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Objective: In December 2019, a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused an outbreak of coronavirus disease 2019 (COVID-19) that resulted in a global pandemic with substantial morbidity and mortality. Currently, there is no specific treatment or approved vaccine against COVID-19. The underlying associated comorbidity and diminished immune function of some pituitary patients (whether caused by the disease and its sequelae or treatment with excess glucocorticoids) increases their risk of contracting and developing complications from COVID-19 infection., Methods: A review of studies in PubMed and Google Scholar published between January 2020 to the time of writing (May 1, 2020) was conducted using the search terms 'pituitary,' 'coronavirus,' 'COVID-19', '2019-nCoV', 'diabetes mellitus', 'obesity', 'adrenal,' and 'endocrine.', Results: Older age and pre-existing obesity, hypertension, cardiovascular disease, and diabetes mellitus increase the risk of hospitalization and death in COVID-19 patients. Men tend to be more severely affected than women; fortunately, most men, particularly of younger age, survive the infection. In addition to general comorbidities that may apply to many pituitary patients, they are also susceptible due to the following pituitary disorder-specific features: hypercortisolemia and adrenal suppression with Cushing disease, adrenal insufficiency and diabetes insipidus with hypopituitarism, and sleep-apnea syndrome and chest wall deformity with acromegaly., Conclusion: This review aims to focus on the impact of COVID-19 in patients with pituitary disorders. As most countries are implementing mobility restrictions, we also discuss how this pandemic has affected patient attitudes and impacted our decision-making on management recommendations for these patients., Abbreviations: ACE = angiotensin-converting enzyme; AI = adrenal insufficiency; ARB = angiotensin receptor blocker; ARDS = acute respiratory disease syndrome; COVID-19 = coronavirus disease 2019; CPAP = continuous positive airway pressure; DI = diabetes insipidus; DM = diabetes mellitus; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2., (© 2020 American Association of Clinical Endocrinologists. Published by Elsevier, Inc. All rights reserved.)

Pituitary adenomas are benign tumors, but still cause significant morbidity and in some cases increases in mortality. Surgical resection is not without risks, and approximately 40% of adenomas are incompletely resected. Medical therapies such as dopamine agonists, somatostatin analogues, and growth hormone antagonists are associated with numerous side effects. Understanding the molecular biology of pituitary adenomas may yield new therapeutic approaches. Additional studies are needed to help determine which genes or pathways are "drivers" of tumorigenesis and should be therapeutic targets. Further studies may also enable pituitary adenoma stratification to tailor treatment approaches., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Unlabelled: OBJECT.: While transsphenoidal surgery is associated with low morbidity, the degree to which morbidity increases after reoperation remains unclear. The authors determined the morbidity associated with repeat versus initial transsphenoidal surgery after 1015 consecutive operations., Methods: The authors conducted a 5-year retrospective review of the first 916 patients undergoing transsphenoidal surgery at their institution after a pituitary center of expertise was established, and they analyzed morbidities., Results: The authors analyzed 907 initial and 108 repeat transsphenoidal surgeries performed in 916 patients (9 initial surgeries performed outside the authors' center were excluded). The most common diagnoses were endocrine inactive (30%) or active (36%) adenomas, Rathke's cleft cysts (10%), and craniopharyngioma (3%). Morbidity of initial surgery versus reoperation included diabetes insipidus ([DI] 16% vs 26%; p = 0.03), postoperative hyponatremia (20% vs 16%; p = 0.3), new postoperative hypopituitarism (5% vs 8%; p = 0.3), CSF leak requiring repair (1% vs 4%; p = 0.04), meningitis (0.4% vs 3%; p = 0.02), and length of stay ([LOS] 2.8 vs 4.5 days; p = 0.006). Of intraoperative parameters and postoperative morbidities, 1) some (use of lumbar drain and new postoperative hypopituitarism) did not increase with second or subsequent reoperations (p = 0.3-0.9); 2) some (DI and meningitis) increased upon second surgery (p = 0.02-0.04) but did not continue to increase for subsequent reoperations (p = 0.3-0.9); 3) some (LOS) increased upon second surgery and increased again for subsequent reoperations (p < 0.001); and 4) some (postoperative hyponatremia and CSF leak requiring repair) did not increase upon second surgery (p = 0.3) but went on to increase upon subsequent reoperations (p = 0.001-0.02). Multivariate analysis revealed that operation number, but not sex, age, pathology, radiation therapy, or lesion size, increased the risk of CSF leak, meningitis, and increased LOS. Separate analysis of initial versus repeat transsphenoidal surgery on the 2 most common benign pituitary lesions, pituitary adenomas and Rathke's cleft cysts, revealed that the increased incidence of DI and CSF leak requiring repair seen when all pathologies were combined remained significant when analyzing only pituitary adenomas and Rathke's cleft cysts (DI, 13% vs 35% [p = 0.001]; and CSF leak, 0.3% vs 9% [p = 0.0009])., Conclusions: Repeat transsphenoidal surgery was associated with somewhat more frequent postoperative DI, meningitis, CSF leak requiring repair, and greater LOS than the low morbidity characterizing initial transsphenoidal surgery. These results provide a framework for neurosurgeons in discussing reoperation for pituitary disease with their patients.

Object: Pituitary apoplexy is associated with worse outcomes than are pituitary adenomas detected without acute clinical deterioration. The association between pituitary apoplexy and socioeconomic factors that may limit access to health care has not been examined in prior studies., Methods: This study involved retrospectively evaluating data obtained in all patients who underwent surgery for nonfunctioning pituitary adenoma causing visual symptoms between January 2003 and July 2012 at the University of California, San Francisco. Patients were grouped into those who presented with apoplexy and those who did not ("no apoplexy"). The 2 groups were compared with respect to annual household income, employment status, health insurance status, and whether or not the patient had a primary health care provider. Associations between categorical variables were analyzed by chi-square test and continuous variables by Student t-test. Multivariate logistic regression was also performed., Results: One hundred thirty-five patients were identified, 18 of whom presented with apoplexy. There were significantly more unmarried patients and emergency room presentations in the apoplexy group than in the "no apoplexy" group. There was a nonsignificant trend toward lower mean household income in the apoplexy group. Lack of health insurance and lack of a primary health care provider were both highly significantly associated with apoplexy. In a multivariate analysis including marital status, emergency room presentation, income, insurance status, and primary health care provider status as variables, lack of insurance remained associated with apoplexy (OR 11.6; 95% CI 1.9-70.3; p = 0.008)., Conclusions: The data suggest that patients with limited access to health care may be more likely to present with pituitary apoplexy than those with adequate access.

Acromegaly is debilitating disease occasionally refractory to surgical and medical treatment. Stereotactic radiosurgery, and in particular Gamma Knife surgery (GKS), has proven to be an effective noninvasive adjunct to traditional treatments, leading to disease remission in a substantial proportion of patients. Such remission holds the promise of eliminating the need for expensive medications, along with side effects, as well as sparing patients the damaging sequelae of uncontrolled acromegaly. Numerous studies of radiosurgical treatments for acromegaly have been carried out. These illustrate an overall remission rate over 40%. Morbidity from radiosurgery is infrequent but can include cranial nerve palsies and hypopituitarism. Overall, stereotactic radiosurgery is a promising therapy for patients with acromegaly and deserves further study to refine its role in the treatment of affected patients.

Background: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of hyponatremia in hospitalized patients and is frequently associated with neurologic disorders and neurosurgical procedures. Traditional therapies such as fluid restriction, sodium repletion, and diuretics can help correct hyponatremia but do not address the underlying pathophysiology of excess arginine vasopressin secretion. Conivaptan is an arginine vasopressin receptor antagonist that has been shown to be both safe and effective in the treatment of euvolemic and hypervolemic hyponatremia., Objective: To analyze the use of conivaptan to treat SIADH in a mixed neurosurgical population., Methods: We conducted a retrospective review of 13 patients with neurosurgical disorders with SIADH that were treated with intravenous conivaptan at our institution between 2007 and 2009., Results: The mean pretreatment serum sodium concentration was 125.8 ± 3.5 mEq/L. Conivaptan administration resulted in a rise in serum sodium to 132.5 ± 5.6 mEq/L at 12 hours (P < .01) and 134.1 ± 4.7 mEq/L at 24 hours posttreatment (P < .01). The mean time to an increase in serum sodium ≥ 6 mEq/L was 17.8 hours. There were no instances of rapid overcorrection. There were 3 cases of asymptomatic hyperkalemia, 3 cases of asymptomatic hypotension, and 1 case of elevated creatinine associated with conivaptan administration., Conclusion: These data provide further support that conivaptan can be safely used for the treatment of SIADH-induced hyponatremia in the neurosurgical arena.

It is widely accepted that the standard first-line treatment for most endocrine inactive pituitary macroadenomas (EIA) is surgery, usually via a transsphenoidal approach. What is less clear is what approach to take when these tumors recur, especially when this recurrence involves areas which are difficult to surgically remove tumor from, such as the suprasellar region or cavernous sinuses. We present long term follow-up for a series of 81 patients who underwent repeat surgery for recurrent non-secreting pituitary adenomas. We analyzed data collected from all adult patients undergoing their second microsurgical transsphenoidal resection of a histologically proven endocrine-inactive pituitary adenoma at the University of California at San Francisco between January 1970 and March 2001. Data for these patients were collected by review of medical records, mail, and/or telephone interviews. Visual function, anterior pituitary function, and tumor control rates were analyzed for the series. Records were available for a total of 81 recurrent EIA patients. The median time between their initial and repeat operations was 4.1 years. The mean tumor size was 2.2 +/- 0.2 cm. A total of 35/81 patients had greater than 5 years of follow-up. A total of 24/81 patients had greater than 10 years of follow-up. Over one half of these patients presented with visual disturbance, and we found that 39% of these patients experienced improved vision with a second surgery. More importantly, no one with normal vision suffered any appreciable decline in vision. Approximately, 35% of patients with pre-operative anterior pituitary dysfunction recovered function after surgery in our series; and no patient's function worsened. A total of 4/52 (8%) patients with greater than 2 years of post-op follow-up experienced a clinically meaningful tumor recurrence requiring additional treatment. Our data suggest that when performed by experienced transsphenoidal surgeons, durable tumor control can be obtained in these frequently locally aggressive tumors with acceptable rates of post-operative morbidity.

Background: Several investigators have recommended serial measurements of serum cortisol in the days following pituitary surgery to identify patients at risk of recurrence., Objective: We systematically reviewed the literature on this topic and analyzed the usefulness of this test in our own patient population., Methods: We identified studies publishing data regarding recurrence rates after transsphenoidal surgery for Cushing's disease, focusing on studies with data regarding patients with early postoperative cortisol levels. We determined a cumulative relative risk of having a subnormal vs normal cortisol level postoperatively using a fixed-effects meta-analysis model. Additionally, we analyzed our own patients with Cushing's disease undergoing transsphenoidal surgery and performed Kaplan-Meier analysis of recurrence-free survival for patients with undetectable, subnormal but detectable, and normal immediate 8 AM serum cortisol levels., Results: Fourteen studies met inclusion criteria. The length of follow-up varied between 32 and 115 months. The cumulative rate of recurrence in the group of patients with subnormal cortisol levels was 9% (95% confidence interval: 6%-12%). The cumulative rate of recurrence in the group with normal cortisol levels was 24% (95% confidence interval: 17%-31%). We analyzed 73 of our own patients and found similar recurrence rates in patients with subnormal vs normal early postoperative cortisol levels (4% vs 22%, chi2 test, P < .05)., Conclusion: Although a subnormal early postoperative cortisol level is predictive of improved outcome after transsphenoidal surgery for Cushing's disease, it is not analogous with cure, nor is a normal level completely predictive of future failure.

The evaluation and management of patients with residual Cushing's disease is one of the more complex issues facing neurosurgeons and neuroendocrinologists in clinical practice. There is considerable controversy over several relevant issues such as the timing of the assessment of whether a patient is in remission, what biochemical parameters define remission, the most appropriate course of action to take after residual disease has been defined, etc. As a consequence of the controversies, treating physicians develop notions and fall into certain practice patterns based on evidence of varying levels, their anecdotal experiences, and information gleaned from scientific meetings. This practice pattern, we believe, constitutes the "art of medicine." We conducted a PubMed literature search to identify manuscripts containing data relevant to Cushing's disease, outcomes of various therapeutic modalities, and recurrences. Reference lists were used to identify additional relevant manuscripts. We focused our review on manuscripts that included reasonably large series of patients, those reflecting the experience of pituitary centers and physicians recognized as experts in the field, and those papers felt to represent seminal contributions to the literature. Furthermore, trends in the evaluation and management of relevant patients have been incorporated by the senior author who has seen and evaluated over 750 patients with documented Cushing's syndrome over the past 18 years in clinical practice. An analysis of current evidence indicated that, despite advances in neurosurgical techniques and recent developments in adjuvant therapies, patients with residual Cushing's disease present significant management challenges to treating physicians. In this era, however, it is indeed possible to gain control of the hypercortisolism in most patients. Despite the wide variability in research methodology designed to collect relevant data, a step-wise approach to the management of these patients can be achieved. A logical step-wise approach to the evaluation of postoperative patients with Cushing's disease is essential. Patients with residual disease require the development of an individualized plan of management that takes into account numerous factors pertaining to status of disease, the experience of treating physicians, and available therapeutic modalities.

Purpose of Review: Description of recent outcomes and approaches to the treatment of patients with de-novo and recurrent acromegaly., Recent Findings: Radiosurgery for acromegaly results in a higher likelihood of remission and an earlier time to remission than does conventional radiotherapy. Somatostatin analogs results in control of acromegaly and one half of patients. Combining treatment with pegvisomant and somatostatin analogs results in overall improved quality of life., Summary: Existing treatments offer patients and their treating physicians opportunities to restore life expectancy to normal and reverse many of the symptoms and signs of acromegaly.

Pregnancy and Cushing's syndrome rarely coexist. When they do, it is generally the result of the presence of an adrenal adenoma. Because of significantly increased morbidity and mortality in both the mother and fetus when hypercortisolism is present, it is imperative that it be treated when recognized. This treatment can take the form of definitive surgical treatment or temporary medical treatment until after delivery, both of which carry risks and benefits. Complicating the evaluation, however, it is well known that pregnancy itself can induce many of the symptoms and laboratory abnormalities associated with hypercortisolism. We present the case of a 35-year-old woman who was noted to have an adrenal mass before pregnancy, but then during evaluation became pregnant. Her case is particularly intriguing because she had only vague clinical symptoms and mild laboratory abnormalities but also had a complicating pituitary mass noted on MRI. We outline the evaluation process and eventual laparoscopic adrenalectomy during the second trimester in this unique and difficult case, and discuss risks and benefits of different treatment options for hypercortisolism during pregnancy.

Objective: Normalization of serum prolactin concentrations in patients with prolactinomas is an accepted endpoint of therapy. Clinical signs and symptoms of hyperprolactinemia are usually resolved when prolactin levels are lowered to within the normal range. While most patients are treated with dopamine agonist drugs, some patients require surgical resection of their tumors. We sought to determine whether preoperative treatment with dopamine agonists alters the outcome of surgical intervention., Methods and Results: We present an analysis of 253 patients with prolactinomas treated surgically during the period of time when dopamine agonist therapy was first introduced and prior to its widespread use as first-line therapy. We compared both short- and long-term outcomes of patients treated with dopamine agonists prior to surgery with those undergoing surgery as their initial treatment modality. Our data showed that that patients treated with dopamine agonists prior to surgery experienced greater reductions in prolactin levels, had lower prolactin levels, were more likely to have normal prolactin levels at long term follow-up, and were less likely to require additional therapy to control their prolactin levels., Conclusion: Our study provides strong evidence suggesting that, regardless of initial prolactin level, preoperative dopamine agonist therapy is not detrimental. In fact, pretreatment with dopamine agonist drugs, possibly by inducing tumor regression, seemed to improve the surgeon's ability to resect a greater percentage of the tumor and led to better control of the prolactin level.

Objective: To determine the prevalence of valvular heart disease in a cohort of patients taking cabergoline for the management of hyperprolactinemia., Methods: A retrospective review of medical records identified patients with hyperprolactinemia who underwent evaluation at Vanderbilt University Medical Center between January and June 2007. The medical records of those patients who were prescribed cabergoline and who underwent elective echocardiography were reviewed for details pertaining to cardiac valvular abnormalities and cabergoline use., Results: Forty-five patients (mean age, 41 +/- 10 years [SD]) taking 0.91 +/- 0.96 mg of cabergoline per week for a mean duration of 39 +/- 29 months underwent echocardiography. Abnormalities of the cardiac valves were present in 3 patients (7%): 1 patient exhibited mild mitral regurgitation, 1 patient had focal aortic valve thickening, and 1 patient demonstrated mitral valve thickening. We found no significant difference in either the cumulative dose of cabergoline (P = .800) or the duration of cabergoline therapy (P = .745) between those patients with and those without these echocardiographic abnormalities., Conclusion: We found echocardiographic valve abnormalities in 3 of 45 patients (7%) who had been prescribed cabergoline for the management of hyperprolactinemia. This prevalence of valvular heart disease after approximately 3 years of cabergoline treatment is no different from that previously reported in normal populations as determined by echocardiography.

Objective: Endothelial progenitor cells (EPCs) mobilize from the bone marrow secondary to a stimulus and home to sites of injury, where they differentiate into endothelial cells and contribute to the repair of damaged vasculature. We hypothesized that growth hormone (GH) administration would increase the number of circulating EPCs in adults and thereby represent a mechanism to enhance vascular health., Design: A prospective trial of low-dose GH (0.03mg/kg/week for 4 weeks followed by 0.06mg/kg/week for a maximum of four additional weeks) in 10 healthy adults (6 males and 4 females; mean age 37 years, range 26-65). Primary outcomes measured included the number of circulating EPCs as assessed by colony-forming unit (CFU) assay and flow cytometry. Secondary outcomes included plasma measurements of known mediators of EPC mobilization and indices of nitric oxide (NO). Outcomes were measured at baseline and at study completion., Results: GH administration increased serum IGF-1 (143ng/mL [IQR 121-164] to 222 [IQR 194-244]; P=0.005). The increase in early-outgrowth EPCs (13 CFU per high-power field [IQR 6-24] to 19 [IQR 13-40]; P=0.005) correlated with the peak IGF-1 after adjustment for the baseline number of early-outgrowth EPCs (r=0.719 [95% CI 0.06, 0.93]; P=0.027). The number of late-outgrowth EPCs as well as CD34+, VEGFR2(KDR)+, and AC133+ cells did not significantly change. Other mediators of EPC mobilization were stable while plasma nitrite trended upwards (1.3micromol/L [IQR 0-2.5] to 3.7 [IQR 2.2-8.9]; P=0.052)., Conclusions: GH administration selectively augments the early-outgrowth EPC population in healthy individuals. These findings both support GH replacement in the setting of GH deficiency to maintain vascular integrity and have implications for the use of GH in future regenerative cell-based therapies. Furthermore, the decrease in EPCs observed with aging may in part be explained by the declining somatotropic axis, and thereby contribute to cardiovascular senescence.

Context: Adults with GH deficiency (GHD) have multiple cardiovascular risk factors, including an unfavorable lipid profile and body composition as well as impairments in endothelial function and cardiac performance. We hypothesized that GHD is associated with elevated levels of plasminogen activator inhibitor-1 (PAI-1), the major inhibitor of plasminogen activation in the circulation., Objective: The objective of the study was to determine the fibrinolytic profile of adults with GHD in comparison with controls., Study Design and Participants: This was a prospective, observational study including 12 adults with GHD. Twelve gender-, age-, and body mass index-matched adults served as controls., Main Outcome Measures: The primary outcome measures were circadian plasma PAI-1 antigen with corresponding tissue-plasminogen activator (tPA) activity values. Endothelial function was assessed by flow-mediated vasodilation and fibrinolytic potential by venous occlusion test., Results: Adults with GHD exhibited an unfavorable 24-h fibrinolytic profile characterized by a mean 62% elevation in PAI-1 antigen (2.77 ng/ml after adjustment for baseline PAI-1; P = 0.049) in the setting of a mean 24% reduction in tPA activity (-0.17 IU/ml after adjustment for baseline tPA; P = 0.003). Fibrinolytic response was defective in GHD, as demonstrated by a sustained elevation in PAI-1 activity greater than 4 IU/ml after venous occlusion [7.2 IU/ml (interquartile range 0.8-17.4); P = 0.018]. Endothelial function was impaired in GHD, as quantified by percent flow-mediated vasodilation over 120 sec [area under the curve 3.8 (interquartile range -2.4 to 7.9) vs. 12.8 (interquartile range 2.1-19.4); P = 0.043]., Conclusions: Adults with GHD demonstrate alterations in plasma fibrinolytic balance, including elevated levels of PAI-1 antigen with decreased tPA activity. These changes may contribute to the increased cardiovascular morbidity within this population.

Disorders of water metabolism are a common complication of pituitary surgery. The primary purpose of this study was to determine the incidence and duration of post-surgical diabetes insipidus (DI) at our institution. Secondary objectives included characterizing the incidence of post-operative hyponatremia as well as delineating factors associated with the onset of these complications. Records of 319 patients who underwent transsphenoidal pituitary surgery at the authors' institution between 1998 and 2005 were reviewed for the presence of disorders of water metabolism using pre-specified criteria. DI was diagnosed in 59 (18.5%) of our patients at a mean time of 13.6 h following surgery. DI resolved in nearly half of our patients within one week. Approximately 80% of our patients enjoyed resolution of DI at a mean time of 2.9 months following surgery. Duration of DI was not significantly influenced by tumor size or location. Additionally, 28 (8.8%) of our patients exhibited a period of hyponatremia at a mean time of 4 days following surgery. One quarter of these patients carried a diagnosis of Cushing's disease. We herein report an incidence of DI as well as hyponatremia within our post-operative population comparable to that reported by other high-volume pituitary centers. Over half of our patients still exhibited DI at the time of discharge, therefore, patient education regarding the treatment of DI, signs of its resolution, and symptoms consistent with the onset of hyponatremia should be an integral part of every hospitalization.

Objective: To present a rare case of primary paraganglioma of the lung, which caused the syndrome of ectopic adrenocorticotropic hormone (ACTH) hypersecretion., Methods: The clinical, biochemical, and imaging findings in this case are described, and the pathologic features of the resected tumor tissue are depicted. In addition, the related literature on paragangliomas is reviewed., Results: In a 39-year-old woman with hypertension, weight gain, and easy bruising, laboratory studies showed hypercortisolemia, high plasma ACTH levels, and suppression of cortisol by high-dose dexamethasone. An indium-labeled octreotide whole-body scan disclosed a tumor in the left lower lung field. Thoracoscopic wedge resection of the pulmonary mass was performed. Postoperative microscopic findings and immunohistochemical stains revealed nests of rounded and polyhedral cells and S-100 protein-positive sustentacular (supporting) cells, charac-, Conclusion: This unusual case of Cushing's syndrome was attributable to an ACTH-secreting primary pulmonary paraganglioma.

Objective: To review one physician's management of glucocorticoid replacement therapy in adult patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and to determine the efficacy and the range of effective doses of dexamethasone in managing the clinical and biochemical consequences of this disorder., Methods: We conducted a retrospective clinical practice audit of nine patients treated by a single physician for 21-hydroxylase deficiency during the period from March 1998 to January 2002. We documented biochemical control and clinical features of glucocorticoid excess or deficiency for various doses of dexamethasone., Results: The final dosage of dexamethasone needed to normalize serum 17-hydroxyprogesterone levels, to arrest progression of hirsutism, and to eliminate the symptoms and signs of adrenocortical insufficiency while avoiding manifestations of glucocorticoid excess ranged from 0.0625 to 0.875 mg/day, with a mean dosage of 0.4 mg/day. Seven patients had adequate control during the observation period with use of dosages of dexamethasone of 0.5 mg/day or less., Conclusion: Adequate control of 21-hydroxylase can be achieved with relatively low doses of dexamethasone; thus, the long-held notion that 0.75 mg of dexamethasone is "equivalent" in glucocorticoid effect to the estimated daily production of cortisol is challenged. These data suggest that physicians should evaluate the doses of glucocorticoids used in their patients with CAH and other forms of primary and central adrenocortical insufficiency because considerable decreases in glucocorticoid doses may be in order.

We report the case of an adolescent boy who presented with hypertension and hypokalemia. A systematic work-up revealed hyperreninemic hyperaldosteronism. Further study revealed Page kidney caused by trauma-associated renal hematoma. The evaluation and management of hyperaldosteronism and Page kidney are discussed.

Objective: To heighten the awareness of treating physicians of the potential for serious and fatal thromboembolic complications after inferior petrosal sinus sampling in patients with Cushing's syndrome., Methods: We retrospectively reviewed inpatient and outpatient medical records for a 12-year period to identify patients with Cushing's syndrome who had thromboembolic complications after inferior petrosal sinus sampling at a single institution. Case reports of affected patients are presented., Results: Of 34 patients with corticotropin-dependent Cushing's syndrome who underwent inferior petrosal sinus sampling, 2 had deep venous thrombosis. One of these patients succumbed to pulmonary thromboembolism., Conclusion: Serious and potentially fatal thromboembolic disorders may complicate inferior petrosal sinus sampling. Prospective studies should be undertaken to determine the true incidence of deep venous thrombosis after this procedure in patients with Cushing's syndrome.

Although almost all pituitary tumors are benign adenomas, a surprisingly large number of these tumors invade tissues outside of the pituitary gland. Such invasion, by itself, is not diagnostic of pituitary carcinomas, which are exceedingly rare (0.13% of 2,342 pituitary tumors in one series). Several different criteria are available to determine whether a tumor is invasive. Intraoperative biopsies demonstrate an 85% incidence of microscopic invasion of the dura. Evidence of gross invasion at surgery and radiologic evidence of invasion on magnetic resonance imaging (MRI) and computed tomographic (CT) scans occur at a much lower incidence but may be more predictive of surgical cure. Invasive adenomas also have higher proliferation rates than do noninvasive adenomas, as shown by immunohistochemical detection of proliferating cell nuclear antigen (PCNA), Ki-67, and MIB-1. The expression of p53, increased epidermal growth factor receptors, and protein kinase C activity also correlate with invasion and aggressive behavior. Clinically significant invasion is more frequent with macroadenomas. Macroadenomas of all pituitary tumor subtypes except gonadotroph macroadenomas have a greater than 50% incidence of gross invasion. Currently, there is no accepted means of predicting an adenoma's clinically significant invasiveness and long-term aggressiveness.

Currently, the most popular test for adrenal insufficiency is the conventional rapid ACTH stimulation test (250 microg ACTH). This method is quick and safe, but incorporates a dose of ACTH that is supraphysiological and capable of transiently stimulating the adrenal cortex in many patients with documented central adrenal insufficiency. In recent years, several investigators have published substantial evidence for a more sensitive ACTH stimulation test using a lower dose of ACTH (1 microg). Further analysis of these data, including the calculation of likelihood ratios, demonstrates that the 1-microg test performs significantly better than the 250-microg test compared to the gold standard, insulin tolerance test. We suggest that the 1-microg ACTH stimulation test replace the conventional 250-microg test when evaluating for central adrenal insufficiency. A cortisol level below 500 nmol/L after 30 min signifies impaired adrenocortical reserve. An insulin tolerance test should be performed if this low dose test results in a borderline value and the diagnosis is questioned. The 1-microg test should not be used if recent pituitary injury is suspected. Pharmaceutical companies should be encouraged to provide synthetic ACTH in 1-microg vials.

We reviewed our experience with 21 patients who had Cushing's disease due to ACTH-secreting macroadenomas to clarify the natural history of this disease. All patients had typical clinical and biochemical features of ACTH-dependent hypercortisolism. Their mean maximal tumor diameter was 1.6 +/- 0.1 cm, and the range was 1.0-2.7 cm. Six patients had cavernous sinus invasion, three had invasion of the floor of their sella, and nine had suprasellar extension. The observed remission rate was significantly lower in macroadenoma patients than in microadenoma patients (67% vs. 91%; chi 2 = 5.7; P < 0.02). Cavernous sinus invasion (odds ratio, 35; 95% confidence interval, 2.6-475; P < 0.008) and presence of a maximum tumor diameter 2.0 cm or more (odds ratio, 12.9; 95% confidence interval, 1.4-124; P < 0.02) emerged as the only predictors of residual disease after surgery. The observed recurrence rate was significantly higher in macroadenoma patients than in microadenoma patients (36% vs. 12%; chi 2 = 4.2; P < 0.05). Macroadenoma patients tended to suffer from recurrences earlier than did microadenoma patients (16 vs. 49 months). Stepwise multiple logistic regression did not identify any predictors of disease recurrence in macroadenoma patients. Eight macroadenoma patients underwent a total of nine repeat surgical procedures, but none of these resulted in clinical remissions. Only four of seven (57%) patients followed for a sufficient period of time achieved normal urinary free cortisol levels after conventional radiotherapy. Three (75%) of these four patients had re-recurrent hypercortisolism after brief periods of eucortisolism. Pharmacological agents and adrenalectomy were effective in the management of hypercortisolism in patients with residual and recurrent disease. Our results indicate that ACTH-secreting macroadenomas are more refractory to conventional treatments than are ACTH-secreting microadenomas.

Pharmacologic agents are useful in the management of some patients with pituitary tumors. The diagnosis and management of pituitary adenomas are discussed.

A 72-year-old woman with chronic fatigue, malaise, weight loss, nausea, and vomiting was treated unsuccessfully for gastroparesis for more than 2 years. Clinical and biochemical features of hypopituitary disease and symptoms of a nonsecreting pituitary tumor had been overlooked and became apparent only after the differential diagnosis of hyponatremia was considered. Transsphenoidal resection of the pituitary tumor and appropriate 1-thyroxine and hydrocortisone replacement returned her gastric emptying time to normal and relieved her symptoms. Primary and secondary deficits of l-thyroxine and cortisol should be considered when making a possible diagnosis of gastroparesis.

A 24-year-old woman with ataxia-telangiectasia had traumatic arthritis, elevated serum transaminase values, polyuria, polydipsia, and a serum glucose level of 575 mg/dL. A relatively high daily dose of insulin (2.8 U/kg) was required to achieve near normoglycemia. The fasting insulin concentration was elevated. During an insulin-modified frequently sampled intravenous glucose tolerance test, the first phase of insulin release in response to the administration of glucose was blunted. The insulin sensitivity was similar to that found in individuals with non-insulin-dependent diabetes mellitus. Insulin receptor antibodies were not detected in the serum. We conclude that insulin resistance and islet beta-cell dysfunction are characteristics of diabetes mellitus in ataxia-telangiectasia. Contrary to a previous report, our findings do not support a cause-and-effect relationship between insulin receptor antibodies and insulin resistance in this disorder.

A 61-year-old Caucasian man presented with otalgia, dysarthria, and weight loss. Neurological examination revealed palatal hypomotility, and weakness of the facial and tongue muscles. Magnetic resonance imaging of the head demonstrated the presence of a soft tissue mass in the clivus. Histologic examination of resected tumor disclosed well-differentiated thyroid follicles that invaded the local osseous tissues. Physical examination and radioiodine images of the thyroid gland were normal. The serum thyroglobulin concentration was markedly elevated (1011 ng/mL). A 0.9-cm well-differentiated benign-appearing left thyroid lobe follicular neoplasm with a thick fibrous capsule was found following diagnostic thyroidectomy. This report illustrates that clinically significant distant metastases can arise from occult follicular thyroid neoplasms that, according to standard histologic criteria, are benign. The presence of a thick fibrous capsule, even in the absence of vascular or capsular invasion, may identify follicular neoplasms that have metastatic potential.

The authors studied 15 patients at risk for central adrenocortical insufficiency to evaluate the role of naloxone in establishing the integrity of the hypothalamic-pituitary-adrenal axis. Each patient was admitted to the General Clinical Research Center for 2 days. Naloxone, 125 micrograms/kg body weight, was administered intravenously, and plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations were measured at -15, 0, 30, 45, 60, 90, and 120 minutes. Metyrapone, 30 mg/kg body weight, was administered orally at 11 PM on the second day of hospitalization. Plasma ACTH, cortisol, and 11-deoxycortisol concentrations were measured at 8 AM pre- and postmetyrapone. The results of the metyrapone test were used to distinguish patients who had central adrenal insufficiency from those who were normal. In 11 patients who had a normal metyrapone test, the plasma ACTH level increased from 6 +/- 1 pmol/L at baseline to 11 +/- 2 pmol/L 30 minutes after naloxone administration. The plasma cortisol increased from 191 +/- 21 nmol/L at baseline to 379 +/- 47 nmol/L 45 minutes after naloxone administration. In four patients with central adrenal insufficiency, the plasma ACTH and cortisol concentrations did not increase after naloxone administration. Reliance solely on the individual ACTH and cortisol responses to naloxone would have permitted a correct decision regarding glucocorticoid replacement therapy in 14 (93%) of 15 patients. Naloxone stimulation testing may have a role in the clinical evaluation of patients with suspected central adrenocortical insufficiency.

We now have conclusive proof that intensive treatment reduces the microvascular complications of IDDM. ACE inhibitors appear to slow the progression of established nephropathy. Drug-induced malabsorption has the potential to increase levothyroxine dose requirement.

Adrenal insufficiency occurs in approximately two thirds of patients with adrenomyeloneuropathy. Its development may precede or follow the onset of neurological disease. To define the sensitivity of various tests of adrenal cortical function, we reviewed adrenocortical function tests in 28 patients with adrenomyeloneuropathy who had normal ACTH stimulation tests at the time of enrollment into an ongoing dietary study. Endocrine studies performed at 6-month intervals included a conventional ACTH stimulation test, plasma ACTH and cortisol concentrations, and 24-h urinary cortisol and aldosterone excretion rates. Eleven patients (39%) developed an elevated plasma ACTH concentration after a median follow-up of 3 yr. Their 24-h urinary cortisol and plasma basal and ACTH-stimulated cortisol concentrations were all normal. The mean basal cortisol level tended to be lower in patients who had increased plasma ACTH levels than in patients who maintained a normal plasma ACTH concentration during the study period (408 +/- 22 vs. 491 +/- 33 nmol/L; P = 0.05). Patients who had an increased plasma ACTH concentration and symptoms consistent with adrenal insufficiency had a lower mean 24-h urinary free cortisol level than those with normal plasma ACTH (196 +/- 22 vs. 281 +/- 30 nmol/day; P < 0.05). Plasma ACTH concentrations were persistently elevated in six patients in whom subsequent values were available. One individual later developed a subnormal ACTH-stimulated cortisol concentration consistent with overt adrenal insufficiency. Our results suggest that conventional provocative and integrative tests of adrenocortical function may not be sufficient to identify patients with adrenomyeloneuropathy who have compensated adrenal hypofunction. An elevated plasma ACTH concentration may represent an early marker for adrenocortical dysfunction and incipient adrenal insufficiency in AMN patients.

Historically, ethanol exposure has been thought to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. However, recent studies have demonstrated decreased responsiveness to metyrapone and insulin-induced hypoglycemia in alcoholic subjects. The present study investigated in more detail the effect of acute ethanol ingestion (0.75 g/kg) on the HPA axis in healthy nonalcoholic men (n = 14). In study 1, plasma ACTH/cortisol levels were determined basally and every 30 min over a 180-min period after the ingestion of placebo or ethanol (n = 8). When the subjects were analyzed as a group, ethanol did not alter ACTH or cortisol levels. However, in two of eight subjects, ethanol ingestion was accompanied by a rise in plasma ACTH. In study 2, ethanol or placebo was ingested over 15 min, and 1 microgram/kg ovine (o) CRH was administered (n = 9). Hormone levels were determined at 20 min before and 0, 15, 30, 60, and 90 min after iv oCRH. Compared to responses to placebo, plasma ACTH responses to oCRH were blunted during the ethanol session [peak ACTH, 14.2 +/- 1.4 vs. 20.3 +/- 3.1 pmol/L (P = 0.036); peak value minus baseline (delta), 7.3 +/- 1.4 vs. 13.4 +/- 2.6 pmol/L (P = 0.017); delta divided by baseline x 100, 131 +/- 28 vs. 197 +/- 29% (P = 0.041); area under the ACTH curve, 1082 +/- 116 vs. 1529 +/- 232 pmol/min.L (P = 0.024)]. Ethanol ingestion also significantly blunted plasma cortisol levels after oCRH compared to placebo treatment. In study 3, ethanol or placebo was ingested over 15 min, and 0.25 microgram ACTH-(1-24) was administered (n = 5). Cortisol levels, determined 20 min before and 0, 30, 60, and 90 min after ACTH treatment, were not altered by ethanol administration. In summary, mildly intoxicating doses of ethanol did not stimulate the HPA axis in six of eight subjects. However, mild intoxication significantly impaired oCRH-stimulated ACTH/cortisol secretion. We speculate that mild intoxication with ethanol may impair the ability of the HPA axis to respond to physiological stressors.

A 40-year-old white woman presented with hirsutism, amenorrhea, generalized fatigue, diffuse weight gain, acral changes, and coarsened facial features. Physical examination revealed mild diastolic hypertension, acromegalic features, hirsutism, and seborrhea. The growth hormone concentration was elevated and did not suppress after glucose administration. Urinary free cortisol excretion was increased and was not suppressed during a 2 mg low-dose dexamethasone suppression test. Magnetic resonance imaging of the sella demonstrated a 1.3 x 1.2 x 0.8 cm pituitary adenoma. Trans-sphenoidal resection was performed, and portions of the resected tumor were analyzed by routine pathologic methods. Histopathologic and immunohistochemical findings indicated discrete growth hormone- and adrenocorticotropic hormone-producing pituitary adenomas. Coexisting acromegaly and Cushing's syndrome due to pituitary neoplasia was previously reported in two patients. However, to the authors' knowledge, this represents the first description of a patient with acromegaly and Cushing's disease resulting from discrete synchronous adenomas of the pituitary gland as defined by modern histopathologic techniques.

Objectives: To review the pathophysiology, diagnosis, and treatment of the syndromes of diabetes insipidus with an emphasis on those situations likely to be encountered in the critical care setting., Data Sources: Extensive clinical experience and relevant publications from the English literature identified via MEDLINE search, citation in reviews, publications of original data, and endocrine texts., Study Selection and Data Extraction: Landmark papers pertaining to all aspects of diabetes insipidus were selected. Reviews, primary articles, and case reports pertaining to diabetes insipidus in the critical care setting were identified and selected according to their content of clinically useful information., Data Synthesis and Conclusions: Diabetes insipidus may result from impaired synthesis and release of vasopressin from the hypothalamic-pituitary unit (neurogenic) or renal insensitivity to circulating vasopressin (nephrogenic). A number of interventions, diseases, and drugs commonly encountered in the critical care setting may result in the development or exacerbation of diabetes insipidus. The diagnosis of diabetes insipidus requires the exclusion of other causes of polyuria and a systematic demonstration of the response of homeostatic mechanisms to controlled dehydration. The treatment of diabetes insipidus depends on many factors, including the clinical setting, degree and pathophysiologic classification, ability of the patient to compensate for free water losses, and expected duration of the abnormality. Underlying disorders should be treated appropriately whenever possible.