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Long-term stimulation of thyroid follicular epithelium by high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in patients with acromegaly can lead to thyroid dysfunction, goiter, thyroid nodules, and even thyroid cancer and thyroid-associated ophthalmopathy (TAO). Excessive GH/IGF-1 promotes goiter and thyroid nodule formation, which can be reversed by normalizing the IGF-1 levels with surgery or medical treatment. Whether patients with acromegaly have an increased risk of thyroid cancer remains controversial, and routine thyroid ultrasonography and regular cancer screening are recommended in such cases, especially when the nodules possess malignant propensity. TAO is an autoimmune disease and newer treatments are being discovered against it. Recent studies have reported that the IGF-1 receptor (IGF-1R) plays an important role in the pathogenesis of TAO, and the IGF-1R inhibitor teprotumumab involves significantly improved disease endpoints in patients with active TAO. Thyroid-stimulating hormone (TSH) receptor (TSHR) and IGF-1R co-immunoprecipitate in orbital and thyroid tissues to form a functional complex; thus, combined therapy targeting TSHR and IGF-1R may be more effective than single therapy.

Acromegaly is often complicated by impaired glucose tolerance. The accuracy of glycated hemoglobin (HbA 1c ) and glycated albumin (GA) levels in representing glycemic profiles in patients with endocrine disorders, such as acromegaly, is unclear. This retrospective study reviewed data from patients whose GA levels had been recorded. 14 patients with acromegaly without diabetes mellitus (DM) (the acromegaly group), 15 patients with severe adult GH deficiency without DM (the growth hormone deficiency (GHD) group), and 55 nondiabetic patients (the control group) were included in this study. GA levels were significantly increased in the acromegaly group compared with the control and GHD groups, but no significant differences were observed between the control and GHD groups. The three groups were matched using propensity score matching (13 patients with acromegaly, 13 with GHD, and 13 control patients). Nonetheless, the results after matching were the same as those before matching. GA levels in the acromegaly group were significantly associated with plasma glucose (PG) levels at 0, 30, and 120 min after a 75-g oral glucose tolerance test (OGTT). Further, GH levels at 120 min after a 75-g OGTT in the acromegaly group were significantly correlated with GA levels and the difference in PG levels at baseline and 30 min. Our findings suggest that increases in PG levels attributable to excess GH after glucose loading are related to increases in GA levels in patients with acromegaly without DM. Hence, both HbA 1c and GA should be checked to accurately assess impaired glucose tolerance in patients with acromegaly.

Male patients with acromegaly frequently have hypogonadism. However, whether excess GH affects gonadal function remains unclear. We retrospectively compared clinical features affecting total testosterone (TT) and free testosterone (FT) levels between 112 male patients with acromegaly and 100 male patients with non-functioning pituitary adenoma (NFPA) without hyperprolactinemia. Median maximum tumor diameter (14.4 vs. 26.5 mm) and suprasellar extension rate (33 vs. 100%) were lower in acromegaly, but LH, FSH, TT, and FT were not significantly different. In acromegaly, TT was less than 300 ng/dL in 57%, and FT was below the age-specific reference range in 77%. TT and FT were negatively correlated with GH, IGF-1, and the tumor size, and positively correlated with LH. In NFPA, they were positively correlated with IGF-1, LH, FSH, ACTH, cortisol, and free T4, reflecting hypopituitarism. Multiple regression analysis showed that TT and FT had the strongest correlation with GH in acromegaly, and with LH in NFPA. Surgical remission was achieved in 87.5% of 56 follow-up patients with acromegaly. TT and FT increased in 80.4 and 87.5%, respectively, with a significant increase in LH. In acromegaly, the degree of postoperative increase in TT(FT) correlated with the fold increase of TT(FT)/LH ratio, a potential parameter of LH responsiveness, but not with fold increase of LH, whereas in NFPA it correlated with both. These results suggest that excessive GH is the most relevant factor for hypogonadism in male acromegaly, and may cause impaired LH responsiveness as well as the suppression of LH secretion.

Acromegaly is characterized by autonomous excessive growth hormone (GH) secretion, generally due to GH-producing pituitary adenoma, and is associated with various systemic comorbidities including diabetes mellitus. Polycystic kidney disease (PKD) is characterized by the growth of numerous cysts in the kidneys that deteriorate renal function. While possible renal effects of excessive GH exposure have been a current issue in experimental medicine, only five cases of coexisting acromegaly and PKD have been reported previously, and little is known regarding the influence of acromegaly on renal disease. We treated a 50-year-old male with diabetes mellitus who showed a sudden and rapid decline of renal function along with increasing proteinuria, which led to diagnoses of PKD and acromegaly. His urinary protein levels were increased together with excessive GH secretion and worsening glycemic control. An increase of total kidney volume was also noted. Transsphenoidal surgery for the pituitary adenoma was successfully performed. Marked improvement of hyperglycemia and proteinuria were observed after the surgery, but renal function was unchanged. The patient's clinical course suggested common aspects of excessive GH secretion as an accelerating factor of the progression of diabetic nephropathy and PKD via direct and indirect pathways. Although coexisting acromegaly and PKD is clinically rare, vigilance for early diagnosis of acromegaly is appropriate in patients with diabetes and/or PKD, especially in those showing unexpected exacerbation of renal dysfunction.

Nodular thyroid disease is a very common disorder in patients with acromegaly. Insulin-like growth factor-1 (IGF-1) is a thyroid growth factor, and there is a correlation between IGF-1 levels and thyroid volume (TV) in patients with acromegaly. There is no study investigating the impact of somatostatin analog (SSA) treatment on thyroid nodule volume in patients with acromegaly. We aimed to assess thyroid nodule volume change with SSA treatment in patients with persistent acromegaly. We retrospectively analyzed data from 108 consecutive patients with acromegaly who were followed up by our clinic after undergoing surgery between 2002 and 2014. Patients who were cured after surgery were excluded. We only selected 43 patients (21 males, 22 females, mean age 52.8 ± 11.9 years) who did not meet the criteria of remission postoperatively, who were treated with SSA for at least six months and had normal thyroid function. Patients were divided into three groups (well-controlled, controlled, and active) according to their IGF-1 and growth hormone (GH) levels. All patients underwent an evaluation of TV and total thyroid nodule volume (TTNV) by ultrasound. TTNV decreased significantly in patients with well-controlled acromegaly (0.44 [0.75] to 0.23 [0.73], p < 0.001). TTNV did not change in controlled patients (0.18 [1.28] to 0.13 [1.54], p = 0.959); however TTNV increased in patients with active acromegaly (0.77 [1.46] to 1.03 [1.88], p = 0.028). Successful medical treatment of patients with active acromegaly decreases thyroid nodule volume. Sustained exposure to IGF-1 may cause an increase in thyroid nodule volume in patients with acromegaly.

This study aimed to determine the prevalence of colorectal neoplasms and to investigate the rate of and time required for cecal intubation in patients with acromegaly. A database search performed at our institution identified 29 patients with acromegaly who underwent colonoscopy. Data regarding the endoscopic, biological, and pathological examinations performed were retrospectively reviewed from the clinical records. Subsequently, the rate of and time required for cecal intubation were investigated in 23 patients with acromegaly and compared with the corresponding data of the control group. Control subjects were selected from a 2:1 matched historical control cohort, according to baseline characteristics. The mean age of the acromegaly group (17 female and 12 male) was 60.4 ± 12.6 years. Twelve patients had adenoma (41.4%), eight patients had hyperplastic polyps (27.6%), three patients had sessile serrated adenoma/polyps (10.3%), and three patients had colon cancer (10.3%). Successful cecal intubation was achieved in all patients in both groups. The difference in the time required for successful intubation between the acromegaly group (15.7 ± 9.8 minutes) and the control group (8.7 ± 6.0 minutes) was statistically significant. Linear regression analysis revealed that increased patient age was significantly related to longer colonoscope insertion times. In conclusion, although cecal intubation during colonoscopy was successful in all participants, it required a longer time in patients with acromegaly. Our results underscore the importance of and certain technical difficulties involved in colonoscopy procedures in patients with acromegaly, especially in older patients.

A 67-year-old female with hypertension and impaired glucose tolerance was admitted to our hospital because of a typical acromegalic appearance, including large, thickened bulky hands and feet, and a large prominent forehead and tongue. She did not have a Cushingoid appearance, such as a moon-face, buffalo hump, purple striae or central obesity. The laboratory data revealed a serum GH level of 4.6 ng/mL and serum insulin-like growth factor-1 level of 811 ng/mL. The oral glucose tolerance test showed no suppression of the GH values. An endocrine examination showed a lack of circadian rhythmicity of ACTH and cortisol. Cortisol was not suppressed by a low dose of dexamethasone during the suppression test, but was suppressed by a high dose of dexamethasone. A radiological study revealed two isolated adenomas in the pituitary and a left adrenal tumor. These findings strongly suggested a diagnosis of acromegaly with subclinical Cushing's disease and a left adrenal incidentaloma. Transsphenoidal surgery was performed. Hematoxylin and eosin staining showed that the left and right pituitary adenomas were composed of basophilic and acidophilic cells, respectively. Immunohistochemical staining showed the left adenoma to be positive for ACTH and negative for GH. In contrast, the right adenoma was GH-positive and ACTH-negative. This is a rare case of independent double pituitary adenomas with distinct hormonal features. We also provide a review of the previously reported cases of double pituitary adenomas and discuss the etiology of these tumors.

Acromegaly is frequently accompanied by left ventricular hypertrophy (LVH) which causes ventricular dysfunction. Ventricular arrhythmia is one of the important complications in acromegalic patients. Hypertrophic cardiomyopathy (HCM) is characterized by LVH with a nondilated chamber. About 10 % of HCM evolve into dilated phase of HCM, which is associated with an increased incidence of ventricular tachycardia (VT). However there is no report about a combination of dilated phase of HCM and VT in acromegalic patients. Octreotide is a somatostatin analog that has been used for medical therapy for acromegaly. We herein report that the first case of the change of serum octreotide concentration affected the control of VT, which was induced by dilated phase of HCM. A 56-year-old Japanese man was referred to our hospital for treatment of acromegaly. The patient was diagnosed the dilated phase of HCM with sustained VT. The frequency and severity of VT were gradually ameliorated by subcutaneous octreotide injection. However VT was deteriorated when its injection was changed to octreotide long-acting release (LAR) injection. The temporary drop in serum octreotide concentration was known at the transition from subcutaneous injection to LAR injection. This clinical course gives us the important information that subcutaneous octreotide injection for two weeks should be necessary to keep serum octreotide concentration when switing to octreotide LAR administration in acromegalic patients with severe arrhythmia.

Pregnancy in acromegalic patients is a rare event, but is usually uneventful, with stable GH and IGF-I levels and no tumor enlargement. Medical treatment can usually be withdrawn without problems and although no major adverse event has been reported, the suspension of drug treatments is generally recommended. No case report exists in the literature regarding evolution of a somatotropinoma with invasiveness markers throughout pregnancy. We report a case of an acromegalic patient who was submitted to surgery and treated with octreotide LAR maintaining a stable residual tumor and an IGF-I close to the normal levels. Her tumor presented with a high Ki-67 (11.6%) and a low aryl hydrocarbon receptor-interacting protein (AIP) expression. When she became pregnant, octreotide LAR was withdrawn, and despite remaining asymptomatic during pregnancy, tumor growth occurred with compression of surrounding structures. In conclusion, pregnancy in acromegalic patients has usually a favorable prognosis with no tumor growth. However, in the presence of high Ki-67 labeling index and low AIP expression, tumor enlargement may occur and somatostatin analogue treatment throughout the pregnancy should be considered.

A 67-year-old woman with familial clustering of thyroid papillary adenocarcinoma was diagnosed with acromegaly due to pituitary macroadenoma. She had multiple skin vegetations, but had no parathyroid and pancreas diseases. Before transsphenoidal surgery, she was further diagnosed as having a duodenal tumor and multiple hypervascular liver nodules. Biopsy specimens from the duodenal tumor and liver nodules were diagnosed histologically as moderately differentiated adenocarcinoma. Immunohistochemically, the tumor cells were positive for chromogranin, synaptophysin and somatostatin receptor 2a, suggestive for neuroendocrine features. After surgery, the patient was not in biochemical remission, and octreotide treatment was initiated. The duodenal cancer was treated with chemotherapy (neoadjuvant cisplatin and S-1). After 24 months, the patient's insulin-like growth factor I level had been normalized, and her liver tumors had not progressed macroscopically. This is a rare case of acromegaly associated with multiple endocrine tumors, not being categorized as conventional multiple endocrine neoplasia. Octreotide treatment might have had beneficial effects on our patient's duodenal adenocarcinoma and liver metastases, both directly via SSTR2a and indirectly via GH suppression, thereby contributing to their slow progression.

Sleep-disordered breathing (SDB), especially sleep apnea-hypopnea syndrome (SAS), is often observed in patients with active acromegaly. This complication is a risk factor for cardiovascular disease and associated with increased morbidity and mortality in acromegaly. However there is little information on SDB in Japanese patients with acromegaly. We investigated the prevalence of SDB and association between the severity of SDB and various features and biomarkers in Japanese patients with acromegaly. Twenty-four Japanese patients with active acromegaly underwent overnight cardiorespiratory monitoring, hormonal assays and cephalometric measurements on X-ray. A high prevalence of SDB was detected in acromegaly (87.5%). Log apnea-hypopnea index (AHI) correlated positively with soft palate length / body height (X-ray) (r=0.44, p=0.043), but not with log growth hormone levels and insulin-like growth factor type-1 standard deviation scores, size of pituitary adenoma, disease duration, body mass index, waist circumference, estimated visceral fat area, heel pad thickness / height, tongue thickness/ height, or oropharyngeal dimension/ height. In conclusion, our study demonstrated a high prevalence of SDB in Japanese patients with acromegaly, and its severity correlated with soft palate length. Based on the high incidence of SDB identified in the present study, we recommend that all patients with acromegaly are routinely screened for SDB for early diagnosis and treatment.

GH-producing pituitary adenomas frequently co-produce other certain anterior pituitary hormones, such as prolactin (PRL). In contrast, GH-producing adenomas which express all of corticotropin-releasing factor (CRF), urocorin1 (Ucn1) and urocortin3 (Ucn3) have not been reported. A 39-year-old woman was admitted for evaluation of the pituitary tumor. The diagnosis of acromegaly was confirmed by elevated serum GH and IGF-I levels, and the absence of GH suppression by oral glucose tolerance test. ACTH response to desmopressin (DDAVP) was observed (plasma ACTH levels increased from 13.9 to 50.4 pg/ml at 90 min). Although it is known that ACTH response to DDAVP is considerably useful for the diagnosis of ACTH-dependent Cushing's syndrome, the diagnosis of Cushing's disease was not supported by the criteria. The patient underwent transsphenoidal resection of the pituitary tumor. Immunohistological examination confirmed a GH- and PRL-producing adenoma, whereas ACTH was negative. ACTH response to DDAVP disappeared after tumor removal. To determine the cause of preoperative ACTH response to DDAVP, we examined expression of CRF family peptides and vasopressin V1b receptor in the pituitary adenoma by immunohistochemistry. Immunohistochemistry revealed positive immunostaining for CRF, Ucn1, Ucn3 and vasopressin V1b receptor in the adenoma. These observations raised the possibility that DDAVP caused an ACTH response, perhaps via the paracrine effects of tumor-derived CRF and Ucn1. When ACTH response to DDAVP is observed in patients with pituitary tumor, not only the direct effect of DDAVP on ACTH secretion, but also a possible involvement of CRF and/or urocortins expressed in the pituitary adenoma, should be considered.

We report a rare case of polycystic ovary syndrome (PCOS) complicated with acromegaly due to a growth hormone (GH)-producing pituitary adenoma. Complete removal of the pituitary adenoma successfully reduced circulating levels of GH and insulin-like growth factor (IGF)-1, which, in turn, resulted in the amelioration of gonadal dysfunction, hyperandrogenism, lutenizing hormone hypersecretion, and severe insulin resistance. This clinical complication suggests that activation of systemic GH-IGF-1 axis is potentially involved in the development of PCOS.

It has been reported that patients with acromegaly may have an increased risk of developing several types of cancers, such as colorectal, breast and prostate tumors. However, some reports do not support these findings and therefore the prevalence of cancers in patients with acromegaly remains controversial. In this study, we determined the prevalence of benign and malignant neoplasms in patients with acromegaly. A retrospective chart analysis was performed on 140 patients with active acromegaly who had attended our outpatient clinic (M/F 54/86, age 55 +/- 25 yr, range 21-86). Colon cancer was found in 10 patients, thyroid cancer in 5, breast cancer in 4 and gastric cancer in 2. When compared with the local population, the standardized incidence ratios (SIRs) for thyroid cancer in patients with acromegaly were 61.74 (95% confidence interval (CI): 0.51-114.63) for females and 272.4 (95% CI: 29.12-876.71) for males. The SIRs for colon cancer in the acromegalic patients were 17.4 (95% CI: 4.74-44.55) for females and 19.0 (95% CI: 5.18-48.64) for male patients in comparison with the local population. Of the benign tumors, multinodular goiter and colonic, gastric and gallbladder polyps were observed in 57% (47/83), 40% (35/87), 23% (10/43), and 14% (11/77) [corrected] of the patients, respectively. This study suggested that patients with acromegaly have an increased risk of colon cancer and polyps. Moreover, it is speculated that the risk for thyroid cancer is increased in male patients. It is therefore recommended that patients with acromegaly should undergo screening colonoscopy and ultrasonography of the thyroid.

Pituitary apoplexy (PA), which is one of the most serious life-threatening complications of pituitary adenoma, is characterized by abrupt onset of headache, nausea, vomiting, visual disturbances and oculomotor paresis. Combination of oculomotor cranial nerve paralysis with normal visual fields is very rare in PA. We report a 60-year-old acromegalic man presented with panhypopituitarism and bilateral total opthalmoplegia without a visual field defect. At initial evaluation his clinical findings were compatible with adrenal crisis and eye examination revealed total opthalmoplegia, bilateral ptosis and normal vision. MRI showed a large heterogeneous mass in the pituitary fossa. Although clinical findings due to adrenal crisis improved after glucocorticoid therapy there was no improvement in opthalmoplegia and ptosis. The patient underwent transsphenoidal excision of the pituitary mass. Histological examination revealed an adenoma with large areas of hemorrhagic infarction and most of the cells were positive for GH in immunohistochemical analysis. Although opthalmoplegia was severe at presentation, total recovery was achieved 3 months after transsphenoidal surgery. Therefore the presented case clearly demonstrates that opthalmoplegia without a visual field defect due to PA has a good prognosis and early diagnosis and treatment including surgical decompression are crucially important.

Acromegaly is caused by excessive secretion of growth hormone (GH), and a resultant persistent elevation of insulin-like growth factor-1 (IGF-1) levels. Diabetes mellitus is accompanied in some acromegalic patients with insulin resistance. We encountered a type-2 diabetic patient who had a poorly controlled glycemic state and was diagnosed as acromegaly with normal IGF-1 levels. The patient showed definite acromegalic features. However, in the first screening test, GH levels were high and IGF-1 levels were inappropriately normal so the results were not close to the diagnosis of acromegaly. After moderate glycemic control, an oral glucose suppression test was performed, showing no suppressed GH response. TRH test revealed paradoxical increases in growth hormone levels and a brain MRI discovered a pituitary adenoma. After several-months insulin treatment, IGF-1 levels were increased to the abnormal state and GH levels were decreased without treatment for acromegaly. Here we report the rare case of acromegaly that presents inappropriately normal IGF-1 levels at the time of diagnosis in uncontrolled type 2 diabetic patient and shows increased IGF-1 levels after glycemic control with insulin therapy. When evaluating acromegaly in type 2 diabetes under poorly controlled glycemia, cautious IGF-1 analysis is needed after sufficient glycemic control.

We report a case showing deterioration of glycemic control during octreotide long-acting release (LAR) treatment in an acromegalic Japanese patient with type 2 diabetes mellitus. The patient did not show much improvement of insulin sensitivity (QUICKI; 0.33 before treatment, 0.35 during octreotide LAR treatment), and showed a significant reduction in early insulin secretion (insulinogenic index; 0.28 before treatment, 0.08 during octreotide LAR treatment) on 75 g oral glucose tolerance test (75gOGTT), despite decreases in GH and IGF-I levels during the course of octreotide LAR treatment. Postoperatively, both insulin sensitivity and early insulin secretion on 75gOGTT were improved (QUICKI 0.59, insulinogenic index 0.35). There are some reports that insulinogenic index is lower in most Japanese patients with type 2 diabetes mellitus and that early insulin secretions are significantly suppressed after administration of octreotide LAR. Although the influence of octreotide LAR on glucose metabolism varies among individuals, it is necessary to manage the deterioration of glucose tolerance during octreotide LAR treatment in acromegalic Japanese patients with decreased insulinogenic index.

Acromegalic arthropathy is one of the most frequent manifestations occurring in acromegaly patients. In contrast, rheumatoid arthritis (RA) is a rare clinical complication in acromegaly patients. Here, we report a 70-year-old Japanese woman with acromegaly, who complained of bilateral finger stiffness and polyarthralgia two months after transsphenoidal surgery of a growth hormone (GH)-secreting pituitary adenoma. Postoperative levels of serum GH and insulin-like growth factor-1 (IGF-1) were markedly decreased without any secretory deficiency of other anterior pituitary hormones. Hand X-ray did not show typical RA changes; however, erosive changes in carpal bones were clearly detected by magnetic resonance imaging with gadolinium enhancement. Based on the levels of serological markers in the patient following surgery including C-reactive protein, rheumatoid factor and matrix metalloproteinase-3, anti-rheumatic therapy was subsequently commenced. Regardless of the levels of GH and IGF-1, acromegaly patients frequently complain about joint-related symptoms even after remission. Therefore, careful observation of bone erosive changes and immunological activity in acromegaly patients is required when joint-related symptoms persist.

Here we report the case of a 65-year-old woman with acromegaly complicated with monoclonal gammopathy of undetermined significance (MGUS). The patient visited Shimane University Hospital for treatment of spinal canal stenosis, and was diagnosed as acromegaly with GH 43.1 ng/ml, insulin-like growth factor (IGF)-I 510 ng/ml and the detection of a pituitary adenoma by MRI. She was also diagnosed as MGUS with IgG 2208 mg/dl, the existence of IgG-kappa type monoclonal protein, and 5.6% plasma cells in bone marrow. After a pituitary adenoma was operatively removed by transsphenoidal approach, IgG levels, as well as GH and IGF-I levels, decreased spontaneously and simultaneously. We suspect a pathogenetic link between acromegaly and MGUS in this case, because both GH and IGF-I are known to directly promote immunoglobulin production from plasma cells, thus inducing the proliferation of the cells in vitro.

A 54-year-old man with type 2 diabetes was referred to our hospital for endocrine evaluation of acromegaly. Physical examination showed typical acromegalic features without Cushingoid features. Magnetic resonance imaging of the brain revealed the presence of a pituitary macroadenoma. Basal plasma levels of GH and insulin-like growth factor-I under fasting hyperglycemia (202 mg/dl) were markedly elevated. Plasma GH levels paradoxically increased after stimulation with TRH and LH-RH, and decreased after bromocriptine and octreotide administration. Endocrine examination of the hypothalamo-pituitary-adrenal (HPA) axis showed a lack of circadian rhythm of ACTH and cortisol, non-suppressibility to low-dose (1 mg), but suppressibility to high-dose (8 mg) dexamethasone, and normal response to CRH stimulation. The tumor resected by transsphenoidal surgery was histopathologically consistent with the diagnosis of eosinophilic adenoma: positive immunoreactivities of GH, PRL and ACTH were demonstrated, but negative immunoreactivities of prohormone convertase (PC) 1/3 by immunohistochemical method. After surgery, plasma GH and IGF-I levels decreased along with normalization of HPA axis. Metabolic co-morbidities such as diabetes and hypertension disappeared after removal of the pituitary tumor. This is a very rare case of GH-producing pituitary adenoma causing typical acromegaly with concomitant production of ACTH causing subclinical Cushing's disease.

The syndrome of McCune-Albright syndrome (MAS) is clasically defined as a triad presentation with the findings of polyostotic fibrous dysplasia, café-au-lait spots, and sexual precocity. However, not all patients present with complete symptoms. A 52-year-old man was diagnosed as having a variant of McCune-Albright syndrome with the following findings: polyostotic fibrous dysplasia, acromegaly due to pituitary tumor and subclinical hyperthyroidism due to toxic multinodular goiter. Sexual precocity and café-au-lait spots were not noted. Acromegaly was confirmed by laboratory examination (IGF-1, glucose suppression test and TRH stimulation test). Long acting somatostatin analogue was used as treatment. Although the pituitary tumor could not be removed due to technical problems, mass lesions on the cranium were removed subtotally. Histopathological evaluation demonstrated that the lesion complied with fibrous dysplasia. Genomic DNAs were isolated from the craniofacial bones and peripheral leucocytes of the patient. After amplifying the related regions, Gs alpha (Gs alpha) gene was analysed by automatic DNA sequence analysis. An activating mutation of the Gs alpha gene (Arg 201 Cys) was found in the genomic DNA isolated from the bone tissue of the patient, but not in the genomic DNA isolated from the blood. We described a case of MAS associated with Gs alpha mutation in the bone tissue, presenting with polyostotic fibrous dysplasia, subclinical hyperthyroidism and acromegaly.

We report a rare case of type 1 diabetes in a woman associated with acromegaly who was treated with surgery after pregnancy. An 18-year-old woman came to our hospital in April, 1998, complaining of thirst, polydipsia, polyuria, appetite loss, body weight loss of 8 kg in a month, and amenorrhea beginning 2 months earlier. Based on laboratory data, she was diagnosed as having type 1 diabetes mellitus. Although we suspected her of having acromegaly because of high growth hormone (GH) levels (6.9 or 8.5 ng/ml), blood levels of insulin-like growth factor 1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) were within normal range and the circadian rhythm of her blood GH levels was normally maintained. Her blood GH level was elevated to 12.6 ng/ml 15 minutes after a TRH administration. Blood GH levels were suppressed from 49 ng/ml to 1.5 ng/ml 4 hours after an oral administration of 2.5 mg of bromocriptine. A magnetic resonance images (MRIs) showed pituitary swelling, but no nodules were found in the pituitary. Therefore, we diagnosed her as having acromegaly and observed her without surgery, while prescribing diet therapy and intensive insulin therapy for diabetes. We started a treatment of oral administration of 7.5 mg of bromocriptine per day for the acromegaly from April 28, 2000, because her elevated GH was suspected of causing her diabetes to be poorly controlled. During a pregnancy from October, 2000 to September, 2001, diabetic control was improved with increased administration of insulin under a constant dose of bromocriptine. She delivered a normal full-term infant. After the bromocriptine therapy was stopped as she hoped to breastfeed, blood levels of GH and IGF-1 became elevated and her diabetic control deteriorated. As her pituitary tumor observed in pituitary MRIs became larger during the course, a transsphenoidal surgery was performed on March 8, 2002. After the surgery, blood levels of GH and IGF-1 lowered and diabetic control improved again. We concluded as follows: to rule out acromegaly in patients with poorly controlled diabetes, 1) measurements of serum GH and IGF-1 should be performed, and 2) pituitary MRIs should be performed if blood levels of GH or IGF-1 are high.

The McCune-Albright syndrome (MAS) is characterized by a triad of poly/monostotic fibrous dysplasia, café-au-lait macules and hyperfunctioning endocrinopathies including growth hormone (GH) excess. Polyostotic bone lesions and café-au-lait macules are common while monostotic bone lesions are rare. Similarly, acromegaly as a manifestation of endocrine hyperfunction with MAS is uncommon and in most of the instances somatotropinoma has not been documented. We report 3 patients, two of them had monostotic lesion, none had café-au-lait macules and all had GH secreting pituitary macroadenoma. All of them underwent transfrontal pituitary adenomectomy and had histopathological confirmation of GH secreting pituitary adenoma. A brief review of literature is also presented.

To determine the effects of surgery and adjuvant therapy on the mortality rate of Japanese patients with acromegaly, 154 surgically treated patients were followed until death or December 2000. Mean follow-up period was 10.0 +/- 6.5 (SD) years. Postoperative GH levels, mean values of GH levels measured in the first postoperative month, were <2.5 ng/mL in 73 (47.4%), 2.5-5.0 ng/mL in 50 (32.5%), and >5.0 ng/mL in 31 patients (20.1%). Three of 123 patients with postoperative GH levels <5.0 ng/mL underwent a second transsphenoidal surgery (TSS), the other 120 received no further treatment. Additional treatments, including second TSS, medical treatment, and gamma-knife irradiation for residual tumor, were administered to 25 of 31 patients whose postoperative GH was >5.0 ng/mL. Among the total 154 patients surveyed, 11 (7.1%) died during the follow-up period. The standard mortality ratio (SMR) was 1.17, not different from age- and sex-matched controls. The SMR of the 72 patients with postoperative GH <2.5 ng/mL was better than that of the 51 patients whose postoperative GH was 2.5-5.0 ng/mL (1.09 vs. 1.64); however, the difference was not statistically significant. In conclusion, TSS and adequate adjuvant treatment decreased the excess mortality rate of acromegalics to nearly the same level as that of the general Japanese population.

Octreotide usually induces long-acting inhibition of GH secretion without rebound hypersecretion. We report a patient with acromegaly who showed rebound elevation of GH and insulin-like growth factor-1 (IGF-1) after octreotide withdrawal. The patient responded remarkably to octreotide therapy with normalization of GH and IGF-1 and shrinkage of pituitary macroadenoma. Octreotide therapy was stopped when he developed liver dysfunction. GH and IGF-1 were markedly elevated for two weeks after cessation of octreotide.

Pituitary apoplexy has been reported as a very rare complication of combined tests of anterior pituitary function and of TRH or gonadotropin-releasing hormone (GnRH) administration in pituitary tumor. A 34-year-old man with a GH-secreting pituitary macroadenoma and diabetes mellitus received an injection of 400 microg TRH, 100 microg GnRH, and 0.15 U/Kg regular insulin. Twenty minutes later, he complained of a severe headache and vomited. Visual acuity and visual field did not change and his headache was persistent during the next 24 hours of conservative management. Magnetic resonance imaging (MRI) of the sella turcica done the day after the event showed definitive elevation of the optic chiasm and slight enlargement of tumor and focal areas of mixed high signal and low signal intensities in the macroadenoma on noncontrast T1-weighted images. Headache subsided markedly within a day of octreotide therapy. Transsphenoidal removal of the pituitary tumor was performed 9 days after the hormone study. Ischemic necrosis and hemorrhage were confirmed in the acidophilic adenoma with positive immunostaining for GH. Postoperative course was uneventful and his serum insulin-like growth factor-1 (IGF-1) level and blood glucose levels were normalized. Three months after the surgery the dynamic test was repeated without adverse effects. To our knowledge, this is a very rare case of apoplexy of GH-secreting pituitary adenoma after a combined stimulation test of anterior pituitary function.

Neoplasms may be one of the systemic complications to which we attribute high mortality in acromegaly. The present study was designed to investigate the incidence of malignant tumors in patients with acromegaly in the Japanese population. In this report, 44 patients (25 men and 19 women) with biochemically proven acromegaly were studied retrospectively and had a total 670 patient years of the duration of acromegaly. We investigated the incidence of malignant tumors. There were 5 patients with malignant tumors (5 in men) in this study (11%). Male patients with acromegaly had nearly a 3.5 times higher ratio of malignancy than expected and this increased cancer incidence was considered significant (P=0.01). There was no significant increase in cancer incidence of either the total patient population or female patients. The malignant tumors were two thyroid cancers and one colon, one gastric and one bladder cancer. It is of note that the colon cancer of one patient was diagnosed 2 years after transsphenoidal surgery even though the levels of serum GH and insulin-like growth factor (IGF-1) were reduced to normal after operation. This preliminary study has suggested that male patients with acromegaly might have a high risk of malignancy and that careful screening for tumors is needed both before and after surgical and medical treatment, even in patients with normalized serum GH and IGF-1 levels.

We saw a remarkable effect of octreotide, the long-acting somatostatin analogue, in reducing the number of ventricular premature complexes (VPCs) in a 59-year-old woman with acromegaly. Her basal GH and IGF-1 levels were up to 22.9 ng/ml and 934.9 ng/ml respectively. MRI revealed a 14 x 12 x 10 mm mass lesion in the pituitary gland. She had hypertension and echocardiography showed an increase in left ventricular wall thickness. Electric cardiography showed the presence of frequent VPCs and 24-h Holter monitoring revealed 24,277 beats of multifocal VPCs/24 h. She was treated with 300 microg/day of octreotide for four weeks before transsphenoidal surgery. After octreotide treatment, GH and IGF-1 were suppressed to 1.8 ng/ml and 145.3 ng/ml respectively, and the tumor size was remarkably reduced. Furthermore, the number of VPCs was also dramatically reduced to 2062 VPCs/24-h (8.5% of pretreatment) with 24-h Holter monitoring. This case shows that VPCs of acromegalic patients can be controlled by suppressing GH and IGF-1 with octreotide, and this agent is useful for reducing both tumor size and frequency of VPCs prior to surgery.

Purpose: Although routine mechanical nasal packing after transsphenoidal surgery (TS) is thought to increase respiratory disorders during sleep, there has been little in the literature about the pre- and post-operative airway assessment of acromegalics with sleep apnea (SA). We describe 4 acromegalic patients with SA, who underwent transsphenoidal surgery. METHODS AND CASES: The patients were all men, aged from 47 to 59 years. The pre- and post-operative sleep study consisted with a computer calculated oximetry parameter of oxygen desaturation index (ODI), which was defined as the number/hour of oxygen desaturation episodes exceeding 4% from the base line (normal range < 15). The postoperative (postop.) sleep study was carried out from the 1st postop. day to the 8th day, for 1 to 8 days, varying for each patient., Results: Only the worst postop. result is shown. Patient 1 had 2 operations, 2 years apart. ODI was 39.6 before the 1st operation and 45.9 postop.. In the second operation ODI was 21.8 preoperatively (preop.) and 57.9 postop.. Preop. and postop. ODI was 18.1 and 22.2 in patient 2, 21.6 and 22.5 in patient 3 and 45.5 and 18.9 in patient 4, respectively. ODI of patient 4 was 39.6, 3 weeks later., Conclusion: Our data showed that the postop. oxymetric study commonly showed worse results in acromegalics with nasal packing. The better result of patient 4 was probably due to a postop. sleepless state. REM sleep usually increases in the first several postop. days, when cardiopulmonary complications are more likely to occur. Since acromegalics with severe SA and postop. nasal packing may more readily suffer from cardiopulmonary complications, postoperative meticulous respiratory monitoring and care should be mandatory.

Sleep-disordered breathing (SDB) is common in patients with growth hormone (GH) secreting pituitary adenomas. Since long-term untreated SDB aggravates systemic conditions (hypertension and arrhythmia etc.), the therapeutic outcome of SDB is important in reducing morbidity and mortality rates. But the results of a quantitative analysis of the lowered GH and IGF-1 levels in SDB in a relatively large number of patients are not detailed. Ten consecutive acromegalic patients were studied with a bedside oximeter. Preoperatively they were divided into two groups based on the presence (SDB group = 6 patients) or absence (non-SDB group = 4 patients) of clinical symptoms of SDB such as habitual snoring, excessive daytime somnolence and nocturnal apneic episodes. The serum IGF-1 averaged 931.7 ng/ml in SDB group and 898.3 ng/ml in non-SDB group. The oxygen desaturation index (ODI) (the number of oxygen desaturations exceeding 4% from the base line) was 29.1+/-15.4 in the SDB group and 2.5+/-1.8 in the non-SDB group (P=0.01). Other oximeter parameters such as the percent of the time spent at O2 saturation < 90% and the mean and the lowest O2 saturations closely correlated with the degree of the clinical symptoms. A postoperative sleep study was conducted in 5 patients in the preoperative SDB group, 4 months or more after the surgery. The serum GH and IGF-1 levels normalized in 3 patients but remained slightly high in 2. ODI became 9.1+/-5.6, which was significantly lower than the preoperative value (P=0.026). One patient had a complete clinical resolution. The other 4 obtained slight to moderate improvement clinically and oximetrically despite normalized or decreased hormonal levels. This study clarified that the response of SDB to lowering of the GH level varies from one patient to another and persisting SDB despite the normalization of the hormonal levels suggests the involvement of other factors in the production of SDB.

We encountered a 58-year-old woman with acromegaly accompanied by a cortisol-secreting adrenal tumor without clinical features of hypercortisolism. The simultaneous occurrence of these two endocrinopathies in one individual is extremely rare. She was diagnosed as having diabetes mellitus 8 years ago. Afterwards, in spite of insulin therapy, her hyperglycemia could not be well controlled. Her acromegaly and preclinical Cushing's syndrome were histopathologically proven to be due to a pituitary adenoma and an adrenocortical adenoma, respectively. Successful treatment for these endocrinopathies resulted in greatly improved blood sugar control because of a reduction in insulin resistance. In this case of preclinical Cushing's syndrome, replacement therapy with glucocorticoid was able to be discontinued at only 8 weeks after adrenalectomy, so that the period of necessary replacement was much shorter than that for overt Cushing's syndrome. This is the first report describing insulin resistance before and after treatment in a case of acromegaly accompanied by adrenal preclinical Cushing's syndrome.

We studied functional and histopathological changes in acromegalic cardiomyopathy following intermittent subcutaneous infusion of octreotide. A 68-year-old female patient with acromegaly associated with congestive heart failure due to dilated cardiomyopathy was initially treated with cardioactive medication for three months, but it was not effective in correcting echocardiographic abnormalities. Further treatment with intermittent subcutaneous infusion of octreotide (20 microg/2 h) for 12 months not only reduced circulating GH and insulin-like growth factor-I (IGF-I) levels but also considerably improved histopathological changes in the myocardial specimen biopsied. These findings provide the first evidence of the favorable effect of octreotide on histopathological changes in acromegalic cardiomyopathy.

Acromegaly is an uncommon disease due to excessive amounts of growth hormone. Benign and malignant tumors have been reported in acromegalic patients. A 41-year-old female patient who had been followed up because of acromegaly by the endocrinology department for two years, was admitted to the hematology department for the evaluation of pancytopenia and the related signs and symptoms. Dopamine agonists were being used till a diagnosis of 'acute promyelocytic leukemia' was made. Occurrence of 'acute promyelocytic leukemia' in the course of acromegaly may have been caused by excessive endogenous GH or may be a coincidental situation.

To elucidate the short-term effects of octreotide, a somatostatin analogue, on glucose tolerance in acromegaly, the plasma glucose and insulin responses to a 75-g oral glucose tolerance test (75-g OGTT) were examined in 6 patients. The glucose disposal rate (GDR) was also measured by the hyperinsulinemic euglycemic clamp method before and after the administration of octreotide. Before octreotide therapy, 2 patients had normal responses of plasma glucose and insulin to 75-g OGTT (normal glucose tolerance: NGT) and 4 showed hyperinsulinemia or glucose intolerance (glucose intolerance: GIT). GDR-insulin dose-response curves showed a normal pattern in patients with NGT and pattern of insulin resistance in patients with GIT. After 2-3 weeks of octreotide administration, plasma growth hormone (GH) levels decreased in all of the patients. The plasma glucose response to 75-g OGTT was not changed in any patient. In contrast, the plasma insulin response to 75-g OGTT was enhanced in patients with NGT but lessened in patients with GIT. Patients with NGT showed no significant change in GDR-insulin dose-response curves. Patients with GIT showed improvement in GDR at low levels of plasma insulin, but did not show complete improvement at high levels. These results indicate that octreotide improves insulin resistance at the insulin receptor site by lowering plasma levels of GH and insulin in acromegalic patients with glucose intolerance.

We describe a woman with acromegaly who had acanthosis nigricans and hirsutism. Serum growth hormone (GH) and testosterone levels were markedly elevated. Standard oral glucose tolerance test (OGTT) showed a diabetic curve and no suppressed GH levels. Fasting insulin levels were very high while plasma glucose levels were not hypoglycemic. Insulin tolerance test revealed blunted hypoglycemic response. Acanthosis nigricans was present in the right axilla and face. Ultrasonogram demonstrated bilateral polycystic changes in the ovaries. From the above findings this patient's condition is characteristic of a very rare syndrome consisting of acromegaly, polycystic ovaries (PCO), hyperandrogenism, hirsutism, insulin resistance and acanthosis nigricans.

A 27-yr-old woman was referred for evaluation of acromegaly and hyperprolactinemia. She had undergone left adrenalectomy at 12 and right adrenalectomy at 17 for Cushing's syndrome due to adrenocortical nodular hyperplasia. At this time a pituitary tumor was found by brain computerized tomography, but plasma levels of growth hormone (GH), prolactin (PRL) and adrenocorticotropin (ACTH) were normal. When she was 23, symptoms and signs of acromegaly and subsequently galactorrhea-amenorrhea had developed. Plasma GH and PRL were increased and she was followed up by the administration of bromocriptine (2.5 mg-12.5 mg/day, p.o.). However the plasma GH level had been increasing gradually. On admission, plasma GH and PRL were high (19.5 micrograms/L, 61.0 micrograms/L, respectively) and increased in response to thyrotropin releasing hormone (TRH, 500 micrograms i.v.). An intrasella mass, which had been detected when she was 17, had become enlarged and was removed by Hardy's operation. Microscopically, the resected tumor was an eosinophilic adenoma. Immunohistochemical studies showed GH, PRL and ACTH positive cells localized in the tumor. Immunoultrastructural analysis of the tumor confirmed that GH, PRL and ACTH were present in secretory granules and Golgi apparatus in the tumor cells. The patient was a rare case of acromegaly with hyperprolactinemia developed after bilateral adrenalectomy of Cushing's syndrome due to adrenocortical nodular hyperplasia, all of which manifestations may be caused by a GH, PRL and ACTH secreting pituitary adenoma.