, Anderson EJ 1999 Impact of binge eating on metabolic and leptin dynamics in normal young women. J Clin Endocrinol Metab 84:428 434 109. Spalter AR, Gwirtsman HE, Demitrack MA, Gold PW 1993 Thyroid function in bulimia nervosa. Biol Psychiatry 33:408 414 110. Gendall KA, Joyce PR, Carter FA, McIntosh VV, Bulik CM 2003 Thyroid indices and treatment outcome in bulimia nervosa. Acta Psychiatr Scand 108:190 195 111. Birketvedt GS, Drivenes E, Agledahl I, Sundsfjord J, Olstad R, Florholmen JR 2006 Bulimia nervosaa primary defect in the hypothalamic-pituitary-adrenal axis? Appetite 46:164 167 112. Ludescher B, Leitlein G, Schaefer JE, Vanhoeffen S, Baar S, Machann J, Claussen CD, Schick F, Eschweiler GW 2009 Changes of body composition in bulimia nervosa: increased visceral fat and adrenal gland size. Psychosom Med 71:9397 113. Monteleone P, Di Lieto A, Tortorella A, Longobardi N, Maj M 2000 Circulating leptin in patients with anorexia nervosa, bulimia nervosa or binge-eating disorder: relationship to body weight, eating patterns, psychopathology and endocrine changes. Psychiatry Res 94:121129 114. Fassino S, Daga GA, Mondelli V, Piero A, Broglio F, Picu A, ` Giordano R, Baldi M, Arvat E, Ghigo E, Gianotti L 2005 Hormonal and metabolic responses to acute ghrelin administration in patients with bulimia nervosa. Psychoneuroendocrinology 30:534 540 115. Naessen S, Carlstrom K, Glant R, Jacobsson H, Hirschberg AL 2006 Bone mineral density in bulimic womeninfluence of endocrine factors and previous anorexia. Eur J Endocrinol 155:245251 116. Warren MP, Voussoughian F, Geer EB, Hyle EP, Adberg CL, Ramos RH 1999 Functional hypothalamic amenorrhea: hypoleptinemia and disordered eating. J Clin Endocrinol Metab 84:873 877 117. De Souza MJ, Hontscharuk R, Olmsted M, Kerr G, Williams NI 2007 Drive for thinness score is a proxy indicator of energy deficiency in exercising women. Appetite 48:359 367 118. De Souza MJ, Lee DK, VanHeest JL, Scheid JL, West SL, Williams NI 2007 Severity of energy-related menstrual disturbances increases in proportion to indices of energy conservation in exercising women. Fertil Steril 88:971975 119. Schneider LF, Monaco SE, Warren MP 2008 Elevated ghrelin level in women of normal weight with amenorrhea is related to disordered eating. Fertil Steril 90:121128 120. De Souza MJ, Leidy HJ, ODonnell E, Lasley B, Williams NI 2004 Fasting ghrelin levels in physically active women: relationship with menstrual disturbances and metabolic hormones. J Clin Endocrinol Metab 89:3536 3542 121. Scheid JL, Williams NI, West SL, VanHeest JL, De Souza MJ 2009 Elevated PYY is associated with energy deficiency and indices of subclinical disordered eating in exercising women with hypothalamic amenorrhea. Appetite 52:184 192 122. Constantini NW, Warren MP 1994 Special problems of the female athlete. Baillieres Clin Rheumatol 8:199 219 123. Zanker CL, Cooke CB, Truscott JG, Oldroyd B, Jacobs HS 2004 Annual changes of bone density over 12 years in an amenorrheic athlete. Med Sci Sports Exerc 36:137142 124. Cobb KL, Bachrach LK, Sowers M, Nieves J, Greendale GA, Kent KK, Brown Jr BW, Pettit K, Harper DM, Kelsey JL 2007 The effect of oral contraceptives on bone mass and stress fractures in female runners. Med Sci Sports Exerc 39:1464 1473 125. Vescovi JD, Jamal SA, De Souza MJ 2008 Strategies to reverse bone loss in women with functional hypothalamic amenorrhea: a systematic review of the literature. Osteoporos Int 19:465 478 126. Fredericson M, Kent K 2005 Normalization of bone density in a previously amenorrheic runner with osteoporosis. Med Sci Sports Exerc 37:14811486 127. Ihle R, Loucks AB 2004 Dose-response relationships between energy availability and bone turnover in young exercising women. J Bone Miner Res 19:12311240