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Developing a Model of Nutritional Amenorrhea in Rhesus Monkeys

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DOI: 10.1210/en.2005-0821 · Source: PubMed

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Developing a Model of Nutritional Amenorrhea in
Rhesus Monkeys
Marla E. Lujan, Alicja A. Krzemien, Robert L. Reid, and Dean A. Van Vugt
Departments of Physiology (M.E.L., D.A.V.V.) and Obstetrics and Gynecology (A.A.K., R.L.R., D.A.V.V.), Queen’s University,
Kingston, Ontario, Canada K7L 3N6
Nutritional amenorrhea is defined as cessation of menstrual
cycles resulting from a chronic negative energy balance. Al-
though it is agreed that nutritional amenorrhea results from
reduced secretion of GnRH, the neuroendocrine mechanisms
leading to GnRH inhibition are poorly defined. Because the
invasiveness of many neuroendocrine experimental ap-
proaches precludes its use in the clinical setting, we set out to
establish a model of nutritional amenorrhea in rhesus mon-
keys. Studies were conducted in four normal-weight and one
obese female rhesus monkey. Dietary intake was gradually
reduced with the goal of achieving a 15–20% weight reduction.
Dietary restriction inhibited ovulation in all animals. The
weight loss required to inhibit ovulation ranged from 2–11% in
the four normal-weight animals and was achieved with a 23%
reduction in dietary intake. The time of initiating reduced
C HRONIC NEGATIVE ENERGY balance results in the
cessation of menstrual cycles in primates and of
estrous cycles in nonprimate species (1). Anorexia nervosa
and hypothalamic amenorrhea resulting from strenuous
exercise are examples of nutritional amenorrhea caused by
chronic energy deficits. Although amenorrhea is no longer
considered a diagnostic criteria of anorexia nervosa, it
remains a hallmark of anorexia nervosa, occurring in the
vast majority of subjects when weight is less than 80 – 85%
of ideal body weight (2). A high incidence of amenorrhea
also occurs in women whose lifestyle includes strenuous
exercise (3). Although the etiology and degree of negative
energy balance differ in anorexia nervosa and exercise-
induced amenorrhea, similarities between the two condi-
tions exist. Both are characterized by decreased gonado-
tropin pulse frequency leading to suppression of ovarian
cyclicity and impaired gonadal steroid production (3–7).
Moreover, women whose life style includes a rigorous
exercise component have a higher incidence of disordered
eating (8).
Although many studies have described in detail the hy-
pothalamic-pituitary-ovarian axis parameters associated
with nutritional amenorrhea (3, 4, 6, 9 –11) these studies
cannot address the neuroendocrine events that lead to am-
enorrhea. Investigations of the neuroendocrine mechanisms
of nutritional amenorrhea in women are limited by the in-
First Published Online September 29, 2005
Abbreviations: BMI, Body mass index; CV, coefficient of variation; ⌬,
change; Lutexp, time of the expected luteal phase.
Endocrinology is published monthly by The Endocrine Society (http://
www.endo-society.org), the foremost professional society serving the
endocrine community.
483
Endocrinology 147(1):483– 492
Copyright © 2006 by The Endocrine Society
doi: 10.1210/en.2005-0821
food intake to first missed ovulation was 62 ⴞ 13 d. Greater
weight loss (46% reduction) over a longer period (10 months)
was required to inhibit ovulation in the obese monkey. The
onset of anovulation was not preceded by changes in men-
strual cycle length or progesterone secretion. Realimentation
initiated ovulation at a weight that approximated the animal’s
weight at the time of the last ovulatory cycle during dietary
restriction. By contrast, caloric intake at the return of ovu-
lation during realimentation was 28% greater. This is the first
demonstration that chronic dietary restriction can inhibit
ovulation in rhesus monkeys. This model will be useful for
studying the neuroendocrine mechanisms involved in diet-
induced anovulation in primates. (Endocrinology 147:
483– 492, 2006)
ability to conduct prospective studies. In addition, a thor-
ough investigation of neuroendocrine mechanisms involves
a level of invasiveness unacceptable in the clinical setting.
Although inhibition of the reproductive axis by reduced
energy intake has been demonstrated in several rodent spe-
cies (12), accurate translation of results to humans is uncer-
tain given the many differences between the primate men-
strual cycle and rodent estrous cycles. Nonhuman primate
studies in this area are limited and primarily acute in nature.
It has been extensively documented that acute fasting or
glucoprivation can inhibit gonadotropin secretion in rhesus
monkeys (13–16). However, the few chronic studies con-
ducted in nonhuman primates to date demonstrated differ-
ent menstrual cycle responses to a chronic metabolic chal-
lenge. Chronic negative energy balance achieved by
strenuous exercise inhibited ovulation in cynomolgus mon-
keys (17), whereas a 30% reduction in dietary intake did not
inhibit menstrual cycles in rhesus monkeys (18).
Given the similarities between the reproductive axes of
humans and nonhuman primates and the inhibitory effects
of negative energy balance on reproductive cycles of women
and nonprimate species, we hypothesized that dietary re-
striction would inhibit ovulation in rhesus monkeys. The
purpose of the current study was to determine the degree of
dietary restriction required to inhibit ovulation in rhesus
monkeys. The level of dietary restriction required is impor-
tant to the feasibility of establishing a model of diet-induced
amenorrhea in rhesus monkeys, because the utility of such
an animal model would require that ovulation was inhibited
at a level of dietary restriction that did not unduly compro-
mise animal health.
484 Endocrinology, January 2006, 147(1):483– 492 Lujan et al. • Dietary Restriction Induces Anovulation in Monkeys

Materials and Methods Effect of dietary restriction on ovulation in rhesus monkeys

Animal husbandry
Studies were conducted in five adult female rhesus monkeys (Macaca
mulatta). Monkeys ranged in age from 6 –10 yr and weighed between
5.8 –11.9 kg. Animals were housed in groups of two or three in a light-
and temperature-controlled environment (lights on, 0700 –1900 h; tem-
perature, 22 C). Diets consisted of a twice-daily ration of Purina monkey
chow (Hi Protein Monkey Diet Jumbo, Ralston Purina, St. Louis, MO)
supplemented with fruits and vegetables. Water was available ad libitum.
All animal husbandry practices and experimental procedures con-
formed to regulations of the Canadian Council on Animal Care and were
approved by the Queen’s University animal care committee.
Normalizing body weight to a uniform body mass index
Group housing results in the establishment of hierarchies that can
impact on food availability and consequently adiposity. The clinical
impression of varying degrees of adiposity in these five monkeys was
confirmed using a modified method of calculating body mass index
(BMI). The weight in kilograms divided by crown-rump length in meters
squared produces an index in rhesus monkeys that is highly correlated
with percent body fat (19). Because BMIs were 39.3, 27.2, 25.0, 24.2, and
22.1 kg/m2, group-housed animals were separated during meal times
(0900 –1100 and 1400 –1600 h) to standardize their weights and subse-
quently regulate their dietary intake. Four monkeys were initially placed
on a daily ration of 15 biscuits (calculated to provide 1887 kJ/d), whereas
the obese animal was restricted to 1415 kJ/d (12 biscuits). Diets were
further individualized in the subsequent months to achieve a uniform
BMI of 24 –23 kg/m2, which translates into a lean body habitus. Ad-
justments to diets included 1) increasing the vegetable component, 2)
modifying the number of monkey chow biscuits allotted, and 3) elim-
inating high carbohydrate treats to those monkeys whose BMI exceeded
24 kg/m2. Food intake was monitored daily, and monkeys were
weighed monthly during the initial phase of the experiment using a
transfer box that eliminated the need for sedation. Animals were trained
to present a limb through an opening in the cage for blood sampling by
venipuncture. Blood samples (1.5–2 ml) were drawn three times a week
before the morning meal.
Once a BMI of 24 –23 kg/m2 was attained, animals were placed on a
16-wk regimen of dietary restriction with the goal of decreasing weight
by 20%. This was accomplished by decreasing the amount of monkey
chow allotted to each animal. The rate and extent of dietary restriction
were dependent on the rate of weight loss in each animal. Every 2 wk,
one cube of monkey chow was removed if weight loss had not exceeded
the desired rate of decline. In each case, the aim of dietary restriction was
to decrease weight by no more than 20% and dietary restriction by no
more than 40% over the 16-wk period. An attempt was made to maintain
the bulk of each animal’s diet by increasing the amount of low calorie
vegetables given between the morning and afternoon feedings. An iron-
rich vitamin supplement was given daily. Once animals became anovu-
latory, we attempted to maintain each animal’s weight just below
(within 500 g) the animal’s weight at the time of the first missed ovu-
lation (i.e. time of the expected luteal phase). Animals were maintained
on dietary restriction for 8 –10 months, during which time the effects of
leptin administration on ovulation were tested (our manuscript in prep-
aration). This was followed by a period of realimentation in which the
goal was to determine the weight and dietary intake level at which
ovulations returned. Throughout dietary restriction and realimentation,
weights were measured weekly using a transfer box, and blood samples
were drawn by venipuncture three times a week before the morning
meal. Samples were assayed for progesterone and FSH. A veterinarian’s
assessment was performed at the start of the study and at 6-month
intervals. Hematology and blood chemistry (including liver and renal
function tests) were performed at 6-month intervals.
RIAs
Blood samples were refrigerated overnight, and serum was isolated
after centrifugation (2500 rpm). All serum samples were assayed for
progesterone using a commercial RIA kit available from Diagnostic
Products Corp. (Los Angeles, CA). The assay sensitivity was 0.02 ng/ml.
The intraassay coefficient of variation (CV) was 3.6%, and the interassay
CV was 3.9%. We have validated this progesterone assay for use in the
nonhuman primate (20). A minimum of three consecutive serum pro-
gesterone values of 4.0 ng/ml or greater was considered indicative of the

FIG. 1. Establishment of dietary re-

quirements for normalization of BMI
and ovulation in female rhesus mon-
keys. Daily food consumption, BMI,
and progesterone concentrations are
shown for two monkeys initiated on a
standard allotment of monkey chow
(1887 kJ/d). One animal consistently
consumed less than the entire meal
(B). Weights stabilized between 22
and 24 kg/m2, and seven or eight ovu-
lations were documented during this
period.
Lujan et al. • Dietary Restriction Induces Anovulation in Monkeys
luteal phase. This cutoff was based on progesterone measurements over
six consecutive cycles in five rhesus monkeys with regular ovulatory
menstrual cycles (mean follicular phase progesterone, 1.8 ⫾ 0.1 ng/ml;
range, 1.0 –3.7 ng/ml; mean luteal phase progesterone, 8.5 ⫾ 0.4 ng/ml;
range, 4.0 –21.9 ng/ml). An integrated weekly FSH value was deter-
mined for serum pools generated by combining equal volumes of each
serum sample collected during a 1-wk period. Serum pools were sep-
arated into follicular and luteal phases based on earlier progesterone
measurements. Serum pools were assayed in duplicate for FSH in a
single assay using reagents provided by the National Hormone and
Pituitary Program. The standard curve consisted of FSH reference prep-
aration AFP 6940A. Unknowns were incubated with recombinant FSH
antibody (AFP 782594), followed by the addition of 125I-radiolabeled
FSH (AFP 6940A). A sheep antirabbit ␥-globulin (Prince Laboratories,
Toronto, Canada) was used to precipitate the antigen-antibody complex.
Precipitation was facilitated by adding 12.5% Carbowax (Sigma-Aldrich
Corp., St. Louis, MO) before centrifugation. Assay sensitivity, defined as
the amount of reference preparation required to reduce binding by 2 sd
below the zero standard divided by the sample volume, was 0.1 ng/ml.
The intraassay CV was 9.6%.
Statistics
A repeated measures ANOVA and Tukey’s multiple comparison test
were used to determine differences in mean BMI and dietary intake at
baseline, last ovulation, first missed ovulation, and first ovulation after
realimentation. Menstrual cycle length, follicular phase length, luteal
phase length, and mean luteal phase progesterone and FSH concentra-
tions before, during, and after dietary restriction were compared using
a repeated measures ANOVA and Tukey’s multiple comparison test.
The level of significance was set at P ⱕ 0.05. The effects of dietary
restriction and realimentation on ovulation were assessed by visual
inspection of the progesterone profiles.
FIG. 2. Dietary requirements for normalization of BMI and ovulation in female rhesus monkeys. Daily food consumption, BMI, and progesterone
concentrations are shown for two other monkeys initiated on a regimented diet. One animal lost weight and became anovulatory on a diet of
1887 kJ/d (A). Ovulation resumed after dietary intake was increased to 2358 kJ/d. The second animal was initially below the desired BMI and
anovulatory (B). Ovulatory cycles were established after approximately 100 d on a regimented diet of 1887 kJ/d that resulted in weight gain.
Endocrinology, January 2006, 147(1):483– 492 485
Results
A moderate reduction in weight was required in three
animals (monkeys 1, 2, and 3) to bring their BMI into the
23–24 kg/m2 range, whereas a moderate increase was re-
quired in one animal (monkey 4). These four monkeys were
initiated on a fixed allotment of monkey chow totaling 1887
kJ/d. The effects of a regimented diet on BMI and proges-
terone secretion are presented in Figs. 1 and 2. BMI declined
in the two monkeys depicted in Fig. 1. Monkey 2 consistently
consumed less than the entire meal and consequently fell
below the target BMI of 23–24 kg/m2 (Fig. 1B). This animal
eventually increased her food consumption, and BMI in-
creased to 22.1 kg/m2. Both animals exhibited a cyclical
pattern of progesterone secretion indicative of ovulation. Eight
ovulatory cycles were documented in each animal over the
8-month baseline period. The two monkeys depicted in Fig. 2
had discrepant responses to the fixed diet. Monkey 3 depicted
in Fig. 2A had an initial BMI of 27.2 kg/m2, but underwent
rapid weight loss when fed 1887 kJ/d. Two ovulations were
documented in this animal before it became anovulatory. Ca-
loric intake was increased to 2358 kJ/d, and its BMI increased
from 21.3 to 24 kg/m2, at which point ovulation resumed. The
second monkey depicted in Fig. 2 had an initial BMI of 22.1
kg/m2, which was below the desired BMI. This animal was
anovulatory for the first 3 months of the study. BMI increased
to 24.6 kg/m2 after 16 wk of individual feeding, and cyclical
progesterone secretion indicative of regular ovulations ensued.
486 Endocrinology, January 2006, 147(1):483– 492 Lujan et al. • Dietary Restriction Induces Anovulation in Monkeys

The effects of dietary restriction and subsequent realimen-
tation on BMI and progesterone secretion in these four mon-
keys are presented in Figs. 3 and 4 (presented in the same
sequence as in Figs. 1 and 2; data from Figs. 1 and 2 are
included for added perspective). The two monkeys depicted
in Fig. 3 exhibited a linear reduction in BMI during dietary
restriction. Dietary restriction inhibited ovulation in both
animals, as evidenced by an abrupt cessation in cyclic pro-
gesterone secretion. Despite a higher initial dietary intake
and BMI, ovulation offset occurred sooner in monkey 1 than
in monkey 2 (36 vs. 93 d). Dietary intake was increased
subsequently in both animals to maintain their weight near
the weight of ovulation offset. Therefore, dietary intake at the
time of initiating realimentation in these two animals was
similar to dietary intake at baseline. An additional increase
in food intake during realimentation initiated ovulation.
Ovulation onset occurred within a similar time frame as
ovulation offset in these two animals (55 and 101 d to onset
vs. 36 and 93 d to offset). Dietary intake, BMI, and proges-
terone secretion during food restriction and realimentation
are shown in Fig. 4 for the other two monkeys (same animals
as depicted in Fig. 2). Neither animal exhibited a linear re-
duction in BMI during dietary restriction. Monkey 3 (Fig. 4A)
exhibited a delayed pattern of weight loss in response to
dietary restriction. The first missed ovulation occurred after
a very small decline in weight (BMI declined from 24 to 23.5
kg/m2). This monkey subsequently experienced a precipi-
tous weight loss that required increasing the dietary intake
from 13 to 18 biscuits/d over a 3-wk period to stabilize her
weight. Weight declined in monkey 4 (Fig. 4B) during the
initial stages of dietary restriction and then stabilized despite
an additional reduction in dietary intake that resulted in
anovulation. Realimentation stimulated ovulation in both
animals. The times from initiating realimentation to first
ovulation were 85 and 64 d (similar to the previous
examples).
Weight and changes in weight associated with ovulation
offset and onset are reported in kilograms and BMI units in
Tables 1 and 2, respectively. Ovulation offset occurred at a
mean weight of 5.8 ⫾ 0.3 kg (BMI of 21.8 ⫾ 0.9 kg/m2)
compared with a starting weight of 6.2 ⫾ 0.2 kg (BMI of
23.4 ⫾ 0.4 kg/m2). This constituted an average weight loss
of 0.4 ⫾ 0.10 kg (0.1– 0.7 kg). The weight at the time of the last
luteal phase during caloric restriction was identical with the
weight at the time of the first luteal phase during realimen-
tation (5.9 ⫾ 0.2 kg). Likewise, the change in BMI (⌬BMI) was
similar for ovulation offset and onset (1.6 ⫾ 0.5 vs. 1.9 ⫾ 0.3
kg/m2). The time from initiating dietary restriction or reali-
mentation to ovulation offset and onset, respectively, corre-
lated with the absolute change in weight (r ⫽ 0.93; P ⫽
0.0009).
Dietary intake and changes in energy intake associated
with ovulation offset and onset are shown in Table 3. The
mean change in food consumption required to inhibit ovu-

FIG. 3. Effects of dietary restriction (DR) and realimentation (RA) on BMI and ovulation. Dietary intake, BMI, and progesterone secretion
resulting from DR and after RA are shown for the same two monkeys depicted in Fig. 1. The shaded areas represent the time from initiating
DR or RA to ovulation offset or onset, respectively. Both animals exhibited a linear reduction in BMI during DR. DR inhibited ovulation in both
animals. Ovulation offset was more abrupt in monkey 1 (A) than in monkey 2 (42 vs. 114 d). Dietary intake was subsequently adjusted to maintain
both monkeys near the weight of ovulation offset. RA resulted in weight gain and initiation of ovulation.
Lujan et al. • Dietary Restriction Induces Anovulation in Monkeys Endocrinology, January 2006, 147(1):483– 492 487

FIG. 4. Effects of dietary restriction (DR) and realimentation (RA) on BMI and ovulation. Dietary intake, BMI, and progesterone secretion
resulting from DR and after RA are shown for the same two monkeys depicted in Fig. 2. The shaded areas represent the time from initiating
DR or RA to ovulation offset or onset, respectively. Neither animal exhibited a linear reduction in BMI during DR. Monkey 3 (A) exhibited a
delayed pattern of weight loss. The first missed ovulation occurred before significant weight loss. Subsequent weight loss required adjusting
the level of DR. Weight declined in monkey 4 (B) during the initial stages of DR and then stabilized despite an additional reduction in dietary
intake that resulted in anovulation. Realimentation resulted in weight gain and initiation of ovulation in both animals.

lation was similar to the magnitude of the increase that
stimulated ovulation (443 ⫾ 30 vs. 413 ⫾ 102 kJ/d). However,
the level of dietary intake at first ovulation during realimen-
tation was considerably greater than the energy intake at
offset [2123 ⫾ 174 vs.1504 ⫾ 148 kJ/d at the time of the
expected luteal phase (Lutexp)]. Even when compared with
the energy levels during the last follicular phase of dietary
restriction, dietary intake at the time of first ovulation during
realimentation was 25% greater (2123 ⫾ 174 vs. 1710 ⫾ 228
kJ/d). These results are shown graphically in Fig. 5. Dietary
intake at first missed ovulation was significantly reduced
compared with food intake before dietary restriction (Lutexp
vs. basal, P ⬍ 0.01), but was not different from food intake
at the time of the last ovulation during dietary restriction.
Dietary intake at first ovulation during realimentation (cycle
1) was significantly greater than dietary intake at all relevant
time points (most notable comparisons being the follicular
phase of final ovulation during dietary restriction and the
dietary intake at the time realimentation was initiated). The
same comparisons were not statistically significant when
performed for BMI.
The transition from ovulatory to anovulatory status (and

TABLE 1. A comparison of body weight (kg) at the onset and offset of anovulation in diet-restricted rhesus monkeys

Dietary restriction Realimentation

Monkey
Kgi Kgfol Kglut Kganov ⌬Kg Daysanov Kgi Kgov ⌬Kg Daysov
1 6.2 6.1 6.0 6.0 0.2 36 5.1 5.4 0.3 55
2 5.7 5.3 5.1 5.0 0.7 93 5.0 5.6 0.6 101
3 6.2 6.3 6.2 6.1 0.1 48 5.6 6.2 0.6 85
4 6.6 6.0 6.0 6.0 0.6 70 5.9 6.3 0.4 64
Mean 6.2 5.9 5.9 5.8 0.4 62 5.4 5.9 0.5 76
SEM 0.2 0.2 0.2 0.3 0.1 13 0.2 0.2 0.1 10
SEM/mean (%) 2.8 3.9 4.1 4.4 4.0 3.7
Kgi, Initial weight immediately prior to dietary restriction or realimentation; Kgfol, mean weight during the last follicular phase before
anovulation; Kglut, mean weight during the last luteal phase before anovulation; Kganov, mean weight at the onset of anovulation; ⌬Kg, change
in weight required to inhibit or stimulate ovulation; Daysanov, number of days to achieve anovulation; Kgov, weight when ovulation resumed
(follicular phase and luteal phase values were identical); Daysov, number of days to resume ovulation.
488 Endocrinology, January 2006, 147(1):483– 492 Lujan et al. • Dietary Restriction Induces Anovulation in Monkeys

TABLE 2. A comparison of body mass index (kg/m2) at the onset and offset of anovulation in diet-restricted rhesus monkeys

Dietary restriction Realimentation

Monkey
BMIi BMIfol BMIlut BMIanov ⌬BMI BMIi BMIov ⌬BMI
1 23.8 23.5 23.2 22.9 0.9 19.6 20.8 1.2
2 22.1 20.2 19.8 19.3 2.8 19.2 21.7 2.5
3 24.0 24.2 24.0 23.5 0.5 21.7 24.0 2.3
4 23.5 21.5 21.4 21.4 2.1 21.0 22.4 1.4
Mean 23.4 22.4 22.1 21.8 1.6 20.4 22.2 1.9
SEM 0.4 0.9 0.9 0.9 0.5 0.6 0.7 0.3
SEM/mean (%) 1.8 4.1 4.3 4.3 2.9 3.0
BMIi, Initial BMI immediately before dietary restriction or realimentation; BMIfol, mean BMI during the last follicular phase before
anovulation; BMIlut, mean BMI during the last luteal phase before anovulation; BMIanov, mean BMI at the onset of anovulation; ⌬BMI, change
in BMI required to inhibit or stimulate ovulation; BMIov, BMI when ovulation resumed (follicular phase and luteal phase values were identical).

vice versa) was abrupt. Mean menstrual cycle length, follic-
ular phase length, luteal phase length, and luteal phase pro-
gesterone concentrations of the last two menstrual cycles
observed during dietary restriction and the first two ovula-
tory cycles after realimentation were comparable to these
same cycle parameters in cycles before and during the earlier
stages of dietary restriction (Table 4).
A fifth animal included in this study was inordinately
obese (BMI of 39.3 kg/m2). As shown in Fig. 6, this animal
progressively lost weight and attained a lean BMI after 8 –9
months on a diet of 1415 kJ/d. Cyclic progesterone secretion
confirmed normal ovulatory function during this extended
period of weight loss. An additional reduction in caloric
intake inhibited ovulation. Anovulation occurred at a BMI of
21.5 kg/m2 (within the range of the four normal-weight
monkeys). The animal remained anovulatory for several
months while maintained on a diet of 1061–1533 kJ/d. She
was removed from the study before realimentation due to
development of a central nervous system infection.
Also shown in Fig. 6 are integrated weekly FSH concen-
trations for this animal. Several large excursions in FSH tem-
porally associated with ovulations were seen. These large
fluctuations were absent during the subsequent anovulatory
period. Mean weekly FSH concentrations normalized to ovu-
lation offset during dietary restriction and ovulation onset
after realimentation are shown in Fig. 7. Mean FSH concen-
trations were more variable during the 10 wk before anovu-
lation compared with the 15 wk of documented anovulation
(see Fig. 7A). In addition, FSH levels determined at 4-wk
intervals showed a significant decline in FSH secretion with
anovulation (see inset). The onset of ovulation after reali-
mentation was accompanied by a return to a variable pattern
of FSH secretion (Fig. 7B).
The degree of dietary restriction necessary to inhibit ovu-
lation was not associated with significant morbidity. Ani-
mals remained attentive to their surroundings and continued
to use perches in the exercise pens. They retained their ap-
petites throughout the study. Routine biochemical and he-
matological parameters remained within normal limits
throughout the period of dietary restriction. No measures of
bone metabolism were performed. One animal exhibited sig-
nificant alopecia during dietary restriction, which was re-
versed by realimentation. Realimentation was accompanied
by weight gain and resumption of ovulation. Animals remain
in good health 2 yr after study completion.
Discussion
This study demonstrates that ovulation in rhesus monkeys
was inhibited by a reduction in dietary intake. This is the first
documentation that dietary restriction can inhibit ovulation in
nonhuman primates. A previous study concluded that ovula-
tion in rhesus monkeys was not inhibited by a 30% reduction
in dietary intake (18). A greater degree of dietary restriction in
the current study is the most likely explanation for the differ-
ence in outcomes. Anovulation occurred in our study when
food intake was decreased by 21%, resulting in an average
dietary intake of 1504 ⫾ 148 kJ/d. By contrast, a 30% reduction
in dietary intake in the study by Lane et al. (18) translated into
a daily intake of 1709 ⫾ 55 kJ. Although the level of dietary

TABLE 3. A comparison of food intake (kJ/d) at the onset and offset of anovulation in caloric-restricted rhesus monkeys

Dietary restriction Realimentation

Monkey
kJi kJfol kJlut kJanov ⌬kJ kJi kJov ⌬kJ
1 1887 1887 1769 1533 354 2005 2123 118
2 1533 1179 1179 1179 374 1415 2005 590
3 2359 2241 2123 1887 472 2123 2595 472
4 1887 1592 1533 1415 472 1297 1769 472
Mean 1916.5 1724.8 1651.0 1503.5 418.0 1710.0 2123.0 413.0
SEM 169.5 225.1 198.6 147.5 31.5 207.2 173.7 102.0
SEM/mean (%) 8.8 13.1 12.0 9.8 12.1 8.2
kJi, Initial food intake immediately before dietary restriction or realimentation; kJfol, mean food consumption during the last follicular phase
before anovulation; kJlut, mean food consumption during the last luteal phase before anovulation; kJanov, mean food consumption at the onset
of anovulation; ⌬kJ, change in food intake required to inhibit or stimulate ovulation; kJov, food consumption when ovulation resumed (follicular
phase and luteal phase values were identical).
Lujan et al. • Dietary Restriction Induces Anovulation in Monkeys
FIG. 5. Effects of dietary intake and BMI nor-
malized to menstrual cycle events during di-
etary restriction and realimentation (Real).
Basal dietary intake, expressed in kilojoules
per day, and weight, expressed as BMI, are
compared with three time points during di-
etary restriction [the follicular phase of the
last menstrual cycle (Foll), the luteal phase of
the last menstrual cycle (Lut), and the time of
the expected luteal phase (Lutexp)] and two
time points during realimentation. Dietary in-
take at first missed ovulation was signifi-
cantly reduced (†, P ⬍ 0.01, Lutexp vs. basal).
Dietary intake at first ovulation during reali-
mentation (cycle 1) was greater than at all
relevant time points (*, P ⬍ 0.05 vs. Foll; **,
P ⬍ 0.01 vs. Lut; ***, P ⬍ 0.001 vs. Lutexp; *,
P ⬍ 0.05 vs. initiation of realimentation). The
same comparisons for BMI were not statisti-
cally significant (n ⫽ 4).
restriction employed was greater in terms of percent decrease
from habitual levels, according to our study this absolute level
of dietary intake would not be expected to inhibit ovulation.
Our results in rhesus monkeys complement those of Wil-
liams et al. (17), who observed that chronic strenuous exercise
induced amenorrhea in cynomolgus monkeys. Their study
concluded that anovulation resulted from a negative energy
balance rather than some other factor associated with exer-
cise, because ovulation was reinitiated in exercising monkeys
by increasing food availability (21). In contrast to exercise-
induced amenorrhea, our study showed that dietary restric-
tion did not produce transitional menstrual cycles. Follicular
phase length, luteal phase length, and luteal phase proges-
terone secretion in the last two cycles during dietary restric-
tion were comparable to these cycle parameters before or
during the early stages of dietary restriction. This observa-
tion is at variance with that by Williams et al. (17), who
reported that follicular phase length was increased and
plasma LH and luteal phase progesterone secretion were
reduced in the menstrual cycle immediately preceding ex-
ercised-induced amenorrhea. The much shorter time span
from initiation to anovulation observed with dietary restric-
tion compared with exercise (62 ⫾ 13 d vs. 14.3 ⫾ 2.2 months,
respectively) may account for the absence of transitional
menstrual cycles in our study. A regimen of dietary restric-
tion that produces over a 2-month period a negative energy
balance that inhibits ovulation may be too short a time frame
for borderline energy levels to produce transitional men-
strual cycles. Because neither study quantified the degree of
energy deficit, this explanation remains speculative. A sec-
ond difference that merits consideration is the method by
which a state of negative energy balance was achieved in the
two studies. If the energy available to fuel processes such as
TABLE 4. A comparison of menstrual cycle parameters during dietary restriction and realimentation in rhesus monkeys
Dietary restriction
Cycle ⫺3⫹ Cycle ⫺2
MC length (d) 27.6 ⫾ 0.8 28.6 ⫾ 1.3
FP length (d) 16.0 ⫾ 0.9 15.6 ⫾ 2.2
LP length (d) 10.9 ⫾ 1.2 11.2 ⫾ 2.2
LP P4 (ng/ml) 9.5 ⫾ 0.6 10.2 ⫾ 0.7
MC, Menstrual cycle (d); FP, follicular phase (d); LP, luteal phase (d); LP P4, luteal phase progesterone (ng/ml); n/a, not available.
Endocrinology, January 2006, 147(1):483– 492 489
ovulation is simply the difference between energy intake and
energy expended, then a deficit, regardless of how it was
achieved, should adversely affect ovulation. This premise is
supported by the demonstration that LH pulse frequency in
women was inhibited by a negative energy balance regard-
less of whether it was achieved by reducing energy intake or
increasing energy expenditure (22). It is also supported by
the two nonhuman primate studies combined, because ovu-
lation was inhibited in both. However, it remains to be de-
termined whether the subtle differences cited above are due
to differences in how the energy deficits were achieved.
Our demonstration that dietary restriction reversibly in-
hibits ovulation in rhesus monkeys also establishes the link
between energy intake and reproductive function in pri-
mates. Energy deficit has been documented previously as the
root cause of reproductive axis dysfunction in women with
hypothalamic amenorrhea resulting from self-imposed di-
etary restriction or strenuous exercise (3, 6, 23). Several stud-
ies have demonstrated that acute energy deficits resulting
from short-term fasting or increased energy expenditure in-
hibited the hypothalamic-gonadotropic axis, as reflected by
reduced LH pulse frequency in human and nonhuman pri-
mates (13, 22, 24, 25), although females may be more resistant
to acute fasting-induced inhibition of LH secretion compared
with males (26 –28). Although the current study did not at-
tempt to characterize changes in LH pulse frequency, inhi-
bition of ovulation is the expected outcome if dietary restric-
tion chronically reduced LH pulse frequency below the
threshold that supports follicular maturation or that is nec-
essary to generate an LH surge. We have demonstrated that
a similar degree of dietary restriction in ovariectomized rhe-
sus monkeys inhibits the elaboration of the estrogen/pro-
gesterone-induced gonadotropin surge (29). Anovulation
Realimentation
Cycle ⫺1 Cycle 1 Cycle 2
29.0 ⫾ 1.5 n/a 33.0 ⫾ 2.4
17.5 ⫾ 2.7 n/a 20.5 ⫾ 3.2
12.1 ⫾ 1.6 12.0 ⫾ 2.9 12.5 ⫾ 1.0
10.2 ⫾ 0.9 10.2 ⫾ 2.0 10.9 ⫾ 0.7
490 Endocrinology, January 2006, 147(1):483– 492
FIG. 6. Effects of dietary restriction on BMI, progesterone, and FSH
in an obese monkey. A regimented diet of 1415 kJ/d caused BMI to
decline from 39.3 to 21.5 kg/m2 over the course of 10 months. Large
excursions of FSH just before increased progesterone secretion prob-
ably reflect the preovulatory FSH surge. An additional reduction in
dietary intake and weight loss resulted in anovulation and a more
static pattern of FSH secretion.
was not preceded by a reduction in FSH concentrations. A
reduced GnRH pulse frequency may explain the mainte-
nance of FSH concentrations while inhibiting ovulation, be-
cause a low GnRH pulse frequency can stimulate FSH se-
cretion while inhibiting LH secretion (30 –32).
This study provides insight into the dietary intake re-
quired to support ovulation in rhesus monkeys. Three of four
normal-weight monkeys ovulated when given a diet of 1887
kJ/d. Monkey 1 had a stable weight on this diet and ovulated
regularly. Monkey 2 consumed less than the entire meal and
lost weight. Eventually, food consumption increased to 1533
kJ/d, and weight stabilized at a BMI of 22.1 kg/m2. The
decreased appetite followed by partial recovery may reflect
acclimatization to being separated twice a day at mealtime.
In addition, this animal was the smallest of the four, weigh-
ing approximately 10% less than the others. In contrast, mon-
key 4 gained weight and became ovulatory after 3 months on
a diet of 1887 kJ/d. This response is probably the result of
Lujan et al. • Dietary Restriction Induces Anovulation in Monkeys
inadequate food intake in a communal setting being resolved
by separating pairs at mealtime. Monkey 3 was exceptional
because it underwent rapid weight loss and became anovu-
latory when fed 1887 kJ/d. Food intake was increased to 2358
kJ/d, and its BMI increased from 21.3 to 24 kg/m2, at which
point ovulation resumed.
Although these data indicate that the level of energy intake
is a critical determinant of ovulatory status, they also suggest
that energy stores may play a role. Inadequate energy stores
may explain why monkeys 3 and 4 did not ovulate for several
months while on a diet that eventually stimulated ovulation.
Both animals gained weight before ovulating. Conversely,
monkey 2 continued to ovulate despite dietary intake being
reduced 1 month earlier to 1179 kJ/d. Ovulation offset occurred
without an additional reduction in dietary intake, but was ac-
companied by a modest weight loss. Much more striking was
the delayed effect of dietary restriction on ovulation in the obese
monkey. This animal continued to ovulate at regular intervals
despite a 42% decline in weight (11.9 to 6.8 kg) over 10 months.
By contrast, the normal-weight monkeys became anovulatory
after an average weight loss of 0.43 ⫾ 0.1 kg (0.1– 0.7 kg). The
extended period of weight loss in the obese monkey indicated
that this animal was chronically exposed to a negative energy
balance. Despite a chronic energy deficit, anovulation did not
ensue until BMI reached a level similar to that at which the other
animals became anovulatory. Our speculation that energy
stores maintained ovulatory function during the first 9 months
of dietary restriction is tempered by dietary intake having been
further reduced just before the first missed ovulation. There-
fore, anovulation may have been affected by an additional
reduction in dietary intake alone or a reduction in dietary intake
in combination with reduced availability of oxidizable meta-
bolic fuels. Several reports suggest that fatness affects the re-
sponse of the reproductive axis to caloric restriction. Fat ham-
sters were less susceptible to starvation-induced anestrus than
lean hamsters (33). Lean women were more prone to disruption
of the neuroendocrine axis in response to a 72-h fast compared
with normal-weight women (34), whereas gonadotropin secre-
tion in obese women was not affected by a 21-d fast (35). How-
ever, in distinction to the above findings, it has been reported
that morbidly obese women who had a 25% weight loss after
biliopancreatic diversion became amenorrheic despite still be-
ing obese (mean BMI of 35 kg/m2) (36).
The mean dietary intake during the follicular phase of the
last menstrual cycle before ovulation offset was 1725 ⫾ 225
kJ/d. However, there was considerable variability (1179,
1592, 1887, and 2241 kJ/d). In fact, of the three measures
(weight, BMI, and dietary intake), the variability in dietary
intake was considerably greater than that for weight and BMI
(see sem expressed as a percentage of the mean in Tables 1–3).
Normalizing dietary intake to weight or BMI reduced vari-
ability only slightly. Normalizing dietary intake to fat-free
mass or some other measure of body composition may better
predict the threshold for ovulation in future studies.
The inhibitory effect of dietary restriction on ovulation was
reversed by realimentation. The absolute change in food intake
(⌬ kJ) and weight (⌬ BMI) associated with ovulation during
realimentation was similar to the absolute change in these same
variables associated with inhibition of ovulation during dietary
restriction. However, ovulation occurred at a significantly
Lujan et al. • Dietary Restriction Induces Anovulation in Monkeys Endocrinology, January 2006, 147(1):483– 492 491

FIG. 7. Effects of dietary restriction (DR) and reali-

mentation (RA) on FSH secretion. A, Mean (⫾SEM)
integrated weekly FSH concentrations during DR (n ⫽
5). The ovulatory period is represented by the shaded
area. The inset in A shows mean integrated FSH con-
centrations expressed at 4-wk intervals. FSH secre-
tion was significantly reduced during anovulation (by
Tukey-Kramer test: a, P ⬍ 0.05 compared with 5– 8 wk
before anovulation; b, P ⬍ 0.05 compared with 1– 4 wk
before anovulation). B, Mean (⫾SEM) integrated
weekly FSH concentrations during RA (n ⫽ 4). The
ovulatory period is represented by the shaded area.
FSH secretion was more variable during ovulatory
periods.

higher energy intake level during realimentation compared
with the energy consumption during the final follicular phase
of dietary restriction (2123 ⫾ 174 kJ vs. 1725 ⫾ 225 kJ). This
difference was seen in all animals. The hysteresis exhibited in
our dataset is not due to a lag effect caused by a faster rate of
realimentation. The rate of realimentation (⌬kJ/d of realimen-
tation to ovulation onset, 5.2 ⫾ 1.1 kJ/d) was actually slower
than the rate of dietary restriction (⌬kJ/d of food restriction to
ovulation offset, 7.1 ⫾ 1.1 kJ/d). This finding may have impli-
cations for dietary requirements to reestablish menstrual cy-
clicity in women with anorexia nervosa and is consistent with
the report that return of menses in women with anorexia ner-
vosa occurred at a mean weight that was 2.05–3.6 kg greater
than the weight at which menses were interrupted (37, 38).
In summary, moderate dietary restriction of lean rhesus
monkeys reliably inhibited ovulation. The level of dietary
restriction required to inhibit ovulation did not compro-
mise the health of the animals. Ovulation was reestab-
lished by realimentation. The level of dietary intake re-
quired to reestablish ovulation was significantly greater
than the level that supported ovulation during dietary
restriction. This primate model of nutritional amenorrhea
affords opportunities to prospectively study the neuroen-
docrine mechanisms that inhibit the menstrual cycle in
response to inadequate nutrition. Although it remains to
be documented, it is likely that this primate model will
prove useful for studying changes in bone metabolism
associated with long periods of anovulation induced by
dietary restriction.
Acknowledgments
We acknowledge Dr. A. F. Parlow and the National Hormone and
Peptide Program for supplying FSH assay reagents.
Received July 7, 2005. Accepted September 22, 2005.
Address all correspondence and requests for reprints to: Dr. Dean A.
Van Vugt, Department of Obstetrics and Gynecology, 3022 Etherington
Hall, Queen’s University, Kingston, Ontario, Canada K7L 3N6. E-mail:
vanvugtd@post.queensu.ca.
This work was supported by the Canadian Institutes of Health Re-
search Grant MOP-57934 (to D.A.V.V.).
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endocrine community.

Geoffrey Harris Prize in Neuroendocrinology

The European Federation of Endocrine Societies (EFES) announces the 2006 Geoffrey Harris Prize to
recognize a senior European endocrinologist active in basic clinical or translational neuroendocrinology
research. The €12,000 prize will be presented at the 8th European Congress of Endocrinology in Glasgow,
UK from April 1– 4, 2006. The recipient will be invited to present a lecture at this meeting, as well as two
subsequent lectures at future EFES scientific activities.

Letters proposing candidates should be sent by December 31, 2005 to: Professor Philippe Bouchard, Service
d’Endocrinologie, Hôpital Saint Antoine, 184 rue du Faubourg Saint Antoine, 75012 Paris, France. Email:
philippe.bouchard@sat.ap-hop-paris.fr. The Harris Prize is supported by the Ipsen Group. For more infor-
mation about the prize and application details, see: http://www.euro-endo.org/about/harrisprize.htm.

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