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Effect rates of different modalities for treatment of prolactin adenomas
Effect Rates of Different Modalities Treatment of Prolactin Adenomas
FLEMMING
WOLLESEN,
M.D.
Glostnrp, Denmark BIRGITTE BJERG BENDSEN,
M.D.
Vordingborg. Denmark
From the Department of Internal Medicine, Glostrup University Hospital, Copenhagen School of Medicine, Glostrup, Denmark, and County Hospital. Vordingborg, Denmark. This work was supported by an institutional grant from the University of Copenhagen, Denmark. Requests for reprints should be addressed to Dr. Flemming Wollesen, Department of Internal Medicine, Glostrup University Hospital, 2600 Glostrup, Denmark. Manuscript accepted May 2, 1984.
114
January 1985
Results of treatment of 963 patients with prolactin adenomas described in the literature were reviewed. The patient population was strattfled into four subgroups: women and men with serum prolactln levels above and below 100 rig/ml for each of the treatment modalities: transsphenoldal surgery, bromocriptine, heavy ion radiation, conventional radiation, and transsphenoldal surgery plus conventional radiation. The five largest series within each subgroup were included. Success rates and recurrence rates were calculated for: (1) reduction of tumor size, (2) normalizatton of serum prolactin levels, and (3) normalization of other pitultary functions. Compllcation rates were calculated for procedural impairment of other pituitary functions. TransqWno& Isurgerywasfoundtobethemost effective treatment for lasting control, and bromocriptlne for temporary control, of prolactin adenomas. Recurrent adenomas were most effectively treated by transsphenoidal surgery If serum prolactin levels were below 100 rig/ml. tf serum prolactln levels were above 100 rig/ml, bromocriptine was the most effective treatment. Heavy ion radiation, whh success rates comparable to those of transsphenoidal surgery and bromocriptlne, but with lower recurrence rates, may eventually prove the most effective treatment of all. Prolactin-secreting adenomas are currently treatable by surgery, radiation, or medication. The three modalities have different success rates, complication rates, and recurrence rates. The effect rates of all three modalities are closely correlated to the secretory activity and the size of the adenoma [l-4]. At present, no single treatment is superior with respect to all effects. Combinations of different treatments are advantageous to many patients. A prudent alternative to treatment is often observation. Selection of an optimal approach for each individual patient requires updated insight into the effect rates of available alternatives. Many institutions specialize in single modalities of treatment, and selection among these rests with the referring physician through his or her choice of institution, rather than with a specialist. The following is an account of effect rates of different treatment modalities for prolactln adenomas based on reports published in the medical literature. DEFINITIONS
OF EFFECTS
Calculations of effect rates treatment, heavy particle combined transsphenoldal based on series of patients
The American Journal of Medicine
Volume 75
OF TREATMENT
for transsphenoidal surgery, bromocriptine radiation, conventional radiation, and surgery and conventional radiation were described in the literature from the intro-
TREATMENT
duction of serum prolactin assays until September 1983 [ 4-371. Effect rates were expressed as the fraction of patients who had responses to treatment. Responses to treatment were defined as success, complication, and recurrence. Success rates were determined for: (1) reduction of tumor mass, as demonstrated by radiology, perimetry, or surgery, (2) normalization of serum prolactin levels, and (3) normalization of one or more impaired pituitary functions other than prolactin secretion. Normalization of one function was counted as such, regardless of deterioration of any other pituitary function in the same patient. Com@afion rates were determined for procedural impairment of normal pituitary functions, regardless of improvement of any other pituitary function in the same patient. Recurrence rates were determined for the same three parameters as success rates. No data have been published on recurrent impairment of pituitary function, except for prolactin secretion. Increases in serum prolactin levels, which had not been normalized by treatment, were not counted as recurrence. Growth of tumor mass following reduction by treatment was counted as recurrence. Effect rates were calculated separately for four subgroups of patients: women of childbearing age with pretreatment serum prolactin levels below (Table I) and above (Table II) 100 rig/ml (2,000 mlU/ml) and men with serum prolactin levels below (Table Ill) and above (Table IV) 100 rig/ml. Serum prolactin concentration rather than tumor size was used to differentiate between large and small prolactin adenomas, as serum prolactin is more easily and accurately measured than tumor size. The value of 100 rig/ml provided the greatest difference between success rates of any serum prolactin concentration between 50 and 200 rig/ml. Included in the calculation were patients with verified adenoma size before and after treatment and patients treated in series. Excluded were patients with functional hyperprolactinemia, postmenopausal women, and patients with adenomas known to secrete more than one hormone. All series published were reviewed. Results from the five largest series in each of the four subgroups were included. REPORTED
EFFECTS
OF TREATMENT
A total of 1,939 patients treated specifically for prolactin adenomas with transsphenoidal surgery, bromocriptine, or radiation were reviewed. Of these 1,939 patients, 963 patients fulfilled the inclusion criteria. Excluded were 23 series comprising 840 women and 13 men treated
January
OF PROLACTIN
ADENOMAS-WOLLESEN
and BENDSEN
with transsphenoidal surgery. (The five largest series of these are presented in the Appendix section in Tables I and II.) Excluded were eight series of 43 women and five men treated with bromocriptine. Finally, 28 publications of 75 individual cases of adenoma size reduction during bromocriptine treatment were excluded, because they were not treated in series. Of 963 patients included, 298 women of childbearing age had pretreatment serum prolactin levels below 100 rig/ml and 448 women had pretreatment serum prolactin levels above 100 rig/ml; 34 men had pretreatment serum prolactin levels below 100 rig/ml and 183 men had pretreatment serum prolactin levels above 100 rig/ml. Transsphenoidal surgery was performed in 642 patients (67 percent): 182 women with serum prolactin levels below 100 rig/ml, 341 women with serum prolactin levels above 100 rig/ml, 18 men with serum prolactin levels below 100 rig/ml, and 101 men with serum prolactin levels above 100 @ml. Bromocriptine treatment was reported in 193 patients (20 percent): 88 women with serum prolactin levels below 100 rig/ml, 45 women with serum prolactin levels above 100 ngjml, 10 men with serum prolactin levels below 100 rig/ml, and 50 men with serum prolactin levels above 100 rig/ml. The remaining 128 patients (13 percent) were treated with radiation. Median success rates for normalization of serum prolactin levels by transsphenoidal surgery and bromocriptine, respectively, were: women with serum prolactin levels below 100 rig/ml: 83 and 95 percent; women with serum prolactin levels above 100 rig/ml: 31 and 50 percent; men with serum prolactin levels below 100 rig/ml: 100 and 100 percent: men with serum prolactin levels above 100 rig/ml: 17 and 50 percent. Median success rates for normalization of one or more other pituitary functions by transsphenoidal surgery and bromocriptine, respectively, were: women with serum prolactin levels below 100 rig/ml: 82 and 80 percent: women with serum prolactin levels above 100 rig/ml: 55 and 67 percent; men with serum prolactin levels below 100 rig/ml: 40 and 100 percent; men with serum prolactin levels above 100 rig/ml: 25 and 67 percent. Median success rates for reduction of adenoma size by transsphenoidal surgery and bromocriptine treatment, respectively, were: women with serum prolactin levels below 100 rig/ml: 100 and 0 percent; women with serum prolactin levels above 100 rig/ml: 100 and 80 percent: men with serum prolactin levels below 100 rig/ml: 100 and 0 percent; men with serum prolactin levels above 100 mg/ml: 100 and 62 percent. Success rates of 100 percent for transsphenoidal surgery are estimates. Success rates of 0 percent in-
1995
The American
Journal
of Medicine
Volume
78
115
Surgery
0 0
22 15 22 14
;::; t::;
Radiation
83 78 86
79 72 21
[221
;::;
74 54
35 27
100O(l)
0
t:;;
Radiation
33 50
21
1 and Conventional
43
86 40
95 80 100 95
80
[::I
Transsphenoidai
1181
t:;;
;:i;
107
0
15
Treatment
[91
63 90 93
73 62(13)
-(per-w Serum Pfolactin
Adenomas
86 78 78 85 76
0 0
100 67 0
lO(29)’
100 59
73 84 82 79
95
Pituitary Function
in Women
l
Prolactin
surgery.
8 0 21
3(29)’
0 lO(52)’ 13(300)’ 0 21
Compikatii (P-w PM=Y FlUlCtkll
with Serum
For definitions of individual effect rates, see Definitions of Effects of Treatment. Parentheses indicate number of patients when different from the entire series. Not subdivided with respect to serum proiactin level. f Serum pro&tin level below 200 rig/ml or “microproiactinomas” treated with transsphenoidai
Appendixt
Combined
94 39 14
t?’
181
20 15
ion Radiation
Conventional
Heavy
Bromocrtptine
nJmor Mass
Number of Patients
Surgery
of Prolactin
Effect Rates of Treatment
;:;
Transsphenoidai
Reference(s)
TABLE I
3(100)’
0
100 rig/ml
5 20(45)’ 17(30)’
100(33)*
50(24) 9
Recurrence (percent) Serum Roiactin
below
TWllOf Mass
Levels
Pituitaty Functkn
12 <3
1 l/2 <3 <3
l-915.0 l/2-12/5.0-7.5 3-5812.5-20.0 3-10/2.5-20.0 l-5517.5-50.0
15 <3 60(24) 36 6
Fobw-Up l-v
Reference(s)
II
Radiation
1211
;:i;
tW
[281
;:y
[291
Transaphanoidal
;:i;
;:i;
t::;
Surgery
46 44
18 28
90 0 0 0 23 29 39
Radiation
33 0 0 0
0 11
71 80 50
38 47
31 50 55
2W
wlth
8 33 40 44 39
0
43
17 25 100 0
lO(29)’
63 50 80 71
60 50 52(124)
71
WrItarT Fuastfen
in Women
success (percenl) 8erum prokHn
Adenomas
13 21 67
and Conventional 231 6 1 1
6 4 2 2
7 9
88-100 80 100
75 75(4)
Turner Mass
of Prolactin
l
Prolactln
surgery.
6(13)
23
39
3(29)’
14
0 10(32) 13(300)’
0
(per-w mw FUltctfOn
Complkatkn
Serum
For definitions of individual effect rates, see Definitions of Effects of Treatment. Parentheses indicate number of patients when different from the entire series. Not subdivided with respect to serum prolactin level. t Serum prolactin level above 200 nglml or “macroprolactinomas” treated with transsphenoidal
Appendix+
Combined
Conventional
Heavy
57 6
52 45 42 181
21
Number ot Patients
of Treatment
;zi; [27l Ion Radiation
Rates
198
Treatment
[GM]
Surgery
Effect
1::;
Bromocriptlna
;:;I [41
Transsphenoldal [51
TABLE
above
TUllIOf Mass
3(100)’
75(4) 1 OO(3)
Levels
(percent)
rig/ml
20(45)’ 36111)
29
95 lOO(8) 1OO(3)
1 O(29) 0 80(5)
Ret&In
Recunence
100
Pih-Y FlMUZtrOn
<3 <3 1 l/2
<3 12
3-5813.5-20.0 617.5-15.0 4517.5-15.0 3-2217.5-30.0 l-16/5.0-20.0
18 3 38 <3 60
FOfbW-up m@wl bomoaip#ne (ns)
TREATMENT
OF PROLACTIN
ADENOMAS-WOLLESEN
and BENDSEN
dicate lack of sensitive means of detecting size changes in small adenomas. Results of preoperative dynamic tests of pituitary reserves in patients with prolactin adenomas were reported by 20 of the 34 authors referenced in Tables I to IV. Blunted prolactin responses to thyrotropin-releasing hormone were observed in 249 of 256 patients tested (97 percent), blunted prolactin responses to chlorpromazine in 167 of 169 (99 percent), blunted prolactin responses to hypoglycemia in 90 of 125 (72 percept), and blunted prolactin responses to Ldopa in 26 of 44 (59 percent). Luteinizing hormone responses to luteinizing hormone-releasing hormone were increased in 46 of 20 1 patients tested (23 percent). Growth hormone responses to hypoglycemia were subnormal in 111 of 297 patients tested (37 percent). ACTH responses to hypoglycemia were subnormal in 18 of 179 patients (10 percent). Thyrotropin responses to thyrotropin-releasing hormone were subnormal in 16 of 158 patients (10 percent). Luteinizing hormone levels were subnormal in 91 of 201 patients tested. COMPARISON OF EFFECTS TREATMENT MODALITIES
5: 0dg
118
January 1985
The American Journal of Medicine
OF DIFFERENT
The present calculations of median effect rates are biased by differences in selection criteria and in diagnostic, therapeutic, and follow-up procedures. Statistical comparisons between these effect rates, therefore, would be misleading. The median effect rates of transsphenoidal surgery and bromocriptine treatment differed in four important respects: (1) transsphenoidal surgery was superior to bromocriptine with respect to recurrence, regardless of pretreatment serum prolactin concentrations in both women and men: (2) bromocriptine was superior to transsphenoidal surgery with respect to complications in all four subgroups of patients; (3) bromocriptine was superior to transsphenoidal surgery in normalizing serum prolactin levels above 100 rig/ml in both women and men; (4) bromocriptine was superior to transsphenoidal surgery with respect to normalization of impaired pituitary function in all four subgroups of patients. This means that transsphenoidal surgery is preferable to bromocriptine for long-lasting normalization of serum prolactin levels and control of tumor growth. Bromocriptine is ideal for temporary normalization of serum prolactin levels and control of tumor growth, e.g., during temporary normalization of fertility. Recurrence rates of 50 to 80 percent five to 10 years after transsphenoidal surgery demonstrate that the effects of transsphenoidal surgery are not permanent [38]. In some patients who have previously undergone surgery but who have recurrent adenomas with serum
Volume 78
[751
1 15 7 1
idal Surgery and Conventional
1
31
low) 62-100 100
3W) 7
Tumu Mass
l
33(3)
0
83 50(4)
17 32(19)’ 3
0
Pituitary FlMCtkll
60
WV
0
0 0 25
17
complkatkn (percw PitUlt~ FUllCtkll
in Men with Serum Prolactin
of Effects of Treatment. from the entire series.
0 0 77(G) 0
0
0
0
50 83 0
57 44
17 28 18
17
!iwcess (percent) serum Prolactin
Adenomas
Radiation
of Prolactin
For definitions of individual effect rates, see Definitions Parentheses indicate number of patients when different Not subdivided with respect to serum prolactin level.
[18j
[=I
;::j CotnbfnedTranqMno
;:l
Convantional Radiation
2
68 6
# I371
Heavy Ion Radiation
16 14
Treatment
12 36 11
;::j [ii;
Sromocrlptina t::;
30
Surgery
Number of Patknts
Effect Rates of Treatment
[231
Transsphanoldal
Reference(s)
TABLE IV
Levels
Tumor Mass
above
Prdactln
Recurrence
100 rig/ml (percent) PilUil~
Functkn
12
4-3312.8-40.0 3-5812.5-20.0 4-2017.5-12.5 3-l 1120.0 6-1217.5
36 12 12
3
ha)
~om=wne
Folks-Up i-11
TREATMENT
OF PROLACTIN
ADENOMAS-WOLLESEN
and SENDSEN
prolactin levels above 100 rig/ml, bromocriptine is preferable because of increased complication rates in second surgical procedures. The success rate of heavy particle radiation with respect to normalization of serum prolactin levels below 100 rig/ml was as high as that of transsphenoidal surgery and bromocriptine in both women and men. In patients with serum prolactin levels above 100 rig/ml, effect rates were low in both sexes. The complication rate of heavy particle radiation was low, but may increase with longer follow-up periods. Low recurrence rates, which characterize heavy particle radiation in the treatment of other types of pituitary adenomas [ 151, have not yet been documented for prolactin adenomas. This means that heavy particle radiation in time may prove superior to any known treatment modality for prolactin adenomas with serum prolactin levels below 100 rig/ml in both sexes. At present, application of heavy particle radiation is limited by availability of cyclotrons and expertise, especially outside the United States. The success rate of conventional radiation with respect to normalization of serum prolactin levels was the lowest of any treatment modality in all four groups of patients. However, success rates as well as recurrence rates may improve for several years following radiation treatment [ 181. Follow-up periods are presently too short to reveal ultimate effects. The number of patients treated exclusively with conventional radiation for prolactin adenomas was small, but two larger, still unpublished, series exist (Sheline, International Symposium on Pituitary Tumors, Boston, June 4 to 7, 1983). Published experience does not yet justify the use of conventional radiation alone in the treatment of prolactin adenomas for other than investigational purposes. The effect rates of combined transsphenokfal surgery and conventional radiation were heavily biased by the reservation of this treatment for difficult cases and were no better than the effect rates of either treatment alone. With longer follow-up periods of less biased material, effect rates of combined treatments may rise above those of either treatment. Results of combined transsphenoidal surgery and bromocriptine (Hardy, International Symposium on Pituitary Tumors, Boston, June 4 to 7, 1983) and of radiation and bromocriptine [39] are preliminary.
lamic mechanisms [40], i.e., chlorpromazine [8,20,27,40,42], carbidopah-dopa [43,44,46], nomifensine [43,45], and hypoglycemia [8,33,40,42] tests, also showed blunted prolactin responses (the chlorpromazine test in 99 percent of cases). Dynamic tests acting directly on the pituitary distinguish significantly between hyperprolactinemias due to prolactin adenomas and hyperprolactinemias due to hypothalamic tumors [43,46]. Hypothalamic tumors are rare. The tests do not distinguish between prolactin adenomas and other causes of hyperprolactinemia [43]. Dynamic tests are highly sensitive for prolactin adenomas, but are nonspecific and therefore add little to the diagnostic information obtained by measurement of basal serum prolactin alone. Following successful removal of prolactin a&non%%, serum prolactin levels return to normal in a matter of hours [4] or may become subnormal [41]. However, normalization of results of dynamic tests acting via pituitary receptors i.e., thyrotropin-releasing hormone [ 19,20,32,40,41], metoclopramide [ 19,411, and Ldopa [44], may lag behind for several months and may not occur until one year after transsphenoidal surgery [ 12,19,42]. It is not certain whether abnormal dynamic test results for more than one year after treatment might indicate subsequent recurrence [38]. Normalization of results of dynamic tests acting via hypothalamic mechanisms occurs rarely within several years after transsphenoidal surgery [ 19,20,27,38-421, with the exception of the carbidopa/Ldopa test [44]. Responses of other pituitary hormones to dynamic tests were attenuated in patients with prolactin adenomas (luteinizing hormone in 45 percent, growth hormone in 37 percent, ACTH in 10 percent, and thyrotropin in 10 percent of cases tested). In addition to local pressure by tumor mass on normal pituitary cells, a general endocrine effect may be responsible for the altered pituitary functions. Blockade of pituitary dopamine receptors led to an exaggerated thyrotropin release [42], and luteinizing hormone responses to luteinizing hormone-releasing hormone were often exaggerated (23 percent of cases tested), particularly in patients with small adenomas [ 12,321. Both effects might result from an increased secretion of dopamine from the median eminence [41,45] in response to the hyperprolactinemia [47,48].
DYNAMIC
CONCLUSIONS
TESTS
OF PITUITARY
FUNCTIONS
Dynamic tests acting on prolactin secretion via pituitary receptors [40], i.e., thyrotropin-releasing hormone [7,8,12,20,23,30,32-34,37,40-431, L-dopa [8,23,28,44], metoclopramide [41,42], domperidone [45], and sulpiride [43] tests, all showed blunted prolactin responses before treatment in patients with prolactin adenomas (the thyrotropin-releasing hormone test in 97 percent of cases). Tests acting via hypotha120
January
1995
The American
Journal
of Mediclne
Volume
The immediate aims of therapy in patients with small prolactin-secreting adenomas are normalization of levels of serum prolactin and gonadotropins and arrest of tumor growth. In patients with large adenomas, further aims are normalization of additional impairment of pituii functions and reduction of tuner size. The long range aims of therapy for all patients wtth prolactir+ secreting adenomas are minimal recurrence rates. 79
TREATMENT
OF PROLACTIN
ADENOMAS-WOLLESEN
and BENDSEN
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1985
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of Medicine
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46.
78
Molitch ME, Goodman RH. Post KD, et al: Surgical cure of prolactinoma reverses abnormal prolactin response to carbidopa/Ldopa. J Clin Endocrinol Metab 1962; 55: 1116-1123. Scanlon MF, Rodriguez-Amao MD, McGregor AM, et al: A new approach to the identification of prolactin-secreting microadenomas? Prog Reprod Biol 1960; 6: 222-23 1. Kapcala LP, Molitch ME, Post KD, Biller BJ, Jackson IMD, Reichlln S: Galactorrhea, oligo/amenorrhea, and hyperprolactinemla in patients with craniopharynglornas. J Clln Endocrlnol Metab 1960; 51: 796-601. Grudelsky GA, Porter JC: Release of dopamine from tuberoinfundibular neurons into pituitary stalk blood after prolactln or haloperidol administration. Endocrinology 1960; 106: 526-529. Qulgley ME, Judd SJ, Gilliland GB, et al: Functional studies of dopamine control of prolactin secretion in normal women and women with hyperprolactinemic pituitary mlcroadenomas. J Clin Endocrinol Metab 1960; 50: 994996.
FLEMMING
WOLLESEN,
M.D.
Glostnrp, Denmark BIRGITTE BJERG BENDSEN,
M.D.
Vordingborg. Denmark
From the Department of Internal Medicine, Glostrup University Hospital, Copenhagen School of Medicine, Glostrup, Denmark, and County Hospital. Vordingborg, Denmark. This work was supported by an institutional grant from the University of Copenhagen, Denmark. Requests for reprints should be addressed to Dr. Flemming Wollesen, Department of Internal Medicine, Glostrup University Hospital, 2600 Glostrup, Denmark. Manuscript accepted May 2, 1984.
114
January 1985
Results of treatment of 963 patients with prolactin adenomas described in the literature were reviewed. The patient population was strattfled into four subgroups: women and men with serum prolactln levels above and below 100 rig/ml for each of the treatment modalities: transsphenoldal surgery, bromocriptine, heavy ion radiation, conventional radiation, and transsphenoldal surgery plus conventional radiation. The five largest series within each subgroup were included. Success rates and recurrence rates were calculated for: (1) reduction of tumor size, (2) normalizatton of serum prolactin levels, and (3) normalization of other pitultary functions. Compllcation rates were calculated for procedural impairment of other pituitary functions. TransqWno& Isurgerywasfoundtobethemost effective treatment for lasting control, and bromocriptlne for temporary control, of prolactin adenomas. Recurrent adenomas were most effectively treated by transsphenoidal surgery If serum prolactin levels were below 100 rig/ml. tf serum prolactln levels were above 100 rig/ml, bromocriptine was the most effective treatment. Heavy ion radiation, whh success rates comparable to those of transsphenoidal surgery and bromocriptlne, but with lower recurrence rates, may eventually prove the most effective treatment of all. Prolactin-secreting adenomas are currently treatable by surgery, radiation, or medication. The three modalities have different success rates, complication rates, and recurrence rates. The effect rates of all three modalities are closely correlated to the secretory activity and the size of the adenoma [l-4]. At present, no single treatment is superior with respect to all effects. Combinations of different treatments are advantageous to many patients. A prudent alternative to treatment is often observation. Selection of an optimal approach for each individual patient requires updated insight into the effect rates of available alternatives. Many institutions specialize in single modalities of treatment, and selection among these rests with the referring physician through his or her choice of institution, rather than with a specialist. The following is an account of effect rates of different treatment modalities for prolactln adenomas based on reports published in the medical literature. DEFINITIONS
OF EFFECTS
Calculations of effect rates treatment, heavy particle combined transsphenoldal based on series of patients
The American Journal of Medicine
Volume 75
OF TREATMENT
for transsphenoidal surgery, bromocriptine radiation, conventional radiation, and surgery and conventional radiation were described in the literature from the intro-
TREATMENT
duction of serum prolactin assays until September 1983 [ 4-371. Effect rates were expressed as the fraction of patients who had responses to treatment. Responses to treatment were defined as success, complication, and recurrence. Success rates were determined for: (1) reduction of tumor mass, as demonstrated by radiology, perimetry, or surgery, (2) normalization of serum prolactin levels, and (3) normalization of one or more impaired pituitary functions other than prolactin secretion. Normalization of one function was counted as such, regardless of deterioration of any other pituitary function in the same patient. Com@afion rates were determined for procedural impairment of normal pituitary functions, regardless of improvement of any other pituitary function in the same patient. Recurrence rates were determined for the same three parameters as success rates. No data have been published on recurrent impairment of pituitary function, except for prolactin secretion. Increases in serum prolactin levels, which had not been normalized by treatment, were not counted as recurrence. Growth of tumor mass following reduction by treatment was counted as recurrence. Effect rates were calculated separately for four subgroups of patients: women of childbearing age with pretreatment serum prolactin levels below (Table I) and above (Table II) 100 rig/ml (2,000 mlU/ml) and men with serum prolactin levels below (Table Ill) and above (Table IV) 100 rig/ml. Serum prolactin concentration rather than tumor size was used to differentiate between large and small prolactin adenomas, as serum prolactin is more easily and accurately measured than tumor size. The value of 100 rig/ml provided the greatest difference between success rates of any serum prolactin concentration between 50 and 200 rig/ml. Included in the calculation were patients with verified adenoma size before and after treatment and patients treated in series. Excluded were patients with functional hyperprolactinemia, postmenopausal women, and patients with adenomas known to secrete more than one hormone. All series published were reviewed. Results from the five largest series in each of the four subgroups were included. REPORTED
EFFECTS
OF TREATMENT
A total of 1,939 patients treated specifically for prolactin adenomas with transsphenoidal surgery, bromocriptine, or radiation were reviewed. Of these 1,939 patients, 963 patients fulfilled the inclusion criteria. Excluded were 23 series comprising 840 women and 13 men treated
January
OF PROLACTIN
ADENOMAS-WOLLESEN
and BENDSEN
with transsphenoidal surgery. (The five largest series of these are presented in the Appendix section in Tables I and II.) Excluded were eight series of 43 women and five men treated with bromocriptine. Finally, 28 publications of 75 individual cases of adenoma size reduction during bromocriptine treatment were excluded, because they were not treated in series. Of 963 patients included, 298 women of childbearing age had pretreatment serum prolactin levels below 100 rig/ml and 448 women had pretreatment serum prolactin levels above 100 rig/ml; 34 men had pretreatment serum prolactin levels below 100 rig/ml and 183 men had pretreatment serum prolactin levels above 100 rig/ml. Transsphenoidal surgery was performed in 642 patients (67 percent): 182 women with serum prolactin levels below 100 rig/ml, 341 women with serum prolactin levels above 100 rig/ml, 18 men with serum prolactin levels below 100 rig/ml, and 101 men with serum prolactin levels above 100 @ml. Bromocriptine treatment was reported in 193 patients (20 percent): 88 women with serum prolactin levels below 100 rig/ml, 45 women with serum prolactin levels above 100 ngjml, 10 men with serum prolactin levels below 100 rig/ml, and 50 men with serum prolactin levels above 100 rig/ml. The remaining 128 patients (13 percent) were treated with radiation. Median success rates for normalization of serum prolactin levels by transsphenoidal surgery and bromocriptine, respectively, were: women with serum prolactin levels below 100 rig/ml: 83 and 95 percent; women with serum prolactin levels above 100 rig/ml: 31 and 50 percent; men with serum prolactin levels below 100 rig/ml: 100 and 100 percent: men with serum prolactin levels above 100 rig/ml: 17 and 50 percent. Median success rates for normalization of one or more other pituitary functions by transsphenoidal surgery and bromocriptine, respectively, were: women with serum prolactin levels below 100 rig/ml: 82 and 80 percent: women with serum prolactin levels above 100 rig/ml: 55 and 67 percent; men with serum prolactin levels below 100 rig/ml: 40 and 100 percent; men with serum prolactin levels above 100 rig/ml: 25 and 67 percent. Median success rates for reduction of adenoma size by transsphenoidal surgery and bromocriptine treatment, respectively, were: women with serum prolactin levels below 100 rig/ml: 100 and 0 percent; women with serum prolactin levels above 100 rig/ml: 100 and 80 percent: men with serum prolactin levels below 100 rig/ml: 100 and 0 percent; men with serum prolactin levels above 100 mg/ml: 100 and 62 percent. Success rates of 100 percent for transsphenoidal surgery are estimates. Success rates of 0 percent in-
1995
The American
Journal
of Medicine
Volume
78
115
Surgery
0 0
22 15 22 14
;::; t::;
Radiation
83 78 86
79 72 21
[221
;::;
74 54
35 27
100O(l)
0
t:;;
Radiation
33 50
21
1 and Conventional
43
86 40
95 80 100 95
80
[::I
Transsphenoidai
1181
t:;;
;:i;
107
0
15
Treatment
[91
63 90 93
73 62(13)
-(per-w Serum Pfolactin
Adenomas
86 78 78 85 76
0 0
100 67 0
lO(29)’
100 59
73 84 82 79
95
Pituitary Function
in Women
l
Prolactin
surgery.
8 0 21
3(29)’
0 lO(52)’ 13(300)’ 0 21
Compikatii (P-w PM=Y FlUlCtkll
with Serum
For definitions of individual effect rates, see Definitions of Effects of Treatment. Parentheses indicate number of patients when different from the entire series. Not subdivided with respect to serum proiactin level. f Serum pro&tin level below 200 rig/ml or “microproiactinomas” treated with transsphenoidai
Appendixt
Combined
94 39 14
t?’
181
20 15
ion Radiation
Conventional
Heavy
Bromocrtptine
nJmor Mass
Number of Patients
Surgery
of Prolactin
Effect Rates of Treatment
;:;
Transsphenoidai
Reference(s)
TABLE I
3(100)’
0
100 rig/ml
5 20(45)’ 17(30)’
100(33)*
50(24) 9
Recurrence (percent) Serum Roiactin
below
TWllOf Mass
Levels
Pituitaty Functkn
12 <3
1 l/2 <3 <3
l-915.0 l/2-12/5.0-7.5 3-5812.5-20.0 3-10/2.5-20.0 l-5517.5-50.0
15 <3 60(24) 36 6
Fobw-Up l-v
Reference(s)
II
Radiation
1211
;:i;
tW
[281
;:y
[291
Transaphanoidal
;:i;
;:i;
t::;
Surgery
46 44
18 28
90 0 0 0 23 29 39
Radiation
33 0 0 0
0 11
71 80 50
38 47
31 50 55
2W
wlth
8 33 40 44 39
0
43
17 25 100 0
lO(29)’
63 50 80 71
60 50 52(124)
71
WrItarT Fuastfen
in Women
success (percenl) 8erum prokHn
Adenomas
13 21 67
and Conventional 231 6 1 1
6 4 2 2
7 9
88-100 80 100
75 75(4)
Turner Mass
of Prolactin
l
Prolactln
surgery.
6(13)
23
39
3(29)’
14
0 10(32) 13(300)’
0
(per-w mw FUltctfOn
Complkatkn
Serum
For definitions of individual effect rates, see Definitions of Effects of Treatment. Parentheses indicate number of patients when different from the entire series. Not subdivided with respect to serum prolactin level. t Serum prolactin level above 200 nglml or “macroprolactinomas” treated with transsphenoidal
Appendix+
Combined
Conventional
Heavy
57 6
52 45 42 181
21
Number ot Patients
of Treatment
;zi; [27l Ion Radiation
Rates
198
Treatment
[GM]
Surgery
Effect
1::;
Bromocriptlna
;:;I [41
Transsphenoldal [51
TABLE
above
TUllIOf Mass
3(100)’
75(4) 1 OO(3)
Levels
(percent)
rig/ml
20(45)’ 36111)
29
95 lOO(8) 1OO(3)
1 O(29) 0 80(5)
Ret&In
Recunence
100
Pih-Y FlMUZtrOn
<3 <3 1 l/2
<3 12
3-5813.5-20.0 617.5-15.0 4517.5-15.0 3-2217.5-30.0 l-16/5.0-20.0
18 3 38 <3 60
FOfbW-up m@wl bomoaip#ne (ns)
TREATMENT
OF PROLACTIN
ADENOMAS-WOLLESEN
and BENDSEN
dicate lack of sensitive means of detecting size changes in small adenomas. Results of preoperative dynamic tests of pituitary reserves in patients with prolactin adenomas were reported by 20 of the 34 authors referenced in Tables I to IV. Blunted prolactin responses to thyrotropin-releasing hormone were observed in 249 of 256 patients tested (97 percent), blunted prolactin responses to chlorpromazine in 167 of 169 (99 percent), blunted prolactin responses to hypoglycemia in 90 of 125 (72 percept), and blunted prolactin responses to Ldopa in 26 of 44 (59 percent). Luteinizing hormone responses to luteinizing hormone-releasing hormone were increased in 46 of 20 1 patients tested (23 percent). Growth hormone responses to hypoglycemia were subnormal in 111 of 297 patients tested (37 percent). ACTH responses to hypoglycemia were subnormal in 18 of 179 patients (10 percent). Thyrotropin responses to thyrotropin-releasing hormone were subnormal in 16 of 158 patients (10 percent). Luteinizing hormone levels were subnormal in 91 of 201 patients tested. COMPARISON OF EFFECTS TREATMENT MODALITIES
5: 0dg
118
January 1985
The American Journal of Medicine
OF DIFFERENT
The present calculations of median effect rates are biased by differences in selection criteria and in diagnostic, therapeutic, and follow-up procedures. Statistical comparisons between these effect rates, therefore, would be misleading. The median effect rates of transsphenoidal surgery and bromocriptine treatment differed in four important respects: (1) transsphenoidal surgery was superior to bromocriptine with respect to recurrence, regardless of pretreatment serum prolactin concentrations in both women and men: (2) bromocriptine was superior to transsphenoidal surgery with respect to complications in all four subgroups of patients; (3) bromocriptine was superior to transsphenoidal surgery in normalizing serum prolactin levels above 100 rig/ml in both women and men; (4) bromocriptine was superior to transsphenoidal surgery with respect to normalization of impaired pituitary function in all four subgroups of patients. This means that transsphenoidal surgery is preferable to bromocriptine for long-lasting normalization of serum prolactin levels and control of tumor growth. Bromocriptine is ideal for temporary normalization of serum prolactin levels and control of tumor growth, e.g., during temporary normalization of fertility. Recurrence rates of 50 to 80 percent five to 10 years after transsphenoidal surgery demonstrate that the effects of transsphenoidal surgery are not permanent [38]. In some patients who have previously undergone surgery but who have recurrent adenomas with serum
Volume 78
[751
1 15 7 1
idal Surgery and Conventional
1
31
low) 62-100 100
3W) 7
Tumu Mass
l
33(3)
0
83 50(4)
17 32(19)’ 3
0
Pituitary FlMCtkll
60
WV
0
0 0 25
17
complkatkn (percw PitUlt~ FUllCtkll
in Men with Serum Prolactin
of Effects of Treatment. from the entire series.
0 0 77(G) 0
0
0
0
50 83 0
57 44
17 28 18
17
!iwcess (percent) serum Prolactin
Adenomas
Radiation
of Prolactin
For definitions of individual effect rates, see Definitions Parentheses indicate number of patients when different Not subdivided with respect to serum prolactin level.
[18j
[=I
;::j CotnbfnedTranqMno
;:l
Convantional Radiation
2
68 6
# I371
Heavy Ion Radiation
16 14
Treatment
12 36 11
;::j [ii;
Sromocrlptina t::;
30
Surgery
Number of Patknts
Effect Rates of Treatment
[231
Transsphanoldal
Reference(s)
TABLE IV
Levels
Tumor Mass
above
Prdactln
Recurrence
100 rig/ml (percent) PilUil~
Functkn
12
4-3312.8-40.0 3-5812.5-20.0 4-2017.5-12.5 3-l 1120.0 6-1217.5
36 12 12
3
ha)
~om=wne
Folks-Up i-11
TREATMENT
OF PROLACTIN
ADENOMAS-WOLLESEN
and SENDSEN
prolactin levels above 100 rig/ml, bromocriptine is preferable because of increased complication rates in second surgical procedures. The success rate of heavy particle radiation with respect to normalization of serum prolactin levels below 100 rig/ml was as high as that of transsphenoidal surgery and bromocriptine in both women and men. In patients with serum prolactin levels above 100 rig/ml, effect rates were low in both sexes. The complication rate of heavy particle radiation was low, but may increase with longer follow-up periods. Low recurrence rates, which characterize heavy particle radiation in the treatment of other types of pituitary adenomas [ 151, have not yet been documented for prolactin adenomas. This means that heavy particle radiation in time may prove superior to any known treatment modality for prolactin adenomas with serum prolactin levels below 100 rig/ml in both sexes. At present, application of heavy particle radiation is limited by availability of cyclotrons and expertise, especially outside the United States. The success rate of conventional radiation with respect to normalization of serum prolactin levels was the lowest of any treatment modality in all four groups of patients. However, success rates as well as recurrence rates may improve for several years following radiation treatment [ 181. Follow-up periods are presently too short to reveal ultimate effects. The number of patients treated exclusively with conventional radiation for prolactin adenomas was small, but two larger, still unpublished, series exist (Sheline, International Symposium on Pituitary Tumors, Boston, June 4 to 7, 1983). Published experience does not yet justify the use of conventional radiation alone in the treatment of prolactin adenomas for other than investigational purposes. The effect rates of combined transsphenokfal surgery and conventional radiation were heavily biased by the reservation of this treatment for difficult cases and were no better than the effect rates of either treatment alone. With longer follow-up periods of less biased material, effect rates of combined treatments may rise above those of either treatment. Results of combined transsphenoidal surgery and bromocriptine (Hardy, International Symposium on Pituitary Tumors, Boston, June 4 to 7, 1983) and of radiation and bromocriptine [39] are preliminary.
lamic mechanisms [40], i.e., chlorpromazine [8,20,27,40,42], carbidopah-dopa [43,44,46], nomifensine [43,45], and hypoglycemia [8,33,40,42] tests, also showed blunted prolactin responses (the chlorpromazine test in 99 percent of cases). Dynamic tests acting directly on the pituitary distinguish significantly between hyperprolactinemias due to prolactin adenomas and hyperprolactinemias due to hypothalamic tumors [43,46]. Hypothalamic tumors are rare. The tests do not distinguish between prolactin adenomas and other causes of hyperprolactinemia [43]. Dynamic tests are highly sensitive for prolactin adenomas, but are nonspecific and therefore add little to the diagnostic information obtained by measurement of basal serum prolactin alone. Following successful removal of prolactin a&non%%, serum prolactin levels return to normal in a matter of hours [4] or may become subnormal [41]. However, normalization of results of dynamic tests acting via pituitary receptors i.e., thyrotropin-releasing hormone [ 19,20,32,40,41], metoclopramide [ 19,411, and Ldopa [44], may lag behind for several months and may not occur until one year after transsphenoidal surgery [ 12,19,42]. It is not certain whether abnormal dynamic test results for more than one year after treatment might indicate subsequent recurrence [38]. Normalization of results of dynamic tests acting via hypothalamic mechanisms occurs rarely within several years after transsphenoidal surgery [ 19,20,27,38-421, with the exception of the carbidopa/Ldopa test [44]. Responses of other pituitary hormones to dynamic tests were attenuated in patients with prolactin adenomas (luteinizing hormone in 45 percent, growth hormone in 37 percent, ACTH in 10 percent, and thyrotropin in 10 percent of cases tested). In addition to local pressure by tumor mass on normal pituitary cells, a general endocrine effect may be responsible for the altered pituitary functions. Blockade of pituitary dopamine receptors led to an exaggerated thyrotropin release [42], and luteinizing hormone responses to luteinizing hormone-releasing hormone were often exaggerated (23 percent of cases tested), particularly in patients with small adenomas [ 12,321. Both effects might result from an increased secretion of dopamine from the median eminence [41,45] in response to the hyperprolactinemia [47,48].
DYNAMIC
CONCLUSIONS
TESTS
OF PITUITARY
FUNCTIONS
Dynamic tests acting on prolactin secretion via pituitary receptors [40], i.e., thyrotropin-releasing hormone [7,8,12,20,23,30,32-34,37,40-431, L-dopa [8,23,28,44], metoclopramide [41,42], domperidone [45], and sulpiride [43] tests, all showed blunted prolactin responses before treatment in patients with prolactin adenomas (the thyrotropin-releasing hormone test in 97 percent of cases). Tests acting via hypotha120
January
1995
The American
Journal
of Mediclne
Volume
The immediate aims of therapy in patients with small prolactin-secreting adenomas are normalization of levels of serum prolactin and gonadotropins and arrest of tumor growth. In patients with large adenomas, further aims are normalization of additional impairment of pituii functions and reduction of tuner size. The long range aims of therapy for all patients wtth prolactir+ secreting adenomas are minimal recurrence rates. 79
TREATMENT
OF PROLACTIN
ADENOMAS-WOLLESEN
and BENDSEN
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Journal
of Medlclne
Volume
78
121
TREATMENT
40.
41.
42.
43.
122
OF PROLACTIN
ADENOMAS-WCLLESEN
and BENDSEN
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1985
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47.
46.
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