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Objective: To evaluate the value of the thyrotropin-releasing hormone (TRH) test in the diagnosis of central hypothyroidism (CH) in patients with pituitary disease., Methods: Systematic evaluation of 359 TRH tests in patients with pituitary disease including measurements of thyroxine (T4), TBG-corrected T4 (T4 corr ), baseline TSH (TSH 0 ) and relative or absolute TSH increase (TSH fold , TSH absolute )., Results: Patients diagnosed with CH (n=39) show comparable TSH 0 (p-value 0.824) but lower T4 corr (p-value <0.001) and lower TSH increase (p-value <0.001) compared to patients without CH. In 54% (42 of 78 cases) of patients with low T4 corr , the CH diagnosis was rejected based on a high TSH fold . In these cases, a spontaneous increase and mean normalization in T4 corr (from 62 to 73 nmol/L, p-value <0.001) was observed during the follow-up period (7.6 ± 5.0 years). Three of the 42 patients (7%) were started on replacement therapy due to spontaneous deterioration of thyroid function after 2.8 years. Patients diagnosed with CH reported significantly more symptoms of hypothyroidism (p-value 0.005), although, symptoms were reported in most patients with pituitary disease. The TRH test did not provide clinical relevant information in patients with normal T4 or patients awaiting pituitary surgery (78%, 281 of 359). There were only mild and reversible adverse effects related to the TRH test except for possibly one case (0.3%) experiencing a pituitary apoplexy., Conclusion: The TRH test could be reserved to patients with pituitary disease, low T4 levels without convincing signs of CH. Approximately 50% of patients with a slightly decreased T4 were considered to have normal pituitary thyroid function based on the TRH test results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Christensen, Smith, Rosendal, Gulisano, Ettrup, Vestergaard, Nielsen, Karmisholt and Dal.)

The pituitary gland is either directly or indirectly impacted by SARS-CoV-2 infection. As a consequence of SARS-CoV-2 infection, hypothalamic-pituitary dysfunction or pituitary apoplexy can occur. This study aimed to investigate severe COVID-19 outcomes and COVID-19-related mortality in patients with underlying pituitary disease in Korea using a nationwide cohort database. The data required for this study were obtained from the Health Insurance Review and Assessment Service of Korea. Patients with SARS-CoV-2 infection between January 2020 and December 2021 were divided into the following three groups and analyzed: Group A, those who were hospitalized for SARS-CoV-2 infection without underlying pituitary disease (n = 725,170); Group B, those who were hospitalized for SARS-CoV-2 infection with underlying pituitary disease without exposure to systemic steroids (n = 1509); and Group C, patients with underlying pituitary disease and exposure to systemic steroids (n = 365). Differences in severe COVID-19, requirement for oxygen therapy, intensive care unit admission, application of invasive ventilation or use of extracorporeal membrane oxygenation, and COVID-19-related deaths between groups were then analyzed. Group C had the highest rates of hospitalization after COVID-19 infection (82.2%) and mortality within 30 days of infection (6.8%). Group B had a 1.3-fold increase in severe COVID-19 outcomes compared to Group A. Group C had 1.8-fold and 1.3-fold increases in severe COVID-19 outcomes compared to Group A and Group B, respectively. Group C also had 2.34 and 3.24 times higher mortality rates within 30 days of COVID-19 infection than Group A and Group B, respectively. In conclusion, patients with pituitary disease who are receiving systemic steroids have poorer outcomes and higher mortality associated with COVID-19. Therefore, thorough COVID-19 infection control is required in these patients.

Background: The endoscopic endonasal approach (EEA) is a well-established technique for the treatment of pituitary neuroendocrine tumor Preservation of normal gland tissue is crucial to retain effective neuroendocrine pituitary function. The aim of this paper is to analyze pituitary endocrine secretion after EEA for pituitary neuroendocrine tumor to identify potential predictors of functioning gland recovery., Methods: Patients who underwent an exclusive EEA for pituitary neuroendocrine tumors between October 2014 and November 2019 were reviewed. Patients were divided into groups according to postoperative pituitary function (Group 1, unchanged; group 2, recovering; group 3, worsening)., Results: Among the 45 patients enrolled, 15 presented a silent tumor and showed no hormonal impairment, and 30 patients presented pituitary dysfunction. A total of 19 patients (42.2%) were included in group 1, 12 (26.7%) patients showed pituitary function recovery after surgery (group 2), and 14 patients (31.1%) exhibited the onset of new pituitary deficiency postoperatively (group 3). Younger patients and those with functioning tumor were more likely to have complete pituitary hormonal recovery ( p = 0.0297 and p = 0.007, respectively). No predictors of functional gland worsening were identified., Conclusion: EEA for pituitary neuroendocrine tumor is a reliable and safe technique regarding postoperative hormonal function. Preserving pituitary function after tumor resection should be a primary goal in a minimally invasive approach.

Rare endocrine conditions present specific diagnostic and management challenges for healthcare providers, one of which is the understudied transition of care. Despite the need for guidance regarding transition, consensus on structured and protocolled approaches is lacking. Therefore, we aimed to map the current clinical practice and identify unmet needs regarding transition of care for patients with pituitary disease in the reference centers (RCs) of the European Reference Network on Rare Endocrine Conditions (Endo-ERN). A survey-based, cross-sectional study using the EU Survey tool was performed and completed by 46 physicians (n) from 30 RCs (N). Transition is a common practice among RCs (n = 44/46), usually accomplished by a multidisciplinary team meeting (N = 20/30). Criteria for start and end of transition were defined in half of the RCs, with 16.7% of centers providing dissimilar answers. Transition readiness was assessed by >75% of the RCs, mostly by unvalidated means (e.g. subjective opinions, informal consultations). Pituitary-specific transition assessment tool was applied in one RC only. Transition protocols were present in only 9% of RCs, while in many RCs, transition decisions were taken in combined adult-pediatric meetings or based on clinicians' personal judgment. A minority of physicians evaluated the effectiveness of transition-related interventions (n = 11/46) or medical outcomes (n = 8/46). Patient-reported outcome measures were infrequently used (n = 4/46). Identified unmet needs included the development of guidelines (n = 5/46) and EU-wide approach (n = 2/46). This study exemplifies the unmet needs for a structural definition of the transition period and transition management for patients with rare hypothalamic and pituitary conditions from healthcare providers' perspective.

Background: Hypercortisolism accounts for relevant morbidity and mortality and is often a diagnostic challenge for clinicians. A prompt diagnosis is necessary to treat Cushing's syndrome as early as possible., Objective: The aim of this study was to develop and validate a clinical model for the estimation of pre-test probability of hypercortisolism in an at-risk population., Design: We conducted a retrospective multicenter case-control study, involving five Italian referral centers for Endocrinology (Turin, Messina, Naples, Padua and Rome). One hundred and fifty patients affected by Cushing's syndrome and 300 patients in which hypercortisolism was excluded were enrolled. All patients were evaluated, according to current guidelines, for the suspicion of hypercortisolism., Results: The Cushing score was built by multivariable logistic regression, considering all main features associated with a clinical suspicion of hypercortisolism as possible predictors. A stepwise backward selection algorithm was used (final model AUC=0.873), then an internal validation was performed through ten-fold cross-validation. Final estimation of the model performance showed an average AUC=0.841, thus reassuring about a small overfitting effect. The retrieved score was structured on a 17.5-point scale: low-risk class (score value: ≤5.5, probability of disease=0.8%); intermediate-low-risk class (score value: 6-8.5, probability of disease=2.7%); intermediate-high-risk class (score value: 9-11.5, probability of disease=18.5%) and finally, high-risk class (score value: ≥12, probability of disease=72.5%)., Conclusions: We developed and internally validated a simple tool to determine pre-test probability of hypercortisolism, the Cushing score, that showed a remarkable predictive power for the discrimination between subjects with and without a final diagnosis of Cushing's syndrome., Competing Interests: MS was employed by Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Parasiliti-Caprino, Bioletto, Frigerio, D’Angelo, Ceccato, Ferraù, Ferrigno, Minnetti, Scaroni, Cannavò, Pivonello, Isidori, Broglio, Giordano, Spinello, Grottoli and Arvat.)

Several different proteins regulate, directly or indirectly, the production of growth hormones from the pituitary gland, thereby complex genetics is involved. Defects in these genes are related to the deficiency of growth hormones solely, or deficiency of other hormones, secreted from the pituitary gland including growth hormones. These studies can aid clinicians to trace the pattern of the disease between the families, start early treatment and predict possible future consequences. This paper highlights some of the most common and novel genetic anomalies concerning growth hormones, which are responsible for various genetic defects in isolated growth and combined pituitary hormone deficiency disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Acromegaly is a rare disease that requires modern treatment to decrease the risk of mortality, mainly from vascular diseases. Identifying acromegalic patients with increased cardiovascular risk is challenging. Speckle-tracking echocardiography (STE) is a modern, well-validated, and reproducible method of assessing left ventricular longitudinal deformation and providing a sensitive assessment of myocardial contractility. We hypothesized that STE may be useful in evaluating subclinical dysfunction of the left heart in acromegalic patients, especially when a left ventricle (LV) assessment is completed with STE of the left atrium (LA). Purpose: To assess the diagnostic value of speckle-tracking echocardiography in identifying the occurrence of LV and LA functional impairment in patients with acromegaly, in comparison to patients without this rare pituitary disease. Methods: Echocardiographic assessments of LV and LA function using the new STE method were performed in 60 subjects: 30 acromegalic (ACRO group) patients and a CONTROL group with 30 patients matched in terms of age, gender, systolic/diastolic pressure, and history of hypertension for at least 12 months. Results: The ACRO group, compared to the CONTROL group, presented: (1) higher left ventricular mass (left ventricular mass index: 132 vs. 108 g/m 2 , p < 0.001) and, in consequence, more frequent LV hypertrophy (80.0 vs. 53.3%; p = 0.028); (2) impaired LV systolic function measured by both left ventricular ejection fraction (LVEF) (63.4 vs. 66.9%, p < 0.001) and global longitudinal strain (GLS) (-18.1 vs. -19.4%, p = 0.023); (3) greater LA anteroposterior diameter (40.3 vs. 36.9 mm, p = 0.003) and indexed left atrial volume (37.9 vs. 27.6 ml/m 2 , p < 0.001); and (4) impaired echocardiographic strain parameters corresponding with LA function. Conclusions: Acromegaly, even in young patients with good blood pressure control, may be associated with left ventricular hypertrophy and subclinical impairment of the left ventricular and left atrial mechanical function, which may be identified by speckle-tracking echocardiography. Further research in this area is necessary to clarify the prognostic value of these phenomena., (Copyright © 2020 Uziȩbło-Życzkowska, Jurek, Witek, Zieliński, Gielerak and Krzesiński.)

Prolactinoma is a clinically common intracranial tumor. When serum prolactin levels are not controlled despite administration of a dopamine agonist, the condition is referred to as drug-resistant prolactinoma. The mechanism underlying persistent prolactin secretion in drug-resistant prolactinoma remains unclear. MicroRNAs play an important role in tumorigenesis and development as well as chemotherapeutic resistance. This study was conducted to investigate the mechanism by which miRNA regulates prolactin secretion in drug-resistant prolactinoma. We first found that miR-1299 was elevated in drug-resistant prolactinoma and inhibited FOXO1 in a targeted manner through miRNA sequencing and luciferase assays. We then confirmed that FOXO1 binds to the promoter of the prolactin gene to inhibit its expression through chromatin immunoprecipitation-quantitative PCR and cytological experiments. Finally, inhibition or overexpression of miR-1299 in primary tumor cells confirmed that drug-resistant prolactinoma promoted prolactin secretion by promoting miR-1299 expression and reducing intracellular FOXO1. These results indicate that FOXO1 and miR-1299 are potential therapeutic targets for drug-resistant prolactinoma as well as other pituitary diseases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Thyroid disease mainly has a thyroid origin but can occasionally have a pituitary origin. Clinicians face several challenges when these conditions occur together. We aimed to determine the prevalence of thyroid disorders in patients undergoing trans-sphenoidal adenomectomy (TSA) for pituitary disease. We reviewed the medical records of patients undergoing TSA for pituitary disease between 2008 and 2017 at Severance Hospital. Thyroid disorders were categorized using blood test results and medical histories at the time of preoperative evaluation. Among 2202 patients, 44 (2%), 218 (9.9%), and 74 (3.4%) had hyperthyroidism, hypothyroidism, and post-thyroidectomy status before TSA, respectively. Among the 44 patients with hyperthyroidism, 30 (68.2%) had central hyperthyroidism. Among the 218 patients with hypothyroidism, 165 (75.7%) had central hypothyroidism. Central hypothyroidism was more common in patients with adrenocorticotropic hormone-secreting pituitary adenomas (aOR (adjusted odds ratio) 1.85), Rathke's cleft cysts (aOR 2.34), and craniopharyngiomas (aOR 2.58) (all p < 0.05) than in those with nonfunctioning pituitary adenomas. Contrastingly, thyroid cancer had an increased prevalence in patients with growth hormone- (aOR 3.17), prolactin- (aOR 3.66), and thyroid-stimulating hormone-secreting (aOR 6.28) pituitary adenomas (all p < 0.05). Pituitary disease sometimes accompanies thyroid disorders; their characteristics vary according to the type of pituitary disease., Competing Interests: The authors declare no conflicts of interest.

The diagnosis and treatment of pituitary disease in pregnancy represents a special clinical challenge. Not least because there is very little data on the treatment of pregnant patients with pituitary disorders. A selective search of the literature was carried out with the aim of compiling evidence about the diagnosis and treatment of pituitary disease in pregnancy. The search covered the databases PubMed/MEDLINE including PubMed Central and also used the Livivo (ZB MED) search engine. Recent studies were evaluated for recommendations about the care of pregnant patients with hormone-inactive and hormone-active pituitary adenomas (prolactinoma, acromegaly and Cushing's disease), pituitary insufficiency, pituitary apoplexy and hypophysitis. The most well-established forms of treatment are for prolactinoma, due to the incidence of this disease and its impact on fertility. When pregnancy has been confirmed, prolactinoma treatment with dopamine agonists should be paused. Although microprolactinomas rarely increase significantly in size after the administration of dopamine agonists is discontinued, symptomatic tumor growth of macroprolactinomas can occur. In such cases, treatment with dopamine agonists can be resumed. If the primary tumor is large and the risk that it will continue to grow is high, it may be necessary to continue medical treatment from the start of pregnancy. If one of the partners has a pituitary disorder, it is often still possible for many couples to achieve their wish of having children if they receive medical support to plan and the pregnancy is carefully monitored. Given the complexity of pituitary disease, pregnant patients with pituitary disorders should be cared for and treated by a multidisciplinary team in centers specializing in the diagnosis and treatment of pituitary disease.

Background Pituitary cysts have been speculated to cause endocrinopathies. We sought to describe the prevalence and volumetry of pituitary cysts in patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS). Methods Six hundred and eighteen children evaluated for growth failure at the Division of Pediatric Endocrinology at New York Medical College between the years 2002 and 2012, who underwent GH stimulation testing and had a brain magnetic resonance imaging (MRI) prior to initiating GH treatment were randomly selected to be a part of this study. High resolution MRI was used to evaluate the pituitary gland for size and the presence of a cyst. Cyst prevalence, cyst volume and percentage of the gland occupied by the cyst (POGO) were documented. Results Fifty-six patients had a cyst, giving an overall prevalence of 9.1%. The prevalence of cysts in GHD patients compared to ISS patients was not significant (13.5% vs. 5.7%, p=0.46). Mean cyst volume was greater in GHD patients than ISS patients (62.0 mm3 vs. 29.4 mm3, p=0.01). POGO for GHD patients was significantly greater (p=0.003) than for ISS patients (15.3%±12.8 vs. 7.1%±8.0). Observers were blinded to patient groups. Conclusions GHD patients had a significantly greater volume and POGO compared to ISS patients. This raises the question of whether cysts are implicated in the pathology of growth failure.

Objectives  Internal carotid artery (ICA) injury remains a rare but potentially fatal complication of transsphenoidal pituitary or anterior skull base surgery. Preoperative imaging must be scrutinized to minimize risk. On axial computed tomography (CT), the protrusions of the ICAs into the sphenoid resemble a "teddy bear." This article aims to describe the sign, its grading system (0-2) and quantify its presence. Design  Retrospective review of preoperative CT imaging. Setting  Tertiary referral center in the United Kingdom. Participants  One hundred patients who underwent endoscopic transsphenoidal surgery for pituitary disease were enrolled. Main Outcome Measure  The presence and grading of the "teddy bear" sign were assessed on preoperative CT imaging. Results  A grade 2 (strongly positive) "teddy bear" sign was identified in 40% at the level of the superior pituitary fossa, 78% at the inferior pituitary fossa, and 59% at the clivus. A grade 1 (intermediate) sign was seen in 23.5, 7.5, and 10% of cases, respectively. In 5% of cases, the sign was grade 0 at all levels-indicating poor intraoperative localization of the ICA. Conclusion  The "teddy bear" sign is a useful preoperative tool for identification of anatomy predisposing patients to a higher risk of ICA injury. Those patients who have an absent or grade 0 "teddy bear" sign require extra care to ensure intraoperative localization of the ICAs which may include the use of neuronavigation or a Doppler probe. A grade 2 sign predicts good intraoperative localization of the ICA intraoperatively to inform the safe lateral limit of sellar bone resection.

Background:  Sellar and parasellar region lesions spectrum includes a wide variety of diseases. This study aimed at providing a comprehensive overview of such lesions in patients from  Faiha Specialized Diabetes, Endocrine and Metabolism Center (FDEMC) in Basrah (Southern Iraq). Methods: Retrospective data analysis from FDEMC for the period January 2012 through June 2017. We included all patients with sellar and parasellar region lesions who received a MRI scan on their pituitary region Results: The total enrolled patients were 232 (84 men and 148 women),with age range 15-75 years.Pituitary disease and adenoma were more common among women. Those with macroadenoma were older than those with microadenoma, with nearly equal gender prevalence of macroadenoma. Pituitary adenoma constituted the bulk of pituitary disease in this setting (67.2%). Growth hormone secreting adenoma were the most common adenoma seen in 41.0%, followed by clinically non-functioning pituitary adenoma (NFPA) in 31.4% and prolactinoma in 26.9%. About 64.8% of pituitary adenoma was macroadenoma. Macroadenoma was seen in 73.4% of growth hormone secreting adenoma (acromegaly), 61.2% in NFPA and 62.0% of prolactinom a(of them six were giant prolactinoma). Conclusion : Pituitary adenoma constituted the bulk of sellar and parasellar region lesions, growth hormone secreting adenoma is the the most common adenoma followed by NFPA and prolactinoma due to referral bias. A change  in  practice of adenoma treatment is needed., Competing Interests: No competing interests were disclosed.

Background: Pituitary disorders spectrum includes a wide variety of diseases.This study aimed at a comprehensive description of such disorders for patients from  Faiha Specialized Diabetes, Endocrine and Metabolism Center (FDEMC) in Basrah (Southern Iraq). Methods:  Retrospective data analysis of FDEMC for the period from January 2012 through June 2017. We included all patients with pituitary disorders who have MRI pituitary. Results:  The pituitary disorders were more common among women. Those with macroadenoma were older than those with microadenoma with nearly equal gender prevalence of macroadenoma. Pituitary adenoma constituted the bulk of pituitary disorders in this registry (67.2%). Growth hormone secreting adenoma were the commonest adenoma seen in 41.0% followed by clinically non-functioning pituitary adenoma(NFPA)in 31.4% and prolactinoma in 26.9%. About 64.8% of pituitary adenoma was macroadenoma. Macroadenoma was seen in 73.4 % of growth hormone secreting adenoma, 61.2% in NFPA and 62.0% of prolactinoma (of them six were giant prolactinoma) Conclusion : Pituitary adenoma constituted the bulk of pituitary disorders in Basrah, growth hormone secreting adenoma is the commonest adenoma followed by NFPA and prolactinoma due to referral bias. A change  in  practice of pituitary adenoma treatment is needed., Competing Interests: No competing interests were disclosed.

Purpose: Measuring IGF-1, a biomarker for GH activity, is critical to evaluating disordered hypothalamic-pituitary GH axis. Inconsistent IGF-1 measurements among different immunoassays are well documented. We switched from Immulite 2000 immunoassay to narrow-mass-extraction, high-resolution liquid chromatography mass-spectrometry (LC-MS) compliant with recent consensus recommendations on assay standardization. Comparability of these two assays in patients with pituitary disease in a clinical practice setting is not known. We sought to compare IGF-1 levels on Immulite 2000 and LC-MS in samples from naïve and treated patients with secretory and non-secretory pituitary masses., Methods: We prospectively collected serum samples from 101 patients treated at the Cedars-Sinai Pituitary Center between February 2012 and March 2014. We intentionally recruited more patients with acromegaly or GH deficiency to ensure a clinically representative cohort. Samples were classified as in or out of the respective reference ranges. Bland-Altman analysis was used to assess agreement between assays., Results: Twenty-four percent of samples were classified differently as below, in, or above range. Agreement between the assays was poor overall, with a significant bias for immunoassay reporting higher values than LC-MS. This pattern was also observed in patients with acromegaly and those with ≥ 2 pituitary hormone deficiencies., Conclusions: IGF-1 results may differ after switching from an older immunoassay to a consensus-compliant assay such as LC-MS. Clinicians should consider the potential impact of assay switching before altering treatment due to discrepant results, particularly in patients monitored over time, such as those with acromegaly and GH deficiency.

Context: Cabergoline (CAB) is very effective in the treatment of macroprolactinomas, but there are few data on the CAB dose necessary to achieve and maintain normal prolactin (PRL) levels., Design and Patients: We retrospectively studied 260 patients. CAB was introduced at a mean dose of 0.83 ± 0.52 mg/wk. When the PRL level had normalized, the patient's physician chose to either maintain the CAB dose (fixed-dose group) or to taper it (de-escalation group) until the minimal effective dose required to maintain a normal PRL level was established., Results: PRL normalized in 157 patients (60.8%) during CAB treatment. CAB de-escalation was attempted in 84 (53.5%) of these 157 patients and was successful in 77 (91.7%) cases. The mean CAB dose was reduced from 1.52 ± 1.17 mg/wk to 0.56 ± 0.44 mg/wk at the last visit ( P < 1 × 10 -4 ). De-escalation was also possible in some "CAB-resistant" patients, namely those requiring ≥2 mg/wk to normalize PRL. CAB de-escalation had no negative long-term effect on tumor size. At the last visit, maximal diameter was 8.8 ± 8.8 mm in the de-escalation group and 13.4 ± 8.5 mm in the fixed-dose group ( P < 0.01)., Conclusion: In patients with macroprolactinomas, the CAB dosage required to maintain a normal PRL level long term is lower than the initial dosage necessary to normalize the PRL level. After PRL normalization, CAB tapering was almost always successful, even when very high initial doses were necessary. CAB tapering does not undermine tumor control and may attenuate the potential adverse effects of CAB, which appear to be dependent on the cumulative dose.

Sex hormone-binding globulin (SHBG) is a serum glycoprotein exhibiting the unique feature of binding sex steroids with high affinity and specificity. Its serum levels are regulated not only by androgens and estrogens but also by thyroid hormones and other metabolic factors. Several disease conditions are accompanied by altered SHBG levels such as hyper- and hypoandrogenism, thyroid disorders, pituitary diseases, liver disorders, and breast as well as prostate cancer. Additionally, several drugs and alcohol consumption influence serum concentrations of SHBG. In some cases, altered SHBG levels are a specific result of the underlying pathology. In others, they merely constitute an epiphenomenon, which still might offer the possibility of using serum measurements of SHBG as surrogate marker. This review article portrays the different disorders associated with altered SHBG levels and discusses the usefulness of SHBG as disease biomarker from a clinicians as well as from an endocrinological researchers point of view., (Copyright © 2015 Elsevier Ltd. All rights reserved.)