Cortisol Levels Predict Remission in Cushing’s Patients Undergoing Transsphenoidal Surgery

In patients with Cushing’s disease, removing the pituitary tumor via an endoscopic transsphenoidal surgery (TSS) leads to better remission rates than microscopic TSS, according to new research.

But regardless of surgical approach, plasma cortisol levels one day after surgery are predictive of remission, researchers found.

The study, “Management of Cushing’s disease: Changing trend from microscopic to endoscopic surgery,” was published in the journal World Neurosurgery.

Because it improves visualization and accessibility, endoscopic TSS has been gaining popularity over microscopic TSS to remove pituitary tumors in Cushing’s disease patients. Yet, although this surgery has been associated with high remission rates, whether it outperforms microscopic surgery and determining the factors affecting long-term outcomes may further ease disease recurrence after TSS.

A team with the All India Institute of Medical Sciences addressed this topic in 104 patients who underwent surgery from January 2009 to June 2017. Among these patients, 47 underwent microscopic surgery and 55 endoscopic surgery. At presentation, their ages ranged from 9 to 55 (mean age of 28). Also, patients had been experiencing Cushing’s symptoms over a mean duration of 24 months.

Eighty-seven patients showed weight gain. Hypertension (high blood pressure) and diabetes mellitus were among the most common co-morbidities, found in 76 and 33 patients, respectively. Nineteen patients had osteoporosis and 12 osteopenia, which refers to lower-than-normal bone mineral density.

As assessed with magnetic resonance imaging, 68 patients had a microadenoma (a tumor diameter smaller than one centimeter) and 27 had a macroadenoma (a tumor one centimeter or larger). Only two patients had an invasive pituitary adenoma.

Two patients with larger tumors were operated on transcranially (through the skull). The surgery resulted in total tumor removal in 90 cases (86.5%). A blood loss greater than 100 milliliter was more common with endoscopic than with microscopic TSS.

Ten patients developed transient diabetes inspidus, two experienced seizures after surgery, and six of nine patients with macroadenoma and visual deterioration experienced vision improvements after TSS.

The incidence of intraoperative leak of cerebrospinal fluid — the liquid surrounding the brain and spinal cord — was 23.2%, while that of post-operative leak was 7.7% and was more common in microadenoma than macroadenoma surgery (9.8% vs. 5.0%).

Seventeen patients were lost to follow-up and two died due to metabolic complications and infections. The average follow-up was shorter for endoscopic than with microscopic surgery (18 months vs. 35 months).

Among the remaining 85 cases, 65 (76.5%) experienced remission, as defined by a morning cortisol level under 5.0 μg/dL, restored circadian rhythm (the body’s internal clock, typically impaired in Cushing’s patients), and suppression of serum cortisol to below 2 μg/dl after overnight dexamethasone suppression test.

The remission rate was 54.5% in pediatric patients and was higher with endoscopic than with microscopic TSS (88.2% vs. 56.6%). Also, patients with microadenoma showed a trend toward more frequent remission than those with macroadenoma (73.2% vs. 64.3%).

Ten of the remaining 20 patients experienced disease recurrence up to 28 months after surgery. Sixteen cases revealed signs of hypopituitarism, or pituitary insufficiency, which were managed with replacement therapy.

A subsequent analysis found that morning cortisol level on day one after surgery was the only significant predictor of remission. Specifically, a one-unit increase in cortisol lowered the likelihood of remission by 7%. A cortisol level lower than 10.7 μgm/dl was calculated as predicting remission.

Overall, the study showed that “postoperative plasma cortisol level is a strong independent predictor of remission,” the researchers wrote, and that “remission provided by endoscopy is significantly better than microscopic approach.”

From https://cushingsdiseasenews.com/2019/09/24/cortisol-levels-predict-remission-cushings-patients-undergoing-transsphenoidal-surgery/

ACTH Levels After Surgery Help Predict Remission, Recurrence in Cushing’s

Levels of adrenocorticotropic hormone (ACTH) in circulation after pituitary surgery may help predict which Cushing’s disease patients will achieve early remission and which will eventually see the disease return, a study shows.

Also, the earlier that patients reached their lowest peak of ACTH levels, the better their long-term outcomes.

The study, “Prognostic usefulness of ACTH in the postoperative period of Cushing’s disease,” was published in the journal Endocrine Connections.

Removing the pituitary tumor through a minimally invasive surgery called transsphenoidal surgery is still the treatment of choice for Cushing’s disease patients. But not all patients enter remission, and even among those who do, a small proportion will experience disease recurrence.

While cortisol levels have been suggested as a main predictor of remission and recurrence, there is no consensus as to which cutoff point should be used after surgery, or the best time for measuring this hormone.

Because Cushing’s disease is caused by an ACTH-producing tumor in the pituitary gland, and ACTH has a short half-life (approximately 10 minutes), it is expected that ACTH levels drop markedly within a few hours after surgery.

Thus, a group of researchers in Spain aimed to determine whether blood levels of ACTH could be useful for predicting remission of Cushing’s disease both immediately after surgery (defined as less than 72 hours) and in the long term.

Researchers analyzed 65 patients with Cushing’s disease who had undergone transsphenoidal surgery (seven required a second intervention) between 2005 and 2016. Remission within three months was seen in 56 of 65 cases; late disease recurrence was seen in 18 of 58 cases.

Investigators measured the ACTH nadir concentration (defined as the lowest concentration) and the time taken to reach nadir levels after surgery, as well as the plasma ACTH concentration before hospital discharge.

While ACTH levels had no predictive value, the team found that people who went into remission had significantly lower ACTH nadir levels and ACTH levels at discharge. On the other hand, levels of ACHT nadir and at discharge were significantly higher for people who experienced a relapse, compared to those who remained in remission.

Using artificial intelligence algorithms, the researchers further found that ACTH nadir, ACTH at discharge, and cortisol nadir values were all of great relevance to predict remission within three months.

Analysis indicated that using a cutoff point of 3.3 pmol/L of ACTH after surgery and before discharge gave the best sensitivity and specificity for predicting a patient’s prognosis.

Researchers further found that the time patients took to reach their ACTH nadir, regardless of nadir levels, also influenced their outcomes. In fact, patients reaching this nadir in less than than 46 hours more likely achieved early remission.

And taking longer than 39 hours to reach the ACTH nadir was significantly more frequent in patients who experienced recurrence. This indicates that the time to ACTH nadir is an important measure for prognosis.

“In the immediate postoperative period of patients with [Cushing’s disease], the ACTH concentration is of prognostic utility in relation to late disease remission,” the researchers said.

Overall, “we propose an ACTH value <3.3 pmol/L as a good long-term prognostic marker in the postoperative period of CD. Reaching the ACTH nadir in less time is associated to a lesser recurrence rate,” the study concluded.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.

Even in Remission, Cushing’s Patients Have Excess Mortality

Cushing’s disease patients in Sweden have a higher risk of death than the general Swedish population, particularly of cardiovascular complications, and that increased risk persists even in patients in remission, a large nationwide study shows.

The study, “Overall and disease-specific mortality in patients with Cushing’s disease: a Swedish nationwide study,” was published in the Journal of Clinical Endocrinology and Metabolism.

The outcomes of Cushing’s disease patients have improved with the introduction of several therapeutic approaches, such as minimally invasive surgery and cortisol-lowering therapies. However, mortality is still high, especially among those who do not achieve remission.

While currently patients in remission are thought to have a better prognosis, it is still unclear whether these patients still have a higher mortality than the general population. Understanding whether these patients are more likely to die and what risk factors are associated with increased mortality is critical to reduce death rates among Cushing’s patients.

A team of Swedish researchers thus performed a retrospective study that included patients diagnosed with Cushing’s disease who were part of the Swedish National Patient Registry between 1987 and 2013.

A total of 502 patients with Cushing’s disease were included in the study, 419 of whom were confirmed to be in remission. Most patients (77%) were women; the mean age at diagnosis was 43 years, and the median follow-up time was 13 years.

During the follow-up, 133 Cushing’s patients died, compared to 54 expected deaths in the general population — a mortality rate 2.5 times higher, researchers said.

The most common causes of death among Cushing’s patients were cardiovascular diseases, particularly ischemic heart disease and cerebral infarctions. However, infectious and respiratory diseases (including pneumonia), as well as diseases of the digestive system, also contributed to the increased mortality among Cushing’s patients.

Of those in remission, 21% died, compared to 55% among those not in remission. While these patients had a lower risk of death, their mortality rate was still 90% higher than that of the general population. For patients who did not achieve remission, the mortality rate was 6.9 times higher.

The mortality associated with cardiovascular diseases was increased for both patients in remission and not in remission. Also, older age at the start of the study and time in remission were associated with mortality risk.

“A more aggressive treatment of hypertension, dyslipidemia [abnormal amount of fat in the blood], and other cardiovascular risk factors might be warranted in patients with CS in remission,” researchers said.

Of the 419 patients in remission, 315 had undergone pituitary surgery, 102 had had their adrenal glands removed, and 116 had received radiation therapy.

Surgical removal of the adrenal glands and chronic glucocorticoid replacement therapy were associated with a worse prognosis. In fact, glucocorticoid replacement therapy more than twice increased the mortality risk. Growth hormone replacement was linked with better outcomes.

In remission patients, a diagnosis of diabetes mellitus or high blood pressure had no impact on mortality risk.

Overall, “this large nationwide study shows that patients with [Cushing’s disease] continue to have excess mortality even after remission,” researchers stated. The highest mortality rates, however, were seen in “patients with persistent disease, those who were treated with bilateral adrenalectomy and those who required glucocorticoid replacement.”

“Further studies need to focus on identifying best approaches to obtaining remission, active surveillance, adequate hormone replacement and long-term management of cardiovascular and mental health in these patients,” the study concluded.

From https://cushingsdiseasenews.com/2019/02/28/even-in-remission-cushings-patients-have-excess-mortality-swedish-study-says/

Faster Adrenal Recovery May Predict Cushing’s Disease Recurrence

A shorter duration of adrenal insufficiency — when the adrenal gland is not working properly — after surgical removal of a pituitary tumor may predict recurrence in Cushing’s disease patients, a new study suggests.

The study, “Recovery of the adrenal function after pituitary surgery in patients with Cushing Disease: persistent remission or recurrence?,” was published in the journal Neuroendocrinology.

Cushing’s disease is a condition characterized by excess cortisol in circulation due to a tumor in the pituitary gland that produces too much of the adrenocorticotropic hormone (ACTH). This hormone acts on the adrenal glands, telling them to produce cortisol.

The first-line treatment for these patients is pituitary surgery to remove the tumor, but while success rates are high, most patients experience adrenal insufficiency and some will see their disease return.

Adrenal insufficiency happens when the adrenal glands cannot make enough cortisol — because the source of ACTH was suddenly removed — and may last from months to years. In these cases, patients require replacement hormone therapy until normal ACTH and cortisol production resumes.

However, the recovery of adrenal gland function may mean one of two things: either patients have their hypothalamus-pituitary-adrenal axis — a feedback loop that regulates ACTH and cortisol production — functioning normally, or their disease returned.

So, a team of researchers in Italy sought to compare the recovery of adrenal gland function in patients with a lasting remission to those whose disease recurred.

The study included 61 patients treated and followed at the Ospedale Maggiore Policlinico of Milan between 1990 and 2017. Patients had been followed for a median of six years (minimum three years) and 10 (16.3%) saw their disease return during follow-up.

Overall, the median time to recovery of adrenal function was 19 months, but while most patients in remission (67%) had not yet recovered their adrenal function after a median of six years, all patients whose disease recurred experienced adrenal recovery within 22 months.

Among those with disease recurrence, the interval from adrenal recovery to recurrence lasted a median of 1.1 years, but in one patient, signs of disease recurrence were not seen for 15.5 years.

Statistical analysis revealed that the time needed for adrenal recovery was negatively associated with disease recurrence, suggesting that patients with sorter adrenal insufficiency intervals were at an increased risk for recurrence.

“In conclusion, our study shows that the duration of adrenal insufficiency after pituitary surgery in patients with CD is significantly shorter in recurrent CD than in the persistent remission group,” researchers wrote.

“The duration of AI may be a useful predictor for CD [Cushing’s disease] recurrence and those patients who show a normal pituitary-adrenal axis within 2 years after surgery should be strictly monitored being more at risk of disease relapse,” they concluded.

From https://cushingsdiseasenews.com/2019/01/29/faster-adrenal-recovery-may-predict-recurrence-cushings-disease/

Transsphenoidal Surgery Leads to Remission in Children with Cushing’s Disease

Transsphenoidal surgery — a minimally invasive surgery for removing pituitary tumors in Cushing’s disease patients — is also effective in children and adolescents with the condition, leading to remission with a low rate of complications, a study reports.

The research, “Neurosurgical treatment of Cushing disease in pediatric patients: case series and review of literature,” was published in the journal Child’s Nervous System.

Transsphenoidal (through the nose) pituitary surgery is the main treatment option for children with Cushing’s disease. It allows the removal of pituitary adenomas without requiring long-term replacement therapy, but negative effects on growth and puberty have been reported.

In the study, a team from Turkey shared its findings on 10 children and adolescents (7 females) with the condition, who underwent microsurgery (TSMS) or endoscopic surgery (ETSS, which is less invasive) — the two types of transsphenoidal surgery.

At the time of surgery, the patients’ mean age was 14.8 years, and they had been experiencing symptoms for a mean average of 24.2 months. All but one had gained weight, with a mean body mass index of 29.97.

Their symptoms included excessive body hair, high blood pressure, stretch marks, headaches, acne, “moon face,” and the absence of menstruation.

The patients were diagnosed with Cushing’s after their plasma cortisol levels were measured, and there was a lack of cortical level suppression after they took a low-dose suppression treatment. Measurements of their adrenocorticotropic (ACTH) hormone levels then revealed the cause of their disease was likely pituitary tumors.

Magnetic resonance imaging (MRI) scans, however, only enabled tumor localization in seven patients: three with a microadenoma (a tumor smaller than 10 millimeters), and four showed a macroadenoma.

CD diagnosis was confirmed by surgery and the presence of characteristic pituitary changes. The three patients with no sign of adenoma on their MRIs showed evidence of ACTH-containing adenomas on tissue evaluation.

Eight patients underwent TSMS, and 2 patients had ETSS, with no surgical complications. The patients were considered in remission if they showed clinical adrenal insufficiency and serum cortisol levels under 2.5 μg/dl 48 hours after surgery, or a cortisol level lower than 1.8 μg/dl with a low-dose dexamethasone suppression test at three months post-surgery. Restoration of normal plasma cortisol variation, eased symptoms, and no sign of adenoma in MRI were also requirements for remission.

Eight patients (80%) achieved remission, 4 of them after TSMS. Two patients underwent additional TSMS for remission. Also, 1 patient had ETSS twice after TSMS to gain remission, while another met the criteria after the first endoscopic surgery.

The data further showed that clinical recovery and normalized biochemical parameters were achieved after the initial operation in 5 patients (50%). Three patients (30%) were considered cured after additional operations.

The mean cortisol level decreased to 8.71 μg/dl post-surgery from 23.435 μg/dl pre-surgery. All patients were regularly evaluated in an outpatient clinic, with a mean follow-up period of 11 years.

Two patients showed pituitary insufficiency. Also, 2 had persistent hypocortisolism — too little cortisol — one of whom also had diabetes insipidus, a disorder that causes an imbalance of water in the body. Radiotherapy was not considered in any case.

“Transsphenoidal surgery remains the mainstay therapy for CD [Cushing’s disease] in pediatric patients as well as adults,” the scientists wrote. “It is an effective treatment option with low rate of complications.”

 

From https://cushingsdiseasenews.com/2019/01/15/transsphenoidal-surgery-enables-cushings-disease-remission-pediatric-patients-study/

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