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Contents
1. Introduction 4
2. Ghrelin Actions on Somatotropic Axis 5
2.1 GH-Releasing Action 5
2.2 Potential Uses of Ghrelin in GH Secretion Disorders 7
3. Ghrelin Actions on the Gonadal Axis 11
3.1 General Effects 11
3.2 Effects on Male and Female Puberty 13
3.3 Ghrelin in Male Reproduction 13
3.4 Ghrelin in Female Reproduction 14
3.5 Pregnancy 15
References 16
Abstract
Ghrelin, a 28 amino-acid octanoylated peptide predominantly produced by the stom-
ach, was discovered to be the natural ligand of the type 1a GH secretagogue receptor
(GHS-R1a). It was thus considered as a natural GHS additional to GHRH, although later
on ghrelin has mostly been considered a major orexigenic factor. The GH-releasing
action of ghrelin takes place both directly on pituitary cells and through modulation of
GHRH from the hypothalamus; some functional antisomatostatin action has also been
shown. However, ghrelin is much more than a natural GH secretagogue. In fact, it also
modulates lactotroph and corticotroph secretion in humans as well as in animals and
plays a relevant role in the modulation of the hypothalamic-pituitary-gonadal function.
Several studies have indicated that ghrelin plays an inhibitory effect on gonadotropin
pulsatility, is involved in the regulation of puberty onset in animals, and may regulate
spermatogenesis, follicular development and ovarian cell functions in humans.
In this chapter ghrelin actions on the GH/IGF-I and the gonadal axes will be revised.
The potential therapeutic role of ghrelin as a treatment of catabolic conditions will also
be discussed.
1. INTRODUCTION
an increase in lean body mass. Preliminary clinical data show that ghrelin
maintains its GH releasing and orexigenic effect in the setting of cancer.
However, further investigations should evaluate the effects of ghrelin admin-
istration on tumor growth.5
2.2.3 AIDS Associated Cachexia
During the early periods of the human immune deficiency virus (HIV)/
AIDS epidemic, cachexia was a common condition. Aberrations in GHRH-
GH-IGF-I axis are common in the complex of HIV and AIDS, particularly
in case of lipodystrophy which results in complications such as chronic
inflammation, insulin resistance, lipid and metabolic abnormalities. The
processes involved in lipodystrophy are related to the suppression of GH
production. The mechanism of low GH levels is due to increased somato-
statin tone and decreased ghrelin secretion. The GHRH analog Tesamorelin
is the only therapeutic option, which is FDA approved, to reduce abdominal
fat excess in patients with HIV-associated lipodystrophy.79,80
On the other hand, elevated GH and low IGF-I levels are present in
AIDS wasting syndrome, suggesting GH resistance.81 To date, no reports of
ghrelin or GHS use in this clinical setting are available.5
2.2.4 Anorexia Nervosa
Anorexia nervosa (AN) is a severe psychiatric disorder affecting about 0.9%
of women and 0.3% of men82 and has the highest mortality rate of any mental
disorder.83
Total ghrelin levels, mostly in the UAG form, and GH levels are higher
than controls in AN69,84,85 and refeeding leads to a decrease in the peptide
levels.86 Elevated ghrelin levels are probably due to a decreased postprandial
decline or to a state of ghrelin resistance in these patients.87 Higher ghrelin
levels in AN are likely to represent an adaptive response in order to stimulate
eating and thereby increase bodyweight and fat.83
Hotta et al. demonstrated that the intravenous administration of ghrelin
twice a day for 14 days in four out of five patients with restrictive AN improves
epigastric discomfort or constipation and increases the hunger score and daily
energy intake compared with the pretreatment period. These results imply
that ghrelin has the potential as a new treatment for AN.5,88
In contrast, Miljic et al. reported that single-dose continuous adminis-
tration of ghrelin in 15 patients with AN for 5 h failed to affect appetite.89 It is
possible that a single infusion is not sufficient to counteract the many factors
that play a role in AN (such as anxiety, depression, and obsessive–compulsive
10 Giovanna Motta et al.
2.2.5 Ageing
Ghrelin decline with ageing has been demonstrated by several studies.53,93
However, the pituitary ghrelin receptor content does not decline with age94
and the secretory response of the pituitary to ghrelin and GH secretagogues
in the elderly is maintained.31
Age-related sarcopenia refers to the loss of muscle mass and muscle
strength that is associated with aging. A number of mechanisms have been
reported in age-related sarcopenia, including decreased appetite, reduced
levels of anabolic hormones such as GH and IGF-I, increased muscle cell
apoptosis, and increased proinflammatory cytokines.95
Nass etal. investigated the effects of MK-677 versus placebo in 65 healthy
and nonsarcopenic elderly subjects. Fat-free mass and appendicular skeletal
muscle mass (lean limb) increased with MK-677 treatment, but there was no
change in functional capacity or quality of life.57 However, this study
included mainly active healthy older adults and the results may not be
applicable to the general elderly population.
The absence of functional improvement with GH therapy has also been
described by other studies, indicating that increasing GH levels in elderly
subjects is not sufficient to treat sarcopenia.96 Future larger studies focusing
on sarcopenic elderly individuals are warranted to determine if strength and
functional capacity will respond to ghrelin treatment or if combination
therapy (i.e., with nutritional supplements) will be effective.
Ghrelin Actions on Somatotropic and Gonadotropic Function in Humans 11
3.5 Pregnancy
Both ghrelin and GHSR mRNAs have been detected in the morula and in
more advanced stages of embryo development,104,137 showing a role in
embryo preimplantation and development.
Tanaka et al. (2003) have also documented strong ghrelin expression in
human placenta during the first trimester, especially in extravillous tropho-
blasts on the tips of chorionic villi, whereas at term the hormone levels are
undetectable.69
Additionally, GHSR-1 mRNA has been found in the decidua, and invitro
studies have shown that ghrelin is able to enhance human endometrial
stromal cell decidualization.69 These findings support the hypothesis that
ghrelin, together with other messengers (including cytokines, interleukins,
sex steroids, and prostaglandins, which are released by the invading chorionic
tissue), may be a chemical mediator (in a paracrine and autocrine manner) of
the regulation of endometrial stromal cell differentiation, which is essential
for embryo implantation and the maintenance of pregnancy.137,141–143
16 Giovanna Motta et al.
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