GH-secreting Pituitary Adenomas Research Articles

The role of stereotactic radiosurgery in the multimodal management of growth hormone–secreting pituitary adenomas

Growth hormone (GH)-secreting pituitary adenomas represent a common source of GH excess in patients with acromegaly. Whereas surgical extirpation of the culprit lesion is considered first-line treatment, as many as 19% of patients develop recurrent symptoms due to regrowth of previously resected adenomatous tissue or to continued growth of the surgically inaccessible tumor. Although medical therapies that suppress GH production can be effective in the management of primary and recurrent acromegaly, these therapies are not curative, and lifelong treatment is required for hormonal control. Stereotactic radiosurgery has emerged as an effective adjunctive treatment modality, and is an appealing alternative to conventional fractionated radiation therapy. The authors reviewed the growing body of literature concerning the role of radiosurgical procedures in the treatment armamentarium of acromegaly, and identified more than 1350 patients across 45 case series. In this review, the authors report that radiosurgery offers true hormonal normalization in 17% to 82% of patients and tumor growth control in 37% to 100% of cases across all series, while minimizing adverse complications. As a result, stereotactic radiosurgery represents a safe and effective treatment option in the multimodal management of primary or recurrent acromegaly secondary to GH-secreting pituitary adenomas.

Acromegaly without Imaging Evidence of Pituitary Adenoma

GH-secreting pituitary adenomas are nearly always visible on conventional magnetic resonance (MR) imaging. However, management and outcome of acromegalic patients lacking imaging evidence of GH-secreting pituitary adenomas are undefined. The aim was to evaluate surgical exploration for MR-invisible GH-secreting pituitary adenomas. We conducted a retrospective review at two tertiary care centers. Consecutive acromegalic patients without imaging evidence of a pituitary adenoma on pre- and postcontrast, spin echo T1-weighted MR imaging and who lacked evidence of an ectopic (nonpituitary) source causing GH excess were included. Surgical exploration with identification and resection of a pituitary adenoma was performed. Laboratory values (GH, IGF-I), surgical findings, and clinical outcome were analyzed. Six patients (three males, three females; 3% of all patients) with suspected GH-secreting adenomas did not demonstrate imaging evidence of pituitary adenoma on conventional MR imaging. Three patients underwent a postcontrast, volumetric interpolated breath-hold examination MR-imaging sequence (1.2-mm slice thickness), which revealed a 4-mm pituitary adenoma not seen on the spin echo T1-weighted MR imaging in one patient. A pituitary adenoma was identified and removed in all patients (mean diameter, 5.6 mm; range, 5 to 6.7 mm). Histological analysis confirmed that the lesions were GH-secreting adenomas. All patients achieved biochemical remission after surgical resection. Acromegaly can be caused by GH-secreting pituitary adenomas that are not evident on conventional MR imaging. Adenomas in some of these patients become evident using volumetric interpolated breath-hold examination MR imaging. Surgical exploration of the pituitary gland in acromegalic patients with endocrine findings consistent with a GH-secreting adenoma but negative MR imaging can lead to identification and removal of an adenoma.

Pasireotide (SOM230) Demonstrates Efficacy and Safety in Patients with Acromegaly: A Randomized, Multicenter, Phase II Trial

Pasireotide (SOM230) is a novel multireceptor ligand somatostatin analog with affinity for somatostatin receptor subtypes sst(1-3) and sst(5). Because most GH-secreting pituitary adenomas express sst(2) and sst(5), pasireotide has the potential to be more effective than the sst(2)-preferential somatostatin analogs octreotide and lanreotide. Our objective was to evaluate the efficacy and safety of three different doses of pasireotide in patients with acromegaly. We conducted a phase II, randomized, multicenter, open-label, three-way, crossover study. Sixty patients with acromegaly, defined by a 2-h five-point mean GH level higher than 5 microg/liter, lack of suppression of GH to less than 1 microg/liter after oral glucose tolerance test, and elevated IGF-I for age- and sex-matched controls. Patients could have had previous surgery, radiotherapy, and/or medical therapy or no previous treatment. After treatment with octreotide 100 microg s.c. three times daily for 28 d, each patient received pasireotide 200, 400, and 600 microg s.c. twice daily in random order for 28 d. A biochemical response was defined as a reduction in GH to no more than 2.5 microg/liter and normalization of IGF-I to age- and sex-matched controls. After 4 wk of octreotide, 9% of patients achieved a biochemical response. After 4 wk of pasireotide 200-600 microg s.c. bid, 19% of patients achieved a biochemical response, which increased to 27% after 3 months of pasireotide; 39% of patients had a more than 20% reduction in pituitary tumor volume. Pasireotide was generally well tolerated. Pasireotide is a promising treatment for acromegaly. Larger studies of longer duration evaluating the efficacy and safety of pasireotide in patients with acromegaly are ongoing.

Absence of activating mutations of CXCR4 in pituitary tumours

Mutations of the gsp oncogene are responsible for 30-40% of GH-producing pituitary adenomas and 10% of nonfunctioning pituitary adenomas (NFPAs). However, the pathogenetic mechanism of the remaining pituitary tumours still remains to be identified. Recently, the interaction between the chemokine stromal cell-derived factor 1 and its receptor CXCR4 was found to play an important role in GH production and cell proliferation in various pituitary adenoma cell lines. As CXCR4 is a Gi-coupled chemokine receptor, its constitutive activating mutations may be involved in pituitary tumour formation by cyclic adenosine monophosphate (cAMP)-independent, ERK-related pathways. We investigated whether somatic activating-mutations of CXCR4 might be a possible tumourigenic mechanism for gsp-negative GH-secreting pituitary adenomas and NFPAs. Direct sequencing of polymerase chain reaction-amplified products for coding exons of CXCR4 were performed using genomic deoxyribonucleic acid samples from 37 GH-producing pituitary tumour tissues that were negative for the gsp mutation and 14 CXCR4 expressing NFPAs. Immunohistochemical analyses and double immunofluorescent staining of sectioned paraffin-embedded pituitary tissues revealed that CXCR4 is highly expressed in GH-producing pituitary adenomas and NFPAs. Direct sequencing showed that two synonymous mutations in exon 2 (87 C > T and 414 C > T) were detected in 4 out of 51 pituitary tumours. Our results indicate that an activating mutation of the CXCR4 may not be a common pathogenetic mechanism in GH-producing pituitary tumours and NFPAs.

The value of the oral glucose tolerance test, random serum growth hormone and mean growth hormone levels in assessing the postoperative outcome of patients with acromegaly

The nadir GH value following an oral glucose tolerance test (OGTT) and the mean GH levels obtained from a GH day curve (GHDC) are among the tools currently used for assessing therapeutic end-points in surgically treated acromegaly. The latter test, however, is cumbersome and costly. To evaluate, by using a modern, two-site chemiluminescent immunometric GH assay, the degree of discordance between the nadir GH following an OGTT and the mean GH obtained from a GHDC after surgical treatment of acromegaly and to check whether the OGTT can replace reliably the GHDC for the assessment of the disease status postoperatively. Forty-nine patients [25 males/24 females, median age 52 years (range 18-70)] with a GH-secreting pituitary adenoma who had been surgically treated previously underwent hormonal evaluation of their disease status. The GHDC comprised of 9 x 30-min samples for GH collected in the morning after an overnight fast and rest. Seven per cent of patients with mean GH <1.7 mug/l (5 mU/l) in the GHDC had nadir GH >0.7 mug/l (2 mU/l) in the OGTT, and 10% of those with mean GH >1.7 mug/l had nadir GH <0.7 mug/l in the OGTT (all cases with discrepancies had normal IGF-I). GH value at time 0 min <0.6 mug/l in the OGTT had positive predictive value 100% and negative predictive value 75% in predicting nadir GH <0.3 mug/l (1 mU/l) in the OGTT. Nadir GH <0.8 mug/l in the OGTT had positive predictive value 97% and negative predictive value 95% in predicting mean GH <1.7 mug/l in the GHDC. Mean GH in the OGTT <1.4 mug/l had a positive predictive value 90% and negative predictive value 95% in predicting mean GH <1.7 mug/l in the GHDC. Mean GH in the OGTT <2.5 mug/l had positive predictive value 100% and negative predictive value 81% in predicting normal IGF-I. GH at time 0 min in the GHDC <2.1 mug/l had positive predictive value 90% and negative predictive value 90% in predicting mean GH <1.7 mug/l in the GHDC. The hormonal data obtained from an OGTT (mean and nadir GH) can provide comprehensive information on the status of acromegaly following surgery and can replace the GHDC cost-effectively. Furthermore, a morning fasting GH sample has an excellent positive predictive value in predicting biochemical cure and an optimal prognostic profile in predicting "safe" mean GH levels.

Evolution of an Aggressive Prolactinoma into a Growth Hormone Secreting Pituitary Tumor Coincident with GNAS Gene Mutation

Mixed PRL- and GH-secreting pituitary adenomas are relatively common because somatotrophs and lactotrophs share the common somato-mammotroph progenitor lineage. Conversely, the occurrence of a prolactinoma evolving into clinically and biochemically active acromegaly is a rare phenomenon. We report a patient with a prolactinoma who after 15 yr of disease control by bromocriptine became resistant to dopaminergic drugs and due to the rapid tumor growth was submitted to four neurosurgeries and two stereotactic radiotherapies in the subsequent 5 yr. Unexpectedly, in the last 1.5 yr, after the fourth neurosurgery and second gamma-knife, she complained of signs and symptoms of acromegaly that was biochemically confirmed. Histological examination of the surgical specimens revealed high Ki67 and p53 and low D2 receptor expression. Although samples from the initial surgery were positive for prolactin and negative for GH, about 10% of GH-positive cells were detected in tissue from the last surgery, consistent with the observed clinical shift to acromegaly. Molecular screening failed to find mutations in RAS, TP53, and BRAF hot spots, whereas Arg201His mutation in GNAS gene (gsp oncogene), absent in the previous surgical materials, was detected in the tumor from the last surgery, which was found to be monoclonal. These observations suggest that 1)treatment of prolactinomas resistant to dopaminergic drugs is still a challenge, and 2) the appearance of gsp oncogene in a prolactinoma evolving into acromegaly might be the underlying mechanism of this rare transition, further confirming that this mutational change is associated with somatotroph growth and transformation.

Acromegaly pathogenesis and treatment

Dysregulated growth hormone (GH) hypersecretion is usually caused by a GH-secreting pituitary adenoma and leads to acromegaly - a disorder of disproportionate skeletal, tissue, and organ growth. High GH and IGF1 levels lead to comorbidities including arthritis, facial changes, prognathism, and glucose intolerance. If the condition is untreated, enhanced mortality due to cardiovascular, cerebrovascular, and pulmonary dysfunction is associated with a 30% decrease in life span. This Review discusses acromegaly pathogenesis and management options. The latter include surgery, radiation, and use of novel medications. Somatostatin receptor (SSTR) ligands inhibit GH release, control tumor growth, and attenuate peripheral GH action, while GH receptor antagonists block GH action and effectively lower IGF1 levels. Novel peptides, including SSTR ligands, exhibiting polyreceptor subtype affinities and chimeric dopaminergic-somatostatinergic properties are currently in clinical trials. Effective control of GH and IGF1 hypersecretion and ablation or stabilization of the pituitary tumor mass lead to improved comorbidities and lowering of mortality rates for this hormonal disorder.

Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro

The effect of mammalian target of rapamycin (mTOR) inhibitors on pituitary tumors is unknown. Akt overexpression was demonstrated in pituitary adenomas, which may render them sensitive to the anti-proliferative effects of these drugs. The objective of the study was to evaluate the anti-proliferative efficacy of the mTOR inhibitor, rapamycin, and its orally bioavailable analog RAD001 on the GH-secreting pituitary tumor GH3 and MtT/S cells and in human GH-secreting pituitary adenomas (GH-omas) in primary cell cultures. Treatment with rapamycin or RAD001 significantly decreased the number of viable cells and cell proliferation in a dose- and time-dependent manner. This was reflected by decreased phosphorylation levels of the downstream mTOR target p70S6K. Rapamycin treatment of GH3 cells induced G0/G1 cell cycle arrest. In other tumor cell types, this was attributed to a decrease in cyclin D1 levels. However, rapamycin did not affect cyclin D1 protein levels in GH3 cells. By contrast, it decreased cyclin D3 and p21/CIP, which stabilizes cyclin D/cyclin-dependent kinase 4 (cdk4) complexes. Rapamycin inhibited FCS-induced retinoblastoma phosphorylation and subsequent E2F-transcriptional activity. In response to decreased E2F activity, the expression of the E2F-regulated genes cyclin E and cdk2 was reduced. Our results showed that mTOR inhibitors potently inhibit pituitary cell proliferation, suggesting that mTOR inhibition may be a promising anti-proliferative therapy for pituitary adenomas. This therapeutic manipulation may have beneficial effects particularly for patients harboring invasive pituitary tumors resistant to current treatments.

Intra-sellar schwannoma co-existing with GH-secreting pituitary adenoma

We present a unique example of an intra-sellar schwannoma co-existing with a growth hormone (GH)-secreting pituitary adenoma. The patient presented with acromegaly and magnetic resonance imaging (MRI) revealed an intra-sellar mass. The tumour was totally resected via a sub-labial trans-sphenoidal approach. Histopathology demonstrated the presence of a GH-secreting adenoma as well as a schwannoma at the periphery of the adenoma. After surgical excision, remission of the acromegaly occurred. Follow-up monitoring showed no evidence of recurrence of the adenoma two years after surgery. To the best of our knowledge, this is the first example of an intra-sellar schwannoma co-existing with a GH-secreting pituitary adenoma.

Acromegaly Accompanied by Turner Syndrome with 47,XXX/45,X/46,XX Mosaicism

A 33-year-old woman was hospitalized for examination of edematous laryngopharynx. She was acromegalic. A pituitary adenoma with elevated serum levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I) was detected, indicating acromegaly caused by GH-secreting pituitary adenoma. Multiple pigmented nevi were also noted without overt short stature and cubitus valgus. Chromosome analysis revealed that she had contracted Turner syndrome with 47,XXX/45,X/46,XX mosaicism. Transsphenoidal resection of the tumor decreased serum GH and IGF-I levels, but the edema was not improved. Both premature ovarian failure and hypertension appeared after surgery. This case may indicate the important relationships between GH/IGF-I and Turner syndrome.

Surgical Results of Growth Hormone-Secreting Pituitary Adenoma

We retrospectively analyzed the surgical outcomes of 42 patients with growth hormone (GH)-secreting pituitary adenoma to evaluate the clinical manifestations and to determine which preoperative factors that significantly influence the remission. Forty-two patients with GH-secreting pituitary adenoma underwent transsphenoidal surgery (TSS) between 1995 and 2007. The patient group included 23 women and 19 men, with a mean age of 40.2 (range 13-61) years, and a mean follow-up duration of 49.4 (range 3-178) months after the operation. For comparable radiological criteria, we classified parasellar growth into five grades according to the Knosp classification. We analyzed the surgical results of the patients according to the most recent stringent criteria for cure. The overall rate of endocrinological remission in the group of 42 patients after primary TSS was 64% (26 of 42). The remission rate was 67% (8 of 12) for microadenoma and 60% (18 of 30) for macroadenoma. The remission rate was 30% (3 of 10) for the group with cavernous sinus invasion and 72% (23 of 32) for the group with intact cavernous sinus. Cavernous sinus invasion in Knosp grade III and IV was significantly correlated with the remission rate. There was a significant relationship between preoperative mean GH concentration and early postoperative outcome, with most patients in remission having a lower preoperative GH concentration. TSS is thought to be an effective primary treatment for GH-secreting pituitary adenomas according to the most recent criteria of cure. Because the remission rate in cases with cavernous sinus invasion is very low, early detection of the tumor before it extends into the cavernous sinus and a long-term endocrinological and radiological follow-up are necessary in order to improve the remission rate of acromegaly.

Activation of calcium and cAMP-signalling in GH-secreting pituitary adenomas

Activation of calcium and cAMP-signalling in GH-secreting pituitary adenomas

Long‐term basal and dynamic evaluation of hypothalamic–pituitary–adrenal (HPA) axis in acromegalic patients

Long-term effects of trans-naso-sphenoidal surgery (TNS) or long-acting somatostatin analogs (SSA) on the function of hypothalamic-pituitary-adrenal (HPA) axis have been poorly investigated. Aim of this study was to evaluate HPA axis integrity during the follow-up in patients with GH-secreting pituitary adenomas and preserved HPA function post-TNS or prior SSA. This retrospective study investigated 36 acromegalic patients (16M and 20F, age: 47 +/- 13 years), 20 of whom cured by TNS and 16 controlled by SSA therapy (12 previously operated and 4 in primary medical therapy), before and after long-term follow-up (median: 72 months, range: 12-240). No patient previously underwent radiotherapy. HPA function was studied by morning circulating cortisol and ACTH levels, 24-h urinary free cortisol (UFC) and cortisol response to low-dose short Synacthen test (LDSST, 1 microg) with a peak > 500 nmol/l as cut-off for normal function. Serum basal cortisol, ACTH and UFC levels were in the normal range and did not significantly change over time. As far as the cortisol peak after LDSST is concerned, 12 patients (32%, 8 TNS and 4 SSA) developed biochemical hypoadrenalism. None of the patients in primary medical therapy showed cortisol peak < 500 nmol/l. No significant correlations between HPA axis deterioration and follow-up duration, serum GH/IGF-I levels, occurrence of other pituitary deficiencies, presence of secondary empty sella, changes in tumour or residual volume were observed. The HPA axis function must be carefully monitored over the time by dynamic testing in all acromegalic patients, independently from the type of treatment.

Actualités thérapeutiques dans la prise en charge médicale des adénomes hypophysaires

Currently, the role of dopaminergic and somatostatinergic agonists in the treatment of pituitary adenomas is quite well established. Nevertheless, a clearer understanding of the expression of dopaminergic and somatostatinergic receptors at the cellular level of pituitary adenomas as well as the development of newer analogues compounds may drastically change current therapeutic modalities. In particular, the emphasis on the co-expression of different receptors types or subtypes in adenomatous cells highlights functional interactions between receptors leading to an increase in their activity. Newer molecules are also in the process of development : new somatostatin analogues with more universal binding properties to different receptors subtypes, as well as chimeric molecules capable of binding to somatostatinergic and dopaminergic receptors. In the midst of GH-secreting pituitary adenomas, a positive correlation exists between the expression of Sst2 mRNA and the inhibition of GH release by somatostatin analogues. The involvement of Sst5 subtype in adenomas resistant to preferential Sst2 agonists has recently been proved. Another recently developed compound has a more universal Sst binding profile. This compound, named SOM-230, has a 25, 5 and 40 times higher binding affinity to Sst1, Sst3 and Sst5 receptors respectively, and 2,5 times lower affinity to Sst2, when compared to octreotide. SOM-230 could therefore allow for much more effective methods in treating patients suffering from acromegaly. Besides, the use of a chimeric molecule presenting a binding affinity to both Sst2 and D2 subtypes (BIM-23A287) inhibits the secretion of GH in ways similar to the Sst2 or D2 agonists used alone or concurrently but however in a concentration 50 times lower than that of the latter. The discovery of Sst5 and D2 subtypes at the level of corticotropic adenomas reveals newer therapeutic perspectives with promising preliminary results with the use of SOM-230 ; these finding lead to a rise in interest in cabergoline. In the midst of non-functioning pituitary adenomas, the expression of Sst2, Sst3 and D2 receptors will perhaps allow the use of combined therapies associating the new somatostatin analogues to the dopaminergic agonists or even use dopastatin (BIM-23A760, chimeric molecule Sst2-Sst5-D2). The preliminary results obtained in vitro with this molecule are actually encouraging since they show a dose dependent inhibition of the cellular replication mechanisms in 60 % of the cases. Finally, concerning prolactinomas the discovery of Sst5 receptors lead to consider the use of somatostatinergic agonists specific to the Sst5 receptor, SOM-230 in particular. Nevertheless, it seems that adenomas resistant to dopaminergic agonist due to a lack of expression of D2 receptor fail to express Sst5 receptors as well. On the other hand, dopastatin appears to be more efficient than cabergoline in the management of this type of adenomas. Therefore, the growing awareness concerning the mechanisms involved in the control of pituitary secretions as well as cellular proliferation will perhaps allow physicians to treat the pathology of pituitary adenomas, macroadenomas in particular, using solely pharmacological means instead of invasive surgical procedures and/or radiotherapy.

Expression of vascular endothelial growth factor in growth hormone-secreting pituitary adenomas: special reference to the octreotide treatment

Objective: The present study was designed to investigate the localization of VEGF in GH-secreting pituitary adenomas and to evaluate the characteristic differences of VEGF expression in relation to the clinical effect of preoperative treatment with octreotide.Methods: Fifty-six cases of GH-secreting adenomas, which were divided into three groups and three normal pituitary glands, were studied using immunohistochemistry for expression of VEGF. The octreotide group consisted of 33 patients who received the octreotide before the surgery. The bromocriptine group consisted of 11 patients who received bromocriptine orally. The control groups consisted of 12 patients who were not treated with octreotide or bromocriptine pre-operatively. VEGF staining patterns for each specimen were examined under light microscopy and graded in a scale. These findings were correlated with clinical characteristics.Results: VEGF was displayed in a diffuse cytoplasmic pattern in all cases. VEGF staining was strongly seen in the cytoplasm in normal pituitary glands. Moderately positive staining with VEGF appeared in six of 33 (18%) cases of the octreotide group, and in eight of 12 (67%) cases of the control group. In contrast, weakly positive staining was observed in 25 of 33 (76%) cases of the octreotide group, and in three of 12 (25%) cases of the control group. The staining pattern differs statistically between the octreotide and control group, typically in densely granulated GH cell adenomas. Weak staining with VEGF appeared in all ten cases in which the tumor had shrunk. Age, gender, tumor size, tumor invasiveness and adenoma type did not influence VEGF expression.Conclusion: We conclude that octreotide may inhibit the angiogenesis through down-regulation of VEGF.

Prognostic Significance of the Ki-67 Labeling Index in Growth Hormone-Secreting Pituitary Adenomas

Ki-67 is a marker of proliferation activity associated with invasiveness and prognosis in human tumors. The aim of the study was to evaluate the Ki-67 index prognostic relevance in a group of acromegalic patients who underwent transsphenoidal surgery for a GH-secreting pituitary adenoma. We selected 68 consecutive acromegalic patients referred to our hospital during a 5-yr period. The Ki-67 index was determined by immunohistochemistry on tissue samples obtained from each adenoma after surgery. Those patients who were not completely cured after surgery began medical therapy with somatostatin analogs (SSAs). Periodical pituitary magnetic resonance imaging and hormonal evaluation were performed during the follow-up. Twenty-eight of 68 patients were cured after surgery (41%). Among the 40 patients treated with SSAs, 13 were considered uncontrolled. Pituitary magnetic resonance imaging showed residual/recurrent disease in 25 of 68 patients after 6 months. No correlation was found between Ki-67 index and age, tumor size, GH, or IGF-I plasma levels. Tumors described as having cavernous sinus invasion had a higher mean Ki-67 index as compared with noninvasive tumors (P < 0.01). The Ki-67 index was significantly lower in tumors in patients cured after surgery as compared with patients considered not cured (P < 0.01) and in tumors in patients controlled by SSA therapy as compared with patients considered as uncontrolled (P < 0.05). The Ki-67 labeling index may predict clinical outcome in postsurgical management of acromegalic patients. We suggest routine Ki-67 evaluation in GH-secreting pituitary adenomas.

Aportación de la tomografía por emisión de positrones al diagnóstico de un caso de acromegalia

Diagnosis of acromegaly is based on biochemical tests demonstrating increased growth hormone (GH) secretion. More than 95% of patients with acromegaly harbor a GH-secreting pituitary adenoma. The technique of choice in the diagnosis of an adenoma is magnetic resonance imaging (MRI). The use of new techniques such as (111)In-octreotide scintigraphy (OctreoScan) and positron emission tomography (PET) can provide additional information in some cases. We report the case of a woman with acromegaly. The results of several MRI scans and OctreoScan were normal and other diagnostic possibilities were ruled out. The pituitary origin of the increased GH secretion was identified by PET. In acromegaly, the absence of MRI findings and identification of location by means of PET are exceptional.

Intrasellar internal carotid aneurysm coexisting with GH-secreting pituitary adenoma in an acromegalic patient

A 58 years old female presented with headache and acromegalic phenotype. She had hypertension for 10 years and galactorrhea for 3 years. Mean plasma GH was 8.1 hg/mL and mean IGF-1 level was 703 hg/mL (Reference: 78–258 hg/mL by immunoradiometric assay) […] Intrasellar internal carotid aneurysm coexisting with GH-secreting pituitary adenoma in an acromegalic patient

Clinical and biochemical improvement in acromegaly during pregnancy

Numerous case reports of pregnancy in acromegaly exist, however detailed descriptions of changes in placental and pituitary GH and IGF-I throughout gestation are rare. A 19-yr-old female presented to this institution with signs and symptoms of a GH-secreting pituitary adenoma. Following transphenoidal hypophysectomy, she had 3 unplanned pregnancies, despite ongoing active disease. No pregnancy was complicated by glucose intolerance or hypertension and 3 healthy newborns were delivered near or at term. Clinical improvement was observed during each pregnancy, accompanied by IGF-I levels lower than in the non-pregnant state, the majority lying within the normal range. This was despite increasing placental GH levels, and was not consistent with previous reports in the literature. Further surgical and medical therapies for acromegaly failed to normalize nonpregnant GH or IGF-I levels in this woman. Estrogen is known to alter GH signaling via its interaction with Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways. We hypothesize that increasing concentrations of estrogen or other pregnancy-related hormones resulted in her clinical and biochemical improvement during pregnancy. This may be used for future therapeutic benefit.

A growth hormone-secreting adenoma with incomplete nerve bundle formation

We present a unique case of an adenoma secreting growth hormone (GH), showing incomplete nerve bundle formation without ganglion cells. A 47-year-old man presenting with acromegaly was revealed to have high serum GH and IGF-1 levels. The concentrations of the other adenohypophysial hormones were within the normal range. Histology revealed an unusual pituitary adenoma containing many nerve bundle-like structures. Adenoma cells with ovoid or round hyperchromatic nuclei and eosinophilic cytoplasms lacked the typical features of ganglion cells. The nerve bundles consisted of slender elongated cells. These fibers were arranged into groups in a roughly parallel fashion. By immunohistochemistry, many adenoma cells were positive for GH, prolactin, thyrotropin beta, synaptophysin and chromogranin. Fibrous bodies revealed by keratin immunostaining were found only in adenoma cells. Scattered star-shaped adenoma cells showed the same immunoreactivity as folliculo-satellite cells. Adenoma cells, but not the bundle-like structures, were also positive for Pit-1. Immunostaining for neurofilament protein, GFAP, vimentin, and S-100 protein revealed variable amounts of fibrils within the bundle-like structures. Scattered immunoreactivity for myelin basic protein and synaptophysin was also found in the bundle area. Our case is the first GH-secreting pituitary adenoma showing incomplete nerve bundle differentiation and lacking mature ganglion cells.