ACTH/Cortisol Ratio May Be Simple, Reliable Test to Diagnose Cushing’s Disease

The ratio between adrenocorticotropic hormone levels and cortisol levels in the blood is higher among Cushing’s disease patients than in healthy people, a new study has found, suggesting that measurement could be used to help diagnose the disease.

Also, higher values at diagnosis could predict if the disease will recur and indicate larger and more invasive tumors.

The research, “The Utility of Preoperative ACTH/Cortisol Ratio for the Diagnosis and Prognosis of Cushing’s Disease,” was published in the Journal of Neurosciences in Rural Practice.

Cushing’s syndrome (CS) is characterized by excess levels of cortisol. In patients with suspected CS, clinicians recommend testing late-night salivary or plasma (blood) cortisol, 24-hour urine-free cortisol (UC), as well as morning cortisol levels after low-dose suppression with dexamethasone, a corticosteroid.

CS may be ACTH-dependent or ACTH-independent, meaning that the high cortisol levels are caused by excess ACTH production.

Patients with CD have elevated levels of ACTH. A tumor, usually an adenoma, causes the pituitary gland to produce excess levels of ACTH, which stimulate the release of cortisol from the adrenal glands. Cortisol usually inhibits ACTH production. However, in CD patients, this feedback mechanism is absent.

Despite extensive research and clinical data, the variable and usually nonspecific signs and symptoms of CD still represent relevant challenges for diagnosis. Clinical manifestations must be associated with biochemical tests, which often have led to conflicting results.

Studies showed that although ACTH levels correlate with the size of the pituitary adenoma, the levels of cortisol do not increase as much. In fact, lower cortisol/ACTH ratios have been reported in patients with macroadenoma – which is greater than 10 millimeters in size – than in those with microadenoma, which is smaller than 10 millimeters.

Conversely, the research team hypothesized that besides their utility for determining the cause of CS, the inverse ratio – ACTH/cortisol – also may be useful for diagnosis.

The team evaluated the pretreatment plasma ACTH/cortisol levels in CS patients with excess cortisol production due to abnormal pituitary or adrenal function. Data from patients were compared with that of individuals without CS.

The study included 145 CS patients diagnosed from 2007 to 2016, 119 patients with CD, 26 with ACTH-independent CS (AICS), and 114 controls with no CS.

Patients’ clinical, laboratory, imaging, postsurgical and follow-up data were analyzed.

Results showed that patients with CD had a significantly higher basal ACTH/cortisol ratio than controls or those with AICS.

“These results showed ACTH/cortisol ratio might be a simple and useful test for the diagnosis of ACTH-dependent CS,” the researchers wrote.

Importantly, the scientists observed that a ACTH/cortisol ratio above 2.5 indicated identified 82 percent of positive CS cases and 63 percent of controls.

Overall, “an ACTH/cortisol ratio [greater than] 2.5 would be beneficial to diagnose CD together with other diagnostic tests,” they concluded.

Patients with recurrent CD showed higher pretreatment ACTH levels and ACTH/cortisol ratio than those who achieved sustained remission. CD patients also exhibited more invasive, atypical and larger tumors, as well as lower postoperative remission and higher recurrence rates.

“Higher ACTH/cortisol ratio might predict poorer prognosis,” the investigators said.


Mild Cortisol Increases Affect Cardiovascular Changes Linked to Heart Disease in Cushing’s

Increases in cortisol secretion, even if mild, induce early heart and blood vessel changes that may increase the risk for cardiovascular disease, according to Italian researchers.

The findings continue to support the role of the hormone cortisol in heart disease, and demonstrate the need for carefully monitoring cardiovascular risk in patients with high levels of the hormone, including those with Cushing’s disease.

The study, “Cardiovascular features of possible autonomous cortisol secretion in patients with adrenal incidentalomas,” was published in the European Journal of Endocrinology.

While most patients with adrenal incidentalomas don’t have symptoms, nearly half have excess cortisol production. Adrenal incidentalomas are masses in the adrenal glands discovered only when a patient undergoes imaging tests for another unrelated condition.

These asymptomatic, mild cortisol-producing cases are defined as possible autonomous cortisol secretion (pACS), according to the European Society of Endocrinology Guidelines.

Excess production of the hormone, seen in Cushing’s disease patients, is associated with increased mortality, mainly due to heart diseases. Patients with asymptomatic adrenal adenomas and mild cortisol secretion also have more cardiovascular events and generally die sooner than those with normal cortisol levels.

But little is known about the causes behind cardiac and vessel damage in these patients.

To shed light on this matter, a research team at Sapienza University of Rome evaluated the cardiovascular status of patients with pACS. This allowed them to study the impact of cortisol in the heart and blood vessels without the interference of other hormone and metabolic imbalances seen in Cushing’s disease.

The ERGO trial (NCT02611258) included 71 patients. All had been diagnosed with adrenal incidentalomas, 34 of which were pACS with mildly increased levels of the hormone and 37 were defined as nonfunctioning adenoma (NFA) — adrenal masses with normal hormone levels.

The two groups were very similar, with no significant differences in metabolic and cardiovascular risk factors. Adrenal lesions in the pACS group, however, were significantly bigger, which was linked to cortisol levels.

Looking at the heart morphology, researchers found that pACS patients had a significantly higher left ventricular mass index (LVMI), which is a well-established predictive measure of adverse cardiovascular events.

Further analysis revealed that LVMI scores were associated with levels of the hormone, suggesting it has an “independent effect of cortisol on cardiac function,” the researchers wrote.

Slightly more than half of pACS patients (53%) also had a thicker left ventricle, a feature that was seen only in 13.5% of NFA patients. The performance of the left ventricle during diastole (muscle relaxation) was also affected in 82.3% of pACS patients, compared to 35.1% in those with NFA.

Patients with pACS also had less flexible arteries, which may contribute to the development of vascular diseases.

The results show that “mild autonomous cortisol secretion can sustain early cardiac and vascular remodeling” in patients who appear apparently healthy, the researchers said.

“The morphological and functional cardiovascular changes observed in pACS underline the need for further studies to correctly define the long-term management of this relatively common condition,” they added.


Case Report Shows Rare Adrenal Tumors Associated with Cushing’s Disease

Pituitary tumors that produce too much adrenocorticotropic hormone (ACTH) have been associated with the development of rare tumors on the adrenal glands, called adrenal myelolipomas, for the first time in a case report.

The study, “Case report of a bilateral adrenal myelolipoma associated with Cushing disease,” was published in the journal Medicine.

Myelolipomas, composed of mature fat cells and blood-forming cells, are usually asymptomatic and do not produce hormones. In many cases, these tumors are detected by accident when patients undergo imaging scans for other conditions.

The cause of these tumors is unknown, but due to their benign nature, they do not spread to other parts of the body. However, they can grow up to 34 centimeters (about 13 inches), leading to tissue death and hemorrhage.

Researchers at Soon Chun Hyang University College of Medicine in Seoul, Korea, described the case of a 52-year-old man with myelolipoma possibly caused by an ACTH-secreting pituitary tumor.

During a routine checkup, researchers detected a mass in the patient’s spleen. Further abdominal evaluations identified tissue lesions in both adrenal glands consistent with myelolipoma. Besides the masses, the patient did not show any other Cushing-associated physical characteristics.

However, the patient’s ACTH levels were two times higher than the normal upper limit. Cortisol levels were also increased and unresponsive to low-dose dexamethasone treatment.

No additional lesions were found that could help explain the high ACTH and cortisol levels. But analysis of blood samples collected from the veins draining the pituitary glands revealed the right gland was producing too much ACTH, strongly suggesting Cushing’s disease.

Both the left adrenal gland and pituitary tumor were surgically removed. The samples collected during surgery confirmed the benign nature of the adrenal tumors, and the diagnosis of abnormal, ACTH-positive pituitary gland tissue.

Three days after the surgeries, hormone levels were back to normal. But a follow-up evaluation five months later again showed increased ACTH levels. Cortisol levels, however, were normal.

For the next seven years, the patient was evaluated every six months. During a five-year period, the size of the right adrenal gland was found to have grown. Imaging analysis confirmed the existence of small, new lesions in both pituitary glands.

“This case confers valuable information about the clinical course of adrenal myelolipoma associated with Cushing disease,” the researchers said. It also “supports the notion that ACTH can be associated with the development of bilateral adrenal myelolipomas.”


High Levels of MMP-9 Enzyme May Predict Tumor Recurrence in Cushing’s Patients

Measuring the levels of a specific enzyme in pituitary tumors producing excess adrenocorticotrophic hormone (ACTH) may help predict the recurrence of Cushing’s disease in patients, a study shows.

The study, “Expression of MMP-9, PTTG, HMGA2, and Ki-67 in ACTH-secreting pituitary tumors and their association with tumor recurrence,” was published in the journal World Neurosurgery.

Cushing’s syndrome is characterized by excess cortisol levels in the blood. In 70 percent of cases, this is caused by pituitary tumors making too much ACTH, a hormone that regulates cortisol production. This condition is called Cushing’s disease.

While transsphenoidal adenomectomy, a surgery to remove a pituitary gland tumor, is the first treatment choice, tumor recurrence rates can be as high as 45 percent.

Only a few studies have investigated the association between biomarkers and the risk of ACTH-secreting pituitary tumors recurring, leaving physicians with limited methods to predict which patients will have a recurrence.

Identifying biomarkers that can effectively predict the potential recurrence of Cushing’s disease would allow clinicians to look for early signs in patients and start appropriate follow-up and therapeutic protocols, avoiding long-term mortality.

Many studies have suggested that matrix metalloproteinase-9 (MMP-9) enzymes, the pituitary tumor transforming gene (PTTG), and high mobility group A 2 proteins (HMGA2) all play vital roles in the development of pituitary tumors.

Metalloproteinases (MMPs) are enzymes that work to degrade the cell’s extracellular matrix, which anchors the cell, thus enabling tumor invasion. PTTG is highly expressed in pituitary tumors, and is a marker of malignancy in many types of tumors. HMGA2 is overexpressed in various tumors, and is also associated with high malignancy.

However, whether levels of MMP-9, PTTG, and HMGA2 are related to ACTH-secreting tumor recurrence has not been investigated.

Researchers set out to determine the expression levels of MMP-9, PTTG, HMGA2, and Ki-67 (a marker of cell growth) in ACTH-secreting pituitary tumors, and evaluate their association with tumor behavior and recurrence.

They conducted a retrospective study that included 55 patients with sporadic Cushing’s disease with long-term remission after a transsphenoidal adenomectomy. Their tumor specimens were collected and examined.

Patients were divided into two groups based on whether or not they had tumor recurrence. There were 28 patients in the non-recurrent group, and 27 in the recurrent.

Results showed there was significantly increased expression of MMP-9 in tumor samples of recurrent patients, compared with the non-recurrent group. Levels of MMP-9 were also strongly associated with a shorter time period to recurrence (recurrence-free interval).

On the other hand, PTTG, HMGA2, and Ki-67 expression was not significantly different between the recurrent group and the non-recurrent group.

“ACTH-secreting pituitary tumors with higher levels of MMP-9 were associated with a higher recurrence rate and a shorter recurrence-free interval. MMP-9 could be a valuable tool for predicting recurrence of ACTH-secreting pituitary tumors,” the researchers concluded.


Endoscopic and Microscopic Surgery Equally Effective in Cushing’s Disease

Using endoscopic or microscopic techniques to surgically remove the pituitary glands leads to similar remission and recurrence rates in Cushing’s disease patients, a review of 24 studies shows.

The study, titled “Outcome of endoscopic vs microsurgical transsphenoidal resection for Cushing’s disease,” was published in the journal Endocrine Connections.

In endoscopic transsphenoidal surgery, a surgeon uses a tiny camera as a guide, allowing for a panoramic surgical view with increased illumination of anatomic structures. In microsurgical transsphenoidal resection, a surgeon views through a microscope and uses minute instruments or lasers. Both procedures are used in transsphenoidal (TS) surgery to remove pituitary gland tumors, the root cause of Cushing’s disease. In transsphenoidal surgery, a surgeon accesses the pituitary gland through the nose and sinuses.

While endoscopic surgery seems to lead to better patient outcomes, it was unclear before this study if it has any advantages in patients with Cushing’s disease.

To gain more insight into the remission and recurrence rates of both techniques, researchers examined a total of 24 studies that included 1,670 adult patients with Cushing’s syndrome. Of these patients, 702 underwent endoscopic TS, and 968 underwent microsurgical TS.

The study’s authors found that remission rates were similar in both groups. In the endoscopic group, an average of 79.7 percent of patients experienced remission versus 76.9 percent in the microscopic group.

Patients who underwent endoscopic surgery experienced recurrence less often than those who underwent microscopic surgery, with recurrence rates of 11 percent and 15.9 percent, respectively. But researchers pointed out that follow-up times in the studies varied, making comparisons unreliable.

When recurrence rates were calculated by person per year, which takes follow-up time into account, both groups had a recurrence rate of approximately 4 percent per person per year.

Previous studies have shown that complications following either type of surgery occurred at comparable rates. These complications include hypothyroidism (underactivity of the thyroid gland), diabetes insipidus (a condition characterized by increased thirst), CSF leakage (leakage of fluid that normally bathes the brain and spinal cord), visual defects, hypocortisolemia (low cortisol blood levels), and hypogonadism (little or no hormones produced by the sex glands).

“We found that overall remission proportion was the same in CD patients who underwent endoscopic TS compared to patients who underwent microscopic TS. However, patients treated with the endoscopic approach for micro-adenomas were more likely to achieve remission than those treated microsurgically. Patients treated endoscopically were less likely to experience recurrence; however, when follow-up time is taken into account, this advantage disappears,” the researchers concluded.



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