A perspective on the autoimmune/cortisol/etc. controversy

[Guest guest]

Hi All,

Remember the big controversy around that " letter " from C. Stimmel and

his views on the role of hydrocortisone/adrenal/autoimmunie disorders

and RSS? I took the liberty to ask the moderator of another listserve

to which I belong (HGF-Peds) to take a close look at the lengthy letter

and analyze it from an objective, research-oriented and analytical

view. For those of you familiar with the listserve, you know that if

nothing else, Earl is a research fanatic and is really good at sniffing

out papers and journal articles related to Growth hormone topics.

Anyway, here is his view on the whole issue. It is a long email, but I

hope worth reading to those of you still interested in getting some

other opinions on this topic. The beginning of his email paraphrases

the basic arguments that C. Stimmel sets forth. Make sure you read on

past this section! The end of the email summarizes Earl's belief that

these arguments, as listed in the letter, do not necessarily hold up to

any rigorous analysis. Rightfully so, Earl chose not to comment on any

of the personal or mean-spirited comments made towards individuals. He

only looked at the medical/scientific validity of the points stated in

the letter.

As always, remember that this is just a layperson's view and that we

should always check with our docs on new theories that come across the

internet.

And, Happy New Year to everyone!

Katy

Earl's Response Begins Here:

--------------------------------------------------------------

12/31/00

Katy,

The following is in response to your request of December 16, 2000, for

my views on Chandler Stimmel's presentation of his views on the

treatment of RSS with hydrocortisone and, related matters, set forth in

his correspondence of December 7, 2000.

Chandler states that his research shows the following: The basis for

RSS resides in polyglandular autoimmune diseases and disorders that

affect the thyroid and adrenal glands: adrenal insufficiency, thyroid

disease, insulin-dependent diabetes mellitus, gonadal failure, diabetes

insipidus, virtiligo, alopecia, pernicious enema, myasthenia gravis,

immune thrombocytopenia purpura, Sjogren's syndrome, and rheumatoid

arthritis. Those autoimmune diseases and disorders are either the cause

of or are contributory to RSS, or are an indication that some other kind

of autoimmune disease or disorder may be the cause of or contributory to

many of the symptoms seen in RSS children: hypothyroidism, sub-clinical

hypoadrenalism, 's disease, short stature, hypothyroidism,

ectodermal dysplasia, allergies, chronic fatigue syndrome, hypoglycemia,

caloric deprivation from poor appetite, and low blood pressure.

Physicians fail to diagnose properly hypothyroidism and sub-clinical

hypoadrenalism because the thyroid stimulating hormone (TSH) and the

adrenocorticotropin hormone (ACTH) normal values are not representative

of the population (i.e., they are based on a fatally skewed population

that understates the underlying thyroid and adrenal deficiencies).

Also, physicians are not trained adequately in the clinical symptoms of

hypothyroidism and hypoadrenalism. Based on the erroneous acceptance of

normal TSH levels that are, in fact, too high (i.e, indicates thyroxin

is too low), and normal ACTH levels that are, in fact, too low

(indicates that cortisol is sufficiently high); and, on the failure of

physicians to recognize the clinical symptoms of hypothyroidism and

hypoadrenalism, physicians fail to treat patients with those disorders

with safe, physiological levels of cortisone, which could reduce or

eliminate many of the problems underlying the symptoms of RSS children.

" GH is not the optimal approach for RSS children because 'hypoglycemia

in children with cortisol or GH deficiency or both is generally preceded

caloric deprivation that is largely corrected by glucocorticoid

(cortisol therapy). . . '. " He also states that growth hormone masks,

rather than addresses, those hormonal deficiencies. (Citations

omitted).

Chandler relies on a survey he conducted of RSS parents (57 of 310

responded) that shows significantly higher thyroid disorders, 's

disease, diabetes, Lupus, scleroderma, and Crohn's disease in RSS

children relative to the general population. There is not enough

information presented about the survey protocol, methodology, or

execution to show which, if any of the responders, reported children who

had autoimmune diseases and those who didn't because there are many

causes of those diseases and disorders other than autoimmune defects.

For the same reasons, there is no basis to establish that the responders

constituted a representative sample of the queried parents of the RSS

children from which it would be possible to project the results of the

survey to the population of all RSS children. That the RSS children

would have significantly higher endocrine, autoimmune, or other diseases

or disorders in relation to the general population would not be

surprising because RSS children are a subset of children born

intrauterine growth retardation, which can be accompanied by or be a

part of other disorders and diseases including those of genetic origin.

Although thyroxin deficiency can cause or contribute to attention

deficit disorder, it is only one of a number of possible causes of

attention deficit disorder that occur in children, including those with

RSS.

To the extent that a cortisol deficiency is responsible for failing to

counteract hypoglycemia, Chandler is correct that " GH is not the optimal

approach for RSS children because 'hypoglycemia in children with

cortisol or GH deficiency or both is generally preceded caloric

deprivation . . . .that is largely corrected by glucocorticoid

replacement [cortisol] therapy) whereas human growth hormone has little

effect. . . . " Textbook of Endocrinology, 9th Ed. (W.B.

Saunders, Philadelphia: 1998) at p. 957. Howeer, the prinicipal

hormone that counteracts hypoglycemia is glucogen, followed by

epinephrine, GH, and cortisol. The levels of those " counterregulatory "

hormones normally rise in response to hypoglycemia. In persons who are

deficient in the counterregulatory hormones, appropriate replacement

therapy is given as indicated. But, there is no basis to treat with

cortisol therapy in the absence of a deficiency in cortisol.

Chandler also relies collectively on the following physicians for his

views: Drs. Robban Sica, Ridha Arem, A. P. Weetman, ph ,

Mussey, Hauser, and Jefferies, According to

Chandler, those physicians are knowledgeable in the areas of adrenal,

thyroid disorders, and autoimmune diseases involving the thyroid and

adrenal glands. A cursory review of Medline abstracts under " growth

hormone " (subject field) and their respective names (title field)

revealed no reports by any of those physicians of investigations or

studies involving the association of thyroid or adrenal disorders or

auto immune diseases with any disorder of growth including GHD in RSS

children. Thus, it appears that Chandler supports his positions by

selecting and linking certain overlapping symptoms of various adrenal,

thyroid, and growth hormone disorders and autoimmune diseases related to

those hormones without any significant evidence to demonstrate a causal

relationship that is unique to any specific disorder of growth,

including GHD in RSS children.

It is well documented that thyroid and adrenal hormones, among others,

can have substantial adverse impacts on the secretion, uptake, and

utilization of growth hormone whether in idiopathic GHD or non-GHD

children, including those with RSS. It is also recognized that

Likewise, there is no question that hypopituitarism and polyglandular

syndromes can involve the interactions of thyroid, adrenal, and growth

hormones in ways that cause differences in their respective blood levels

based on many different variables. It is also known that cortisol

insufficiency can contribute to hypoglycemia. A cursory review of

Medline abstracts shows that today's competent and experienced

pediatric endocrinologists are well aware of (i) those variables and

their impact; (ii) the specific tests that can differentially diagnose

the various endocrine disorders and diseases including autoimmune

diseases; (iii) the clinical presentation of those disorders and

diseases; and (iv) the available treatment modalities and their

administration for those disorders and diseases. It is therefore,

unlikely that a child with sub-clinical hypoadrenalism or hypothyroidism

would go undiagnosed and untreated, regardless of any other diagnosis

such as GHD in RSS children. Thus, there is no material issue of

whether rGH masks or doesn't address any underlying adrenal or thyroid

disorder. Further, autoimmune diseases of the pituitary, thyroid,

adrenal or other glands ultimately result in the destruction of those

glands, and the administration of available replacement therapies or

other treatment modalities.

Chandler states that the investigative reports of Drs. S. Cassidy, J.

Hall, and T. Limbird in the areas of hypopituitarism, slipped capital

femoral epiphysis, hypothyroidism, hypoglycemia, and growth hormone

deficiency, as those disorders relate to RSS children, show a lack of

recognition of the role and significance of adrenal hormones as a cause

or contributing factor to those disorders. It was obviously not within

the scope of the studies giving rise to those reports to focus on the

adrenal hormones, which are not central to the diagnosis or to the

treatment of RSS, but are discussed in reports of studies involving

intrauterine growth retardation, of which RSS is a subset.

In conclusion, I find no basis in the medical literature or in

Chandler's presentation to show that RSS is grounded in polyglandular

autoimmune disease. Although its etiology is not fully known, the

medical literature shows that RSS is associated with several different

genetic defects; that rGH therapy can be beneficial in final height

outcome, that bone age is not a reliable parameter to predict final

height in RSS children, and that the absence of " catch down " growth in

non-GHD RSS children shows that short-term rGH therapy may be

efficacious (i.e., meaning that such a child can grow at a normal rate

with short-term treatment).

Earl

[Guest guest]

p.s. If anyone has any questions about this email, you can contact Earl

Gershenow at:

EGersh@....

Take care!

Katy