Zisheng Yan
Chen Liang2
Yuntao Li- 1Department of Neurosurgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
- 2Department of Neurology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
- 3Department of General Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
Pituitary adenomas (PAs), accounting for 10–15% of intracranial tumors, cause significant morbidity through endocrine dysfunction and mass effects. While current treatments (surgery, pharmacotherapy, radiation) face challenges such as drug resistance, recurrence, and metabolic complications, curcumin emerges as a promising multi-target agent for PA management. This review synthesizes evidence on curcumin’s dual roles: suppressing tumor progression and ameliorating hormone-driven metabolic disorders.
Antitumor mechanisms: Curcumin inhibits PA proliferation by modulating cell cycle proteins, inducing apoptosis via pro-apoptotic protein upregulation and anti-apoptotic suppression. It targets key pathways like NF-κB, reducing VEGF/HIF-1α-driven angiogenesis and MMP-9-mediated invasion. Synergistic effects enhance existing therapies: low-dose curcumin potentiates bromocriptine in prolactinomas by regulating ERK/EGR1 and AKT/GSK-3β, while in aggressive PAs, it may overcome temozolomide resistance by downregulating DNA repair enzymes.
Metabolic regulation: Beyond antitumor effects, curcumin mitigates hormone-induced metabolic dysregulation. It suppresses excess ACTH, GH, and prolactin secretion in functional PAs. For GH adenomas, curcumin improves insulin resistance by activating AMPK, enhancing skeletal muscle glucose uptake, and suppressing hepatic gluconeogenesis. It also reduces inflammatory cytokines and oxidative stress, protecting against cortisol-induced glycometabolic dysfunction and PRL/GH-mediated bone loss via RANKL/OPG pathway modulation.
Conclusion: Curcumin’s ability to concurrently target tumor growth, hormone hypersecretion, and metabolic complications positions it as a unique “one drug, multiple effects” candidate. Future research must prioritize PA-specific mechanistic studies and advanced delivery systems to realize its clinical potential.
1 Introduction
PAs are tumors that originate in the pituitary gland and currently account for 10-15% of intracranial tumors, including functioning pituitary adenomas (FPAs, approximately 70%) as well as non-functioning pituitary adenomas (NFPAs, approximately 30%) (1). NFPAs mainly cause locoregional effects in the saddle region, whereas FPAs can additionally produce excessive amounts of pituitary hormones, leading to pathophysiological changes that result in hormonal imbalances in the human body, such as prolactin adenoma that may lead to male dysfunction, and growth hormone (GH) adenoma that may induce acromegaly, which can lead to a range of metabolic disorders (2). Although the majority of PAs are benign and manageable with a combination of surgery, pharmacotherapy, and radiation (3). treatment challenges remain. For example, dopamine agonists like cabergoline and bromocriptine, the first-line therapy for prolactinomas, exhibit unsatisfactory efficacy in 10-30% of patients due to resistance or intolerance (4). There is a lot of research on targeted drugs that may potentially act on PAs, but fewer types are available to put into clinical trials at this stage (5). Similarly, there is still a high recurrence rate of surgical treatment of aggressive PAs and the risk of hypopituitarism associated with radiation therapy (6).
Curcumin is a naturally occurring polyphenolic compound extracted from the rhizome of the plant Curcuma longa, whose structure consists of two benzene rings connected by a β-diketone bridge, which confers on it a unique antioxidant and electron-donor capacity (7). Curcumin has been used for thousands of years in some traditional medicines, mainly for anti-inflammatory, antioxidant and anti-infective treatments (7). In previous studies, curcumin has demonstrated positive effects in the treatment of a variety of tumors (8, 9). Recently, it has been suggested in several studies that curcumin may play a role in the growth, autophagy, and drug resistance of PAs (10, 11), thereby exerting an anti-tumor effect. Further, curcumin has been studied in numerous endocrine studies for its potential role in improving glucose metabolism, regulating lipid metabolism, and as an anti-inflammatory and antioxidant (12, 13). These features give curcumin a unique advantage in the treatment of PAs, as it may target multiple aspects of proliferation, hormone secretion, and metabolic disorders simultaneously, thus compensating for the single-acting limitations of existing drugs (e.g., dopamine agonists, somatostatin analogs). Two databases, PubMed and Web of Science, were used for this literature screening. Titles were screened for the terms “pituitary adenoma” and “curcumin”, and relevant articles including basic research, clinical research, and reviews were retained.
Molecular mechanism of curcumin against pituitary adenomas
1. Inhibition of tumor cell proliferation and induction of apoptosis
Previous studies in other tumor cells have shown that curcumin has a corresponding antitumor potential (8). Inhibition of cell proliferation and induction of apoptosis are considered to be one of the main mechanisms by which curcumin exerts its anticancer effects. On the one hand, curcumin enhances the expression of pro-apoptotic proteins such as Bax, PUMA, Noxa, Bak and Bim, or apoptosis receptors such as TRAIL-R1/DR4 and TRAIL-R2/DR5 (14, 15); on the other hand, curcumin reduces the expression of anti-apoptotic proteins such as Bcl-2, Bcl-XL, survin, and XIAP(Table 1). Further, curcumin can directly induce apoptosis (20). or directly inhibit cell proliferation by arresting the cell cycle in the G2/M phase (21). As early as 2002, Mukhopadhy et al. showed that curcumin can regulate the levels of cell cycle protein-dependent kinases (CDK) and cell cycle proteins by increasing the expression of CDK inhibitors (22).
Table 1. Mechanism of curcumin in the treatment of pituitary adenomas.
And in PAs, a 2008 study by Miller et al. noted that curcumin inhibited the colony-forming ability of PA cells (17). The growth-inhibitory effect of curcumin was accompanied by decreased expression of cyclin D3 and ser 780 phosphorylation of retinoblastoma protein. However, at the time, this study did not explore the molecular mechanism of this effect any further. Subsequent studies have suggested that curcumin may affect the proliferation of PA cells by modulating some of the classical signaling pathways, and curcumin has been shown to be a potent inhibitor of the NF-κB pathway, which has been implicated in the growth of colon, breast, and prostate cancers, among others, in the literature. For instance, one study demonstrated that curcumin induced growth inhibition in mouse AtT20 cells by suppressing NF-κB activity (23). In addition, curcumin down-regulated the anti-apoptotic protein Bcl-xL, depolarizing the mitochondrial membrane and leading to apoptotic cell death (18). Another study in the same year similarly demonstrated that curcumin leads to decreased expression of NF-κB in other types of PA cells (24). And this study showed that curcumin-induced apoptosis involves inhibition of Bcl-2, stimulation of cleaved caspase-3, and induction of DNA fragmentation.
2 Anti-angiogenesis and invasion inhibition
The anti-angiogenic effect of curcumin has been demonstrated in a variety of tumor cells. Tumor growth, especially in tumors with malignant behavior, where continuous blood supply is the common denominator, tumor vasculature is widely used as a potential target for the treatment of various cancers (25). In studies as early as 2006, it was noted that curcumin was able to inhibit NF-κB-induced VEGF expression, which led to a reduction in angiogenesis (26). In addition, curcumin treatment may lead to a reduction in the expression of MMP-9, an enzyme that degrades the extracellular matrix and is therefore an important marker of tumor invasion and metastasis (27). Several subsequent studies have also indicated that curcumin may inhibit tumor angiogenesis and tumor invasion and metastasis in other tumors such as liver cancer and glioma (28, 29).
In 2012, Shan et al. showed that curcumin may inhibit the growth of PAs by inhibiting the synthesis of HIF-1α and the release of VEGFA in PAs (19). These two key components are involved in tumor neovascularization through angiogenesis, and this inhibitory effect of curcumin was demonstrated in AtT20 cells in mice and GH3 cells in rats. In our previous study, we also found that PA cells were able to induce monocyte osteoclast differentiation and promote bone invasion in a paracrine manner by activating the PKCθ/NF-κB/IL-1β pathway, which also provides a theoretical basis for the inhibition of angiogenesis and invasion of PAs by curcumin (30).
3 Regulation of hormone secretion and metabolic homeostasis
The secretion of hormones is accomplished by different glands in the body, affecting a variety of physiological functions, and abnormalities in their secretion can also cause a variety of pathological manifestations. Curcumin is one of the most widely researched drugs for the treatment of endocrine disorders and has unique antioxidant and anti-inflammatory properties. The use of curcumin can lead to significant changes in the levels of many hormones in the body. Polycystic ovary syndrome is a common condition affecting women of childbearing age that can manifest with marked inappropriate gonadotropin secretion and hyperandrogenemia. The disease is strongly associated with oxidative stress. Treatment with curcumin leads to downregulation of the inflammatory state through activation of Nrf 2, IL-SIRT 1 and PGC-1α activation (31). Dehydroepiandrosterone levels were significantly reduced while patients’ estradiol levels remained stable (32). It has been noted in several studies that curcumin-treated patients with type 2 diabetes experienced a significant decrease in serum leptin levels and significant weight loss (33, 34). In fact as early as 2006, the anti-inflammatory effect of curcumin, perhaps effective in the treatment of obesity, was noted in a study by Matchanickal et al (35). On the other hand, curcumin’s effectiveness in treating thyroid dysfunction has been mentioned in many studies. In some models of thyroid function impairment caused by lithium or sodium fluoride exposure, the addition of curcumin significantly elevated TSH secretion levels in rats and improved the symptoms of thyroid dysfunction. In cell lines of papillary thyroid carcinoma, curcumin also effectively inhibited the survival and invasive behavior of tumor cells, and these effects might be related to endoplasmic reticulum stress and cell autophagy.
The key pathological feature of FPAs is excessive secretion of anterior pituitary hormones, leading to associated metabolic abnormalities and clinical manifestations. Bangaru et al.’s study demonstrated that curcumin significantly reduces the secretion of adrenocorticotropic hormone (ACTH) in PA cells, and curcumin exhibits a relatively pronounced concentration-dependent inhibitory effect on ACTH secretion in AtT20 cells (18). This effect may be related to the inhibition of NF-κB transcriptional activity, thereby reducing the expression of its downstream target genes (such as Bcl-xL). In studies using GH3 and MMQ cells, high concentrations of curcumin may also inhibit the excessive secretion of prolactin and growth hormone (16). Although there are minor differences in the doses and patterns of curcumin’s inhibitory effects on hormone secretion across these studies, this does not preclude the hypothesis that such effects indeed exist. The molecular mechanisms underlying these hormone-inhibitory effects have not been fully elucidated, but these phenomena suggest that curcumin may possess objective therapeutic potential in FPAs.
4 Therapeutic effects in synergy with drugs
In previous studies, curcumin in many cases acted as a synergistic existing drug to act as an anti-tumor agent. Most of the current cancer treatments recommend combination chemotherapy, and the main advantages utilized may be to reduce the chances of tumor resistance, improve the effective outcome as well as reduce the drug dose. For example, Sudakaran et al. proposed that the combination of curcumin and polyethylene significantly enhances the effect of elastic polyethylene, producing stronger tumor cell inhibition when used alone, for breast cancer treatment (36). In prostate cancer, the combination of low concentrations of curcumin and low concentrations of α-tomatine synergistically inhibited PC-3 cell growth and induced apoptosis, inhibited NF-κB activity and potentially reduced the expression of its downstream gene, Bcl-2, in cells (37). In lung cancer, in vivo studies of curcumin and quercetin may synergistically induce apoptosis in lung cancer cells, with better efficacy than the treatment group alone (38). The synergistic anti-tumor effect of curcumin was demonstrated to varying degrees in a variety of tumor cells.
The drug synergistic effect of curcumin in PA cells has been mentioned in previous studies. For prolactin adenomas, dopamine receptor agonists(DAs) are currently the first line of therapy (2, 39). Interestingly, studies suggest that curcumin may potentiate bromocriptine-mediated inhibition of MMQ cell proliferation. Miller et al. treated MMQ cells with bromocriptine in the presence of 5 μ M curcumin and showed that this dose of curcumin by itself did not have a significant growth inhibitory effect on MMQ cell proliferation; however, when MMQ cells were exposed to bromocriptine in the presence of curcumin, even with a lower dose of bromo cryptamine, significant inhibition of cell proliferation was detected (17). In a study by Tang et al. it was proposed that curcumin may sensitize prolactinoma cells to bromocriptine by activating ERK/EGR1 and inhibiting the Akt/GSK-3β signaling pathway (40). On the other hand, the current study suggests that there are abnormalities in miRNA expression in DAs-resistant patients (39). It has been proposed in previous studies that curcumin can affect autophagy in prolactinoma cells by upregulating miR-206 (10). In ovarian cancer studies, curcumin-specific regulation of autophagy by miRNA targeting ATG5 has been validated (41). A study by Wu et al. demonstrated that miR-93 was upregulated in drug-resistant prolactinoma cells and mediated DA resistance through downregulation of autophagy targeting ATG7 (42). These studies provide new research directions for curcumin synergistic therapy.
Temozolomide (TMZ), as an important treatment for aggressive and refractory PAs, has been classified by the European Society of Endocrinology (ESE) as the first-line treatment for aggressive PAs and pituitary carcinomas, but the objective remission rate of its single-agent treatment is only 37% (43). Currently, the regimen of temozolomide combined with radiotherapy is mostly used to improve the remission rate. However, the problems of hypopituitarism, optic nerve damage, and increased intracranial pressure associated with radiotherapy cannot be ignored (44). Research in other tumor areas, especially in intracranial tumors, curcumin as a combination of temozolomide is relatively promising. It is generally believed that curcumin can sensitize glioma cells to various chemotherapeutic regimens by down-regulating Bcl-2 and IAP family members, as well as DNA repair enzymes (e.g., MGMT, DNA-PK, and ERCC-1) (11). In the published clinical study by Liang et al, curcumin may play an important role in the inhibition of temozolomide resistance with low toxicity and side effects by injecting curcumin along with temozolomide through a carrier into the tumor cavity of gliomas (45). Based on these molecular mechanisms and clinical findings, curcumin may be able to potentiate temozolomide in aggressive pituitary tumors as well.
Therapeutic potential of curcumin for pituitary-related metabolic disorders
One of the most important reasons for curcumin’s potential as a therapeutic agent for PAs is that in addition to its current highly promising research on anti-tumor effects, there is also an endocrine metabolism therapeutic component for which a great deal of research already exists. This may have a multiplier effect for PAs, a tumor that may cause severe endocrine symptoms. It has already been mentioned that curcumin may alleviate FPA symptoms by inhibiting the overproduction of PA-related hormones (GH, PRL, ACTH, etc.) (16, 17). The overproduction of these anterior pituitary hormones can itself lead to more associated metabolic abnormalities.
Growth hormone, as a potent glucagon, may interfere with glucose metabolic homeostasis through multiple pathways.GH overproduction persistently activates the JAK2-STAT5 signaling pathway in liver and muscle tissue, leading to abnormal phosphorylation of insulin receptor substrate (IRS) and impeding insulin signaling (46). In the liver, GH increases hepatic glucose output by stimulating the expression of key enzymes of gluconeogenesis (phosphoenolpyruvate carboxykinase, glucose-6-phosphatase), and in muscle and adipose tissues, it decreases glucose uptake by inhibiting GLUT4 translocation. Studies have shown that insulin sensitivity in patients with acromegaly can be reduced by more than 40% compared with normal subjects, which is the main mechanism by which GH adenomas cause hyperglycemia (47). On the other hand, early GH elevation produces a pro-proliferative effect on β-cells, which is manifested by a compensatory increase in insulin secretion and the formation of hyperinsulinemia. However, long-term GH overstimulation will lead to β-cell endoplasmic reticulum stress enhancement and de-differentiation phenomenon, and eventually trigger β-cell failure (48). In addition, GH also promotes lipolysis and increases the level of free fatty acids (FFA), which further impairs β-cell function through lipotoxicity and competitively inhibits glucose oxidation in muscle tissue through the Randle cycle, exacerbating insulin resistance (49). Patients with large limbs are often associated with visceral fat accumulation, thus creating a vicious circle. Currently, surgical treatment is the fundamental means to relieve growth hormone overproduction (50). In the past, our center also succeeded in normalizing blood glucose in patients with GH adenoma through satisfactory tumor resection, which shows that early surgical intervention has a definite alleviating effect on diabetes mellitus caused by pituitary growth hormone adenoma. For those GH adenomas with strong aggressiveness and high recurrence rate, the drug treatment plan needs to be formulated more according to individual differences. Currently, the preferred drug is Somatostatin analogs (SSA), which inhibits GH secretion by activating the SSTR2/SSTR5 receptors of pituitary tumor cells (51).
Current insulin sensitizers (metformin, etc.) are the mainstay of the treatment of diabetes with insulin resistance, however, the long-term clinical use of these drugs is associated with several harmful side effects. The study of new drugs that can avoid these side effects is currently a hot topic of research. It has been shown that curcumin, on the one hand, attenuates insulin resistance by decreasing IRS-1 serine phosphorylation and increasing IRS-1 tyrosine phosphorylation in rat skeletal muscle (52). On the other hand, curcumin can reduce hepatic glucose output by activating the AMPK pathway to enhance glucose uptake in skeletal muscle, which in turn inhibits key enzymes of gluconeogenesis (e.g., PEPCK) and improves glucose tolerance abnormality in patients with PAs (53). In addition, curcumin reduced TNF-α and C-reactive protein (CRP) levels and inhibited extracellular kinase 1/2 (ERK 1/2) and p38 expression in rat skeletal muscle (54). This study emphasizes that curcumin possesses significant antioxidant and anti-inflammatory properties and has considerable potential in the treatment of glucose intolerance and insulin resistance. Also in other studies, curcumin induced the production of other pro-inflammatory cytokines (IL-6, etc.) and the activation of antioxidant factors (Nrf-2, etc.) in adipose tissue and liver, and these inflammatory macrophages promoted insulin resistance (55). Ahmed et al. showed that curcumin could reduce the metabolic syndrome in the context of hyperglycemia-induced vascular endothelial injury by interfering with the formation of AGEs and AGE-induced vascular injury. vascular injury to attenuate excessive vasoconstriction in metabolic syndrome (56). Free radical scavenging and direct vasodilatory activity may also contribute to the favorable vascular effects of curcumin. Curcumin has also been shown to play an active role in insulin resistance in a number of other diseases. polycystic ovary syndrome (PCOS) patients are mostly characterized by insulin resistance. In a recent study, curcumin showed synergistic effects with metformin in improving insulin resistance in PCOS patients. Curcumin may attenuate insulin resistance and maintain the integrity of pancreatic islets by increasing the levels of PI3K/Akt/mTOR (32). This suggests that if curcumin is applied to pituitary GH adenomas, it may inhibit tumor growth and hormone secretion, while at the same time play a protective role against target organ damage caused by abnormal glucose metabolism.
Cortisolism due to ACTH adenomas can likewise trigger abnormalities in glycolipid metabolism and oxidative stress injury in humans. In a study by Bangaru et al, it was noted that curcumin alleviated the above damage in mouse pituitary adrenocorticotropic hormone cytoma AtT20 cells by reducing the release of inflammatory factors (e.g., IL-6, TNF-α) through inhibition of the NF-κB signaling pathway by a mechanism similar to that in GH adenomas (18). As for the reduction of bone mineral density induced by PRL, ACTH and GH excess, Cirano et al. pointed out that curcumin can maintain bone metabolism by inhibiting the RANKL/OPG pathway to reduce osteoclast differentiation, improve the level of β-catenin, and promote the activity of osteoblasts. This suggests that curcumin may play a complex role not only in GH adenomas, but also in other FPAs with more efficient therapeutic effects.
5 Challenges to the current clinical application of curcumin
5.1 Poor penetration across the blood-brain barrier
PAs originate in the saddle region, and the selection of an appropriate method to deliver curcumin across the blood-brain barrier is a prerequisite for the drug to work. The bottleneck for curcumin to penetrate the blood-brain barrier stems from its physicochemical properties and metabolic defects; its water solubility is only 0.012 mg/mL, which makes it difficult to penetrate the blood-brain barrier by passive diffusion. On the other hand, P-glycoprotein (P-gp) and other efflux pumps on the blood-brain barrier will actively expel curcumin from the brain tissue, which will further reduce the accumulation of curcumin in the brain (57).
Research in nanotechnology (brain-targeted peptide modification, lipid emulsions) and novel delivery systems such as supramolecular carriers and slow-release hydrogels has now led to breakthroughs (58). Significant enhancement of blood-brain barrier penetration by targeting transferrin receptor (TfR). Studies have shown that nanoparticles loaded with curcumin and S1-peptide successfully reduced Aβ plaques and neuroinflammation in an Alzheimer’s disease (AD) model (58). Further, following the study of curcumin in gliomas, targeted delivery of curcumin could be considered using, for example, similar transferrin-modified nanovesicles. The characteristics of existing nanocarriers are summarized in detail in the review by Hussain et al (59). We have created Table 2 based on that review. In the future, there is a greater need to focus research on the precise delivery of curcumin as well as individualized dose adjustment for its use.
Table 2. Advantages and Limitations of existing curcumin nanocarriers.
5.2 Low bioavailability of curcumin
Curcumin is highly lipid-soluble and poorly water-soluble, making it difficult to be effectively absorbed through the intestinal tract. More than 90% of orally administered curcumin is metabolized in the liver to inactive, inert glucuronide conjugates with a short molecular half-life. High-dose administration has been attempted in previous studies, but the attendant hepatotoxicity problems are impossible to ignore. High doses of curcumin may lead to tolerance problems beyond the patient’s control, such as experiencing allergies, gastrointestinal disturbances such as nausea, diarrhea, or stomach upset (7). In addition, curcumin may affect blood clotting. Numerous studies have shown that curcumin has anticoagulant and antiplatelet properties that may increase the risk of bleeding when anticoagulants (e.g., warfarin) are applied, and this is a possible pitfall to be aware of with high doses of curcumin (60).
Currently there are three main categories of approaches regarding the enhancement of curcumin bioavailability. The first category is through the association of other catabolic antagonists (e.g., desmethoxycurcumin) to reduce curcumin metabolism or potentiators (e.g., piperine, etc.) to increase the area under the curve (AUC) at the time of pharmacological administration (61). The second category is through the use of novel delivery systems (e.g., the nano-formulations mentioned above) that not only allow curcumin to cross the blood-brain barrier, but also improve its solubility and delay metabolism. The third category is the direct structural modification of curcumin, such as the incorporation of hydrophilic structures (hydroxyethyl starch, etc.), in order to improve the water solubility and antioxidant activity of the medication (61).
5.3 Little research in the field of PAs
The molecular mechanism of curcumin in PAs is not well studied and few clinical studies have been reported. The current direction of research is mostly based on extrapolation of findings from other tumors such as colon cancer, prostate cancer and breast cancer. The molecular mechanism, efficacy and safety of curcumin in the treatment of PAs need to be explored in more studies.
6 Conclusion
Curcumin, with its multi-targeted anti-tumor properties, has shown potential value in the treatment of PAs. However, its clinical application is limited by its low bioavailability and insufficient targeting. Curcumin not only inhibits the progression of pituitary adenomas through multi-targets, but also systematically improves the metabolic complications caused by hormonal abnormalities, which has the potential of “one drug, multiple effects”. In the future, it is necessary to combine the novel delivery technology and mechanism research to promote its translation from laboratory to clinic. We need to combine targeted delivery technology and metabolomics research to promote its application in the comprehensive treatment of pituitary adenomas.
Author contributions
ZY: Data curation, Writing – review & editing, Writing – original draft. CL: Writing – original draft, Formal analysis. FN: Writing – original draft, Investigation. GP: Writing – original draft, Supervision. YL: Resources, Writing – original draft. JG: Writing – original draft, Supervision. RP: Visualization, Supervision, Writing – review & editing, Validation. GS: Visualization, Validation, Supervision, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Acknowledgments
The authors are grateful to Ting Lei, Xueyan Wan, Yimin Huang (Tongji Hospital, Wuhan, China) for their help and advice.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Yan Z, Wan X, Zhang Z, Lu L, Chen J, Xu Y, et al. Predictors of testosterone recovery in male patients with nonfunctioning pituitary adenoma treated with transnasal transsphenoidal extrapseudocapsular microsurgery. Metab Target Organ Damage. (2025) 5:7. doi: 10.20517/mtod.2024.56
2. Yan Z and Lei T. Hypogonadism in male patients with pituitary adenoma and its related mechanism: A review of literature. Brain Sci. (2022) 12:796. doi: 10.3390/brainsci12060796
3. Casar-Borota O, Burman P, and Lopes MB. The 2022 WHO classification of tumors of the pituitary gland: An update on aggressive and metastatic pituitary neuroendocrine tumors. Brain Pathology. (2024) 35:e13302. doi: 10.1111/bpa.13302
4. Astafieva LI, Chernov IV, Kobyakov GL, Trunin YY, Shishkina LV, Shkarubo AN, et al. Prolactin-secreting pituitary carcinomas with intra- and extracranial metastasis: case report and review. Burdenko’s J Neurosurg. (2025) 89:83–93. doi: 10.17116/neiro20258901183
5. Tan Z, Lei Z, Yan Z, Ji X, Chang X, Cai Z, et al. Exploiting D2 receptor β-arrestin2-biased signalling to suppress tumour growth of pituitary adenomas. Br J Pharmacol. (2021) 178:3570–86. doi: 10.1111/bph.15504
6. Cozzi R, Simona Auriemma R, De Menis E, Esposito F, Ferrante E, Iatì G, et al. Italian guidelines for the management of prolactinomas. Endocrine Metab Immune Disord - Drug Targets. (2023) 23:1459–79. doi: 10.2174/1871530323666230511104045
7. Amaroli A, Panfoli I, Bozzo M, Ferrando S, Candiani S, and Ravera S. The bright side of curcumin: A narrative review of its therapeutic potential in cancer management. Cancers. (2024) 16:2580. doi: 10.3390/cancers16142580
8. Giordano A and Tommonaro G. Curcumin and cancer. Nutrients. (2019) 11:2376. doi: 10.3390/nu11102376
9. Zhang BY, Shi YQ, Chen X, Dai J, Jiang ZF, Li N, et al. Protective effect of curcumin against formaldehyde-induced genotoxicity in A549 Cell Lines. J Appl toxicology: JAT. (2013) 33:1468–73. doi: 10.1002/jat.2814
10. Duan JF, Zhang QJ, Zhu J, and Lu JH. Curcumin affects autophagy of prolactinoma cells by upregulating miR-206 to exert antitumor effects. J Biochem Mol Toxicol. (2024) 38:e23734. doi: 10.1002/jbt.23734
11. Dhandapani KM, Mahesh VB, and Brann DW. Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFκB transcription factors. J Neurochemistry. (2007) 102:522–38. doi: 10.1111/j.1471-4159.2007.04633.x
12. Zhong SJ, Xing YD, Dong LY, Chen Y, Liu N, Wang ZM, et al. Progress in the study of curcumin metabolism in vivo. J Asian Natural products Res. (2025) 27:639–57. doi: 10.1080/10286020.2024.2420619
13. Chang R, Chen L, Qamar M, Wen Y, Li L, Zhang J, et al. The bioavailability, metabolism and microbial modulation of curcumin-loaded nanodelivery systems. Adv colloid Interface science. (2023) 318:102933. doi: 10.1016/j.cis.2023.102933
14. Gogada R, Amadori M, Zhang H, Jones A, Verone A, Pitarresi J, et al. Curcumin induces Apaf-1-dependent, p21-mediated caspase activation and apoptosis. Cell Cycle (Georgetown Tex). (2011) 10:4128–37. doi: 10.4161/cc.10.23.18292
15. Shankar S, Chen Q, Sarva K, Siddiqui I, and Srivastava RK. Curcumin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells: molecular mechanisms of apoptosis, migration and angiogenesis. J Mol Signaling. (2007) 2:10. doi: 10.1186/1750-2187-2-10
16. Schaaf C, Shan B, Buchfelder M, Losa M, Kreutzer J, Rachinger W, et al. Curcumin acts as anti-tumorigenic and hormone-suppressive agent in murine and human pituitary tumour cells in vitro and in vivo. Endocrine-Related Cancer. (2009) 16:1339–50. doi: 10.1677/ERC-09-0129
17. Miller M, Chen S, Woodliff J, and Kansra S. Curcumin (diferuloylmethane) inhibits cell proliferation, induces apoptosis, and decreases hormone levels and secretion in pituitary tumor cells. Endocrinology. (2008) 149(8):4158–67. doi: 10.1210/en.2007-1760
18. Bangaru ML, Woodliff J, Raff H, and Kansra S. Growth suppression of mouse pituitary corticotroph tumor AtT20 cells by curcumin: a model for treating Cushing's disease. PLoS One. (2010) 5(4):e9893. doi: 10.1371/journal.pone.0009893
19. Shan B, Schaaf C, Schmidt A, Lucia K, Buchfelder M, Losa M, et al. Curcumin suppresses HIF1A synthesis and VEGFA release in pituitary adenomas. J Endocrinol. (2012) 214:389–98. doi: 10.1530/JOE-12-0207
20. Wang JB, Qi LL, Zheng SD, and Wu TX. Curcumin induces apoptosis through the mitochondria-mediated apoptotic pathway in HT-29 cells. J Zhejiang Univ Sci B. (2009) 10:93–102. doi: 10.1631/jzus.B0820238
21. Ye Z, Chen D, Zheng R, Chen H, Xu T, Wang C, et al. Curcumin induced G2/M cycle arrest in SK-N-SH neuroblastoma cells through the ROS-mediated p53 signaling pathway. J Food Biochem. (2021) 45:e13888. doi: 10.1111/jfbc.13888
22. Mukhopadhyay A, Banerjee S, Stafford LJ, Xia C, Liu M, and Aggarwal BB. Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation. Oncogene. (2002) 21:8852–61. doi: 10.1038/sj.onc.1206048
23. Coker-Gurkan A, Ozakaltun B, Akdeniz B-S, Ergen B, Obakan-Yerlikaya P, Akkoc T, et al. Proinflammatory cytokine profile is critical in autocrine GH-triggered curcumin resistance engulf by atiprimod cotreatment in MCF-7 and MDA-MB-231 breast cancer cells. Mol Biol Rep. (2020) 47:8797–808. doi: 10.1007/s11033-020-05928-z
24. Schaaf C, Shan B, Onofri C, Stalla GK, Arzt E, Schilling T, et al. Curcumin inhibits the growth, induces apoptosis and modulates the function of pituitary folliculostellate cells. Neuroendocrinology. (2010) 91:200–10. doi: 10.1159/000287236
25. Shankar S and Srivastava RK. Bax and Bak genes are essential for maximum apoptotic response by curcumin, a polyphenolic compound and cancer chemopreventive agent derived from turmeric, Curcuma longa. Carcinogenesis. (2007) 28:1277–86. doi: 10.1093/carcin/bgm024
26. Yoysungnoen P, Wirachwong P, Bhattarakosol P, Niimi H, and Patumraj S. Effects of curcumin on tumor angiogenesis and biomarkers, COX-2 and VEGF, in hepatocellular carcinoma cell-implanted nude mice. Clin hemorheology microcirculation. (2006) 34:109–15.
27. Moideen FM, Rahamathulla MP, Charavu R, Alghofaili F, Sha M, and Bhandary YP. PAI-1 influences and curcumin destabilizes MMP-2, MMP-9 and basement membrane proteins during lung injury and fibrosis. Int Immunopharmacol. (2024) 143:113587. doi: 10.1016/j.intimp.2024.113587
28. Shelash Al-Hawary SI, Abdalkareem Jasim S, Kadhim MM, Jaafar Saadoon S, Ahmad I, Romero Parra RM, et al. Curcumin in the treatment of liver cancer: From mechanisms of action to nanoformulations. Phytotherapy research: PTR. (2023) 37:1624–39. doi: 10.1002/ptr.7757
29. Xiu Z, Sun T, Yang Y, He Y, Yang S, Xue X, et al. Curcumin enhanced ionizing radiation-induced immunogenic cell death in glioma cells through endoplasmic reticulum stress signaling pathways. Oxid Med Cell longevity. (2022) 2022:5424411. doi: 10.1155/2022/5424411
30. Wang Q, Lei Z, Wang Z, Jiang Q, Zhang Z, Liu X, et al. PKCθ Regulates pituitary adenoma bone invasion by activating osteoclast in NF-κB/IL-1β-dependent manner. Cancers (Basel). (2023) 15:1624. doi: 10.3390/cancers15051624
31. Abuelezz NZ, Shabana ME, Abdel-Mageed HM, Rashed L, and Morcos GNB. Nanocurcumin alleviates insulin resistance and pancreatic deficits in polycystic ovary syndrome rats: Insights on PI3K/AkT/mTOR and TNF-α modulations. Life Sci. (2020) 256:118003. doi: 10.1016/j.lfs.2020.118003
32. Heshmati J, Moini A, Sepidarkish M, Morvaridzadeh M, Salehi M, Palmowski A, et al. Effects of curcumin supplementation on blood glucose, insulin resistance and androgens in patients with polycystic ovary syndrome: A randomized double-blind placebo-controlled clinical trial. Phytomedicine. (2021) 80:153395. doi: 10.1016/j.phymed.2020.153395
33. Yaikwawong M, Jansarikit L, Jirawatnotai S, and Chuengsamarn S. Curcumin extract improves beta cell functions in obese patients with type 2 diabetes: a randomized controlled trial. Nutr J. (2024) 23:119. doi: 10.1186/s12937-024-01022-3
34. Chuengsamarn S, Rattanamongkolgul S, Phonrat B, Tungtrongchitr R, and Jirawatnotai S. Reduction of atherogenic risk in patients with type 2 diabetes by curcuminoid extract: a randomized controlled trial. J Nutr Biochem. (2014) 25:144–50. doi: 10.1016/j.jnutbio.2013.09.013
35. Matchanickal R and Rafi M. Curcumin: potential health benefits, molecular mechanism of action, and its anticancer properties in vitro and in vivo. Herbs: Challenges in Chemistry and Biology. (2006) 925:92–107. doi: 10.1021/bk-2006-0925.ch007
36. Sudakaran SV, Venugopal JR, Vijayakumar GP, Abisegapriyan S, Grace AN, and Ramakrishna S. Sequel of MgO nanoparticles in PLACL nanofibers for anti-cancer therapy in synergy with curcumin/β-cyclodextrin. Materials Sci Engineering: C. (2017) 71:620–8. doi: 10.1016/j.msec.2016.10.050
37. Wang H, Huang H, Chen X, Li D, He Y, Li Y, et al. Combination of α-tomatine and curcumin inhibits growth and induces apoptosis in human prostate cancer cells. PloS One. (2015) 10:e0144293. doi: 10.1371/journal.pone.0144293
38. Zhang P and Zhang X. Stimulatory effects of curcumin and quercetin on posttranslational modifications of p53 during lung carcinogenesis. Hum Exp Toxicology. (2017) 37:618–25. doi: 10.1177/0960327117714037
39. Wan X, Yan Z, Tan Z, Cai Z, Qi Y, Lu L, et al. MicroRNAs in dopamine agonist-resistant prolactinoma. Neuroendocrinology. (2022) 112:417–26. doi: 10.1159/000517356
40. Tang C, Zhu J, Yuan F, Yang J, Cai X, and Ma C. Curcumin sensitizes prolactinoma cells to bromocriptine by activating the ERK/EGR1 and inhibiting the AKT/GSK-3β Signaling pathway in vitro and in vivo. Mol Neurobiol. (2021) 58:6170–85. doi: 10.1007/s12035-021-02541-4
41. Ravindran F, Mhatre A, Koroth J, Narayan S, and Choudhary B. Curcumin modulates cell type-specific miRNA networks to induce cytotoxicity in ovarian cancer cells. Life Sci. (2023) 334:122224. doi: 10.1016/j.lfs.2023.122224
42. Wu Z, Cai L, Lu J, Wang C, Guan J, Chen X, et al. MicroRNA-93 mediates cabergoline resistance by targeting ATG7 in prolactinoma. J endocrinology. (2019) 240:1–13. doi: 10.1530/JOE-18-0203
43. Nishioka H. Aggressive pituitary tumors (PitNETs). Endocrine J. (2023) 70:241–8. doi: 10.1507/endocrj.EJ23-0007
44. González-Virla B, Vargas-Ortega G, and Romero-Gameros CA. Radiotherapy and mortality in pituitary adenomas. Arch Med Res. (2023) 54:102900. doi: 10.1016/j.arcmed.2023.102900
45. Liang Q, Zhuo Y, Wu X, Zheng S, Zhuang J, Wang K, et al. Curcumin combining temozolomide formed localized nanogel for inhibition of postsurgical chemoresistant glioblastoma. Nanomedicine (London England). (2023) 18:907–21. doi: 10.2217/nnm-2023-0058
46. Huang TT, Du ML, Ma HM, Su Z, and Gu YF. Correlation between growth hormone/insulin-like growth factor-1 resistance and insulin resistance in non catch-up growth rats born small for gestational age. Zhonghua yi xue za zhi. (2007) 87:2292–6.
47. Geng L, Wang X, Wu X, Zhou Z, Mu W, Ye B, et al. The IGF-1/GH-GLUTs-plasma glucose regulating axis in hybrid grouper (Epinephelus fuscoguttatus♀ × epinephelus lanceolatus♂) fed a high-carbohydrate diet. Gen Comp endocrinology. (2021) 307:113744. doi: 10.1016/j.ygcen.2021.113744
48. Wang S, Wu J, Wang N, Zeng L, and Wu Y. The role of growth hormone receptor in β cell function. Growth hormone IGF research: Off J Growth Hormone Res Soc Int IGF Res Society. (2017) 36:30–5. doi: 10.1016/j.ghir.2017.08.002
49. Hjelholt A, Høgild M, Bak AM, Arlien-Søborg MC, Bæk A, Jessen N, et al. Growth hormone and obesity. Endocrinol Metab Clinics North America. (2020) 49:239–50. doi: 10.1016/j.ecl.2020.02.009
50. Chen J, Xiang Z, Zhang Z, Yang Y, Shu K, and Lei T. Cognitive dysfunction, an increasingly valued long-term impairment in acromegaly. J Clin Med. (2023) 12:2283. doi: 10.3390/jcm12062283
51. Amarù J, Barbieri F, Arvigo M, Solari A, Bajetto A, Nista F, et al. Octreotide and pasireotide combination treatment in somatotroph tumor cells: predominant role of SST(2) in mediating ligand effects. Cancers (Basel). (2021) 13:1816. doi: 10.3390/cancers13081816
52. Maithilikarpagaselvi N, Sridhar MG, Swaminathan RP, and Zachariah B. Curcumin prevents inflammatory response, oxidative stress and insulin resistance in high fructose fed male Wistar rats: Potential role of serine kinases. Chemico-biological interactions. (2016) 244:187–94. doi: 10.1016/j.cbi.2015.12.012
53. Chien YJ, Chang CY, Wu MY, Chen CH, Horng YS, and Wu HC. Effects of curcumin on glycemic control and lipid profile in polycystic ovary syndrome: systematic review with meta-analysis and trial sequential analysis. Nutrients. (2021) 13:684. doi: 10.3390/nu13020684
54. Balakumar P, Venkatesan K, Abdulla Khan N, Raghavendra NM, Venugopal V, Bharathi DR, et al. Mechanistic insights into the beneficial effects of curcumin on insulin resistance: Opportunities and challenges. Drug Discov Today. (2023) 28:103627. doi: 10.1016/j.drudis.2023.103627
55. Jiménez-Osorio AS, Monroy A, and Alavez S. Curcumin and insulin resistance-Molecular targets and clinical evidences. BioFactors (Oxford England). (2016) 42:561–80. doi: 10.1002/biof.1302
56. Ahmed OAA, El-Bassossy HM, Azhar AS, Tarkhan MM, and El-Mas MM. Interference with AGEs formation and AGEs-induced vascular injury mediates curcumin vascular protection in metabolic syndrome. Sci Rep. (2020) 10:315. doi: 10.1038/s41598-019-57268-z
57. Zhuo W, Wang W, Zhou W, Duan Z, He S, Zhang X, et al. A targeted and responsive nanoprodrug delivery system for synergistic glioma chemotherapy. Small (Weinheim an der Bergstrasse Germany). (2024) 20:e2400630. doi: 10.1002/smll.202400630
58. Yang Y, Wang Y, Jiang X, Mi J, Ge D, Tong Y, et al. Modified ce/zr-MOF nanoparticles loaded with curcumin for alzheimer’s disease via multifunctional modulation. Int J nanomedicine. (2024) 19:9943–59. doi: 10.2147/IJN.S479242
59. Hussain A, Kumar A, Uttam V, Sharma U, Sak K, Saini RV, et al. Application of curcumin nanoformulations to target folic acid receptor in cancer: Recent trends and advances. Environ Res. (2023) 233:116476. doi: 10.1016/j.envres.2023.116476
60. Keihanian F, Saeidinia A, Bagheri RK, Johnston TP, and Sahebkar A. Curcumin, hemostasis, thrombosis, and coagulation. J Cell Physiol. (2018) 233:4497–511. doi: 10.1002/jcp.26249
Keywords: curcumin, pituitary adenoma, hormone disorder, metabolic disorder, nanovesicle
Citation: Yan Z, Liang C, Nian F, Peng G, Li Y, Guan J, Pan R and Song G (2025) Curcumin for the treatment of pituitary adenomas: the potential of a single agent for multifaceted therapeutic effects. Front. Endocrinol. 16:1648521. doi: 10.3389/fendo.2025.1648521
Received: 17 June 2025; Accepted: 22 September 2025;
Published: 03 October 2025.
Edited by:
Sadishkumar Kamalanathan, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), IndiaReviewed by:
Alma Ortiz Plata, National Institute of Neurology and Neurosurgery, MexicoDiwakar Aggarwal, Maharishi Markandeshwar University, Mullana, India
Copyright © 2025 Yan, Liang, Nian, Peng, Li, Guan, Pan and Song. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ruihan Pan, Y29vbHBhbjk0QGhvdG1haWwuY29t; Gaochao Song, c3NzZ2FvY2hhb0AxNjMuY29t