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Ghrelin Secretion in Humans Is Sexually Dimorphic, Suppressed by Somatostatin, and Not Affected by the Ambient Growth Hormone Levels

Division of Endocrinology and Metabolism, University of Michigan and Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Ariel L. Barkan, M.D., Division of Endocrinology and Metabolism, 1500 East Medical Center Drive, 3920 Taubman Center, Box 0354, Ann Arbor, Michigan 48109-0354. E-mail: abarkan{at}umich.edu.

	Abstract

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We studied plasma ghrelin and GH concentrations over a 24-h period in young healthy men and women and in patients with acromegaly. Healthy subjects were restudied after administration of GH-lowering agents, octreotide or GHRH antagonist. Ghrelin concentrations in women studied during the late follicular stage of the cycle were about 3-fold higher than in men. Suppression of GH secretion by GHRH antagonist did not alter ghrelin concentration profiles. In the presence of high GH levels (acromegaly), ghrelin levels were similar to those found in healthy men. Administration of somatostatin analog octreotide suppressed both GH and ghrelin concentration profiles. We conclude that: 1) ghrelin secretion is sexually dimorphic in humans, with women in the late follicular stage having higher levels than men; 2) ghrelin secretion is suppressed by somatostatin; and 3) GH has no influence over ghrelin secretion.

	Introduction

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UNTIL RECENTLY, THE regulation of GH secretion was believed to be accomplished exclusively through the interaction of two hypothalamic hormones, GHRH and somatostatin (SRIF). The development of synthetic peptide and nonpeptidyl compounds collectively called GH secretagogues (GHS), which bind to a specific hypothalamic and pituitary receptor and promote massive GH release, strongly suggested the existence of yet another endogenous GH regulator. Isolation of the gastric hormone ghrelin (a natural ligand for the GHS receptor) thus added yet another level of complexity to the understanding of the GH regulatory network but offered a dramatic paradigm shift in our approach to the studies of pituitary physiology (1). Pituitary-portal circulation in humans is inaccessible for blood sampling; thus, any studies of endogenous GHRH and SRIF involvement in the regulation of GH in humans are by necessity indirect. Research into physiology of ghrelin, in contrast, offers a unique and exciting opportunity to directly measure the secretion of a GH-releasing substance in the peripheral blood.

The understanding of the mechanisms of regulation of ghrelin secretion is only beginning to emerge. Ghrelin levels are low in obesity (2, 3) and high in malnutrition (4, 5, 6), are relatively high after an overnight fast (4), are suppressed by food intake (4), and may be elevated during late evening/early morning hours (3). These relative changes are in complete agreement with the known effects of nutrition on GH regulation and with the existence of a nocturnal GH rise, implying that ghrelin may be an important regulator of GH secretion in humans.

We have performed a series of experiments to assess potential alterations in ghrelin secretion in conditions associated with distinct GH changes. Our data map out potential areas for future research into ghrelin/GH interactions.

	Materials and Methods

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The studies were approved by the Institutional Review Board of the University of Michigan Medical School and the Operating Subcommittee of the General Clinical Research Center (GCRC). All subjects signed an informed consent document before participation in the studies. All subjects in protocols 1 and 2 were healthy young men and women who did not take any medications and whose histories, physical examinations, and screening biochemical and hematological tests were normal. Protocol 3 involved three male patients with newly diagnosed and untreated acromegaly. All were hospitalized in the GCRC, fed a standard hospital diet (meals served at 0700, 1200, and 1800 h), and were allowed to sleep (lights-off) between 2300 h and 0700 h. During the rest of the day, the lights were on, and sleeping and snacking were not allowed. Blood sampling was performed through an indwelling venous cannula. Both healthy subjects and the patients with acromegaly participated in different research protocols, usually involving sampling every 10 min for 24 h. For the purposes of this study, we have assayed plasma ghrelin and GH in hourly samples.

Protocol 1

Six young men [age, 23.3 ± 1.1 yr; body mass index (BMI), 24.1 ± 0.6 kg/m²] and five young women (age, 22.6 ± 0.9 yr; BMI, 21.6 ± 0.9 kg/m²) in the late follicular stage of the cycle (as established by menstrual diaries) were studied twice, once receiving a normal saline infusion for 24 h and, on another occasion, during an iv infusion of the GHRH receptor antagonist [(N-Ac-Tyr₁, D-Arg₂)GHRH 1–29] at a rate of 33 µg/kg·h (7) for the same duration. Studies were performed in random order, with men studied at least 1 wk apart and women at least 1 month apart (to equalize ovarian hormone milieu).

Protocol 2

Nine young men (age, 26 ± 6 yr; BMI, 23.3 ± 1.2 kg/m²) were studied twice; once during continuous sc infusion of normal saline and, on another occasion, during continuous sc infusion of octreotide acetate (Novartis, New Hanover, NJ) 600 µg/24 h. Studies were performed in random order, at least 1 wk apart.

Protocol 3

Blood samples drawn every 30 min for 24 h from three men with newly diagnosed and untreated acromegaly were used.

Assays

Plasma GH was measured in the immunochemiluminescent assay (Nichols, San Juan Capistrano, CA) with the sensitivity 0.01 µg/liter.

Plasma ghrelin was measured by an in-house sandwich ELISA as previously described (8). In brief, polyclonal antibodies against the C terminus (amino acids 16–28) and full-length ghrelin peptide were raised in rabbits. Biotinylated antibody (Ab) against the full-length peptide was used as the capture Ab, and anti-C-terminus Ab was conjugated to horseradish peroxidase and used as the detection Ab. The assay was performed on avidin-coated plates blocked with BSA. The zero standard was human plasma that was first adsorbed against anti-ghrelin Ab conjugated to Sepharose and then subjected to repeated freeze-thaw cycles. Standard curves were made by the addition of synthetic acylated human ghrelin (Phoenix Pharmaceuticals, Inc., Belmont, CA) to the zero standard. The assay detects ghrelin concentration as low as 30 pg/ml. Inter- and intra-assay coefficients of variance were less than 10% for ghrelin concentrations 0.1–5.0 ng/ml. Des-acyl human ghrelin cross-reacted 20% with the acylated standard. There was no cross-reactivity with GH, LH, FSH, prolactin, or GHRH. Plasma samples serially diluted with the zero standard ran parallel to the synthetic standards. After one or two freeze-thaw cycles, approximately 40% of ghrelin activity was lost in plasma samples. Subsequent freeze-thaw cycles (up to six) had no further effect.

Analysis

Data are shown as mean ± SE. Statistical analysis was done using paired or nonpaired Student’s t tests as appropriate. Serial data were analyzed by ANOVA with repeated measures and Tukey’s pairwise comparisons. P values less than 0.05 were regarded as indicating statistical significance.

	Results

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Protocol 1 (Fig. 1)

During saline infusion, plasma GH concentrations in men were, as expected, low during the day, with only occasional elevations. In women, GH concentration profiles showed multiple daytime peaks. The highest GH values were seen at 0100 h in both sexes (P < 0.01), although women had a relatively attenuated (vs. men) nocturnal GH surge. Mean 24-h GH concentrations were slightly higher in women than in men (1.86 ± 0.25 µg/liter vs. 1.08 ± 0.26 µg/liter; P = 0.062). Administration of GHRH receptor antagonist powerfully suppressed mean 24-h GH release in women (to 0.82 ± 0.22 µg/liter; P = 0.036 vs. saline) and in men (to 0.25 ± 0.053 µg/liter; P = 0.0003 vs. saline).

View larger version (34K): [in this window] [in a new window]   Figure 1. Plasma GH and ghrelin in healthy men and women during con-trol study (normal saline) and during the continuous infusion of GHRH antagonist.

Protocol 2 (Fig. 2)

During normal saline infusions, the plasma GH concentration profile was identical to that observed in young men in protocol 1: low levels during the day, occasional daytime secretory discharges, and a pronounced nocturnal GH peak at 0100 h with gradual decline to baseline levels after 0300 h. Mean daily plasma ghrelin levels during saline infusion were similar to those observed in young men in protocol 1 (220 ± 47 ng/liter and 271 ± 56 ng/liter for protocols 1 and 2, respectively; P = 0.53). Plasma ghrelin levels were highest between 0100 and 0800 h and preprandially at 1200 and 1800 h (P = 0.001).

View larger version (30K): [in this window] [in a new window]   Figure 2. Plasma GH and ghrelin in healthy men during the administration of normal saline or continuous sc infusion of octreotide.

Protocol 3

In three patients with acromegaly, mean 24-h GH concentrations were grossly elevated at 92, 16, and 14 µg/liter, respectively. However, their mean plasma ghrelin concentrations (291 ± 112 ng/liter) were indistinguishable from those seen in healthy men, and their individual mean ghrelin concentrations (104, 318, and 451 ng/liter) were all in the range seen in the control subjects. Figure 3 shows a composite picture of plasma GH and ghrelin profiles in all three patients.

View larger version (43K): [in this window] [in a new window]   Figure 3. Plasma GH and ghrelin in three untreated male patients with acromegaly.

	Discussion

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GH secretory patterns are sexually dimorphic. In both rats (11) and humans (12), interpulse GH levels are higher, and GH pulsatility is more haphazard in females. This could be due to lower SRIF secretion, as shown in experiments with SRIF antiserum in rats (11) or in SRIF-knockout mice (13). Additionally, higher interpulse GH levels in female, as opposed to male, rats may be maintained by GHRH as evidenced by experiments involving administration of GHRH antiserum to both sexes (11). We have recently shown that GHRH receptor antagonist suppresses interpulse GH in women but not in men, suggesting the similarity of the GH-regulatory mechanisms between rats and humans (14). We now present evidence for yet another mechanism potentially responsible for the higher interpulse GH levels and, possibly, for the more frequent occurrence of GH pulses in women, i.e. tonically elevated ghrelin levels. Because continuous infusions of synthetic ghrelin analogs (GHS) potentiate the effects of GHRH (15), one might hypothesize that chronically elevated ghrelin levels in women would also make the pituitary more sensitive to baseline endogenous GHRH concentrations and small GHRH pulses. This could explain the male/female difference in the daytime GH profiles (12). Continuous infusion of GHRP-2 potently stimulated basal interpulse GH levels in postmenopausal women, and this was further augmented by estrogen (16), analogous to women in our study who were in the estrogen-replete late follicular phase. It might be interesting to investigate whether plasma ghrelin levels vary between the different stages of the menstrual cycle. Perhaps that may account for the differential GH secretion parameters during the menstrual cycle (17, 18).

The genesis of nocturnal GH rise needs to be further explored. We have shown previously that frequent sampling disclosed nocturnal augmentation of ghrelin secretion in healthy men (8). We could not consistently confirm high nocturnal ghrelin levels in all protocols reported here. Potentially, the infrequent sampling was the underlying reason for the inconsistency. Another group asserted the existence of a nocturnal ghrelin rise in healthy subjects (3). This, however, was not substantiated statistically and thus remains unproven. Because diurnal rhythm of ghrelin may be augmented during the fasting state (19), the regular thrice-daily feedings in our subjects might have made the detection of nocturnal ghrelin rise more difficult. Nocturnal GH augmentation absolutely requires endogenous GHRH (20), suggesting augmented nocturnal GHRH secretion. On the other hand, it persists during frequent bolus injections of a stable dose of GHRH (21). Thus, there is a major component of increased pituitary sensitivity to GHRH. This is unlikely to be due to a nocturnal decline in SRIF secretion because nocturnal GH rise persists during continuous infusion of the powerful SRIF analog, octreotide (22, 23). Potentially, nocturnal GH rise may result from a combined effect of GHRH pulses of stable amplitude superimposed upon raised ghrelin levels. The lower nocturnal output of GHRH in women (24), despite high ghrelin levels as shown in this study, may thus explain the attenuated nocturnal GH secretion in women.

It has been asserted (3) that ghrelin secretion exhibits marked periprandial dynamics, with preprandial elevations and rapid postprandial declines. However, this claim was not substantiated with proper statistical analysis. In protocol 2 of our study, normal men appeared to have higher ghrelin concentrations before lunch and supper, but that was not consistently seen in other groups of subjects. Thus, whether ghrelin is indeed elevated preprandially is still an open question. One has to consider, of course, the potential loss of ghrelin activity in our study as a result of the previous freeze-thaw procedure needed for the GH assay. We believe that this is unlikely to be the case, because marked differences in ghrelin concentrations were seen in our study between different protocols (e.g. men vs. women) or even within the same protocol (e.g. octreotide infusion) despite identical freeze-thaw treatments. Another potential explanation is the use of different ghrelin assays with potential detection of different isoforms. These considerations need to be taken into account in future studies.

All endocrine systems are characterized by the existence of a negative feedback loop, and it would not be impossible to imagine one with GH adjusting its own secretion by inhibiting gastric ghrelin release. However, our data do not support this hypothesis. Despite major diminution of GH output under the influence of GHRH receptor antagonist or grossly elevated GH levels in patients with acromegaly, there were no differences in the plasma levels of ghrelin. Our conclusion is supported by the data from other investigators (2, 19, 25), who could not detect any change in plasma ghrelin concentration in a variety of models: GH deficiency, acute and chronic GH administration, and GH receptor blockade.

Gastric activity is powerfully regulated by SRIF. Somatostatin lowers gastrin release, acid output, and gastric motility (26). We now show that the somatostatin analog octreotide also lowers gastric ghrelin output. Until now, the inhibitory effects of somatostatin on GH secretion were thought to be due primarily to its direct pituitary effects and, potentially, to the inhibition of hypothalamic GHRH secretion (27). Here, we present evidence for yet another tier of GH regulation by somatostatin, i.e. suppression of ghrelin release. One has to appreciate, of course, the grossly supraphysiological concentrations and the higher potency of the synthetic SRIF analog used in this study. However, the gastric ghrelin-secreting cells may be exposed to high somatostatin levels of gastrointestinal origin in physiological situations. Additionally, ghrelin was shown to inhibit pancreatic somatostatin secretion (28), and thus, a classic negative feedback loop may be active under physiological conditions. Most importantly, our findings are particularly relevant to pharmacological studies involving administration of somatostatin or its analogs. In all future experiments of that nature, the potential involvement of ghrelin will have to be taken into account. After this manuscript was submitted for publication, another group (29) has shown that both somatostatin-14 and octreotide suppress plasma ghrelin concentrations in normal subjects and in patients with acromegaly, respectively. This is in full agreement with our data.

In summary, we present evidence that ghrelin secretion in humans is sexually dimorphic and is suppressible by somatostatin. Whether it is also rhythmic (pulsatile, meal-related, or diurnal) is still uncertain. These areas need to be explored further in more detailed studies for better understanding of the mechanisms regulating GH secretion in humans.

	Footnotes

 
This work was supported by the Veterans Affairs Medical Research Service and the University of Michigan General Clinical Research Center (NIH Grant M01-RR-00042).

Abbreviations: Ab, Antibody; BMI, body mass index; GHS, GH secretagogue(s); SRIF, somatostatin.

Received July 25, 2002.

Accepted January 27, 2003.

	References

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