MEKT1 Could Be a Potential New Therapy for Treating Cushing’s Disease

MEKT1, a type of therapy called a PPAR-γ agonist, acts to reduce levels of the adrenocorticotropic hormone and could be a potential new therapy for Cushing’s disease, according to researchers.

Their study, “Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells,” was published in the journal PPAR Research.

Cushing’s disease is caused by a tumor in the pituitary gland — generally a type of tumor called an adenoma that produces high levels of adrenocorticotropic hormone (ACTH).

ACTH causes the adrenal glands to make too much cortisol, leading to the classic symptoms associated with Cushing’s disease.

PPAR-gamma (PPAR-γ) is a transcription factor protein (meaning it regulates the levels of certain genes by acting through other proteins), and is seen in high levels in the normal human pituitary and in ACTH-secreting pituitary adenomas.

The Pomc gene is a precursor molecule to ACTH. While it is known that PPAR-γ plays a role in regulating Pomc levels, its mechanism has not yet been clarified in pituitary cells.

PPAR-γ agonists — agents that activate PPAR-γ — include the medications rosiglitazone and pioglitazone, both of which are used to treat type 2 diabetes. Some studies have shown that rosiglitazone and pioglitazone have an effect on Pomc suppression, which would lead to lower levels of ACTH and help treat patients with Cushing’s disease.

However, the benefits of PPAR-γ agonists in the treatment of Cushing’s disease are still controversial.

Researchers examined the effects of a new PPAR-γ agonist, MEKT1, on Pomc levels and ACTH secretion using a mouse pituitary tumor-derived cell line called AtT20 cells. They also compared its effects with the well-established PPAR-γ agonists rosiglitazone and pioglitazone.

AtT20 cells were treated with either MEKT1, rosiglitazone, or pioglitazone at various concentrations ranging from 1 nM to 10 μM (micrometers) for 24 hours.

Results showed that 10 μM of MEKT1 significantly inhibited Pomc gene levels compared to rosiglitazone and pioglitazone. Additionally, ACTH secretion from AtT20 cells was also significantly inhibited by the agonist.

To see if it worked to decrease Pomc levels by acting specifically on PPAR-γ, researchers eliminated the PPAR-γ protein using a technique called siRNA knockdown. In this case, the effects of MEKT1 on Pomc levels were significantly halted.

It is known that other proteins, such as Nur77, Nurr1, and Tpit activate Pomc levels by binding to the promoter region of Pomc — the area of the gene responsible for activating gene levels.

To determine whether these proteins could be targeted by MEKT1, researchers also looked at levels of Nur77, Nurr1, and Tpit. The PPAR-γ agonist was found to significantly suppress the levels of the three genes that encode these proteins.

“Although clinical trials of MEKT1 are needed to determine its drug efficacy in the future, it can be speculated that MEKT1 is much more effective than the previously recognized PPAR-γ agonists rosiglitazone, and pioglitazone for the suppression of Pomc expression/ACTH secretion from our in vitro [laboratory] research,” they added.

Results from this study suggest MEKT1 could be a potential new therapy for the treatment of Cushing’s disease.

From https://cushingsdiseasenews.com/2018/06/12/mekt1-could-be-potential-therapy-treatment-cushings-disease/

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.

From https://cushingsdiseasenews.com/2018/03/16/acth-cortisol-ratio-reliable-test-diagnose-cushings-disease/

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.

From https://cushingsdiseasenews.com/2018/03/02/mmp-9-enzyme-levels-may-predict-tumor-recurrence-in-cushings-study/

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.

From https://cushingsdiseasenews.com/2017/11/09/paradoxical-effects-of-somatostatin-analogs-on-adrenal-ectopic-acth-tumor/

Patients Undergoing Adrenalectomy Should Receive Steroid Substitutive Therapy

All patients who undergo removal of one adrenal gland due to Cushing’s syndrome (CS) or adrenal incidentaloma (AI, adrenal tumors discovered incidentally) should receive a steroid substitutive therapy, a new study shows.

The study, “Predictability of hypoadrenalism occurrence and duration after adrenalectomy for ACTH‐independent hypercortisolism,” was published in the Journal of Endocrinological Investigation.

CS is a rare disease, but subclinical hypercortisolism, an asymptomatic condition characterized by mild cortisol excess, has a much higher prevalence. In fact, subclinical hypercortisolism, is present in up to 20 percent of patients with AI.

The hypothalamic-pituitary-adrenal axis (HPA axis) is composed of the hypothalamus, which releases corticotropin-releasing hormone (CRH) that acts on the pituitary to release adrenocorticotropic hormone (ACTH), that in turn acts on the adrenal gland to release cortisol.

To avoid excess cortisol production, high cortisol levels tell the hypothalamus and the pituitary to stop producing CRH and ACTH, respectively. Therefore, as CS and AI are characterized by high levels of cortisol, there is suppression of the HPA axis.

As the adrenal gland is responsible for the production of cortisol, patients might need steroid substitutive therapy after surgical removal of AI. Indeed, because of HPA axis suppression, some patients have low cortisol levels after such surgeries – clinically known as post-surgical hypocortisolism (PSH), which can be damaging to the patient.

While some researchers suggest that steroid replacement therapy should be given only to some patients, others recommend it should be given to all who undergo adrenalectomy (surgical removal of the adrenal gland).

Some studies have shown that the severity of hypercortisolism, as well as the degree of HPA axis suppression and treatment with ketoconazole pre-surgery in CS patients, are associated with a longer duration of PSH.

Until now, however, there have been only a few studies to guide in predicting the occurrence and duration of PSH. Therefore, researchers conducted a study to determine whether HPA axis activity, determined by levels of ACTH and cortisol, could predict the occurrence and duration of PSH in patients who undergo an adrenalectomy.

Researchers studied 80 patients who underwent adrenalectomy for either CS or AI. Prior to the surgery, researchers measured levels of ACTH, urinary free cortisol (UFC), and serum cortisol after 1 mg dexamethasone suppression test (1 mg-DST).

After the surgery, all patients were placed on steroid replacement therapy and PSH was determined after two months. For those with PSH, levels of cortisol were determined every six months for at least four years.

Results showed that PSH occurred in 82.4 percent of CS patients and 46 percent of AI patients. PSH lasted for longer than 18 months in 50 percent of CS and 30 percent of AI patients. Furthermore, it lasted longer than 36 months for 35.7 percent of CS patients.

In all patients, PSH was predicted by pre-surgery cortisol levels after the 1 mg-DST, but with less than 70 percent accuracy.

In AI patients, a shorter-than-12-month duration of PSH was not predicted by any HPA parameter, but was significantly predicted by an absence of pre-surgery diagnosis of subclinical hypercortisolism.

So, this study did not find any parameters that could significantly predict with high sensitivity and specificity the development or duration of PSH in all patients undergoing adrenalectomy.

Consequently, the authors concluded that “the PSH occurrence and its duration are hardly predictable before surgery. All patients undergoing unilateral adrenalectomy should receive a steroid substitutive therapy.”

From https://cushingsdiseasenews.com/2017/12/08/therapy-cushings-patients-adrenalectomy/

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