Circulating ghrelin levels and the polycystic ovary syndrome: correlation with the clinical, hormonal and metabolic features.

Abstract

Dysregulation of ghrelin levels may lead to physiological problems including obesity and polycystic ovary syndrome (PCOS). The aim of the study was to compare ghrelin levels in women with and without PCOS.
Serum ghrelin levels (pre- and post-prandial) were compared between 30 Saudi women suffering from PCOS and 30 healthy controls. The relationship between circulating ghrelin levels and other hormones was investigated. Anthropometric measurements were made for all subjects. Biochemical and hormonal investigations included plasma glucose, insulin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), 17β-estradiol (E2), progesterone, testosterone and sex hormone binding globulin (SHGB), and serum ghrelin levels. The data were statistically analyzed using independent T-test and ANOVA. Correlation studies were performed between ghrelin levels and other variables.
No differences were observed in the levels of ghrelin during fasting and the postprandial period in the PCOS (p=0.487) and control groups (p=0.378). A significant inverse correlation was observed in ghrelin levels (fasting and postprandial) levels and BMI (PCOS: r=-0.529; p=0.009, controls: r=-0.670; p=0.005); PCOS: r=-0.421; p=0.007, controls: r=-0.491; p=0.004 respectively). No correlations between ghrelin levels and other parameters were observed.
The findings of the study suggest that circulating plasma ghrelin levels were found to be normal and were inversely related to BMI in women with PCOS. No relationship between circulating ghrelin levels and the abnormal hormonal pattern of the PCOS were observed.

Full text

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Circulating ghrelin levels and the polycystic ovary syndrome: correlation with the
clinical, hormonal and metabolic features
Maha H. Daghestania,*, Mazin H. Daghestanib, Akmal El-Maznyb
aKing Saud University, Department of Zoology, College of Science, P.O. Box 22452, Riyadh11495, Saudi Arabia
bDepartment of Obstetrics and Gynecology, Umm-Al-Qura University, P.O. Box 424, Makkah 21955, Saudi Arabia
1. Introduction
Polycystic ovary syndrome (PCOS) is a complex multifactorial
genetic disorder with dysregulated steroidogenesis [1]. It is one of
the most common causes of infertility, affecting up to 10% of
women of reproductive age. The disease is characterized by
chronic anovulation, functional hyperandrogenism and polycystic
ovaries on ultrasound examination [2]. PCOS is considered a
plurimetabolic syndrome associated with insulin resistance and
central obesity [3]. Although obesity and PCOS are strongly
correlated, the cause of this association remains unclear. Obesity is
presentinatleast30%ofcasesbuttheproportionmaybeashighas
75% in some series [4]. In women with PCOS, the presence of
hyperinsulinemia, dyslipidemia and/or hypertension is associated
with obesity. The obesity and PCOS place this group of women at
highriskofdevelopingadversemetabolicprofilesincludinginsulin
resistance [5].
Ghrelin was discovered in the recent past as a 28 amino acid
peptide hormone, produced predominantly by endocrine cells in
the stomach. It plays an important role in release of growth
hormone, feeding behavior, glucose metabolism and memory, and
acts as an antidepressant. It is a potent orexigenic peptide that
stimulates food intake and body weight gain, thus regulating
energy homeostasis [6]. Several studies revealed high levels of
ghrelin during fasting, which returned to basal levels after re-
feeding [7–9]. Plasma ghrelin levels are lower in obese subjects
[10], while in lean ones, plasma ghrelin levels rise progressively
during fasting and fall after eating, a pattern reciprocal to that of
insulin. This observation supports the possibility that ghrelin may
be acting as a ‘‘trigger’’ for meal initiation [11] and that it might
play a role in the pathogenesis of human obesity [12].
In PCOS, low levels of ghrelin were observed during fasting
compared to those in control groups [13–16], though not in all
studies [17–22]. Furthermore, plasma ghrelin is lower in Pima
Indians, a population predisposed to obesity, compared with age-
and weight-matched caucasians [23]. Postprandial ghrelin was not
European Journal of Obstetrics & Gynecology and Reproductive Biology xxx (2011) xxx–xxx
A R T I C L EI N F O
Article history:
Received 6 July 2010
Received in revised form 23 October 2010
Accepted 29 November 2010
Keywords:
Fasting and postprandial ghrelin levels
Polycystic ovary syndrome
Body mass index
A B S T R A C T
Objectives: Dysregulation of ghrelin levels may lead to physiological problems including obesity and
polycystic ovary syndrome (PCOS). The aim of the study was to compare ghrelin levels in women with
and without PCOS.
Study design: Serum ghrelin levels (pre- and post-prandial) were compared between 30 Saudi women
suffering from PCOS and 30 healthy controls. The relationship between circulating ghrelin levels and
other hormones was investigated. Anthropometric measurements were made for all subjects.
Biochemical and hormonal investigations included plasma glucose, insulin, luteinizing hormone
(LH), follicle-stimulating hormone (FSH), 17b-estradiol (E2), progesterone, testosterone and sex
hormone binding globulin (SHGB), and serum ghrelin levels. The data were statistically analyzed using
independent T-test and ANOVA. Correlation studies were performed between ghrelin levels and other
variables.
Results: No differences were observed in the levels of ghrelin during fasting and the postprandial period
in the PCOS (p = 0.487) and control groups (p = 0.378). A significant inverse correlation was observed in
ghrelin levels (fasting and postprandial) levels and BMI (PCOS: r = ?0.529; p = 0.009, controls:
r = ?0.670; p = 0.005); PCOS: r = ?0.421; p = 0.007, controls: r = ?0.491; p = 0.004 respectively). No
correlations between ghrelin levels and other parameters were observed.
Conclusion: The findings of the study suggest that circulating plasma ghrelin levels were found to be
normal and were inversely related to BMI in women with PCOS. No relationship between circulating
ghrelin levels and the abnormal hormonal pattern of the PCOS were observed.
? 2010 Elsevier Ireland Ltd. All rights reserved.
* Corresponding author. Tel.: +966 050 4157812; fax: +966 01 4767296.
E-mail addresses: mdaghestani@ksu.edu.sa, mahadaghestani@yahoo.com (M.H.
Daghestani), mhdaghestani@uqu.edu.sa (M.H. Daghestani),
dr_akmalelmazny@yahoo.com (A. El-Mazny).
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the clinical, hormonal and metabolic features. Eur J Obstet Gynecol (2011), doi:10.1016/j.ejogrb.2010.11.019
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and
Reproductive Biology
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examined in most of these studies. It is unclear from these studies
whetherghrelinhomeostasisisimpairedinPCOS.Theobjectivesof
this study were to investigate fasting and postprandial ghrelin
levels in Saudi women with or without PCOS and the relationship
of these levels to the clinical, hormonal and metabolic features of
PCOS.
2. Materials and methods
2.1. Samples
Data were collected from 60 female volunteers, recruited from
the out-patient clinic, Department of Obstetrics and Gynecology,
Al-Noor Hospital, Makkah, Kingdom of Saudi Arabia. The purpose
of the protocol was explained to the patients and the control
women, and signed informed consent was obtained from all the
subjects, as approved by the local ethical committee.
2.2. Subjects
Thirty women were enrolled in this study fulfilling two of the
following three criteria for having PCOS [2]:
(1) Irregular or absent ovulation confirmed by luteal progesterone
and normal serum FSH levels (normal range: 1.0–10.0 IU/l).
(2) Clinical and/or biochemical signs of raised androgens; elevated
serum androgen levels (total testosterone >2 nmol/l), and/or
androstenedione >0.15 nmol/l, and/or dehydroepiandroster-
one sulphate (DHEAS) >10 mmol/l); LH to FSH ratio >2.
(3) At least one ovary examined by ultrasound contained ?12
follicles measuring 2–9 mm in diameter and/or increased
ovarian volume of at least 10 ml.
Thirty healthy women were enrolled as the control group. They
had regular ovulatory cycles, no clinical or biochemical signs of
raised androgens, and normal ovarian morphology on ultrasound.
The health status of the women in the control group was
determined by medical history, physical and pelvic examination,
and complete blood chemistry. Hormonal investigations were also
done if needed. Their normal ovulatory state was confirmed by
trans-vaginal ultrasound and plasma progesterone assay during
the luteal phase of the cycle.
ThePCOSandcontrolgroupswerematchedforage(?twoyears)
[PCOS: 27.22 ? 0.60 years, controls: 26.05 ? 1.11 years; p = 0.511]
andBMI(?10%)
28.31 ? 6.97 kg/m2; p = 0.835]. In each group, the percentage of
overweight and obese women was about 70% (21/30 women).
Exclusion criteria for all the subjects included pregnancy, hypothy-
roidism,hyperprolactinemia,Cushing’ssyndrome,congenitaladrenal
hyperplasia, current or previous (within the last six months) use of
oral contraceptives, glucocorticoids, antiandrogens, ovulation induc-
tion agents, antidiabetic and anti-obesity drugs or other hormonal
drugs. None of the patients was affected by neoplastic, metabolic and
cardiovascular disorder or other concurrent medical illness such as
diabetes, renal disease, and hepatic disorders. All the subjects were
non-smokers and had normal physical activity.
[PCOS:29.35 ? 7.25 kg/m2,controls:
3. Anthropometric measurements
For each woman weight and height were measured to calculate
the BMI (weight in kg divided by height in m2). Waist
circumference (the narrowest circumference between the lower
costal margins and the iliac crest) and hip circumference (the
maximum circumference at the level of the femoral trochanters)
werealsomeasuredinthestandingpositiontocalculatethewaist–
hip ratio (WHR).
3.1. Biochemical measurements
Bloodwassampledinthemorningbetween08.00 hand09.00 h
after anovernightfast. During the early follicular phase(2nd or3rd
day), 5 ml of blood was drawn in plain red-top tubes for the
determination of LH, FSH, E2 and insulin levels in the serum. Two
millilitres of blood were collected into chilled tubes containing
1.2 mg EDTA and aprotinin (500 KIU/ml; Trasylol; Bayer Corp.,
Leverkusen, Germany) for total ghrelin levels and 2 ml were drawn
in fluoride tubes (gray top) for glucose estimation. Following
fasting blood sample collection, subjects consumed a standard
mixed breakfast of about 527 kcal during 15 min. The meal
consisted of 50 g white bread, 33 g black bread, 18 g margarine,
30 g cheese, 9 g jam and 200 ml of 0.5% fat milk (24.1% fat, 54.4%
carbohydrate, 21.5% protein). Two millilitres of blood were
collected 60 min after the meal ingestion for determination of
postprandial ghrelin levels. On day 20 or 21 of the menstrual cycle,
5 ml blood samples were obtained for determination of 17OH-
progesterone (17OH-P), testosterone (T), androstenedione (A) and
sex-hormone binding globulin (SHBG) levels. All blood samples for
each woman were immediately centrifuged, and the serum was
stored at ?80 8C until analysis.
The basal serum levels of LH, FSH, E2, P, T, SHBG and insulin
were estimated using the electrochemiluminescence immunoas-
say ‘‘ECLlA’’ on a Roche Elecsys 1010/2010 and MODULAR
ANALYTICS E170 (Elecsys module) immunoassay analyzers (Roche
Diagnostic, Mannheim, Germany). Androstenedione levels were
estimated by using the Gamma Coat Androstenedione Radioim-
munoassay Kit (DiaSorin Inc, Stillwater, USA). Total ghrelin levels
were measured in duplicate using a commercial ghrelin (human)
enzyme immunoassay kit (EIA) from (Phoenix Pharmaceuticals,
Inc., Belmont, CA, USA), with a lower limit of detection of 0.06 ng/
ml. Plasma glucose levels were determined by the glucose oxidase
method on a Beckman Glucose Analyzer (Fullerton, CA).
3.2. Statistical analysis
Data are presented as mean ? SEM. The comparisons between
PCOS patients and their matched control were done using indepen-
dent T- and ANOVA tests. The Pearson correlation coefficient (r) was
usedtofindoutthecorrelationbetweenghrelinandothervariables.A
probability value p ? 0.05 was considered statistically significant. All
analyses were run using the StatView program for Windows (version
8.0; SAS). In this study, due to the relatively small sample size, the
statisticalpowerindetectingtheminimumdifference = 6.1%andthat
of detecting the maximum difference = 50% adjusting a error at 0.05.
4. Results
Clinical, hormonal and metabolic features of women with PCOS
and controls are summarized in Table 1. In the PCOS group, WHR,
LH, LH/FSH ratio, E2, 17OH-P, T, A, SHBG and serum insulin levels
were significantly different in comparison with the control group
(p < 0.05). No difference in fasting ghrelin levels was detected
between the PCOS and control groups (p = 0.487). One-hour
postprandial, ghrelin levels were decreasing in both groups, but
the difference between the two groups was not statistically
significant (p = 0.378) as shown in Fig. 1.
Correlation of fasting ghrelin levels to the clinical, hormonal
and metabolic features of women with PCOS and controls is
presented in Table 2. In both PCOS and control groups, there was a
significant inverse correlation between fasting ghrelin levels and
BMI (PCOS: r = ?0.529; p = 0.009, controls: r = ?0.670; p = 0.005).
In both groups, fasting ghrelin levels did not correlate with either
age, WHR, LH, FSH, LH/FSH ratio, E2, 17OH-P, T, A, SHBG, 1-hour
postprandial ghrelin, fasting glucose and insulin levels (p = NS).
M.H. Daghestani et al./European Journal of Obstetrics & Gynecology and Reproductive Biology xxx (2011) xxx–xxx
2
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Page 3

Correlation of 1-hour postprandial ghrelin levels to the clinical,
hormonal and metabolic features of women with PCOS and
controls is presented in Table 3. In both PCOS and control groups,
there was a significant inverse correlation between 1-hour
postprandial ghrelin levels and BMI (PCOS: r = ?0.421; p = 0.007,
controls: r = ?0.491; p = 0.004). In both groups, 1-hour postpran-
dialghrelinlevelsdidnot correlatewithage,WHR,LH,FSH,LH/FSH
ratio, E2, 17OH-P, T, A, SHBG, fasting ghrelin, fasting glucose and
insulin levels (p = NS).
5. Comments
This study investigated fasting and 1-hour postprandial ghrelin
levels in patients with PCOS in comparison to those in control
women matched for age and BMI. In this regard this study was
different from most other reports, which have not attempted to
studythepostprandialghrelinlevel.Weestimatedthetotalghrelin
level, which is composed of active (acyl-) and inactive (des-acyl)
ghrelin. In a recent report the active/total ghrelin ratio was
reported to be significantly lower in PCOS patients compared to a
control group but the levels of active and total ghrelin, though
lower, did not reach significance [24]. Both active and inactive
ghrelin are found in the circulation, where the latter is the more
abundant form. Some actions of inactive ghrelin oppose those of
the active form, suggesting that the ratio of active to inactive
ghrelin may play a critical role in the overall physiological
response. The majority of the studies on ghrelin, however, has
investigated total ghrelin, in line with this present study, and there
is a discrepancy in the reported results. In the present investiga-
tion, the fasting and 1-hour postprandial ghrelin levels in patients
with PCOS are comparable to those of the control group and no
correlation was demonstrated between circulating total ghrelin
levels and the hormonal pattern characteristic of PCOS, suggesting
that ghrelin secretion is not associated with increased circulating
levels of LH, 17b-estradiol, testosterone, androstenedione, or
SHBG. In contrast to our findings, some previous studies [13–16]
have reported decreased fasting ghrelin levels in PCOS women
compared to controls, though others have failed to show any
variation [17–22].
In contrast to our findings, Glintborg et al. [13] concluded that
ghrelin levels were decreased in hirsute PCOS patients and showed
a significant negative correlation with testosterone, independent
of body composition. Micic et al. [14] demonstrated that women
with PCOS had lower fasting ghrelin levels and decreased insulin
sensitivity independently of their BMI, compared to controls. On
theotherhand, Was ´koet al.[19] concludedthat PCOSwomenhave
higher ghrelin levels compared to controls. A PCOS group showed
negative correlation between BMI and insulin levels. A correlation
between ghrelin and SHBG was also observed. This discrepancy of
results may be explained by the relatively small sample size in our
study, or may be related to certain genetic or social factors that
need further investigation.
In agreement with our results, however, Schofl et al. [17] found
that in insulin-sensitive PCOS women, ghrelin levels were similar
to those in healthy controls; suggesting that ghrelin could be
Table 1
Clinical, hormonal and metabolic features of women with PCOS and controls.
PCOS (n=30)Controls (n=30)
p
Sig.
Age (yr)
BMI (kg/m2)
WHR
LH (IU/l)
FSH (IU/l)
LH/FSH ratio
E2 (pmol/l)
P (nmol/l)
T (nmol/l)
A (nmol/l)
SHBG (nmol/l)
Fasting ghrelin (ng/ml)
1h ghrelin (ng/ml)
Glucose (mmol/l)
Insulin (pmol/l)
27.22?0.60
29.35?7.25
0.84?0.02
13.64?1.21
5.22?0.46
2.81?0.19
201.07?14.13
3.23?0.46
2.69?0.16
0.23?0.10
27.41?2.64
0.42?0.02
0.34?0.01
5.10?0.09
97.46?25.86
26.05?1.11
28.31?6.97
0.77?0.01
4.65?0.22
5.09?0.29
0.98?0.06
134.97?7.72
26.12?3.02
1.20?0.11
0.04?0.00
45.76?3.04
0.43?0.02
0.32?0.01
4.73?0.09
73.73?5.94
0.511
0.835
<0.001
<0.001
0.576
<0.001
0.001
<0.001
<0.001
0.021
0.015
0.487
0.378
0.140
0.040
NS
NS
S
S
NS
S
S
S
S
S
S
NS
NS
NS
S
NS=non-significant=p>0.05.
S=significant=p?0.05.
Fig. 1. Fasting and 1-hour postprandial ghrelin levels in women with PCOS and
controls.
Table 2
Correlation of fasting ghrelin levels to the clinical, hormonal and metabolic features
of women with PCOS and controls.
PCOS (n=30) Controls (n=30)
rp
Sig.
rp
Sig.
Age (yr)
BMI (kg/m2)
WHR
LH (IU/l)
FSH (IU/l)
LH/FSH ratio
E2 (pmol/l)
P (nmol/l)
T (nmol/l)
A (nmol/l)
SHBG (nmol/l)
1h ghrelin (ng/ml)
Glucose (mmol/l)
Insulin (pmol/l)
?0.057
?0.529
?0.044
?0.034
0.124
?0.086
?0.122
0.088
?0.189
?0.205
0.024
0.751
?0.038
?0.144
0.504
0.009
0.145
0.873
0.602
0.625
0.536
0.372
0.362
0.265
0.675
0.072
0.699
0.537
NS
S
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
?0.117
?0.670
?0.232
?0.168
0.158
?0.129
?0.381
0.072
?0.154
?0.130
0.313
0.536
?0.252
?0.332
0.613
0.005
0.619
0.480
0.150
0.475
0.096
0.597
0.413
0.356
0.199
0.308
0.278
0.059
NS
S
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS=non-significant=p>0.05
S=significant=p?0.05
Table 3
Correlation of 1-hour postprandial ghrelin levels to the clinical hormonal and
metabolic features of women with PCOS and controls.
PCOS (n=30)Controls (n=30)
rp
Sig.
rp
Sig.
Age (yr)
BMI (kg/m2)
WHR
LH (IU/l)
FSH (IU/l)
LH/FSH ratio
E2 (pmol/l)
P (nmol/l)
T (nmol/l)
A (nmol/l)
SHBG (nmol/l)
Fasting ghrelin (ng/ml)
Glucose (mmol/l)
Insulin (pmol/l)
?0.045
?0.421
?0.035
?0.027
0.099
?0.068
?0.097
0.070
?0.150
?0.163
0.019
0.751
?0.030
?0.115
0.401
0.007
0.115
0.694
0.479
0.497
0.426
0.296
0.288
0.211
0.537
0.072
0.556
0.427
NS
S
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
?0.086
?0.491
?0.170
?0.123
0.116
?0.095
?0.279
0.053
?0.113
?0.095
0.230
0.536
?0.185
?0.243
0.450
0.004
0.4539
0.352
0.110
0.348
0.070
0.438
0.303
0.261
0.146
0.308
0.204
0.053
NS
S
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS=non-significant=p>0.05.
S=significant=p?0.05.
M.H. Daghestani et al./European Journal of Obstetrics & Gynecology and Reproductive Biology xxx (2011) xxx–xxx
3
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Please cite this article in press as: Daghestani MH, et al. Circulating ghrelin levels and the polycystic ovary syndrome: correlation with
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Page 4

linkedtothedegreeofinsulinresistanceinPCOS.Ghrelinlevelsdid
not correlate to any of the parameters of hyperandrogenemia or to
the LH/FSH ratio in PCOS. Orio et al. [18] demonstrated that in
women with PCOS, ghrelin concentrations are not different from
those of weight-matched controls. There was no relationship
between circulating ghrelin and the abnormal hormonal pattern of
PCOS.
In comparison to matched controls, PCOS women had greater
serum insulin levels, confirming previous reports [25]. In our
study, ghrelin did not significantly correlate with fasting insulin
levels, suggesting that increased insulin production of PCOS
women does not adversely affect ghrelin secretion. This result is
apparently in contrast with observations demonstrating a possible
negative feedback regulation between insulin and ghrelin in
humans. An inverse relationship has been reported between the
circulating levels of the two hormones [23]. It has also been shown
that ghrelin administration to healthy humans at pharmacological
doses reduces insulin secretion [26] and, conversely, that insulin
administration in high doses is capable of reducing ghrelin
secretion [27]. Our results demonstrate that, despite different
circulating insulin levels, ghrelin levels were similar in PCOS and
control groups, suggesting that modest changes in fasting insulin
levels are not sufficient to modulate ghrelin secretion.
In both groups, PCOS as well as control, fasting and 1-hour
postprandial ghrelin levels were significantly and inversely
correlated with BMI. The result indicates that in women with
PCOS, the abundance of fat mass reduces ghrelin levels, in
accordance with observations in obese subjects [23]. The inverse
correlation between ghrelin levels and BMI, as well as the increase
ofghrelinlevelsafterweightloss[28],supportsthehypothesisthat
levels of ghrelin modulate food intake through both a short-acting
feedback related to meal consumption [11] and a long-term
feedback related to body weight and composition [12].
In conclusion, we have reported fasting and postprandial
ghrelin levels in PCOS women. Our data demonstrate that in Saudi
women with PCOS, ghrelin levels are not different from those of
age- and BMI-matched controls and are inversely correlated with
BMI. There is no relationship between circulating ghrelin levels
and the abnormal hormonal pattern of the PCOS.
Acknowledgments
This work Grant No. (08-MED 604-2) was supported thankfully
by NPST Program at King Saud University to Dr. Maha Daghestani.
We thank all the subjects for their cooperation and participation in
the study. We would also like to thank all the participants
(researchers, technicians and nurses) for their notable contribution.
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ovarysyndrome.AmJClin Nutr
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Please cite this article in press as: Daghestani MH, et al. Circulating ghrelin levels and the polycystic ovary syndrome: correlation with
the clinical, hormonal and metabolic features. Eur J Obstet Gynecol (2011), doi:10.1016/j.ejogrb.2010.11.019