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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 9 4139-4143
Copyright © 2003 by The Endocrine Society

Testosterone Replacement Therapy Restores Normal Ghrelin in Hypogonadal Men

Uberto Pagotto, Alessandra Gambineri, Carla Pelusi, Silvia Genghini, Mauro Cacciari, Baerbel Otto, Tamara Castañeda, Matthias Tschöp and Renato Pasquali

Endocrine Unit, Department of Internal Medicine and Gastroenterology, and Center for Applied Biomedical Research (U.P., A.G., C.P., S.G., M.C., R.P.), Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy 40138; Department of Gastroenterology (B.O.), Innenstadt University Hospital, Munich, 80336 Germany; and German Institute of Human Nutrition (T.C., M.T.), 14558 Bergholz-Rehbrücke, Berlin, Germany

Address all correspondence and requests for reprints to: Renato Pasquali, M.D., Endocrinology Unit, Department of Internal Medicine and Gastroenterology, Sant’Orsola-Malpighi Hospital, Via Massarenti 9, 40138 Bologna, Italy. E-mail: rpasqual{at}almadns.unibo.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We recently described a connection between androgens and ghrelin in women affected by the polycystic ovary syndrome. To further investigate the interaction between sex steroids and ghrelin, we investigated circulating ghrelin levels in a group of hypogonadal men before and after therapeutic intervention aiming at normalization low testosterone (T) concentrations. Seven hypogonadal men were compared with nine overweight/moderately obese men matched for body mass index and body fat distribution parameters, as well as with 10 normal weight controls. Total and free T and plasma ghrelin levels were significantly lower in the hypogonadal men than in the control groups. Hypogonadal men also had a significantly higher insulin resistance state. Ghrelin levels were positively correlated with both total and free T concentrations. A significant correlation was also found between ghrelin and the anthropometric parameters and the insulin resistance indexes. However, in a multiple regression analysis in which a correction for all covariants was performed, only the relationship with total and free T persisted. After the 6-month replacement T therapy, ghrelin levels of hypogonadal patients increased and did not differ significantly in comparison with both control groups. The positive correlation between ghrelin and androgens still persisted after T replacement therapy, after adjusting for confounding variables. These data further indicate that sex hormones modulate circulating ghrelin concentrations in humans. This may be consistent with the concept that ghrelin may exert a relevant role in the endocrine network connecting the control of the reproductive system with the regulation of energy balance.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THREE YEARS AFTER its identification, ghrelin has turned out to be the only circulating factor to promote appetite, food intake, and positive energy balance (1, 2, 3). Ghrelin is predominantly produced and secreted by the stomach and the gut (4). Its production site, in combination with its main biological effects, already indicated that this novel peptide hormone might represent a mediator transducing quantitative and qualitative changes in nutrient intake into central circuits regulating metabolic balance (1). Although ghrelin has a potent orexigenic activity and causes weight gain (1, 4), a widespread peripheral distribution of ghrelin receptor suggests a pleiotropic and multifunctional role of this gastric hormone (5). In this context, gonadal tissues have been proposed as being a target for ghrelin based on a high number of binding sites in both ovary and testis (5). In addition to this first descriptive evidence that ghrelin might play a role in the regulation of reproductive physiology, a recent study has shown that ghrelin affects the chorionic gonadotropin- and cAMP-induced testosterone (T) secretion in rat testis by inhibiting key enzymes of steroidogenic pathways (6). Moreover, it has been recently demonstrated that gonads are not only target tissues for ghrelin, but also relevant sites of ghrelin production. Notably, in both testis and ovary, ghrelin is coexpressed with sex hormones in androgen-producing cells like Leydig and hilus interstitial cells (7, 8). These in vitro findings suggested a potential interaction between ghrelin and androgens and prompted us to additionally investigate the existence of mutual influences between ghrelin and sex steroids in vivo. Recently, we found that obese women with the polycystic ovary syndrome (PCOS), a condition characterized by hyperandrogenism, have even lower ghrelin levels than expected on the basis of their obese phenotype (9). We also described a highly significant negative correlation between ghrelin and circulating androgen parameters, particularly androstenedione, and we suggested that suppressed ghrelin concentrations observed in PCOS women may be caused by high androgen levels. The results of a controlled follow-up study in a separate group of obese PCOS women demonstrated that long-term treatment with the antiandrogen agent flutamide significantly increased circulating ghrelin levels, regardless of changes in body weight, fat topography, and insulin sensitivity (10). To provide direct proof that androgens regulate ghrelin secretion, we have now investigated basal ghrelin levels along with insulin sensitivity and body composition in overweight/moderately obese hypogonadal men before and after T replacement therapy in comparison with age- and weight-matched eugonadal men as well as with normal weight age-matched healthy individuals.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study population consisted of three groups. The first group included seven hypogonadal men (four with Klinefelter’s syndrome, one with primary testicular dysfunction due to long-term complicated varicocele, and two with Kallmann’s syndrome); the second group included nine overweight/moderately obese men matching the hypogonadal patients for body mass index (BMI) and body fat distribution parameters; a third group consisted of 10 normal weight healthy men. Anthropometric and biochemical characteristics of patients and healthy volunteers are shown in Table 1Go. Based on the clinical history, physical examination, and routine laboratory findings, none of the subjects enrolled in the study were affected by diabetes or other endocrine diseases, cardiovascular, renal, or liver disorders. All subjects were maintaining their regular diet, none of the patients or healthy individuals were undergoing caloric restriction or taking medication before and during the study period. None of the patients or control subjects drank more than 30 g alcohol/d. Hypogonadism was defined by morning T levels less than 3.5 ng/ml (12 nmol/liter) (11). The diagnosis of primary hypogonadism was based on normal to elevated gonadotropin levels. Karyotype analysis supported the diagnosis of Klinefelter’s syndrome. Primary gonadal dysfunction associated with varicocele was confirmed by echo-color-Doppler analysis and testicular biopsy morphology. Kallmann’s syndrome was defined by the presence of secondary hypogonadism, characterized by low basal gonadotropin levels in combination with their blunted response to GnRH and anosmia after the exclusion of primary neoplasms of the hypothalamic-pituitary region with magnetic resonance imaging scans.


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  		TABLE 1. Anthropometric, hormonal, and metabolic parameters at baseline in hypogonadal men and overweight/obese and normal weight controls

 
Anthropometry

In all subjects, body height was measured without shoes, and body weight was assessed without clothes. Body fat distribution was evaluated by waist-to-hip ratio (WHR) according to the recommendations of the World Health Organization (12). Waist circumference was obtained as the minimum value between the iliac crest and the lateral costal margin, whereas hip circumference was determined as the maximum value over the buttocks, using a 1-cm-wide metal measuring tape.

Protocol study

All subjects were admitted to the Endocrine Unit of the Department of Internal Medicine of the Sant’Orsola-Malpighi Hospital in Bologna in the morning after an overnight fast. A single blood sample was drawn for glucose and hormone measurements. Over the next few days, the hypogonadal men were assigned to replacement therapy with im injection of T enanthate at the dose of 200 mg every other week (five subjects) or with oral administration of T undecanoate in a dose of 120 mg/d (two subjects). Compliance with the therapy was checked by regular monthly assessment of T levels and clinical monitoring. After 6 months of T replacement therapy, blood samples for hormonal and metabolic parameters and anthropometric and clinical data were collected again. The study was approved by the Ethics Committee of the Medical Faculty of the University of Bologna, and informed written consent was obtained from each subject before the start of the study.

Hormone assays and data analysis

After sampling, blood was immediately chilled on ice and centrifuged, and serum as well as plasma aliquots were frozen at -80 C until assayed. All samples from individual subjects were analyzed in duplicate for each endocrine and biochemical parameter. Plasma glucose levels were determined by the glucose-oxidase method. Insulin, T, and SHBG were analyzed as previously described (13). Free T values were obtained by calculation from T and SHBG values in agreement with the method proposed by Vermeulen et al. (14). The intraassay coefficient of variation in our laboratory was 7.0% for total T, 6.5% for SHBG, and 3.0% for insulin. The Quantitative Insulin-Sensitivity Check Index (QUICKI) was calculated according to the formula proposed by Mather et al. (15). The Homeostasis Model Assessment (HOMA) insulin resistance index was calculated as proposed by Matthews et al. (16). Plasma samples were assayed in duplicate for immunoreactive ghrelin concentration by a commercially available RIA (Phoenix Pharmaceuticals, Mountain View, CA) using 125I-labeled bioactive ghrelin as a tracer and a rabbit polyclonal antibody raised against the c-terminal end of human ghrelin. This assay recognizes both acylated and deacylated ghrelin (17). The antiserum does not cross-react with any relevant peptide as previously shown (17, 18). Intra- and interassay coefficients of variation were less than 5.3 and 13.6%, respectively.

Statistical analysis

Results are reported as the mean values ± SD, unless stated otherwise. Statistical analysis between groups was performed by using ANOVA. Within-subject ANOVA was used to compare the modifications observed in the group of hypogonadal men during the T replacement therapy. All statistical analyses including correlation and multiple regression analysis were performed using StatView software (Abacus Concepts Inc., Berkeley, CA). P values of less than 0.05 were regarded as statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline hormonal and metabolic parameters (Table 1Go)

Compared with the two control groups, hypogonadal men had lower total and free T, not significantly different SHBG concentrations, higher fasting glucose and insulin levels, lower QUICKI, and higher HOMA values. However, within the two control groups, fasting insulin and the HOMA index were significantly higher in the obese compared with the normal weight subjects, without any difference in the other parameters. Ghrelin levels were significantly lower in hypogonadal men when compared with both control groups. Interestingly, men with primary hypogonadism had ghrelin values (92.1 ± 66.6 fmol/ml) comparable to those with secondary hypogonadism (108.1 ± 57.7 fmol/ml). Blood concentrations of ghrelin were positively correlated with both total (r = 0.749; P < 0.0001) and free (r = 0.693; P < 0.0001) T concentrations in all groups (Fig. 1Go). Moreover, they were negatively correlated with BMI (r = -0.510; P < 0.01), WHR (r = -0.463; P < 0.05), fasting glucose (r = -0.530; P < 0.01), fasting plasma insulin levels (r = -0.493; P < 0.01), and HOMA values (r = -0.567; P < 0.01), whereas ghrelin plasma levels were positively correlated with the QUICKI values (r = 0.576; P < 0.01). However, in a multiple regression model, only the relationship between ghrelin and total (t = 3.014; P < 0.01) as well as free (t = 2.351; P < 0.05) T remained significant.



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  		FIG. 1. Simple correlation coefficients between ghrelin and total and free T levels at baseline in all subjects; •, hypogonadal men; {blacksquare}, overweight/obese controls; and {triangleup}, normal weight controls. The relationship of ghrelin with total T (t = 3.014; P < 0.01) and free T (t = 2.351; P < 0.05) levels persisted in the multiple regression model, whereas the relationship with BMI, WHR, insulin fasting, glucose fasting, QUICKI, and HOMA became nonsignificant. To convert total T to nanomoles per liter, multiply by 3.467; to convert free T to picomoles per liter, multiply by 0.2884; to convert glucose to millimoles per liter, multiply by 0.056; to convert insulin to picomoles per liter, multiply by 7.175.

 
Effect of T replacement in hypogonadal men (Table 2Go)

Six months of T replacement therapy caused a significant increase in total and free T, a decrease in SHBG and fasting insulin levels and an improvement in insulin resistance in the hypogonadal men, whereas no significant changes occurred in BMI, WHR, and the fasting glucose levels. Moreover, plasma ghrelin significantly increased to values similar to those of both normal weight and BMI-matched overweight controls (Table 2Go and Fig. 2Go). When data derived from pre- and postandrogen replacement therapy were analyzed together, a positive correlation between plasma ghrelin and both total (r = 0.563; P < 0.05) and free (r = 0.629; P < 0.01) T concentrations was still observed.


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  		TABLE 2. Anthropometric, hormonal, and metabolic parameters at baseline and after 6 months of T replacement therapy in the hypogonadal men

 


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  		FIG. 2. Individual plasma ghrelin concentrations at baseline and after 6 months of T replacement therapy in the hypogonadal men.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This is the first report showing that circulating ghrelin levels in hypogonadal men are lower when compared with weight-matched eugonadal men or normal weight controls. In agreement with other studies, normal weight subjects tended to present with higher circulating ghrelin levels in comparison with overweight/obese eugonadal males (17, 19, 20). In the past, the correlation between decreased ghrelin concentration and increased body weight has been attributed to the presence of an insulin resistance state (20, 21). On the other hand, controversy still remains on this issue, as documented by the findings in patients with type 2 diabetes in whom ghrelin concentrations remained within the normal range in lean subjects and only decreased in obese patients (19). To clarify this assumption, we investigated the relationship between plasma ghrelin levels and indexes of insulin resistance, proving the existence of a negative correlation between these parameters. This generally agrees with similar findings observed in subjects with states of insulin resistance, such as obesity, type 2 diabetes, and PCOS (9, 10, 17, 19, 21). However, after statistically adjusting for androgen levels, the correlation between ghrelin and insulin resistance was abrogated at least in the cohort of PCOS (9, 10). On the other hand, a positive correlation between plasma ghrelin and circulating T levels was found throughout the examined population enrolled in this study, regardless of the androgen status. In fact, the relationship between ghrelin and T levels was found in both hypogonadal and eugonadal subjects. We therefore hypothesize that the correlation between ghrelin and androgens that we have described here and in previous studies (9, 10) is a phenomenon that is independent of body fat, body composition, and the presence of insulin resistance. The demonstration of a marked increase of plasma ghrelin in the hypogonadal men after T replacement therapy, which occurred regardless of changes in body weight and insulin sensitivity, rather provides further support to the notion of a close relationship between androgens and ghrelin. The fact that posttreatment plasma levels of ghrelin in hypogonadal patients became similar to values observed in the BMI-matched controls even suggests that changes in androgen levels rather than variations in body composition are responsible for this normalization. Although our results were derived from one single measurement of ghrelin that was also not able to discriminate between the active and the inactive ghrelin, these data confirm and extend our recent findings in a population of obese women with PCOS, a condition featured by a hyperandrogenic state, in whom we found a significant correlation between ghrelin and androgens independent of body weight, fat distribution, and insulin resistance (9). Furthermore, when the PCOS patients underwent a long-term antiandrogen therapy, a significant increase in plasma ghrelin levels was observed, again regardless of changes in body weight and insulin sensitivity (10). In summary, our findings support the concept that androgens play an important regulatory role regarding ghrelin secretion or catabolism. However, the relationship between androgens and ghrelin is negative in female, but positive in male individuals. Further studies have to show why there is a gender-specific regulatory influence of androgens on ghrelin. We however propose that the normalization of the androgen status, rather than an unnatural increase or decrease, may recover suppressed ghrelin secretion and therewith may possibly reestablish a balanced energy homeostasis. Until now, no significant gender difference regarding circulating ghrelin levels has been found (22). Data derived from experimental studies, all performed in animal models, are also contradictory. In fact, Gualillo et al. (23) reported that ghrelin expression in rat stomach was similar in male and female rats, whereas Liu et al. (24) found a relevant sexual dimorphism in aged mice, showing higher stomach ghrelin mRNA expression in females when compared with males. We speculate that a serious imbalance of endocrine factors regulating reproduction may suppress ghrelin levels, whereas physiological sexual hormone levels in both genders do not affect them.

Mechanisms by which abnormal androgen conditions may alter ghrelin concentrations are at present unknown. Theoretically, androgens may act directly on both peptide expression and synthesis as well as on its metabolic pathways. This mode of action, however, has not yet been investigated. Alternatively, androgens may modulate ghrelin in an indirect way, through other regulatory factors. These players may putatively be represented by leptin or free fatty acids (FFA). T substitution is known to normalize serum leptin secretion in hypogonadal patients; we can therefore hypothesize that leptin normalization may be involved in the elevation of ghrelin levels observed in our patients (25). Moreover, it is well known that the adipose visceral depots are important sites of production of FFA and that androgens influence visceral fat mass in a gender-specific manner. In particular, in males, T stimulates lipolysis inducing an increase of FFA release from the visceral fat depots, whereas in females, androgen administration increases lipogenesis in the visceral depots (26). This is clearly mirrored by the fact that low T levels in men as well as hyperandrogenism in women are usually associated with increased abdominal fatness (27). A link between FFA and ghrelin has been shown very recently by Broglio et al., who demonstrated that FFA infusion reduces the ability of ghrelin to induce GH secretion from the pituitary (28). Additionally, it has been shown that a fat-rich diet, known to increase circulating FFA, was able to decrease circulating ghrelin levels in experimental rats (29). On the other hand, there are also studies in humans showing no changes in ghrelin levels caused by lipid infusion, a stimulus known to increase circulating FFA levels (30). Therefore, the putative role of FFA on ghrelin regulation still remains to be defined. Gonadotropins may also be involved in the modulation of ghrelin expression or secretion. In fact, Dieguez and colleagues (31) have shown that cyclic ovarian mRNA ghrelin expression was disrupted by blockade of preovulatory gonadotropin surge as obtained by the administration of a potent GnRH antagonist. Moreover, the same group found that the Leydig cell-specific expression of ghrelin in rat testis is under the regulation of LH (7). In our patients, no correlation was found between gonadotropins and ghrelin (data not shown), and no differences were found in circulating ghrelin between patients with primary hypogonadism and those with secondary hypogonadism. Therefore, the possibility that gonadotropins play a role in the regulation of ghrelin blood concentrations cannot be confirmed by us and needs further investigation.

A further improvement will be also given by the possibility to understand by more specific RIAs whether the changes in total ghrelin observed will also be followed by a similar change in active ghrelin in the same experimental setting.

In conclusion, this work provides further evidence that androgens influence blood ghrelin concentrations. Considering the role of ghrelin in the regulation of metabolic processes, our present data seem to further support the notion that ghrelin may constitute an important link between the regulation of reproduction and the control of metabolic homeostasis. Further highlights on this issue will be provided by studies in which the interaction of androgens and ghrelin will be monitored in physiological conditions as the prepuberal and postpuberal phases or in situations in which abnormal and acute changes of androgens will be induced by pharmacological or surgical treatments.


   Acknowledgments
 
We thank Dr. A. M. Morselli-Labate for statistical analysis and Ms. Susan West for language editing of this manuscript.


   Footnotes
 
This work was supported by a grant awarded by the Fondazione Cassa di Risparmio (Bologna, Italy) and a grant of the Italian Ministry of University (Rome, COFIN, 2002, to U.P.).

Abbreviations: BMI, Body mass index; FFA, free fatty acids; HOMA, homeostasis model assessment; PCOS, polycystic ovary syndrome; QUICKI, quantitative insulin-sensitivity check index; T, testosterone; WHR, waist-to-hip ratio.

Received March 31, 2003.

Accepted June 2, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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