Cushing’s Syndrome, Prostate Cancer and Adrenocortical Carcinoma

Posted on March 11, 2013 by MaryO

Orphagen has identified and characterized small molecule antagonists to steroidogenic factor-1 (SF-1). SF-1 binds to and regulates DNA promoter elements in the major transporters and enzymes required for adrenal steroid synthesis. It is also required for development of the adrenal gland. SF-1 antagonists inhibit cortisol secretion in adrenal cells and have potential application in two orphan indications, Cushing’s syndrome and adrenocortical carcinoma. In addition, SF-1 appears to have an important role in the progression of advanced prostate cancer.

 

cushings-adrenocortical-crop

 

Cushing’s syndrome:
An estimated 20,000 people in the US have Cushing’s, with more than 3,000 new cases diagnosed each year. The incidence is similar in Europe. Cushing’s syndrome disproportionately affects females, who make up about 75% of the diagnosed cases. Symptoms of Cushing’s syndrome can include obesity, diabetes, psychiatric disorders, osteoporosis and immune suppression. Cushing’s syndrome is caused by elevated secretion of cortisol from the adrenal gland, in association with pituitary, adrenal or other cancers.

Orphagen has identified small molecule antagonists to SF-1 that have the potential to suppress cortisol levels in all Cushing’s patients without serious side effects.

Adrenocortical carcinoma (ACC):
ACC is a rare malignancy with an extremely poor prognosis (5-year overall survival: 37-47%). Complete surgical resection offers hope for long-term survival but surgery is not an option in up to two-thirds of patients because metastasis has usually occurred by the time of diagnosis.

SF-1 is recognized as a potential mechanism-based therapeutic target for control of ACC and an SF-1 antagonist could be used in the treatment of ACC.

Pediatric ACC:
Pediatric ACC is a very rare but aggressive cancer with a long-term survival rate of about 50%. Approximately 60% of children with adrenocortical tumors are diagnosed before the age of four. The SF-1 gene is amplified and SF-1 protein is overexpressed in the vast majority of childhood adrenocortical tumors strongly implicating SF-1 in pediatric adrenocortical tumorigenesis.

Castration resistant prostate cancer (CRPC):
CRPC is the most common cancer in males. Surgery is not an option if the cancer has spread beyond the prostate gland, at which point patients typically receive hormonal therapy, essentially chemical castration. This course of therapy usually fails within two years, resulting in castration resistant prostate cancer (CRPC). Most patients eventually succumb to CRPC, which is the second leading cause of cancer deaths in men.
SF-1 antagonists may: (1) block the adrenal androgens that circumvent chemical castration, and are a primary cause of CRPC; and (2) inhibit synthesis of androgens within the prostate tumor itself, where SF-1 may control induction of enzymes for de novo androgen synthesis in treatment-resistant cancers.

From http://www.orphagen.com/research_cushings.html

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Early Detection, Treatment Needed To Reduce Risk Of Death, Cardiovascular Disease In Cushing’s Disease Patients

Posted on February 20, 2013 by MaryO

Even after successful treatment, patients with Cushing’s disease who were older when diagnosed or had prolonged exposure to excess cortisol face a greater risk of dying or developing cardiovascular disease, according to a recent study accepted for publication in The Endocrine Society’s Journal of Clinical Endocrinology & Metabolism (JCEM).

Cushing’s disease is a rare condition where the body is exposed to excess cortisol – a stress hormone produced in the adrenal gland – for long periods of time.

Researchers have long known that patients who have Cushing’s disease are at greater risk of developing and dying from cardiovascular disease than the average person. This study examined whether the risk could be eliminated or reduced when the disease is controlled. Researchers found that these risk factors remained long after patients were exposed to excess cortisol.

“The longer patients with Cushing’s disease are exposed to excess cortisol and the older they are when diagnosed, the more likely they are to experience these challenges,” said Eliza B. Geer, MD, of Mount Sinai Medical Center and lead author of the study. “The findings demonstrate just how critical it is for Cushing’s disease to be diagnosed and treated quickly. Patients also need long-term follow-up care to help them achieve good outcomes.”

The study found cured Cushing’s disease patients who had depression when they started to experience symptoms of the disease had an elevated risk of mortality and cardiovascular disease. Men were more at risk than women, a trend that may be explained by a lack of follow-up care, according to the study. In addition, patients who had both Cushing’s syndrome and diabetes were more likely to develop cardiovascular disease.

The study examined one of the largest cohorts of Cushing’s disease patients operated on by a single surgeon. The researchers retrospectively reviewed charts for 346 Cushing’s disease patients who were treated between 1980 and 2011. Researchers estimated the duration of exposure to excess cortisol by calculating how long symptoms lasted before the patient went into remission. The patients who were studied had an average exposure period of 40 months.

The findings may have implications for people who take steroid medications, Geer said. People treated with high doses of steroid medications such as prednisone, hydrocortisone or dexamethasone are exposed to high levels of cortisol and may experience similar conditions as Cushing’s disease patients.

“While steroid medications are useful for treating patients with a variety of conditions, the data suggests health care providers need to be aware that older patients or those who take steroid medications for long periods could be facing higher risk,” Geer said. “These patients should be monitored carefully while more study is done in this area.”

From http://www.medicalnewstoday.com/releases/256284.php

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Adrenal Insufficiency – Female Patient found Unconscious with Syringe Nearby

Posted on October 31, 2012 by MaryO

Crew’s misdiagnosis of drug overdose could have cost patient her life

Kimberly Doran | From the October 2012 Issue |

 

A call comes in to 9-1-1 dispatch. “Help” is all that’s spoken before the operator hears the phone hit the floor. The 9-1-1 dispatcher calls back only to get a busy signal. Police and EMS are dispatched for a well-being call.

On arrival, the front door is found to be slightly ajar. The crew knocks, but there’s no reply. They find a young woman  lying on the floor, naked, and in a pool of vomit. A syringe with an unknown substance is on the ground nearby. Suspecting a drug overdose, the EMS crew begins treating the patient for this condition. The patient is unconscious with emesis around her head and face. Her vital signs are blood pressure 60/45, heart rate of 130 bpm and respiratory rate of 10.

The patient shows no signs of waking. The crew clears the airway and administers oxygen. An IV is established, and the patient is readied for transport. As the crew leaves the scene, one of the medics turns to shut the door and sees a vial under a chair. He retrieves it and notes that the label says Solu-Cortef (a glucocorticoid). He bags it for the emergency department (ED). Following his instinct, he looks around the area for medications and finds two bottles. One is labeled dexamethosone and the other is labeled fludrocortisone. He takes his findings and rushes out the door into the awaiting ambulance. During transport, the patient continues to deteriorate.

The medic administers 0.5 mg of narcan and a 500mL bolus of normal saline with no response. He radios ahead to let the hospital know that they’re en route. Now questioning the original diagnosis of drug overdose, he reports the medications he found on the scene in hopes it will help the receiving physician determine the cause of the patient’s condition.

Arrival at the ED
On arrival to the ED, the medic hands over the loaded syringe containing 2mL of unidentified solution, as well as the empty vial of Solu-Cortef and the bottles of dexamethosone and fludrocortisones.

As the crew arrives at the hospital, the ED physician meets the crew and informs them that he’s familiar with the medications. He says they’re all used for people who have various forms of adrenal insufficiency (AI). The symptoms seen in this patient coincide with life-threatening adrenal crisis. The physician administers 100 mg of Solu-Cortef via IV and within minutes, the patient rouses. In 30 minutes, she can explain what happened in the desperate moments before her crisis.

Adrenal Insufficiency
Adrenal Insufficiency (AI) is a life-threatening in which the body is unable to produce enough cortisol to sustain life. In other words, their adrenal cortex is “asleep.” People suffering from AI take daily cortisol/glucocorticoid steroid replacement because whatever adrenal function is depleted. These patients are glucocorticoid dependent. In times of injury, dehydration, illness or surgery, they require an injection of Solu-Cortef. Solu-Cortef contains both glucocorticoid and mineralocorticoid properties, helping the body to compensate during a stress event.

The adrenal medulla (inside of the adrenal gland) secretes epinephrine and norepinephrine. The adrenal cortex (outer layer of the adrenal gland) secretes cortisol and aldosterone. Cortisol, a glucocorticoid, is often called the “stress” hormone. One of cortisol’s functions is elevating blood glucose levels in times of stress. It also functions as a mediator for several inflammatory pathways.

Absence of cortisol can result in hypotension, hypoglycemia and death. Aldosterone, a mineralocorticoid, is responsible for the regulation of sodium and water. Absence of aldosterone can result in hypotension and electrolyte imbalance. AI in the prehospital setting may be difficult to recognize in the absence of a good history, including medications, to point providers in the cause of the problem. Two life-threatening conditions associated with AI include hypotension and hypoglycemia.

If not managed, these two conditions are life threatening. Prehospital treatment should include management of the patient’s airway, vascular access and fluid resuscitation. If blood glucose levels are low, the patient should receive dextrose per local protocol. It’s important to complete a thorough physical assessment and obtain a complete patient history before treating patients with this condition. Providers may confuse patients having an adrenal crisis with drug overdose patients because of their similar symptoms. Although AI is rare, it should still be considered as a potential diagnosis.

Authors’ note: Parts of the above case are taken from a true story. However, the difference is that there was no syringe on the floor, no vial under the chair and no one found the medications. The patient was treated with charcoal and diagnosed as a drug-overdose patient. She likely would have died, but her mother charged into the ED and expressed the need for Solu-Cortef. Security was called, but luckily someone listened, researched and called the patient’s treating physician. The patient was treated and released. 

From Journal of Emergency Medical Services

 

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Day Nineteen, Cushing’s Awareness Challenge

Posted on April 19, 2012 by MaryO

In Day 10 on April 10, 2012, I wrote about how we got the Cushing’s colors of blue and yellow.  This post is going to be about the first Cushing’s ribbons.

 

I was on vacation  in September, 2001 when SuziQ called me to let me know that we had had our first Cushie casualty (that we knew about).

On the message boards, Lorrie wrote: Our dear friend, Janice died this past Tuesday, September 4, 2001. I received an IM from her best friend Janine, tonight. Janine had been reading the boards, as Janice had told her about this site, and she came upon my name and decided to IM me. I am grateful that she did. She said that she knew that Janice would want all of us to know that she didn’t just stop posting.

For all of the newcomers to the board that did not know Janice, she was a very caring individual. She always had something positive to say. Janice was 36 years old, was married and had no children. She had a miscarriage in December and began to have symptoms of Cushing’s during that pregnancy. After the pregnancy, she continued to have symptoms. When discussing this with her doctor, she was told that her symptoms were just related to her D&C. She did not buy this and continued until she received the accurate diagnosis of Cushing’s Syndrome (adrenal) in March of 2001. Tragically, Janice’s tumor was cancerous, a very rare form of Cushing’s.

Janice then had her tumor and adrenal gland removed by open adrenalectomy, a few months ago. She then began chemotherapy. She was very brave through this even though she experienced severe side effects, including weakness and dizziness. She continued to post on this board at times and even though she was going through so much, she continued with a positive attitude. She even gave me a referral to a doctor a few weeks ago. She was my inspiration. Whenever I thought I had it bad, I thought of what she was dealing with, and I gained more perspective.

Janice was having difficulty with low potassium levels and difficulty breathing. She was admitted to the hospital, a CT scan was done and showed tumor metastasis to the lungs. She then was begun on a more aggressive regimen of chemo. She was discharged and apparently seemed to be doing well.

The potassium then began to drop again, she spiked a temp and she was again admitted to the hospital. She improved and was set to be discharged and then she threw a blood clot into her lungs. She was required to be put on a ventilator. She apparently was at high risk for a heart attack. Her husband did not want her to suffer anymore and did not want her to suffer the pain of a heart attack and so chose for the doctors to discontinue the ventilator on Tuesday. She died shortly thereafter.

Janice was our friend. She was a Cushie sister. I will always remember her. Janine asked me to let her know when we get the Cushing’s ribbons made as she and the rest of Janice’s family would like to wear them in her memory. She said that Janice would want to do anything she could to make others more aware of Cushing’s.

The image at the top of the page shows the first blue and yellow ribbon which were worn at Janice’s funeral.  When we had our “official ribbons” made, we sent several to Janice’s family.

Janice was the first of us to die but there have been more, way too many more, over the years.  I’ll write a bit more about that on Day 21.

 

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Day Twelve, Cushing’s Awareness Challenge

Posted on April 12, 2012 by MaryO

Today’s Cushing’s Awareness Challenge post is about kidney cancer (renal cell carcinoma). You might wonder how in the world this is related to Cushing’s. I think it is, either directly or indirectly.

I alluded to this in Day Nine when I said:

I finally started the Growth Hormone December 7, 2004.
Was the hassle and 3 year wait worth it?
Stay tuned for Day 12, April 12, 2012 when all will be revealed.

So, as I said, I started Growth Hormone for my panhypopituitarism on December 7, 2004.  I took it for a while but never really felt any better, no more energy, no weight loss.  Sigh.

April 14 2006 I went back to the endo and found out that the argenine test that was done in 2004 was done incorrectly. The directions were written unclearly and the test run incorrectly, not just for me but for everyone who had this test done there for a couple years. My endo discovered this when he was writing up a research paper and went to the lab to check on something.

So, I went off GH again for 2 weeks, then was retested. The “good news” was that the argenine test is only 90 minutes now instead of 3 hours.

Wow, what a nightmare my argenine retest started! I went back for that Thursday, April 27, 2006. Although the test was shorter, I got back to my hotel and just slept and slept. I was so glad that I hadn’t decided to go home after the test.

Friday I felt fine and drove back home, no problem. I picked up my husband for a biopsy and took him to an outpatient surgical center. While I was there waiting for the biopsy to be completed, I started noticing blood in my urine and major abdominal cramps. I left messages for several of my doctors on what I should do. I finally decided to see my PCP after I got my husband home.

When Tom was done with his testing, his doctor took one look at me and asked if I wanted an ambulance. I said no, that I thought I could make it to the emergency room ok – Tom couldn’t drive because of the anaesthetic they had given him. I barely made it to the ER and left the car with Tom to park. Tom’s doctor followed us to the ER and became my new doctor.

They took me in pretty fast since I was in so much pain, and had the blood in my urine. They thought it was a kidney stone. After a CT scan, my new doctor said that, yes, I had a kidney stone but it wasn’t the worst of my problems, that I had kidney cancer. Wow, what a surprise that was! I was admitted to that hospital, had more CT scans, MRIs, bone scans, they looked everywhere.

My open radical nephrectomy was May 9, 2006 in another hospital from the one where the initial diagnosis was made. My surgeon felt that he needed a specialist from that hospital because he believed preop that my tumor had invaded into the vena cava because of its appearance on the various scans. Luckily, that was not the case.

My entire left kidney and the encapsulated cancer (10 pounds worth!) were removed, along with my left adrenal gland and some lymph nodes. Although the cancer (renal cell carcinoma AKA RCC) was very close to hemorrhaging, the surgeon believes he got it all. He said I was so lucky. If the surgery had been delayed any longer, the outcome would have been much different. I will be repeating the CT scans every 3 months, just to be sure that there is no cancer hiding anywhere. As it turns out, I can never say I’m cured, just NED (no evidence of disease). This thing can recur at any time, anywhere in my body.

I credit the argenine re-test with somehow aggravating my kidneys and revealing this cancer. Before the test, I had no clue that there was any problem. The argenine test showed that my IGF is still low but due to the kidney cancer I couldn’t take my growth hormone for another 5 years – so the test was useless anyway, except to hasten this newest diagnosis.

So… either Growth Hormone helped my cancer grow or testing for it revealed a cancer I might not have learned about until later.

My five years are up now.  My kidney surgeon *thinks* it would be ok to try the growth hormone again.  I’m still a little leery about this, especially where I didn’t notice that much improvement.

What to do?

 

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