ORIGINAL ARTICLE

Macroprolactinomas in Children and Adolescents:

Factors Associated With the Response to Treatment in
77 Patients

Sylvie Salenave, Deborah Ancelle, Thibaut Bahougne, Gérald Raverot,

Peter Kamenicky´, Jérôme Bouligand, Anne Guiochon-Mantel, Agnès Linglart,

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Pierre-François Souchon, Marc Nicolino, Jacques Young, Françoise Borson-Chazot,
Brigitte Delemer, and Philippe Chanson*
Background: Pituitary adenomas are rare in children and adolescents. The response of macropro-
lactinomas to dopamine agonists (DA) in this age group has been less extensively studied than in
adults.

Objective: We retrospectively analyzed data on a large cohort of young patients with

macroprolactinomas.

Patients and Methods: Patients aged younger than 20 years at macroprolactinoma diagnosis and seen
in three tertiary referral centers between 1983 and 2013 were studied by analyzing their clinical and
genetic (AIP and MEN1) characteristics. Hormonal and tumoral responses to DA were analyzed, and the
patients’ status at their last visit, after a mean (⫾SD) follow-up of 8.2 ⫾ 5.8 years, was assessed.

Results: The cohort comprised 77 patients (26 males, 51 females). Mean age at diagnosis was 16.1 ⫾
2.5 years (range, 4.5–20 y). In both sexes, the most frequent revealing symptom was a pubertal
disorder (49%), followed by visual problems (24%) and growth retardation (24%). Basal prolactin
(PRL) levels and maximal tumor diameter were significantly higher in boys than in girls (7168 ng/mL,
202– 40 168 vs 1433 ng/mL, 115–20 000, P ⫽ .002; and 33 ⫾ 14 mm, 15– 64 vs 19 ⫾ 9 mm; 10 –50, P ⬍
.001, respectively). PRL levels normalized in 74% of the patients treated with DA. A mutation of AIP
or MEN1 was found in 14% of the patients. Factors associated with resistance to DA were young
age, higher PRL levels, larger volume, and the presence of a MEN1 (but not an AIP) mutation.

Conclusion: Macroprolactinomas are rare below the age of 20 years, mainly occurring in girls and
during adolescence. Like adults, young patients are very sensitive to DA, which should therefore
be considered the first-line treatment. DA resistance is associated with a higher PRL level and larger
tumor size, both parameters being closely linked together. About 14% of these young patients
have an AIP or MEN1 mutation, this latter being an independent predictor of DA resistance. (J Clin
Endocrinol Metab 100: 1177–1186, 2015)

he prevalence of pituitary adenomas is much lower in
T childhood and adolescence than in adulthood (1). As
in adults, most pituitary adenomas are prolactinomas,
representing 50% of all pituitary adenomas in this age
group (2–5). There are few studies of prolactinomas in
children and adolescents (6 –13), and data on the effects of
dopamine agonists (DA) and long-term patient outcome
are scarce (8, 11).
The AIP gene has been implicated in pituitary tumor-
igenesis in families with pituitary adenomas, particularly
those with somatotropinomas (14, 15). AIP mutations
have also been detected in patients with apparently spo-
radic adenomas: we found that 2.2% of 433 patients in
whom an adenoma was diagnosed in adulthood had
AIP mutations; such mutations were more frequent in
children (23%), particularly those with a GH- or mixed

ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2015 by the Endocrine Society
Received September 28, 2014. Accepted December 17, 2014.
First Published Online December 22, 2014
* Author Affiliations are shown at the bottom of the next page.
Abbreviations: DA, dopamine agonist; MEN1, multiple endocrine neoplasia type 1 syn-
drome; PRL, prolactin.

doi: 10.1210/jc.2014-3670 J Clin Endocrinol Metab, March 2015, 100(3):1177–1186 jcem.endojournals.org 1177
1178 Salenave et al Macroprolactinomas in Children and Adolescents J Clin Endocrinol Metab, March 2015, 100(3):1177–1186

GH-prolactin (PRL)-secreting macroadenoma and also,
but more rarely, those with prolactinomas (16, 17). Ap-
parently sporadic pituitary adenomas in young patients
may also be one of the first manifestations of multiple
endocrine neoplasia type 1 syndrome (MEN1) (18).
Here we report clinical, therapeutic and genotypic data
on a cohort of 77 children and adolescents with macrop-
rolactinomas, collected over the past 30 years.
quinagolide, or 3.5 mg/wk cabergoline taken for at least 3
months (19 –22).
Serial pituitary images of all the patients were reviewed by a
neuroradiologist and an endocrinologist. Tumor resistance was
defined as a failure to normalize PRL levels and to reduce tumor
volume by at least 50% (21, 22) after 6 months of DA therapy.
Genetic analysis
Information on genetic or familial diagnoses was systemati-
cally sought from the patients’ files (MEN1, Carney complex,
families with pituitary adenomas, or McCune-Albright syn-
drome) and more than two-thirds of the patients had a genetic

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Patients and Methods
Clinical and biochemical data
The cohort comprised 77 patients in whom a macroprolacti-
noma was diagnosed before age 20 years in one of three French
teaching hospitals (Hôpital Bicêtre in Hôpitaux Universitaires
Paris-Sud, Centre Hospitalier Universitaire de Reims, and Centre
Hospitalier Universitaire de Lyon) between 1983 and 2013 and
who were followed up for an average (⫾SD) of 8.2 ⫾ 5.8 years.
A macroprolactinoma was diagnosed when a macroadenoma
(⬎10 mm maximal diameter on magnetic resonance imaging)
was associated with an increased PRL level (⬎150 ␮g/L); the PRL
level was below 150 ␮g/L in five patients, but the diagnosis was
finally retained because the macroadenoma, which was cystic
(patients 24, 32, and 54) or necrotic (patient 11), shrank during
DA therapy (patients 11, 24, and 32) or because its lactotroph
nature was confirmed by immunohistochemical analysis after
surgery (patients 21 and 54).
The following clinical data were extracted from the patients’
records: sex, age and body mass index, menstrual history (pri-
mary or secondary amenorrhea), presence of galactorrhea or
gynecomastia in boys, age at puberty and pubertal delay (Tanner
stage), growth retardation (⬎⫺2SD), and the presence of a mass
effect with headache and/or visual problems at diagnosis.
PRL levels and other pituitary functions were determined at
diagnosis and regularly during follow-up, using commercial as-
says and procedures proper to each center. Corticotropic defi-
ciency was defined by a 8:00 AM plasma cortisol level of less than
4 ␮g per 100 mL and normal or low plasma ACTH level or an
abnormal response (plasma cortisol ⬍20 ␮g per 100 mL) to
ACTH-stimulation or to insulin-tolerance tests; GH deficiency
was defined by a serum IGF-1 less than ⫺2 SD or abnormal
response to GH stimulation tests.
Magnetic resonance imaging signs of tumor invasion in-
cluded evidence of bone destruction and/or tumor extension
within the sphenoid and/or the cavernous sinuses and/or brain.
Hormonal resistance to DA was defined by the absence of
control at DA doses up to 15 mg/d bromocriptine, 600 ␮g/d
analysis: the entire AIP coding region (exons 1– 6) and intron-
exon junctions were amplified and sequenced as reported (17).
All these patients were also screened for large deletions or du-
plication of the AIP and MEN1 genes by multiplex ligation-
dependent probe amplification (17, 23).
All the patients gave their informed consent for the study.
Statistical analysis
Statistical analyses were carried out using SPSS statistical soft-
ware, version 13.0 (SPSS Inc). Medians were compared using the
nonparametric Kruskal-Wallis test and frequencies using the ␹2
test. The correlation study was performed by the linear regres-
sion analysis calculating the Pearson’s coefficient. The multiple
regression analysis was performed among the variables corre-
lated at the linear correlation. P values are given for these anal-
yses. The significance was set at 5%.
Results
Clinical, biochemical, and imaging characteristics at
diagnosis (Table 1)
Age at diagnosis
Seventy-seven patients were included in the study (26
males and 51 females). The mean age at diagnosis was
16.1 ⫾ 2.5 years (range 4.5–20 y), and median age was 17
years (Figure 1). Eighteen patients (23%) were younger
than 15 years old at diagnosis; only two patients (both
boys) were diagnosed during childhood (10 y and 4 y).
The mean age at diagnosis did not differ between boys
(15.5 ⫾ 3.2 y; range 4.5–20 y) and girls (16.5 ⫾ 2 y; range
11–20 y) (P ⫽ .12; Figure 1).
Signs and symptoms at diagnosis
In both sexes the most frequent revealing symptom was
a pubertal disorder (49% of cases), followed by visual
problems (24%) and growth retardation (24%).

Service d’Endocrinologie et des Maladies de la Reproduction and Centre de Référence des Maladies Endocriniennes Rares de la Croissance (S.S., T.B., P.K., J.Y., P.C.), and Service de
Génétique Moléculaire, Pharmacogénétique, et Hormonologie (J.B., A.G.-M.), and Service d’Endocrinologie Pédiatrique and Centre de Référence des Maladies Rares du Métabolisme
Phospho-Calcique, (A.L.), Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Le Kremlin-Bicêtre, F-94275, France; Service d’Endocrinologie (D.A., B.D.) and Service de Pédiatrie
(P.-F.S.), Centre Hospitalier Universitaire de Reims, Hôpital Robert Debré, Reims, F-51092, France; Faculté de Médecine (G.R., M.N., F.B.-C.), Université de Lyon, Lyon 1, Lyon-Est, Lyon
F-69372 France; Fédération d’Endocrinologie (G.R., F.B.-C.) and Service d’Endocrinologie Pédiatrique (M.N.), Hôpital Femme-Mère-Enfant, Groupement Hospitalier Est, Hospices Civils
de Lyon, Lyon, F-69003, France; Institut National de la Santé et de la Recherche Médicale Unité 1028 (G.R.), Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5292,
Lyon Neuroscience Research Center, Service de Neurooncology-Neuroinflammation, and INSERM Unité 1052 (F.B.-C.), Unité Mixte de Recherche Centre National de la Recherche
Scientifique Unité 5286, Centre de Recherche en Cancérologie de Lyon, Equipe Tumeurs Endocrines, Lyon, F-69000, France; Unité Mixte de Recherche Scientifique Unité 693 (P.K., J.B.,
A.M., A.L., J.Y., P.C.), Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre F-94276, France; INSERM Unité 986 (A.L.) and INSERM Unité 693 (P.K., J.B., A.M., J.Y.,
P.C.), Le Kremlin-Bicêtre F-94276, France
doi: 10.1210/jc.2014-3670
Weight gain was one reason for seeking medical advice
in 18 cases (23%). At diagnosis, 24 of the 52 patients with
available information (46%) were overweight or obese.
In girls, primary amenorrhea was the leading symptom
in 22 of the 51 cases (43%) and was associated with
growth retardation in six cases (12%); only three girls had
no signs of puberty. Eight of the 22 amenorrheic patients
had galactorrhea. Twenty-seven (53%) patients presented
with secondary amenorrhea, associated with galactorrhea
in 24 cases. One patient had oligomenorrhea and galac-
torrhea and another patient had regular but short men-
strual cycles and galactorrhea. A mass effect with visual
problems was also present at diagnosis in seven female
patients (14%).
In boys, the diagnosis was suggested by pubertal delay
in 16 of the 26 cases (61%); seven boys had no signs of
puberty and 13 had growth retardation. Gynecomastia
and visual problems were found in five and seven cases,
respectively. Isolated visual problems were the presenting
symptom in five patients. Twelve (46%) of the 26 boys had
visual disorders at diagnosis, and the youngest two boys
were blind in one eye (patients 1 and 2). In four other
patients, the main presenting symptom was headaches in
one case, gynecomastia in two cases (associated with
galactorrhea in one case), and isolated diminished libido in
one case; the tumor was discovered fortuitously in one
case.
Eight patients (10%) had panhypopituitarism, nine
(11%) had thyrotropic deficiency, and four (5%) had cor-
ticotropic deficiency.
Prolactin levels
The mean basal PRL level at diagnosis was 3278 ng/mL
(115– 40 168). Basal PRL levels were significantly higher
in boys (7168 ng/mL, 202– 40 168) than in girls (1433
ng/mL, 115–20 000) (P ⫽ .002, Figure 2). Age and PRL
levels were significantly associated (r ⫽ 0.380, P ⫽ .001).
Tumor characteristics
The average maximal diameter of the adenoma was
24 ⫾ 13 mm (10 – 64 mm) (Figure 3). The macroadenoma
was invasive, particularly into the cavernous sinus, in 29
of the 59 patients for whom this information was available
(49%). The adenomas were significantly larger in boys
(33 ⫾ 14 mm; range 15– 64 mm) than in girls (19 ⫾ 9 mm;
range 10 –50 mm) (P ⬍ .001, Figure 3). The size of the
tumor was not related to age at diagnosis.
The adenomas were more frequently invasive in boys
(14 of 20 documented cases, 70%) than in girls (15 of 39,
38%).
jcem.endojournals.org 1179
Genetic analysis (Table 1)
Respectively, 55 and 59 patients were analyzed for AIP
and MEN1 mutations. Five patients (three girls and two
boys) had an AIP mutation (9%), and three patients (two
girls and one boy) (5%) had a MEN1 mutation. Each
patient had a distinct mutation. None of the mutated pa-
tients were consanguineous.
Effect of DA treatment on PRL levels
One patient (patient 21) never received DAs because he
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was operated on immediately because of pituitary apo-
plexy associated with visual disorders. He was cured by
surgery and had no recurrence of the hyperprolactinemia
or the tumor. All the remaining 76 patients received DAs,
either as first-line treatment or after surgery.
Sixty-eight patients received DAs as first-line treat-
ment. Cabergoline was prescribed in 58 cases, either im-
mediately (n ⫽ 49) or after a trial of another DA (n ⫽ 9),
whereas 10 patients received a DA other than cabergoline.
The results of medical treatment could not be as-
sessed in two patients (patients 44 and 63), who dis-
continued treatment very early because of intolerance
or nonadherence.
Nine patients received first-line surgery for visual dis-
orders (n ⫽ 4, patients 16, 45, 47, and 62), personal pref-
erence (n ⫽ 1, patient 65), doubtful diagnosis (n ⫽ 1,
patient 54), or other reasons (n ⫽ 3, patients 13, 49, and
69). These nine patients received DAs after surgery (cab-
ergoline immediately in five cases and after another DA in
four cases) because hyperprolactinemia either recurred
(n ⫽ 2, patients 54 and 65) or persisted (n ⫽ 7).
Overall, PRL levels normalized in 56 of the 76 patients
treated with DA (74%) (Table 1).
Twenty of the 76 patients (26%) were resistant to DAs
as soon as the treatment was initiated: 16 of these patients
received DA as first-line therapy and four after surgery.
Eight of the 16 patients resistant to first-line DAs sub-
sequently underwent surgery (patients 1, 7, 17, 27, 40, 43,
51, and 56). Surgical debulking normalized PRL levels
without the need to resume DA therapy in one case (pa-
tient 27) and after DA resumption in two other cases, at a
low dose in one patient (patient 43) and a high dose (3.5
mg/wk) in the second patient (patient 17).
In two patients who were persistently DA resistant,
PRL finally normalized after radiotherapy (patients 1 and
56), allowing cabergoline discontinuation. Irradiation
failed to control the PRL level in another patient (patient
40). Among the resistant patients, two received replace-
ment therapy for gonadotropic insufficiency (patients 40
and 51), one patient still has moderate hyperprolactinemia
but has regular menstrual cycles (patient 7), and PRL levels
1180 Salenave et al Macroprolactinomas in Children and Adolescents J Clin Endocrinol Metab, March 2015, 100(3):1177–1186

Table 1. Clinical, Biochemical, Neuroradiological, Pharmacological, and Genetic Characteristics of a Cohort of

77 Patients Aged Less Than 20 y With Macroprolactinomas
Patient Age at Signs and Other Pituitary Serum PRL Tumor Maximal
Number Gender Diagnosis, y Symptoms at Diagnosis Hormone Deficiencies Levels, ng/mL Diameter, mm
1 67 M 4.5 VFD, H, PGD TSH, ACTH, GH 36 000 39
2 62 M 10 VFD, H, PGD, GAL ACTH, TSH, GH 2500 40
3 21 F 11 AI, H, PGD None 528 22
4 27 M 13 VFD, PGD, Gy ACTH, TSH, GH 9898 45
5 35 F 13 AI, GAL, WG None 485 14
6 44 M 13 VFD, H TSH, ACTH 6200 40
7 64 F 13 AII None 151 19 (C)
8 3 F 14 AI, GAL None 447 13
9 5 F 14 AI, GAL, H None 885 13

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10 11 F 14 AI, WG TSH, ACTH 761 25
11 16 F 14 AI, GAL, WG None 130 15
12 19 F 14 AII, GAL None 270 27
13 37 F 14 AI, GAL, PGD, H None 2400 ND
14 50 M 14 VFD, H, PD None 930 20
15 52 M 14 Fortuitous None 6659 40
16 55 M 14 H, VFD TSH, ACTH, GH 40 168 64
17 65 M 14 PGD, H GH 2264 25
18 66 F 14 VFD, AI, H, WG None 1340 19
19 18 F 15 AI, PGD None 280 15
20 20 F 15 AI, H, PGD None 20 000 ND
21 28 M 15 VFD, H ACTH, TSH, GH 6, 2a NA
22 33 F 15 AI None 343 19
23 38 F 15 AII, GAL None 769 12
24 40 F 15 AII, GAL, H, WG None 115 16 (C)
25 49 F 15 AII, GAL, H None 448 10
26 53 F 15 VFD, AI, GAL None 5400 32
27 57 M 15 PD None 202 12
28 58 M 15 PGD, H None 641 16
29 69 F 15 GAL None 180 15
30 73 M 15 PGD, H, Gy, GAL TSH 2946 19
31 2 F 16 AII, GAL, WG None 358 17
32 10 F 16 AII None 140 12 (C)
33 15 F 16 AII, GAL, WG None 480 22
34 23 F 16 AII, WG None 300 15
35 41 F 16 AI None 510 14
36 47 F 16 AII, GAL None 238 15
37 51 M 16 VFD, PGD, H, TSH, GH 1320 42
38 60 F 16 VFD, AII, GAL, H TSH 1160 25
39 1 F 17 AI, GAL GH 1993 28
40 4 F 17 AII, GAL TSH 3030 32
41 8 F 17 AII, GAL, H None 598 16
42 12 F 17 AI ACTH 430 22
43 22 F 17 VFD, AII, GAL, WG None ND ND
44 24 M 17 H, WG ACTH, TSH, GH 5300 46
45 25 M 17 VFD, PGD ACTH, TSH, GH 33 000 60
46 26 M 17 PGD, Gy TSH, GH 1865 35
47 30 M 17 VFD None 320 30
48 31 M 17 Gy, WG None 979 27
49 36 F 17 AII, GAL, H None ND 33
50 45 M 17 H, PD TSH 4200 35
51 48 F 17 VFD, AI, H, PGD TSH 11 139 44
52 56 M 17 VFD, Gy, GAL None 276 12
53 70 F 17 AII, GAL, WG None 260 12
54 72 F 17 VFD, H, AI, PGD none 100 20 (C)
55 76 M 17 Gy, GAL None 490 15
56 7 F 18 VFD, AII, GAL ACTH, GH 514 50
57 9 F 18 AII, GAL None 915 17
58 14 F 18 AII, GAL None 380 15
59 29 M 18 PGD None 2020 30
60 42 F 18 AI, GAL, H None 880 11
61 54 M 18 PGD, WG, Gy TSH, ACTH, GH 4800 35
62 63 F 18 AII, GAL, WG None 192 12
63 74 F 18 AI, GAL, H, WG None 397 10
64 75 F 18 AII, GAL None 341 ND
65 6 F 19 AII, GAL None 164 13
66 13 F 19 AII, GAL None 1160 14
67 34 F 19 AII, GAL, WG None 397 ND
68 39 F 19 AII, GAL, H None 3317 27
69 46 F 19 AI None 611 20
70 61 M 19 VFD, H, Gy, PGD TSH, GH 6860 53
(Continued)
doi: 10.1210/jc.2014-3670 jcem.endojournals.org 1181

Table 1. Continued

Cavernous Maximal Dose (CAB, mg/w, Hormonal Shrinkage, AIP MEN1 Follow-Up,
Sinus Invasion DA QUI, ␮g/d, and BRC, mg/d) Sensitivity to DA % Mutation Mutation y
⫹ BRC 25 R ⬍50% Negative Negative 16
⫹ BRC 15 R ⬍50% Positive Negative 14
ND CAB 0.5 S No remnant Negative Negative 3
⫹ CAB 4.5 R ⬎50% Negative Negative 8
0 CAB 0.75 S ⬎50% Négative Negative 1
0 CAB 2.0 S No remnant Negative Negative 7
0 CAB 3.5 R ⬍50% (C) ND ND 7, LTF
0 CAB 1.0 S No remnant Negative Negative 9
0 CAB 1.5 S ⬎50% Negative Negative 10

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0 CAB 0.5 S 90% Positive Negative 3
0 CAB 3.0 S 75% Negative Negative 9
⫹ CAB 1.0 S 75% Negative Negative 12
⫹ CAB 1.0 S ⬎50% Negative Negative 27
ND CAB 1.0 S ⬎50% Negative Negative 7
ND CAB 3.0 S ⬎50% Negative Negative 11
⫹ CAB 7.0 R ⬍50% Negative Negative 2
⫹ CAB 10.5 R ⬍50% Negative Negative 16
0 CAB 3.5 R ⬎50% ND ND 8
0 CAB 0.5 S No remnant Negative Negative 13
ND CAB 7.0 R ⬎50 Negative Negative 3
NA No treatment NA NA No remnant Positive Negative 6
⫹ CAB 2.0 S ⬎50% Negative Negative 3
ND CAB 3.0 S ⬍50% ND ND 6, LTF
0 CAB 1.0 S ⬍50% Negative Negative 4
ND CAB 0.5 S ⬎50% Negative Negative 6
0 CAB 7.0 R ⬍50% Negative Positive 12
0 CAB 9.0 R ⬍50% ND Negative 17, LTF
ND CAB 3.5 S ⬎50% Negative Negative 8, LTF
ND BRC 15.0 S ⬎50% ND ND 8, LTF
0 CAB 1.5 S ⬎50% Negative Negative 5
0 CAB 0.5 S No remnant Negative Negative 3
0 CAB 0.5 S 75% ND ND 6
⫹ BRC 2.5 S 75% ND Negative 4, LTF
0 CAB 0.5 S ⬎50% Negative Negative 1
ND CAB 1.0 S ⬎50% ND ND 15, LTF
ND CAB 0.5 S No remnant ND ND 4, LTF
ND QUI 300 S No remnant ND ND 11, LTF
⫹ CAB 0.5 S ⬎50% ND Negative 4, LTF
⫹ CAB 3.5 R 75% Negative Negative 3
⫹ CAB 3.5 R 0% Negative Negative 5
0 CAB 0.5 S No remnant ND Negative 6, LTF
0 QUI 75 S No remnant Negative Negative 9
0 CAB 4.5 R ⬍50% Negative Negative 3
⫹ CAB 3.0 Noncompliant ⬎50% Negative Negative 12
⫹ CAB 1.5 S 75% Negative Negative 5
⫹ CAB 2.5 S 75% Negative Negative 9
⫹ CAB 8.0 R ⬎50% Negative Positive 15
⫹ CAB 2.5 S ⬍50% Positive Negative 1.5
0 CAB 3.5 R ⬍50% Negative Negative 27
⫹ CAB 3.5 S ⬍50% Negative Negative 13
⫹ CAB 7.0 R ⬎50% Negative Negative 5,5
0 CAB 0.5 S No remnant Negative Negative 18, LTF
0 CAB 0.5 S ⬎50% Negative Negative 6
ND CAB 0.5 S No remnant ND ND 5
ND CAB 1.0 S ⬎50% ND ND 1, LTF
⫹ CAB 4.0 R 0% Negative Positive 4
0 CAB 3.5 R ⬍50% Positive Negative 1, LTF
⫹ CAB 2.0 S ⬎50% ND Negative 13
⫹ CAB 2.0 S ⬎50% Negative Negative 8
ND CAB 1.0 S No remnant ND ND 13, LTF
0 CAB 3.5 R ⬍50% Negative Negative 9
0 CAB 1.0 S ⬎50% Negative Negative 10
⫹ CAB 3.0 Noncompliant ⬍50% ND ND 6
ND QUI 75 S ND ND ND 13, LTF
0 CAB 1.0 S No remnant Negative Negative 9
⫹ CAB 0.5 S 75% Negative Negative 14
⫹ CAB 7.0 R No remnant Negative Negative 11
0 CAB 1.0 S ⬎50% Negative Negative 3
ND CAB 1.0 S ⬎50% ND ND 16, LTF
⫹ CAB 1.0 S ⬎50% Negative Negative 4
(Continued)
1182 Salenave et al Macroprolactinomas in Children and Adolescents J Clin Endocrinol Metab, March 2015, 100(3):1177–1186

Table 1. Continued
Patient Age at Signs and Other Pituitary Serum PRL Tumor Maximal
Number Gender Diagnosis, y Symptoms at Diagnosis Hormone Deficiencies Levels, ng/mL Diameter, mm
71 71 F 19 AII, GAL None 300 11
72 77 F 19 AII, GAL None 400 10
73 17 F 20 O, GAL None 274 15
74 32 M 20 Decreased libido None 1200 24
75 43 M 20 H, PGD GH 3265 24
76 59 F 20 AI, H None 3400 27
77 68 F 20 AI, H, WG None 2150 19

Abbreviations: AI, primary amenorrhea; AII, secondary amenorrhea; BRC, bromocriptine; C, cystic adenoma; CAB, cabergoline; F, female; GAL,
galactorrhea; GY, gynecomastia; H, headache; LTF, lost to follow up after the duration indicated; M, male; NA, not applicable; ND, not

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determined; O, oligomenorrhea; PD, pubertal delay; PGD, pubertal and growth delay; QUI, quinagolide; VFD, visual field defect; WG, weight gain.
a
Patient with apoplexy.

normalized in two patients after increasing the dose of
cabergoline to 7 mg/wk (patients 26 and 67).
Among the four patients who were resistant to DA after
initial surgery, one received replacement therapy for go-
nadotropic insufficiency (patient 16), one patient had PRL
normalization after increasing the dose of cabergoline to
8 mg/wk (patient 47), one patient underwent further sur-
gery and resumed cabergoline postoperatively, leading to
PRL normalization (patient 49), and one patient had PRL
normalization after radiotherapy (patient 2), allowing
cabergoline withdrawal.
At last follow-up, nine patients had panhypopituita-
rism (but two of them had been irradiated), five patients
had both gonadotropic and thyrotropic deficits, five pa-
tients had isolated persistent gonadotropic failure, and
five patients had isolated thyrotropic failure. All four of
the patients with isolated secondary adrenal failure recov-
ered after DA treatment, allowing the discontinuation of
hydrocortisone treatment.
Impact of DA on tumor volume
Fourteen of the 20 patients with hormonal resistance to
DA (70%) also had tumoral DA resistance, whereas only
four (patients 23, 24, 38, and 50; 8%) of the 54 patients
whose PRL normalized on DA had no tumor shrinkage
(patient 24 had a cystic adenoma).
Overall, DA treatment achieved tumor shrinkage in 56
of 74 assessable patients (76%).
Factors associated with hormonal resistance to DA
(Table 2)
Patients with DA-resistant adenomas were younger,
had higher baseline PRL levels, and had larger tumors.
Patients with MEN1 mutations were also more often re-
sistant to DA. The presence of an AIP mutation did not
influence the response to DA (Table 2). In a univariate
analysis, MEN1 mutation (r ⫽ 0.348; P ⫽ .007), PRL
levels (r ⫽ ⫺0.342; P ⫽ .003), and tumoral diameter (r ⫽
⫺0.403; P ⫽ .001) were significantly correlated to DA
resistance. In a multivariate analysis, the correlation be-
tween resistance to DA and the presence of a MEN1 mu-
tation remains highly significant after adjusting for PRL
levels and/or tumoral diameter (P ⬍ .005). After adjust-
ment for the MEN1 mutation, the correlations between
resistance to DA and PRL levels or tumoral diameter re-
main significant (P ⬍ .009). Regression analysis showed

Figure 1. Age at diagnosis in a series of 77 young patients with Figure 2. Individual serum PRL levels at diagnosis in a series of
macroprolactinomas. 77 young patients with macroprolactinomas.
doi: 10.1210/jc.2014-3670 jcem.endojournals.org 1183

Table 1. Continued
Cavernous Maximal Dose (CAB, mg/w, Hormonal Shrinkage, AIP MEN1 Follow-Up,
Sinus Invasion DA QUI, ␮g/d, and BRC, mg/d) Sensitivity to DA % Mutation Mutation y
⫹ QUI 75 S ⬎50% ND ND 4, LTF
0 CAB 1.0 S ⬎50% ND ND 2
0 CAB 0.5 S No remnant Negative ND 8
0 CAB 2.0 S 75% Negative Negative 3
⫹ CAB 2.0 S ⬎50% ND ND 2
ND BRC 15 S ⬍50% Negative Negative 25
⫹ CAB 1.5 S ⬎50% Negative Negative 6

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that PRL levels and tumoral diameter were closely asso-
ciated because significance disappeared when each
variable was withdrawn from the model. By contrast,
the presence of a MEN1 mutation was a significant and
independent predictor of DA resistance (t ⫽ 3.052;
P ⫽ .004).
In eight patients resistant to DA who were operated on
and in whom histological and immunocytochemical data
were available, prolactinoma was invasive in six cases. In
those patients, mitosis were rarely described except in two
cases (patients 16 and 49) (up to four mitosis per field) and
proliferation index, Ki67, positivity was present in greater
than 3% of adenomatous cells (10%, 13%, 5%, 4%, and
3% in patients 40, 16, 56, 51, and 43, respectively); in the
two other patients, there were no mitosis (patients 7 and
17), and Ki67 was 1%–2%. In the patients responsive to
DA who were operated on, only three had available his-
tological and immunocytochemical data: none of the tu-
mors display mitosis and Ki67 was positive in 3% and less
than 5% of cells in patients 65 and 54, respectively.
Figure 3. Maximal macroprolactinoma diameter at diagnosis in a
series of 77 young patients.
Discussion
In this retrospective study of a large cohort of patients aged
younger than 20 years at macroprolactinoma diagnosis,
we found that most patients were adolescent girls in whom
amenorrhea led to diagnosis. The pituitary adenomas had
an average maximal diameter of approximately 20 mm
and were invasive in half the cases. Mass effects were
relatively rare. DA therapy normalized PRL levels in three-
quarters of these young patients. An AIP or MEN1 mu-
tation was found in 14% of cases. Resistance to DA was
associated with baseline PRL level, tumor size (both pa-
rameters being closely linked together), and the presence
of a MEN1 mutation.
Pituitary adenomas are rare in children and adoles-
cents; they are generally lactotrophic and are more fre-
quent in girls than in boys. A compilation of various series
involving 386 patients shows that, in this age group, pro-
lactinomas are mainly observed in girls (79%) and that
macroprolactinomas are more prevalent than micropro-
lactinomas (58% vs 42%) (6 –13). In our experience at
Bicêtre Hospital, of 52 patients (43F/9M), 23 (45%) had
a microprolactinoma (20 females, three males), and 29
(55%) had a macroprolactinoma (23 females, six males)
(S. Salenave, P. Chanson, unpublished results). This high
proportion of macroprolactinomas is clearly very differ-
ent from what is observed in adults (1, 24, 25) in whom
microprolactinomas predominate. As previously reported
(6 –13), most macroprolactinomas in this age group were
diagnosed during adolescence (median 17 y) and only two
patients were younger than 10 years old at diagnosis.
Prolactinomas appear to develop around puberty, a
phase associated with increased sex steroid secretion. It is
conceivable that they develop earlier but are diagnosed
only because of their effect on puberty (eg, amenorrhea).
The impact on gonadotroph function is more likely due to
hyperprolactinemia than to a mass effect on normal pitu-
itary cells because growth perturbations were not as fre-
quent as pubertal disorders (24% vs 49% in our series)
1184 Salenave et al Macroprolactinomas in Children and Adolescents
Table 2. Comparison Between DA-Resistant and DA-Sensitive Children and Adolescents With
Macroprolactinomas.
Mean Mean PRL,
n Males, % age, y ␮g/L
DA-resistant 20 8/25 (32%) 15 ⫾ 1 7835 ⫾ 2835 33 ⫾ 2
adenomas
DA-sensitive 56 12/51 (23%) 16.5 ⫾ 0.8 1858 ⫾ 598 21.5 ⫾ 1.5
adenomas
P value NS .03 .002 .0006
a
The number in each category may be lower due to lack of available data in some patients.
and panhypopituitarism was relatively rare (only eight
patients).
Our data on the pubertal and growth consequences of
macroprolactinomas largely confirm previous reports (6 –
13). Growth impairment was more frequent in older pub-
lications (12, 26 –28), but this may be related to the def-
inition (slowing of the growth rate, or true growth
retardation to ⬍⫺2 SD or less than the third percentile).
GH treatment is rarely necessary (only five of our patients
received GH; data not shown) because DA therapy is gen-
erally sufficient to normalize GH deficiency and to restore
growth (11, 28 –30).
Weight gain represented one reason for seeking medical
advice in 18 of our patients (23%, both sexes), and about
half of our patients were overweight or obese at diagnosis,
as is also reported in a study of similarly aged patients (11)
and also in adults (31, 32). This is clearly a higher prev-
alence than that observed in the French general population
within this age range (14.3% and 3.5% for overweight
and obesity, respectively) according to a survey covering a
similar period (33). The precise mechanisms of this weight
gain remains speculative. It seems to be related to the high
levels of PRL because it is also observed in patients with
microprolactinomas, which have no hypopituitarism or
hypothalamic involvement; moreover, at similar rate of
hypopituitarism or hypothalamic involvement, patients
with macroprolactinomas gained more weight than pa-
tients with nonfunctioning pituitary macroadenomas
(32); this may also be a direct feedback regulatory effect
of hyperprolactinemia on dopaminergic tone (34) or to
the inhibitory effect of prolactin on adiponectin secre-
tion by adipose tissue, which promotes insulin resis-
tance (35).
We found some differences between boys and girls with
macroprolactinomas: in particular, the tumors seemed to
affect puberty or growth more often in boys than in girls
(61% vs 43% and 46% vs 14%, respectively). This cannot
be explained by age at diagnosis, which was similar in the
two genders, but is probably rather related to the size of the
adenoma, which was larger in boys, as it is in male adults
(11, 36); this would also explain the higher prevalence of
J Clin Endocrinol Metab, March 2015, 100(3):1177–1186
Maximal
Diameter of Invasive Patients AIP Patients MEN1
the Adenoma Tumors, %a Mutated, %a Mutated, %a
11/19 (57%) 2/17 (11%) 3/18 (16%)
18/40 (45%) 2/37 (5%) 0/40 (0%)
NS NS .026
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visual consequences in boys. It must be also pointed out
that many of the youngest patients do not complain of
visual disorders, which can delay the diagnosis (6 –13);
this was the case of the two youngest boys in our series,
who had unilateral blindness.
A DA is the first-line treatment of choice for adults with
macroprolactinomas (37). This was also the treatment
chosen for 89% of our patients, only three of whom ini-
tially underwent surgery, for visual problems. The re-
sponse to DA (cabergoline in 87% of cases) was good,
with PRL normalization in more than three-quarters of
cases during first-line treatment and half of the cases when
started after surgery. Overall, PRL levels normalized in
73% of these young patients and tumor shrinkage was
observed in 76% of cases. These results confirm that DA
therapy is as effective at this young age as in adulthood
(6 –13). We also show for the first time that, in this age
range, DA-resistant patients tend to be younger males with
larger adenomas, as in adults (19, 21, 38 – 40). Finally, it
seems that DA-resistant prolactinomas are more often in-
vasive, as in adults (19, 41), and display higher prolifer-
ation index. Because this was a retrospective study, we
have no data on cardiac valve status in most of these 76
DA-treated patients.
In this series of young patients with apparently sporadic
macroprolactinomas, the prevalence of AIP mutations
was relatively low (five patients, 9%) and close to that of
MEN1 mutations (three patients, 5%). A genetic analysis
was not possible for the entire cohort, owing to the ret-
rospective design of the study: only 70% and 74% of pa-
tients were tested, respectively. The prevalence of AIP mu-
tations was similar to that already published in this age
range (42– 44), and our findings confirm that screening for
MEN1 mutations is also important in children and ado-
lescents (18, 42). AIP mutations are less frequent than in
patients of the same age with pure GH- or mixed PRL-
GH-secreting adenomas (16 –18, 42– 44). AIP mutations
did not seem to be associated with DA resistance in our
patients, contrary to their reported effect on somatostatin
analog efficacy in acromegaly (45, 46). MEN1 mutations,
in contrast, may be associated with more aggressive and
doi: 10.1210/jc.2014-3670
more resistant macroprolactinomas (18, 21, 42, 47– 49).
To confirm this relationship, it would be useful to study a
higher number of MEN1-positive patients. The low prev-
alence of AIP and MEN1 mutations and the fact that each
patient had a distinct mutation impair to perform any
genotype/phenotype analysis, as already emphasized in
the literature (18). Nevertheless, DA resistance was more
frequent whereas PRL levels or tumor size appears to be
similar in mutated (AIP or MEN1 as a whole) patients,
compared with nonmutated patients (data not shown).
In conclusion, macroprolactinomas are rare before the
age of 20 years. They generally affect girls, occur during
adolescence, and are very rare in young children. They are
as sensitive to DA therapy as macroprolactinomas in
adults, making this the first-choice treatment for this
young population. As in adult patients, DA resistance is
associated with higher PRL levels and larger tumors, the
latter two parameters being linked, as expected with re-
gard to adult patients with macroprolactinoma. AIP mu-
tations are less frequent than in young patients with ac-
romegaly or gigantism. MEN1 mutations are not rare in
these patients and seem to be an independent predictor of
DA resistance. More studies are needed before recom-
mending routine MEN1 screening in young patients with
isolated, nonfamilial macroprolactinomas.
Acknowledgments
Address all correspondence and requests for reprints to:
Philippe Chanson, MD, Service d’Endocrinologie et des Mal-
adies de la Reproduction, Hôpital de Bicêtre, 78 Rue du
Général Leclerc, 94275 Le Kremlin-Bicêtre, France, E-mail:
philippe.chanson@bct.aphp.fr.
Disclosure Summary: The authors have nothing to declare.
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