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From the Clinical Research Centers |
Department of Reproductive Medicine, University of California-San Diego School of Medicine, La Jolla, California 92093-0633
Address all correspondence to: G. A. Laughlin, Department of Reproductive Medicine, 0633, University of California-San Diego School of Medicine, La Jolla, California 92093-0633. Reprints not available.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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During the feeding phase of the day, FHA exhibited lower glucose (P < 0.05) and insulin (P < 0.01) levels than NC, and the degree of hypoinsulinemia was directly related to relative dietary fat (r = 0.73). Although 24-h mean GH levels did not differ, the pattern of GH release in FHA was distinctly altered from that in NC. GH pulse amplitude was blunted, pulse frequency was accelerated 40% (P < 0.01), and interpulse GH concentrations were elevated 2-fold (P < 0.01) throughout the day for FHA compared to NC. This distorted pattern of GH pulses was associated with a 40% decrease (P < 0.01) in GH-binding protein levels. Levels of the insulin-dependent insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) were elevated (P < 0.001) during the feeding portion of the day in FHA and were inversely related to insulin (r = -0.50) and directly related to cortisol (r = 0.64) levels for FHA and NC groups together. Although levels of IGF-I and IGFBP-3 did not differ, the elevation of IGFBP-1 levels in FHA resulted in a reduced (P < 0.01) ratio of IGF-I/IGFBP-1, which may decrease the bioactivity and hypoglycemic effect of IGF-I. Twenty-four-hour mean leptin levels and the diurnal excursion of leptin in FHA did not differ from those in NC. LH pulse frequency was slowed 50% (P < 0.001) in FHA, with unaltered pulse amplitude, resulting in 45% lower (P < 0.01) 24-h mean LH levels for FHA compared to NC. LH pulse frequency for the two groups was related positively to insulin (r = 0.80) levels and the ratio of IGF-I/IGFBP-1 (r = 0.70) and negatively with cortisol (r = -0.61) and IGFBP-1 (r = -0.72) concentrations.
In summary, we found evidence of subclinical eating disorders in weight-stable, nonathletic women with FHA accompanied by a severe restriction of dietary fat intake. Unbalanced nutrient intake in psychogenic FHA was associated with multiple endocrine-metabolic alterations. Among these, reduced levels of plasma glucose and serum GHBP, a decrease in the ratio of IGF-I/IGFBP-1, accelerated GH pulse frequency, and elevated interpulse GH levels are indicative of a hypometabolic state. In addition, the magnitude of glucoregulatory responses (increased cortisol secretion and decreased insulin/IGF-I action) were directly related to the degree of suppression of GnRH/LH pulse frequency. These results are remarkably similar to those seen in highly trained athletes with FHA (1). Thus, nutritional deficits may represent a common contributing factor to the development and maintenance of multiple neuroendocrine-metabolic aberrations underlying both psychogenic and exercise-related FHA.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Common to FHA with and without related exercise is the association of hypercortisolemia and slowing of GnRH/LH pulsatile activities (3, 4, 9, 10, 11, 12). Although activation of the hypothalamic-pituitary-adrenal axis in response to stress is well known (for review, see Ref.13), elevations of cortisol levels also occur with nutritional deficiency (14, 15). We have recently reported (4) unbalanced dietary intake in women athletes with FHA associated with relative hypoglycemia/hypoinsulinemia and a series of glucoregulatory adaptations, including hypercortisolemia, suggesting a metabolic basis for the development of hypercortisolemia in exercise-related FHA. Limited information exists regarding the potential role of nutritional intake and substrate availability in the development of FHA in the absence of exercise and weight loss. Our previous studies showing enhanced nocturnal GH secretion and reduced serum T3 and T4 (11) together with hypercortisolemia support the view that compensatory metabolic adaptations to nutritional deficits may play a role in psychogenic FHA.
In the present study, nutritional and endocrine-metabolic features were simultaneously assessed in women with FHA not associated with exercise or weight loss and in age- and body mass index-matched regular cycling controls. Body composition, dietary intake, insulin sensitivity, and 24-h insulin/glucose, somatotropic axis, cortisol, and leptin dynamics were evaluated. These studies were designed to gain insight into the possibility that nutritional deficits and compensatory endocrine-metabolic adaptations contribute to the development and maintenance of FHA in the absence of exercise and weight loss.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Eight women with FHA and eight women with regular menstrual cycles [normal controls (NC)] were recruited for this study. Organic causes of amenorrhea, including hyperprolactinemia, thyroid and adrenal disease, premature ovarian failure, and hyperandrogenism, were excluded. The protocol was approved by the committee on investigations involving human subjects of the University of California, and written informed consent was obtained from each participant. Subjects were rigorously screened and characterized to exclude confounding conditions. The initial screening included questionnaires on medical, menstrual, and exercise histories, the Beck Depression Test and Eating Disorder Inventory (16). Subjects with overt depression or eating disorders were excluded. Amenorrhea was defined as the absence of menses for at least 6 months. Subjects with primary amenorrhea were excluded. Daily exercise energy expenditure determined by activity records was limited to less than 200 Cal/day for both NC and FHA groups. All subjects were nonsmokers and took no medications.
Body composition was determined by dual energy x-ray absorptiometry (QDR-2000, Hologic, Waltham, MA). Diet and activity records were kept prospectively for 7 days, during which the subjects maintained their usual dietary and exercise habits. Dietary records were evaluated by a clinical dietitian using the Nutritionist III, version 7, database (N-Squared Computing, Salem, OR). Recipes and ingredients for food items not included in the database, especially nonfat and low fat foods, were obtained from subjects and added to the database. Average daily exercise energy expenditure was estimated from the exercise records using energy expenditure tables (17).
Procedures
Regularly cycling subjects were studied during the early follicular phase (days 3–6) of their menstrual cycles, and amenorrheic subjects were studied on an arbitrary day. Subjects were admitted to the Clinical Research Center of the University of California-San Diego Medical Center at 0700 h after an overnight fast. Blood samples were drawn through an indwelling iv catheter every 10 min for 24 h beginning at 0800 h. Subjects refrained from napping and drinking caffeinated beverages during the study and received standard meals at 0800, 1200, and 1700 h and a 200-Cal snack at 2200 h. The total caloric content of meals was adjusted to 33 Cal/kg BW with a nutrient composition of 15% protein, 55% carbohydrate, and 30% fat and a caloric division of 1/5, 2/5, 2/5 for breakfast, lunch, and dinner, respectively. A clinical dietitian guided each subject in selecting items from a menu to conform to these requirements. Meals were consumed within 30 min of mealtimes. Meal trays were collected, and actual calories and compositions of foods consumed were determined to confirm adherence to a controlled content. Subjects were encouraged to sleep from 2300–0700 h in an unlighted, well shaded room. To avoid sleep disturbance, blood sampling took place via a long iv line that exited through a port in the wall. Sleep times were recorded by an experienced observer via an in-room camera.
Serum GH and LH levels were determined at 10-min intervals, and cortisol concentrations were determined at 30-min intervals for 24 h. Plasma glucose, serum insulin, and insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) concentrations were measured hourly and at 30 min after each meal. Serum leptin levels were determined hourly. Each individual’s samples were analyzed in the same assay in duplicate. A pooled sample with equal aliquots from each hourly sample was made for each subject, and serum concentrations of IGF-I, IGFBP-3, GHBP, PRL, sex hormone-binding globulin (SHBG), FSH, and steroid hormones were determined in duplicate in the same assay.
Frequently sampled iv glucose tolerance test
Insulin sensitivity (SI) was determined by a rapid frequently sampled iv glucose tolerance test after an overnight fast; an iv line was established in each forearm, and baseline samples were drawn at 10 and 0 min before administration of an iv bolus of glucose (0.3 g/kg 50% dextrose) over 1 min in the opposite arm. At 20 min after the glucose injection, 0.02 U regular insulin/kg was injected over 20 s, and the line immediately flushed with saline. Blood samples were then drawn at 2, 4, 8, 19, 22, 30, 40, 50, 70, 90, 120, 150, and 180 min. Serum insulin and plasma glucose levels were determined for each sample. Insulin sensitivity (SI) was determined using the MINMOD program (copyright R. N. Bergman, 1986) (18).
Assays
Plasma glucose concentrations were determined by the glucose oxidase method (Yellow Springs Instrument Co., Yellow Springs, OH) with an intraassay coefficient of variation (CV) less than 2% and an interassay CV of 3%. Serum insulin levels were analyzed by a double antibody RIA with a sensitivity of 15 pmol/L and intra- and interassay CVs of 7% and 9%, respectively. Serum GH concentrations were determined using a RIA (19) with an interassay CV of 6% at 1.4 and 6.0 µg/L, intraassay CVs of 8% at 1.0 µg/L and 2.5% at 4.2 µg/L, and a sensitivity of 0.9 µg/L. IGFBP-1 was measured by time-resolved immunofluorometric assay; the sensitivity was 0.06 µg/L, and the intra- and interassay CVs were 4% and 10%, respectively (20). IGF-I levels were measured after acid-ethanol extraction using the Corning Nichols Institute RIA kit (San Juan Capistrano, CA); the intraassay CV was 6%. SHBG concentrations were determined by time-resolved immunofluorometric assay (Delfia, Wallac, Gaithersburg, MD) with a sensitivity of 0.8 nmol/L and an intraassay CV of 7%. IGFBP-3 was measured using a RIA kit (Corning Nichols Institute, San Juan Capistrano, CA) with a sensitivity of 0.1 mg/L and an intraassay CV of 3%. Total functional GHBP concentrations were measured by Corning Nichols Institute (San Juan Capistrano, CA) using a ligand-mediated immunofunctional assay with a sensitivity of 8 pmol/L and an intraassay CV of 6.4% (21). Serum leptin levels were determined by RIA using recombinant human leptin as a standard (Linco Research, St. Charles, MO) (22) with intra- and interassay CVs of 5% or less. Serum LH concentrations were measured by a highly sensitive time-resolved immunofluorometric assay LH ß-subunit-specific kit (LH Spec, Delfia, Wallac, Turku, Finland) with a sensitivity of 0.05 IU/L, an intraassay CV of less than 5% for concentrations ranging from 0.3–40 IU/L, and an interassay CV of 8%. Serum concentrations of steroid hormones, FSH, and PRL were measured by standard, well established RIAs with intraassay CVs less than 7%.
Data analysis
Because metabolic activity is primarily determined by lean body mass (LBM), dietary intake results were adjusted for LBM. Values for each subject were multiplied by the ratio of the mean LBM for the NC group divided by the LBM of the subject in question. GH and LH pulsatile activities were analyzed using the Cluster pulse detection algorithm (23). Dose (x)-dependent intrasample variance was assessed by employing a second degree polynomial regression of SD as a function of hormone concentration. Cluster configurations of 2 x 1 and 2 x 2 and t statistics of 2.8 x 2.8 and 3 x 3 were chosen for LH and GH, respectively, to minimize false positive and false negative errors. Pulse amplitude was defined as the difference in concentration between the preceding nadir and the pulse peak, and interpulse concentration was defined as the mean hormone level between pulse nadirs. Pulse characteristics were determined for 24 h, for the waking hours, and during sleep. LH and GH pulse frequencies during waking and sleep times were normalized to 8 h. Mean feeding (0800–2300 h) and fasting (2300–0800 h) levels for circulating glucose, insulin, cortisol, and IGFBP-1 were calculated.
Statistical analyses
The number of subjects studied was intended to yield a probability of 0.80 of detecting group differences of 1.4 SD in unpaired comparisons. Non-Gaussian-distributed variables were logarithmically transformed before analysis. Results were compared by one-factor ANOVA, followed by Dunnett’s post-hoc comparisons. Relationships between variables were sought by Pearson product-moment correlations. When more than five correlations were carried out, a protected P value of 0.01 was used to reduce false positive assignment of significance to no more than 1/100. Stepwise multivariate linear regression analyses with forward selection were used as indicated. The presence of a diurnal rhythm of leptin was defined as a significant difference in leptin levels between 0900 and 0100 h by Student’s paired t tests (24). Results are expressed as the mean ± SE. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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NC and FHA were of similar age (18–37 yr) and body mass index
(15–23 kg/m2; Table 1
). The
percent fat body mass was lower (P = 0.05) and lean
body mass was higher (P < 0.05) in FHA than in NC. The
age at menarche was later (P < 0.01) for FHA than for
NC, and the duration of amenorrhea ranged from 0.6–11 yr. Levels of
LH, PRL, estrone, estradiol, and the ratio of estradiol/SHBG were lower
(all P < 0.01) for FHA compared to early follicular
phase values for NC (Table 2).
Androstenedione levels were reduced (P < 0.05) in FHA,
with no difference in levels of FSH, testosterone, or the ratio of
T/SHBG between FHA and NC.
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FHA with clinical eating disorders or overt depression were excluded from the study; nonetheless, ratings for FHA were higher than those for NC on both the Eating Disorder Inventory and the Beck Depression Test. The Eating Disorder Inventory score is divided into eight subscales. FHA scored higher on two of the eight subscales: Drive for Thinness (FHA, 6.0 ± 2.9; NC, 0.2 ± 0.2; P < 0.05) and Ineffectiveness (FHA, 2.1 ± 1.1; NC, 0.1 ± 0.1; P < 0.05). The total Eating Disorder Inventory score was 3-fold higher (P < 0.05) for FHA (36 ± 10) than for NC (12 ± 2). The Beck Depression Test rating was also higher (P < 0.05) for FHA (7.4 ± 2.2) than for NC (2.1 ± 0.6).
The results of daily dietary intake assessed by 7-day diet records and
adjusted for LBM are presented in Table 3. The daily caloric intakes reported by
FHA were similar to those in NC; however, FHA consumed 50% fewer
(P < 0.001) grams of fat and twice (P
< 0.05) as much fiber as NC. Expressed as a percentage of the nutrient
intake (Fig. 1A), the relative fat
content of the FHA diet was only 16.3 ± 2.2%, half
(P < 0.01) that of the NC diet (31.6 ± 1.9%),
and was compensated for by increased carbohydrate intake (FHA,
63.1 ± 3.3; NC, 51.6 ± 4.1%; P < 0.05).
Relative dietary protein intake was similar for FHA (15.4 ±
2.3%) and NC (17.5 ± 1.7%).
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Insulin sensitivity values and 24-h mean glucose/insulin levels
are presented in Fig. 1B
, with glucose/insulin levels during
feeding/fasting and for the 24-h period shown in Table 4. Insulin sensitivity (SI)
in FHA did not differ from that in NC, although there was a trend
toward higher levels in FHA. FHA displayed lower plasma glucose levels
than NC during feeding (P < 0.05) and for 24 h
(P < 0.01). This relative hypoglycemia in FHA was
accompanied by hypoinsulinemia during feeding (P <
0.01) and for 24 h (P < 0.001; Fig. 1B). Stepwise
regression analysis for the study groups as a whole revealed that 24-h
mean insulin, but not glucose, levels were positively related to
relative dietary fat (r = 0.73; P = 0.001), with
no significant contribution from other dietary components to the
model.
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A diurnal rhythm of IGFBP-1 was evident for both FHA and NC (Fig. 2A). IGFBP-1 levels were higher in FHA
than in NC during feeding (P < 0.001) and for 24
h (P < 0.01; Table 4). FHA also displayed relative
hypercortisolemia for the 24-h period (P < 0.05), with
the increased levels occurring primarily during the feeding portion of
the day (P = 0.07; Table 4). IGFBP-1 levels during
feeding were independently related inversely with levels of insulin
(r = -0.50; P = 0.02) during feeding and
positively with levels of cortisol (r = 0.64; P =
0.007) during feeding for the two groups considered together (Fig. 2B).
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Representative GH profiles are presented in Fig. 3A, mean 24-h GH profiles for each group
are shown in Fig. 3B, and GH pulsatility characteristics are presented
in Table 5. Pulse amplitude was decreased
60% (P < 0.001) in FHA during waking, but not
sleeping, hours, resulting in a 50% (P < 0.01)
reduction in 24-h mean pulse amplitude. Twenty-four-hour GH pulse
frequency was accelerated 40% (P < 0.01), and
interpulse GH concentrations were elevated 2-fold (P <
0.01) in FHA, and these changes persisted during both waking and sleep
periods. The combined effects of increased frequency and decreased
amplitude during the waking hours resulted in unaltered wake time GH
levels for FHA, whereas GH levels during sleep were higher
(P < 0.05) in FHA than in NC (Fig. 3B and Table 5).
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), statistical comparisons of GH
pulsatility parameters were repeated with percent body fat as a
covariate. The elevation of GH levels in FHA during sleep was fully
accounted for by body fat differences, and a reduction in GH pulse
amplitude became apparent during sleep as well as wake time. The
acceleration of pulse frequency and elevation of interpulse
concentrations remained significant. Thus, GH pulsatility in FHA is
characterized by blunted pulse amplitude, accelerated pulse frequency,
and elevated interpulse levels throughout the day, with no difference
in 24-h mean GH levels compared to those in NC when differences in
adiposity are accounted for.
Twenty-four-hour GHBP concentrations were 40% (P <
0.01) lower in FHA than in NC (Table 5). IGF-I and IGFBP-3 levels as
well as the ratio of IGF-I/IGFBP-3 did not differ between FHA and NC
groups (Table 5). The elevation of 24-h IGFBP-1 levels in FHA resulted
in a lower ratio of IGF-I/IGFBP-1 for FHA compared to NC
(P < 0.01; Table 5).
Leptin levels and dynamics
Leptin levels for both FHA and NC exhibited similar diurnal
patterns, with lowest levels at 0900 h after nocturnal fasting,
rising gradually to maximal levels at 0100 h, followed by a rapid
fall and return to early morning levels by 0900 h (Fig. 4A). Although significance was not
reached, 24-h mean leptin levels for FHA (7.0 ± 1.5 ng/mL) tended
to be lower than those for NC (10.1 ± 1.3 ng/mL). Leptin levels
for FHA and NC were highly correlated with percent body fat (r =
0.88; P < 0.0001), and the difference between FHA and
NC was fully accounted for by the lower percentage body fat in FHA
(Table 1 and Fig. 4B). The relative excursion of leptin levels from
morning nadir to nocturnal peak in FHA (42 ± 19%) did not differ
from that in NC (54 ± 7%).
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LH pulsatility characteristics are presented in Table 6. LH pulse frequency was slowed 50%
(P < 0.001) in FHA compared to NC with unaltered pulse
amplitude, resulting in 45% lower 24-h mean LH levels for FHA
(P < 0.01). LH pulse frequency for the two groups
together related positively to concentrations of insulin (r =
0.80; P < 0.001) and the ratio of IGF-I/IGFBP-1
(r = 0.70; P = 0.005) and negatively to IGFBP-1
(r = -0.72; P = 0.003) and cortisol (r =
-0.61; P = 0.02) and was unrelated to IGF-I alone. LH
pulsatility parameters and levels were not related to levels of leptin
or the absolute or relative diurnal excursion of leptin.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Insulin/glucose homeostasis was also altered in FHA. During the feeding phase of the day, FHA exhibited lower glucose and insulin levels than cycling women. Although reductions of insulin and glucose occur in response to acute psychological stress (29, 30), we are not aware of studies addressing the effects of chronic psychological stress on glycemic control. Thus, it is difficult to discern whether the presence of hypoglycemia/hypoinsulinemia in FHA is a stress response or a metabolic adaptation to nutritional deficits. The positive relationship between dietary fat intake and circulating insulin levels (r = 0.67) seen in this study suggests the latter. In addition, imposition of a high carbohydrate/high fiber/low fat diet similar to that of FHA has been shown to increase peripheral insulin sensitivity (31) and lower plasma glucose and insulin levels (32). Thus, unbalanced dietary composition may negatively influence general metabolic fuel availability in FHA. Taken together with our previous observation of reduced T3 and T4 concentrations in stress-associated FHA (11), lower levels of insulin and glucose indicate an overall negative energy balance in FHA compared to NC.
Evidence of metabolic adaptation in FHA extended to the somatotropic axis as well. Although 24-h mean GH levels in FHA were similar to those in cycling controls, the pattern of GH pulsatility was distinctly altered, with blunted pulse amplitude, accelerated pulse frequency, and elevated interpulse GH levels for FHA throughout the sleep/wake cycle. This study confirmed our earlier report of elevated nocturnal GH levels in FHA (11). However, given the inverse influence of adiposity on GH secretion (33), we found that this difference was fully accounted for by the lower level of body fat in the FHA compared to the NC subjects. Thus, augmented nocturnal GH secretion is not dependent on menstrual status per se. Accelerated GH pulse frequency and elevated interpulse GH levels have been described in states of nutritional deprivation, however, usually accompanied by hypersecretion of GH (for review, see Refs. 33 and 34). The mechanism underlying the blunting of GH pulse amplitude and the maintenance of normal GH levels in FHA is unclear. GH responses to hypoglycemia are blunted in women with depression (35), and cerebrospinal fluid levels of somatostatin are reduced in depressive illness (36). Hypothalamic regulation of GH release is also influenced by catecholamines and metabolic substrates, including glucose and free fatty acids (37). It is evident that the mechanism(s) underlying the complex pattern of GH secretion in FHA is multifactorial and may be related to both psychogenic stress and nutritional deficits.
The status of downstream effectors of GH action in women with psychogenic FHA has not been previously characterized. IGFBP-1 levels were elevated in FHA, consistent with the well known negative regulation of IGFBP-1 by insulin (38, 39) and the presence of hypoinsulinemia in FHA. Glucocorticoids have been shown to increase circulating levels of IGFBP-1 in conditions with low insulin levels (40) and to stimulate IGFBP-1 gene expression (39). Regression analysis indicated that the presence of hypercortisolemia in FHA contributed positively to the elevation of IGFBP-1 levels, independent of the negative influence of insulin. Thus, the combined effects of hypoinsulinemia (disinhibition) and hypercortisolemia (stimulation) account for the augmentation of IGFBP-1 in FHA. Although serum levels of IGF-I were not reduced in FHA, as would be expected in an energy-deficient state (41), the elevation of IGFBP-1 levels resulted in a lower IGF-I/IGFBP-1 ratio for FHA than cycling controls. IGFBP-1 is a potent inhibitor of the insulin-like activity of IGF-I (42); thus, the reduction in the ratio of IGF-I/IGFBP-1 in FHA may act as an energy-conserving strategy by minimizing the hypoglycemic action of IGF-I. GHBP concentrations, a reflection of the extracellular domain of hepatic GH receptors (43), were reduced 40% in FHA, consistent with more severe hypometabolic states, such as anorexia nervosa (34, 44) and fasting (43).
Surprisingly, both leptin levels and its diurnal rhythm were unaltered in FHA. We have recently reported a reduction in leptin levels in highly trained athletes regardless of menstrual status and the absence of a diurnal rhythm in athletes with FHA (24). The association of these alterations with hypoinsulinemia and hypercortisolemia in that study suggested that metabolic adaptations to chronic energy deficits influence leptin regulation. A growing body of evidence supports the contention that leptin is acutely regulated by energy balance as well, independent of body fat stores (for review, see Ref.45). However, reports of body fat-appropriate leptin levels in severely energy-deficient patients with anorexia nervosa (46, 47) suggest that unknown factors influence the interaction of energy status and leptin regulation in chronic conditions.
LH pulse frequency was slowed 50% in FHA, consistent with previous reports (9, 11, 48, 49, 50), and was related positively to insulin levels (r = 0.80) and the ratio of IGF-I/IGFBP-1 (r = 0.70) and negatively to cortisol (r = -0.61) and IGFBP-1 (r = -0.72) concentrations. The multiple interdependent interactions among these metabolic factors limits the interpretation of these results. Nonetheless, the possibility that a peripheral marker of metabolic fuel availability may be involved in the suppression of GnRH/LH pulsatile activities in FHA of the psychogenic type is introduced. Further, although the association of hypercortisolemia with slowing of GnRH/LH pulsatile activity in psychogenic FHA is well known, these results suggest that the underlying activation of hypothalamic CRF long suspected to subserve this relationship (51, 52, 53) may be in part a response to metabolic, rather than psychogenic, challenges. Interestingly, despite the greater level of metabolic activation in women with exercise-related amenorrhea (hypoglycemia, hypoinsulinemia, hypercortisolemia, and elevated IGFBP-1 levels extend to the fasting as well as the feeding portion of the day) (4), the degree of inhibition of GnRH/LH pulse frequency is similar for psychogenic (9, 11, 48, 49, 50) and athletic (3, 4) amenorrhea. Furthermore, in contrast to the normal 24-h mean LH levels seen in amenorrheic athletes (3, 4), in this study 24-h mean LH levels for FHA were reduced 45%. Whether the coupling of nutritional deficits with psychogenic stress has an additive or a synergistic effect on hypothalamic control of GnRH/LH pulsatility can only be discerned by interventional studies.
In summary, we found evidence of subclinical eating disorders in weight-stable, nonathletic women with FHA accompanied by a severe restriction of dietary fat intake. Unbalanced nutrient intake in psychogenic FHA was associated with multiple endocrine-metabolic alterations. Among these, reduced levels of plasma glucose and serum GHBP, a decrease in the ratio of IGF-I/IGFBP-1, accelerated GH pulse frequency, and elevated interpulse GH levels are indicative of a hypometabolic state. In addition, the magnitudes of glucoregulatory responses (increased cortisol secretion and decreased insulin/IGF-I action) were directly related to the degree of suppression of GnRH/LH pulse frequency. These results are remarkably similar to those seen in highly trained athletes with FHA (4). Thus, nutritional deficits may represent a common contributing factor in the development and maintenance of multiple neuroendocrine-metabolic aberrations underlying both psychogenic and exercise-related FHA. Assessment of nutritional intake and intervention to correct imbalances should be considered in the management of these women.
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Acknowledgments |
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Footnotes |
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2 Former fellow in reproductive endocrinology, University of
California, San Diego.
3 Investigator with The Clayton Foundation.
Received August 21, 1997.
Revised September 26, 1997.
Accepted October 6, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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M. Misra, K. K. Miller, J. Bjornson, A. Hackman, A. Aggarwal, J. Chung, M. Ott, D. B. Herzog, M. L. Johnson, and A. Klibanski Alterations in Growth Hormone Secretory Dynamics in Adolescent Girls with Anorexia Nervosa and Effects on Bone Metabolism J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5615 - 5623. [Abstract] [Full Text] [PDF]
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M. J. de Souza, J. Van Heest, L. M. Demers, and B. L. Lasley Luteal Phase Deficiency in Recreational Runners: Evidence for a Hypometabolic State J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 337 - 346. [Abstract] [Full Text] [PDF]
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G. Kilciler, M. Ozata, C. Oktenli, S.Y. Sanisoglu, E. Bolu, N. Bingol, M. Kilciler, I. C. Ozdemir, and M. Kutlu Diurnal Leptin Secretion Is Intact in Male Hypogonadotropic Hypogonadism and Is Not Influenced by Exogenous Gonadotropins J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5023 - 5029. [Abstract] [Full Text] [PDF]
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 S. Andrico, A. Gambera, C. Specchia, C. Pellegrini, L. Falsetti, and E. Sartori Leptin in functional hypothalamic amenorrhoea Hum. Reprod., August 1, 2002; 17(8): 2043 - 2048. [Abstract] [Full Text] [PDF]
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 E. Weimann Gender-related differences in elite gymnasts: the female athlete triad J Appl Physiol, May 1, 2002; 92(5): 2146 - 2152. [Abstract] [Full Text] [PDF]
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L. Falsetti, A. Gambera, L. Barbetti, and C. Specchia Long-Term Follow-Up of Functional Hypothalamic Amenorrhea and Prognostic Factors J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 500 - 505. [Abstract] [Full Text] [PDF]
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R. B. Perkins, J. E. Hall, and K. A. Martin Aetiology, previous menstrual function and patterns of neuro-endocrine disturbance as prognostic indicators in hypothalamic amenorrhoea Hum. Reprod., October 1, 2001; 16(10): 2198 - 2205. [Abstract] [Full Text] [PDF]
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T. Sir-Petermann, S.E. Recabarren, A. Lobos, M. Maliqueo, and L. Wildt Secretory pattern of leptin and LH during lactational amenorrhoea in breastfeeding normal and polycystic ovarian syndrome women Hum. Reprod., February 1, 2001; 16(2): 244 - 249. [Abstract] [Full Text] [PDF]
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L. K. Hilton and A. B. Loucks Low energy availability, not exercise stress, suppresses the diurnal rhythm of leptin in healthy young women Am J Physiol Endocrinol Metab, January 1, 2000; 278(1): E43 - E49. [Abstract] [Full Text] [PDF]
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Author's Response J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4751 - 4751. [Full Text]
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T. Sir-Petermann, M. Maliqueo, A. Palomino, D. Vantman, S.E. Recabarren, and L. Wildt Episodic leptin release is independent of luteinizing hormone secretion Hum. Reprod., November 1, 1999; 14(11): 2695 - 2699. [Abstract] [Full Text] [PDF]
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 L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]
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R. K. Støving, J. D. Veldhuis, A. Flyvbjerg, J. Vinten, J. Hangaard, O. G. Koldkjær, J. Kristiansen, and C. Hagen Jointly Amplified Basal and Pulsatile Growth Hormone (GH) Secretion and Increased Process Irregularity in Women with Anorexia Nervosa: Indirect Evidence for Disruption of Feedback Regulation within the GH-Insulin-Like Growth Factor I Axis J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 2056 - 2063. [Abstract] [Full Text]
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S. B. Seminara, F. J. Hayes, and W. F. Crowley Jr. Gonadotropin-Releasing Hormone Deficiency in the Human (Idiopathic Hypogonadotropic Hypogonadism and Kallmann's Syndrome): Pathophysiological and Genetic Considerations Endocr. Rev., October 1, 1998; 19(5): 521 - 539. [Abstract] [Full Text]
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 A. B. Loucks and M. Verdun Slow restoration of LH pulsatility by refeeding in energetically disrupted women Am J Physiol Regulatory Integrative Comp Physiol, October 1, 1998; 275(4): R1218 - R1226. [Abstract] [Full Text] [PDF]
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K. K. Miller, M. S. Parulekar, E. Schoenfeld, E. Anderson, J. Hubbard, A. Klibanski, and S. K. Grinspoon Decreased Leptin Levels in Normal Weight Women with Hypothalamic Amenorrhea: The Effects of Body Composition and Nutritional Intake J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2309 - 2312. [Abstract] [Full Text]
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