Glucose metabolism outcomes after pituitary surgery in patients with acromegaly.

AIM: To investigate the impact of pituitary surgery on glucose metabolism and to identify predictors of remission of diabetes after pituitary surgery in patients with acromegaly. METHODS: A national multicenter retrospective study of patients with acromegaly undergoing transsphenoidal surgery for the first time at 33 tertiary Spanish hospitals (ACRO-SPAIN study) was performed. Surgical remission of acromegaly was evaluated according to the 2000 and 2010 criteria. RESULTS: A total of 604 acromegaly patients were included in the study with a total median follow up of 91 months (interquartile range [IQR] 45-163). At the acromegaly diagnosis, 23.8% of the patients had diabetes mellitus (DM) with a median glycated hemoglobin (HbA1c) of 6.9% (IQR 6.4-7.9) [51.9 mmol/mol (IQR 46.4-62.8)]. In the multivariate analysis, older age (odds ratio [OR] 1.02, 95% CI 1.00-1.05), dyslipidemia (OR 5.25, 95% CI 2.81 to 9.79), arthropathy (OR 1.39, 95% CI 2.82 to 9.79), and higher IGF-I levels (OR 1.30, 95% CI 1.05 to 1.60) were associated with a greater prevalence of DM. At the last follow-up visit after surgery, 21.1% of the DM patients (56.7% of them with surgical remission of acromegaly) experienced diabetes remission. The cure rate of DM was more common in older patients (hazard ratio [HR] 1.77, 95% CI 1.31 to 2.43), when surgical cure was achieved (HR 2.10, 95% CI 1.01 to 4.37) and when anterior pituitary function was not affected after surgery (HR 3.38, 95% CI 1.17 to 9.75). CONCLUSION: Glucose metabolism improved in patients with acromegaly after surgery and 21% of the diabetic patients experienced diabetes remission; being more frequent in patients of older age, and those who experienced surgical cure and those with preserved anterior pituitary function after surgery.

Magnetic resonance imaging as a predictor of therapeutic response to pasireotide in acromegaly.

OBJECTIVE: Hyperintensity signal in T2-weighted magnetic resonance imaging (MRI) has been related to better therapeutic response during pasireotide treatment in acromegaly. The aim of the study was to evaluate T2 MRI signal intensity and its relation with pasireotide therapeutic effectiveness in real-life clinical practice. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective multicentre study including acromegaly patients treated with pasireotide. Adenoma T2-weighted MRI signal at diagnosis was qualitatively classified as iso-hyperintense or hypointense. Insulin-like growth factor (IGF-I), growth hormone (GH) and tumour volume reduction were assessed after 6 and 12 months of treatment and its effectiveness evaluated according to baseline MRI signal. Hormonal response was considered 'complete' when normalization of IGF-I levels was achieved. Significant tumour shrinkage was defined as a volume reduction of ≥25% from baseline. RESULTS: Eighty-one patients were included (48% women, 50 ± 1.5 years); 93% had previously received somatostatin receptor ligands (SRLs) treatment. MRI signal was hypointense in 25 (31%) and hyperintense in 56 (69%) cases. At 12 months of follow-up, 42/73 cases (58%) showed normalization of IGF-I and 37% both GH and IGF-I. MRI signal intensity was not associated with hormonal control. 19/51 cases (37%) presented a significant tumour volume shrinkage, 16 (41%) from the hyperintense group and 3 (25%) from the hypointense. CONCLUSIONS: T2-signal hyperintensity was more frequently observed in pasireotide treated patients. Almost 60% of SRLs resistant patients showed a complete normalization of IGF-I after 1 year of pasireotide treatment, regardless of the MRI signal. There was also no difference in the percentage tumour shrinkage over basal residual volume between the two groups.

Prolactin and Growth Hormone Signaling and Interlink Focused on the Mammosomatotroph Paradigm: A Comprehensive Review of the Literature.

Prolactin (PRL) and growth hormone (GH) are peptide hormones that bind to the class 1 cytokine receptor superfamily, a highly conserved cell surface class of receptors. Both hormones control their own secretion via a negative autocrine loop in their own mammosomatotroph, lactotroph or somatotroph. In this regard, GH and PRL are regulated by similar signaling pathways involving cell growth and hormone secretion. Thus, GH and PRL dysregulation and pituitary neuroendocrine tumor (PitNET) development may have common pathogenic pathways. Based on cell linage, lactotroph and somatotroph PitNETs come from pituitary-specific POU-class homeodomain transcription factor (Pit-1). Mammosomatotroph and plurihormonal PitNETs are a unique subtype of PitNETs that arise from a single-cell population of Pit-1 lineage. In contrast, mixed somatotroph-lactotroph PitNETs are composed of two distinct cell populations: somatotrophs and lactotrophs. Morphologic features that distinguish indolent PitNETs from locally aggressive ones are still unidentified, and no single prognostic parameter can predict tumor aggressiveness or treatment response. In this review, we aim to explore the latest research on lactotroph and somatotroph PitNETs, the molecular mechanisms involved in PRL and GH axis regulation and the signaling pathways involved in their aggressiveness, particularly focused on mammosomatotroph and mixed subtypes. Finally, we summarize epidemiological, clinical, and radiological features of these exceptional tumors. We aim to shed light, from basic to clinical settings, on new perspectives and scientific gaps in this field.

Effect of cabergoline on tumor remnant after surgery in nonfunctioning pituitary adenoma.

BACKGROUND: In recent years, dopamine agonists (DAs) have become an attractive therapeutic option to prevent both tumor growth and post-surgical tumor remnant growth in clinically non-functioning pituitary adenoma (NFPA). AIM: To analyze our experience on the effect of cabergoline (CAB) on tumor remnant after initial surgery in NFPA patients. PATIENTS AND METHODS: A retrospective and multicenter study of NFPA patients with tumor remnant after surgery treated with CAB was performed. RESULTS: From a total of 142 NFPA patients (79 men, 55.2%; mean age 57.2 ± 14.2 year) who underwent surgery, we selected 62/142 (43.7%) patients (32 men, 51.6%; mean age 59.3 ± 13.9 year) with tumor persistence (TP) after surgery. In 22/62 (35.5%) TP patients CAB was used (CAB group), while the rest of the patients (40/62, 64.5%) underwent active surveillance [observation (OBS) group)]. The maximum diameter of the tumor remnant did not change significantly in either the CAB group [11.5 (6.0-16.9) mm vs. 12.0 (7.0-15.0) mm, p = 0.85) or the OBS group [8.5 (6.0-13.7) mm vs. 9.0 (6.2-14.0) mm, p = 0.064) at the end of the follow-up [13 (10.5-17) vs. 77.5 (50.2-107.2) months, CAB vs. OBS group; p < 0.001]. At the end of the treatment period with CAB most of the patients (n = 20/22, 90.9%) showed no progression of the tumor remnant [stable disease, SD (n = 17/22, 77.2%) and partial response, PR (n = 3/22, 13.6%)], while 2/22 patients (9.1%) exhibited progression. Similar response rates were observed in the OBS group [SD (n = 32/40, 80%), PR (n = 2/40, 5%), and progression (n = 6/40, 15%)]. Although no statistically significant differences (p = 0.42) were found in these responses, the percentage of progression was 1.65 times higher in the OBS group compared to the CAB group. On the contrary, the percentage of PR was 2.72 times higher in the CAB group compared to the OBS group, despite a significantly shorter follow-up period in the CAB group. CONCLUSION: Although the present study showed no significant differences in the type of tumor response between the CAB and OBS groups of patients, the percentage of PR was higher and that of progression lower in the CAB group compared to the OBS group. This finding does not rule out a potential therapeutic benefit of CAB in the management of tumor remnant in patients with NFPA undergoing surgery.

Pituitary Apoplexy: Risk Factors and Underlying Molecular Mechanisms.

Pituitary apoplexy is a rare syndrome, graded from asymptomatic subclinical apoplexy to a life-threatening condition due to pituitary ischemia or haemorrhage of an enlarged pituitary gland. The risk factors and the molecular underlying mechanisms are yet to be elucidated. We provide an overview of the general concepts, the potential factors associated with pituitary adenoma susceptibility for apoplectic events and the molecular mechanisms that could be involved such as HIF-1α/VEGF pathways and metalloproteinases activation, among others. The knowledge of the molecular mechanisms that could participate in the pathogenesis of pituitary apoplexy is crucial to advancement in the identification of future diagnostic tools and therapeutic targets in this rare but sometimes fatal condition.

Craniopharyngioma in the Elderly: A Multicenter and Nationwide Study in Spain.

BACKGROUND: Craniopharyngioma (CP) is a rare tumor in the elderly whose clinical features and prognosis are not well known in this population. AIM: To evaluate the clinicopathological features and therapeutic outcomes of CP diagnosed in the elderly. PATIENTS AND METHODS: This was a retrospective, multicenter, national study of CP patients diagnosed over the age of 65 years and surgically treated. RESULTS: From a total of 384 adult CP patients, we selected 53 (13.8%) patients (27 women [50.9%], mean age 72.3 ± 5.1 years [range 65-83 years]) diagnosed after the age of 65 years. The most common clinical symptoms were visual field defects (71.2%) followed by headache (45.3%). The maximum tumor diameter was 2.9 ± 1.1 cm. In most patients, the tumor was suprasellar (96.2%) and mixed (solid-cystic) (58.5%). The surgical approach most commonly used was transcranial surgery (52.8%), and more than half of the patients (54.7%) underwent subtotal resection (STR). Adamantinomatous CP and papillary CP were present in 51 and 45.1%, respectively, with mixed forms in the remaining. Surgery was accompanied by an improvement in visual field defects and in headaches; however, pituitary hormonal hypofunction increased, mainly at the expense of an increase in the prevalence of diabetes insipidus (DI) (from 3.9 to 69.2%). Near-total resection (NTR) was associated with a higher prevalence of DI compared with subtotal resection (87.5 vs. 53.6%, p = 0.008). Patients were followed for 46.7 ± 40.8 months. The mortality rate was 39.6% with a median survival time of 88 (95% CI: 57-118) months. DI at last visit was associated with a lower survival. CONCLUSION: CP diagnosed in the elderly shows a similar distribution by sex and histologic forms than that diagnosed at younger ages. At presentation, visual field alterations and headaches are the main clinical symptoms which improve substantially with surgery. However, surgery, mainly NTR, is accompanied by worsening of pituitary function, especially DI, which seems to be a predictor of mortality in this population.

HOMA-IR in acromegaly: a systematic review and meta-analysis.

PURPOSE: This review is aimed at examining whether the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) is higher in Caucasian, adult, treatment-naïve patients with acromegaly (ACRO) than in the reference population independently of diabetes presence and to evaluate the impact of treatment [surgery and somatostatin analogues (SSAs)] on its assessment. METHODS: We systematically reviewed in PubMed and Web of Science from July 1985 to December 2019, registered with the code number CRD42020148737. The inclusion criteria comprised studies conducted in Caucasian adult treatment-naïve patients with active ACRO in whom HOMA-IR or basal insulin and glucose were reported. Three reviewers screened eligible publications, extracted the outcomes, and assessed the risk of biases. RESULTS: Of 118 originally selected studies, 15 met the inclusion criteria. HOMA-IR was higher in ACRO than the reference population, with mean difference and (95% confidence intervals) of 2.04 (0.65-3.44), even in ACRO patients without diabetes, 1.89 (1.06-2.73). HOMA-IR significantly decreased after treatment with either surgery or SSAs - 2.53 (- 3.24- - 1.81) and - 2.30 (- 3.05- - 1.56); respectively. However, the reduction of HOMA-IR due to SSAs did not improve basal glucose. CONCLUSION: HOMA-IR in treatment-naïve ACRO patients is higher than in the reference population, even in patients without diabetes. This finding, confirms that insulin resistance is an early event in ACRO. Our results also suggest that HOMA-IR is not an adequate tool for assessing insulin resistance in those patients treated with SSAs.

Molecular Pathways in Prolactinomas: Translational and Therapeutic Implications.

Prolactinoma has the highest incidence rate among patients with functional pituitary tumours. Although mostly benign, there is a subgroup that can be aggressive. Some clinical, radiological and pathology features have been associated with a poor prognostic. Therefore, it can be considered as a group of heterogeneous tumours. The aim of this paper is to give an overview of the molecular pathways involved in the behaviour of prolactinoma in order to improve our approach and gain deeper insight into the better understanding of tumour development and its management. This is essential for identifying patients harbouring aggressive prolactinoma and to establish personalised therapeutics options.

GH/IGF-1 Abnormalities and Muscle Impairment: From Basic Research to Clinical Practice.

The impairment of skeletal muscle function is one of the most debilitating least understood co-morbidity that accompanies acromegaly (ACRO). Despite being one of the major determinants of these patients' poor quality of life, there is limited evidence related to the underlying mechanisms and treatment options. Although growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels are associated, albeit not indisputable, with the presence and severity of ACRO myopathies the precise effects attributed to increased GH or IGF-1 levels are still unclear. Yet, cell lines and animal models can help us bridge these gaps. This review aims to describe the evidence regarding the role of GH and IGF-1 in muscle anabolism, from the basic to the clinical setting with special emphasis on ACRO. We also pinpoint future perspectives and research lines that should be considered for improving our knowledge in the field.

Diagnosis, treatment and follow-up of patients with acromegaly in a clinical practice setting in Spain: the ACROPRAXIS program Delphi survey.

AIM: The ACROPRAXIS program aims to describe the management of acromegaly in Spain and provide guidance. METHODS: Ninety-three endocrinologists were organized into 13 panels to discuss the practical issues in managing acromegaly. Based on the key learnings, an online Delphi survey with 62 statements was performed, so those statements achieving consensus could be used as guidance. Statements were rated on a 9-point scale (9, full agreement; consensus > 66.6% of response in the same tertile). RESULTS: Ninety-two endocrinologists (98.8%) answered two rounds of the survey (mean age 47.6 years; 59.8% women; median 18.5 years of experience). Consensus was achieved for 49 (79%) statements. DIAGNOSIS: The levels of insulin-like growth factor I (IGFI) is the preferred screening test. If IGFI levels 1-1.3 ULN, the test is repeated and growth hormone (GH) after oral glucose tolerance test (OGTT) is assessed. A pituitary magnetic resonance is performed after biochemical diagnosis. TREATMENT: Surgery is the first treatment choice for patients with microadenoma or macroadenoma with/without optical pathway compression. Pre-surgical somatostatin analogues (SSA) are indicated when surgery is delayed and/or to reduce anaesthesia-associated risks. After unsuccessful surgery, reintervention is performed if the residual tumor is resectable, while if non-resectable, SSA are administered. Follow-up First biochemical and clinical controls are performed 1-3 months after surgery. Disease remission is considered if random GH levels are < 1 µg/L or OGTT is < 1 or ≤ 0.4 µg/L, depending on the assay's sensitivity. CONCLUSION: Current clinical management for acromegaly is homogeneous across Spain and generally follows clinical guidelines.

Cystatin-C and epicardial adipose tissue as noninvasive predictors of cardiovascular risk in acromegaly.

BACKGROUND: Acromegaly (ACRO) is associated with elevated cardiovascular risk, although the prevalence of coronary artery disease (CAD) is unclear. Increased epicardial adipose tissue (EAT) and elevated cystatin-C (Cys-C) levels are cardiovascular risk factors, also related to the progression of CAD in several populations. AIMS: To measure the severity and extent of CAD in patients with ACRO and to determine whether either EAT or Cys-C reflect higher cardiovascular risk in patients with ACRO than in healthy controls. SUBJECTS AND METHODS: Case-control study, of 35 patients with ACRO (19 males, 17 with active disease) and 35 age-, gender- and body mass index (BMI)-matched healthy controls; mean age was 48·1 ± 8·1 years and mean BMI was 27·6 ± 4·8 kg/m2 . Cys-C was measured by an immunoturbidimetric assay. The 10-year risk of developing a coronary event was calculated using the Framingham Risk Score (FRS). EAT index (volume indexed to body surface area), and severity and extent of CAD were measured using a 256-slice multidetector computed tomography scanner (iCT-256 Philips Healthcare, Amsterdam). RESULTS: Coronary artery disease lesions, EAT index and severity/extent of CAD were similar between patients with ACRO and controls. Forty-four per cent of patients with ACRO had mild coronary lesions associated with greater EAT index (ß = 0·022, P = 0·036). Cys-C levels correlated with both EAT index (ρ = 0·386, P = 0·031) and FRS (ρ = 0·477, P = 0·004) in patients with ACRO only, despite similar prevalence of traditional cardiovascular risk factors. In a multiple linear regression model, both Cys-C levels (ß = 0·369, P = 0·007) and EAT index (ß = 0·29, P = 0·025) predicted FRS (R2 = 0·613). CONCLUSIONS: In patients with ACRO, both Cys-C and EAT index might be used as noninvasive predictors of cardiovascular risk.

Escape and lipodystrophy in acromegaly during pegvisomant therapy, a retrospective multicentre Spanish study.

BACKGROUND: Pegvisomant is an effective treatment for acromegaly. OBJECTIVE: To investigate escape (loss of biochemical control in patients previously controlled) and lipodystrophy in acromegalic patients treated with pegvisomant and to evaluate possible associations with clinical features. PATIENTS AND METHODS: Multicentre retrospective study involving 19 Spanish centres. RESULTS: Ninety-seven patients were included (59% women, mean age at diagnosis 42 ± 13 years, 80% macroadenomas); mean follow-up on pegvisomant was 5 ± 2·5 years, and 89 (92%) achieved normal IGF-1. Escape was reported in 30/89 (34%) of responders, after a mean treatment duration of 25 ± 21 months. The mean initial dose of pegvisomant was 11 ± 5 mg/day, and mean dose at escape was 14 ± 7 mg/day. Most patients (26/30, 87%) achieved control with dose increase (57%), additional medical treatment (3%) or both (27%). Mean new dose that controlled IGF-1 after escape was 20 ± 7 mg/day. Treatments associated were somatostatin analogues (SSA in 47%), cabergoline (CAB in 47%) and both (6%). Lipodystrophy was observed in 15 patients (13 females), mild in six, moderate in six, severe in three and persistent in four. Among patients with lipodystrophy, three escaped and three were nonresponders to pegvisomant. Four patients discontinued the drug, and four had dose reductions because of lipodystrophy. It tended to be more frequent in females (P = 0·06) and in patients treated with triple association SSA+CAB+PEG (P = 0·018). No relationship between escape and clinical variables was found, except prior CAB (P = 0·04) and metformin treatment (0·02) and grade of lipodystrophy (P = 0·02). CONCLUSIONS: A significant proportion of patients treated with pegvisomant escaped (34%); however, the majority (87%) was easily controlled with either dose increase, further medical treatment or both. Lipodystrophy developed in 15%, mostly females, and influenced the response to treatment.

Predictors of biochemical response to somatostatin receptor ligands in acromegaly.

Although predictors of response to first-generation somatostatin receptor ligands (fg-SRLs), and to a lesser extent to pasireotide, have been studied in acromegaly for many years, their use is still not recommended in clinical guidelines. Is there insufficient evidence to use them? Numerous biomarkers including various clinical, functional, radiological and molecular markers have been identified. The first ones are applicable pre-surgery, while the molecular predictors are utilized for patients not cured after surgery. In this regard, factors predicting a good response to fg-SRLs are specifically: low basal GH, a low GH nadir in the acute octreotide test, T2 MRI hypointensity, a densely granulated pattern, high immunohistochemistry staining for somatostatin receptor 2 (SSTR2), and E-cadherin. However, there is still a lack of consensus regarding which of these biomarkers is more useful or how to integrate them into clinical practice. With classical statistical methods, it is complex to define reliable and generalizable cut-off values for a single biomarker. The potential solution to the limitations of traditional methods involves combining systems biology with artificial intelligence, which is currently providing answers to such long-standing questions that may eventually be finally included into the clinical guidelines and make personalized medicine a reality. The aim of this review is to describe the current knowledge of the main fg-SRLs and pasireotide response predictors, discuss their current usefulness, and point to future directions in the research of this field.

Hyponatremia after COVID-19 is frequent in the first year and increases re-admissions.

Hyponatremia on admission has been related to worse outcomes in patients with COVID-19 infection. However, little is known about the frequency and the associated risk factors of hyponatremia after COVID-19 discharge. We performed an observational 24-month follow-up study of patients admitted during the first COVID-19 wave. Kaplan-Meier curves and Cox proportional hazard models were used to assess the main variables in predicting hyponatremia on follow-up (HYPO-FU). A total of 161 out of 683 (24.4%) developed HYPO-FU. The group with HYPO-FU comprised of more men [(62.3%) vs. (49.2%); p < 0.01], older [65.6 ± 18.2 vs. 60.3 ± 17.0; p < 0.01] and more frequently re-admitted [(16.2%) vs. (3.8%); p < 0.01). The rate of HYPO-FU was higher in the first year 23.6 per 100 individuals per year. After Cox regression analysis, the independent risk factors of HYPO-FU were diabetes [OR 2.12, IC 95% (1.48-3.04)], hypertension [OR 2.18, IC 95% (1.53-3.12)], heart failure [OR 3.34, IC 95% (1.72-6.48)] and invasive ventilation support requirement [OR: 2.38, IC 95% (1.63-3.50)]. To conclude, HYPO-FU was frequent in the first year after COVID-19 infection, and the risk was higher in older men with comorbidities, increasing rehospitalisation. Further studies aimed at evaluating the beneficial effects of correcting hyponatremia in these patients are warranted.

Natural history and surgical outcomes of Rathke's cleft cysts: a Spanish multicenter study.

Rathke's cleft cysts (RCC) are a common type of lesion found in the sellar or suprasellar area. They are usually monitored clinically, but in some cases, surgery may be required. However, their natural progression is not yet well understood, and the outcomes of surgery are uncertain. The objective of this study is to evaluate the natural history of Rathke's cleft cysts in patients who are clinically monitored without treatment, and to determine the outcomes of surgery and the incidence of recurrences over time. Design and patients: National multicentric study of patients diagnosed of Rathke's cleft cyst (RCC- Spain) from 2000 onwards and followed in 15 tertiary centers of Spain. A total of 177 patients diagnosed of RCC followed for 67.3 months (6-215) and 88 patients who underwent surgery, (81 patients underwent immediate surgery after diagnosis and 7 later for subsequent growth) followed for 68.8 months (3-235). Results: The cyst size remained stable or decreased in 73.5% (133) of the patients. Only 44 patients (24.3%) experienced a cyst increase and 9 of them (5.1%) experienced an increase greater than 3 mm. In most of the patients who underwent surgery headaches and visual alterations improved, recurrence was observed in 8 (9.1%) after a median time of 96 months, and no predictors of recurrence were discovered. Conclusions: Rathke's cleft cysts without initial compressive symptoms have a low probability of growth, so conservative management is recommended. Patients who undergo transsphenoidal surgery experience rapid clinical improvement, and recurrences are infrequent. However, they can occur after a long period of time, although no predictors of recurrence have been identified.

Personalized medicine in acromegaly: The ACROFAST study.

Medical treatment of acromegaly is currently performed through a trial-error approach using first generation somatostatin receptor ligands (fgSRLs) as first-line drugs, with an effectiveness of about 50%, and subsequent drugs are indicated through clinical judgment. Some biomarkers can predict fgSRLs response. Here we report the results of the ACROFAST study, a clinical trial in which a protocol based on predictive biomarkers of fgSRLs was evaluated. METHODS AND SUBJECTS: prospective trial (21 university hospitals) comparing the effectiveness and time-to control of two treatment protocols during 12 months: A) A personalized protocol in which first option were fgSRLs as monotherapy or in combination with pegvisomant or, pegvisomant as monotherapy depending on the short Acute Octreotide Test (sAOT) results, tumor T2 Magnetic Resonance (MRI) signal or immunostaining for E-cadherin and, B) A control group with treatment always started by fgSRLs and the other drugs included after demonstrating inadequate control. RESULTS: Eighty-five patients participated; 45 in the personalized and 40 in the control group. More patients in the personalized protocol achieved hormonal control compared to those in the control group (78% vs 53%, p < 0.05). Survival analysis revealed a hazard ratio for achieving hormonal control adjusted by age and sex of 2.53 (CI 1.30-4.80). Patients from personalized arm were controlled in a shorter period of time (p = 0.01). CONCLUSION: Personalized medicine is feasible using a relatively simple protocol and allows a higher number of patients achieving control in a shorter period of time.

Integrative clinical, hormonal, and molecular data associate with invasiveness in acromegaly: REMAH study.

INTRODUCTION: Growth hormone (GH)-secreting pituitary tumors (GHomas) are the most common acromegaly cause. At diagnosis, most of them are macroadenomas, and up to 56% display cavernous sinus invasion. Biomarker assessment associated with tumor growth and invasion is important to optimize their management. OBJECTIVES: The study aims to identify clinical/hormonal/molecular biomarkers associated with tumor size and invasiveness in GHomas and to analyze the influence of pre-treatment with somatostatin analogs (SSAs) or dopamine agonists (DAs) in key molecular biomarker expression. METHODS: Clinical/analytical/radiological variables were evaluated in 192 patients from the REMAH study (ambispective multicenter post-surgery study of the Spanish Society of Endocrinology and Nutrition). The expression of somatostatin/ghrelin/dopamine system components and key pituitary/proliferation markers was evaluated in GHomas after the first surgery. Univariate/multivariate regression studies were performed to identify association between variables. RESULTS: Eighty percent of patients harbor macroadenomas (63.8% with extrasellar growth). Associations between larger and more invasive GHomas with younger age, visual abnormalities, higher IGF1 levels, extrasellar/suprasellar growth, and/or cavernous sinus invasion were found. Higher GH1 and lower PRL/POMC/CGA/AVPR1B/DRD2T/DRD2L expression levels (P < .05) were associated with tumor invasiveness. Least Absolute Shrinkage and Selection Operator's penalized regression identified combinations of clinical and molecular features with areas under the curve between 0.67 and 0.82. Pre-operative therapy with DA or SSAs did not alter the expression of any of the markers analyzed except for DRD1/AVPR1B (up-regulated with DA) and FSHB/CRHR1 (down-regulated with SSAs). CONCLUSIONS: A specific combination of clinical/analytical/molecular variables was found to be associated with tumor invasiveness and growth capacity in GHomas. Pre-treatment with first-line drugs for acromegaly did not significantly modify the expression of the most relevant biomarkers in our association model. These findings provide valuable insights for risk stratification and personalized management of GHomas.

Differences between GH and PRL co-secreting and GH-secreting pituitary adenomas. A series of 604 cases.

PURPOSE: To evaluate differences in clinical presentation and in surgical outcomes between growth hormone-secreting pituitary adenomas (GH-PAs) and GH and prolactin co-secreting pituitary adenomas (GH&PRL-PAs). METHODS: Multicenter retrospective study of 604 patients with acromegaly submitted to pituitary surgery. Patients were classified into two groups according to serum PRL levels at diagnosis and immunohistochemistry (IHC) for PRL: a) GH&PRL-PAs when PRL levels were above the upper limit of normal and IHC for GH and PRL was positive or PRL levels were >100ng/and PRL IHC was not available (n=130) and b) GH-PAs who did not meet the previously mentioned criteria (n=474). RESULTS: GH&PRL-PAs represented 21.5% (n=130) of patients with acromegaly. The mean age at diagnosis was lower in GH&PRL-PAs than in GH-PAs (P<0.001). GH&PRL-PAs were more frequently macroadenomas (90.6% vs. 77.4%, P=0.001) and tended to be more invasive (33.6% vs. 24.7%, P=0.057) than GH-PAs. Furthermore, they had presurgical hypopituitarism more frequently (OR 2.8, 95% CI 1.83-4.38). IGF-1 upper limit of normality (ULN) levels at diagnosis were lower in patients with GH&PRL-PAs (median 2.4 [IQR 1.73-3.29] vs. 2.7 [IQR 1.91-3.67], P=0.023). There were no differences in the immediate (41.1% vs 43.3%, P=0.659) or long-term post-surgical acromegaly biochemical cure rate (53.5% vs. 53.1%, P=0.936) between groups. However, there was a higher incidence of permanent arginine-vasopressin deficiency (AVP-D) (7.3% vs. 2.4%, P=0.011) in GH&PRL-PAs patients. CONCLUSIONS: GH&PRL-PAs are responsible for 20% of acromegaly cases. These tumors are more invasive, larger and cause hypopituitarism more frequently than GH-PAs and are diagnosed at an earlier age. The biochemical cure rate is similar between both groups, but patients with GH&PRL-PAs tend to develop permanent postsurgical AVP-D more frequently.

Effectiveness of combined first-line medical treatment in acromegaly with prolactin cosecretion.

OBJECTIVE: The aim of this study is to compare the response to first-line medical treatment in treatment-naive acromegaly patients with pure growth hormone (GH)-secreting pituitary adenoma (GH-PA) and those with GH and prolactin cosecreting PA (GH&PRL-PA). DESIGN: This is a retrospective multicentric study of acromegaly patients followed from 2003 to 2023 in 33 tertiary Spanish hospitals with at least 6 months of first-line medical treatment. METHODS: Baseline characteristics, first-line medical treatment strategies, and outcomes were analyzed. We employed a multiple logistic regression full model to estimate the impact of some baseline characteristics on disease control after each treatment modality. RESULTS: Of the 144 patients included, 72.9% had a GH-PA, and 27.1% had a GH&PRL-PA. Patients with GH&PRL-PA were younger (43.9 ± 15.0 vs 51.9 ± 12.7 years, P < .01) and harboring more frequently macroadenomas (89.7% vs 72.1%, P = .03). First-generation somatostatin receptor ligand (fgSRL) as monotherapy was given to 106 (73.6%) and a combination treatment with fgSRL and cabergoline in the remaining 38 (26.4%). Patients with GH&PRL-PA received more frequently a combination therapy (56.4% vs 15.2%, P < .01). After 6 months of treatment, in the group of patients under fgSRL as monotherapy, those patients with GH&PRL-PA had worse control compared to GH-PAs (29.4% vs 55.1%, P = .04). However, these differences in the rate of disease control between both groups disappeared when both received combination treatment with fgSRL and cabergoline. CONCLUSION: In GH&PRL-PA, the biochemical control achieved with fgSRL as monotherapy is substantially worse than in patients harboring GH-PA, supporting the inclusion of cabergoline as first-line medical treatment in combination with fgSRLs in these subgroups of patients.

Pegvisomant and pasireotide in PRL and GH co-secreting vs GH-secreting Pit-NETs.

The objective of the study was to evaluate the efficacy of second-line therapies in patients with acromegaly caused by a growth hormone (GH) and prolactin (PRL) co-secreting pituitary neuroendocrine tumor (GH&PRL-Pit-NET) compared to their efficacy in patients with acromegaly caused by a GH-secreting pituitary neuroendocrine tumor (GH-Pit-NET). This is a multicenter retrospective study of patients with acromegaly on treatment with pasireotide and/or pegvisomant. Patients were classified in two groups: GH&PRL-Pit-NETs when evidence of hyperprolactinemia and immunohistochemistry (IHC) for GH and PRL was positive or if PRL were >200 ng/dL regardless of the PRL-IHC and GH-Pit-NETs when the previously mentioned criteria were not met. A total of 28 cases with GH&PRL-Pit-NETs and 122 with GH-Pit-NETs met the inclusion criteria. GH&PRL-Pit-NETs presented at a younger age, caused hypopituitarism, and were invasive more frequently than GH-Pit-NETs. There were 124 patients treated with pegvisomant and 49 with pasireotide at any time. The efficacy of pegvisomant for IGF-1 normalization was of 81.5% and of pasireotide of 71.4%. No differences in IGF-1 control with pasireotide and with pegvisomant were observed between GH&PRL-Pit-NETs and GH-Pit-NETs. All GH&PRL-Pit-NET cases treated with pasireotide (n = 6) and 82.6% (n = 19/23) of the cases treated with pegvisomant normalized PRL levels. No differences in the rate of IGF-1 control between pegvisomant and pasireotide were detected in patients with GH&PRL-Pit-NETs (84.9% vs 66.7%, P = 0.178). We conclude that despite the more aggressive behavior of GH&PRL-Pit-NETs than GH-Pit-NETs, no differences in the rate of IGF-1 control with pegvisomant and pasireotide were observed between both groups, and both drugs have shown to be effective treatments to control IGF-1 and PRL hypersecretion in these tumors.