Full text of DOI:10.1007/BF03343883

J. Endocrinol. Invest. 24: 503-509, 2001
The effect of liver transplantation on circulating levels of
estradiol and progesterone in male patients: Parallelism
with hepatopulmonary syndrome and systemic
hyperdynamic circulation improvement
R. Aller*, D.A. de Luis**, V. Moreira***, D. Boixeda***, J.L. Moya***, C.M. Fernandez-
Rodriguez*, A.L. San Román***, S. Ávila***, and R. Bárcena**
*Fundación Hospital Alcorcón and **Hospital Ramón y Cajal, Madrid; ***Institute of Endocrinology-H
Universitario Rio Hortega, Valladolid, Spain
ABSTRACT. The correction of hepatopulmonary
syndrome (HPS) after liver transplantation (LT)
remains controversial. The aims of our study
were to: 1) analyze whether LT reverses HPS; 2)
note any relationship between HPS and the sys-
temic hemodynamic disturbance; and 3) note
changes in circulating sex hormones and the pos-
sible association with pulmonary and systemic
hemodynamic changes. Systemic hemodynamic
parameters, cardiac output and systemic vascu-
lar resistance (SVR), sex hormones, and intrapul-
monary vasodilatation assessed by contrast trans-
esophageal echocardiography, and gas exchange
abnormalities were investigated in 19 patients
with advanced cirrhosis prior to and 6 months
(176.8 30 days) after LT. LT was followed by a
marked reduction in cardiac output (6.6 1.7 vs
3.5 0.5 l/min; p<0.001) and SVR (1039 460 vs
1978 294 dyn·sec·cm-5; p<0.005). Before LT, cir-
culating estradiol and progesterone levels were
invariably elevated (66 22 pg/ml and 1.8 1.1
ng/ml, respectively, normal values <31 pg/ml and
0.35 ng/ml, respectively), and dropped after LT
(28 12 pg/ml p<0.001 and 0.38 0.2 ng/ml;
p<0.001, respectively). Seventeen of 19 patients
had intrapulmonary vasodilatation and increased
alveolar-arterial oxygen difference, thereby ful-
filling diagnostic criteria for HPS. Patients with
HPS presented higher cardiac output (p<0.05),
lower SVR (p<0.01), and higher progesterone
and estradiol levels than patients without HPS
(p<0.05). LT produced normalization of intrapul-
monary vasodilatation in all patients. LT normal-
ized hyperdynamic circulation and is a useful
therapeutic option in patients with HPS. Norma-
lization of sex hormone levels after LT suggests
that they could play a pathogenic role in the de-
velopment of HPS.
(J. Endocrinol. Invest. 24: 503-509, 2001)
©2001, Editrice Kurtis
INTRODUCTION
cation to liver transplantation (LT) (6), this view has
been recently challenged (7-9). Reasons for abnor-
mal gas exchange in patients with liver disease are
the following: pulmonary vasodilatation (PV), ana-
tomical intrapulmonary shunts, decreased DLco (dif-
fusion of co), ventilation perfusion mismatching,
and restrictive-obstructive defects (10).
Intrapulmonary vasodilatation, abnormal gas ex-
change and the presence of advanced liver disease
are accepted criteria for hepatopulmonary syn-
drome (HPS). This syndrome is associated with a
high mortality rate (1-5). While severe hypoxemia
due to HPS was considered an absolute contraindi-
Pathogenesis of HPS is unclear. Thus far, some
studies have evaluated hypoxemia and hyperdyna-
mic circulation in cirrhosis (11), but little is known
about a possible relationship between pulmonary
and systemic hyperdynamic circulation. Overactivity
of vasodilating factors, including endothelial-derived
factors (12) and humoral agents (13), is a possible
contributor to peripheral vasodilatation and PV in
cirrhotic patients. Estradiol and progesterone are
Key words: Hepatopulmonary syndrome, liver transplantation, sex hor-
mones.
Correspondence: Prof. Daniel A. De Luis Román, Professor Associated
of Endocrinology, Head of Institute of Endocrinology, Medical School,
C/Caamaño 51bis 3 C, Valladolid 47013, Spain.
E-mail: ddlr@pulso.com
Accepted December 4, 2000.
503

R. Aller, D.A. de Luis, V. Moreira, et al.
increased in liver cirrhosis (14-16) and have shown
vasodilating action (17). It has also been docu-
mented that increased values of estradiol and pro-
gesterone levels return to normal range after LT
(14-16).
The aim of this prospective longitudinal study was
to analyze a possible relationship between param-
eters of hyperdynamic circulation, plasma levels of
sex hormones and HPS.
mmHg. AaPO2 was calculated following the equa-
tion: {[(BP-47)x0,2093] - (1,15xPaCO2)} - PaO2 (BP:
barometric pressure).
Description of study of intrapulmonary
vasodilatation
Contrast transesophageal echocardiography (CTEE)
was performed with 5 MHz transesophageal probe
(ATL Ultramarck 9 equipment, UK) and an integrat-
ed video-recording system to register the studies.
After introducing the probe, a four-cameral plane
was selected in order to visualize the 2 atrial cavi-
ties, and simultaneous bi-dimensional images and
images in M mode through both atria were record-
ed. Five cc of 0.9% saline previously agitated was
injected through a three-way stopcock connected
to two syringes of 10 cc. A few seconds after injec-
tion an increased echogenicity was observed in the
right atrium due to the arrival of the injected sub-
stance. Five or 6 heartbeats were observed to de-
tect the passing of microbubbles to the left cham-
bers, in order to exclude permeable foramen ovale
or intracardiac shunts. The injection was repeated
twice, once the contrast had been cleared in both
chambers, accepting as definitive the largest pass
of microbubbles. All studies were recorded on
videotape.
Grading: In order to objectively grade and make
the procedure reproducible (the pass of microbub-
bles to the left atrium), a semiquantitative scale was
made (19): grade 1, absence of passing; grade 2,
passing of few isolated microbubbles (approxi-
mately <15 bubbles); grade 3, passing of numer-
ous isolated microbubbles; grade 4, passing of nu-
merous microbubbles that obtain an increase in
background echogenicity; grade 5, opacification of
the left atrium, but less extent than the right atri-
um; grade 6, opacification of left atrium similar to
right atrium. Given the excellent image quality of
CTEE, passing of isolated microbubbles was consi-
dered as normal. Therefore, grades 1 and 2 were
considered as no PV, grade 3 as mild PV, and >4
as significant PV.
SUBJECTS AND METHODS
Subjects
Nineteen patients with cirrhosis admitted to the
Liver Transplantation Unit of Hospital Ramon y Cajal
for LT evaluation were included in the study. All pa-
tients had histologically proven cirrhosis (mean age
48 7 yr). Causes of cirrhosis were alcohol abuse in
8 patients, chronic hepatitis C in 6, chronic hepati-
tis B in 4, and autoimmune hepatitis in 1 patient.
Sixteen patients had ascites at entry into the study,
16 had esophageal varices and 6 had bled from the
varices. Eleven patients (58%) were classified as
Child-Turcotte class B (18), and the remaining (42%)
as class C. All measurements performed on these
19 patients were repeated 6 months (176.8 30
days) after LT. Patients with a history of chronic
bronchopulmonary disease, abnormal chest X-ray
and electrocardiographic evidence of right ventric-
ular hypertrophy, cardiac complications, recently
ruptured esophageal varices or pre-menopausal
women were not included. None of the patients re-
ceived treatment with vasoactive drugs. All patients
were afebrile. Informed written consent was obtai-
ned from all patients and the study was approved
by the Hospital Ethics Committee.
Diagnosis of HPS
All patients with HPS had the following criteria:
1) demonstration of PV;
2) presence of gas exchange abnormalities defined
by an upper limit-widened age-corrected alveo-
lar-arterial oxygen difference (AaPO2) >15 brea-
thing room air, in sitting position, in rest, and with
local anesthesia;
Hormone assays
3) absence of primary cardiopulmonary disease de-
monstrated by normal pulmonary function test (1-5).
Estradiol and progesterone levels were measured
by Immulite chemiluminescent enzyme immunoas-
says (Diagnosis Products Corporation, Los Angeles,
CA, USA). For the estradiol assay, the intra-assay
coefficient of variation (CV) was 6.3%, the inter-as-
say CV was 10.5%. The assay has a working range
of 20 to 2000 pg/ml. For the progesterone assay,
the intra-assay CV was 9.2% and the inter-assay CV
was 10.2% with a range of 0.2 to 40 ng/ml. All de-
terminations were done on the same day. The
Arterial blood gas analysis
Arterial blood gas analysis included the determi-
nation of the pH, PaO2, PaCO2, by mean of selec-
tive electrodes and with IL 16/40 pH/blood gas ana-
lyzer equipment (Milano, Italy), in supine and
breathing room air. Hypoxemia was defined by
PaO2<70 mmHg, and hypocapnia by a PaCO2<35
504

Liver transplantation and circulating sex hormones
Table 1 - Arterial blood gases before and after liver transplan-
tation (no.=19). Data X (SD). The table shows improvement in
blood gas parameters after liver transplantation (LT).
Table 2 - Gas exchange abnormalities in patients with and with-
out hepatopulmonary syndrome (HPS). Data X (SD). The table
shows low PaO2 and high PCO2 levels in patients with HPS.
Pre-LT (SD) Post-LT (SD)
p-value
<0.001
<0.05
HPS (SD)
63.5 (12)
32.4 (4)
37.3 (8.7)
No HPS (SD)
77.7 (13.6)
33.4 (4.2)
23.7 (13.9)
p-value
<0.05
NS
PaO2 (mmHg)
70.9 (14.5)
12
86.8 (6.9)
PaO2 (mmHg)
PaO2 (mmHg)
AaPO2 (mmHg)
PaO2<70 mmHg (n)
PaO2 (mmHg)
2
32.8 (4)
16
36.4 (1.3)
<0.001
<0.001
<0.001
<0.05
<0.05
PaO2<35 mmHg (n)
AaPO2 (mmHg)
1
12.8 (6.3)
2
30.2 (13.4)
12
tained. The area under the velocity curves or time-
velocity integral was derived by planimetry. An av-
erage of three cardiac cycles was made. Stroke vol-
ume was determined as (cross-sectional area · time-
velocity integral). Cardiac output was determined
as (stroke volume·cardiac rate). Peripheral vascular
resistance was assessed as [(mean arterial blood
pressure·80)/cardiac output]. Blood pressure mea-
surements were taken with a cuttmercury sphyg-
momanometer at the time of echocardiography
with the patient in supine position.
Increased AaPO2 (n)
(age-corrected)
mean progesterone and estradiol levels of healthy
patients in our own reference group were 0.35
ng/ml and <31 pg/ml, respectively.
Study of cardiac output and peripheral
vascular resistance
Study of cardiac output and peripheral vascular re-
sistance was performed using a Ultramarck 9 ultra-
sonographer (ATL) equipped with a 3.5 mHz com-
bined imaging and Doppler transducer. Patients
were studied in left lateral decubitus. Two-dimen-
sional guided M-mode tracings were recorded at
50 mm*sg-1, with the transducer placed in the third
to fifth left intercostal space. Left ventricular inter-
nal dimensions were measured at end-diastole and
end-systole, according to the American Society of
Echocardiography Guidelines (20).
Statistical analysis
Data are expressed as the mean SD. Statistical
analysis was carried out using two-tailed paired or
unpaired Student’s t-test, as needed, and analysis
of variance (ANOVA). Ordinal variables were eval-
uated by the χ2 test. Correlation between variables
were determined by Pearson test. P<0.05 was con-
sidered significant. For analysis purposes, SPSS
Statistic pack were used.
The left ventricular outflow tract diameter was mea-
sured through the paraesternal long-axis view, just
below the insertion of the anterior and posterior
aortic valve leaflet during early systole. Diameter
was measured between the two inner echocardio-
graphic edges. An average of three measurements
was made. Cross-sectional area was calculated as
(3.14·diameter2)/4. For the velocity recording at the
left ventricular outflow tract, pulsed-Doppler echo-
cardiography was used. The apical window was
used and the sample volume was placed into the
valve leaflet and gradually moved backward until
the first clear ventricular outflow velocity was ob-
RESULTS
The mean time of follow-up after LT in this series
was 176.8 30 days. Hepatic function remained nor-
mal throughout the follow-up period.
Gas exchange before and after LT
Arterial blood gas analysis pre- and post-LT is pre-
sented in Table 1. Before LT, 16 of 19 patients
(84.2%) had evidence of alveolar hyperventilation
(PaCO2<35 mmHg). Twelve patients were hypox-
emic (PaO2<70 mmHg) and showed a widened
AaPO2. There was not association between etiolo-
Table 3 - Sex hormones data for 19 patients before and after liver transplantation (LT), and for patients with hepatopulmonary syn-
drome (HPS) (no.=10) and without HPS (no.=9). Data X (SD). The table shows high estradiol and progesterone levels in patients with
pre-LT and with HPS.
Pre-LT
66 (22)
1.8 (1.1)
Post-LT(SD)
28 (12)
p
HPS
No HPS
61.2 (20.2)
1.4 (0.8)
p
Estradiol (pg/ml)
<0.001
<0.001
79.5 (27.9)
2.4 (1.2)
0.05
<0.05
Progesterone (ng/ml)
0.38 (0.2)
505

R. Aller, D.A. de Luis, V. Moreira, et al.
7
6
5
4
3
2
1
Sex hormones data
Table 3 shows estradiol and progesterone levels
before and 6 months after LT and levels of these
hormones in function of HPS status. As shown, prior
to LT, significant increase in estradiol and proges-
terone levels were observed in all patients. Patients
with HPS manifested higher estradiol (p<0.05) and
progesterone levels (p<0.05) than patients without
HPS.
Cardiac output and systemic vascular resistance
0
Before LT
After LT
Figures 1 and 2 show cardiac output and peripher-
al vascular resistance in patients before and after
LT. Cirrhotic patients had hyperdynamic circulation,
with high cardiac output and low peripheral vascu-
lar resistance. LT was followed by marked changes
in these parameters at 6 months, with significant
reductions in cardiac output (6.6 1.7 vs 3.5 0.5
l/min; p<0.001) and significant increases in systemic
vascular resistance (SVR) (1039 460 vs 1978 294
dyn·sec·cm-5; p<0.005). As Figure 3 shows, patients
with HPS had significant higher cardiac output and
lower SVR than patients without HPS. Figure 4
shows the correlation between estradiol and pro-
gesterone levels and parameters of hyperdynamic
circulation.
Fig. 1 - High cardiac output (CO) before liver transplantation
(LT) in 19 patients (p<0.001).
gy of liver disease and hypoxemia, hypocapnia or
abnormal AaPO2. After 6 months of LT, 10 of 12
patients with hypoxemia or widened AaPO2 before
LT returned to normal situation. One patient con-
tinued hypoxemic, due to interstitial pneumonia as-
sociated to CMV infection; persistent hypoxemia
could not be explained in the remaining trans-
planted. Fifteen of 16 patients exhibiting alveolar
hyperventilation before LT, presented normal
PaCO2 after LT.
Intrapulmonary vasodilatation and
hepatopulmonary syndrome
*
6
None of 19 patients presented intracardiac shunt
or right ventricular hypertrophy. All patients un-
derwent CTEE. PV was demonstrated in 10 of 19
patients (52.6%). All these patients presented gas
exchange abnormalities, thus fulfilling diagnostic
criteria of HPS. Table 2 shows gas exchange abnor-
malities in patients with and without HPS. Patients
with HPS presented significant lower mean PaO2
levels, and higher mean AaPO2 levels. However
there was not significant difference between the
two groups in mean PaCO2 levels.
5
4
3
2
1
0
HPS
No HPS
*
2500
2000
1500
1000
500
3000
2000
1000
0
0
HPS
No HPS
Fig. 3 - High cardiac output (CO) and low systemic vascular re-
sistance (SVR) in cirrhotic patients before liver transplantation
(LT) with and without hepatopulmonary syndrome (HPS)
(no.=19). *p<0.001.
Before LT
After LT
Fig. 2 - Low systemic vascular resistance (SVR) before liver trans-
plantation (LT) in 19 patients (p<0.005).
506

Liver transplantation and circulating sex hormones
160
140
120
100
80
160
140
120
100
80
r=0.4; p=0.05
r=-0.5; p<0.05
60
60
40
40
20
20
1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
400 600 800 1000 1200 1400 1600 1800 2000
-5
2
.
.
.
SVR (dyn sec cm )
CO (L/min m )
6
5
4
3
2
1
0
6
5
4
3
2
1
0
r=0.5; p<0.05
r=-0.6; p<0.01
1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
400
600 800 1000 1200 1400 1600 1800 2000
-5
2
.
.
.
SVR (dyn sec cm )
CO (L/min m )
Fig. 4 - Correlation of estradiol and progesterone levels with cardiac output (CO) and systemic vascular resistance (SVR) in 19 cirrhotic
patients prior to liver transplantation (LT).
DISCUSSION
vanced liver disease in patients of our study (58% had
Our study confirmed the high frequency of gas ex-
change abnormalities, hyperdynamic circulation (high
cardiac output and low peripheral vascular resistance),
and elevated levels of plasma sex hormone levels in
patients with severe liver disease submitted to eval-
uation for LT. The most prominent finding of this
study was the correction of PV and HPS after LT.
These results were in accordance with previous re-
ports (6-10), showing that PV and gas exchange ab-
normalities ameliorate by LT in patients with cirrhosis.
The high prevalence of PV and HPS observed in this
study was explained by the use of CTEE in the
demonstration of PV. Contrast echocardiography is
the most useful screening test for patients with HPS
(21). Previous studies have found a better correlation
between gas exchange abnormalities and presence
of PV, when CTEE is employed (19, 22); the higher
sensitivity of this technique and the presence of ad-
Child’s class B and 42% had Child’s class C) are pos-
sible explanations of the higher prevalence of HPS
observed in this study (52.6%). This finding was in
keeping with other studies using CTEE, which have
demonstrated intrapulmonary shunt in 51% of cir-
rhotic patients (22).
As previously documented (23-27), significant eleva-
tions of progesterone and estradiol levels were found
in our cirrhotic patients as compared with the refer-
ence values. Although there is a unique study show-
ing correlation between progesterone and estradiol
levels and alveolar hyperventilation in patients with
liver disease (23), our work was the first study evalu-
ating the association of these hormones to the ex-
tent of HPS. In addiction, a significant association be-
tween increased progesterone levels and presence
of HPS was observed. Progesterone inhibits vascular
tone (28). Vasodilatation in pregnant women is well
507

R. Aller, D.A. de Luis, V. Moreira, et al.
3. Davis H.H., Schwartz D.J., Lefrak S.S., Susanan N.,
Schainker B.A.
known, where progesterone concentration markedly
increases during pregnancy (29). In addition, the an-
tiprogestin RU486 significantly inhibited the vasore-
laxation induced by progesterone (30). Return to nor-
mal progesterone levels and resolution of HPS after
LT support a contributory role of progesterone on
the pathogenesis of this disorder. In our study, estra-
diol levels were directly correlated with cardiac output
and inversely correlated with SVR, being more in-
creased in patients with HPS. It has been demon-
strated that estradiol dilates blood vessels in both re-
productive and non-reproductive tissues (31). The
mechanism of this vasodilatation is believed to in-
volve activation of nitric oxide synthesis (32) or calci-
um-channel blockade (33). Moreover, estradiol in-
creases the number of progesterone receptors in an-
imals and may facilitate actions of progesterone (34).
Increased plasmatic levels of other vasodilating sub-
stances may also contribute to the development of
intrapulmonary vasodilatation, and normalization of
these circulating peptides after restitution of liver
function allows an adequate regulation of vascular
tone at pulmonary and peripheral level. In support
of these findings, increased levels of estradiol and
progesterone showed direct correlation with cardiac
output and inverse correlation with SVR. Of interest,
our results showed a significant association between
the presence of HPS and systemic hyperdynamic cir-
culation. These findings support the view that a com-
mon pathogenic mechanism could be involved in
the pathogenesis of PV and peripheral vasodilata-
tion. In keeping with previous studies (35), our re-
sults showed that most hemodynamic and hormon-
al abnormalities of advanced cirrhosis return to nor-
mal or almost-normal range 2 weeks after LT.
Alveolar-capillary oxygen desequilibrium in hepatic
cirrhosis.
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Ann. Intern. Med. 1995, 122: 521-529.
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