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DOI:10.4158/EP13173.OR Endocrine Practice © 2013
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ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. DOI:10.4158/EP13173.OR © 2013 AACE. Original Article EP13173.OR
PRECLINICAL ATHEROSCLEROSIS IN PATIENTS WITH PROLACTINOMA
Running title: Prolactinoma and cardiovascular risk
Muyesser Sayki Arslan, MD1; Oya Topaloglu, MD1; Mustafa Sahin, MD2; Esra Tutal,
MD1; Askin Gungunes, MD1 ; Evrim Cakir, MD1; Ilknur Unsal Ozturk, MD1; Basak Karbek, MD1; Bekir Ucan, MD1 ;Zeynep Ginis, MD3; Erman Cakal, MD1; Mustafa Ozbek, MD1 ; Tuncay
Delibasi, MD1
From the 1Diskapi Yildirim Beyazit Training and Research Hospital, Department of Endocrinology and Metabolic Diseases, Ankara, Turkey, 2Ankara University, School of Medicine, Department of Endocrinology and Metabolic Diseases, Ankara, Turkey, 3Diskapi Yildirim Beyazit Training and Research Hospital, Department of Biochemistry, Ankara, Turkey. Address correspondence to Tuncay Delibasi, Prof., Diskapi Yildirim Beyazit Training and Research Hospital, Department of Endocrinology and Metabolic Diseases, Ankara, Turkey. E-mail: [email protected]
DOI:10.4158/EP13173.OR Endocrine Practice © 2013
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ABSTRACT
Objective: The aim of this study was to evaluate the effect of hyperprolactinemia on body
fat, insulin sensitivity, inflammatory markers, and cardiovascular risk in patients with
prolactinoma.
Methods: The study included 35 untreated hyperprolactinemic patients with pituitary
adenomas, and 36 age-, gender-, and BMI-matched healthy controls without any known disease.
Serum glucose, insulin, homeostasis model assessment of insulin resistance, lipid profile, high
sensitive C-reactive protein, and heart-type fatty acid binding protein levels were measured. Waist
and hip circumference were measured in all the participants. The body fat percentage was
measured, and the visceral fat and abdominal fat percentage was measured via bioelectrical
impedance. In addition, carotid intima media thickness was measured using high-resolution B-
mode ultrasound.
Results: The serum glucose level, homeostasis model assessment of insulin resistance,
triglyceride level, and waist circumference were significantly higher in the patient group than in
the control group. The high sensitive C-reactive protein level and carotid intima media thickness
were significantly higher in the hyperprolactinemic patients. Visceral and truncal fat percentages
were significantly higher in the patients with prolactinoma. Heart-type fatty acid binding protein
levels were similar in the patient and control groups, and there was a positive correlation between
the prolactin and heart-type fatty acid binding protein levels.
Conclusions: Based on the present findings, hyperprolactinemia is associated with
preclinical atherosclerosis and metabolic abnormalities. Patients with hyperprolactinemia might
experience cardiovascular disease in the long-term. Metabolic control should be achieved in
addition to the control of hyperprolactinemia, in the clinical management of patients diagnosed
with prolactinoma.
Keywords: Hyperprolactinemia; atherosclerosis; cardiovascular risk; metabolic profile
DOI:10.4158/EP13173.OR Endocrine Practice © 2013
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Abbreviations
BIA = bioelectrical impedance analysis; BMI = body mass index; CIMT = carotid artery intima
media thickness; H-FABP = heart type fatty acid binding protein; HDL = high density
lipoprotein; HOMA-IR = homeostasis model assessment of insulin resistance; hs-CRP = high
sensitive C-reactive protein; LDL = low density lipoprotein
INTRODUCTION
Prolactinoma has been associated with metabolic and inflammatory conditions that might
increase cardiovascular risk, including obesity, insulin resistance, dyslipidemia, low-grade
inflammation, and hypercoagulability (1-6). Furthermore, the supraphysiological prolactin (PRL)
level may play a role in accelerated arteriosclerosis and may be correlated with cardiovascular
mortality in early menopause (7). There is increasing evidence that suggests hyperprolactinemia
plays a role in various components of atherogenesis. PRL receptors were observed in coronary
artery plaques in patients without hyperprolactinemia (8). In vitro studies have demonstrated that
PRL can modulate inflammatory responses, stimulate vascular smooth muscle cell proliferation,
and play a role in adhesion of circulating mononuclear cells to endothelium, all of which might
alter vascular structure and function (9-11). In addition PRL might alter endothelial function via
modification of peripheral and central hemodynamics through its vasoconstrictive features (12).
There have been reports of impaired endothelial vasodilatory function, based on flow-mediated
dilatation of the brachial artery, in patients with hyperprolactinemia (6,13). Whereas
hyperprolactinemia is a common endocrine disorder, cardiovascular risk assessment is under
performed.
Heart-type fatty acid binding protein (H-FABP) is a soluble small cardiomyocyte protein
that may protect myocardial cells from oxidation of long fatty acids (14). It was proposed that H-
FABP is an early diagnostic biochemical marker of acute coronary syndrome (15). In addition, an
DOI:10.4158/EP13173.OR Endocrine Practice © 2013
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elevated serum H-FABP level has been observed in such conditions as heart failure,
cardiomyopathy, pulmonary embolism, and metabolic syndrome (16-18). Carotid artery intima
media thickness (CIMT) is a validated non-invasive structural marker of preclinical atherosclerosis
with predictive value for cardiovascular outcome (19). The aim of the present study was to
evaluate the effect of hyperprolactinemia on H-FABP, high sensitive C-reactive protein (hs-CRP)
and CIMT and their relation with body fat and insulin sensitivity in addition to the CV risk in
patients diagnosed with prolactinoma and healthy controls.
METHODS
The study included 35 patients (27 female and 8 male) with active disease (both micro- and
macroprolactinoma) from our outpatient clinic. Prolactinoma was diagnosed based on an elevated
PRL level in 2 distinct samples and pituitary gland MRI findings indicative of prolactinoma.
Among the patients, 7 had macroprolactinoma and 28 had microprolactinoma. Patients with other
causes of hyperprolactinemia and hypopituitarism were excluded. None of the patients included in
the study had an endocrine diseases other than hyperprolactinoma. Only 1 of the female patients
was postmenopausal. Hyperprolactinemic patients were recruited to participate in the study prior
to beginning medical treatment. The control group included 36 healthy volunteers without any
known disease that were matched in terms of age, gender, and BMI. Participants with a history of
cardiovascular disease, cardiomyopathy, renal disease, and immunological disorders, or those that
were receiving any treatment that could affect cardiovascular and metabolic parameters were
excluded from the study. The Diskapi Training and Research Hospital Ethics Committee approved
the study protocol and all the participants provided written informed consent.
Serum glucose, high-density lipoprotein (HDL) cholesterol, and triglyceride levels were
measured using commercial enzymatic kits. PRL and insulin levels were measured via
chemiluminescence assay (Advia Centaur, Siemens Healthcare Diagnostics, USA). Intra-assay and
inter-assay variation coefficients for insulin levels of 14.68, 45.72, and 124.51 mUL–1 were 4.6%,
DOI:10.4158/EP13173.OR Endocrine Practice © 2013
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3.2%, and 3.3%, respectively, and 5.9%, 2.6%, and 4.8%, respectively. Intra-assay and inter-assay
variation coefficients for PRL levels of 10.2 and 60.4 ngmL–1were 2.3% and 2.8%, respectively,
and 2.0% and 3.4%, respectively. The normal PRL level was 2.7-18.3 ngmL–1.
Measurement of H-FABP was performed using an EPOCH system (BioTek Instruments,
USA) anda commercially available ELISA kit (Hycult, Netherlands). The assay range of the H-
FABP ELISA kit was 102-25,000 pgmL–1. The samples were carried out together in the same
experiment. BMI and the homeostasis model assessment of insulin resistance (HOMA-IR) were
calculated (20). The total fat percentage (%), and abdominal and visceral fat composition of the
participants were assessed via bioelectrical impedance analysis (BIA) using a TBF-310GS™
(Tanita Corporation, Tokyo, Japan) (21). CIMT was measured via high-resolution B-Mode
ultrasonography using a 12-MHz linear probe (Hitachi EUB 7000 HV). Three arterial wall
segments of the carotid artery were measured bilaterally after imaging from a fixed lateral
transducer angle and designated as mean CIMT.
Descriptive data for the obtained measurements are presented as number, percentage, and
arithmetic mean±SD. The Kolmogorov-Smirnov test was used to test the normality of the
distribution of numerical data. Student’s T test, the chi-square test, and the Mann-Whitney U test
were used for between-group comparisons. Associations between parameters were determined via
Pearson’s correlation analysis. The backward elimination method was used to determine the
association between H-FABP and numerical measurements using multivariate multiple regression
analysis. The level of statistical significance was set at p<0.05. PASW v.18.0 for Windows was
used for all statistical calculations.
RESULTS
Serum fasting glucose, triglyceride, and waist circumference were significantly higher in
the patients with prolactinoma than in the controls (P<0.05). There wasn’t a significant difference
in HDL-C or LDL-C levels between the patients and controls (Table 1). The mean HOMA-IR
DOI:10.4158/EP13173.OR Endocrine Practice © 2013
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value was significantly higher in the patient group than in the control group (2.6±1.6 vs. 1.9±0.9,
respectively, P <0.05). CIMT was significantly higher in the patient group than in the control
group (0.58±0.11 vs. 0.47±0, P <0.05), and the hs-CRP concentration was significantly higher in
the patients with prolactinoma than in the control group; however, there wasn’t a significant
difference in the H-FABP level between the patient and control groups (Table 2). Metabolic
variables and CIMT were adjusted for BMI (using BMI as a covariate by ANCOVA) because BMI
was higher in the patients than in the controls (P =0.075), which showed that fasting insulin (FI)
was significantly higher in the patients than in the controls (P =0.006), in addition to other
significant parameters. A relationship was observed between the serum H-FABP and PRL levels
(P <0.05, rho=0.365), based on correlation analysis. Additionally, there was a trend towards a
correlation between serum H-FABP and CIMT levels (P <0.05, rho=0.269); however, a positive
correlation was noted only between age and H-FABP, based on multiple regression analysis.
According to BIA, the total body fat percentage was higher in the patients with
prolactinoma than in the controls; however, the difference was not significant (30.3% ±8.8%
vs.26.2% ±10.8%, P =0.197). VIScan analysis showed that visceral and truncal fat percentages
were significantly higher in the patients with prolactinoma than in the control group (visceral fat:
13.4% ±5.5% vs. 9.4% ±5.3%, P =0.049; truncal fat: 41.4% ±6.1% vs. 34.7% ±10.3%, P =0.032);
however, there wasn’t a significant correlation between serum PRL or H-FABP levels, and the
body fat percentage, and visceral fat and truncal fat ratios. Moreover, thyroid-stimulating hormone
(TSH), free T4, and insulin growth factor-1 (IGF-1) levels were similar in the patient and control
groups (P >0.05) (Table 1).
DISCUSSION
The present study’s findings confirm that hyperprolactinemia is associated with features of
metabolic syndrome, including impaired insulin sensitivity, hypertriglyceridemia, and increased
waist circumference. The present findings also show that visceral and truncal fat percentages were
DOI:10.4158/EP13173.OR Endocrine Practice © 2013
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higher in patients with prolactinoma. These metabolic abnormalities are a well-known precursor of
early atherosclerosis and cardiovascular disease; thus, patients diagnosed as prolactinoma with
increased insulin resistance or metabolic syndrome tend to have a higher cardiovascular risk.
Earlier studies have shown that PRL has a wide range of effects including immunoregulatory and
metabolic effects on multiple systems other than the reproductive and osmoregulatory systems
(2,22). PRL is also produced in extrapituitary tissues, including endothelial cells, and its receptor
belongs to the superfamily of hematopoietic cytokine receptors (23).
A growing body of data suggests that PRL can modulate inflammation due to its
immunostimulatory features (9).An animal study by Molinari et al. (12) reported that PRL induced
vasoconstriction, including constriction of coronary arteries, via inhibition of a vasodilatory β2-
adrenergic receptor-mediated effect related to the nitric oxide intracellular pathway. Reuwer et al.
(24) demonstrated that the PRL receptor is abundantly present in macrophages of atherosclerotic
plaques in the most prominent sites of inflammation and posited that the PRL receptor plays a role
in atherogenesis. In menopausal women physiological PRL levels have been correlated with a risk
score that predicts 10-year cardiovascular mortality (7). These data suggest that chronic
hyperprolactinemia might contribute to atherogenesis; however, adequate data regarding the effect
of PRL on cardiovascular circulation do not exist. Endothelial dysfunction is recognized as an
early atherogenic event (25). Yavuz et al. (13) and Serri et al. (6) reported that hyperprolactinemia
is associated with a high level of cardiovascular inflammatory markers, including hs-CRP,
homocysteine, interleukin-6 (IL-6), soluble E-selectin, and tumor necrosis factor-α (TNF-α) (6,13).
Serri et al. (6) observed that short-term dopamine agonist therapy can reduce the level of
inflammatory markers. Yavuz et al. (13) also showed that the hyperprolactinemic state is
associated with decreased endothelial function, based on the flow-mediated dilatation technique.
It was reported that CIMT is a widely used and validated early marker of cardiovascular
diseasecan accurately assess the structural components of the arterial wall (19). CIMT measured
DOI:10.4158/EP13173.OR Endocrine Practice © 2013
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using ultrasonography correlates well with histological findings (26). Several longitudinal studies
have investigated the relationship between CIMT and cardiovascular events, and it is accepted as a
marker of preclinical atherosclerosis (27). In the present study preclinical atherosclerosis was
investigated via CIMT measurement. CIMT was significantly higher in the patients with
hyperprolactinemia than in the controls. It has been reported that H-FABP induces cardiac
myocyte hypertrophy, stimulating an increase in cell surface area, c-Jun expression, and protein
synthesis (28). H-FABP was recently proposed to be an early diagnostic marker of coronary events
(15). Moreover, elevated plasma levels of H-FABP have been associated with conditions of high
cardiovascular risk, such as metabolic syndrome (17); therefore, H-FABP was evaluated in the
present study’s patients with hyperprolactinemia, as they were expected to have higher levels than
the controls due to the vasoconstrictive, chronotropic, and metabolic effects of PRL hormones
(29); however, there wasn’t a significant difference in H-FABP between the patients and controls,
despite a significant difference in PRL and some metabolic syndrome components. As in earlier
studies, in the present study the patients had higher hs-CRP levels. It was reported that hs-CRP is
an independent prognostic marker of coronary artery disease, both in patients with acute coronary
events and in healthy males. In addition, hs-CRP is a marker of low-grade inflammation (30).
These data taken together suggest that inflammation accompanies hyperprolactinemia.
In addition to the effects of hyperprolactinemia on the cardiovascular system,
hyperprolactinemia effects body fat distribution. PRL receptors have been found in human adipose
tissue and PRL reduces lipoprotein lipase activity in fat cells in vitro (31). Nalioto et al. (32)
evaluated body fat in non-obese women with prolactinoma that were treated with dopamine
agonists, and reported that the body fat percentage was similar in the patients and controls. Body
fat was measured using dual energy X-ray absorptiometry, and arm, leg, truncal, android, gynoid,
and total body fat were positively associated with the PRL level. In the present study body fat was
measured via BIA and abdominal fat was measured using VIScan, a non-invasive validated
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technique. The body fat percentage in patients was higher than in controls, despite both groups
having a similar BMI. Obese patients were not excluded from the present study and the mean BMI
in the patient group was characterized as overweight. The effect of dopamine agonists on body fat
has been investigated in a few studies. Dopamine agonists were reported to improve the metabolic
profile; however; a significant reduction in body weight was not observed in prolactinoma patients
after 6 months of treatment (33).
The effect of hypothyroidism and growth hormone excess on metabolic parameters and
atherosclerosis was excluded in the present study by evaluating TSH, free T4, and IGF-1 levels.
Furthermore, the study participants were not receiving any type of treatment. Based on the present
findings, H-FABP is not a useful marker in prolactinoma patients. In consideration of the elevated
CIMT value observed in the present study’s patients and its link with cardiovascular risk, we think
that additional research is warranted in order to confirm the present findings and to further
investigate the underlying mechanisms associated with preclinical atherosclerosis. Nonetheless,
the present study has several limitations. Firstly, this study was cross-sectional in design.
Secondly, the study population was small and, therefore, the findings regarding H-FABP should be
re-evaluated in a larger population and, in particular, obese prolactinoma patients. Based on the
present findings, hyperprolactinemia is associated with an increase in atherogenesis and, therefore,
cardiovascular evaluation should be a consideration in the clinical management of patients
diagnosed with prolactinoma.
DOI:10.4158/EP13173.OR Endocrine Practice © 2013
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1
Table 1. Demographic characteristics and biochemical data in the patient and control groups.
Patients
(n=35)
Controls
(n=35)
P
Male/female
Age (years)
PRL (ngmL–1)
BMI (kgm–²)
WC (cm)
HC (cm)
FBG (mgdL–1)
HDL-C (mgdL–1)
LDL-C (mgdL–1)
TG (mgdL–1)
FI (IU mL–1) HOMA-IR
TSH
fT4
IGF-1
8/27
40.1 ± 11.9
119.2 ± 116.0
28.6 ± 4.2
96.7 ± 12.8
104.4 ± 9.4
89.3 ± 9.7
50.8 ± 10.7
112.2 ± 32.8
144.2 ± 53.9
11.7 ± 6.3
2.6 ± 1.6
2.1 ± 1.0
1 ± 0.2
175.8 ± 68.4
9/26
39.0 ± 9.4
9.9 ± 5.6
26.7 ± 3.7
86.8 ± 8.0
92.2 ± 8.9
84.5 ± 7.2
49.1 ± 16.0
113.9 ± 24.6
108.0 ± 51.8
9.4 ± 4.3
1.9 ± 0.9
1.7 ± 0.9
1.1 ± 0.2
184.6 ± 42.3
0.634
0.682
0.0001
0.075
0.003
0.0001
0.021
0.612
0.812
0.008
0.093
0.026
0.11
0.08
0.8
*Data are presented as mean±SD.
PRL:Prolactin;BMI: body mass index; WC: waist circumference; HC: hip circumference; FBG: fasting blood glucose; HDL-C: high-density
cholesterol; LDL-C: low-density cholesterol; TG: triglyceride;FI: fasting insulin; HOMA-IR: homeostasis model assessment of insulin
resistance;TSH: thyroid-stimulating hormone; fT4: free T4; IGF-1: insulin like growth factor-1.
1
Table 2.Cardiovascular risk parameters in the patient and control groups.
Patients (n=35) Controls (n=35) P
H-FABP (pg mL–1))
hs-CRP (IUmL–1)
CIMT (mm)
10.6±3.8
2.2±1.3
0.58±0.11
10.1±2.9
1.1±1.2
0.47±0
0.56
0.006
0.0001
H-FABP: Human-fatty acid binding protein; hs-CRP: high sensitive C-reactive protein;
CIMT: carotid intima media thickness.