Gamma Knife Radiosurgery...

...A safe alternative for treatment of ACTH-producing pituitary adenomas?

For the next few posts, I'm going to examine the latest research about the use of Gamma Knife (GK) radiosurgery in the treatment of pituitary adenomas, especially ACTH-producing adenomas.

Although GK is called radiosurgery, there is no cutting involved. 201 "beams" of cobalt-60 gamma radiation are focused on the region to be treated. The beams go through the skull in different spots, with each beam too weak to hurt normal tissue. However, when they all come together in the area to be treated, they are then strong enough to destroy the tumor. It is a type of single-fraction radiosurgery.

Another method often used is fractionated stereotactic radiotherapy. The Johns Hopkins' site explains FSR this way:

[With FSR] multiple fractionated doses or fractionated stereotactic radiation can be delivered. The main advantage of fractionation is that it allows higher doses to be delivered to the tumor because of increased tolerance of the surrounding normal tissues to these smaller fractionated doses. In other words, while single-dose stereotactic radiation takes advantage of differences in the pattern of radiation given, fractionated stereotactic radiation takes advantage of not only the pattern, but more importantly of the differing radiosensitivities of normal and surrounding tissues. Another advantage is so-called ”iterative” treatment, meaning the shape and intensity of the treatment plan can be modified during the course of therapy.

Dr. Molitch and Professor Grossman¹, in the March 2009 issue of Pituitary which focuses on radiotherapy for pituitary tumors, introduce the issue as guest editors. In their introduction, they say:

As of yet, there are no adequate studies to conclude whether there is one mode of single-dose radiotherapy that has superior efficacy or safety, and indeed direct comparisons of single-dose vs. fractionated stereotactic radiotherapy (FSR) are all but non-existent.

GK radiosurgery is done in one session. FSR takes multiple sessions spread over a period of time. The head must be in the exact position during each session. For many reasons, including ease, GK has become the preferred method.

In the same issue of Pituitary, Dr. Mary Vance at the University of Virginia² discusses the use of radiation therapy in the treatment of Cushing's disease. According to Dr. Vance, radiation therapy is used "most commonly as adjunctive therapy after unsuccessful pituitary surgery."

Dr. Vance reiterates the fact that GK is "not suitable for a large lesion close to the optic nerves or optic chiasm" and that all radiation therapies do cause loss of pituitary function eventually. She also emphasizes "There are no prospective studies comparing the results among different methods of radiation delivery regarding efficacy, development of new pituitary hormone deficiency or complications."

Points that Dr. Vance makes about any type of radiation therapy:

• Basically used when transsphenoidal surgery doesn't work
• Takes time (months to years) before it works
• Medical therapy (ketoconazole or metyrapone) to lower cortisol may be needed in conjunction with radiation treatment until it works
• Patient needs to be monitored closely for liver problems due to drug therapy and for lower natural production of cortisol

Dr. Vance has a nice summary of the various types of radiation therapy which include gamma knife (GK).

The Gamma knife series of 90 patients treated at the University
of Virginia found that a normal 24 h UFC level occurred in 49 patients (54%) at an average time of 13 months (range 2–67 months). Ten patients (20%) had relapse of Cushing’s with the mean time to relapse of 27 months (range 6–60 months). Seven of these patients underwent a second Gamma knife treatment, three achieved remission. Five of the seven patients (71%) who had a second Gamma knife treatment developed a new visual or 3rd, 4th or 6th cranial nerve deficit. These cranial nerve deficits either resolved (two patients), improved (two patients) or persist(one patient) (New pituitary hormone deficiency developed in 20 patients (22%)

This research also indicates there is no known safe radiation value for second attempts with GK.

The development of cranial nerve deficits and visual loss after a second Gamma knife treatment, in this study and in an another report [14], suggests that the presumed safe radiation dose to the cavernous sinus and optic chiasm and optic nerves is not known. For this reason, and until more definitive information is obtained, a second Gamma knife treatment should probably be avoided.

Dr. Vance points out that although radiation therapy is not perfect, there really is no perfect treatment for Cushing's disease at this time.

More posts on GK as a treatment coming this week.



1. Mark E. Molitch, Ashley B. Grossman (2008). Pituitary radiotherapy Pituitary, 12 (1), 1-2 DOI: 10.1007/s11102-008-0148-9

2. Mary Lee Vance (2008). Cushing’s disease: radiation therapy Pituitary, 12 (1), 11-14 DOI: 10.1007/s11102-008-0117-3

BackTrack: Dynamic MR Imaging of the Pituitary: Same tools, different technique (but wow, what a difference!)

(This article was first posted on July 29, 2008. It's worth repeating.)

Those of us who have suffered or still suffer with pituitary adenomas have heard way too many times "your MRI is normal". I did, for years. Yet, I ultimately did have a proven adenoma which caused my Cushing's disease. If the MRI had shown even an inkling of the tumor to the trained eye, perhaps a doctor would have taken my symptoms more seriously.

So, what makes a difference, then?

Two things made a huge difference for me. First, my current endocrinologist insisted on a dynamic MRI. Secondly, I sent the films and/or CDs to neurosurgeons who remove a lot of pituitary adenomas. What my local radiologist called a "normal" MR image of my pituitary was actually deemed NOT NORMAL by three world-renowned neurosurgeons.

(My local hospital is excellent, but they had never done a dynamic protocol with MR imaging. However, the Taper Imaging Center at Cedars-Sinaii Hospital in Los Angeles bent over backwards to prepare them through phone calls, emails, and reading materials. What a good group of folks! I've met several of them.)

What is a dynamic MRI?

In order to understand that, you need to first understand what an MRI is. Typically, pituitary MRI's are done "without contrast" and "with contrast". The Magnetic Resonance Imaging is done with no radioactivity (aka x-rays). It uses a strong magnetic field produced by a large magnet to send radio waves through the body which "jiggle" the body's atoms. When these atoms move back into place, they send out radio waves of their own which are picked up by the scanner and fed into a computer. This computer then uses programmed algorithms to turn them into pictures. To learn more about it, visit How Stuff Works.

A contrast is often used with MR imaging, especially of the head, to enhance the images. Solutions of gadolinium compounds are typically used as contrast agents. Tumors enhance after gadolinium is given because they tend to absorb the contrast agent either more quickly or less quickly than "normal" tissue. This leads to a "contrast" between the two types of tissue.

What makes a dynamic MRI different from any MRI using contrast?

Typically, a series of images are taken prior to contrast and then the MR imaging is stopped while contrast is injected. Once that is finished, the MRI proceeds with another series of images. With the dynamic protocol, the contrast is infused over a period of time while the MR imaging is taking place. In one study the gadolinium solution was injected via IV over a period of 180 seconds. In another study the gadolinium was dripped via IV between 2 and 3 minutes.

Why does that make a difference?

Pituitary tumors and normal gland tissue absorb the gadolinium at different speeds. The contrast between the normal tissue and tumor may be easier to see in the earlier images when compared to the later ones. Usually the pituitary adenoma enhances slower than the gland. (However, there have been documented cases of just the reverse if the tumor encases a blood supply.) When the tumor enhances slower, a "dark spot", in layman terms, shows up on the pituitary. These are called areas of "hypointensity". This is transitory and if not imaged as it happens, the tumor will enhance to match the gland. (In the picture, the upper image does not clearly show a tumor. The lower image shows the tumor well including its contact with the right internal carotid artery.)

Although I did not mention the strength of the MRI scanners being used, it's probably obvious that the stronger they are (measured in Tesla), the better they work. A 3T scanner is preferable if available, but the authors of the studies used scanners as low as 0.5T in their studies. A scanner is only as good as those operating it, those reading the scans, and the protocols used not matter how strong it is.

Pretty dynamic, huh?

---

For more information in prior threads, see:

Recent Advances in Neuroendocrine Imaging Lead to Improved Diagnosis

Testing 101: Imaging

Central Hypothyroidism: A Cushing's Disease problem, too

Since approximately 80% of Cushing's Disease/Syndrome is caused by a pituitary adenoma, other hormones produced by the interaction of the hypothalamic-pituitary-adrenal (HPA) axis are often deficient. This includes thyroid-stimulating hormone (TSH).

Primary hypothyroidism is often detected by elevated TSH values. This is due to the normal feedback-loop of the HPA axis. Central hypothyroidism (CH), however, is not typically detected by measuring TSH which is low due to a disruption of the pituitary's stimulus and is not produced as needed. The most common cause is a pituitary adenoma.

In Mechanisms Related to the Pathophysiology and Management of Central Hypothyroidism, the authors state, "Given that the prevalence of pituitary adenomas in the general population is greater than 10%, the true prevalence of CH might be much higher than that reported". When speaking of the method of measuring TSH levels alone, they say this "approach works, however, only if the hypothalamic-pituitary-thyroid axis is normal. Conversely, the strategy of first-line TSH measurement can miss patients with CH."

The authors give a very nice synopsis of the HPA axis' role in thyroid regulation and function. The diagrams are well-done, also. In Table 1, the causes of CH are listed:

Table 1. Causes of Central Hypothyroidism

Cause	Congenital	Acquired
Classic causes
Space-occupying lesions (brain or pituitary; pituitary adenoma, craniopharygioma, etc.)	Yes	Yes
Radiation	No	Yes
Vascular disease (Sheehan syndrome, etc.)	Yes	Yes
Nonclassic causes
Traumatic brain injury or subarachnoid hemorrhage	No	Yes
Drug-induced (bexarotene, carbemazepine, etc.)	No	Yes
Growth hormone therapy	No	Yes
Infection (lymphocytic adenohypophysitis, lymphocytic hypophysitis)	No	Yes
Set point diseases (infant's born to mothers with inadequately controlled Graves disease, etc.)	Yes	No
Genetic mutations	Yes	No
Idiopathic	Yes	Yes

CH usually appears concurrently with other hormone deficiencies. "Hormone deficiencies were seen for luteinizing hormone/follicle-stimulating hormone (LH/FSH) in 85% of patients, growth hormone in 65%, adrenocorticotropic hormone (ACTH) in 62%, TSH in 60%, antidiuretic hormone in 23% and prolactin in 15%."

The authors also detail non-classic causes of CH, including genetic mutations. With one familial case inheritance was determined to be autosomal recessive. Interestingly, the values of TSH measured varied by assay with one mutation.

The researchers make a case for using free T4 and free T3 to determine CH while levels of TSH have no diagnostic value. They also indicate that although the "nocturnal surge of serum TSH level has been used to assess CH, this approach is still controversial. MRI could be required for most suspected cases of CH to detect origin of hypothalamic or pituitary disorders."

Treatment is much the same as for any hypothyroidism. Levoxythyroxine is the first line of treatment. They also carefully point out the following:

Deficiencies of hormones other than TSH should be considered before starting
treatment. When ACTH deficiency is also present, glucocorticoid therapy should
be started at least 1 week before initiation of levothyroxine to avoid increased
consumption of cortisol and worsening of the ACTH deficiency, which can
induce crisis. (emphasis mine)

An algorithm was developed for treating CH sufferers. Interestingly, this does not show using any form of T3, although there are folks who do not convert forms of T4 to the needed T3. They do empasize, however, the importance of achieving "free T4 in the upper end of the normal range rather than within the middle or lower values".

On a positive note for those who have or will undergo pituitary surgery, they authors conclude, "Surgery is reported to lead to an improvement in anterior pituitary function in approximately 35% of patients with pituitary adenoma and CH."

Masanobu Yamada, Masatomo Mori (2008). Mechanisms related to the pathophysiology and management of central hypothyroidism Nature Clinical Practice Endocrinology & Metabolism, 4 (12), 683-694 DOI: 10.1038/ncpendmet0995

Adrenalectomy improves quality of life for Cushing's patients although it may take years

Although adrenalectomies are only a first-line treatment for those with ACTH-independent tumors in Cushing's Syndrome (ectopic and adrenal tumors, benign and malignant), they are also often a treatment for those with Cushing's Disease when pituitary surgery fails to totally remove the source of excess ACTH.

Hypercortisolemia, the result of excess ACTH from the pituitary or from overproduction in ectopic or adrenal tumors, is very debilitating for those who suffer from CS/CD. According to the authors, "Untreated Cushing’s syndrome can cause significant physical and mental morbidity and mortality, with a mortality rate in untreated that is 4 times greater than the baseline population."

This study looked at the outcomes of 60 patients who underwent either a unilateral (53%) or bilateral adrenalectomy (47%) to treat their Cushing's. Except for one patient, all adrenalectomies were done laproscopically. The median follow-up time was 41.4 months. At that median time, 9 patients had died. 4 patients had died from the progression of malignant disease, 2 from unknown causes, 1 from pulmonary embolus 2 months after surgery, and 2 five months post-op from severe complications due to pituitary (ACTH-dependent) Cushing's Disease.

Around 75% of the common physical signs/symptoms of Cushing's resolved after surgery, but the central obesity only had a resolution rate of 57%. Diabetes was cured in 79%, hypertension "improved dramatically or was cured in 67%."

Symptoms took anywhere from a few weeks to 4 years to resolve with most of the physical changes resolving in a mean of 7-9 months. There was a great variability with no good predictor of this variability.

The remark that I find so telling is this:

In fact, we had several patients with ‘‘subclinical’’ Cushing’s who took over 2 years for their symptoms to resolve.

Too often those of us who suffer with Cushing's are told to wait until the disease "gets worse" before being diagnosed/treated.

The authors point out the complication rates which are typically higher for Cushing's patients than for others who undergo adrenalectomies for whatever reason. Immunosuppression leads to greater risk of infection. Addisonian crisis is another prevalent complication. However, overall they conclude that adrenalectomies are a safe and effective treatment option, but both physicians and patients must not expect overnight improvements. This is another case of where slow and steady wins the race.



R SIPPEL, D ELARAJ, E KEBEBEW, S LINDSAY, J TYRRELL, Q DUH (2008). Waiting for change: Symptom resolution after adrenalectomy for Cushing's syndrome Surgery, 144 (6), 1054-1061 DOI: 10.1016/j.surg.2008.08.024

Dynamic MR Imaging of the Pituitary: Same tools, different technique (but wow, what a difference!)

Those of us who have suffered or still suffer with pituitary adenomas have heard way too many times "your MRI is normal". I did, for years. Yet, I ultimately did have a proven adenoma which caused my Cushing's disease. If the MRI had shown even an inkling of the tumor to the trained eye, perhaps a doctor would have taken my symptoms more seriously.

So, what makes a difference, then?

Two things made a huge difference for me. First, my current endocrinologist insisted on a dynamic MRI. Secondly, I sent the films and/or CDs to neurosurgeons who remove a lot of pituitary adenomas. What my local radiologist called a "normal" MR image of my pituitary was actually deemed NOT NORMAL by three world-renowned neurosurgeons.

(My local hospital is excellent, but they had never done a dynamic protocol with MR imaging. However, the Taper Imaging Center at Cedars-Sinaii Hospital in Los Angeles bent over backwards to prepare them through phone calls, emails, and reading materials. What a good group of folks! I've met several of them.)

What is a dynamic MRI?

In order to understand that, you need to first understand what an MRI is. Typically, pituitary MRI's are done "without contrast" and "with contrast". The Magnetic Resonance Imaging is done with no radioactivity (aka x-rays). It uses a strong magnetic field produced by a large magnet to send radio waves through the body which "jiggle" the body's atoms. When these atoms move back into place, they send out radio waves of their own which are picked up by the scanner and fed into a computer. This computer then uses programmed algorithms to turn them into pictures. To learn more about it, visit How Stuff Works.

A contrast is often used with MR imaging, especially of the head, to enhance the images. Solutions of gadolinium compounds are typically used as contrast agents. Tumors enhance after gadolinium is given because they tend to absorb the contrast agent either more quickly or less quickly than "normal" tissue. This leads to a "contrast" between the two types of tissue.

What makes a dynamic MRI different from any MRI using contrast?

Typically, a series of images are taken prior to contrast and then the MR imaging is stopped while contrast is injected. Once that is finished, the MRI proceeds with another series of images. With the dynamic protocol, the contrast is infused over a period of time while the MR imaging is taking place. In one study the gadolinium solution was injected via IV over a period of 180 seconds. In another study the gadolinium was dripped via IV between 2 and 3 minutes.

Why does that make a difference?

Pituitary tumors and normal gland tissue absorb the gadolinium at different speeds. The contrast between the normal tissue and tumor may be easier to see in the earlier images when compared to the later ones. Usually the pituitary adenoma enhances slower than the gland. (However, there have been documented cases of just the reverse if the tumor encases a blood supply.) When the tumor enhances slower, a "dark spot", in layman terms, shows up on the pituitary. These are called areas of "hypointensity". This is transitory and if not imaged as it happens, the tumor will enhance to match the gland. (In the picture, the upper image does not clearly show a tumor. The lower image shows the tumor well including its contact with the right internal carotid artery.)

Although I did not mention the strength of the MRI scanners being used, it's probably obvious that the stronger they are (measured in Tesla), the better they work. A 3T scanner is preferable if available, but the authors of the studies used scanners as low as 0.5T in their studies. A scanner is only as good as those operating it, those reading the scans, and the protocols used not matter how strong it is.

Pretty dynamic, huh?

---

For more information in prior threads, see:

Recent Advances in Neuroendocrine Imaging Lead to Improved Diagnosis

Testing 101: Imaging

Wednesday's News

Onetouch Ping Diabetes System Gets FDA Approval:

The two Johnson & Johnson companies Animas, an insulin pump manufacturer, and Onetouch, a well-known producer of glucose meters and strips, have teamed up to produce the Onetouch Ping, which received FDA Clearance today. The Ping is the first glucose-meter and insulin pump combo that employs wireless communication.

OneTouch Ping provides patients the advanced insulin pump technology from Animas plus the OneTouch blood glucose technology they trust, put together into a system that offers the discretion, convenience and option of remote insulin dosing," said Juan Frias, M.D., Chief Medical Officer and Vice President of Medical Affairs, Animas Corporation. “People using OneTouch Ping will no longer have to access their pump to deliver a bolus, ultimately making life with diabetes a little easier.”



Silent Corticotropinoma:

Pawlikowski M, Kunert-Radek J, Radek M.
Departments of Neuroendocrinology and Clinical Endocrinology, Chair of Endocrinology and Department of Neurosurgery and Surgery of Peripheral Nerves, Medical University of Lodz, Poland.

OBJECTIVES: The aim of the study was to evaluate the ACTH-immunopositive pituitary adenomas, especially those without manifestation of Cushing's disease....

CONCLUSIONS: (i) "Silent" corticotropinomas are rather frequent. (ii) This adenoma type should be considered as aggressive. (iii) It is hypothetized that -like in Nelson's syndrome - the lack of hypercortisolism or even presence of hypocortisolism favorizes the exaggerated growth of tumoral corticotrophs.

Sarcoidosis and Obesity:

INTRODUCTION: Polypliagia and morbid obesity appears in patients with sarcoidosis may be signs of neurosarcoidosis in the medial hypothalmus where satiety center is located. It is estimated that about 1% of all patients with sarcoidosis may have sarcoidosis of the hypothalamus. It is of utmost importance to diagnose and treat hypothalamic sarcoidosis as early as possible......

My legs are killing me....

I know...another whine. But it's really not. It just another day in the life of a "Cushie". A (hopefully) cured Cushie. I woke up this morning with my shoulders hurting so badly I could not manage to get out of bed. No strength, lots of hurt. My left shoulder started bothering me last night but I shrugged it off ‘cause I’d carried in groceries and done some major house-cleaning. Ok, major for me, but probably not for you white-glove folks. Thankfully, none of my friends own white gloves.

Back to this morning. Since my surgery to remove the pituitary adenoma which caused my Cushing's Disease, I have been adrenally insufficient although now at 18 months out, I am producing some cortisol on my own. But, I have had enough bouts with adrenal insufficiency (AI) to be prepared. My good friend, Linda, told me to be a good Girl Scout and keep cortef (hydrocortisone, the replacement I take when I don't make enough on my own) beside my bed at all times. I do. Therefore, I was able to reach over and take a dose. What would be non-effort most of the time was tough this morning. Just reaching. Frankly, I was waiting on my merit badge to put on my sash after that.

Ok...so what does that have to do with the legs? Just bear with me. The pain moved down the course of my body. The other time I remember this progression was when I "crashed" after surgery and my cortisol level fell 28 points in a very short time. Yep...that hurt. And I don't mean crash as in falling. I mean my cortisol level crashed. I was sore for days.

So, it took me 2 hours to this morning to be able to function. And later, I had to take more to stay functioning. I was hurting, cold, dizzy, and my ears were ringing.

Just to be safe, since I have bouts of hypokalemia (low potassium), I took extra potassium (prescribed). I took ibuprofen. Nothing worked except cortef. It eased things. I have been able to wean down, for the most part, to 5 mg of cortef a day. Since this sinus infection, that hasn't been so. But I thought I was on the mend with that and haven't had to take as much the last couple of days. I guess it caught up with me. As we jokingly say in the Cushie community, I overdrew at the cortisol bank. I guess.

That's the problem. It's a guessing game. I think that's what happened. Since I've had to dose extra twice today to make it through the day, and that is all that has helped with the pain, it makes sense. Short of going to the ER to have bloodwork done, I really have no way of knowing otherwise. I did/do have symptoms other than the pain. I'm cold, and was freezing at an outdoor reception in 90 degree heat today after going to a wedding. My face and head have hurt. I haven't really been nauseated, but I have not wanted any food, except I've been craving salty foods. That's atypical for me unless I'm AI. I even passed up the buffet and wedding cake!!

I feel like I've been run over by a Mack truck. Flu, you say? That's exactly how my endocrinologist described how I'd feel when I started into AI.

For more information on AI, see the following links:
911! Adrenal Crisis, Addison's/Adrenal Insufficiency
Adrenal Insufficiency: What Pharmacists Should Know
Drugs and the HPA-Axis
Guidelines for Stress-dosing
Life-threatening Electrolyte Abnormalities
Anterior Pituitary Hormone Replacement Therapy

Now, my arms and shoulders hurt again....

Where's the cheese??

One for the money, two for the show, three to make ready....

Just how many kinds of tumors are there associated with Cushing's? Wait, are we talking about pituitary tumors? Or adrenal tumors? How about ectopic tumors? Are you beginning to get the picture of why this illness is so hard to diagnose?

PITUITARY TUMORS/ADENOMAS:

So, let's talk about tumors. These are also sometimes called adenomas. Pituitary adenomas are classified several ways. They may be classified by pathology, by size, and by hormone production. I'm going to keep it simple here and list the basic types of tumors by the hormones they produce. Bear in mind that many pituitary adenomas produce more than one hormone. This production is not held in check by the body's normal feedback loops, thus they aren't controlled.

• Corticotroph (ACTH-Producing) Adenomas :
  The corticotroph adenoma secretes adrenocorticotropic hormone (ACTH), which results in Cushing Disease because it stimulates the adrenal glands to overproduce cortisol. These tumors are initially confined to the sella turcica, but they may enlarge and become invasive especially after bilateral adrenalectomy. This is called Nelson's Syndrome.
  
• Somatotroph (GH-Producing) Adenomas:
  Somatotroph adenomas produce growth hormone (GH), resulting in gigantism in younger patients and acromegaly in adults. These tumors may also extend beyond the sella.
  
• Thyrotroph (TSH-Producing) Adenomas:
  Thyrotroph adenomas secrete thyroid-stimulating hormone (TSH), also known as thyrotropin, which results in hyperthyroidism without TSH suppression. Many are large and invasive and typically have other types of adenoma cells included, such as ACTH and/or GH.
  
• Lactotroph (PRL-Producing) Adenomas:
  Lactotroph adenomas secrete prolactin (PRL) and are typically an intrasellar tumor. However, they can become large enough to enlarge the sella turcica.
  
• Nonfunctioning (Endocrine-Inactive) Adenomas:
  These tumors cause symptoms when they extend beyond the sella, which results in pressure on the surrounding structures such as optic nerves and carotid veins. They are not associated with clinical and biochemical evidence of hormone excess.
  
• Carcinomas:
  Pituitary carcinomas, although extremely rare, are usually endocrinologically functional, and ACTH-producing and PRL-producing tumors are the most frequent.
  
• Other Tumors:
  Other tumors of the pituitary include craniopharyngiomas, meningiomas, and germ cell tumors. Even rarer are the granular cell tumors, pituicytomas, and gangliogliomas. Most rare include gangliocytomas, lymphomas, astrocytomas, and ependymomas.

ADRENAL TUMORS/ADENOMAS:

When a tumor in an adrenal gland overproduces hormones, the tumor is called a functioning tumor. A tumor in an adrenal gland that does not produce hormones is, understandably, called a nonfunctioning tumor. A tumor can start in an adrenal gland (called a primary adrenal tumor) or it can begin in another organ, such as the lungs, and then metastasize (spread) to the adrenal glands. I'm going to focus on primary adrenal gland tumors.

• Adenoma:
  An adenoma is a benign nonfunctioning tumor of the adrenal cortex. Also called an adrenocortical adenoma, this tumor usually does not cause symptoms, and, if it is small, may not require any treatment. However, as it grows it can put pressure on parts of the gland causing it to under or overproduce hormones. The cause of adrenal adenomas is unknown, but the current accepted theory is that they arise because of mutations in certain genes. Adrenal adenomas are more common in some inherited diseases, including multiple endocrine neoplasia type I, Beckwith-Wiedemann syndrome and the Carney complex.
  
  Chronic adrenal stimulation by ACTH leads to bilateral adrenocortical hyperplasia and, if long-standing, nodular transformation according to recent research. Thus, an ACTH producing tumor of the pituitary or ectopic tumor may stimulate the adrenals to form tumors or become hyperplastic (more about hyperplasia in a bit).
  
• Adrenocortical carcinoma:
  Although exceedingly rare this is the most common type of malignant adrenal gland tumor, affecting the cortex, also called an adrenal cortical carcinoma. Adrenocortical carcinoma can be a functioning or nonfunctioning tumor. If the tumor is functioning, it may produce more than one hormone.
  
• Pheochromocytoma:
  A pheochromocytoma is a rare tumor that develops in the core of an adrenal gland. It secretes excessive amounts of catecholamines, usually epinephrine and norepinephrine.
  
• Neuroblastoma:
  Neuroblastoma is a disease in which malignant cells form in nerve tissue of the adrenal gland. It is very rare.

If that isn't enough, there is another form of tumor that isn't a tumor. It's called hyperplasia. These tumor cells may invade the pituitary or the adrenals in nests throughout the gland. Rather than go in-depth right now, I'll post some links to articles so you can explore the topic:

Pituitary Hyperplasia: A Review
Adrenal Hyperplasia

This is just a basic, no-frills outline of various tumors/adenomas associated with Cushing's Disease. And now....four to go.....to bed, that is....

It's not just apples and oranges.....

Oh, I know you've heard it before. "She's just depressed." As if anyone can be "just" depressed. And it's said like it's all just a mental thing. (Around here you'd hear that pronounced "thang". It sorta works with this topic.)

Well, the problem is, with those of us who have had our pituitaries sliced and diced after they were first suppressed with a "tumah" of varying proportions, it isn't "just depression". In the article "Apathy and Pituitary Disease: It Has Nothing to Do with Depression" the authors make some very valid points.

Of course, when I read the following, I just about got depressed. After all, they are describing me!

Patients who are diagnosed with pituitary disease experience many physical changes that have been well documented in the literature. These patients may have significant fluctuations in their weight as well as changes in their physical appearance, as seen in patients with adrenocorticotropic hormone-producing adenomas (ACTHomas), prolactinomas, and growth hormone-producing adenomas (GHomas). They may also experience changes in their sexual and reproductive functioning, such as amenorrhea, impotence, and impaired orgasm. Many patients with pituitary disease develop comorbid medical illnesses as a result of their pituitary dysfunction. The development of diabetes mellitus, hypertension, and coronary artery disease are a few examples.

They go on to talk about the problems of "lethargy, increased sleepiness, cyclic mood instability, impaired cognitive function (i.e., deficits in concentration and memory), and personality change" which occur with Cushing's Disease. Although I'm skipping a lot, basically they studied numerous patients who had pituitary surgery, and summarized with "apathy is an emerging concept in neuropsychiatry, and major depressive disorder and chronic fatigue syndrome are important syndromes from which apathy must be differentiated.... these patients with pituitary disease appeared to be suffering from depression, given their constricted affect. However, when asked about their mood, all stated that they were not depressed but, instead, stated that they had chronic fatigue and lack of motivation." Apathy, not depression, was a major factor in the quality of life for these patients.

The pituitary gland is a very tiny gland, actually, at the base of the brain. It is often described as "pea-sized" or "lima-bean" shaped. It is divided, basically, into anterior and posterior sections. Each part of the pituitary is responsible for multiple hormones.

Since adenomas (tumors) of the pituitary are typically measured in millimeters, it becomes obvious that size does not matter here. Adenomas under 10 mm in diameter are called microadenomas, while those 10 mm and larger are termed macroadenomas. In other words, one centimeter is LARGE in the pituitary world. Placement, size, and cell type(s) all vary so greatly that there really is not one, or two, or even three standard outcomes with these tumors.

Many adenomas/tumors suppress the pituitary so it cannot produce multiple hormones while the tumor overproduces one or more hormones. (Another topic for another day.) The point I'm trying to make is that we know what happens to the body with just one hormone problem. Think in terms of multiples and it obvious that what is seen as depression is often a by-product of pituitary malfunction.

Growth Hormone (GH) is a powerful brain hormone that is believed to play an important role in stimulating and controlling areas of the brain that regulate moods and emotions. It is not just important in growth. Certain chemicals in the brain, called neurotransmitters are dependent on the effects of GH to help them carry their messages between brain centers. If GH is not available, these functions may not occur appropriately and the result can be uncontrolled changes in psychological functioning. It can cause anxiety, depression or worry for no apparent reason when this happens, and this may cause changes in behavior or decline in social functioning. Negative and sad feeling often dominate the deficient person's mood, and positive or joyful feelings can be dampened. An affected individual could feel unable to enjoy life and lack the motivation to make change in their circumstance.

I am GH deficient. I have probably been GH deficient (as well as thyroid deficient) for over 20 years, and maybe 30 years. Since I don't have access to any records that far back, it's hard to tell. When I had the Arginine GHRH Stimulation test at the University of North Carolina back in the spring, I only stimmed to 0.13 ng/ml. I started out at 0.02 ng/ml. When normal is around 10 ng/ml, that's mighty low. I have been on GH (Genotropin) for about 2 months and can tell a huge difference in my attitude and fortitude. Ok...I now have 'tude!! Seriously, I have less apathy, much more social presence, and I'm not hiding in my den so much. I see a return of the "old Robin" in many ways. Yes, less apathy.

Back to the apples and oranges....depression is not the same as apathy. Sliced or diced.....still two different fruits.

Every journey has a beginning

Sure, every journey has a beginning, but sometimes it's hard to know when everyday life ended and the journey began. Or is all of life a journey and the illness just a rough patch in the road? Heck, I don't know. I just know that I don't really know when I started getting sick. And at this moment, that really doesn't matter. What matters is getting well.

You know, wellness is relative. Since perfection isn't readily achievable, and wellness would seem to me to be perfection, I guess none of us are really totally "well". However, there are degrees of wellness, and my journey has been an effort to achieve varying degress if it.

Maybe we need a wellness meter, something like a glucometer. "Well-o-meter"? I'll invent one when I get around to it. ;)

I'm not much of a philosopher, so I can't wax eloquent very well, but I do know how to tell it like it is. Thus, my attempts for this blog were born. In short, this is a blog about my journey with Cushing's Disease, but it really is much, much more than that. I've learned a lot along the way with the help of some wonderful friends. I hope to pay it forward somehow and help others. And I have the need to tell my story.