Metformin Inhibits Cell Proliferation and ACTH Secretion In AtT20 Cells Via Regulating the Mapk Pathway

Posted on January 16, 2024 by MaryO

Abstract

We investigated the impact of metformin on ACTH secretion and tumorigenesis in pituitary corticotroph tumors. The mouse pituitary tumor AtT20 cell line was treated with varying concentrations of metformin. Cell viability was assessed using the CCK-8 assay, ACTH secretion was measured using an ELISA kit, changes in the cell cycle were analyzed using flow cytometry, and the expression of related proteins was evaluated using western blotting. RNA sequencing was performed on metformin-treated cells. Additionally, an in vivo BALB/c nude xenograft tumor model was established in nude mice, and immunohistochemical staining was conducted for further verification. Following metformin treatment, cell proliferation was inhibited, ACTH secretion decreased, and G1/S phase arrest occurred. Analysis of differentially expressed genes revealed cancer-related pathways, including the MAPK pathway. Western blotting confirmed a decrease in phosphorylated ERK1/2 and phosphorylated JNK. Combining metformin with the ERK1/2 inhibitor Ulixertinib resulted in a stronger inhibitory effect on cell proliferation and POMC (Precursors of ACTH) expression. In vivo studies confirmed that metformin inhibited tumor growth and reduced ACTH secretion. In conclusion, metformin inhibits tumor progression and ACTH secretion, potentially through suppression of the MAPK pathway in AtT20 cell lines. These findings suggest metformin as a potential drug for the treatment of Cushing’s disease.

Introduction

Pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors with an incidence of 1/1000, and pituitary corticotroph tumors (corticotroph PitNETs) account for approximately 15% of all PitNETs. Most corticotroph PitNETs are functional tumors with clinical manifestations of Cushing’s disease characterized by central obesity, hypertension, diabetes mellitus, and psychosis (Cui et al., 2021). The increased cortisol due to the overproduction of adrenocorticotropic hormone (ACTH) significantly reduces the overall quality of survival and life expectancy of patients (Sharma et al., 2015; Barbot et al., 2018). Currently, treatment of corticotroph PitNETs mainly relies on surgery resection, pharmacologic therapy or radiotherapy may be considered for patients with residual tumors or those who are unable to undergo surgery. While several agents, such as cabergoline and pasireotide, are clinically approved, the effect is unsatisfactory, and potentially serious side effects exist. Therefore, there is an urgent need to develop novel therapeutic drugs for corticotroph PitNETs.

Metformin is a biguanide hypoglycemic agent for the treatment of type 2 diabetes. In addition to its hypoglycemic effect, numerous studies identified the therapeutic role of metformin in the prevention and treatment of various tumors including small cell lung cancer, colorectal cancer, breast cancer, ovarian cancer, and neuroendocrine tumors (Lu et al., 2022; Kamarudin et al., 2019; Wang et al., 2019; Thakur et al., 2019), making metformin a promising adjuvant drug in the therapy of cancers. Besides, it has been reported that metformin improves metabolic and clinical outcomes in patients treated with glucocorticoids. However, to date, limited studies explore the potential anti-cancer effect of metformin in corticotroph PitNETs. Recent studies report the use of metformin for blood glucose and body weight control in patients with Cushing’s disease (Ceccato et al., 2015), while the role of metformin on ACTH secretion and tumor growth in corticotroph PitNETs remains to be elucidated.

In the current study, we investigated the effect of metformin in corticotroph PitNETs and performed RNA-sequencing to identify the potential mechanisms of metformin. We found that metformin inhibited cell proliferation and ACTH secretion of AtT20 cells in a dose-dependent manner. Besides, metformin induced cell cycle arrest via decreased ERK1/2 phosphorylation and increased P38 phosphorylation. Our results revealed that metformin is a potential drug for corticotroph PitNET therapy.

Section snippets

Cell culture

The ACTH-secreting mouse pituitary tumor cell line AtT-20 was purchased from the American Type Culture Collection (ATCC; Manassas, VA, USA). Cells were cultured in F-12K medium (ATCC; Catalog No. 30-2004), supplemented with 15% fetal bovine serum (FBS; Gibco), and 2.5% horse serum (Gibco) as suggested. AtT20 cells were cultured in a humidified incubator at 37 °C in 5% CO2.

Reagents and drugs

Metformin and Ulixertinib were purchased from MedChemExpress (MCE), Metformin was dissolved in sterile H2O and prepared as a

Results

Metformin inhibits cell proliferation and ACTH secretion, and leads to cell cycle arrest in AtT20 cells.

We used CCK-8 assay to detect the cell viability of AtT20 cells after treatment with different concentrations of metformin at 24 h, 48 h, and 72 h. The results showed that metformin significantly inhibited the proliferation of AtT20 cells in a dose-dependent manner (Fig. 1A). Similarly, prolonged (6 days) treatment of AtT20 cells with a lower concentration (400 μM) of metformin also inhibited

Discussion

Metformin, acting by binding to PEN2 and initiating the subsequent AMPK signaling pathway in lysosomes, is the most commonly used oral hypoglycemic agent (Hundal et al., 2000; Ma et al., 2022). Previous reports demonstrated metformin as a potential anti-tumor agent in cancer therapy (Evans et al., 2005). Metformin, either alone or in combination with other drugs, has been shown to reduce cancer risk in a variety of tumors including pituitary neuroendocrine tumors (PitNETs) (Thakur et al., 2019;

Conclusion

Our study demonstrated that metformin suppressed cell proliferation and decreased ACTH secretion in AtT20 cells via the MAPK pathway. Our results revealed that metformin is a potential anti-tumor drug for the therapy of corticotroph PitNETs, which deserves further study.

Funding

This study was supported by the National Natural Science Foundation of China (82072804, 82071559).

CRediT authorship contribution statement

Yingxuan Sun: Conceptualization, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Jianhua Cheng: Data curation, Formal analysis, Visualization, Writing – original draft, Writing – review & editing. Ding Nie: Formal analysis, Writing – review & editing. Qiuyue Fang: Data curation, Formal analysis, Writing – review & editing. Chuzhong Li: Conceptualization, Supervision, Writing – original draft, Writing – review & editing, Funding acquisition. Yazhuo Zhang:

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

We thank Mr. Hua Gao (Cell Biology Laboratory, Beijing Neurosurgical Institute, China) for support with the techniques.

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From https://www.sciencedirect.com/science/article/abs/pii/S0303720723002915

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Cushing’s Syndrome caused by ACTH Precursors Secreted from a Pancreatic Yolk Sac Tumor in an Adult

Posted on January 8, 2024 by MaryO

Here, we report the first adult case of pancreatic yolk sac tumor with ectopic adrenocorticotropic hormone (ACTH) syndrome. The patient was a 27-year-old woman presenting with abdominal distension, Cushingoid features, and hyperpigmentation. Endogenous Cushing’s syndrome was biochemically confirmed. The ACTH level was in the normal range, which raised the suspicion of ACTH precursor-dependent disease. Elevated ACTH precursors were detected, supporting the diagnosis of ectopic ACTH syndrome. Functional imaging followed by tissue sampling revealed a pancreatic yolk sac tumor. The final diagnosis was Cushing’s syndrome due to a yolk sac tumor. The patient received a steroidogenesis inhibitor and subsequent bilateral adrenalectomy for control of hypercortisolism. Her yolk sac tumor was treated with chemotherapy and targeted therapy. Cushing’s syndrome secondary to a yolk sac tumor is extremely rare. This case illustrated the utility of ACTH precursor measurement in confirming an ACTH-related pathology and distinguishing an ectopic from a pituitary source for Cushing’s syndrome.

Introduction

Ectopic adrenocorticotrophic hormone (ACTH) syndrome, also termed paraneoplastic Cushing’s syndrome, can be caused by the secretion of ACTH and/or ACTH precursors from ectopic tumors. The tumors concerned secrete ACTH precursors, including unprocessed proopiomelanocortin (POMC) and POMC-derived peptides, owing to the altered post-translational processing of POMC (1). These tumors are associated with intense hypercortisolism and various complications, such as hypertension, hyperglycemia, osteoporosis, infection risks, and thrombotic tendencies (2). Distinguishing ectopic from pituitary-dependent Cushing’s syndrome is often challenging. The two conditions are classically distinguished by their variable responses to dynamic endocrine tests, including the high-dose dexamethasone suppression test, the corticotrophin-releasing-factor (CRF) test, and the desmopressin test (3). Pituitary imaging may sometimes provide a diagnosis if a pituitary macroadenoma is identified at this juncture. The gold standard for diagnosing pituitary Cushing’s is a positive inferior petrosal sinus sampling (IPSS) result. The measurement of ACTH precursors is reported to have diagnostic value in this scenario (4).

The most common source of ectopic ACTH is intrathoracic tumors, including bronchial carcinoid and small cell lung cancers. Other possible sources include gut neuroendocrine tumors and medullary thyroid cancer. Recognizing the potential causes of ectopic ACTH syndrome is essential as this provides guidance in locating the causative tumor and allows tumor-directed therapies. A yolk sac tumor as a cause of ectopic ACTH syndrome has only been reported in a 2-year-old child but not in adults (5). Here, we present a case of a 27-year-old Chinese woman who had Cushing’s syndrome due to ectopic ACTH precursor production from a pancreatic yolk sac tumor.

Case description

A 27-year-old Chinese woman, who had unremarkable past health and family history, presented with right upper quadrant abdominal pain and nausea in early 2020. Abdominal ultrasonography was unrevealing. A few months later, she developed Cushingoid features and oligomenorrhea. At presentation, her blood pressure was 160/95 mmHg, body weight was 65.6 kg, and body mass index was 23.2 kg/m2. She had a moon face, hirsutism, proximal myopathy, bruising, thinning of the skin, and acne. She also had hyperpigmentation on the nails and knuckles of both hands (Figure 1).

Figure 1
www.frontiersin.orgFigure 1. Cushingoid features at presentation include moon face, acne, thin skin, and easy bruising. Hyperpigmentation on the nails and knuckles was also noted.

Diagnostic assessments

Her 9 am and 9 pm cortisol were both >1,700 nmol/L. Her 24-h urine-free cortisol was beyond the upper measurable limit at >1,500 nmol/L. Her serum cortisol was 759 nmol/L after a 1 mg overnight-dexamethasone suppression test, confirming endogenous Cushing’s syndrome. The morning ACTH was 35 pg/mL (upper limit of normal is 46 pg/mL). After excluding a high dose-hook effect, her blood sample was concomitantly sent for ACTH measurement using two different platforms to eliminate possible interference, which might cause a falsely low ACTH reading. ACTH was 19 pg/mL (upper limit of normal is 46 pg/mL) using an IMMULITE 2000 XPI, Siemens Healthineers, Erlangen, Germany, and 17 pg/mL (reference range: 7–63 pg/mL) using a Cobas e-801, Roche Diagnostics, Indianapolis, IN, United States, therefore verifying the ACTH measurement.

In view of this being ACTH-dependent Cushing’s syndrome, a high-dose-dexamethasone suppression test (HDDST) was performed, and her cortisol was not suppressed at 890 nmol/L, with ACTH 42 pg/mL. The serum cortisol day profile showed a mean cortisol level of >1,700 nmol/L (i.e., higher than the upper measurable limit of the assay) and an ACTH of 17 pg/mL. A CRF test using 100 μg of corticorelin showed less than a 50% rise in ACTH and no rise in cortisol levels (Supplementary Table S1). She suffered from multiple complications of hypercortisolism, including thoracic vertebral collapse with back pain, diabetes mellitus (HbA1c 6.7% and fasting glucose 7.6 mmol/L), and hypokalemic hypertension, with a lowest potassium level of 2.3 mmol/L.

The rapid onset of intense hypercortisolism and refractory hypokalemia, as well as the responses in the HDDST and CRF tests raised the suspicion of ectopic ACTH syndrome. Tumor markers were measured. Alpha-fetoprotein (AFP) was markedly raised at 33,357 ng/mL (reference range: <9 ng/mL). Beta-human chorionic gonadotropin (beta-hCG) was not elevated. Carcinoembryonic antigen (CEA) was 4.0 ng/mL (reference range: <3 ng/mL) and CA 19–9 was 57 U/mL (reference range: <37 U/mL). The marked hyperpigmentation in the context of normal ACTH levels pointed to the presence of an underlying tumor producing circulating ACTH precursors. Hence, magnetic resonance imaging (MRI) of the pituitary gland was not performed at this juncture. ACTH precursors were measured using a specialized immunoenzymatic assay (IEMA) employing in-house monoclonal antibodies against the ACTH region and the gamma MSH region. Both monoclonal antibodies have to bind to these regions in POMC and pro-ACTH to create a signal. The patient had a level of 4,855 pmol/L (upper limit of normal is 40 pmol/L) (6). This supported Cushing’s syndrome from an ectopic source secondary to an excess in ACTH precursors.

Localization studies were arranged to identify the source of ectopic ACTH precursors. Computed tomography (CT) of the thorax did not show any significant intrathoracic lesion but incidentally revealed a pancreatic mass. Dedicated CT of the abdomen confirmed the presence of a 7.9 × 5.6 cm lobulated mass in the pancreatic body; the adrenal glands were unremarkable. 18-FDG and 68Ga-DOTATATE dual-tracer positron-emission tomography-computed tomography (PET-CT) showed that the pancreatic mass was moderately FDG-avid and non-avid for DOTATATE (Supplementary Figure S1). Multiple FDG-avid nodal metastases were also present, including left supraclavicular fossa lymph nodes.

Fine needle aspiration of the left supraclavicular fossa lymph node yielded tumor cells featuring occasional conspicuous nucleoli, granular coarse chromatin, irregular nuclei, and a high nuclear-to-cytoplasmic ratio. Mitotic figures were infrequent. On immunostaining, the tumor cells were positive for cytokeratin 7 and negative for cytokeratin 20. Focal expression of CDX-2, chromogranin, and synaptophysin was noted. They were negative for TTF-1, GCDPF, Gata 3, Pax-8, CD56, ACTH, inhibin, and S-100 protein. Further immunostaining was performed in view of highly elevated AFP. The tumor cells expressed AFP, Sall4, and MNF-116. They were negative for c-kit, calretinin, Melan A and SF-1. Placental ALP (PLAP) was weak and equivocal. The features were in keeping with a yolk sac tumor.

Therapeutic intervention and outcome

The patient had significant hypokalemic hypertension requiring losartan 100 mg daily, spironolactone 100 mg daily, and a potassium supplement of 129 mmol/day. Co-trimoxazole was given for prophylaxis against Pneumocystis jirovecii pneumonia. Metyrapone was started and up-titrated to 1 gram three times per day. However, in view of persistent hypercortisolism, with urinary free cortisol persistently above the upper measurable limit of the assay, bilateral adrenalectomy was performed. The tumor was mainly in the periadrenal soft tissue, with vascular invasion. The tumor formed cords, nests, and ill-defined lumen (Figure 2). The tumor cells were polygonal and contained pale to eosinophilic cytoplasm and pleomorphic nuclei, some with large nucleoli. Mitosis was present while tumor necrosis was not obvious. The stroma was composed of vascular fibrous tissue, with minimal inflammatory reaction. Immunohistochemical study showed that the tumor was positive for cytokeratin 7, MNF-116, AFP, and glypican-3, and also positive for Sall4 and HNF1β. The tumor cells were negative for cytokeratin 20, PLAP, CD30, negative for neuroendocrine markers including S100 protein, synaptophysin, chromogranin, and also negative for Melan-A, inhibin, and ACTH. Histochemical study for Periodic acid–Schiff–diastase (PAS/D) showed no cytoplasmic zymogen granules like those of acinar cell tumor. The features were compatible with yolk sac tumor. She was put on glucocorticoid and mineralocorticoid replacements post-operatively.

Figure 2
www.frontiersin.orgFigure 2. Histology and immunohistochemical staining pattern of tumor specimen. (A) HE stain x 40 showing tumor cells in the soft tissue and peritoneum. (B) HE × 400 showing that the tumor forms cords, nests, and ill-formed lumen in the vascular stroma. The tumor cells are polygonal with pale cytoplasm and pleomorphic nuclei. (C) PAS/D stain showing no cytoplasmic zymogen granules. (D) Tumor is diffusely positive for cytokeratin 7. (E) Tumor is positive for AFP. (F) Tumor is positive for glypican-3. (G) Tumor is diffusely positive for HNF1β. (H) Tumor is diffusely positive for SALL4.

Regarding her oncological management, she received multiple lines of chemotherapy, but the response was poor. Due to limited access to the ACTH precursor assay, serial measurement was unavailable. Treatment response was monitored by repeated imaging and monitoring of AFP. Figure 3 shows a timeline indicating the key events of the disease, showing the trends of the AFP and cortisol levels. Apart from (i) bleomycin, etoposide, and platinum, she was sequentially treated with (ii) etoposide, ifosfamide with cisplatin, and (iii) palliative gemcitabine with oxaliplatin. Next-generation sequencing showed a BRAF V600E mutation, for which (iv) dabrafenib and trametinib were given. Unfortunately, the disease progressed, and the patient succumbed approximately one year after the disease was diagnosed.

Figure 3
www.frontiersin.orgFigure 3. Timeline with serial cortisol and alpha-fetoprotein levels from diagnosis to patient death.

Discussion

This case demonstrates the diagnostic value of ACTH precursor measurement in the diagnosis of ectopic Cushing’s syndrome. ACTH precursors are raised in all ectopic tumors responsible for Cushing’s syndrome and could be useful in distinguishing ectopic from pituitary Cushing’s syndrome (4). Moreover, Cushing’s syndrome due to a yolk sac tumor has been reported only once in a pediatric case, and this is the first adult case reported in the literature (5).

POMC is sequentially cleaved in the anterior pituitary into pro-ACTH and then into ACTH, which is released into the circulation and binds to ACTH receptors in the adrenal cortex, leading to glucocorticoid synthesis (5, 7). Due to incomplete processing, ACTH precursors are found in normal subjects at a concentration of 5–40 pmol/L (6). Pituitary tumors are traditionally well-differentiated and can also relatively efficiently process ACTH precursors. However, this processing is less efficient in ectopic tumors that cause Cushing’s syndrome (8). Some less differentiated pituitary macroadenomas can secrete ACTH precursors into the circulation; however, these tumors are diagnosed by imaging and so do not, in general, cause problems with differential diagnosis (9).

Measurement of ACTH precursors by immunoradiometric assay (IRMA) was first described by Crosby et al. (10). The assay utilized monoclonal antibodies specific for ACTH and the other binding gamma-MSH. The assay only detects peptides expressing both epitopes and therefore measures POMC and pro-ACTH. The assay does not cross-react with other POMC-derived peptides such as beta-lipotropin, ACTH, and N-POMC.

Oliver et al. demonstrated that, compared to the pituitary adenomas in Cushing’s disease, all ectopic tumors responsible for Cushing’s syndrome in their study produce excessive POMC and pro-ACTH (4). The excessive production of ACTH precursors may reflect neoplasm-induced modification and amplification of POMC production. It is suggested that POMC binds to and activates the ACTH receptor because it contains the ACTH amino-acid sequence, or it is cleaved to ACTH in the adrenal glands to cause hypercortisolism (5) (Figure 4). Moreover, cleavage of POMC may produce peptides that exert mitogenic actions on adrenal cells and lead to adrenocortical growth. Outside the adrenal tissue, excessive ACTH precursors in Cushing’s syndrome caused by ectopic tumors can lead to marked hyperpigmentation. Both hypercortisolism and hyperpigmentation were observed in the reported case.

Figure 4
www.frontiersin.orgFigure 4. Postulated pathological mechanism of ectopic ACTH precursors.

In patients with ACTH-dependent Cushing’s syndrome, ectopic tumors should be distinguished from pituitary tumors. The HDDST, at a cut-off of 50% cortisol suppression, gives a sensitivity of 81% and a specificity of 67% for pituitary dependent Cushing’s syndrome (11). The CRF test provides 82% sensitivity and 75% specificity for pituitary disease (8). IPSS is the gold standard in distinguishing pituitary from ectopic tumors in Cushing’s syndrome. Utilization of CRF-stimulated IPSS provides 93% sensitivity and 100% specificity for pituitary disease. It also allows correct lateralization in 78% of patients with pituitary tumors. However, it is only available in specialized centers.

In a retrospective cohort, the ACTH precursor level distinguished well between Cushing’s disease and ectopic ACTH syndrome (4). With a cut-off of 100 pmol/L, the test achieved 100% sensitivity and specificity for ectopic ACTH syndrome. More recently, this assay has been used to diagnose patients with occult ectopic ACTH syndrome, with ACTH precursors above 36 pmol/L (8). Unfortunately, the immunoassay for ACTH precursor measurement utilizes in-house monoclonal antibodies, which are not widely available.

Cross-reactivity of POMC in commercially available ACTH assays ranges from 1.6% to 4.7% (12). In cases of ectopic tumors causing Cushing’s syndrome with markedly raised ACTH-precursors and intense hypercortisolism, the cross-reactivity would give significantly high ‘ACTH’ measurements to suggest an ACTH-related pathology. The degree of cross-reactivity, which is variable, should ideally be provided by the assay manufacturer as it affects result interpretation. Lower levels of ACTH precursor production might not be detected, especially by assays with low precursor cross-reactivity. Clinical vigilance is crucial in reaching the correct diagnosis. In patients with marked hypercortisolism and a normal ACTH concentration, like in this case, the measurement of ACTH precursors would allow the accurate diagnosis of Cushing’s syndrome caused by ACTH precursors.

Ectopic tumors causing Cushing’s syndrome are associated with more intense hypercortisolism than Cushing’s disease (11). However, due to variable cross-reactivity, commercial ACTH assays might not accurately detect the excessive ACTH precursors responsible for the clinical syndrome. For this reason, ACTH measurements in these two conditions can significantly overlap and may not differentiate between ectopic and pituitary diseases (4). On the other hand, the more specific POMC assay described in 1996, which does not cross-react with pro-ACTH, has a low sensitivity of 80% for ectopic Cushing’s syndrome and is not now available (13). Hence, the ACTH precursor assay used in this reported case, which detects POMC and pro-ACTH, appears to provide the best diagnostic accuracy from the available literature.

Serial measurement of ACTH precursors may play a role in monitoring the treatment response in an ACTH precursor secreting tumor. In the case of ectopic ACTH secretion, the corticotropic axis is slowed down and ACTH is almost exclusively of paraneoplastic origin. Immunotherapy is known to alter the functioning of the hypothalamic–pituitary corticotropic axis; however, its effect on ectopic secretions is not known. More data is required before the role of ACTH precursor measurement for disease monitoring in these scenarios can be ascertained.

The incidence of endogenous Cushing’s syndrome is reported to be 2 to 4 per million people per year (14). Ectopic sources of Cushing’s syndrome are responsible for 9 to 18% of these cases. Typical sources of these ectopic tumors include bronchial carcinoid tumors, small-cell lung cancer, and gut neuroendocrine tumors. Notably, germ cell tumors, including teratomas, ovarian epithelial tumors, and ovarian endometrial tumors, are also possible ectopic sources of Cushing’s syndrome.

The histological diagnosis of germ cell tumor in a non-genital site is challenging, especially for the poorly differentiated, or with somatic differentiation. Immunostaining, chromosomal, or genetic study are very important in confirming the diagnosis. AFP elevation in our case limited the differential diagnoses to germ cell tumors/yolk sac tumors, hepatocellular carcinoma, and rare pancreatic tumors. The specimen was biopsied from the retroperitoneum, and the morphology was a dominant trabecular pattern or a hepatoid pattern. It showed diffuse positive immunostaining for cytokeratin, AFP, and glypican-3. It was also diffusely and strongly positive for HNF1β and SALL4, supporting the diagnosis of yolk sac tumor. Both HNF1β and SALL4, being related with the expression of genes associated with stem cells or progenitor cells, are used as sensitive and specific markers for germ cell tumors/yolk sac tumors (15, 16).

Staining related to pancreatic acinar cell carcinoma and neuroendocrine tumor were performed. PAS/D staining showed a lack of zymogen granules. A lack of nuclear β-catenin positivity was shown. Staining for neuroendocrine markers, including chromogranin and synaptophysin, was negative. Bcl-10 and trypsin were not available in the local setting.

Cushing’s syndrome due to a yolk sac tumor was reported only once, in a 2-year-old child (5). The abdominal yolk sac tumor was resistant to cisplatin, with rapid disease progression, and the patient succumbed 1.5 years after initial presentation. Yolk sac tumor in the pancreas is also rare, with only 4 cases reported so far. The first case was reported in a 57-year-old woman with an incidentally detected abdominal mass (17). The tumor stained positive for AFP, PLAP, and CEA. The second case was a 70-year-old asymptomatic woman with histology showing a group of tumor cells with features of a yolk sac tumor, and another group showing features of pancreatic ductal adenocarcinoma with mucin production, suggesting a yolk sac tumor derived from pancreatic ductal adenocarcinoma (18). The tumor showed partial positivity for AFP, Sall4, glypican-3, and cytokeratin 7, as found in our case, while MNF-116 and PLAP staining results were not described. The third was in a 33-year-old man with a solitary pancreatic head mass with obstructive jaundice (19). The patient had undergone Whipple’s procedure followed by cisplatin-based chemotherapy, resulting in at least 5 years of disease remission. The latest reported case was in a 32-year-old man presenting with abdominal pain (20). Notably, initial imaging showed diffuse enlargement of the pancreas and increased FDG uptake without a distinct mass. Reassessment imaging 11 months later showed a 13 cm pancreatic mass. The initial imaging findings suggested initial intraductal growth of the tumor, as reported in some subtypes of pancreatic carcinoma. None of the reported cases of adult pancreatic yolk sac tumors were associated with abnormal hormone secretion. We reported the first adult case of pancreatic yolk sac tumor with ectopic ACTH syndrome. The case represents an overlap of two rarities. It demonstrates that pancreatic yolk sac tumor is a possible cause of ectopic ACTH syndrome.

Conclusion

ACTH precursor measurement helps to distinguish ectopic ACTH syndrome from Cushing’s disease. The test has superior diagnostic performance and is less invasive than IPSS. Nonetheless, the limited availability of the assay may restrict its broader use in patient management. We describe the first adult case of pancreatic yolk sac tumor with ACTH precursor secretion resulting in Cushing’s syndrome. This adds to the list of origins of ectopic ACTH syndrome in adults.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

Ethics statement

Written informed consent was obtained from the individual to publish any potentially identifiable images or data in this article.

Author contributions

JC wrote the manuscript. JC, CW, WC, AW, KW, and PT researched the data. WC, AL, EL, YW, KT, KL, and CL critically reviewed and edited the manuscript. DL initiated and conceptualized this case report and is the guarantor of this work. All authors contributed to the article and approved the submitted version.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

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.

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.

Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2023.1246796/full#supplementary-material

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Keywords: Cushing’s syndrome, ectopic ACTH syndrome, yolk sac tumor, pancreatic tumor, ACTH precursor

Citation: Chang JYC, Woo CSL, Chow WS, White A, Wong KC, Tsui P, Lee ACH, Leung EKH, Woo YC, Tan KCB, Lam KSL, Lee CH and Lui DTW (2023) Cushing’s syndrome caused by ACTH precursors secreted from a pancreatic yolk sac tumor in an adult—a case report and literature review. Front. Med. 10:1246796. doi: 10.3389/fmed.2023.1246796

Received: 18 July 2023; Accepted: 20 November 2023;
Published: 05 December 2023.

Edited by:

Alessandro Vanoli, University of Pavia, Italy

Reviewed by:

Petar Brlek, St. Catherine Specialty Hospital, Croatia
Wafa Alaya, Hospital University Tahar Sfar, Tunisia

Copyright © 2023 Chang, Woo, Chow, White, Wong, Tsui, Lee, Leung, Woo, Tan, Lam, Lee and Lui. 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: David Tak Wai Lui, dtwlui@hku.hk

Disclaimer: 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.

From https://www.frontiersin.org/articles/10.3389/fmed.2023.1246796/full

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Evaluation of Psoriasis Patients With Long-Term Topical Corticosteroids for Their Risk of Developing Adrenal Insufficiency, Cushing’s Syndrome and Osteoporosis

Posted on January 3, 2024 by MaryO

In this study, we will investigate the possible side effects of psoriasis patients using long-term topical corticosteroids (TCS) such as adrenal insufficiency, Cushing’s Syndrome (CS) and osteoporosis and determine how these side effects develop.

Forty-nine patients were included in the study. The patients were divided into two groups based on the potency of the topical steroid they took and the patients’ ACTH, cortisol and bone densitometer values were evaluated.

There was no significant difference between the two groups regarding the development of surrenal insufficiency, CS and osteoporosis. One patient in group 1 and 4 patients in group 2 were evaluated as iatrogenic CS. ACTH stimulation tests of these patients in group 2 showed consistent results with adrenal insufficiency, while no adrenal insufficiency was detected in the patient in Group 1. Patients who used more than 50g of superpotent topical steroids per week compared to patients who used 50g of superpotent topical steroids per week. It was identified that patients who used more than 50g of superpotent topical steroids had significantly lower cortisol levels, with a negatively significant correlation between cortisol level and the amount of topical steroid use ( < .01).Osteoporosis was detected in 3 patients in group 1 and 8 patients in Group 2. Because of the low number of patients between two groups, statistical analysis could not be performed to determine the risk factors.

Our study is the first study that we know of that investigated these three side effects. We have shown that the development of CS, adrenal insufficiency and osteoporosis in patients who use topical steroids for a long time depends on the weekly TCS dosage and the risk increases when it exceeds the threshold of 50 grams per week. therefore, our recommendation would be to avoid long-term use of superpotent steroids and to choose from the medium-potent group if it is to be used.

ABOUT THE CONTRIBUTORS

Betul Erdem

Department of Dermatology, Van Training and Research Hospital, Van, Turkey.

Muzeyyen Gonul

Department of Dermatology, Ministry of Health, Ankara Etlik City Hospital, Ankara, Turkey.

Ilknur Ozturk Unsal

Department of Endocrine and Metabolic Disease, Ministry of Health, Ankara Etlik City Hospital, Ankara, Turkey.

Seyda Ozdemir Sahingoz

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Restoration of Intra-patient Variability and Diurnal Range of ACTH with Remission in Cushing’s Disease

Posted on December 6, 2023 by MaryO

The following is a summary of “Diurnal Range and Intra-patient Variability of ACTH Is Restored With Remission in Cushing’s Disease,” published in the November 2023 issue of Endocrinology by Alvarez, et al.

 

Distinguishing Cushing’s disease (CD) remission from other conditions using single adrenocorticotropic hormone (ACTH) measurements poses challenges. For a study, researchers sought to analyze changes in ACTH levels before and after transsphenoidal surgery (TSS) to identify trends confirming remission and establish ACTH cutoffs for targeted clinical trials.

A retrospective analysis involved 253 CD patients undergoing TSS at a referral center from 2005 to 2019. Remission outcomes were assessed based on postoperative ACTH levels.

Among 253 patients, 223 achieved remission post-TSS. The remission group exhibited higher ACTH variability at morning (AM) (P = .02) and evening (PM) (P < .001) time points compared to the nonremission group. Nonremission cases had a significantly narrower diurnal ACTH range (P < .0001). A ≥50% decrease in plasma ACTH from mean preoperative levels, especially in PM values, predicted remission. Absolute plasma ACTH concentration and the ratio of preoperative to postoperative values were associated with nonremission (adj P < .001 and .001, respectively).

ACTH variability suppression was observed in CD, with remission linked to restored variability. A ≥50% decrease in plasma ACTH may predict CD remission post-TSS. The insights can guide clinicians in developing rational outcome measures for interventions targeting CD adenomas.

Source: academic.oup.com/jcem/article-abstract/108/11/2812/7187942?redirectedFrom=fulltext

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Interpetrosal Sphingosine-1-Phosphate Ratio Predicting Cushing’s Disease Tumor Laterality and Remission After Surgery

Posted on November 20, 2023 by MaryO

Background: Cushing’s disease (CD) poses significant challenges in its treatment due to the lack of reliable biomarkers for predicting tumor localization or postoperative clinical outcomes. Sphingosine-1-phosphate (S1P) has been shown to increase cortisol biosynthesis and is regulated by adrenocorticotropic hormone (ACTH).

Methods: We employed bilateral inferior petrosal sinus sampling (BIPSS), which is considered the gold standard for diagnosing pituitary sources of CD, to obtain blood samples and explore the clinical predictive value of the S1P concentration ratio in determining tumor laterality and postoperative remission. We evaluated 50 samples from 25 patients who underwent BIPSS to measure S1P levels in the inferior petrosal sinuses bilaterally.

Results: Serum S1P levels in patients with CD were significantly higher on the adenoma side of the inferior petrosal sinus than on the nonadenoma side (397.7 ± 15.4 vs. 261.9 ± 14.88; P < 0.05). The accuracy of diagnosing tumor laterality with the interpetrosal S1P and ACTH ratios and the combination of the two was 64%, 56% and 73%, respectively. The receiver operating characteristic curve analysis revealed that the combination of interpetrosal S1P and ACTH ratios, as a predictor of tumor laterality, exhibited a sensitivity of 81.82% and a specificity of 75%, with an area under the curve value of 84.09%. Moreover, we observed that a high interpetrosal S1P ratio was associated with nonremission after surgery. Correlation analyses demonstrated that the interpetrosal S1P ratio was associated with preoperative follicle-stimulating hormone (FSH), luteinizing hormone (LH), and postoperative ACTH 8 am levels (P < 0.05).

Conclusion: Our study demonstrated a significant association between the interpetrosal S1P ratio and tumor laterality, as well as postoperative remission in CD, suggesting that the interpetrosal S1P ratio could serve as a valuable biomarker in clinical practice.

1 Introduction

Cushing’s disease (CD), also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, arises from the pituitary corticotroph cells and induces endogenous hypercortisolism by stimulating the adrenal glands to produce excessive amount of cortisol (1). Patients with CD typically exhibit symptoms of hypercortisolism, such as hypertension, diabetes, purplish skin striae, mental disturbances, hyposexuality, hirsutism, menstrual disorders, acne, fatigue, obesity, and osteoporosis (1). The overall mortality of patients with CD is twice that of the general population, and if left untreated, hypercortisolism resulting from CD increases this rate to approximately four times the expected value (2–4). Transsphenoidal surgery continues to be the primary treatment for CD (5). However, previous studies reported variable remission rates, ranging from 45% to 95% (6–8). Long-term follow-up data have revealed recurrence in 3–66% of patients who had initially achieved complete remission (9, 10). The rate of surgical remission in CD can be influenced by various factors, including the size and location of the tumor, expertise of the neurosurgeon, and criteria used for assessing remission (11). Preoperative clinical variables, such as age, gender, disease duration, and severity of clinical signs and symptoms, cannot reliably identify patients at a higher risk of nonremission (12, 13). Therefore, predicting postsurgical remission in CD remains a challenging goal.

Accumulating evidence has shown that sphingosine-1-phosphate (S1P), an intracellular pleiotropic bioactive sphingolipid metabolite synthesized by sphingosine kinase 1 (SPHK1), plays a pivotal role in diverse endocrine disorders (14–16). Overexpression of SPHK1 promotes the progression of multiple neuroendocrine tumors (17, 18). ACTH can rapidly activate sphingolipid metabolism, causing an increase in S1P secretion in the adrenal cortex (19). Furthermore, the activation of S1P signaling in H295R cells, a human adrenocortical tumor cell line, has been suggested to induce increased transcription of hormone-sensitive lipase and steroidogenic acute regulatory protein, ultimately elevating cortisol production (20). Recently, surgical removal of ACTH-secreting adenoma has been reported to cause a decline in sphingomyelin levels (21). However, whether they have a similar role in the pituitary gland remains to be investigated.

Bilateral inferior petrosal sinus sampling (BIPSS) is a highly effective procedure for diagnosing pituitary sources of ACTH in CD (22, 23). Contemporaneous differences in ACTH concentration during venous sampling between the two sides of the adenoma can predict the location of the adenoma within the pituitary (on the side of the gland with a microadenoma) and may guide surgical treatment in cases with inconclusive magnetic resonance imaging findings. Previous studies demonstrated that an ACTH gradient of ≥1.4 between the inferior petrosal sinuses can indicate microadenoma lateralization in patients with CD (24–26). However, the correct lateralization only occurs in 57–68% of all cases (27–29).

Therefore, we analyzed the clinical behavior of a well-characterized cohort of patients with CD who underwent BIPSS before surgery. We measured the difference in the concentration of S1P in bilateral petrosal sinus blood samples and explored the clinical predictive value of the S1P concentration ratio in determining tumor laterality and postoperative remission.

2 Materials and methods

2.1 Patients and study design

This study was conducted at a tertiary center, involving a cohort of 25 patients diagnosed with CD who had undergone BIPSS and surgery, with a minimum follow-up duration of 2 years. Comprehensive chart reviews were conducted to collect data on demographics, clinical characteristics, pituitary imaging findings, tumor pathology, and biochemical tests.

The criteria used for diagnosing CD encompassed the presence of characteristic signs and symptoms of hypercortisolism, along with biochemical evaluation of two urinary free cortisol measurements exceeding the normal range for the respective assay, serum cortisol level >1.8 μg/dL (50 nmol/L) after an overnight 1-mg dexamethasone suppression test, and two late-night salivary cortisol measurements exceeding the normal range for the respective assay (30). A diagnosis of Cushing’s syndrome was established if the patient had positive test results for at least two of the three aforementioned tests. Adrenal insufficiency was diagnosed if patients exhibited symptoms or signs of adrenal insufficiency or if serum cortisol levels were ≤3 μg/dL, even in the absence of clinical signs or symptoms. Remission was defined as normalization of the levels of 24-h urinary free cortisol, late-night salivary cortisol, and overnight 1-mg dexamethasone suppression test in patients without concurrent central adrenal insufficiency after surgery (31).

2.2 Patients and tissue/serum samples

Surgical specimens of CD-affected tissues were collected from Xiangya Hospital, Central South University. Three normal pituitary tissues were obtained from cadaveric organ donors without any history of endocrine disease (Central South University). A total of 25 CD tissue samples were obtained for immunohistochemistry analysis. This study was conducted in compliance with the Helsinki Declaration and was ethically approved by the Xiangya Hospital Ethics Committee, Xiangya Hospital (Changsha, China). Tumor samples and corresponding clinical materials were obtained with written consent from all patients.

2.3 BIPSS

After obtaining informed consent, BIPSS was performed using standard techniques described in previous studies (32, 33). Briefly, the patient’s head was immobilized to ensure midline positioning and prevent any potential bias towards asymmetric pituitary drainage by the petrosal sinuses. After placing peripheral catheters and cannulating both inferior petrosal sinuses, blood samples were collected at baseline and at 3, 5, 10, and 15 min following intravenous administration of DDAVP, which stimulates pituitary production of ACTH. Additional samples for experimental purposes were collected immediately following the 15-min sample collection to avoid interference with the patient’s diagnostic study.

2.4 Measurement of baseline plasma S1P concentration

Blood samples were obtained from both petrosal sinuses and were centrifuged to remove cellular components. Samples that exhibited hemolysis or coagulation were excluded from the study. Plasma samples were stored at −80°C. The S1P levels in plasma were analyzed using a S1P competitive ELISA kit (Echelon Biosciences, Salt Lake City, UT) according to the manufacturer’s instructions (34).

2.5 Immunofluorescence staining

The pituitary tissues were post-fixed and dehydrated with alcohol as follows: 70% for 24 h, 80% for 3 h, 90% for 4 h, 95% for 3 h, and finally in absolute alcohol for 2 h. Tissue slices with a 5-μm thickness were cut using a microtome (Thermo Fisher Scientific), blocked with 3% BSA, and then treated with primary antibodies to SPHK1 (CST, #3297) and ACTH (Proteintech, CL488-66358). Subsequently, the tissue slides were incubated with Alexa Fluor 488-conjugated anti-rabbit (Invitrogen, A21206, 1:200) or Alexa Fluor 555-conjugated anti-rabbit (Invitrogen, A21428, 1:200) secondary antibodies. Specimens were visualized and imaged using a fluorescence microscope.

2.6 Statistical analysis

The Mann–Whitney U test was used to assess the clinical–molecular associations in adenoma samples, whereas the chi-square test was used to compare categorical data. The Kruskal–Wallis analysis and ANOVA were conducted for multiple comparisons. Statistical analyses were conducted using SPSS v20 and GraphPad Prism version 7. All results were presented in graphs and tables as median ± interquartile range. The distribution of each parameter was presented as the minimum–maximum range. Parametric or nonparametric statistical tests were applied, as appropriate, after testing for normality. The receiver operating characteristic curve was used to determine the cut-off value for predicting tumor laterality. Pearson correlation analyses was used to examine the correlations between variables. Proportions were expressed as percentages, and significance was defined as P < 0.05.

3 Results

3.1 Clinical characteristics of remission and nonremission in patients with CD

This study included 25 patients with CD who underwent BIPSS before surgery (Figure 1). Among them, 12 patients had microadenomas, whereas the remaining 13 had inconclusive magnetic resonance imaging findings; clinicopathological data are summarized in Supplementary Table 1. Table 1 displays the demographics of patients who achieved remission (n = 16) and those who did not (n = 9). No significant differences were observed in terms of sex, age at diagnosis, or radiological variables between patients who achieved and those who did not achieve remission (P > 0.05). Patients who achieved remission exhibited a higher prevalence of emotional lability (P < 0.05). However, no significant differences were observed in other parameters (P > 0.05).

Figure 1
www.frontiersin.orgFigure 1 Flowchart of the screening process employed to select eligible participants for the study.

Table 1
www.frontiersin.orgTable 1 Baseline clinical features of patients with pituitary tumors secreting adrenocorticotropin.

Several recent studies have established morning cortisol level measured on postoperative day 1 (POD1) as a predictive biomarker for long-term remission of CD (35, 36). For biochemical features, patients who did not achieve remission exhibited higher serum cortisol (19.16 ± 5.55 vs. 5.95 ± 1.42; P = 0.014) and median serum (8 am) ACTH (10.26 ± 8.24 vs. 5.15 ± 3.68; P = 0.042) levels on POD1. No significant differences were observed in the preoperative baseline 4 pm serum cortisol levels, preoperative baseline 0 am serum cortisol levels, preoperative 8 pm ACTH levels, 4 pm ACTH levels, and 0 am ACTH levels (P > 0.05) (Table 2). In addition preoperative FT3, FT4, TSH, GH, FSH, LH, and PRL levels were comparable in patients with and without remission.

Table 2
www.frontiersin.orgTable 2 Baseline clinical and biochemical features of patients with pituitary tumors secreting adrenocorticotropin.

3.2 Overexpression of SPHK1 and higher concentrations of serum S1P on the tumor side in patients with CD

Prior studies have demonstrated that ACTH acutely activates SPHK1 to increase S1P concentrations (19). Upregulation of SPHK1 is associated with poor prognosis in endocrine-related cancer (17, 18, 21). To investigate the role of SPHK1 in CD, we performed a heatmap analysis of key genes involved in phospholipid metabolism and signaling pathways in CD adenomas and surrounding normal tissues using the GEO dataset (GEO208107). This analysis revealed the activation of crucial genes involved in phospholipid metabolism and signaling pathways in ACTH-secreting pituitary adenomas (Supplementary Figure 1). Subsequently, we compared the association between pituitary SPHK1 expression and proopiomelanocortin, corticotropin-releasing hormone, corticotropin releasing hormone receptor 1, and corticotropin releasing hormone receptor 2 in pituitary tumor tissues and identified a positive correlation between SPHK1 and ACTH tumor-related genes in the TNM plot database (Supplementary Figure 2). To investigate the potential role of SPHK1 in CD, we compared the expression values of SPHK1 in the normal pituitary tissues and those obtained from patients with CD in the remission/nonremission groups. Immunofluorescence staining (Figures 2A, B; Supplementary Figure 3) revealed an increased number of double-positive cells for SPHK1 and ACTH in CD-affected pituitary tissues than those in the normal pituitary tissues. Furthermore, the proportion of double-positive cells for SPHK1 and ACTH was significantly higher in the nonremission CD adenomas tissues than that in the remission CD adenomas. Furthermore, we investigated the concentration of S1P in bilateral petrosal sinus blood samples and observed that the concentration was significantly higher on the adenoma side than that on the nonadenoma side (397.7 ± 15.4 vs. 261.9 ± 14.88; P < 0.05, Figure 2C). Thus, these findings suggested a close association between S1P concentration and the development of ACTH-secreting tumor.

Figure 2
www.frontiersin.orgFigure 2 (A) Representative images of immunofluorescence double staining for SPHK1 (green) and ACTH (pink) in normal pituitary glands and ACTH-secreting pituitary adenomas from the remission and nonremission groups (Normal: n = 3, ACTH pituitary adenoma: remission vs. nonremission: n = 16 vs. 9); scale bars: 100-μm upper and 50-μm lower. (B) Quantitative analysis; white arrows indicate double-positive cells for ACTH and SPHK1. (C) The concentration of S1P in the plasma obtained from the inferior petrosal sinus of the adenoma side and nonadenoma side. ***P < 0.001. Bar represents mean ± SD.

3.3 Combination of interpetrosal S1P and ACTH ratios improved the diagnostic performance for adenoma laterality

The pathology of patients with CD was classified based on adenomatous tissue with ACTH-positive immunostaining into adenoma or nonadenoma sides. To evaluate the correlation between the interpetrosal S1P ratio lateralization and tumor location, we compared the accuracy of predicting tumor laterality using the interpetrosal S1P ratio (>1) and interpetrosal ACTH ratio (>1.4) (the interpetrosal ACTH ratio >1.4 is acknowledged for its positive role in predicting tumor laterality), as well as their combination. Our results indicated that using the interpetrosal S1P or ACTH ratios alone yielded accuracies of 64% and 56% respectively. Notably, the combination of both demonstrated a significantly improved accuracy of 73% (Figure 3A).

Figure 3
www.frontiersin.orgFigure 3 (A) Bar graph illustrating the accuracy of predicting tumor laterality. (B) Receiver operating characteristic (ROC) curve analysis of interpetrosal ACTH ratio to predict tumor location. (C) ROC curve analysis of the interpetrosal S1P ratio to predict tumor location. (D) ROC curve analysis of the combination of the interpetrosal S1P and ACTH ratios to predict tumor location.

Thereafter, the receiver operating characteristic analysis was performed to determine the role of predicting tumor laterality. In particular, the interpetrosal ACTH ratio with an AUC of 75.32% (95% CI: 60.06–97.46%, P < 0.05) and the interpetrosal S1P ratio demonstrated a clinically significant diagnostic accuracy for lateralization, with an AUC of 79.17% (95% CI: 44.40–85.84%, P < 0.05). Furthermore, combining the interpetrosal S1P and ACTH ratios generated an receiver operating characteristic curve with an AUC of 84.09% (95% CI: 52.3–96.77%, P < 0.05) for predicting lateralization with tumor location (cutoff value: interpetrosal S1P ratio ≥1.06, interpetrosal ACTH ratio ≥2.8, 81.82% sensitivity, and 75% specificity) (Figures 3B–D).

3.4 Interpetrosal S1P ratio serves as a predictive factor for early remission in CD

To investigate whether the interpetrosal S1P ratio is associated with early postoperative remission in CD, we compared the baseline interpetrosal S1P ratio between patients with CD in the remission and nonremission groups. Interestingly, we observed that the nonremission group exhibited higher interpetrosal S1P ratios than those of the remission group (median, 1.28 ± 0.25 vs. 1.10 ± 0.09, P = 0.012) (Figure 4).

Figure 4
www.frontiersin.orgFigure 4 Left picture: Scatter plot of bilateral S1P concentrations in the remission and nonremission groups; the slope represents the interpetrosal S1P ratio, blue dots represent the remission group, and red dots represent the nonremission group. Right picture: The interpetrosal S1P ratio in the remission and nonremission groups. *P < 0.05. Bar represents mean ± SD.

To investigate potential factors affecting the interpetrosal S1P ratio, we compared the correlation between interpetrosal S1P ratio and various clinical indicators. This analysis revealed that the interpetrosal S1P ratio positively correlated with preoperative FSH and LH levels, as well as with postoperative 8 am ACTH levels. No significant difference was observed between the interpetrosal S1P ratio and other indicators (Supplementary Figure 4).

4 Discussion

The use of BIPSS involves collection of samples from each inferior petrosal sinus simultaneously, enabling a direct comparison of ACTH concentrations between the left and right petrosal sinuses. BIPSS is used for two purposes: 1) to assist in the differential diagnosis of Cushing’s syndrome; and 2) to determine which side of the pituitary gland contains an adenoma in patients with CD. The interpetrosal ACTH ratio is also useful in determining the location/lateralization of pituitary microadenomas (24, 30, 37), thereby providing guidance to the neurosurgeon during surgery.

To our knowledge, this is the first study to demonstrate that serum S1P levels in patients with CD are significantly higher on the adenoma side of the inferior petrosal sinus than on the nonadenoma side. The interpetrosal S1P ratio exhibited a positive significance in predicting tumor laterality, and the predictive performance was improved when S1P was combined with the interpetrosal ACTH ratio. Notably, the interpetrosal S1P ratio exhibited a positive significance in predicting remission after surgery. Furthermore, the interpetrosal S1P ratio demonstrated a positive and significant correlation with preoperative FSH and LH levels, as well as 8 am ACTH levels on POD1.

ACTH is recognized for its role in controlling the expression of genes involved in steroid production and cortisol synthesis in the human adrenal cortex through sphingolipid metabolism (19). Specifically, ACTH rapidly stimulates SPHK1 activity, leading to an increased in S1P levels, which in turn, increases the expression of multiple steroidogenic proteins (20). Our study demonstrated that higher S1P concentrations were present on the tumor side than on the nontumor side in patients with CD, indicating that the regulatory relationship between ACTH and S1P also exists in ACTH-secreting pituitary adenomas. Several pieces of evidence have supported the potential relationship between S1P and the occurrence of CD. Interestingly, SPHK1 and S1P are known to be integral to the regulation of epidermal growth factor receptor (EGFR) (38), which is highly expressed in human corticotropinomas, where it triggers proopiomelanocortin (the precursor of ACTH) transcription and ACTH synthesis (39). Blocking EGFR activity with an EGFR inhibitor can attenuate corticotroph tumor cell proliferation (40). Furthermore, SPHK1 and proopiomelanocortin share a common transcriptional coactivator, P300 (41, 42). Notably, S1P also directly binds to and inhibits histone deacetylase 2, thereby regulating histone acetylation and gene expression (43). Notably, histone deacetylase 2 expression is deficient in ACTH-pituitary adenomas in CD, contributing to glucocorticoid insensitivity (44), which is a hallmark of CD and a feature associated with nonremission. These studies further demonstrated an association between high S1P ratio and nonremission of CD. Our study, for the first time, established an association between SPHK1/S1P and ACTH adenoma. Nevertheless, further experimental verification is required to confirm the existence of common pathways linking SPHK1 and ACTH. Thus, these findings indicated that the S1P ratio can, to some extent, reflect the differences in ACTH levels and may serve as a surrogate marker for detecting ACTH-secreting pituitary adenomas.

BIPSS is a highly effective procedure for diagnosing pituitary sources of ACTH in CD and remains the gold standard diagnostic method. However, some findings indicated certain limitations associated with the use of the inferior petrosal sinus sampling (IPSS) method in predicting tumor lateralization. The possible causes of error include asymmetrical or underdeveloped petrosal sinus anatomy and placement of the catheter (27). The present study revealed a notable increase in the interpetrosal ACTH ratio among patients with accurate predictions of tumor laterality than among those with inaccurate predictions, although the positive predictive value remained low. These findings suggested that other mechanisms may exist that contribute to false-positive results. The limitations on lateralization highlighted the need for further research to understand the underlying mechanisms contributing to the accuracy of IPSS in predicting tumor lateralization. Further investigation is required to understand these potential mechanisms and improve the accuracy of IPSS in predicting tumor lateralization.

We observed that the interpetrosal S1P ratio was slightly more effective than the ACTH ratio in predicting tumor laterality. However, combining both methods significantly improved the diagnostic sensitivity and specificity. These results have important implications for clinical practice as accurate tumor lateralization is essential for the correct management and treatment of pituitary adenomas. Overall, these findings highlighted the importance of using multiple measures in predicting tumor lateralization and suggested that combining measures may be more effective than relying on any single measure alone. Future research should investigate additional measures to improve the accuracy of tumor lateralization and optimize the use of existing measures for making clinical decisions.

The initial treatment recommendation for CD is surgery. However, long-term surveillance is necessary because of the high recurrence rate (12). Therefore, identifying patients who are at a greater recurrence risk would be helpful in establishing an effective surveillance strategy. Our study revealed that the expression of SPHK1 in pituitary tissue was higher in postoperative nonremission group than in postoperative remission group. Moreover, patients in the nonremission group exhibited significantly higher interpetrosal S1P ratios than those of patients in the remission group. SPHK1 catalyzes the direct phosphorylation synthesis of S1P, and the S1P ratio can thus reflect the expression level of SPHK1 in ACTH tumors. Since S1P can increase the expression of multiple steroidogenic proteins, including steroidogenic acute regulatory protein, 18-kDa translocator protein, low-density lipoprotein receptor, and scavenger receptor class B type I (20), the interpetrosal S1P ratios may be indicative of disease prognosis. This finding is consistent with previous findings indicating the overexpression of SPHK1 is associated with poor prognosis in various neuroendocrine tumors, as factors associated with tumor proliferation, S1P and SPHK1, may play a key role in the proliferation and survival of ACTH pituitary adenomas. The high proportions of SPHK1/ACTH double-positive cells are likely associated with greater phenotypic severity, and CD tumors with this phenotype may have a poor prognosis. These findings hold clinically significance for predicting early postoperative remission in patients with CD. As aforementioned, the interpetrosal S1P ratios have been suggested as a useful diagnostic tool for determining adenoma lateralization in CD, which can also serve as a prognostic indicator for postoperative remission.

Pearson correlation analysis indicated that ACTH 8 am on POD1 and FSH/LH levels were significantly associated with the interpetrosal S1P ratio, suggesting that these pituitary dysfunctions may have a role in the early remission of CD. However, the sample size in this study was relatively small, and further studies with larger sample sizes are needed to confirm these findings. Additionally, other factors affecting surgical outcomes, such as the experience of the surgeon, extent of surgical resection, and use of adjuvant therapy, should be considered when predicting postoperative remission in patients with CD.

This study has some limitations. First, the study was retrospective in design, which limited the control of confounding factors. Additionally, because of the limited sample size, we did not specifically investigate cases where the ACTH ratio failed to accurately identify the correct tumor location. Finally, we did not explore the functional evidence of a common pathway between SPHK1 and ACTH. Despite these limitations, the study contributes to our understanding of the potential utility of the interpetrosal S1P ratio as a biomarker for CD and provides a basis for future research in this area.

In conclusion, our study demonstrated a significant association between the interpetrosal S1P ratio and tumor laterality, as well as in early remission in CD. These findings suggested that the interpetrosal S1P ratio could serve as a useful biomarker in clinical practice. Moreover, targeting genes and drugs related to SPHK1/S1P could provide novel therapeutic strategies for treating CD.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Ethics statement

The studies involving humans were approved by The Xiangya Hospital Ethics Committee, Xiangya Hospital (Changsha, China). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

HS: conceptualization, methodology, software, visualization, and investigation. CW and BH: software. YX: writing – review & editing. All authors contributed to the article and approved the submitted version.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Acknowledgments

The authors gratefully acknowledge contributions from the GEO databases and TNMplot database (https://www.tnmplot.com/).

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.

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.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2023.1238573/full#supplementary-material

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Keywords: ipss, sphingosine-1-phosphate, Cushing’s disease, remission, tumor laterality

Citation: Sun H, Wu C, Hu B and Xiao Y (2023) Interpetrosal sphingosine-1-phosphate ratio predicting Cushing’s disease tumor laterality and remission after surgery. Front. Endocrinol. 14:1238573. doi: 10.3389/fendo.2023.1238573

Received: 12 June 2023; Accepted: 17 October 2023;
Published: 31 October 2023.

Edited by:

Anton Luger, Medical University of Vienna, Austria

Reviewed by:

Guangwei Wang, Hunan University of Medicine, China
Marie Helene Schernthaner-Reiter, Medical University of Vienna, Austria

Copyright © 2023 Sun, Wu, Hu and Xiao. 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: Yuan Xiao, xiaoyuan2021@csu.edu.cn

Disclaimer: 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.

From https://www.frontiersin.org/articles/10.3389/fendo.2023.1238573/full

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