Download Hormonal Content of Thyroid Replacement Preparations

Psychosomatic disturbances, includ¬
ing irritability, insomnia, and anorex¬
ia, follow. Other mental disturbances
may develop, such as mood swings,
mania, declining intellect, apathy,
and hallucinations.'
Subcutaneous injection of metallic
mercury is always harmful, causing
local abscess and granuloma forma¬
tion.2,3 Subcutaneous deposits of mer¬
cury are also systemically absorbed.
Our patient as well as several
patients in previously reported cases
demonstrated high levels of mercury
in blood and urine, without clinical
signs or symptoms of a toxic reac¬
tion.34
Blood and urinary mercury levels
may not accurately indicate CNS
accumulation and toxic reactions. In¬
dustrial workers exposed on a longterm basis to dangerous environmen¬
tal levels of metallic mercury (air
threshold concentration, 100 Mg/cu m)
experienced CNS toxic reactions, with
blood and urinary levels lower than
those of our patient (6 Mg/dL in blood
and 260 ug/L in urine corresponding
to
their threshold of toxicity).'
Experience with occupational and
industrial metallic mercury poisoning
proves the effectiveness of chelation
therapy for CNS toxic reactions.1 We
did not chelate our patient, because
he did not have a CNS toxic reaction
or altered renal function.
Surgical excision of mercury granu¬
lomas effectively lowered serum and
urinary mercury concentrations in
our patient and in a previously
reported case.3 It is especially inter¬
esting in our patient that, despite
roentgenographically detectable re¬
sidual mercury, his urinary and
serum mercury levels dropped sub¬
stantially after surgery.
Based on experience with our
patient and those recorded by others,
Hormonal Content of Thyroid
the following steps seem appropriate
in the management of subcutaneously
injected metallic mercury: (1) prompt
excision of all readily accessible sub¬
cutaneous areas in which mercury is
demonstrated, irrespective of wheth¬
er there are manifestations of toxicity, (2) appropriate monitoring of CNS
and renal function for evidence of
mercurial toxicity, (3) chelation ther¬
apy when there is such systemic tox¬
icity, and (4) psychiatric consultation
and treatment when indicated.
References
1. Gerstner HB, Huff JE: Clinical toxicology
of mercury. J Toxicol Environ Health 2:491-526,
1977.
2. Rachman R: Soft tissue injury by mercury
from a broken thermometer. Am J Clin Pathol
61:296-300,1974.
3. Hill DM: Self-administration of mercury by
subcutaneous injection. Br Med J 1:342-343,
1967.
4. Kern FB, Condo R, Michel SL: Mercury
granuloma with systemic absorption. JAMA
222:88-89, 1972.
Replacement Preparations
Robert W. Rees-Jones, MD; Arturo R. Rolla, MD; P. Reed Larsen, MD
ACCORDING to present pharmaceutical industry estimates, there were
15 million prescriptions written in the
last year for thyroid replacement in
the United States. Of these, approximately 50% were for synthetic hor-
See also p 525.
mones, and the remainder were for
preparations derived from animal
sources. At present, both generic thyroid and levothyroxine preparations
are available, and their use has been
encouraged by recent changes in prescription regulations. Since the Food
From the Howard Hughes Medical Institute
Laboratory and Thyroid Unit, Department of Medicine, Peter Bent Brigham Hospital and Harvard
Medical School (Drs Rees-Jones and Larsen),
and the Department of Medicine, New England
Deaconess Hospital (Dr Rolla), Boston. Dr ReesJones is currently with the Department of Medicine, Presbyterian University Hospital, Columbia
College of Physicians and Surgeons, New York.
Reprint requests to Thyroid Unit, Peter Bent
Brigham Hospital, 721 Huntington Ave, Boston,
MA 02115 (Dr Larsen).
and Drug Administration still accepts
the United States Pharmacopeia standard based on organic iodine content
for this medication, there is no specification of the precise hormonal content of these tablets. This study
reports the triiodothyronine (T3) and
thyroxine (T4) content of a number of
generic thyroid and T4 preparations,
using a radioimmunoassay.1 This survey was occasioned by the experience
of a patient who received a biologically ineffective thyroid tablet.
Report of
a
Case
A 54-year-old woman with primary
hypothyroidism since age 29 years had
been treated with 3 grains of thyroid a day
without difficulty. In 1978 she renewed her
prescription, purchasing 5,000 tablets (1
grain each) of a less expensive generic
brand. After several months, the patient
noted the recurrence of hypothyroid symp¬
toms that continued despite an increase in
her daily dosage to 4 grains. On physical
examination, the patient was clinically
hypothyroid, and the serum T4 level was
2.5 Mg/dL; the T3 resin uptake value was
24%; and the serum thyroid-stimulating
hormone (TSH) level was 81 mU/hiL (nor¬
mal, less than 10 mU/hiL). The patient's
medication was switched to 0.2 mg of T4,
with subsequent disappearance of the symp¬
toms and signs of hypothyroidism. Two
months later, the serum T4 level was 10.8
Mg/dL; the T3 resin uptake value was 30%;
and the level of TSH was 2.2 mU/hiL.
Materials and Methods
Eight generic 1-grain thyroid prepara¬
tions and four generic 0.1-mg T„ prepara¬
tions were obtained from pharmacies in
the Boston area. For comparison, 1-grain
tablets of Thyroid (Armour) and 100-Mg
tablets of T4 (Synthroid, from Flint Divi¬
sion, Baxter-Travenol; and Letter, from
Armour) were also assayed. In addition,
several tablets of 1-grain thyroid prepara¬
tions manufactured more than two and ten
years ago (Thyroid, Armour; and Thyroid,
Parke-Davis, respectively) were assayed.
Radioimmunoassays of T, and T4 were
performed of Pronase digests of thyroid
tablets or of a suspension of synthetic T„
preparations in buffer.1 Three tablets of
each medication were measured in each
assay to avoid interassay variations, and
six to nine tablets were measured in all.
Downloaded from jama.ama-assn.org at Northwestern University on February 1, 2012
Triiodothyronine (T3) and Thyroxine (T4)
Content of Pronase
T. Content per Tablet,
M9 per Tablet (Mean±SD)
Preparation,
Supplier
Hydrolysates of 1-Grain Thyroid Preparations
T4 in Armour
%
Ts Content
Tablet,
(MearttSD)
per
m9 per Tablet
T, In Armour
Preparation, %
Armour_58±3.9_100_15+1.6_100
A
(lot No. 1),
A
(lot No. 2)
biologically
deficient
8.8±0.35
49±3.7
15"
84'
7.9±0.48
18±1.4
53'
117t
B_46±4.6_79J_14±2.4_93
C_42±1.9_72J_11±2.2_73*
D
39+2.3
67'
E
F
G
101
59±3.3
14±3.0
17±1.9
93
113
_47±2.7_81J_18±1.8_120*
55±1.8
94
14±0.5
90t
*P<.001 In difference from Armour product.
tP<.0S.
tP<.01.
Total iodine analyses of tablets were per¬
formed by Boston Medical Laboratory,
Waltham, Mass. Statistical comparisons
were performed by Student's t test.
tions tested contained less than 2%
T,
Results
The Table shows the T4 and T,
content of eight generic 1-grain thy¬
roid preparations. The Armour tablet
was arbitrarily used as a standard for
reference purposes, since its T4 and T3
content is constant based on our
previous experience.1 The preparation
purchased by the aforementioned pa¬
tient is lot No. 1 of company A. These
1-grain tablets contained only 9 ßg of
T„ and 8 ßg of T3, values that are 15%
and 53%, respectively, of the quanti¬
ties of these hormones in the Armour
preparation. A second lot of thyroid
from the same distributor had mod¬
estly less T4 and slightly more T3 than
the Armour product. The remainder
of the generic preparations contained
from 67% to 100% of the amount of T4
and from 73% to 120% of the T3
present in the Armour preparation.
Differences of greater than 10% were
generally statistically significant,
121±6 and 137±8 ßg of T4, which was
significantly greater than the 100 ßg
expected (P<.001). All T4 prepara¬
as
indicated in the Table. The tablets
from companies A (lot No. 1), C, and
F were assayed for total iodine con¬
tent, which were 0.19% ±0.01%,
0.09% ±.02%, and 0.08% ±0.02%, re¬
spectively, by weight (mean±SE). The
2-year-old Armour thyroid tablets
contained 56±1.5 ßg of T4 (SD) and
15±1 ßg of T3 results not significantly
different from fresh tablets. The
Parke-Davis preparation manufac¬
tured more than ten years ago con¬
tained 42±5 (SD) and 9±0.4 ßg of T3.
The T4 content of Synthroid and
Letter and two generic T„ tablets was
not significantly different from the
stated value. The other two contained
Comment
The USP requires only that desic¬
cated thyroid contain between 0.17%
and 0.23% organic iodine by weight.
The present study indicates this crite¬
rion is not adequate for this animal
product. There were notable varia¬
tions in hormonal content among the
generic thyroid preparations, with
one clinically ineffective lot extreme¬
ly deficient in T„ and T3, despite
meeting the USP standard for iodine
content. The relatively normal as¬
sayed hormonal content of the prepa¬
rations manufactured two and ten
years ago suggests that these varia¬
tions in generic thyroid are not age
related but are secondary either to
manufacturing technique or to char¬
acteristics of the original animal
material employed. Interestingly, two
of the four generic 0.1-mg T4 prepara¬
tions studied had significantly more
T4 per tablet than indicated.
Biologically ineffective prepara¬
tions of thyroid have been reported on
previously.2"5 While in the past prepa¬
rations from unknown or unreliable
manufacturers could be avoided by
specifying a brand name, this practice
is discouraged by the recent emphasis
on generic "equivalents." The data in
the Table suggest that many of the
generic preparations of thyroid are
not "equivalent," at least to Armour
Thyroid. The latter was taken as a
standard primarily because of its uni¬
form composition and popularity.1
Because there is no absolute standard
for T3 and T4 content of thyroid, its
selection is arbitrary. Arguments
against the use of thyroid as replace¬
ment therapy because of its supraphysiological T3/T4 ratio compared
with that of human thyroid have been
presented previously and will not be
reviewed here.1,57 However, the results
of analyses of four generic T4 tablets
indicate that two of these had greater
than 120% of the stated hormonal
content. Thus, it seems that the phy¬
sician or pharmacist, in a well-inten¬
tioned attempt to reduce (albeit mod¬
estly) medication costs, may supply
patient with a generic thyroid
replacement preparation with either
more or less than the expected biolog¬
ic activity. This undesirable situation
might be avoided by the establish¬
ment of appropriate guidelines for
the hormonal content of these widely
prescribed medications.
the
This study was supported in part
Health Service grant AM18616.
by Public
References
1. Rees-Jones RW, Larsen PR: Triiodothyronine and thyroxine content of desiccated thyroid tablets. Metabolism 26:1213-1218,1977.
2. Catz B, Ginsberg E, Salenger S: Clinically
inactive thyroid USP: A preliminary report. N
Engl J Med 266:136-137,1962.
3. Braverman LE, Ingbar SH: Anomalous
effects of certain preparations of desiccated
thyroid on serum protein bound iodine. N Engl J
Med 270:439-442,1964.
4. Williams AD, Meister L, Florsheim WH:
Chemical identification of defective thyroid
preparations. J Pharm Sci 52:833-839,1963.
5. Mangieri CN, Lund MH: Potency of United
States Pharmacopeia desiccated thyroid tablets
as determined by the anti-goitrogenic assay in
rats. J Clin Endocrinol Metab 30:102-104,1970.
6. Surks MI, Schadlow AR, Oppenheimer JH:
A new radioimmunoassay for plasma 1-triiodothyronine: Measurements in thyroid disease and
in patients maintained on hormonal replacement. J Clin Invest 51:3104-3113,1972.
7. Jackson IMD, Cobb WE: Why does anyone
still use desiccated thyroid USP? Am J Med
64:284-288, 1978.
Downloaded from jama.ama-assn.org at Northwestern University on February 1, 2012