Functional Hypothalamic Amenorrhea: Hypoleptinemia
and Disordered Eating
M. P. WARREN, F. VOUSSOUGHIAN, E. B. GEER, E. P. HYLE, C. L. ADBERG, AND
R. H. RAMOS
Departments of Obstetrics and Gynecology and Medicine, Columbia College of Physicians and
Surgeons, New York, New York 10032
Because the exact etiology of functional, or idiopathic, hypotha-
lamic amenorrhea (FHA) is still unknown, FHA remains a diagnosis
of exclusion. The disorder may be stress induced. However, mounting
evidence points to a metabolic/nutritional insult that may be the
primary causal factor.
We explored the thyroid, hormonal, dietary, behavior, and leptin
changes that occur in FHA, as they provide a clue to the etiology of
this disorder. Fourteen cycling control and amenorrheic nonathletic
subjects were matched for age, weight, and height. The amenorrheic
subjects denied eating disorders; only after further, detailed ques-
tioning did we uncover a higher incidence of anorexia and bulimia in
this group. The amenorrheic subjects demonstrated scores of abnor-
mal eating twice those found in normal subjects (P ? 0.05), partic-
ularly bulimic type behavior (P ? 0.01). They also expended more
calories in aerobic activity per day and had higher fiber intakes (P ?
0.05); lower body fat percentage (P ? 0.05); and reduced levels of free
T4(P ? 0.05), free T3(P ? 0.05), and total T4(P ? 0.05), without a
significant change in rT3or TSH. Cortisol averaged higher in the
amenorrheics, but not significantly, whereas leptin values were sig-
nificantly lower (P ? 0.05). Bone mineral density was significantly
lower in the wrist (P ? 0.05), with a trend to lower BMD in the spine
(P ? 0.08). Scores of emotional distress and depression did not differ
The alterations in eating patterns, leptin levels, and thyroid func-
tion present in subjects with FHA suggest altered nutritional status
and the suppression of the hypothalamic-pituitary-thyroid axis or the
alteration of feedback set-points in women with FHA. Both lower
leptin and thyroid levels parallel changes seen with caloric restric-
tion. Nutritional issues, particularly dysfunctional eating patterns
and changes in thyroid metabolism, and/or leptin effects may also
have a role in the metabolic signals suppressing GnRH secretion and
the pathogenesis of osteopenia despite normal body weight. These
findings suggest that the mechanism of amenorrhea and low leptin in
these women results mainly from a metabolic/nutritional insult.
(J Clin Endocrinol Metab 84: 873–877, 1999)
hypothalamic amenorrhea. Women who are of normal
weight may also experience hypothalamic amenorrhea, but
the etiology is often unclear. The amenorrhea is thought to
identified. This is generally referred to as functional idio-
pathic hypothalamic amenorrhea (FHA).
The etiology of FHA is not clearly understood, and it
remains a diagnosis of exclusion. Women with FHA have
been found to have neuroendocrine dysfunction, suggesting
that central regulation of multiple pituitary hormones is dis-
A common denominator in FHA is suppression of GnRH
primates suggest that energy availability or overall energy
deficit may be the common denominator in the suppression
of GnRH secretion (4, 5). Research has uncovered a constel-
lation of hormonal abnormalities that occur in FHA (1) and
are compatible with an energy deficit despite the lack of a
history of dietary insult (6, 7). Osteopenia has also been
OMEN WITH very low body weight and body fat are
known to be at high risk for the development of
The discovery of the hormone leptin has provided a pos-
sible mechanism by which metabolic signals may be com-
municated to the reproductive axis. Leptin is secreted by the
adipocyte and is influenced by multiple metabolic pathways
affecting appetite, energy requirements, and eating behavior
(9). This may provide a link for other metabolic and hor-
monal pathways that are known to affect reproduction to
communicate nutritional status and the degree of fat stores
to the reproductive axis. Recently, low leptin levels have
been reported in hypothalamic amenorrhea, although the
etiology remains unclear (10).
We examined a group of patients with idiopathic hypo-
thalamic amenorrhea in depth to determine whether the
metabolic abnormalities in their disorder were suggestive of
abnormal eating patterns and therefore reflective of an en-
ergy deficit or dysregulation, as suggested by our previous
Materials and Methods
We studied 14 subjects with amenorrhea who were matched with 14
normally menstruating controls on the basis of age, height, and weight.
All were volunteers and were solicited from advertisements in college
publications and by physician referral. Volunteers were told that the
for amenorrhea of at least 5-month duration. All subjects denied recent
weight loss, eating disorders, or athletic activity and had participated in
past studies on bone density (11, 12) and hypothalamic amenorrhea (7).
were approved by the institutional review board of St. Luke’s-Roosevelt
Hospital Center. The educational levels of the subjects were determined
Received August 14, 1998. Revision received December 4, 1998. Ac-
cepted December 8, 1998.
Address all correspondence and requests for reprints to: Michelle P.
Warren, M.D., Department of Obstetrics and Gynecology, PH 16–20,
Columbia University, 622 West 168th Street, New York, New York
The Journal of Clinical Endocrinology & Metabolism
Copyright © 1999 by The Endocrine Society
Vol. 84, No. 3
Printed in U.S.A.
by the seven-point scale developed by Hollingshead and Redlich, as
described previously (13). All subjects were white and from middle to
upper class families.
Each subject was interviewed by a nurse practitioner, who obtained
data on present and past illnesses, weight changes, fractures, and com-
plete menstrual and medication histories. All patients with a chronic
illness of any kind were eliminated from the study. The nurse practi-
tioner also measured weight and height.
Ideal weights were obtained from tables of average weight-height
relations for young adults, as described previously (13), and the subjects
were compared and categorized as being above or below normal weight
standards. We used Sargent’s tables for subjects aged 17 yr or older;
these tables include six categories from underweight to obese (13). Per-
cent body fat was determined by measuring skinfolds at four sites
(biceps, triceps, subscapular, and supra-iliac) and converting the values
to body fat according to the method described by Durnin and Wom-
examination, and none was receiving hormone therapy at the time the
data were collected. All patients with secondary amenorrhea fit the
criteria for hypothalamic amenorrhea: normal PRL, testosterone, and
and LH levels. Two patients were eliminated from the study because
their medical and hormonal evaluations revealed a chronic anovulatory
syndrome consistent with polycystic ovary disease with normal estro-
Hormonal studies were performed on a venous blood sample ob-
tained in the midafternoon. Assays for LH, FSH, PRL, testosterone, and
DHEAS were performed as previously described (15). Levels of T3and
T4(both total and free), rT3, and TSH were measured. Free T3was
interassay coefficient of variation was 2.8–4.8%, the intraassay coeffi-
cient of variation was 4–11%, and the lower limit of sensitivity was 0.2
pg/mL. Free T4was measured by125I RIA (Diagnostic Products Corp.).
The interassay coefficient of variation was 6–10%, the intraassay coef-
ng/dL. Total T4was measured by125I RIA (Diagnostic Products Corp.).
The interassay coefficient of variation was 4.2–14.5%, the intraassay
coefficient of variation was 3.1–8.9%, and the lower limit of sensitivity
Corp.). The interassay coefficient of variation was 5.7–10.0%, the in-
traassay coefficient of variation was 2.7–3.8%, and the lower limit of
Diagnostics, Medfield, MA). The interassay coefficient of variation was
6.5–9.9%, the intraassay coefficient of variation was 5.2–7.8%, and the
lower limit of sensitivity was 0.005 ng/mL. Serum TSH was determined
by an immunoradiometric assay (Diagnostic Products Corp.). The in-
terassay coefficient of variation was 1.8–4.2%, the intraassay coefficient
of variation was 1.2–2.0%, and the lower limit of sensitivity was 0.03
?IU/mL. The assay was standardized in terms of the WHO Second
International Reference Preparation of TSH for immunoassay (80/558).
Leptin was measured by an immunoradiometric assay (Linco Research,
Inc., St. Charles, MO). The interassay coefficient of variation was 3.6–
4.0%, the intraassay coefficient of variation was 3.04–4.03%, and the
lower limit of sensitivity was 0.5 ng/mL. Midafternoon cortisol was
measured in serum by RIA (Diagnostic Products Corp.). In this assay,
the intra- and interassay coefficients of variation were 2.5–8.0% and
4.5–6.36%, respectively. The detection limit was less than 0.2 ?g/dL.
during the early follicular phase in menstruating subjects (days 3–7).
Food intake was determined by use of a 2-day dietary history (two
measure is designed to target frequently consumed food items that
contain relatively high values for those nutrient groups known to either
D, fiber, and caffeine (16). During the nutrition interview, subjects were
asked about the average frequency per week with which they ate each
of the specified food items in the past year. There are nine responses,
ranging from never to six or more times per day. The items are listed in
quantities that represent standardized portion sizes and natural units.
The 24-h recall food intake diary is an improved version of that
described by Frank et al. (17). The subject filled out the Saturday diary
before her scheduled visit with the nutritionist. During the visit, the
subject reviewed the Saturday diary and generated a recall for the
weekday diary. These established good intake information through the
listing of food items consumed during six specified eating times. For
each item, the type and standardized amount were recorded, and in-
caloric intake was derived from the sample 24-h intake diary. Repro-
ducibility and validity were quantified in large prospective studies
among women; intraclass correlation coefficients were calculated with
1-week dietary recall measures. The overall mean of correlation coeffi-
cients comparing intakes for 18 nutrients measured on both Walter
Willett Semiquantitative Food Frequency Questionnaire and the dietary
recall measure was 0.60.
The food frequency questionnaire measured the subject’s food intake
over the past year. Seasonal consumption of some foods (summer fruits
and hot breakfast cereals, for example) was averaged over the entire
Activity level was determined based on the number of calories ex-
pended per day according to the method of Bouchard et al., previously
The existence and severity of eating problems was assessed through
both questionnaires and subject interviews. Subjects were asked to com-
plete Garner and Garfinkel’s EAT-26, an abbreviated version of their
EAT-40 Eating Attitudes Test. Questions on this scale relate to three
factors: dieting, bulimia and food preoccupation, and oral control, as
previously described (13).
During a semistructured interview with the study’s research assis-
thoughts or behaviors required by the Diagnostic and Statistical Manual
of Mental Disorders (DSM-III) for a diagnosis of anorexia, bulimia, and
atypical eating disorder. The results of these interviews were also res-
cored according to DSM-III-R criteria for these disorders (13).
Bone mineral densities of the spine, wrist and metatarsal were de-
termined using a DP3/SP2 Lunar dual photon spine/femur scanner
(Lunar Corp., Madison, WI) as previously described (13).
The Hopkins Symptom Checklist (18) was used to measure the level
of emotional distress and depressive symptoms currently experienced.
depression, and anxiety (4-point Likert scale). Mean scores range from
1–4, with higher scores indicating more severe emotional distress.
The Mann-Whitney test and t tests for paired samples were used for
statistical analysis. To control for variables showing significant differ-
ences in the paired samples, variables were further assessed by analysis
Cycling controls and amenorrheics were matched for age,
disorders, but our evaluation showed that they had a higher
not on a history but on our in-depth testing for eating dis-
on the scale of disordered eating behavior (EAT; 23.62 vs.
behavior (P ? 0.01). They also had higher fiber intakes (23.84
vs. 12.56 g/day; P ? 0.05). Although their total expended
calories per day were similar to the controls, they expended
more calories in aerobic activity per day (444.20 vs. 174.52
TABLE 1. Characteristics of the subjects
Characteristics of the
% of ideal wt
Body fat (%)
(n ? 14)
23.43 ? 3.96
64.52 ? 2.03
113.87 ? 11.67
90.69 ? 11.20
21.55 ? 3.99
(n ? 14)
23.29 ? 3.79
64.55 ? 1.81
118.61 ? 7.28
93.60 ? 13.04
25.16 ? 3.54
874 WARREN ET AL.
JCE & M • 1999
Vol 84 • No 3
Cal/day; P ? 0.05; Table 2), and they tended to have a lower
body fat percentage (21.55% vs. 25.16%; P ? 0.053; Table 1).
Leptin values were significantly lower in amenorrheic
groups even when controlling for body fat (P ? 0.05). The
mean scores on the Hopkins Symptom Checklist did not
differ, nor did fat intake.
In amenorrheic subjects, the hormonal studies revealed
significantly reduced levels of free T4(1.19 vs. 1.51 ng/dL;
0.05; Table 3), without a significant change in rT3or TSH.
Consistent with past experiments, cortisol averaged higher
in the amenorrheics, but not significantly. Bone mineral den-
sity was significantly lower in the wrists of amenorrheics
0.08), but values in the metatarsal did not differ (Table 3).
These results indicate that alterations in leptin levels and
thyroid function are present in normal weight subjects with
out obvious caloric deficits. The reproductive abnormalities
is the first report to link the hypoleptinemia to disordered
eating and lower bone mass. Decreased leptin levels may
reflect the lower body fat, restrictive eating behavior, or
possibly a combination of both, but are significantly lower in
amenorrheics independent of body fat. This suggests that
restrictive eating behavior is more important. Although lep-
tin is a metabolic hormone correlated with fat mass and
metabolic rate (19–22) and affects appetite and eating be-
havior (19), it is thought to be a mediator of puberty (23), and
recent research is emerging in animals showing that falling
leptin seen with starvation may suppress reproduction and
thyroid function while activating the hypothalamic-pitu-
itary-adrenal axis (24). Leptin has been implicated in the
neuroendocrine response to fasting and has been found to
blunt the starvation-induced responses of the gonadal, thy-
roid, and adrenal axis when administered to male mice (25).
Other studies in rats show that the hypothalamic-pituitary-
thyroid axis may serve as a critical locus to mediate the
central actions of leptin by regulating pro-TSH gene expres-
sion (26, 27), and reports of leptin mutations in the human
indicate lack of pubertal development and suppression of
TSH (28). Thus, the role of leptin may be not only to control
the neuroendocrine responses to starvation. This pattern of
was prevented by leptin repletion (25). The findings in our
subjects suggest that chronic disordered eating may cause
similar metabolic changes without an energy deficit.
The diurnal rhythm of leptin is absent in amenorrheic
other types of hypothalamic amenorrhea that are weight or
exercise induced, syndromes associated with negative en-
ergy balance. Thus, low leptin levels may be a sensitive
indication of overall nutritional status and may also be as-
sociated with the metabolic changes associated with restric-
tive eating in women of normal weight. Low body fat may
contribute to the problem in normal weight women.
The potential mechanism by which leptin links the met-
abolic and reproductive axes remains unknown. One possi-
ble hypothesis is that a caloric deficit, even with no loss of fat
mass, will trigger a cascade that will affect leptin secretion
from the fat adipocytes. Leptin appears to be regulated by
energy balance as well as fat stores (30), and energy depri-
vation has a disproportionately acute effect on lowering lep-
tin levels even short term (9, 25, 31–33). Thus, the disordered
eating, particularly the fasting-gorge behavior of bulimia,
may disproportionally lower leptin levels. Leptin also reg-
ulates the basal metabolic rate, another factor that is altered
in exercise-induced amenorrhea (34). Changes in the thyroid
axis may also be key players in regulation of the basal met-
abolic rate (25, 26, 33).
The sick euthyroid, or low T3, syndrome is seen in cases
of rT3(35), which is also present in cases of anorexia nervosa
(36). Although our results do not show a rise in absolute rT3,
it is possible that the conversion rate from T4to rT3is de-
and with nutritional restriction in normal individuals (34, 37,
38). Bosello et al. also found an increase in rT3in a dieting
TABLE 2. Eating disorders and nutritional patterns
Eating disorders and nutritional
EAT 26 scores
Hopkin’s syndrome checklist
Fiber intake (g/day)
Fat intake (g/day)
Cal expended at activities/24 h
Amenorrheic (n ? 14) Matched controls (n ? 14)
23.62 ? 14.99
14.54 ? 8.74
5.77 ? 4.29
3.31 ? 3.38
1.82 ? 0.47
2360.80 ? 480.14
1993.97 ? 732.87
23.84 ? 10.40
57.12 ? 28.26
10.69 ? 7.91
6.69 ? 6.02
0.92 ? 1.66
3.08 ? 3.33
1.60 ? 0.30
2504.57 ? 465.27
1566.94 ? 494.18
12.56 ? 9.86
59.50 ? 32.50
444.20 ? 301.72
1627.42 ? 425.46
382.35 ? 155.67
174.52 ? 197.34
1851.13 ? 381.57
370.65 ? 82.75
DISORDERED EATING AND LEPTIN IN AMENORRHEA 875
group, but no change in a diet plus exercise group (39). The
patients with FHA in this study showed a pattern similar to
subjects in Bosello’s study, with both abnormal eating be-
havior and high caloric expenditure.
Reduced thyroid function is associated with a depressed
resting metabolic rate, which results in lower levels of leptin.
A recent study by Valcavi et al. (40) underscores this corre-
lation between lower levels of leptin and hypothyroidism,
and recent studies suggest that the reduced concentration of
leptin may play a role in producing the decreased energy
expenditure of patients with low thyroid hormone levels.
The concentration of thyroid hormones may control the ac-
tive function of leptin by affecting either leptin-binding pro-
teins and/or leptin receptors (40). Thus, the role of the thy-
roid and leptin changes may be to preserve energy when
nutritional intake is compromised. Our subjects with idio-
pathic FHA showed restrictive eating patterns, which could
explain these changes and may be associated with changes
in metabolic rate.
The extreme sensitivity of the GnRH pulse generator is
suggested by numerous experiments. Although stress can
cause a patient to alter her food intake in either amount or
type, research by Schreilhofer et al. in the primate confirm
that it is mainly the energy deficit induced by short term
fasting, and not stress, that causes the irregular LH secretion
associated with disruption of reproductive function (5, 41).
Although stress has been shown to disrupt cyclicity in mon-
keys, nutritional metabolic insults are more significant (42).
stress induced, but the effects on GnRH pulses are more
likely due to the former. In fact, replacing low leptin restores
GnRH pulses in fasted monkeys (43).
In a recently published study, Berga et al. attributed FHA
to stress, showing that only women with FHA had increased
levels of cortisol; cycling women and women with amenor-
rhea of other origins (excluding eating disorders and exer-
cise) showed no changes in cortisol (44). The characteristics
of our subjects were very similar to those in Berga’s study,
especially in that none of the women was a confessed an-
orexic, bulimic, or heavy exerciser, and we too observed
these increases in cortisol concentration in our subjects with
FHA. Although our results were not significantly increased,
our cortisol levels represent only one time sampling. The
EAT scores in this study as well as the nutritional and ex-
ercise patterns and the low leptin levels suggest an associ-
ation between hidden nutritional abnormalities and amen-
orrhea. Information was not available for Berga’s subjects on
leptin concentrations, EAT scores, or other nutritional data
(45), and subtle nutritional differences between the two
different conclusions drawn by the two similar studies. Low
leptin levels were also detected in a new study (10), but the
mechanism remained unknown.
Increased cortisol levels may affect thyroid function; how-
ever, past studies have shown that glucocorticoids suppress
TSH levels as well as T3(24, 46). Our results show normal
TSH concentrations in subjects with FHA.
Our results suggest that FHA may be more a function of
expenditure than purely stress induced. Previous studies
suggest that nutritional abnormalities in FHA are subtle and
need to be searched for in depth (6, 7). These results in a
carefully matched sample also suggest that small or unre-
ported nutritional insufficiencies may cause many cases of
so-called idiopathic hypothalamic amenorrhea. This is im-
portant, as osteopenia is a serious complication, and inter-
vention may need to address nutritional issues as well as
hormonal replacement. Alternately, stress may induce these
dietary patterns, but studies suggest that GnRH suppression
rarely occurs with stress alone but requires a setting of nu-
tritional restriction (42).
The active form of thyroid hormone is a potent stimulator
of bone turnover (47), and both nutritional issues and
changes in thyroid metabolism may have a role in the patho-
genesis of osteopenia and may be important metabolic links
to the GnRH pulse generator, possibly via a leptin pathway.
Interestingly, leptin has recently been found to have recep-
tors in bone, may be a physiological regulator of bone mass
(48, 49), and thus may be the link between amenorrhea and
TABLE 3. Endocrine studies
Bone density (g/cm2)
Values are the mean ? SD.
Amenorrheic (n ? 14)
6.61 ? 2.27
3.57 ? 3.81
137.24 ? 155.04
1.70 ? 0.99
6.54 ? 4.35
7.05 ? 2.86
12.44 ? 5.21
1.19 ? 0.30
2.46 ? 0.61
5.45 ? 0.85
96.07 ? 17.85
0.14 ? 0.06
1.30 ? 0.83
5.06 ? 2.18
Matched controls (n ? 14)
7.10 ? 2.26
8.19 ? 8.24
207.63 ? 131.43
1.50 ? 0.74
6.01 ? 3.23
11.52 ? 8.13
10.25 ? 4.95
1.51 ? 0.43
3.28 ? 0.98
8.46 ? 1.80
108.22 ? 21.57
0.18 ? 0.08
1.13 ? 0.35
9.03 ? 3.47
0.6692 ? 0.082
1.1748 ? 0.200
0.8531 ? 0.136
0.6770 ? 0.050
1.2575 ? 0.126
0.8771 ? 0.120
876WARREN ET AL.
JCE & M • 1999
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ThechangesseeninFHAareparticularlyintriguing,asthe Download full-text
depressed leptin level suggests that metabolic factors are
present in this syndrome. Understanding the dysregulation
that occurs in this syndrome may provide a clue to treating
the amenorrhea and to understanding the central signal sup-
pressing GnRH in hypothalamic amenorrhea.
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