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...

---

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

Racial/Socioeconomic factors predictors to admission in high-quality pituitary centers

"The prevalence of clinically significant pituitary tumors has been reported to be as high as 94 +/- 19.3 cases per 100,000 population."

The authors of this study, done at the Johns Hopkins School of Medicine, reviewed a number of reports which "suggest that patients with surgical pituitary disease are much more likely to have improved surgical outcomes if diagnosed and treated by more experienced surgeons..." They looked at a national survey of neurosurgeons done in the U.S. and a similar study published in the U.K., both of which "found that complication rates were inversely related to surgical experience".

These studies showed patients undergoing the preferred method of pituitary adenoma removal, transsphenoidal resection, had lower mortality rates and less complications if admitted to "high-volume centers".

Referring to "recent reports in general surgery" which "indicate that referral to high-volume hospitals is dependent on racial and socioeconomic factors", the authors realized that little is known about the same possible disparity with the aforementioned pituitary surgery patients.

Using the data from 1988-2005 found in the National Inpatient Sample (NIS) in-hospital discharge database, they identified the pituitary tumor patients by operative code (vs. diagnostic code) for its "higher fidelity". Then, socioeconomic and environmental factors were "assessed through Area Resource File (ARF), maintained by the Health Resources and Services Administration". Only patients over 18 years of age were identified, and only those meeting the criteria of codes were included.

Centers which did over 25 pituitary surgeries per year were defined as "high-volume centers". Age, gender, race, income, wealth, insurance status and the Charlson comorbidity index score were variables used to delineate the racial and socioeconomic factors.

"There was no statistically significant difference between African-Americans (OR: 0.86, 95% CI: 0.74-1.00) and whites in access to high-volume centers (Table 3). On the other hand, Hispanic (OR: 0.53, 95% CI: 0.45-0.63) and Asian (OR: 0.78, 95% CI: 0.61-0.98) patients were significantly less likely to be seen at high-volume centers."

However, when using only the last five years (2001-2005), there was a significantly greater chance that Caucasians would admitted to high volume centers.

In this study, they also found "patients from counties with high neurosurgeon density experience a greater chance of admission to quality medical centers". Younger patients were more likely to be admitted to these same centers as compared to older patients. This was partially attributed to a "widespread access to internet in younger patients".

Females were also more likely to be admitted to high-volume centers than males. Since women are more likely to be uninsured and have less healthcare than men according to the authors, this was surprising. They surmised the need to preserve pituitary and hormonal function in women may have an active role.

What I found more telling, but only mentioned briefly, was how skewed the numbers were for those who were referred anywhere. The number of patients receiving care in the >$60,000/yr income-bracket was almost double the other income levels. In fact, the other income levels were very close.

The authors conclude: "This study demonstrates potential key policy areas for meaningful intervention to help ease disparities in access to quality care for surgical pituitary disease."

---

Mukherjee, D., Zaidi, H., Kosztowski, T., Chaichana, K., Salvatori, R., Chang, D., & Quinones-Hinojosa, A. (2009). Predictors of Access to Pituitary Tumor Resection in the United States, 1988-2005 European Journal of Endocrinology DOI: 10.1530/EJE-09-0043

Vitamin D deficiency is associated with increased mortality

A recent letter published in the New England Journal of Medicine emphasized the importance of treating Vitamin D deficiency in acute as well as chronic illness. Dr. Paul Lee and others followed a group of 42 patients in the ICU of St. Vincent's Hospital in Sydney, Australia over the course of a year.

When testing the "serum level of 25-hydroxyvitamin D" in 42 "referred patients", the mean was 41±22 nmol per liter (16±9 ng per milliliter). 45% were deficient in Vitamin D. The Simplified Acute Physiology Score II (SAPS II) "in patients with sufficient, insufficient, and deficient levels of vitamin D were 34±11, 45±13, and 51±13, with predicted mortality rates of 16%, 35%, and 45%, respectively."

The current study involving patients in the ICU reveals a high prevalence of hypovitaminosis D that was associated with adverse outcomes, independently of hypocalcemia and hypoalbuminemia.

Vitamin D deficiency is associated with increased mortality. This study cannot establish causality between hypovitaminosis D and adverse outcomes.

In a press release, Dr. Lee said, "There may be a bias, in that all patients were referred to endocrinology, so the numbers may not reflect the prevalence in a standard ICU cohort. However 45% is still a significant proportion. ...when we are very sick, the "sick organs" draw upon any vitamin D available to function properly, therefore we may need extra Vitamin D to maintain organ function during critical illness. However, at this stage, we don't know whether Vitamin D deficiency is just a marker of ill health, or whether it contributes to disease severity."

---

Lee p, Eisman JA, Center JR (2009). Vitamin D Deficiency i Critically Ill Patient New England Journal of Medicine, 360 PMID: 19403914

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.

---

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

Distinguishing PCOS and Cushing's: Does testosterone tell the tale?

Cushing's Syndrome (CS) has been considered rare, but thoughts are changing about that. This article notes that fact, pointing out "most published articles on CS have examined patients with sustained and severe hypercortisolism." It also points out the increased recognition of the prevelance of "mild" and "episodic" CS which have both normal and high values with testing. (Image source)

CS and polycystic ovarian syndrome (PCOS) present similarly, but are treated much differently.

Both diseases can present with weight gain, hirsutism, acne, and irregular periods in women. However, CS usually includes symptoms such as easy bruising, sleep disturbances, decreased libido, a buff alo hump, and stretch marks, which are not present in PCOS. Women with mild and/or periodic CS, however, can be difficult to diagnose as they may lack classic manifestations of the disease and the diagnosis may require multiple hormonal measurements [4, 5, 7] . The treatment of CS is primarily the surgical removal of a pituitary, adrenal, or ectopic tumor. The treatment for PCOS is primarily medical and includes oral contraceptives, biguanides (metformin), thiazolidinediones (rosiglitazone or pioglitazone) or androgen antagonists (spirolactone or flutamide) [8] . Thus, distinguishing the two conditions is important.

This study used women who, under the 1990 NIH criteria, have PCOS. These were compared to women who had been diagnosed with mild CS due to a pituitary adenoma. The study goes into great detail about the criteria for each set.

The authors hypothesized "either total testosterone (TT) or bioavailable testosterone (BT) levels or the calculation of the free androgen index (FAI) would be low in patients with mild CS and elevated in patients with PCOS, and could help differentiate the two conditions." According to their statistical analyses:

Total testosterone gave the highest sensitivity, positive predictive value (PPV)and negative predictive value (NPV) while BT gave the highest specifi city for the diagnosis of CS. Determinations AUC demonstrate that use of a TT level gave “ good ” diagnostic accuracy, while BT and FAI gave “ fair ” diagnostic accuracy.

The authors emphasize "[m]ost commercial assays lack the accuracy and precision of assays when measuring testosterone in women, as recently reviewed in an Endocrine Society position statement [35]". They used mass spectroscopy analysis done at Esoterix Laboratories. They also determined there is overlap between the two groups when dexamethasone suppression is used due to the mild/cyclic nature of these CS patients. Most of all, the phenotypes between the two groups may be similar. Testosterone analysis, when using an accurate and precise assay at a validated laboratory, may be another tool to distinguish between the two.

Note: There are some great graphs and charts in the full-text article. It is well worth perusing. My previous post has some of them included in the first scribd presentation by Dr. Friedman.

Pall, M., Lao, M., Patel, S., Lee, M., Ghods, D., Chandler, D., & Friedman, T. (2008). Testosterone and Bioavailable Testosterone Help to Distinguish between Mild Cushing's Syndrome and Polycystic Ovarian Syndrome Hormone and Metabolic Research, 40 (11), 813-818 DOI: 10.1055/s-0028-1087186

What's the real deal about Metabolic Syndrome?

The other day Dr. Rob, who blogs at Musings of a Distractible Mind, tweeted about a patient he had seen that day. He asked for input and wow, did he get it! I promised some information via this blog a the end of the discussion. Thus, this post, which will continue after the dialog.

To get the gist of the dialog, you must start at the bottom and read up. I may have missed some tweets about his original statement and I apologize if so. I tried to find them all.

---

staticnrg
04:33 PM Mar 06, 2009
@doc_rob I'll include this, too. I'm loaded for bear. ;) (reference to PCOS statement made by doc_rob)

staticnrg
04:32 PM Mar 06, 2009
@doc_rob Too much to tweet about. Will blog about it and post URL this weekend.

doc_rob
04:28 PM Mar 06, 2009
@staticnrg I can see how Low-grade cushings will present as Met Synd. That does not = Metabolic syndrome is low-grade cushings.

doc_rob
04:27 PM Mar 06, 2009
@staticnrg Skeptical. Show me the research. Genetics strongly tied to type 2 DM. Related to Polycystic ovaries as well.

staticnrg
04:25 PM Mar 06, 2009
@doc_rob No...beg to differ. Remove cause of hypercortisolism which causes met syndrome (insulin resistance). Treat cause, not symptom

doc_rob
04:21 PM Mar 06, 2009
@staticnrg Perhaps, but for practical purposes, the treatment is to use a "typical" Metabolic syndrome approach. Insulin resistance is root

staticnrg
04:19 PM Mar 06, 2009
@doc_rob Research now says met syndrome a symptom of subclinical Cushing's

doc_rob
04:14 PM Mar 06, 2009
@staticnrg Seeing all comers (as I do), Met. Syndrome is REALLY common. At best, cushings is 1% of the cases.

staticnrg
03:51 PM Mar 06, 2009
@doc_rob Blunt again: statistics are wrong, but slowly being changed. New research/literature does that.

doc_rob
03:50 PM Mar 06, 2009
@staticnrg Yeah, but most metabolic syndrome is hyperinsulinism due to wt, etc. If he was 50, I'd just assume - Just statistic likelihood.

staticnrg
03:48 PM Mar 06, 2009
@doc_rob Gonna be blunt: metabolic syndrome is a catch-all. Many w/Cushing's get shunted into that. You are wonderful PCP for testing. :)

staticnrg
03:40 PM Mar 06, 2009
@staticnrg Have articles if you want them. Can email.

doc_rob
03:36 PM Mar 06, 2009
@staticnrg Normal K (was talking about Conn's - Aldosterone Deficiency). I do Urine Metanephrines for pheo screening. - Follow UpToDate rec

staticnrg
03:27 PM Mar 06, 2009
@doc_rob @ARUPlabs has great site for tests. http://bit.ly/1upxeW

doc_rob
03:36 PM Mar 06, 2009
@staticnrg Normal K (was talking about Conn's - Aldosterone Deficiency). I do Urine Metanephrines for pheo screening. - Follow UpToDate rec

staticnrg
03:27 PM Mar 06, 2009
@doc_rob @ARUPlabs has great site for tests. http://bit.ly/1upxeW

laikas
03:27 PM Mar 06, 2009
@doc_rob Googling 4 Pheochromocytoma + glucose + triglycerides gives many results: http://is.gd/mcjU - just confirms. Will look up Williams

staticnrg
03:24 PM Mar 06, 2009
@laikas @doc_rob Pheo has to be caught when "on". Test for plasma free metanephrines, I believe.

staticnrg
03:21 PM Mar 06, 2009
@doc_rob What @laikas said. I could have "normal" K (low end), then days later have very low K and end up in ER. Other hormones off?

laikas
03:20 PM Mar 06, 2009
@doc_rob But Elevated blood glucose level + high triglycerides (+HBP of course) occur in Pheochromocytoma. Wikipedia :) : http://is.gd/iQ8y

laikas
03:16 PM Mar 06, 2009
@doc_rob Bc of storage of K in muscles low K doesn't always show in blood until a late stage. =safeguard. Almost never abnormal Na in Conn.

doc_rob
03:11 PM Mar 06, 2009
@laikas Conn's yes, but BMP with normal Na, K. makes mineralcorticoid less likely.

doc_rob
01:59 PM Mar 06, 2009
@cushings Well, cushings certainly needs to be ruled out in this circumstance. I think of my cushings pals when I see things like this.

cushings
01:56 PM Mar 06, 2009
@doc_rob sounds like Cushing's in dogs again! Hope he doesn't have it

KidneyNotes
01:31 PM Mar 06, 2009
@doc_r0b Sounds like someone taking prednisone, an unlikely drug of abuse.

KidneyNotes
01:29 PM Mar 06, 2009
@doc_rob Renal artery stenosis...

doc_rob
01:26 PM Mar 06, 2009
@joemd Thanks.

joemd
01:21 PM Mar 06, 2009
@doc_rob Got it. Urine tox screen might help. Love your avitar. :-)

doc_rob
01:19 PM Mar 06, 2009
@joemd This is not real acute - New patient here a month ago with abnormal labs. Today came in with higher BP. Seen by Nephrology alreday

joemd
01:18 PM Mar 06, 2009
@doc_rob Other possibilities: migrane, ruptured aneurysm, other CNS stuff. Head CT? MRI?

joemd
01:17 PM Mar 06, 2009
@doc_rob Yes (cocaine, etc.). Also can see serotonin syndrome with antidepressants (SSRIs, SNRIs, Tricyclics...). Also EtOH w/d

doc_rob
01:14 PM Mar 06, 2009
@joemd None. I am also wondering about drugs.

joemd
01:13 PM Mar 06, 2009
@doc_rob Is he on an antipsychotic (metabolic syndrome)? If so, neuroleptic malignant syndrome?

doc_rob
01:12 PM Mar 06, 2009
not fur, for - he does not have Fur cushings.

doc_rob
01:11 PM Mar 06, 2009
Workup includes Check fur cushings, insulin resistance, renal problems. Anything I am missing?

doc_rob
01:10 PM Mar 06, 2009
Teenage boy with HTN, Headache, Elevated Blood Sugar, Triglycerides - Metabolic Syndrome picture. Strong genetics, but BP very high.

---

My intent with this post was to verify for Dr. Rob and others what I said briefly in my tweets. However, it has evolved into so much more than that. I have tried to be as brief as possible yet give enough concrete information (with resources) to validate my statements.

A brief history of the term "metabolic syndrome" helps one to understand the rest of the post. Dr. Gerald Reaven (Stanford University) proposed the “syndrome X” concept in 1988, but the term "Metabolic Syndrome" was coined in 1998 by the World Health Organization, and thus made popular.

In The Metabolic Syndrome: Time for a Critical Appraisal (Joint statement from the American Diabetes Association and the EuropeanAssociation for the Study of Diabetes), the popularity of the terminology is explained:

It has been defined and institutionalized, principally by the World Health organization(WHO) (26) and the Third Report of the National Cholesterol Education Program’s Adult Treatment Panel (ATPIII) (27,28), albeit with different definitions. In addition, other organizations have developed similar, but again not identical, definitions (29,30). The fact that a version of the metabolic syndrome has its own ICD-9 code (277.7) also suggests that it is well thought out (31,32).

However, the article continues with explanations of how this happened and reasons why the term is not a valid one:

In summary, the attempt to define themetabolic syndrome as the result of a single (or even major) unifying pathophysiological process, e.g., insulin resistance, is problematic. Although insulin resistance or hyperinsulinemia is clearly an important feature of the syndrome, many other as yet unidentified factors are also important. Insulin resistance may simply be one of many abnormalities linked to a more fundamental, truly unifying pathophysiology. Moreover, the definition of the syndrome includes risk factors that are only weakly related to insulin resistance or hyperinsulinemia (e.g., blood pressure) and excludes others that are closely related(e.g., CRP, adiponectin). Finally, although many clinical values are significantly associated with insulin resistance/hyperinsulinemia, the strength of their association (which has not exceeded acorrelation coefficient of 0.7 and is usually0.3– 0.6) is not
particularly impressive.

As the article continues, the authors show how there is little to no valid data to show how the old or new definitions actually have any benefit to the diagnosis and treatment of patients. In fact, they contend there is "much fundamental, clinically important,and critically missing information about the metabolic syndrome ...a presumed disease that does not stand on firm ground. [P]atients with diabetes or clinical CVD should be excluded from the case definition of metabolic syndrome, as they provide no additional understanding of risk or treatment recommendations that are otherwise not currently recommended."

According to Clinical Use of the Metabolic Syndrome: Why the Confusion? , there several factions vying for the conclusive definition of metabolic syndrome. The issue, though, is the change of the terminology from a pathophysiological approach to a clinical definition defined by an ICD-9 code (277.7). With multiple factions offering different perspectives, the article offers a requiem, "given the seemingly arbitrary clinical definitions and the uncertain clinical utility, the metabolic syndrome should be declared dead".

Even Reaven, who first coined the term "Syndrome X" which later became "metabolic syndrome", published an article recently: The Metabolic Syndrome: Requiescat in Pace . \

Professor Edwin A M Gale of even more recently wrote Should we dump the metabolic syndrome?: Yes. He says, "Diagnosis of the metabolic syndrome is redundant in those who already have diabetes and adds nothing to the management of those who do not. "

He continues, "This is not a turf war: the confrontation reflects genuine perplexity within the diabetes community. One party maintains that a working definition is needed to resolve existing confusion; the other party argues that an inadequate definition merely adds to it. "

Dr. Gale alleges the use of "metabolic syndrome" is outdated and outperformed by other scoring systems which treat "continuous variables as continuous, whereas the metabolic syndrome treats them as dichotomous." He emphatically says, "the metabolic syndrome is a handy clinical label that lacks a useful definition."

Assuming the aforementioned "metabolic syndrome" is not declared dead, what is its value? Is it merely a set of symptoms which are part of a bigger whole or not actually related at all?

In Is the "Metabolic Syndrome" a Mild Form of Cushing's Syndrome? The Curious Story of 11beta-Hydroxysteroid Dehydrogenase, Dr. Ashok Balasubramanyam explores the role of 11beta-HSD (types 1 and 2). (There is a lot of current research ongoing with 11beta-HSD, easily found by using the term in PubMed and other medical search engines.)

Dr. Balasubramanyam elaborates:

One intriguing question is: Could a single primary defect trigger a cascade of diverse events leading to these apparently disparate metabolic, cardiovascular, and reproductive defects? Since Cushing's syndrome also encompasses many of these disorders, it is worthwhile considering whether the metabolic syndrome could be a "forme fruste" of Cushing's.

In Glucocorticoids, metabolism and metabolic diseases (full text version), the author states:

Indeed, hyperactivity of the HPA axis is positively correlated with the metabolic
syndrome as demonstrated in subjects with glucose intolerance, hypertension, and
insulin resistance (Reynolds et al., 2001a,b; Phillips et al., 1998; Phillips et al.,2000; Walker et al., 1998), suggesting a causative role for [glucocorticosteriods] in the obese phenotype...Taken together, increased GC levels or sensitivity in muscle have been associated with conditions related to the metabolic syndrome in several studies and models.

In Cortisol--cause and cure for metabolic syndrome? (full text version), the author makes the case for the similarity of metabolic syndrome and Cushing's syndrome.

Similarities between the metabolic syndrome and Cushing's syndrome, and reversibility of the features of Cushing's syndrome, suggest that cortisol may contribute to the pathophysiology of both conditions and that reducing cortisol action may provide a novel therapeutic approach in the metabolic syndrome...

...We have collected evidence that the HPA axis is ‘activated’in the metabolic syndrome. In cohort studies, we have shown that 09.00 h plasma cortisol after overnight fasting is elevated in subjects with relative glucose intolerance, hypertension, insulin resistance and hypertriglyceridaemia (Fig. 1) [2–6].This elevation of plasma cortisol in metabolic syndrome associates with increased cortisol response to low-dose (1μg)ACTH1−24, consistent with adrenal hypertrophy [7]. Integrated cortisol secretion, measured using mass spectrometry to assess total urinary cortisol metabolite excretion, is variably increased in subjects with the metabolic syndrome.

I have much, much more information, but shall save it for another post later this week. I hope to tie in information about PCOS, also.

Radiosurgery and increased mortality: Is there a connection?

This study takes a brief look at radiosurgery and its possible link to increased mortality. It does not distinguish between single-fractionated radiotherapy such as gamma knife and fractionated stereotactic radiotherapy (FSR).

The authors explore four (4) major areas:

• Cerebrovascular disease following pituitary radiotherapy
• Cerebrovascular mortality following pituitary radiotherapy for non-functioning adenomas
• Impact of pituitary radiotherapy on mortality in acromegaly
• Hypopituitarism and excess mortality following pituitary radiotherapy

I am mainly interested in the first and the last in the list above. These impact those with Cushing's who are considering or have undergone radiotherapy.

Cerebrovascular disease is already a risk with Cushing's patients. In Mortality in Patients Treated for Cushing’s Disease Is Increased, Compared with Patients Treated for Nonfunctioning Pituitary Macroadenoma (Dekkers, et al), the authors conclude:

[M]ortality is increased in patients with Cushing’s disease, compared with both NFMA and acromegaly. This implicates that transient exposure to cortisol excess is a major contributor of the increased mortality, even after cure of Cushing’s disease. This observation may also be of relevance for patients treated with exogenous glucocorticoids for nonendocrine diseases.

Cited in the same study, "Causes of death were cardiovascular disease in 23.4%, cerebrovascular disease in 12.8%, malignancy in 19.1%, and infectious diseases in 17% of all patients. " Thus, there is already a link to mortality due to cerebrovascular disease and Cushing's.

The Ayuk/Stewart analysis cited a "study of 331 patients with pituitary adenomas treated with surgery and radiotherapy [where] increasing doses of radiotherapy were associated with increasing risk of cerebral infarction." They go on to admit there is a lot of debate about what caused the cerebrovascular events, with radiation thought to be a cause due to "changes to the cerebral vasculature".

The Dekkers study counters that: "By regression analysis, in a model adjusted for age and gender, radiotherapy and hypopituitarism were not associated with increased mortality risk."

Ayuk and Stewart, when analyzing the data from multiple sources, disagree. Hypopituitarism is common after treatement for pituitary adenomas. They cite several studies which show "over 50% of patients treated with pituitary radiotherapy will develop deficiencies in one or more anterior pituitary hormones over the following decade." They then analyzed numerous studies which "examined mortality in patients with hypopituitarism and which found increased mortality compared with age-matched controls, predominantly due to cerebrovascular and cardiovascular disease."

In two of the studies analyzed, radiotherapy did not seem to attribute to increased mortality. But in another, larger study of over 1000 patients, "treatment with radiotherapy was associated with a significantly increased mortality rate" when comparing patients who had hypopituitarism from radiotherapy with patients who had hypopituitarism from other treatments or due to tumor.

Age may play a part, also:

The authors also reported higher mortality in patients who had been diagnosed at a younger age, with a standardized mortality ratio of 4.87 in the group younger than 20 years, decreasing to 1.0 in those older than 60 years. This is of particular relevance as over half of the radiotherapy-treated patients were younger than 50 years at the time of treatment.

Overall, the data is unclear about the link between radiotherapy and mortality. The authors were also unclear about whether the hypopituitarism was treated with hormone replacements and what significance this may have. I suspect this was partially due to the information available to them from the studies they analyzed.

John Ayuk, Paul M. Stewart (2008). Mortality following pituitary radiotherapy Pituitary, 12 (1), 35-39 DOI: 10.1007/s11102-007-0083-1

Hypopituitarism and Gamma Knife Radiotherapy

Does radiotherapy cause hypotituitarism when treating pituitary adenoma(s)?

Sometimes tumors cause damage to the pituitary gland which results in hypopituitarism and panhypopitituarism. Surgery to remove the tumor(s) can also cause damage to the pituitary which leads to hypopitutiarism. Sometimes, depending on tumor placement and the amount of pituitary removed, the pituitary regains total function. Nothing is cut-and-dry with this due to the numerous factors surrounding tumors and their removal.

This article takes a look at the effect of radiotherapy on the pituitary. Is hypopituitarism a "given" with radiotherapy or can it be avoided? According to the authors, this depends on the total dose, the fraction size of each irradiation, and the time between each fraction.

Since Gamma Knife is a single-fraction radiosurgery, all radiation is delivered in one dose.

Radiation-induced hypopituitarism occurs in a significant number of patients treated for pituitary adenomas with either stereotactic radiosurgery (SRS), which involves a single dose of stereotactic radiotherapy, as well as following fractionated stereotactic radiotherapy (FSRT).

The authors point out the risk is difficult to establish due to the multiple factors involved, which include:

• surgery
• variations in dosages of radiation
• technique used (SFR vs. FSRT)
• accuracy of placement and imaging
• pre-existing hypopituitarism
• lack of consisten protocol for diagnosing hypopituitarism

They also point out hypopituitarism is "more likely to occur following stereotactic irradiation for
secretory adenomas, as higher doses are generally required to achieve hormonal control." This includes gamma knife.

Since hypopitituarism can include multiple hormones, which are the most apt to be affected? Growth hormone (GH) has the greatest vulnerability. "With higher radiation doses (30–50 Gy), however,the frequency of GH insufficiency substantially increases and can be as high as 50–100%."

Patients irradiated for pituitary tumors have an increased risk for gonadotrophin deficiency with the data presenting "severity from subtle subclinical) abnormalities in secretion detected only by
GnRH testing to severe impairment associated with diminished circulating sex hormone levels."

Normal ACTH deficiency "dramatically increases (27–35%) after intensive irradiation [6, 9, 12] and more so (31–60%) in patients with pituitary adenomas [20, 25, 26]." TSH deficiency follows almost identically with patients irradiated for pituitary tumors.

Women tend to develop hyperprolactemia after SRS/GK which tends to normalize over time. The article was not very clear on this and just briefly touched on it. There didn't seem to be much data on it, either.

More on GK later this week.

Ken H. Darzy, Stephen M. Shalet (2008). Hypopituitarism following radiotherapy Pituitary, 12 (1), 40-50 DOI: 10.1007/s11102-008-0088-4

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

Low Vitamin D levels linked to upper respiratory tract infections

Research about the values of Vitamin D has been in the news a lot lately. A new study reinforces its value. According to this study, the lower the levels of serum 25(OH)D levels the higher the prevalence of flu and colds in the patients studied.

"The findings of our study support an important role for vitamin D in prevention of common respiratory infections, such as colds and the flu," says Adit Ginde, MD, MPH, UC Denver Division of Emergency Medicine and lead author of the study in a recent news release. "Individuals with common lung diseases, such as asthma or emphysema, may be particularly susceptible to respiratory infections from vitamin D deficiency."

Information from approximately 19,000 subjects who participated in the Third National Health and Nutrition Examination Survey (NHANES III) was analyzed for this study.

Compared with individuals with serum 25(OH)D levels of 30 ng/mL or more, those with levels less than 10 ng/mL or 10 to less than 30 ng/mL had 55% and 27% higher odds of recent URTI, respectively (Table 2, model 1). In further stratification of the group with 25(OH)D levels of 30 ng/mL or more, those with levels of 30 to less than 40 ng/mL had similar odds of recent URTI compared with those with levels of 40 ng/mL or more (OR, 0.99; 95% CI, 0.81-1.21). After adjusting for season, lower serum 25(OH)D levels were still associated with a significantly higher URTI (Table 2, model 2). Indeed, the 25(OH)D-URTI association was consistent across all seasons.

"A respiratory infection in someone with otherwise healthy lungs usually causes a few days of relatively mild symptoms," explains Carlos Camargo, MD, DrPH, MGH Department of Emergency Medicine and senior author of the study. "But respiratory infections in individuals with an underlying lung disease can cause serious attacks of asthma or COPD that may require urgent office visits, emergency department visits or hospitalizations. So the impact of preventing infections in these patients could be very large."

The authors stress that the study's results need to be confirmed in clinical trials before vitamin D can be recommended to prevent colds and flu.

...randomized controlled trials are valuable for determining the causal nature of an observed association. Reverse causation (ie, lower serum 25[OH]D levels due to recent URTI and, thus, decreased outdoor activity) seems unlikely because the half-life of serum 25(OH)D is 2 to 3 weeks11 and URTIs last only 3 to 4 days,3 but it may affect the enhanced vitamin D–URTI association in participants with asthma and COPD owing to longer symptom duration in those individuals....Randomized controlled trials are warranted to explore the direct effect of vitamin D supplementation and to establish optimal levels of serum 25(OH)D in the prevention of RTI.

Previous articles about which I've blogged, Vitamin D and the thyroid gland... and Vitamin D: "Normal" isn't normal anymore support greater daily intake of Vitamin D.


To read more:

• Assay Variation Confounds the Diagnosis of Hypovitaminosis D: A Call for Standardization
• Assessment of dietary vitamin D requirements during pregnancy and lactation
• Circulating Vitamin D3 and 25-hydroxyvitamin D in Humans: An Important Tool to Define

Adit A. Ginde, MD, MPH; Jonathan M. Mansbach, MD; Carlos A. Camargo Jr, MD, DrPH (2009). Association Between Serum 25-Hydroxyvitamin D Level and Upper Respiratory Tract Infection in the Third National Health and Nutrition Examination Survey Archives of Internal Medicine, 169(4)

Urinary tract infections full of iron thieves

Research in the differences between E. Coli in the gut and in these UTIs help target treatment options.


Bacteria need iron, and as soon as they invade the human body, they are on the hunt for it. There is a limited supply of iron inside the human body where it is stored by the proteins tranferrin and ferritin.

Disease-causing bacteria have evolved by producing siderophores which are iron-chelating molecules. These molecules can bind to iron stored in ferritin and transferrin and "steal" it for the bacteria.

In this new study, the authors compared Escherichia coli taken from it's natural habitat in the gut and compared it to E. coli found in the urinary tracts of subjects suffering from urinary tract infections (UTIs). They found "epigenetic optimization" of the E. coli from the urinary tract:

Urinary tract infections (UTIs) are among the most common bacterial infections treated by physicians worldwide. Although symptoms of acute infection are often resolved with a course of antibiotics, the same bacterial strain often causes subsequent bouts of symptomatic infection. Escherichia coli are the most common bacteria causing UTI and the infecting strains are widely believed to originate from the gastrointestinal tract where multiple E. coli strains reside. Here, we use a novel mass spectrometric technique in a population of patients with recurrent UTI to identify how strains that cause UTI differ from other strains that were present in the gastrointestinal tract at the same time. We found that urinary E. coli strains preferentially expressed two small molecules called yersiniabactin and salmochelin. These molecules are called siderophores, meaning they are able to scavenge iron to support bacterial survival and growth. Synthesis and transport of these small molecules requires a coordinated network of proteins encoded by a collection of different genes. These findings suggest that new antibiotics directed against yersiniabactin or salmochelin-producing E. coli strains may be an improved, and more targeted, strategy to prevent recurrent UTIs.

Since some iron-transport systems also naturally transport antibiotics into the cell it is important to understand the molecular mechanism of iron transport here. Understanding these pathogenic bacteria may lead to new ways of either delivering or designing drugs which exploit this difference.

Many of us with Cushing's Syndrome/Disease (even if in remission) suffer from low ferritin. When we have an infection, due to our compromised immune system, we often have a difficult time recovering. When accounting for the iron-depleting nature of our infections, we are doubly plagued.

To read more:

• How some bacteria may steal iron from their human host
• Acquisition of siderophores in Gram-negative bacteria
• Pathogenic E. coli
  

Jeffrey P. Henderson, Jan R. Crowley, Jerome S. Pinkner, Jennifer N. Walker, Pablo Tsukayama, Walter E. Stamm, Thomas M. Hooton, Scott J. Hultgren (2009). Quantitative Metabolomics Reveals an Epigenetic Blueprint for Iron Acquisition in Uropathogenic Escherichia coli PLoS Pathogens, 5 (2) DOI: 10.1371/journal.ppat.1000305

Central actions of glucocorticoids in the control of body fluid homeostasis

Cushing's patients have a lot of problems with fluid regulation. Since the hypothalamic-pituitary-adrenal (HPA) axis is involved in the control of body fluid, it isn't surprising glucocorticoids are involved. This research indicates glucocorticoids play a role.

The data presented here suggest that glucocorticoids are not only involved in the mechanisms underlying the fast release but also in the transcriptional events that lead to decreased synthesis and secretion of these neuropeptides, particularly oxytocin, under diverse experimental conditions of altered fluid volume and tonicity.

To read more, the full-text article may be found here:

Central actions of glucocorticoids in the control of body fluid homeostasis: Review

S.G. Ruginsk, A. Lopes da Silva, R.R. Ventura, L.L.K. Elias, J. Antunes-Rodrigues (2009). Central actions of glucocorticoids in the control of body fluid homeostasis: Review Brazilian Journal of Medical and Biological Research, 42 (1) DOI: 10.1590/S0100-879X2009000100010

Bariatric surgery: Not the answer for obesity and "hidden" Cushing's Syndrome

Although I'm posting this as research (which it is), this is also personal for me. I was told by multiple doctors to have bariatric surgery. This included endocrinologists. I even went as far as making an appointment with a bariatric surgeon, going through the pre-surgical "talk" and consult, and asking a lot of questions. I didn't find him cognizant of the endocrine problems that might hinder recovery with bariatric surgery. Frankly, he dismissed my questions and walked out on me.

I'm glad I did my research. And now, the medical community is looking at the repercussions of bariatric surgery to control weight without first testing for endocrine-related causes, especially Cushing's Syndrome.

The first article cited below is a plea for screening of obese patients prior to bariatric surgery. Dr. Ludlam is well-known in the Cushing's patient community because of his stringent protocol for diagnosis and treatment of Cushing's. He and the others who authored this article have dealt with Cushing's patients for a very long time.

In this article, the authors cite two cases where bariatric surgery caused the CS to be overlooked, resulting in a poor outcome. "One patient had progression of obesity, multiple vertebral compression fractures, poorly controlled diabetes and HTN during a 10-year period, and the second patient ultimately died." The second patient was 27 years old. His death is a tragedy.

The second patient had a rapid weight-gain at the age of 20. By the age of 24 he had undergone a Roux-en-Y gastric bypass to control the weight. After losing 170 pounds and with a BMI of 20 kg/m² he still presented with "symptoms suggestive of hypercortisolism. These included
lower extremity edema, facial plethora, facial rounding, a dorsocervical hump, acne, proximal muscle weakness, and neuropsychiatric symptoms." These had been present prior to bariatric surgery, also.

The article goes into much more depth than I am presenting here. It is one which I believe all doctors who treat obese patients should read. The authors suggest who to screen , which can be summarized:

1. Anyone with an adrenal incidentaloma
2. Anyone presenting with HTN and Type II diabetes
3. Patients with a "history of easy bruising, evidence of proximal muscle weakness, the presence of reddish-purple striae 1 cm wide, and facial plethora"
4. Patients with rapid weight gain, especially in combination with other symptoms
5. Young patients with "old" symptoms (i.e. HTN, osteoporosis, kidney stones, multiple infections)
6. Any combination of the above.

The authors also suggest following the guidelines of research previously quoted in this blog.

The second article cited below is a response to the first article. In this article, the authors emphasize the need for screening of obese patients.

...a recently published meta-analysis reported a prevalence of hypercortisolism in ≤2–5% when Cushing syndrome is systematically screened for in patients with poorly controlled type 2 diabetes and adrenal incidentalomas [2]. Conversely, the prevalence of Cushing syndrome in those with simple obesity is largely unknown. Moreover, a condition of functional hypercortisolism with subtle alterations of hypothalamic-pituitary-adrenal axis is frequently evidenced in those with simple obesity...

...However, despite the probability that the diagnosis of Cushing syndrome might be overlooked, the possibility arises that Cushing syndrome might be unrecognized among obese patients.

This article outlines possible contra-indications of bariatric surgery for obese patients, especially those with possible Cushing's. Those, along with the delay in diagnosis may cause "irreversible sequelae in patients with undiagnosed Cushing syndrome".

M FLESERIU, W LUDLAM, S TEH, C YEDINAK, C DEVENEY, B SHEPPARD (2009). Cushing's syndrome might be underappreciated in patients seeking bariatric surgery: a plea for screening Surgery for Obesity and Related Diseases, 5 (1), 116-119 DOI: 10.1016/j.soard.2008.09.011


S SAVASTANO, R PIVONELLO, A COLAO (2009). Bariatric surgery for obesity and hidden Cushing syndrome Surgery for Obesity and Related Diseases, 5 (1), 121-122 DOI: 10.1016/j.soard.2008.07.006

CT imaging in the hunt for ectopic ACTH tumors

Once the biochemical evidence of excess ACTH production leads to the diagnosis of Cushing's Syndrome for a patient, the next step is determining the source of excess ACTH production. Usually the source for the excess ACTH is a tumor on the pituitary gland. However, ectopic sources may also be ACTH secreting tumors.

Eighty to 85% of Cushing’s syndrome is ACTH-dependent, of which 80–90% will be due to a pituitary adenoma—Cushing’s disease (CD) [1]. Ten to 15% will have a nonpituitary source, referred to as ectopic ACTH secretion (EAS) [2], of which 80% have an identified source within the chest and abdomen whilst 20% have no detected source and are referred to as occult [1].

This article talks about the use of computed tomography (CT) to locate the source of the EAS. According to the authors, a bilateral inferior petrosal venous sampling (BIPPS) is the first step in determining whether the source of excess ACTH is ectopic, with a 95% sensitivity. They say "false positives are extremely rare (<1%)> and there is a false negative rate of 2–4%".

The authors include information about imaging multiple tumors including the following:

Bronchial carcinoids

Thymic carcinoids

Gastrointestinal carcinoids

Pancreatic neuroendocrine tumours

Medullary thyroid carcinomas

Phaeochromocytomas

They also mention other tumors briefly:

Many tumours have been reported in the literature to result in EAS such asovarian carcinoid, ovarian adenocarcinoma, ovarian androblastoma, ovarian teratoma, ovarian Sertoli cell carcinoma, ovarian dermoid cyst, prostatic adenocarcinoma, prostatic small cell carcinoma, small cell carcinoma of the uterine cervix and olfactory neuroblastoma [6].

The authors recommend the use of ¹¹¹In-octreotide in some cases and mention the enlargement of the adrenals, as well as shape and hyperplasia depending on the type of EAS. They conclude that CT imaging can lead to earlier diagnosis and treatment of these excess ACTH sources.

(Picture is from the article)

Paul A. Sookur, Anju Sahdev, Andrea G. Rockall, Andrea M. Isidori, John P. Monson, Ashley B. Grossman, Rodney H. Reznek (2009). Imaging in covert ectopic ACTH secretion: a CT pictorial review European Radiology DOI: 10.1007/s00330-008-1274-5

Future Treatment Strategies in Managing Aggressive Pituitary Tumors

Within this article, the authors discuss possible future treatments of pituitary tumors. The other day I discussed what is presently done in Current Treatment Strategies in Managing Aggressive Pituitary Tumors. Most of the time transsphenoidal endoscopic surgery is the first-line approach.

According to the authors, dopamine agonists (DAs) will continue to be the best treatment for prolactinomas, with new somatostatin receptor subtype 5 (SSTR5) possible alternatives in the future. The somatostatin analogs, octreotide and lanreotide, will continue to be the treatment of choice for acromegaly.

With Cushing's disease and incidentalomas, there really aren't any long-term pharmacological treatments. The authors offer hope for SSTR5 analogs within the next few years which will effectively treat the Cushing's. A combination of SSTR5 and SSTR2 combinations for treating the incidentalomas and preventing recurring tumor growth is a future possibility.

The authors conclude:

SSTR5 analogs, alone or in combination with DAs, may play a role in the
future medical management of Cushing’s disease, but not in the most aggressive
tumors, and ongoing trials may elucidate the future role of such agents. Until
then, surgery and radiotherapy will remain the mainstay of treatment for these
tumors.

Steven W. J. Lamberts, Leo J. Hofland (2008). Future treatment strategies of aggressive pituitary tumors Pituitary DOI: 10.1007/s11102-008-0154-y

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

Is there a genetic component to varying IGF-1 levels with AGHD?

Adults who become growth hormone deficient (AGHD)are typically undiagnosed for a long time. Generally, pituitary tumors or other medical issues lead the diagnostician to question GH levels in an adult. IGF-I, even if measured, often is normal with AGHD. Due to cardiovascular and other risks which cause increased mortality and decreased quality of life, understanding AGHD is of utmost importance.

In The use of a GH receptor antagonist (GHRA) to explore the relationship between GH and IGF-I in adults with severe growth hormone deficiency (GHD), the authors research the question of why some folks with deficient GH still have "normal" IGF-I levels but others with deficient GH have low IGF-I levels.

[A]pproximately 50% of middle-aged patients diagnosed with severe GHD, defined by peak stimulated GH levels of <3>Using Pegvisonmant, a highly selective GH receptor antagonist used to treat acromegaly by blocking GH action, they determined those who had low IGF-I levels with AGHD could not increase secretion of GH but "[i]n those with a normal IGF-I, baseline and stimulated GH secretion can be increased by reducing IGF-I." This suggested to them that patients with low IGF-I levels were that way because they weren't regulated by GH (GH independent) but that patients with normal IGF-I levels were GH-dependent.

Does this mean there is a difference in severity in the two types of patients? According to the authors it does:

These data show that in these patients, who meet the consensus criteria for severe adult GHD, the hypothalamic-pituitary axis is capable of increasing GH secretion in response to a fall in IGF-I thereby implying that the previously unexplained paradox of patients with severe adult GHD having normal IGF-I levels can be accounted for by subtle differences in on-going physiological GH secretion not discernable by the ‘crude’ stimulation tests used to diagnose adult GHD. Hence, this study shows that patients with normal and low IGF-I differ in the severity of GHD.

They do admit the need for further study, indicating a possible "genetic contribution to the difference in IGF-I levels between [AGHD] patients with low and normal IGF-I."

CA Berg, A Pokrajac, M Bidlingmaier, CJ Strasburger, SM Shalet, PJ Trainer (2008). The use of a GH receptor antagonist (GHRA) to explore the relationship between GH and IGF-I in adults with severe growth hormone deficiency (GHD) Clinical Endocrinology DOI: 10.1111/j.1365-2265.2008.03481.x

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

Vitamin D: "Normal" isn't normal anymore

Dr. Bruce Hollis' latest published research on Vitamin D questions the definition of "normal". Since many of us with Cushing's Disease and/or other endocrine problems suffer with extremely low Vitamin D ranges, defining a normal range is very important.

Vitamin D is not really a vitamin. It is a steriod and exists in two forms, D2 (ergocalciferol) and D3 (cholecalciferol). D3 is the more active form and is found naturally in the human body. D2 is derived from radiating fungi and is only found in very small amounts in the body. Most over-the-counter (OTC) supplements use the D2 form rather than D3. Also, there are two prescription forms of it: Drisdol and Calciferol. D3 may be purchased without a prescription.

The Vitamin D Council says "Current research has implicated vitamin D deficiency as a major factor in the pathology of at least 17 varieties of cancer as well as heart disease, stroke, hypertension, autoimmune diseases, diabetes, depression, chronic pain, osteoarthritis, osteoporosis, muscle weakness, muscle wasting, birth defects, periodontal disease, and more."

According to Dr. Hollis' article, it has been almost 4 decades since the definition of "normal" was established for Vitamin D using the first assay assessing circulating 25-hydroxyvitamin D [25(OH)D] in human subjects. These "normal" results were obtained by sampling human subjects who appeared to be free from disease, and by assessing "normal" circulating 25(OH)D levels using a Gaussian distribution of the values.

Hollis states, "...the ‘normals’ were actually vitamin D deficient." He says this is similar to defining “normal” estrogen levels by sampling a population of women who are primarily postmenopausal.

He goes on to say:

To make matters worse, the dietary requirement for vitamin D in adults is 200
IU/d, as defined by the Adequate Intake (AI) by the Food and Nutrition Board and
is essentially meaningless.

The article delineates the methods which have been FDA approved and compares them to the newer LC/MS methods which have not been calibrated against the standard DiaSorin methods. Dr. Hollis calls for standardization of reference ranges and testing.

In an interview a couple of years ago, Dr. Hollis was quoted:

It is maddening to me to hear physicians say "drink some milk and you will
obtain all the vitamin D you need." It is wrong and harmful to the patient. No
one should have a circulating 25(OH) D level—this is the metabolite that defines
nutritional vitamin D status—less than 80 nmol. I try to keep my own level at
125 nmol minimum and consume between 2,000-8,000 IU/day depending on the season.

Based on this information and other research (see references at the end of the article), the
“optimum level” of Vitamin D in the human body is much higher than the ranges used now, and it has yet to be determined.

Bruce W. Hollis (2008). Assessment of vitamin D status and definition of a normal
circulating range of 25-hydroxyvitamin D Current Opinion in Endocrinology, Diabetes & Obesity, 15 (6), 489-494 DOI: 10.1097/MED.0b013e328317ca6c

---

To read more:

• Assay Variation Confounds the Diagnosis of Hypovitaminosis D: A Call for Standardization
• Assessment of dietary vitamin D requirements during pregnancy and lactation
• Circulating Vitamin D3 and 25-hydroxyvitamin D in Humans: An Important Tool to Define Adequate Nutritional Vitamin D Status
• Presentation by Dr. Hollis