Pancreatic GHRHomas in Patients with or without Multiple Endocrine Neoplasia Type 1 (MEN 1) : An Analysis of 36 Reported Cases.

Pancreatic GHRHomas (pGHRHomas) with acromegaly have unique conditions, harboring the existence of multiple endocrine neoplasia type 1 (MEN 1). Moreover, pituitary lesions are affected by both protracted ectopic GHRH and loss of menin function. Of significance is the clarification of clinicopathological aspects of pGHRHomas in patients with or without MEN 1. From 1977-2016, thirty-six patients with pGHRHomas were reported. Twenty-two out of 36 patients (61%) had pGHRHomas with MEN 1 and 14 patients did not. The former had a tendency of male predominance, benign tumor behavior and fewer metastasis rather than the latter. The latter is a single pGHRHoma accompanied by pituitary enlargement with somatotroph hyperplasia (hyperplasia) caused by protracted ectopic GHRH. Nine patients with MEN 1 underwent transsphenoidal surgery (TSS). The hyperplasia associated with various pituitary adenomas (PAs) including three GH-related adenomas was observed in seven subjects (32%). In these patients, the resection of their pGHRHomas was feasible. Furthermore, all patients with acromegaly due to pGHRHomas without MEN 1 had non-TSS, whereas approximately 70% of those with MEN 1 had unnecessary TSS. The association with hyperplasia and various PAs suggested that formation of the three GH-related adenomas may be induced by the foundations of MEN 1 gene mutations. J. Med. Invest. 71 : 1-8, February, 2024.

Increased mortality in acromegaly is due to vascular and respiratory disease and is normalised by control of GH levels-A retrospective analysis from the UK Acromegaly Register 1970-2016.

CONTEXT: Epidemiological studies involving patients with acromegaly have yielded conflicting results regarding cancer incidence and causes of mortality in relation to control of growth hormone (GH) excess. OBJECTIVE: The objective of this retrospective cohort study is to clarify these questions and identify goals for treatment and monitoring patients. METHODS: We studied 1845 subjects from the UK Acromegaly Register (1970-2016), obtaining cancer standardised incidence rates (SIR) and all causes standardised mortality rates (SMR) from UK Office for National Statistics, to determine the relationship between causes of mortality-age at diagnosis, duration of disease, post-treatment and mean GH levels. RESULTS: We found an increased incidence of all cancers (SIR, 1.38; 95% CI: 1.06-1.33, p < .001), but no increase in incidence of female breast, thyroid, colon cancer or any measure of cancer mortality. All-cause mortality rates were increased (SMR, 1.35; 95% CI: 1.24-1.46, p < .001), as were those due to vascular and respiratory diseases. All-cause, all cancer and cardiovascular deaths were highest in the first 5 years following diagnosis. We found a positive association between post-treatment and mean treatment GH levels and all-cause mortality (p < .001 and p < .001), which normalised with posttreatment GH levels of <1.0 µg/L or meantreatment GH levels of <2.5 µg/L. CONCLUSION: Acromegaly is associated with increased incidence of all cancers but not thyroid or colon cancer and no increase in cancer mortality. Excess mortality is due to vascular and respiratory disease. The risk is highest in the first 5 years following diagnosis and is mitigated by normalising GH levels.

Assessment of multimodal treatment options in recurrent and persistent acromegaly: a systematic review and meta-analysis.

PURPOSE: In patients with acromegaly, secondary treatment options in cases of hormonal non-remission or tumor progression include repeat transsphenoidal surgery (TSS), radiation-based treatment (RT), or medical therapy (MT). In this study, we aim to evaluate the clinical effectiveness of various second-line treatment options for acromegaly. METHODS: Using the PRISMA guideline, a systematic review was performed by searching MEDLINE (PubMed), Web of Science, Scopus, and Cochrane electronic bibliographic databases from conception to the end of 2022. Outcomes of interest included hormonal remission rate, complications, and mortality associated with each treatment modality for refractory acromegaly. RESULTS: A total of 79 studies including 3,208 refractory acromegaly patients (44.90% males) were analyzed, with a mean patient age of 43.89 years. There was a statistically significant difference between various therapeutic modalities in terms of remission rate, with MT offering the highest remission rate (62.55%), followed by RT (50.15%) and TSS (37.39%). Subgroup analysis of radiotherapeutic and medical modalities did not show a significant difference in remission rate between different kinds of sub-modalities in each treatment approach. Recurrence following secondary treatment was not different in patients treated with reoperation TSS compared to other modalities. CONCLUSIONS: The management of persistent and recurrent acromegaly optimally requires a multimodal approach. In different scenarios of refractory acromegaly based on previous treatment, secondary treatments may vary in terms of remission rate and complications. Medical agents provide considerable effectiveness as a second-line therapy for recurrent or persistent disease. In selected cases, however, reoperation still provides an opportunity for cure or freedom from medications. The findings of this study may help clinicians to prioritize varying options involved in this multifaceted decision-making process.

Changes in acromegaly comorbidities, treatment, and outcome over three decades: a nationwide cohort study.

Objective: To study the time-dependent changes in disease features of Danish patients with acromegaly, including treatment modalities, biochemical outcome, and comorbidities, with a particular focus on cancer and mortality. Methods: Pertinent acromegaly-related variables were collected from 739 patients diagnosed since 1990. Data are presented across three decades (1990-1999, 2000-2009, and 2010-2021) based on the year of diagnosis or treatment initiation. Results: Adenoma size and insulin-like growth factor I (IGF-I) levels at diagnosis did not differ significantly between study periods. The risk of being diagnosed with diabetes, heart disease, sleep apnea, joint disease, and osteoporosis increased from the 1990s to the later decades, while the mortality risk declined to nearly half. The risk of cancer did not significantly change. Treatment changed toward the use of more medical therapy, and fewer patients underwent repeat surgeries or pituitary irradiation. A statistically significant increase in the proportion of patients achieving IGF-I normalization within 3-5 years was observed over time (69%, 83%, and 88%). The proportion of patients with three or more deficient pituitary hormones decreased significantly over time. Conclusion: Modern medical treatment regimens of acromegaly as well as increased awareness and improved diagnostics for its comorbidities have led to better disease control, fewer patients with severe hypopituitarism, and declining mortality in the Danish cohort of acromegaly patients. The risk of cancer did not increase over the study period.

Pregnancy and acromegaly: clinical outcomes of retrospectively analysed data from the German acromegaly registry.

CONTEXT: Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion, mostly induced by pituitary adenomas. The care of pregnant women with acromegaly is challenging, in part due to existing clinical data being limited and not entirely consistent with regard to potential risks for mother and child. OBJECTIVE: To retrospectively examine data on pregnancy and maternal as well as neonatal outcomes in patients with acromegaly. DESIGN & METHODS: Retrospective data analysis from 47 pregnancies of 31 women treated in centers of the German Acromegaly Registry. RESULTS: 87.1% of the studied women underwent transsphenoidal surgery before pregnancy. In 51.1% a combination of dopamine agonists and somatostatin analogs were used before pregnancy. Three women did not receive any therapy for acromegaly. During pregnancy only 6.4% received either somatostatin analogs or dopamine agonists. In total, 70.2% of all documented pregnancies emerged spontaneously. Gestational diabetes was diagnosed in 10.6% and gravid hypertension in 6.4%. Overall, no preterm birth was detected. Indeed, 87% of acromegalic women experienced a delivery without complications. CONCLUSION: Pregnancies in women with acromegaly are possible and the course of pregnancy is in general safe for mother and child both with and without specific treatment for acromegaly. The prevalence of concomitant metabolic diseases such as gestational diabetes is comparable to the prevalence in healthy pregnant women. Nevertheless, larger studies with more data in pregnant patients with acromegaly are needed to provide safe and effective care for pregnant women with this condition.

Beware of epistaxis: fatal pseudoaneurysm rupture 30 years after treatment of acromegaly.

We present a fatal complication of treatment in a patient with early-onset acromegaly, treated with two transsphenoidal operations, radiotherapy, radiosurgery and pegvisomant. He was diagnosed in his 30s, and controlled from his 40s, with stable residual tumour within the left cavernous sinus. In his 60s, 30 years after surgery/radiotherapy and 14 years after radiosurgery, he developed recurrent episodes of mild epistaxis. A week later, he presented at his local hospital's emergency department with severe epistaxis and altered consciousness. He was diagnosed with a ruptured internal carotid artery (ICA) pseudoaneurysm, but unfortunately died before treatment could be attempted.ICA pseudoaneurysms are rare complications of surgery or radiotherapy and can present with several years of delay, often with epistaxis. This case highlights the importance of life-long monitoring in patients with previous pituitary interventions and early recognition of epistaxis as a herald sign of a potentially catastrophic event, thus leading to timely treatment.

Predictive factors and the management of hyperglycemia in patients with acromegaly and Cushing's disease receiving pasireotide treatment: post hoc analyses from the SOM230B2219 study.

Introduction: Pasireotide, a somatostatin receptor ligand, is approved for treating acromegaly and Cushing's disease (CD). Hyperglycemia during treatment can occur because of the drug's mechanism of action, although treatment discontinuation is rarely required. The prospective, randomized, Phase IV SOM230B2219 (NCT02060383) trial was designed to assess optimal management of pasireotide-associated hyperglycemia. Here, we investigated predictive factors for requiring antihyperglycemic medication during pasireotide treatment. Methods: Participants with acromegaly or CD initiated long-acting pasireotide 40 mg/28 days intramuscularly (acromegaly) or pasireotide 600 µg subcutaneously twice daily during pre-randomization (≤16 weeks). Those who did not need antihyperglycemic medication, were managed with metformin, or received insulin from baseline entered an observational arm ending at 16 weeks. Those who required additional/alternative antihyperglycemic medication to metformin were randomized to incretin-based therapy or insulin for an additional 16 weeks. Logistic-regression analyses evaluated quantitative and qualitative factors for requiring antihyperglycemic medication during pre-randomization. Results: Of 190 participants with acromegaly and 59 with CD, 88 and 15, respectively, did not need antihyperglycemic medication; most were aged <40 years (acromegaly 62.5%, CD 86.7%), with baseline glycated hemoglobin (HbA1c) <6.5% (<48 mmol/mol; acromegaly 98.9%, CD 100%) and fasting plasma glucose (FPG) <100 mg/dL (<5.6 mmol/L; acromegaly 76.1%, CD 100%). By logistic regression, increasing baseline HbA1c (odds ratio [OR] 3.6; P=0.0162) and FPG (OR 1.0; P=0.0472) and history of diabetes/pre-diabetes (OR 3.0; P=0.0221) predicted receipt of antihyperglycemic medication in acromegaly participants; increasing baseline HbA1c (OR 12.6; P=0.0276) was also predictive in CD participants. Investigator-reported hyperglycemia-related adverse events were recorded in 47.9% and 54.2% of acromegaly and CD participants, respectively, mainly those with diabetes/pre-diabetes. Conclusion: Increasing age, HbA1c, and FPG and pre-diabetes/diabetes were associated with increased likelihood of requiring antihyperglycemic medication during pasireotide treatment. These risk factors may be used to identify those who need more vigilant monitoring to optimize outcomes during pasireotide treatment.

Trends of correlations between serum levels of growth hormone and insulin-like growth factor-I in general practice.

Serum levels of growth hormone (GH) and insulin-like growth factor (IGF)-I are crucial in the diagnosis and management of GH-related diseases. However, these levels are affected by nutritional and metabolic status. To elucidate the correlations between GH and IGF-I in various conditions, a retrospective analysis was performed for adult patients in which GH levels were examined by general practitioners during the period from January 2019 to December 2021. Of 642 patients, 33 patients were diagnosed with acromegaly, 21 were diagnosed with GH deficiency (GHD), and 588 were diagnosed with non-GH-related diseases (NGRD). In contrast to the positive correlations found between the levels of GH and IGF-I in patients with acromegaly (R=0.50; P<0.001) and patients with GHD (R=0.39; P=0.08), a negative correlation was found in the NGRD group (R=-0.23; P<0.001). In that group, the results of multivariable analysis showed that GH levels were predominantly influenced by gender and body mass index (BMI), whereas IGF-I levels were modulated by albumin in addition to age and GH. Of note, in the NGRD group, there was an enhanced negative correlation between GH and IGF-I under conditions of BMI < 22 and albumin < 4.0 g/dL (R=-0.45; P<0.001), and the negative correlation between GH and IGF-I was reinforced by excluding patients with other pituitary diseases and patients taking oral steroids (R=-0.51; P<0.001 and R=-0.59; P<0.001, respectively). Collectively, the results indicate that attention should be given to the presence of a negative correlation between serum levels of GH and IGF-I, especially in lean and low-nutritious conditions.

The molecular biology of sporadic acromegaly.

GH-secreting tumors represent 15 % to 20 % of all pituitary neuroendocrine tumors (pitNETs), of which 95 % occur in a sporadic context, without an identifiable inherited cause. Recent multi-omic approaches have characterized the epigenomic, genomic, transcriptomic, proteomic and kynomic landscape of pituitary tumors. Transcriptomic analysis has allowed us to discover specific transcription factors driving the differentiation of pituitary tumors and gene expression patterns. GH-secreting, along with PRL- and TSH-secreting pitNETs are driven by POU1F1; ACTH-secreting tumors are determined by TBX19; and non-functioning tumors, which are predominantly of gonadotrope differentiation are conditioned by NR5A1. Upregulation of certain miRNAs, such as miR-107, is associated with tumor progression, while downregulation of others, like miR-15a and miR-16-1, correlates with tumor size reduction. Additionally, miRNA expression profiles are linked to treatment resistance and clinical outcomes, providing insights into potential therapeutic targets. Specific somatic mutations in GNAS, PTTG1, GIPR, HGMA2, MAST and somatic variants associated with cAMP, calcium signaling, and ATP pathways have also been associated with the development of acromegaly. This review focuses on the oncogenic mechanisms by which sporadic acromegaly can develop, covering a complex series of molecular alterations that ultimately alter the balance between proliferation and apoptosis, and dysregulated hormonal secretion.

Double pituitary adenomas: report of two cases and systematic review of the literature.

Objective: Double pituitary adenomas (DPA) are a rare clinical condition, and our knowledge of them is limited. Missing the second lesion leading to incomplete biochemical remission after surgery is an important challenge in DPA management. This study aims to analyze independent prognostic factors in DPA patients and summarize clinical experiences to prevent surgical failure. Methods: Two cases of DPA patients with Cushing's disease diagnosed and surgically treated at Peking Union Medical College Hospital are reported. A literature review was performed on the online database Pubmed, and 57 DPA patients from 22 retrieved articles were included. Demographic characteristics, endocrine manifestations, diagnostic methods, tumor size, and immunohistochemical features of 59 patients were analyzed. Binary logistic regression models were used to identify independent prognostic factors affecting postoperative biochemical remission. Results: Among 59 DPA patients, the mean ± SD age was 43.64 ± 14.42 years, with 61.02% being female (n = 36). The most common endocrine manifestations were Cushing's syndrome (23/59, 38.98%) and acromegaly (20/59, 33.90%). The most prevalent immunohistochemical types were ACTH-immunopositive (31/118, 26.27%) and GH-immunopositive (31/118, 26.27%) tumors. Microadenomas (<1cm) were the most frequent in terms of tumor size (62/92, 67.39%). The detection rate for double lesions on 3.0T MRI was 50.00% (14/28), which significantly higher than 1.5T MRI (P = 0.034). Univariate analysis revealed that female, Cushing's syndrome and only single lesion detected by surgical exploration were associated with significantly worse prognosis (P<0.05). Multivariate analysis identified double lesion detected by surgical exploration (OR = 0.08, P = 0.003) and contiguous type tumor (OR = 0.06, P = 0.017) as independent protective factors for DPA patients. Conclusions: The double lesion detected by surgical exploration is independently associated with a better prognosis for DPA patients. Comprehensive intraoperative exploration are crucial measures to avoid missing causative lesions.

"Micromegaly": Acromegaly with apparently normal GH, an entity on its own?

A small proportion of the patients with acromegaly present with apparently normal basal GH levels and suppressible GH levels despite increased IGF-1 levels, a pattern called micromegaly by some authors. Whether this pattern represents a distinct entity or is just an expression of acromegaly in its early stages is still a matter of debate. Nevertheless, these patients have some peculiar characteristics such as being more likely older and male, mostly harbour microadenomas or small macroadenomas, and have lower IGF-1 and postglucose GH levels. Even though, the frequency and severity of clinical signs and comorbidities are similar to those of patients with classic acromegaly. In conclusion, micromegaly seems to be a distinct clinical entity with a different biological behavior characterized by a low GH output.

Genetic diagnosis in acromegaly and gigantism: From research to clinical practice.

It is usually considered that only 5% of all pituitary neuroendocrine tumours are due to inheritable causes. Since this estimate was reported, however, multiple genetic defects driving syndromic and nonsyndromic somatotrophinomas have been unveiled. This heterogeneous genetic background results in overlapping phenotypes of GH excess. Genetic tests should be part of the approach to patients with acromegaly and gigantism because they can refine the clinical diagnoses, opening the possibility to tailor the clinical conduct to each patient. Even more, genetic testing and clinical screening of at-risk individuals have a positive impact on disease outcomes, by allowing for the timely detection and treatment of somatotrophinomas at early stages. Future research should focus on determining the actual frequency of novel genetic drivers of somatotrophinomas in the general population, developing up-to-date disease-specific multi-gene panels for clinical use, and finding strategies to improve access to modern genetic testing worldwide.

Real-world experience with 11C-methionine positron emission tomography in the management of acromegaly.

BACKGROUND: L-[methyl-11C]-methionine-positron emission tomography (Met-PET) is a potentially important imaging adjunct in the diagnostic workup of pituitary adenomas, including somatotroph tumors. Met-PET can identify residual or occult disease and make definitive therapies accessible to a subgroup of patients who would otherwise require lifelong medical therapy. However, existing data on its use are still limited to small case series. Here, we report the largest single-center experience (n = 61) in acromegaly. METHODS: A total of 189 cases of acromegaly were referred to our national Met-PET service in the last 12 years. For this analysis, we have reviewed outcomes in those 61 patients managed exclusively by our multidisciplinary team (single center, single surgeon). Referral indications were as follows: indeterminate magnetic resonance imaging (MRI; n = 38, 62.3%), occult residual (n = 14, 23.0%), (radio-)surgical planning (n = 6, 9.8%), and occult de novo tumor (n = 3, 4.9%). RESULTS: A total of 33/61 patients (54.1%) underwent PET-guided surgery. Twenty-four of 33 patients (72.7%) achieved complete biochemical remission following (re-)surgery. Insulin-like growth factor 1 levels were reduced to <2 × upper limit of normal (ULN) in 6 of the remaining 9 cases, 3 of whom achieved levels of <1.1 × ULN compared with mean preoperative levels of 2.4 × ULN (SD 0.8) for n = 9. Only 3 patients developed single new hormonal deficits (gonadotropic/thyrotropic insufficiency). There were no neurovascular complications after surgery. CONCLUSION: In patients with persistent/recurrent acromegaly or occult tumors, Met-PET can facilitate further targeted intervention (surgery/radiosurgery). This led to complete remission in most cases (24/33) or significant improvement with comparatively low risk of complications. L-[methyl-11C]-methionine-positron emission tomography should therefore be considered in all patients who are potential candidates for further surgical intervention but present no clear target on MRI.

Immunological signatures and predictive biomarkers for first-generation somatostatin receptor ligand resistance in Acromegaly.

PURPOSE: Predicting resistance to first-generation Somatostatin Receptor Ligands (fg-SRL) in Acromegaly patients remains an ongong challenge. Tumor-associated immune components participate in various pathological processes, including drug-resistance. We aimed to identify the immune components involved in resistance of fg-SRL, and to investigate biomarkers that can be targeted to treat those drug-resistant Acromegaly. METHODS: We conducted a retrospective study involving 35 Acromegaly patients with somatotropinomas treated postoperatively with fg-SRL. Gathering clinicopathological data, SSTR2 expression, and immunological profiles, we utilized univariate, binary logistic regression, and ROC analyses to assess their predictive roles in fg-SRL resistance. Spearman correlation analysis further examined interactions among interested characteristics. RESULTS: 19 patients (54.29%) exhibited resistance to postoperative fg-SRL. GH level at diagnosis, preoperative tumor volume, T2WI-MRI intensity, granularity, PD-L1, SSTR2, and CD8 + T cell infiltration showed association with clinical outcomes of fg-SRL. Notably, T2WI-MRI hyperintensity, PD-L1-IRS > 7, CD8 + T cell infiltration < 14.8/HPF, and SSTR2-IRS < 5.4 emerged as reliable predictors for fg-SRL resistance. Correlation analysis highlighted a negative relationship between PD-L1 expression and CD8 + T cell infiltration, while showcasing a positive correlation with preoperative tumor volume of somatotropinomas. Additionally, 5 patients with fg-SRL resistance underwent re-operation were involved. Following fg-SRL treatment, significant increases in PD-L1 and SSTR5 expression were observed, while SSTR2 expression decreased in somatotropinoma. CONCLUSION: PD-L1 expression and CD8 + T cell infiltration, either independently or combined with SSTR2 expression and T2WI-MRI intensity, could form a predictive model guiding clinical decisions on fg-SRL employment. Furthermore, targeting PD-L1 through immunotherapy and embracing second-generations of SRL with higher affinity to SSTR5 represent promising strategies to tackle fg-SRL resistance in somatotropinomas.

A Potent Neutralizing Monoclonal Antibody to Human Growth Hormone Suppresses Insulin-Like Growth Factor-1 in Female Rats.

Acromegaly and gigantism are disorders caused by hypersecretion of growth hormone (GH), usually from pituitary adenomas. Although somatostatin analogues (SSA), dopamine agonists, and GH receptor antagonists are important therapeutic agents, all of these have issues with their effectiveness, safety, and/or convenience of use. To overcome these, we developed a GH-specific potent neutralizing a mouse monoclonal antibody (mAb) named 13H02. 13H02 selectively bound both to human and monkey GH with high affinity, and strongly inhibited the biological activity of GH in the Nb2 rat lymphoma cell proliferation assay. In hypophysectomized/GH-supplemented rats, a single subcutaneous administration of 13H02 significantly and dose-dependently lowered the serum insulin-like growth factor-1 levels. To pursue the therapeutic potential of this antibody for acromegaly and gigantism, we humanized 13H02 to reduce its immunogenicity and applied a single amino acid mutation in the Fc region to extend its serum half-life. The resulting antibody, Hu-13H02m, also showed GH-specific neutralizing activity, similar to the parental 13H02, and showed improved binding affinity to human FcRn.

Machine learning-based algorithms applied to drug prescriptions and other healthcare services in the Sicilian claims database to identify acromegaly as a model for the earlier diagnosis of rare diseases.

Acromegaly is a rare disease characterized by a diagnostic delay ranging from 5 to 10 years from the symptoms' onset. The aim of this study was to develop and internally validate machine-learning algorithms to identify a combination of variables for the early diagnosis of acromegaly. This retrospective population-based study was conducted between 2011 and 2018 using data from the claims databases of Sicily Region, in Southern Italy. To identify combinations of potential predictors of acromegaly diagnosis, conditional and unconditional penalized multivariable logistic regression models and three machine learning algorithms (i.e., the Recursive Partitioning and Regression Tree, the Random Forest and the Support Vector Machine) were used, and their performance was evaluated. The random forest (RF) algorithm achieved the highest Area under the ROC Curve value of 0.83 (95% CI 0.79-0.87). The sensitivity in the test set, computed at the optimal threshold of predicted probabilities, ranged from 28% for the unconditional logistic regression model to 69% for the RF. Overall, the only diagnosis predictor selected by all five models and algorithms was the number of immunosuppressants-related pharmacy claims. The other predictors selected by at least two models were eventually combined in an unconditional logistic regression to develop a meta-score that achieved an acceptable discrimination accuracy (AUC = 0.71, 95% CI 0.66-0.75). Findings of this study showed that data-driven machine learning algorithms may play a role in supporting the early diagnosis of rare diseases such as acromegaly.

[Ectopic acromegaly due to bronchial neuroendocrine tumors: the first description in Russia of three clinical cases].

 Acromegaly is a neuroendocrine disorder caused by excessive production of growth hormone (GH). In the majority of cases the cause of acromegaly is a pituitary tumor producing GH. Cases of ectopic acromegaly are much rarer. Ectopic acromegaly occurs in cases of tumors which produce growth hormone-releasing hormone (GHRH) or extrapituitary tumors which produce GH. The main sources of excessive GHRH production are neuroendocrine tumors (NETs) of the lung or pancreas. Treatment of ectopic acromegaly consists of surgical removal of the source of GHRH hyperproduction and in cases where surgery is not an option, somatostatin analogues, pegvisomant, chemotherapy, immunotherapy or radiation therapy are used.In this article three cases of ectopic acromegaly due to GHRH-producing lung NETs are presented, each of them being notable for a number of features. In the first two cases, clinical symptoms were mild, besides in the second case ectopic acromegaly was accompanied by primary hyperparathyroidism. In the third case ectopic acromegaly was accompanied by pituitary macroadenoma, and after surgical removal of the lung NET remission of acromegaly was not achieved. In all three cases, lung NETs were detected incidentally on radiologic chest screening for other conditions.

High mortality risk among women with acromegaly still persists.

Introduction: The mortality ratio in patients with acromegaly has improved over the last few decades. We aimed to determine the mortality rate and correlated factors in patients with acromegaly before and after the introduction of national protocols for treatment. In addition, we determined whether there are sex-related differences in mortality of patients with acromegaly. Methods: This observational retrospective study included 399 consecutive patients with acromegaly between January 2001-December 2022. Paraclinical data included random growth hormone (GH) and insulin-like growth factor-I (IGF1) levels, maximal pituitary tumor diameter at diagnosis, first visit, and last evaluation. Standardized mortality ratio (SMR) was calculated by dividing the observed and expected mortality rates. Cox regression analysis revealed the independent factors associated with mortality. Results: At the last visit, 31.07% (124) of patients were cured, 22.05% (88) had controlled acromegaly with medication, and 45.31% (181) had not controlled acromegaly. During follow-up (13.03 ± 5.65 years, 5216.62 person-years), 89 patients died (0.017%), resulting in an SMR of 1.18 [95% CI 0.95-1.45]. The independent factors associated with mortality were the last IGF1 level/last random GH level, absence of surgery, gonadotropin deficiency, and age. Patients with normal IGF1 after treatment showed an SMR of 0.71, whereas patients with IGF1 ratio > 1 showed SMR=1.51. Patients diagnosed between 1975-2007 and 2008-2022 had SMR = 1.25 [95% CI 0.97-1.58] and SMR = 1.09 [95% CI 0.68-1.65], respectively. In females with acromegaly, SMR was 1.63 [95% CI 1.24-2.11]; 1.76 [95% CI 1.30-2.34] in women diagnosed before 2008 and 1.33 [95% CI 0.69-2.33] in those diagnosed after 2008. Males with acromegaly had a mortality ratio similar to males from the general population (SMR = 0.99, [95% CI 0.66-1.41]). Conclusion: Patients diagnosed with acromegaly in the last 15 years had lower mortality rates than those diagnosed before 2008, due to the availability of new medications, primarily somatostatin receptor analogs and to a higher proportion of patients undergoing surgery. Females still have a high mortality ratio owing to older age at diagnosis and higher risk of metabolic complications. Therefore, efforts should be made for early diagnosis of acromegaly in women.

Case report: Management of pediatric gigantism caused by the TADopathy, X-linked acrogigantism.

X-linked acrogigantism (X-LAG) is a rare form of pituitary gigantism that is associated with growth hormone (GH) and prolactin-secreting pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) that develop in infancy. It is caused by a duplication on chromosome Xq26.3 that leads to the misexpression of the gene GPR101, a constitutively active stimulator of pituitary GH and prolactin secretion. GPR101 normally exists within its own topologically associating domain (TAD) and is insulated from surrounding regulatory elements. X-LAG is a TADopathy in which the duplication disrupts a conserved TAD border, leading to a neo-TAD in which ectopic enhancers drive GPR101 over-expression, thus causing gigantism. Here we trace the full diagnostic and therapeutic pathway of a female patient with X-LAG from 4C-seq studies demonstrating the neo-TAD through medical and surgical interventions and detailed tumor histopathology. The complex nature of treating young children with X-LAG is illustrated, including the achievement of hormonal control using a combination of neurosurgery and adult doses of first-generation somatostatin analogs.