Keywords
Metabolic syndrome - prolactinoma - treatment duration
Introduction
The prevalence of metabolic syndrome (Met.S) is increasing worldwide, and it is responsible for an increased morbidity and mortality, mainly due to cardiovascular disease and cancer.[[1]] Some endocrine disorders are known to be related to the pathogenesis of some components of Met.S. It is believed that hyperprolactinemia (HPL) is linked to alteration in glucose homeostasis, insulin sensitivity, and lipid parameters as well as weight gain.[[2]] It was suggested that HPL with direct effects on the growth of islet cells and insulin secretion, can impair glucose metabolism.[[3]] Moreover, other factors such as low adiponectin, hypogonadism with or without associated leptin resistance, as well as decreased dopaminergic tone could contribute to weight gain.[[4]] Indeed, patients with HPL have mostly involved with dyslipidemia.[[5]] It is largely attributed to a decrease in lipoprotein lipase activity in fat cells and subsequent effects on adipose tissue.[[5]] Previous studies have shown that dopamine (DA) agonists as the choice of therapeutic option for HPL can effect on body weight, glucose, and lipid homeostasis.[[3]],[[4]],[[5]]
The present study was designed to determine the effect of treatment duration on metabolic parameters as after cabergoline treatment in comparison with baseline in patients with prolactinoma in Iranian individuals.
Patients and Methods
This is a prospective, longitudinal study conducted from April 2016 to June 2018. The study was performed at the Institute of Endocrinology and Metabolism, Iran University of Medical Sciences. Thirty consecutive patients with prolactin (PRL) secreting pituitary adenoma were included in the study. Out of the 30 patients, three women were excluded due to noncompliance. Thus, the final sample consisted of 27 patients (24 women and 3 men). Patients with elevated PRL levels (PRL >30 µg/l) on at least two occasions and magnetic resonance imaging evidence of pituitary adenoma were included. The diagnosis of prolactinoma requires both radiographic evidence of pituitary adenoma and laboratory analyses, documenting the presence of sustained hyperprolactinemia. Normal PRL levels in women and men are below 25 and 20 µg/l, respectively, with the more commonly used assays (1 µg/l is equivalent to 21.2 mIU/l, WHO Standard 84/500).[[6]]
Exclusion criteria were secondary causes of HPL, pregnancy, or patients on medication for dyslipidemia and diabetes mellitus at study entry. In this study, a control group was not recruited, as our aim was to evaluate the metabolic parameters during treatment, and for this purpose, we used patients as their own controls.
In addition, we conducted food record template for all patients. The participants were assessed for anthropometric and laboratory measurements at baseline and at 3 and 6 months after achieving normal PRL following cabergoline administration. Blood samples were taken after an overnight fast for the measurement of metabolic parameters (glucose and lipid profile) and PRL.
At once, all the patients were treated with cabergoline (0.5 mg orally/week) with dosage titration to normalize serum PRL. All patients had their normal PRL level 8 weeks after prescribing up to 3 mg cabergoline weekly. During the study period, the patients were instructed to continue their routine homemade diets according to food record template and their activity.
Anthropometric data were examined by the measurement of weight and height, using standard measurements. Body mass index (BMI) was calculated as weight in kilogram divided by square of height in meters (kg/m[[2]]). Obesity was defined as per “Asia-Pacific guidelines of obesity classification.”[[7]] BMI classifications were considered as follows: ≤18.5 kg/m[[2]]: underweight, 18.5–24.9 kg/m[[2]]: normal weight, 25–29.9 kg/m[[2]]: overweight, and 30–34.9 kg/m[[2]]: obesity.[[7]] In addition, waist circumferences (WCs) were measured (cm) and the cutoff points for Iranian people were considered as 99.5 cm for men and 94.25 cm for women.[[8]]
Blood samples for PRL, uric acid (UA), fasting blood sugar (FBS), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) were obtained at baseline and at 3 and 6 months after normalization PRL by cabergoline. All laboratory measurements were performed in the laboratory of the Institute of Endocrinology and Metabolism in Iran University of Medical Sciences.
Serum PRL was measured by using a commercial immunoradiometric assay (Beckman Coulter Unicel, DXI Brea, Calif, USA): normal range: 1–27 μg/L (women) and 1–20 μg/L (men). Enzymatic method with photometric assay was used for blood glucose, lipid, and UA. Met.S was defined by American Heart Association criteria.[[9]]
Statistical analysis
Continuous variables were shown in terms of descriptive statistics including mean, standard deviation (SD), median, and interquartile range. The paired t-test was used to analyze the data at baseline with 3 months and with 6 months after normalization of serum PRL by cabergoline administration. All results have been described on 5% level of significance, i.e., P < 0.05 being considered as statistically significant.
Based on the data structure, a measurement in the baseline and two measurements after treatment with cabergoline, then the longitudinal logistic regression were deemed appropriate. A longitudinal study refers to an investigation where participant outcomes and possibly treatments or exposures are collected at multiple follow-up times.[ ] A longitudinal study with measurements at times can simultaneously characterize multiple time scales. In this study, the effects of treatment with cabergolin on Met.S have been evaluated in different time periods. Therefore, longitudinal logistic regression was used for evaluating the treatment effect on covariants if Met.S is considered as outcome. The statistical software SPSS version 20 was used to analyze the data IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.
Results
Out of 27 patients, 25 had microadenoma and two had macroadenoma. Among women, 20 (80%) of them were diagnosed with secondary amenorrhea and six with infertility. Two men had primary hypothyroidism and were on adequate doses of levothyroxine at the time of entry to the study. Adrenal insufficiency was not detected among our patients. The supra extension of pituitary mass to optic chiasma and left cavernous sinuous was seen in one patient.
Serum PRL normalized in all patients up to 8 weeks after adjusting cabergoline dose [[Figure 1]]. The median range of PRL level was obtained as 63.5 (32–280) ng/dl at baseline and 8.25 (0.8–20) ng/dl and 10 (0.1–19) ng/dl after 3 and 6 months, respectively (P < 0.001). Metabolic abnormality at the baseline has been described as follows: two (7.4%) were morbidly obese, seven (25.9%) were obese, seven (25.9%) were overweight, and two had impaired fasting glucose [[Table 1]].
Figure 1: Comparison between the prolactin level and the rate of metabolic syndrome at baseline and at 3 and 6 months after normalizing prolactin
Table 1: Anthropometric and hormonal profile of patients at diagnosis and after 3 and 6 months of normoprolactinemia
Metabolic changes with normalization of prolactin
Metabolic parameters before and after normalizing of PRL are shown in [[Table 1]]. Five patients had impaired fasting glucose, of which two patients achieved normoglycemia 3 months after the PRL normalization. Hypertriglyceridemia (TG > 150 mg/dl) was reported in six patients at the beginning of the study and a nonsignificant reduction was seen after 3 months. Moreover, Met.S was reported in five (18.5) patients at baseline compared with three (11.5) and two (7.4) patients 3 and 6 months after normalization of PRL. Similarly, there was a significant decline in mean (SD) TC at baseline from 192.56 (48.33) to 186.71 (40.41), P = 0.07, and UA from 4.95 (1.63) to 4.62 (1.33), P = 0.05, after 3 months. Moreover, similar results were obtained for TC (192.56 {48.33}–182.43 {37.89}, P = 0.01) and UA (4.95 [1.63]–4.53 [1.14], P = 0.03) at baseline comparing with 6 months after cabergoline therapy. Similarly, a trend was seen in diastolic blood pressure (DBP) falling from 69.81 (7.66) mmHg at baseline to 73.26 (6.15) mmHg (P = 0.02) after 6 months of treatment [[Table 1]].
On longitudinal logistic regression analysis, the time effect was evaluated on the components of Met.S [[Table 2]]. No significant time effect was seen during the study.
Table 2: Longitudinal logistic regression for evaluating treatment effect on covariates, taking metabolic syndrome as outcome
Discussion
We found that the normalization of PRL could reduce the rate of Met.S significantly and progressively during the treatment. However, we found no significant effect of treatment on metabolic parameters except TC, UA, and DBP in patients with prolactinoma.
There are limited epidemiological studies on the prevalence of Met.S in patients with HPL. However, the PRL multiple metabolic effects, leading to Met.S, are well documented in animal and human cell line studies.[[3]] Furthermore, several clinical studies have shown the metabolic benefit of HPL treatment, however their results may be not reliable and extensible because of their small sample size.[[10]],[[11]],[[12]]
This study showed the benefits of normalization of PRL on Met.S prevalence. There was a statistically significant decrease of Met.S at 3 months (P = 0.01), with a further decline at 6 months (P < 0.001) of cabergoline therapy. However, no significant relationship was found between the duration of treatment and better clinical outcome. Accordingly, the reduction of Met.S as the clinical outcome may be obtained even after 3 months after treatment [[Table 2]].
Nevertheless, our results showed no significant and optimal changes in most components of Met.S (WC, systolic blood pressure, FBS, and TG). However, these findings were probably due to small sample size of this study as well as short time of duration.
Pala et al. in 2015 suggested that patients with prolactinoma have adverse metabolic profile compared with matched controls. Normalization of PRL with cabergoline corrects the metabolic abnormalities significantly.[[13]]
It was believed that HPL may have induced weight gain as an important parameters in Met.S.[[7]],[[14]] However, in this study, BMI and WC have no significant correlation with PRL levels. Similar findings were reported by dos Santo Silva et al. in 2011.[[10]] They showed no significant decrease of BMI, insulin resistance (IR), Homeostasis Model Assessment, and lipid profile after treatment in patients with prolactinoma.[[10]] Indeed, several authors verified that normalization of PRL reduces weight only after a long follow-up of more than 1 year after treatment of the cases with prolactinoma.[[13]] Possibly, a longer period of treatment would be necessary to see any influence on body weight.
The mechanism by which HPL may cause weight gain is poorly understood. Because hypogonadism could be a possible pathological mechanism involved in weight gain in patients with prolactinoma,[[13]] we did not find whether it was a determinant factor for obesity in our population. Another explanation could be the reduction in dopaminergic tone.[[10]],[[15]] Schmid et al. demonstrated that an increase of hypothalamic pressure could be a possible mechanism of weight gain in patients with prolactinoma; however, there were no further confirmatory studies.[[16]]
Moreover, there was no significant reduction of fasting plasma glucose at baseline compared with after treatment. Many previous case–control studies have documented higher IR and abnormal glucose tolerance in patients with prolactinoma compared with healthy controls, implying that diabetogenic effect of HPL may be independent of gender and body weight.[[13]],[[17]]
Pala et al. in 2015 documented significant reduction of fasting plasma glucose after 3 months of cabergoline treatment with a further decline after 6 months of treatment.[[13]] Although some short-term studies involving treatment of HPL with DA up to 12 weeks did not reveal any changes in IR and blood glucose,[[11]] many studies have demonstrated significant improvement in IR after 6 months to 5 years of DA treatment.[[12]] However, these inconsistent results may be due to insufficient sample size due to rarity of the studied cases.
We also showed an improvement of lipid profile in patients after the treatment; TC decreased significantly after 6 months compared with baseline but significant variation was not considered among TG, LDL, and HDL. The association between HPL and hyperlipidemia has been documented as early as 1982 in a case–control study.[[18]] In a subsequent case–control study, low HDL-cholesterol has been documented though there was no difference in serum TG and LDL-cholesterol.[[19]] The direct effect of PRL on plasma lipids is difficult to establish because many factors that influence lipid metabolism are altered during HPL.[[19]] In addition, improvement in lipid parameters has also been shown with higher doses of cabergoline and/or longer follow-up duration.[[20]] Therefore, limited cabergoline dose (up to 3 mg weekly) could be suggested as a confounding factor in our study.
Another valuable finding in this study was no significant relationship between the treatment duration and improvement of metabolic parameters. There are many studies investigating the effect of treatment duration on some metabolic parameters, for instance, BMI, IR, or lipid profile. However, there are few and limited studies examining the effect of treatment duration on Met.S. dos Santos Silva et al. have shown that a significant reduction in some metabolic parameters was seen more than 6 months after achieving normoprolactinemia.[[10]] In contrast, some studies have shown that the improvement in metabolic parameters can be as early as 2 months after normoprolactinemia.[[13]],[[14]] Nevertheless, Ciresi et al., in 2013, suggested that there was no association between PRL levels and metabolic parameters either at baseline or after 12 months of treatment.[[20]]
It seems that further studies with a larger cohort and longer duration of follow-up are required, perhaps including long-term cardiovascular outcomes as well.
Two important limitations of the present study include small sample size and short follow-up. This study was a prospective, longitudinal study, performed during 6 months, with small sample size; therefore, its accuracy was low. Further studies with a larger cohort and longer duration of follow-up are required, perhaps including long-term cardiovascular outcomes as well.
This was the first study that investigated the effect of treatment duration on metabolism due to normalization of PRL with DA agonist in prolacinoma.
Conclusions
The current study demonstrated that there is no significant effect of treatment on improving some of the metabolic parameters. We demonstrated a significant reduction in the rate of Met.S during 3 and 6 months after DA agonist therapy. We suggest that it is important to consider the metabolic profile of patients with prolactinoma, indicating important causes for treating HPL. However, no significant relationship was found between the duration of treatment and better clinical outcome (Met.S as outcome). Accordingly, patients may benefit even after 3 months after treatment.
Authors' contributions
All authors contributed to the conception and conduct of the study and to drafting and revision of the manuscript. They all reviewed and approved the final version of the article.
Compliance with ethical principles
The Institutional Ethics Committee of Iran University of Medical Science approved the study, and informed consent was obtained from all patients.
