Refractory Headache in Macroprolactinoma Resolved After Neurosurgery: A Challenging Clinical Case and Literature Review

Abstract

Introduction

Pituitary tumors are present in approximately 15% of the population and are often discovered incidentally during imaging for headache evaluation. Headaches are prevalent in patients with pituitary adenomas, occurring in 37-70% of cases. However, determining whether the tumor itself causes the pain is frequently challenging.

Case presentation

A 27-year-old woman presented with progressive daily holocranial headaches, photophobia, phonophobia, nausea, and secondary amenorrhea. Laboratory tests and pituitary imaging confirmed a macroprolactinoma. Initial treatment with cabergoline and bromocriptine was unsuccessful due to intolerable side effects. Transsphenoidal surgery produced marked clinical improvement and a partial reduction in serum prolactin. However, tumor regrowth occurred with recurrence of daily headaches, and a second surgery was delayed due to the COVID-19 pandemic. Multiple medical treatments, which included topiramate, divalproex sodium, amitriptyline, propranolol, and riboflavin with magnesium resulted in no improvement. After the second neurosurgery, she presented normoprolactinemia with no residual tumor and once again a complete resolution of the headache episodes.

Discussion

Risk factors for headache related to adenoma include high prolactin or IGF-1 levels, cavernous sinus invasion (but not adenoma size), and a history of primary headache disorder. International diagnosis criteria emphasize headache resolution following endocrine normalization or tumor removal.

Conclusion

This case highlights the intricate relationship between prolactinomas and headaches, underscoring the need for individualized treatment strategies.

Resumo

Introdução

Os tumores hipofisários estão presentes em aproximadamente 15% da população e são frequentemente descobertos incidentalmente durante exames de imagem para avaliação de cefaleia. Cefaleias são prevalentes em pacientes com adenomas hipofisários, ocorrendo em 37-70% dos casos. No entanto, determinar se o próprio tumor causa a dor é frequentemente um desafio.

Apresentação do caso

Uma mulher de 27 anos apresentou cefaleia holocraniana diária progressiva, fotofobia, fonofobia, náuseas e amenorreia secundária. Exames laboratoriais e exames de imagem da hipófise confirmaram um macroprolactinoma. O tratamento inicial com cabergolina e bromocriptina não obteve sucesso devido a efeitos colaterais intoleráveis. A cirurgia transesfenoidal produziu melhora clínica significativa e redução parcial da prolactina sérica. No entanto, houve recidiva do tumor com recorrência das cefaleias diárias, e uma segunda cirurgia foi adiada devido à pandemia de COVID-19. Diversos tratamentos medicamentosos, incluindo topiramato, divalproato de sódio, amitriptilina, propranolol e riboflavina com magnésio, não resultaram em melhora. Após a segunda neurocirurgia, ela apresentou normoprolactinemia sem tumor residual e, mais uma vez, resolução completa dos episódios de cefaleia.

Discussão

Os fatores de risco para cefaleia relacionada a adenoma incluem níveis elevados de prolactina ou IGF-1, invasão do seio cavernoso (mas não o tamanho do adenoma) e histórico de cefaleia primária. Os critérios diagnósticos internacionais enfatizam a resolução da cefaleia após a normalização endócrina ou a remoção do tumor.

Conclusão

Este caso destaca a relação complexa entre prolactinomas e cefaleias, ressaltando a necessidade de estratégias de tratamento individualizadas.

Keywords

prolactin - prolactinoma - pituitary tumor - headache - migraine

Palavras-chave

prolactina - prolactinoma - tumor hipofisário - cefaleia - enxaqueca

Introduction

Pituitary tumors have an estimated prevalence of 15%[1] and are frequently discovered when brain imaging is performed to investigate secondary causes of headache. In addition, headache itself is common in patients with pituitary adenomas, varying between 37-70% of cases.[2] [3] [4] However, determining whether a pituitary lesion is the source of recurrent headache can be difficult, because primary migraine and tension-type headache are highly prevalent, and the adenoma itself might represent just an incidentaloma.[5]

In some cases, the treatment of pituitary adenoma with medication or neurosurgery tends to attenuate the headache to some degree.[6] However, not all patients will improve or tolerate the proposed therapeutic agent.[7]

Thus, the main aim of this article is to perform a narrative review of the literature regarding pituitary adenoma, its relationship with headaches and treatment options. A clinical case is also presented to further explore and illustrate these topics.

Case Presentation

A 27-year-old woman presented with a moderate pulsatile, holocranial headache. Over several weeks, these episodes progressed to a daily pattern with severe intensity. Associated symptoms included worsening with physical exertion, photophobia, phonophobia, nausea, and nocturnal awakening due to the pain. She reported menarche at the age of 11 and was referred to our hospital following the onset of secondary amenorrhea after discontinuing oral contraceptives. Additional complaints included bilateral spontaneous galactorrhea and visual disturbances. There was no family history of pituitary disorders or migraine.

Initial laboratory evaluation revealed serum prolactin (PRL) levels exceeding 10 times the upper limit of the reference range ([Fig. 1]). Sellar magnetic resonance imaging (MRI) demonstrated a pituitary adenoma with low signal intensity on both T1 and T2 weighted sequences. The lesion, located on the left side, measured 1.1 × 0.9 × 0.6 cm and was classified as Knosp grade 0 ([Fig. 2A] and [2B]).

Fig. 1 Prolactin levels concerning clinical course and surgical procedures. ULN: upper limit of normal.

Fig. 2 Sellar MRI during follow-up. (A) Initial (08/2017) coronal T1 weighted post-gadolinium image showing a hypointense lesion on the left, measuring 1.1 × 0.9 × 0.6 cm. (B) Initial coronal T2 with low signal intensity lesion. (C) MRI after 6 months of neurosurgery (10/2018), T1 coronal view, demonstrating a residual hypoenhancing lesion of 0.9 × 0.7 × 0.6 cm. (D) MRI 1 month after the second neurosurgery (08/2024), T1 coronal view, showing complete tumor resection.

Based on the clinical, biochemical, and radiologic findings, a diagnosis of macroprolactinoma was established, and treatment with cabergoline was initiated. However, the patient experienced significant adverse effects (hypotension, nausea) even on very low doses of 0.125 mg per week. Consequently, therapy was switched to bromocriptine, but intolerable side effects persisted. Due to this dopamine agonist intolerance, the patient underwent transsphenoidal neurosurgery. Histopathological examination of the resected tumor showed >50% immunoreactivity for PRL and a Ki-67 proliferation index of 3–5%.

Six months after the surgery, the patient presented a rapid return of menstruation, complete resolution of the headache episodes, and a decrease in PRL levels, although they remained above the normal range (42 ng/mL; reference range: 3.4-18.6 ng/mL).

An attempt to reintroduce cabergoline was unsuccessful due to continued drug intolerance. Over time, the patient presented recurrence of galactorrhea and an increase in PRL levels to 101.6 ng/mL. Simultaneously, she also reported a recurrence of severe daily headaches resembling her initial presentation and began taking naratriptan daily for relief.

Follow-up sellar MRI revealed tumor regrowth, with dimensions comparable to the initial lesion (0.9 × 0.7 × 0.6 cm, [Fig. 2C]). Given the recurrence of the prolactinoma and continued dopamine agonist intolerance, another surgical approach to remove the lesion was decided. Unfortunately, the procedure was delayed by three years due to the global COVID-19 pandemic.

During this time, the symptoms related to headache persisted, despite numerous medical treatments, which included topiramate, divalproex sodium, amitriptyline, propranolol, and riboflavin with magnesium, all suspended because of side effects or no improvement. Pericranial nerve blocks provided only short relief of the pain, for about 2 days.

One month after the second neurosurgery, PRL levels normalized, and MRI showed no residual tumor ([Fig. 2D]). She significantly improved once again from the pain, presenting only two episodes of mild to moderate pulsating headaches, accompanied by photophobia, phonophobia, and nausea, over six months of follow-up. These episodes were quickly managed with simple analgesics.

Discussion

Definition and Risk Factors

In 1998, a classical study described that the most common headache features associated with pituitary adenomas were bilateral pain, head heaviness, continuous and more frequent in the anterior half of the head.[2] However, no consistent or pathognomonic pattern has been established for headaches associated with pituitary adenomas, as they are often described as resembling primary migraine,[8] tensional type headache,[9] and even trigeminal autonomic cephalalgias (such as cluster headache, hemicrania continua, and SUNCT/SUNA).[10]

It must be stated that trigeminal autonomic cephalalgias are relatively uncommon, even in patients without pituitary adenoma, and are seen only in hormone-producing adenomas, mainly prolactinomas.[10] [11] Interestingly, when autonomic features are present, they often correlate with the side of the tumor.[12]

This overlap presents a diagnostic challenge for clinicians. Relying solely on headache phenotype is often insufficient for distinguishing secondary from primary headache. Some characteristics, although not pathognomonic, might indicate more a secondary headache related to the pituitary adenoma rather than a primary etiology: younger age and nicotine abuse,[9] high PRL or IGF-1 levels,[6] and cavernous sinus invasion[8] (but not adenoma size itself[4]). Some of these factors are related to its believed physiopathology, commented below. Family history for primary cephalalgia can also be a risk factor for pain related to pituitary adenoma,[4] [8] and should not be seen as a useful tool to differentiate primary from secondary etiology. In people with a personal history of a primary disorder, the pituitary adenoma can also resemble a pre-existing headache and exacerbate a previously well-controlled disease.[5]

Although controversy remains, in 2005, Levy et al.[3] proposed some modified diagnostic criteria for the headache associated with pituitary disease:

• A. Bilateral or unilateral frontotemporal and/or retro-orbital headache fulfilling criteria C and D

• B. Either a functioning or a non-functioning pituitary tumor is identified by biochemical testing or appropriate brain imaging (with or without cavernous sinus involvement)

• C. Headache develops in close temporal proximity to endocrine abnormality or with structural symptoms attributable to pituitary disease, such as visual loss

• D. Headache resolves or there is marked improvement, within 3 months after surgical resection or specific and effective medical therapy

On the other hand, the third International Classification of Headache Disorders (ICHD-3)[13] proposed the following:

• A. Any headache fulfilling criterion C

• B. Hypothalamic or pituitary hyper- or hyposecretion associated with pituitary adenoma has been demonstrated

• C. Evidence of causation demonstrated by at least two of the following:

  1. headache has developed in temporal relation to onset of hypothalamic or pituitary hyper- or hyposecretion

  2. either or both of the following:

     • a) headache has significantly worsened in parallel with worsening of the hypothalamic or pituitary hyper- or hyposecretion

     • b) headache has significantly improved in parallel with improvement in the hypothalamic or pituitary hyper- or hyposecretion

  3. headache is associated with at least one of the following:

     • a) disorder of temperature regulation

     • b) abnormal emotional state

     • c) altered thirst and/or appetite

• D. Not better accounted for by another ICHD-3 diagnosis.

Proposed Mechanism

The cavernous sinus contains several pain-sensitive structures, including the internal carotid artery and the ophthalmic (V1) and maxillary (V2) branches of the trigeminal nerve. When a pituitary tumor invades this region, it may trigger nociceptive pathways through mechanical stretching of the dural lining of the sella or by compressing the perivascular nerve plexus surrounding the internal carotid artery.[5] Therefore, patients complaining of a unilateral headache, that is ipsilateral to the sinus cavernous invasion, may have a plausible causal relationship.[3] [8] [14] Notably, the Knosp grading system, which assesses the degree of cavernous sinus invasion, was previously correlated with headache severity.[8]

Contrary to what might be expected, tumor size is not correlated with the presence of headache. Previous studies hypothesized that large tumors could promote distension of the dura mater and increase intrasellar pressure,[15] but the majority of real-world data did not encounter a direct correlation between the prevalence of headache and tumor volume.[2] [4] [8] [9] Perhaps the most determinant of headache is the rapid increase in intrasellar pressure. This explains why this symptom is so common in apoplexy and in rapidly expanding tumor situations (i.e. pituitary metastasis) and is less likely to correlate in slowly growing tumors, even in the larger ones, due to time for accommodation.[6] In fact, in benign pituitary adenoma, a higher tumor proliferation (evaluated by the Ki-67 index) had been previously correlated with headache prevalence.[9]

The production of hormones, such as PRL (in prolactinomas, the more common subtype of pituitary adenoma) and GH/IGF-1 (in acromegaly), is also related to increased prevalence in reported headaches.[5] [16] These neuroendocrine mechanisms are further supported by the observation that meningiomas, as other parasellar masses, do not show the same propensity to headache as pituitary adenomas.[17] Moreover, the alleviation of headaches after somatostatin analog or dopamine agonist treatment, even when there is no corresponding reduction in the size of the tumor, also acts as a concept proof.[4] [5]

PRL appears to be one of the key hormones, since prolactinoma subtype has the highest prevalence of reported headache.[2] [14] PRL secretion follows a circadian rhythm and is tightly regulated by the hypothalamus, an area also implicated in the pathogenesis of migraine. PRL receptors are expressed throughout the trigeminal pain pathway, including on peripheral nociceptors, the trigeminal ganglion, central trigeminal terminals, and within the trigeminal nucleus caudalis. Activation of these sites can modulate sensory transmission in the trigeminovascular system, promoting inflammation and triggering nociception.[18]

Some authors also suggested that PRL and GH-producing adenomas are particularly pronociceptive, and could release “algesic” peptides, interfering with endogenous analgesic agents such as endorphins and kyotorphins.[19]

Treatment

Prolactinomas are mainly treated with dopamine agonists instead of surgery. On the other hand, for the other hormone-secreting and non-functioning pituitary adenomas, the primary treatment should be transsphenoidal surgery.[20]

The most used dopamine agonist is cabergoline, due to its higher efficacy and tolerability compared to bromocriptine.[7] Treatment with cabergoline can achieve headache control in approximately 80-90% of patients.[21] [22] However, some patients may experience a paradoxical effect, with worsening pain and the onset of severe migraine-like attacks following the introduction of dopamine agonists, due to their ergot alkaloid properties. It is believed that this effect induces irritation in the trigeminal nerve system, mainly in the ophthalmic division. Unlike a high dose of parenteral dihydroergotamine, which blocks this pathway and helps prevent headache,[23] dopamine agonists do not achieve a clinically relevant dose and paradoxically stimulate this route.[5] In addition, there is evidence that migraineurs have highly sensitive D2 receptors,[24] which could be activated after dopamine agonist intake. In these cases of intolerance, surgery should be offered.[7]

Somatostatin analogs are used as adjuvant therapy in cases of acromegaly when surgery did not achieve remission. Octreotide can improve up to 64% of headaches.[3] One theory is that somatostatin analogs modulate the opioidergic system, resulting in analgesic effects and preventing unknown pronociceptive peptides from being released from the tumor.[17] This justifies the relief previously reported when used in a randomized clinical trial focused on primary cluster headache[25] and in a prolactinoma despite maintaining hyperPRL,[26] respectively.

Of note, the pain relief of these drugs (dopamine agonists and somatostatin analogs) in other scenarios, such as Cushing's Disease, TSHoma or non-functioning pituitary adenomas, is not yet fully documented.

Transsphenoidal surgery can ameliorate approximately 50-70%[3] [27] of headache complaints and usually is seen as early as the first post-surgery month.[28] However, a placebo effect and postoperative analgesia are some biases that could lead to a false high resolution of this symptom.[5] To date, no precise clinical factor has predicted postoperative headache relief.[27] Radiotherapy, which is mainly used in aggressive tumors, does not have strong evidence for alleviating pituitary adenoma associated headache.[3]

[Fig. 3] presents a flowchart with a suggestion for managing pituitary adenoma harboring headache as a main complaint.

Fig. 3 Suggested algorithm for treatment of headache in patients with pituitary adenoma. *In some patients, dopamine agonists can have a paradoxical effect and deflagrate headache in a migraine-like attack. NSAIDs = non-steroidal anti-inflammatory drugs; TSS = transsphenoidal surgery.

Conclusion

The relationship between pituitary adenomas and headache is multifaceted, involving neuroendocrine, structural, and nociceptive mechanisms. In prolactinomas specifically, elevated prolactin levels may influence the trigeminal pain pathway, while cavernous sinus invasion further contributes to symptomatology. Dopamine agonists, particularly cabergoline, remain the cornerstone of treatment for prolactinomas and have demonstrated efficacy in lowering PRL levels and alleviating headaches in most patients. Nonetheless, drug intolerance or paradoxical headache exacerbation presents a therapeutic challenge. In such cases, transsphenoidal surgery offers a valuable alternative, frequently resulting in both biochemical control and headache resolution. Given the complexity of the underlying mechanisms, treatment strategies should be individualized, particularly in refractory cases. A multidisciplinary approach, integrating endocrinology, neurology, and neurosurgery, is essential to optimize outcomes.

Conflict of Interests

The authors declare no conflict of interest.

Ethics Approval and Consent to Participate

Signed informed consent has been obtained directly from the patient. This study was approved by the Research Ethics Committee of Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (CAAE: 80733624.1.0000.0068).

• References

• 1 Ezzat S, Asa SL, Couldwell WT. et al. The prevalence of pituitary adenomas: a systematic review. Cancer 2004; 101 (03) 613-619
• 2 Abe T, Matsumoto K, Kuwazawa J, Toyoda I, Sasaki K. Headache associated with pituitary adenomas. Headache 1998; 38 (10) 782-786
• 3 Levy MJ, Matharu MS, Meeran K, Powell M, Goadsby PJ. The clinical characteristics of headache in patients with pituitary tumours. Brain 2005; 128 (Pt 8): 1921-1930
• 4 Levy MJ, Jäger HR, Powell M, Matharu MS, Meeran K, Goadsby PJ. Pituitary volume and headache: size is not everything. Arch Neurol 2004; 61 (05) 721-725
• 5 Suri H, Dougherty C. Clinical Presentation and Management of Headache in Pituitary Tumors. Curr Pain Headache Rep 2018; 22 (08) 55
• 6 Kreitschmann-Andermahr I, Siegel S, Weber Carneiro R, Maubach JM, Harbeck B, Brabant G. Headache and pituitary disease: a systematic review. Clin Endocrinol (Oxf) 2013; 79 (06) 760-769
• 7 Stumpf MAM, Pinheiro FMM, Silva GO. et al. How to manage intolerance to dopamine agonist in patients with prolactinoma. Pituitary 2023; 26 (02) 187-196
• 8 Yu B, Ji N, Ma Y, Yang B, Kang P, Luo F. Clinical characteristics and risk factors for headache associated with non-functioning pituitary adenomas. Cephalalgia 2017; 37 (04) 348-355
• 9 Schankin CJ, Reifferscheid AK, Krumbholz M. et al. Headache in patients with pituitary adenoma: clinical and paraclinical findings. Cephalalgia 2012; 32 (16) 1198-1207
• 10 Kawazoe Y, Kumon M, Tateyama S, Moriya S. Efficacy of cabergoline and triptans for cluster-like headache caused by prolactin-secreting pituitary adenoma: A literature review and case report. Clin Neurol Neurosurg 2020; 196: 106005
• 11 De Pue A, Lutin B, Paemeleire K. Chronic cluster headache and the pituitary gland. J Headache Pain 2016; 17: 23
• 12 Wang SJ, Hung CW, Fuh JL, Lirng JF, Hwu CM. Cranial autonomic symptoms in patients with pituitary adenoma presenting with headaches. Acta Neurol Taiwan 2009; 18 (02) 104-112
• 13 Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders. 3rd edition. Cephalalgia Int J Headache 2018; 38 (01) 1-211
• 14 Gondim JA, de Almeida JPC, de Albuquerque LAF, Schops M, Gomes E, Ferraz T. Headache associated with pituitary tumors. J Headache Pain 2009; 10 (01) 15-20
• 15 Arafah BM, Prunty D, Ybarra J, Hlavin ML, Selman WR. 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 (05) 1789-1793
• 16 Levy MJ, Matharu M, Goadsby PJ. Chronic headache and pituitary tumors. Curr Pain Headache Rep 2008; 12 (01) 74-78
• 17 Levy MJ. The association of pituitary tumors and headache. Curr Neurol Neurosci Rep 2011; 11 (02) 164-170
• 18 Al-Karagholi MAM, Kalatharan V, Ghanizada H, Gram C, Dussor G, Ashina M. Prolactin in headache and migraine: A systematic review of clinical studies. Cephalalgia 2023; 43 (02) 3331024221136286
• 19 Williams G, Ball JA, Lawson RA, Joplin GF, Bloom SR, Maskill MR. Analgesic effect of somatostatin analogue (octreotide) in headache associated with pituitary tumours. Br Med J (Clin Res Ed) 1987; 295 (6592) 247-248
• 20 Petersenn S, Fleseriu M, Casanueva FF. et al. Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement. Nat Rev Endocrinol 2023; 19 (12) 722-740
• 21 Colao A, Vitale G, Cappabianca P. et al. Outcome of cabergoline treatment in men with prolactinoma: effects of a 24-month treatment on prolactin levels, tumor mass, recovery of pituitary function, and semen analysis. J Clin Endocrinol Metab 2004; 89 (04) 1704-1711
• 22 Oliveira MDC, Barea LM, Horn APK. et al. Resolution of headache after reduction of prolactin levels in hyperprolactinemic patients. Arq Neuropsiquiatr 2020; 78 (01) 28-33
• 23 Hoskin KL, Kaube H, Goadsby PJ. 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
• 24 Mascia A, Afra J, Schoenen J. Dopamine and migraine: a review of pharmacological, biochemical, neurophysiological, and therapeutic data. Cephalalgia 1998; 18 (04) 174-182
• 25 Matharu MS, Levy MJ, Meeran K, Goadsby PJ. Subcutaneous octreotide in cluster headache: randomized placebo-controlled double-blind crossover study. Ann Neurol 2004; 56 (04) 488-494
• 26 Williams G, Ball J, Bloom S, Joplin GF. Improvement in headache associated with prolactinoma during treatment with a somatostatin analogue: an “N of 1” study. N Engl J Med 1986; 315 (18) 1166-1167
• 27 Hantelius V, Ragnarsson O, Johannsson G. et al. Headache in patients with non-functioning pituitary adenoma before and after transsphenoidal surgery - a prospective study. Pituitary 2024; 27 (05) 635-643
• 28 Jang MK, Park CG, Jang S, Kim EH. Prevalence and Impact of Postoperative Headaches in Nonfunctioning Pituitary Macroadenoma Patients: A Longitudinal Cohort Study. World Neurosurg 2020; 133: e633-e639

Publikationsverlauf

Eingereicht: 15. September 2025

Angenommen: 10. November 2025

Artikel online veröffentlicht:
29. Dezember 2025