Hypopituitarism.

Partial or complete deficiency of anterior or posterior pituitary hormone production leads to central hypoadrenalism, central hypothyroidism, hypogonadotropic hypogonadism, growth hormone deficiency, or arginine vasopressin deficiency depending on the hormones affected. Hypopituitarism is rare and likely to be underdiagnosed, with an unknown but rising incidence and prevalence. The most common cause is compressive growth or ablation of a pituitary or hypothalamic mass. Less common causes include genetic mutations, hypophysitis (especially in the context of cancer immunotherapy), infiltrative and infectious disease, and traumatic brain injury. Clinical features vary with timing of onset, cause, and number of pituitary axes disrupted. Diagnosis requires measurement of basal circulating hormone concentrations and confirmatory hormone stimulation testing as needed. Treatment is aimed at replacement of deficient hormones. Increased mortality might persist despite treatment, particularly in younger patients, females, and those with arginine vasopressin deficiency. Patients with complex diagnoses, pregnant patients, and adolescent pituitary-deficient patients transitioning to adulthood should ideally be managed at a pituitary tumour centre of excellence.

Cushing's syndrome.

Endogenous Cushing's syndrome results from excess glucocorticoid secretion, which leads to a myriad of clinical manifestations, comorbidities, and increased mortality despite treatment. Molecular mechanisms and genetic alterations associated with different causes of Cushing's syndrome have been described in the last decade. Imaging modalities and biochemical testing have evolved; however, both the diagnosis and management of Cushing's syndrome remain challenging. Surgery is the preferred treatment for all causes, but medical therapy has markedly advanced, with new drug options becoming available. Nevertheless, several comorbidities remain even after patient remission, which can affect quality of life. Accurate and timely diagnosis and treatment are essential for mitigating chronic complications of excess glucocorticoids and improving patient quality of life. In this Seminar, we aim to update several important aspects of diagnosis, complications, and treatment of endogenous Cushing's syndrome of all causes.

Diffusion-weighted imaging does not seem to be a predictor of consistency in pituitary adenomas.

PURPOSE: To prospectively evaluate the usefulness of T1-weighted imaging (T1WI) and diffusion-weighted imaging (DWI) sequences in predicting the consistency of macroadenomas. In addition, to determine their values ​​as prognostic factors of surgical outcomes. METHODS: Patients with pituitary macroadenoma and surgical indication were included. All patients underwent pre-surgical magnetic resonance imaging (MRI) that included the sequences T1WI before and after contrast administration and DWI with the apparent diffusion coefficient (ADC) map. Post-surgical MRI was performed at least 3 months after surgery. The consistency of the macroadenomas was evaluated at surgery, and they were grouped into soft and intermediate/hard adenomas. Mean ADC values, signal on T1WI and the ratio of tumor ADC values ​​to pons (ADCR) were compared with tumor consistency and grade of surgical resection. RESULTS: A total of 80 patients were included. A softened consistency was found at surgery in 53 patients and hardened in 27 patients. The median ADC in the soft consistency group was 0.532 × 10-3 mm2/sec (0.306 - 1.096 × 10-3 mm2/sec), and in the intermediate/hard consistency group was 0.509 × 10-3 mm2/sec (0.308 - 0.818 × 10-3 mm2/sec). There was no significant difference between the median values ​​of ADC, ADCR and signal on T1W between the soft and hard tumor groups, or between patients with and without tumor residue. CONCLUSION: Our results did not show usefulness of the DWI and T1WI for assessing the consistency of pituitary macroadenomas, nor as a predictor of the degree of surgical resection.

Refractory somatotroph adenomas.

Somatotroph adenomas are usually controlled with standard therapy, which can include surgery, medical treatment and radiotherapy. Some tumors have a more aggressive behavior and are refractory to standard therapy. In this review, we summarize the phenotype of these tumors and the current options for their management.

Importance of 24 h ambulatory blood pressure monitoring in patients with acromegaly and correlation with cardiac magnetic resonance findings.

INTRODUCTION: Arterial hypertension (AH) is prevalent in acromegaly, but few studies using 24-h ambulatory blood pressure monitoring (24 h-ABPM) suggest that its frequency may be different from office blood pressure (OBP). Left ventricular hypertrophy (LVH) is one of the most frequent cardiac abnormalities. Cardiac magnetic resonance (CMR) is considered the gold standard to evaluate the heart. OBJECTIVES: To compare the frequency of AH when measured by 24 h-ABPM and by OBP and to correlate BP with cardiac mass. METHODS: Patients over 18 years of age with acromegaly underwent OBP evaluation and were later referred to the 24 h-ABPM. Treatment-naïve patients were submitted to CMR. RESULTS: We evaluated 96 patients. From 29 non hypertensive patients by OBP, 9 had AH on 24 h-ABPM. In the group of patients with a previous diagnosis of AH by OBP, 25 had controlled BP and 42 had abnormal BP on 24 h-ABPM, when analyzed by OBP there were 28 with controlled BP. We observed a positive correlation between diastolic BP measured in 24 h-ABPM and IGF-I levels, but we did not observe the same correlation with age, sex, body mass index and GH levels. The CMR was performed in 11 patients. We found a positive correlation of left ventricular mass (LVM) and BP of 24 h-ABPM. In contrast, there was no correlation of OBP with CMR parameters. CONCLUSIONS: We observed, that 24 h-ABPM in acromegaly allows the diagnosis of AH in some patients with normal BP in OBP and also to allow a better treatment. 24 h-ABPM shows a better correlation with VM by CMR.

miR-383-5p, miR-181a-5p, and miR-181b-5p as Predictors of Response to First-Generation Somatostatin Receptor Ligands in Acromegaly.

Acromegaly is a chronic systemic disease caused in the vast majority of cases by growth hormone (GH)-secreting adenoma, with surgery being the first-line treatment. When a cure is not attained with surgery, first-generation somatostatin receptor ligands (fg-SRLs) are the most common medication prescribed. Predictors of response to fg-SRLs have been studied; however, they cannot fully predict the response to fg-SRL. MicroRNAs are small RNAs, the main role of which is messenger RNA (mRNA) post-transcriptional regulation. This study aimed to identify the microRNAs involved in resistance to treatment with fg-SRLs in acromegaly. Ten patients with acromegaly undergoing treatment with fg-SRLs were selected to undergo miRNA sequencing: five controlled and five uncontrolled with treatment. Bioinformatic analysis was performed to detect differentially expressed miRNAs. Then, the same 10 samples were used for validation by qPCR and an additional 22 samples were analyzed, totaling 32 samples. e We found 59 differentially expressed miRNAs in the first analysis. miR-181a-5p and miR-181b-5p were downregulated, and miR-383-5p was upregulated in the uncontrolled group. Receiver operating characteristic (ROC) curve analysis of miR-383-5p showed an NPV of 84.3% and a PPV of 84.5%. In summary, miR-181a-5p, miR-181b-5p, and miR-383-5p are biomarkers of response to fg-SRLs, and they can be used individually or included in prediction models as tools to guide clinical decisions.

Pituitary acting drugs: cabergoline and pasireotide.

First-line treatment for Cushing´s disease is transsphenoidal surgery. But in cases of persistent or recurrent disease after surgery, contraindications to surgery, severe hypercortisolism control before surgery, or for patients waiting for radiotherapy effects, medical therapy may be indicated. Pituitary-directed agents include cabergoline and pasireotide. Both drugs present similar potential for biochemical control and pasireotide has additionally been proved to reduce tumor volume. Moreover, pasireotide was evaluated in high quality studies. In respect to safety, both drugs are well tolerated and safe, but special attention should be given for cardiac valve disease and psychiatric disorder for cabergoline, and hyperglycemia for pasireotide.

Opioids and pituitary function: expert opinion.

PURPOSE: Opioids are highly addictive potent analgesics and anti-allodynics whose use has dramatically increased in recent decades. The precipitous rise in opioid dependency and opioid use disorder is an important public health challenge given the risks for severely adverse health outcomes. The long-term opioid impact on hypothalamic-pituitary axes is particularly underappreciated among both endocrinologists and primary care physicians. We review the effects of opioids on hypothalamic-pituitary-target gland function and their implications for clinical practice. METHODS: Experts in hypothalamic-pituitary disorders and opioid pharmacology reviewed recently published literature and considered strategies for diagnosing and managing these opioid-induced endocrine effects. RESULTS: Opioid suppression of hypothalamic-pituitary axes can lead to hypogonadotropic hypogonadism, central adrenal insufficiency, and hyperprolactinemia. These important clinical manifestations are often under-estimated, poorly evaluated, and typically either untreated or not optimally managed. Data on biochemical testing for diagnosis and on the effect of hormone replacement in these patients is limited and prospective randomized controlled studies for guiding clinical practice are lacking. CONCLUSIONS: Patients should be informed about risks for hypogonadism, adrenal insufficiency, and hyperprolactinemia, and encouraged to report associated symptoms. Based on currently available evidence, we recommend clinical and biochemical evaluation for potential central adrenal insufficiency, central hypogonadism, and/or hyperprolactinemia in patients chronically treated with opioids as well as the use of current expert guidelines for the diagnosis and treatment of these conditions.

Characterization of sporadic somatotropinomas with high GIP receptor expression.

PURPOSE: To analyze the expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in somatotropinomas specimens and compare clinical, biochemical, radiological, therapeutic, molecular, and pathological data among those who overexpressed (GIPR +) and those who did not overexpress (GIPR - ) GIPR. METHODS: Clinical, biochemical, radiological, molecular, and pathological data were collected. GNAS1 sequencing was performed with the Sanger method. Protein expression of somatostatin receptor subtypes 2 and 5 and CAM 5.2 were analyzed by immunohistochemistry. Quantitative real-time PCR was performed to analyze the mRNA expression of GIPR with the TaqMan® method. Positive expression was considered when the fold change (FC) was above 17.2 (GIPR +). RESULTS: A total of 74 patients (54% female) were included. Eighteen tumors (24%) were GIPR + . Gsp mutation was detected in 30 tumors (40%). GIPR + tumors were more frequently densely granulated adenomas (83% vs 47%, p = 0.028). There was no difference in clinical, biochemical, radiological, therapeutic (surgical cure or response to medical therapy), or other pathological features between GIPR + and GIPR -  tumors. Twenty-eight out of 56 (50%) GIPR -  tumors harbored a gsp mutation, whereas two out of 18 (11%) GIPR + tumors harbored a gsp mutation (p = 0.005). CONCLUSION: We described, for the first time, that GIPR + and gsp mutations are not mutually exclusive, but gsp mutations are less common in GIPR + tumors. GIPR + and GIPR -  tumors have similar clinical, biochemical, radiological, therapeutic, and pathological features, with the exception of a high frequency of densely granulated adenomas among GIPR + tumors.

MicroRNA in Acromegaly: Involvement in the Pathogenesis and in the Response to First-Generation Somatostatin Receptor Ligands.

Acromegaly is a chronic and systemic disease due to excessive growth hormone and insulin-like growth factor type I caused, in the vast majority of cases, by a GH-secreting pituitary adenoma. About 40% of these tumors have somatic mutations in the stimulatory G protein alpha-subunit 1 gene. The pathogenesis of the remaining tumors, however, is still not fully comprehended. Surgery is the first-line therapy for these tumors, and first-generation somatostatin receptor ligands (fg-SRL) are the most prescribed medications in patients who are not cured by surgery. MicroRNAs are small, non-coding RNAs that control the translation of many mRNAs, and are involved in the post-transcriptional regulation of gene expression. Differentially expressed miRNAs can explain differences in the pathogenesis of acromegaly and tumor resistance. In this review, we focus on the most validated miRNAs, which are mainly involved in acromegaly's tumorigenesis and fg-SRL resistance, as well as in circulating miRNAs in acromegaly.

Glucocorticoid use in patients with adrenal insufficiency following administration of the COVID-19 vaccine: a pituitary society statement.

PURPOSE: Side effects of the coronavirus disease 2019 (COVID-19) vaccines include pain at the injection site, fatigue, headache, myalgias, arthralgias, chills, and fever, all of which can be early indicators of an increased need for glucocorticoid replacement in patients with adrenal insufficiency. The Pituitary Society surveyed its membership to understand planned approaches to glucocorticoid management in patients with adrenal insufficiency who will receive a COVID-19 vaccine. METHODS: Members were asked to complete up to 3 questions regarding their planned approach for use of glucocorticoid replacement in patients with proven adrenal insufficiency. RESULTS: Surveys were sent to 273 members and 103 responded. Thirty-six percent plan to recommend that patients automatically increase glucocorticoid dosage with administration of the first vaccine injection. Of these, 84% plan to increase glucocorticoid dose on the day of vaccination, and 49% plan to increase glucocorticoid dose prior to vaccination. Of the 64% who do not plan to recommend automatic glucocorticoid dose increase with vaccine administration, 88% plan to increase the dose if the patient develops a fever, and 47% plan to increase the dose if myalgias and arthralgias occur. CONCLUSIONS: Most clinicians plan to maintain the current glucocorticoid dose with vaccine administration. The vast majority plan and to increase glucocorticoid dose in case of fever, and just under half in case of arthralgias and myalgias. These survey results offer suggested management guidance for glucocorticoid management in patients with adrenal insufficiency.

Identification of mutant K-RAS in pituitary macroadenoma.

PURPOSE: RAS genes are among the most frequently mutated genes in cancer, where their mutation frequency varies according to the distinct RAS isoforms and tumour types. Despite occurring more prevalent in malignant tumours, RAS mutations were also observed in few benign tumours. Pituitary adenomas are examples of benign tumours which vary in size and aggressiveness. The present study was performed to investigate, via liquid biopsy and tissue analysis, the presence of K-RAS mutations in a pituitary macroadenoma. METHODS: Molecular analysis was performed to investigate K-RAS mutations using the droplet digital PCR (ddPCR) method by evaluating both plasma (liquid biopsy) and the solid tumour of a patient diagnosed with a giant clinically non-functioning pituitary tumour. RESULTS: The patient underwent surgical resection due to visual loss, and the histopathological analysis showed a gonadotrophic pituitary macroadenoma. The molecular analysis revealed the presence of mutant K-RAS both in the plasma and in the tumour tissue which, to our knowledge, has not been previously reported in the literature. CONCLUSION: Our findings highlight the exceptional capacity of the digital PCR in detecting low frequency mutations (below 1%), since we detected, for the first time, K-RAS mutations in pituitary macroadenoma. The potential impact of K-RAS mutations in these tumours should be further investigated.

A Pituitary Society update to acromegaly management guidelines.

Guidelines and consensus statements ensure that physicians managing acromegaly patients have access to current information on evidence-based treatments to optimize outcomes. Given significant novel recent advances in understanding acromegaly natural history and individualized therapies, the Pituitary Society invited acromegaly experts to critically review the current literature in the context of Endocrine Society guidelines and Acromegaly Consensus Group statements. This update focuses on how recent key advances affect treatment decision-making and outcomes, and also highlights the likely role of recently FDA-approved therapies as well as novel combination therapies within the treatment armamentarium.

Accuracy of microcystic aspect on T2-weighted MRI for the diagnosis of silent corticotroph adenomas.

INTRODUCTION: A single study suggested that silent corticotropinomas (SCAs) have a different imaging phenotype, with microcystic aspect on T2-weighted sequence of magnetic resonance imaging (T2-MRI). This study only analysed manifest and silent corticotropinomas and nonfunctioning gonadotroph adenomas. Therefore, the prevalence of microcystic patterns of other tumours is not known. AIM: To analyse frequency of microcystic patterns on T2-MRI in all subtypes of pituitary adenomas and determine accuracy of this radiological finding for diagnosing SCA. METHODS: Consecutive pituitary adenoma patients who underwent surgery between 2013 and 2016 at a single centre were included. T2-MRIs were evaluated by a radiologist and an endocrinologist blinded to histological diagnosis. RESULTS: A total of 143 patients (52% female) with median age of 49 years (14-80) were included. Clinically, there were 90 nonfunctioning pituitary adenomas (NFPAs), 32 somatotropinomas, 13 corticotropinomas, five prolactinomas and three TSH-secreting adenomas. Of the patients with NFPA, 12 (13%) were SCAs, 73 (79%) were gonadotropinomas and five (6%) were positive for prolactin (three) or TSH (two). A microcystic pattern was observed in 16 tumours (11%): one somatotropinoma, one corticotropinoma, seven SCAs and seven gonadotropinomas, and in no prolactinomas or TSH-secreting adenomas. It was more common in SCAs than in other tumours (58.3% vs 6.9%, respectively, P < .001) and had a sensitivity of 58%, a specificity of 93% and an accuracy of 90% to define an SCA. CONCLUSION: Microcystic aspect on T2-MRI is able to define SCA with a good accuracy and can be a useful tool, considering the more aggressive behaviour of these tumours.

Multidisciplinary management of acromegaly: A consensus.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.

Molecular evidence and clinical importance of ß-arrestins expression in patients with acromegaly.

ß-arrestins seem to have a role in endocytosis and desensitization of somatostatin receptor subtype 2 (sst2) and could be associated with the responsiveness to somatostatin receptor ligands (SRL) in patients with acromegaly. To investigate the in vivo correlation between ß-arrestins 1 and 2 with sst2, sst5 and dopamine receptor subtype 2 (D2) expressions, and the association of ß-arrestins with response to first-generation SRL and invasiveness in somatotropinomas. ß-arrestins 1 and 2, sst2, sst5 and D2 mRNA expressions were evaluated by quantitative real-time RT-PCR on tumoral tissue of 96 patients. Moreover, sst2 and sst5 protein expressions were also evaluated in 40 somatotropinomas by immunohistochemistry. Response to SRL, defined as GH <1 µg/l and normal IGF-I levels, was assessed in 40 patients. The Knosp-Steiner criteria were used to define invasiveness. Median ß-arrestin 1, ß-arrestin 2, sst2, sst5 and D2 mRNA copy numbers were 478; 9375; 731; 156; and 3989, respectively. There was a positive correlation between ß-arrestins 1 and 2 (R = 0.444, P < 0.001). However, no correlation between ß-arrestins and sst2, sst5 (mRNA and protein levels) or D2 was found. No association was found between ß-arrestins expression and SRL responsiveness or tumour invasiveness. Although previous data suggest a putative correlation between ß-arrestins and sst2, our data clearly indicated that no association existed between ß-arrestins and sst2, sst5 or D2 expression, nor with response to SRL or tumour invasiveness. Therefore, further studies are required to clarify whether ß-arrestins have a role in the response to treatment with SRL in acromegaly.

Treatment escape reduces the effectiveness of cabergoline during long-term treatment of acromegaly in monotherapy or in association with first-generation somatostatin receptor ligands.

BACKGROUND: Few studies evaluated the use of cabergoline (CAB) for acromegaly treatment in monotherapy or in combination with first-generation somatostatin receptor ligands (SRLs). AIM: To evaluate the efficacy, predictors of response and safety of CAB treatment in acromegaly both in monotherapy and in combination with SRLs. METHODS: We retrospectively collected demographic, biochemical, tumour and treatment data. Short-term disease control was defined as random GH level < 1.0 µg/L and normal age-matched IGF-I level after 3-6 months of treatment with the higher dose used. Long-term disease control was defined as maintenance of normal GH and IGF-I levels at the last visit (at least 9 months of treatment). RESULTS: Eighty-two patients were studied. The median total time of treatment in monotherapy or in combination with SRLs was 14 months (3-124) and 34 months (3-88), respectively. Short-term disease control was observed in 6 (21%) patients in the monotherapy group and in 20 (32%) in the combination group. Treatment escape was observed in 1 patient after 16 months of CAB monotherapy and in 6 (30%) patients with combination therapy (after a median of 38 months), resulting in long-term disease control of 18% and 23%, respectively. Hyperprolactinemia was a predictor of response to monotherapy and pretreatment GH level to combination treatment. CONCLUSION: We presented the results of the largest single-centre study with CAB in monotherapy and in combination with SRL. The efficacy of CAB in acromegaly seems to be lower than that of other drugs, and treatment escape may occur after a long-term follow-up.

Apoplexy in nonfunctioning pituitary adenomas.

Pituitary apoplexy is an uncommon event, occurring due to the infarction and/or haemorrhage usually of a previously unknown pituitary adenoma. It can occur in all adenoma subtypes but is more common in nonfunctioning pituitary adenomas. The physiopathology is not completely clear, and precipitating factors, such as major surgeries, anticoagulant use or pituitary dynamic tests, can be found in up to 40% of patients. The clinical presentation is characterized by a rapid onset with a headache as the main symptom, but visual disturbances can also be present as well as meningism and intracranial hypertension. The diagnosis is based on imaging evaluations, mainly using magnetic resonance imaging, which can show various patterns depending on the timeframe following the occurrence of the apoplectic event. Pituitary hormonal deficits are also common, and the evaluation of hormonal levels is mandatory. Pituitary apoplexy can be managed by surgery or conservative treatment, and a multidisciplinary team is essential for the decision-making process. The outcome is usually positive with both surgical and conservative approaches, but surveillance is needed due to the risk of re-bleeding or tumour recurrence.

Long-Term Remission of Acromegaly after Octreotide Withdrawal Is an Uncommon and Frequently Unsustainable Event.

BACKGROUND: Long-term remission of acromegaly after somatostatin analog withdrawal has been reported in 18-42% of patients in studies with a relatively small number of patients using different inclusion and remission criteria. The objectives of this study were to establish the probability and predictive factors for short- and long-term remission [normal IGF-1 for age/sex: IGF-1 ≤1.00 × upper limit of normal (ULN)] after octreotide long-acting release (LAR) withdrawal in a larger population of well-controlled patients with acromegaly (normal mean IGF-1 in the last 24 months). METHODS: This is a prospective multicenter study in which 58 well-controlled patients with acromegaly receiving only octreotide LAR as a primary or postsurgical treatment were included in 14 university centers in Brazil. All patients had been on stable doses and dose intervals of octreotide LAR in the last year, and none had been submitted to radiotherapy. The main outcome measure was serum IGF-1 after 8 weeks (short-term) and 60 weeks (long-term) of octreotide LAR withdrawal. RESULTS: Seventeen of 58 patients (29%) were in remission in the short term, and only 4 patients achieved long-term remission after treatment withdrawal. The Kaplan-Meier estimated remission probability at 60 weeks was 7% and decreased to 5% at 72 weeks. The short-term remission rate was significantly higher (44%; p = 0.017) in patients with pretreatment IGF-1 <2.4 × ULN. No other predictive factor for short- or long-term remission was found. CONCLUSION: Our results show that long-term remission of acromegaly after octreotide LAR withdrawal was an uncommon and frequently unsustainable event and do not support the recommendation of a systematic withdrawal of treatment in controlled patients.

The genetic background of acromegaly.

Acromegaly is caused by a somatotropinoma in the vast majority of the cases. These are monoclonal tumors that can occur sporadically or rarely in a familial setting. In the last few years, novel familial syndromes have been described and recent studies explored the landscape of somatic mutations in sporadic somatotropinomas. This short review concentrates on the current knowledge of the genetic basis of both familial and sporadic acromegaly.