Metabolic effects of dopamine-agonists treatment among patients with prolactinomas

To evaluate the effect of cabergoline treatment on metabolic parameters including the Triglyceride-glucose (TyG) index in newly diagnosed patients with prolactinoma. 71 consecutive nondiabetic patients with prolactinoma were enrolled. Anthropometric and laboratory tests including TyG index were measured at baseline, 3 and 6 months visits. Treatment with cabergoline at the dose of 0.25 mg twice weekly was started and increased according to prolactin levels and continued for 6 months. At the baseline examination, the mean (SD) age, body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), and diastolic blood pressure (DBP) of patients were 36.2 (10.5) years, 29.2 (5.0) kg/m2, 98.2 (13.7) cm, 115.3 (13.3) mmHg, and 71.4 (8.1) mmHg, respectively. Forty-one (57.7%) of patients were women and 46 (64.8%) had microadenoma. Cabergoline treatment significantly improved anthropometric and metabolic measures including BMI, WC, fasting plasma glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, uric acid (only among women), TyG index, and hypogonadism. Blood pressure (both systolic and diastolic) levels remained steady except for a significant decrease in DBP after 6 months of treatment only among women. A declining trend in MetS prevalence was found from baseline to a 3-month evaluation in both genders which was statistically significant among men. Short-term treatment with cabergoline can significantly improve cardiovascular risk factors except for blood pressure. Moreover, the TyG index as a surrogate marker of insulin resistance decreased significantly after the reduction of prolactin by treatment. Generally, results were similar among both genders.


Introduction
Prolactinoma is one of the most prevalent pituitary adenomas affecting about 40% of all pituitary adenoma patients [1]. It is speculated that high prolactin (PRL) level is associated with the increased risk of cardiovascular morbidity, and mortality [2][3][4] that might be mediated through cardiovascular disease (CVD) risk factors including dyslipidemia, insulin resistance [5], obesity, and glucose intolerance [6]. However, this association is not consistent and the effect of high prolactin levels on CVD and its risk factors seem to be different among men and women [7,8]. Previous studies have shown that dopamine agonists treatment improved endothelial dysfunction, an initial event of atherogenesis, alongside decreased hsCRP levels among patients with hyperprolactinemia. This effect may show the vascular benefits of dopamine agonists with an unknown mechanism or anti-inflammatory role [9,10].
A link between the normalization of PRL with dopamine agonists and metabolic abnormalities has been addressed in some previous studies. Recently, results of a systematic review and meta-analysis [11] showed that treatment with a dopamine agonist in patients with prolactinomas could result in a reduction of weight as well as an improved lipid profile and glucose tolerance. However, the results of this systematic review were associated with high heterogeneity, and the effect of treatment on markers of insulin resistance including the Triglyceride-glucose (TyG) index and according to gender is not clarified.
This study aimed to evaluate the short-term consequences of cabergoline treatment on the prevalence of metabolic syndrome (MetS) and also metabolic parameters including BMI, waist circumference (WC), blood pressure, fasting plasma glucose (FPG), lipid profile, and TyG index in non-diabetic men and women with prolactinoma.

Study participants
Seventy-one patients with newly diagnosed prolactinoma were defined as (1) symptoms and signs of hyperprolactinemia for >6 months; (2) serum PRL levels ≥2 fold the normal range; (3) magnetic resonance imaging (MRI) demonstrating pituitary adenoma were recruited from the outpatient endocrinology clinic of Sayad Shirazi hospital in Golestan, Iran. We excluded those with hypothyroidism, using drugs that could increase PRL level, history of malignancy, known diabetes (using glucose-lowering medications), patients on lipid-lowering medications, and pregnant women.

Clinical and laboratory measurements
Treatment with cabergoline at the dose of 0.25 mg twice weekly was started. The increase in the dose was stepwise and guided by prolactin levels for each patient and continued for 6 months. Patients were examined for anthropometric data consisting of weight, height, and WC as well as systolic and diastolic blood pressures at the beginning of the study, 3 and 6 months after starting treatment with cabergoline. Blood samples for PRL levels, FPG, lipid profile, and uric acid were collected in the morning after a 12-h fasting period at baseline and after 3 and 6 months of treatment.

Definition of terms
To define metabolic syndrome MetS, we used the criteria proposed by the Joint Interim Statement (JIS) [12] as follows: (1) central obesity defined as WC ≥ 90 cm, and the cut-off proposed for the adult Iranian population for both sexes; [13] (2) FPG ≥ 100 mg/dl (5.6 mmol/l) or using antidiabetes drugs; (3) low serum HDL-C defined as <50 mg/dl (1.29 mmol/l) in women and <40 mg/dl (1.03 mmol/l) in men or using lipid-lowering drugs; (4) elevated blood pressure defined as SBP ≥ 130 mmHg or DBP ≥ 85 mmHg or using antihypertensive drugs; and (5) hypertriglyceridemia, defined as fasting TG levels ≥150 mg/dl (1.7 mmol/ l) or being on treatment for elevated TG level. Patients were considered to have metabolic syndrome if they had ≥3 components of the MetS. TyG index was computed by Ln [TG (mg/dL) × fasting glucose (mg/dL)/2]. Body mass index (BMI) was calculated through body weight (kg) divided by the square of height (m²). Then, BMI was categorized according to the WHO BMI definition as follows: Normal weight BMI <25 kg/m 2 , overweight BMI ≥ 25 and <30 kg/m 2 , and obese BMI ≥ 30 kg/m 2 . Hypogonadism in the current study was central and defined as amenorrhea for >3 months in women and sexual dysfunction in men with low levels of gonadal hormones and normal to low levels of LH and FSH. Normal prolactin was defined as serum prolactin <25 ng/ml for women and <20 ng/ml for men [14].

Statistical analysis
Baseline characteristics of continuous variables were presented using mean (standard deviation; SD) or median (interquartile range; IQR), and categorical ones were shown as frequencies (%). The comparison between the baseline and follow-up measurements (3 or 6 months later) was done using paired t-tests or Wilcoxon rank-sum tests for normally distributed or not normally distributed variables, respectively. Additionally, the McNemar test was used for comparing the paired proportions of MetS between baseline and follow-up. Moreover, a point-biserial correlation was run to determine the relationship between the engagement of all baseline variables and tumor size, and no significant correlation was observed. Besides, to assess whether the improvement of MetS parameters was dependent on the reduction of BMI or WC, a multivariable analysis was performed. The statistical software Stata version 14 is used to analyze the data. The statistical significance level was chosen to be 0.05.

Results
Baseline clinical characteristics of patients among the total population and by sex are shown in Table 1. Of a total of 71 patients, 41 (57.7%) were women. Mean (SD) age was 36.2 (10.5) years for the total population, 33.8 (7.5) years for women, and 39.5 (13.1) years for men. At baseline, the mean (SD) BMI, WC, SBP and DBP of all patients were 29.2 (5.0) kg/m 2 , 98.2 (13.7) cm, 115.3 (13.3) mmHg and 71.4 (8.1) mmHg, respectively. Moreover, the median (IQR) PRL levels were 100 ng/ml (58-220). Forty-six (64.8%) of patients had microadenoma (tumor sizes range between 4 mm and 34 mm in diameter), and MetS found in 59.2% of the patients. There were significant differences in baseline characteristics between men and women for age, BMI, WC, SBP, and MetS. Compared with women, men were older and had higher values for BMI, WC, SBP, and MetS prevalence. Table 2 illustrated the effects of treatment with cabergoline (starting dose of 0.25 mg twice weekly with a stepwise increase in the dose) on different characteristics according to sex. Regarding, the anthropometric measures, we found a decreasing trend in BMI between baseline and 6-month evaluation (28.03 (3.8) vs 27.8 (3.6) kg/m 2 ; P = 0.12 for women and 30.7 (5.9) vs 30.5 (5.8) kg/m 2 ; P = 0.008 for men). Similarly, WC showed a decreasing trend that was significant between baseline visit and 3month, as well as 6-month, follow-up among both genders (93.4 (10.9) vs 90.8(11.2) cm; P = 0.02 for women and 104.8 (14.5) vs 98.3 (13.1) cm; P = 0.03 for men at 6-month evaluation). Blood pressure (both systolic and diastolic) levels remained steady between baseline measurement and follow-up except for a significant decrease in DBP after 6 months of treatment only among women (72.3 Regarding metabolic parameters, there was a significant decline in mean (SD) FPG from 94.5 (11.1) mg/dl at  At the end of the study, 97.6% of women, and 86.7% of men reach normal prolactin levels (only one woman and four men had prolactin values above the normal levels). A comparison between the difference in weight loss and other parameters between those who had normal prolactin at end of the study and those with increased was performed among men. The results showed that among those with abovenormal levels of PRL at the end of the study, only the levels of WC decreased and the levels of HDL increased significantly (Supplementary Table 2).

Discussion
A present study of nondiabetic women and men with prolactinomas showed that even short-term treatment with cabergoline can significantly improve anthropometric and metabolic profiles (including BMI, WC, lipid profile, and FPG) and hypogonadism. Moreover, the TyG index which is a surrogate marker of insulin resistance decreased significantly after the reduction of PRL by dopamine agonist treatment. Furthermore, despite the older age and higher values for BMI, WC, SBP, and MetS prevalence among men at baseline examination compared to women, the effect of treatment was generally similar among both genders except that the improvement of MetS prevalence and the uric acid level was seen only among men and women, respectively.
The metabolic manifestation of high PRL levels could be explained by the wide distribution of PRL receptors in metabolic-related organs, including the liver, endocrine pancreas, and adipose tissue [11]. Some possible mechanisms related to weight gain among patients with high PRL include reduced dopaminergic tone, leptin resistance, decreased adiponectin levels, increased hypothalamic pressure, and hypogonadism [6,15]. Furthermore, the PRL effect on the pancreas islet cell growth and insulin production contribute to alternation in glucose hemostasis and insulin sensitivity. In other words, hyperprolactinemia causes insulin resistance due to insulin receptor downregulation alongside hyperinsulinemia. Adverse lipid profiles are also found among these patients due to lipoprotein lipase activity decrease in adipose cells [9,15,16]. In addition, hypogonadism due to hyperprolactinemia may contribute to the alteration of lipid profile and glucose tolerance, alongside playing a role in weight gain [11]. Moreover, PRL as an immune modulator factor is associated with chronic immune response and inflammatory markers, like high sensitivity CRP (hsCRP), an independent risk factor for cardiovascular disease. In addition, the existence of PRL receptors in atherosclerotic plaque may provide evidence for its contribution to atherosclerosis by playing a role in the inflammatory response within the atherosclerotic plaque. Furthermore, insulin resistance due to hyperprolactinemia may be a part of atherosclerosis by initiating chronic inflammation [4,5,9].
Some studies revealed that reducing PRL level using dopamine agonists significantly improve metabolic impairments; [5,6,15,[17][18][19][20][21] however, no study has examined the effect of this treatment on the TyG index. The findings of previous studies regarding the effect of normalization of PRL on anthropometric measures were inconsistent. BMI did not change [5,6,21] or significantly decreased after treatment among different patients [15,18,22]. Moreover, in the study by Berinder et al, improvement in anthropometric measures was only seen among men [19]. Our results showed that treatment with cabergoline was related to a decreasing trend in BMI that was statistically significant after 6 months. Similarly, WC significantly decreased in both the short-term (3 months) and long-term (6 months) follow-ups; the pattern was similar among both genders. The reduction of PRL effect on the appetite-regulating system and dopaminergic tone along with hypogonadism improvement due to cabergoline treatment may explain our results. Hypogonadism could affect body composition by increasing body fat and facilitating lean mass reduction, especially among male patients [6,11,23]. Therefore, a significant decrease in hypogonadism among both gender in our study may provide evidence for this claim. Furthermore, we found no study regarding the effect of dopamine agonists therapy on BP among patients with prolactinoma and our study showed no change in BP except for a decrease in DBP after a 6-month follow-up only among women.
With regard to metabolic parameters, treatment with dopamine agonists was associated with a decrease in cholesterol, LDL-C [9], in most [6,15,[19][20][21][22][23], but not all studies [5] in this field. Besides, data on the effect of hyperprolactinemia treatment on TG and HDL is more controversial. Similarly, most but not all studies have documented a reduction in FPG after treatment [15,20]. Enhanced suppression of endogenous glucose products, increased splanchnic glucose uptake after glucose ingestion, and/or a central action in the hypothalamus are potential mechanisms by which dopamine agonists could improve glucose metabolism [6,15,20,22]. In a recent metaanalysis of randomized controlled trial studies among type 2 diabetes participants, treatment with dopamine agonists reduced FPG, HBA1c, and TG levels without serious adverse effects [24]. Bromocriptine mesylate-quick release, the Food and Drug Administration (FDA) approved medication for type 2 diabetes mellitus treatment, appears to have a weak lowering effect on HbA1c and potentially decreases cardiovascular events among high-risk populations [25]. Moreover, few previous studies evaluated the anti-diabetic effect of cabergoline, which was not approved by the FDA for type 2 diabetes treatment [26][27][28]. In our patients, among both genders, treatment with cabergoline improved lipid profile and FPG levels. Furthermore, prolactinoma seems to be associated with metabolic syndrome [17]. Few studies [18,20,22] revealed a significant decline in metabolic syndrome prevalence in patients with hyperprolactinemia receiving treatment with dopamine agonists that might be a consequence of the significant improvement in body weight, glucose, and lipid profile. Findings of the current study showed a declining trend from baseline to a 3-month evaluation in both genders that was statistically significant from baseline to 3-month evaluation among men.
To our knowledge, discordant results have been reported about the effects of dopamine agonists on insulin sensitivity. Using HOMA-IR, some studies [5,15,20] revealed a significant improvement in IR while others [6,22] found no effects. Moreover, using euglycemic hyperinsulinemic clamps, Berinder et al. [19], found a trend of improvement that was not statistically significant (P = 0.08). Triglycerideglucose (TyG) index calculated using fasting triglyceride and fasting glucose measurements as a surrogate marker of insulin resistance is strongly associated with diabetes, nonalcoholic fatty liver disease, obesity, and metabolic syndrome [29][30][31][32] and has been used to predict cardiovascular events [33]. Moreover, it is demonstrated that the TyG index is more accurate than FPG, TG, HDL, small dense LDL, and even HOMA-IR in diagnosing metabolic syndrome [34,35]. To the best of our knowledge, this is the first study that showed the TyG index significantly diminished after treatment with dopamine agonists.
As for the strengths of our study, it is the first to be conducted among an Iranian population with a high CVD burden [36]. Other strengths are the relatively large sample size, using the TyG index for the first time, and reporting results in both genders. Nevertheless, there are some important limitations. First, it's an observational study so we couldn't conclude the relationship between parameters. The short duration of the study is another limitation.
In conclusion, short-term treatment with cabergoline can significantly improve cardiovascular risk factors including the TyG index; with results that were generally similar among both genders. Hence, it might be important to consider the metabolic profile, when approaching patients with hyperprolactinemia

Data availability
All data and materials are available upon request.
Author contributions M.K., H.A, and F.G. planned the study, researched the data, and wrote the manuscript. S.M. and A.K analyzed the data and edited the manuscript. H.S. reviewed and edited the manuscript.

Compliance with ethical standards
Conflict of interest The authors declare no competing interests.
Ethical Approval This study was approved by the Ethics Committee of the Golestan University of Medical Science (Protocol no. IR.GOUMS.REC.1398.300) and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Consent to participate Informed consent was obtained from all individual participants included in the study.
Consent to publish Informed consent for publication was obtained from patients.