Review

Endocrine consequences of anorexia nervosa

Madhusmita Misra, Anne Klibanski

Anorexia nervosa is prevalent in adolescents and young adults, and endocrine changes include hypothalamic Lancet Diabetes Endocrinol 2014
amenorrhoea; a nutritionally acquired growth-hormone resistance leading to low concentrations of insulin-like Published Online
growth factor-1 (IGF-1); relative hypercortisolaemia; decreases in leptin, insulin, amylin, and incretins; and April 2, 2014
http://dx.doi.org/10.1016/
increases in ghrelin, peptide YY, and adiponectin. These changes in turn have harmful eects on bone and might
S2213-8587(13)70180-3
aect neurocognition, anxiety, depression, and the psychopathology of anorexia nervosa. Low bone-mineral
Neuroendocrine Unit and
density (BMD) is particularly concerning, because it is associated with changes in bone microarchitecture, Pediatric Endocrine Unit,
strength, and clinical fractures. Recovery leads to improvements in manybut not allhormonal changes, and Massachusetts General
decits in bone accrual can persist. Oestrogen-replacement therapy, primarily via the transdermal route, increases Hospital and Harvard Medical
School, Boston, MA, USA
BMD in adolescents, although catch-up is incomplete. In adults, oral oestrogencombined with recombinant
(M Misra MD,
human IGF-1 in one study and bisphosphonates in anotherincreased BMD, but not to the normal range. Prof A Klibanski MD)
Morestudies are necessary to investigate the optimum therapeutic approach in patients with, or recovering from, Correspondence to:
anorexia nervosa. Dr Madhusmita Misra, BUL 457,
Neuroendocrine Unit,
Massachusetts General Hospital,
Introduction Nutrient intake and resting energy expenditure 55 Fruit Street, Boston,
Anorexia nervosa is a prevalent cause of severe under- Macronutrients MA 02114, USA
nutrition in adolescent girls and young women, and Individuals with anorexia nervosa have lower total mmisra@mgh.harvard.edu
aects 0210% of these populations in developed caloric intake than normal-weight controls, primarily
countries.15 The disorder is characterised by an altered due to substantial reductions in fat intake, but also
body image and very low weight, and is associated with an from some decreases in protein and carbohydrate
inability to gain or maintain weight. In girls and women intake.24,25 Reduced fat intake is associated with reduced
amenorrhoea (for at least three cycles) was included in fat mass.24 Individuals with anorexia nervosa have lower
the diagnosis in the Diagnostic and Statistical Manual of resting energy expenditure than normal-weight
Mental Disorders (DSM) IV criteria,6 but the weight controls,24 probably because of an adaptive mechanism
criteria in DSM 5 have become less stringent, and to preserve energy for vital functions. Consistent with
amenorrhoea is no longer a dening criterion.7 The ndings of reduced resting energy expenditure, the
disorder occurs predominantly in girls and women, and proportion of brown adipose tissue (a form of fat
most frequently begins during adolescence.8,9 Boys and responsible for thermogenesis26) is also reduced.27
young men comprise 10% of all diagnosed cases,10 Another study showed that individuals with anorexia
although some studies suggest the prevalence could be nervosa had lower resting metabolic rates and lower
higher.5 In response to the severe energy restriction, energy intake than constitutionally thin individuals and
alterations occur in many endocrine axesmost of which normal-weight controls.28
are adaptiveto stimulate food intake, help maintain
euglycaemia, and divert available energy for essential Micronutrients
body functions. Hypothalamic oligoamenorrhoea in Intake of saturated and unsaturated fat is lower in
anorexia nervosa leads to infertility that typically reverses individuals with anorexia nervosa than in controls;
with restoration of a stable weight.11,12 Hormonal whereas intake is higher for soluble and insoluble
alterations contribute to low bone-mineral density (BMD), bre, oxalates, and phytates,24 which could potentially
which substantially increases the risk of fractures.13 reduce absorption of other nutrients. Thus, attention to
Furthermore, neuropsychiatric comorbidities, such as diet composition is important. Vitamin intake from diet
anxiety and depressive symptoms, might be associated and supplements, including of vitamin D, is typically
with hormonal changes in anorexia nervosa.1417 higher in individuals with anorexia nervosa than in
Although 50% of adults with anorexia nervosa recover controls, mostly because of greater use of supplements.
after behavioural, psychiatric, and medical therapy,18 about In a study of teenagers with anorexia nervosa, 76%
30% only partly recover, and the remainder are of girls, compared with 50% of controls, achieved
characterised by remission and relapse or chronic recommended dietary intake of vitamin D.24 Another
disease.19,20 Of major concern is the high risk of suicide, study found a lower prevalence of vitamin D deciency
which is a common cause of death in patients with in adolescents with anorexia nervosa than in controls
anorexia nervosa.21 Among adolescents with anorexia (2% vs 24%).29 Similarly, intakes of calcium, magnesium,
nervosa, relapses are seen after inpatient hospital and zinc are generally higher in individuals with
admissions and before medical recovery in 30% of patients, anorexia nervosa than in controls, and about 59% of
although 7075% completely recover over 510 years, with girls with anorexia nervosa compared with 30% of
a low risk of relapse.22,23 About 30% of patients will develop controls achieve the recommended dietary intake for
binge-eating behaviours in the long term.22 calcium.24

www.thelancet.com/diabetes-endocrinology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(13)70180-3 1

 Review

A B
35 Anorexia nervosa Normal-weight control 7
*
Hormone concentration (g/L)

30 6

25 5

Mean GH (g/L)
20 4

15 3

10 2

5 1

0 0

35 1048
Hormone secretion (g L1 min 1)

30
786
25

IGF-1 (nmol/L)
*
20
524
15
10 262
05
0 0
Anorexia Controls
0 100 200 300 400 500 600 700 800 0 100 200 300 400 500 600 700 800
nervosa
Time (min) Time (min)

Figure 1: Eects of anorexia nervosa on concentrations of growth hormone and IGF-1

(A) Representative overnight growth-hormone secretory characteristics: secretion is greater in a teenage girl with anorexia nervosa than in a normal-weight control.
(B) Mean overnight growth-hormone concentrations and fasting IGF-1 concentrations in 22 adolescent girls with anorexia nervosa and 20 normal-weight controls:
the girls with anorexia nervosa have lower IGF-1 levels than controls despite higher growth-hormone concentrations. IFG-1=insulin-like growth factor 1. *p<005.
Adapted from reference 36 by permission of the Endocrine Society..

Eects on body composition and liver function controls after weight gain,30 whereas in adults, these
In addition to reduced BMI, individuals with anorexia nal values might exceed those in controls.31
nervosa have reduced fat and lean mass, particularly in
the proportion of trunk fat, ratio of trunk to extremity Endocrine eects
fat, and percentage of extremity lean mass.3032 In patients with or recovering from anorexia nervosa,
Reductions in trunk fat are related to increased changes occur in multiple endocrine axes. The severity of
concentrations of growth hormone (GH),32 whereas these changes is related to the degree of undernutrition
reductions in the percentage of extremity lean mass are and in most cases recovery from anorexia nervosa leads to
related to increased cortisol concentrations.32 Girls with improvements in the function of aected endocrine axes.
the highest GH and lowest cortisol concentrations have
the least trunk fat. GH and cortisol are gluconeogenic Growth-hormoneinsulin-like growth factor-1 axis
hormones, and their concentrations rise in conditions of Adolescents35,36 and adults3740 with anorexia nervosa have
energy deprivation to mobilise energy for vital functions. higher concentrations of GH than controls (gure 1),36,38
GH eects are mediated primarily through increased and those with the lowest BMI and fat mass have the
lipolysis, which provides the required substrate for highest GH concentrations.36,38 Systemic concentrations
gluconeogenesis.33 This relation is consistent with of IGF-1, however, are low in individuals with anorexia
inverse associations of GH with body fat, particularly nervosa,3640 which suggests a nutritionally acquired
trunk fat. Relative hypercortisolaemia in individuals resistance to GH. This eect is probably due to
with anorexia nervosa who have reduced percentages of downregulation of GH-receptor expression, as
extremity lean mass are consistent with the muscle corroborated by low concentrations of GH-binding
wasting reported in other disorders associated with protein (the cleaved extracellular domain of the GH
raised cortisol concentrations,34 although other factors receptor).37,39 A state of GH resistance is further conrmed
might also contribute to muscle wasting. The eect of by the absence of an increase in IGF-1 concentration
weight recovery on body composition varies by age after administration of supraphysiological doses of
group. Adolescents and adults show increases in fat and recombinant human GH in women with anorexia
lean mass, percentage body fat, percentage trunk fat, nervosa.41,42 IGF-1 is an important bone anabolic hormone
and ratio of trunk to extremity fat with weight gain. In and GH resistance is associated with low IGF-1
adolescents, the percentage of trunk fat and ratio of concentrations, which is an important determinant of
trunk to extremity fat approach those in normal-weight impaired bone metabolism.

2 www.thelancet.com/diabetes-endocrinology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(13)70180-3


A B
32
Hormone concentration (g/dL)
28
24
20
16
12
8
4
0 0
Hormone secretion (g dL1 min 1)
125
100
075
050
025
0
0 100 200
Figure 2: Impact of anorexia nervosa on cortisol secretion
(A) Representative overnight cortisol secretory characteristics: cortisol secretion is greater in a teenage girl with anorexia nervosa than in a normal-weight control.
(B) 24 h UFC concentrations are higher in adolescent girls with anorexia nervosa (n=23) than in controls (n=21). UFC= urinary free cortisol. cr=creatinine. SA=surface
area. Adapted from reference 44 by permission of the Endocrine Society.
High GH in individuals with anorexia nervosa is
consistent with its gluconeogenic role to maintain
euglycaemia in a state of low energy availability, which is
mediated though increased lipolysis. Low concentrations
of IGF-1, which normally limits GH secretion by negative
feedback,36,37 and increased levels of ghrelin, which is a
GH secretagogue,35,43 result in increased GH con-
centrations. Importantly, eects of GH on carbohydrate
metabolism and lipolysis are not mediated by IGF-1, and
these eects are preserved in people with anorexia
nervosa. Hence, supraphysiological administration of
GH in adult women with anorexia nervosa leads to a
decrease in fat mass, even though IGF-1 levels do not
change.41 Weight gain leads to a normalisation of GH
secretion37 and GH-binding protein concentrations,37,39
which are consistent with adaptation to the individuals
nutritional status.
Hypothalamic-pituitary-adrenal axis
Anorexia nervosa is associated with hypercortisolaemia in
adults and adolescents compared with healthy controls
(gure 2).15,40,4451 However, levels rarely exceed twice the
upper limit of normal and are not associated with features
of Cushings syndrome. Increased ghrelin secretion,
which is frequently seen in individuals with anorexia
nervosa,43 might stimulate secretion of corticotropin-
releasing hormone.46,51 This hormone stimulates increased
secretion of adrenocorticotropic hormone and, therefore,
cortisol. Positive associations are reported between ghrelin
and cortisol secretory parameters in anorexia nervosa.43
Individuals with the lowest BMI, fat mass, and fasting
glucose and insulin concentrations have the highest
www.thelancet.com/diabetes-endocrinology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(13)70180-3
Review
Anorexia nervosa Normal-weight control 005
*
004
UFC(cr.SA (103/m2)
003
002
001
Anorexia Controls
nervosa
300 400 500 600 700 800 0 100 200 300 400 500 600 700 800
Time (min) Time (min)
cortisol concentrations, consistent with the increase in
cortisol being an adaptive mechanism to maintain
euglycaemia in a state of low energy availability.44
High cortisol levels predict reduced percentage of
extremity lean mass32 and BMD in individuals with
anorexia nervosa.15,44 One study has suggested that
increased baseline cortisol concentration in girls with
anorexia nervosa is associated with increases in fat mass,
which in turn is associated with resumption of menses.52
By contrast, a dierent study suggested that increased
secretion of corticotropin-releasing hormone in anorexia
nervosa contributes to the severity of weight loss owing
to the strong anorexigenic drive of this hormone.53 High
cortisol secretion also predicts increased psychopathology,
independent of BMI.16 No pharmacological approaches
are currently recommended to address the relative
hypercortisolaemia in anorexia nervosa because the
changes are probably adaptive.
Hypothalamic-pituitary-thyroid axis
Changes in the hypothalamic-pituitary-thyroid axis in
individuals with anorexia nervosa are consistent with
starvation or the sick euthyroid syndrome, and do not
need to be treated. Levels of total tri-iodothyronine (T3)
are low, probably because of an adaptive mechanism to
reduce resting energy expenditure and conserve energy
for vital functions. Reduced T3 concentrations are
associated with reduced BMI and leptin concentration,
and increased ghrelin and cortisol concentrations.43,44 Free
thyroxine varies from normal to low dependent on the
severity of anorexia nervosa, whereas levels of thyroid-
stimulating hormone are typically normal to
3
 Review
low-normal.40,43,44 In adults with anorexia nervosa, the
response of thyroid-stimulating hormone to treatment
with exogenous thyrotropin-releasing hormone is
blunted.54 Although thyroid hormone concentrations are
frequently measured as part of the initial workup of
anorexia nervosa, continued monitoring is not necessary
unless weight loss owing to hyperthyroidism is a concern.
Insulin, gut peptides, and adipokines
Low weight and BMI, and reduced glucose con-
centrations in individuals with anorexia nervosa are
associated with reduced concentrations of fasting insulin
compared with that in controls.55 Low levels of insulin
lead to the induction of counter-regulatory mechanisms,
including glycogenolysis, lipolysis, and gluconeogenesis.
Amylin is secreted by pancreatic cells in a 1:1 ratio with
insulin. Concentrations of this hormone are reduced in
individuals with anorexia nervosa,56 and are associated
with low BMI and percentage of body fat. Similar
associations are seen with reduced concentrations of the
incretins: glucagon-like peptide-1,57 and glucose-
dependent insulinotropic peptide.56,58 Reduced insulin
and amylin concentrations in people with anorexia
nervosa might help preserve euglycaemia by reducing
cellular glucose uptake and glycogenesis, but contribute
to declines in BMD because both insulin and amylin are
bone-anabolic hormones. Increased secretion of counter-
regulatory hormones in response to reduced insulin and
amylin in turn would induce glycogenolysis, lipolysis,
and gluconeogenesis.
Other changes in gut peptides are also seen in
anorexia nervosa. Whether all changes are related to
adaptive mechanisms and return to normal with
sustained weight recovery or whether some have roles
in the pathogenesis of anorexia nervosa is unknown.
As well as being a GH secretagogue, ghrelin is an
orexigenic hormone that is secreted by the oxyntic cells
of the stomach.59 In healthy individuals, ghrelin
concentrations increase immediately before meals and
nadir about 30 min after food intake.59 High fasting and
overnight ghrelin levels have been reported in people
with anorexia nervosa35,43,60 and are inversely associated
with BMI, fat mass, and insulin levels. Studies have
reported dierences in ghrelin concentrations in
restrictive anorexia nervosa (raised61,62), bingepurge
anorexia nervosa (unchanged61,62), and bulimia nervosa
(reduced62) compared with controls. Concentrations of
obestatin, a ghrelin gene product that inhibits appetite
and gastric motility, are also increased in adults with
anorexia nervosa61,62 and are positively associated with
increased ghrelin concentrations.63,64
A genetic variation of the ghrelin activator gene
MBOAT4 was implicated in one study as a causal factor
in anorexia nervosa,65 and the 3056TC single-
nucleotide polymorphism of the ghrelin gene was
suggested in another to be related to recovery from
restrictive anorexia nervosa.66 A further study, however,
4 www.thelancet.com/diabetes-endocrinology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(13)70180-3
found no increased occurrence of three ghrelin gene
polymorphisms in patients with eating disorders
compared with in healthy controls.67 Thus, whether these
polymorphisms contribute to anorexia nervosa is unclear.
Raised ghrelin concentrations are consistent with
induction of adaptive mechanisms to increase food
intake. Twice daily infusions of ghrelin given for 2 weeks
to ve women with anorexia nervosa led to reduced
gastrointestinal symptoms and increased hunger and
caloric intake.68 Further study is needed to conrm these
ndings. Additionally, ghrelin stimulates secretion of GH
and adrenocorticotropic hormone,46 which contribute to
the counter-regulatory response aimed at maintaining
euglycaemia, and inhibits secretion of gonadotropins.69,70
In girls with anorexia nervosa, high ghrelin
concentrations predict increased GH and cortisol
secretion and reduced secretion of luteinising hormone
and oestradiol.43 Weight gain is associated with a
reduction in ghrelin concentrations, which suggests that
increased ghrelin secretion in anorexia nervosa is part of
an adaptive response similar to that seen in starvation;
however, levels may remain higher in individuals who
previously had anorexia nervosa than in normal-weight
controls.43 Circulating ghrelin is present in acylated
(active) and desacylated (inactive) forms. After short-
term weight gain, the concentration of acylated ghrelin
and the ratio of acylated to total ghrelin increase, whereas
desacylated ghrelin levels decrease.60
PYY is an anorexigenic hormone secreted by the
L (endocrine) cells of the distal gut. Concentrations rise
1530 min after food intake and induce postprandial
satiety. PYY concentrations are variably reported to be
higher,16,71,72 unchanged,61 and lower62 in individuals with
anorexia nervosa than in normal-weight controls, but
they have been consistently reported to correlate
inversely with BMI and fat mass.16,71,72 Increased
concentrations of PYY seem to have no adaptive role for
energy balance. A possible but as yet undetermined role
for PYY in the pathogenesis of anorexia nervosa has
been hypothesised.16,71
Concentrations of adipokines, including leptin and
adiponectin, and inammatory cytokines, such as
interleukin 6, are altered in people with anorexia nervosa
compared with controls.17,55,73,74 Leptin levels are
substantially reduced,17,73,74 but correlate positively with fat
mass. Weight gain is associated with increases in leptin
concentrations.73 By contrast, adiponectin levels are
variably reported to be unchanged,55 higher,7577 and lower78
in individuals with anorexia nervosa, but dierences
might be due to measurement of specic adiponectin
isoforms.79 Reduced concentrations of adiponectin in
people with very severe anorexia nervosa78 could be a
consequence of substantial reductions in fat mass
(because adiponectin is secreted from adipocytes).
Adipokine changes might contribute to hypogonadism
and low BMD,8086 yet there are no studies that indicate
that these changes need to be addressed pharmacologically.

Inammatory cytokines, such as interleukin 6, are
secreted by adipose tissue and concentrations are raised
in people with anorexia nervosa.55 Increased
concentrations of interleukin 6 might contribute to
reductions in BMD by activating osteoclastic activity.87
Hypothalamic-pituitary-gonadal axis
Decreased energy availability in anorexia nervosa is
believed to cause hypothalamic amenorrhoea.88 Women
with anorexia nervosa frequently have pulsatile secretion
of luteinising hormone that resembles that in
prepubertal or early pubertal girls, with either very low
amplitude luteinising hormone pulses or increased
pulse amplitude during sleep only.89 Altered
gonadotropin secretion in individuals with anorexia
nervosa has been associated with decreases in fat mass,
which reects reduced energy stores, and alterations in
hormones that are secreted by adipocytes (leptin and
adiponectin) or regulated by fat and energy stores
(ghrelin, PYY, and cortisol).69,70,9093 Normal leptin levels
are a permissive factor in the onset of puberty and
facilitate normal gondadotropin secretion.80 Therefore,
reduced concentrations in patients with anorexia
nervosa might contribute to disruption of menses.
Alterations to the secretion of luteinising hormone
manifest as hypothalamic amenorrhoea. Some women
with anorexia nervosa present with irregular periods
rather than complete amenorrhoea, which might reect
changes in energy status over time. With weight gain
and an increase in fat mass, menstrual function resumes
in a large proportion of women with anorexia nervosa,
and data suggest that an increase in fat mass is the most
important factor in resumption of menstrual cycles
(gure 3).52,94 Although fat content overlaps signicantly
in individuals who do and do not recover weight and
menses, a study in adolescents with anorexia nervosa
reported that all girls with body fat greater than 24%
resumed menses, compared with those with body fat
less than 18%, of whom none resumed menses.52
Menstrual recovery might lag behind increases in
bodyweight in individuals with anorexia nervosa, and it
is prudent to wait for at least 6 months after target
weight is attained before considering further
investigations. Some studies have suggested that
persistent amenorrhea after weight recovery in women
with anorexia nervosa might indicate an underlying
predisposition for polycystic ovarian syndrome.95,96
Hypothalamic oligoamenorrhoea leads to oestrogen
deciency and decreased gonadal secretion of
testosterone.97,98 Decreased gonadal steroid secretion has a
harmful eect on bone metabolism, and hypogonadotropic
hypogonadism causes infertility, although the condition
reverses on recovery from anorexia nervosa.11,12
Women with anorexia nervosa or with anorexia and
bulimia nervosa take a longer time to conceive and are
more likely to be taking fertility treatment when they
conceive than women with bulimia nervosa alone or
www.thelancet.com/diabetes-endocrinology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(13)70180-3
Review
A B
40 25
35
20
30
*
Final body fat (%)
25
Body fat (%)
15
20
10
15
10
5
5
0
Menses not Menses
0
Amenorrhoeic Eumenorrhoeic
recovered recovered
Figure 3: Proportion of body fat and relation to menstrual function
(A) Adolescent girls with anorexia nervosa who recovered menstrual function by 1 year of follow-up (n=19) had
greater mean percentage body fat than those who did not (n=14). (B) Despite similarly low weight (mean
BMI 168 [SD 02] kg/m vs 171 [02] kg/m), adult women who were eumenorrhoeic (n=42) had greater
percentage body fat than those who were amenorrhoeic (n=74). *p<005. Panel A reproduced from reference 52
by permission of the International Paediatric Research Foundation, and panel B adapted from reference 94 by
permission of the Endocrine Society.
healthy women, and women with eating disorders
frequently have negative feelings during pregnancy.99 In
women with infertility that persists after recovery from
anorexia nervosa, ovulation can be induced with assisted
reproduction techniques, such as ovulation induction
with clomiphene or combinations of recominant human
follicle-stimulating hormone and human chorionic
gonadotropin, and in vitro fertilisation.12,100 Despite
reduced fertility, unplanned pregnancies are reported to
be more common in women with anorexia nervosa than
in the general population,101 possibly because pregnan-
cies occur during occasional ovulatory cycles in women
not taking contraceptive measures. Increased risks of
miscarriage, caesarean delivery, premature birth, and
perinatal death are reported in women with a history of
anorexia nervosa,11,102 which indicates the need for
careful monitoring of women during pregnancy and of
ospring during and after birth.
Anorexia nervosa also adversely aects male fertility.
In one study 50 of 140 women with anorexia nervosa
were reported to have given birth to 86 children, but
none of 11 men with anorexia nervosa had children.102
Although these numbers are small, perturbations in
the male reproductive axis might have a greater impact
on fertility than those in women. One longitudinal
study of the hypothalamic-pituitary-gonadal axis in
three men with anorexia nervosa reported low
concentrations of leptin, gonadotropins, and
testosterone in the morning at baseline, all of which
increased with weight gain.103 Another study showed
reduced secretion of luteinising hormone, follicle-
stimulating hormone, and testosterone, but normal
inhibin concentrations, in men with anorexia nervosa
compared with controls.101 Low testosterone secretion in
5
 Review

young men with anorexia nervosa has harmful eects eects of antidepressants.105 Women with anorexia
on bone and body composition.71,104 nervosa have lower sodium concentrations in plasma
and reduced osmolality, higher levels of antidiuretic
Posterior pituitary hormones and renal function hormone, and more concentrated urine than controls.106
Some studies have reported altered osmoregulation in After water deprivation, however, secretion of antidiuretic
anorexia nervosa that has been attributed to abnormalities hormone becomes suboptimum in patients with anorexia
in vasopressin secretion, intrinsic renal defects and the nervosa, which decreases their ability to concentrate
urine.106 Cases of nephrocalcinosis, renal calculi,
rhabdomyolysis, and renal failure were previously
A frequently reported in individuals with anorexia nervosa,
8 Posterior-anterior spine
Hip but such renal complications are now seldom
6 reported,107112 probably because of early diagnosis and
timely medical care. Rhabdomyolysis has been associated
4 *
with both hypokalaemia and hypophosphataemia.109,111
Change in BMD (%)

2
Hypokalaemia can also occur from purging behaviours,
as well as from restrictive behaviours, particularly in
0 bulimia nervosa, and from abuse of laxatives and
diuretics.113,114 Hypophosphataemia might occur during
2
refeeding111 and, therefore, electrolyte levels should be
4 carefully monitored in individuals with anorexia nervosa.
The posterior pituitary and osteoblast-derived hormone
6
Improved weight and Neither improved weight nor
oxytocin is also aected by anorexia nevosa. Pooled
B resumed menses resumed menses nocturnal oxytocin values are lower in adult women with
5 * anorexia nervosa than in controls, and are associated
4 with lower fat mass.115 Oxytocin has anorexigenic eects
3
and is bone anabolic through eects on osteoblasts.116
Oestrogen in turn regulates oxytocin secretion by
Change in BMD (%)

2
osteoblasts.117 Thus, reduced oestrogen secretion in
1 individuals with anorexia nervosa might lead to a
0 decrease in oxytocin secretion, which in turn might
1 contribute to impaired bone metabolism. Importantly,
2
food-induced oxytocin secretion in people with restrictive
anorexia nervosa and in recovered individuals predicts
3
the degree of psychopathology of eating disorders and
4 hypoactivation of food-motivation circuitry.118
Resumed menses Did not resume menses
C
15
*
Bone-mineral metabolism
10 One of the most concerning consequences of anorexia
05 nervosa, which might persist even with weight recovery,
0
is low BMD.98,119,120 This side-eect is associated with
altered bone microarchitecture121,122 and reduced
Change in BMD (%)

05
strength.121,123 The risk of fracture is higher in women
10 with anorexia nervosa than in the general population.13,124
15
20 Bone-mineral density
25 Adults and adolescents with anorexia nervosa have low
30
areal BMD at the spine and the hip compared with
controls, which indicates that both trabecular and cortical
35
Improved weight Did not improve weight sites are aected.96,119,120,125 In one study, BMD was reduced
at one or more skeletal sites by at least 10 SD in 92%
Figure 4: Eects of weight, menstrual recovery, or both on BMD in adult
women with anorexia nervosa not receiving oral contraceptives
and by at least 25 SD in 38% of women with anorexia
(A) Women with improved weight and resumed menses over time with attention nervosa.125 In the absence of weight and menstrual
to caloric intake had increased spinal and hip BMD, but those with neither did recovery, women with anorexia nervosa lose bone mass
not. (B) Resumed menses were associated with increased spinal but not hip BMD, at an annual rate of 26% at the spine and 24% at the
but neither improved in those who did not recover menstrual function.
(C) Weight gain was associated with increased hip but not spinal BMD, but
hip (gure 4).119 With weight gain, preferential increase is
neither increased if weight did not improve. BMD=bone-mineral density. seen in total hip BMD, whereas with menstrual recovery
*p<005. Reproduced from reference 119 by permission of the Endocrine Society. a preferential gain is noted at the spine (gure 4).119

6 www.thelancet.com/diabetes-endocrinology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(13)70180-3


Similar to adults, low areal BMD is characteristic of
anorexia nervosa in adolescents. Early studies indicated
that up to 50% of girls with anorexia nervosa had areal
BMD Z-scores lower than 20 at diagnosis.126 Later
studies, however, show more encouraging results, probably
because of increased awareness of anorexia nervosa and
early diagnosis and treatment. We found that 52% of
adolescents with anorexia nervosa had areal BMD Z scores
lower than 10 at one or more sites, with the spine (a site
of predominantly trabecular bone) being the most
aected.120 Additionally, in contrast to healthy adolescents,
in whom continued bone accrual is necessary to attain
optimum peak bone mass, in adolescents with anorexia
nervosa bone accrual plateaus.98,127 This nding raises
concerns for attainment of peak bone mass, which is a
critical determinant of future bone health and fracture
risk. With recovery of weight and menses, bone accrual
increases127 but does not catch up to that in normal-weight
controls. In fact, areal BMD Z scores frequently continue
to decrease even after weight gain.127 Low BMD is also
observed in adolescent boys with anorexia nervosa72,128 but,
in contrast to girls, sites of predominantly cortical bone,
such as the hip, are involved to a greater extent than the
spine. The proportions of boys with anorexia nervosa who
have Z scores lower than 10 at the femoral neck and
spine are 65% and 50%, respectively, compared with 18%
and 24% in normal-weight boys.72
Bone microarchitecture and strength
Adult women with anorexia nervosa have decreased
cortical thickness and cortical volumetric BMD at the distal
radius, as assessed by high-resolution peripheral
quantitative CT.129 Trabecular bone is also altered, with
reductions in the number and thickness of trabeculae and
increased trabecular separation.121,129 Strength, estimated by
micronite element analysis, shows lower values in
women with anorexia nervosa than in normal-weight
controls.123 Similarly, adolescents with anorexia nervosa
have altered bone microarchitecture, with reduced cortical
and trabecular thickness, cortical area, and total and
trabecular volumetric BMD, and increased trabecular area,
compared with controls.121 Cortical porosity is increased in
individuals with anorexia nervosa, and stiness and failure
load (strength estimates) are decreased.121
Determinants of impaired bone metabolism
Important determinants of low BMD in individuals
with anorexia nervosa include low BMI and lean body
mass,119,120,125 consistent with the eects of mechanical
loading on bone strength. Specically, low lean mass
predicts low hip and whole body BMD, and size
parameters of bone microarchitecture, such as cortical
thickness and total area.
Low BMD and impaired bone microarchitecture are
associated with hypogonadism, late age at menarche, and
long-term amenorrhoea.72,97,120,125 Low concentrations of
oestradiol and testosterone predict reduced BMD in
www.thelancet.com/diabetes-endocrinology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(13)70180-3
Review
individuals with anorexia nervosa.72,97,120,125 Oral oestrogen
monotherapy does not eectively increase BMD in adults
or adolescents with anorexia nervosa,130,131 which is thought
to be because this treatment lowers concentrations of
IGF-1.132,133 Importantly, a more physiological approach to
hormone-replacement therapy with oestrogen replacement
via transdermal oestradiol and cyclic progesterone
increases spine and hip areal BMD Z scores in adolescents
with anorexia nervosa (gure 5).134 However, complete
catch-up does not occur, probably because alterations
persist in other hormones that aect bone, such as
persistence of low levels of IGF-1 and a state of relative
hypercortisolaemia. In a randomised, placebo-controlled
study, transdermal testosterone replacement did not
improve BMD in adult women with anorexia nervosa.135
Oral prasterone (dehydroepiandrosterone) with ethinylo-
estradiol prevented further decreases in BMD Z scores in
one study of young women with anorexia nervosa.136 Data
on the ecacy of testosterone replacement on BMD in
boys or men with anorexia nervosa are not available.
A key determinant of impaired bone metabolism in
anorexia nervosa is GH resistance leading to low IGF-1
concentrations.36,41,98 In individuals with anorexia nervosa,
IGF-1 levels correlate positively with markers of bone
turnover, areal BMD,36,98 and bone structural
characteristics.122 Administration of 3040 g/kg
recombinant human IGF-1 twice daily increases
concentrations of bone formation markers in adolescents
and adults.137,138 In a 9-month randomised, controlled
study in adults with anorexia nervosa, those who received
oral oestrogen and recombinant human IGF-1 showed
increases in areal BMD compared with those who
received no treatment or treatment with oestrogen or
IGF-1 alone.139 Studies are being done of similar
treatments in adolescents with anorexia nervosa.
8 No oestrogen replacement
Oestrogen replacement
Control
*
6 * *
Change in lumbar BMD (%)
*
*
4
*
2
0
2
06 012 018
Time (months)
Figure 5: Eects of physiological oestrogen replacement on BMD in adolescent girls with anorexia nervosa
Girls with anorexia nervosa who received oestrogen-replacement therapy had signicant increases in lumbar BMD
at 6, 12, and 18 months similar to bone accrual rates seen in controls, whereas those with anorexia nervosa who
received no therapy had no gains in BMD. Values are adjusted for baseline age and weight. BMD=bone-mineral
density. Reproduced from reference 134 by permission of the American Society for Bone and Mineral Research.
7
 Review

Calorie and fat intake Exercise energy expenditure

Low energy availability

GH-IGF-1 axis Hormones regulating HPA axis HPT axis HPG axis Posterior Adiponectin, incretins,
Acquired GH resistance appetite/food intake CRH, ACTH Normal or low TSH Impaired LH pulsatility pituitary insulin
GHBP Orexigens Relative hypercortisolaemia * Total T3 Oestradiol and Oxytocin Adiponectin*
IGF-1* Ghrelin* Normal or low normal free T4 testosterone GLP-1 and GIP
GH Anorexigens Insulin*; amylin
PYY*
Leptin*

Lipolysis Gluconeogenesis Muscle breakdown Glycogenesis, glucose

uptake and lipogenesis

Euglycaemia and glucose available for essential functions

Figure 6: Endocrine changes in anorexia nervosa that maintain euglycaemia, preserve energy for vital functions, and contribute to impaired bone metabolism
GH=growth hormone. IGF-1=insulin-like growth factor 1. GHBP=growth-hormone binding protein. PYY=peptide YY. HPA=hypothalamic-pituitary-adrenal. CRH=corticotrophin-releasing hormone.
ACTH=adrenocorticotropic hormone. HPT=hypothalamic-pituitary-thyroid. TSH=thyroid-stimulating hormone. T3=tri-iodothyronine. T4=tetra-iodothyronine. HPG=hypothalamic-pituitary-gonadal.
LH=luteinising hormone. GLP-1=glucagon like peptide-1. GIP=glucose-dependent insulinotropic peptide. *Hormonal changes implicated in altered LH pulsatility. Hormonal changes implicated in
impaired bone metabolism.

adiponectin and apparent spine BMD in people with

Search strategy and selection criteria
We searched PubMed for articles published in English from
January, 1990, to October, 2013, with the search terms
anorexia nervosa or eating disorders in combination with
the terms hypogonadism, estrogen, testosterone,
growth hormone, IGF-1, cortisol, thyroid, ghrelin,
leptin, peptide YY, adiponectin, amylin, GLP-1,
GIP, bone density, bone structure or microarchitecture,
nite element analysis, or fractures. We largely selected
those published in the past 15 years, but did not exclude
commonly referenced and seminal older articles. We also
searched the reference lists of retrieved articles to identify
further relevant papers. Review articles and book chapters
were included to provide readers with more details and
references than can be accommodated in this Review.
Other determinants of low BMD include high
concentrations of cortisol15,44 and PYY71,140 and low levels
of leptin, insulin, and amylin.54,55 PYY inhibits
osteoblastic activity, and decreased bone formation is
seen in transgenic mice that produced an excess of
PYY.141 In individuals with anorexia nervosa, high PYY
concentrations correlate with low BMD in adults, and
with low levels of bone-turnover markers in
adolescents.71,140 Leptin, insulin, and amylin all have
bone anabolic eects, and reduced concentrations of
these hormones in individuals with anorexia nervosa
correlate with reduced BMD.55,56,122 Finally, adiponectin is
harmful to bone, and inverse associations exist between
anorexia nervosa.55
Management of low bone-mineral density and impaired
bone accrual
The most important strategy to improve BMD and bone
accrual in adolescents with anorexia nervosa is recovery
of weight and menstrual function, although bone accrual
rates and Z scores do not recover to control values.127
This lack of catch-up might reect persistent
abnormalities in levels of hormones, such as cortisol, or
frequent relapses of anorexia nervosa. Vitamin D
supplementation is important to maintain 25(OH)
vitamin D levels higher than 30 ng/mL. Many individuals
with anorexia nervosa, however, regularly take calcium
and vitamin D supplements. Therefore, vitamin D
concentrations should be measured every 612 months
to avoid over-replacement. Because the teenage years are
such a narrow window of time during which to optimise
bone accrual, physiological transdermal oestrogen
replacement (with cyclic progesterone)134 could be
considered in teenage girls with anorexia nervosa who
have completed growth and have history of fractures or
very low and deteriorating BMD Z scores (lower than
20).142 The eect of oestrogen replacement on fracture
risk in adolescents with anorexia nervosa, however,
remains unclear. Testosterone replacement does not
increase BMD in women with anorexia nervosa.135
Bisphosphonates increase BMD in adults with anorexia
nervosa,135 but do not increase spine BMD in
adolescents.143 If used as a therapeutic strategy,

8 www.thelancet.com/diabetes-endocrinology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(13)70180-3


bisphosphonates should be given cautiously in women
of reproductive age because of their long half-life and
possible harmful eects on the developing fetus.
Eating disorder psychopathology, anxiety,
and depression
Reduced levels of gonadal hormones, oxytocin, and leptin,
and raised concentrations of cortisol and PYY have been
implicated in psychopathology and symptoms of anxiety
and depression in individuals with anorexia nervosa.16,17,118,143
Administration of transdermal oestradiol reduces anxiety
in girls with anorexia nervosa without aecting eating
attitudes or perception of body shape.144 In addition,
oestrogen-replacement therapy prevents the increase in
aberrant eating attitudes and body dissatisfaction noted
with weight gain in anorexia nervosa.145
Conclusions
Anorexia nervosa is associated with mostly adaptive
changes in multiple endocrine axes. These changes are
part of a physiological response to optimise energy
intake and availability for vital functions (gure 6).
These changes, however, contribute to low BMD and
possibly to neurocognitive changes and psychopathology.
Studies are being done to assess the eects of various
therapeutic strategies on bone accrual and bone
structure in individuals with anorexia nervosa, and to
better understand the links between various hormonal
changes and food motivation pathways that involve
reward and satiety.
Contributors
MM did the literature search and writing and AK reviewed the drafts and
provided feedback.
Declaration of interests
We declare that we have no competing interests.
Acknowledgments
MM is supported by the National Institutes of Health grants 1 R01
HD060827 and 1 K24 HD07184301A and Clinical Translational Science
Center grant 5UL1RR025758, and AK by grant 2 RO1 DK062249.
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