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Abstract

Aim

The aim of this article is to investigate the phenotype and etiology of prolactinoma-associated headache as well as present and discuss the plausible pain-relieving effect of dopamine agonist treatment.

Methods

In this case-based audit we included 11 patients with prolactinomas and one patient with idiopathic hyperprolactinemia presenting with headache that subsequently improved or resolved after dopamine agonist treatment.

Results

A significant ipsilateral location of tumor mass and reported headache symptoms was observed (p = 0.018). After dopamine agonist treatment seven out of 12 patients became pain free within 2.5 months; after one year of treatment 11 out of 12 reported headache improvement or resolution. Average tumor volume reduction after treatment was 47 ± 22% during 9.5 ± 8.4 months of follow-up. There was no significant association between headache relief and tumor shrinkage (p = 0.43) or normalization of serum prolactin (p = 1.00), respectively.

Conclusions

1) The significant association between lateralization of tumor and headache suggests a mechanical origin of the headache, 2) headache responded to dopamine agonist treatment in most patients, and 3) our observations encourage future prospective controlled trials to investigate the role of hyperprolactinemia in the pathogenesis of headache as well as the therapeutic effects of dopamine agonists.

Keywords

Prolactinomas pituitary adenomas pituitary tumors headache trigeminal autonomic cephalalgias migraine dopamine agonists

Introduction

Headache is frequent in patients with pituitary adenomas, especially in hormone-secreting adenomas such as prolactinomas (1,2). Previous studies indicate that prolactinomas may present with headaches similar to migraine (3 –5) and trigeminal autonomic cephalalgias (TAC), such as cluster headache (6 –9), paroxysmal hemicrania (10) and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) (11 –14). The underlying mechanisms leading to headache in patients with prolactinomas remain uncertain. Previous studies have proposed that tumor compression of pain-sensitive structures in the cavernous sinus, dural stretch, increased intrasellar pressure and dysfunction of the dopamine-prolactin axis and the trigeminovascular system play a causative role (7,15 –17). Furthermore, expression of “nociceptive peptides” such as calcitonin gene-related peptide, substance P, neuropeptide Y, pituitary adenylate cyclase-activating protein and vasoactive intestinal polypeptide have been proposed to be related to headache in pituitary tumors, but no clear association has been discovered (18 –21). Prolactinomas respond well to dopamine agonists, which inhibit prolactin production and induce tumor shrinkage. Anecdotal evidence suggests that dopamine agonists have a favorable effect on headache via uncertain mechanisms (3,4,8,10,11,22,23). We present a retrospective case-based audit involving 12 patients with hyperprolactinemia. All cases except one were secondary to a prolactinoma, accompanied by headache, which resolved or was relieved following dopamine agonist treatment. Our objectives were to characterize the phenotype and investigate the etiology of headache in patients with prolactinomas and hyperprolactinemia and present and discuss the plausible headache-relieving effect of dopamine agonist treatment.

Patients and methods

Study population

The study population consisted of selected patients presenting with hyperprolactinemia and headache that subsequently improved or resolved after treatment with dopamine agonists at the department of endocrinology, Aarhus University Hospital, Denmark, from 2002 to 2013. The study participants were consecutively included in the audit and comprised 11 patients with prolactinomas and one patient with idiopathic hyperprolactinemia.

Endocrine assessment and response to treatment

All patients were followed by the same pituitary endocrinologist (JOLJ). Serum prolactin was determined at the department of clinical biochemistry, Aarhus University Hospital, Denmark, using sandwich immunometric assay (Serum prolactin normal range: 0.09—0.58 IU/l). All charts were reviewed and subjective feedback regarding headache relief (partial or total pain relief) was recorded in order to assess timing of headache response after dopamine agonist treatment.

Evaluation of headache characteristics

All patients were invited to participate in a semi-structured interview based on principles by Olesen and Dodick (24) with a dedicated neurologist (HK) in order to evaluate the prolactinoma-associated headache characteristics. Previous number of headache days during the last year was reported from zero, one to two, three to seven, 8–14, 15–30, 31–60, 61–90, 91–180 and 181–360 days. In order to estimate the headache burden experienced before the previous year, patients were asked if they before last year had experienced headache more than 14 days/month, up to 14 days/month, up to seven days per month or never had headache before last year. Number of sick-listed days during the last year was reported from zero, one to two, three to seven, 8–14, 15–30, 31–60, 61–90, 91–180 and 181–360 days. Present headache was rated by means of a visual analog box of 11-point scales for present, worst and average pain during the last two weeks. Furthermore, a Headache Impact Test Score (HIT-6 score, range 36–78) was calculated to quantify the actual impact of the headache on daily life (25). The total number of headache attacks due to prolactinomas was estimated by the patients ranging from: one, two to four, five to nine, 10–49, 50–99 and 100+. A headache diary was completed by the patients. All patients participating in the retrospective headache assessment underwent this semi-structured interview and afterwards a full neurological examination was performed. Although the patients by definition suffered from a secondary headache associated with intracranial neoplasm (International Classification of Headache Disorders, second edition (ICHD II), G44.822), we aimed to classify the clinical appearance of the headache in each patient (26). For the actual headache due to prolactinomas: 1) an HIT-6 score ≥ 60 was considered significant, 2) and/or number of sick-listed days > 14 days last year, 3) and/or number of headache days ≥ 181–365 days/year were considered significant. For grading of the previous headache burden, it was more difficult to estimate the impact. However, we chose to consider patients with a total of more than 100 headache attacks due to prolactinomas and/or a frequency of up to 14 or more prolactinoma-associated headache days per month as significant. The study was not primarily designed to detect eventual treatment effect of dopamine agonist treatment. Based on the above estimates we tried to establish a quantification of eventual effect based on change from significant to nonsignificant headache.

Radiological assessment

A pituitary magnetic resonance imaging (MRI) scan was performed before and after treatment with dopamine agonists and evaluated by the same dedicated neuroradiologist (EN) blinded to the headache symptoms of the patients. In the auditing process all scans were evaluated on the same day in all but two cases. Tumors were categorized as microadenomas (diameter <1 cm) or macroadenomas (diameter >1 cm). Tumor lateralization and tumor dimensions were assessed before and after dopamine agonist treatment and tumor volume reduction was calculated (15,27). Furthermore, cavernous sinus invasion and effect on internal carotid artery was assessed. For statistical analysis tumor reduction of ≥ 40% was considered significant.

Statistical analysis

Data were analyzed using Stata/IC_12 (StataCorp LP, TX, USA). Fisher's exact test was applied for categorical variables and nonparametric correlations (Spearman) for continuous variables. Two-tailed p values < 0.05 were considered significant. Descriptive data are presented as mean ± SD.

Results

Twelve patients (female (F) = 7; male (M) = 5; mean age 39.7 ± 12.9 years) were included. Ten patients were diagnosed with macroprolactinomas, one with a microprolactinoma and one with idiopathic hyperprolactinemia.

Headache characteristics

All patients experienced unilateral headache. Nine patients agreed to participate in a retrospective headache interview where headache severity and characteristics were determined. Mean follow-up time from neuroimaging at time of diagnosis to participation in the retrospective headache interview was 2.9 ± 1.7 years (range: 0.5–5.5 years). As presented in Table 1, headache phenotypes were characterized as cluster headache (one patient), SUNCT (three patients) and migraine (four patients). One patient presented with two headache components: migraine and SUNCT.

Table 1.

Headache characteristics.

PROLACTINOMA HEADACHE	1	2	3	4	5	6	7	8	9	10	11	12
Age of onset	26	46	41	64	57	23	27	53	42	31	49	29
Gender (M/F)	F	F	M	F	F	F	M	M	F	F	M	M
Headache characteristics
Quality
pulsating	MD	+	−	−	−	−	−	MD	MD	MD	MD	+
ice pick	MD	−	−	−	−	+	−	MD	MD	MD	MD	−
squeezing	MD	−	+	+	+	+	+	MD	MD	MD	MD	−
Location
Unilateral Y/N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
Lateralization L/R	R	L	R	L	L	R	L	R	R	R	L	L
Orbital	+	+	−	+	−	+	+	+	+	+	−	+
Frontal	−	−	+	−	−	−	−	+	−	−	+	+
Temporal	−	−	−	−	+	−	−	−	−	+	−	−
Occipital	−	−	−	+	−	−	−	−	−	−	+	−
Facial/Jaw	+	−	−	−	−	−	−	−	+	−	−	−
Autonomic symptoms during headache
Lacrimation	−	+	−	+	−	+	+	−	−	+	−	−
Conjunctival injection	−	+	−	+	−	+	+	−	−	+	−	−
Rhinorrhea	+	+	−	+	−	−	+	−	−	+	+	−
Ptosis	−	−	−	+	−	−	+	−	−	−	−	−
Associated symptoms
Nausea/Vomiting	MD	+	+	−	+	−	−	−	MD	+	MD	−
Photophobia	MD	+	+	+	+	−	+	−	MD	−	MD	+
Phonophobia	MD	+	+	−	+	−	+	−	MD	−	MD	+
Prodromas	MD	−	+	−	+	−	−	+	MD	+	MD	−
Trigger-factors	MD	Menses	No	Sharp light, red wine	Sharp light, stress	Activity	No	No	MD	No	MD	Sharp light, stress
Headache character
Phenotype^a	MD	5 + 2	5	1	5	2	2	5	MD	2	MD	5
ICD-10NA code	MD	G43.0 G44.08	G43.83	G44.0	G43.1	G44.08	G44.08	G43.1	MD	G44.08	MD	G43.0
Headache before treatment
Headache attacks due to prolactinoma/hyperprolactinemia	MD	10–49	NA	>100	NA	>100	>100	50–99	MD	>100	MD	>100
Headache days/month	MD	7	14	14	14	>14	>14	7	MD	>14	MD	14
Duration headache attacks (hours)	MD	4–24	0.5–4	2–4	4–24	<0.5	<0.5	0.5–4	MD	<0.5	MD	0.5–4
Headache after treatment
Sick-listed days/year due to headache	MD	0	3–7	1–2	0	8–14	0	0	MD	0	MD	0
Headache days/year	MD	0	91–180	MD	91–180	91–180	15–30	MD	MD	181-365	MD	8–14
HIT-6 (range 36–78)	MD	36	52	38	57	36	54	40	MD	63	MD	48
VAS Headache _(0–10)
VAS Worst	MD	0	8	0	8	0	4	5	MD	8	MD	3
VAS Average	MD	0	4	0	6	0	1	1	MD	4	MD	1
VAS Present	MD	0	2	0	3	0	6	0	MD	2	MD	0
EFFECT on Headache Y/N (Retrospective headache interview)
Significant headache before treatment^b	MD	N	Y	Y	Y	Y	Y	N	MD	Y	MD	Y
Significant headache after treatment^c	MD	N	N	N	N	N	N	N	MD	Y	MD	N
Significant headache relief	MD	N	Y	Y	Y	Y	Y	N	MD	N	MD	Y

Headache/Pain character: 1) Cluster headache; 2) short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT); 3) short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA); 4) Trigeminal Neuralgia; 5) Migraine; 6) Unspecified Headache.

Significant headache: ≥ 100 headache attacks due to prolactinoma and/or up to ≥ 14 headache days per month.

Significant headache: > 14 sick-listed days/year and/or ≥ 181–365 headache days/year and/or HIT-6 ≥ 60.

HIT-6: Headache Impact Test; VAS: visual analog scale; ICD: International Classification of Diseases; M: male; F: female; Y: yes; N: no; L: left; R: right; MD: Missing data. NA: Not applicable. Headache characterizations are based on retrospective headache interview. Information on patients 1, 9 and 12 are obtained from charts.

Association between tumor characteristics, serum prolactin and development of headache symptoms

Eleven patients presented with a pituitary tumor. Tumor growth was strictly unilateral in eight patients whereas tumor growth was bilateral in the remaining three patients (Table 2). In patients presenting with a unilateral tumor (n = 8), headache symptoms were ipsilateral in all cases and a statistically significant association between headache and tumor mass was revealed (p = 0.018). Six patients exhibited obvious tumor invasion into the cavernous sinus with plausible compression of the first and second branch of the trigeminal nerve (V1 + V2). In all of these cases tumor growth into the cavernous sinus and headache symptoms were ipsilateral. Ten patients had tumor growth affecting the internal carotid artery that in eight cases was strictly ipsilateral to the headache. Five patients had tumor tissue surrounding the internal carotid artery. One patient had no tumor effect on the internal carotid artery.

Table 2.

Tumor characteristics and effect of dopamine agonist treatment.

PROLACTINOMA HEADACHE	1	2	3	4	5	6	7	8	9	10	11	12
Tumor characteristics
Location of headache^a	R	L	R	L	L	R	L	R	R	R	L	L
Location of tumor^a	B	L	R	L	L	R	B	NA	B	R	L	L
Tumor volume (cm³)	9.54	14.93	3.39	2.02	1.96	10.0	16.2	NA	2.26	0.73	0.74	4.78
Cavernous sinus invasion	−	+	+	+	+	+	−	NA	−	−	−	+
Affection of internal carotid artery	−	+	+	+	+	+	+	NA	+	+	+	+
Hormone levels
Serum prolactin (0.09–0.58 iu/l)	25.5	109.7	9.8	18.3	12.0	103.1	19.9	1.4	8.1	8.4	11.2	22.6
Treatment effect
Headache response (subjective)
Partial headache resolution	+
Total headache resolution	+	+	+	+	+	+	+	+	+	+	+
Headache response time (months)	2	2	1	0.5	2.5	2	0.5	7	16	12	8	2
Tumor reduction (percentages)	49.6	68.5	19.8	61.4	47.0	63.3	62.7	NA	58.0	0.0	MD	36.8
Normalisation of serum prolactin	−	−	+	+	+	+	−	+	+	+	+	−

^aR: right; L: left; B: Bilateral. NA: Not applicable; MD: Missing data. For assessment of tumor volume V Cavalieri's principle was used with the following equation where a, b and c are the three orthogonal lines through the tumor: V = 4/3π * ((a/2 * (b/2) * (c/2)). Headache response (subjective) and headache response time (months) are obtained from charts at the regular ambulatory visits and are measures of the subjective headache relieving effect of dopamine agonist treatment and the amount of time from start of dopamine agonist treatment until the patients describe a pain relieving effect, respectively. Mean time between subjective headache response given at ambulatory visits and follow-up neuroimaging was 4.6 ± 10.4 months.

By definition all patients had hyperprolactinemia ranging between 1.44 and 109.70 IU/l (normal range: 0.09—0.58 IU/l). Patient 11 was treated with a second-generation antipsychotic drug, which may have contributed to the observed hyperprolactinemia. Before start of treatment a positive correlation was recorded between serum prolactin and tumor volume (r = 0.74, p = 0.010).

Effects of dopamine agonist treatment

By definition, all patients reported headache improvement or resolution from dopamine agonist treatment. All patients were treated with cabergoline except patient 8, who received quinagolide. Two patients reported pain resolution within two weeks of treatment (patients 4 and 7); seven reported total pain resolution after 2.5 months. After one year 11 patients reported headache improvement or resolution. Interestingly, patient 12 reported immediate reoccurrence of severe headache attacks after temporarily pausing dopamine agonist treatment.

Headache severity

Nine patients underwent a retrospective structured interview to quantify headache severity before and after dopamine agonist treatment (Table 1). Seven out of nine patients interviewed fulfilled the criteria of significant headache before dopamine agonist treatment. Six of seven patients had significant headache relief according to the criteria. Two patients did not meet the criteria of significant headache before treatment; one patient, however, reported moderate headache before treatment that following treatment completely subsided. The last patient experienced moderate headache before as well as after treatment.

Tumor size and normalization of serum prolactin

Information on change in tumor volume following dopamine agonist treatment was available for 10 out of 11 adenoma patients (Table 2). Average tumor reduction was 47 ± 22% after a mean treatment period of 9.5 ± 8.4 months. Seven out of ten patients had a significant tumor reduction ≥ 40%. Patient 10 did not have a change in total tumor volume. Detectable tumor regression in the cavernous sinus occurred in three out of six patients. Please see Figure 1.

Figure 1.

Case 6: Magnetic resonance imaging (MRI) brain scans before and after treatment with dopamine agonists showing tumor reduction. (a) June 17, 2007. MRI brain scan before dopamine agonist treatment. (b) September 29, 2007. MRI brain scan after dopamine agonist treatment.

Out of the seven patients fulfilling the criteria of significant headache before treatment, four patients experienced significant headache relief and significant tumor reduction. Two patients had significant headache relief but no significant tumor reduction and the remaining patient experienced neither significant headache relief nor tumor reduction. There was no association between significant headache relief and tumor reduction (p = 0.43) and no correlation between follow-up time for neuroimaging and change in tumor volume (r = –0.42, p = 0.23).

Information on serum prolactin at the time of headache response was available for all patients. Eight out of 12 patients had normal or near normal levels of serum prolactin at the time of headache response to treatment. In the evaluation of the seven patients with significant headache before treatment we did not record a significant association between normalization of prolactin and headache relief (p = 1.00). Four patients experienced significant headache relief with concomitant normalization of serum prolactin. Two patients had significant headache relief but without normalization of prolactin, and the remaining patients did not experience significant headache relief despite normalization of prolactin.

Discussion

Headache phenotypes in patients with prolactinomas

Headache is a frequent complaint in patients with prolactinomas and the prevalence ranges between 57% and 83% (2,28). The headache phenotypes are not fully characterized, but frequently resemble TAC including SUNCT (11 –14), cluster headache (6 –9) and paroxysmal hemicrania (10) as well as migraine with visual aura (3 –5).

In the present case series, all patients experienced unilateral headache and we were able to characterize the headaches as cluster headache (one patient), SUNCT (three patients) and migraine (four patients). One patient suffered from a combination of migraine and SUNCT-like headache.

Headache mechanisms

The pathogenesis underlying prolactinoma-associated headache is uncertain. Compression of nociceptive nerve fibers as well as disturbance in the hypothalamic-pituitary axis have been proposed (2,7,16). In our case series we recorded a significant consistency between lateralization of tumor and headache (p = 0.018) as well as a significant correlation between baseline serum prolactin and tumor volume (r = 0.74, p = 0.010). Headache ipsilateral to the tumor has previously been reported in patients with prolactinomas (8,10 –13,23,29 –31). Chitsantikul and Becker recently presented five patients with pituitary adenomas of whom three had prolactinomas with ipsilateral headache and tumor growth (14). The association between headache symptoms and tumor mass indicates direct compression of pain-sensitive structures as a mechanism in development of headache, and impingement of the second and third trigeminal nerve branch in the cavernous sinus has been proposed as one such mechanism. We were able to detect tumor tissue in the cavernous sinus in six out of 11 patients and several of the remaining patients had a trigeminal component to their headaches. It thus remains plausible that trigeminal nerve affection of the tumor contributes to the pathogenesis of headache. However, in a prospective study of 63 patients with pituitary tumors no association between clinical headache score and pituitary volume or between cavernous sinus invasion and headache was found (15). Another plausible pain-producing structure is the nerve plexus surrounding the internal carotid artery. We observed that 10 out of 11 patients had tumor growth affecting the artery and in all but two cases it was strictly ipsilateral to the headache.

A well-known paradox is the observation that even small microprolactinomas may cause headache. This has led to the suggestion that biochemical and neuroendocrine properties of the tumor play a causative role. This is indirectly supported by the observation that meningeomas and certain other large parasellar mass lesions are not typically associated with headache (16). Moreover, it is reported that the prevalence of headache is higher in patients with hormone-secreting (growth hormone and prolactin) pituitary adenomas compared to clinically nonfunctioning adenomas (15). It has also been suggested that headache associated with microadenomas depends on the location of the tumor (32). Indeed, patient 4 in our audit had a microprolactinoma extending to the left cavernous sinus and this could be the mechanism behind the patient's left-sided headache. Finally, the possibility that headaches in patients with microprolactinomas may be triggered in predisposed patients by a change in estradiol levels due to hyperprolactinemia has been proposed (16).

Bosco et al. showed an association between hyperprolactinemia and headache attacks in a population of 29 patients with microprolactinoma-associated migraine or tension-type-headache and reported that elevations in serum prolactin induced severe headache attacks in several patients (5). In our study, patient 12 reported recurrence of headache symptoms after temporary discontinuation of dopamine agonist treatment. All patients included in this audit presented with hyperprolactinemia that disturbs the prolactin-dopamine pathway. Increased prolactin levels stimulate hypothalamic neuroendocrine dopaminergic neurons to secrete dopamine that in turn suppresses the synthesis and release of prolactin from the pituitary gland (33). Dysfunction of the hypothalamic-pituitary axis is considered to be involved in the pathogenesis of primary headache disorders (34 –36); this supports the theory that biochemical-neuroendocrine mechanisms may also be involved in the development of headache in patients with prolactinomas (1,37).

Effects of dopamine agonists

Anecdotal evidence suggests a positive effect of dopamine agonists on headache in prolactinomas through uncertain mechanisms (3,4,8,10,11,22,23).

Treatment with dopamine agonists are known to cause tumor shrinkage (38) and we recorded an average tumor volume reduction of ≍ 50% after ≍ 10 months treatment.

We also recorded that four out of seven patients with significant headache before treatment experienced significant headache relief and tumor reduction > 40% after dopamine agonist treatment. We did not, however, find an association between significant headache relief and tumor reduction (p = 0.43).

Serum prolactin had normalized in six out of 12 patients by the time of headache response to treatment and four out of seven patients with significant headache before treatment experienced significant headache relief with concomitant normalization of serum prolactin. When assessing the data we did not reveal any association between normalization of prolactin and significant headache relief (p = 1.00) and discrepancies between normalization of prolactin and headache have previously been reported (12,29). Thus, it remains uncertain to which degree prolactin per se is causally linked to the pathogenesis of headache and its resolution following dopamine agonist treatment.

Interestingly, patient 8 with idiopathic hyperprolactinemia and migraine experienced robust and sustained pain relief after dopamine agonist treatment, suggesting a pharmacological effect rather than tumor reduction. It is noteworthy that certain dopamine agonists including cabergoline share chemical properties with ergot alkaloids used for the treatment of migraine and that are known to affect the trigeminovascular system (1,39). Moreover, direct neuronal interactions between the hypothalamo-pituitary axis and the trigeminal nucleus have been discovered in animal studies (40). Another theory suggests that dopamine and hence dopamine agonists may directly influence pain processing. The dopaminergic system is implicated in the modulation of pain, and previous studies have shown that dopamine originating in the mesencephalic brainstem project to the dorsal horn of the spinal cord and exert a modulating effect on dorsal horn nociceptive neurons (41,42). In addition it has been suggested that dopaminergic compounds may have an analgesic effect via D2 receptors in the striatum of the brain (43).

Dopamine agonist treatment has also been associated with exacerbation of headache (12,13,30,31,44). This seemingly bimodal effect of dopamine agonists has been suggested to support a biochemical-neuroendocrine mechanism in relation to headache (5,15). Two of our patients experienced almost immediate pain resolution in accordance with previous reports (3,4,7), and we believe this suggests a direct pharmacological or biochemical-neuroendocrine mechanism.

Limitations

The present study was observational and the study population was limited and consisted of pre-selected individuals with hyperprolactinemia and headache responding positively to dopamine agonist treatment. Moreover, structured headache evaluations were performed retrospectively, which may bias the results. Pain relief was not implied when the patients were informed about the indications for dopamine agonist treatment, but this does not rule out a placebo effect. These limitations have important implications. First of all, it is not possible from this case series to ascertain the prevalence of headache among the general population of patients with hyperprolactinemia before and after dopamine agonist treatment. Secondly, to document a positive effect of dopamine agonist treatment on headache in these patients would require a placebo-controlled trial. Finally, it is uncertain if headache is caused by prolactin or by the presence of a tumor. It also remains an open question whether the positive effects of dopamine agonists can be attributed to normalization of prolactin, tumor shrinkage or other mechanisms. It would be of interest to study the effect of dopamine agonist treatment in TAC patients with normal prolactin levels in a placebo-controlled trial.

Conclusion

We consider our data of interest since they comprise the largest series of patients who experienced sustained relief of headache coinciding with dopamine agonist treatment. Moreover, we consider the pain relief in many of our patients truly remarkable. One patient had suffered from TAC for more than ten years that had been completely resistant to treatment (with sumatriptan injections, β-blockers, calcium antagonists, methysergide, valproic acid, topiramate, oxygen and lithium). It was subsequently revealed that the patient had been diagnosed with a prolactinoma in the past that was left untreated since the tumor was relatively small and since the patient at that time point was menopausal without symptoms of galactorrhoea. The patient started cabergoline treatment in 2002 and the headache permanently resolved in less than two weeks. This is anecdotal evidence but we believe that such observations merit translation into prospective trials. At this point we suggest that prolactin measurements should be considered in patients with TAC-like headache.

Clinical implications

Headache is ipsilateral to the pituitary tumor in prolactinoma patients and resembles trigeminal autonomic cephalalgia or migraine.

Headache associated with hyperprolactinemia is responsive to dopamine agonists in many cases and measurements of prolactin levels should thus be considered in patients presenting with trigeminal autonomic cephalalgias.

Future prospective controlled trials to ascertain the role of hyperprolactinemia in the pathogenesis of headache and the role of dopamine agonists in the treatment of headache are encouraged.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

None declared.

References

Levy

Matharu

Meeran

. The clinical characteristics of headache in patients with pituitary tumours. Brain 2005; 128(Pt 8): 1921–1930.

Abe

Matsumoto

Kuwazawa

. Headache associated with pituitary adenomas. Headache 1998; 38: 782–786.

Hartman

Voron

Hershman

. Resolution of migraine following bromocriptine treatment of a prolactinoma (pituitary microadenoma). Headache 1995; 35: 430–431.

Gabrielli

Gasbarrini

Fiore

. Resolution of migraine with aura after successful treatment of a pituitary microadenoma. Cephalalgia 2002; 22: 149–150.

Bosco

Belfiore

Fava

. Relationship between high prolactine levels and migraine attacks in patients with microprolactinoma. J Headache Pain 2008; 9: 103–107.

Favier

van Vliet

Roon

. Trigeminal autonomic cephalgias due to structural lesions: A review of 31 cases. Arch Neurol 2007; 64: 25–31.

Negoro

Kawai

Tada

. A case of postprandial cluster-like headache with prolactinoma: Dramatic response to cabergoline. Headache 2005; 45: 604–606.

Porta-Etessam

Ramos-Carrasco

Berbel-García

. Clusterlike headache as first manifestation of a prolactinoma. Headache 2001; 41: 723–725.

Greve

Mai

. Cluster headache-like headaches: A symptomatic feature? A report of three patients with intracranial pathologic findings. Cephalalgia 1988; 8: 79–82.

10.

Sarov

Valade

Jublanc

. Chronic paroxysmal hemicrania in a patient with a macroprolactinoma. Cephalalgia 2006; 26: 738–741.

11.

Matharu

Levy

Merry

. SUNCT syndrome secondary to prolactinoma. J Neurol Neurosurg Psychiatry 2003; 74: 1590–1592.

12.

Massiou

Launay

Levy

. SUNCT syndrome in two patients with prolactinomas and bromocriptine-induced attacks. Neurology 2002; 58: 1698–1699.

13.

Levy

Matharu

Goadsby

. Prolactinomas, dopamine agonists and headache: Two case reports. Eur J Neurol 2003; 10: 169–173.

14.

Chitsantikul

Becker

. SUNCT, SUNA and pituitary tumors: Clinical characteristics and treatment. Cephalalgia 2013; 33: 160–170–160–170.

15.

Levy

Jager

Powell

. Pituitary volume and headache: Size is not everything. Arch Neurol 2004; 61: 721–725.

16.

Levy

. The association of pituitary tumors and headache. Curr Neurol Neurosci Rep 2011; 11: 164–170.

17.

Arafah

Prunty

Ybarra

. The dominant role of increased intrasellar pressure in the pathogenesis of hypopituitarism hyperprolactinemia, and headaches in patients with pituitary adenomas. J Clin Endocrinol Metab 2000; 85: 1789–1793.

18.

Levy

Classey

Maneesri

. The association between calcitonin gene-related peptide (CGRP), substance P and headache in pituitary tumours. Pituitary 2004; 7: 67–71.

19.

Levy

Classey

Maneesri

. The relationship between neuropeptide Y expression and headache in pituitary tumours. Eur J Neurol 2006; 13: 125–129.

20.

Nathoo

Classey

Levy

. Pituitary adenylate cyclase activating protein (PACAP) expressed in pituitary tumours does not account for headache: A clinical-pathological correlation. Cephalalgia 2004; 24: 1101–1101.

21.

Nathoo

Classey

Levy

. No relationship between vasoactive intestinal polypeptide expression and headache in pituitary tumours. Acta Neurol Scand 2005; 111: 317–322.

22.

Millán Guerrero

Isaís Cárdenas

. Headache associated with pituitary adenomas. Headache 1999; 39: 522–523.

23.

King

Molitch

Gittinger

JW Jr

. Cavernous sinus syndrome due to prolactinoma: Resolution with bromocriptine. Surg Neurol 1983; 19: 280–284.

24.

Olesen J and Dodick DW. The history and examination of headache. In: Olesen J, Goadsby PJ, Ramadan NM, et al. (eds) The headaches, 3rd edn. Philadelphia, USA: Lippincott Williams & Wilkins, 2006.

25.

Lipton

. How useful is the HIT-6 for measuring headache-related disability? Nat Clin Pract Neurol 2006; 2: 70–71.

26.

Committee of the International Headache Society. The International Classification of Headache Disorders. Cephalalgia 2004; 24: 1–160.

27.

Lundin

Pedersen

. Volume of pituitary macroadenomas: Assessment by MRI. J Comput Assist Tomogr 1992; 16: 519–528.

28.

Gondim

de Almeida

de Albuquerque

. Headache associated with pituitary tumors. J Headache Pain 2009; 10: 15–20.

29.

Leone

Curone

Mea

. Cluster-tic syndrome resolved by removal of pituitary adenoma: The first case. Cephalalgia 2004; 24: 1088–1089.

30.

Jiménez Caballero

. SUNCT syndrome in a patient with prolactinoma and cabergoline-induced attacks. Cephalalgia 2007; 27: 76–78.

31.

Leroux

Schwedt

Black

. Intractable SUNCT cured after resection of a pituitary microadenoma. Can J Neurol Sci 2006; 33: 411–413.

32.

Fleseriu

Yedinak

Campbell

. Significant headache improvement after transsphenoidal surgery in patients with small sellar lesions. J Neurosurg 2009; 110: 354–358.

33.

Anderson

Gunn

. Prolactin specifically activates signal transducer and activator of transcription 5b in neuroendocrine dopaminergic neurons. Endocrinology 2005; 146: 5112–5119.

34.

Silberstein

. Sex hormones and headache. Rev Neurol (Paris) 2000; 156(Suppl 4): 4S30–4S41.

35.

Mascia

Afra

Schoenen

. Dopamine and migraine: A review of pharmacological, biochemical, neurophysiological, and therapeutic data. Cephalalgia 1998; 18: 174–182.

36.

Matharu

May

. Functional and structural neuroimaging in trigeminal autonomic cephalalgias. Curr Pain Headache Rep 2008; 12: 132–137.

37.

Schankin

Reifferscheid

Krumbholz

. Headache in patients with pituitary adenoma: Clinical and paraclinical findings. Cephalalgia 2012; 32: 1198–1207.

38.

Colao

Di Sarno

Landi

. Long-term and low-dose treatment with cabergoline induces macroprolactinoma shrinkage. J Clin Endocrinol Metab 1997; 82: 3574–3579.

39.

Hoskin

Kaube

Goadsby

. Central activation of the trigeminovascular pathway in the cat is inhibited by dihydroergotamine. A c-Fos and electrophysiological study. Brain 1996; 119(Pt 1): 249–256.

40.

Malick

Strassman

Burstein

. Trigeminohypothalamic and reticulohypothalamic tract neurons in the upper cervical spinal cord and caudal medulla of the rat. J Neurophysiol 2000; 84: 2078–2112.

41.

Viisanen

Ansah

Pertovaara

. The role of the dopamine D2 receptor in descending control of pain induced by motor cortex stimulation in the neuropathic rat. Brain Res Bull 2012; 89: 133–143.

42.

Jensen

Yaksh

. Effects of an intrathecal dopamine agonist, apomorphine, on thermal and chemical evoked noxious responses in rats. Brain Res 1984; 296: 285–293.

43.

Hagelberg

Jaaskelainen

Martikainen

. Striatal dopamine D2 receptors in modulation of pain in humans: A review. Eur J Pharmacol 2004; 500: 187–192.

44.

Larner

. Headache induced by dopamine agonists prescribed for prolactinoma: Think SUNCT!. Int J Clin Pract 2006; 60: 360–361.

Prolactinoma-associated headache and dopamine agonist treatment

Abstract

Aim

Methods

Results

Conclusions

Keywords

Introduction

Patients and methods

Study population

Endocrine assessment and response to treatment

Evaluation of headache characteristics

Radiological assessment

Statistical analysis

Results

Headache characteristics

Association between tumor characteristics, serum prolactin and development of headache symptoms

Effects of dopamine agonist treatment

Headache severity

Tumor size and normalization of serum prolactin

Discussion

Headache phenotypes in patients with prolactinomas

Headache mechanisms

Effects of dopamine agonists

Limitations

Conclusion

Clinical implications

Footnotes

Funding

Conflict of interest

References