Prolactinoma is characterized by excessive secretion of prolactin from the pituitary gland, accounting for one-half of pituitary adenomas, 80% of which are microadenomas . Non-functional adenomas account for one-third of pituitary adenomas, and the vast majority of them do not cause clinical manifestations due to the lack of excessive hormone secretion and their small size. Non-functional microadenomas often exhibit no clinical symptoms, and their diagnosis needs to entail the evaluation of multiple hormone levels and the making of an exclusion diagnosis [11, 5]. For patients with a specific imaging diagnosis of microadenomas, clinical manifestations combined with laboratory tests, such as growth hormone, insulin-like growth factor 1, adrenocorticotropic hormone, cortisol, and thyroid-stimulating hormone, can effectively exclude growth hormone adenoma, adrenal hormone adenoma, and thyroid-stimulating hormone adenoma. The remaining prolactin microadenomas and non-functional microadenomas are distinguished by examining the excessive secretion of prolactin in the pituitary gland. Excluding some physiological or pathological conditions, such as pregnancy, thyroid disorders, and antidepressants, hyperprolactinemia can effectively manifest as excessive secretion of pituitary prolactin . However, macroprolactinemia is a pseudohyperprolactinemia caused by the accumulation of macromolecular prolactin, mainly the complex of prolactin and its autoantibody, in the circulation, which is not an excessive secretion of pituitary prolactin [12, 7]. Therefore, neglecting the existence of macroprolactinemia can lead to the misdiagnosis of non-functional microadenomas as prolactin microadenomas and even result in the wrong treatments.
Through gel filtration chromatography and prolactin luminescence detection, we confirmed that prolactin in macroprolactin microadenoma samples was mainly in the form of macromolecules, and there was no accumulation of small molecule prolactin, which confirmed that this was a non-functional microadenoma combined with the presence of macroprolactinemia. The presence of macroprolactin microadenomas indicated that we should not make a diagnosis of prolactin microadenomas for patients with clear imaging diagnosis of microadenoma and hyperprolactinemia unless the macroprolactinemia screening is accomplished. The macroprolactinemia screening could prevent non-functional microadenomas from being misdiagnosed as prolactin microadenomas. In addition, several chemiluminescence immunoassay analyzers were used to detect the value of prolactin in the chromatographic elution from the sample of macroprolactin microadenomas. These results showed that various commercial prolactin detection reagents, including Roche's second-generation prolactin testing reagent, have high cross-reactivity with macroprolactin. Therefore, screening for macroprolactinemia in hyperprolactinemia cases is indispensable and universal, regardless of the detection reagents and instruments used.
In this study, we identified 9 patients (10.7%) with macroprolactin microadenomas among 84 patients with hyperprolactinemia microadenomas, which is lower than the prevalence rate (15% – 46%) of macroprolactinemia in hyperprolactinemia [13, 14] and higher than the incidence (3.5%) of macroprolactinemia in prolactinomas . During the follow-up of patients with macroprolactin microadenoma: (1) the 5 patients receiving bromocriptine treatment showed no change in tumor size and had no corresponding clinical symptoms as the 4 patients without bromocriptine treatment, indicating that bromocriptine therapy was not only ineffective, but also unnecessary for patients with macroprolactin microadenomas. (2) The results in Table 1 suggest that there was no statistically significant difference in the related symptoms between the two groups of macroprolactin microadenomas and non-functional microadenomas. (3) After screening for macroprolactinemia, the concentration of prolactin in patients with macroprolactin microadenomas was within the normal range and similar to that in patients with non-functional microadenomas. These data fully demonstrate that the nature of macroprolactin microadenoma is actually non-functional microadenoma . Moreover, there are few or no associated symptoms in macroprolactin microadenomas in the absence of biological activity of macroprolactin in the body. Menstrual disorders, in some cases, may be related to other factors besides the pituitary, which is consistent with related reports .
Although the macroprolactin microadenomas are actually non-functional microadenomas, the prolactin concentration within them is moderately elevated (50 ~ 150 ng/mL) before macroprolactin screening (Figure. 3C). Due to the absence of screening for macroprolactinemia, some patients with macroprolactin microadenomas were mistakenly treated with bromocriptine. The rate of drug use reached 55.6%, which was significantly higher than that of non-functional microadenomas (0.0%, P < 0.05). However, there was no significant difference in the rate of drug use between the macroprolactin microadenomas and prolactin microadenomas (38.7%, P > 0.05).