Endocrine DOI 10.1007/s12020-012-9857-y
ORIGINAL ARTICLE
Effect of cabergoline on insulin sensitivity, inflammation, and carotid intima media thickness in patients with prolactinoma Serap Soytac Inancli • Alper Usluogullari • Yusuf Ustu • Sedat Caner • Abbas Ali Tam Reyhan Ersoy • Bekir Cakir
•
Received: 6 August 2012 / Accepted: 4 December 2012 Ó Springer Science+Business Media New York 2012
Abstract The aim of this study was to evaluate the effect of Cabergoline on insulin sensitivity, inflammatory markers, and carotid intima media thickness in prolactinoma patients. Twenty-one female, newly diagnosed patients with prolactinoma were included in the study. None of the patients were treated previously. Cabergoline was given as treatment, starting with 0.5 mg/day and tapered necessarily. Blood samples were taken for prolactin, highly sensitive C-reactive protein, homocysteine, total cholesterol, low density lipoprotein (LDL) cholesterol, fasting glucose, insulin, and HOMA (homeostasis model assessment of insulin resistance) score was calculated, prior to and 6 months after starting treatment. The body mass index (BMI) was measured and carotid intima media thickness (CIMT) was evaluated for each patient prior to and 6 months after the treatment. The prolactin levels and LDL decreased significantly after cabergoline treatment. Insulin sensitivity improved independently from the decrease in prolactin levels and BMI. The significant decrease in
S. S. Inancli (&) Department of Endocrinology and Metabolism, School of Medicine, Near East University, Nicosia, Cyprus e-mail:
[email protected] S. S. Inancli Hakki Boratas Cad, Kemal Sayin Apartment. No: 8 Daire 3, Girne, KKTC, Mersin 10, Turkey A. Usluogullari S. Caner A. A. Tam R. Ersoy B. Cakir Department of Endocrinology and Metabolism, Yildirim Beyazit University, Ankara Ataturk Education and Research Hospital, Ankara, Turkey Y. Ustu Department of Family Medicine, Ankara Ataturk Education and Research Hospital, Ankara, Turkey
homocysteine and hs-CRP was not related with the decrease in prolactin levels. The significant decrease in CIMT was independent from the decrease in prolactin levels, HOMA score, and BMI. Our data suggest that cabergoline treatment causes an improvement in insulin sensitivity and inflammatory markers and causes a decrease in CIMT independent from the decrease in prolactin, LDL cholesterol, and BMI. We conclude that short term cabergoline treatment can improve endothelial function independently from the changes in metabolic disturbances and inflammatory markers. Keywords Prolactinoma Carotid intima media thickness Insulin resistance Inflammation Atherosclerosis
Introduction The main role of prolactin is to ensure lactation [1]. Hyperprolactinemia causes amenorrhea, infertility, galactorrhea, radiologic vertebral fractures in women and infertility, gynecomastia, and radiologic vertebral fractures in men. These clinical outcomes result mainly from hypogonadism due to the negative effects of prolactin hormone on the gonadotropine releasing hormone pulsation. The increased risk of radiologic fractures were found to be independent from the decrease in prolactin levels and hypogonadism both in men and women patients with prolactinoma [2, 3]. Recent studies have shown that it plays a crucial role in carbohydrate and lipid metabolism. In animal studies, prolactin causes suppression in lipid storage and adipokine release from the adipose tissue [4]. Additionally, it causes glucose induced insulin release in rats with chronic
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hyperprolactinemia [5]. Furthermore, female mice develop glucose intolerance due to an increase in insulin resistance by the help of the effect of estrogen [6]. When compared with normal individuals, patients with hyperprolactinemia were found to have insulin resistance and glucose intolerance [7, 8]. The fact that prolactin acts on the islet b-cell growth and differentiation and on insulin production/ secretion may be the main point [9]. However, the signaling pathways and major elements critical for prolactin hormone induction of insulin gene transcription have not been identified. Obesity, insulin resistance, and endothelial dysfunction have been related to the increase in prolactin levels [7, 10, 11]. Increased prolactin levels are associated with increased food intake and increased body weight. Furthermore, there is controversy whether prolactinoma patients loose weight, improve metabolic disturbances [10, 12], or have no effect on weight change after DA treatment [13]. The response to prolactin might be different between individuals due to the variations in prolactin receptor expression and signaling [4]. With the current data prolactin hormone cannot be a major factor in obesity. Prolactin is an immune modulator and has been linked with chronic immune response [14, 15]. On the other hand, inflammatory markers, such as hsCRP, have been found to be increased in hyperprolactinemic patients [11]. Prolactin receptors have been shown in atherosclerotic plagues. It has been proposed that prolactin receptor signaling may contribute to a local inflammatory response within atherosclerotic plaque and contribute to atherosclerosis. But is not clear how hyperprolactinemia causes impairment in endothelial function [15]. Atherosclerosis, a disease which is caused by chronic inflammation and several hormonal changes, have been associated with hyperprolactinemia [11]. This relationship has not been clearly understood. Nevertheless, it may be the direct action of prolactin in endothelial tissue itself. Hyperprolactinemia causes endothelial dysfunction. Increased CIMT is associated with further cardiovascular diseases and stroke [16]. Georgiopoulos et al. [17] showed that prolactin was associated with arterial stiffness. However, the association of prolactinoma patients with endothelial dysfunction and increased cardiovascular risk is poorly documented. Recently prolactin has been related to a risk score which is related to cardiovascular mortality [17]. The aim of this study was to evaluate endothelial dysfunction in prolactinoma patients and determine the effect of short term cabergoline treatment on endothelial function.
local ethical committee and written informed consent was obtained from all subjects. Study protocol Our study included 21 female (mean age 30 ± 10.2 years, range 18–51) with prolactin secreting pituitary adenoma who were admitted to our outpatient Endocrinology and Metabolism clinic of Ankara Ataturk Education and Research Hospital, Ankara, Turkey between January and June 2011. Eighteen patients had microadenoma and three patients had macroadenoma. The diagnosis of prolacinoma was based on elevated prolactin levels found on two occasions and magnetic resonance imaging of the pituitary gland confirming a prolactinoma. The presumed disease duration was calculated from the time of the appearance of symptoms, such as irregular menses, amenorrhea, hirsutism, and galactorrhea probably related to hyperprolactinemia. The median duration of symptoms was 10.7 ± 3.5 (range: 4–17) months. No patients used cabergoline before and had no history of pituitary surgery and/or radiotherapy. Exclusion criteria were: postmenopausal period, coronary heart disease, cerebrovascular disease, hypothyroidism, hyperthyroidism, diabetes mellitus, hypertension, secondary causes of hyperprolactinemia, patients using antihyperlipidemic drugs and drugs that could increase prolactin levels (antidepressants, opiates, estrogens, gastrointestinal prokinetics, etc.), the use of drugs that could influence BMI (sibutramine orlistat). None of the patients were cigarette smokers and none of them had a history of alcohol intake. Formal tests of hypothalamo-pituitary function and pelvic ultrasonography examination were normal. Growth hormone deficiency was not tested by dynamic tests but all patients had IGF-1 (Insulin-like growth factor-1) values in the normal ranges for age. Patients were studied at baseline and at 6 months after initiating cabergoline treatment. Prior to and 6 months after the initiation of cabergoline treatment serum glucose, insulin, highly sensitive C-reactive protein (hsCRP), homocysteine, total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides (TG) were measured in the morning after a 12 h fasting period. Anthropometric data was also measured at baseline and 6 months after cabergoline treatment. Height and body weight of all the patients were measured and BMI was calculated for every patient. Oral glucose tolerance test with 75 g glucose
Materials and methods This prospective study was conducted in the Department of Endocrinology and Metabolism. It was approved by the
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After a 12 h fasting, oral glucose tolerance test with 75 g glucose was performed to every patient at baseline and at 6 month. Venous cannula was placed in the forearm after a
Endocrine
10–12 h fasting between 08.00 and 09.00 a.m. Blood samples were taken for the measurement of plasma glucose, insulin. Then, patients drank 75 g glucose dissolved in 300 mL water in 5 min, and serum glucose and insulin levels were measured after 30, 60, 90, and 120 min.
Spearman Rank order correlation test. The cabergoline induced difference for a parameter was calculated by subtracting the base line value from the value obtained on cabergoline treatment. p values \ 0.05 were considered statistically significant.
Measuring carotid intima media thickness Endothelial function was determined by measuring CIMT on high resolution external ultrasonography. CIMT was measured by using high resolution B mod ultrasound imaging Esaote color Doppler machine (Esaote 796FDII, Taipei, Taiwan) and a superficial probe (Esaote LA523– 5.5–12.5 MHz, Taipei, Taiwan) and was performed as described previously. CIMT was measured at the beginning and 6 months after initiation of cabergoline treatment. Three paired segments were taken; right and left common carotid artery, the carotid bulb, and the internal carotid artery. The average of the maximal intima media thickness from all of the six carotid segments was defined as the mean CIMT from each segment used separately. In each segment, three measurements of the maximal CIMT were averaged. All of the scans were performed by the same physician. Laboratory examinations Fasting glucose, total cholesterol, and LDL cholesterol were measured using Advia 2400 Chemistry System (Advia 2400 Chemistry System, USA) kits. Insulin was measured using Immunotech IM3210 IRMA (Beckman Coulter Inc., Fullerton, CA) kit. Analytic sensitivity was 0.5 lIU/mL. Insulin sensitivity was estimated according to homeostasis model assessment of insulin resistance index (HOMA-IR; fasting plasma glucose (mg/dL) 9 fasting serum insulin (lU/mL)/405) [18]. HOMA-IR score [2.5 was considered as insulin resistance.
Results Data before and after cabergoline treatment are shown on Tables 1, 2, and 3. All of the patients reached normal prolactin levels (\20 mg/dL) within 6 months after starting cabergoline (151 ± 58 vs. 12.4 ± 7.2 ng/mL, respectively; p \ 0.001). BMI significantly decreased after cabergoline treatment (BMI before and after treatment, 27.1 ± 5.9 vs. 26.7 ± 5.6 kg/m2, respectively; p = 0.03). There were two patients with a BMI C30 kg/m2 and two patients with BMI C40 kg/m2 at the time of diagnosis. Four patients gained weight at 6 months of therapy. Serum total cholesterol and LDL levels decreased significantly and HDL increased after 6 months after cabergoline treatment (174 ± 32.1 vs. 160 ± 41.8, 106.2 ± 27.1 vs. 91.7 ± 34.0, and 49 ± 8.9 vs. 53.5 ± 10.8 mg/dL, respectively; p \ 0.05). This decrease in total cholesterol and LDL was probably due to the positive association between the changes in prolactin levels. (r = 0.04, p = 0.45 and r = 0.47, p = 0.03). Insulin sensitivity, which was calculated using HOMAIR, improved at 6 months after cabergoline therapy (before and after therapy, 1.25 (0.22–4.5) vs. 1.02 (0.24–4.1), respectively, p = 0.02) (Fig. 1). The improvement in insulin sensitivity was not correlated with prolactin, LDL, and hs-CRP levels (r = -0.03, p = 0.88 and r = -0.10, p = 0.64 and r = 0.26, p = 0.24, respectively). Additionally, the decrease in BMI did not effect insulin sensitivity (r = -0.17, p = 0.45).
Statistical analysis Data are expressed as mean ±SD, except for variables with non-normal distribution, which are expressed as medians (interquartile ranges). The data were tested for normality of distribution using Shapiro–Wilk test due to the small size of the study group. BMI, prolactin, total cholesterol, LDL, and CIMT were distributed normally. Accordingly, the differences between these parameters before and after cabergoline treatment were compared using the paired sample t test. HsCRP, HOMA-IR, and homocysteine had a non-normal distribution and Wilcoxon signed-rank test was used to compare the differences before and after cabergoline treatment. Correlation analysis was performed using
Table 1 Serum concentrations of hs-CRP, HOMA, and Homocysteine before and after cabergoline treatment Before treatment hs-CRP (mg/dL)
After treatment
p value \0.001
1.5 (0.2–10.9)
0.88 (0.1–3.1)
HOMA
1.25 (0.22–4.5)
1.02 (0.24–4.1)
Homocysteine (lmol/L)
13.8 (7.0–28.0)
8.5 (2.3–26.4)
0.02 \0.001
Values are medians hs-CRP highly sensitive C-reactive protein, HOMA homeostasis model assessment of insulin resistance
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Endocrine Table 2 Serum concentrations of prolactin, LDL, and carotid intima media thickness before and after cabergoline treatment Before treatment Prolactin (ng/dL) LDL (mg/dL)
151 ± 58 106.2 ± 27.1
HDL (mg/dL)
49 ± 8.9
After treatment
p value
12.4 ± 7.2
\0.001
91.7 ± 34.1
0.01
53.5 ± 10.8
0.02
Tkol (mg/dL)
174 ± 32.1
160 ± 41.8
0.03
CIMT
0.58 ± 0.15
0.52 ± 0.12
0.03
BMI (kg/m2)
27.1 ± 5.9
26.7 ± 5.6
0.03
Values are mean ± SD LDL low density lipoprotein, HDL high density lipoprotein, CIMT carotid intima media thickness, BMI Body mass index
The significant decrease in hs-CRP (1.5 mg/L (0.2–10.9) vs. 0.88 mg/L (0.1–3.1), respectively; p \ 0.001) and homocysteine levels (13.8 (7–28) lmol/L vs. 8.5 (2.3–26.4) lmol/L, respectively; p \ 0.001) 6 months after cabergoline treatment did not effect the decrease in CIMT. The decrease in hs-CRP and homocysteine levels had no correlation with the decrease in prolactin and LDL levels. Endothelial function measured as CIMT was significantly improved after cabergoline treatment (0.58 ± 0.15 and 0.52 ± 0.12 before and after treatment, respectively; p = 0.03) (Fig. 2). Although the patients did not have an increased CIMT, there was a reduction after treatment. This decrease was not correlated with the decrease in prolactin, total cholesterol, LDL, hs-CRP, and homocysteine levels. Additionally, the improvement in insulin sensitivity did not effect CIMT. The duration of symptoms or hyperprolactinemia neither effected the endothelial function nor the insulin sensitivity. There were no correlations between cabergoline induced reduction in prolactin and reductions in HOMA-IR, hs-CRP, LDL, and homocysteine levels, and CIMT.
Discussion Hyperprolactinemia causes hyperinsulinemia and insulin resistance [8, 19–22]. Insulin resistance may be caused by the down regulation of insulin receptors [4, 8, 23]. By initiating chronic inflammation, insulin resistance can be a part of atherosclerosis. The effect of cabergoline on CIMT has not been studied before. Therefore, we aimed to evaluate CIMT, determine the effect of cabergoline treatment on CIMT, and determine its relation with insulin sensitivity. Although some of our patients had insulin resistance, our data demonstrates that improvement in insulin sensitivity can be achieved with cabergoline treatment
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independent from the change in BMI and normalization of prolactin levels. These findings were inconsistent with the findings of Yavuz et al. [24]. In a study where euglycemic hyperinsulinemic clamp technique was used, insulin sensitivity was found to be lower in hyperprolactinemic patients than controls [19]. DA treatment decreases HOMA-IR in hyperprolactinemia patients which may [11] or may not [13] be related to the decrease in BMI. Patients with hyperprolactinemia may [25, 26] or may not loose [10, 27] weight after normalization of prolactin after cabergoline treatment. In our study group there was a significant change in BMI after cabergoline therapy. Hyperprolactinemia has been associated with lipid abnormalities. In some studies there was an improvement in the lipid profile [7, 28, 29] and in other studies no improvement [20] was seen after DA treatment. Treatment with bromocriptine in obese Type 2 Diabetes Mellitus patients has been shown to reduce total cholesterol [30] while another study showed no changes in total cholesterol levels [31]. In our study, the decrease in LDL cholesterol was related with the decrease in prolactin levels after cabergoline treatment. On the other hand, this decrease was not related with weight loss. Our results may suggest a direct relation between prolactin levels and LDL cholesterol. Additionally, hyperprolactinemia may be a part of chronic inflammation and atherosclerosis. Serri et al. [11] found that hsCRP increased in patients with hyperprolactinemia and was related with increased BMI. We found that hs-CRP decreased after cabergoline therapy but this was not related with the decrease in HOMA-IR or BMI. Prolactin receptors have been shown to be expressed in atherogenic plaques but it is not proved whether prolactin itself is the direct cause [18]. Hyperprolactinemia potentiates ADP induced platelet aggregation [32, 33]. On the other hand, prolactin levels have been shown to be increased in patients with thrombosis, ischemic stroke, and acute coronary syndromes [34]. The fact that hyperprolactinemia may cause endothelial dysfunction was shown by Yavuz et al. [24]. Endothelial function was measured as flow mediated dilation (FMD) on a brachial artery. FMD was impaired in hyperprolactinemic patients and improved after DA treatment. In our study, although CIMT was normal in the study group, we found a decrease after cabergoline treatment. The decrease in CIMT was independent from the decrease in LDL, homocysteine, hsCRP, HOMA-IR, and BMI. The effect of cabergoline on CIMT was not mediated by prolactin normalization. Additionally, the decrease in inflammatory markers was independent from each other indicating a direct effect of cabergoline on endothelium. May be a direct metabolic D2 receptor mediated dopaminergic effect can be the cause. This hypothesis must be further
Endocrine Table 3 Serum concentrations of prolactin, LDL, HDL, HOMA, homocysteine, and CIMT of every patient Prolactin basal (ng/mL)
Prolactin 6 months (ng/mL)
HOMA score
HOMA 6 months
LDL basal (mg/dL)
LDL 6 months (mg/dL)
HDL basal (mg/dL)
HDL 6 months (mg/dL)
CIMT basal
CIMT 6 months
Homocysteine basal (lmol/L)
Homocysteine 6 months (lmol/L)
Patient 1
90.1
25
2.7
2.4
128
88
38
45
0.54
0.55
15.9
7.4
Patient 2
143.6
6
1.4
0.4
97
64
41
58
0.53
0.54
17.0
12.2
Patient 3
246.0
5
0.6
0.4
157
135
54
70
0.63
0.63
16.4
12.2
Patient 4
100.0
9
1.9
1.2
73
70
43
50
0.54
0.56
12.0
6.0
Patient 5
120.0
1
1.5
1.8
110
113
62
73
0.37
0.53
13.1
11.4
Patient 6
98.0
5
3.9
4.1
62
81
47
50
0.34
0.46
19.7
10.0
Patient 7
256.0
19
1.3
0.4
62
27
46
63
0.61
0.54
11.4
13.5
Patient 8
211.0
22
0.4
0.3
119
76
67
76
0.64
0.63
22.5
12.2
Patient 9
267.0
13
1.0
1.1
103
45
43
42
0.35
0.39
13.4
6.2
Patient 10
141.0
12
1.1
0.8
116
113
51
45
0.51
0.48
18.2
17.0
Patient 11
191.0
9
1.2
1.6
92
74
52
51
0.53
0.58
28.0
26.4
Patient 12
181.0
6
1.7
1.4
109
137
44
37
0.81
0.68
23.1
8.0
Patient 13
112.0
10
0.2
2.4
150
130
40
45
0.96
0.85
10.4
10.4
Patient 14
150.0
5
0.5
0.3
90
34
52
46
0.76
0.56
13.3
8.2
Patient 15
107.6
12
0.9
0.7
105
98
64
62
0.65
0.50
8.7
4.2
Patient 16
107.0
25
2.2
2.2
75
75
52
54
0.55
0.45
15.3
14.7
Patient 17
102.0
21
1.3
0.9
97
95
42
50
0.67
0.52
11.2
5.6
Patient 18
211.0
19
4.5
2.2
147
130
45
50
0.56
0.42
13.8
8.5
Patient 19
150.0
13
1.5
1.0
89
90
68
65
0.55
0.30
13.7
7.2
Patient 20
95.0
17
1.2
0.7
131
150
45
42
0.46
0.39
7.0
2.3
Patient 21
96.0
8
0.4
0.2
119
102
45
50
0.57
0.48
16.0
5.0
LDL low density lipoprotein, HDL high density lipoprotein, CIMT carotid intima media thickness, HOMA homeostasis model assessment of insulin resistance
investigated in order to find a potential cause. Currently, the mechanisms of improvement of insulin sensitivity and CIMT by cabergoline are unknown. The finding that cabergoline therapy improves endothelial dysfunction in prolactinoma, independently from the changes in metabolic
parameters may lead to changes in the management of prolactinomas. The decrease in CIMT may be the vascular benefit of cabergoline treatment. If this is the case, CIMT may be another indication for starting treatment in prolactinoma patients.
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References
Fig. 1 Change in CIMT 6 months after cabergoline therapy CIMT, carotid intima media thickness p \ 0.05
Fig. 2 Change in HOMA-IR 6 months after cabergoline therapy HOMA-IR, homeostasis model assessment of insulin resistance p \ 0.05
As a conclusion, our study demonstrated that patients with prolactinoma may be under risk for atherosclerosis. Cabergoline treatment may have a beneficial change on the endothelium independently from the changes on inflamatory and metabolic parameters. Further prospective studies must be done to determine a specific cause. Conflict of interest
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Authors declare no conflict of interest.
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