Growth hormone receptor exon 3 isoforms may have no importance in the clinical setting of multiethnic Brazilian acromegaly patients.

BACKGROUND: Acromegaly is associated with significant morbidity and increased mortality, but has a variable severity phenotype. The presence of the exon 3-deleted isoform of the growth hormone receptor (d3-GHR) may influence the disease phenotype and treatment outcomes, including the frequency of biochemical discordance after medical treatment. AIMS: The objective of this study was to analyze the influence of the d3-GHR isoform on clinical and biochemical characteristics and in the treatment outcomes of Brazilian multiethnic acromegaly patients. METHODS: We retrospectively analyzed our acromegaly outpatient clinic databank and collected demographic, clinical, biochemical and treatment outcome data from those patients who agreed to participate in the study. A blood sample was collected from all patients, the DNA was extracted and the GHR isoforms were evaluated by PCR, with the full length (fl)-GHR represented by a 935-bp fragment and the d3-GHR represented by a 532-bp fragment. RESULTS: A total of 121 patients were included. Fifty-six patients (46.3 %) were full-length homozygous (fl/fl), 48 (39.7 %) were heterozygous (fl/d3) and 17 (14.0 %) were d3-GHR homozygous (d3/d3). There was no difference between patients homozygous for the fl isoform and those harboring at least one d3-GHR allele in the demographic, clinical and biochemical data or in the treatment outcomes, including somatostatin receptor ligands (SRL) monotherapy, combination therapy with SRL and cabergoline and pegvisomant treatment. There was also no difference between the groups for the frequency of GH and IGF-I discordance after medical treatment. CONCLUSION: GHR exon 3 genotyping appears to have no clinical significance, at least in Brazilian acromegaly patients.

Impact of gsp oncogene on the mRNA content for somatostatin and dopamine receptors in human somatotropinomas.

INTRODUCTION: It has been reported in some series that gsp+ somatotropinomas are more sensitive to somatostatin analogues (SA) and dopamine's actions which may be related to their somatostatin receptor (SSTR) and dopamine receptor (DR) profile. No previous studies have been undertaken to evaluate the SSTR and DR profile related with the gsp status in somatotropinomas. OBJECTIVES: To determine if (1) gsp status is correlated with response to octreotide LAR (LAR) and tumor expression patterns of SSTR1-5 and DR1-5 and (2) cAMP level can directly modulate SSTR and DR mRNA levels. METHODS: Response to SA was evaluated by GH and IGF-I percent reduction after 3 and 6 months of treatment with LAR. Conventional PCR and sequencing were used to identify gsp+ tumors. Quantitative real-time PCR was used to determine SSTR and DR tumor expression. Primary pituitary cell cultures of primates were used to study whether SSTR and DR expression is regulated by forskolin. RESULTS: The response to LAR did not significantly differ between patients with gsp+ and gsp- tumors; however, gsp+ tumors expressed higher levels of SSTR1, SSTR2, DR2 and a lower level of SSTR3. Forskolin increased SSTR1, SSTR2, DR1 and DR2 expression in cell cultures. CONCLUSION: Elevated SSTR1, SSTR2, and DR2 tumor expression may help improve responsiveness to SA and DA therapy; however, this study may not have been appropriately powered to observe significant effects in the clinical response. Elevated cAMP levels could be directly responsible for the upregulation in SSTR1, SSTR2 and DR2 mRNA levels observed in gsp+ patients.

Two hour mean GH is not superior to basal GH for the follow-up of acromegalic patients treated with Octreotide LAR.

BACKGROUND: GH secretion, in acromegaly, is characterized by increased basal levels, as well as by increased frequency and amplitude of pulses. Evaluation of disease activity during follow-up of treated patients is frequently done with mean GH levels, although there is no established protocol for sample collection. OBJECTIVE: Determine mean GH value of 5 blood samples collected 30 min apart for 2 consecutive hours in the follow-up of acromegalic patients treated with octreotide LAR. METHODS: Ninety-one GH curves of 44 patients (25 women) were evaluated as were the respective IGF-I values (basal). Normal IGF-I for age and sex was considered standard for control of disease activity. Correlations between basal and mean GH were studied as were correlations between both values and %IGF-I above the upper limit of reference values (%ULRV). RESULTS: Median age of the group was 45.5 years (range 28-73). Twenty-five patients (56.8%) had previous surgery and 7 (15.9%) had both surgery and radiotherapy. A positive correlation was found between mean and basal GH (r=0.953; p<0.001). Both basal and mean GH were correlated to %ULRV (r=0.645 and 0.661; p<0.001 for both). In only 3 of the 91 curves (3.3%) there were discordances between basal GH and IGF-I, however the latter was concordant with mean GH. In 3 other curves there was concordance between basal GH and IGF-I although the latter was discordant with mean GH. CONCLUSIONS: There was no benefit to perform GH curves with the present protocol. It may be due to our established outpatient follow up protocol. The use of more complex protocols and the cost of multiple GH assays should be acknowledged, and probably reserved for patients with basal GH levels between 1 and 5 microg/L with discordant GH and IGF-I.