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.


Adrenal Gland Lump Led to 5-year-old Developing Cushing’s, Starting Puberty

Non-cancerous adrenal gland tumors can lead to rare cases of Cushing’s syndrome in young children and puberty starting years before it should, a case study of a 5-year-old boy shows.

Removing his right adrenal gland eliminated the problems, the Saudi Arabian researchers said.

Their report dealt with tumors in epithelial cells, which line the surface of many of the body’s structures and cavities.

The research, “Testosterone- and Cortisol-secreting Oncocytic Adrenocortical Adenoma in the Pediatric Age-group,” appeared in the journal Pediatric and Developmental Pathology.

Most tumors in adrenal gland epithelial cells are benign and generate normal levels of hormones. But there are cases when the tumors over-produce steroids and other kinds of hormones, including sex hormones. Sometimes the over-production can lead to Cushing’s syndrome.

The 5-year-old boy’s over-production of adrenal gland hormones led to both symptoms of Cushing’s syndrome and signs that he was starting puberty, the researchers said.

One reason the case was rare is that the average age when Cushing’s develops is 40, doctors say. Another is that epithelial adrenal gland tumors account for only 0.2 percent of all tumors in children, the researchers said.

Signs that the boy was starting puberty began appearing eight months before his parents took him for treatment. Doctors discovered he had the weight gain and rounded face associated with Cushing’s, but a battery of tests detected no other problems. No family members were experiencing the symptoms he was, doctors added.

Biochemical tests showed that the boy had a high level of cortisol in his blood, which doctors were unable to lower with the corticosteroid suppression medication dexamethasone.

Physicians also discovered that the boy had elevated levels of the male hormone testosterone, the cortisol precursor 17-hydroxyprogestrone, the cortisol-releasing hormone adrenocorticotropin, and another male hormone that the adrenal gland produces — dehydroepiandrosterone sulfate

In contrast, doctors discovered a below-normal level of luteinising, a sex hormone that the pituitary gland generates.

Another unusual manifestation of the boy’s condition was that his bone growth was that of a child a year older than he.

Doctors discovered a non-cancerous tumor in his right adrenal gland that they decided to remove. When they did, they discovered no evidence of bleeding, tissue scarring or cell death.

They put the boy on a hydrocortisone supplement, which they reduced over time and finally ended.

Twenty-eight months after the surgery, the boy showed no signs of Cushing’s disease or early puberty. And his weight, cortisol and adrenocorticotropin hormone levels were normal.

“To the best of our knowledge, our patient represents the first male patient” with a benign epithelial-cell adrenal gland tumor “in the pediatric population, with clinical presentation of precocious [early] puberty and Cushing’s syndrome,” the researchers wrote.

“As these tumors are exceptionally rare, reporting of additional cases and investigation of clinicopathological [disease] data are needed for better characterization of these tumors,” they wrote.


Common Cushing’s Treatment, Somatostatin Analogs, May Sometimes Worsen Disease Course

Doctors often prescribe somatostatin analogs to manage the hormonal imbalance that characterizes Cushing’s syndrome. However, in rare situations these medicines have paradoxically made patients worse than better.

This recently happened with a 48-year-old Spanish woman whose Cushing’s syndrome was caused by an adrenal gland tumor that was producing excess adrenocorticotropic hormone (ACTH). Her case was recently reported in the study “Ectopic Cushing’s syndrome: Paradoxical effect of somatostatin analogs,” and published in the journal Endocrinología, Diabetes y Nutrición.

Cushing’s syndrome occurs when the body produces too much cortisol. This can happen for many reasons, including an oversupply of ACTH, the hormone responsible for cortisol production, due to a tumor in the pituitary gland.

But sometimes, tumors growing elsewhere can also produce ACTH. This feature, known as ectopic ACTH secretion (EAS), may also cause ACTH-dependent Cushing’s syndrome.

Two-thirds of EAS tumors are located in the thorax, and 8 to 15 percent are in the abdominal cavity. Only 5 percent of EAS tumors are located in the adrenal gland, and up to 15 percent of EAS tumors are never detected.

Doctors usually use cortisol synthesis inhibitors such as ketoconazole or Metopirone (metyrapone) to control EAS, due to their efficacy and safety profiles. But somatostatin analogs (SSAs) such as Somatuline (lanreotide) have also been used to treat these tumors. However, these drugs produce mixed results.

The woman in the case study, reported by researchers at the University Hospital Vall d’Hebron in Barcelona, Spain, had an EAS tumor on the adrenal gland. She experienced s life-threatening cortisol and ACTH increase after receiving high-dose Somatuline.

The patient had been recently diagnosed with hypertension, and complained of intense fatigue, muscular weakness, easy bruising and an absence of menstruation. Laboratory analysis revealed that she had triple the normal levels of free cortisol in the urine, elevated levels of plasma cortisol, and high ACTH levels. In addition, her cortisol levels remained unchanged after receiving dexamethasone. The patient was therefore diagnosed with ACTH-dependent Cushing syndrome.

To determine the origin of her high cortisol levels, the team conducted magnetic resonance imaging (MRI). They found no tumors on the most common places, including the pituitary gland, neck, thorax or abdomen. However, additional evaluation detected a small alteration on the left adrenal gland, suggesting that was the source of ectopic ACTH production.

The team initiated treatment with 120 mg of Somatuline, but a week later, her condition had worsened and become life-threatening. Doctors started Ketoconazole treatment immediately, three times daily. The affected adrenal gland was surgically removed, and tissue analysis confirmed the diagnosis. The patient’s clinical condition improved significantly over the follow-up period.

“We highlight the need to be aware of this rare presentation of EAS, and we remark the difficulties of EAS diagnosis and treatment,”  researchers wrote.

The team could not rule out the possibility that the patient’s clinical development was due to the natural course of the disease. However, they believe “she had a paradoxical response on the basis of her dramatical worsening just after the SSAs administration, associated to an important rise in ACTH and UFC levels.”

For that reason, researchers think a new version of SSAs, such as Signifor (pasireotide) — which has improved receptor affinity — could provide better therapeutic response.


ACTH-producing Lung Tumors Hard to Detect, But May Be Cured with Surgery

Ectopic Cushing’s syndrome can be challenging to diagnose, especially when it comes identifying the problem source. But appropriate hormone management protocols, used in combination with advanced imaging methods, may help physicians identify ectopic ACTH-producing tumors.

The findings in a case report of a young man with ectopic Cushing’s syndrome were published in the International Journal of Surgery Case Reports, under the title “Case report: Ectopic Cushing’s syndrome in a young male with hidden lung carcinoid tumor.”

Cushing’s syndrome is caused by high amounts of glucocoticosteroids in the blood. The most common cause is a malfunction of the glands that produce these hormones. In some cases, however, the disease may be caused by tumors elsewhere in the body that have the ability to produce adrenocorticotropic hormone (ACTH).

In half of all Cushing’s patients, ectopic ACTH is produced by small lung cell carcinomas or lung carcinoids (a type of slow-growing lung cancer). But some tumors in the thymus and pancreas also have been found to produce ACTH.

Researchers at Damascus University Hospital in Syria presented the case of a 26-year-old man who had ectopic Cushing’s syndrome due to lung carcinoids.

The patient presented with increased appetite and rapid weight gain for more than a year. These were associated with headache, fatigue, proximal muscle weakness, and easy bruising. He had no family history of hormonal disorder.

Based on the initial physical and symptom evaluation, the clinical team suspected Cushing’s syndrome. Blood analysis revealed high levels of cortisol and ACTH hormones, which supported the diagnosis.

Administration of dexamethasone, a treatment used to inhibit the production of glucocoticosteroids by the pituitary gland, reduced cortisol levels within normal range, but not ACTH levels. This led to the diagnosis of ectopic Cushing’s syndrome.

The next step was to identify the tumor causing the syndrome. The team conducted imaging studies of the brain, chest, and abdomen, but found no tumor.

Because ectopic ACTH is commonly produced by lung cancers, the team then analyzed the patient’s lungs. Again, they failed to detect a tumor.

The patient was discharged with prescription of 200 mg of Nizoral (ketoconazole) once-daily, calcium, and vitamin D. After three months of treatment, he remained stable, with no evidence of symptom improvement.

At this point, the team decided to surgically remove both adrenal glands in an attempt to reduce the hormone levels. Treatment with prednisolone 5 mg and fludrocortisone 0.1 mg once daily was initiated, along with calcium and vitamin D.

Eighteen months later, the patient’s condition worsened and he required hospitalization.

Imaging tests targeting the neck, chest, and abdomen were conducted again. This time, physicians detected a 2 cm mass in the middle lobe of the right lung, which was removed surgically. Detailed analysis of the small tumor confirmed that it was the source of the excessive ACTH.

“ACTH secreting tumors can be very hard to detect,” the researchers stated. “Initial failed localization is common in ectopic ACTH syndrome and it is usually due to carcinoid.”

Cases where the ectopic ACTH production is caused by a carcinoid tumor can be challenging to diagnose because tumors are small and relatively slow-growing. Imaging data is often hard to analyze and the tumors can be confused with pulmonary vessels, the researchers explained.

“In such cases we should first aim to lower blood cortisol medically or through bilateral adrenalectomy to avoid Cushing’s complications,” which should then “be followed up through imaging studies (CT, MRI, scintigraphy or PET) to detect the tumor and resect it, which is the definitive treatment of these patients,” the researchers concluded.


Delayed complications after transsphenoidal surgery for pituitary adenomas

World Neurosurg. 2017 Oct 5. pii: S1878-8750(17)31710-2. doi: 10.1016/j.wneu.2017.09.192. [Epub ahead of print]


Perioperative complications after transsphenoidal surgery for pituitary adenomas have been well documented in the literature; however, some complications can occur in a delayed fashion postoperatively and reports are sparse about their occurrence, management, and outcome.

Here, we describe delayed complications after transsphenoidal surgery and discuss the incidence, temporality from the surgery, and management of these complications based on the findings of studies that reported delayed postoperative epistaxis, delayed postoperative cavernous carotid pseudoaneurysm formation and rupture, vasospasm, delayed symptomatic hyponatremia (DSH), hypopituitarism, hydrocephalus, and sinonasal complications.

Our findings from this review revealed an incidence of 0.6-3.3% for delayed postoperative epistaxis at 1-3 weeks postoperatively, 18 reported cases of delayed carotid artery pseudoaneurysm formation at 2 days to 10 years postoperatively, 30 reported cases for postoperative vasospasm occurring 8 days postoperatively, a 3.6-19.8% rate of DSH at 4-7 days postoperatively, a 3.1% rate of new-onset hypopituitarism at 2 months postoperatively, and a 0.4-5.8% rate of hydrocephalus within 2.2 months postoperatively.

Sinonasal complications are commonly reported after transsphenoidal surgery, but spontaneous resolutions within 3-12 months have been reported. Although the incidence of some of these complications is low, providing preoperative counseling to patients with pituitary tumors regarding these delayed complications and proper postoperative follow-up planning is an important part of treatment planning.


carotid pseudoaneurysm; cerebrospinal fluid leak; delayed complications; epistaxis; hydrocephalus; hyponatremia; hypopituitarism; pituitary; sinonasal complication; transsphenoidal surgery; tumor

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