The Basic And Clinical Research Of Acromegalic Patients With Hyperprolactinemia

ObjectiveAcromegaly is a rare disease characterized by excess secretion of growth hormone (GH) and increased circulating concentrations of insulin-like growth factor-1(IGF-1). It is characterized by slowly progressive acquired somatic disfigurement (mainly involving face and extremities) and systemic manifestations. The disease is associated with increased morbidity and premature mortality, due to cardiovascular, cerebrovascular, or respiratory causes. In general, the underlying abnormality in most cases is hypersecretion of GH by the pituitary GH-producing tumors. Nonetheless, about16-27%of these patients have increased GH and prolactin (PRL) levels. Therefore, the characteristics of acromegaly with increased growth hormone (GH) and hyperprolactinemia in patients were not clearly established, probably due to the relatively low annual incidence. The aim of this study is to evaluate clinical data from a large cohort of acromegalic patients with and without hyperprolactinemia.Design and methodsPart1. patients and their characteristics before surgeryA retrospective chart review was performed on all patients with GH producing adenomas treated between January2002and June2010at the Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan. A total of279patients had a complete set of data before and one year after surgery. Magnetic resonance imaging (MRI) examinations were done in all patients. Based on the preoperative GH and PRL levels, patients were classified as follows:GH group (acromegalic patients with elevated GH levels), GH+PRL group (acromegalic patients with both elevated GH and prolactin levels) and PRL group (patients with prolactinoma). GH and PRL levels were assessed before surgery and3days and12months after surgery respectively. A stabilization or a further improvement of postoperative changes in clinical, hormonal, immunohistochemical and magnetic resonance imaging (MRI) parameters was observed in all patients throughout the follow-up period.Part2. immunohistochemistry examinationAll specimens were fixed in10%formalin, embedded in paraffin and stained by the haematoxylin-eosin method. All the resected tissues were examined by immunohistochemistry with antibodies against GH and PRL.ResultsPart1. Clinical features before surgeryIn GH group,50.5%of the patients were male; the mean age at diagnosis was45.6±13.9years (range,11.4-75.2years). The mean time interval from the onset of acromegaly-specific symptoms and signs to the date of diagnosis was66.0±65.3months (range,0.5-324months). The mean maximal diameter of adenomas was2.2±0.9cm (range,0.6-4.2cm). In GH+PRL group,42.3%of the patients were male; the mean age at diagnosis, the mean time interval and the mean maximal diameter of adenomas were40.4±11.4years (range,20.1-72.6years),52.8±49.4months (range,1.0-240months) and2.6±1.1cm (range,0.5-5.8cm) respectively. The mean age at diagnosis and mean maximal diameter of adenomas were significantly different between the two groups (P=0.001and P=0.004, respectively), but gender and the mean time interval had no significant differences. The most common presenting clinical manifestations and complications encountered in the two groups (GH group vs. GH+PRL group) were coarse facial features (75.4%vs.54.3%), large hands and feet (73.8%vs.58.6%), headache (38.5%vs.41.9%), dizziness (10.0%vs.10.1%), nausea and vomiting (4.6%vs.3.9%), fatigue (3.8%vs.3.9%), distension and numbness (3.8%vs.1.6%), hypertension (10.0%vs.3.9%), diabetes mellitus (17.7%vs.6.9%) and those of pituitary endocrinological disturbances:polyuria and polydipsia (16.2%vs.5.4%), hyposexuality (4.6%vs.10.9%), and in females, menstrual disorder (13.8%vs.54.3%) and galactorrhea (3.1%vs.22.4%). No significant differences were observed in headache (P=0.613), dizziness (P=1.0), nausea and vomiting (P=1.0), hyposexuality (P=0.066), distension and numbness (P=0.447), fatigue (P=1.0) and hypertension (P=0.085). But there were significant differences between the two groups:coarse facial features (P=0.013), polyuria and polydipsia (P=0.008), large hands and feet (P<0.001), menstrual disorder (P<0.001), galactorrhea (P<0.001) and diabetes mellitus (P=0.013). So, data indicated that there were higher incidences of coarse facial features, polyuria and polydipsia, large hands and feet and diabetes mellitus in GH group patients, but the incidences of menstrual disorder and galactorrhea in female patients were especially lower than that of GH+PRL group.Part2. Comparison of hormone levelsThe levels of GH and PRL in GH group before surgery were42.35±30.48ng/ml and15.21±12.26ng/ml, while those in GH+PRL group were23.43±15.78ng/ml and131.29±76.62ng/ml respectively. Therefore, the GH level of GH group was significantly higher than that of GH+PRL group (P<0.001), whereas the PRL was extremely lower (P<0.001). The GH and PRL levels of the two groups decreased obviously after surgery, except the PRL of GH group. The GH levels of GH group were20.37±18.31ng/ml at3days,19.26±18.22ng/ml at3months and23.87±20.01ng/ml at12months after the operation, and there were no significant differences with each other (P=0.526). In GH+PRL group, the postoperative levels of GH at the three time points were13.61±10.86ng/ml,13.22±11.52ng/ml and14.84±11.62ng/ml respectively, while those of PRL were32.96±15.91ng/ml, 31.82±17.63ng/ml and33.44±15.38ng/ml respectively. Also, both the postoperative GH and PRL levels in GH+PRL group had no significant differences with each other (P=0.584and P=0.778, respectively). However, there were significant differences when the postoperative levels of GH or PRL were compared between two groups. Moreover, except the PRL of GH group, there were also significant differences when pre-and postoperative levels of GH or PRL were compared (P<0.01,P<0.01and P<0.01,respectively). The preoperative PRL level was169.2±92.0ng/ml, and the postoperative PRL levels were45.4±30.5ng/ml at3days and42.9±34.8ng/ml at12months.Part3. Immunohistochemistry evaluationIt showed that the positive rates of GH and PRL in GH group were91.2%and30.7%, and those results of GH+PRL group were84.5%and86.6%respectively. So, significant difference was observed between the PRL positive rates of the two groups (P<0.05), whereas GH, as expected, did not (P=0.11). Moreover, there is no significant correlation between the preoperative mean GH or PRL concentrations and the immunostaining positive rates (r=+0.348, P>0.05and r=+0.457, P>0.05, respectively).Part4. MRI findingsThe proportion of preoperative meso-and macro-adenoma of GH+PRL group was significantly higher than that of GH group (60.4%vs.45.1%, P=0.041). According to the MRI findings at3-month after surgery, the overall resection rate of GH+PRL group was distinctly lower than that of GH group (69.1%vs.80.7%, P=0.037).Part5. recurrence rateHormone and MRI examinations were performed on all patients12-month after surgery. By analyzing these data, we found the recurrence rates of GH and GH+PRL group were7.1%and11.3%, and no significant difference was observed between the two groups (P=0.185).Conclusions 1. Compared to patients with merely GH-secreting adenomas, acromegalic patients with hyperprolactinemia are characterized by an earlier onset of disease, lesser acromegalic features, lower GH levels, but larger tumor sizes, whereas in female patients, GH-prolactin secreting adenomas are associated with higher incidences of menstrual disorders and galactorrhea.2. Compared to patients with merely GH-secreting adenomas, acromegalic patients with hyperprolactinemia have lower GH but higher PRL levels and higher PRL but normal GH positive rates. Moreover, no significant correlations between the preoperative mean GH or PRL concentrations and the immunostaining positive rates were observed.3. Compared to patients with merely GH-secreting adenomas, the resection rate is lower in acromegalic patients with hyperprolactinemia, but there is no significant differences in recurrence rate between these patients.