Neurology India
Open access journal indexed with Index Medicus
  Users online: 501  
 Home | Login 
  About Current Issue Archive Ahead of print Search Instructions Online Submission Subscribe Etcetera Contact  
  Navigate Here 
 Search
 
  » Next article
  » Previous article 
  » Table of Contents
  
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (41 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  


  In this Article
 »  Abstract
 »  Introduction
 »  Classification
 »  Pathogenesis
 »  Oncogenes
 »  Tumor Suppressor...
 »  Clinical diagnos...
 »  Future Prospects
 »  Conclusion
 »  References

 Article Access Statistics
    Viewed38504    
    Printed482    
    Emailed36    
    PDF Downloaded572    
    Comments [Add]    
    Cited by others 9    

Recommend this journal

   
REVIEW ARTICLE
Year : 2003  |  Volume : 51  |  Issue : 4  |  Page : 461-465

The management of non-functioning pituitary adenomas


Department of Neurosurgery, University of Virginia Health System, Charlottesville, Virginia

Correspondence Address:
Department of Neurosurgery, Box 800212, University of Virginia Health System, Charlottesville, Virginia
el5g@virginia.edu

  »  Abstract

Non-functioning pituitary adenomas most commonly present secondary to mass effect and are classified according to their size and immunohistochemical staining. Local intrasellar mass effect may cause varying degrees of hypopituitarism. With extrasellar growth, neurological signs and symptoms develop. Appropriate therapy for these tumors requires close interaction across multiple disciplines. Trans-sphenoidal surgery offers safe and effective treatment in the overwhelming majority of patients with relatively low risk of new neurological and endocrinologic deficits. The multidisciplinary management of non-functioning adenomas, their diagnosis and therapeutic outcomes, is discussed.

How to cite this article:
Jane J A, Laws E R. The management of non-functioning pituitary adenomas. Neurol India 2003;51:461-5


How to cite this URL:
Jane J A, Laws E R. The management of non-functioning pituitary adenomas. Neurol India [serial online] 2003 [cited 2017 Feb 23];51:461-5. Available from: http://www.neurologyindia.com/text.asp?2003/51/4/461/5014



  »   Introduction Top


Pituitary adenomas are the third most frequently encountered primary intracranial neoplasm after gliomas and meningiomas.[1] These tumors present with an annual incidence of between 0.5 and 8.2 per 100,000.[1],[2],[3],[4],[5],[6] Most series estimate the prevalence to be approximately 10%, a figure supported by data from magnetic resonance imaging (MRI) series.[7],[8],[9],[10] Currently, a more detailed understanding of the classification, pathogenesis, diagnosis, and treatment of pituitary adenomas is available. In this article we will discuss the current concepts in the management of non-functioning adenomas.


  »   Classification Top


Because of the variety of tumor types and clinical presentations, an assortment of classification systems has been proposed to codify these tumors. Clinically, our approach primarily distinguishes tumors based on size and functional status. Pituitary adenomas that are < 10 mm are termed microadenomas; those greater than 10 mm are identified as macroadenomas. Clinically non-functioning adenomas (NFA) are actually a diverse group of tumors that include glycoprotein adenomas (a-subunit, luteinizing hormone (LH), follicle-stimulating hormone (FSH)), the null cell adenoma and oncocytoma.
Although the clinical and biochemical functional status generally correlates with the immunohistochemical findings, exceptions do exist. A notable exception is the silent corticotroph (ACTH) adenoma that clinically behaves as a non-functioning adenoma but stains positively for ACTH. The most comprehensive classification schema that accounts for virtually all the exceptions is that of the World Health Organization which codifies tumors based upon: 1) clinical presentation and biochemical secretory activity, 2) size and invasiveness (i.e. micro vs. macroadenoma), 3) histologic features (adenoma versus carcinoma), 4) immunohistochemical profile, and 5) ultrastructural features on electron microscopy.[11]


  »   Pathogenesis Top


Authors have generally argued that pituitary tumors result from either an abnormal response to hypothalamic stimulation or from intrinsic abnormalities within the pituitary gland itself. These theories are not mutually exclusive as extrinsic factors can provide a permissive environment for molecular events to occur within the gland. At the beginning of the previous decade, it was recognized that pituitary tumors are monoclonal in origin.[12],[13] This phenomenon suggested that pituitary tumors result from genetic mutations in a single cell involving activation of oncogenes, inactivation of tumor suppressor genes, and alterations of transcription factors regulating cell growth and differentiation. Although the precise mechanisms of tumorigenesis are yet to be fully elucidated, the previous decade has provided some clues as to the origin and progression of pituitary adenomas.


  »   Oncogenes Top


Several oncogenes have been implicated in the development of non-functioning pituitary adenomas. These oncogenes include the stimulatory guanine nucleotide-binding protein (gsp) gene that produces an independently active adenyl cyclase signaling system that increases cyclic AMP, leading to cell cycle progression and GH hypersecretion.[14],[15] Mutations of the gsp gene have been noted in about 40% of GH adenomas but also in 10% of NFAs.[16],[17],[18],[19],[20],[21],[22],[23] The c-myc oncogene, located on chromosome 8q24, has been reported in nearly one-third of all pituitary adenomas including NFAs, and also in prolactinomas, GH adenomas and ACTH adenomas.[24],[25],[26] The pituitary tumor transforming gene (PTTG) appears to induce basic fibroblast growth factor (bFGF) expression and secretion and may foster genetic instability.[27],[28] PTTG gene expression is increased in a majority of NFAs.[27],[28]
Other oncogenes have been noted in more clinically aggressive tumors. These include the Cyclin D1 (CCND1) and the H-ras oncogene, both of which have been reported in pituitary carcinomas and invasive tumors.[29],[30],[31],[32],[33] The absence of these oncogenes in clinically benign tumors indicates that their activation may be a late event causing progression to a more aggressive type and is evidence against them having a major role in initiating tumor formation.[18]


  »   Tumor Suppressor Genes Top

Tumor suppressor gene inactivation has also been implicated in the development of pituitary adenomas. Among the earliest recognized tumor suppressor genes associated with pituitary adenomas is the MEN-1 gene located on chromosome 11q13.[34],[35] Twenty-five per cent of patients with the autosomal dominant inherited germline mutation (MEN-1 syndrome) develop pituitary tumors.[13],[15],[16],[35],[36],[37] Several other tumor suppressor genes have been implicated in the progression to invasive tumor types. These include the mutated p53 gene, located on chromosome 17p13, a yet uncharacterized deletion in a locus near the retinoblasoma (Rb) gene (on the long arm of chromosome 13), and loss of heterozygosity (LOH) on chromosomes 11q13, 13q12-14, and 10q26.[31],[38],[39],[40],[41],[42]


  »   Clinical diagnosis and management Top

Clinical presentation and diagnosis
Clinically, NFAs account for approximately 25 to 35% of tumors resected surgically.[43],[44] Because of the increased availability and use of MRI, an increasing numbers of patients present with incidentally diagnosed pituitary adenomas. On further evaluation, approximately 5% will have evidence of visual deficits and around 15% will have some degree of pituitary dysfunction.[45] About two-thirds are microadenomas at diagnosis and although these can often be followed conservatively, more than one-third of incidental macroadenomas will show significant growth on serial imaging.[8],[45],[46],[47],[48]
NFAs are actually a diverse group of tumors including gonadotroph adenomas and null-cell adenomas. Gonadotroph adenomas occur at approximately twice the frequency as the true non-secreting adenomas.[49] Despite this diversity, the tumor subtypes appear to behave in a uniform manner clinically.[50],[51] Patients generally present with signs and symptoms relating to local (sellar) and extrasellar mass effect.
Local intrasellar growth may cause varying degrees of pituitary dysfunction. The cell populations that appear most susceptible are the gonadotrophs (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)), followed by the thyrotrophs (TSH), somatotrophs, and corticotrophs. Hypogonadism in men causes diminished libido and erectile dysfunction. Female hypogonadism causes amenorrhea and diminished libido. Hypothyroidism can cause an array of symptoms including headache, weight gain, constipation, cold intolerance, depression, and diminished mental acuity. Growth hormone deficiency is characterized by decreased exercise tolerance, increased central adiposity, anxiety, and mood changes. Relative adrenal insufficiency manifests with proximal weakness, fatigue, anorexia, myalgias, arthralgias, gastrointestinal symptoms, and orthostasis. Sudden pituitary insufficiency may occur in the setting of pituitary apoplexy. When acute, cortisol deficiency, or Addisonian crisis, may cause headaches, visual disturbance, hyponatremia, mental status changes, and cardiovascular collapse.
As the tumor expands beyond the confines of the sella, neurological signs begin to manifest. Headache, a common complaint, occurs as the expanding tumor stretches the sellar dura and diaphragma sellae. Suprasellar growth and resultant chiasmal compression commonly causes varying degrees of visual disturbance and bitemporal hemianopsia. Massive suprasellar growth may, less commonly, cause obstructive hydrocephalus. Lateral growth into the cavernous sinus may cause diplopia and facial pain or numbness. Further lateral growth into the mesial temporal lobe may also provoke seizures. An expanding tumor often compresses the pituitary stalk and disrupts the tonic hypothalamic inhibition of prolactin secretion. This “stalk effect” causes increased prolactin levels mimicking those seen in prolactinomas, however, prolactin levels secondary to stalk effect should be mild and generally do not exceed 150 ng/ml.
Although two-thirds of the NFAs are glycoprotein adenomas, these tumors do not efficiently secrete ±-subunit (±SU), FSH, or LH. Only about one-third of these have biochemical elevations in one of these markers.[51],[52],[53] For this reason, the diagnosis of NFA preoperatively entails ruling out the secretory syndromes and confirming a pituitary mass on MRI.
Despite our individualized approach, certain protocols are universal. A careful neurological and endocrinological history is essential in all patients. The subsequent biochemical diagnosis should be followed by a careful screening of the pituitary axis to establish any preoperative endocrine insufficiency. Reasonable laboratory evaluation should include baseline PRL, GH, insulin-like growth factor type 1 (IGF-1), ACTH, cortisol, LH, FSH, TSH, thyroxine, testosterone, and estradiol. Of particular importance is the detection of cortisol and thyroid deficiency because failure to establish this preoperatively can have dire consequences. All patients will also need pretreatment high-resolution MRI using specific pituitary protocols. The gadolinium enhanced sagittal and coronal planes are most helpful in surgical planning, but serial volumetric analysis is also essential in gauging the efficacy of therapy. Also, prior to medical or surgical therapy, patients should have neuro-ophthalmologic testing including fundoscopy, formal visual field testing (automated perimetry), and quantified visual acuity.
The goals of therapy are improved quality of life and survival, relief of mass effect and reversal of its associated signs and symptoms, normalization of hormonal hypersecretion, preservation or recovery of normal pituitary function, and prevention of recurrence. This effort requires a multidisciplinary team approach that includes endocrinologists, neurosurgeons, neuroophthalmologists, radiation therapists, and neuroradiologists.

Therapy
The primary treatment of NFAs is transsphenoidal surgery. The standard technique involves either an endonasal or sublabial approach to the sellae with a microsurgical resection of the tumor. Pediatric patients, adults with small nares, and patients with very large tumors are often approached via a sublabial incision. In the vast majority of patients, however, the endonasal corridor provides adequate exposure. More recently, endoscopic techniques have been developed that have added to the surgical armamentarium.[54],[55],[56] The endoscope allows for a relatively atraumatic approach to the sellae and provides an excellent panoramic view of the regional anatomy and its relationship to the tumor. The angled views allow inspection of suprasellar regions that are simply not possible with the microscope. In our hands, we have found it most useful as an adjunct in verifying the adequacy of microsurgical resection. Studies confirming improved outcomes using the endoscope, however, are not yet available.
Those patients undergoing surgery are administered perioperative hydrocortisone for the first 24 hours following surgery. Morning cortisol levels are measured on postoperative days 2 and 3. Patients with serum cortisol levels< 8¼g/dl (225 nmol/L) are given steroid replacement. Those with preoperative cortisol deficiency are tapered postoperatively to their preoperative regimen. Patients are also monitored closely for diabetes insipidus by monitoring daily weight, urine specific gravity every 4 hours, fluid intake and output, and serum sodium.
Visual field deficits improve in 70 to 87% of patients with preoperative deficits.[44],[57],[58] Normalization of vision is reported in approximately 25%.[57] Improvement in pituitary deficiency is seen in up to 27% and normalized endocrine function in nearly 15%.[57],[58],[59] Normal pituitary function is preserved in approximately 70%.[60] Nevertheless, 90% of premenopausal women with preoperative preserved menstruation retain normal menstruation postoperatively.[61] Regular menstruation is restored in those with preoperative amenorrhea in 56%.[61]
New endocrine deficits, seen more frequently in macroadenomas, have been reported in up to 40%.[57],[58],[60] However, our results indicate that only 3% of patients with microadenomas and 5% of patients with macroadenomas with preoperative normal pituitary function experienced new hormonal deficits.[62] Immediate postoperative polyuria occurs in about 30% of patients, but in only 3 to 10% does this polyuria persist beyond the first week of surgery.[62],[63] Delayed hyponatremia, occurring most often 7 to 10 days after surgery, is evident in 1 to 2.4%.[62],[63] Worsening in preoperative vision can be seen in 1 to 4%.[59],[64] Anatomic complications include nasal septal perforations in 7% and fat graft hematomas in 4%.[60],[64] Postoperative cerebrospinal fluid leaks and meningitis are reported in 0.5 to 3.9%.[64],[65]
Recurrence does develop over time and in our series, at 10 years, 16% experienced recurrent disease.[44] However, recurrence requiring repeat surgery occurs in only 6% of patients. Completeness of resection as judged on postoperative MRI can predict recurrence. Although one-third of patients with residual tumor have recurrent tumor growth, less than 3% with complete resection experience recurrent disease within a mean of 3.3 years.[66]
For tumors with incomplete resection, medical and radiation therapy can be considered. However, neither medical therapy nor radiation therapy is recommended as primary treatment. Although dopamine agonists, GnRH agonists, and octreotide therapy have been employed, their efficacy has not been proven. Postoperative adjuvant radiation therapy has been advocated for incompletely removed tumors and tumors with cavernous sinus invasion.[67],[68] Our practice has been to delay radiation therapy until there is evidence of progressive regrowth of the tumor. In many such cases, repeat trans-sphenoidal surgery for debulking is recommended prior to radiation therapy.
External beam radiotherapy has long been applied to treat patients with tumor recurrence and residual disease. Although this therapy effectively reduces the risk of recurrent disease, there are several distinct disadvantages.[69],[70] These include the inconvenience of repeated treatments over time, the high incidence of progressive pituitary dysfunction, the albeit small risk of late secondary tumors, delayed cognitive deficits, and slow regression response.[71],[72]
A growing literature is available that has investigated the efficacy of Gamma Knife radiosurgery.[73],[74],[75],[76] Control of tumor growth is reported in up to 100% of microadenomas and 90% of macroadenomas. Volume reduction of greater than 50% has been reported in nearly 30% of patients.[76] New cranial nerve deficits are rare and appear to occur in less than 5%. New hormonal deficits are, in some series, reported to be quite rare, occurring in less than 5%.[73],[76] However, this is likely a function of the generally short follow-up in each study. In studies with longer follow-up (4.6 years), new hormonal deficits are seen most commonly in thyroid function (24%) and least commonly in cortisol levels (9%).[74] With even longer follow-up, a higher rate of endocrinopathy will likely be evident. Gamma knife radiosurgery has a limited role in tumors that have continued optic nerve or chiasmal compression. Tumors that are less than 3 mm from the visual pathways are not amenable to radiosurgery and these patients require either repeated surgery to create the required distance or conventional external beam radiotherapy.


  »   Future Prospects Top

Gene therapy may play a role in the future treatment of pituitary adenomas. Rats harboring estrogen-induced prolactinomas were treated with a tetracycline-regulated adenovirus carrying the gene for tyrosine hydroxylase (the rate limiting enzyme in dopamine synthesis). Researchers found a significant reduction in both tumor growth and plasma prolactin levels.[77]
Tissue-specific promoters may also play a role in directing gene therapy. Researchers have shown that stereotactically injected recombinant adenoviruses containing the human growth hormone and the human glycoprotein hormone alpha-subunit promoter can selectively drive the expression of the beta-galactosidase gene in cells expressing those hormones.[78],[79] Tissue culture experiments have also indicated that these tissue-specific promoters can selectively drive the expression of toxic gene therapy with excellent cytotoxicity to specific pituitary cell lines. Future in vivo studies evaluating the efficacy of tissue-specific promoters that drive the expression of toxic gene therapy agents are anticipated.


  »   Conclusion Top

Although NFAs present most commonly with visual field deficits, careful screening for pituitary insufficiency is mandatory. Transsphenoidal surgery effectively relieves mass effect and preserves normal endocrine function in the majority of patients. Medical therapy and radiation therapy are reserved for refractory tumors. With improved understanding of the molecular pathogenesis, future therapy should treat these tumors more effectively. 

  »   References Top

1.Monson JP. The epidemiology of endocrine tumours. Endocrine-Related Cancer 2000;7:29-36.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Annegers JF, Coulam CB, Abboud CF, Laws ER Jr, Kurland LT. Pituitary adenoma in Olmsted County, Minnesota, 1935-1977. A report of an increasing incidence of diagnosis in women of childbearing age. Mayo Clin. Proc 1978;53:641-3.  Back to cited text no. 2  [PUBMED]  
3.Clayton RN. Sporadic pituitary tumours: from epidemiology to use of databases. Best Practice and Research Clinical Endocrinology and Metabolism 1999;13:451-60.  Back to cited text no. 3  [PUBMED]  
4.Lovaste MG, Ferrari G, Rossi G. Epidemiology of primary intracranial neoplasms. Experiment in the Province of Trento, (Italy), 1977-1984. Neuroepidemiology 1986;5:220-32.  Back to cited text no. 4  [PUBMED]  
5.Percy AK, Elveback LR, Okazaki H, Kurland LT. Neoplasms of the central nervous system. Epidemiologic considerations. Neurology 1972;22:40-8.  Back to cited text no. 5  [PUBMED]  
6.Robinson N, Beral V, Ashley JS. Incidence of pituitary adenoma in women. Lancet 1979;2:630.  Back to cited text no. 6  [PUBMED]  
7.Burrow GN, Wortzman G, Rewcastle NB, Holgate RC, Kovacs K. Microadenomas of the pituitary and abnormal sellar tomograms in an unselected autopsy series. N Engl J Med 1981;304:156-8.  Back to cited text no. 7  [PUBMED]  
8.Molitch ME, Russell EJ. The pituitary “incidentaloma”. Ann Intern Med 1990;112:925-31.  Back to cited text no. 8  [PUBMED]  
9.Hall JE, Martin KA, Whitney HA, Landy H, Crowley WF Jr. Potential for fertility with replacement of hypothalamic gonadotropin-releasing hormone in long term female survivors of cranial tumors. J Clin Endocrinol Metab 1994;79:1166-72.  Back to cited text no. 9  [PUBMED]  
10.Aron DC, Howlett TA. Pituitary incidentalomas. Endocrinology & Metabolism Clinics of North America 2000;29:205-21.  Back to cited text no. 10    
11.Kovacs K, Scheithauer BW, Horvath E, Lloyd RV. The World Health Organization classification of adenohypophysial neoplasms. A proposed five-tier scheme. Cancer. 1996;78:502-10.  Back to cited text no. 11    
12.Alexander JM, Biller BM, Bikkal H, Zervas NT, Arnold A, Klibanski A. Clinically nonfunctioning pituitary tumors are monoclonal in origin. J Clin Invest 1990;86:336-40.  Back to cited text no. 12    
13.Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S. Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 1990;71:1427-33.  Back to cited text no. 13    
14.Blatt C, Eversole-Cire P, Cohn VH, Zollman S, Fournier RE, Mohandas LT, et al. Chromosomal localization of genes encoding guanine nucleotide-binding protein subunits in mouse and human. Proceedings of the National Academy of Sciences of the United States of America. 1988;85:7642-6.  Back to cited text no. 14    
15.Thakker RV, Pook MA, Wooding C, Boscaro M, Scanarini M, Clayton RN. Association of somatotrophinomas with loss of alleles on chromosome 11 and with gsp mutations. J Clin Invest 1993;91:2815-21.  Back to cited text no. 15    
16.Boggild MD, Jenkinson S, Pistorello M, Boscaro M, Scanarini M, McTernan P, et al. Molecular genetic studies of sporadic pituitary tumors. J Clin Endocrinol Metab 1994;78:387-92.  Back to cited text no. 16    
17.Clementi E, Malgaretti N, Meldolesi J, Taramelli R. A new constitutively activating mutation of the Gs protein alpha subunit-gsp oncogene is found in human pituitary tumours. Oncogene 1990;5:1059-61.  Back to cited text no. 17    
18.Suhardja AS, Kovacs KT, Rutka JT. Molecular pathogenesis of pituitary adenomas: a review. Acta Neurochirurgica 1999;141:729-36.  Back to cited text no. 18    
19.Vallar L, Spada A, Giannattasio G. Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas. Nature 1987;330:566-8.  Back to cited text no. 19    
20.Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 1989;340:692-6.  Back to cited text no. 20    
21.Tordjman K, Stern N, Ouaknine G, Yossiphov Y, Razon N, Nordenskjold M, et al. Activating mutations of the Gs alpha-gene in nonfunctioning pituitary tumors. J Clin Endocrinol Metab 1993;77:765-9.  Back to cited text no. 21    
22.Williamson EA, Daniels M, Foster S, Kelly WF, Kendall-Taylor P, Harris PE. Gs alpha and Gi2 alpha mutations in clinically non-functioning pituitary tumours. Clin Endocrinol 1994;41:815-20.  Back to cited text no. 22    
23.Williamson EA, Ince PG, Harrison D, Kendall-Taylor P, Harris PE. G-protein mutations in human pituitary adrenocorticotrophic hormone-secreting adenomas. Eur J Clin Invest 1995;25:128-31.  Back to cited text no. 23    
24.Wang DG, Johnston CF, Atkinson AB, Heaney AP, Mirakhur M, Buchanan KD. Expression of bcl-2 oncoprotein in pituitary tumours: comparison with c-myc. J Clin Pathol 1996;49:795-7.  Back to cited text no. 24    
25.Woloschak M, Roberts JL, Post K. c-myc, c-fos, and c-myb gene expression in human pituitary adenomas. J Clin Endocrinol Metab 1994;79:253-7.  Back to cited text no. 25    
26.Raghavan R, Harrison D, Ince PG, James RA, Daniels M, Birch P, et al. Oncoprotein immunoreactivity in human pituitary tumours. Clin Endocrinol 1994;40:117-26.  Back to cited text no. 26    
27.Heaney AP, Melmed S. New pituitary oncogenes. Endocrine-Related Cancer. 2000;7:3-15.  Back to cited text no. 27    
28.Zhang X, Horwitz GA, Heaney AP, Nakashima M, Prezant TR, Bronstein MD, et al. Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab 1999;84:761-7.  Back to cited text no. 28    
29.Cai WY, Alexander JM, Hedley-Whyte ET, Scheithauer BW, Jameson JL, Zervas NT, et al. ras mutations in human prolactinomas and pituitary carcinomas. J Clin Endocrinol Metab 1994;78:89-93.  Back to cited text no. 29    
30.Karga HJ, Alexander JM, Hedley-Whyte ET, Klibanski A, Jameson JL. Ras mutations in human pituitary tumors. J Clin Endocrinol Metab 1992;74:914-9.  Back to cited text no. 30    
31.Pei L, Melmed S, Scheithauer B, Kovacs K, Prager D. H-ras mutations in human pituitary carcinoma metastases. J Clin Endocrinol Metab 1994;78:842-6.  Back to cited text no. 31    
32.Hibberts NA, Simpson DJ, Bicknell JE, Broome JC, Hoban PR, Clayton RN, et al. Analysis of cyclin D1 (CCND1) allelic imbalance and overexpression in sporadic human pituitary tumors. Clin Cancer Res 1999;5:2133-9.  Back to cited text no. 32    
33.Jordan S, Lidhar K, Korbonits M, Lowe DG, Grossman AB. Cyclin D and cyclin E expression in normal and adenomatous pituitary. Eur J Endocrinol 2000;143:R1-6.  Back to cited text no. 33    
34.Weil RJ, Vortmeyer AO, Huang S, Boni R, Lubensky IA, Pack S, et al. 11q13 allelic loss in pituitary tumors in patients with multiple endocrine neoplasia syndrome type 1. Clin Cancer Res 1998;4:1673-8.  Back to cited text no. 34    
35.Bystrom C, Larsson C, Blomberg C, Sandelin K, Falkmer U, Skogseid B, et al. Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors. Proceedings of the National Academy of Sciences of the United States of America. 1990;87:1968-72.  Back to cited text no. 35    
36.Eubanks PJ, Sawicki MP, Samara GJ, Gatti R, Nakamura Y, Tsao D, et al. Putative tumor-suppressor gene on chromosome 11 is important in sporadic endocrine tumor formation. Am J Surg 1994;167:180-5.  Back to cited text no. 36    
37.Bale AE, Norton JA, Wong EL, Fryburg JS, Maton PN, Oldfield EH, et al. Allelic loss on chromosome 11 in hereditary and sporadic tumors related to familial multiple endocrine neoplasia type 1. Cancer Res 1991;51:1154-7.  Back to cited text no. 37    
38.Bates AS, Farrell WE, Bicknell EJ, McNicol AM, Talbot AJ, Broome JC, et al. Allelic deletion in pituitary adenomas reflects aggressive biological activity and has potential value as a prognostic marker. J Clin Endocrinol Metab 1997;82:818-24.  Back to cited text no. 38    
39.Simpson DJ, Magnay J, Bicknell JE, Barkan AL, McNicol AM, Clayton RN, et al. Chromosome 13q deletion mapping in pituitary tumors: infrequent loss of the retinoblastoma susceptibility gene (RB1) locus despite loss of RB1 protein product in somatotrophinomas. Cancer Res 1999;59:1562-6.  Back to cited text no. 39    
40.Buckley N, Bates AS, Broome JC, Strange RC, Perrett CW, Burke CW, et al. p53 Protein accumulates in Cushings adenomas and invasive non-functional adenomas. J Clin Endocrinol Metab 1994;79:1513-6.  Back to cited text no. 40    
41.Clayton RN, Boggild M, Bates AS, Bicknell J, Simpson D, Farrell W. Tumour suppressor genes in the pathogenesis of human pituitary tumours. Horm Res 1997;47:185-93.  Back to cited text no. 41    
42.Thapar K, Scheithauer BW, Kovacs K, Pernicone PJ, Laws ER, Jr. p53 expression in pituitary adenomas and carcinomas: correlation with invasiveness and tumor growth fractions. Neurosurgery. 1996;38:763-70.  Back to cited text no. 42    
43.Horvath E, Scheitauer BW, Kovacs K, Lloyd R. Regional neuropathology: hypothalamus and pituitary. In: Graham DI, Lantos PL, editors. Greenfield's Neuropathology. New York: Oxford University Press; 1997. pp. 1027-35.  Back to cited text no. 43    
44.Laws ER, Jane JA Jr. Pituitary tumors-long-term outcomes and expectations. Clinical Neurosurgery. 2001;48:306-19.  Back to cited text no. 44    
45.Feldkamp J, Santen R, Harms E, Aulich A, Modder U, Scherbaum WA. Incidentally discovered pituitary lesions: high frequency of macroadenomas and hormone-secreting adenomas - results of a prospective study. Clin Endocrinol Oxf 1999;51:109-13.  Back to cited text no. 45    
46.Donovan LE, Corenblum B. The natural history of the pituitary incidentaloma. Arch Intern Med 1995;155:181-3.  Back to cited text no. 46    
47.Nishizawa S, Ohta S, Yokoyama T, Uemura K. Therapeutic strategy for incidentally found pituitary tumors (“pituitary incidentalomas”). Neurosurgery 1998;43:1344-8.  Back to cited text no. 47    
48.Molitch ME, Thorner MO, Wilson C. Management of prolactinomas. J Clin Endocrinol Metab 1997;82:996-1000.  Back to cited text no. 48    
49.Arafah BM, Nasrallah MP. Pituitary tumors: pathophysiology, clinical manifestations and management. Endocrine-Related Cancer 2001;8:287-305.  Back to cited text no. 49    
50.Samuels MH, Ridgway EC. Glycoprotein-secreting pituitary adenomas. Baillieres Clin Endocrinol Metab 1995;9:337-58.  Back to cited text no. 50    
51.Snyder PJ. Extensive personal experience: gonadotroph adenomas. J Clin Endocrinol Metabol 1995;80:1059-61.  Back to cited text no. 51    
52.Daneshdoost L, Gennarelli TA, Bashey HM, Savino PJ, Sergott RC, Bosley TM, et al. Recognition of gonadotroph adenomas in women. N Engl J Med 1991;324:589-94.  Back to cited text no. 52    
53.Daneshdoost L, Gennarelli TA, Bashey HM, Savino PJ, Sergott RC, Bosley TM, et al. Identification of gonadotroph adenomas in men with clinically nonfunctioning adenomas by the luteinizing hormone beta subunit response to thyrotropin-releasing hormone. J Clin Endocrinol Metab 1993;77:1352-5.  Back to cited text no. 53    
54.Cappabianca P, Alfieri A, de Divitiis E. Endoscopic endonasal transsphenoidal approach to the sella: towards functional endoscopic pituitary surgery (FEPS). Minim Invasive Neurosurg 1998;41:66-73.  Back to cited text no. 54    
55.Jho HD, Alfieri A. Endoscopic endonasal pituitary surgery: evolution of surgical technique and equipment in 150 operations. Minim Invasive Neurosurg 2001;44:1-12.  Back to cited text no. 55    
56.Jho HD, Carrau RL. Endoscopic endonasal transsphenoidal surgery: experience with 50 patients. J Neurosurg 1997;87:44-51.  Back to cited text no. 56    
57.Colao A, Cerbone G, Cappabianca P, Ferone D, Alfieri A, Di Salle F, et al. Effect of surgery and radiotherapy on visual and endocrine function in nonfunctioning pituitary adenomas. J Endocrinol Invest 1998;21:284-90.  Back to cited text no. 57    
58.Kurosaki M, Ludecke DK, Flitsch J, Saeger W. Surgical treatment of clinically nonsecreting pituitary adenomas in elderly patients. Neurosurgery 2000;47:  Back to cited text no. 58    
59.843-8.  Back to cited text no. 59    
60.Laws ERJJA, Jr. Pituitary tumors-long-term outcomes and expectations. Clin Neurosurg 2001;48:306-19.  Back to cited text no. 60    
61.Webb SM, Rigla M, Wagner A, Oliver B, Bartumeus F. Recovery of hypopituitarism after neurosurgical treatment of pituitary adenomas. J Clin Endocrinol Metab 1999;84:3696-700.  Back to cited text no. 61    
62.Arita K, Uozumi T, Yano T, Kurisu K, Hirohata T, Eguchi K, et al. Effect of surgery on gonadal function of premenopausal women with pituitary adenomas other than prolactinomas. Endocr J 1996;43:131-8.  Back to cited text no. 62    
63.Laws ER Jr, Thapar K. Pituitary surgery. Endocrinol Metab Clin North Am 1999;28:119-31.  Back to cited text no. 63    
64.Hensen J, Henig A, Fahlbusch R, Meyer M, Boehnert M, Buchfelder M. Prevalence, predictors and patterns of postoperative polyuria and hyponatraemia in the immediate course after transsphenoidal surgery for pituitary adenomas. Clin Endocrinol Oxf 1999;50:431-9.  Back to cited text no. 64    
65.Woollons AC, Balakrishnan V, Hunn MK, Rajapaske YR. Complications of trans-sphenoidal surgery: the Wellington experience. Aust NZ J Sur 2000;70:405-8.  Back to cited text no. 65    
66.Ciric I, Ragin A, Baumgartner C, Pierce D. Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience. Neurosurgery 1997;40:225-36.  Back to cited text no. 66    
67.Losa M, Franzin A, Mangili F, Terreni MR, Barzaghi R, Veglia F, et al. Proliferation index of nonfunctioning pituitary adenomas: correlations with clinical characteristics and long-term follow-up results. Neurosurgery 2000;47:1313-8.  Back to cited text no. 67    
68.Ebersold MJ, Quast LM, Laws ER, Jr., Scheithauer B, Randall RV. Long-term results in transsphenoidal removal of nonfunctioning pituitary adenomas. J Neurosurg 1986;64:713-9.  Back to cited text no. 68    
69.Turner HE, Stratton IM, Byrne JV, Adams CB, Wass JA. Audit of selected patients with nonfunctioning pituitary adenomas treated without irradiation - a follow-up study. Clin Endocrinol Oxf 1999;51:281-4.  Back to cited text no. 69    
70.Brada M, Rajan B, Traish D, Ashley S, Holmes-Sellors PJ, Nussey S, et al. The long-term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas. Clin Endocrinol 1993;38:571-8.  Back to cited text no. 70    
71.McCollough WM, Marcus RB Jr, Rhoton AL Jr, Ballinger WE, Million RR. Long-term follow-up of radiotherapy for pituitary adenoma: the absence of late recurrence after greater than or equal to 4500 cGy. Int J Radiat Oncol Biol Phys 1991;21:607-14.  Back to cited text no. 71    
72.Littley MD, Shalet SM, Beardwell CG, Ahmed SR, Applegate G, Sutton ML. Hypopituitarism following external radiotherapy for pituitary tumours in adults. Quarterly J Med 1989;70:145-60.  Back to cited text no. 72    
73.McCord MW, Buatti JM, Fennell EM, Mendenhall WM, Marcus RB Jr, Rhoton AL, et al. Radiotherapy for pituitary adenoma: long-term outcome and sequelae. Int J Radiat Oncol Biol Phys 1997;39:437-44.  Back to cited text no. 73    
74.Sheehan JP, Kondziolka D, Flickinger J, Lunsford LD. Radiosurgery for residual or recurrent nonfunctioning pituitary adenoma. J Neurosurg 2002;97:408-14.  Back to cited text no. 74    
75.Feigl GC, Bonelli CM, Berghold A, Mokry M. Effects of gamma knife radiosurgery of pituitary adenomas on pituitary function. J Neurosurg 2002;97:415-21.  Back to cited text no. 75    
76.Wowra B, Stummer W. Efficacy of gamma knife radiosurgery for nonfunctioning pituitary adenomas: a quantitative follow up with magnetic resonance imaging-based volumetric analysis. J Neurosurg 2002;97:429-32.  Back to cited text no. 76    
77.Petrovich Z, Yu C, Giannotta SL, Zee CS, Apuzzo ML. Gamma knife radiosurgery for pituitary adenoma: early results. Neurosurgery 2003;53:51-9.  Back to cited text no. 77    
78.Williams JC, Stone D, Smith-Arica JR, Morris ID, Lowenstein PR, Castro MG. Regulated, adenovirus-mediated delivery of tyrosine hydroxylase suppresses growth of estrogen-induced pituitary prolactinomas. Molecular Therapy 2001;4:593-602.  Back to cited text no. 78    
79.Lee EJ, Anderson LM, Thimmapaya B, Jameson JL. Targeted expression of toxic genes directed by pituitary hormone promoters: a potential strategy for adenovirus-mediated gene therapy of pituitary tumors. J Clin Endocrinol Metab 1999;84:786-94.  Back to cited text no. 79    
80.Lee EJ, Thimmapaya B, Jameson JL. Stereotactic injection of adenoviral vectors that target gene expression to specific pituitary cell types: implications for gene therapy. Neurosurgery 2000;46:1461-8.  Back to cited text no. 80    

 

Top
Print this article  Email this article
Previous article Next article
Online since 20th March '04
Published by Wolters Kluwer - Medknow