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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 8 3202-3205
Copyright © 2007 by The Endocrine Society

Ghrelin Suppresses Secretion of Luteinizing Hormone in Humans

Michael Kluge, Petra Schüssler, Manfred Uhr, Alexander Yassouridis and Axel Steiger

Max-Planck Institute of Psychiatry, 80804 Munich, Germany

Address all correspondence and requests for reprints to: Dr. Michael Kluge, Max-Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany. E-mail: kluge{at}mpipsykl.mpg.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Ghrelin affects the hypothalamic-pituitary-gonadal axis in various nonhuman mammalians, predominantly by suppressing secretion of LH. However, for humans, no such evidence exists.

Objective: Our objective was to study the effect of ghrelin on secretion of LH and testosterone in humans.

Design, Participants, and Intervention: Nocturnal (2000–0700 h) secretion profiles of LH and testosterone were determined in 10 healthy males (25.7 ± 3.0 yr) twice, receiving 50 µg ghrelin or placebo at 2200, 2300, 2400, and 0100 h, in this single-blind, randomized, cross-over study.

Results: Ghrelin was associated with significantly (P < 0.05) lower mean plasma levels of both LH (2340–0200 h) and testosterone (0040–0300 h) than placebo. LH peak levels of the pulse after first administration of ghrelin/placebo were significantly (P = 0.014) smaller in the ghrelin (2.98 ± 1.34 mIU/ml) than in the placebo condition (4.37 ± 1.09 mIU/ml). In addition, the interval between this and the preceding peak was significantly (P = 0.010) longer in the ghrelin (255.8 ± 79.1 min) than in the placebo condition (190.8 ± 51.0 min). Significantly (P = 0.005) more LH pulses occurred with placebo (3.2 ± 0.75) than ghrelin (2.6 ± 0.7) subsequent to ghrelin/placebo administration.

Conclusions: Ghrelin caused both a delay and suppression of the amplitude of LH pulses. These findings are in accordance with those in nonhuman mammalians.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GHRELIN, AN ACYLATED peptide consisting of 28 amino acids, is the natural ligand of the GH secretagogue receptor (GHS-R). It is synthesized predominantly in the stomach but has also been identified in a variety of other organs, such as bowels, kidney, thyroid, lung, lymphatic tissue, placenta, hypothalamus, and pituitary (1, 2). Alike, a wide range of central and peripheral endocrine and nonendocrine actions has been described, e.g. being a releasing factor of GH, prolactin and ACTH, a modulator of cell proliferation and apoptosis, a regulator of sleep-wake regulation, and an orexigenic hormone (1, 2, 3, 4).

In addition, increasing evidence suggests that ghrelin could also be involved in the control of gonadal function (5). Ghrelin and the GHS-R were detected in both rat and human testis, predominantly in interstitial Leydig cells (6, 7, 8), and ovary (9, 10). Intracerebroventricular (icv) injection of ghrelin in rats suppressed pulsatile secretion of hypothalamic LHRH and LH (11, 12, 13, 14). In in vitro experiments in rat pituitary tissue, in contrast, ghrelin stimulated LH secretion (12). In rhesus monkeys, iv administered ghrelin significantly decreased LH pulse frequency (15). Similarly in sheep, a single ghrelin bolus (icv) significantly suppressed LH secretion (16). However, in humans, a single dose of iv administered ghrelin did not influence LH levels (17). Thus, there has been no evidence so far that ghrelin affects the secretion of hormones of the hypothalamic-pituitary-gonadal axis in humans. However, opposite effects have been repeatedly reported, indicating an interrelation between ghrelin and sex hormones also in humans. Testosterone caused a significant decrease of ghrelin in healthy men (18) and short peripubertal boys who underwent priming for GH testing (19), and an increase of ghrelin in hypogonadal men undergoing replacement therapy, respectively (20).

It is well known that hormones of the hypothalamic-pituitary-gonadal axis are secreted in a pulsatile manner (21, 22). We hypothesized that potential effects of ghrelin, which has also been reported to be released in pulses (23, 24), would become apparent when a pulsatile release was imitated. Therefore, the aim of this study was to investigate the effect of pulsatile ghrelin administration on the nocturnal secretion patterns of LH and testosterone in young men.


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

There were 10 healthy males, aged 20–30 yr (25.7 ± 3.0; body mass index 22.0 ± 1.9 kg/m2), without a lifetime history of endocrine or psychiatric disorders included in this study. Further exclusion criteria comprised a pathological electroencephalogram or electrocardiogram. All subjects had to be drug free for at least 3 months before study entry. The study was conducted in accordance with the guidelines in The Declaration of Helsinki. Written informed consent was obtained from all participants. Ethical review board approval was given.

Study design

This single-blind, placebo-controlled, randomized, cross-over study comprised two blocks of two consecutive nights, separated by at least 1 wk. The first night of each block served for adaptation to the sleep laboratory setting. On the second night, 4 ml blood was drawn every 30 min (2000–2200 h) and 20 min (2200–0700 h), respectively, from the adjacent room, using an iv cannula and a tubic extension. On one of the second nights, 50 µg acylated ghrelin (Clinalfa, Läufelfingen, Switzerland), in the other, placebo was injected at 2200, 2300, 2400, and 0100 h. The order of administration was chosen at random. In addition, polysomnography was recorded between 2300 and 0700 h (data will be presented elsewhere). Substances (e.g. coffee, alcohol) or activities (e.g. naps during the day, excessive exercises) potentially influencing vigilance were restricted or prohibited.

Hormone analysis

Blood samples were centrifuged immediately, and plasma was frozen at –25 C. Blood samples had not been defrosted before analysis. Concentrations of LH and total testosterone were measured using an electrochemiluminescence immunoassay in an automated analyzer (Elecsys 2010; Roche Diagnostics, Mannheim, Germany). The detection limits were 0.1 mIU/ml for LH and 0.02 ng/ml for testosterone. Intraassay and interassay coefficients of variance were less than 5 and 8%, respectively.

Statistical methods

Differences of mean LH and testosterone plasma levels subsequent to placebo/ghrelin injection at single time points were tested for significance by a test with contrasts in a multivariate ANOVA (level of significance {alpha} = 0.05). In addition, the three curve characteristics area under the curve (AUC) as calculated by the trapezoid rule (25), mean location, and {delta} amplitude (highest minus lowest value) were determined for the preintervention (2000–2200 h), intervention (2200–0200 h), and post-intervention periods (0200–0700 h). The intervention period was defined as time between the first injection of ghrelin/placebo until last injection plus one plasma half-life of LH (approximately 60 min) (26). For LH, pulses were identified using three analysis criteria, as described previously (15). First, the LH peak should occur within 30 min of the previous nadir. Second, the LH increase should exceed the intraassay variance at least 3-fold, and third, the decrease subsequent to the peak should be in accordance with LH half-life. Pulses identified in this way were additionally verified using Pulse4 from PulseXp software (27). Number of peaks after ghrelin/placebo administration, interpeak intervals, and peak values were determined. These pulse characteristics were compared between both conditions using a paired t test. Less than 2% of all samples were missing that were not replaced. Metric demographic variables and pulse characteristics are expressed as mean ± SD; hormone variables in Fig. 1Go are depicted as mean ± SEM.


Figure 1
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  		FIG. 1. Secretion profiles of LH and testosterone (mean, SEM) in 10 healthy males receiving ghrelin or placebo. *, Significant differences as calculated by tests with contrasts in a multivariate ANOVA (P < 0.05).

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
LH

Mean LH plasma levels were significantly (P < 0.05) lower in the ghrelin than placebo condition between 2340 and 0200 h (Fig. 1Go). Accordingly, all determined curve characteristics were significantly lower in the intervention period. In contrast, curve characteristics in the preintervention and post-intervention periods did not differ between both conditions (Table 1Go).


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  		TABLE 1. Curve characteristics of nocturnal LH and testosterone secretion of 10 males receiving ghrelin or placebo

 
LH peak levels of the pulse after first administration of ghrelin/placebo were significantly (P = 0.014) smaller in the ghrelin (2.98 ± 1.34 mIU/ml) than placebo condition (4.37 ± 1.09 mIU/ml). In addition, the interval between this and the preceding peak was significantly (P = 0.010) longer in the ghrelin (255.8 ± 79.1 min) than placebo condition (190.8 ± 51.0 min). However, compared with that interval, the following interpeak interval was significantly (P = 0.013) shorter in the ghrelin condition (158.0 ± 72.4 min) but similar in the placebo condition (198.0 ± 62.3 min). Significantly (P = 0.005) more LH pulses occurred with placebo (3.2 ± 0.75) than ghrelin (2.6 ± 0.7) subsequent to ghrelin/placebo administration. Exemplary secretion profiles are depicted in Fig. 2Go.


Figure 2
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  		FIG. 2. Exemplary nocturnal LH secretion profiles of a healthy man receiving ghrelin or placebo. *, LH pulse.

 
Testosterone

Mean testosterone plasma levels were significantly (P < 0.05) lower in the ghrelin than placebo condition between 0040 and 0300 h (Fig. 1Go). Curve characteristics (AUC, {delta} amplitude, mean location) did not significantly differ in any of the periods (Table 1Go).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Ghrelin suppressed the LH secretion in young males by delaying the next pulse after ghrelin administration and decreasing its amplitude. Although the then following peak interval was shorter, overall, less pulses occurred subsequent to ghrelin injection compared with placebo. The described patterns suggest a transient, complete, or partly suppression of the hypothalamic pulse generator of LHRH. The LH suppression became apparent about 90 min after the first ghrelin injection and lasted about the same time longer than the last injection. This course appears in line with a biomathematical feedback and feedforward model, integrating apart from the LHRH pulse generator the two other functional control nodes of the male hypothalamic-pituitary-gonadal axis and their hormones, the anterior pituitary gland (LH) and the Leydig cells in the testes (testosterone). That model posits a time-delayed feedback in the human male hypothalamic-pituitary-gonadal axis (28). Accordingly, a transient suppression of the LHRH pulse generator could result in a delayed secretion of LH. Shifted by another hour, testosterone levels were also transiently lower in the ghrelin condition, therefore suggesting an indirect suppression caused by lowered LH, and not a direct ghrelin effect at gonadal level. This assumption is substantiated by the repeated finding that testosterone secretion lags behind LH secretion by approximately 40–60 min (29, 30).

To our knowledge, this is the first report that ghrelin affects the hypothalamic-pituitary-gonadal axis in humans. At first glance, our findings appear to contrast with those of a study reporting no significant changes of LH plasma levels after ghrelin injection (17). Only a single dose of ghrelin was administered in this study in six young males. Therefore, ghrelin’s LH suppressing effect in humans could be dependent on pulsatile release as initially hypothesized. However, mean LH patterns after ghrelin administration were comparable in both studies (e.g. minimum LH plasma levels after about 90 min). However, because that study did not include a placebo arm, potential effects such as a suppressed LH secretion could not have been identified (17).

Our findings in humans are in accordance with those in mammalians of both sexes, namely male and female rats (11, 12, 13, 14), as well as ovariectomized sheep (16) and rhesus monkeys (15). Independent of way (icv, iv) and manner of administration (single injection, repeated injection, continuous infusion) in all ghrelin caused a suppression of LH secretion.

Ghrelin was found to affect the hypothalamic-pituitary-gonadal axis at all levels. However, only for the hypothalamic level has evidence been provided from both in vitro and in vivo experiments (5). Ghrelin significantly decreased hypothalamic LHRH in vitro (12). In addition, a decrease of the LH pulse frequency in vivo, as found in animals (14, 15) and humans (this study), strongly indicates an inhibition of the hypothalamic LHRH pulse generator. This inhibitory effect was suggested to be mediated by hypothalamic neuropeptide Y and agouti-related peptide (14, 15) because both peptides have inhibited pulsatile LH release (31, 32), and their synthesis has been decreased by ghrelin (33, 34). Interestingly, not only acylated ghrelin but also the unacylated isoform of ghrelin, which has been considered widely inert (1), decreased LH secretion in rats to a similar extent as the acylated isoform. This finding indicates that central effects of ghrelin on the hypothalamic-pituitary-gonadal axis are not, or at least not only, mediated through the GHS-R that the unacylated form does not bind to (13).

At the pituitary level, ghrelin initially enhanced in vitro LHRH-stimulated LH increase (after 60 min of incubation) but inhibited it after 120 and 180 min. Ghrelin added to pure rat pituitary tissue (without LHRH), in contrast, stimulated LH secretion at all time points (11). These LH-stimulating effects in vitro are in clear-cut contrast to the LH inhibiting in vivo effects. It has been speculated that the LH increasing action could be mediated by nitric oxide (11), which has stimulated LH release and mediated ghrelin’s effects on food intake (35) and GH secretion (36).

At the gonadal level, ghrelin was shown to inhibit human chorionic gonadotropin or cAMP-stimulated testicular testosterone secretion in the rat in vitro. However, ghrelin did not affect basal testosterone secretion (8). The inhibitory effect on stimulated testosterone release was rather moderate (on average 30%) and manifest after 90 min of incubation being the first measurement after baseline. Our study does not allow the precise assessment of if and to what extent direct inhibition at the gonadal level might have contributed to the lower mean testosterone levels in the present study. However, considering the results of those in vitro experiments, the lack of different mean testosterone levels between ghrelin and placebo condition within the first 90 min after ghrelin injection does not support the idea of a major direct ghrelin effect at the gonadal level. As discussed in the first paragraph of the Discussion section, the testosterone decrease after about 1 h after the LH changes rather indicates an indirect inhibition of testosterone secretion secondary to changes of LH.

In conclusion, ghrelin suppressed LH secretion in young men by delaying the next pulse after ghrelin administration and decreasing its amplitude.


   Acknowledgments
 
We thank Doreen Schmidt for her technical assistance.


   Footnotes
 
This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Ste-486/5-4).

Disclosure Statement: The authors have nothing to disclose.

First Published Online June 5, 2007

Abbreviations: AUC, Area under the curve; GHS-R, GH secretagogue receptor; icv, intracerebroventricular.

Received March 15, 2007.

Accepted May 29, 2007.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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