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Current status of thyrotropin-releasing hormone therapy in amyotrophic lateral sclerosis.

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HEALTH CARE ISSUES
Current Status of
Thyrotropin-Releasing Hormone Therapy in
Amyotrophc Lateral Sclerosis
Committee on Health Care Issues, American Neurological Association"
Amyotrophic lateral sclerosis (ALS) and its variants are
feared progressive neurological diseases of which the
etiology and pathogenesis are unknown and for which
therapy is unavailable. In 1983, Engel and associates
111 reported that infusion of thyrotropin-releasing hormone (TRH) improved strength and lessened spasticity in patients with ALS. Their report generated hope
that, at long last, an effective treatment may exist. In
this report we assess the current status of the evidence
for using TRH in the management of patients with
ALS.
TRH
TRH is a tripeptide with the structure of L-pyroglutamyl-L-histidyl-L-prolinamide;it plays a central role in
the hypothalamic control over thyroid function. TRH
is normally released from the hypothalamus and, in
turn, controls the release of thyroid-stimulating hormone (TSH) from the pituitary gland. TSH, on entering the blood, is taken up by the thyroid, and the
thyroid responds by increasing the release of thyroid
hormone. The blood concentration of thyroid hormone regulates the release of TRH and TSH. TRH
was the first of the hypophysiotropic peptides to be
characterized structurally [2, 31, and is generated, in
the rat, from a prohormone precursor [47.
In addition to effects on the pituitary gland, TRH
may act directly on the nervous system. It is not
known whether TRH released from the hypothalamus
reaches other areas of the brain outside the pituitary,
or whether TRH is synthesized elsewhere within the
central nervous system. TRH receptors are scattered
throughout the central nervous system, especially the
dorsal and ventral horns of the spinal cord [5]. TRH
may act on these receptors directly, in combination
with other neuropeptides such as serotonin or sub'This report was authored by John N . Whitaker, MD, Department
of Neurology, University of Alabama at Birmingham, Birmingham,
AL; Jasper R. Daube, MD, Department of Neurology, the Mayo
Clinic. Rochester, MN; and T. R. Johns, MD, Department of Neurology, University of Virginia, Charlottesville, VA. It was developed
for the American Neurological Association Committee on Health
Care Issues. Members of the ANA Committee on Health Care
Issues are: Peter James Dyck, MD (chairman). Roger N. Rosenberg,
MD, Nickolas A. Vick, MD, and Joseph J. Volpe, MD.
stance P [GI, or potentiate the effects of established
neurotransmitters such as acetylcholine 171. TRH may
also have a trophic effect on anterior horn motor
neurons without invoking a neurotransmitter-like
function or a specific TRH receptor 187.
Initial Studies with TRH in ALS
Based on reports that TRH lessened spasticity in cats
after cervical spinal cord trauma [9, 101, an open trial
of TRH in ALS was conducted by Engel and associates
111. High doses (2-19 mdmin) of TRH given intravenously to 12 patients with ALS were said to be followed by improvement of both weakness and spasticity. Improvement was most obvious within the first
hour of infusion, but sometimes the effect lasted for
20 hours. These results were supported by the results
of another uncontrolled trial by the same investigators
using the subcutaneous route [ 111. The intrathecal
route was used in another uncontrolled trial of TRH in
ALS patients reported by Munsat and associates [l2],
again with beneficial results; the intrathecal route was
selected to bypass the blood-brain barrier, permitting
the use of smaller doses of TRH and resulting in fewer
side effects (see below). However, other investigators
conducted open trials of TRH given intrathecally
which resulted in no clinical improvement in patient
function 113, 147.
Double-Blind Placebo-Controlled Trials
of TRH in ALS
In contrast to the reported benefit seen in the
open trials of intravenous or subcutaneous 11, 11, 15191, and one of intrathecal 1121, TRH therapy, controlled studies have provided little, if any, evidence of
the beneficial effect of TRH in ALS. Four separate
controlled studies have now been reported [ 14, 20Received Apr 17, 1987. Accepted for publication Apr 17, 1987.
Address reprint requests
Dr Whit&er, Depment of Neuralogv, university of Alabama, OHB 358 university station, ~ i ~
AL 35294,
541
~
,
~
~
223. In these studies, TRH was given intravenously
114, 22) or by periodic subcutaneous 114, 223 or intramuscular [20,2 11 injections. Overall, there was little
objective or quantifiable improvement. Because of the
side effects, the studies could not be blind. Also, in
one study some patients showed a brief increase in
dynamometric strength 1141, but there was no effect
in six other measures. In another study, some patients
improved subjectively on medication and reported
subjective worsening when the TRH was stopped, but
there was no objective change [221. In a third study,
some patients experienced a transient increase in
strength in only 4 of 34 muscles tested and no functional improvement E20). These studies provided no
evidence of convincing objective benefit, and the subjective improvement could have been a placebo effect.
the trial itself or the lack of an objective response may
be due to the rather prominent side effects, which
limit attempts to perform a double-blind study and the
total dose that can be given. Quantitative measurement
and timing of the tests of muscle strength have also
created problems. Which upper and lower motor
neuron functions to assess and how the changes should
be weighed are questions that need to be addressed.
The lack of clear-cut effects has been attributed to a
therapeutic window; chat is, beneficial effects may not
be seen if doses were either too high or too low, or if
the patient was examined too soon or too late. Engel
and associates 1111 reported an autorefractory period
in which there was no improvement after the initial
benefit, but that phenomenon was not seen by others
r 141.
Side Effects of TRH Treatment
One of the difficulties in using TRJ3 and in performing
a double-blind trial is that the side effects are obvious
to both patient and examiner. There is usually increased fasciculation, shivering, sweating, increased
body temperature, tachypnea, nausea and vomiting,
paresthesias, dysesthesias, sensations of bowel and
bladder fullness, and vaginal warmth {I}. Side effects
seem to be most evident with intravenously administered TRH but may be seen with other routes of administration 1141. Side effects are usually less evident
with the intrathecal route 112). The pathogenesis of
these manifestations is unclear. Measurements of thyroid hormone levels 1221 disclosed no substantial
change.
Summary and Recommendations
The reported improvement in strength effected by
TRH in ALS patients, even though temporary and
difficult to quantitate, has to be accorded attention
under any circumstances. Optimization of dose, timing, route, or use of derivatives of TRH with desirable
effects but fewer side effects 1103 may improve TRH
therapy. However, ithe results of controlled therapeutic studies have provided no evidence that use of TRH
in ALS either is clinically indicated in individual patients or warrants a new controlled stiidy. TRH cannot
now be recommended for the management of patients
with ALS. Moreover, the TRH experience shows the
need for double-blind controlled studies of new therapeutic agents in ALS.
Limitations in Performance
of Therapeutic Trials in ALS with TRH
The short-term, transient, and usually slight improvement in strength after TRH treatment reported in the
open trials was encouraging, as were a few aspects of
the double-blind placebo-controlled studies. Certainly,
the most prominent improvement has been subjective;
the objective change has been difficult to assess and to
quantitate 115, 16, 181. The variables of dose, timing,
route of administration, and clearance must all be considered in identifying a real change, optimizing the
benefit, and limiting the side effects.
It is clear that TRH can cross the blood-brain barrier 1231, but it is not clear that there is any TRH
deficiency in the spinal cord or the brain of ALS patients. There is a diminution of TRH receptors in the
spinal cord of ALS patients, but that could be due to
cell loss; also, it involves both ventral and posterior
horns [5]. Cerebrospinal fluid levels of TRH were reported to be low in ALS patients by some investigators
f l l , but others found normal values 1241. Thus, the
rationale for the trials of TRH is tenuous.
On a more practical level, the problems with either
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Vol 2 2
No 4 October 1087
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Health Care Issues: TRH Therapy in ALS
543
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