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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 7 2982-2988
Copyright © 2001 by The Endocrine Society

Endocrine Care

Serum Leptin, Gonadotropin, and Testosterone Concentrations in Male Patients with Anorexia Nervosa during Weight Gain

Martin Wabitsch, Anne Ballauff, Reinhard Holl, Werner F. Blum, Eberhard Heinze, Helmut Remschmidt and Johannes Hebebrand

Department of Pediatrics and Institute of Biomedical Technology (M.W., R.H., E.H.), University of Ulm, Ulm D-89075, Germany; Department of Child and Adolescent Psychiatry (A.B., H.R., J.H.), University of Marburg, Marburg D-35033, Germany; and Lilly Deutschland (W.F.B.), Bad Homburg D-61350, Germany

Address all correspondence and requests for reprints to: Johannes Hebebrand, Clinical Research Group, Department of Child and Adolescent Psychiatry, Hans-Sachs-Strasse 6, 35033 Marburg, Germany. E-mail: Hebebran{at}post.med.uni-marburg.de

Abstract

Amenorrhea in female patients with anorexia nervosa is associated with low leptin secretion, thus suggesting a causal link. In an attempt to address the hypothesis that leptin also influences the hypothalamo-pituitary-gonadal function in males, we studied three male patients with acute anorexia nervosa longitudinally. Serum levels of leptin, LH, FSH, testosterone, and SHBG were measured on a biweekly basis during weight gain. Leptin levels at low body mass index values were below the 5th percentile. During weight gain, leptin levels reached or surpassed the 95th percentile. The temporal dynamics of body mass index and fat mass were closely related to those of leptin concentrations in serum. Leptin increments were paralleled by increments of gonadotropins, testosterone, and the free androgen index (FAI). In each of the patients, serum concentrations of leptin were positively correlated with those of testosterone (P = 0.0001, P = 0.01, P = 0.07, respectively) and FAI (P = 0.0001, P = 0.0001, P = 0.09, respectively). In addition, in the combined data set of all patients changes of leptin over time were positively correlated with changes in LH (P = 0.01), FSH (P = 0.0001), testosterone (P = 0.002), and FAI (P = 0.002). In conclusion, these data suggest that leptin might also play an important role in the regulation of the hypothalamo-pituitary-gonadal axis and fertility in underweight males as has previously been shown in underweight females.

THE ROLE OF leptin in the regulation of body weight is associated with several other regulatory functions in endocrine systems including the hypothalamo-pituitary-gonadal axis. In ob/ob mice, treatment with leptin initiates fertility (1). In wild-type mice, leptin triggers the time of puberty (2). Administration of leptin to food-deprived animals blunts the drop of LH and FSH levels normally observed during starvation (3). Leptin has been shown to act both at the hypothalamic and at the pituitary level to stimulate LH-RH as well as LH and FSH secretion (4, 5).

Female patients with mutations leading to either biologically inactive leptin or leptin receptor are characterized by primary amenorrhea (6, 7). In cross-sectional studies, it was observed that in healthy boys and girls, before and during puberty, the percentage of body fat rises resulting in an increment of leptin serum levels and in increments of FSH and LH as well as estradiol in girls (8, 9). It has been suggested that there is a leptin threshold level for menarche (10), and it has been hypothesized that the increment in leptin in early puberty might be a critical event for further pubertal development in boys (9, 11).

In postmenarcheal women, a critical leptin level is seemingly a prerequisite for menstruation (12, 13, 14). Furthermore, studies in female adolescents with eating disorders or underweight showed that low leptin levels predicted amenorrhea (14). In a recent study, female adolescents with secondary amenorrhea due to acute anorexia nervosa were followed up during weight gain. It was found that the observed increments of LH levels generally tracked the increments of leptin levels. There was a critical serum leptin level of 1.85 µg/L below which LH levels were insufficient to trigger menstruation (15).

The suggestion that leptin plays a crucial role in pubertal development and that there is a critical level being necessary for onset of puberty is, however, still not proven. The regulatory system as it is described shortly here is much more complex and a causal relationship between leptin and pubertal development is not always demonstrable. Some of the patients with congenital or acquired generalized lipodystrophy are infertile and enter late into maturation, whereas others have normal pubertal development and are fertile showing that the very low leptin levels in these patients do not inhibit puberty and fertility (16, 17).

Until now, almost all data on a possible regulation of the hypothalamo-pituitary-gonadal axis and fertility by leptin in humans were obtained in females as summarized above. No data are available for males, probably due to the fact that in males extremely low body weights associated with sterility are uncommon and due to the lack of an easily measurable biological marker indicating appropriate gonadal function like menstruation in females. We had the unique opportunity to follow three male patients with acute anorexia nervosa during therapeutically induced weight gain. We hypothesize that—similar to females—leptin levels predict the function of the hypothalamo-pituitary-gonadal axis.

Patients and Methods

Three male patients with a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis of anorexia nervosa at the ages of 12, 17, and 17 years, respectively, were studied longitudinally as inpatients during therapeutically induced weight gain (18). The patients did not receive any medications. The assessment procedure has been delineated in detail previously (17, 19). Briefly, measurements of height and weight, bioelectrical impedance measurements (2000-S; Data Input, Frankfurt, Germany), and blood sampling were performed concomitantly after an overnight fast between 0800 and 0830 h within 3 days after admission and on a biweekly basis thereafter. Body fat mass was calculated from measured resistance according to an equation derived from underweight females (20).

Serum leptin levels were determined with a specific RIA previously described in detail (8) (detection limit 0.03 µg/L). LH and FSH were determined using commercially available microparticle enzyme immunoassays (Abbott Diagnostika, Wiesbaden, Germany). Testosterone was measured with a specific RIA from ImmunoBiological Laboratories (Hamburg, Germany) and sex hormone-binding globulin (SHBG) was determined using a RIA from BioMerieux (Nürtingen, Germany). The inter and intraassay coefficients of variation for the RIAs did not exceed 10%. The free androgen index (FAI) representing the biological active hormone was calculated according to Carter et al. (21).

The reference ranges for serum leptin levels in relationship to gender, age, and pupertal status have been delineated previously (8). Normal ranges for the variables under investigation used in our laboratory were obtained in 100 normal weight postpubertal males as well as in 50 normal-weight males aged 11–13 yr. The 5th and 95th percentiles are as follows for the postpubertal males:0.0.5–6.0 mIU/mL for LH, 1–11 mIU/mL for FSH, 3–10 ng/mL for testosterone, 4–21 ng/ml for SHBG. For males aged 11–13 yr, the corresponding values are: <3.0 mIU/mL for LH, <5.0 mIU/mL for FSH, 0.06–0.5 ng/mL for testosterone, 4–21 ng/mL for SHBG.

This study was approved by the Ethics Committee of the University of Marburg. Written informed consent was obtained from the patients and their parents.

Statistics and presentation of data

Due to the low number of subjects and measurements, data are presented in a descriptive manner. In addition, to examine the relationship between serum concentrations of leptin and those of other hormones, Pearson’s correlation coefficients were calculated.

In the figures showing the longitudinal changes of leptin and the other hormonal data, log transformed data are presented. It has to be remembered that this technique magnifies small changes in absolute numbers. We also present all measured serum parameters separately in tables in absolute numbers.

Results

At referral, body mass index (BMI) values of the patients ranged from 12.5–17.3 kg/m2 with leptin levels ranging from below 0.03 µg/L to 1.3 µg/L. The increments in serum leptin levels during weight gain in relation to the achieved BMI values are shown in Fig. 1Go. Leptin levels at low BMI values were generally below the 5th percentile. During weight gain, leptin levels reached or surpassed the 95th percentile (Fig. 1Go). The temporal dynamics of BMI, fat mass, leptin, gonadotropin, and testosterone levels are shown in Figs. 2Go, A and B, 3, and 4 for each patient.



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  		Figure 1. Serum concentrations of leptin (log-transformed) in patient A (• first stay; {circ}, second stay), B ({diamondsuit}), and C ({blacktriangleup}) in relation to their BMIs during weight changes. Dotted lines indicate 5th and 95th percentile of leptin for postpubertal males (8 ).

 


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  		Figure 2. Time course of BMI, % body fat, and hormonal parameters in patient A during first (A) and second inpatient treatment period (B). Parameters were measured every second week. Hormonal parameters were log-transformed. The symbols indicate BMI (*), % body fat (•), leptin ({circ}), testosterone ({blacksquare}), FAI ({diamondsuit}), LH ({blacktriangleup}), and FSH ({blacktriangledown}).

 
Patient A, 17 yr old, Tanner stage PH 4, had developed anorexia nervosa at age 14. Upon two previous inpatient treatment episodes at ages 14 and 16, he had been admitted with weights of 44 and 43 kg, respectively. He was subsequently treated in a therapeutic home where he, however, was still not able to maintain his target weight of 60 kg. After his weight had declined to 57.5 kg, the critical weight at which another inpatient treatment had been scheduled in advance to ensure an early intervention, he presented with a BMI of 17.3 kg/m2 for the first of the two treatment episodes, which were assessed longitudinally within this study.

Upon the first referral, patient A had normal levels of leptin, LH, FSH, testosterone, and SHBG (Table 1GoA). During this inpatient treatment episode, the maximal BMI was 19.3 kg/m2 and the BMI at discharge was 18.6 kg/m2. As shown in Fig. 2AGo, for the most part changes of BMI and of body fat mass were associated with changes in leptin levels. These in turn were paralleled precisely by LH and testosterone levels as well as the free androgen index. This close association of the hormonal changes were also seen when the changes in leptin were not obviously related to changes in BMI.


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  		Table 1. Biweekly measured data of BMI and hormonal parameters during the first (Table 1GoA) and second (Table 1GoB) inpatient treatment period of patient A

 
After discharge, the patient refused to return to the therapeutic home and instead lived on his own. Over the next 4 months the patient again lost 21 kg, resulting in a BMI of 12.5 kg/m2 upon renewed referral. Upon this admission, the patient had extremely low levels of LH, FSH, and testosterone and a rather high level of SHGB (Table 1GoB). During this inpatient treatment period, the patient continuously gained weight with exception of the last 4 weeks, resulting in a maximal BMI of 17.6 kg/m2 (Fig. 2BGo). Concomitant with the increments in BMI and body fat mass, serum leptin levels rose 100-fold (2.4 µg/L) in comparison to the minimal leptin level observed at referral. Interestingly, serum levels of LH and testosterone as well as free androgen index also changed with a pattern comparable to that of leptin. The marked increase in leptin between week 2 and week 6 was also paralleled by a marked increase in FSH.

Patient B, 17 yr old, Tanner stage PH 4, with a premorbid weight of 68 kg was admitted for inpatient treatment of anorexia nervosa after losing a total of 18 kg over a period of 9 months. As shown in Table 2Go, his BMI was 15.8 kg/m2 at referral and his serum leptin level was below the detection limit. Initial serum testosterone level was 2.6 ng/ml and below the normal range. However, LH and FSH levels were still within the expected range. During therapeutically induced weight gain, serum leptin levels were above detection limit after 4 weeks and increased thereafter in parallel to increases in percentage body fat mass. At discharge, the patient had a BMI of 19.1 kg/m2. During weight gain associated with an increase in leptin, LH and FSH levels rose almost 2-fold from 3.7 to 6.6 mIU/mL and from 4.2 to 9.8 mIU/mL, respectively. Testosterone increased to normal levels (4.2 ng/mL), and the free androgen index rose 3-fold from 0.18 to 0.6 (Table 2Go, Fig. 3Go).


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  		Table 2. Biweekly measured data of BMI and hormonal parameters during the inpatient treatment period of patient B (n.d., not detectable, below the detection limit of 0.03 ng/mL)

 


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  		Figure 3. Time course of BMI, % body fat, and hormonal parameters in patient B during the inpatient treatment period. Parameters were measured every second week. Hormonal parameters were log-transformed. The symbols indicate BMI (*), % body fat (•), leptin ({circ}), testosterone ({blacksquare}), FAI ({diamondsuit}), LH ({blacktriangleup}), and FSH ({blacktriangledown}).

 
Patient C, 12 yr old, Tanner stage PH1, lost 5 kg over the year preceding admission.

At the time of referral, his BMI was 12.9 kg/m2 and his serum leptin level, the only measured hormone at this time, was at the detection limit of 0.03 µg/L (Table 3Go, Fig. 4Go). After 10 weeks of treatment leading to weight gain of 10.2 kg, serum concentrations of LH, FSH, and testosterone were still very low. Concomitant with the subsequent marked increments in leptin (100-fold) during weight and fat mass gain, marked increases in LH and FSH (10-fold, respectively) as well as in total testosterone (10-fold) and free androgen index (6-fold) were observed.


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  		Table 3. Biweekly measured data of BMI and hormonal parameters during the inpatient treatment period of patient C

 


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  		Figure 4. Time course of BMI, % body fat, and hormonal parameters in patient C during the inpatient treatment period. Parameters were measured every second week. Hormonal parameters were log-transformed. The symbols indicate BMI (*), % body fat ({blacksquare}), leptin ({circ}), testosterone ({blacksquare}), FAI ({diamondsuit}), LH ({blacktriangleup}), and FSH ({blacktriangledown}).

 
Correlation analysis

To further characterize the relationship between leptin and testosterone or the FAI, correlation analyses were performed. In a linear correlation analysis between leptin and the other hormonal parameters, it was found that in each of the patients leptin concentrations were positively correlated with levels of testosterone and FAI (Table 4Go). In addition, we performed a correlation analysis in the combined set of data of all patients using the calculated changes of hormones from one time point to the next time point. We found not only positive correlations between {Delta}leptin and {Delta}testosterone and {Delta}FAI, but also between {Delta}leptin and {Delta}LH, and {Delta}FSH (Table 5Go).


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  		Table 4. R values (and P values) of Pearson correlation coefficients between leptin and testosterone and FAI (values were used log-transformed)

 

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  		Table 5. R values (and P values) of Pearson correlation coefficients between {Delta} Leptin and {Delta} LH, {Delta} FSH, {Delta} ratio LH/FSH, {Delta} Testosterone, and {Delta} FAI in the combined data set of all patients

 
Discussion

Although our study is limited by the small number of patients, it has the advantage of providing longitudinal data on the relationship between serum concentrations of leptin, LH, FSH, and testosterone in three male patients with anorexia nervosa during therapeutically induced weight gain. A close temporal association over a time period of several weeks was evident between serum levels of leptin and those of gonadotropins and testosterone. The hormonal patterns during extreme underweight and during weight gain associated with increments in body fat percentage support the hypothesis that leptin as a signal from white adipose tissue might also regulate gonadotropin secretion, gonadal function and possibly fertility in males as has been repeatedly demonstrated in females (6, 7, 12, 13, 14, 15).

Males with anorexia nervosa are characterized by low testosterone levels, causing decreased sexual drive and performance (22, 23). The restoration of healthy weight is associated with an increased testosterone level and a normalization of gender-related behaviors (22). Leptin levels in our patients showing low values in the acute underweight stage and rather high values during weight gain followed the same characteristic pattern as known from females with anorexia nervosa (19). Our data suggest that the low testosterone levels characteristic for anorectic males might be related to the low leptin levels and that the increments in leptin levels during weight gain could be related to the subsequent increments of LH and testosterone levels and the FAI. Temporally close associations between leptin and LH, testosterone, and FAI were seen in all three patients most readily demonstrable in patient A. The every other week sampling performed here is of course not frequent enough to clearly show that leptin levels increase before gonadotropin levels. More frequent sampling might have permitted further delineation of the temporal relationship between leptin levels and gonadotropin and testosterone levels. Further arguments for a possible regulation of the hypothalamo-pituitary-gonadal axis in males with anorexia nervosa by leptin are provided by the finding that the changes of leptin levels over time were significantly correlated with those of gonadotropins, testosterone, and FAI.

Studies in animals support our hypothesis (1, 2, 3, 4, 5). In rodents, most data have also been obtained with female animals since reproductive function in terms of amenorrhea or menstruation and fertility in terms of pregnancy are more readily measurable than in male animals. However, similar to ob/ob females, the sterility of ob/ob males was also corrected after leptin substitution (24). Leptin treatment induced an elevation of testis weight and the mostly atrophied interstitial Leydig cells regained their usual morphology and clustering characteristic (25) and resulted in a rise in FSH and LH secretion (26).

Similar to the male patients presented here, in females with anorexia nervosa (15) LH levels track leptin levels precisely, whereas FSH levels only track leptin when BMI is very low [e.g. patient A second referral (Fig. 2BGo), patient C (Fig. 4Go)]. Assuming a regulation of gonadotropin release by leptin in males, the gonadotropin response in patient B could have a higher sensitivity for leptin because, despite the very low leptin levels at referral, LH and FSH levels were still relatively high and a relationship between their week-to-week changes and the changes of leptin was not discernible. The dynamics of weight loss before admission most likely is also a critical variable. However, also in patient B gonadotropin levels paralleled long-term leptin changes and increased 2-fold during the whole period of weight gain. In this context, it is interesting to see that in females with anorexia nervosa after LH and FSH levels have peaked during weight gain a further relationship to the leptin levels was less evident as shown in the study of Ballauff et al. (15).

An association between release patterns of leptin and LH has also been found in an analysis of blood samples of a 24 h cycle in healthy women during their menstrual cycle (27), suggesting that leptin may regulate the minute-to-minute oscillations in the levels of LH and estradiol. The diurnal and ultradian rhythmic secretion of gonadotropins was not addressed in our study nor in the study of Ballauff et al. (15), representing a limitation of both studies. However, our longitudinal study design allowed the analysis of the relationships between leptin and gonadotropin and testosterone secretion in male patients with anorexia nervosa during extended periods of weight changes. We could demonstrate that leptin and the parameters of the pituitary-gonadal axis show a temporal synchronization in the underweight state and during weight gain.

Our findings are also interesting in another respect. It has been repeatedly shown that androgens inhibit leptin production in adipose tissue (8, 28) and thus contribute to the gender difference in leptin levels. Our present data in underweight male patients do not demonstrate that increasing testosterone levels decrease leptin levels. This is probably due to strong overriding mechanisms associated with weight gain, leading to an exaggerated leptin increment in anorectic patients (19).

It has to be pointed out that the system regulating fertility in which leptin is suggested to be involved is much more complex than it is described by our hypothesis raised above. Some of the data, especially the relatively high gonadotropin levels of patient B despite low leptin levels as mentioned above, do not fully support our hypothesis. We also have to mention that one of our anorectic patients was clinically in a prepubertal stage; thus, the respective findings cannot directly be related to fertility. The present data are observations of associations among several variables with simultaneously changing values. Although not proving causality, the data presented here can support the hypothesis of a possible role of leptin in the regulation of the hypothalamo-pituitary-gonadal axis in anorectic males.

In conclusion, this is to our knowledge the first report on male patients with anorexia nervosa in which serum concentrations of leptin and those of selected parameters of the reproductive system were analyzed longitudinally during extreme underweight and therapeutically induced weight gain. The positive associations between serum concentrations of leptin and those of gonadotropins, testosterone, and FAI, measured on a biweekly basis, are of interest and might support the hypothesis of a possible regulatory function of leptin in the hypothalamic-pituitary-gonadal axis also in males in the underweight range. Further studies are necessary to prove the regulation of the hypothalamo-pituitary-gonadal function and sterility in underweight males by leptin. Such studies could potentially also be performed in males with chronic diseases leading to cachexia and weight loss.

Received July 20, 2000.

Revised January 8, 2001.

Revised March 19, 2001.

Accepted March 25, 2001.

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