Treatment of gonadotroph and other clinically nonfunctioning adenomas
- Peter J Snyder, MD
Peter J Snyder, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Pituitary Disease; Male Reproductive Endocrinology
- Professor of Medicine
- University of Pennsylvania School of Medicine
Gonadotroph adenomas are the most common pituitary macroadenomas, comprising about 80 percent of clinically nonfunctioning adenomas. These adenomas are difficult to identify because their secretory products usually do not cause a recognizable clinical syndrome and because they often secrete so inefficiently that serum concentrations of intact gonadotropins and their subunits are often only minimally abnormal or not abnormal at all. Consequently, they are typically not detected until they become sufficiently large to cause neurologic symptoms, most often impaired vision due to pressure on the optic chiasm. Clinically nonfunctioning or “silent” somatotroph and corticotroph adenomas are also being identified with increasing frequency.
The treatment of gonadotroph and other clinically nonfunctioning adenomas will be reviewed here. Their clinical manifestations and diagnosis are discussed separately. (See "Clinical manifestations and diagnosis of gonadotroph and other clinically nonfunctioning pituitary adenomas".)
Overview — Gonadotroph or other nonfunctioning macroadenomas are typically diagnosed when they become large enough to cause neurologic symptoms (eg, headaches, visual loss), a hormonal deficiency state, when an imaging study is performed for unrelated reasons, or less commonly, because of hormonal hypersecretion.
Once identified, treatment should be promptly instituted for those with impaired vision, and considered for those at high risk for loss of vision (marked suprasellar tumor extension). Standard first-line therapy is transsphenoidal surgery. If there is no or little discernible residual adenoma tissue by magnetic resonance imaging (MRI), the patient should be monitored by MRI and hormonally, initially at six-month intervals. If there is considerable residual adenomatous tissue, radiation should be administered. Long-term monitoring is necessary because the risk of tumor regrowth is significant, particularly after surgery alone. Life-long management of pituitary hormone deficiencies is required in many patients. (See 'Adjuvant radiation therapy' below and 'Hormonal abnormalities' below.)
Goals of treatment — The goals of treatment in patients with gonadotroph or nonfunctioning adenomas include:
- 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.
- Wilson CB. Surgical management of pituitary tumors. J Clin Endocrinol Metab 1997; 82:2381.
- Dekkers OM, Pereira AM, Romijn JA. Treatment and follow-up of clinically nonfunctioning pituitary macroadenomas. J Clin Endocrinol Metab 2008; 93:3717.
- Messerer M, De Battista JC, Raverot G, et al. Evidence of improved surgical outcome following endoscopy for nonfunctioning pituitary adenoma removal. Neurosurg Focus 2011; 30:E11.
- Inder WJ, Hunt PJ. Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management. J Clin Endocrinol Metab 2002; 87:2745.
- Ausiello JC, Bruce JN, Freda PU. Postoperative assessment of the patient after transsphenoidal pituitary surgery. Pituitary 2008; 11:391.
- Adams JR, Blevins LS Jr, Allen GS, et al. Disorders of water metabolism following transsphenoidal pituitary surgery: a single institution's experience. Pituitary 2006; 9:93.
- Kristof RA, Rother M, Neuloh G, Klingmüller D. Incidence, clinical manifestations, and course of water and electrolyte metabolism disturbances following transsphenoidal pituitary adenoma surgery: a prospective observational study. J Neurosurg 2009; 111:555.
- Zada G, Liu CY, Fishback D, et al. Recognition and management of delayed hyponatremia following transsphenoidal pituitary surgery. J Neurosurg 2007; 106:66.
- Streeten DH, Anderson GH Jr, Bonaventura MM. The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test. J Clin Endocrinol Metab 1996; 81:285.
- Murad MH, Fernández-Balsells MM, Barwise A, et al. Outcomes of surgical treatment for nonfunctioning pituitary adenomas: a systematic review and meta-analysis. Clin Endocrinol (Oxf) 2010; 73:777.
- Losa M, Mortini P, Barzaghi R, et al. Early results of surgery in patients with nonfunctioning pituitary adenoma and analysis of the risk of tumor recurrence. J Neurosurg 2008; 108:525.
- Kerrison JB, Lynn MJ, Baer CA, et al. Stages of improvement in visual fields after pituitary tumor resection. Am J Ophthalmol 2000; 130:813.
- Jakobsson KE, Petruson B, Lindblom B. Dynamics of visual improvement following chiasmal decompression. Quantitative pre- and postoperative observations. Acta Ophthalmol Scand 2002; 80:512.
- Barker FG 2nd, Klibanski A, Swearingen B. Transsphenoidal surgery for pituitary tumors in the United States, 1996-2000: mortality, morbidity, and the effects of hospital and surgeon volume. J Clin Endocrinol Metab 2003; 88:4709.
- Woollons AC, Hunn MK, Rajapakse YR, et al. Non-functioning pituitary adenomas: indications for postoperative radiotherapy. Clin Endocrinol (Oxf) 2000; 53:713.
- Tsang RW, Brierley JD, Panzarella T, et al. Radiation therapy for pituitary adenoma: treatment outcome and prognostic factors. Int J Radiat Oncol Biol Phys 1994; 30:557.
- McCord MW, Buatti JM, Fennell EM, et al. Radiotherapy for pituitary adenoma: long-term outcome and sequelae. Int J Radiat Oncol Biol Phys 1997; 39:437.
- van den Bergh AC, van den Berg G, Schoorl MA, et al. Immediate postoperative radiotherapy in residual nonfunctioning pituitary adenoma: beneficial effect on local control without additional negative impact on pituitary function and life expectancy. Int J Radiat Oncol Biol Phys 2007; 67:863.
- Loeffler JS, Shih HA. Radiation therapy in the management of pituitary adenomas. J Clin Endocrinol Metab 2011; 96:1992.
- Snyder PJ, Fowble BF, Schatz NJ, et al. Hypopituitarism following radiation therapy of pituitary adenomas. Am J Med 1986; 81:457.
- Zierhut D, Flentje M, Adolph J, et al. External radiotherapy of pituitary adenomas. Int J Radiat Oncol Biol Phys 1995; 33:307.
- Brada M, Ford D, Ashley S, et al. Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma. BMJ 1992; 304:1343.
- Tsang RW, Laperriere NJ, Simpson WJ, et al. Glioma arising after radiation therapy for pituitary adenoma. A report of four patients and estimation of risk. Cancer 1993; 72:2227.
- Minniti G, Traish D, Ashley S, et al. Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: update after an additional 10 years. J Clin Endocrinol Metab 2005; 90:800.
- Paek SH, Downes MB, Bednarz G, et al. Integration of surgery with fractionated stereotactic radiotherapy for treatment of nonfunctioning pituitary macroadenomas. Int J Radiat Oncol Biol Phys 2005; 61:795.
- Pollock BE, Cochran J, Natt N, et al. Gamma knife radiosurgery for patients with nonfunctioning pituitary adenomas: results from a 15-year experience. Int J Radiat Oncol Biol Phys 2008; 70:1325.
- Pamir MN, Kiliç T, Belirgen M, et al. Pituitary adenomas treated with gamma knife radiosurgery: volumetric analysis of 100 cases with minimum 3 year follow-up. Neurosurgery 2007; 61:270.
- Colin P, Jovenin N, Delemer B, et al. Treatment of pituitary adenomas by fractionated stereotactic radiotherapy: a prospective study of 110 patients. Int J Radiat Oncol Biol Phys 2005; 62:333.
- Mackley HB, Reddy CA, Lee SY, et al. Intensity-modulated radiotherapy for pituitary adenomas: the preliminary report of the Cleveland Clinic experience. Int J Radiat Oncol Biol Phys 2007; 67:232.
- Ronson BB, Schulte RW, Han KP, et al. Fractionated proton beam irradiation of pituitary adenomas. Int J Radiat Oncol Biol Phys 2006; 64:425.
- Feigl GC, Bonelli CM, Berghold A, Mokry M. Effects of gamma knife radiosurgery of pituitary adenomas on pituitary function. J Neurosurg 2002; 97:415.
- Sheehan JP, Niranjan A, Sheehan JM, et al. Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium. J Neurosurg 2005; 102:678.
- Mingione V, Yen CP, Vance ML, et al. Gamma surgery in the treatment of nonsecretory pituitary macroadenoma. J Neurosurg 2006; 104:876.
- Greenman Y, Tordjman K, Osher E, et al. Postoperative treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists decreases tumour remnant growth. Clin Endocrinol (Oxf) 2005; 63:39.
- Ikuyama S, Nawata H, Kato K, et al. Specific somatostatin receptors on human pituitary adenoma cell membranes. J Clin Endocrinol Metab 1985; 61:666.
- Reubi JC, Heitz PU, Landolt AM. Visualization of somatostatin receptors and correlation with immunoreactive growth hormone and prolactin in human pituitary adenomas: evidence for different tumor subclasses. J Clin Endocrinol Metab 1987; 65:65.
- de Bruin TW, Kwekkeboom DJ, Van't Verlaat JW, et al. Clinically nonfunctioning pituitary adenoma and octreotide response to long term high dose treatment, and studies in vitro. J Clin Endocrinol Metab 1992; 75:1310.
- Katznelson L, Oppenheim DS, Coughlin JF, et al. Chronic somatostatin analog administration in patients with alpha-subunit-secreting pituitary tumors. J Clin Endocrinol Metab 1992; 75:1318.
- Daneshdoost L, Pavlou SN, Molitch ME, et al. Inhibition of follicle-stimulating hormone secretion from gonadotroph adenomas by repetitive administration of a gonadotropin-releasing hormone antagonist. J Clin Endocrinol Metab 1990; 71:92.
- McGrath GA, Goncalves RJ, Udupa JK, et al. New technique for quantitation of pituitary adenoma size: use in evaluating treatment of gonadotroph adenomas with a gonadotropin-releasing hormone antagonist. J Clin Endocrinol Metab 1993; 76:1363.
- Roman SH, Goldstein M, Kourides IA, et al. The luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6-Pro9-NEt]LHRH increased rather than lowered LH and alpha-subunit levels in a patient with an LH-secreting pituitary tumor. J Clin Endocrinol Metab 1984; 58:313.
- Sassolas G, Lejeune H, Trouillas J, et al. Gonadotropin-releasing hormone agonists are unsuccessful in reducing tumoral gonadotropin secretion in two patients with gonadotropin-secreting pituitary adenomas. J Clin Endocrinol Metab 1988; 67:180.
- Klibanski A, Jameson JL, Biller BM, et al. Gonadotropin and alpha-subunit responses to chronic gonadotropin-releasing hormone analog administration in patients with glycoprotein hormone-secreting pituitary tumors. J Clin Endocrinol Metab 1989; 68:81.
- Dekkers OM, Pereira AM, Roelfsema F, et al. Observation alone after transsphenoidal surgery for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab 2006; 91:1796.
- O'Sullivan EP, Woods C, Glynn N, et al. The natural history of surgically treated but radiotherapy-naïve nonfunctioning pituitary adenomas. Clin Endocrinol (Oxf) 2009; 71:709.
- Chang EF, Zada G, Kim S, et al. Long-term recurrence and mortality after surgery and adjuvant radiotherapy for nonfunctional pituitary adenomas. J Neurosurg 2008; 108:736.
- Biermasz NR, van Thiel SW, Pereira AM, et al. Decreased quality of life in patients with acromegaly despite long-term cure of growth hormone excess. J Clin Endocrinol Metab 2004; 89:5369.
- van Aken MO, Pereira AM, Biermasz NR, et al. Quality of life in patients after long-term biochemical cure of Cushing's disease. J Clin Endocrinol Metab 2005; 90:3279.
- Dekkers OM, van der Klaauw AA, Pereira AM, et al. Quality of life is decreased after treatment for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab 2006; 91:3364.
- van der Klaauw AA, Biermasz NR, Pereira AM, et al. Patients cured from craniopharyngioma or nonfunctioning pituitary macroadenoma (NFMA) suffer similarly from increased daytime somnolence despite normal sleep patterns compared to healthy controls. Clin Endocrinol (Oxf) 2008; 69:769.
- Biermasz NR, Joustra SD, Donga E, et al. Patients previously treated for nonfunctioning pituitary macroadenomas have disturbed sleep characteristics, circadian movement rhythm, and subjective sleep quality. J Clin Endocrinol Metab 2011; 96:1524.
- Arita K, Tominaga A, Sugiyama K, et al. Natural course of incidentally found nonfunctioning pituitary adenoma, with special reference to pituitary apoplexy during follow-up examination. J Neurosurg 2006; 104:884.
- Dekkers OM, Hammer S, de Keizer RJ, et al. The natural course of non-functioning pituitary macroadenomas. Eur J Endocrinol 2007; 156:217.
- Karavitaki N, Collison K, Halliday J, et al. What is the natural history of nonoperated nonfunctioning pituitary adenomas? Clin Endocrinol (Oxf) 2007; 67:938.
- MANAGEMENT APPROACH
- Goals of treatment
- Surgical approach
- - Preoperative preparation
- - Choice of procedure
- - Perioperative management
- Diabetes insipidus and SIADH
- - Short-term monitoring
- - Outcomes
- Residual adenoma
- Visual function
- Hormonal abnormalities
- Adjuvant radiation therapy
- - "Conventional" radiation therapy
- - Stereotactic radiation
- Unproven therapies
- Long-term follow-up
- - Adenoma regrowth
- - Quality of life
- ASYMPTOMATIC ADENOMAS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS