Version May 2024
INTRODUCTION — Anorexia nervosa (AN) is a disorder characterized by severe restriction of nutritional intake, despite extremely low body weight, that predominantly affects young women [1]. In addition to restricting food intake, some women with AN binge eat and/or purge. AN is associated with significant medical complications, including endocrine dysfunction, and the highest mortality rate of any psychiatric disorder [2]. Endocrine complications are significant and include hypothalamic-pituitary abnormalities that contribute to severe bone loss.
The pathophysiology, clinical manifestations, evaluation, and management of endocrine complications in AN are reviewed here. The medical complications of AN and their management, as well as other aspects of eating disorders and their management, are found separately. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management" and "Eating disorders: Overview of epidemiology, clinical features, and diagnosis" and "Eating disorders: Overview of prevention and treatment".)
PATHOPHYSIOLOGY OF ENDOCRINE COMPLICATIONS — Anorexia nervosa (AN) is associated with multiple endocrine abnormalities, primarily in neuroendocrine axes [3-5]. Some of the endocrine abnormalities in AN represent physiologic adaptive responses to chronic starvation and serve to shunt limited resources to the most essential physiologic processes. Others are present even after weight recovery, suggesting a potential role in disease pathophysiology or lagging recovery of endocrine dysregulation. Some contribute to the development of low bone density, one of the serious endocrine consequences of AN. In addition to bone loss, other important endocrine consequences of AN include amenorrhea (and as a result, anovulatory infertility) and hyper- or hyponatremia.
Hypothalamic-pituitary abnormalities — AN affects multiple hypothalamic-pituitary axes, which results in abnormal levels of several hormones.
Reproductive — Suppression of the hypothalamic-pituitary-ovarian axis results in hypogonadotropic hypogonadism with amenorrhea, estradiol deficiency, and infertility [6]. Amenorrhea is thought to be due to the relative energy deficit associated with AN, low fat mass, and possibly changes in the hormone leptin. (See 'Appetite-regulating hormones' below.)
Frequent sampling studies for gonadotropins over 24 hours in women with AN demonstrate low mean serum concentrations of luteinizing hormone (LH) with a variety of LH secretory patterns including low amplitude and an early pubertal pattern of nighttime pulses, both a reflection of impaired hypothalamic gonadotropin-releasing hormone (GnRH) secretion [6-8].
Low estradiol and testosterone levels may contribute to bone loss [9-13]. Women with AN also have anovulatory infertility until their hypothalamic-pituitary-ovarian axis recovers [6]. Reproductive function is restored in approximately 85 percent of women following weight recovery [14], usually within six months but sometimes taking up to 18 months following weight restoration.
Adrenal — Increased hypothalamic-pituitary-adrenal (HPA) activity in the setting of the stress of chronic starvation leads to hypercortisolemia [15-19]. Hypercortisolemia has been linked to severity of anxiety and depressive symptoms as well as osteopenia in AN [9,20]. There is no clinical role for evaluating these women for Cushing syndrome.
Growth hormone — Although growth hormone (GH) levels are high in AN, levels of the downstream hormone insulin-like growth factor-1 (IGF-1) are low, indicating a state of "resistance" to GH due to chronic starvation [21-23]. The GH axis is an important regulator of bone formation, and dysregulation of this system contributes to AN-associated bone loss [12,22,24,25]. There is no clinical role for measuring GH or IGF-1.
Thyroid — Women with AN often have a "euthyroid-sick" pattern of thyroid function tests due to chronic undernutrition: triiodothyronine (T3) levels are low, and reverse T3 (rT3) levels and the ratio of thyroxine (T4) to T3 are high [26,27]. Thyroid-stimulating hormone (TSH) and T4 levels may be normal or low [26,28]. (See "Thyroid function in nonthyroidal illness".)
These changes in thyroid hormone levels reduce the metabolic rate, leading to conservation of limited resources [29]. When women gain weight, thyroid function returns to normal.
Posterior pituitary
●Secretion of vasopressin (or antidiuretic hormone [ADH]), a hormone that allows the kidney to reabsorb free water and maintain serum sodium balance, can be low or high in AN, with the associated risks of arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus) (rare) and syndrome of inappropriate antidiuretic hormone secretion (SIADH), respectively [30]. Complications due to SIADH, such as seizures, are of particular concern since these women may have other risk factors for hyponatremia such as excessive water consumption, hypovolemia due to poor nutrition and purging behaviors, impaired renal sodium reabsorption secondary to chronic starvation, and use of psychotropic medications that result in SIADH or polydipsia [31-33].
●Basal levels of oxytocin, a hormone that is involved in a range of physiologic processes including social behaviors, modulation of anxiety and depressive symptoms, energy homeostasis, and bone metabolism, are decreased [34-37]. Low nocturnal levels have been linked to severity of bone loss in AN [35,38].
Abnormal oxytocin secretion following a meal is associated with the severity of disordered eating psychopathology, anxiety and depressive symptoms, and hypoactivation of regions of the brain involved in food motivation in AN [36,39]. The finding of persistent abnormal oxytocin secretion after weight recovery suggests that this hormone may contribute to symptoms and interfere with recovery [36,40]. Although oxytocin may play a role in the pathophysiology of AN, there is currently no clinical role for measurement of serum oxytocin concentrations.
Appetite-regulating hormones — Levels of leptin, a fat-derived hormone that signals energy availability and inhibits appetite, are low in AN and return to normal when these women gain weight [41-43]. (See "Evaluation and management of secondary amenorrhea", section on 'Functional hypothalamic amenorrhea'.)
Secretion of ghrelin, a hormone released by the stomach that increases appetite, is increased in AN, as one might expect in the starved state [44,45]. Levels of peptide YY (PYY), a hormone secreted by the gut that suppresses appetite, are high in AN and do not appear to normalize with weight recovery [46,47]. Although leptin, ghrelin, and PYY are important regulators of appetite, there is no role for measuring levels of these hormones in the diagnosis or evaluation of patients with AN. (See "Ghrelin", section on 'Food intake and energy balance' and "Pancreatic polypeptide, peptide YY, and neuropeptide Y", section on 'Clinical implications of the PP/PYY/NPY family of peptides'.)
Bone
●Females – Females with AN can experience profound bone loss and failure to accrue normal bone mass:
In one study of 130 young female outpatients with AN (mean age 24 years), more than 90 percent had osteopenia and nearly 40 percent met World Health Organization (WHO) criteria for osteoporosis [48].
Bone mineral density (BMD), geometry, and microarchitecture are impaired; bone marrow fat is increased; and estimated bone strength is diminished [12,48-53].
A two- to sevenfold increase in fractures has been reported [54,55]. Fracture risk improves but does not normalize with recovery [56].
In adults, markers of bone resorption are increased, and markers of bone formation are decreased [25]. In contrast, during adolescence, normally a time of increased bone turnover, there is a reduction of both bone resorption and formation [22,24].
The severity of bone loss in women with AN is greater than in those with normal-weight hypothalamic amenorrhea, indicating that, in addition to estradiol deficiency, there are other factors including nutritional deficiencies and hormonal abnormalities that contribute to bone loss [10]. GH resistance, hypercortisolemia, and low testosterone have all been implicated in AN-associated osteopenia [9,11,12,20,22,24]. In addition, abnormalities in hormones involved in appetite regulation, such as oxytocin, leptin, and PYY, may play a role in bone loss in AN, though the evidence is less clear [12,35,38,57,58].
●Males – Although research on males with anorexia nervosa (AN) is limited, studies indicate that they are also at risk for bone loss [59-63]. Similar to girls with AN, boys have reduced markers of bone turnover and BMD at the hip and spine [61]. A cross-sectional study of 103 men, aged 18 to 63 years, with eating disorders (26 with AN) and 48 controls found that BMD Z-scores at the spine and hip were lower in individuals with AN than healthy individuals, with 65 percent of those with AN having BMD Z-scores below -2 at least one site [63].
Hypoglycemia — Dietary restriction accompanied by weight loss and excessive exercise deplete hepatic glycogen stores and disrupt hepatic gluconeogenesis. However, symptomatic hypoglycemia in ambulatory adults with AN is very rare. In severely malnourished patients, hypoglycemia can occur upon refeeding. In one study of 25 consecutive adult patients with AN (mean body mass index [BMI] 13.1 kg/m2) admitted to a medical stabilization unit, 12 percent developed a glucose <40 mg/dL upon refeeding, and severe liver function abnormalities predicted the development of hypoglycemia [64]. There was no mention of symptomatic hypoglycemia. Nutritional rehabilitation guidelines now emphasize strategies that use <40 percent of calories from carbohydrates in patients with AN to prevent development of hypoglycemia during refeeding [65]. Other medical complications in AN are reviewed separately. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management" and "Anorexia nervosa in adults: Evaluation for medical complications and criteria for hospitalization to manage these complications".)
Hypothermia — Hypothalamic abnormalities in thermoregulation occur in women with AN and can result in hypothermia [66]. An outpatient study reported hypothermia in 22 percent of patients with AN [67]. In contrast, 23 of 25 patients (92 percent) with AN admitted to a medical stabilization unit for refeeding had hypothermia [64].
CLINICAL MANIFESTATIONS
Endocrine-related features — Endocrine-related features of anorexia nervosa (AN) include the following:
●Reproductive dysfunction (eg, amenorrhea, loss of libido, infertility), which is common. Prior to the Diagnostic and Statistical Manual of Disorders, Fifth Edition (DSM-5), amenorrhea was a prerequisite for diagnosis. (See 'Reproductive' above.)
●Bone loss (eg, stress fractures). Most women with AN have low bone mineral density (BMD) and approximately 40 percent have osteoporosis [48]. A two- to sevenfold increase in fracture risk has been reported [54,55]. (See 'Bone' above.)
●Hyponatremia (with associated nausea and headache). In a study of 215 ambulatory women with AN, 20 percent had hyponatremia [67]. (See 'Posterior pituitary' above.)
●Hypernatremia (increased thirst, polyuria) is rare.
●Physical examination is generally not helpful in uncovering endocrine-related complications. Patients with lower weight and body fat are more likely to have lower leptin levels and amenorrhea.
Laboratory and imaging — Laboratory and imaging data may include the following:
●Serum sodium – Although rare, serum sodium levels may be high due to decreased vasopressin secretion. More commonly, serum sodium levels are low due to syndrome of inappropriate antidiuretic hormone (SIADH), hypovolemia, or excessive water intake. (See 'Hypothalamic-pituitary abnormalities' above.)
●Thyroid – Thyroid function tests typically demonstrate "euthyroid-sick" syndrome (thyroid function test abnormalities associated with nonthyroidal illness). (See "Thyroid function in nonthyroidal illness".)
●Bone – BMD testing using dual-energy x-ray absorptiometry (DXA) typically shows low BMD. (See "Screening for osteoporosis in postmenopausal women and men", section on 'Dual-energy x-ray absorptiometry'.)
As noted above, almost all women with AN have low bone density, and approximately 40 percent have osteoporosis at one or more sites [48]. While all sites (spine, hip, femoral neck, and whole body) are affected in AN, the greatest decreases in bone mass and bone density are usually seen at the lumbar spine, which is primarily trabecular bone [48,68]. (See 'Bone' above.)
In adults with AN, a decrease in markers of bone formation and an increase in markers of bone resorption are observed [25]. In contrast, during adolescence, normally a time of increased bone turnover, there is a reduction of both bone resorption and formation in AN [22,24]. (See "Evaluation and treatment of premenopausal osteoporosis".)
SUGGESTED EVALUATION
History — Key endocrine-related questions to ask a female presenting with anorexia nervosa (AN) address the following complications (see 'Endocrine-related features' above):
●Reproductive dysfunction (eg, history of amenorrhea, infertility)
●Bone loss (eg, history of low-trauma fractures; assessment of osteoporosis risk based on family history, lifestyle factors, medications, and other medical problems)
●Hyponatremia (eg, nausea, headache; assessment of other factors related to risk of hyponatremia and complications, eg, medications, water loading, purging, seizure history)
●Hypernatremia (increased thirst, polyuria)
Examination — Aside from low body weight, the physical examination is usually not helpful in terms of endocrine-related complications. (See 'Endocrine-related features' above.)
Biochemical and bone density testing — In general, we suggest the following testing:
●Serum/plasma sodium, potassium, and glucose levels in all patients
●In amenorrheic patients – Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, prolactin (PRL), thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG) (to rule out causes of amenorrhea other than AN)
●25-hydroxyvitamin D (25[OH]D) level and dual-energy x-ray absorptiometry (DXA) for bone mineral density (BMD; adults at spine and hip; children at spine and whole body [less head])
MANAGEMENT — Many of the hormonal abnormalities associated with anorexia nervosa (AN) represent adaptive responses to chronic undernutrition; following nutritional repletion, secretion of these hormones usually normalizes, but normalization may lag behind weight recovery. The following are key management issues related to endocrine complications of AN:
Reproductive dysfunction — Nutritional repletion is the treatment for reproductive dysfunction in AN. In most cases, menstrual cycles return and reproductive function is restored when patients gain weight [14,69]. (See "Anorexia nervosa in adults and adolescents: Nutritional rehabilitation (nutritional support)".)
If menses do not resume with weight recovery, further evaluation for causes of amenorrhea is indicated but may not reveal an etiology, as a small percentage of patients will not resume menses even with weight recovery.
Although it is possible for amenorrheic women to conceive by inducing ovulation using gonadotropins, the presence of active AN is considered to be a contraindication to ovulation induction, given the increased risk of adverse pregnancy outcomes [70,71]. (See "Evaluation and management of secondary amenorrhea", section on 'Initial evaluation'.)
"Euthyroid-sick" syndrome — This characteristic pattern of thyroid function tests is a physiologic adaptation to chronic starvation. Treatment with levothyroxine is not indicated in the absence of overt hypothyroidism and could be potentially harmful given the risk for cardiac arrhythmias and bone loss in these patients. Thyroid function tests normalize when patients return to a normal weight. (See 'Thyroid' above and "Thyroid function in nonthyroidal illness".)
Bone loss — Given the profound bone loss associated with AN, measurement of bone mineral density (BMD) using dual-x-ray absorptiometry (DXA) is important. Evidence of bone loss can be useful in motivating women to recover from AN. We suggest a baseline measurement with periodic follow-up in females who are persistently low weight.
Assessment of other risk factors for osteopenia, such as reproductive and family history, smoking, excessive alcohol use, and use of medications affecting bone metabolism, should be assessed. Evaluation for other contributors such as celiac disease or hyperparathyroidism, particularly in women with severe bone loss, should be considered. (See "Evaluation and treatment of premenopausal osteoporosis", section on 'Evaluation'.)
We suggest measuring a 25-hydroxyvitamin D (25[OH]D) level and encouraging adequate calcium (eg, 1200 mg) and vitamin D (eg, 800 international units) daily, from diet and supplements. Exercise regimens must be individualized. While weightbearing exercise is generally beneficial to bone, over-exercise in these women can perpetuate weight loss and amenorrhea, thereby leading to bone loss [72]. In addition, women with severe bone loss are at risk for exercise-related stress fractures. Weight gain and restoration of menstrual cycles can independently improve BMD, and they remain the primary goal [68,73,74].
Other options for preventing and treating bone loss are limited, and there are no US Food and Drug Administration (FDA)-approved therapies.
Estrogen therapy — High-dose estrogen (oral contraceptives) has not been effective for AN-associated bone loss in adults or adolescents, but lower-dose physiologic estrogen appears more promising.
●Prospective trials have failed to show a benefit of combination estrogen-progestin oral contraceptives in treating AN-associated bone loss in adolescents or adults [75-77]. Oral contraceptive pills should therefore not be prescribed for prevention of bone loss in AN.
●However, a trial of "physiologic" estrogen replacement in 110 adolescent girls ages 12 to 18 years with AN over 18 months resulted in improved BMD at the spine and hip [78]. In this study, girls with a bone age ≥15 years were randomized to receive 100 mcg transdermal 17-beta-estradiol with cyclic micronized progesterone, whereas immature girls with a bone age <15 years were randomized to receive low incremental doses of oral ethinyl estradiol to mimic pubertal increases (3.75 mcg daily from zero to six months, 7.5 mcg daily from 7 to 12 months, 11.25 mcg daily from 13 to 18 months) versus placebo. These "physiologic" strategies for replacing estradiol resulted in BMD gains at the spine and hip compared with placebo, though the therapy did not increase BMD to normal.
In a second study of 23 young females with AN ages 14 to 25 years receiving transdermal 17-beta-estradiol (100 mcg daily) with cyclic micronized progesterone (100 mcg daily for 10 days of every month) resulted in improvements in volumetric BMD, geometry, structure, and strength estimates at the distal radius and tibia that were similar to or exceeded changes seen in eumenorrheic, normal-weight, healthy controls. Physiologic estrogen replacement also led to greater increases in areal BMD at the lumbar spine, total hip, and whole body in comparison with the menstruating controls [79].
In a six-month, open-label study of transdermal estradiol (0.045 mg/day) plus levonorgestrel (0.015 mg/day) in 11 women with AN (mean age 37 years), BMD increased at the lumbar (2.4 percent) and lateral (3.6 percent) spine [80]. To date there are no randomized controlled trials of physiologic estrogen replacement in adult women with AN.
In females with low BMD and sustained low weight and amenorrhea, we suggest that causes other than hypothalamic amenorrhea from AN be ruled out before estradiol/progesterone therapy is considered. Once other causes of amenorrhea have been excluded, if menses have not resumed within 6 to 12 months of nutrition, psychological, and exercise modifications, we recommend short-term estrogen replacement for bone health. In women and girls with a bone age of ≥14 years, we recommend transdermal 17-beta-estradiol (100 mcg daily) with cyclic progesterone (micronized progesterone 100 to 200 mg daily for 12 days of every month). Starting with a lower dose, such as transdermal 17-beta-estradiol (50 mcg daily) with cyclic progesterone (micronized progesterone 100 mg daily for 12 days of every month), initially for a few months may reduce side effects.
There are few data for girls with bone age <14 years upon which to make a recommendation, but we suggest an approach similar to that for inducing puberty in girls with delayed puberty or Turner syndrome. (See "Approach to the patient with delayed puberty", section on 'Estradiol therapy'.)
Therapies used infrequently
●Bisphosphonates – Limited data suggest that bisphosphonates may be of benefit in women with AN-associated bone loss; this has not been demonstrated in adolescents, and there are safety concerns for both groups. Most importantly, bisphosphonates should not be prescribed in patients in whom pregnancy could occur.
A 12-month, randomized, placebo-controlled trial of risedronate in 77 women with AN and osteopenia or osteoporosis demonstrated improvements in BMD of 3 percent at the posterior-anterior spine, 4 percent at the lateral spine, and 2 percent at the hip compared with placebo [81]. In contrast, transdermal testosterone replacement, which was also studied in this trial, did not improve BMD in these women.
Bisphosphonates are not approved in the United States for this indication and have not been shown to be effective or safe in adolescents [82]. In adults, bisphosphonates may be prescribed for AN-associated bone loss that is not responsive to other treatments. Rarely, bisphosphonates are used in premenopausal females with severe osteoporosis. If bisphosphonates are prescribed to females of reproductive age, a negative pregnancy test is advised prior to starting therapy, and contraception is recommended even in women with amenorrhea. (See "Evaluation and treatment of premenopausal osteoporosis", section on 'Pharmacologic therapy for selected women'.)
●Teriparatide – Although several small studies suggest that teriparatide (recombinant human parathyroid hormone) may improve BMD in adult women with AN, its role in the treatment of AN-induced bone loss is not yet clear. For women of reproductive age, teriparatide is currently only approved in the United States for treatment of bone loss from glucocorticoid use. It should not be prescribed to children or adolescents under any circumstances and should not be prescribed to patients at risk of becoming pregnant or patients at increased risk for osteosarcoma. Safety in young adults is also uncertain. Endocrine Society guidelines on management of hypothalamic amenorrhea suggest that short-term teriparatide may be used in rare cases of delayed fracture healing and very low BMD [83].
Data in females with AN include the following:
•In a randomized, placebo-controlled trial in 21 women with AN, mean age 47 years old, six months of teriparatide (20 mcg subcutaneously) resulted in marked increases in BMD at the posteroanterior (6 versus 0.2 percent for placebo) and lateral (10.5 versus -0.6 percent for placebo) spine [84].
•An open-label study of teriparatide at the same dose for 24 months in 10 adult women with AN, ages 18 to 35 years, showed an increase in BMD at the spine (13.5 percent), femoral neck (5 percent), and total hip (4 percent) and decreased cortical bone density (2.6 percent) and thickness (6.4 percent) at the radius [85]. Further studies involving more patients and longer follow-up will be important to determine the safety and efficacy of teriparatide for this indication.
●Denosumab – We do not suggest the use of denosumab in this population. In a 12-month study of women with AN randomized to denosumab (a human monoclonal antibody with antiresorptive effects on bone; 20 women receiving 60 mg subcutaneously every six months) versus placebo (10 women), denosumab reduced bone turnover markers and increased spine BMD (5.5 versus 2.2 percent for placebo) [86]. (See "Denosumab for osteoporosis", section on 'Safety information'.)
Water balance — Serum sodium levels should be monitored, and, if abnormalities are identified, evaluation for the cause of hyper- or hyponatremia pursued. Hypernatremia is typically mild and responds to drinking free water. An appropriate history and physical examination for evaluation of hyponatremia is important as there are numerous potential causes in this population, and management of hyponatremia differs dependent on the etiology. (See 'Posterior pituitary' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Eating disorders" and "Society guideline links: Amenorrhea".)
SUMMARY AND RECOMMENDATIONS
●Pathophysiology – Anorexia nervosa (AN) is a psychiatric disorder characterized by restriction of food intake, despite extremely low weight, that predominantly affects young women. AN is associated with significant medical complications, including endocrine dysfunction, and the highest mortality rate of any psychiatric disorder. (See 'Pathophysiology of endocrine complications' above.)
●Endocrine manifestations – Females with AN can experience profound bone loss and failure to accrue normal bone mass. Other important endocrine consequences of AN include amenorrhea (and as a result, anovulatory infertility), hyper- or hyponatremia, and abnormal secretion of appetite-regulating peptides. (See 'Hypothalamic-pituitary abnormalities' above and 'Appetite-regulating hormones' above.)
●Evaluation – Evaluation should include (see 'Suggested evaluation' above):
•Serum/plasma sodium, potassium, and glucose levels in all patients
•In amenorrheic patients – Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, prolactin (PRL), thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG; to rule out causes of amenorrhea other than AN)
•25-hydroxyvitamin D (25[OH]D) level and dual-energy x-ray absorptiometry (DXA) for bone mineral density (BMD)
●Management
•Reproductive dysfunction – Reproductive dysfunction generally, but not always, returns to normal after weight restoration.
•"Euthyroid-sick" syndrome – This is a normal adaptive response to reduce the metabolic rate and conserve resources in the setting of chronic undernutrition and should not be treated with thyroid hormone. (See '"Euthyroid-sick" syndrome' above.)
•Profound bone loss – Profound bone loss due to nutritional deficiencies and hormone abnormalities is common, and BMD assessment is important. Weight restoration and normalization of menstrual cycles have independent effects in improving BMD. (See 'Bone loss' above.)
-For females with amenorrhea and low bone density, we suggest nutritional interventions weight restoration as initial therapy.
-In females whose menstrual cycles are not restored in spite of nutritional, psychological, and exercise modifications, we use physiologic estrogen rather than pharmacologic doses of estrogen (combined oral contraceptives; COCs). The approach is similar to that for women with functional hypothalamic amenorrhea. (See 'Estrogen therapy' above and "Functional hypothalamic amenorrhea: Evaluation and management", section on 'Estrogen replacement'.)
-For most patients with AN and low bone density, we suggest against the use of teriparatide (Grade 2C). However, in rare cases (patients with delayed fracture healing with very low BMD), it is sometimes used.
•Water balance – Serum sodium can be high or low due to abnormal vasopressin secretion and should be monitored. Other causes of hyponatremia include excessive water intake and hypovolemia due to poor nutrition and purging. (See 'Water balance' above.)
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