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or desiccated thyroid in physiologic dosage
Hydrocortisone and/or Desiccated Thyroid in Physiologic Dosage XII.
Effects of Thyroid Hormone Excesses on Urinary Solutes and Steroids C. MOSES
Bq T. S. DANOWSKI, G. P. RODNAN, M. E. SARVER AND
17-ketosteroids remained constant. The comparable responses to mepyrapone (Metopirone or SU 4885) prior to and during thyroid administration indicate that pituitary-adrenal responsiveness had not been altered by this therapy. The decrease in the urinary 17-ketosteroid and perhaps the compound S responses to exogenous ACTH in our studies indicates that the secretion, conversion, or excretion of these classes of steroids is altered by induced excesses of thyroid The urinary Porter-Silher hormone. chromogen response to exogenous ACTH was not altered. Urinary gonadotropins decreased during treatment with large dosages of thyroid hormone. Total and free hydroxyproline excretion in urine increased during administration of desiccated thyroid in large dosages.
The administration of a preparation of desiccated thyroid in 20 or 25 grain dosages to healthy adult male prisoners was associated with increases in the mean daily urine volume, mean daily creatinine clearance and, sporadically, with an appearance or accentuation of creatinuria. Urine calcium and phosphorus excretion also appeared to increase but the changes were not statistically significant. The origins of the trends to hypercalciuria and hyperphosphaturia cannot be identified because balance data are lacking, but presumably variables such as the increased intake of food and the loss of skeletal calcium and phosphorus which characterize thyrotoxicosis were operative. The tubular reabsorption of filtered phosphorus remained constant. The daily excretion of urinary PorterSilber chromogens increased, while the MONG
A
OTHER
human
mav develop
AND URINARY glomerular
if already
rate
in thyrotoxicosis
increases,lR*”
present,sa-i the urinary the metabolism
excretion and
steroids is often alteredJa-V and the output
increases.5a, 1’ Onr findings
thyroid
(Proloid)
keeping
with these findings,
in large
dosages
during
ing that the urinary
steroid
(Metopirone
responses
of Endocrinology
the
for a limited
In addition,
venous mepyrapone ._ _______ From. the Section
CH,4NGES
filtration
rises,.?“-” the secretion,
of adrenal
in lirinr
the
or increase
and phosphorrls cretion
RENAL
subjects
in
creatinuria of calcium
the urinary
ex-
of hydroxyproline
administration
of desiccated
period
are largely
evidence
of time
has been
to exogenous
ACTH
obtained but
cr SU 4885)
may be altered
and Metabolism
and the Section
in
indicat-
not to intraby these
large
of Rheumatology
of the Departmcvlt of Medicine. the Addkon H. Gibson Laboratory, Unicersity of Pittsburgh, c11lt1tht, ,\letlicul Center und Shadyside Hospitah, Pittsburgh, Penn&xmia. Aided by grunts from the John A. Hartford Foundation, Inc., the Western Pennsyhati Chapter of tllc iL\rtlwitisand Rheumatism Foundation, the Muscular Dystrophy Assocbtions of dmericw Inc., the Medical Research Fourukrtion of Pennsylcania, Inc., tk ~~,nl~r,o,lccrclltlt of Pewwylcunk. the Deportment of ffenlth. Education nnd Welfare. unc( U,‘clrfler-Larr!bert L&oratories. Rwcirwl
for 7~uOlication Feb.
14. 7964.
h[ETABOLISM,
\'OL. 13, NO. 8 (AUGUST),
1964
730
DANOWSKI,
Table I.-Efects
of Large
Dosages of Desiccated Thyroid Creatinine, and Creatinine Clearance ~~__
__-______ Week of
Urine Volume (ml/d.)
Dosage
Therapy
(grains)
0
0
0 0 7th
RODNAN,
Mean
& S.D.
830 *
SARVER AND MOSES
on Urine Volume,
Urine Creatinine (mg./d.) Mean i S.D.
(#)
Creatinine Clearance (ml./min.) Mean 2 S.D.
(#)
(#)
241
(8)
1460 2 445.1
(3)
0
1008 2 311
(8)
1513 % 423.7
(8)
106.3 I
32.07
0
1107 ZL 720
(7)
1285 *
357.7
(7)
32.3 ?
19.68
(7)
20t
1245 & 763
(10)
1027 t
489.0
(10)
80.7 ?
52.37
(10)
127.4 f
62.15
91.7 5 28.97
(8) (8)
9th
25
1511 r!~ 528***
(10)
1363 *
464.5
(5)
10th
25
1680 % 752***
(10)
1440 2 625.0
(10)
11th
25
1455 f
470***
(8)
1596 -t 365.2
(5)
151.x 2 52.37*
(5)
13th
0
1267 2
382*
(6)
1691 ?
221.4
(6)
152.1 i
31.31***
(6)
14th
0
1448 ?I 423’**
(6)
1851 *
426.6
(5)
126.2 i
38.11
(5)
15th
0
1232 % 319**
(6)
1512 t
408.5
(6)
105.3 ?
28.57
17th
0
llfiO?
(6)
Difference
from
pretherapy
546’ values
~___.
statistically
significant:
*p
by 2 weeks
therapy
for
period
dosages such
each
2 weeks
(weeks
I3
of thyroid
a regimen
on grains
3,
(weeks
7 and
through
17).
hormones
urinary
10 and
8):
25 per
administered
gonadotropins MATERIALS
Twenty-four
15 per
grains
hour specimens
of urine
(6)
__..
..-.
.02-.Ol.
***p tpreeeded
_~_
(10)
.O5&.02.
**p
was continued
(5)
117.4 I75.01
.Ol-<.OOl.
day
(weeks
day
for
1 through
4 weeks
for brief
6);
(weeks
periods,
grains
20 per
day
9 through
12):
Post-
and that
under
may decrease. AND
METHODS
were collected
with refrigeration
prior
to, during
and after the administration of desiccated thyroid (Proloid: Lots 2827072A, 156905A and 459312) in daily dosages increasing up to 25 grains. The volumes of the specimens were measured
and aliquots were analyzed or assayed for creatinine, creatine, calcium, phos17-ketosteroids, Porter-Silber chromogens, 11-desoxycortisol ( compound S) phorus, metaholites, pressor activity, gonadotropins and hydrosyproline by methods in use in this and in other laboratories. err Also, the effects of such excesses of thyroid hormone on the urinary
steroid
intravenous
responses
to subcutaneous
mepyrapone,
ACTH,
200
units
36 mg. per Kg. of body weight,
per day for 4 days,
were
and to
examined.
RESULTS
Urine Volz~me, Creatinine The
%&hour
desiccated
also increased (table
1).
urine
thyroid
Creatinuria
urinary
present
neither effect
clearly
during
upon urinary
with
not
associated
with
therapy
during 1).
The
the daily
ingestion
creatinine
of
clearance
desiccated
did not increase. equal
but it was almost
the treatment period ( SU 4885 ) nor ACTH creatine
with
of creatinine
approximately
frequency always
prior
to
and
more pronounced
(table 2). It is to be noted that administration had anv consistent
excretion.
Uritbe Calcium and Phosphorus; ‘- Treatment
(table
to 151.7 from a base line level of 91.7 ml. per minute
thyroid
mepyrapcne
increased
dosage
excretion
occurred
duringdesiccated when
volumes
in 25 grain
strikingly
The
and Creatine
Tubular
thyroid
statistically
Reabsorption
of Phosphorus
in 20 to 25 grain per day dosages significant changes in urine calcium
was and
though a trend to increases was recorded (table 3). phosphorus excretion, None of these differences was statistically significant. Since the intake of
THYROID
HORhIONE
ON
URINARY
Pretherapy Week2
C. Ba. w.
B.
0
0
12
68
731
STEROIDS
Prior to, during,
25 grains/d.*
~_____ Week
Week1
2
Week
3
Post-Therapy
SU-4885t
213
32
311
0
0
45
I,
C. Br. G. c.
AND
of Creatine in Urine (mg./d) and after Thyroid Therapy ~ .-.___
Table 2.-Excretion
Subject
SOLUTES
Week1
ACTHZ 36
6
0
40
90
0
50
Week2 ~.__
Week
0
0
43
0
16
0
107 0
56 12
88 125
0 0
0
0
43
0
0
J. M.
0
16
0
0
44
86
8
0
Y
Ii. s.
0
18
0
0
0
0
0
0
R. H. K. Mc.
*During
2nd
and
3rd
I)
weeks
then
3 __
0
of
25
20 per
grains
day
for
of
thyroid
grains
3, 10,
15 and
tall
values
in
this
column
obtained
on
2 weeks day
iAll
values
in
this
column
obtained
on
fourth
per
day
immediately
by,
preceded
in
0 succession.
each.
of
intravenous day
of
SU-4885
ACTH
test.
stimulation
test.
‘I‘able 3.-Urinary Calcium and Phosphorus Excretion and Tubular Reabsorption of Phosphorus Prior to, during and after Desiccated Thyroid Therapy in Large Dosages Urine Week of Therapy
Dosage (grains)
_~~_
Tubular Reabsorption of Phosphorus (‘A.) Mean 5 S.D. (#)
0
176 i
98
(8)
774 t
203
(9)
84.1 f
3.0
18)
0
I,
164 1+ 75
(i)
144 t- 265
(9)
88.0 f
3.3t
(8)
fi74 -c 91
I)
7th
20*
104
17)
194 & 148
182 ?
(IO)
(R)
83.4 5
3.2
(7)
683 2
395
110)
81.2 2
8.0
(10)
9th
“5
261 I+ 112
(19)
885 ‘-
333
110)
86.8 t- 4.9
(5)
10th
25
272 ?
203
(10)
801 & 325
(9)
84.7 % 4.3
(10)
1lth
“5
212 -+r 202
(i)
912 t
432
(8)
82.6 2
5.6
(3)
13th
0
155 ?
63
(6)
947 2
310
(6)
90.2 ?
2.6t
(5)
14th
0
231 i
169
(6)
860 f
497
(6)
X6.9 2
3.1
(5)
15th
0
215 t- 68
(5)
975 t- 181
(6)
82.5 i- 5.2
(6)
17th
0
141 *
(5)
655 ?z 202
(6)
*Preceded
by
continued
therapy
2 weeks for
period
tDiffewnce
these
(weeks
The
during
tubular
25 per
day
(weeks
day
for
1 through
4 weeks
6);
(weeks
grains
20 per
9 through
121;
day post-
is statistically
significant
intake,
p .05&.02.
it is not possible
endogenous
release,
etc.
to assess the rela-
in the trends
to hvper-
reabsorption
urinary
of filtered
of desiccated Porter-Silber excretion
of
phosphate thyroid
(per
in large
Chrom.ogrrzs 17-ketosteroids
and
cent
TRP)
dosages Compound
remained
was
(table
not
3 ).
S
quite
constant
the ingestion
of 20 to 25 grains of desiccated thyroid (table 4). On as much as twofold increases in Porter-Silber chromogens
hand, during
urinary
not change
the same period. excretion
consistently
Stcroi&
Thcrapv adrenal
15 per
grains
could not be estimated,
I;-Kctosteroids, meau
other
Urirwrrl
8);
17).
value
hv the ingestion
occurred The
3, 10 and
7 and
_.__~.
and hyperphosphaturia.
ZTriwrrl The
54
grains
13 through
of dietary
calciuria
on
(weeks
pretherapy
constituents
altered
each
2 weeks
from
tive roles
the
___
Phosphorus (mg./d.) Mean -t S.D. (#)
0 0
was
Calcium (mg./d.) Mean -+: S.D. (#)
with
of compound (table
S ( 11-desoxycortisol)
follotcjing SU 4885 (hletopirone) desiccated
responsiveness,
metabolites
did
4).
thyroid
judging
from
did
not
or Exo,oenow enhance
the results
nor
ACTH
reduce
of intravenous
pituitary
mepyrapone
739
DAiYOWSKI,
Table
RODNAN,
SARVER
AND
MOSES
4.-Eflects of Large Dosages of Desiccated Thyroid on the Urinary Excretion (mg./d.) of l?-Ketosteroids, Porter-Silber Chromogens, and 11-Desoxycortisol (Compound S) Metabolites Dosage (grains)
Week of Therapy
17-Ketosteroids Mean k S.D. (#)
Porter-Silber Chromogens Mean k S.D. (#)
Compound Mean k S.D.
S (#)
II
0
10.7 e
4.3
(8)
4.8 k 2.2
(8)
0.37 5 0.2
(8)
0
0
11.8 4
3.6
(8)
5.2 r+ 1.9
(8)
0.34 f
0.2
(8)
0
”
6.4 f
(7)
0.48 +- 0.3
(1)
0
10.3 t 3.2 10.1 2 3.2
(7)
0
(10)
0.29 k 0.4
(10)
0.64 t
(7)
7th
20
9.4 rtr 5.2
(19)
9th
26
10.5 k 3.5
(10)
10th
25
10.2 t
(10)
11th
25
10.0 -c 3.4
(8)
14th
0
12.6 f
3.3
(6)
15th
0
11.2 i
3.3
(6)
9.2 k 3.9 --___~__~
(6)
0
17th ______~ *p < 0.01.
6.9
2.7
6.6 zk 5.4 10.6 2
3.6*
0.4
(9) (10)
Table 5.-Comparable
Urinary 17-Ketosteroid, Porter-Silber Chromogen, 11-Desoxycortisol (Compound S Metabolites) Responses to lntravenous Mepyrapone Prior to and during Large Dosage Thyroid Therapy ~--_ .____ 17-Ketosteroids (mg./d.) MeaIl (#I ______
Porter-Silber Chromogens (mg./d.) MeaIl (#)
and
Compound S (mg./d.) Meall (#)
Before Thyroid Therapy Pre-SU
4885
Day of SU 4885
11.4
(7) (7)
5.5 14.7
(6) (7)
0.5
15.8
4.6
(6) (7)
11.3 14.8 11.5
(7) (7) (7)
9.8 15.1 10.8
(7) (7) (7)
0.6 5.7 1.0
(7) (7) (7)
During Thyroid Therapy” Pre-SU
4885
Day of SU 4885 Day after SU 4885
____ ‘During
the fourth week of treatment
grains 3, 10, 15 and 20 per day during dosages.
with 25 grains per day preceded successive
periods
of 2 weeks
by therapy on each
with
of these
tests (11-desoxycortisol metabolites and Porter-Silber chromogens as indices) in the 7 subjects tested before and during the administration of this hormone (table 5). The slight 17-ketosteroid change is in keeping with one of the patterns seen during intravenous mepyrapone tests and has no significance as an index of pituitary-adrenal responsiveness. The responses to exogenous ACTH may have been changed by desiccated thyroid therapy. During the treatment period exogenous ACTH produced comparable increases in urinary Porter-Silber chromogens but the 17-ketosteroid and ll-desoxycortisol metabolite responses were less (table 6). It should be pointed out, however, that the comparisons in table 6 are based on control studies conducted in another group of prisoners and may not be valid. Urinary
Gonadotropin
and
Hydroxyproline
Excretion
Gonadotropin excretion in urine decreased during thyroid feeding (fig. 1). Urinary hydroxyproline levels (total and free) increased during thyroid administration in all of the men on whom observations are available (table 7).
Table 6.-Decrease during Large Dosage Thyroid Therapy in the Usual Urinary 17-Ketosteroid Response (mg./d.) to Exogenous ACTH (200 units S.C. per day for 4 days) Pwter-Silber (mean
17-Ketosteroids (mean (f) ) AC’TH
Thyroid
NolIe
:j days
4 days
Non.2
3 days
4 days
.57.:!
52.1
7.4
32.6
27.1
0.4
4.4
4.4
1X0)
(2!J)
(29,
(45)
(X)
(17)
(6)
(4)
(4)
11.2
1X.B
25.0
9.8
33.1
:i.i.4
0.6
1.9
1.x
(7)
(7)
(71
(7)
(7)
17)
(7)
(7)
(7)
3 days
Its+
grou,~
“Prisoners
other
iDuring 3. 10,
4 days
12.3
NOIF2
nx
i’,,ntr<,ls”
than
fourth
15 and
The
20
those
week per
of
day
increase
dosages
participating
25 for
grains
of
2 weeks
in the
of desiccated
daily
intake
that such increased
of water,
The
solute
increase
dosages
load,
filtration
and
other
most attractive and decrease tration.
renal
data
in
succession.
from
therapy
by
during
mains
points
Also,
one ma) of water
as a result
administration
levels,
amine activity
that
variables
clearance,
of large
of glomerular
hyperthyroidism.lH,ll
is the increase which
the observed
demonstrable
glomerular
in blood
clinical
of
is lacking.
is in line with the enhancement during
large by an
losses
or in urine the
with
accompanied
increased
on these
clearances
albumin
a role by altering
during
are not available.
for this change
pressor
ceding
of urine
of hypermetaholism
It may well he, however,
role in the decrease
preceded,
1) was presumably stemmed
function
explanation
of the rise in creatinine
study.
immediately
hut informaticn
medullary
in plasma favor
increase
The volume
glomerular in the
fil-
adreno-
in the urine of these suhpectsTa
filtration.
irrespective
such increases
NPN and serum
may have
of the origins in turn played
uric acid described
a
in the pre-
report.‘”
The increased creatine
urinary
observed
of pre-existent
of animals
ale.“;‘-” One might evident
it is possible
there
reason
ness and myopathy
during
rise. in the plasma
creatinuria
in part the rises in serum with
can develop
observed to store in clinical
hand grip strength creatine
hormone
in growing
and urinarv
was
excretion
creatinuria
children
that in experimental creatine
phosphate to the muscle
thyrotosicosis@
in our studie+
phosphokinase
excesses
the
males and the aggravation
that this is in some way related
the lowered levels
reflects
et al. suggest
is an inability
which
thyroid
2)
thyrotoxic
of Dinning
as decreased
that
(tzhle
patients.- I” It is in keeping
in spontaneously
in women.2n-i The studies toxicosis
creatine
in these
may develop
thyrotoxicosis
subjects
thirst
thyroid
in plasma
therapy
day
hut intake
also plays
became
(table
in creatinine
of desiccated
per
volumes
skin as a consequence
an increased
thyroid
Proloid
thyroid
increased through
in
each.
speculate
which
11-Desosyeortisol Metabolites (mean (#) )
Chromogens (#) )
activity
in part of creatine.
by and
thyroin musx\reak-
and which Alternatively, noted
responsible
in our for
the
734
DANOWSKI,
0-4
CBDBWB-
l emo
0000
l eoo
0.40 0000 0000 0000 ..+o 0 00 0000
l
RI-IRM-
oooo l ooo
KMJM-
l eoeoo
l..+
000 l @*@O
JMi-
0000 0000
l
0000
0000
OeOO
OSDTm
‘.OOO
0.04
GWKTCBr-
0.00 0000
0000 0000
moo0 0000
0000
0004 0.40 0000
-44 0000
000 0.00 0.00 0000
0000
0000
0000
0.00
0.00
0000 0000 0000
0000 0.0.
P20
P25
lO/l7-18
lo/w-17
0000
0000
0000
. ..*+ ..o..O ..q
0000 0000
0000
0000
m.@
0000 0000 0000
0.40
RS- soeooo 0.4. RSc-
a.04 0.00 0000 0000 0000
..+0
0.00 oo l oooee
WPSBGC-
SARVER AND MOSES
0000 0000 0.00 0000 0000
4.40
DBi- 0000
RODNAN,
11127
12112
.3/b-7
0000
0000
00.0
0000
P25
P25
3113-14 3120-21
3127-28
Fig. l.- Decrease in urinary gonadotropins during therapy with desiccated thyroid in large dosages. The frequency of positive assays for urinary gonadotropins and the amount of gonadotropins present decreased during ingestion of Proloid in increasing dosages. Solid circles indicate uterine and ovarian hyperemia and weight increase in both mice at the particular dilution of urine protein indicated, i.e., 1:3.3, 6.6, 13, etc. Open circles with vertical bar indicates that a positive response was obtained in only 1 of the 2 mice at the dilution indicated. Open circles indicate no response in both mice.
Urine Calcium and Phosphorus; The during (table lacking.
origins the 3)
of the
ingestion cannot
Published
trend
Tubular Reabsorption
to increases
of thyroid
be identified balance
in urine
hormones because
data
are
calcium
in excess
as already compatible
of Phosphorus
indicated with
and
phosphorus
of replacement intake
an increased
needs data
are
calcium
THYROID
HORMONE
ON
URINARY
Table 7.-Urinary Administration
SOLUTES
735
STEROIDS
Hydroxyproline Excretion of Desiccated Thyroid OH-Proline
Before
AND
Prior to and during
the
in Large Dosages
(mg./d.) During
Rx
Rx*
Creatinine
Total
Fvee
Total
Frcr
18.8 22.5 38.3
0.8 0.X 1.*5
77.4 93.8 36.3
2.4 2.1 0.8
.96 1.27 1.83
1.30 1.28 ,92
18.”
1.1
80.7 117.2
1.7 2.5
1.06
1.03 1.39
IL ;\I. J. XI. R. S. C. Br.
‘IIllring trwtmcnt with 25 grains of desiccated 8 weeks of continuous thyroid therapy, i.e.. grains day for 2 weeks each.
thyroid. 3, and
Rx
During
Subject c.
Ba.
Before
(a./cl.)
This tlosagt> was prrcetld then IO, 15 and 20 grains
Rx-i
1,~. pm
and phosphcrus loss from exogenous and endogenous sources. increased fecal representing largely skeletal and urinary excretion, and negative balance, losses, of these two elements. The constancy of the tubular reabsorption of phosphorus suggests that parathyroid activity and effects were not altered ‘by the large dosages of thvroid. C7rincmy 17-Kctosteroitls, Jlctaho1itc.s
Pffrter-Silber
Chromogens
anrf
11 -De.roxrpr-tisol
It has been concluded on the basis of hydrocortisone degradation estimates that in clinical thyrotoxicosis there is an increased demand for this steroid. This is almost always met by an adequate increase in the secretion of hydrocortisone, though occasionally adrenocortical insuf&iencv and a crisis ma\’ resu1t.l’~~ Our data are consonant with this hvpothesis in that the urinarv (Yi cretion of Porter-Silber chromogens increased twofold during thyroid ‘therap\’ ( table 3 ). ~lrinnrrl Steroids
after
Mep~yqmne
or ACTH
Injection
The constancy of the 11-desoxycortisol metabolite and Porter-Silber chromogen responses to intravenous mepyrapone (table 5) prior to and during thvroid administration establishes that pituitary-adren:ll function was not aliercd by excesses of those hormones. Our data, which show only the usual increase in urinarv Porter-Silher chromogen excretion after exogenous ACTH (table 6), are not in keeping with the general hypothesis that adrenocortical activity may be increased in clinical thvrotoxicosis. It could be that the absence of such increases in ollr stlldies are attributable to the exog;enous source of the thyroid excess or to c the short period of treatment and the relatively small dosages of thyroid used. The decreased urinary 17-ketosteroid excretion after exogenous ACTS in our treated sllbjects (table 6) suggests that steroidogenesis or metabolic and txretorv processes productive of urinarv 17-ketosteroids are altered b\, illt111ced clxcesses of thvroid hormones,
736
DANOWSKI,
Urinary Gonudotropins The
decrease
diminished available The
rise in total
with findings of collagen
levels
of urinary
secretion
on the libido
SARVER
AND MOSES
and Hydroxyproline
in the
pituitary
RODNAN,
or sexual
and free
activity
urinary
in spontaneous
gonadotropins
or increased
during
from connective
tissues
thyroid
hydroxyproline
thyrotoxicosis5B~b
(fig.
metabolism.
1)
No
may
reflect
information
is
feeding.
(table
7)
and presumably
is in keeping reflects
release
and bone.
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Corcoran,
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738
DANOWSKI,
cortisone
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physiologic dosage. XIV. thyroid hormone excesses activity and epinephrine Metabolism 7h.
13:747,
thyroid
in
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1964.
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8c. -,
8b.
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and -:
AND MOSES
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1232, 1960. 9a. Dcnowski, T. S., Sarver, M., and Bonessi, J. V.: Skeletal muscles and endocrine
status.
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123473,
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excesses on lipids and serum solutes.
Proc.
-,
SARVER
l-C14 by vitamin E-deficient and hyperthyroid rats. Am. J. Physiol. 198:
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RODNAN,
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of
Gerald P. Rodnun, M.D., Associate Professor of Medicine, University of Pittsburgh Scho,ol of Medicine, Pittsburgh, Pa. Margaret E. Sarver, M.D., Fellow in Diabetes, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Campbell Moses, M.D., Associate Professor of Medicine, Ulziversity of Pittsburgh School of Medicine, Pittsburgh, Pa.
Effects of Thyroid Hormone Excesses on Urinary Solutes and Steroids C. MOSES
Bq T. S. DANOWSKI, G. P. RODNAN, M. E. SARVER AND
17-ketosteroids remained constant. The comparable responses to mepyrapone (Metopirone or SU 4885) prior to and during thyroid administration indicate that pituitary-adrenal responsiveness had not been altered by this therapy. The decrease in the urinary 17-ketosteroid and perhaps the compound S responses to exogenous ACTH in our studies indicates that the secretion, conversion, or excretion of these classes of steroids is altered by induced excesses of thyroid The urinary Porter-Silher hormone. chromogen response to exogenous ACTH was not altered. Urinary gonadotropins decreased during treatment with large dosages of thyroid hormone. Total and free hydroxyproline excretion in urine increased during administration of desiccated thyroid in large dosages.
The administration of a preparation of desiccated thyroid in 20 or 25 grain dosages to healthy adult male prisoners was associated with increases in the mean daily urine volume, mean daily creatinine clearance and, sporadically, with an appearance or accentuation of creatinuria. Urine calcium and phosphorus excretion also appeared to increase but the changes were not statistically significant. The origins of the trends to hypercalciuria and hyperphosphaturia cannot be identified because balance data are lacking, but presumably variables such as the increased intake of food and the loss of skeletal calcium and phosphorus which characterize thyrotoxicosis were operative. The tubular reabsorption of filtered phosphorus remained constant. The daily excretion of urinary PorterSilber chromogens increased, while the MONG
A
OTHER
human
mav develop
AND URINARY glomerular
if already
rate
in thyrotoxicosis
increases,lR*”
present,sa-i the urinary the metabolism
excretion and
steroids is often alteredJa-V and the output
increases.5a, 1’ Onr findings
thyroid
(Proloid)
keeping
with these findings,
in large
dosages
during
ing that the urinary
steroid
(Metopirone
responses
of Endocrinology
the
for a limited
In addition,
venous mepyrapone ._ _______ From. the Section
CH,4NGES
filtration
rises,.?“-” the secretion,
of adrenal
in lirinr
the
or increase
and phosphorrls cretion
RENAL
subjects
in
creatinuria of calcium
the urinary
ex-
of hydroxyproline
administration
of desiccated
period
are largely
evidence
of time
has been
to exogenous
ACTH
obtained but
cr SU 4885)
may be altered
and Metabolism
and the Section
in
indicat-
not to intraby these
large
of Rheumatology
of the Departmcvlt of Medicine. the Addkon H. Gibson Laboratory, Unicersity of Pittsburgh, c11lt1tht, ,\letlicul Center und Shadyside Hospitah, Pittsburgh, Penn&xmia. Aided by grunts from the John A. Hartford Foundation, Inc., the Western Pennsyhati Chapter of tllc iL\rtlwitisand Rheumatism Foundation, the Muscular Dystrophy Assocbtions of dmericw Inc., the Medical Research Fourukrtion of Pennsylcania, Inc., tk ~~,nl~r,o,lccrclltlt of Pewwylcunk. the Deportment of ffenlth. Education nnd Welfare. unc( U,‘clrfler-Larr!bert L&oratories. Rwcirwl
for 7~uOlication Feb.
14. 7964.
h[ETABOLISM,
\'OL. 13, NO. 8 (AUGUST),
1964
730
DANOWSKI,
Table I.-Efects
of Large
Dosages of Desiccated Thyroid Creatinine, and Creatinine Clearance ~~__
__-______ Week of
Urine Volume (ml/d.)
Dosage
Therapy
(grains)
0
0
0 0 7th
RODNAN,
Mean
& S.D.
830 *
SARVER AND MOSES
on Urine Volume,
Urine Creatinine (mg./d.) Mean i S.D.
(#)
Creatinine Clearance (ml./min.) Mean 2 S.D.
(#)
(#)
241
(8)
1460 2 445.1
(3)
0
1008 2 311
(8)
1513 % 423.7
(8)
106.3 I
32.07
0
1107 ZL 720
(7)
1285 *
357.7
(7)
32.3 ?
19.68
(7)
20t
1245 & 763
(10)
1027 t
489.0
(10)
80.7 ?
52.37
(10)
127.4 f
62.15
91.7 5 28.97
(8) (8)
9th
25
1511 r!~ 528***
(10)
1363 *
464.5
(5)
10th
25
1680 % 752***
(10)
1440 2 625.0
(10)
11th
25
1455 f
470***
(8)
1596 -t 365.2
(5)
151.x 2 52.37*
(5)
13th
0
1267 2
382*
(6)
1691 ?
221.4
(6)
152.1 i
31.31***
(6)
14th
0
1448 ?I 423’**
(6)
1851 *
426.6
(5)
126.2 i
38.11
(5)
15th
0
1232 % 319**
(6)
1512 t
408.5
(6)
105.3 ?
28.57
17th
0
llfiO?
(6)
Difference
from
pretherapy
546’ values
~___.
statistically
significant:
*p
by 2 weeks
therapy
for
period
dosages such
each
2 weeks
(weeks
I3
of thyroid
a regimen
on grains
3,
(weeks
7 and
through
17).
hormones
urinary
10 and
8):
25 per
administered
gonadotropins MATERIALS
Twenty-four
15 per
grains
hour specimens
of urine
(6)
__..
..-.
.02-.Ol.
***p tpreeeded
_~_
(10)
.O5&.02.
**p
was continued
(5)
117.4 I75.01
.Ol-<.OOl.
day
(weeks
day
for
1 through
4 weeks
for brief
6);
(weeks
periods,
grains
20 per
day
9 through
12):
Post-
and that
under
may decrease. AND
METHODS
were collected
with refrigeration
prior
to, during
and after the administration of desiccated thyroid (Proloid: Lots 2827072A, 156905A and 459312) in daily dosages increasing up to 25 grains. The volumes of the specimens were measured
and aliquots were analyzed or assayed for creatinine, creatine, calcium, phos17-ketosteroids, Porter-Silber chromogens, 11-desoxycortisol ( compound S) phorus, metaholites, pressor activity, gonadotropins and hydrosyproline by methods in use in this and in other laboratories. err Also, the effects of such excesses of thyroid hormone on the urinary
steroid
intravenous
responses
to subcutaneous
mepyrapone,
ACTH,
200
units
36 mg. per Kg. of body weight,
per day for 4 days,
were
and to
examined.
RESULTS
Urine Volz~me, Creatinine The
%&hour
desiccated
also increased (table
1).
urine
thyroid
Creatinuria
urinary
present
neither effect
clearly
during
upon urinary
with
not
associated
with
therapy
during 1).
The
the daily
ingestion
creatinine
of
clearance
desiccated
did not increase. equal
but it was almost
the treatment period ( SU 4885 ) nor ACTH creatine
with
of creatinine
approximately
frequency always
prior
to
and
more pronounced
(table 2). It is to be noted that administration had anv consistent
excretion.
Uritbe Calcium and Phosphorus; ‘- Treatment
(table
to 151.7 from a base line level of 91.7 ml. per minute
thyroid
mepyrapcne
increased
dosage
excretion
occurred
duringdesiccated when
volumes
in 25 grain
strikingly
The
and Creatine
Tubular
thyroid
statistically
Reabsorption
of Phosphorus
in 20 to 25 grain per day dosages significant changes in urine calcium
was and
though a trend to increases was recorded (table 3). phosphorus excretion, None of these differences was statistically significant. Since the intake of
THYROID
HORhIONE
ON
URINARY
Pretherapy Week2
C. Ba. w.
B.
0
0
12
68
731
STEROIDS
Prior to, during,
25 grains/d.*
~_____ Week
Week1
2
Week
3
Post-Therapy
SU-4885t
213
32
311
0
0
45
I,
C. Br. G. c.
AND
of Creatine in Urine (mg./d) and after Thyroid Therapy ~ .-.___
Table 2.-Excretion
Subject
SOLUTES
Week1
ACTHZ 36
6
0
40
90
0
50
Week2 ~.__
Week
0
0
43
0
16
0
107 0
56 12
88 125
0 0
0
0
43
0
0
J. M.
0
16
0
0
44
86
8
0
Y
Ii. s.
0
18
0
0
0
0
0
0
R. H. K. Mc.
*During
2nd
and
3rd
I)
weeks
then
3 __
0
of
25
20 per
grains
day
for
of
thyroid
grains
3, 10,
15 and
tall
values
in
this
column
obtained
on
2 weeks day
iAll
values
in
this
column
obtained
on
fourth
per
day
immediately
by,
preceded
in
0 succession.
each.
of
intravenous day
of
SU-4885
ACTH
test.
stimulation
test.
‘I‘able 3.-Urinary Calcium and Phosphorus Excretion and Tubular Reabsorption of Phosphorus Prior to, during and after Desiccated Thyroid Therapy in Large Dosages Urine Week of Therapy
Dosage (grains)
_~~_
Tubular Reabsorption of Phosphorus (‘A.) Mean 5 S.D. (#)
0
176 i
98
(8)
774 t
203
(9)
84.1 f
3.0
18)
0
I,
164 1+ 75
(i)
144 t- 265
(9)
88.0 f
3.3t
(8)
fi74 -c 91
I)
7th
20*
104
17)
194 & 148
182 ?
(IO)
(R)
83.4 5
3.2
(7)
683 2
395
110)
81.2 2
8.0
(10)
9th
“5
261 I+ 112
(19)
885 ‘-
333
110)
86.8 t- 4.9
(5)
10th
25
272 ?
203
(10)
801 & 325
(9)
84.7 % 4.3
(10)
1lth
“5
212 -+r 202
(i)
912 t
432
(8)
82.6 2
5.6
(3)
13th
0
155 ?
63
(6)
947 2
310
(6)
90.2 ?
2.6t
(5)
14th
0
231 i
169
(6)
860 f
497
(6)
X6.9 2
3.1
(5)
15th
0
215 t- 68
(5)
975 t- 181
(6)
82.5 i- 5.2
(6)
17th
0
141 *
(5)
655 ?z 202
(6)
*Preceded
by
continued
therapy
2 weeks for
period
tDiffewnce
these
(weeks
The
during
tubular
25 per
day
(weeks
day
for
1 through
4 weeks
6);
(weeks
grains
20 per
9 through
121;
day post-
is statistically
significant
intake,
p .05&.02.
it is not possible
endogenous
release,
etc.
to assess the rela-
in the trends
to hvper-
reabsorption
urinary
of filtered
of desiccated Porter-Silber excretion
of
phosphate thyroid
(per
in large
Chrom.ogrrzs 17-ketosteroids
and
cent
TRP)
dosages Compound
remained
was
(table
not
3 ).
S
quite
constant
the ingestion
of 20 to 25 grains of desiccated thyroid (table 4). On as much as twofold increases in Porter-Silber chromogens
hand, during
urinary
not change
the same period. excretion
consistently
Stcroi&
Thcrapv adrenal
15 per
grains
could not be estimated,
I;-Kctosteroids, meau
other
Urirwrrl
8);
17).
value
hv the ingestion
occurred The
3, 10 and
7 and
_.__~.
and hyperphosphaturia.
ZTriwrrl The
54
grains
13 through
of dietary
calciuria
on
(weeks
pretherapy
constituents
altered
each
2 weeks
from
tive roles
the
___
Phosphorus (mg./d.) Mean -t S.D. (#)
0 0
was
Calcium (mg./d.) Mean -+: S.D. (#)
with
of compound (table
S ( 11-desoxycortisol)
follotcjing SU 4885 (hletopirone) desiccated
responsiveness,
metabolites
did
4).
thyroid
judging
from
did
not
or Exo,oenow enhance
the results
nor
ACTH
reduce
of intravenous
pituitary
mepyrapone
739
DAiYOWSKI,
Table
RODNAN,
SARVER
AND
MOSES
4.-Eflects of Large Dosages of Desiccated Thyroid on the Urinary Excretion (mg./d.) of l?-Ketosteroids, Porter-Silber Chromogens, and 11-Desoxycortisol (Compound S) Metabolites Dosage (grains)
Week of Therapy
17-Ketosteroids Mean k S.D. (#)
Porter-Silber Chromogens Mean k S.D. (#)
Compound Mean k S.D.
S (#)
II
0
10.7 e
4.3
(8)
4.8 k 2.2
(8)
0.37 5 0.2
(8)
0
0
11.8 4
3.6
(8)
5.2 r+ 1.9
(8)
0.34 f
0.2
(8)
0
”
6.4 f
(7)
0.48 +- 0.3
(1)
0
10.3 t 3.2 10.1 2 3.2
(7)
0
(10)
0.29 k 0.4
(10)
0.64 t
(7)
7th
20
9.4 rtr 5.2
(19)
9th
26
10.5 k 3.5
(10)
10th
25
10.2 t
(10)
11th
25
10.0 -c 3.4
(8)
14th
0
12.6 f
3.3
(6)
15th
0
11.2 i
3.3
(6)
9.2 k 3.9 --___~__~
(6)
0
17th ______~ *p < 0.01.
6.9
2.7
6.6 zk 5.4 10.6 2
3.6*
0.4
(9) (10)
Table 5.-Comparable
Urinary 17-Ketosteroid, Porter-Silber Chromogen, 11-Desoxycortisol (Compound S Metabolites) Responses to lntravenous Mepyrapone Prior to and during Large Dosage Thyroid Therapy ~--_ .____ 17-Ketosteroids (mg./d.) MeaIl (#I ______
Porter-Silber Chromogens (mg./d.) MeaIl (#)
and
Compound S (mg./d.) Meall (#)
Before Thyroid Therapy Pre-SU
4885
Day of SU 4885
11.4
(7) (7)
5.5 14.7
(6) (7)
0.5
15.8
4.6
(6) (7)
11.3 14.8 11.5
(7) (7) (7)
9.8 15.1 10.8
(7) (7) (7)
0.6 5.7 1.0
(7) (7) (7)
During Thyroid Therapy” Pre-SU
4885
Day of SU 4885 Day after SU 4885
____ ‘During
the fourth week of treatment
grains 3, 10, 15 and 20 per day during dosages.
with 25 grains per day preceded successive
periods
of 2 weeks
by therapy on each
with
of these
tests (11-desoxycortisol metabolites and Porter-Silber chromogens as indices) in the 7 subjects tested before and during the administration of this hormone (table 5). The slight 17-ketosteroid change is in keeping with one of the patterns seen during intravenous mepyrapone tests and has no significance as an index of pituitary-adrenal responsiveness. The responses to exogenous ACTH may have been changed by desiccated thyroid therapy. During the treatment period exogenous ACTH produced comparable increases in urinary Porter-Silber chromogens but the 17-ketosteroid and ll-desoxycortisol metabolite responses were less (table 6). It should be pointed out, however, that the comparisons in table 6 are based on control studies conducted in another group of prisoners and may not be valid. Urinary
Gonadotropin
and
Hydroxyproline
Excretion
Gonadotropin excretion in urine decreased during thyroid feeding (fig. 1). Urinary hydroxyproline levels (total and free) increased during thyroid administration in all of the men on whom observations are available (table 7).
Table 6.-Decrease during Large Dosage Thyroid Therapy in the Usual Urinary 17-Ketosteroid Response (mg./d.) to Exogenous ACTH (200 units S.C. per day for 4 days) Pwter-Silber (mean
17-Ketosteroids (mean (f) ) AC’TH
Thyroid
NolIe
:j days
4 days
Non.2
3 days
4 days
.57.:!
52.1
7.4
32.6
27.1
0.4
4.4
4.4
1X0)
(2!J)
(29,
(45)
(X)
(17)
(6)
(4)
(4)
11.2
1X.B
25.0
9.8
33.1
:i.i.4
0.6
1.9
1.x
(7)
(7)
(71
(7)
(7)
17)
(7)
(7)
(7)
3 days
Its+
grou,~
“Prisoners
other
iDuring 3. 10,
4 days
12.3
NOIF2
nx
i’,,ntr<,ls”
than
fourth
15 and
The
20
those
week per
of
day
increase
dosages
participating
25 for
grains
of
2 weeks
in the
of desiccated
daily
intake
that such increased
of water,
The
solute
increase
dosages
load,
filtration
and
other
most attractive and decrease tration.
renal
data
in
succession.
from
therapy
by
during
mains
points
Also,
one ma) of water
as a result
administration
levels,
amine activity
that
variables
clearance,
of large
of glomerular
hyperthyroidism.lH,ll
is the increase which
the observed
demonstrable
glomerular
in blood
clinical
of
is lacking.
is in line with the enhancement during
large by an
losses
or in urine the
with
accompanied
increased
on these
clearances
albumin
a role by altering
during
are not available.
for this change
pressor
ceding
of urine
of hypermetaholism
It may well he, however,
role in the decrease
preceded,
1) was presumably stemmed
function
explanation
of the rise in creatinine
study.
immediately
hut informaticn
medullary
in plasma favor
increase
The volume
glomerular in the
fil-
adreno-
in the urine of these suhpectsTa
filtration.
irrespective
such increases
NPN and serum
may have
of the origins in turn played
uric acid described
a
in the pre-
report.‘”
The increased creatine
urinary
observed
of pre-existent
of animals
ale.“;‘-” One might evident
it is possible
there
reason
ness and myopathy
during
rise. in the plasma
creatinuria
in part the rises in serum with
can develop
observed to store in clinical
hand grip strength creatine
hormone
in growing
and urinarv
was
excretion
creatinuria
children
that in experimental creatine
phosphate to the muscle
thyrotosicosis@
in our studie+
phosphokinase
excesses
the
males and the aggravation
that this is in some way related
the lowered levels
reflects
et al. suggest
is an inability
which
thyroid
2)
thyrotoxic
of Dinning
as decreased
that
(tzhle
patients.- I” It is in keeping
in spontaneously
in women.2n-i The studies toxicosis
creatine
in these
may develop
thyrotoxicosis
subjects
thirst
thyroid
in plasma
therapy
day
hut intake
also plays
became
(table
in creatinine
of desiccated
per
volumes
skin as a consequence
an increased
thyroid
Proloid
thyroid
increased through
in
each.
speculate
which
11-Desosyeortisol Metabolites (mean (#) )
Chromogens (#) )
activity
in part of creatine.
by and
thyroin musx\reak-
and which Alternatively, noted
responsible
in our for
the
734
DANOWSKI,
0-4
CBDBWB-
l emo
0000
l eoo
0.40 0000 0000 0000 ..+o 0 00 0000
l
RI-IRM-
oooo l ooo
KMJM-
l eoeoo
l..+
000 l @*@O
JMi-
0000 0000
l
0000
0000
OeOO
OSDTm
‘.OOO
0.04
GWKTCBr-
0.00 0000
0000 0000
moo0 0000
0000
0004 0.40 0000
-44 0000
000 0.00 0.00 0000
0000
0000
0000
0.00
0.00
0000 0000 0000
0000 0.0.
P20
P25
lO/l7-18
lo/w-17
0000
0000
0000
. ..*+ ..o..O ..q
0000 0000
0000
0000
m.@
0000 0000 0000
0.40
RS- soeooo 0.4. RSc-
a.04 0.00 0000 0000 0000
..+0
0.00 oo l oooee
WPSBGC-
SARVER AND MOSES
0000 0000 0.00 0000 0000
4.40
DBi- 0000
RODNAN,
11127
12112
.3/b-7
0000
0000
00.0
0000
P25
P25
3113-14 3120-21
3127-28
Fig. l.- Decrease in urinary gonadotropins during therapy with desiccated thyroid in large dosages. The frequency of positive assays for urinary gonadotropins and the amount of gonadotropins present decreased during ingestion of Proloid in increasing dosages. Solid circles indicate uterine and ovarian hyperemia and weight increase in both mice at the particular dilution of urine protein indicated, i.e., 1:3.3, 6.6, 13, etc. Open circles with vertical bar indicates that a positive response was obtained in only 1 of the 2 mice at the dilution indicated. Open circles indicate no response in both mice.
Urine Calcium and Phosphorus; The during (table lacking.
origins the 3)
of the
ingestion cannot
Published
trend
Tubular Reabsorption
to increases
of thyroid
be identified balance
in urine
hormones because
data
are
calcium
in excess
as already compatible
of Phosphorus
indicated with
and
phosphorus
of replacement intake
an increased
needs data
are
calcium
THYROID
HORMONE
ON
URINARY
Table 7.-Urinary Administration
SOLUTES
735
STEROIDS
Hydroxyproline Excretion of Desiccated Thyroid OH-Proline
Before
AND
Prior to and during
the
in Large Dosages
(mg./d.) During
Rx
Rx*
Creatinine
Total
Fvee
Total
Frcr
18.8 22.5 38.3
0.8 0.X 1.*5
77.4 93.8 36.3
2.4 2.1 0.8
.96 1.27 1.83
1.30 1.28 ,92
18.”
1.1
80.7 117.2
1.7 2.5
1.06
1.03 1.39
IL ;\I. J. XI. R. S. C. Br.
‘IIllring trwtmcnt with 25 grains of desiccated 8 weeks of continuous thyroid therapy, i.e.. grains day for 2 weeks each.
thyroid. 3, and
Rx
During
Subject c.
Ba.
Before
(a./cl.)
This tlosagt> was prrcetld then IO, 15 and 20 grains
Rx-i
1,~. pm
and phosphcrus loss from exogenous and endogenous sources. increased fecal representing largely skeletal and urinary excretion, and negative balance, losses, of these two elements. The constancy of the tubular reabsorption of phosphorus suggests that parathyroid activity and effects were not altered ‘by the large dosages of thvroid. C7rincmy 17-Kctosteroitls, Jlctaho1itc.s
Pffrter-Silber
Chromogens
anrf
11 -De.roxrpr-tisol
It has been concluded on the basis of hydrocortisone degradation estimates that in clinical thyrotoxicosis there is an increased demand for this steroid. This is almost always met by an adequate increase in the secretion of hydrocortisone, though occasionally adrenocortical insuf&iencv and a crisis ma\’ resu1t.l’~~ Our data are consonant with this hvpothesis in that the urinarv (Yi cretion of Porter-Silber chromogens increased twofold during thyroid ‘therap\’ ( table 3 ). ~lrinnrrl Steroids
after
Mep~yqmne
or ACTH
Injection
The constancy of the 11-desoxycortisol metabolite and Porter-Silber chromogen responses to intravenous mepyrapone (table 5) prior to and during thvroid administration establishes that pituitary-adren:ll function was not aliercd by excesses of those hormones. Our data, which show only the usual increase in urinarv Porter-Silher chromogen excretion after exogenous ACTH (table 6), are not in keeping with the general hypothesis that adrenocortical activity may be increased in clinical thvrotoxicosis. It could be that the absence of such increases in ollr stlldies are attributable to the exog;enous source of the thyroid excess or to c the short period of treatment and the relatively small dosages of thyroid used. The decreased urinary 17-ketosteroid excretion after exogenous ACTS in our treated sllbjects (table 6) suggests that steroidogenesis or metabolic and txretorv processes productive of urinarv 17-ketosteroids are altered b\, illt111ced clxcesses of thvroid hormones,
736
DANOWSKI,
Urinary Gonudotropins The
decrease
diminished available The
rise in total
with findings of collagen
levels
of urinary
secretion
on the libido
SARVER
AND MOSES
and Hydroxyproline
in the
pituitary
RODNAN,
or sexual
and free
activity
urinary
in spontaneous
gonadotropins
or increased
during
from connective
tissues
thyroid
hydroxyproline
thyrotoxicosis5B~b
(fig.
metabolism.
1)
No
may
reflect
information
is
feeding.
(table
7)
and presumably
is in keeping reflects
release
and bone.
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