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.

Surveillance Imaging Strategies for Pituitary Adenomas: When, How Frequent, and When to Stop.

OBJECTIVE: To describe a practical approach of when and how often to perform imaging, and when to stop imaging pituitary adenomas (PAs). METHODS: A literature review was carried out and recommendations provided are derived largely from personal experience. RESULTS: Magnetic resonance imaging is the mainstay imaging modality of choice in the assessment, treatment planning, and follow-up of PAs. These adenomas are discovered incidentally during imaging for a variety of unrelated conditions, because of clinical symptoms related to mass effects on the adjacent structures, or during workup for functional alterations of the adenoma. Imaging is also used in the preoperative and postoperative phases of assessment of PAs, for surgical and radiotherapy planning, for postoperative surveillance to assess for adenoma stability and detection of adenoma recurrence, and for surveillance to monitor for adenoma growth in unoperated PAs. Currently, because there are no evidence-based consensus recommendations, the optimal strategy for surveillance imaging of PAs is not clearly established. Younger age, initial adenoma size, extrasellar extension, mass effect, cavernous sinus invasion, functional status, histopathologic characteristics, cost considerations, imaging accessibility, patient preference, and patient contraindications (eg, implanted metallic devices and patient claustrophobia) are all important factors that influence the strategy for surveillance imaging. CONCLUSIONS: This review provides a practical approach of performing surveillance imaging strategies for PAs that should be individualized based on clinical presentation, history, adenoma morphology on imaging, and histopathologic characteristics.

Silent somatotroph pituitary adenomas: an update.

Silent growth hormone adenomas (SGHA) are a rare entity of non-functioning pituitary neuroendocrine tumors. Diagnosis is invariably made post-operatively of a tumor immunopositive for GH (and Pit-1 in selected cases) but without clinical acromegaly. Mainly young females are affected, and tumors are often uncovered by investigation for headaches or oligoamenorrhea. Integration of clinical, pathological and biochemical data is required for proper diagnosis. Beside normal IGF-1 levels, a third of SGHAs displays elevated GH levels and some will eventually progress to acromegaly. Almost two-thirds will be mixed GH-prolactin tumors and sparsely-granulated monohormonal GH tumors seems the more aggressive subtype. Recurrence and need for radiation is higher than other non-functioning tumors so close follow-up is warranted.

Predictors of silent corticotroph adenoma recurrence; a large retrospective single center study and systematic literature review.

PURPOSE: Silent corticotroph adenomas (SCAs) are clinically silent and non-secreting, but exhibit positive adrenocorticotropic hormone (ACTH) immunostaining. We characterized a single center cohort of SCA patients, compared the SCAs to silent gonadotroph adenomas (SGAs), identified predictors of recurrence, and reviewed and compared the cohort to previously published SCAs cases. METHODS: Retrospective review of SCA and SGA surgically resected patients over 10 years and 6 years, respectively. Definitions; SCA-no clinical or biochemical evidence of Cushing's syndrome and ACTH positive immunostaining, and SGA-steroidogenic factor (SF-1) positive immunostaining. A systematic literature search was undertaken using Pubmed and Scopus. RESULTS: Review revealed 814 pituitary surgeries, 39 (4.8%) were SCAs. Mean follow-up was 6.4 years (range 0.5-23.8 years). Pre-operative magnetic resonance imaging demonstrated sphenoid and/or cavernous sinus invasion in 44%, 33% were > 50% cystic, and 28% had high ACTH levels pre-operatively. Compared to SGAs (n = 70), SCAs were of similar size and invasiveness (2.5 vs. 2.9 cm, p = 0.2; 44 vs. 41%, p = 0.8, respectively), but recurrence rate was higher (36 vs. 10%, p = 0.001) and more patients received radiation therapy (18 vs. 3%, p = 0.006). Less cystic tumors (0 vs. 50%, p < 0.001) and higher pre-operative ACTH levels (54 vs. 28 pg/ml, p = 0.04) were predictors of recurrence for SCAs. CONCLUSION: This review is unique; a strict definition of SCA was used, and single center SCAs were compared with SGAs and with SCAs literature reviewed cases. We show that SCAs are aggressive and identify predictors of recurrence. Accurate initial diagnosis, close imaging and biochemical follow up are warranted.

An individualized approach to the management of Cushing disease.

Cushing disease caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary corticotroph adenoma leads to hypercortisolaemia with high mortality due to metabolic, cardiovascular, immunological, neurocognitive, haematological and infectious conditions. The disorder is challenging to diagnose because of its common and heterogenous presenting features and the biochemical pitfalls of testing levels of hormones in the hypothalamic-pituitary-adrenal axis. Several late-night salivary cortisol and 24-h urinary free cortisol tests are usually required as well as serum levels of cortisol after a dexamethasone suppression test. MRI might only identify an adenoma in 60-75% of patients and many adenomas are small. Therefore, inferior petrosal sinus sampling remains the gold standard for confirmation of ACTH secretion from a pituitary source. Initial treatment is usually transsphenoidal adenoma resection, but preoperative medical therapy is increasingly being used in some countries and regions. Other management approaches are required if Cushing disease persists or recurs following surgery, including medications to modulate ACTH or block cortisol secretion or actions, pituitary radiation, and/or bilateral adrenalectomy. All patients require lifelong surveillance for persistent comorbidities, clinical and biochemical recurrence, and treatment-related adverse effects (including development of treatment-associated hypopituitarism). In this Review, we discuss challenges in the management of Cushing disease in adults and provide information to guide clinicians when planning an integrated and individualized approach for each patient.

Hypophysitis, the Growing Spectrum of a Rare Pituitary Disease.

Hypophysitis is defined as inflammation of the pituitary gland that is primary or secondary to a local or systemic process. Differential diagnosis is broad (including primary tumors, metastases, and lympho-proliferative diseases) and multifaceted. Patients with hypophysitis typically present with headaches, some degree of anterior and/or posterior pituitary dysfunction, and enlargement of pituitary gland and/or stalk, as determined by imaging. Most hypophysitis causes are autoimmune, but other etiologies include inflammation secondary to sellar tumors or cysts, systemic diseases, and infection or drug-induced causes. Novel pathologies such as immunoglobulin G4-related hypophysitis, immunotherapy-induced hypophysitis, and paraneoplastic pituitary-directed autoimmunity are also included in a growing spectrum of this rare pituitary disease. Typical magnetic resonance imaging reveals stalk thickening and homogenous enlargement of the pituitary gland; however, imaging is not always specific. Diagnosis can be challenging, and ultimately, only a pituitary biopsy can confirm hypophysitis type and rule out other etiologies. A presumptive diagnosis can be made often without biopsy. Detailed history and clinical examination are essential, notably for signs of underlying etiology with systemic manifestations. Hormone replacement and, in selected cases, careful observation is advised with imaging follow-up. High-dose glucocorticoids are initiated mainly to help reduce mass effect. A response may be observed in all auto-immune etiologies, as well as in lymphoproliferative diseases, and, as such, should not be used for differential diagnosis. Surgery may be necessary in some cases to relieve mass effect and allow a definite diagnosis. Immunosuppressive therapy and radiation are sometimes also necessary in resistant cases.

Acromegaly: pathogenesis, diagnosis, and management.

Growth hormone-secreting pituitary adenomas that cause acromegaly arise as monoclonal expansions of differentiated somatotroph cells and are usually sporadic. They are almost invariably benign, yet they can be locally invasive and show progressive growth despite treatment. Persistent excess of both growth hormone and its target hormone insulin-like growth factor 1 (IGF-1) results in a wide array of cardiovascular, respiratory, metabolic, musculoskeletal, neurological, and neoplastic comorbidities that might not be reversible with disease control. Normalisation of IGF-1 and growth hormone are the primary therapeutic aims; additional treatment goals include tumour shrinkage, relieving symptoms, managing complications, reducing excess morbidity, and improving quality of life. A multimodal approach with surgery, medical therapy, and (more rarely) radiation therapy is required to achieve these goals. In this Review, we examine the epidemiology, pathogenesis, diagnosis, complications, and treatment of acromegaly, with an emphasis on the importance of tailoring management strategies to each patient to optimise outcomes.

What to Do with Incidentally Discovered Pituitary Abnormalities?

Pituitary incidentalomas are discovered in approximately 10% to 40% of brain images. A complete patient history, physical examination, and dedicated pituitary function testing are needed, and subsequent results should lead to appropriate patient management. However, most lesions are asymptomatic pituitary adenomas or Rathke cleft cysts with a benign course. Many lesions can be clinically significant, including prolactinomas or other pituitary adenomas that warrant specific pituitary disease treatment. In other cases, mass effect causing visual compromise or refractory headache indicates a need for surgery. Here, various facets of a complex evaluation and treatment algorithm for pituitary incidentalomas are reviewed.

Hypercoagulability in Cushing's syndrome: From arterial to venous disease.

Cushing's syndrome (CS) is associated with multisystemic complications; the hematological system is not spared. Alteration in hemostatic parameters and in vivo endothelial dysfunction lead to increased thrombotic events. Arterial and venous thrombotic events carry significant morbidity and mortality. Death from cardiovascular and pulmonary embolism account for more than 50% of mortality. Surgery is a critical period; close to 50% of events occur in the 1-2 months after intervention. The evaluation and risk stratification of patients with CS is key to prevent events, balancing the risk-benefit of anticoagulation in this population. This current review will focus on up-to-date data on epidemiology, pathophysiology and management of hypercoagulability in CS.

MANAGEMENT OF ENDOCRINE DISEASE: Cardiovascular risk assessment, thromboembolism, and infection prevention in Cushing's syndrome: a practical approach.

Cushing's syndrome (CS) is associated with increased mortality that is driven by cardiovascular, thromboembolic, and infection complications. Although these events are expected to decrease during disease remission, incidence often transiently increases postoperatively and is not completely normalized in the long-term. It is important to diagnose and treat cardiovascular, thromboembolic, and infection complications concomitantly with CS treatment. Management of hyperglycemia/diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with clinical care standards. Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism, and treatment adjustments can be made based on disease pathophysiology and drug-drug interactions. Thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding. Pneumocystis jiroveci pneumonia prophylaxis should be considered for patients with high urinary free cortisol at the initiation of hypercortisolism treatment.

Updates in rare and not-so-rare complications of acromegaly: focus on respiratory function and quality of life in acromegaly.

Acromegaly is a complex disease with excessive growth hormone and insulin-like growth factor 1 (IGF-1) causing multisystem effects, particularly cardiovascular, respiratory, and metabolic. Psychological concerns and poor quality of life (QoL) are also major disease consequences. This review is intended for clinicians and focuses on the latest developments related to respiratory and QoL effects of long-term growth hormone excess. Along with biochemical disease control, patient treatment satisfaction and outcomes have become major treatment objectives; current knowledge and tools to evaluate and manage this aspect of the disease are described. Sleep apnea syndrome and other derangements of lung function and apparatus, from pathophysiology to treatment, and evaluation tools and determinants of QoL in patients with acromegaly are discussed.

High prevalence of adrenal insufficiency at diagnosis and headache recovery in surgically resected Rathke's cleft cysts-a large retrospective single center study.

BACKGROUND: Rathke's cleft cysts (RCC) are lesions that arise from Rathke's pouch. Though frequently incidental, resulting symptoms in a minority of cases are indicators for surgical resection, which may prove beneficial. OBJECTIVE: To characterize a cohort of surgically-resected RCC cases at Oregon Health & Science University; tabulate associated hormonal imbalances and symptoms, possible symptom reversal with surgery, determine recurrence risk; identify predictors of recurrence and headache improvement. METHOD: Electronic records of all RCC resected cases (from 2006-2016; 11 years) were retrospectively reviewed. Patients had been evaluated by one neuroendocrinologist using a uniform protocol. RESULTS: A pathological RCC diagnosis was established in 73 of 814 (9%) surgical pituitary cases. The RCC cohort was 77% (n = 56/73) female, mean age was 39.5 ± 14.9 years at first surgery, and at presentation headache was reported in 88% and visual defects/diplopia in 18% of patients. Initial RCC maximum diameter was 1.3 ± 0.7 cm. The most frequent hormonal deficit was cortisol; 24% of patients had a new adrenal insufficiency (AI) diagnosis, however, 36% also had AI at 3 months post-operatively. Mean follow up was 4.0 ± 4.5 years. Two-thirds of patients (41/62) had headache improvement 3 months post-operatively. Post-operative imaging revealed no residual cyst in 58% (38/65). In those patients with no residual RCC, 29% had recurrence and 71% had long lasting cure. From the 42% (27/65) of patients with residual cyst on post-operative imaging; 59% (16/27) remained stable, 26% (7/27) progressed and 15% (4/27) regressed. CONCLUSION: Symptomatic RCC present mostly in women, with a high proportion reporting headaches. Prevalence of AI at diagnosis is high. Surgery may not achieve adrenal axis recovery, but renders a high percentage of headache improvement. Approximately 25% of RCC will recur by 4 years postoperatively. Clinicians should cautiously screen patients with symptomatic RCC, regardless of lesion size for AI.

Pituitary-Directed Therapies for Cushing's Disease.

Cushing's disease (CD) is caused by a pituitary corticotroph neuroendocrine tumor inducing uncontrolled hypercortisolism. Transsphenoidal surgery is the first-line treatment in most cases. Nonetheless, some patients will not achieve cure even in expert hands, others may not be surgical candidates and a significant percentage will experience recurrence. Many patients will thus require medical therapy to achieve disease control. Pharmacologic options to treat CD have increased in recent years, with an explosion in knowledge related to pathophysiology at the molecular level. In this review, we focus on medications targeting specifically pituitary adrenocorticotropic hormone-secreting tumors. The only medication in this group approved for the treatment of CD is pasireotide, a somatostatin receptor ligand. Cabergoline and temozolomide may also be used in select cases. Previously studied and abandoned medical options are briefly discussed, and emphasis is made on upcoming medications. Mechanism of action and available data on efficacy and safety of cell cycle inhibitor roscovitine, epidermal growth factor receptor inhibitor gefitinib, retinoic acid, and silibinin, a heat shock protein 90 inhibitor are also presented.

Hypercoagulability and Risk of Venous Thromboembolic Events in Endogenous Cushing's Syndrome: A Systematic Meta-Analysis.

Background: Hypercortisolism has been implicated in the development of venous thromboembolic events (VTE). We aimed to characterize VTE risk in endogenous Cushing's syndrome (CS) patients, compare that risk to other pathologies, and determine if there are any associated coagulation factor changes. Methods: Medline and Scopus search for "hypercortisolism" and "thromboembolic disease" from January 1980 to April 2017 to include studies that reported VTE rates and/or coagulation profile of CS patients. A systematic review and meta-analysis were performed. Results: Forty-eight studies met inclusion criteria. There were 7,142 CS patients, average age was 42 years and 77.7% female. Odds ratio of spontaneous VTE in CS is 17.82 (95%CI 15.24-20.85, p < 0.00001) when comparing to a healthy population. For CS patients undergoing surgery, the odds ratio (both with / without anticoagulation) of spontaneous VTE is 0.26 (95%CI 0.07-0.11, p < 0.00001)/0.34 (0.19-0.36, p < 0.00001) when compared to patients undergoing hip fracture surgery who were not treated with anticoagulants. Coagulation profiles in patients with CS showed statistically significant differences compared to controls, as reflected by increases in von Willebrand factor (180.11 vs. 112.53 IU/dL, p < 0.01), as well as decreases in activated partial thromboplastin time (aPTT; 26.91 vs. 30.65, p < 0.001) and increases in factor VIII (169 vs. 137 IU/dL, p < 0.05). Conclusion: CS is associated with significantly increased VTE odds vs. general population, but lower than in patients undergoing major orthopedic surgery. Although exact timing, type, and dose of anticoagulation medication remains to be established, clinicians might consider monitoring vWF, PTT, and factor VIII when evaluating CS patients and balance advantages of thromboprophylaxis with risk of bleeding.

Recent Progress in the Medical Therapy of Pituitary Tumors.

Management of pituitary tumors is multidisciplinary, with medical therapy playing an increasingly important role. With the exception of prolactin-secreting tumors, surgery is still considered the first-line treatment for the majority of pituitary adenomas. However, medical/pharmacological therapy plays an important role in controlling hormone-producing pituitary adenomas, especially for patients with acromegaly and Cushing disease (CD). In the case of non-functioning pituitary adenomas (NFAs), pharmacological therapy plays a minor role, the main objective of which is to reduce tumor growth, but this role requires further studies. For pituitary carcinomas and atypical adenomas, medical therapy, including chemotherapy, acts as an adjuvant to surgery and radiation therapy, which is often required to control these aggressive tumors. In the last decade, knowledge about the pathophysiological mechanisms of various pituitary adenomas has increased, thus novel medical therapies that target specific pathways implicated in tumor synthesis and hormonal over secretion are now available. Advancement in patient selection and determination of prognostic factors has also helped to individualize therapy for patients with pituitary tumors. Improvements in biochemical and "tumor mass" disease control can positively affect patient quality of life, comorbidities and overall survival. In this review, the medical armamentarium for treating CD, acromegaly, prolactinomas, NFA, and carcinomas/aggressive atypical adenomas will be presented. Pharmacological therapies, including doses, mode of administration, efficacy, adverse effects, and use in special circumstances are provided. Medical therapies currently under clinical investigation are also briefly discussed.

Update on adrenal insufficiency: diagnosis and management in pregnancy.

PURPOSE OF REVIEW: Adrenal insufficiency in pregnancy, although relatively rare, has significant clinical implications on both maternal and fetal outcomes. Hypothalamo-pituitary-adrenal axis dynamics and physiological changes are complex, thus diagnosis and management of adrenal insufficiency in pregnancy remain challenging. RECENT FINDINGS: Studies consistently demonstrate a rise in total serum cortisol with pregnancy, but less data are available on free cortisol levels. Salivary cortisol values have been measured in normal pregnancy and in a few studies using healthy nonpregnant women controls. Although this adds to our current knowledge of hypothalamo-pituitary-adrenal axis changes in pregnancy, clear-cut cortisol reference ranges are yet to be established. Serum cortisol and the cosyntropin stimulation test (albeit with higher peak cortisol thresholds) are currently the diagnostic tests of choice. Hydrocortisone is the preferred glucocorticoid replacement in pregnancy as it is inactivated by placental 11-ß-hydroxysteroid dehydrogenase 2; dose titration may be required, but should be individualized depending on clinical course and mode of delivery. SUMMARY: Further studies on the long-term effects of maternal glucocorticoid regimens on the fetus and potential modulators of fetal glucocorticoid sensitivity and placental 11-ß-hydroxysteroid dehydrogenase 2 are needed and will be useful in guiding clinical management strategies in pregnant women with adrenal insufficiency.

Falsely Elevated Steroid Hormones in a Postmenopausal Woman Due to Laboratory Interference.

Laboratory interference is a drawback in hormonal testing, and clinicians should have a high index of suspicion when faced with biochemical results discordant with the patient's clinical manifestations. A 62-year-old postmenopausal woman initially consulted her primary care physician for mood lability; laboratory workup showed markedly elevated levels of total serum estradiol, progesterone, testosterone, and cortisol as measured by immunoassay. Further investigation demonstrated no evidence of estrogen effect on uterus, no adrenal or adnexal mass, and no evidence of Cushing syndrome. Conventional techniques to unmask laboratory interference, such as dilution, antigen precipitation, and using a different immunoassay did not unveil a potential laboratory interference. The patient had no apparent risk factor for analytic interference, such as absent rheumatoid factor and heterophilic antibodies, but had only mild monoclonal IgG hypergammaglobulinemia. In this case, mass spectrometry unmasked the false elevation in steroid hormones. Interference of gammaglobulins or antibodies with the labeling and separation process of the assay could be the culprits. In conclusion, we report a unique case of multiple steroid hormones elevations due to laboratory interference unmasked by mass spectrometry.

Clinical profile of silent growth hormone pituitary adenomas; higher recurrence rate compared to silent gonadotroph pituitary tumors, a large single center experience.

PURPOSE: Study and comparison of characteristics of silent growth hormone adenomas (SGHA), silent corticotroph adenomas (SCA), and silent gonadotroph adenomas (SGA) in a single institution cohort of surgically treated pituitary adenomas. METHODS: Retrospective analysis of SGHA surgically resected over 10 years: SGHA was defined as no clinical or biochemical evidence of acromegaly and positive GH immunostaining. RESULTS: Of 814 pituitary surgeries; 2.1% (n = 17) were SGHA, 4.5% (n = 37) SCA, and 18.9% (n = 70/371; 2011-2016) SGA. Mean age at SGHA diagnosis was 43 years, with a large female predominance (82%). Mean tumor size and cavernous/sphenoid sinus invasiveness for SGHA, SCA, and SGA were 1.5 ± 1.0 cm and 25%, 2.5 ± 1.2 cm and 43%, 2.9 ± 2.0 cm and 41%, respectively (tumor size p = 0.009, SGHA vs. SGA, and invasion p; not-significant). During mean follow-up of 3.9 years, two patients (11%) developed elevated insulin-like growth factor-1 and five patients (29%) required a second surgery for tumor recurrence. Rate of surgical reintervention was similar to SCA (31%), but higher than SGA (10%) (p = 0.035, SGHA vs. SGA), and 18% underwent radiation therapy, similar to SCA (19%, p; not-significant) but higher than SGA (2.9%, p = 0.018). CONCLUSION: This is the largest single center study characterizing SGHA behavior with SGA and SCA control groups in a cohort of surgically resected pituitary adenomas. SGHA present mostly in young females, and should be closely followed due to their higher likelihood of recurrence and potential of progression to clinical acromegaly. We propose that a complete hormonal staining panel be routinely performed for all pituitary adenomas.

Ghrelin levels are associated with hunger as measured by the Three-Factor Eating Questionnaire in healthy young adults.

Weight gain and appetite regulation are complex interplays between internal and external cues. Our aim was to investigate the association of eating behaviors with ghrelin taking into account lifestyle. We conducted a cross-sectional analysis in a sample of first-year university students at the Université de Sherbrooke. We collected medical history, anthropometric measurements, vital signs, fitness index, and fasting blood samples. Questionnaires included a lifestyle questionnaire and the Three-Factor Eating Questionnaire (TFEQ) estimating dietary restraint, disinhibition and hunger. We recruited 308 participants aged 20.7±3.2 years and a mean BMI of 23.3±3.4 kg/m(2). Hunger score was significantly associated with ghrelin levels (r=0.11, P<0.05). In women, this association was independent of age, BMI, dietary and lifestyle factors (P=0.02). The association between ghrelin level and hunger score was observable in leaner individuals (r=0.28, p<0.0001) but not in heavier individuals (r=-0.08, p=0.34; stratified by BMI < vs > 22.6 kg/m(2)). Restraint (R) and disinhibition (D) were not associated with ghrelin levels. The three eating behaviors demonstrated expected correlations with lifestyle supporting the validity of the TFEQ in this cohort. In conclusion, we demonstrated that ghrelin, a biological marker, is associated with self-reported perception of hunger, independently of anthropometric measures and lifestyle.