In this study, a comprehensive assessment of cognitive function, clinical and sociodemographic characteristics, and detailed radiologic imaging of patients with prolactinoma was performed. Patients with prolactinoma were found to have impaired cognitive function compared to the healthy population. Long-term, visual and verbal memory, attention, concentration, and language functions were lower than in the healthy group. While patients with normoprolactinemia had higher short-term memory scores, hypoprolactinemia, and hyperprolactinemia had the lowest scores. When evaluated with DTI, the R-UF tract was impaired in patients with prolactinoma compared to healthy controls, but no significant difference between the tracts was found after multiple corrections. The low FA values in the R-UF tract were associated with poorer scores on neuropsychological tests. In addition, measured R-UF FA values were lowest in patients with hypoprolactinemia and highest in patients with normoprolactinemia.

The observation that cognitive abilities are impaired in patients with prolactinoma has attracted the attention of clinicians and has become the subject of research. Bala et al. reported that the attention and working memory of patients with prolactinoma are lower than in the normal population. They explained that the impairment of cognitive function is related to the prolactin level but not to the size of the adenoma [24]. Another study reported that patients with prolactinoma performed worse on tests of verbal and nonverbal memory and attention than healthy controls, emphasizing the negative effects of high prolactin levels on cognitive function [4]. Chen et al. reported that patients with prolactinoma showed slower responses and impaired attentional processing abilities. This study emphasizes the inverse relationship between cognitive function and prolactin levels [25]. Montalvo et al. prospectively followed seven patients with prolactinoma for cognitive function. They subjected the patients to a cognitive assessment at the time of diagnosis and one year after starting treatment with cabergoline. They showed significant improvements after treatment compared to baseline in processing speed, working memory, visual learning, reasoning, and problem-solving ability. They cited the normalization of prolactin levels and possible procognitive effects of cabergoline as potential mechanisms for this improvement [26]. In this study, we subjected patients with prolactinoma to a comprehensive assessment of cognitive function. The result was that the long-term visual and verbal memory, attention, concentration, and language functions of patients with prolactinoma were impaired compared to the healthy population. These results emphasize the presence of cognitive dysfunction in patients with prolactinoma reported in the literature. We also found that short-term memory was impaired in patients with hyper- and hypoprolactinemia, especially in patients with hypoprolactinemia. It is well known that low prolactin levels are associated with decreased sexual desire, sexual dysfunction, and reduced quality of life [27,28,29]. However, this study is significant in showing that prolactin levels that are too low and too high negatively affect cognitive function for the first time. This finding emphasizes that clinicians should avoid overtreatment of patients with prolactinoma.

The mechanism underlying the cognitive impairment observed in patients with prolactinoma is still unclear. Many studies reported an association between elevated prolactin and cognitive impairment but did not specify how it affects cognitive function [24,25,26]. Cao et al. investigated the cause of cognitive impairment in patients with prolactinoma using attention EEG. They reported that patients with prolactinoma showed greater frontoparietal theta and alpha coherence in the right lateral hemisphere and that this increase in coherence correlated with prolactin levels. It has been suggested that increased frontoparietal alpha and theta coherence is a marker of poor attentional processing in patients with prolactinoma [30]. Another study found that response activation and inhibition measured by EEG were lower in patients with prolactinoma than in healthy controls. They found that this was associated with decreased frontal theta wave oscillation and that prolactin elevation and theta wave oscillation were inversely related. They concluded that this may be the underlying mechanism of cognitive dysfunction in patients with prolactinoma [6]. In one study, patients with prolactinoma were reported to have impaired cognitive flexibility and lower performance in task situations. EEG showed decreased frontal theta energy as a marker of this cognitive dysfunction. It was also reported that frontoparietal connectivity was impaired [5]. Yao et al. found that cognitive impairment in female patients with prolactinoma was associated with a decrease in brain gray matter volume. A correlation was found between decreased brain volume and prolactin level [7]. Since the volume of brain gray matter has been reported to be reduced in patients with prolactinoma and connectivity between the centers of cognitive functions is impaired, the need for structural assessment of the pathways in patients with prolactinoma has become apparent.

The main pathways connecting the cortex regions in the brain where cognitive functions are carried out are the pathways in the brain’s white matter [31]. DTI is an imaging technique that can assess white matter microstructures in the central nervous system. DTI measures the directionality of water molecule diffusion to generate tissue contrasts that can be used to evaluate axonal organization in the central nervous system [8]. The directional information can be used to select and trace ascending and descending pathways in the brain, known as tractography [23]. This study examined white matter tracts in the brains of patients with prolactinoma and healthy controls for the first time and compared them with DTI. We found lower FA values in the R-UF tract in patients with prolactinoma compared to the healthy population, indicating neuronal damage. However, no significant difference was found between the tracts after multiple corrections for the measured low FA values. The UF is a bidirectional, long-range white matter pathway that connects the lateral orbitofrontal cortex and Brodmann area 10 to the anterior temporal lobe [32]. Abnormalities in the UF are associated with various psychiatric disorders and play a role in memory, language, and social-emotional processing [33]. In our study, neuropsychological tests showed that long-term visual and verbal memory, attention, concentration, and language functions were impaired in patients with prolactinoma compared to the healthy population. In addition, a correlation was found between the FA values measured in the R-UF tract and the results of the neuropsychological tests. Another finding was that the lowest FA levels of R-UF measurements occurred in patients with hypoprolactinemia and the highest in patients with normoprolactinemia. These results suggest that high and too-low levels of prolactin may lead to cognitive dysfunction by causing structural disruption of brain tracts.

An explanation is why a difference was only found in R-UF among the 42 tracts evaluated. One possible explanation is that UF is one of the last tracts of white matter to reach its peak of maturation, with the developmental period completed at 28–35 years of age [34]. In our study population, the age of patients was 30 ± 7 years, and the UF tract may have been more affected by prolactinoma than others due to its progressive development. However, the reason for the observed right-left lateralization is unclear. Similarly, different lateralization findings are reported in the small but growing literature on UF [35,36,37]. One possible explanation could be that we recruited right-hand dominant participants to ensure the most significant possible standardization of the study. All results and explanations are hypothetical, and further studies are needed.

The prolactin mediates neuroprotection, plays a role in the proliferation of oligodendrocyte precursor cells, releases neurotrophic factors, and increases white matter volume [38,39,40,41,42,43,44,45,46]. In their study, Paul et al. reported that moderately high prolactin levels reduced retinal nerve fiber layer damage in patients with pituitary macroadenoma and compression of the optic chiasm. In contrast, the opposite effect was observed at very high and low prolactin levels [43]. In addition, the protective role of prolactin in white matter damage has been demonstrated in patients with multiple sclerosis and mouse models of spinal cord injury [44,45,46]. These studies link increased oligodendrocyte proliferation and remyelination after injury to increased prolactin levels and white matter volume [44,45,46]. In another study, remyelination after anterior visual pathway compression injury in a patient with empty sella syndrome was shown to be sensitive to changes in serum prolactin levels [47]. The low FA values observed in our study of the neurons that form the tracts in the white matter of the brain responsible for cognitive function in patients with prolactinoma underscores the relationship between high prolactin and neurotoxicity or neuroprotection previously reported in other studies. On the other hand, we report that lower than normal prolactin levels may also cause damage to neurons in the white matter of the brain and corresponding cognitive dysfunction, which has not been previously reported.

This study has some limitations. First, the study’s cross-sectional nature and the fact that the patients participated at different stages, such as using cabergoline or not, during their treatment. However, we applied strict exclusion criteria to rule out many conditions that could affect the assessment of cognitive function. This allowed us to ensure that the results obtained could be attributed to prolactinoma. Furthermore, by recruiting patients at different treatment stages, we assessed the impact of treatment outcomes on cognitive function. Another limitation was that the findings could indicate neuronal damage and could not be confirmed at the pathological and molecular levels. However, the detailed clinical, radiological, and neuropsychological evaluation provided new insights and a different perspective for understanding cognitive dysfunction in patients with prolactinoma.