In this prospective study we have evaluated headache by using the MIDAS questionnaire before and at 12-months after TSS in 101 patients with NFPA. We found that 67% of patients reporting disabling headache prior to surgery had a clinically relevant improvement whereas 15% of patients without preoperative disabling headache developed headache post-surgery. Among patients who reported disabling headache before surgery, there were improvements in headache frequency and intensity, as well as in the MIDAS score, at 12 months post-surgery. In these patients, as well as for the cohort as a whole, the QoL improved 12 months after surgery. However, patients who reported deterioration, no improvement, or the development of new headaches did not experience any improvement in QoL.

Although these results agree with two previous prospective studies of similar sizes [15, 16], the present study focused on a more homogenous cohort comprising only patients with NFPAs and across a longer follow-up time of 12 months. Other smaller studies have also reported similar findings, two of them using headache evaluations before and 6-months after surgery using the Headache Impact Test (HIT)-6 [7, 8]. One previous study had an 18-month follow-up period including patients with both functioning and NFPAs, which was noted as a study limitation [13].

Our results showed that younger age and Ki-67 > 3% was associated with disabling headache before surgery in univariable analysis. Other previous studies of patients with pituitary tumors and headache have shown similar relationships between patient age [2, 12, 15, 30], age and Ki-67 level [13, 31]; however, in our multivariable analysis, only younger age was independently associated with headache.

The association between headache and younger age could be partially explained by the MIDAS questionnaire’s emphasis on the impact of headaches on working ability, as younger patients are more likely to be below retirement age. Moreover, the association between Ki-67 as a proliferative marker with headache may be explained by the relationship of different headache-specific pathophysiological mechanisms with more progressive pituitary tumors. Furthermore, other studies have identified increased intracranial pressure due to mass effect, as well as pain-receptor activation due to intrasellar pressure, as possible causes of pituitary tumor-associated headache [10, 32]. Other studies suggest a more multifactorial mechanism, including cavernous sinus invasion, dural stretch, compression of the optic chiasm, cystic or solid mass of tumors, and hormone hypersecretion [5, 33].

It has been suggested that tumor extension rather than tumor size might cause headache [5, 10, 34]. An intact sellar diaphragm and cavernous sinus has the potential of increasing the intrasellar pressure [5, 10, 35], although headache might also develop secondary to more extensive and infiltrative growth [5]. In this study we chose to define tumor configuration as more extensive upward tumor growth if compression of the optic chiasm was present and lateral extension as cavernous sinus invasion. We observed that patients diagnosed with optic chiasm compression reported disabling headaches less frequently. This phenomenon could be explained by patients seeking care earlier due to headaches, leading to the diagnosis of NFPA before symptoms from optic chiasm compression occur. Another possible explanation may be a reduction in intrasellar pressure resulting from when tumor growth causes penetration of the sellar diaphragm. No association between grade of cavernous sinus invasion and preoperative headache was, however, found.

Considering the high prevalence of headaches in the general population [9], it is improbable that every case of reported disabling headache is associated with a pituitary tumor. However, our findings of improved headache post-surgery in a significant number of patients suggest that their status according to the International Classification of Headache Disorders ICHD-3 criteria [22] qualified them as presenting pituitary tumor-associated headache prior to surgery. Our results agree with previous studies showing similar post-surgical improvements (49–81%) [10, 15, 30, 36] and deteriorations in symptoms (8–17%) [7, 15, 36]. These findings offer important information that should be provided to patients during preoperative assessment regarding possible improvement, deterioration, or development of new headache after TSS.

Discovery of factors associated with improvement of headache after TSS would be beneficial for preoperative clinical decision-making. However, in this study no such predictive factors were found in regression analyses, including preserved hormonal function or presence of postoperative residual tumor.

Previous studies suggest that headache, both before and after TSS adversely affects patients through reduced QoL [8, 18]. In the present study, patients reporting a clinically relevant improvement in their headache also showed significant improvement in their QoL at 12-months post-surgery. The patients that reported deteriorated symptoms, no improvement, or development of a new headache post-surgery, did not show significant improvement in their QoL.

This study has limitations. These include the relatively small number of patients reporting disabling headache, which made obtaining statistical significance and analytical power difficult and complicated the identification of predictive factors. Additionally, because patients with microadenomas rarely meet the criteria for TSS, we did not assess tumor size according to volume rather than classifying them as either a micro- or macroadenoma. Furthermore, although MIDAS and HIT-6 are both accepted as clinically accurate instruments for measuring headache, it is possible that headache intensity can more significantly influence HIT-6 scores, whereas headache frequency may disproportionately influence MIDAS scores [37].

Strengths of the study include its prospective design and a homogenous cohort of patients with the same diagnosis, frequently lacking in previous studies [7]. By focusing exclusively on NFPA patients we increase the likelihood that observed postoperative changes in headache are related to the tumor itself, rather than a being consequences changes in of hormone overproduction. Additionally, this study offers information across a longer time period (12-months after TSS) compared to most previous studies.