Shozo Yamada, Noriaki Fukuhara, Hiroshi Nishioka, Akira Takeshita, Hisanori Suzuki, Megumi Miyakawa and Yasuhiro Takeuchi
The aim of this study was to determine the frequency and characteristics of severe GH deficiency (sGHD) in patients after treatment of acromegaly by surgery alone.
Design and methods
One hundred and eighty-six patients fulfilling the criteria for cure of acromegaly were examined by GH-releasing peptide-2 stimulation test or arginine stimulation test as well as oral glucose tolerance test (GTT). In addition, the Japanese adult hypopituitarism questionnaire was completed to determine the quality of life (QoL).
sGHD was found in 17 patients (9.1%; the GH-deficient group), and not found in 169 patients (90.9%; the GH-sufficient group). There were no significant differences in preoperative serum GH levels, IGF1 levels, incidence of hyperprolactinemia, tumor volumes, or incidence of microadenoma between the two groups. Upon follow-up examination, IGF1 levels and Z-scores of IGF1 levels were significantly lower in the GH-deficient group than in the GH-sufficient group, whereas neither basal GH levels nor nadir GH levels during 75 g GTT were significantly different between the two groups. Moreover, sGHD patients had a substantially higher incidence of multiple pituitary failures (17.6 vs 2.4%) and dyslipidemia (60 vs 16.2%). sGHD patients had a substantially poorer condition-related QoL.
This is the first large-scale, single-center, clinical study to evaluate sGHD in patients after cure of acromegaly by surgery alone. This study found that sGHD occurred in ∼9% of patients and assessment of GHD by stimulation tests is critical after successful treatment of acromegaly by surgery.
Kyohei Hayashi, Naoko Inoshita, Kohei Kawaguchi, Arif Ibrahim Ardisasmita, Hisanori Suzuki, Noriaki Fukuhara, Mitsuo Okada, Hiroshi Nishioka, Yasuhiro Takeuchi, Masayuki Komada, Akira Takeshita and Shozo Yamada
Somatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one- to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion.
Our objective was to determine the impact of USP8 mutations on the clinicopathological features of CD.
Subjects and methods
USP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry.
USP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT.
Microadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT.
Yorinari Ochiai, Naoko Inoshita, Toshiro Iizuka, Hiroshi Nishioka, Shozo Yamada, Masanobu Kitagawa and Shu Hoteya
Patients with acromegaly are at increased risk of colorectal polyps. However, their risk of colorectal cancer remains unclear. This study aimed to identify the histopathological features of colorectal polyps in patients with acromegaly and compare their risk of colorectal cancer with that in healthy controls.
The study participants were 178 patients who underwent Hardy’s operation and perioperative colonoscopy at our hospital between April 2008 and September 2016. For the control group, we randomly selected 356 age- and sex-matched patients who underwent colonoscopy at our hospital during the same period. The incidence, size, location, and histology of the colorectal polyps detected were compared between the groups.
Colorectal polyps were detected in 66.8% of the acromegaly group and 24.2% of the control group (P < 0.001). The average number and size of the polyps were 2.44 and 4.74 mm, respectively, in the acromegaly group and 1.77 and 3.89 mm in the control group (P = 0.001). Polyps in the acromegaly group were more likely to be in the rectosigmoid region (P = 0.006). In the acromegaly group, the frequency of polyps ≥5 mm was 34.3% and that for polyps ≥10 mm was 15.2%; the respective values were 7.6% and 2.2% in the control group (P < 0.001). We found no evidence of between-group histopathological differences in the polyp specimens resected by endoscopy.
Patients with acromegaly are at an increased risk of colorectal polyps, especially in the rectosigmoid region. However, there is no pathological evidence that they are at greater risk of colorectal cancer than the general population.
Naohiro Yoshida, Hiromasa Goto, Hisanori Suzuki, Kaoru Nagasawa, Akira Takeshita, Minoru Okubo, Megumi Miyakawa, Yasumichi Mori, Noriaki Fukuhara, Hiroshi Nishioka, Shozo Yamada and Yasuhiro Takeuchi
Excess GH causes insulin resistance and impaired glucose metabolism. The objective of this study was to clarify the prevalence of ketoacidosis as the initial presenting symptom of acromegaly.
Design and methods
Data were collected from 860 patients with acromegaly who underwent pituitary surgery at Toranomon Hospital over the last 32 years, between 1980 and 2011.
Nine cases had ketoacidosis before being diagnosed with acromegaly, including seven males and two females with a mean±s.d. age of 38.8±14.2 years. Serum GH and IGF1 levels were 155±203 ng/ml and 9.86±0.68 SDS before pituitary surgery and 3.6±1.7 ng/ml and 3.72±3.40 SDS after surgery respectively. The maximum tumor diameter was 28.2±11.6 mm (ranging from 15 to 47 mm, n=8). None of the patients were diagnosed with diabetes mellitus (DM) nor were they positive for antibodies related to type 1 DM. A possible precipitating factor for ketoacidosis in six cases was excessive ingestion of sugar-containing soft drinks. All the cases had invasive pituitary adenomas. After pituitary surgery, plasma glucose levels were under control without requiring insulin in all cases. Furthermore, six patients did not need oral hypoglycemic agents.
Approximately 1% of patients with acromegaly presented with diabetic ketoacidosis as their first clinical condition.