Prolactinomas
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《新英格兰医药杂志》
To the Editor: In the study protocol described by Colao et al. (Nov. 20 issue),1 cabergoline was given at a dose of 0.5 mg per week to patients with nontumoral hyperprolactinemia, microprolactinomas, or macroprolactinomas and then stopped abruptly. I propose that cabergoline be tapered off rather than abruptly stopped, to avoid potential rebound hyperprolactinemia. The dose can be reduced from the typical dose of 0.25 mg twice a week, to 0.25 mg once a week, and then to 0.25 mg every other week before discontinuation. Serum prolactin levels can be measured one month after dose reduction and the reduction continued if the prolactin levels are normal. It is likely that cabergoline tapering, rather than withdrawal, will lessen the incidence of complications of hyperprolactinemia.
Theodore C. Friedman, M.D., Ph.D.
Charles R. Drew University
Los Angeles, CA 90059
References
Colao A, Di Sarno A, Cappabianca P, Di Somma C, Pivonello R, Lombardi G. Withdrawal of long-term cabergoline therapy for tumoral and nontumoral hyperprolactinemia. N Engl J Med 2003;349:2023-2033.
To the Editor: Colao et al. indicate that many patients harboring prolactinomas who are treated with cabergoline remain in remission after drug withdrawal. Of the 36 percent of patients with macroprolactinomas in their study who had a recurrence of hyperprolactinemia after discontinuation of the drug (with a median time to recurrence of 18 months), none had recurrent tumor growth. The apparent discordance between the recurrence of hyperprolactinemia (indicating the potential for tumor growth) and the magnetic resonance imaging (MRI) findings suggests that follow-up was insufficient to determine the true rate of tumor control. Slow growth of prolactinomas has been recognized and may be anticipated in some patients after the discontinuation of cabergoline; similarly, in some patients prolactin levels have been reported to rise after the discontinuation of bromocriptine.1
In an article in the same issue, Schlechte2 provides an overview of the current approach to the management of prolactinoma. Although we agree that surgery for prolactinomas is recommended when medical therapy is ineffective, a surgical option for the treatment of microprolactinomas should be emphasized. A 91 percent cure rate over a follow-up period of at least five years was observed in a large series of patients with microprolactinomas.3 Other surgeons have reported similar results,4,5 indicating that resection is a reasonable option, especially in patients with microadenomas associated with prolactin levels of less than 200 ng per milliliter in whom surgical cure would be anticipated.6
William T. Couldwell, M.D., Ph.D.
University of Utah School of Medicine
Salt Lake City, UT 84132
william.couldwell@hsc.utah.edu
Martin H. Weiss, M.D.
University of Southern California
Los Angeles, CA 90033
Edward R. Laws, Jr., M.D.
University of Virginia
Charlottesville, VA 22908
References
Johnston DG, Hall K, Kendall-Taylor P, Patrick D, Watson M, Cook DB. Effect of dopamine agonist withdrawal after long-term therapy in prolactinomas: studies with high-definition computerised tomography. Lancet 1984;2:187-192.
Schlechte JA. Prolactinoma. N Engl J Med 2003;349:2035-2041.
Amar AP, Couldwell WT, Chen JCT, Weiss MH. Predictive value of serum prolactin levels measured immediately after transsphenoidal surgery. J Neurosurg 2002;97:307-314.
Jane JA Jr, Laws ER Jr. The surgical management of pituitary adenomas in a series of 3,093 patients. J Am Coll Surg 2001;193:651-659.
Randall RV, Laws ER Jr, Abboud CF, Ebersold MJ, Kao PC, Scheithauer BW. Transsphenoidal microsurgical treatment of prolactin-producing pituitary adenomas: results in 100 patients. Mayo Clin Proc 1983;58:108-121.
Couldwell WT, Rovit RL, Weiss MH. Role of surgery in the treatment of microprolactinomas. Neurosurg Clin N Am 2003;14:89-92.
To the Editor: An omission in the discussion of prolactinoma by Schlechte is the problem presented by macroprolactin.1,2,3,4 In the flowchart presented as Figure 2 of the article, an initial step in evaluating hyperprolactinemia should be the determination of whether increased measured levels of prolactin represent increased levels of active hormone. Consultation with the laboratory may be of value.
Macroprolactin, a complex of prolactin and immunoglobulins, is not physiologically active.1,2,3,4 However, macroprolactin has a longer half-life in the circulation than does free prolactin, resulting in increased total levels of circulating prolactin. Macroprolactinemia may account for up to 20 percent of all cases of hyperprolactinemia.1,2 Identification of macroprolactinemia requires laboratory techniques that separate prolactin from macroprolactin before analysis,1,2,3,4 although it may be suspected when different assay methods yield different results.4
Glen L. Hortin, M.D., Ph.D.
National Institutes of Health Clinical Center
Bethesda, MD 20892
ghortin@mail.cc.nih.gov
References
Suliman AM, Smith TP, Gibney J, McKenna TJ. Frequent misdiagnosis and mismanagement of hyperprolactinemic patients before the introduction of macroprolactin screening: application of a new strict laboratory definition of macroprolactinemia. Clin Chem 2003;49:1504-1509.
Fahie-Wilson M. In hyperprolactinemia, testing for macroprolactin is essential. Clin Chem 2003;49:1434-1436.
Strachan MW, Teoh WL, Don-Wauchope AC, Seth J, Soddart SJ, Beckett GJ. Clinical and radiological features of patients with macroprolactinaemia. Clin Endocrinol (Oxf) 2003;59:339-346.
Smith TP, Suliman AM, Fahie-Wilson MN, McKenna TJ. Gross variability in the detection of prolactin in sera containing big big prolactin (macroprolactin) by commercial immunoassays. J Clin Endocrinol Metab 2002;87:5410-5415.
Drs. Colao and Lombardi reply: We thank Dr. Friedman and Dr. Couldwell and colleagues for their letters, which allow us to discuss a few important points related to the treatment of prolactinomas and the methods of cabergoline withdrawal. The issue of tapering cabergoline is very important. We withdrew cabergoline only from those patients whose prolactin levels remained normal during the reduction of the dose to 0.5 mg once a week or 0.25 mg twice a week. Whether a further dose reduction, to 0.25 mg once a week, would have improved the outcome of withdrawal should be the subject of further investigation. However, the nadir prolactin level during treatment correlated with persistent normoprolactinemia to a greater extent than did the dose of cabergoline. The patients in whom there was suppression of prolactin levels (to less than 5 μg per liter) during cabergoline therapy had the highest likelihood of maintaining normoprolactinemia after withdrawal. There was no difference in the outcome of withdrawal in patients with microprolactinomas and those with macroprolactinomas whose tumors disappeared on MRI studies.
Couldwell and colleagues suggest that surgery and its high rates of cure in the management of microprolactinomas (e.g., a 91 percent rate of cure over a follow-up period at least five years)1,2 should not be forgotten, especially in patients with base-line prolactin levels of less than 200 μg per liter. We found higher base-line prolactin levels in patients with microprolactinomas who had a recurrence of hyperprolactinemia after withdrawal, and Amar et al.1 observed a 100 percent rate of cure after five years in patients whose prolactin levels immediately after surgery were below 5 μg per liter. In this respect, the results of surgery and medical therapy of microprolactinomas share some features: the outcome is better in patients with lower base-line prolactin levels than in those with higher base-line levels.
The most relevant differences between surgery and medical therapy can be summarized as follows. Surgery should be performed in highly specialized centers, it is expensive, and it is not without complications,3 even when new surgical techniques are used.4 Medical therapy, in contrast, can be easily performed in any center where an endocrinologist is experienced in treating pituitary tumors. Medical therapy is inexpensive and can be successfully used for patients with microprolactinomas or macroprolactinomas. Although we agree that surgery can be offered to young patients with microprolactinomas, our study shows that lifelong treatment with cabergoline can be avoided by careful periodic treatment withdrawal, without clinical or neuroradiologic consequences.
Annamaria Colao, M.D., Ph.D.
Gaetano Lombardi, M.D., Ph.D.
University of Naples
80131 Naples, Italy
colao@unina.it
References
Amar AP, Couldwell WT, Chen JCT, Weiss MH. Predictive value of serum prolactin levels measured immediately after transsphenoidal surgery. J Neurosurg 2002;97:307-314.
Jane JA Jr, Laws ER Jr. The surgical management of pituitary adenomas in a series of 3,093 patients. J Am Coll Surg 2001;193:651-659.
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;40:225-237.
Cappabianca P, Cavallo LM, Colao A, de Divitiis E. Surgical complications associated with the endoscopic endonasal transphenoidal approach for pituitary adenomas. J Neurosurg 2002;97:293-298.
Dr. Schlechte replies: The incidence of macroprolactinemia ranges from 18 to 42 percent when samples from reference laboratories are assayed, whereas the incidence is about 10 percent among patients in an endocrinology practice.1,2,3 Most women with a preponderance of high-molecular-weight prolactin (i.e., those with macroprolactinemia) do not have the typical symptoms of hyperprolactinemia, but some have amenorrhea or galactorrhea, and the presence of macroprolactin does not totally rule out pituitary adenoma.3 The ability to detect macroprolactin might help in the evaluation of idiopathic hyperprolactinemia and in some cases might eliminate the need for MRI studies of the pituitary. The difficulty is in the detection of macroprolactin.
Smith et al.4 compared nine different assay systems commonly used in the United States and Europe and noted marked variability in the detection of prolactin in serum samples containing macroprolactin; Schneider et al.5 also noted that prolactin assays vary substantially in their reactivity for macroprolactin. Although some are better than others, there is no single prolactin assay that will yield a normal level of monomeric prolactin in the presence of macroprolactin. Furthermore, there is no simple method of detecting macroprolactin, and many assays do not even describe techniques for its detection. Gel-filtration chromatography is expensive and is not used in clinical laboratories. Polyethylene glycol precipitation is simple and inexpensive but is not specific or quantitative, and serum pretreated with polyethylene glycol may not be compatible with all instrumented assays. Equipment manufacturers and clinical laboratories should clearly characterize assays with respect to macroprolactin and provide a procedure for its detection.
Janet Schlechte, M.D.
University of Iowa
Iowa City, IA 52242
janet-schlechte@uiowa.edu
References
Fahie-Wilson MN, Soule SG. Macroprolactinaemia: contribution to hyperprolactinaemia in a district general hospital and evaluation of a screening test based on precipitation with polyethylene glycol. Ann Clin Biochem 1997;34:252-258.
Vallette-Kasic S, Morange-Ramos I, Selim A, et al. Macroprolactinemia revisited: a study on 106 patients. J Clin Endocrinol Metab 2002;87:581-588.
Olukoga A, Kane J. Macroprolactinaemia: validation and application of the polyethylene glycol precipitation test and clinical characterization of the condition. Clin Endocrinol (Oxf) 1999;51:119-126.
Smith TP, Suliman AM, Fahie-Wilson MN, McKenna TJ. Gross variability in the detection of prolactin in sera containing big big prolactin (macroprolactin) by commercial immunoassays. J Clin Endocrinol Metab 2002;87:5410-5415.
Schneider W, Marcovitz S, Al-Shammari S, Yago S, Chevalier S. Reactivity of macroprolactin in common automated immunoassays. Clin Biochem 2001;34:469-473.
Theodore C. Friedman, M.D., Ph.D.
Charles R. Drew University
Los Angeles, CA 90059
References
Colao A, Di Sarno A, Cappabianca P, Di Somma C, Pivonello R, Lombardi G. Withdrawal of long-term cabergoline therapy for tumoral and nontumoral hyperprolactinemia. N Engl J Med 2003;349:2023-2033.
To the Editor: Colao et al. indicate that many patients harboring prolactinomas who are treated with cabergoline remain in remission after drug withdrawal. Of the 36 percent of patients with macroprolactinomas in their study who had a recurrence of hyperprolactinemia after discontinuation of the drug (with a median time to recurrence of 18 months), none had recurrent tumor growth. The apparent discordance between the recurrence of hyperprolactinemia (indicating the potential for tumor growth) and the magnetic resonance imaging (MRI) findings suggests that follow-up was insufficient to determine the true rate of tumor control. Slow growth of prolactinomas has been recognized and may be anticipated in some patients after the discontinuation of cabergoline; similarly, in some patients prolactin levels have been reported to rise after the discontinuation of bromocriptine.1
In an article in the same issue, Schlechte2 provides an overview of the current approach to the management of prolactinoma. Although we agree that surgery for prolactinomas is recommended when medical therapy is ineffective, a surgical option for the treatment of microprolactinomas should be emphasized. A 91 percent cure rate over a follow-up period of at least five years was observed in a large series of patients with microprolactinomas.3 Other surgeons have reported similar results,4,5 indicating that resection is a reasonable option, especially in patients with microadenomas associated with prolactin levels of less than 200 ng per milliliter in whom surgical cure would be anticipated.6
William T. Couldwell, M.D., Ph.D.
University of Utah School of Medicine
Salt Lake City, UT 84132
william.couldwell@hsc.utah.edu
Martin H. Weiss, M.D.
University of Southern California
Los Angeles, CA 90033
Edward R. Laws, Jr., M.D.
University of Virginia
Charlottesville, VA 22908
References
Johnston DG, Hall K, Kendall-Taylor P, Patrick D, Watson M, Cook DB. Effect of dopamine agonist withdrawal after long-term therapy in prolactinomas: studies with high-definition computerised tomography. Lancet 1984;2:187-192.
Schlechte JA. Prolactinoma. N Engl J Med 2003;349:2035-2041.
Amar AP, Couldwell WT, Chen JCT, Weiss MH. Predictive value of serum prolactin levels measured immediately after transsphenoidal surgery. J Neurosurg 2002;97:307-314.
Jane JA Jr, Laws ER Jr. The surgical management of pituitary adenomas in a series of 3,093 patients. J Am Coll Surg 2001;193:651-659.
Randall RV, Laws ER Jr, Abboud CF, Ebersold MJ, Kao PC, Scheithauer BW. Transsphenoidal microsurgical treatment of prolactin-producing pituitary adenomas: results in 100 patients. Mayo Clin Proc 1983;58:108-121.
Couldwell WT, Rovit RL, Weiss MH. Role of surgery in the treatment of microprolactinomas. Neurosurg Clin N Am 2003;14:89-92.
To the Editor: An omission in the discussion of prolactinoma by Schlechte is the problem presented by macroprolactin.1,2,3,4 In the flowchart presented as Figure 2 of the article, an initial step in evaluating hyperprolactinemia should be the determination of whether increased measured levels of prolactin represent increased levels of active hormone. Consultation with the laboratory may be of value.
Macroprolactin, a complex of prolactin and immunoglobulins, is not physiologically active.1,2,3,4 However, macroprolactin has a longer half-life in the circulation than does free prolactin, resulting in increased total levels of circulating prolactin. Macroprolactinemia may account for up to 20 percent of all cases of hyperprolactinemia.1,2 Identification of macroprolactinemia requires laboratory techniques that separate prolactin from macroprolactin before analysis,1,2,3,4 although it may be suspected when different assay methods yield different results.4
Glen L. Hortin, M.D., Ph.D.
National Institutes of Health Clinical Center
Bethesda, MD 20892
ghortin@mail.cc.nih.gov
References
Suliman AM, Smith TP, Gibney J, McKenna TJ. Frequent misdiagnosis and mismanagement of hyperprolactinemic patients before the introduction of macroprolactin screening: application of a new strict laboratory definition of macroprolactinemia. Clin Chem 2003;49:1504-1509.
Fahie-Wilson M. In hyperprolactinemia, testing for macroprolactin is essential. Clin Chem 2003;49:1434-1436.
Strachan MW, Teoh WL, Don-Wauchope AC, Seth J, Soddart SJ, Beckett GJ. Clinical and radiological features of patients with macroprolactinaemia. Clin Endocrinol (Oxf) 2003;59:339-346.
Smith TP, Suliman AM, Fahie-Wilson MN, McKenna TJ. Gross variability in the detection of prolactin in sera containing big big prolactin (macroprolactin) by commercial immunoassays. J Clin Endocrinol Metab 2002;87:5410-5415.
Drs. Colao and Lombardi reply: We thank Dr. Friedman and Dr. Couldwell and colleagues for their letters, which allow us to discuss a few important points related to the treatment of prolactinomas and the methods of cabergoline withdrawal. The issue of tapering cabergoline is very important. We withdrew cabergoline only from those patients whose prolactin levels remained normal during the reduction of the dose to 0.5 mg once a week or 0.25 mg twice a week. Whether a further dose reduction, to 0.25 mg once a week, would have improved the outcome of withdrawal should be the subject of further investigation. However, the nadir prolactin level during treatment correlated with persistent normoprolactinemia to a greater extent than did the dose of cabergoline. The patients in whom there was suppression of prolactin levels (to less than 5 μg per liter) during cabergoline therapy had the highest likelihood of maintaining normoprolactinemia after withdrawal. There was no difference in the outcome of withdrawal in patients with microprolactinomas and those with macroprolactinomas whose tumors disappeared on MRI studies.
Couldwell and colleagues suggest that surgery and its high rates of cure in the management of microprolactinomas (e.g., a 91 percent rate of cure over a follow-up period at least five years)1,2 should not be forgotten, especially in patients with base-line prolactin levels of less than 200 μg per liter. We found higher base-line prolactin levels in patients with microprolactinomas who had a recurrence of hyperprolactinemia after withdrawal, and Amar et al.1 observed a 100 percent rate of cure after five years in patients whose prolactin levels immediately after surgery were below 5 μg per liter. In this respect, the results of surgery and medical therapy of microprolactinomas share some features: the outcome is better in patients with lower base-line prolactin levels than in those with higher base-line levels.
The most relevant differences between surgery and medical therapy can be summarized as follows. Surgery should be performed in highly specialized centers, it is expensive, and it is not without complications,3 even when new surgical techniques are used.4 Medical therapy, in contrast, can be easily performed in any center where an endocrinologist is experienced in treating pituitary tumors. Medical therapy is inexpensive and can be successfully used for patients with microprolactinomas or macroprolactinomas. Although we agree that surgery can be offered to young patients with microprolactinomas, our study shows that lifelong treatment with cabergoline can be avoided by careful periodic treatment withdrawal, without clinical or neuroradiologic consequences.
Annamaria Colao, M.D., Ph.D.
Gaetano Lombardi, M.D., Ph.D.
University of Naples
80131 Naples, Italy
colao@unina.it
References
Amar AP, Couldwell WT, Chen JCT, Weiss MH. Predictive value of serum prolactin levels measured immediately after transsphenoidal surgery. J Neurosurg 2002;97:307-314.
Jane JA Jr, Laws ER Jr. The surgical management of pituitary adenomas in a series of 3,093 patients. J Am Coll Surg 2001;193:651-659.
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;40:225-237.
Cappabianca P, Cavallo LM, Colao A, de Divitiis E. Surgical complications associated with the endoscopic endonasal transphenoidal approach for pituitary adenomas. J Neurosurg 2002;97:293-298.
Dr. Schlechte replies: The incidence of macroprolactinemia ranges from 18 to 42 percent when samples from reference laboratories are assayed, whereas the incidence is about 10 percent among patients in an endocrinology practice.1,2,3 Most women with a preponderance of high-molecular-weight prolactin (i.e., those with macroprolactinemia) do not have the typical symptoms of hyperprolactinemia, but some have amenorrhea or galactorrhea, and the presence of macroprolactin does not totally rule out pituitary adenoma.3 The ability to detect macroprolactin might help in the evaluation of idiopathic hyperprolactinemia and in some cases might eliminate the need for MRI studies of the pituitary. The difficulty is in the detection of macroprolactin.
Smith et al.4 compared nine different assay systems commonly used in the United States and Europe and noted marked variability in the detection of prolactin in serum samples containing macroprolactin; Schneider et al.5 also noted that prolactin assays vary substantially in their reactivity for macroprolactin. Although some are better than others, there is no single prolactin assay that will yield a normal level of monomeric prolactin in the presence of macroprolactin. Furthermore, there is no simple method of detecting macroprolactin, and many assays do not even describe techniques for its detection. Gel-filtration chromatography is expensive and is not used in clinical laboratories. Polyethylene glycol precipitation is simple and inexpensive but is not specific or quantitative, and serum pretreated with polyethylene glycol may not be compatible with all instrumented assays. Equipment manufacturers and clinical laboratories should clearly characterize assays with respect to macroprolactin and provide a procedure for its detection.
Janet Schlechte, M.D.
University of Iowa
Iowa City, IA 52242
janet-schlechte@uiowa.edu
References
Fahie-Wilson MN, Soule SG. Macroprolactinaemia: contribution to hyperprolactinaemia in a district general hospital and evaluation of a screening test based on precipitation with polyethylene glycol. Ann Clin Biochem 1997;34:252-258.
Vallette-Kasic S, Morange-Ramos I, Selim A, et al. Macroprolactinemia revisited: a study on 106 patients. J Clin Endocrinol Metab 2002;87:581-588.
Olukoga A, Kane J. Macroprolactinaemia: validation and application of the polyethylene glycol precipitation test and clinical characterization of the condition. Clin Endocrinol (Oxf) 1999;51:119-126.
Smith TP, Suliman AM, Fahie-Wilson MN, McKenna TJ. Gross variability in the detection of prolactin in sera containing big big prolactin (macroprolactin) by commercial immunoassays. J Clin Endocrinol Metab 2002;87:5410-5415.
Schneider W, Marcovitz S, Al-Shammari S, Yago S, Chevalier S. Reactivity of macroprolactin in common automated immunoassays. Clin Biochem 2001;34:469-473.