Androgen Metabolism in Cirrhosis of the Liver

By A. Louis Southren, Gary G. Gordon, Jaime Olivo,

Fereidoon Rafii, and William S. Rosenthal
Androgen metabolism was studied in male
patients with cirrhosis of the liver. The
plasma level, metabolic clearance, and
production rates of testosterone were de-
creased while the conversion ratio and
rate transport constant of testosterone to
androstenedione was increased. Admin-
istration of testosterone produced a marked
increase in the metabolic clearance rate of
testosterone indicating that parenchymal
hepatic dysfunction per se was not the
cause for the reduced clearance rate.
Moreover, the patients were found to have
normal testicular reserve for the bio-
synthesis of testosterone as indicated by
an almost fourfold increase in the plasma
PIRRHOSIS of the liver in males is associated with clinical evidence of
b hypogonadism such as decreased facial and body hair growth, gyne-
comastia, and testicular atrophy. It has been suggested that the hypogonadism
is related to increased circulating estrogens due to deficient metabolism of
these steroids by the diseased liver. 1 More recently, Korenman, Perrin, and
McCallum2 have confirmed the presence of increased plasma levels of
estradiol-17 /3 in cirrhosis. In addition, Coppage and Cooner3 have demon-
strated decreased plasma levels of testosterone in several male cirrhotics.
However, a lowered plasma level of testosterone may reflect either a decreased
concentration of testosterone following the
administration of human chorionic gonado-
tropin. These data demonstrate that the
reduced production rate of testosterone in
male cirrhotics is not due primarily to
testicular disease but possibly reflects
hypothalamic-pituitary suppression secon-
dary to increased circulating estrogens.
The increase in the rate of conversion of
testosterone to androstenedione, found in
the present study, is consistent with this
hypothesis. The present investigation thus
provides quantitative data on the hypo-
gonadal state in cirrhosis and suggests
possible mechanisms for the alteration in
androgen metabolism.
From the Endocrine Section of the Department of Medicine, the New York Medical
College-Mefropotifm Hospital Center, New York, N.Y.
Received for publication October 9, 1972.
Supporfed by Grant AM 12845 from the Nafionnl Institute of Arthritis and Metabolic
Diseases, NI H, Bethesda, Md.
A. Louis Southren, M.D.: Professor of Medicine, and Chief, Endocrine Section, New York
Medical College-Metropolitan Hospital Center, New York, N.Y.; Career Scientist of the
Health Research Council of the City of New York (I-281). Gary G. Gordon, M.D.:
Associate Professor of Medicine, New York Medical College-Metropolitan Hospital
Center, New York, N.Y. Jaime Olivio, M.D.: Assistant Professor of Medicine, New York
Medical College-Mefropolitan Hospital Center, New York, N.Y.; Trainee in the Training
Program in Endocrinology and Metabolism sponsored by the Nafional lnstitufe of Arthritis
and Metnbolic Diseases (T 1 AM 5473-04). Fereidoon Raffii, M.D.: Instructor, Depnrttncnt
of Medicine, New York Medical College-Metropolitan Hospital Center, New York, N.Y.
William S. Rosenthal, M.D.: Professor of Medicine, and Chief, Section of Gastroenterology,
New York Medical College-Metropolitan Hospital Center, New York, N.Y.
Reprint requests should be addressed to William S. Rosenthal, M.D., 7249 Fifth Avenl*e,
New York, N.Y. 10029.
0 1973 by Grune 6 Stratton, I nc.
Metabolism, Vol. 22, No. 5 (May), 1973
695
696 SOUTHREN ET AL.
production or an altered metabolism of the steroid. In order to answer this
question and to investigate the possible mechanism(s) for this change, a
study was designed to measure the kinetics of testosterone metabolism in
the plasma and ascitic fluid in a group of cirrhotics with disease of varying
severity.
MATERIALS AND METHODS
In the present study the plasma concentration (PCT), metabolic clearance (MCRT) and
plasma production rates (PRT), the conversion ratio of testosterone to androstenedione
(ZA/ZT), and the rate transfer constant ([pITA) of testosterone as well as the metabolic
clearance rate of androstenedione (MCRA), conversion ratio of androstenedione to testos-
terone (Xr/XA), and its rate transfer constant ([p]*T) were studied in the following groups
of patients: (1) six normal male subjects, ages 21-28 yr (Table 1); and (2) thirteen male
patients (ages 32-70 yr) with cirrhosis of the liver (Table 1). The patients with cirrhosis
were all chronic alcoholics with histories of numerous admissions to Metropolitan Hospital
Medical Center for treatment of their liver disease. The diagnosis of liver disease was
based on the clinical picture, liver function tests, and the histologic appearance of the
liver from biopsy material. None of the patients had a surgical portacaval anastomosis. In
each instance, the measurements of androgen metabolism were performed after the
patients had been hospitalized from one to several weeks. The extent of the liver disease
was graded as mild (I+), moderate (2+), and severe (3+) based on the clinical state
and liver function at the time of the androgen studies and then divided into groups I, II,
and III according to increasing severity of their disease (Table 1). The presence of
ascites, gynecomastia, and testicular atrophy is denoted by footnotes to Tabel 1.
In two of the cirrhotics with ascites, an indwelling catheter was placed into the peri-
toneal cavity, and sequential samples of ascitic fluid were obtained concurrently with the
blood samples during a constant intravenous infusion of 3H-testosterone for the deter-
mination of the MCRT. The ascitic fluid was handled in a manner similar to plasma
and the concentration of JH-testosterone and its conversion to 3H-androstenedione was
measured. In addition, measurements of the disappearance. rate of 19*Au-colloidal gold,
as an index of hepatic blood flow,* were carried out in normal and cirrhotic subjects.
In five of the cirrhotics the kinetic studies were repeated during the intramuscular
administration of testosterone enanthate (200 mg weekly for 2 wk). The effect of human
chorionic gonadotropin (5000 units daily for 3 days by intramuscular injection) on the
PCT was measured in five of the other cirrhotics. In addition, plasma was obtained at
8 a.m. and 10 p.m. for determination of the diurnal variation of testosterone in these
patients.
A constant intravenous infusion procedure was used for the determination of the
MCRT and the MCRA as described previously .4,5 The plasma production rate (PR) of
testosterone was calculated from the expression: PR (mg/day) = MCRr(l/day x PCr,
where PCT was the fasting morning plasma concentration of testosterone (since no diurnal
variation of plasma testosterone was noted in the cirrhotic subjects).
Calculations of the conversion ratios and rate transfer constants were carried out
according to the method of Horton and Tait.6
The plasma concentration of testosterone was measured by the protein displacement
method of Mayes and Nugent.7 The disappearance rate of IosAu-colloidal gold was
*It should be noted that the disappearance rate of
IogAu-colloidal gold is at best onIy
an approximate index of hepatic blood flow, and for this reason we have avoided calculating
hepatic blood flow in liter/day. However, even in the absence of absolute values the
comparative values in each patient, before and during therapy, are sufficient to suggest
whether an alteration in hepatic blood flow occurred.
ANDROGEN METABOLISM IN CIRRHOSIS OF LIVER
697
determined following administration of approximately 150 / *Ci of the isotope. The data
were handled according to the method of Vetter, Falkner, and Neumayr.8
RESULTS
Met&& Clearance Rates
Table 1 shows the MCRT in the six normal men. Combining our present
and previous data4vg gives an overall mean MCRT for 31 normal men of
1190 k 231 (SD) liter/day. This larger series was used in the subsequent
statistical analyses.
In cirrhosis (Table 1) the mean MCRT in the 13 patients was approximately
50% of that found in normal men (p <O.OOl). There was no correlation
between the level of the MCRT and the age of the patient, the severity of the
disease or the presence or absence of ascites. Correction of the clearance
rates for body surface area (sq m) did not alter the statistical significance of
these observations.*
The mean MCR* in seven cirrhotics (Table 1) was significantly lower than
normal (p <0.005). However, correction for body surface area (sq m) showed
that there was no significant difference between the two groups (p >O.l).
Plnsma Concentration of Tesfosferone
The mean plasma concentration of testosterone (PCT) in the 13 male
patients with cirrhosis (Table 1) was significantly lower (p <O.OOl) than
those found in our normal male series (Table 1).
There was no diurnal variation in the PC*s in the four male cirrhotics
who were studied.
Plnsma Proclzlction Rates of Testosterone
The pIasma production rates of testosterone (PRT) in the men with
cirrhosis are seen in Table 1. The mean PRTs in these patients were
significantly lower than normal men (Table 1) (p <O.OOl).
Conversion Ratios of Testosterone (Z/Z) and Androstenedione
(X/X) nnd Rnte Transfer Constants of These Steroids ([pITA and
[p], Respectively)
Table 1 shows the conversion ratios of labeled testosterone (Z*/Z*) and
androstenedione (XT/X*) and the rate transfer constants of these steroids
-
*It should be noted that the mean age of the patients with cirrhosis was greater than
the control subjects in the present (Table I) and previous studies from our laboratory.
This suggests that the effect of age on the MCRT and PCT should be considered. Hudson
et al.10 and Kent and Acone 11 did not find any significant effect of age on the PC?.
Our experience with a large number of elderly men is in agreement with their findings.
Although Kent and Aconell did note a somewhat reduced MCRT in elderly patients, their
series was small (N = 6) and the average age of their patients (76 yr) was considerably
greater than our cirrhotic group (51 yr). Furthermore, our own unpublished observations
on the relationship of age to the MCRT does not indicate any consistent effect in the fourth
through the sixth decades of life. Therefore, it appears that the alterations in the MCRT
and PCT in the present study can be ascribed to the effect of cirrhosis rather than age.
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-

ANDROGEN METABOLISM IN CIRRHOSIS OF LIVER 699
(bITA and blATI
respectively) in normal and cirrhotic males. The conversion
ratios in the present normal series were combined with the previously
published normal series to give data in 1.2 normal men (Z/Z = 0.033 2:
0.013 [SD] and XT/X* = 0.119 -C 0.033 [SD]).
The mean ratio of ZA/ZT in the patients with cirrhosis (Table 1) was
0.068 -C 0.040 (SD), which is twice that of the combined normal series (p
<O.Ol). The ratios of XT/X* in the cirrhotics (Table 1) were not statistically
different from the normal series (p > 0.6).
Thus, the percentage conversion of testosterone to androstenedione was
increased in cirrhosis while the percentage conversion of androstenedione
to testosterone was not changed.
The mean values for [pITA in cirrhosis was greater than the combined group
of normals (0.086 * 0.034 [SD] [N = 121) (p <0.005). The mean values for
[PI AT
in these patients was slightly lower than combined normal group
(0.045 -e 0.015 [SD] [N = 121) (0.025 > p < 0.05).
Conversion Ratio of Testosterone to Androstenedione in the Ascitic Flttid
The conversion ratios of testosterone to androstenedione in the ascitic
fluid in two patients following the intravenous administration of 3H-testos-
terone (constant infusion) were 0.207 and 0.381. These values were four- and
sixfold higher than their corresponding blood values (0.055 and 0.063,
respectively). It should be noted that the percentage of 3H-testosterone in the
ascitic fluid relative to the blood was 3% and 4%, respectively, indicating
that only a small amount of the infused 3H-testosterone was sequestered
in the ascitic fluid. Thus, there was no factitious alteration in the MCRT due
to loss of 3H-testosterone into the ascitic fluid.
Effect of Testosterone Administration on the Kinetics of Testosterone
Metabolism and the Hepatic Clearance of 1g8Au-Colloidal Gold
The effect of testosterone administration of the MCRT, PCT and conversion
ratio was studied in five male cirrhotics (without significant ascites). Increasing
the PCT resulted in a marked increase in the mean MCRT (621 2 107 [SD]
to 1069 -+ 272 [SD] (p <O.Ol) with no significant change in the mean
ZA/ZT (0.048 * 0.017 [SD] to 0.066 -c 0.019 [SD] (p > 0.10).
The disappearance constant (K [min-l]) and the T112 (min) of s8Au-colloidal
gold prior to the administration of testosterone in these five male cirrhotics
was 0.158 -C 0.10 (SD) and 4.5 -C 0.3 (SD) respectively. There was no
significant change in these values (0.101 2 0.10 [SD] and 3.7 * 0.3 [SD],
respectively) following administration of testosterone (p > 0.05 and 0.1,
respectively). Thus, the increase in the MCRT was not associated with a rise
in this index of hepatic blood flow.
The Effect of Administration of Human Chorionic Gonadotropin (HCG)
on the PCT
The administration of HCG to five male cirrhotics produced an almost
fourfold increase in the mean PCT (1.7 f 0.3 [SD] pg/liter to 6.4 -I 1.3 [SD]
pglliter, respectively) indicating a normal testicular reserve for the bio-
synthesis of testosterone.
700
SOUTHREN ET AL.
DISCUSSION
The present study demonstrates a decreased plasma level and production
rate of testosterone and cirrhosis of the liver. The mechanism of the hypo-
gonadism is probably secondary to hypothalamic-pituitary suppression rather
than to primary testicular dysfunction since stimulation of the testes with
HCC produced a prompt and marked increase in the plasma concentration
of testosterone to normal male levels. Korenman, Perrin, and McCallums
demonstrated elevated plasma estradiol levels in cirrhosis, which suggests
that the hypothalamic-pituitary inhibition may be a result of this increase.
Consistent with this is the report Rosselin and Dolaisr2 who showed a
decreased plasma level of FSH in cirrhosis. Plasma LH levels however, were
not reported.
The decreased MCRT in the male cirrhotics is not unexpected, since it has
previously been shown that both estrogen therapyr3*14 and male hypogonad-
ism4 are associated with a fall in this parameter. The increase in the MCRT
in response to the administration of testosterone indicates that the diseased
liver is still capable of removing the steroid (unbound fraction) presented
to it and suggests that the lowered MCRT is not a result of parenchymal
insufficiency but probably is related to prehepatic factors such as the decreased
hepatic blood flow and possibly plasma-binding factors. The observation that
the MCR* sq m is normal in cirrhosis is most likely a reflection of its very
considerable extrahepatic metabolism is well as the lack of a specific high
affinity pIasma-binding protein for the steroid.
Migeon, Rivarola, and Forest13 in a study of male patients on estrogens
found an increased conversion of testosterone to androstenedione. Our obser-
vations of an increase in both the conversion ratio of testosterne to andro-
stenedione (ZZ) and the rate transfer constant from the testosterone to the
androstenedione pool [pITA) are consistent with their findings. Similarly,
Breuer, Breuer, and Lisboar5, in an in vitro study, demonstrated an increase
in the 17/3 oxidoreductase pathway (i.e., an increased conversion of the 17P
hydroxy [testosterone] to the 17 ketone [androstenedione]) in cirrhosis of the
liver. The accelerated conversion of testosterone to androstenedione may
explain, in part at least, the presence of increased circulating estrogens in
cirrhosis, since it has been reported that androstenedione is a more efficient
precursor than testosterone for estrogen synthesis.le This hypothesis would
suggest that the increased circulating estrogens in cirrhosis may not only
result from a defective hepatic catabolism of these steroids but may, in part,
be related to increased production through androstenedione, a favored
precursor.
Thus, there are two alterations in the kinetics of testosterone metabolism
in cirrhosis. The first is a reduction in the MCRT and the second is an
increase in the percentage conversion of testosterone to its redox partner,
androstenedione. Both of these phenomena may be due to an increase in
circulating estrogens. The increase in the percentage conversion of testosterone
to androstenedione is most likely related to an estrogen-mediated alteration
in hepatic enzymatic activity rather than purely to binding phenomena,
ANDROGEN METABOLISM IN CIRRHOSIS OF LIVER 701
since in hyperthyroidism the conversion ratio is decreased although the plasma
binding of testosterone is markedly increased.5
It was considered that the ascitic compartment might sequester testosterone
during the infusion without metabohsm of the steroid and thus give a falsely
elevated value for the MCRT. However, the total 3H-testosterone found in the
ascitic fluid was only 3%~4% of the administered dose, and this would not
significantly alter the clearance rates. It is of interest that the conversion ratio
of testosterone to androstenedione in the ascitic fluid was four- and sixfold
greater than in peripheral plasma. This suggests that the liver is the primary
site for the accelerated conversion of testosterone to androstenedione in this
disorder and that there is a direct pathway for delivery of androstenedione
converted from testosterone directly into the ascitic compartment bypassing
the systemic circulation. A similar phenomenon has been observed by Zimmon
et a1.l for the delivery of albumin newly synthesized from labeled
bicarbonate.
Thus, it is apparent that the hypogonadism of cirrhosis is due to a
decreased production of testosterone rather than to an altered peripheral
metabolism of the steroid.
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