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Decreased Leptin Levels in Normal Weight Women with Hypothalamic Amenorrhea: The Effects of Body Composition and Nutritional Intake¹

Neuroendocrine Unit (K.K.M., M.S.P., E.S., A.K., S.K.G.) and the General Clinical Research Center (E.A., J.H.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

	Abstract

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Leptin is a protein encoded by the ob gene and expressed in adipocytes. A sensitive marker of nutritional status, leptin is known to correlate with fat mass and to respond to changes in caloric intake. Leptin may also be an important mediator of reproductive function, as suggested by the effects of leptin infusions to restore ovulatory function in an animal model of starvation. We hypothesized that leptin levels are decreased in women with hypothalamic amenorrhea and that leptin may be a sensitive marker of overall nutritional status in this population. We, therefore, measured leptin levels and caloric intake in 21 women with hypothalamic amenorrhea (HA) and 30 age-, weight-, and body fat-matched eumenorrheic controls. Age (24 ± 5 vs. 24 ± 3 yr), body mass index (20.6 ± 1.3 vs. 21.1 ± 1.5 kg/m²), percent ideal body weight (94.9 ± 5% vs. 96.3 ± 6.3%), and fat mass (14.2 ± 3.6 vs. 15.5 ± 2.9 kg, determined by dual energy x-ray absortiometry) did not differ between the groups. Leptin levels were significantly lower in the HA subjects compared with those in the controls (7.1 ± 3.0 vs. 10.6 ± 4.9 µg/L; P = 0.005). Total caloric intake (1768 ± 335 vs. 2215 ± 571 cal/day; P = 0.003), fat intake (333 ± 144 vs. 639 ± 261 cal/day; P < 0.0001), and insulin levels (5.6 ± 1.2 vs. 7.4 ± 3.2 µU/mL; P = 0.015) were lower in the women with HA than in the eumenorrheic controls. The difference in leptin levels remained significant after controlling for insulin (P = 0.023). These data are the first to demonstrate hypoleptinemia, independent of fat mass, in women with HA. The hypoleptinemia may reflect inadequate calorie intake, fat intake, and/or other subclinical nutritional disturbances in women with HA. The mechanism and reproductive consequences of low leptin in this large population of women remain unknown.

	Introduction

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LEPTIN, a protein encoded by the ob gene and expressed in adipocytes (1, 2, 3, 4, 5), may be an important modulator of ovulatory function. Animal studies suggest that leptin administration can prevent starvation-induced anovulation (6). In humans, leptin levels correlate with body weight and body fat. Serum leptin levels are decreased in conditions of chronic starvation, such as anorexia nervosa (7), and also among women with low body fat, such as excessive exercisers (8), and may contribute to anovulation in these patients. In this study we investigated the effects of body composition and nutritional intake on serum leptin levels in normal weight women with hypothalamic amenorrhea (HA). Our data demonstrate decreased leptin levels in women with HA. Although weight and body fat were equivalent to those in a normal control population, caloric intake and fat intake were lower in women with HA. These data suggest that nutritional abnormalities are present among normal weight women with HA, which may contribute to decreased leptin levels and ovulatory dysfunction.

	Experimental Subjects

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Twenty-one women with HA and 30 eumenorrheic age-matched control subjects were admitted to the General Clinical Research Center at the Massachusetts General Hospital for a 26-h period. The subjects with HA had been amenorrheic for at least 3 months, weighed between 90–110% of ideal body weight (IBW), and had been of stable weight for at least 1 yr. Subjects with abnormal TSH levels; elevated FSH, PRL, or testosterone levels; or a ratio of LH/FSH greater than 2.5 were excluded from participating in the study. None of the subjects received estrogen within 3 months of the study, and none had a prior history of anorexia nervosa. Control subjects with regular menses were studied in the early follicular phase, defined as within 7 days of the onset of menses. All subjects gave written consent, and the study was approved by the Subcommittee on Human Studies of the Massachusetts General Hospital.

	Materials and Methods

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Hormonal assessment

Fasting 0800 h serum leptin concentrations were measured by RIA (Linco Diagnostics, St. Louis, MO) with intraassay coefficients of variation of 3.0–6.2% and a sensitivity of 0.5 µg/L (9). Samples from each individual were measured in duplicate and run in the same assay. Fasting serum insulin levels were measured by RIA (Diagnostic Products Corp., Los Angeles, CA) with intraassay coefficient of variations of 3–13%. FSH, LH, TSH, testosterone, free testosterone, estradiol, and PRL were measured using previously described methods (10).

Body composition analysis

Fat and fat-free mass were determined by dual x-ray absorptiometry (DXA) using a Hologic-4500 densitometer (Hologic, Waltham, MA). The DXA technique has a precision error of 3% for fat and 1.5% for fat-free mass (11).

Nutritional assessment

Study subjects were given an ad libitum diet, and their food intake was observed in the hospital for 24 h. Analysis of total calorie, protein, fat, and carbohydrate contents was performed using the Minnesota Nutrition Data Systems, version 8A/2.6 (Minneapolis, MN). For each patient, body mass index (BMI) and percent IBW were calculated as defined by the 1959 Metropolitan Life Insurance Co. tables.

Activity assessment

Current activity was assessed by the Modifiable Activity Questionnaire (12, 13). This questionnaire assesses occupational and leisure activities, including exercise, over the past year.

Statistical analysis

Leptin, fat mass, caloric and macronutrient intake (protein, fat, and carbohydrate), age, weight, BMI, estradiol, and other clinical variables were compared between groups by Student’s t test. The regression equations for leptin vs. fat mass were analyzed separately for the HA and control groups and compared by analysis of covariance to determine whether there was a difference in slopes (JMP Statistical Discovery Software, SAS Institute, Cary, NC). Unless otherwise indicated, all data are expressed as the mean ± SD.

	Results

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Women with HA and eumenorrheic controls were matched for age, weight, BMI, percent IBW, and fat mass, as measured by DXA (Table 1). Total caloric intake (1768 ± 335 vs. 2215 ± 571 cal/day; P = 0.003), fat intake (333 ± 144 vs. 639 ± 261 cal/day; P < 0.0001), and insulin levels (5.6 ± 1.2 vs. 7.4 ± 3.2 µIU/mL; P = 0.015) were lower in the HA subjects than in the control group (Table 1). There were no significant differences in carbohydrate or protein ingestion between the two groups. Leptin levels were lower in the HA group than in the eumenorrheic controls (7.1 ± 3.0 vs. 10.6 ± 4.9 µg/L; P = 0.005; Table 1), and this difference remained significant after controlling for insulin levels (P = 0.023). All normal volunteers were studied during the early follicular phase. Estradiol levels did not differ between the groups (27.9 ± 28.4 vs. 27.9 ± 9.6 pg/mL; Table 1). The 24-h urinary free cortisol levels were significantly higher in the HA group compared to those in the control subjects (P = 0.004; Table 1). However, there was no correlation between urinary free cortisol and leptin levels, and the difference in leptin remained significant after controlling for urinary free cortisol (P = 0.003). The number of hours a week of activity performed was greater in the HA than in the control subjects (12.8 ± 13.5 vs. 6.2 ± 6.0 h/week; P = 0.021; Table 1), but the difference in leptin also remained significant after controlling for exercise (P = 0.016).

The slopes of the regression equation were significantly different between the two groups (P = 0.037).

	Discussion

Top Abstract Introduction Experimental Subjects Materials and Methods Results Discussion References

 
In this study we demonstrate reduced leptin levels in normal weight women with HA. Although weight and body fat were equivalent to those in a healthy control population, total caloric intake, fat intake, and insulin levels were lower in the women with HA. These data suggest that nutritional abnormalities are present among women with HA, which may contribute to decreased leptin levels and ovulatory dysfunction.

Hypoleptinemia has been demonstrated in underweight women with anorexia nervosa and in extensive exercisers with low body fat and HA (7, 8). However, decreased leptin levels in women with HA, independent of weight or fat mass, has not been shown previously. In this study we demonstrate nutritional differences in terms of caloric intake and fat intake that may account for the differences in leptin. Moreover, we demonstrate that the relationship between leptin and fat mass differs between the groups, such that the expected rise in leptin for a given increase in fat mass is decreased in HA patients compared with that in eumenorrheic controls.

The etiology of the decreased leptin levels and the abnormal relationship of fat mass to leptin in women with HA is not known. In a prior study, Laughlin et al. compared leptin levels in women with HA and normal control subjects (14). No significant differences in leptin levels were observed between the groups. In contrast, we demonstrate significantly lower leptin levels in women with HA. Differences in sample size as well as nutritional status may account for these contrasting results. For example, we demonstrate decreased total caloric and fat intake in subjects with HA, which may contribute to decreased leptin in this population. In addition, we show that insulin levels are lower in the HA subjects than in the normal controls. Insulin is known to correlate with leptin and is considered a potential leptin secretagogue (15, 16, 17). Reduced insulin levels in normal weight HA subjects, therefore, may contribute in part to reduced leptin levels in this population. These data suggest that leptin is a sensitive integrated marker of nutritional status in women with HA.

Decreased energy intake may contribute to decreased leptin levels and ovulatory dysfunction in women with HA. Subjects with HA in this study ingested fewer total calories and fat than normal controls, but had been weight stable over the past year, suggesting the need for further studies to determine overall energy balance in this population. The sensitivity of gonadotropin pulsatility to caloric restriction has been shown in studies of food-restricted animals by the return of LH pulses within 12–24 h of refeeding, before a significant change in weight or body composition (18). Similarly, calorie restriction over 4 days is known to decrease LH pulsatility in young healthy women (19).

The mechanism by which inadequate energy intake inhibits ovulatory function is unknown, but may relate to decreased endogenous leptin secretion. Leptin levels are known to decrease with fasting in humans and to respond to changes in caloric intake (20, 21, 22). Furthermore, the administration of leptin has been shown to restore ovulatory function in an animal model of starvation, suggesting that leptin may be an important, nutritionally dependent mediator of neuroendocrine function (6). Future studies will be necessary to determine more directly the effects of increased caloric intake and fat on leptin and ovulatory function in women with HA.

Alternatively, other factors may contribute to the decreased leptin levels in HA. Our study subjects with HA demonstrated increased activity scores compared with those in controls. Three previous studies have shown no effect of exercise on leptin levels in men (23, 24, 25). In contrast, two studies in women suggest that leptin levels are reduced in response to exercise. In the larger of these studies, Kohrt et al. demonstrated reduced leptin levels in association with decreased fat mass in 61 postmenopausal women participating in an 11-month exercise training program (26). However, an independent effect of exercise on leptin, unrelated to changes in fat mass, was shown by Hickey et al. in a study of 9 sedentary women (25). These data suggest that increased physical activity and exercise among women with HA may contribute to decreased leptin levels in this population.

As previously described, women with HA demonstrate increased urinary free cortisol levels compared to those in control subjects (27, 28). There was no correlation between urinary free cortisol and leptin levels among our study subjects. Moreover, the differences in leptin between the HA and control subjects remained significant after controlling for urinary free cortisol. In addition, recent studies suggest that cortisol stimulates leptin production (29). Therefore, hypercortisolemia is not likely to be the cause of the hypoleptinemia in our study subjects with HA.

We found no difference in estradiol levels between our normal volunteers and the women with HA to account for the observed differences in leptin. Normal control subjects, however, were sampled during the early follicular phase when estradiol levels are low. Serum leptin levels rise during the luteal phase in regularly cycling women (30), such that an even greater difference from HA subjects might be expected at other times during the menstrual cycle.

These data are the first to demonstrate decreased serum leptin levels in normal weight women with HA. Although the hypoleptinemia cannot be attributed to decreased body fat or weight, it may reflect inadequate caloric and fat consumption and reduced insulin levels. Decreased serum leptin levels in HA may, in turn, contribute to anovulation and irregular menstrual function. Ahima et al. demonstrated that leptin administration prevents fasting-induced anovulation in an animal model (6). Moreover, Barash et al. found that leptin-treated ob/ob mice had significantly increased LH levels, ovarian and uterine weights, and stimulated ovarian and uterine histology compared with placebo-treated mice (31). Further studies are need to investigate the mechanisms and reproductive consequences of low leptin in the large population of women with HA.

	Acknowledgments

 
The authors thank Gregory Neubauer and Sheila Saltzman for their technical assistance, and the General Clinical Research Center staff for its expert patient care.

	Footnotes

 
Address requests for reprints to: Steven K. Grinspoon, M.D., Neuroendocrine Unit, Bulfinch 457b, Massachusetts General Hospital, Boston, Massachusetts 02114.

¹ This work was supported in part by NIH Grants M01-RR-0166, R01-DK-52625–01, and 5-T32-DK-07028–23.

Received February 19, 1998.

Revised March 30, 1998.

Accepted April 6, 1998.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Miller, K. K. Articles by Grinspoon, S. K. Search for Related Content PubMed PubMed Citation Articles by Miller, K. K. Articles by Grinspoon, S. K.