Search

Objective: We aimed to determine the prevalence and clinical characteristics of self-reported hyperthyroidism in patients with sarcoidosis., Methods: A national registry-based study investigating 3836 respondents to the Sarcoidosis Advanced Registry for Cures questionnaire in the period between June 2014 and August 2019 was conducted. This registry is generated from a web-based questionnaire that is self-reported by patients with sarcoidosis. We compared patients with sarcoidosis who had hyperthyroidism with those who did not. We used multivariate logistic regression analysis to study the association between hyperthyroidism and different cardiac manifestations in patients with sarcoidosis., Results: Three percent of the study respondents self-reported having hyperthyroidism and were generally middle-aged Caucasian women. Compared with patients without hyperthyroidism, patients with hyperthyroidism had more sarcoidosis-related comorbidities (59% vs 43%, P = .001) and more steroid-related comorbidities (56% vs 44%, P = .01), but there was no difference in the sarcoidosis-specific treatments they received, which included corticosteroids. Patients with hyperthyroidism reported sarcoidosis involvement of the heart (26.6% vs 14.9%, P = .005), kidneys (14.9% vs 8%, P = .033) and sinuses (17.7% vs 10.2%, P = .030) more frequently. Cardiac manifestations that were more frequently reported in patients with hyperthyroidism included atrial arrhythmias (11.3% vs 6.3%, P = .046), ventricular arrhythmias (17.2% vs 7.5%, P < .001), congestive heart failure (10.4% vs 5%, P = .017), and heart block (9.4% vs 4.7%, P = .036)., Conclusion: Hyperthyroidism is infrequent in patients with sarcoidosis but is potentially associated with different cardiac manifestations. We suggest considering routine screening for hyperthyroidism in patients with sarcoidosis, especially in those with cardiac involvement. Further studies are needed to investigate the impact of identifying and treating hyperthyroidism in patients with sarcoidosis., (Copyright © 2022 AACE. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess long-term quality of life (QoL) in patients with sustained biochemical control of acromegaly, comparing those receiving vs not receiving pharmacotherapy (primary analysis); to assess change in QoL over time (secondary analysis)., Methods: Cross-sectional study, with a secondary longitudinal component, of 58 patients with biochemically controlled acromegaly. All had participated in studies assessing QoL years previously, after having undergone surgery ± radiotherapy. One cohort received medical therapy [MED (n = 33)]; the other did not [NO-MED (n = 25)]. QoL was assessed by the 36-Item-Short-Form Health Survey (SF-36), Acromegaly Quality of Life Questionnaire (AcroQoL), Gastrointestinal Quality of Life Index (GIQLI), Symptom Questionnaire, and QoL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA)., Results: Mean (± SD) duration of biochemical control was 15.0 ± 6.4 years for MED and 20.4 ± 8.2 years for NO-MED (p = 0.007). 58% of subjects scored < 25% of normal on ≥ 1 SF-36 domain and 32% scored < 25% of normal on ≥ 4 of 8 domains. Comparing MED vs NO-MED and controlling for duration of biochemical control, there were no significant differences in QoL by SF-36, AcroQOL, GIQLI, Symptom Questionnaire, or QoL-AGHDA. Growth hormone deficiency (GHD) but not radiotherapy predicted poorer QoL. In MED, QoL improved over time in three AcroQoL domains and two GIQLI domains. In NO-MED, QoL worsened in two SF-36 domains and two Symptom Questionnaire domains; QoL-AGHDA scores also worsened in subjects with GHD., Conclusion: A history of acromegaly and development of GHD, but not pharmacologic or radiotherapy, are detrimental to QoL, which remains poor over the long-term despite biochemical control., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Amyloid goiter, defined as excess amyloid within the thyroid gland in such quantities that it produces a clinically apparent goiter, is a very rare manifestation of systemic amyloidosis with cases commonly seen in the setting of Amyloid A (AA) amyloidosis. Amyloid goiter as the primary clinical manifestation secondary to Amyloid light chain (AL) amyloidosis is very rare. We present a case of AL amyloidosis with initial manifestation as goiter with amyloid deposition in the thyroid and the parathyroid gland., Case Presentation: A 73 year old male presented with goiter and compressive symptoms of dysphagia and hoarseness. Laboratory workup revealed normal thyroid function, nephrotic range proteinuria, elevated serum calcium level with an elevated parathyroid hormone level (PTH) consistent with primary hyperparathyroidism. Thyroid ultrasound showed an asymmetric goiter with three dominant nodules. Cervical computed tomography revealed a goiter with substernal extension and deviation of the trachea. Fine needle aspiration was unsatisfactory. There was also evidence of osteoporosis and hypercalciuria with negative Sestamibi scan for parathyroid adenoma. The patient underwent a total thyroidectomy and one gland parathyroidectomy. Pathology revealed benign thyroid parenchyma with diffuse amyloid deposition in the thyroid and parathyroid gland that stained apple green birefringence under polarized light on Congo Red stain. Immunochemical staining detected AL amyloid deposition of the lambda type. Bone marrow biopsy revealed an excess monoclonal lambda light chain of plasma cells consistent with a diagnosis of AL amyloidosis secondary to multiple myeloma affecting the kidney, thyroid, parathyroid gland, and heart. He was treated with 4 cycles of chemotherapy with a decrease in the M spike and light chains with a plan to pursue a bone marrow transplant., Conclusion: Amyloid goiter as the primary clinical manifestation secondary to AL amyloidosis with deposition in the thyroid and parathyroid gland is rare. The top differential for amyloid deposits in the thyroid includes systemic amyloidosis or medullary thyroid carcinoma. The definitive diagnosis lies in the histopathology of the thyroid tissue. To diagnose systemic amyloidosis as the etiology for a goiter, a solid understanding of the causes of systemic amyloidosis coupled with a thorough evaluation of the patient's history and laboratory data is necessary., (© 2022. The Author(s).)

Little is known about the prevalence, clinical characteristics and impact of hypothyroidism in patients with sarcoidosis. We aimed to determine the prevalence and clinical features of hypothyroidism and its relation to organ involvement and other clinical manifestations in patients with sarcoidosis. We conducted a national registry-based study investigating 3835 respondents to the Sarcoidosis Advanced Registry for Cures Questionnaire between June 2014 and August 2019. This registry is based on a self-reported, web-based questionnaire that provides data related to demographics, diagnostics, sarcoidosis manifestations and treatment. We compared sarcoidosis patients with and without self-reported hypothyroidism. We used multivariable logistic regression and adjusted for potential confounders to determine the association of hypothyroidism with nonorgan-specific manifestations. 14% of the sarcoidosis patients self-reported hypothyroidism and were generally middle-aged white women. Hypothyroid patients had more comorbid conditions and were more likely to have multiorgan sarcoidosis involvement, especially with cutaneous, ocular, joints, liver and lacrimal gland involvement. Self-reported hypothyroidism was associated with depression (adjusted odds ratio (aOR) 1.3, 95% CI 1.01-1.6), antidepressant use (aOR 1.3, 95% CI 1.1-1.7), obesity (aOR 1.7, 95% CI 1.4-2.1), sleep apnoea (aOR 1.7, 95% CI 1.3-2.2), chronic fatigue syndrome (aOR 1.5, 95% CI 1.2-2) and was borderline associated with fibromyalgia (aOR 1.3, 95% CI 1-1.8). Physical impairment was more common in patients with hypothyroidism. Hypothyroidism is a frequent comorbidity in sarcoidosis patients that might be a potentially reversible contributor to fatigue, depression and physical impairment in this population. We recommend considering routine screening for hypothyroidism in sarcoidosis patients especially in those with multiorgan sarcoidosis, fatigue and depression., Competing Interests: Conflict of interest: B.N. Alzghoul has nothing to disclose. Conflict of interest: F.N. Amer has nothing to disclose. Conflict of interest: D. Barb has nothing to disclose. Conflict of interest: A. Innabi has nothing to disclose. Conflict of interest: M.T. Mardini has nothing to disclose. Conflict of interest: C. Bai has nothing to disclose. Conflict of interest: B. Alzghoul has nothing to disclose. Conflict of interest: T. Al-Hakim reports helping with the FSR-SARC registry design and enrollment. Conflict of interest: N. Singh reports helping with the FSR-SARC registry design and enrollment. Conflict of interest: M. Buchanan reports helping with the FSR-SARC registry design and enrollment. Conflict of interest: L. Serchuck reports helping with the FSR-SARC registry design and enrollment. Conflict of interest: D. Gomez Manjarres has nothing to disclose. Conflict of interest: W.W. Woodmansee has nothing to disclose. Conflict of interest: L.A. Maier reports being a nonpaid member of the Scientific Advisory Board of the FSR, and receives grant funding for research as a member of the FSR-Clinical Studies Network. She helped with the FSR-SARC registry design and enrolment. Conflict of interest: D.C. Patel has nothing to disclose., (Copyright ©The authors 2021.)

Pregnancy is associated with alterations in pituitary hormonal function and enlargement of the pituitary gland. Pituitary dysfunction diagnosis can be challenging during pregnancy due to known alterations in hormonal status. Pituitary disorders are relatively common; with advancements in medical care, more women with pituitary disorders are becoming pregnant. Management includes optimization of hormonal function and close monitoring for signs of tumor progression during pregnancy. Tumor-directed medical therapy is generally discontinued during pregnancy but can be reinitiated if there is evidence of tumor growth. Most women do not show aggressive tumor growth during pregnancy and can be managed conservatively until delivery., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: This 2-year analysis assessed frequency of comorbidities and comorbidity screening in the Somatuline ® (lanreotide, LAN) Depot for Acromegaly (SODA) registry., Methods: Patient data collected included pituitary hormone deficiencies, sleep studies, echocardiograms, gallbladder sonographies, colonoscopies, and glycated hemoglobin (HbA1c) levels. Insulin-like growth factor-1 (IGF-1) and growth hormone levels in patients with (DM) and without (non-DM) diabetes mellitus were analyzed., Results: There were 241 patients enrolled. Pituitary hormone deficiencies were reported more frequently at enrollment in male (56.9%) vs female patients (32.0%; p < 0.001). TSH deficiency was the most common endocrine deficiency (69.8%), followed by gonadotropin deficiency (62.3%). Screening tests reported at enrollment: sleep studies in 29.9% (79.2% had sleep apnea), echocardiogram in 46.1% (46.8% abnormal), gallbladder sonography in 18.7% (17.8% had gallstones), and colonoscopy in 48.1% (35.3% had polyps). Follow-up studies were reported less frequently at 1 and 2 years. HbA1c data were reported in 30.8% and 41.2% after 1 and 2 years. HbA1c levels were similar at 1 and 2 years of LAN therapy among DM and non-DM patients with available data. Fewer DM vs non-DM patients achieved IGF-1 below upper limit of normal at Month 24 (58.3% vs 80.6%; p = 0.033)., Conclusions: Fewer than half of patients in SODA had screening results reported at enrollment for sleep apnea, cardiomyopathy, and colon polyps. Gallbladder imaging was reported in a minority of patients. Lower IGF-1 control rates were observed in DM vs non-DM patients at Month 24. These data suggest a need for better monitoring of comorbidities in US acromegaly patients.

Purpose: This analysis evaluates the 2-year effectiveness and safety of lanreotide depot/autogel (LAN), as well as treatment convenience and acromegaly symptom relief, from the Somatuline ® Depot for Acromegaly (SODA) registry, a post-marketing, open-label, observational, multicenter, United States registry study., Methods: Patients with acromegaly treated with LAN were eligible for enrollment. Demographics, LAN dose, extended dosing interval (EDI) (interval of injections ≥42 days), insulin-like growth factor 1 (IGF-1), growth hormone (GH), glycated hemoglobin, adverse events (AEs), injection convenience, and symptom data were collected., Results: As of September 29, 2014, 241 patients were enrolled in SODA. IGF-1 levels below age- and gender-adjusted upper normal limit (ULN) were achieved in 71.2% at month (M) 12 and 74.4% at M24; GH ≤2.5 µg/L in 83.3% at M12 and 80.0% at M24; GH <1.0 µg/L in 61.7% at M12 and 61.4% at M24. Both IGF-1 < ULN and GH ≤2.5 µg/L were achieved in 65.0% at M12 and 54.8% at M24; both IGF-1 < ULN and GH < 1.0 µg/L were achieved in 51.7 and 42.9% at M12 and M24, respectively. EDI regimen was 5.0% at baseline and 12.0% at M24. At M24, acromegaly symptoms appeared stable or improved. The most common AE was arthralgia (25.7%). Among 106 serious AEs reported by 42 patients, 10 were deemed related to therapy in 9 patients. At M24, 73.1% of patients rated LAN as convenient., Conclusions: SODA indicates 2-year biochemical control with majority of patients achieving both IGF-1 < ULN and GH ≤2.5 µg/L. LAN was generally well tolerated with no new or unexpected safety signals reported during the observation period. clinicaltrials.gov Clinical Trial Identifier: NCT00686348.

Context: Acromegaly is characterized by growth hormone (GH) and insulinlike growth factor-1 (IGF-1) hypersecretion, and GH and IGF-1 play important roles in regulating body composition and glucose homeostasis., Objective: The purpose of our study was to investigate body composition including ectopic lipids, measures of glucose homeostasis, and gonadal steroids in patients with active acromegaly compared with age-, body mass index (BMI)-, and sex-matched controls and to determine changes in these parameters after biochemical control of acromegaly., Design: Cross-sectional study of 20 patients with active acromegaly and 20 healthy matched controls. Prospective study of 16 patients before and after biochemical control of acromegaly., Main Outcome Measures: Body composition including ectopic lipids by magnetic resonance imaging/proton magnetic resonance spectroscopy; measures of glucose homeostasis by an oral glucose tolerance test; gonadal steroids., Results: Patients with active acromegaly had lower mean intrahepatic lipid (IHL) and higher mean fasting insulin and insulin area under the curve (AUC) values than controls. Men with acromegaly had lower mean total testosterone, sex hormone-binding globulin, and estradiol values than male controls. After therapy, homeostasis model assessment of insulin resistance, fasting insulin level, and insulin AUC decreased despite an increase in IHL and abdominal and thigh adipose tissues and a decrease in muscle mass., Conclusions: Patients with acromegaly were characterized by insulin resistance and hyperinsulinemia but lower IHL compared with age-, BMI-, and sex-matched healthy controls. Biochemical control of acromegaly improved insulin resistance but led to a less favorable anthropometric phenotype with increased IHL and abdominal adiposity and decreased muscle mass., (Copyright © 2017 Endocrine Society)

Purpose of Review: The pituitary gland is one of the key components of the endocrine system. Congenital or acquired alterations can mediate destruction of cells in the gland leading to hormonal dysfunction. Even though pharmacological treatment for pituitary disorders is available, exogenous hormone replacement is neither curative nor sustainable. Thus, alternative therapies to optimize management and improve quality of life are desired., Recent Findings: An alternative modality to re-establish pituitary function is to promote endocrine cell regeneration through stem cells that can be obtained from the pituitary parenchyma or pluripotent cells. Stem cell therapy has been successfully applied to a plethora of other disorders, and is a promising alternative to hormonal supplementation for resumption of normal hormone homeostasis., Summary: In this review, we describe the common causes for pituitary deficiencies and the advances in cellular therapy to restore the physiological pituitary function.

Background: Functional gonadotroph adenomas (FGAs) are rare tumors of the pituitary gland that secrete biologically active gonadotropins., Objective: To advance clinical understanding of FGAs., Methods: We performed a retrospective review of adult patients who underwent resection of a pituitary lesion between August 1997 and October 2014 and remain under care at our center. We identified patients who had pathologic and biochemical confirmation of FGAs, as defined by a lack of serum follicle-stimulating hormone/luteinizing hormone suppression in the setting of elevated gonadal steroids, associated clinical symptoms, or both., Results: FGAs were documented in 7 patients (5 men, 2 women) over a 17-year period. Clinical findings at presentation included visual field deficits in 5 patients, headache in 3, sexual dysfunction in 3, and ovarian cysts in both women. Each patient underwent lesion resection (6 via the endonasal transsphenoidal approach and 1 via a craniotomy with transsphenoidal reoperation). Analysis of tumor samples revealed immunopositivity for follicle-stimulating hormone/luteinizing hormone in 5 patients and FSH only in 2 patients. Postoperative follow-up (median, 10 months; range, 4-213 months) indicated remission in 6 of 7 patients., Conclusion: An FGA can pose both a diagnostic and a therapeutic challenge. The tumor is often diagnosed as a nonfunctioning macroadenoma after presenting with nonspecific symptoms and is the cause of significant morbidity. An FGA should be considered in the differential diagnosis of patients harboring pituitary adenomas with reproductive dysfunction. Transsphenoidal resection is the initial treatment of choice and can reduce endocrine dysfunction, resolve headaches, improve visual impairment, and provide tissue for detailed analysis., Abbreviations: FGA, functional gonadotroph adenomaFSH, follicle-stimulating hormoneLH, luteinizing hormoneTSH, thyroid-stimulating hormone.

Purpose: Subsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas., Methods: PD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry., Results: Pituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes., Conclusions: Human pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management.

Objective: To review cases and increase awareness in clinicians treating patients who may be taking biotin., Methods: We describe the presentation and workup of a woman with secondary progressive multiple sclerosis on high dose biotin with laboratory studies suggestive of thyrotoxicosis., Results: Plasma samples showed laboratory evidence of elevated thyroid hormone levels with elevated free thyroxine >7.8 ng/dl (reference interval (RI) 0.9-1.7 ng/dl) and decreased thyroid stimulating hormone <0.02 uIU/ml (RI 0.50-5.70 uIU/ml). Laboratory values normalized when biotin was withheld prior to repeat testing., Conclusions: Our case report demonstrates that ingestion of high dose biotin in multiple sclerosis patients can cause interference with laboratory assessment of thyroid function. This interference causes laboratory values suggestive of thyrotoxicosis and can lead to unnecessary evaluation. Clinicians should be aware of the risk of laboratory interference in this patient demographic.

Background: The prevalence of hypothalamic-pituitary dysfunction after aneurysmal subarachnoid hemorrhage has not been precisely determined, and conflicting results have been reported in the literature., Objective: To perform a systematic review and meta-analysis investigating the prevalence of pituitary insufficiency after aneurysmal subarachnoid hemorrhage and to focus on basal serum and dynamic test differences., Methods: The prevalence of pituitary dysfunction was quantified at 3 to 6 months and >6 months after aneurysmal subarachnoid hemorrhage. Proportions were transformed with the logit transformation. A subgroup analysis was performed focusing on the differences in outcome between basal serum and dynamic tests for the diagnosis of growth hormone deficiency (GHD) and secondary adrenal insufficiency., Results: Overall prevalence of hypopituitarism differed considerably between studies, ranging from 0.05 to 0.45 in studies performed between 3 and 6 months after the event and from 0 to 0.55 in long-term studies (>6 months), with pooled frequencies of 0.31 (95% confidence interval [CI]: 0.22-0.43) and 0.25 (95% CI: 0.16-0.36), respectively. Pooled frequency of GHD at 3 to 6 months was 0.14 (95% CI: 0.08-0.24). At >6 months, GHD prevalence was 0.19 (95% CI: 0.13-0.26) overall, but ranged from 0.15 (95% CI: 0.06-0.33) with the insulin tolerance test to 0.25 (95% CI: 0.15-0.36) using the growth hormone releasing hormone + arginine test., Conclusion: Hypopituitarism is a common complication in patients with aneurysmal subarachnoid hemorrhage, with GHD being the most prevalent diagnosis. We showed that variations in prevalence rates in the literature are partly due to methodological differences among pituitary function tests., Abbreviations: ACTH, adrenocorticotropic hormoneaSAH, aneurysmal subarachnoid hemorrhageGHD, growth hormone deficiencyGHRH, growth hormone-releasing hormoneGST, glucagon stimulation testIGF, insulin-like growth factor 1ITT, insulin tolerance testSAH, subarachnoid hemorrhage.

The purpose of this study was to examine the current indications for transsphenoidal surgery in the prolactinoma patient population, and to determine the outcomes of patients who undergo such operations. Transsphenoidal surgery may be indicated in prolactinoma patients who are resistant and/or intolerant to dopamine agonist (DA) therapy. We performed a retrospective review of the medical records of prolactinoma patients over a 6 year period (April 2008 to April 2014) at a large volume academic center. The median follow-up time was 12.0 months (range: 3-69). All patients who were included in the study (n=66) were treated with DA therapy and subsequently underwent an endonasal transsphenoidal operation. Of the 66 patients, 44 were women (mean age 34.2 years) and 22 were men (mean 41.7 years). There were 29 (43.9%) intolerant patients and 29 (43.9%) resistant patients. Postoperatively, 18 intolerant patients (66.7%) had normalized prolactin levels without the need for DA therapy, and five (17.2%) required DA to normalize their prolactin levels (p=0.02). Six patients (20.6%) had persistently elevated prolactin levels but were no longer receiving DA treatment (p<0.001). Postoperatively, 10 resistant patients (35.7%) had normal prolactin levels without DA therapy, and seven patients (25%) were treated with DA therapy to normalize their prolactin levels (p=0.22). Eight patients (28.6%) had supraphysiologic prolactin levels but were no longer taking a DA (p<0.001). Three patients (10.7%) were hyperprolactinemic, despite postoperative treatment with DA (p<0.001). After an appropriate treatment interval with multiple DA, radiographic follow-up, and careful clinical evaluation, prolactinoma patients can be offered surgery as an effective therapeutic option., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Pituitary lesions are common in the general population. Patients can present with a wide range of signs and symptoms that can be related to tumor mass effects or pituitary hormonal alterations. Evaluation involves assessing patients for the extent of tumor burden and pituitary hyper- or hypofunction and includes clinical exams, hormonal testing, and brain imaging. Preoperative diagnosis and treatment planning generally require a multidisciplinary team approach with expertise from endocrinologists, neurosurgeons, neuro-ophthalmologists, and neuroradiologists. This review will outline considerations for the evaluation and management of patients with pituitary masses at each stage in their treatment including the pre-, peri- and postoperative phases.

Objective: Speculation remains that GH treatment is associated with increased neoplasia risk. Studies in GH-treated childhood cancer survivors suggested higher rates of second neoplasms, while cancer risk data for GH-treated and untreated hypopituitary adults have been variable. We present primary cancer risk data from the Hypopituitary Control and Complications Study (HypoCCS) with a focus on specific cancers, and assessment of recurrence rates for pituitary adenomas (PA) and craniopharyngiomas (CP)., Design: Incident neoplasms during HypoCCS were evaluated in 8418 GH-treated vs 1268 untreated patients for primary malignancies, 3668 GH-treated vs 720 untreated patients with PA history, and 956 GH-treated vs 102 untreated patients with CP history., Methods: Using population cancer rates, standardised incidence ratios (SIRs) were calculated for all primary cancers, breast, prostate, and colorectal cancers. Neoplasm rates in GH-treated vs untreated patients were analysed after propensity score adjustment of baseline treatment group imbalances., Results: During mean follow-up of 4.8 years, 225 primary cancers were identified in GH-treated patients, with SIR of 0.82 (95% CI 0.71-0.93). SIRs (95% CI) for GH-treated patients were 0.59 (0.36-0.90) for breast, 0.80 (0.57-1.10) for prostate, and 0.62 (0.38-0.96) for colorectal cancers. Cancer risk was not statistically different between GH-treated and untreated patients (relative risk (RR)=1.00 (95% CI 0.70-1.41), P=0.98). Adjusted RR for recurrence was 0.91 (0.68-1.22), P=0.53 for PA and 1.32 (0.53-3.31), P=0.55 for CP., Conclusions: There was no increased risk for all-site cancers: breast, prostate or colorectal primary cancers in GH-treated patients during HypoCCS. GH treatment did not increase the risk of PA and CP recurrences., (© 2015 European Society of Endocrinology.)

Lanreotide depot (LD; commercial name Somatuline(®) Depot) is an injectable, extended-release formulation of the synthetic somatostatin analog (SSA) lanreotide. In recent clinical trials, LD was found to be suitable for self or partner administration, avoiding the need to travel to a medical facility. The Somatuline(®) Depot for Acromegaly (SODA) study is an ongoing, multicenter, observational study in the US investigating the efficacy, safety, convenience and symptom relief provided by LD in patients with acromegaly. Sub-analyses explore outcomes according to who administered the injection: patient, partner, healthcare provider (HCP) or a combination. Data reported here reflect one year of patient experience. Patients are eligible for inclusion if they have a diagnosis of acromegaly, are treated with LD and can give signed informed consent. Baseline data include patient demographics, previous acromegaly treatment and investigations, GH and IGF-I levels, LD dose and dose adjustment frequency. Symptom frequency, injection pain and treatment convenience are assessed using patient-reported questionnaires. As of 18 April 2012, 166 patients had enrolled in SODA. Most (72 %) achieved normal IGF-I levels after 12 months of LD treatment. Disease control was similar in self or partner injectors and in patients who received injections from their HCP, although self or partner injecting was deemed more convenient. LD was well-tolerated irrespective of who performed the injection. Self injection led to more injection-site reactions, but this did not increase the rate of treatment interruption. Acromegaly symptoms remained stable. Biochemical, safety and convenience data support the clinical validity of injecting LD at home.

Objective: The purpose of this study was to define an appropriate nadir growth hormone (nGH) cutoff for patients with acromegaly in remission using the Access Ultrasensitive human growth hormone (hGH) assay (Beckman Coulter, Brea, CA)., Methods: This cross-sectional study included 55 acromegalic subjects and 41 healthy adult volunteers. All subjects underwent oral glucose tolerance testing (OGTT) for growth hormones (GHs). An optimal cutoff for nGH for patients with active disease versus those in remission was determined using receiver-operating curve analysis., Results: The nGH of 0.53 ng/mL revealed a sensitivity of 97% (95% confidence interval [CI], 83-100%) and a specificity of 100% (95% CI, 82-100%). All 22 patients with acromegaly in remission suppressed GH to <1 ng/mL, 20/22 (91%) suppressed to <0.4 ng/mL, and 19/22 (86%) of subjects suppressed to <0.3 ng/mL (the maximum nGH measured in our healthy volunteer group)., Conclusion: When using the Access Ultrasensitive hGH assay for OGTT, a cutoff of 0.53 ng/mL was found to most accurately differentiate patients with acromegaly in remission from those with active disease.

The ability to reliably identify patients with new hypocortisolemia acutely following pituitary surgery is critical. We aimed to quantify the postoperative cortisol stress response following selective transsphenoidal adenomectomy, as a marker for postoperative preservation of functional pituitary gland. Records of 208 patients undergoing transsphenoidal operations for pituitary lesions were reviewed. Patients with Cushing's Disease, preoperative adrenal insufficiency, and those receiving intraoperative steroids were excluded. To quantify the postoperative stress response, the ∆ cortisol index was defined as the postoperative day (POD) 1 morning cortisol minus the preoperative morning cortisol level. The incidence of new hypocortisolemia requiring glucocorticoid replacement upon hospital discharge was also recorded. Fifty-two patients met inclusion criteria. The mean preoperative, POD1, and POD2 cortisol levels were 16.5, 29.2, and 21.8 μg/dL, respectively. Morning fasting cortisol levels on POD1 ranged from 4.2 to 73.0 μg/dL. The ∆ cortisol index ranged from -19.0 to +56.2 (mean +12.7 μg/dL). Five patients (9.6%) developed new hypocortisolemia on POD 1-3 requiring glucocorticoid replacement; only one required long-term replacement. The mean ∆ cortisol in patients requiring postoperative glucocorticoids was -2.8 μg/dL, compared with +14.4 μg/dL in patients without evidence of adrenal insufficiency (p = 0.005). Of the 32 patients (61.5%) with a ∆cortisol >25 μg/dL, none developed postoperative adrenal insufficiency. The postoperative cortisol stress response, as quantified by the ∆ cortisol index, holds potential as a novel and complimentary screening method to predict preservation of normal pituitary function and acute development of new ACTH deficiency following transsphenoidal pituitary surgery.

Objective: Childhood cancer survivors are commonly treated with GH for GH deficiency that develops either as a result of primary malignancy or its treatment. One study--the Childhood Cancer Survivor Study (CCSS)--demonstrated increased risk of second neoplasm (SN) in GH-treated childhood cancer survivors compared with non-GH treated, after adjusting for key risk factors. We assessed the incidence of SN in GH-treated childhood cancer survivors in outpatient observational studies of GH replacement., Design: Retrospective analysis of two prospective cohort studies that collected data on safety of GH replacement as prescribed in clinical practice., Methods: Childhood cancer survivors enrolled in Eli Lilly and Company's pediatric (Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS)) and adult (Hypopituitary Control and Complications Study (HypoCCS)) observational studies of GH treatment were assessed for incidence of SN., Results: The percentage of childhood cancer survivors treated with GH who developed a SN was 3.8% in pediatric GeNeSIS participants and 6.0% in adult HypoCCS participants. The estimated cumulative incidence of SN at 5 years of follow-up in these studies was 6.2 and 4.8% respectively., Conclusions: The incidence of SN in GeNeSIS and HypoCCS GH-treated participants is similar to the published literature and is thus consistent with increased risk of SN in childhood cancer survivors treated with GH. As follow-up times were relatively short (<3 years), longer observation is recommended. Nevertheless, clinicians should be alerted to the possibility of increased risk of SN in childhood cancer survivors treated with GH and continue chronic surveillance.

Context: In clinical practice, the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown., Objective: The objective of this study was to compare adverse events (AEs) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement., Design and Setting: This was a prospective observational study in the setting of US clinical practices., Patients and Outcome Measures: AEs were compared between GH-treated (n = 1988) and untreated (n = 442) GH-deficient adults after adjusting for baseline group differences and controlling the false discovery rate. The standardized mortality ratio was calculated using US mortality rates., Results: After a mean follow-up of 2.3 years, there was no significant difference in rates of death, cancer, intracranial tumor growth or recurrence, diabetes, or cardiovascular events in GH-treated compared with untreated patients. The standardized mortality ratio was not increased in either group. Unexpected AEs (GH-treated vs untreated, P ≤ .05) included insomnia (6.4% vs 2.7%), dyspnea (4.2% vs 2.0%), anxiety (3.4% vs 0.9%), sleep apnea (3.3% vs 0.9%), and decreased libido (2.1% vs 0.2%). Some of these AEs were related to baseline risk factors (including obesity and cardiopulmonary disease), higher GH dose, or concomitant GH side effects., Conclusions: In GH-deficient adults, there was no evidence for a GH treatment effect on death, cancer, intracranial tumor recurrence, diabetes, or cardiovascular events, although the follow-up period was of insufficient duration to be conclusive for these long-term events. The identification of unexpected GH-related AEs reinforces the fact that patient selection and GH dose titration are important to ensure safety of adult GH replacement.

Objective: Granulomatosis with polyangiitis (GPA), also known as Wegener's granulomatosis, is an autoimmune disease characterized by inflammation of blood vessels most often seen in the upper respiratory tract, lungs, kidneys, and skin. Central nervous system (CNS) involvement of GPA is rare, particularly in the pituitary, and can be difficult to treat., Methods: Case report., Results: We present a 30-year-old woman with pituitary and ocular GPA, whose unusually recalcitrant disease led to the development of pan-hypopituitarism and near-total vision loss. After failing multiple systemic immunosuppressants, she was ultimately treated with the novel immunomodulatory agent rituximab together with pulse corticosteroids, which achieved a gratifying response., Conclusion: Pituitary and optic chiasm involvement is a rare complication of GPA. We believe this case illustrates the complexity of management of pituitary GPA and provides insight into the potential utility of the biologic agent rituximab in this disease.

Objective: GH and IGFs have mitogenic properties, causing speculation that GH treatment could increase risk of malignancy. While studies in GH-treated childhood cancer survivors have suggested a slight increase in second neoplasms, studies in GH-treated adults have been equivocal. Design Incidence of de novo and second cancers was evaluated in 6840 GH-treated and 940 non GH-treated adult patients in the Hypopituitary Control and Complications Study pharmacoepidemiological database., Methods: Evident cancer cases were evaluated in the main analysis, with sensitivity analyses including probable and possible cancers. Standardized incidence ratios (SIRs) for cancers were calculated using Surveillance, Epidemiology and End Results for the USA and GLOBOCAN for all other countries., Results: During the mean follow-up of 3.7 years/GH-treated patient, 142 evident cancer cases were identified, giving an overall SIR of 0.88 (95% confidence interval (CI) 0.74-1.04); 95% CIs included the value of 1.0 for each country examined. The SIR for GH-treated patients from the USA (71 cases) was 0.94 (95% CI 0.73-1.18), and for non GH-treated patients from the USA (27 cases) was 1.16 (95% CI 0.76-1.69). For GH-treated patients from the USA aged <35 years, the SIR (six cases) was 3.79 (1.39-8.26), with SIR not elevated for all other age categories; SIR for patients from the USA with childhood onset (CO) GH deficiency (GHD) was 2.74 (95% CI 1.18-5.41). The SIR for colorectal cancer in GH-treated patients (11 cases) was 0.60 (95% CI 0.30-1.08)., Conclusions: With relatively short follow-up, the overall primary cancer risk in 6840 patients receiving GH as adults was not increased. Elevated SIRs were found for subgroups in the USA cohort defined by age <35 years or CO GHD.

Object: The 2004 WHO classification of pituitary adenomas now includes an "atypical" variant, defined as follows: MIB-1 proliferative index greater than 3%, excessive p53 immunoreactivity, and increased mitotic activity. The authors review the incidence of this atypical histopathological subtype and its correlation with tumor subtype, invasion, and surgical features., Methods: The records of 121 consecutive patients who underwent transsphenoidal surgery for pituitary adenomas during an 18-month period were retrospectively reviewed for evidence of atypical adenomas., Results: Eighteen adenomas (15%) met the criteria for atypical lesions; 17 (94%) of the 18 were macroadenomas. On imaging, 15 (83%) demonstrated imaging evidence of surrounding invasion, compared with 45% of typical adenomas (p = 0.004). Atypical tumors occurred in 12 female (67%) and 6 male (33%) patients. Patient age ranged from 16 to 70 years (mean 48 years). Nine patients (50%) had hormonally active tumors, and 9 had nonfunctional lesions. Four (22%) of the 18 patients presented to us with recurrent tumors. Immunohistochemical analysis demonstrated the following tumor subtypes: GH-secreting adenoma with plurihormonal staining (5 patients [28%]); null-cell adenoma (5 patients [28%]); silent ACTH tumor (3 patients [17%]), ACTH-staining tumor with Cushing's disease (2 patients [11%]), prolactinoma (2 patients [11%]), and silent FSH-staining tumor (1 patient [6%]). The MIB-1 labeling index ranged from 3% to 20% (mean 7%)., Conclusions: Atypical tumors were identified in 15% of resected pituitary adenomas, and they tended to be aggressive, invasive macroadenomas. More longitudinal follow-up is required to determine whether surgical outcomes, potential for recurrence, or metastasis of atypical adenomas vary significantly from their typical counterparts.

Context: Several studies have reported an association between idiopathic intracranial hypertension (IIH) and deficits of the hypothalamic-pituitary-adrenal (HPA) axis., Case Illustration: A 33-yr-old woman with Cushing's disease underwent successful surgical resection of a pituitary adenoma and developed IIH 11 months later after inadvertent withdrawal of oral glucocorticoids., Methods: A review of the literature was conducted to identify previous studies pertaining to IIH in association with neuroendocrine disease, focusing on reports related to HPA axis dysfunction., Results: A number of patients developing IIH due to a relative deficiency in glucocorticoids, after surgical or medical management for Cushing's disease, withdrawal from glucocorticoid replacement, or as an initial presentation of Addison's disease, have been reported. Hypotheses regarding the underlying pathophysiology of IIH in this context and, in particular, the role of cortisol and its relationship to other neuroendocrine and inflammatory mediators that may regulate the homeostasis of cerebrospinal fluid production and absorption are reviewed., Conclusion: In a subset of patients, dysfunction of the HPA axis appears to play a role in the development of IIH. Hormonal control of cerebrospinal fluid production and absorption may be regulated by inflammatory mediators and the enzyme 11ß-hydroxysteroid dehydrogenase type 1. Further study of neuroendocrine markers in the serum and cerebrospinal fluid may be an avenue for further research in IIH.

Context: Previous exposure to hypercortisolism due to Cushing's disease (CD) may adversely affect long-term metabolic and cardiovascular outcomes. In particular, metabolic and cardiovascular outcomes of patients with previous CD who require GH replacement have not been fully established., Objective: The aim of the study was to compare the prevalence and incidence of metabolic syndrome (Adult Treatment Panel III criteria), diabetes mellitus, cardiovascular disease, and cerebrovascular disease in GH-treated subjects with previous CD with GH-treated subjects with previous nonfunctioning pituitary adenoma (NFPA)., Design: We conducted post hoc analysis of the observational Hypopituitary Control and Complications Study conducted at 362 international centers (1995-2006)., Subjects: We studied adult-onset GH-deficient subjects with previous CD (n = 160) or NFPA (n = 879). All subjects received GH replacement therapy and were GH naive at enrollment. Multiple pituitary deficits were prevalent in both groups., Main Outcome Measures: We measured the prevalence and incidence of metabolic syndrome, diabetes mellitus, cardiovascular disease, and cerebrovascular disease at baseline and at 3 yr, standardized for age and sex differences between groups., Results: Compared with subjects with previous NFPA, subjects with previous CD had a significantly greater 3-yr incidence of metabolic syndrome (CD, 23.4%; NFPA, 9.2%; P = 0.01), baseline (CD, 6.3%; NFPA, 2.2%; P < 0.01) and 3-yr (CD, 7.6%; NFPA, 3.9%; P = 0.04) prevalence of cardiovascular disease, and baseline (CD, 6.4%; NFPA, 1.8%; P = 0.03) and 3-yr (CD, 10.2%; NFPA, 2.9%; P = 0.01) prevalence of cerebrovascular disease., Conclusions: Previous hypercortisolism may predispose GH-treated, GH-deficient subjects with prior CD to an increased risk of metabolic syndrome, cardiovascular disease, and cerebrovascular disease.

Background: The sellar and parasellar region is a confluence of several critical anatomical structures from various physiological systems located in close proximity to one another. Patients with pathology in this critical region of the central nervous system therefore make up a unique subset of neurosurgical patients that require careful preoperative and postoperative attention to numerous management details involving neurological, visual, and neuroendocrine function. A thorough understanding of the underlying anatomical and physiological principles of each of these systems, as well as the medical and surgical nuances involved in each case, is required to provide optimized management for patients with pituitary pathology. In this review, we discuss the major preoperative and postoperative considerations in patients undergoing resection for pituitary lesions in the modern era of transsphenoidal surgery.

Objective: The effects of GH replacement on glucose metabolism in GH-deficient (GHD) adults in clinical practice are not well defined. Therefore, we assessed GH treatment effects on fasting plasma glucose (FPG) and haemoglobin A1c (A1c) concentrations in GHD adults in a clinical setting., Design: Post-hoc analysis of the observational Hypopituitary Control and Complications Study conducted at 157 US centres (1997-2002)., Patients: GH-deficient adults who were GH-naïve at study entry and had at least two FPG measurements., Measurements: Effect of GH treatment on the frequency and time course of abnormal FPG (> or =5.6 mmol/l) development, FPG normalization, progression of increased FPG and abnormal follow-up A1c (>6%) values in GHD patients treated with GH (n = 403) or untreated (n = 169) at their physician's discretion., Results: In subjects without pre-existing diabetes mellitus, development of an abnormal FPG tended to occur in a greater percentage of GH-treated than untreated subjects (35.3% versus 24.5, P = 0.06). Additionally, GH treatment was associated with a mild, transient increase in FPG and shorter time to development of an abnormal FPG in these subjects (P < 0.01). Most ( approximately 80%) abnormal FPG values were below 7 mmol/l and normalized in 69% of GH-treated subjects without diabetes. Treatment with GH had no effect on the rate of FPG normalization, progression of increased FPG or abnormal follow-up A1c values., Conclusions: Initiation of GH replacement in GHD adults was associated with a mild increase in FPG that often normalized spontaneously. Nevertheless, clinicians should monitor FPG in patients receiving GH treatment.

Context: Retinoid X receptor agonists (rexinoids) have demonstrated benefit in patients with certain malignancies but appear to cause central hypothyroidism in some patients with advanced cancer. The influence of rexinoids on thyroid function in healthy subjects is not clear., Objective: The objective of this study was to determine the effect of a single dose of bexarotene on levels of TSH, T4, and T3 in healthy subjects., Design: This study was a randomized, double-blind, placebo-controlled, crossover trial., Setting: This study was conducted at the General Clinical Research Center (University of Colorado Health Sciences Center, Aurora, CO)., Subjects: Six healthy adults (>18 yr old) were studied., Intervention: Single-dose rexinoid (bexarotene, 400 mg/m2) or placebo, with TSH measurements at 0, 1, 2, 4, 8, 12, 24, and 48 h, were used., Main Outcome Measure: The main outcome was the serum TSH level at 24 h., Results: Single-dose bexarotene suppressed serum TSH (P < 0.001) over time. Compared with placebo, levels of TSH were significantly lower by 12 h (P = 0.043); the nadir of 0.32 +/- 0.02 mU/liter (P < 0.001) was seen at 24 h. Free T4 index and free T3 index were also significantly lower than placebo over time (48 h) (P = 0.029; P = 0.004, respectively). Serum prolactin, cortisol, and triglycerides were not affected (P > 0.05 for all). There was no significant effect of single-dose bexarotene on rT3 or T3/rT3 ratio at 24 h., Conclusion: A single dose of a rexinoid can rapidly and specifically suppress serum TSH levels in healthy subjects. These data provide insight into the mechanisms by which rexinoids cause central hypothyroidism and potential ways this effect can be used for treatment of disorders such as thyroid hormone resistance and TSH-secreting pituitary tumors.

In this report we have examined changes in cell growth parameters, cell cycle effectors, and signaling pathways that accompany thyrotrope growth arrest by thyroid hormone (TH) and growth resumption after its withdrawal. Flow cytometry and immunohistochemistry of proliferation markers demonstrated that TH treatment of thyrotrope tumors resulted in a reduction in the fraction of cells in S-phase that is restored upon TH withdrawal. This is accompanied by dephosphorylation and rephosphorylation of retinoblastoma (Rb) protein. The expression levels of cyclin-dependent kinase 2 and cyclin A, as well as cyclin-dependent kinase 1 and cyclin B, were decreased by TH, and after withdrawal not only did these regulators of Rb phosphorylation and mitosis increase in their expression but so too did the D1 and D3 cyclins. We also noted a rapid induction and subsequent disappearance of the type 5 receptor for the growth inhibitor somatostatin with TH treatment and withdrawal, respectively. Because somatostatin can arrest growth by activating MAPK pathways, we examined these pathways in TtT-97 tumors and found that the ERK pathway and several of its upstream and downstream effectors, including cAMP response element binding protein, were activated with TH treatment and deactivated after its withdrawal. This led to the hypothesis that TH, acting through increased type 5 somatostatin receptor, could activate the ERK pathway leading to cAMP response element binding protein-dependent decreased expression of critical cell cycle proteins, specifically cyclin A, resulting in hypophosphorylation of Rb and its subsequent arrest of S-phase progression. These processes are reversed when TH is withdrawn, resulting in an increase in the fraction of S-phase cells.

Glycoprotein-hormone alpha-subunit deficient (alphaSUnull) mice are hypothyroid and hypogonadal due to the absence of functional TSH, LH and FSH, despite normal production of the corresponding beta subunits. Pituitary tumors spontaneously developing in alphaSUnull mice were propagated in hypothyroid mice. The purpose of the current studies was to compare the gene expression profile of these alphaSUnull tumors with previously characterized TtT-97 thyrotropic tumors. A group of animals bearing each tumor type was treated with thyroid hormone (T4) prior to tumor removal. Both tumor types equally expressed TSHbeta mRNA, which significantly decreased when exposed to T4, whereas alpha-subunit mRNA was absent in alphaSUnull tumors. Northern blot analysis was performed using cDNA probes for the following transcription factors: Pit1, GATA2, pLIM, Msx1, Ptx1 and Ptx2. Both tumors were found to contain identical transcripts with similar responses to T4, with the exception of Pit1. In contrast to the signal pattern seen in TtT-97, only two bands were seen in alphaSUnull tumors, which were similar in size to those in alphaTSH cells, a thyrotropic cell line that lacks TSHbeta-subunit expression and Pit1 protein. However, western blot analysis revealed a protein band in the alphaSUnull tumors consistent with Pit1, while this signal was absent in alphaTSH cells. Northern blot analysis was also performed with specific cDNA probes for the following receptors: TRbeta1, TRbeta2, TRalpha1, non-T3 binding alpha2, RXRgamma and Sst5. Similarly-sized transcripts were found in both types of tumor, although the signal for Sst5 was seen in T4-treated alphaSUnull tumors only with a more sensitive RT-PCR analysis. The overall similarity between the two tumor types renders the alphaSUnull tumor as a suitable thyrotropic tumor model.

The molecular mechanism underlying thyroid hormone inhibition of thyrotrope cell growth is poorly understood. A comprehensive screen for T3-regulated genes involved in thyrotrope cell regulation was performed by Affymetrix MGU74A Genechip microarray analyses, which compared total RNA from hypothyroid versus 24 h T3-treated TtT-97 tumors. Of the 13,000 genes screened, a number of novel, T3-responsive candidate genes were identified. Within the Wnt family of growth factors, only Wnt-10A transcripts were abundantly expressed in hypothyroid TtT-97 tumors, and were down-regulated with T3 by 6 h of treatment. In addition, nuclear beta-catenin, which is a downstream mediator of canonical Wnt signaling, was decreased at the protein and functional levels. TtT-97 growth suppression was associated with decreased cyclin A transcript levels. We conclude that treatment of thyrotropic TtT-97 tumors with T3 resulted in the decreased expression of Wnt-10A, and that thyroid hormone may inhibit growth via cyclin A regulation.

Adrenocorticotroph cell pituitary adenomas immunoreactive for adrenocorticotropic hormone (ACTH) but unassociated with preoperative signs of hypercortisolism constitute between 6% and 43% of all ACTH adenomas. Few large series have been published. At our referral center for pituitary diseases, we have encountered 12 patients with silent ACTH adenomas, none of whom exhibited definite clinical features of hypercortisolism preoperatively. Two patients presented with apoplexy, and in 2 patients preoperative neuroimaging studies mimicked craniopharyngioma. Pathological examination revealed 8 adenomas with variably basophilic cytoplasm (type I, including 1 each with coarse basophilic granules and Crooke's hyaline change) and 4 with predominantly chromophobic cytoplasm (type II). Diffuse versus patchy (30% to 50% of cells) immunostaining best distinguished these 2 types; calcitonin staining was focal or negative in both. Two patients had unexpected postoperative courses consistent with acute cortisol insufficiency; 1 patient suffered from a severe flu-like illness, and the other had dizziness and was found to have a serum cortisol level of < 1.0 microg/dL. Both patients improved after cortisol replacement followed by a slow taper. Another patient developed 2 separate pituitary adenomas, a silent ACTH adenoma followed by a pure prolactinoma resected months later. Clonality studies demonstrated that the 2 tumors had arisen from different clonal populations. These cases offer additional insights into clinical, neuroimaging, histological, and biological features of silent ACTH adenomas. Because 2 of these patients seemed to require postoperative cortisol supplementation that otherwise would not have been given, clinicians should be notified about ACTH immunostaining in adenomas from patients without preoperative diagnoses of Cushing's disease, to optimize postoperative care.

Recombinant human TSH (rhTSH) has revolutionized the care of patients with differentiated thyroid cancer. Since its approval for clinical use in 2001 in Europe (1998 in the USA), rhTSH has greatly enhanced the surveillance of these patients by allowing the avoidance of hypothyroidism for TSH stimulation. Previously, a hypothyroid state was required for TSH stimulated diagnostic whole-body radio-iodine scans (DxWBS) and thyroglobulin (Tg) levels. Patients generally prefer rhTSH as a mechanism for TSH stimulation because symptoms of hypothyroidism can be completely avoided. Currently, rhTSH is only approved for diagnostic monitoring of differentiated thyroid cancer patients. There are many other potential uses for rhTSH, including facilitation of treatment of patients with thyroid cancer and nodular goiter. The diagnostic and therapeutic role of rhTSH in patients with differentiated thyroid cancer and nodular goiter will be discussed in this review.

Subclinical hyperthyroidism is a relatively common condition for which prospectively derived evidenced-based management guidelines do not exist. We have conducted a case-based mail survey to solicit opinions from members of the American Thyroid Association (ATA) about various issues that arise in the management of patients with this disorder. The survey was completed and returned by 185 of 300 (62%) of the original survey recipients. Four hypothetical cases varying in age, thyrotropin (TSH) level and underlying etiology were presented. The majority of respondents recommended further evaluation of all cases, most commonly choosing a radioactive iodine uptake (42%-71%), thyroid scan (39%-68%) and antithyroid (TPO/Tg) antibodies (49%-55%) as the additional tests to be ordered. The large majority (84%) recommended observation rather than active treatment for a young patient with a low but detectable serum TSH level. A small majority also recommended observation alone for a young woman with an undetectable serum TSH level (58%) and for an older woman with a low but detectable serum TSH value (63%). However, the majority (66%) favored treating an older woman with an undetectable serum TSH. When treatment was advised in the patients with subclinical hyperthyroidism, the respondents strongly favored anti-thyroid drugs when the etiology was Graves' disease and radioactive iodine when the etiology was toxic nodular thyroid disease. In the absence of adequate evidence-based guidelines, it is hoped that this survey of expert opinions may provide useful guidance for physicians providing care for patients with subclinical hyperthyroidism.

Previous studies showed that Pit-1 functionally cooperates with GATA-2 to stimulate transcription of the TSH beta gene. Pit-1 and GATA-2 are uniquely coexpressed in pituitary thyrotropes and activate transcription by binding to a composite promoter element. To define the domains of Pit-1 important for functional cooperativity with GATA-2, we cotransfected a set of Pit-1 deletions with an mTSH beta-luciferase reporter. Plasmids were titrated to express equivalent amounts of protein. A mutant containing a deletion of the hinge region between the POU and homeodomains retained the ability to fully synergize with GATA-2. In contrast, mutants containing deletions of amino acids 2-80 or 72-125 demonstrated 56 or 34% of the synergy found with the full-length protein, suggesting that these regions contributed to cooperativity. Mutants with deletions of the POU-specific or homeodomain further reduced the effect signifying the requirement for DNA binding. GST interaction studies demonstrated that only the homeodomain of Pit-1 interacted with GATA-2. Finally, several mutations between the Pit-1 and GATA-2 sites on the TSH beta promoter reduced binding for each factor and greatly reduced ternary complex formation. Thus multiple domains of Pit-1 are required for full synergy with GATA-2 and sequences between the two binding sites contribute to co-occupancy with both factors on the proximal TSH beta promoter.

We have previously characterized the structure of the murine somatostatin receptor type 5 gene (sst5). Initial transient transfection studies in pituitary somatolactotropes (GH(3)) mapped the promoter activity of this gene to a region 290 bp upstream of the transcription start site. The current study identifies the sst5 promoter region critical for basal activity. A series of deletions was generated, and promoter activity was localized to a region between -83 and -19. Similar promoter deletion patterns were evident in five pituitary cell types. Seven 10-bp transversion mutations encompassing the region between -83 and -19 were generated, and functional activity was assessed. Promoter activity was reduced by the mutations spanning -67 to -47 compared with the wild-type construct. Another mutation between -26 and -17 resulted in promoter activity reduction in GH(3) cells, but not TtT-97 thyrotropes. Deoxyribonuclease I protection analysis of the sst5 promoter region between -208/+47 was performed using GH(3) and TtT-97 nuclear extracts. The most striking protected regions, located between -61 and -41 and -25 and -3, correlated with functionally important regions identified by transfection studies. In summary, the mouse sst5 gene promoter has been characterized, and functional activity and nuclear factor interactions were mapped to two specific promoter regions. The region between -67 and -47 appears to contain a nucleotide sequence critical for basal transcriptional regulation of the mouse sst5 gene in pituitary cells.

Treatment with thyroid hormone (TH) results in shrinkage of a thyrotropic tumor grown in a hypothyroid host. We used microarray and Northern analysis to assess the changes in gene expression that preceded tumor involution. Of the 1,176 genes on the microarray, 7 were up-regulated, whereas 40 were decreased by TH. Many of these were neuroendocrine in nature and related to growth or apoptosis. When we examined transcripts for cell cycle regulators only cyclin-dependent kinase 2, cyclin A and p57 were down-regulated, whereas p15 was induced by TH. Retinoblastoma protein, c-myc, and mdm2 were unchanged, but E2F1 was down-regulated. TH also decreased expression of brain-derived neurotrophic factor, its receptor trkB, and the receptor for TRH. These, in addition to two other genes, neuronatin and PB cadherin, which were up- and down-regulated, respectively, showed a more rapid response to TH than the cell cycle regulators and may represent direct targets of TH. Finally, p19ARF was dramatically induced by TH, and although this protein can stabilize p53 by sequestering mdm2, we found no increase in p53 protein up to 48 h of treatment. In summary, we have described early changes in the expression of genes that may play a role in TH-induced growth arrest of a thyrotropic tumor. These include repression of specific growth factor and receptors and cell cycle genes as well as induction of other factors associated with growth arrest and apoptosis.

Thyroid hormone inhibits thyrotropin (TSH) production and thyrotrope growth. Somatostatin has been implicated as a synergistic factor in the inhibition of thyrotrope function. We have previously shown that pharmacological doses of thyroid hormone (levothyroxine [LT4]) inhibit growth of murine TtT-97 thyrotropic tumors in association with upregulation of somatostatin receptor type 5 (sst5) mRNA and somatostatin receptor binding. In the current study, we examined the effect of physiological thyroid hormone replacement alone or in combination with the long-acting somatostatin analogue, Sandostatin LAR, on thyrotropic tumor growth, thyrotropin growth factor-beta (TSH-beta), and sst5 mRNA expression, as well as somatostatin receptor binding sites. Physiological LT4 replacement therapy resulted in tumor shrinkage in association with increased sst5 mRNA levels, reduced TSH-beta mRNA levels and enhanced somatostatin receptor binding. Sandostatin LAR alone had no effect on any parameter measured. However, Sandostatin LAR combined with LT4 synergistically inhibited TSH-beta mRNA production and reduced final tumor weights to a greater degree. In this paradigm, Sandostatin LAR required a euthyroid status to alter thyrotrope parameters. These data suggest an important interaction between the somatostatinergic system and thyroid hormone in the regulation of thyrotrope cell structure and function.

Somatostatin is a peptide hormone whose actions are mediated by five somatostatin receptor subtypes (sstl-5). In the pituitary, somatostatin inhibits TSH release from thyrotropes and GH release from somatotropes. We have shown that sst5 transcripts and protein are induced by thyroid hormone in TtT-97 thyrotropic tumors. To map sequences responsible for promoter activity in pituitary cells, we cloned the mouse sst5 coding region of 362 amino acids and 12 kb of upstream DNA. Initial transfection studies in TtT-97 or GH3 cells mapped high levels of basal promoter activity to a 5.6-kb fragment upstream of the translational start, whereas shorter genomic fragments had low activity. To identify the transcriptional start site we used 5' RACE with TtT-97 poly A+ RNA and a sst5 antisense coding region primer. Sequence comparison between the complementary DNA and the gene revealed that the mouse sst5 gene contains 3 exons and 2 introns. The entire coding region was contained in exon 3. Two differently sized RACE products demonstrated alternate exon splicing of two untranslated exons in TtT-97 cells. A promoter fragment from -290/+48 linked to a luciferase reporter demonstrated 600- and 900-fold higher activity over a promoterless control in GH3 mammosomatotropes and TtT-97 thyrotropes, respectively, whereas a larger fragment extending to -6400 exhibited no additional promoter activity. Cloning of the sst5 gene will facilitate the mapping of basal and regulated responses at the transcriptional level.

Most behavioral and neurochemical changes produced by inescapable shock dissipate in 1-3 days. However, daily running activity is depressed for 14-42 days following one to three sessions of inescapable shock. In the present experiments, we sought to determine whether factors known to be important in the development of the short-term effects of exposure to inescapable shock would also be important in the production of the long-term effect of inescapable shock on daily activity. Three factors were examined: a) the escapability of the shock; short-term behavioral changes generally do not occur if the shock is escapable; b) naltrexone pretreatment; the opioid antagonist naltrexone typically prevents many of the short-term behavioral sequelae of inescapable shock; c) treatment with the anxiogenic beta-carboline FG-7142; administration of this compound alone frequently mimics inescapable shock in its ability to transiently disrupt behavior. The inescapable shock-induced reduction in daily activity did not depend upon escapability of the stressor. In addition, naltrexone did not prevent and FG-7142 did not induce the reduction in daily activity associated with stressor exposure.

The behavioral consequences of exposure to stressors such as inescapable shock are usually quite transitory if testing is conducted in an environment different from that in which the stressor was administered. Daily running activity is an exception in that it remains depressed for several weeks following experience with inescapable shock. In the present experiments we found the administration of the triazolbenzodiazepine adinazolam able to both reduce this long-term activity reduction produced by inescapable shock when acutely administered before the inescapable shock, and to reverse the effect when chronically administered after the inescapable shock. Classic 1,4-benzodiazepines such as diazepam have been able to prevent such effects when acutely administered before inescapable shock, but cannot reverse these effects when provided after the inescapable shock. Conversely, classic antidepressants such as desipramine have been unable to prevent these behavioral effects when given before inescapable shock in acute form, but can reverse the effects with chronic administration following the inescapable shock. Our observations that adinazolam can both prevent and reverse the effects of inescapable shock are consistent with reports that this agent has both anxiolytic and antidepressant effects in clinical use.

A wide variety of behavioral changes in the female rat have been associated with the estrous cycle, pregnancy, and the postpartum period and their accompanying hormonal fluctuations. Since monoamine systems have been implicated in the control of these behaviors, the present study examined the tissue concentrations of norepinephrine (NE), dopamine (DA), and serotonin (5HT) and their primary metabolites dihydroxyphenylglycol (DHPG), 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5HIAA) in the anterior cerebral cortex, hippocampus, and cerebellum during the estrous cycle, late pregnancy, and the early postpartum period. Results show no significant differences in neurotransmitter or metabolite levels during the estrous cycle in any of the three brain regions examined. However, profound differences were observed between samples from late pregnancy, early postpartum, and the estrous cycle. In general, NE and 5HT levels in all three brain regions fell from normal values during late pregnancy and rose in the early postpartum period; levels of their metabolites rose in postpartum samples. Conversely, DA levels were elevated in late pregnancy and depressed in the early postpartum period in anterior cortex, while DOPAC levels were depressed in both late pregnancy and the early postpartum period. The finding of changes in monoamine metabolism associated with pregnancy and its termination could be important in understanding the increased susceptibility to affective illness in women during the postpartum period.