Growth Hormone and IGF1 Actions in Kidney Development and Function

Growth hormone (GH) exerts multiple effects on different organs including the kidneys, either directly or via its main mediator, insulin-like-growth factor-1 (IGF-1). The GH/IGF1 system plays a key role in normal kidney development, glomerular hemodynamic regulation, as well as tubular water, sodium, phosphate, and calcium handling. Transgenic animal models demonstrated that GH excess (and not IGF1) may lead to hyperfiltration, albuminuria, and glomerulosclerosis. GH and IGF-1 play a significant role in the early development of diabetic nephropathy, as well as in compensatory kidney hypertrophy after unilateral nephrectomy. Chronic kidney disease (CKD) and its complications in children are associated with alterations in the GH/IGF1 axis, including growth retardation, related to a GH-resistant state, attributed to impaired kidney postreceptor GH-signaling and chronic inflammation. This may explain the safety of prolonged rhGH-treatment of short stature in CKD.

An Update on Pituitary Neuroendocrine Tumors Leading to Acromegaly and Gigantism

An excess of growth hormone (GH) results in accelerated growth and in childhood, the clinical manifestation is gigantism. When GH excess has its onset after epiphyseal fusion at puberty, the overgrowth of soft tissue and bone results in acromegaly. Persistent GH excess in gigantism also causes acromegalic features that become evident in the adult years. The causes of GH excess are primarily lesions in the pituitary, which is the main source of GH. In this review, we provide an update on the clinical, radiological and pathologic features of the various types of pituitary neuroendocrine tumors (PitNETs) that produce GH. These tumors are all derived from PIT1-lineage cells. Those composed of somatotrophs may be densely granulated, resembling normal somatotrophs, or sparsely granulated with unusual fibrous bodies. Those composed of mammosomatotrophs also produce prolactin; rare plurihormonal tumors composed of cells that resemble mammosomatotrophs also produce TSH. Some PitNETs are composed of immature PIT1-lineage cells that do not resemble differentiated somatotrophs, mammosomatotrophs, lactotroph or thyrotrophs; these tumors may cause GH excess. An unusual oncocytic PIT1-lineage tumor known as the acidophil stem cell tumor is predominantly a lactotroph tumor but may express GH. Immature PIT1-lineage cells that express variable amounts of hormones alone or in combination can sometimes cause GH excess. Unusual tumors that do not follow normal lineage differentiation may also secrete GH. Exceptional examples of acromegaly/gigantism are caused by sellar tumors composed of hypothalamic GHRH-producing neurons, alone or associated with a sparsely granulated somatotroph tumor. Each of these various tumors has distinct clinical, biochemical and radiological features. Data from careful studies based on morphologic subtyping indicate that morphologic classification has both prognostic and predictive value.

One Fourth of Adult Patients With Acromegaly Have Tall Stature With Similar Frequency in Males And Females

Introduction: Tall stature (TS) is a manifestation of growth hormone (GH) excess, with higher prevalence reported for males. The aim of this study was (i) to evaluate the relationship between height of patients with GH excess related to midparental height (MPH) and population mean height; (ii) to test whether TS patients with acromegaly come from tall families. Methods: Single-centre, observational study on 101 consecutive adult patients with acromegaly and no family history of pituitary adenoma. Patients were analysed in two subgroups depending on height using country-specific data: 1) normal stature and 2) TS group, defined as either height above gender-specific 97 percentile or as >1.5 country-specific standard deviation (SD) from MPH. Results: Twenty-four percent of acromegaly patients (13 females/11 males) met one or both of the TS criteria. TS patients were significantly younger at the diagnosis (mean±SD, 33.6±13.4 vs 50.6±12.3 years) and at first symptoms (median 27.5, range 23-42 vs 41 (33-54) years) with greater tumour size and higher basal GH concentration than normal stature patients (p<0.01). The TS criteria based on the 1.5 SD above MPH identified more TS patients than the above 97 percentile height (92% vs 38%) and especially increased the diagnosis of TS in women (92% vs 31%). There was no difference in height of family members of acromegaly patients with or without TS. Height of family members were not taller than the population mean. Conclusion: One fourth of adult patients with acromegaly have TS with similar frequency in males and females. Based on our data TS patients with acromegaly do not come from tall families.

ACROMEGALY UNVEILED DURING A NASAL RECONSTRUCTION SURGERY: A CASE REPORT

Acromegaly is a condition of excessive somatic growth and distorted proportion due to hypersecretion of growth hormone(GH) and insulin-like growth factor 1 (IGF-1). Insidious clinical manifestation of GH excess as a result of GH-secreting pituitary adenoma renders acromegaly a disease with typically delayed diagnosis. We report a 29-year old male planned to undergo reconstruction of the nose. The patient was referred for medical tness. Given the clinical features consistent with acromegaly the patient was evaluated further for diagnosis. Laboratory investigation showed raised IGF-1and non-suppressed GH post 75gms glucose, amid normal cortisol, corticotropin(ACTH), prolactin, testosterone, and thyroid function tests. He did not have dysglycemia. Magnetic resonance imaging (MRI) of the pituitary revealed a pituitary macroadenoma consistent with acromegaly. This case highlights the notable absence of recognizing the clinical presentation of acromegaly in this patient by his medical care physician and surgeons, and therefore the importance of thorough history taking, attention, and observation in making a new diagnosis that has the potential to alter a patient's health care and alleviate impending complications, morbidity and/or mortality

AIP variant causing familial prolactinoma

Pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene are increasingly recognised as a cause of familial isolated pituitary adenoma. AIP-associated tumours are most commonly growth hormone (GH) producing. In our cohort of 175 AIP mutation positive patients representing 93 kindreds, 139 (79%) have GH excess, 19 have prolactinoma (17 familial and 2 sporadic cases) and out of the 17 clinically non-functioning tumours 4 were subsequently operated and found to be GH or GH & prolactin immunopositive adenoma. Here we report a family with an AIP variant, in which multiple family members are affected by prolactinoma, but none with GH excess. To our knowledge this is the first reported family with an AIP pathogenic variant to be affected solely by prolactinoma. These data suggest that prolactinoma families represent a small subset of AIP mutation positive kindreds, and similar to young-onset sporadic prolactinomas, AIP screening would be indicated.

SUN-291 Presence of Aberrant Adrenocorticotropic Hormone Precursors in Two Cases of McCune- Albright Syndrome

Background: McCune-Albright syndrome (MAS) is a rare disorder. MAS is caused by an activating postzygotic somatic mutation in the GNAS, and, is classically defined by the occurrence of fibrous dysplasia (FD), café-au-lait skin macules, and precocious puberty. Autonomous GH and/or PRL production in MAS has been reported. However, there have been no reports of ACTH excess in MAS. Method: Plasma ACTH and serum cortisol (F) levels were assessed using electrochemiluminescence immunoassays (Eclusys ACTHTM and Eclusys Cortisol IITM, respectively; Roche Diagnostics K.K., Tokyo, Japan).Clinical Cases: Case1; 42-year-old man showed craniofacial deformities and suffered from multiple bone fractures. He was diagnosed with FD at the age of 23 years. Café-au-lait macules were found on his back. He had slightly acromegaloid features. He showed no cushingoid features. Pituitary adenoma or hyperplasia was not detected by MRI. The diagnosis of GH excess was confirmed by no suppression of serum GH levels by a 75-g oral glucose tolerance test (nadir GH: 2.34 ng/mL) and an elevated serum IGF-I level (307 ng/mL; normal range: 92-257 ng/mL). The patient was treated with monthly subcutaneous lanreotide injection and then GH excess was well controlled. Basal ACTH and F levels in blood were 40.6-63.4 pg/mL and 8.0-10.5 μg/dL, respectively. The urinary free cortisol (UFC) level was 53 μg/day. Autonomous F excess was excluded by the level of midnight F (1.2 μg/dL) and the level of F (0.2 μg/dL) after a low-dose (1 mg) dexamethasone suppression test (DST). Case2; A 32-year-old man was diagnosed with MAS and gigantism at the Pediatrics Department at the age of 5 years. Treatment of GH excess was well controlled by monthly octreotide depot. He had no acromegaloid features and no cushingoid features. Café-au-lait macules were observed from the left flank to the back. Pituitary adenoma or hyperplasia was not detected by MRI. Basal ACTH and F levels in blood were 35.5-73.1 pg/mL and 7.0-11.7 μg/dL, respectively. The UFC level was 61 μg/day. Autonomous F excess was excluded by the level of F (<0.2 μg/dL) after a low-dose (0.5 mg) DST.Possibility of primary adrenal insufficiency was excluded by ACTH stimulation test and/or insulin tolerance test in both cases. The involvement of 11β-HSD1 by GH excess and PC1/3 deficiency were also excluded. Gel exclusion chromatography was then performed. POMC and pro-ACTH were detected and the aberrant ACTH/normal ACTH ratio was 42% in both cases. Conclusion: This is the first report of the presence of aberrant ACTH precursors, particularly POMC, in MAS. A high ratio of circulating ACTH to F may suggest secretion of inactive ACTH precursors in MAS. Further investigations are required to determine whether GNAS mutations or other mechanisms are involved in the presence of aberrant ACTH precursors in MAS.

Significant Benefits of AIP Testing and Clinical Screening in Familial Isolated and Young-onset Pituitary Tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.

Heat Intolerance and Hyperhidrosis as the only Presenting Manifestations of Acromegaly: A Case Report

Acromegaly is a state of Growth Hormone (GH) excess characterised by coarse facial features, acral enlargement, hyperhidrosis, headache, visual disturbances and visceromegaly. The most common cause of acromegaly is pituitary adenoma. The average delay between onset of symptoms and diagnosis is about six years in acromegaly owing to its subtle clinical features at the disease onset.Early diagnosis is important to reduce the morbidities and mortality associated with acromegaly. Familiarisation of physicians with the signs and symptoms of the disease is an effective strategy for the early diagnosis of acromegaly. Here, the authors report a case of 38year-old female patient. After proper clinical examination, history and series of relevant investigations, the serum GH level was estimated and was found to be elevated (40 ng/mL). GH secreting pituitary macroadenoma presenting with heat intolerance and hyperhidrosis without the classical manifestations of acromegaly.

The Clinicopathological Spectrum of Acromegaly

Background: Acromegaly results from a persistent excess in growth hormone with clinical features that may be subtle or severe. The most common cause of acromegaly is a pituitary tumor that causes excessive production of growth hormone (GH), and rare cases are due to an excess of the GH-releasing hormone (GHRH) or the ectopic production of GH. Objective: Discuss the different diseases that present with manifestations of GH excess and clinical acromegaly, emphasizing the distinct clinical and radiological characteristics of the different pathological entities. Methods: We performed a narrative review of the published clinicopathological information about acromegaly. An English-language search for relevant studies was conducted on PubMed from inception to 1 August 2019. The reference lists of relevant studies were also reviewed. Results: Pituitary tumors that cause GH excess have several variants, including pure somatotroph tumors that can be densely or sparsely granulated, or plurihormonal tumors that include mammosomatotroph, mixed somatotroph-lactotroph tumors and mature plurihomonal Pit1-lineage tumors, acidophil stem cell tumors and poorly-differentiated Pit1-lineage tumors. Each tumor type has a distinct pathophysiology, resulting in variations in clinical manifestations, imaging and responses to therapies. Conclusion: Detailed clinicopathological information will be useful in the era of precision medicine, in which physicians tailor the correct treatment modality to each patient.

IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction

Context The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition. Objective We aimed to evaluate the role of IGSF1 in human and murine somatotrope function. Patients, Design, and Setting We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting. Main Outcome Measures We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates. Results IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels. Conclusions We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.