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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References

Hyperprolactinemia might be related to weight gain, metabolic syndrome (MS), and insulin resistance (IR). Treatment with dopamine agonist (DA) has been shown to reduce body weight and improve metabolic parameters. The objectives of this study were to determine the prevalence of obesity, overweight, MS, and IR in patients with prolactinoma before and after therapy with DA and to evaluate the relation between prolactin (PRL), body weight, fat distribution, leptin levels, IR, and lipid profile before treatment. In addition, we investigated the correlation of the reduction in PRL levels with weight loss and metabolic profile improvement. Twenty-two patients with prolactinoma completed 6 months of treatment with DA. These patients were submitted to clinical (BMI, waist circumference, blood pressure (BP)), laboratory evaluation (leptin, glucose, low-density lipoprotein (LDL)-cholesterol, and triglyceride (TG) levels) and abdominal computed tomography (CT) before and after treatment. The statistical analyses were done by nonparametric tests. At the beginning of the study, the prevalence of obesity, overweight, MS, and IR was 45, 27, 27, and 18%, respectively. After 6 months of treatment with DA, PRL levels normalized, but no significant difference in BMI was observed. However, there was a significant decrease on homeostasis model assessment of insulin resistance (HOMAIR) index, glucose, LDL-cholesterol, and TG levels. This study suggests a possible involvement of prolactinoma on the prevalence of obesity. We should consider that DA may be effective on improving metabolic parameters, and we speculate that a period longer than 6 months of treatment is necessary to conclude whether this drug can interfere in the body weight of patients with prolactinoma.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References

The prevalence of obesity 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 obesity, like Cushing syndrome, hypothyroidism, hypogonadism, and growth hormone (GH) deficiency (2). Prolactinoma has been recently associated to obesity (3,4,5,6) and its complications such as metabolic syndrome (MS) and insulin resistance (IR) (6,7).

Several reports described higher body weight in humans, especially in men with macroprolactinoma (3,4,5,6), and in animals with hyperprolactinemia (8,9); however, the mechanisms underlying this association are poorly understood. Some authors suggest that weight loss in humans occurs after complete or near normalization of serum prolactin (PRL) with dopamine agonists (DAs) (3,5,10). In contrast, animals' studies revealed no effect on weight and body fat distribution with changes in PRL levels (11,12).

The possible physiopathological mechanisms involved in weight gain in patients with hyperprolactinemia are as follows: (i) reduction in dopaminergic tone (5,13,14); (ii) leptin resistance (5,15,16); (iii) decreased adiponectin levels (17); (iv) increased hypothalamic pressure; (18) and (v) hypogonadism (19).

Additionally, the role of PRL in glucose metabolism of patients with prolactinoma is unclear. Studies in humans have linked hyperprolactinemia to glucose intolerance and hyperinsulinemia (20). The hypotheses are the involvement of PRL on islet β-cell growth, development, and differentiation, and on insulin production/secretion (20,21). Moreover, PRL can regulate the production/secretion of adiponectin (18) and cause changes in insulin metabolism (20).

The PRL action on lipid metabolism is also not well established. PRL may have a direct effect on adipose tissue. Ling et al. (22) demonstrated an effect of PRL in reducing the lipoprotein lipase activity in human adipose tissue with consequent increase in triglyceride (TG) levels.

The purpose of this study was to determine the prevalence of obesity/overweight, MS, and IR before and after treatment of patients with prolactinoma with bromocriptine (BRC) or cabergoline (CAB), and to evaluate the relationship between PRL and body weight, fat distribution, leptin levels, IR, and lipid profile before treatment. We also investigated whether PRL reduction is correlated to weight loss and improvement in the metabolic profile.

Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References

Study population

The study group consisted of patients with prolactinoma recruited from the outpatient endocrinology clinic of the Hospital Universitário Clementino Fraga Filho (HUCFF), Universidade Federal do Rio de Janeiro, over 1 year (April 2007–March 2008). This study was approved by the Ethics Committee of HUCFF, and all subjects entered the study after written informed consent. Inclusion criteria were patients with prolactinoma, without use of DA in the last 6 months, and no history of pituitary surgery or radiotherapy. The diagnosis of prolactinoma was based on the following: (i) symptoms and signs of hyperprolactinemia for >6 months; (ii) serum PRL levels ≥40 ng/ml; (iii) magnetic resonance imaging or computed tomography (CT) demonstrating pituitary adenoma. The patients were also evaluated according to gonadal function to verify whether hypogonadism was involved in the pathogenesis of obesity/overweight.

Reasons for ineligibility were postmenopausal period, acute or chronic diseases, and use of drugs that could increase PRL levels (including neuroleptics, antidepressants, opiates, cocaine, gastrointestinal prokinetics, and estrogens), pregnancy, lactation, alcohol abuse, and smoking, untreated endocrinopathies (e.g., hypothyroidism or hyperthyroidism, secondary adrenal insufficiency), use of drugs that could influence the prevalence of obesity/overweight (amphetamine, sibutramine, orlistat). Patients with GH deficiency, polycystic ovary syndrome, and those submitted to bariatric surgery were excluded, as well as patients weighing >150 kg (maximum limit of CT equipment to evaluated abdominal fat measurements).

Clinical parameters

The following clinical parameters were evaluated before and after 3 and 6 months of BRC or CAB therapy:

1. Manifestations of hyperprolactinemia (galactorrhea and/or hypogonadism, that was characterized by amenorrhea for >3 months in women and sexual dysfunction/low levels of testosterone in men);

2. BMI (weight (kg) divided by height squared (m2)). Obesity was defined as BMI ≥30 kg/m2 and overweight as BMI ≥25 and <30 kg/m2 (23);

3. Waist circumference in centimeters (measured in the orthostatic position, using fiberglass tape, during expiration, midway between the lower lateral costal margin and the iliac crest);

4. Blood pressure (BP) in mm Hg. Hypertension was defined as systolic BP >130 mm Hg and/or diastolic BP >85 mm Hg) (24).

Hormone assays

Blood samples were collected in the morning after a 12-h fasting period at baseline and after 3 and 6 months of treatment.

Serum PRL levels were measured by chemiluminescent assay (Immulite 2000; Diagnostic Products, Los Angeles, CA), with a sensitivity of 0.16 ng/ml. The intra- and interassay coefficients of variation were 2.3 and 5.9%, respectively. Reference values were 1.9–25 and 2.0–17.7 ng/ml for women and men, respectively.

Serum leptin levels were measured by radioimmunoassay (Diagnostic Systems Laboratories, Webster, TX). The intra- and interassay coefficient of variation values were 2.6 and 4.9%, respectively. Reference values for normal weight were up to 59 ng/ml (women) and 14 ng/ml (men), and for overweight/obesity were 88 ng/ml (women) and 30 ng/ml (men).

Serum insulin levels were measured by chemiluminescent assay (Modular Analytics e170; Roche Diagnostics, Mannheim, Germany). The sensitivity of the method was 0.2 mcIU/ml. The intra- and interassay coefficients of variation were 1.9 and 2.6%, respectively. Reference values were 3.0–16 mcIU/ml. The crossreactivity with proinsulin and insulin-like growth factor type I were 0.05 and 0.04%, respectively.

Cortisol, thyrotropin-stimulating hormone (TSH), free T4 (thyroxine), GH and insulin-like growth factor type I, luteinizing hormone, follicle-stimulating hormone, estradiol, and total testosterone were performed using commercial chemiluminescent assays (Immulite 2000).

Plasma glucose was measured by a hexokinase method (Dimension; Dade Behring, Newark, DE). Total cholesterol, high-density lipoprotein-cholesterol, and TG were determined using automatic standard routine enzymatic methods. Low-density lipoprotein (LDL)-cholesterol was calculated by the Friedewald formula.

Patients with macroprolactinoma and a serum 8 am cortisol below 10 mcg/dl and/or normal insulin-like growth factor type I levels for age were submitted to an insulin tolerance test in order to identify secondary adrenal insufficiency and/or GH deficiency. These conditions were diagnosed whether cortisol level was below 18 mcg/dl or GH level was below 3 ng/ml, respectively, after hypoglycemia stimuli (<40 mg/dl). Patients with low insulin-like growth factor type I levels were considered to be GH deficient and excluded without the need of performing insulin tolerance test.

Definition of MS

According to the International Diabetes Federation, patients were considered to have MS if they presented with central obesity, defined as waist circumference ≥90 cm for men and ≥80 cm for women, plus any two of the following four factors: fasting plasma glucose ≥100 mg/dl or previously diagnosed type 2 diabetes mellitus; systolic BP ≥130 or diastolic BP ≥85 mm Hg, or treatment of previously diagnosed hypertension; high-density lipoprotein-cholesterol <40 mg/dl in males and <50 mg/dl in females, or specific treatment for this lipid abnormality; TG ≥150 mg/dl, or specific treatment for it (25).

IR

IR was estimated according to the homeostasis model assessment of insulin resistance (HOMAIR) index, as the product of fasting glucose (mmol/l) and insulin (mcIU/ml) divided by a constant 22.5. IR status was defined as a HOMAIR index >2.7 (26).

Abdominal fat measurements by CT

All CT images were obtained by Sensation equipment with a 1 mm slice before and after 6 months of therapy with DA. The fat volume was determined at the level of the L4-L5. Subcutaneous fat volume (SFV) was defined as the extraperitoneal fat between skin and muscle, with attenuation value ranging from −30 to −190 Hounsfield units. Visceral fat volume (VFV) was considered to be the intraperitoneal area with the same density as the subcutaneous fat layer. The VFV and SFV were determined by automatic planimetry. Visceral abdominal fat volume >100 cm3 was associated with increased metabolic complications (27).

Statistical analysis

Descriptive statistics were presented as median (minimum-maximum). Comparisons between the patients with and without hypogonadism were done by Mann-Whitney's test. Comparisons between variables before and after treatment were done by Wilcoxon test or by Fisher's exact test. The Spearman rank correlation coefficient (rs) was used to evaluate the relationship between PRL levels and body weight, BMI, SFV, VFV, leptin levels, HOMAIR index, and lipid profile, before and after treatment. Statistical analysis was performed with SPSS 13.0 for Windows (SPSS, Chicago, IL). P values <0.05 were considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References

Of the 35 patients (30 females, median age 34 ranging from 20 to 70 years old) initially enrolled, 22 completed 6 months of treatment. Twelve had used DA previously, but the drug was interrupted at least 6 months before entering the study. All patients, including the two diabetics, were advised not to change lifestyle (diet and physical activity). The treatment of diabetes mellitus was not modified during the study.

The beginning of signs and symptoms of hyperprolactinemia was <5 years in 51%, between 5 and 10 years in 40%, and >10 years in 9%. Both galactorrhea and hypogonadism were found in 74% patients.

During the study, 10 patients were excluded because they discontinued the use of DA, two became pregnant, and one was submitted to transsphenoidal surgery because she had a macroprolactinoma resistant to DA. The prevalence of obesity and overweight in these patients were 54 and 8%, respectively. MS was found in 23% of the patients and the prevalence of IR was 31%. Moreover, no difference in the median BMI, HOMAIR index, glucose, and lipid profile was found between these patients and those who completed 6 months of treatment.

Characterization of the study population before treatment with DAs

The main characteristics of the study population (22 patients) before and after treatment are presented in Table 1.

Table 1.  Metabolic characteristic of patients with prolactinoma before and after treatment with dopamine agonists
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The median PRL levels was 149 ng/ml (49–732 ng/ml). Eighteen percent of the patients had macroprolactinoma and the maximum tumor diameter was 2.1 cm, with no evidence of pressure on the floor of third ventricle. One patient with macroprolactinoma had corticotrophin deficiency and was receiving adequate glucocorticoid replacement. Two patients had GH deficiency and were excluded.

The median BMI and leptin levels were 29.5 kg/m2 (18.6–44.2 kg/m2) and 15.2 ng/ml (1.7–85 ng/ml), respectively. The prevalence of obesity and overweight were 45 and 27%, respectively. MS was found in 27% of the patients and the prevalence of IR was 18%. VFV higher than 100 cm3 was observed in 33% of the patients.

No correlation was found between serum PRL levels and BMI, SFV, VFV, leptin, insulin, HOMAIR index, or lipid profile. As expected, positive correlation was found between BMI and leptin (P = 0.028) and leptin and SFV (P = 0.003).

PRL levels were higher in the hypogonadic group than in the eugonadics (P = 0.002). However, the median BMI, SFV, VFV, leptin, insulin, HOMAIR index, or lipid profile was not different between these two groups.

PRL levels normalized in 17 patients after the first 3 months of treatment. There was no difference on PRL levels between 3 or 6 months of DA use (Figure 1). Therefore, only the 6 months' results were used for the statistical analysis.

image

Figure 1. Prolactin levels in patients with prolactinoma before and after treatment with dopamine agonists.

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Characterization of the study population after 6 months of treatment with DAs

Twenty-two patients (17 females, median age 38 ranging from 23 to 70 years old) used DA regularly for 6 months. Of this group, 19 patients used CAB and three BRC; four patients reported side effects that disappeared within the first few weeks of therapy. Signs and symptoms of hyperprolactinemia resolved in the majority of patients. Galactorrhea persisted in 2/22 patients and hypogonadism in 3/22 patients.

The median PRL levels were 12.4 ng/ml (1.7–133 ng/ml). Five patients had PRL levels above the reference levels, which ranged between 28 and 113 ng/ml (Figure 1). BMI was not significantly different between the group that normalized or not PRL levels (P = 0.86).

The median BMI and leptin levels were 28 kg/m2 (18.9–38.5 kg/m2) and 12.15 ng/ml (1.2–82.5 ng/ml). Considering weight variation, 10 out of 22 patients lost <3 kg, one woman lost 6 kg, and a man lost 4 kg; six patients remained with stable weight and six patients gained <2 kg, one of these patients (woman) gained 15 kg (Figure 2). Nonetheless, the prevalence of obesity and overweight in the follow-up period were 41 and 41%, respectively. Patients with extreme weight variation were not excluded from the final statistical analysis because the differences persisted in the same parameters as compared to the whole group.

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Figure 2. The weight variation in patients with prolactinoma after treatment with dopamine agonists.

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No significant change in body weight occurred when the patients were divided in microprolactinomas or macroprolactinomas. Gonadal function was not associated with weight variation. Table 2 shows the results from hypogonadal and eugonadal patients.

Table 2.  Metabolic characteristic of patients according to gonadal function after treatment with dopamine agonists
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The prevalence of MS was 14%. The prevalence of IR was also 14%. VFV higher than 100 cm3 was observed in 28% of the patients. The reduction in both VFV and SFV achieved borderline statistical significance (P = 0.098; P = 0.088, respectively).

As shown in Table 1, there was a significant decrease in glucose levels (P = 0.014), HOMAIR index (P = 0.033), plasma TG (P = 0.012), and LDL-cholesterol (P = 0.002) levels. Changes in PRL levels did not correlate with any of these parameters.

When the two patients with diabetes mellitus were excluded from the statistical analysis, the decrease in glucose (P = 0.009), LDL-cholesterol (P = 0.009), and TG levels (P = 0.005) persisted. Furthermore, when patients treated with BRC (n = 3) were excluded from the analysis, the decrease in glucose (P = 0.012), LDL-cholesterol (P = 0.006), and TG levels (P = 0.033) also persisted.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References

We found a greater prevalence of obesity/overweight in patients with prolactinoma when compared to the normal general population (28). According to the Brazilian Institute of Geography and Statistics, the prevalence of obesity and overweight in females is 13.8 and 40.7%, respectively, and in males is 10 and 44.4%, respectively (28). In fact, studies in humans have shown that patients with prolactinoma and hyperprolactinemia may have weight gain (3,4,5,6,7). However, in this study, BMI did not correlate positively to PRL levels.

The mechanism by which hyperprolactinemia may cause weight gain is poorly understood. Because hypogonadism could be a possible pathological mechanism involved in weight gain in patients with prolactinoma (19), we investigated whether it was a determinant factor for obesity in our population. Although patients with hypogonadism had higher median PRL levels than the eugonadic group, we did not find statistical difference between median BMI, VFV, SFV, leptin, insulin, HOMAIR, or lipid profile between these groups.

Another explanation could be the reduction in dopaminergic tone. In our patients, however, there was no change on BMI, even after 6 months of treatment with DA and normalization of PRL levels. In contrast, several authors verified weight loss with the use of this class of drug (5,29). Doknic et al. (5) observed changes in BMI even after only 6 months of treatment with DA. However, another study demonstrated weight loss only after 1 year of treatment (29). Possibly, a longer period of treatment would be necessary to see any influence on body weight. Moreover, another possible reason to the lack of effect on weight in this study compared to the loss of weight in prior studies (5,29) was maybe the difference in the drug used (CAB in 19 and BRC in only three patients).

We found that leptin levels were compatible with their high body weight. In humans, leptin levels are influenced by the amount of body fat, being higher in obese individuals (30). We did not observe correlation of PRL with leptin levels neither a decrease in leptin levels during the follow-up.

Schmid et al. (18) demonstrated that an increase of hypothalamic pressure could be a possible mechanism of weight gain in patients with prolactinoma; however, there was no evidence of pressure on the floor of third ventricle in our patients.

Although adiponectin can be related with weight gain in prolactinoma (18), we did not evaluate adiponectin levels in our patients.

Prolactinoma seems to be associated with metabolic abnormalities characterized by IR and hyperlipidemia (31). In this series, the prevalence of MS was similar to other populations (32,33). To confirm this finding, it would be necessary to establish our own data based on local population studies, given that the prevalence of MS varies in all series according to age, sex, weight, and ethnic groups (32,33). Moreover, the prevalence of IR is also similar to that described in the Brazilian population (34,35).

As previously demonstrated (36,37,38), it was evident in our group that the use of DA decreased glucose levels, improved the lipid profile (LDL-cholesterol and TG) and the insulin sensitivity. Because our patients did not present significant changes in body weight, body composition, or regional fat distribution, other mechanisms are possibly involved in the beneficial effects of DA on metabolic profile. The potential mechanisms by which DA could improve glucose metabolism include the following: enhanced suppression of endogenous glucose product, increased splanchnic glucose uptake after glucose ingestion and/or a central action in the hypothalamus (37). These effects were shown in obese type 2 diabetic patients that used quick-release BRC (37,38). In our patients, the improvement in glucose metabolism persisted even after excluding patients that used BRC. Therefore, it is possible that CAB also leads similar outcome on glucose metabolism.

Furthermore, DA can cause modification in TG and LDL-cholesterol levels via its simultaneous antilipogenic action in the liver tissue and antilipolytic action in the adipose tissue (39). Another possible reason for the decrease of glucose, LDL-cholesterol, and TG could be the use of antidiabetic drugs (40). However, after excluding two patients with diabetes mellitus, the changes in these parameters persisted.

This study suggests a possible association of prolactinoma with increased BMI, without the involvement of hypogonadism or serum leptin levels. Additionally, we should consider that DA may be effective in improving metabolic parameters in these patients and we wonder whether the use of this class of drug for >6 months could cause a significant reduction in body weight.

ACKNOWLEDGEMENT

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References