Growth Hormone for Survival: It's not always controversial

"Hypopituitary adults have a reduced life expectancy, with a 2-fold higher risk of death for cardiovascular disease compared with that in the control population, and [growth hormone deficiency] has been considered the underlying factor influencing this increased mortality."

Lately growth hormone has been given a bad rap because of the controversy of its abuse by healthy, adult athletes and body-builders. That's actually very sad when there is a sizable body of chronically afflicted, growth hormone deficient adults. Hypopitiutarism and panhypopituitarism due to pituitary adenomas, surgery as treatment, and/or infarction leaves most Cushing's Disease survivors with growth hormone deficiency (GHD).

According to recent research, quoted here at Stanford and reiterated by Dr. Theodore Friedman, "GH appears to be one of the first hormones to be lost in patients with pituitary tumors and nearly all patients with two or more other pituitary deficiencies also lack GH."

In a recent issue of Pituitary, a study titled "Effects of 5 years of growth hormone (GH) replacement therapy of cardiac parameters and physical performance in adults with GH deficiency" caught my eye. Although not really news to me, it was nice to see some more validation. The research is outlined exceptionally well, with concise but thorough discussion and analysis.

The bottom line: There may be a slight increase in blood pressure and left ventricular mass with treatment, but this is greatly offset by "positive effects on exercise capacity and maximum oxygen uptake".

Another study states:

...there is no doubt that adult patients with hypopituitarism and GH deficiency have an increased CV risk (odds ratio of 2 for men and 3.5 to 4 for women). "

Improvement of systolic and diastolic pressures, lipid profiles, and plaque formation are also documented. A significant decrease in IMT and CRP were favorable outcomes of GH replacement therapy.

GHD has also been linked to apathy, fatigue, lack of motivation and more. Thus, it becomes not only an issue of mortality, but also an issue of quality of life.

I hope the medical community will educate themselves about GHD. The authors of the Pituitary
study elaborated well:

GHD is associated with hypercoagulability, abdominal obesity, insulin resistance, unfavorable lipid profile, atherosclerosis, increased blood pressure (BP), decreased exercise performance and with reduced pulmonary capacity, left ventricular (LV) mass and LV systolic performance...

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Cenci, M., Soares, D., Spina, L., Lima Oliveira Brasil, R., Lobo, P., Mansur, V., Gold, J., Michmacher, E., Vaisman, M., & Conceição, F. (2009). Effects of 5 years of growth hormone (GH) replacement therapy on cardiac parameters and physical performance in adults with GH deficiency Pituitary DOI: 10.1007/s11102-009-0182-2

Medical therapies for ACTH-producing tumors: What's the verdict?

In this article, the authors look at possible medical therapies to treat ACTH-producing tumors including those which cause Cushing's Disease (CD) and silent corticotroph adenoma (SCA). CD is caused by an ACTH producing pititary adenoma. SCA shows the same immunoreactivity of a pituitary adenoma without the same signs or symptoms of Cushing's. The authors take great pains to discuss and define the pathology of each of these.

This study examined the effect of somatostatin receptor (SSTR) subtype (1-5) and dopamine receptor type 2 (D2R) on CD, SCA, and non-functioning pituitary tumors (NFT). It is a meaty report with fairly detailed data for those who are interested and admits some limitations with differnt gene profiles of various pituitary tumors.

The advance publication text is free. In short, the authors concluded:

...the increased expression of SSTR5 in ACTH-secreting pituitary tumors causing overt CD and increased expression of SSTR1 and 2 in SCA...suggest that
somatostatin analogs more selective for SSTR5 and SSTR1 and/or 2 could be used
as an effective drug for medical treatment for CD and SCA, respectively, whereas
the clinical application of dopamine agonists selective for DR2 is very limited
in CD or SCA.

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Toru TATENO, Masako KATO, Yuji TANI, Kenichi OYAMA, Shozo YAMADA and Yukio HIRATA (2009). Differential Expression of Somatostatin and Dopamine Receptor Subtype Genes in Adrenocorticotropin (ACTH)-Secreting Pituitary Tumors and Silent Corticotroph Adenomas Endocrine JournalDOI: 10.1507/endocrj.K08E-186

Diagnosing and Treating Cushing's: Presentations by Dr. Theodore C. (Ted) Friedman

Dr. Friedman's original PowerPoints may be found at his website. These are very informative and easy to follow.

Publish at Scribd or explore others: Health & Medicine Research tumor adrenal

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Publish at Scribd or explore others: Research tumor adrenal

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Publish at Scribd or explore others: Research tumor adrenal

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Publish at Scribd or explore others: Research tumor adrenal

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

In the News: Protein in pituitary critical to women's health...

Discovery In Pituitary Of Protein That Regulates Hormones Critical To Women's Health:

University of Wisconsin-Madison researchers have solved the mystery surrounding
a 'rogue protein' that plays a role in the release of neurotransmitters and hormones in the brain.

The scientists found abundant amounts of the puzzling protein - whose main location and function were unknown until now - in a specific area of the pituitary gland. Like someone at a control knob, the protein may adjust the release of the two hormones that come almost exclusively from the posterior pituitary: oxytocin, which controls many reproductive functions, and vasopressin, which controls fluid balance.

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Wal-Mart's $4 Generic Prescription Drug List Added to Epocrates' Drug Reference Application

What does this mean for you, the patient? It means your physician should be able to readily see what drugs you can get through this program and prescribe accordingly.

Physicians will now be better equipped to help identify lower cost medication options available for their patients at Walmart, Neighborhood Market and Sam's Club pharmacies nationwide.

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Discovery of a compound strong enough to fight off some of the most deadly bacterial infections seen in human beings.

Important in many ways, including those who suffer MRSA and other hard-to-treat infections, a compound isolated while searching for a reason so many coral reefs were dying may help treat resistant infections.

Scientists isolated the compound from the thriving sponge. What they found was a compound that was originally discovered in the late 1990s by scientists searching for anticancer chemicals. Back then it was overlooked. Today, scientists think they may have hit an underwater jackpot.

"We have yet to have a failure. We have yet to find resistant bacteria. We're limited only by our imagination in what we're going to get out of the ocean for human health. It's a big world out there."

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?

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For more information in prior threads, see:

Recent Advances in Neuroendocrine Imaging Lead to Improved Diagnosis

Testing 101: Imaging

Protein That Regulates Hormones Critical To Women’s Health Found In Pituitary

Protein That Regulates Hormones Critical To Women’s Health Found In Pituitary

The scientists found abundant amounts of the puzzling protein - whose main location and function were unknown until now - in a specific area of the pituitary gland. Like someone at a control knob, the protein may adjust the release of the two hormones that come almost exclusively from the posterior pituitary: oxytocin, which controls many reproductive functions, and vasopressin, which controls fluid balance.

Current Treatment Strategies in Managing Aggressive Pituitary Tumors

Michael Buchfelder pulls together recent studies with a good synopsis of current treatments for aggressive pituitary tumors in this article. However, he doesn't address ACTH-producing adenomas which cause Cushing's Disease. He does, however, talk about some of the treatments that are being used for other types of tumors.

Buchfelder discusses the use of dopamine agents to control prolactinomas, and focuses on cabergoline and bromocriptine. Cabergoline is the preferred agent due to its ability to normalize prolactin levels as well as shrink tumor size with few side effects.

In the article, surgery is always the front-line approach for other tumors with secondary treatments to control recurrence and/or regrowth. Transsphenoidal endoscopic surgery is the first-line approach, but he does say surgical techniques can remove the bulk of the tumor "but do nothing to reduce the recurrence of aggressive tumors."

The somatostatin analogs (SSAs) lanreotide and octreotide are mentioned as effective agents for "other kinds of tumors", but only treatment of those causing acromegaly are described in depth.

SSAs can be used as primary therapy, pre-operatively to reduce the tumor volume
and make it more amenable to surgical removal, or post-surgery to control
re-expansion.

He also mentions the recent studies using the chemotherapy agent, temozolomide (another research blog I did recently), to control aggressive pituitary tumors.

Radiotherapy is a non-pharmacological treatment outlined in the article, with stereotactic radiation is only working for small tumors with the "precise location" known. Any type of radiotherapy works best in conjunction with surgical intervention.

He really articulates well the frustrations and complications with treating pituitary tumors with his closing remarks:

...we should not be reticent about using all options available (even in a single patient if necessary) to get the best possible control of symptoms.

Michael Buchfelder (2008). Management of aggressive pituitary adenomas: current treatment strategies Pituitary DOI: 10.1007/s11102-008-0153-z

There is more research on future treatment strategies which I hope to share in the next few days.

To learn more:

Is Temozolomide a new treatment for aggressive pituitary tumors?

A novel pituitary tumor transforming gene identified

A Cushie Champion: Dr. Ian McCutcheon (MD Anderson) (talks about tumors and treatments)

Recent Advances in Neuroendocrine Imaging Lead to Improved Diagnosis

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

Is Temozolomide a new treatment for aggressive pituitary tumors?

The authors of this study, Low 0⁶-methylguanine-DNA methyltransferase[P1] (MGMT) expression and response to temozolomide in aggressive pituitary tumours, detail the use of temozolomide as a possible treatment for the aformentioned tumors. They also evaluate 0⁶-methylguanine-DNA methyltransferase (MGMT) "expression in pituitary tumours and consider whether MGMT expression is associated with response to temozolomide therapy in aggressive pituitary tumours".

Why is this relevant? Because so many ACTH-secreting adenomas of the pituitary invade other structures. The study states:

Clinically significant pituitary tumours occur in approximately 1 in every 1000
individuals ...between 35-55% of adenomas demonstrate invasion into bone,
dura or adjacent structures such as the cavernous or sphenoid sinuses or
brain...

According to this article, some tumors display aggressive behavior and are resistant to current treatments. They can require the patient to have multiple operations and/or radiation therapy in order to control the growth.

Temozolomide works for some patients in the control of their tumors. Widely used for other brain tumors, its success has been mixed when applied to aggressive pituitary tumors. In this study, the relationship of "MGMT immunohistochemistry in two patients with aggressive pituitary tumours treated with temozolomide" is important. "[L]ow expression was demonstrated in a patient who responded to temozolomide whereas high expression was seen in another patient with no response to this agent 20."

When enlarging their study to 88 tissue samples from previous patients, the authors found their "work suggests that low MGMT protein expression, as assessed by immunohistochemistry, may be associated with a clinical response to temozolomide in aggressive pituitary tumours and supports the brief report of Kovacs et al."

The bottom line: MGMT immunohistochemistry is a promising technique for predicting the applicability of temozolomide for controlling aggressive pituitary tumors.


Ann I. McCormack, Kerrie L. McDonald, Anthony J. Gill, Susan J. Clark, Morton G. Burt, Kirsten A. Campbell, Wilton J. Braund, Nicholas S. Little, Raymond J. Cook, Ashley B. Grossman, Bruce G. Robinson, Roderick J. Clifton-Bligh (2008). Low 0(6)-methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours
Clinical Endocrinology DOI: 10.1111/j.1365-2265.2008.03487.x

Rocket Scientist's Laser Scalpel Targets Individual Cells

Rocket Scientist's Laser Scalpel Targets Individual Cells

Using a so-called femtosecond laser, her device emits ultrafast light pulses that don't have enough time to damage surrounding tissue. While femtosecond lasers themselves aren't exactly new—they're standard gear for laser eye surgery—Ben-Yakar is the first to figure out how to make one small enough to be used inside a person. Her blaster fits in a 15-mm surgical probe that shoots the laser's light through a crystal fiber (similar to a fiber-optic strand).

Paired with another fiber for microimaging, it lets surgeons work through a small incision and burn off individual cells in places like the pituitary gland (normally accessed rather awkwardly through the nose) and the spinal cord, which is hidden behind bundles of sensitive neurons and axons.

New technology for the removal of pituitary and brain tumors

According to Advocate Lutheran General Hospital, "[t]he intra-operative Magnetic Resonance Imaging (MRI) system improves the accuracy of brain surgery for children and adults by providing real-time, high-quality images of the brain before, during and after surgery." Due to the shift of the brain and other structures during surgery, the tumor may not be exactly where the pre-surgical MRI showed it. This technology allows the surgeons to check during and post-surgery for accurate and adequate removal of a tumor.

Cushing's patients are notorious for having hard-to-find-and-remove pituitary tumors. Factor in hyperplasia and extension into the adjacent sella and sinus areas, and the problem is magnified. This technology is helping surgeons remove pituitary tumors with a better outcome because surgeons can view detailed, three-dimensional images of the brain in real time during an operation .

The video below tells about one patient's story.




To read more:

Medtronic
Advocate Lutheran General Hospital
University of California, Irvine

Does GH replacement in children with GHD affect their HPA-axis?

Hypopituitarism and panhypopituitarism are common with Cushing's patients (including children) both before and after surgery. Growth hormone deficiency (GHD) treatment also unmasks HPA-axis insufficiencies with adults . But do children respond the same to GH therapy?

A recent article published in Clinical Endocrinology, Effect of Growth Hormone Deficiency and Recombinant hGH (rhGH) Replacement on the Hypothalamic-Pituitary-Adrenal Axis in Children with Idiopathic Isolated GH Deficiency, may be found for free on Medscape (with signup). The authors decided to see if the HPA-axis of children is affected by GH therapy in a similar way adults with GHD are affected. Adults often have central hypoadrenalism which is unmasked when GHD is treated.

The article concludes, "The present study indicates that rhGH therapy has no effect on the HPA in children with idiopathic isolated GHD," and goes on to say, "a reassessment of adrenal function is not required in patient with idiopathic isolated GHD and normal pituitary MRI, during rhGH therapy. These findings further support the view that only in patients with organic hypothalamic-pituitary disease, rhGH treatment may unmask either a hypoadrenal or a hypothyroid state."

For more information, the Magic Foundation is a great resource to learn about growth hormone deficiency (GHD) for children and adults.

Mom was right, as always.....

When Kevin started growing out but quit growing up, his mother knew something was not right, even when Kevin's doctor said, "...you and your husband are big people. He’s just big."

Steven Waguespack, M.D., associate professor in M. D. Anderson’s Department of Endocrine Neoplasia and Hormonal Disorders [said], “Kevin had gained about 30 pounds in a year, but he had not grown any taller, which is very concerning for an underlying endocrine problem in children...Weight gain around the middle is a classic symptom in adults, but in kids the weight gain is often distributed all over the body. That’s how it was with Kevin. However, he didn’t have some of the other classic symptoms of Cushing’s like muscle weakness, stretch marks or skin thinning.”

The type of tumor on Kevin’s pituitary was unusual as well. While most Cushing’s tumors are very small, often not visible even on an MRI, Waguespack says Kevin’s was large.

“Kevin is proof that every case of Cushing’s doesn’t always have classic symptoms,” Waguespack says.

Kevin's tumor was removed by Dr. Ian McCutcheon of M.D. Anderson within a few weeks. A year later, Kevin has lost 18 pounds and grown 3 inches in height.

To read more:
Cancer News and Information - CancerWise - Cushing’s Disease Causes Abnormal Growth

Fiona Apple may just have it right....

He said 'It's all in your head' and I said 'So's everything' but he didn't get it --Fiona Apple in "Paperbag".

Pituitary tumors have a large spectrum pathology. These "little buggers" may cause large problems, also. Dr. Shereen Ezzat of the Toronto Cancer Institute has been studying pituitary tumors for several years, and presents the case for epigenetic disruption of gene expression which causes alterations of normal pituitary cells. Using the information he and others have gathered, he is hopeful treatments for these lesions/tumors can be developed. Since the morbidity/mortality of most with pituitary tumors is greatly increased, and the only long-term therapies so far are surgical or radioactive, improved treatment is anxiously sought by those of us with Cushing's or presently in remission.

According to Dr. Ezzat, pituitary tumors comprise 10% of the tumors surgically removed intercranially with increased morbidity due to invasion of surrounding structures. As a Cushie community, we know this only too well first-hand. All too often the only recourse for the hypercortisolemia due to ACTH producing tumor cells is a bilateral adrenalectomy. Radiation is often a secondary treatment to decrease tumor growth or Nelson's syndrome.

In another article, Dr. Ezzat says, "Some pituitary adenomas grow rapidly, producing symptoms of an intracranial mass, loss of normal anterior pituitary hormone production, and visual-field disturbances due to stretching of the overlying optic chiasm. They can invade downward into paranasal sinuses, laterally into the cavernous sinuses (thereby disrupting coordinated eye movement) and upwards into the brain. They can cause death by invasion of the brain."

But size does NOT always matter with these tumors. Dr. Ezzat also says "they can cause mood disorders, sexual dysfunction, infertility, obesity and disfigurement, hypertension, diabetes mellitus and accelerated heart disease. If untreated, hormone-excess syndromes can be lethal."

In the pre-print, recent article, Epigenetic Control in Pituitary Tumors , Dr. Ezzat discusses epigenetically-mediated gene dysregulation as a cause for the production of pituitary tumors. He explores the role of fibroblast growth factors and histone gene silencing and discusses the implications of the need to find the process or mechanism involved in order to develop new therapies.

Shereen Ezzat, M.D. (2008). Epigenetic Control in Pituitary Tumors Endocrinology Journal DOI: http://dx.doi.org/http://www.jstage.jst.go.jp/article/endocrj/advpub/0/0804240101/_pdf

One Good Thing - by Steve Owens

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I have a dear friend, Steve, who is suffering with Cushing's. I met Steve first online at cushings-help.com's message boards over 2 years ago where he was seeking help for a known adrenal tumor. He was passed around to multiple specialists and no one would do anything.

Steve was suffering mightily from the symptoms of Cushing's, yet no one would even test him for that. He persisted and pursued with two Cushing's specialists all the way across the country and was eventually diagnosed with ACTH-dependent Cushing's due to pituitary tumors. (Since many adrenal tumors are due to high ACTH stimulating the adrenals, it was hoped his would go away with the remission of the high ACTH.) He was referred by one for surgery which was done by a top-notch neurosurgeon at M. D. Anderson. Two tumors were removed, one from his pituitary and one from the sella floor.

Steve was not cured. The hopeful demise of the adrenal tumor did not happen, and he is now facing a bilateral adrenalecomy. It will happen next month. In the meantime, he as been on ketoconazole.

Not only does Steve face this after years of his body failing him due to the high ACTH, but his younger daughter is being tested for Cushing's, too. I've met Steve's family in person, and they are as dear as they come. His wife and girls are so supportive of him, and he continues to support others as much as he can in his fight for his life.

All of the above was simply to preface the story below. Steve wrote it and gave me permission to post it. (Love ya, my friend. I know how difficult this was.)

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One Good Thing

If there was ever any hope it is the hope that someday Cushing's will be easier to diagnose and to treat. That doctors will recognize the symptoms and tests are developed that lead from diagnosis to a cure in weeks, not years. If there is one thing I could want to come of all this, it is that. Not just for me, but for all of you, and especially my daughter. It is the hardest thing in the world looking into her eyes. I just want one good thing to come of all this.

These past few weeks have been filled with a lot of emotions, feelings, and just plain being scared. The closer the BLA gets, the more I don't like it. I have no extra spoons to spare to try and conquer the fear, because I am using them to get through each day. The days have been filled with doctors visits, testing for me and Brooke, and work. Nothing out of the ordinary, other than having an infection we cant seem to clear up.

It was at one doctor visit, with Doctor VJ, my family doc, that is the reason of my story. You see, I haven't seen her in a year. My weekly and bi-weekly visits have all been to endo's who are taking care of everything. Well, since they were out of town, I needed to see my family doctor. This is the doctor who wrote tests and she didn't know why, other than we asked for them. She couldn't read results because Cushing's isn't so black and white. This is the doctor who looked at me and knew I had Cushing's, once she read about the physical and not so physical symptoms. This is the doctor who told us my daughter has Cushing's, like her father. This is the doctor who scoured the medical books, talked to other doctors, and researched the internet to learn what she could to help her patients.

We would learn that Dr VJ would have a new patient come to her, one she suspected had Cushing's. Because the doctor took the time to care about me, she would notice the signs and symptoms and be able to run some tests. Because she was able to see a patient that had Cushing's in the past, she was able to see it in her new one. She was able to send her to my endo because she remembered she was helping us and others. This new patient is on the road to recovery already. She is going to be alright.

This made me stop and think. I found this doctor because of the goodwill of a lawyer. This lawyer spent 10's of thousands of dollars of his own money helping me fight and beat the insurance company. This is money he doesnt want back and will not take from us. He did it out of the goodness of his heart. His words were that "there are some things that are so fundamentally wrong in the world and I am just happy that I can help you right one of them." When our family doctor gave up on us, like so many others, he sent us to Dr VJ's office. From there, the doctor and our family grew into a team to help me get better.

I feel so humbled to meet people like these. There are good people in the world. I wanted to give credit to where it is due as well. It would be easy to say that the doctors learned because I did this....or I did that...and that would NOT be true. I know in my heart that I was led to people who could help me at the time I needed it most because I believed and we prayed. I feel humbled that God put me in these doctor's offices so that I could be an instrument of learning.

I believe that every thing we say or do can be remembered, for good or bad, by those around us. Sure, we remember the big things of our lives, but I have so many vibrant memories of the little things. It isn't the big presents I remember most and hold on to dearly. It is the small random acts of kindness that I cherish the most. Everyday, we have the ability to leave a mark on someone's life, even in the smallest of ways. None of us know God's will, but I believe that in that moment of time, when I was sick and out of options, He put me where He wanted me to be and that was the that doctor's office. I had never thought of it that way. I had ALWAYS prayed that something good would come from this to help the next person. If something good was going to come from it all, it was going to come from the powers of up above, not through my works or anything I could do.

My prayer was answered. I know that something good has come from this all, even if it has helped one single person. For that, I am thankful for my blessings. I am thankful for the brief clarity of mind to write it all down.

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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?

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For more information in prior threads, see:

Recent Advances in Neuroendocrine Imaging Lead to Improved Diagnosis

Testing 101: Imaging

Recent Advances in Neuroendocrine Imaging Lead to Improved Diagnosis

Imaging is critical in the diagnosis and care of neuroendocrine disorders. The exponential growth of technology has improved techniques and engineering with medical imaging. In turn, this has affected the effectiveness of these tools.

Neuroendocrine tumors and lesions are found on multiple endocrine organs. Imaging of the pituitary, adrenal, thyroid and parathyroid glands are discussed in this article with perfusion metrics as a basis for evaluation. The MRI is touted as the most recent advance in imaging due to the comparison of sequences (pulse versus standard).

Pituitary imaging using 3 T-based MRI with three-dimensional anisotropy contrast is a relatively new approach to determining cavernous sinus invasion with a pituitary tumor. Dynamic MRI imaging is valuable when imaging microadenomas of the pituitary. 3T imaging with MRI increased the localization of small lesions/tumors, and both approaches are more accurate for patients with mild/episodic hypercortisolism. The value of CSS and IPSS are also discussed.

The addition of perfusion MRI aids in the evaluation of prolactinomas and the effectiveness of the treatment with dopamine antagonists. This, in turn, allows more informed decisions with respect to surgical intervention.

A similar protocol is used for patients with acromegaly caused by growth hormone-secreting tumors and who are treated with octreotide.

The newest addition to the evaluation of the adrenal glands is the the use of "MIBG, Octreotide or PET". This is key to avoidance of a bilateral adrenalectomy due to the lack of localization of an ectopic source of ACTH.

Chemical shift imaging is also being used to determine adrenal hyperplasia and tumors. This technique is based upon the "slightly differing resonant frequencies of protons in water and fat in an external magnet field." Hyperaldosteronism, a cause of hypertension, is one diagnosis that has been improved by this. Perfusion metrics are used with these techniques to improve accuracy in diagnosis.

In addition to the normal use of MRI, CT and ultrasound in the evaluation of the thyroid and parathyroid glands, the author talks about the increased use of PET-CT in the treatment of differentiated thyroid carcinomas with patients where conventional whole body scanning did not work. Perfusion imaging of the thyroid using (FAIR)-true fast imaging with steady precession (FISP) sequence is noted as a possible alternative for evaluating thyroid nodules. The same techniques are suggested for parathyroidism.

The author suggests the use of MRI with neuroendocrine disorders is still young, and there will be improvements over time.


Keogh, B.P. (2008). Recent advances in neuroendocrine imaging. Current Opinion in Endocrinology, Diabetes & Obesity, 15(4), 371-375.

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??

What is Cushing's Disease?

I have been asked that umpteen times by folks who care about me. Other folks just look at me like I'm from an alien planet, and even others just nod and go on like they already know. I'm sure they go right home and google it. Ok, maybe some of them do.

When you get right down to it, I've become a walking library of sorts with facts and figures most medical students and doctors don't know. It's a matter of self-preservation, but you already know that if you are fighting any illness.

So, what is Cushing's? There are two terms used with Cushing's: Disease and Syndrome. They signify the source of the illness, although the presentation is pretty much the same with both. Cushing's Disease is hypercortisolism due to a pituitary source of stimulation. Cushing's Syndrome is hypercortisolism due to an ectopic or adrenal source. There really is a third type of Cushing's called iatrogenic Cushing's which results from the overuse of corticosteriod medications. And actually another type called pseudo-Cushing's.

I want to discuss Cushing's Disease/Syndrome (CD/CS). CD/CS is an endocrine disorder caused by chronic exposure of the body's tissues to excess levels of cortisol - a hormone naturally produced by the adrenal gland. Pituitary adenomas, usually benign, secrete increased amounts of ACTH (adrenocorticotropic hormone), a substance that controls the release of cortisol in that feedback loop I mentioned the other day. It typically causes an overproduction of cortisol. Tumors of the adrenal gland and ectopic ACTH producing tumors can cause similar problems with cortisol overproduction.

What are the symptoms? The most common symptoms are:

• Striae
• Buffalo hump
• red-faced all the time
• sweaty or hard to control body temp
• High blood pressure (often hard to control even with medication)
• High blood sugars and/or insulin resistance
• Insomnia
• Fatigue
• Altered diurnal rhythm (See previous post)
• Secondary hypothyroidism
• Low hormones such as FH, LSH, testosterone, growth hormone
• Low Vitamin D
• Low ferritin
• Unexplained muscle, bone, and joint pain
• Easy bruising
• Difficulty when drawing blood
• Upper body obesity
• Muscle weakness
• Increased facial hair/body hair (hirsutism)
• Loss of hair on head
• Loss of menstrual cycle and/or ovulation
• Loss of libido
• galactorrhea

Not everyone has all the symptoms. And the weight gain can vary by individual. Some folks don't gain a lot. Others do.

Without prompt treatment for Cushing's syndrome, other complications may occur, such as:

• Bone loss (osteoporosis), due to the damaging effects of excess cortisol
• High blood pressure (hypertension)
• Kidney stones
• Diabetes
• Unusual infections
• Hypothyroidism

When the cause of Cushing's syndrome is a pituitary tumor (Cushing's disease), it can sometimes lead to other problems, such as interfering with the production of other hormones that the pituitary controls. It can also affect the optic nerves and carotid arteries if large. The majority of pituitary tumors that cause Cushing's disease are small (less than one cm in size).

Long-Term Remission Rates After Pituitary Surgery for Cushing's Disease: the Need for Long-Term Surveillance says:

Morbidity and mortality are higher in patients with Cushing's disease, with vascular disease a frequent cause of death.[2,32,33] Cardiovascular complications, including coronary heart disease, congestive heart disease and cerebrovascular events, contribute to the morbidity and mortality of patients with undiagnosed or untreated Cushing's disease.[34,35] Early diagnosis and successful treatment of Cushing's disease is therefore most important.

Now, diagnosis....that's a whole 'nuther ballgame. To mix metaphors, it is no walk in the (ball)park.

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