Levels of S1P can help ID location of pituitary gland tumors in Cushing’s

Molecule also found to predict remission after tumor removal surgery: Study

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Analyzing the levels of a molecule called S1P — fully known as sphingosine-1-phosphate — in the tissue surrounding a pituitary gland tumor in Cushing’s disease patients can help determine the side of the gland on which the tumor is located.

That’s according to a study that made use of bilateral inferior petrosal sinus sampling, called BIPSS, an invasive procedure used in diagnosing the disease. Here, the researchers used BIPSS to assess S1P levels in the two inferior petrosal sinuses, which drain blood from either side of the pituitary gland.

A higher S1P ratio between the two petrosal sinuses also was found to predict a patient’s failure to achieve remission after surgery to remove that tumor.

“The study contributes to our understanding of the potential utility of the interpetrosal S1P ratio as a biomarker for CD [Cushing’s disease] and provides a basis for future research in this area,” the researchers wrote.

The study, “Interpetrosal sphingosine-1-phosphate ratio predicting Cushing’s disease tumor laterality and remission after surgery,” was published in Frontiers in Endocrinology.

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Surgery to remove tumors is first-line treatment in Cushing’s

Cushing’s disease is caused by tumors, called adenomas, on the brain’s pituitary gland. These tumors secrete excess adrenocorticotropic hormone (ACTH), which in turn signals the adrenal glands atop the kidneys to produce too much of the hormone cortisol, causing symptoms of the disease.

Transsphenoidal adenomectomy, a surgery to remove the disease-causing pituitary tumor, is the first-line treatment for Cushing’s. While this approach is curative for many patients, whether an individual achieves remission may be influenced by factors like tumor size and location.

As such, predicting who will achieve remission “remains a challenging goal,” the researchers wrote.

A growing body of evidence suggests that S1P might contribute to the progression of certain hormonal disorders. ACTH release leads to increased S1P, which in turn can promote the production of cortisol or other hormones.

Yet, S1P’s precise role in Cushing’s has not been explored.

Now, a team of researchers in China aimed to determine if S1P levels around the pituitary gland could be used in Cushing’s patients to more precisely determine a tumor’s location before surgery — and to predict post-operative remission.

The researchers used BIPSS, which essentially involves inserting a small catheter, or tube, into both petrosal sinuses surrounding the pituitary gland, and collecting a sample for analysis.

This technique is highly effective at identifying pituitary sources of ACTH and definitively diagnosing Cushing’s. It also can be used to estimate the location of the adenoma prior to surgery: The sinus with higher ACTH concentrations is likely closer to the side with the tumor. This, however, is not always accurate.

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S1P rate correct in determining tumor side in 64% of cases

Here, the team examined samples taken from 25 Cushing’s patients who had undergone BIPSS and pituitary surgery at Central South University’s Xiangya Hospital. More than 60% of these patients — 16 in total —  achieved remission after surgery, with no significant differences between those who did or did not reach remission in terms of clinical or demographic features.

Blood S1P levels were significantly higher in the sinus on the side where the adenoma was found compared with the non-adenoma side among the Cushing’s patients.

“These findings suggested a close association between S1P concentration and the development of ACTH-secreting tumor,” the team wrote.

A S1P ratio of the sinuses higher than 1 could correctly determine the side the tumor was on, or its laterality, in 64% of cases. Meanwhile, an ACTH ratio higher than 1.4 — previously shown to predict tumor laterality — could do so in 56% of cases. When used together, the accuracy rose to 73%.

Additional statistical analyses indicated that the combination of the two measurements — using a S1P ratio of at least 1.06 and an ACTH ration of 2.8 or higher — resulted in the highest diagnostic accuracy for predicting tumor laterality, at about 84.1%

“These results have important implications for clinical practice as accurate tumor lateralization is essential for the correct management and treatment of pituitary adenomas,” the researchers wrote.

“Combining measures may be more effective than relying on any single measure alone,” the team added.

These results have important implications for clinical practice as accurate tumor lateralization is essential for the correct management and treatment of pituitary adenomas. … Combining measures may be more effective than relying on any single measure alone.

Further, the team found that SPHK1, a protein involved in S1P production, was present at higher levels in the tumor tissue of patients who did not achieve remission after surgery than in those that did.

Likewise, patients who failed to achieve remission showed a significantly higher S1P ratio in the petrosal sinuses before surgery than did those who achieved remission (median of 1.28 vs. 1.10). This indicated an association between a higher S1P ratio and failure to achieve remission after surgery.

S1P levels before surgery also were found to be associated with pre-surgery levels of two other hormones released by the pituitary gland, namely follicle-stimulating hormone and luteinizing hormone. These levels also were linked to ACTH levels right after surgery.

“These pituitary dysfunctions may have a role in the early remission of CD,” the researchers wrote, noting that larger studies will be needed to confirm those relationships.

Altogether, the findings “suggested that the interpetrosal S1P ratio could serve as a useful biomarker in clinical practice,” the team wrote. “Targeting genes and drugs related to SPHK1/S1P could provide novel therapeutic strategies for treating CD.”