Pituitary adenomas are tumors that occur in the pituitary gland and account for the largest portion of all intracranial neoplasms with an overall prevalence of approximately 10 % to 25 % (Ezzat et al., 2004[8]). Depending on biological functioning, pituitary adenomas are commonly divided into three categories: benign adenoma, invasive adenoma, and carcinomas (Zhang, 1990[32]). The majority of adenomas are benign, while approximately 35 % are invasive adenoma and just 0.1 % to 0.2 are carcinomas (Daly et al., 2006[5]). However, only a minority of pituitary adenomas are symptomatic. The most characteristic-presenting symptoms of pituitary adenomas include visual deficits and abnormal pituitary hormone secretion (Levy et al., 2005[20]). Moreover, pituitary adenomas have been found to be associated with pituitary disorders and various psychiatric manifestations such as emotional instability, depression, apathy, anxiety, easy hostility and irritability (Donoho et al., 2017[7]). The primary treatments of pituitary adenomas involve adjustment of hormone secretion and resection of the tumor (Wang et al., 2017[28]). Reducing hormone hypersecretion and correcting hormone deficiencies may improve clinical symptoms and decreasing tumor size by surgery may relieve the mass effect of pituitary adenomas (Pineda et al., 1982[22]). Specific treatment plans for pituitary adenomas patients are made depending on the specific type of tumor, and administered with a comprehensive therapy approach that include neurosurgery and endocrinology (Wang, 1988[27]). Transsphenoidal adenectomy is a common strategy for the excision of pituitary tumors, which aims to remove the tumors without affecting the function of optic nerves and the brain (Pituitary Disorders/Neuroendocrinology, 2016[23]). However, in numerous patients, surgery has been found to inevitably damage the function of the brain and impair the cognitive functions (Karki et al., 2017[16]). Moreover, long-term use of endocrine drugs might cause various adverse effects such as fatigue, nausea, and vomiting (Zhang et al., 2017[33]). In addition, incomplete resection and recurrence are still obstacles to the treatment of pituitary tumors (Vonor et al., 2017[25]). Therefore, finding proper postoperative adjuvant drug therapy is in special need.

Recent studies have found that 18 beta-glycyrrhetinic acid (GA), a natural compound extracted from liquorice, inhibits renal 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) and exhibits significant anti-tumor effects on pituitary adenoma (Wang et al., 2014[26]). GA induced apoptosis in pituitary adenoma cells by activating mitochondria-mediated reactive oxygen species (ROS)/mitogen-activated protein kinase pathways (Wang et al., 2014[26]). In particular, GA activated c-Jun N-terminal kinase (JNK), calcium/calmodulin-dependent protein kinase II (CaMKII), and P38 (Wang et al., 2014[26]). These findings provide experimental evidence that GA may serve as a novel chemotherapeutic agent for treating pituitary adenoma.

In the presented study, we recruited 647 pituitary adenoma patients who underwent surgery to further investigate the effects of GA treatment. Patients' cognitive functions were tested when treated with GA or placebo one month and six months after surgery. This paper aimed to explore the role of GA in postoperative clinical recovery of pituitary adenoma patients.

Pituitary adenomas, the most common tumors of all intracranial neoplasms, may cause either symptoms of mass effect or symptoms of hormone abnormal production (Molitch, 2017[21]). Besides physical damages, patients with pituitary adenomas always suffer from cognitive impairments, mainly in memory and executive functions (Kalinin et al., 2017[15]). Surgery has always been considered the best way to treat pituitary adenomas, whereas few studies have been focused on the postoperative treatment of patients (Hendrix et al., 2017[12]). Recent studies have shown that surgeries may inevitably damage the cognitive functions (mainly in executive functions and memory) in patients (Fu et al., 2017[10]). Surgery should not exacerbate the cognitive impairment of patients in theory, so more exhaustive researches are needed to investigate the impact of surgery on cognitive function (Iglesias et al., 2017[14]). Therefore, it is necessary to monitor the changes and to improve the impairment of cognitive function after surgery. In this paper, we recruited patients with pituitary adenomas and tested their cognitive functions when treated with GA or placebo before and after surgery. We aim to investigate the efficacy of GA in postoperative clinical application.

GA and its precursor glycyrrhizin (GN) abundantly exist in the Licorice roots and possess various therapeutic properties (Greaves, 1990[11]). Recent studies have found that GA inhibits 12-O-tetradecanoyl phorbol-13-acetate-induced cutaneous oxidative stress and tumor progression in mice (Agarwal et al., 2005[1]). DMBA/TPA-induced skin tumor formation could also be suppressed by GA (Agarwal et al., 1991[2]). In addition, GA played a protective role in hepatocellular carcinoma development by reducing immunosuppression mediated by hepatic stellate cells in the tumor microenvironment (Kuang et al., 2013[18]). While GA has been shown to exhibit anti-viral and anti-inflammatory effects, it also displays cytotoxic effects on human hepatocellular carcinoma, breast cancer (Wang et al., 2015[29]) and ovarian cancer (Yang et al., 2012[31]). It has been shown that GA induced apoptosis in various cancer cells, including promyelotic leukemia HL-60 cells, human stomach cancer cells, and hepatoma cells (Hibasami et al., 2006[13]). Our study is based on the facts that GA exhibited potent cytotoxicity and induced apoptosis by activating ROS/MAPKs-mediated pathway in pituitary adenoma cells (Wang et al., 2014[26]). These findings suggest that GA may serve as a novel chemotherapeutic potential for treating pituitary adenoma and deserves further clinical research. Previous studies demonstrated the protection of low-dose GA (50 mg/kg) against TP-induced hepatotoxicity in rats, which may mediate via anti-inflammation, antioxidation, and antiapoptosis (Yang et al., 2017[30]). In addition, the protective effect is dose-related, which is only mediated by low-dose GA (50 mg/kg), but not high-dose GA (100 mg/kg) (Yang et al., 2017[30]). Thus, the doses of GA should be carefully considered in treating patients. A recent study examined the kinetics and dynamics of orally administered GA in humans (Krahenbuhl et al., 1994[17]). Different oral doses of GA (500, 1000, or 1500 mg) were administered to healthy volunteers (Krahenbuhl et al., 1994[17]). Based on the single dose kinetics, the kinetic/dynamic analysis revealed that after multiple doses of 1.5. g GA/day, the 11 beta OHSD might be constantly inhibited, whereas at daily doses of 500 mg or less, such an inhibition might occur only transiently (Krahenbuhl et al., 1994[17]). Besides, various previously published pilot studies have applied the dose of 500 mg in human (Farese et al., 2009[9]; Serra et al., 2002[24]). So, a low-dose 500 mg GA was used in our paper. We found that GA exhibited positive effects on orientation, language (expression), memory (recall), practice, abstract thinking, and MMSE one month after surgery, but lost efficacy after six months only except for abstract thinking. Since when six months after surgery, most of the cognitive function scores were higher compared with one month after surgery, so GA might accelerate the recovery of functions in language (expression), memory (recall), practice, and MMSE. Notably, GA possessed a long-termed effect on abstract thinking. These functions might correlate with the anti-pituitary adenoma effect of GA by inducing apoptosis in remaining tumor tissues.

Although pituitary adenomas are commonly considered as benign intracranial neoplasms, they are frequently found to exhibit invasive abilities (Babbo et al., 2014[3]). In numerous patients, peripheral brain tissues including parasellar and suprasellar regions, bilateral cavernous sinus and sphenoid sinus are invaded by pituitary adenomas (Kwancharoen et al., 2014[19]). In addition, pituitary adenomas could even damage brain tissues and structures such as those in the vomer peripheral region and sellar region (Kwancharoen et al., 2014[19]). Thus, pituitary adenomas may possess biological characteristics of malignant tumors, leading to a reduction in complete resection rate and a higher recurrence rate, even being facilitated with radiotherapy or chemotherapy adjuvant therapy (Ding et al., 2014[6]). It is reported that 10 % to 35 % of pituitary adenomas recurred in 4 to 20 years' intervals (Broder et al., 2014[4]). The initial tumor size, the tumor excision extent and the tumor regrowth rate are considered to be determining factors in pituitary adenoma recurrence (Broder et al., 2014[4]). Therefore, the complete treatment of pituitary adenomas is extremely difficult and is now a major health issue that raises a wide range of research concerns. In this paper, we found that GA could significantly reduce the recurrence rate within 5 years after surgery, suggesting that GA could be used as a novel treatment strategy against recurrent pituitary adenoma, although the detailed functional mechanism of GA remains to be further elucidated.

In conclusion, GA significantly improved various cognitive functions at the early stage after surgery and possessed a long-termed efficacy on abstract thinking. In addition, GA inhibited the five-year recurrence rate of the recruited pituitary adenomas patients. These findings suggest that GA might serve as a novel chemotherapeutic potential for inhibiting the recurrence of pituitary adenoma.

Not applicable.

The authors declare that they have no competing interests.

Informed consent was obtained from all individual participants included in the study.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.