Keywords:
headache - pituitary adenomas - prolactin - hyperprolactinemia - dopaminergic agonist
Palavras-chave:
cefaleia - adenomas hipofisários - prolactina - hiperprolactinemia - agonista dopaminérgico
Headache is a common manifestation of pituitary diseases, particularly in adenomas[1],[2],[3], especially the prolactin-secreting adenomas. The headache has its origins in many
factors, isolated or combined, including tumor extension, invasion of perisellar structures,
personal predisposition, family history, and hormonal alterations in the hypothalamus-pituitary
axis[4]. However, it is not clear if the headache is a functional or structural consequence
of pituitary disease[5]. Some evidences point out that hyperprolactinemia per se could interfere in the development of pain by neuro-sensorial modulation[6]. The present study goal was to evaluate the headache frequency in patients with
hyperprolactinemia of distinct etiologies and to observe the headache evolution after
hyperprolactinemia treatment.
METHODS
The study was approved by the Institutional Committee on Ethics and Research (nº 0012/2012)
and conducted in accordance with the Helsinki Declaration. The patients were included
through the signature of Free and Informed Consent Term.
It was conducted a longitudinal study among patients with hyperprolactinemia, regardless
of previous treatment, attended in a Neuroendocrinology Unit in a referral hospital
in southern Brazil. Prolactin (PRL) values above 17.7 ng/mL for men and above 29.2
ng/mL for women were considered hyperprolactinemia. The cases with macroprolactin
excess were excluded. Pituitary adenomas characteristics, as size and presence of
local invasion, were determined by magnetic resonance. Of the patients with macroprolactinoma,
10 invaded the cavernous and/or sphenoidal sinus.
The sample was constituted by 69 patients, 51 females, with a mean age of 43 years
for men and 51 years for women. Concerning the hyperprolactinemia etiology, 48 (69.5%)
patients presented prolactin-secreting adenomas, 29 of them macroadenomas and 19 microadenomas.
Other nine patients presented hyperprolactinemia: associated with medication (4),
polycystic ovary syndrome (1), non-functioning macroadenomas (2), one retro-clivoid
meningioma, and one Rathke’s cleft cyst. In the remaining 12 cases, the origin of
hyperprolactinemia was considered idiopathic. The patients with adenoma were previously
evaluated in relation to the pituitary hormonal axes and received adequate replacement,
except for growth hormone (GH).
The patients were submitted to a complete neurological examination and a questionnaire
related to the headache and its clinical characteristics: frequency and intensity,
presence of associated symptoms (nausea, vomit, photophobia, phonophobia, osmophobia,
and diarrhea), family history, as well the use of medication to treat or prevent headache.
Patients with headache constituted Group I and those without headache Group II. The
headache type was classified according to the International Headache Society Classification
(IHS: ICHD-3 beta 2013)[7]. The patients of Group I were reevaluated in terms of maintenance and pattern of
headache at least six months after the first evaluation, after or during the hyperprolactinemia
treatment. The headache medication used before the inclusion of the patient in the
study remained unchanged until headache reevaluation. Hyperprolactinemia treatment
was prescribed according to its etiology and clinical repercussion, following endocrine
guidelines[8] and the particularities of each patient.
Due to the rupture with gaussian assumptions, quantitative data were described by
median and minimum and maximum value. The group comparisons were made using the Kruskal-Wallis
H test, followed by post-hoc comparisons. Comparisons of the proportional values from
prolactin quantitative suppression presented symmetric distribution and were summarized
by median and standard deviation, then compared among the groups by variance analysis
(ANOVA) and followed by Tukey test. Values lower than p<0.05 were considered statistically
significant. Data were analyzed using SPSS program (version 22.0).
RESULTS
Group I was composed of 36 women and 9 men, with 42.6±14.7 years, and Group II by
15 women and 9 men, with 48.8±16 years.
The interval between the initial diagnosis of hyperprolactinemia and the beginning
of the study was less than one year in 7 cases, between 1 and 5 years in 21 cases
and more than 5 years in 41 cases. The PRL value at the patient’s entry in the study
varied from 33 to 6562 ng/mL; 17 patients presented PRL level lower than 100 ng/mL,
20 between 101 and 200 ng/mL, and 32 higher than 200 ng/mL. The median PRL in those
patients with macroadenomas was 488 ng/mL, in those with microadenomas 153 ng/mL and
in hyperprolactinemia from other etiologies 90 ng/mL, is the median measure of macroadenomas
significantly higher than microadenomas and other hyperprolactinemias (p<0.001).
Headache was reported by 45 patients (65.2% of the total sample), 21 patients (46.6%)
with PRL secreting macroadenomas, 13 (29%) with microadenomas, and 11 (24.4%) with
hyperprolactinemia from other etiologies. In patients with pituitary macroadenomas,
headache frequency was 72.4%, in those with microadenomas was 68.4%, and in the others
was 52.4%. The headache frequency did not vary significantly among the different etiologies
(p=0.32). The median PRL in Group I was 201 ng/mL (38‒5464 ng/mL) and in Group II
was 162 ng/mL (33‒6562 ng/mL). Among the macroadenomas associated to headache, 8 invaded
cavernous and/or sphenoidal sinus. Of the women with headache, 10 were aged between
50 and 75 years, 9 of whom had hypogonadism, either physiological (menopause) or pathological,
due to central hypogonadism due to hyperprolactinemia itself or hypopituitarism associated
with the tumor mass. Concerning headache classification, 31 (68.8%) met the criteria
for migraine phenotype, 8 (17.7%) for tension-type headache, and 6 (13.3%) could not
be classified. Thirty-four patients used specific medication to treat headache, according
to previous medical orientation.
Of the total sample, 12 (17.5%) patients were not submitted to treatment, all of them
with hyperprolactinemia not related to pituitary adenoma and without clinical repercussion.
During follow-up, 39 (56.5%) patients used dopaminergic agonist (DA agonist) alone;
18 (26%) were submitted to pituitary surgery, followed in 5 cases by radiotherapy
and/or in 15 cases by DA agonist. The agonists used were bromocriptine and cabergoline,
in conventional doses, adjusted according to the patient needs. We did not have access
to the final PRL dosage of four patients (two from Group I and two from Group II),
although they completed the neurological exam and the questionnaire. The final PRL
level, available in 53 cases, showed normalization in 29 patients (54.7%). In the
reevaluation, the median PRL was 25 ng/mL (0.3‒2859 ng/mL) and, in 57% of the cases,
less than 30 ng/mL. The final median PRL of Group I (n=43) was 21 ng/mL (3‒335 ng/mL)
and of Group II (n=22) was 29 ng/mL (0.3‒2859 ng/mL). After treatment, the median
PRL of both groups were very similar and did not show significant differences (p=0.835).
Of the 45 patients at the end of the evaluation, two had no recent evaluation of PRL
level, remaining 43 patients for PRL revaluation ([Table 1]); another one did not complete the questionnaire on headache, remaining 44 patients
for analysis of the evolution of pain. It was observed resolution or improvement of
pain in 33 of them (75%): complete in 19 patients and partial in 14. The absence of
episodes of headache was considered as resolution of pain. Reports of pain decrease
in intensity or frequency of the condition were considered as improvement. Maintenance
of the initial presentation of headache was considered unchanged headache. Complete
resolution of headache occurred in 16 women and 3 men, with 44.4±14.3 years; with
partial resolution, 10 women and 4 men, 41.7±11.6 years; without resolution, 10 women
and 2 men, 41±18.9 years.
Table 1
PRL Variation.
|
Headache status
|
Case
|
PRL First Evaluation (ng/mL)
|
PRL Revaluation (ng/mL)
|
PRL Reduction (%)
|
|
Complete headache resolution
(Subgroup I)
|
1
|
2639
|
30
|
98.9
|
|
2
|
610
|
116
|
81.0
|
|
3
|
204
|
33
|
83.8
|
|
4
|
76
|
33
|
56.6
|
|
5
|
75
|
29
|
61.3
|
|
6
|
117
|
4
|
96,5
|
|
7
|
885
|
6
|
99.3
|
|
8
|
127
|
10
|
91.7
|
|
9
|
185
|
10
|
94.2
|
|
10
|
301
|
10
|
96.4
|
|
11
|
174
|
12
|
93.1
|
|
12
|
5001
|
14
|
99.7
|
|
13
|
368
|
14
|
96.0
|
|
14
|
1001
|
16
|
98.4
|
|
15
|
201
|
17
|
91.4
|
|
16
|
1308
|
17
|
98.7
|
|
17
|
150
|
18
|
88.0
|
|
18
|
153
|
19
|
87.5
|
|
19
|
111
|
21
|
81.1
|
|
Group median
|
|
|
|
89.1*
|
|
Partial headache resolution
(Subgroup II)
|
20
|
666
|
30
|
95.6
|
|
21
|
185
|
62
|
66.1
|
|
22
|
2570
|
146
|
94.3
|
|
23
|
5464
|
72
|
98.7
|
|
24
|
213
|
60
|
71.8
|
|
25
|
237
|
100
|
57.8
|
|
26
|
345
|
3
|
99.1
|
|
27
|
488
|
3
|
99.2
|
|
28
|
107
|
4
|
96.2
|
|
29
|
275
|
12
|
95.6
|
|
30
|
169
|
12
|
92.6
|
|
31
|
260
|
14
|
94.5
|
|
32
|
101
|
20
|
80.2
|
|
33
|
49
|
22
|
55.1
|
|
Group median
|
|
|
|
85.5*
|
|
Headache unchanged
(Subgroup III)
|
34
|
71
|
37
|
47.9
|
|
35
|
105
|
67
|
36.2
|
|
36
|
122
|
202
|
+65.8#
|
|
37
|
91
|
55
|
39.6
|
|
38
|
259
|
118
|
54.4
|
|
39
|
540
|
355
|
34.3
|
|
40
|
251
|
178
|
29.1
|
|
41
|
78
|
43
|
44.7
|
|
42
|
795
|
65
|
91.8
|
|
43
|
201
|
13
|
93.5
|
|
Group median
|
|
|
|
40.6*
|
#The percentage represents an increase in the prolactin (PRL) level; *significant
difference between subgroup I versus III and subgroup II versus III (p<0.001).
Among reevaluated patients, 19 still had hyperprolactinemia (30 to 355 ng/mL). This
may be associated to the absence of treatment or loss of dose adjustment of medication,
due to lack of clinical repercussion of hyperprolactinemia and modest elevation of
PRL levels; to irregularity in medication use; to a short time after radiotherapy;
and rarely due to the difficulty in normalizing the level of PRL with a conventional
dose of DA agonist. In the group reevaluated for headache, all those who normalized
PRL used the DA agonist, while in those who remained hyperprolactinemic, 83.3% used
DA agonist.
The median initial PRL in the patients with complete headache resolution (n=19) was
201 ng/mL, in those with partial headache resolution (n=14) was 249 ng/mL, and in
those with unchanged headache (n=11) was 122 ng/mL. In the reevaluation, the median
final PRL was 17 ng/mL in those patients with complete headache resolution, 21 ng/mL
in those with partial resolution, and 66 ng/mL in those in whom the headache did not
change. There was a significant difference among the median PRL of the groups (p=0.003),
between those with headache resolution and those with unchanged headache (p≤0.001)
and between partial headache resolution and unchanged headache (p=0.022).
Among the patients with tension-type headache phenotype, four had complete resolution
of the problem and two partial resolutions; among the patients with migraine phenotype,
10 had complete resolution and 10 partial; among the patients with not classified
headache, three had complete and one partial resolution.
Among the 8 patients with idiopathic hyperprolactinemia and headache, two of them
used DA agonist, one of them showed complete resolution of the pain, and the other
partial recovering. Among those who were not treated, just one presented a partial
resolution, showing spontaneous PRL normalization.
Table shows the individual variation in the reduction of PRL level during reevaluation.
Among the patients with complete headache resolution, the average decrease on PRL
levels was 89.1%, among the patients with a partial resolution was 85.5%, and among
those in whom the headache did not change was 40.6%. The difference in the reduction
of PRL values between the first two subgroups is not significant, but among the patients
with complete or partial headache resolution and the patients with unchanged pain,
it was significantly different (p<0.001).
DISCUSSION
Prolactin is associated to immune modulation, osmoregulation, personal behavior and
metabolism, and has been implicated in the etiology of headache. The hypothalamus,
vital to adjust PRL levels, could be involved in the onset of headache, as suggested
by the occurrence of premonitory symptoms related to hypothalamic dysfunction in migraine
(polyuria, polydipsia, food craving, mood disturbance)[5], by the relation between menstrual cycle and migraine; and by the involvement of
the trigeminovascular system and the presence of hypothalamic nociceptive peptides
as neuropeptide Y, vasoactive intestinal polypeptide, among others[9],[10],[11].
Headache is frequent in several hypophyseal tumor phenotypes, varying from 33 to 72%,
according to Abe et al.[4], and 11 to 73% according to Siegel et al.[12]. Among the possible causes are the local traction of the dura mater; the cavernous
sinus invasion, with stimulus to structures sensitive to pain; hormonal hypersecretion
of GH or PRL; the rise in intrasellar pressure; the predisposition of the patient
and family history[2],[3],[5]. The precise mechanisms remain unknown[13]. Among the tumors, the higher prevalence of headache is in the prolactinomas, varying
from 37 to 83%[3],[4],[14].
Studies on the association between hyperprolactinemia and headache are scarce, with
predominance of isolated case reports[5],[15],[16], cross-sectional studies with limited samples[2],[3],[4],[10],[11],[12],[14],[17]. Besides that, when the headache progression is evaluated, the studies mention the
“post-treatment” condition or “PRL normalization” and not the specific correlation
between headache and the PRL level.
In the present study, patients with hyperprolactinemia showed headache prevalence
of 64.7%, with a predominance of migraine phenotype and tension-type headache phenotype,
independent of tumor volume, which is in agreement with the literature. The majority
of patients received treatment for hyperprolactinemia with DA agonist and, in some
cases, surgical intervention, while others were monitored without intervention. At
the time of the reevaluation, the PRL was normalized in 55% of the cases. Of the patients
with headache, 75% showed complete or partial resolution of the pain.
Headache resolving after treatment of pituitary tumors, including prolactinomas, was
observed with surgical treatment[4] as well as with DA agonist drugs[14]. Levy et al.[14] reported decreased pain in 25% of the cases under DA agonist use. Cavestro et al.[10] observed good responses of the headache to cabergoline in 7 patients with hyperprolactinemia,
from a total sample of 27 patients. Bosco et al.[17], monitoring 29 patients with PRL secreting microadenomas, observed headache improvement
using cabergoline, even with PRL levels after treatment equal to 74 ng/mL. Kallestrup
et al.[11] related the same results using DA agonists with no association between headache
relief and tumor reduction or PRL normalization[11]. On the other hand, the DA agonists can have a paradoxical effect, once there are
cases where its use led to a headache increase[5].
The results of this study supports the hypothesis that the positive effect on headache
is independent of PRL normalization, as observed by Kallestrup et al.[11], but it is related to PRL reduction.
It was already suggested that pain relief in the case of idiopathic hyperprolactinemia
can reflect the pharmacological effect of DA agonists, due to its similar properties
to ergot alkaloids, which are present in the trigeminovascular system, or due to its
influence in the pain process[11]. In this sample, it was observed pain recovering in three cases of idiopathic hyperprolactinemia,
two of them using DA agonists and one not, all showing reduction in the PRL level.
The small number of idiopathic cases prevents conclusions, although the findings reinforce
the PRL role and not direct effect of the drug.
This study has limitations, especially in relation to the size of sample, and also
due to the lack of pairing of the headache treatments that were being used by the
patients at the study entry. Despite these considerations, we suggest that in hyperprolactinemic
patients the reduction (not necessarily normalization) in the PRL level, regardless
of the therapeutic modality, is closely related to the improvement or disappearance
of headache. To be confirmed, this fact should be taken into account in the individual
therapeutic approach, since it suggests the necessity of a more rigorous control of
the PRL levels also in those patients who did not have PRL secreting macroadenomas,
in addition to reaching the required level to avoid clinical repercussion in the gonadal
axis.
