A rare case of acrohygiantism caused by Carney’s complex: diagnostic and treatment challenges

Acromegaly is a rare disease characterized by excess secretion of growth hormone (GH) and increased circulating insulin-like growth factor 1 (IGF-1) concentrations. The disease is associated with increased morbidity and premature mortality, but these effects can be reduced if GH levels are decreased to <2.5 μg/l and IGF-1 levels are normalized. Therapy for acromegaly is targeted at decreasing GH and IGF-1 levels, ameliorating patients' symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, radiotherapy and medical therapies, such as dopamine agonists, somatostatin receptor ligands and the GH receptor antagonist pegvisomant. Medical therapy is currently most widely used as secondary treatment for persistent or recurrent acromegaly following noncurative surgery, although it is increasingly used as primary therapy. This Review provides an overview of current and future pharmacological therapies for patients with acromegaly.

Acromegaly is a rare, chronic, progressive disease characterized by an excess secretion of growth hormone (GH) and increased circulating insulin-like growth factor 1 (IGF-1) concentrations. It is caused by a pituitary adenoma in the vast majority of cases. The clinical diagnosis, based on symptoms related to GH excess, is often delayed due to the insidious nature of the disease. Consequently, patients often have established systemic complications at diagnosis with increased morbidity and premature mortality. Serum IGF-1 measurement is recommended as the initial screen for patients with suspected acromegaly. The gold standard diagnostic test remains the oral glucose tolerance test with concomitant GH measurement. Therapy for acromegaly is targeted at decreasing GH and IGF-1 levels, ameliorating patients' symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, medical therapies (such as dopamine agonists, somatostatin receptor agonists and the GH receptor antagonist pegvisomant) and radiotherapy. A multidisciplinary approach is recommended with often a requirement for combined treatment modalities. With disease control, associated morbidity and mortality can be reduced. The recently published evidence-based guidelines by the Endocrine society addressed important clinical issues regarding the evaluation and management of acromegaly. This review discusses advances in our understanding of the pathophysiology of acromegaly, diagnosis of various forms of the disease and focuses on current treatment modalities, and on future pharmacological therapies for patients with acromegaly.

Acromegaly is a chronic disorder characterized by excessive growth hormone (GH) secretion from pituitary somatotroph cells, resulting in metabolic complications and increased morbidity. Elevated levels of GH and insulin-like growth factor 1 (IGF-1) contribute to various metabolic and morphological abnormalities. Betatrophin, produced in the liver and adipose tissue, plays a significant role in regulating glucose and lipid metabolism. Chemerin, an adipokine, influences insulin sensitivity, lipid metabolism, and inflammation. Additionally, kisspeptin, a neuropeptide, stimulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) through the hypothalamic-pituitary-gonadal axis. This study aimed to investigate the levels of betatrophin, chemerin, and kisspeptin in acromegaly patients and their potential relationship with dyslipidemia and diabetes. This study included 40 patients diagnosed with acromegaly and 40 healthy controls. GH and IGF-1 levels were measured, and venous blood samples were analyzed for betatrophin, chemerin, and kisspeptin levels using ELISA. The analysis revealed no significant difference in betatrophin levels between acromegaly patients and controls (p>0.05). However, significantly lower levels of chemerin and kisspeptin were observed in patients with acromegaly (p<0.001). Furthermore, a significant correlation was identified between IGF-1 and kisspeptin levels, indicating a potential pathway for future research in diagnostics and therapy. This study highlights the altered levels of chemerin and kisspeptin in acromegaly patients, suggesting their involvement in metabolic dysregulation associated with the condition. Further investigation into the correlation between IGF-1 and kisspeptin could provide insights into developing targeted therapeutic strategies.

Background: Acromegaly is a rare, chronic, systemic, and progressive disease characterized by an excess secretion of growth hormone (GH) and increased circulating insulin-like growth factor 1 (IGF-1) concentrations, typically due to a macroadenoma in the pituitary gland. Both GH and IGF-1 are implicated in cancer promotion based on experimental and epidemiological data, but research findings remain conflicting and population-based data are scarce. Although there is a high mortality rate among acromegalic patients due to cardiovascular diseases, cancer is the third leading cause of death. Aim: The aim of the present study was to assess the risk of different types of cancer in acromegaly and the impact of changes in disease control and patient outcomes over time. Methods: Patients diagnosed with acromegaly at the Ankara University Ibn-i Sina Hospital Endocrinology and Metabolic Diseases Department between 2015 and 2019 were included in this study. Data including demographic data, history of cancer, size of adenoma (micro or macro), serum IGF-1 and GH levels at the time of diagnosis, serum prostate-specific antigen (PSA), thyroid ultrasonography, and, if needed, thyroid fine needle aspiration cytology (TFAC), colonoscopy, and mammography results were collected from patient records retrospectively. Results: We screened 83 patients, and 78 patients with the compensatory data (female/male: 39/39, 50%/50%) were included. The mean age of patients was 49.4 ± 11.9 years and 41.7 ± 12.1 years at the time of diagnosis. The median duration of follow-up was 72 (12-420) months. Periodic thyroid ultrasonography was performed in 65/78 (83.3%) of the patients, and a colonoscopy and mammography were also conducted in 27/78 (34.6%) and 32/39 (82%) of the patients at least once over the course of the disease, respectively. Cancer was detected in 17/78 (21.7%) of the patients; 11/78 (14.1%) of them had well-differentiated thyroid cancer and 2/39 (5.1%) had breast cancer. Prostate cancer, renal cell carcinoma, pancreatic cancer, malignant chordoma, schwannoma, and colon cancer were detected in one patient each. The increased cancer risk in acromegalic patients did not correlate with age, sex, age at diagnosis, time to diagnosing acromegaly, duration of acromegaly, GH and IGF-1 levels at diagnosis, pituitary adenoma size, or Ki-67 levels. Conclusions: Cancer was detected in 21.7% of the acromegaly patients, 14.1% of whom had well-differentiated thyroid cancer. In this study, we demonstrated that thyroid cancer is the most common malignancy in Turkish acromegalic patients, consistent with the results of previous studies. The increased cancer risk in acromegalic patients did not correlate with age, sex, age at diagnosis, time to diagnosing acromegaly, duration of acromegaly, or GH and IGF-1 levels at diagnosis.

Acromegaly, predominantly resulting from a pituitary adenoma, is marked by excessive secretion of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). However, normalization of blood glucose levels posttreatment is rarely achieved. This case study aims to highlight the diagnostic challenges posed by overlapping symptoms of acromegaly and diabetes, emphasizing the importance of precise diagnosis and effective treatment strategies for optimal patient outcomes. A 22-year-old male was hospitalized for diabetic ketoacidosis and exhibited classic signs of acromegaly, such as enlarged hands and feet, and distinct facial changes. The patient's diagnosis of acromegaly, attributed to a pituitary adenoma, was confirmed through clinical observations, laboratory findings (notably raised serum GH and IGF-1 levels, and absence of GH suppression after glucose load during an OGTT), and pituitary MRI scans. The patient underwent 2 surgical tumor resections followed by gamma knife radiosurgery (GKRS). After treatment, GH, IGF-1, and blood glucose levels normalized without further need for hypoglycemic intervention. Posttreatment, the patient achieved stable GH, IGF-1, and blood glucose levels. The hyperglycemia was attributed to the GH-secreting tumor, and its resolution followed the tumor's removal. This case emphasizes the need for comprehensive assessment in patients with acromegaly to address coexisting diabetic complications. Surgical and radiotherapeutic management of acromegaly can lead to significant metabolic improvements, highlighting the importance of interdisciplinary care in managing these complex cases.

Information about a real patient is presented in stages (boldface type) to expert clinicians (Dr Beckman), who respond to the information, sharing their reasoning with the reader (regular type). A discussion by the authors follows . Patient presentation: An 89-year-old woman presents to cardiology clinic with the concern of recurrent shortness of breath and dyspnea on exertion during the previous 6 months. Her symptoms are progressive such that she can no longer walk > 10 feet before becoming symptomatic. Previously, she was independent at home and able to climb stairs with groceries or laundry without difficulty. The patient reports dependent lower extremity edema, orthopnea, and paroxysmal nocturnal dyspnea, but neither chest pain, palpitations, diaphoresis, nor lightheadedness. Her medical history is significant for diabetes mellitus, hypertension, hyperlipidemia, and glaucoma. Her medications include insulin, lisinopril, losartan, furosemide, and pravastatin. She has no known medication allergies. The patient’s most recent medical history is notable for a new diagnosis of aortic stenosis now repaired by transcatheter valve replacement (TAVR). She underwent successful valve replacement; however, her hospital and immediate outpatient course were complicated by profound hyperglycemia requiring escalating doses of insulin and readmission to a local hospital. Furthermore, the patient’s dyspnea did not change appreciably after valve replacement, and she was hospitalized twice more with acute on chronic heart failure requiring intravenous diuresis. Before discharge, she was started on high doses of oral furosemide. Ongoing symptoms of heart failure despite TAVR prompted her primary care physician to refer her to a cardiologist at a tertiary care center. The patient’s initial examination showed an elderly appearing woman, sitting comfortably in a wheelchair with her son at her side. Her vitals in the office revealed a heart rate of 91 and blood pressure of 135/77. The patient’s head and neck examination showed a jugular venous pressure …

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.

Chapter 15 - Acromegaly

Chapter 20 - Atypical Pituitary Adenomas

Introduction: Neuroendocrine neoplasms of the small intestine (SI-NENs), although rare, are the most prevalent primary neoplasms of this organ. Acromegaly is characterized by excessive secretion of growth hormone (GH), typically due to a pituitary neuroendocrine tumor but, in rare cases, it can result from ectopic secretion of growth hormone-releasing hormone (GHRH) by non-pituitary tumors, particularly neuroendocrine neoplasms (NENs) of the lung or pancreas. We reported a case of concurrent acromegaly and SI-NENs. Case Presentation: A 68-year-old male with a history of severe restrictive pulmonary syndrome secondary to thoracic kyphoscoliosis was referred for evaluation of iron-deficiency anemia and colorectal polyps. Video capsule endoscopy revealed an ulcerative-vegetative lesion in the distal ileum. Computed tomography (CT) enterography demonstrated multiple hypervascular lesions in the ileum, consistent with NENs. A 68Ga-DOTA-NOC PET/CT scan identified several foci of abnormal uptake, consistent with multiple intestinal NENs and suspected lymph node metastasis. Increased uptake was also observed in the pituitary gland. The patient was referred for endocrinology evaluation, where an acromegaloid phenotype was noted. Laboratory findings showed elevated levels of insulin-like growth factor 1 (IGF1) (454 ng/mL; reference range [RR] <225), GH (66 µg/L; RR ≤3), and chromogranin A (625 ng/mL; RR ≤102). Brain CT scan suggested a pituitary adenoma (the patient could not tolerate MRI). No pathogenic variants were detected in the MEN1 and CDKN1B genes. Given the concurrent diagnoses of acromegaly and SI-NENs, the extent of the disease, the high surgical risk, and the patient’s preference, long-acting octreotide therapy was initiated. Conclusion: The association between SI-NENs and acromegaly is rarely reported in the literature and remains unclear. Proposed mechanisms include the coexistence of independent tumors, the development of NENs in response to excessive IGF1 stimulation, and induction of acromegaly through ectopic GHRH secretion by NENs.

Evaluation of the insulin-like growth factors (IGF) IGF-I and IGF binding protein 3 in patients at high risk for breast cancer

Authors’ response

Objective To observe the effectiveness of long-acting octreotide in the treatment of acromegaly patients who did not achieve biochemical control after neurosurgery or gamma knife therapy of growth hormone-secreting pituitary adenoma. Methods Six acromegaly patients who received long-acting octreotide treatment regularly were included. Five patients had received prior trans-sphenoidal surgery and 1 patient had received prior gamma knife therapy before admission. All patients were admitted monthly for evaluation of pituitary-target gland function and octreotide therapy. Data of treatment with octreotide for 6 months were retrospectively summarized. Results Symptoms were reported to be alleviated. Two patients achieved biochemical control of the disease. Two patients had fasting growth hormone level less than 2.5 μg/L, but insulin-like growth factor-1 (IGF-1) level was still higher than the age-adjusted normal range. Another 2 patients had decreased growth hormone and IGF-1 level, but both still higher than the normal range. Compared with baseline, IGF-1 level was decreased after treatment: (371.83 ± 217.46) μg/L vs. (713.33 ± 198.29) μg/L, and there was statistical difference (P= 0.017). There were no statistical differences in glycated hemoglobin and fasting plasma glucose before and after octreotide treatment (P > 0.05). Conclusions For acromegaly patients who do not achieve biochemical control after neurosurgery or gamma knife therapy, long-acting octreotide can effectively control IGF-1 level and increase the biochemical control rate of the disease. Key words: Acromegaly; Growth hormone-secreting pituitary adenoma; Octreotide; Insulin-like growth factor Ⅰ

Objective To study the clinical efficacy of transnasal transsphenoidal surgery in acromegaly caused by pituitary adenoma and the clinical characteristics of patients achieved early biochemical remission after surgery. Methods Thirty-three patients with acromegaly caused by pituitary adenoma, admitted to and underwent transnasal transsphenoidal surgery in our hospital from September 2014 to June 2017, were chosen in our study. Clinical data and treatment efficacy of these patients were analyzed retrospectively. The patients were divided into biochemical remission group and non-biochemical remission group according to serum growth hormone (GH) trough value and insulin-like growth factor-1 (IGF-1) levels after oral glucose tolerance test (OGTT) 3 months after surgery, and endocrinology test results of the two groups were compared. Results Thirty-three acromegaly patients underwent microscopic transnasal pituitary surgery. For these patients, 24 achieved total resection, two achieved subtotal resection, 5 achieved massive resection, and two achieved partial resection. Patients were followed up for an average of 13.2 (3-36) months. At 3 months after surgery, blood sugar of two patients with diabetes were restored to normal level; reduction or restoration of hypertension was observed in most patients with preoperative hypertension (81.8%, 9/11); improvement of cardiac hypertrophy or cardiac enlargement was observed in about 1/3 patients with preoperative cardiac organic changes; heart enlargement was improved in 4 patients; one patient had normal sinus arrhythmia. The average interventricular septum thickness of the patients after surgery was significantly reduced as compared with that before surgery ([8.36±1.56] mm vs. [9.22±1.24] mm, P<0.05). The early biochemical remission was achieved in 19 patients (57.6%); as compared with the 14 patients failed to achieve early biochemical remission, those patients achieved early biochemical remission had significantly smaller adenoma diameters and volumes, lower percentages of patients with degrees of adenoma packaging internal carotid artery<135° and Knosp grading 0-2, and higher extent of surgical resection, lower IGF-1 level at one week and three months after surgery, lower GH level one, two and three d, one week and three months after surgery, and lower GH trough value after OGTT before surgery, one week and 3 months after surgery, with significant differences (P<0.05). Conclusions Transsphenoidal surgery is effective treatment for acromegaly caused by pituitary adenoma. Most patients could achieve biochemical remission three months after surgery. And the surgery could help in improving the cardiovascular complications of patients. The patients who are able to achieve early biochemical remission may have the features of smaller adenoma, lower GH trough value after OGTT before and one week after surgery, and lower GH and IGF-1 levels after surgery. Key words: Acromegaly; Pituitary adenoma; Surgery; Growth hormone; Insulin-like growth factor-1

Acromegaly is a chronic disease characterized by the presence of a pituitary growth hormone (GH)-producing tumour, excessive secretion of growth hormone, raised levels of insulin-like growth factor I (IGF-I) and characteristic clinical presentation of acral enlargement. Over the past two decades, major advances have occurred in the understanding of some aspects of acromegaly--such as the biology of pituitary tumours, the physiology, molecular mechanisms of GH secretion and IGF-I generation, and the pathogenesis of comorbidities. Moreover, new approaches to diagnosis and surveillance (both in terms of screening and follow-up) of acromegaly have led to increases in the number of patients diagnosed with active disease, many of whom would previously have been missed. The development of sensitive assays for detecting plasma GH and IGF-I levels, as well as the widespread use of MRI for visualization of small tumours, have been major contributing factors to these improvements. Treatment advances have resulted in improved cure rates and disease control through novel neurosurgical techniques and pharmacological approaches. This Review summarizes and discusses the changes in our understanding of the epidemiology, diagnosis, treatment, and follow-up of acromegaly and its comorbidities.