From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
The
Effect
of Testosterone
in
By N.
D
and
influence
and
rodents.
also
used
stimulate
in the
by which
of
lower
been
that
to
The
therapy
on
shown
then,
to
stimulate
therapy
that
with
androgens
testosterone
has
the
been
mechanism
unknown.
erythropoietin
to
of
can
castrated3
However,
remains
increase
plasma
counts
hormones
prolonged
Since
data
blood
sex
indicating
anemia.68
erythropoiesis
shown
primates.9’10
androgen
of
red
been
eunuchs
in humans.
types
the
hypophysectomized,2
reported
of
W. FRr
AND
that
since
normal,
anemia
various
influence
has
and
effects
of
androgens
rodents
mild
in
possibility
have
to
erythropoiesis
therapy
Testosterone
the
McCullagh5
the
SIMONE
differences
suggested
administered
corrected
J.
KILBRIDGE,
Androgens
when
plethoric4
can
T.
has
Levels
Patients
of consistent
females
erythropoiesis.1
erythropoiesis
testosterone
Anemic
RISHPON-MEYERSTEIN,
OCUMENTATION
males
on Erythropoietin
be
production
reported
erythropoietin
here
levels
in
describe
in
five
the
anemic
patients.
METHODS
Five patients
with various
types of anemias
were studied.
ent clinical
data in these patients.
At the various
times indicated
was obtained
by venepunctrire
into a heparinized
syringe.
centrifugation
and
immediately
stored
at
-5
C.
for
Table
1 summarizes
the pertinin Figures
1-5, 10 ml. of blood
The plasma
was separated
by
erythropoietin
capillary
blood obtained
from a finger was used for determination
microcapihlary
tube method
and for determination
of the reticulocyte
The erythropoietin
content
of the plasma
was
measured
using
assay.
At
of the
hematocrit
the
same
time,
by
the
count.
the
polycythemic
mouse-
will be expressed
as
the percentage
Fe5#{176}
uptake
into newly formed
RBC’s after injection
of one-half
ml. of plasma
into assay mice. Assay of plasmas
from non-anemic
patients
consistently
resulted
in Fe59 uptakes
of less than
1 percent.
The values
depicted
in the Figures
represent
the average
of deassay
as
described
terminations
from
by
DeGowin
six
assay
et
al.11
The
plasma
erythropoietin
level
mice.
RESULTS
Studies
performed
on M.M.,
are described
in Figure
1. Prior
a 75 year
to receiving
old male
androgen
with
multiple
therapy,
his
From the Department
of Medicine,
VA West
Side Hospital
and
cine and Pediatrics,
University
of Illinois
College
of Medicine.
This research
was supported
by VA Research
Funds.
First submitted
August
14, 1967; accepted
for publication
October
the Department
myeloma,
hematocrit
of Medi-
15, 1967.
N. RISHPON-MEYERSTEIN,
M.D.:
Resident
in Hematology,
VA West
Side Hospital,
Chicago, illinois.
On leave from Kupat-Holim,
(General
Sick Fund),
Israel.
T. KILBRIDCE,
M.D.:
Staff Physician,
VA West Side Hospital,
Chicago,
Illinois
and Instructor
in Medicine,
University of Illinois
College
of Medicine.
J. SIMONE,
M.D.:
Formerly
Instructor
in Pediatrics,
University
of Illinois
College
of Medicine.
Present
Address:
Staff member
St. Jude Childrens
Research
Hospital
and Assistant
Professor
of Pediatrics,
University
of Tennessee,
Memphis.
\V. FRIED,
M.D.:
Chief,
Hematology
Section,
Department
of Medicine,
VA West
Side
Hospital,
Chicago,
Illinois
and Assistant
Professor
Department
of Medicine,
University
of
Illinois
College
of Medicine.
BLoon,
VOL.
31,
No.
4 (AIiuL),
1968
453
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454
ET
RISHPON-MEYERSTEIN
Table
Patients
M. N.
L. H.
1.-Clinical
Age
Sex
Weight
75
39
M
M
58 kgm.
55 kgm.
Data
on Patients
Diagnosis
Miscellaneous
Multiple Myeloma
Multiple
Myeloma
Chronic
BUN
K. K.
3
F
10 kgm.
D. N.
7
M
16 kgm.
D. L.
7
M
Aplastic
20 kgm.
Renal
40
Disease
percent
mgm.
Creatinine
2.3 mgm.
percent
Secondary
to
choramphenicol
toxicity
Anemia
Idiopathic
Normochromic
Idiopathic
Mental
Norrnocytic
Anemia
Normochromic
Anemia
Retardation
Idiopathic
Mental
Idiopathic
Normocytic
AL.
Retardation
T/t\NUAL
16
4
ula
I-.
<to
0LLJ3.
I..
U
W CtKS
ZOOrnqi.rn.b.s.w.
Fig.
bars
1.-Effects
represent
of testosterone
Fe5#{176}uptakes.
doses, unless otherwise
was
25 percent
and
continued
to
percent.
After
thropoietin
weeks,
be
assay
#{176}Delatestryl
plasma
while
discontinuing
hematocrit
connect
values
of patient
reticulocvte
M.
values.
M.
Black
The
drug
refer to daily doses.
of his
during
rose
content
the
hematologic
lines
IDE
for
erythropoietin
resulted
in 7 percent
patient
then began
to receive
injections
of testosterone
IM twice
weekly).
Eight
days
later,
assay
of his
percent
Fe3#{176}
uptake.
The plasma
erythropoietin
level
elevated
hematocrit
on
Broken
indicated,
Fe5#{176}
incorporation.
The
enanthate*
(200
mgm.
plasma
resulted
in 16.2
M.M.’s
CYCLHOSq!HAM
returned
slowly
he
was
androgen
the
to the
declined
receiving
therapy
testosterone
pretreatment
to 25 percent.
injections
to
a peak
of
level
injections,
level;
The
the
and
plasma
over
testosterone.
of
about
plasma
the
34
ery-
next
erythropoietin
12
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
TESTOSTERONE
ERYTHItOPOIETIN
AND
455
LEVELS
L.H.
!: 30
U
0
25
E
‘A
z
4
5
6
7
6
6
<I
I-
>-
U
D
#{149}
e
#{149}
r\
\
8
Li..
o.6
0
-a
D
,#{149}
U
-
-
I-.
tt
w
z
WEIKS
T(ST0STR0N
tOO mg
mq
‘00
RAD IATION
I
Fl ELP HALAN
L
2mg
11
PRE DNI50N
1
Fig.
mq
20
2.-Effects
represent
Fe5#{176}uptakes.
unless
otherwise
indicated,
given
t\vice weekly.
level
then
about
remained
7 percent.
of a short
weeks
Broken
refer
course
only
at
titer
the
erythropoietin
plasma
a level
form
resulting
had
the
already
(50
mgm.
level
an
L.H.
Fe59
M.M.
daily).
bars
doses,
was
of
incorporation
This
consisted
was
started
four
the
plasma
ery-
level.
subsequent
Black
drug
which
received
after
pretreatment
observed
was
for
injections,
to the
mqJJ
5
values.
The
testosterone,
which
testosterone
returned
t5
of patient
in
of therapy
of cyclophosphamide
thropoietin
values
lines
connect
reticulocyte
to daily
doses,
except
other
discontinuing
after
ZO
on hematologic
constant
The
mq
40
of testosterone
No
change
in
to cyclophosphamide
therapy.
2 describes
Figure
myeloma
and
erythropoietin
Three
twice
capable
of
then
plasma
Fe59
L.H.
6”
The
however,
rise
received
x
12”
the
over
for
a peak
plasma
a course
area
an
the
of
old
plasma
to
to
varied
value
a value
of
part
9
titer.
consisting
upper
thoracic
rose
of
weekly)
over
a
level
and
16
coincident
addition
of
to
testosterone
the
percent
25 percent
and the
2 and 6 percent.
The
percent
In
Testosterone
in
and
plasma
1 percent.
about
twice
21
multiple
his
dose
resulting
between
over
with
mgm.
The
between
most
x-irradiation
and
only
titer
6 percent.
propionate
further
the
of
(100
erythropoietin
over
male
androgens,
therapy
erythropoietin
cervical
year
receiving
Fe5#{176}incorporation
hematocrit
to
a 39
to
testosterone
rose
fluctuated
rose
of
mgm.
titer
count
maximal
uptake
(200
incorporation.
latter,
his
Fe59
increased
L.H.,
Prior
androgen
weekly),
erythropoietin
reticulocyte
in
beginning
increasing
on
disease.
resulted
after
Propionate
studies
renal
level
weeks
was
the
chronic
2500
spine.
to
with
the
testosterone,
r.
directed
He
also
to
received
a
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456
RISHPON-MEYERSTEIN
ET
AL.
K.K.
30
I-
ZO
0
I-
#{163}
Iii
x
Lii
II
WCEKS
mq
METHVLTEST0$TER0NE3O
PRDNIS0NE,
Fig. 3.-Effects
represent
Fe59
doses.
of testosterone
uptakes.
The drug
2 mgm.
of melphalan
doses
of prednisone
subsequently
were
began
to its
to rise
maximal
unlikely
that
daily
which
reduced
after
the
values
the
15
on hematologic
doses,
throughout
rose initially
to 5 mgm.
increase
as the
values
unless
of patient
otherwise
Black
refer
to
bars
daily
the period
of observation
and received
from
20 to 40 mgm.
daily
and which
daily.
The
plasma
erythropoietin
titer
in the dose of prednisone
dose
of prednisone
was
prednisone
K.K.
indicated,
influenced
the
but
reduced.
plasma
continued
to rise
It is therefore
erythropoietin
level
significantly.
an
Figure
3 describes
aplastic
anemia
to starting
therapy
resulted
in an
testosterone
still
over
27
(30
percent
ations
were
D.L.
and
moderate
birth
was
Fe59
20 percent.
from
the results
caused
by
made.
D.N.
27 percent
uptake
mgm.
but
of
of
patient
are
injury.
Both
severity.
The
both
and
her
7 year
results
K.K.,
a three
year
old girl
toxicity.
tier
hematocrit
assay
of her
She
One
daily).
plasma
expired
have
on
10 percent.
orally,
assay
The
of studies
chloramphenicol
month
resulted
one
old
idiopathic
of studies
plasma
was
month
males
with
treated
later,
her
in an
later
mental
normochromic
on
D.N.
for
then
erythropoietin
with
Methyl
hematocrit
was
Fe5#{176}
incorporation
and
no
other
retardation
illustrated
of
determinresulting
normocytic
are
with
prior
anemias
in
Figure
of
4.
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
TESTOSTERONE
AND
ERYTHROPOIETIN
457
LEVELS
D.N.
-4O
0
2.
3
4
5
5
Lii
‘A
I>-
.(
3)
I-
Q.
.
0
-J
U
Li.
‘A
In
10
0
I
2.
3
WEE
KS
T ESTOSTERONE
Fig.
4.-Effects
represent
of testosterone
Fe59
Prior
to
then
began
therapy,
mgm.
twice
rise
and
28
percent
18 weeks
weekly).
for
of
percent.
titers
the
measured
pretreatment
had
to
weeks
of
in
counts
two
weeks
level.
The
14
on
all
values
level.
Assay
D.L.
an
of the
uptake
Fe59
testosterone,
D.L.’s
weeks
reached
Fe59
uptake.
This
Plasma
therapy
ranged
and
17
four
percent.
began
over
a peak
16,
in
with
in
reached
pretreatment
discontinuing
hematocrit
time
to the
percent
He
100
level
measured
after
as 4.7
uptake.
resulted
resulted
and
as high
after
this
treatment
bars
propionate
titers
performed
rise
over
Fe59
which
during
treatment
to
Black
erythropoietin
returned
any
D.N.
percent
weeks
studies
began
resulted
by reticulocyte
accompanied
in
three
level
which
four
count
of
prior
2.8
plasma
after
therapy
After
his
of patient
counts.
(testosterone
erythropoietin
results
erythropoietin
value
later
reticulocyte
the
in
testosterone
level
Plasma
erythropoietin
maximal
resulted
of
week
The
illustrates
plasma
2.7
One
discontinuing
5
plasma
a maximal
3 percent.
after
Figure
his
injections
reached
about
on hematologic
values
connects
reticulocyte
line
of
receive
Fe5#{176}
uptake.
of
plasma
Broken
assay
to
to
value
uptakes.
a
was
erythropoiethad
returned
between
to
and
30
37
percent.
DIscuSsIoN
The
ment
elevated
stantially
levels
therapy,
plasma
level
erythropoietin
while
titers
higher
reached
remained
titers
receiving
before
receiving
during
their
all
treatment.
for
five
patients
Two
testosterone
highest
high
of
testosterone.
In
values
the
duration
and
most
patients
3-4
weeks
of
rose
patients
above
(K.K.
in
both
the
after
treatment,
the
and
the
titers
plasma
had
rose
sub-
erythropoietin
beginning
and
pretreat-
M.M.)
returned
androgen
to
the
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458
RLSHPON-MEYERSTEIN
ET
AL.
5
15
Iiii
>-
5)
9
D
o
2.1:
Iii
In
‘3
0
2.
3
5
WC(KS
-
T(ST0STR0N
Fig.
5.-Effects
represent
of testosterone
Fe59
uptakes.
pretreatment
M.M.
line
shortly
while
ment
level
developed
on hematologic
Broken
value
rose
he
several
elevations
connects
after
was
6
the
values
have
varied
occurred.
ranged
36 and
percent.
between
and
cell
3.1
mgm.
infiltration
with
levels
prior
to beginning
renal
disease.
levels
following
tration
of the
of
therapy
His
including
results
et
to
are
with
al.’3
who
to
the
Both
out,
consistent
with
24
low
elevated
and
these
those
in
rise in red
hematocrit
both
plasma
from
plasma
due
extensive
received
by
Alexanian12
local
to influence
excretion
and with
and
forms
and
seem
urinary
infil-
other
not
erythropoietin
and females;
chronic
erythropoietin
to the
L.H.
between
plasma
erythropoietin
prednisone,
did
reported
hour
urinary
to normal
males
increases
of
pretreatand
D.N.,
therapy.
any
the
resulted
meiphalan,
however,
the
Both
D.L.
testosterone
likely
was
M.M.
cyclophosphamide,
bars
hematocrit
to
serum
creatinine
revealed
marked
The
most
probably
myeloma.
pointed
titer.
observed
and his
aspirate
therapy
respond
Black
resulted
from changes
in the state
pretreatment
erythropoietin
level
only
about
22 percent.
His BUN
percent
marrow
therapy
The
returned
therapy.
during
erythropoiesis.
androgen
failure
marrow
bone
diminished
served
increases
in the
administration
of testosterone
Moores
mgm.
His
testosterone
x-irradiation.
As was
plasma
erythropoietin
These
45
DL.
considerably,
obscuring
The
fluctuations
in
values
within
short
periods
of time probably
of hydration
of these
two
patients.
L.H.’s
was very
low, although
his hematocrit
was
2.1
of patient
therapy.
and
counts
2.1
values.
testosterone
weeks
after
discontinuing
of their
reticulocyte
In both,
the hematocrit
cell
mass
which
might
values
reticulocyte
stopping
receiving
7
plasma
who
the
ob-
after
those
of
erythro-
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TESTOSTERONE
AND
poietin
levels
after
anemic
patients.
in the
plasma
plasma.
We
doses
to
of these
have
stimulate
hours
injecting
and
to injecting
Fe59 48 hours
in
suggest
erythropoiesis
responsive
this
poietin-responsive-cell
erythropoietin
of
has
anemias
SIS,16
of this
in
have
mice.
Both
given
anemia
to
but
WW
in
with
erythropoietin
stimulates
to physiologic
doses.
of concentrated
use.
two
levels
of
and
respond
with
genotype
large
when
rise
even
type
hereditary
to very
Furthermore,
erythropoietin
A similar
varieties
WW,15
and
which
are
the erythro-
to erythropoietin.
human
least
genotype
doses
testosterone
higher
and
the
is corrected.’7
The
data
presented
here
do
not
exclude
also acts directly
on the bone
marrow
of this action,
Reisner18
has shown
that
marrow
the
at
titers
plasma
for
effect
at least
was performed
data
indicate
plasma
development
suitable
large
the
testosterone
refractory
the
erythropoietin
not
mice,
absolutely
in
it is given
would
imply
that
anemias
of a defect
which
renders
reported
mice
plasma
of erythropoietin
is
been
the
whereby
to
in the
given
for erythropoietin
test plasma.
These
await
are
unless
increases
not
must
which
however,
high
but
concept
preparations
defect
This
result
time
circulating
be
Furthermore,
detected
mechanism
patients.
are the
of
activity
must
mice.
be
doses
relatively
test
plethoric
The assay
giving
the
is the
periods
of testosterone
testosterone
cannot
Fe59.14
after
short
erythropoietic-stimulating
result
that
in
for
the
the
pharmacologic
that
in anemic
to androgens
A definitive
was
shown
erythropoiesis
testosterone
level,
patients
that
erythropoiesis
on
prior
72
by
testosterone
unlikely
previously
459
LEVELS
administering
It is highly
of testosterone
that
ERYTHROPOIETIN
cells
action
grown
in tissue
of androgens
culture.
in vivo
the
Whether
and
possibility
to stimulate
testosterone
these
in humans
that
erythropoiesis.
can directly
remains
studies
testosterone
In
stimulate
are
support
bone
applicable
to
to be determined.
SUMMARY
Studies
in five patients
testosterone
can increase
that
testosterone
stimulates
with
various
types
plasma
erythropoietin
erythropoiesis
in
of anemias
have
shown
that
levels
in humans.
We suggest
some
anemic
patients
by this
mechanism.
SUMMARIO
Studios
pote
in
cinque
augnientar
le
patientes
con
concentrationes
que isto es le mechanismo
tientes
con anemia.
IN
vane
typos
plasmatic
per
INTERLINGUA
le qua!
de
anemia
ha
de
erythropoietina
testosterona
stimula
demonstrate
in
le
que
humanos.
testosterona
Es
postulate
in
certe
erythropoiese
pa-
ACKNOWLEDGMENT
We are indebted
to Dr. Irving
their cooperation
and advice.
Schulnian,
Dr.
Charles
Abilgaard
and
Dr.
Paul
Heller
for
REFERENCES
1.
Vollmer,
E.
P.,
Effect
of sex and
on the blood
picture
ogy 29:828, 1941.
2. Crafts,
R. C.:
only,
castration,
and
and
Cordon,
gonadotropic
A.
hormone
of the rat. EndocrinolEffects
testosterone
of
hypophysectpropionate
S.:
on
hemopoiesis
in
the
adult
male
rat. Endo-
crinology
39:40,
3. Steinglass,
Charipper, H.
and
Proc.
1946.
P.,
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1968 31: 453-460
The Effect of Testosterone on Erythropoietin Levels in Anemic Patients
N. RISHPON-MEYERSTEIN, T. KILBRIDGE, J. SIMONE and W. FRIED
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