Bio

Clinical Focus


  • Multiple Endocrine Neoplasias
  • Neuroendocrine - Endocrinology
  • Cushing's Syndrome
  • Endocrine - Endocrinology
  • Endocrine
  • Parathyroid Disease - Endocrinology
  • Parathyroid Disease
  • Hypopituitarism
  • Neuroendocrine - Medical Oncology
  • Hyperprolactinemia
  • Cushing Disease
  • Cancer > Neuro Oncology
  • Neuroendocrine
  • Multiple Endocrine Neoplasias - Endocrinology
  • Cushing's
  • Prolactinoma
  • Growth Hormone-Secreting Pituitary Adenoma
  • acromegaly
  • Adrenal Gland Neoplasms
  • Endocrinology
  • Growth Hormone Deficiency Dwarfism
  • Diabetes andMetabolism
  • Adrenal Cortex Diseases
  • Pituitary Adenomas
  • Pituitary Adenomas - Endocrinology

Academic Appointments


Administrative Appointments


  • Chair, Special Programs Committee, Endocrine Society (2008 - 2011)
  • Director, Endocrinology Fellowship Training Program, Stanford (2005 - Present)
  • Medical Director, Stanford Pituitary Center (2004 - Present)

Honors & Awards


  • Best Doctors in America, Best Doctors (2005-)

Professional Education


  • Board Certification: Endocrinology, Diabetes andMetabolism, American Board of Internal Medicine (2013)
  • Residency:Hospital of the University of Pennsylvania (1989) PA
  • Board Certification, Board of Internal Medicine, Endocrinology and Metabolism (1991)
  • Fellowship:Massachusetts General Hospital (1992) MA
  • Board Certification: Internal Medicine, American Board of Internal Medicine (1988)
  • Internship:Hospital of the University of Pennsylvania (1986) PA
  • Medical Education:UCLA School of Medicine (1985) CA
  • Endocrinology, Mass. General Hosp, Boston, Endocrinology and Metabolism (1992)
  • BS, U.C., Berkeley, Genetics (1981)

Research & Scholarship

Current Research and Scholarly Interests


My clinical and research interests in neuroendocrinology include the following programs:

1. Investigations into the effects of brain injury on pituitary function, with emphasis on the impact of hypopituitarism on rehabilitation

2. Research on the effects of neuroendocrine factors, including growth hormone and glucocorticoids, on neurocognitive function

3. Investigations into novel therapeutic modalities for acromegaly and hypopituitarism

4. Research into the effects of anabolic hormones such as gonadal steroids and growth hormone on body composition

Clinical Trials


  • Safety and Efficacy of Pasireotide Long Acting Release (LAR) vs. Octreotide LAR in Patients With Active Acromegaly Not Recruiting

    The patients will receive either Pasireotide LAR or Octreotide LAR for one year of treatment. The objective of this study is to compare the proportion of patients with a reduction of mean GH level to <2.5 µg/L and the normalization of IGF-1 to within normal limits (age and sex related) between the two treatment groups (pasireotide LAR and octreotide LAR) at 12 months. Following one year of treatment patients may proceed into the study extension. Patients who did not respond to the treatment they were randomized to (based on month 12 assessment results) will be switched to the other treatment arm at month 13.

    Stanford is currently not accepting patients for this trial. For more information, please contact Jacob Petralia, (650) 721 - 2830.

    View full details

  • An Open-Labeled, Extended-Use of XERECEPT (hCRF) for Patients in Studies NTI 0302, 0303, or Other Designated Studies Not Recruiting

    The purpose of this study is to examine the long-term safety and tolerability of human corticotropin-releasing factor (hCRF), XERECEPT®, in patients requiring dexamethasone (Decadron) to treat peritumoral brain edema. This open-label, extended-use study is open to all patients who participate in either of the blinded studies, NTI 0302, NTI 0303, or other designated studies, including patients who may have discontinued blinded study medication early but completed the protocol-stipulated follow-up periods.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lynn Adler, (650) 725 - 8630.

    View full details

  • XERECEPT® (hCRF) for Patients Requiring Dexamethasone to Treat Edema Associated With Brain Tumors Not Recruiting

    The purpose of this study is to compare the safety and efficacy of XERECEPT® to dexamethasone (Decadron) a common treatment for symptoms of brain swelling (edema). This study is specifically aimed at patients who require chronic high doses of dexamethasone to manage symptoms.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lynn Adler, (650) 725 - 8630.

    View full details

  • Study of Pasireotide in Patients With Rare Tumors of Neuroendocrine Origin Recruiting

    This study will assess the effectiveness and safety of pasireotide long-acting release in patients who have rare tumors of neuroendocrine origin.

    View full details

  • XERECEPT® (hCRF) for Primary Glioma Patients Requiring Dexamethasone to Treat Peritumoral Brain Edema Not Recruiting

    The purpose of this study is to examine the safety and efficacy of XERECEPT (human Corticotropin-Releasing Factor, or hCRF) compared to dexamethasone in patients with primary malignant glioma who require increased dexamethasone doses to control symptom of peritumoral brain edema.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cathy Recht, (650) 725 - 8630.

    View full details

  • Pilot Study to Determine Radioiodide Accumulation and Dosimetry in Breast Cancers Using 124I PET/CT Not Recruiting

    This is a pilot imaging study for women whose tumors express NIS [Na+I- symporter, sodium iodide symporter]. Eligibility is limited to the presence of strong (3+) and/or plasma membrane staining in > 20% of cells as determined by immunohistochemical methods. A total of 10 patients will be imaged with 124I PET/CT (serial scans over 24 hour period) to determine radioiodide uptake and distribution in tumor tissue. Thyroid iodide uptake and retention will be blocked beginning one week prior to 124I PET/CT scan with thyroid hormone (T3) and methimazole (impedes organification). Tumor, organ and whole body dosimetry will be calculated in each patient.

    Stanford is currently not accepting patients for this trial. For more information, please contact Marilyn Florero, (650) 724 - 1953.

    View full details

Teaching

2013-14 Courses


Postdoctoral Advisees


Graduate and Fellowship Programs


Publications

Journal Articles


  • Global clinical response in Cushing's syndrome patients treated with mifepristone. Clinical endocrinology Katznelson, L., Loriaux, D. L., Feldman, D., Braunstein, G. D., Schteingart, D. E., Gross, C. 2014; 80 (4): 562-569

    Abstract

    Mifepristone, a glucocorticoid receptor antagonist, improves clinical status in patients with Cushing's syndrome (CS). We examined the pattern, reliability and correlates of global clinical response (GCR) assessments during a 6-month clinical trial of mifepristone in CS.Post hoc analysis of secondary end-point data from a 24-week multicentre, open-label trial of mifepristone (300-1200 mg daily) in CS. Intraclass correlation coefficient (ICC) was used to examine rater concordance, and drivers of clinical improvement were determined by multivariate regression analysis.Forty-six adult patients with refractory CS along with diabetes mellitus type 2 or impaired glucose tolerance, and/or a diagnosis of hypertension.Global clinical assessment made by three independent reviewers using a three-point ordinal scale (+1 = improvement; 0 = no change; -1 = worsening) based on eight broad clinical categories including glucose control, lipids, blood pressure, body composition, clinical appearance, strength, psychiatric/cognitive symptoms and quality of life at Weeks 6, 10, 16, and 24.Positive GCR increased progressively over time with 88% of patients having improved at Week 24 (P < 0·001). The full concordance among reviewers occurred in 76·6% of evaluations resulting in an ICC of 0·652 (P < 0·001). Changes in body weight (P < 0·0001), diastolic blood pressure (P < 0·0001), two-hour postoral glucose challenge glucose concentration (P = 0·0003), and Cushingoid appearance (P = 0·022) were strong correlates of GCR.Mifepristone treatment for CS results in progressive clinical improvement. Overall agreement among clinical reviewers was substantial and determinants of positive GCR included change in weight, blood pressure, glucose levels and appearance.

    View details for DOI 10.1111/cen.12332

    View details for PubMedID 24102404

  • Clinical characteristics, timing of peak responses and safety aspects of two dosing regimens of the glucagon stimulation test in evaluating growth hormone and cortisol secretion in adults PITUITARY Yuen, K. C., Biller, B. M., Katznelson, L., Rhoads, S. A., Gurel, M. H., Chu, O., Corazzini, V., Spiller, K., Gordon, M. B., Salvatori, R., Cook, D. M. 2013; 16 (2): 220-230

    Abstract

    Weight-based (WB: 0.03 mg/kg) and fixed dose (FD: 1-1.5 mg) regimens of the glucagon stimulation test (GST) have been used to evaluate GH and cortisol secretion in children and adults, respectively. However, experience of the WB regimen in assessing GH and cortisol secretion in adults are limited. We describe a multicenter experience using WB and FD regimens in evaluating GH and cortisol secretion in adults suspected of GH deficiency and central adrenal insufficiency. Retrospective case series of GSTs (n = 515) performed at five tertiary centers. Peak and nadir glucose, and peak GH and peak cortisol responses occurred later with WB (mean dose: 2.77 mg) compared to FD (mean dose: 1.20 mg) regimens. Main side-effects were nausea and vomiting, particularly in younger females. Nausea was comparable but vomiting was more frequent in the WB regimen (WB: 10.0 % vs FD: 2.4 %; P < 0.05). Peak and nadir glucose, ΔGH, and peak and Δcortisol were higher in the WB regimen. In both regimens, age correlated negatively with peak cortisol levels, and body mass index (BMI), fasting, peak and nadir glucose correlated negatively with peak GH levels. WB and FD regimens can induce adult GH and cortisol secretion, but peak responses occur later in the WB regimen. Both regimens are relatively safe, and vomiting was more prevalent in the WB regimen. As age, BMI, and glucose tolerance negatively correlated with peak GH and cortisol levels, the WB regimen may be more effective than the FD regimen in older overweight glucose intolerant patients.

    View details for DOI 10.1007/s11102-012-0407-7

    View details for Web of Science ID 000319295500013

    View details for PubMedID 22806554

  • AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE DIAGNOSIS AND TREATMENT OF ACROMEGALY-2011 UPDATE: EXECUTIVE SUMMARY ENDOCRINE PRACTICE Katznelson, L., Atkinson, J. L., Cook, D. M., Ezzat, S. Z., Hamrahian, A. H., Miller, K. K. 2011; 17 (4): 636-646

    View details for Web of Science ID 000294276000014

    View details for PubMedID 21846619

  • Pituitary Incidentaloma: An Endocrine Society Clinical Practice Guideline JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Freda, P. U., Beckers, A. M., Katznelson, L., Molitch, M. E., Montori, V. M., Post, K. D., Vance, M. L. 2011; 96 (4): 894-904

    Abstract

    The aim was to formulate practice guidelines for endocrine evaluation and treatment of pituitary incidentalomas.Consensus was guided by systematic reviews of evidence and discussions through a series of conference calls and e-mails and one in-person meeting.We recommend that patients with a pituitary incidentaloma undergo a complete history and physical examination, laboratory evaluations screening for hormone hypersecretion and for hypopituitarism, and a visual field examination if the lesion abuts the optic nerves or chiasm. We recommend that patients with incidentalomas not meeting criteria for surgical removal be followed with clinical assessments, neuroimaging (magnetic resonance imaging at 6 months for macroincidentalomas, 1 yr for a microincidentaloma, and thereafter progressively less frequently if unchanged in size), visual field examinations for incidentalomas that abut or compress the optic nerve and chiasm (6 months and yearly), and endocrine testing for macroincidentalomas (6 months and yearly) after the initial evaluations. We recommend that patients with a pituitary incidentaloma be referred for surgery if they have a visual field deficit; signs of compression by the tumor leading to other visual abnormalities, such as ophthalmoplegia, or neurological compromise due to compression by the lesion; a lesion abutting the optic nerves or chiasm; pituitary apoplexy with visual disturbance; or if the incidentaloma is a hypersecreting tumor other than a prolactinoma.

    View details for DOI 10.1210/jc.2010-1048

    View details for Web of Science ID 000289242800027

    View details for PubMedID 21474686

  • Fatigue after traumatic brain injury: Association with neuroendocrine, sleep, depression and other factors BRAIN INJURY Englander, J., Bushnik, T., Oggins, J., Katznelson, L. 2010; 24 (12): 1379-1388

    Abstract

    Define associations between post-traumatic brain injury (TBI) fatigue and abnormalities in neuroendocrine axes, sleep, mood, cognition and physical functioning.Survey.Large community hospital-based rehabilitation centre.Convenience sample of 119 individuals at least 1 year post-TBI.Multidimensional Assessment of Fatigue (MAF); Fatigue Severity Scale (FSS); neuroendocrine assessments-growth hormone (GH) reserve, thyroid, cortisol and testosterone levels; visual analogue pain rating; Pittsburgh Sleep Quality Index; Beck Depression Inventory-II; Disability Rating Scale; Craig Handicap Assessment and Reporting Technique; Neurobehavioural Functioning Inventory.Fifty-three per cent reported fatigue on the MAF and one-third on the FSS; 65% were found to have moderate/severe GH deficiency; 64% had adrenal insufficiency (low fasting cortisol); 12% had central hypothyroidism; and 15% of men had testosterone deficiency. Pituitary dysfunction did not correlate with fatigue or other symptoms. Predictors of MAF total scores were female gender, depression, pain and self-assessed memory deficits. Predictors of FSS scores were depression, self-assessed motor deficits and anti-depressant usage.Robust correlates of fatigue were gender, depression, pain and memory and motor dysfunction. Investigation of post-TBI fatigue should include screening for depression, pain and sleep disturbance. There was no correlation between pituitary dysfunction and fatigue; however, the relatively high prevalence of hypothyroidism and adrenal dysfunction suggests screening for these hormone deficiencies.

    View details for DOI 10.3109/02699052.2010.523041

    View details for Web of Science ID 000283200800001

    View details for PubMedID 20961172

  • Fatigue after TBI: Association with neuroendocrine abnormalities BRAIN INJURY Bushnik, T., Englander, J., Katznelson, L. 2007; 21 (6): 559-566

    Abstract

    Evaluate the association between neuroendocrine findings and fatigue after traumatic brain injury (TBI) Research design: Prospective, observational.Sixty-four individuals at least 1 year post-TBI underwent neuroendocrine testing including thyroid, adrenal, gonadal axes and growth hormone (GH) after glucagon stimulation with assessment of fatigue using the Global Fatigue Index (GFI) and the Fatigue Severity Scale (FSS).GFI and FSS scores were significantly higher within this sample compared to published control data. At least one pituitary axis was abnormal in 90% of participants. Higher GH levels were significantly associated with higher FSS scores. There was a noted trend between lower basal cortisol and higher scores on both the FSS and GFI.The association between higher GH levels and greater fatigue contradicted the prevailing hypothesis that post-acute TBI fatigue is associated with GH deficiency. The association between lower basal cortisol and greater fatigue was in the expected direction. While no other trends were noted, the fatigue derived from neuroendocrine abnormalities alone may be masked by fatigue induced by other factors commonly experienced following TBI. Given the high prevalence of pituitary abnormalities, screening for hypopituitarism after TBI is a reasonable recommendation. The contribution of GH deficiency to diminished quality of life post-TBI remains unclear.

    View details for DOI 10.1080/02699050701426915

    View details for Web of Science ID 000248204100002

    View details for PubMedID 17577706

  • Clinical characteristics and pituitary dysfunction in patients with metastatic cancer to the sella. Endocrine practice Ariel, D., Sung, H., Coghlan, N., Dodd, R., Gibbs, I. C., Katznelson, L. 2013; 19 (6): 914-919

    Abstract

    Objective: Metastatic disease to the sella is uncommon and there are limited available data regarding the clinical aspects of this disease. We sought to characterize the clinical demographics of sellar metastases.Methods: Retrospective chart review of adults at Stanford University Medical Center from 1980 to 2011 with metastatic disease to the sella.Results: 13 subjects were identified (9 F). The mean age at diagnosis was 55 years (range: 25-73 y). 6 (46%) had breast carcinoma, 3 (23%) had renal cell carcinoma, 2 (15%) had squamous cell carcinoma of the head and neck, 1 had bronchoalveolar carcinoma of the lung, and 1 had nodular sclerosing Hodgkin's lymphoma. The most common presenting signs and symptoms were headache (58%), followed by fatigue (50%), polyuria (50%), visual field defects (42%), and ophthalmoplegia (42%). 75% presented with at least one pituitary hormone insufficiency, including 6 (50%) with diabetes insipidus (DI). 8 (67%) subjects had secondary hypothyroidism, and 5 (45%) had secondary adrenal insufficiency. Of the patients with stalk involvement, 86% had DI. All patients had a prior diagnosis of malignancy for a mean duration of 95 months.Conclusion: In this retrospective review, the most common neoplastic sources to the sella were breast and renal cell carcinoma. Secondary hypothyroidism was the most common endocrine abnormality, followed by DI, and adrenal insufficiency. New onset central hypothyroidism and diabetes insipidus along with known malignancy in a patient with a sellar lesion should raise the suspicion of a metastatic source.

    View details for DOI 10.4158/EP12407.OR

    View details for PubMedID 23757610

  • Sustained Improvements in Plasma ACTH and Clinical Status in a Patient With Nelson's Syndrome Treated With Pasireotide LAR, a Multireceptor Somatostatin Analog. journal of clinical endocrinology & metabolism Katznelson, L. 2013; 98 (5): 1803-1807

    Abstract

    Context: Nelson's syndrome refers to aggressive pituitary corticotroph adenoma growth after bilateral adrenalectomy for treatment of Cushing's disease (CD). Pasireotide, a novel somatostatin analog, has been effective in treating CD. Here, the first case report of a patient with Nelson's syndrome treated with pasireotide is presented. Case Presentation: A 55-year-old female was diagnosed with CD in 1973 at age 15 years and underwent bilateral adrenalectomy 1 year later. She subsequently developed Nelson's syndrome and underwent multiple surgeries and radiotherapy for adenoma growth. After presentation with ocular pain, third cranial nerve palsy, and a finding of suprasellar tumor enlargement with hemorrhage, she began pasireotide long-acting release 60 mg/28 days im. At baseline, fasting plasma ACTH was 42 710 pg/mL (normal, 5-27 pg/mL), and fasting plasma glucose was 98 mg/dL. After 1 month, ACTH declined to 4272 pg/mL, and it has remained stable over 19 months of follow-up. Hyperpigmentation progressively improved. Magnetic resonance imaging scans show reduction in the suprasellar component. Fasting plasma glucose increased to 124 mg/dL, and the patient underwent diabetes management. Evidence Acquisition and Synthesis: In this clinical case seminar, the current understanding of the treatment of Nelson's syndrome and the use of pasireotide in CD are summarized. Conclusion: A case of Nelson's syndrome with clinically significant and dramatic biochemical and clinical responses to pasireotide administration is reported. Hyperglycemia was noted after pasireotide administration. Pasireotide may represent a useful tool in the medical management of Nelson's syndrome. Further study of the potential benefits and risks of pasireotide in this population is necessary.

    View details for DOI 10.1210/jc.2013-1497

    View details for PubMedID 23539733

  • In Reply: Pituitary Centers of Excellence. Neurosurgery McLaughlin, N., Laws, E. R., Oyesiku, N. M., Katznelson, L., Kelly, D. F. 2013

    View details for PubMedID 23756738

  • Pituitary Centers of Excellence NEUROSURGERY McLaughlin, N., Laws, E. R., Oyesiku, N. M., Katznelson, L., Kelly, D. F. 2012; 71 (5): 916-924

    Abstract

    Pituitary tumors and associated neuroendocrine disorders pose significant challenges in diagnostic and therapeutic management. Optimal care of the "pituitary patient" is best provided in a multidisciplinary collaborative environment that includes not only experienced pituitary practitioners in neurosurgery and endocrinology, but also in otorhinolaryngological surgery, radiation oncology, medical oncology, neuro-ophthalmology, diagnostic and interventional neuroradiology, and neuropathology. We provide the background and rationale for recognizing pituitary centers of excellence and suggest a voluntary verification process, similar to that used by the American College of Surgeons for Trauma Center verification. We propose that pituitary centers of excellence should fulfill 3 key missions: (1) provide comprehensive care and support to patients with pituitary disorders; (2) provide residency training, fellowship training, and/or continuing medical education in the management of pituitary and neuroendocrine disease; and (3) contribute to research in pituitary disorders. As this is a preliminary proposal, we recognize several issues that warrant further consideration including center and surgeon practice volume as well as oversight of the verification process.

    View details for DOI 10.1227/NEU.0b013e31826d5d06

    View details for Web of Science ID 000310360300016

    View details for PubMedID 22902334

  • The dynamics of post-operative plasma ACTH values following transsphenoidal surgery for Cushing's disease PITUITARY Srinivasan, L., Laws, E. R., Dodd, R. L., Monita, M. M., Tannenbaum, C. E., Kirkeby, K. M., Chu, O. S., Harsh, G. R., Katznelson, L. 2011; 14 (4): 312-317

    Abstract

    Rapid assessment of adrenal function is critical following transsphenoidal surgery (TSS) for Cushing's disease (CD) in order to determine surgical efficacy. We hypothesize that there may be a role for ACTH measurement as a rapid indicator of adrenal function. Following surgery for CD, glucocorticoids were withheld and paired plasma ACTH and serum cortisol levels were measured every 6 h. Post-operative hypocortisolemia was defined as serum cortisol <2 mcg/dl or a serum cortisol <5 mcg/dl with the onset of symptoms of adrenal insufficiency within 72 h. We studied 12 subjects, all female, mean age 44.6 years (range 25-55), including 13 surgeries: nine subjects attained hypocortisolemia. Plasma ACTH levels decreased more in subjects with hypocortisolemia (0.9 pg/ml/hr, P = 0.0028) versus those with persistent disease (0 0.2 pg/ml/hr, P = 0.26) within the first 48 h after surgery. In contrast to subjects with persistent disease, all subjects with hypocortisolemia achieved a plasma ACTH <20 pg/ml by 19 h (range 1-19 h). Four of the nine subjects with hypocortisolemia achieved plasma ACTH <20 pg/ml by 13 h and the remaining five subjects by 19 h. Hypocortisolemia occurred between 3-36 h following achievement of a plasma ACTH <20 pg/ml. In CD, a reduction in postoperative plasma ACTH levels differentiates subjects with surgical remission versus subjects with persistent disease. The utility of plasma ACTH measurements in the postoperative management of CD remains to be determined.

    View details for DOI 10.1007/s11102-011-0295-2

    View details for Web of Science ID 000300349800003

    View details for PubMedID 21298507

  • American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly--2011 update. Endocrine practice Katznelson, L., Atkinson, J. L., Cook, D. M., Ezzat, S. Z., Hamrahian, A. H., Miller, K. K. 2011; 17: 1-44

    View details for PubMedID 21846616

  • ECTOPIC ACROMEGALY DUE TO A PANCREATIC NEUROENDOCRINE TUMOR PRODUCING GROWTH HORMONE-RELEASING HORMONE ENDOCRINE PRACTICE Weiss, D. E., Vogel, H., Lopes, M. B., Chang, S. D., Katznelson, L. 2011; 17 (1): 79-84

    Abstract

    To present a case of acromegaly due to ectopic growth hormone-releasing hormone (GHRH) secretion from a pancreatic neuroendocrine tumor in the context of multiple endocrine neoplasia type 1 (MEN 1).We describe the clinical, imaging, and pathologic findings of the study patient.A 46-year-old woman presented with clinical and biochemical findings diagnostic of acromegaly. Magnetic resonance imaging showed a 1.2-cm sellar mass. Following resection of the macroadenoma, serum insulin-like growth factor 1 (IGF-1) and growth hormone (GH) levels remained unchanged. Pathologic examination revealed adenomatous changes, including a nonsecretory focus and a prolactin immunopositive area (GH stain negative in both). Octreotide long-acting release was ineffective. Search for an ectopic tumor included normal octreoscan and abdominal computed tomography. GHRH was greater than 1000 pg/mL. Repeated abdominal computed tomography documented a 6.2-cm mass in the tail and body of the pancreas. Distal pancreatectomy revealed a pancreatic neuroendocrine tumor that stained positive for GHRH. Postoperatively, serum GHRH and IGF-1 normalized. Re-evaluation of the initial pituitary pathologic specimen revealed additional somatotroph hyperplasia of the adjacent, normal pituitary gland. Primary hyperparathyroidism was diagnosed, and multigland parathyroid hyperplasia was noted at surgery. Genetic testing was positive for a mutation in the MEN1 gene.This patient's acromegaly was resistant to somatostatin analogue therapy, reflecting the negative octreoscan imaging. In addition, this case is novel because the patient presented with pituitary adenomatous changes, which were presumably associated with MEN 1 and/or possibly the elevated GHRH levels.

    View details for DOI 10.4158/EP10165.CR

    View details for Web of Science ID 000289272700011

    View details for PubMedID 20713338

  • Retrosellar intracranial extracerebral glioneuronal heterotopion: case report CLINICAL NEUROPATHOLOGY Karamchandani, J., Fischbein, N., Harsh, G., Katznelson, L., Vogel, H. 2010; 29 (5): 297-300

    Abstract

    We report the case of an 18-year-old woman with an intradural retroclival retrosellar glioneuronal heterotopion. At the time of surgery, a well circumscribed pale-tan mass was identified posterior to and distinct from the posterior pituitary. Pathologic examination showed disorganized, non-neoplastic glial tissue characteristic of glioneuronal heterotopia. To our knowledge, this is the first report of such a lesion in this location.

    View details for Web of Science ID 000281967000004

    View details for PubMedID 20860892

  • Approach to the Patient with Persistent Acromegaly after Pituitary Surgery JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Katznelson, L. 2010; 95 (9): 4114-4123

    Abstract

    The approach to a patient with acromegaly and persistent disease after surgery requires a complex diagnostic assessment. Acromegaly is a chronic and insidious disease that is associated with multisystem comorbidities, including cardiovascular disease, hypertension, sleep apnea syndrome, colon polyposis, arthropathy, and metabolic complications including glucose intolerance and type 2 diabetes mellitus. Patients also have a variety of signs and symptoms, including headache, arthralgias, carpal tunnel syndrome, sweating, fatigue, and psychological issues that impact significantly on quality of life. The recommended approach to the evaluation of the postoperative patient includes a biochemical assessment, with measurement of serum IGF-I along with a glucose-suppressed GH value, radiological assessment to determine location of residual tumor and presence of mass effects, a physical examination for evidence of skeletal and soft tissue overgrowth and related signs of acromegaly, and a thorough clinical assessment for the presence of comorbidities. Repeat surgery is indicated if there is residual tumor that is surgically accessible and there may be a chance for surgical cure, or if there are persistent mass effects upon the optic chiasm. Otherwise, medical therapy is indicated, utilizing somatostatin analogs, dopamine agonists, and pegvisomant, a GH receptor antagonist. Radiation therapy is usually relegated to situations where medical therapy is ineffective or poorly tolerated or where patients would prefer not to sustain the cost of long-term medical therapy. The choice of therapy requires close dialog among endocrinologists, neurosurgeons, radiation therapists, and neuroophthalmologists for optimal care of patients.

    View details for DOI 10.1210/jc.2010-0670

    View details for Web of Science ID 000281640300023

    View details for PubMedID 20823464

  • A NOVEL PRKAR1A MUTATION ASSOCIATED WITH PRIMARY PIGMENTED NODULAR ADRENOCORTICAL DISEASE AND THE CARNEY COMPLEX ENDOCRINE PRACTICE Peck, M. C., Visser, B. C., Norton, J. A., Pasche, L., Katznelson, L. 2010; 16 (2): 198-204

    Abstract

    To delineate the genetic and phenotypic features of Carney complex in a family with multiple cases of primary pigmented nodular adrenocortical disease (PPNAD).Detailed clinical, laboratory, genetic, radiologic, and pathologic findings are presented, and the pertinent literature is reviewed.A 17-year-old girl presented with symptoms and physical findings suggestive of hypercortisolemia, in addition to facial lentigines. She was found to have adrenocorticotropic hormone (ACTH)-independent Cushing syndrome. The adrenal glands appeared normal on computed tomographic scanning. Bilateral surgical adrenalectomy revealed PPNAD. Evaluation of her 14-year-old sister revealed ACTH-independent Cushing syndrome as well as facial lentigines, and adrenalectomy revealed PPNAD as well. Genetic testing of the 2 sisters and their mother (who also had multiple facial lentigines but did not have Cushing syndrome) revealed a novel mutation in the PRKAR1A gene.We describe a novel mutation in the PRKAR1A gene in a family with Carney complex and multiple members with PPNAD. PPNAD should be suspected in cases of ACTH-independent Cushing syndrome, and screening for Carney complex and its complications is recommended in all cases of PPNAD, including first-degree relatives.

    View details for DOI 10.4158/EP09245.OR

    View details for Web of Science ID 000277497400011

    View details for PubMedID 19833579

  • Prevalence and clinical demographics of cerebral salt wasting in patients with aneurysmal subarachnoid hemorrhage PITUITARY Kao, L., Al-Lawati, Z., Vavao, J., Steinberg, G. K., Katznelson, L. 2009; 12 (4): 347-351

    Abstract

    Hyponatremia is a frequent complication following subarachnoid hemorrhage (SAH), and is commonly attributed either to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or cerebral salt wasting syndrome (CSW). The object of this study is to elucidate the clinical demographics and sequelae of hyponatremia due to CSW in subjects with aneurysmal SAH. Retrospective chart review of patients >18 years with aneurysmal SAH admitted between January 2004 and July 2007 was performed. Subjects with moderate to severe hyponatremia (serum sodium <130 mmol l(-1)) were divided into groups consistent with CSW and SIADH based on urine output, fluid balance, natriuresis, and response to saline infusion. Clinical demographics were compared. Of 316 subjects identified, hyponatremia (serum sodium <135 mmol l(-1)) was detected in 187 (59.2%) subjects and moderate to severe hyponatremia in 48 (15.2%). Of the latter group, 35.4% were categorized with SIADH and 22.9% with CSW. Compared to eunatremic subjects, hyponatremia was associated with significantly longer hospital stay (15.7 +/- 1.9 vs. 9.6 +/- 1.1 days, p < 0.001). Subjects with CSW had similar mortality and duration of hospital stay vs. those with SIADH. Though less common than SIADH, CSW was detected in approximately 23% of patients with history of aneurysmal SAH and was not clearly associated with enhanced morbidity and mortality compared to subjects with SIADH. Further studies regarding the pathogenesis and management, along with the medical consequences, of CSW are important.

    View details for DOI 10.1007/s11102-009-0188-9

    View details for Web of Science ID 000270977600011

    View details for PubMedID 19462244

  • Lanreotide promotes apoptosis and is not radioprotective in GH3 cells ENDOCRINE-RELATED CANCER Ning, S., Knox, S. J., Harsh, G. R., Culler, M. D., Katznelson, L. 2009; 16 (3): 1045-1055

    Abstract

    Somatostatin analogs are a mainstay of medical therapy in patients with GH producing human pituitary tumors, and it has been suggested that somatostatin analogs may be radioprotective. We utilized GH secreting rat GH3 cells to investigate whether a somatostatin analog may limit the effects of radiation on proliferation and apoptosis in vitro and on tumor growth in vivo. Treatment with lanreotide alone at doses of either 100 or 1000 nM for 48 h reduced clonogenic survival by 5-10%. Radiation alone produced a dose-dependent survival curve with a SF2 of 48-55%, and lanreotide had no effect on this curve. The addition of lanreotide resulted in a 23% increase in the proportion of apoptotic sub-G1 cells following irradiation (P<0.01). In a mouse GH3 tumor xenograft model, lanreotide 10 mg/kg moderately inhibited the growth of GH3 tumors, with a 4x tumor growth delay (TGD) time that ranged from 4.5 to 8.3 days. Fractionated local tumor radiation alone significantly inhibited tumor growth and produced a TGD of 35.1+/-5.7 days for 250 cGy fractions. The combination of lanreotide, either antecedent to or concurrent, with radiation of 250, 200 or 150 cGy/fraction for 5 days inhibited tumor growth and produced the TGD times that were similar to radiation alone (P>0.05). Pretreatment with lanreotide had the most significant radiosensitizing effect. These studies demonstrate that the somatostatin analog lanreotide is not radioprotective in GH3 cells, and further studies are necessary to determine the impact of lanreotide on apoptosis.

    View details for DOI 10.1677/ERC-09-0003

    View details for Web of Science ID 000272670300027

    View details for PubMedID 19528243

  • Non-surgical management of hormone-secreting pituitary tumors JOURNAL OF CLINICAL NEUROSCIENCE Patil, C. G., Hayden, M., Katznelson, L., Chang, S. D. 2009; 16 (8): 985-993

    Abstract

    Hormone-secreting pituitary tumors account for about 30% of all pituitary tumors. Successful long-term management of patients with these tumors frequently requires a multimodality team approach. Given that the role and efficacy of neurosurgical resection of hormone-secreting pituitary tumors is well described, we focus this review on the other important treatment modalities that are becoming increasingly crucial in the management of acromegaly, Cushing's disease and prolactinomas. Medical management with standard and novel drugs as well as the role and effectiveness of radiation therapy and radiosurgery are discussed in detail.

    View details for DOI 10.1016/j.jocn.2008.11.001

    View details for Web of Science ID 000268608000001

    View details for PubMedID 19443220

  • Alterations in body composition in acromegaly PITUITARY Katznelson, L. 2009; 12 (2): 136-142

    Abstract

    Acromegaly is a condition characterized by growth hormone (GH) and insulin-like growth factor-1 (IGF-1) hypersecretion, and is associated with boney overgrowth, and soft tissue abnormalities due to anabolic, lipolytic, and sodium retaining actions of GH. GH and IGF-1 excess is associated with alterations in body composition, including an increase in body water and lean body mass, and a reduction in body fat. Achievement of biochemical control of the disease results in a reduction in body water and fat-free mass, and an increase in body fat. BMD is generally increased in acromegaly, though the anabolic effect of GH excess on bone is reduced, if not negated, by the presence of hypogonadism, particularly with regard to the trabecular compartment. Further studies are necessary to determine the effect of long-term biochemical control on bone density in subjects with acromegaly.

    View details for DOI 10.1007/s11102-008-0104-8

    View details for Web of Science ID 000264629800006

    View details for PubMedID 18369725

  • Endogenous NIS Expression in Triple-Negative Breast Cancers ANNALS OF SURGICAL ONCOLOGY Renier, C., Yao, C., Goris, M., Ghosh, M., Katznelson, L., Nowles, K., Gambhir, S. S., Wapnir, I. 2009; 16 (4): 962-968

    Abstract

    The sodium iodide symporter (NIS) mediates iodide transport into cells and has been identified in approximately 70% of breast cancers. Functional NIS expression raises the possibility of using (131)I for therapeutic targeting of tumor cells. Treatment of triple-negative breast cancers [estrogen/progesterone receptor-negative and HER2-negative (ER-/PR-/HER2-)] is primarily limited to chemotherapy. Our aim was to characterize NIS expression in this subset of tumors.Archival tissue sections from 23 women with triple-negative breast cancer were analyzed for NIS expression using immunohistochemical methods and an anti-human NIS antibody. Tumors were evaluated for the presence of plasma membrane immunoreactivity. One patient with a NIS-expressing positive tumor underwent (123)I scintigraphic imaging with dosimetric analysis.Fifteen cases (65.2%) demonstrated NIS-positivity with 11 tumors (47.8%) exhibiting strong expression. Plasma membrane immunoreactivity was observed in four breast cancers and was equivocal in another four tumors. Tumor-specific radioiodide uptake was demonstrated by (123)I scintigraphy in a patient with a large primary breast cancer unresponsive to neoadjuvant therapy. The tumor concentrated 2.05, 1.53, and 1.96 times more isotope than normal breast tissue at 1, 5, and 21 h. The relative increased uptake is consistent with positive NIS expression in the tumor on definitive surgery; however, the cumulative concentration in the tumor was not sufficient to achieve a therapeutic effect, had the isotope been (131)I.NIS is strongly expressed in a significant proportion of triple-negative breast cancer cells, suggesting a potential role for NIS-directed (131)I-radioablative strategies in this patient population.

    View details for DOI 10.1245/s10434-008-0280-9

    View details for Web of Science ID 000263976000026

    View details for PubMedID 19184238

  • The impact of hypopituitarism on function and performance in subjects with recent history of traumatic brain injury and aneurysmal subarachnoid haemorrhage BRAIN INJURY Srinivasan, L., Roberts, B., Bushnik, T., Englander, J., Spain, D. A., Steinberg, G. K., Ren, L., Sandel, M. E., Al-Lawati, Z., Teraoka, J., Hoffman, A. R., Katznelson, L. 2009; 23 (7-8): 639-648

    Abstract

    To correlate deficient pituitary function with life satisfaction and functional performance in subjects with a recent history of traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH).Cross-sectional study.Eighteen subjects with TBI and 16 subjects with SAH underwent pituitary hormonal and functional assessments 5-12 months following the event. Adrenal reserve was assessed with a 1 mcg cosyntropin stimulation test and growth hormone deficiency (GHD) was diagnosed by insufficient GH response to GHRH-Arginine stimulation. Assessments of life satisfaction and performance-function included the Satisfaction with Life Scale (SWLS), Craig Handicap Assessment and Reporting Technique (CHART) and the Mayo Portland Adaptability Inventory-4 (MPAI-4).Hypopituitarism was present in 20 (58.8%) subjects, including 50% with adrenal insufficiency. Hypothyroidism correlated with worse performance on SWLS and CHART measures. GHD was associated with poorer performance on CHART and MPAI-4 scale.In this series of subjects with history of TBI and SAH, hypothyroidism and GHD were associated with diminished life satisfaction and performance-function on multiple assessments. Further studies are necessary to determine the appropriate testing of adrenal reserve in this population and to determine the benefit of pituitary hormone replacement therapy on function following brain injury.

    View details for DOI 10.1080/02699050902970778

    View details for Web of Science ID 000267370600008

  • Use of high-dose oral bisphosphonate therapy for symptomatic fibrous dysplasia of the skull JOURNAL OF NEUROSURGERY Chao, K., Katznelson, L. 2008; 109 (5): 889-892

    Abstract

    Fibrous dysplasia of the bone in adults is a rare anomaly of skeletal development caused by a defect in differentiation of osteoblasts. This condition is associated with bone pain, bone deformity, and an increased incidence of fracture. Involvement of the skull is associated with headache along with dysmorphic features. Until recently, the principal treatment has been resection or fracture repair, although the latter is often palliative at best. However, new insight into the molecular mechanism of fibrous dysplasia has led to the use of bisphosphonates to treat this disease. The authors examined the effects of high-dose oral alendronate (40 mg daily) for 6 months on 3 adult patients with intractable headache due to fibrous dysplasia of the skull. Each patient had disease processes not amenable to surgery. The patients underwent clinical follow-up at 1, 3, and 6 months. Their pain levels were documented at each visit by using a visual analog scale. All 3 patients demonstrated a significant decrease in pain levels and became independent of scheduled analgesics. Tumor bulk did not progress during this interval in any patient. Overall, alendronate was tolerated well, although in 1 patient it was discontinued early due to esophagitis. High-dose oral bisphosphonate therapy is an alternative therapeutic option for the palliative treatment of patients with fibrous dysplasia of the skull.

    View details for DOI 10.3171/JNS/2008/109/11/0889

    View details for Web of Science ID 000260362100014

    View details for PubMedID 18976079

  • An update on treatment strategies for acromegaly EXPERT OPINION ON PHARMACOTHERAPY Katznelson, L. 2008; 9 (13): 2273-2280

    Abstract

    Acromegaly is an insidious disease due to growth hormone (GH) hypersecretion from a pituitary adenoma, and is associated with multiple comorbidities and risk of premature mortality.To review the therapeutic goals and options for acromegaly.Literature review.Surgery is the mainstay of therapy, but a role for primary medical therapy using somatostatin analogs is described as well. Somatostatin analogs are the mainstay for medical therapy, largely in an adjuvant setting. The GH receptor antagonist is also used and may be considered in addition to the somatostatin analogs, or as second line therapy. Based on these multiple modalities of therapy, it should be possible to achieve biochemical control in almost all patients.

    View details for DOI 10.1517/14656560802358277

    View details for Web of Science ID 000259105400006

    View details for PubMedID 18710352

  • Outcomes after repeat transsphenoidal surgery for recurrent Cushing's disease NEUROSURGERY Patil, C. G., Veeravagu, A., Prevedello, D. A., Katznelson, L., Vance, M. L., Laws, E. R., Kelly, D. F., Oyesiku, N. M., Post, K. D., Esposito, F., Cappabianca, P. 2008; 63 (2): 266-271

    Abstract

    To systematically analyze patient outcomes after repeat transsphenoidal (TS) surgery for recurrent Cushing's disease.We retrospectively reviewed records of all patients with recurrent Cushing's disease who underwent repeat TS surgery for resection of a pituitary corticotroph adenoma at the University of Virginia Medical Center from 1992 to 2006. Remission at follow-up was defined as a normal postoperative 24-hour urine free cortisol, or continued need for glucocorticoid replacement after repeat TS surgery. Recurrence of the disease was defined as an elevated 24-hour urine free cortisol with clinical symptoms consistent with Cushing's disease while not receiving glucocorticoid replacement. Multivariate logistic regression was performed to evaluate the effect of potential predictors on remission. Recurrence rates, subsequent treatments, and the final endocrine status of the patients are presented.We identified 36 patients who underwent repeat TS surgery for recurrent Cushing's disease. The mean age of the patients was 40.3 years (range, 17.1-63.0 yr), and 26 were women. The median time to recurrence after initial successful TS surgery was 36 months (range, 4 mo-16 yr). Remission after repeat TS surgery was observed in 22 (61%) of the 36 patients. During the same time period, of the 338 patients who underwent first-time TS surgery for Cushing's disease, remission was achieved in 289 (85.5%). The odds of failure (to achieve remission) for patients with repeat TS surgery for recurrent Cushing's disease were 3.7 times that of patients undergoing first-time TS surgery (odds ratio, 3.7; 95% confidence interval, 1.8-7.8). Two of the 22 patients with successful repeat TS surgery had a second recurrence at 6 and 11 months, respectively. Complete biochemical and clinical remission after stereotactic radiosurgery, adrenalectomy, and ongoing ketoconazole therapy was achieved in 30 (83.3%) of the 36 patients, and active disease continued in 6 patients (16.7%).Although the success of repeat TS surgery for recurrence of Cushing's disease is less than that of initial surgery, a second procedure offers a reasonable possibility of immediate remission. If the operation is not successful, other treatments, including pituitary radiation, medical therapy, and even bilateral adrenalectomy, are required.

    View details for DOI 10.1227/01.NEU.0000313117.35824.9F

    View details for Web of Science ID 000258944100017

    View details for PubMedID 18797356

  • Late recurrences of Cushing's disease after initial successful transsphenoidal surgery JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Patil, C. G., Prevedello, D. M., Lad, S. P., Vance, M. L., Thorner, M. O., Katznelson, L., Laws, E. R. 2008; 93 (2): 358-362

    Abstract

    Few studies have systematically analyzed the long-term recurrence rates of Cushing's disease after initial successful transsphenoidal surgery.This was a retrospective review of patients treated at the University of Virginia Medical Center.A total of 215 subjects with Cushing's disease who underwent initial transsphenoidal surgery for resection of a presumed pituitary microadenoma from 1992-2006 were included.Remission and recurrence rates of Cushing's disease were examined. Recurrence was defined as an elevated 24-h urine free cortisol with clinical symptoms consistent with Cushing's disease.Of the 215 patients who underwent transsphenoidal surgery for Cushing's disease, surgical remission was achieved in 184 (85.6%). The mean length of follow-up was 45 months. Actuarial recurrence rates of Cushing's disease after initially successful transsphenoidal surgery at 1, 2, 3, and 5 yr were 0.5, 6.7, 10.8, and 25.5%, respectively. Among the 184 patients who achieved remission, 32 (17.4%) patients followed for more than 6 months ultimately had a recurrence of Cushing's disease. The median time to recurrence was 39 months. Immediate postoperative hypocortisolemia (serum cortisol < or = 2 microg/dl within 72-h surgery) was achieved in 97 (45.1%) patients. Patients who had postoperative serum cortisol of more than 2 microg/dl were 2.5 times more likely to have a recurrence than patients who had serum cortisol less than or equal to 2 microg/dl (odds ratio = 2.5; 95% confidence interval 1.12-5.52; P = 0.022).A quarter of the patients with Cushing's disease who achieve surgical remission after transsphenoidal surgery, recur with long-term follow-up. This finding emphasizes the need for continued biochemical and clinical follow-up to ensure remission after surgery.

    View details for DOI 10.1210/jc.2007-2013

    View details for Web of Science ID 000253165800005

    View details for PubMedID 18056770

  • Reninoma: case report and literature review JOURNAL OF HYPERTENSION Wonga, L., Hsu, T. H., Perlroth, M. G., Hofmann, L. V., Haynes, C. M., Katznelson, L. 2008; 26 (2): 368-373

    Abstract

    Reninoma is a tumor of the renal juxtaglomerular cell apparatus that causes hypertension and hypokalemia via hypersecretion of renin. We describe a case of reninoma and provide a review of the literature, with a discussion emphasizing the diagnostic evaluation for such patients. The subject had persistent elevation of both plasma renin activity (PRA) and aldosterone. Imaging studies revealed the presence of a lesion in the renal cortex, which was further identified as a renin-producing lesion via selective venous catheterization following administration of an angiotensin-converting enzyme inhibitor (ACE-I). Following partial nephrectomy, the PRA and plasma aldosterone levels declined rapidly and the blood pressure and potassium supplementation requirements normalized. This case demonstrates the utility of both appropriate imaging studies and selective venous catheterization following provocative administration of an ACE-I for diagnosis.

    View details for Web of Science ID 000252778100030

    View details for PubMedID 18192852

  • Current thinking on the management of the acromegalic patient. Current opinion in endocrinology, diabetes, and obesity Katznelson, L. 2007; 14 (4): 311-316

    Abstract

    Although the concept that acromegaly is associated with heightened cardiovascular risk is not new, it has become apparent that there are a number of risk factors associated with this disease and that specific therapeutic modalities may have variable effects on these risk factors. In addition, it is important to understand the medical therapies available for acromegaly and their role in acromegaly management.Acromegaly is associated with heightened cardiovascular risk, including derangements in glucose homeostasis and lipids, but also in markers of vascular function. Recent studies have demonstrated treatment-specific effects on these markers. In addition, recent studies have detailed further the efficacy and safety of various therapeutic options, in particular that of pegvisomant, the growth hormone receptor antagonist. A role for medical therapy as primary, de-novo therapy has been considered and recent studies support such use.The goals of acromegaly therapy are to control excess growth hormone secretion and limit, if not reverse, the long-term medical consequences and risk of premature mortality associated with acromegaly. It is critical to control both the growth hormone hypersecretion and associated cardiovascular risk factors to prevent the associated risks of cardiovascular disease and enhanced mortality. Medical therapy has an important adjuvant role in the management of acromegaly and use of somatostatin analogs as first-line therapy for specific groups of patients should be considered.

    View details for PubMedID 17940458

  • Pegvisomant for the treatment of acromegaly-translation of clinical trials into clinical practice NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM Katznelson, L. 2007; 3 (7): 514-515

    View details for DOI 10.1038/ncpendmet0533

    View details for Web of Science ID 000247376700008

    View details for PubMedID 17519915

  • Approach to the evaluation of the GH/IGF-axis in patients with pituitary disease: Which test to order PITUITARY Roberts, B., Katznelson, L. 2007; 10 (2): 205-211

    Abstract

    The diagnosis of adult growth hormone deficiency (AGHD) and acromegaly involves assessment of serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) concentrations. The diagnosis of AGHD typically requires a provocative test of GH reserve, but is supported by demonstration of low-serum IGF-1 levels. Therapeutic monitoring of rhGH replacement is performed utilizing measurement of serum IGF-1 concentrations. In patients with suspected acromegaly, the diagnosis is confirmed by elevated serum IGF-1 levels and further validated by the presence of elevated GH levels both before and following an oral glucose load. A goal of acromegaly therapy is to normalize IGF-1 concentrations, and, depending on the therapeutic modality, GH levels as well. Using case based clinical scenarios, we have presented a standard approach to the biochemical diagnosis and therapeutic monitoring of these disorders.

    View details for DOI 10.1007/s11102-007-0026-x

    View details for Web of Science ID 000252303800013

    View details for PubMedID 17429594

  • The role of inferior petrosal sinus sampling in the diagnostic localization of Cushing's disease. Neurosurgical focus Lad, S. P., Patil, C. G., Laws, E. R., Katznelson, L. 2007; 23 (3): E2-?

    Abstract

    Cushing's syndrome can present a complex problem of differential diagnosis. Of cases in which hypercortisolemia results from an adrenocorticotropic hormone (ACTH)-dependent process, approximately 80% are due to a pituitary adenoma (Cushing's disease [CD]), 10% are due to adrenal lesions, and the remaining 10% are secondary to ectopic ACTH secretion. For patients with CD, surgical removal of the pituitary adenoma is the treatment of choice. Thus, localization of the source of ACTH secretion is critical in guiding timely treatment decisions. Inferior petrosal sinus sampling (IPSS) is considered to be the gold standard for confirming the origin of ACTH secretion in patients with Cushing's syndrome. The authors present an overview of IPSS--both the technique and its interpretation--as well as a summary of recent studies. A number of other techniques are discussed including sampling from the cavernous sinus, the jugular vein, and multiple sites to aid the diagnosis and lateralization of ACTH-producing pituitary adenomas. Management is best undertaken by a comprehensive multidisciplinary team taking into account the results of all the biochemical and imaging studies available, to provide the best advice in patient treatment decisions.

    View details for PubMedID 17961020

  • Brain atrophy and cognitive deficits in Cushing's disease. Neurosurgical focus Patil, C. G., Lad, S. P., Katznelson, L., Laws, E. R. 2007; 23 (3): E11-?

    Abstract

    Cushing's disease is associated with brain atrophy and cognitive deficits. Excess glucocorticoids cause retraction and simplification of dendrites in the hippocampus, and this morphological change probably accounts for the hippocampal volume loss. Mechanisms by which glucocorticoids affect the brain include decreased neurogenesis and synthesis of neurotrophic factors, impaired glucose utilization, and increased actions of excitatory amino acids. In this review, the timing, pathology, and pathophysiology of the brain atrophy in Cushing's disease are discussed. The correlation of atrophy with cognitive deficits and its reversibility is also reviewed.

    View details for PubMedID 17961025

  • Efficacy and safety of CyberKnife radiosurgery for acromegaly. Pituitary Roberts, B. K., Ouyang, D. L., Lad, S. P., Chang, S. D., Harsh, G. R., Adler, J. R., Soltys, S. G., Gibbs, I. C., Remedios, L., Katznelson, L. 2007; 10 (1): 19-25

    Abstract

    Acromegaly is a disease characterized by GH hypersecretion, and is typically caused by a pituitary somatotroph adenoma. The primary mode of therapy is surgery, and radiotherapy is utilized as an adjuvant strategy to treat persistent disease. The aim of this study was to determine the efficacy and tolerability of CyberKnife stereotactic radiosurgery in acromegaly.A retrospective review of biochemical and imaging data for subjects with acromegaly treated with CyberKnife stereotactic radiosurgery between 1998 and 2005 at Stanford University Hospital.Nine patients with active acromegaly were treated with radiosurgery using the CyberKnife (CK).Biochemical response based on serum insulin-like growth factor-1 (IGF-1), anterior pituitary hormone function, and tumor size with MRI scans were analyzed.After a mean follow up of 25.4 months (range, 6-53 months), CK radiosurgery resulted in complete biochemical remission in 4 (44.4%) subjects, and in biochemical control with the concomitant use of a somatostatin analog in an additional subject. Smaller tumor size was predictive of treatment success: baseline tumor volume was 1.28 cc (+/- 0.81, SD) vs. 3.93 cc (+/- 1.54) in subjects with a normal IGF-1 vs. those with persistent, active disease, respectively (P = 0.02). The mean biologically effective dose (BED) was higher in subjects who achieved a normal IGF-1 vs. those with persistent, active disease, 172 Gy(3) (+/-28) vs. 94 Gy(3) (+/-17), respectively (P < 0.01). At least one new anterior pituitary hormone deficiency was observed after CK in 3 (33%) patients: two developed hypogonadism, and one developed panhypopituitarism.CK radiosurgery may be a valuable adjuvant therapy for the management of acromegaly.

    View details for PubMedID 17273921

  • Effects of modest testosterone supplementation and exercise for 12 weeks on body composition and quality of life in elderly men EUROPEAN JOURNAL OF ENDOCRINOLOGY Katznelson, L., Robinson, M. W., Coyle, C. L., Lee, H., Farrell, C. E. 2006; 155 (6): 867-875

    Abstract

    One of the factors that may promote deterioration in quality of life and body composition in elderly men is the relative decline in serum testosterone levels with aging. In this study, we assessed the effects of modest doses of testosterone and a home-based strengthening program on quality of life and body composition in elderly men with relative testosterone insufficiency.Double-blind, placebo-controlled randomized study (testosterone), and additional randomization to a resistance exercise program or no additional exercise for 12 weeks in men between ages of 65 and 85 years with relative testosterone insufficiency.Seventy sedentary, community dwelling men were randomized to a 5 mg testoderm transdermal system applied daily vs placebo system, and additionally randomized to a home-based resistance exercise program. Subjects were randomized to Group 1 (testosterone plus exercise), Group 2 (testosterone plus no exercise), Group 3 (placebo plus exercise), and Group 4 (placebo plus no exercise). Endpoints included quality of life (assessed by the short form-36 questionnaire) and body composition (measured by dual x-ray absorptiometry scan).Serum testosterone increased by a mean of 10.0 +/- 1.9, 6.6 +/- 1.6, 0.52 +/- 0.6, and 0.5 +/- 0.6 nmol/l in Groups 1, 2, 3, and 4 respectively. There was a significant interaction of testosterone and exercise on quality of life in the domains of physical functioning (P = 0.03), role physical (P = 0.01), general health (P = 0.049), and social functioning (P = 0.04). There were no effects of testosterone or exercise on quality of life alone, nor in body composition parameters.Modest testosterone supplementation to elderly men with relative testosterone insufficiency improved quality of life when accompanied by an exercise program. The combination of testosterone and exercise may be an important strategy in the elderly, though further studies are necessary to determine the long-term impact on body composition and function and for analysis of risk/benefit ratios as well.

    View details for DOI 10.1530/eje.1.02291

    View details for Web of Science ID 000243357300014

    View details for PubMedID 17132757

  • Isolated Langerhans cell histiocytosis in an adult with central diabetes insipidus: case report and review of literature. Endocrine practice Ouyang, D. L., Roberts, B. K., Gibbs, I. C., Katznelson, L. 2006; 12 (6): 660-663

    Abstract

    To report a case of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) in a patient with two distinct neuroendocrine tumors and to highlight the difficulties of establishing the differential diagnosis of EAS.We describe the clinical presentation of the current case, discuss its management, and report the results of molecular studies undertaken to determine whether the two tumors had a common origin.A 52-year-old woman presented with obvious features of Cushing's syndrome. Findings on hormonal evaluation were consistent with EAS. Pituitary magnetic resonance imaging revealed normal findings. Computed tomographic imaging disclosed two masses, one in the lung and one in the pancreas. Somatostatin receptor scintigraphy showed uptake only in the pancreatic mass, which was surgically removed. It was a well-differentiated neuroendocrine tumor, with negative immunostaining for ACTH. Hypercortisolemia did not resolve after removal of the pancreatic tumor. The lung mass was subsequently excised, and pathology examination showed a carcinoid tumor with immunostaining for ACTH. Thereafter, plasma ACTH became immeasurable. The two tumors had similar patterns of X-chromosome inactivation; thus, whether they arose independently could be neither confirmed nor excluded.This case demonstrates that, in the presence of more than one neuroendocrine tumor, somatostatin receptor scintigraphy may misguide the decision regarding the appropriate surgical course in patients with EAS, and it highlights the need for accurate studies to determine the source of ACTH in patients with EAS.

    View details for PubMedID 17229663

  • Drug Insight: primary medical therapy of acromegaly NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM Katznelson, L. 2006; 2 (2): 109-117

    Abstract

    Acromegaly is an insidious disease that, in most cases, is a result of a pituitary adenoma that hypersecretes growth hormone (GH). The goals of therapy are to control excess GH secretion and limit, if not reverse, the long-term medical consequences and risk of premature mortality associated with acromegaly. Surgery is currently the preferred primary therapeutic option because it can lead to rapid reductions in GH levels and prevent mass effects from local tumor growth. Medical therapy is used most often in an adjuvant, secondary role for patients in whom surgery has been unsuccessful. Radiation therapy is most commonly recommended in the setting of failed surgery and lack of adequate control with medical therapy. A role of primary medical therapy for patients de novo has been proposed, particularly with regard to somatostatin analogues. These analogues may control GH levels and reduce tumor volume in up to 50% of subjects, suggesting that they may be efficacious in this context. The use of somatostatin analogues to improve surgical outcome has also been proposed, but there is a lack of randomized trials available to address this issue. Primary medical therapy is well tolerated and further studies are necessary to identify patients who should be targeted for such therapy.

    View details for DOI 10.1038/ncpendmet0096

    View details for Web of Science ID 000235552100006

    View details for PubMedID 16932265

  • Long-acting somatostatin analog therapy of acromegaly: A meta- analysis JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Freda, P. U., Katznelson, L., van der Lely, A. J., Reyes, C. M., Zhao, S. H., Rabinowitz, D. 2005; 90 (8): 4465-4473

    Abstract

    Although considerable data exist on the use of long-acting somatostatin analogs to treat acromegaly, their reported efficacy differs substantially among trials.We conducted a meta-analysis to derive definitive estimates of their efficacy for biochemical control and tumor shrinkage.A search of literature was conducted through 2003, primarily via PubMed.Inclusion criteria, met in 44 trials, included at least 3 months of secondary octreotide long-acting release (LAR) or lanreotide slow release (SR) therapy or of primary octreotide LAR, lanreotide SR, or sc octreotide therapy and clearly reported data on biochemical efficacy and/or tumor shrinkage. Fifty other trials screened did not meet analysis inclusion criteria.Data were extracted by three independent observers.Among subjects not selected for somatostatin analog responsiveness before study entry, both GH efficacy criteria and IGF-I normalization were met in a greater proportion of those treated with octreotide LAR vs. lanreotide SR (GH: B = 0.2310, P = 0.016; IGF-I: B = 0.2325, P = 0.007). Prestudy selection for somatostatin analog responsiveness was not a significant predictor of meeting GH efficacy criteria (B = 0.0992; P = 0.12). Preselection was a positive predictor of IGF-I normalization rate (B = 0.1213; P = 0.04), which was greater among preselected than unselected subjects (B = 0.1472; P = 0.0475). IGF-I normalization occurred in a greater proportion of secondary octreotide LAR- vs. primary octreotide-treated subjects (B = 0.2056; P = 0.009). The odds of tumor shrinkage more than 10% were lower in the unselected vs. preselected subjects. However, the effect of drug type was an important predictor of shrinkage; such that regardless of preselection or not, the odds of shrinkage with lanreotide SR were lower than with octreotide LAR (P = 0.003). Shrinkage greater than 10% occurred in a higher percentage of primary octreotide LAR-treated vs. primary octreotide sc-treated subjects (odds ratio = 9.4; P < 0.0001). The overall rate of tumor increase was 1.4%.In this meta-analysis, we have shown that the efficacy of octreotide LAR is greater than lanreotide SR among subjects unselected for prior somatostatin analog responsiveness. Preselection is a significant positive predictor of IGF-I normalization and is associated with increased odds of tumor shrinkage, which is also greatest with octreotide LAR. Biochemical efficacy is similar, but tumor shrinkage is greater when these drugs are given as primary vs. secondary therapy.

    View details for DOI 10.1210/jc.2005-0260

    View details for Web of Science ID 000231068500007

    View details for PubMedID 15886238

  • Diagnosis and treatment of acromegaly GROWTH HORMONE & IGF RESEARCH Katznelson, L. 2005; 15: S31-S35

    Abstract

    Acromegaly is an insidious disease that occurs, in the majority of cases, as a result of a pituitary adenoma that hypersecretes growth hormone (GH). The clinical consequences of acromegaly are a function of excess GH secretion and mass effect of the pituitary tumor. The involvement of multiple organ systems may lead to significant morbidity and mortality, prompting the need for rapid and accurate disease recognition and treatment. This brief review will describe current recommendations for management of this uncommon, but debilitating, endocrine disorder.

    View details for DOI 10.1016/j.ghir.2005.06.007

    View details for Web of Science ID 000231443900008

    View details for PubMedID 16023876

  • Diagnostic errors after inferior petrosal sinus sampling JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Swearingen, B., Katznelson, L., Miller, K., Grinspoon, S., Waltman, A., Dorer, D. J., Klibanski, A., Biller, B. M. 2004; 89 (8): 3752-3763

    Abstract

    Although inferior petrosal sinus sampling (IPSS) is useful in the evaluation of Cushing's syndrome, false negative cases have been described, and many patients presumed to have ectopic tumors based upon negative IPSS remain without a final diagnosis. These patients are often managed as if they have as yet undiscovered ectopic tumors. To test this assumption, we conducted a retrospective review of our results to determine the ultimate diagnoses after IPSS. Between 1986 and 2002, 179 patients underwent 185 IPSS procedures as part of their evaluation for Cushing's syndrome. Confirmed diagnoses were available for 149 patients (83%): 139 patients had pituitary adenomas (94%), eight had bronchial carcinoids (5%), and two had adrenal tumors (1%). Threshold criteria for a pituitary source were defined as an inferior petrosal sinus to peripheral (IPS:P) basal ratio of 2:1 or greater without CRH or an IPS:P ratio of 3:1 or greater after CRH stimulation. There were nine patients in whom the IPS:P ratio failed to meet threshold criteria after successful sampling, but were nonetheless found to have pituitary tumors after transsphenoidal exploration (false negatives). Eight of these had received CRH and had a significant rise (>35%) in peripheral ACTH levels after CRH treatment, even though the IPS:P ratio did not reach the threshold. There were two patients in whom the IPS:P ratio reached threshold criteria, and ectopic tumors were demonstrated as the source of ACTH overproduction (false positives). The sensitivity after CRH stimulation was 90% (95% confidence interval, 80.8-95.5%) with a specificity of 67% (95% confidence interval, 11.4-94.5%). The positive and negative predictive values were 99 and 20%, respectively. Our data show that patients with an IPS:P ratio suggestive of a nonpituitary source of ACTH overproduction may still have Cushing's disease. Analyzing the CRH-stimulated peripheral ACTH levels in addition to the standard IPS:P ratios may provide improved diagnostic accuracy. Transsphenoidal exploration should be considered in all cases of unsuccessful sampling and in those cases for which no ectopic source can be identified after further body imaging, even if the IPSS is negative, and especially if peripheral ACTH levels rise significantly with CRH stimulation.

    View details for DOI 10.1210/jc.2003-032249

    View details for Web of Science ID 000223072400023

    View details for PubMedID 15292301

  • Effects of growth hormone secretion on body composition in patients with Crohn's disease JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Katznelson, L., Fairfield, W. P., Zeizafoun, N., Sands, B. E., Peppercorn, M. A., Rosenthal, D. I., Klibanski, A. 2003; 88 (11): 5468-5472

    Abstract

    Crohn's disease is a multisystem disorder characterized by chronic intestinal inflammation. Accumulation of mesenteric fat occurs in patients with Crohn's disease, although the mechanisms underlying site-specific changes in adipose deposition are unclear. To investigate whether there are alterations in site-specific adipose deposition in patients with Crohn's disease and to determine hormonal influences that may underlie such changes, we investigated body composition and serum hormone levels in 20 men with Crohn's disease (mean age, 45 +/- 2 yr) and 20 age-, gender-, and body mass index-matched normal controls (mean age, 43 +/- 3 yr). None of the Crohn's patients was receiving glucocorticoid therapy. Subjects underwent hourly GH sampling for 12 h beginning at 2000 h and fasting serum IGF-I and testosterone measurements. Body composition was assessed by quantitative computed tomography of the abdomen and bioelectrical impedance analysis. In the Crohn's disease and control subjects, mean serum GH levels were 1.07 +/- 0.2 and 1.7 +/- 0.2 ng/ml (P = 0.06), serum IGF-I levels were 162.7 +/- 10.5 and 194.8 +/- 15.7 ng/ml (P = 0.1), and serum testosterone levels were 489 +/- 33 and 514 +/- 38 ng/ml (P = NS), respectively. Percentage body fat was significantly higher in the Crohn's patients (21 +/- 0.8% vs. 17.7 +/- 0.9%, respectively; P = 0.013). Intraabdominal fat (IAF) was significantly higher in the Crohn's subjects vs. controls (115 +/- 11 vs. 69 +/- 7 cm(2), respectively; P = 0.001). The ratio of intraabdominal to total body fat was higher in the Crohn's subjects than in the controls (0.4 +/- 0.1 vs. 0.3 +/- 0.1, respectively; P = 0.025). Subcutaneous fat area was similar in the two groups. IAF was higher in Crohn's patients even when controlling for testosterone and mean serum GH. Mean serum GH contributed independently to the differences in IAF (P = 0.001). The ratio of IAF to total body fat remained higher in the Crohn's subjects when controlling for serum testosterone, but was no longer significant in a model that also included IGF-I and mean serum GH. GH levels contributed independently to the differences in the intraabdominal to total body fat ratio (P = 0.02). In the Crohn's patients, serum GH correlated negatively with intraabdominal and total body fat and the ratio of intraabdominal to total body fat. Crohn's disease is associated with an increase in central fat accumulation, with more IAF and a higher ratio of intraabdominal to total body fat compared with controls. Although serum GH levels were similar in the two groups, GH contributed significantly to the abdominal fat measurements. These data show that GH has an important role in modulating visceral fat distribution in patients with Crohn's disease.

    View details for DOI 10.1210/jc.2003-030608

    View details for Web of Science ID 000186393900064

    View details for PubMedID 14602791

  • Cardiovascular risk factors in acromegaly before and after normalization of serum IGF-I levels with the GH antagonist pegvisomant JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Sesmilo, G., Fairfield, W. P., Katznelson, L., Pulaski, K., Freda, P. U., Bonert, V., Dimaraki, E., Stavrou, S., Vance, M. L., Hayden, D., Klibanski, A. 2002; 87 (4): 1692-1699

    Abstract

    Acromegaly is associated with premature cardiovascular mortality. GH replacement therapy decreases inflammatory markers of cardiovascular risk, but little is known about these markers in patients with acromegaly. The GH receptor antagonist, pegvisomant, reduces IGF-I levels in 98% of patients treated. We investigated the effects of GH receptor blockade on inflammatory and other cardiovascular risk markers in active acromegaly. Forty-eight patients with acromegaly and 47 age- and body mass index-matched controls were included. The study consisted of 3 parts: a cross-sectional study, a prospective randomized 12-wk placebo-controlled study, and a longitudinal open-label study of up to 18 months of pegvisomant treatment. After baseline evaluation, patients with acromegaly were randomized to placebo (n = 14), 10 mg (n = 12), 15 mg (n = 10), or 20 mg (n = 12) daily pegvisomant for 12 wk. Subsequently, all patients received at least 10 mg pegvisomant daily for up to 18 months, with dose adjustments to achieve a normal IGF-I level. Anthropometry, GH, IGF-I, and pegvisomant levels were measured monthly. C-reactive protein (CRP), IL-6, homocysteine, lipoprotein(a), glucose, insulin, triglycerides, total cholesterol, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol were determined at baseline, 4 and 12 wk in the placebo-controlled study and at 3-month intervals (during which IGF-I levels were normal) in the longitudinal study. In the cross-sectional study, patients had lower CRP than did controls [median, 0.3 (range, 0.2-0.8) vs. 2.0 (0.6-3.7) mg/liter; P < 0.0001] and had higher insulin [78.6 (55.8-130.2) vs. 54.5 (36.6-77.5) pM, P = 0.0051]. IL-6, homocysteine, triglycerides, lipoprotein(a), LDL cholesterol and HDL cholesterol were not different between groups. In the placebo-controlled study, CRP increased in patients treated with 20 mg pegvisomant, compared with placebo (mean +/- SEM, 13.7 +/- 3.6 vs. 0.5 +/- 3.3 mg/liter; P = 0.010). There were no significant differences in IL-6, homocysteine, glucose, insulin, triglyceride, total cholesterol, LDL cholesterol and HDL cholesterol levels. In the longitudinal open-label study (median duration, 15.6 months), CRP increased by 2.0 +/- 0.5 mg/liter (P = 0.0002). Total cholesterol and triglycerides increased (0.22 +/- 0.11 mM, P = 0.050; and 0.25 +/- 0.09 mM, P = 0.007, respectively), whereas lipoprotein(a) decreased (-70 +/- 33 mg/liter, P = 0.039). Glucose, insulin, homocysteine, HDL cholesterol, and IL-6 did not change. We conclude that patients with active acromegaly have lower CRP and higher insulin levels than healthy controls. Administration of pegvisomant increases CRP levels. We propose that GH secretory status is an important determinant of serum CRP levels, although additional studies are needed to determine the mechanism and significance of this finding.

    View details for Web of Science ID 000174963100042

    View details for PubMedID 11932303

  • Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist LANCET van der Lely, A. J., Hutson, R. K., Trainer, P. J., Besser, G. M., Barkan, A. L., Katznelson, L., Klibanski, A., Herman-Bonert, V., Melmed, S., Vance, M. L., Freda, P. U., Stewart, P. M., Friend, K. E., Clemmons, D. R., Johannsson, G., Stavrou, S., Cook, D. M., Phillips, L. S., Strasburger, C. J., Hacker, S., Zib, K. A., Davis, R. J., Scarlett, J. A., Thorner, M. 2001; 358 (9295): 1754-1759

    Abstract

    Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days.Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis.Mean serum IGF-1 concentrations fell by at least 50%: 467 mg/L (SE 24), 526 mg/L (29), and 523 mg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0.001), whereas growth hormone increased by 12.5 mg/L (2.1), 12.5 mg/L (3.0), and 14.2 mg/L (5.7) (p<0.001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8.0 mg/L (2.5) at baseline, rose to 15.2 mg/L (2.4) on drug, and fell back within 30 days of withdrawal to 8.3 mg/L (2.7). Antibodies to growth hormone were detected in 27 (16.9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0.05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11.46 months (0.70) decreased by 0.033 cm(3) (0.057; p=0.353).Pegvisomant is an effective medical treatment for acromegaly.

    View details for Web of Science ID 000172385100009

    View details for PubMedID 11734231

  • Somatostatin receptor-specific analogs: Effects on cell proliferation and growth hormone secretion in human somatotroph tumors JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Danila, D. C., Haidar, J. N., Zhang, X., Katznelson, L., Culler, M. D., Klibanski, A. 2001; 86 (7): 2976-2981

    Abstract

    Somatostatin (SST) acts through a family of seven transmembrane domain G protein-coupled receptors to inhibit hormone secretion and cell proliferation in a variety of neuroendocrine tissues. In normal and neoplastic human pituitary somatotroph cells, SST-specific receptor types (SSTR) 1, 2, 3, and 5 are prevalently expressed, and SST and its analogs have been shown to inhibit GH secretion. However, in somatotroph adenomas, little is known regarding: 1) effects of SST and its analogs on pituitary tumor proliferation; 2) the relationship between the effects of SST analogs on GH secretion and tumor cell proliferation; and 3) whether SSTR expression predicts the antiproliferative effects of SST analogs in human somatotroph tumors. We investigated the effects of SST-14, lanreotide, and SSTR 2 (BIM-23190) and SSTR 5 (BIM-23268) specific analogs in 18 somatotroph pituitary adenomas in primary culture. Our results showed that cell proliferation was significantly inhibited by SST-14, lanreotide, BIM-23190, and BIM-23268 in 4, 7, 3, and 4 tumors, respectively (range of proliferation suppression 5-60%; median, 16%). Tumors that were responsive to SSTR 2- and 5-specific analogs were also responsive to lanreotide. SST-14 inhibited GH secretion in 8 of 13 tumors; lanreotide, BIM-23190, and BIM-23268 inhibited GH secretion in six tumors each (range of GH secretion inhibition 23-43%; median 33%). SSTR 2 and 5 messenger RNA was expressed in all tumors investigated, whereas SSTR 1 and 3 messenger RNA was expressed in 11 and 12 tumors, respectively. We observed a dissociation between the in vitro effects of SST-14 or lanreotide on tumor cell proliferation and the effects on GH secretion in human somatotroph tumors. Although differences in receptor concentration and the presence of other SST receptor subtypes may play a role, the presence of SSTR 2 and/or 5 did not have a predictive value. These data suggest that inhibition of cell proliferation occurs independently of effects on GH secretory pathways. Further studies are needed to clarify the mechanism of SST induced antiproliferative effects.

    View details for Web of Science ID 000169838300011

    View details for PubMedID 11443154

  • Hypogonadism in patients with acromegaly: data from the multi-centre acromegaly registry pilot study CLINICAL ENDOCRINOLOGY Katznelson, L., Kleinberg, D., Vance, M. L., Stravou, S., Pulaski, K. J., Schoenfeld, D. A., Hayden, D. L., Wright, M. E., Woodburn, C. J., Klibanski, A. 2001; 54 (2): 183-188

    Abstract

    Because acromegaly is an uncommon disorder, epidemiological data regarding the demographics of the disease such as the prevalence of hypogonadism have been limited. In order to derive clinical and epidemiological information, including underlying hormonal factors, regarding hypogonadism in patients with acromegaly, we performed a pilot study designed to develop a multi-centre acromegaly patient registry.Medical records of patients with acromegaly seen between 1976 and 1996 at three Institutions were reviewed, and data were entered into a database using a secure internet website. Hypogonadism was defined as amenorrhoea in women and testosterone deficiency in men. Subanalysis was performed in patients with microadenomas and women less than 50 years of age, to include women of reproductive age.Information was available on 363 patients, of whom 54% were women. The mean age at diagnosis was 41 +/- 13 years. In subjects less than 50 years of age, hypogonadism was present in 59%. Hyperprolactinaemia was present in 45% and 21% of hypogonadal and eugonadal patients of reproductive age, respectively (P = 0.0003). GH levels were higher in patients with hypogonadism (P = 0.03). In patients < 50 years of age with microadenomas, hypogonadism was present in nine of the 22 (41%) patients, including 55% of the women and 27% of the men (P = ns). Hyperprolactinaemia was present in three of the 10 and four of the 14 of microadenoma patients with hypogonadism and eugonadism, respectively.We developed a web-based acromegaly patient registry and used it to show that hypogonadism is a frequent consequence of acromegaly, even in patients with microadenomas, who are not at risk from hypopituitarism due to local mass effects. We also demonstrated that prolactin and GH hypersecretion contribute to the pathogenesis of hypogonadism in acromegaly, and that hypogonadism may occur in microadenoma patients even in the absence of hyperprolactinaemia.

    View details for Web of Science ID 000166984800007

    View details for PubMedID 11207632

  • Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant NEW ENGLAND JOURNAL OF MEDICINE Trainer, P. J., Drake, W. M., Katznelson, L., Freda, P. U., Herman-Bonert, V., van der Lely, A. J., Dimaraki, E. V., Stewart, P. M., Friend, K. E., Vance, M. L., Besser, G. M., Scarlett, J. A., Thorner, M. O., Parkinson, C., Klibanski, A., Powell, J. S., Barkan, A. L., Sheppard, M. C., Maldonado, M., Rose, D. R., Clemmons, D. R., Johannson, G., Bengtsson, B. A., Stavrou, S., Kleinberg, D. L., Cook, D. M., Phillips, L. S., Bidlingmaier, M., Strasburger, C. J., Hackett, S., Zib, K., Bennett, W. F., Davis, R. J. 2000; 342 (16): 1171-1177

    Abstract

    Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone.We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly.The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups.On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.

    View details for Web of Science ID 000086523700004

    View details for PubMedID 10770982

  • Biochemical assessment of Cushing's disease in patients with corticotroph macroadenomas JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Katznelson, L., Bogan, J. S., Trob, J. R., Schoenfeld, D. A., Hedley-Whyte, E. T., Hsu, D. W., Zervas, N. T., Swearingen, B., Sleeper, M., Klibanski, A. 1998; 83 (5): 1619-1623

    Abstract

    The majority of cases of Cushing's disease are due to an underlying pituitary corticotroph microadenoma (< or = 10 mm). Corticotroph macroadenomas (> 10 mm) are a less common cause of Cushing's disease, and little is known about specific clinical and biochemical findings in such patients. To define further the clinical characteristics of patients with corticotroph macroadenomas, we performed a retrospective review of Cushing's disease due to macroadenomas seen at Massachusetts General Hospital between 1979 and 1995. Of 531 patients identified with a diagnostic code of Cushing's syndrome, 20 were determined to have Cushing's disease due to a macroadenoma based on radiographic evidence of pituitary adenoma greater than 10 mm and pathological confirmation of a pituitary adenoma. A comparison review of charts of 24 patients with Cushing's disease due to corticotroph microadenomas identified on the basis of radiographic evidence of a normal pituitary gland or a pituitary adenoma 10 mm or less in diameter was also performed. The mean ages of the patients (+/- SD) with macroadenomas and microadenomas were similar (39 +/- 12 and 38 +/- 14 yr, respectively). The baseline median 24-h urine free cortisol (UFC) excretion was 1341 nmol/day (range, 304-69,033 nmol/day) and 877 nmol/day (range, 293-2,558 nmol/day) for macroadenoma and microadenoma patients, respectively (P = 0.058). After the 48-h high dose dexamethasone suppression test, UFC decreased by 77 +/- 19% (mean +/- SD) and 91 +/- 7% in macroadenoma and microadenoma subjects, respectively (P = 0.04). Fifty-six percent of macroadenoma patients and 92% of microadenoma patients had greater than 80% suppression of UFC after high dose dexamethasone administration (P = 0.03). The baseline median 24-h urinary 17-hydroxysteroid (17-OHCS) excretion was 52 mumol/day (range, 25-786 mumol/day) and 44 mumol/day (range, 17-86 mumol/day) for macroadenoma and microadenoma subjects, respectively (P = 0.09). After the standard high dose dexamethasone suppression test, 17-OHCS excretion decreased by 46 +/- 33% and 72 +/- 22% for macroadenoma and microadenoma subjects, respectively (P = 0.02). Fifty-three percent of patients with macroadenomas and 86% of patients with microadenomas had greater than 50% suppression of 17-OHCS after high dose dexamethasone administration (P = 0.02). Baseline plasma ACTH values were above the normal range in 83.3% of macroadenoma patients and in 45% of microadenoma subjects (P = 0.05). Tumors were immunostained with the MIB-1 antibody for Ki-67 to investigate proliferation in the adenomas. There was a trend for a higher Ki-67 labeling index in corticotroph macroadenomas, and seven (44%) macroadenomas vs. three (18%) microadenomas had labeling indexes greater than 3%, but this was not statistically significant. In summary, corticotroph macroadenomas are often associated with less glucocorticoid suppressibility than the more frequently occurring microadenomas. Therefore, the lack of suppression of UFC or 17-OHCS after the administration of high dose dexamethasone in a patient with Cushing's disease does not necessarily imply the presence of ACTH-independent Cushing's syndrome and is more commonly seen in patients with corticotroph macroadenomas than in those with microadenomas. Increased plasma ACTH concentrations are typical of patients with corticotroph macroadenomas and may be a more sensitive indicator of neoplastic corticotrophs than the UFC or 17-OHCS response to standard high dose dexamethasone testing.

    View details for Web of Science ID 000073535300039

    View details for PubMedID 9589666

Conference Proceedings


  • Hypothalamic/pituitary function following high-dose conformal radiotherapy to the base of skull: Demonstration of a dose-effect relationship using dose-volume histogram analysis Pai, H. H., Thornton, A., Katznelson, L., Finkelstein, D. M., Adams, J. A., Fullerton, B. C., Loeffler, J. S., Leibsch, N. J., Klibanski, A., Munzenrider, J. E. ELSEVIER SCIENCE INC. 2001: 1079-1092

    Abstract

    To evaluate the incidence and pattern of hypopituitarism from hypothalamic (HT) and pituitary gland (PG) damage following high-dose conformal fractionated proton-photon beam radiotherapy (PPRT) to the base of skull (BOS) region in adults. The relationship between dose, volume, and PG function is explored.Between May 1982 to October 1997, 107 adults with non-PG and non-HT neoplasms (predominantly chordoma and chondrosarcomas) of the BOS were treated with PPRT after subtotal resection(s). The median age was 41.2 years (range, 17-75) with 58 males and 49 females. Median prescribed target dose was 68.4 cobalt gray equivalent (CGE) (range, 55.8-79 CGE) at 1.80-1.92 CGE per fraction per day (where CGE = proton Gy x 1.1). The HT and PG were outlined on planning CT scans to allow dose-volume histograms (DVH) analysis. All patients had baseline and follow-up clinical testing of anterior and posterior pituitary function including biochemical assessment of thyroid, adrenal, and gonadal function, and prolactin secretion.The 10-year actuarial overall survival rate was 87%, with median endocrine follow-up time of 5.5 years, thus the majority of patients were available for long-term follow-up. Five-year actuarial rates of endocrinopathy were as follows: 72% for hyperprolactinemia, 30% for hypothyroidism, 29% for hypogonadism, and 19% for hypoadrenalism. The respective 10-year endocrinopathy rates were 84%, 63%, 36%, and 28%. No patient developed diabetes insipidus (vasopressin deficiency). Growth hormone deficiency was not routinely followed in this study. Minimum target dose (Dmin) to the PG was found to be predictive of endocrinopathy: patients receiving 50 CGE or greater at Dmin to the PG experiencing a higher incidence and severity (defined as the number of endocrinopathies occurring per patient) of endocrine dysfunction. Dmax of 70 CGE or greater to the PG and Dmax of 50 CGE or greater to the HT were also predictive of higher rates of endocrine dysfunction.Radiation-induced damage to the HT & PG occurs frequently after high-dose PPRT to the BOS and is manifested by anterior pituitary gland dysfunction. Hyperprolactinemia was detected in the majority of patients. Posterior pituitary dysfunction, represented by vasopressin activity with diabetes insipidus, was not observed in this dose range. Limiting the dose to the HT and PG when feasible should reduce the risk of developing clinical hypopituitarism.

    View details for Web of Science ID 000167327200020

    View details for PubMedID 11240250

Stanford Medicine Resources: