Hypothalamic-pituitary-gonadal function in men with liver cirrhosis before and after liver transplantation

Abstract

To evaluate the influence of end-stage liver disease and orthotopic liver transplantation in the pituitary function and hormone metabolism before and after liver transplantation.
In a prospective study, serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and prolactin (PRL) of 30 male patients with cirrhosis were determined two to four hours before and six months after liver transplantation. The results were compared according to the Model for End-stage Liver Disease (MELD).
male patients with liver cirrhosis have hypogonadism. FSH was normal, but inappropriately low due to androgen failure; E2 and PRL, on their turn, were high. After liver transplantation, FSH and LH levels increased (p < 0.05), whereas E2 and PRL normalized (p < 0.05). The MELD score did not influence changes in FSH, PRL and LH, however, the more severe the cirrhosis was, the more significant was the normalization of E2 (p = 0.01).
Patients with cirrhosis and male hypogonadism have inappropriately normal levels of FSH and LH, associated with an increase in E2 and LRP. After liver transplantation, FSH and LH increased, while E2 and PRL returned to normal. Changes in E2 levels were most pronounced in patients with MELD > 18. The severity of cirrhosis had no influence on FSH, PRL and LH.

Full text

ZachariasZacharias
ZachariasZacharias
Zacharias
Hypothalamic-pituitary-gonadal function in men with liver cirrhosis before and after liver transplantation
421
Rev. Col. Bras. Cir. 2014; 41(6): 421-425
Original ArticleOriginal Article
Original ArticleOriginal Article
Original Article
Hypothalamic-pituitary-gonadal function in men with liverHypothalamic-pituitary-gonadal function in men with liver
Hypothalamic-pituitary-gonadal function in men with liverHypothalamic-pituitary-gonadal function in men with liver
Hypothalamic-pituitary-gonadal function in men with liver
cirrhosis before and after liver transplantationcirrhosis before and after liver transplantation
cirrhosis before and after liver transplantationcirrhosis before and after liver transplantation
cirrhosis before and after liver transplantation
Função do eixo hipotálamo-hipófise-gonadal em homens cirróticos antes e apósFunção do eixo hipotálamo-hipófise-gonadal em homens cirróticos antes e após
Função do eixo hipotálamo-hipófise-gonadal em homens cirróticos antes e apósFunção do eixo hipotálamo-hipófise-gonadal em homens cirróticos antes e após
Função do eixo hipotálamo-hipófise-gonadal em homens cirróticos antes e após
o transplante hepáticoo transplante hepático
o transplante hepáticoo transplante hepático
o transplante hepático
BRUNO T. ZACHARIAS1; JULIO C. U. COELHO,TCBC-PR2; MÔNICA B. PAROLIN3; JORGE E. F. MATIAS,ACBC-PR1;
ALEXANDRE C. T. DE FREITAS,TCBC-PR1; JOSÉ LUIZ DE GODOY3
ABSTRACTABSTRACT
ABSTRACTABSTRACT
ABSTRACT
Objective:Objective:
Objective:Objective:
Objective: To evaluate the influence of end-stage liver disease and orthotopic liver transplantation in the pituitary function and
hormone metabolism before and after liver transplantation. Methods:Methods:
Methods:Methods:
Methods: In a prospective study, serum levels of follicle stimulating
hormone (FSH), luteinizing hormone (LH), estradiol (E2) and prolactin (PRL) of 30 male patients with cirrhosis were determined two
to four hours before and six months after liver transplantation. The results were compared according to the Model for End-stage
Liver Disease (MELD). ResultsResults
ResultsResults
Results: male patients with liver cirrhosis have hypogonadism. FSH was normal, but inappropriately low due
to androgen failure; E2 and PRL, on their turn, were high. After liver transplantation, FSH and LH levels increased (p < 0.05), whereas
E2 and PRL normalized (p < 0.05). The MELD score did not influence changes in FSH, PRL and LH, however, the more severe the
cirrhosis was, the more significant was the normalization of E2 (p = 0.01). ConclusionConclusion
ConclusionConclusion
Conclusion: Patients with cirrhosis and male hypogonadism
have inappropriately normal levels of FSH and LH, associated with an increase in E2 and LRP. After liver transplantation, FSH and LH
increased, while E2 and PRL returned to normal. Changes in E2 levels were most pronounced in patients with MELD > 18. The
severity of cirrhosis had no influence on FSH, PRL and LH.
Key wordsKey words
Key wordsKey words
Key words: Liver Transplantation, Liver Cirrhosis, Pituitary Gland, Hypogonadism.
1. Department of Surgery of the Digestive System, Clinics Hospital, Federal University of Paraná, Curitiba, Paraná – PR, Brazil; 2. Service of
Surgery of the Digestive System and Liver Transplantation, Federal University of Paraná; 3. Liver Transplantation Service, Federal University of
Paraná.
INTRODUCTIONINTRODUCTION
INTRODUCTIONINTRODUCTION
INTRODUCTION
Patients with end-stage liver disease have several
endocrine dysfunctions, which include alterations in the
functioning of the hypothalamic-pituitary-gonadal axis and
the serum levels of sex hormones 1-4. Testicular atrophy,
decrease in libido, impotence, oligospermia, infertility,
loss of body hair, reduction of prostate size,
gynecomastia, vascular spiders, gynecoid distribution of
fat and palm erythema are often found in cirrhotic men
5-10. These findings are more pronounced in patients with
alcoholic cirrhosis due to the direct harmful effect of
ethanol to the testicles. The pathophysiology of
hypogonadism in patients with advanced liver disease is
complex and controversial.
Few studies have evaluated the dysfunction of
the hypothalamic-pituitary-gonadal axis in men with cirrhosis
before and after orthotopic liver transplantation (OLT). The
correlation between changes in serum levels of sex
hormones and the MELD score (Model for End-stage Liver
Disease) has not yet been studied.
The aim of this study was to evaluate the
influence of terminal liver disease and OLT in the pituitary
function and hormone metabolism by measurement of
serum levels of follicle stimulating hormone (FSH), luteinizing
hormone (LH), estradiol (E2) and prolactin (PRL) before and
after liver transplantation.
METHODSMETHODS
METHODSMETHODS
METHODS
Between August 2008 and April 2011, 93 liver
transplants were performed at the Clinics Hospital of the
Federal University of Paraná. The study included all male
patients who did not present any of the following exclusion
criteria: patients submitted to living-donor transplantation,
re-transplantation, multivisceral transplantation, domino
transplant and split liver transplant. Five patients who died
were also excluded. In total, 30 men were selected and
prospectively followed.
We used the Child-Pugh and MELD scores to
determine the severity of liver disease. Among those
DOI: 10.1590/0100-69912014006007

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Hypothalamic-pituitary-gonadal function in men with liver cirrhosis before and after liver transplantation
included in the study, three patients (12%) were Child-
Pugh class A, 6 (24%) class B, and 16 (64%) class C. The
MELD ranged from 10 to 30 points, averaging 17.7 + 4.2
(95% CI 16.1-19.2). We did not consider the additional
scores for cirrhotic patients with associated hepatocellular
carcinoma. To evaluate the relationship between the
severity of liver disease and the variation in the levels of
sex hormones, we divided the study subjects into two groups,
based on MELD classification, 17 patients with MELD <18,
and 13 with MELD e” 18.
The mean age was 51.4 ± 7.6 years. The main
causes of cirrhosis were infection with hepatitis C and alcohol
abuse (Table 1). All patients with alcoholic cirrhosis were
abstinent for more than six months prior to OLT.
After liver transplantation, all patients underwent
the same standard protocol of immunosuppressive therapy,
consisting of cyclosporine or tacrolimus, mycophenolate
mofetil and corticoids.
We collected peripheral blood samples two to
four hours before induction of anesthesia and six months
after liver transplantation, with determination of levels of
FSH, LH, E2 and PRL through commercial immunoassay
kits. We also measured total bilirubin, prothrombin and
creatinine by routine biochemical tests for determining the
MELD score on the day of transplantation.
The study protocol was in accordance with
guidelines of the Helsinki Declaration of 1975, and was
approved by the Ethics Committee of the Clinics Hospital
of the Federal University of Paraná, Brazil (CAAE:
0159.0.208.000-08, CEP Registration: 1712.129 / 2008- 07).
All patients signed an informed consent form to participate
in the study.
Statistical AnalysisStatistical Analysis
Statistical AnalysisStatistical Analysis
Statistical Analysis
The measures of central tendency and dispersion
are expressed as means and standard deviation (mean ±
SD) for symmetrically distributed, continuous variables, and
as median, minimum and maximum values for the ones
with asymmetric distribution.
The estimated difference of continuous variables
with normal distribution were analyzed by parametric tests,
Student’s t test for dependent samples, and ANOVA for
repeated measures, while for asymmetric distribution
variables we employed the non-parametric Wilcoxon and
Friedman ANOVA tests. We applied the McNemar test in
the study of the behavior of biochemical and hormonal
variables according to the reference values, evaluating the
categories’ variations: normal, below and above the
reference value, before and after liver transplantation. The
results were considered statistically significant when p d”
0.05.
RESULTSRESULTS
RESULTSRESULTS
RESULTS
The FSH and LH levels were within normal limits
and increased, respectively, from 8.1 mIU/ml to 13.4 mIU/
ml (p = 0.002) and from 4.6 mIU/mL to 9.9 mIU/ml (p
<0.001) after OLT. Estradiol was initially high, and returned
to normal after liver transplantation (p = 0.001). Prolactin
levels were also elevated preoperatively. After OLT its levels
decreased to normal (p <0.001) (Table 2).
The multivariate analysis based on generalized
linear models showed no influence of age on the date of
transplantation or the etiology of cirrhosis in the hormonal
changes observed.
In both MELD groups we observed a rise
in serum FSH values before and after OLT (p = 0.004), but
without significant difference (p = 0.89) (Figure 1). There
Table 2 Table 2
Table 2 Table 2
Table 2 -Serum levels of FSH, LH, PRL and EE.
HormoneHormone
HormoneHormone
Hormone ReferenceReference
ReferenceReference
Reference Pre-OLTPre-OLT
Pre-OLTPre-OLT
Pre-OLT Post-OLTPost-OLT
Post-OLTPost-OLT
Post-OLT pp
pp
p
FSH 1.5 – 12.4 mUI/mL 8.1 (0.7 – 73.0) 13.4 (2.2 – 92.5) 0.002
HL 1.7 – 8.6 mUI/mL 4.6 (1.3 – 34.0) 9.9 (2.9 – 82.2) < 0.001
E2 < 43 pg/mL 54.7 (26.0 – 466.0) 33.5 (15.5 – 314.0) 0.001
PRL 2.0 – 15.2 ng/mL 16.5 (4.8 – 68.1) 8.4 (3.2 – 29.0) < 0.001
OLT = Orthotopic Liver Transplantation; FSH = Follicle Stimulating Hormone; HL = Luteinizing Hormone; E2 = Estradiol; PRL = Prolactin.
Table 1 Table 1
Table 1 Table 1
Table 1 -Clinical and Demographic Characteristics of
patients.
FeaturesFeatures
FeaturesFeatures
Features PatientsPatients
PatientsPatients
Patients
Number 30
Age (in years)
Mean ± Sd 51.4 ± 7.6
Variation 25 – 64
IC 95% 48.6 – 54.3
Gender (male/female) 30/0
Etiology of cirrhosis N(%)
HCV infection 10 (33.33)
Alcohol abuse 8(26.67)
NASH 3(10.0)
HBV infection 2(6.67)
Hemochromatosis 2(6.67)
Other 5(16.67)
Associated Hepatocarcinoma 4(13.33)
CI = confidence interval; SD = standard deviation; HCV = hepatitis C
virus; HBV = hepatitis B virus; NASH =
Nonalcoholic Steatohepatitis
.

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was an increase in HL in the MELD group < 18 (p = 0.01),
while there was no change in the MELD group e” 18 (p =
0.26). Nor was there a significant difference between groups
(p = 0.89) (Figure 2). There was a drop in estradiol values
after OLT both in the group with MELD <18 (p = 0.05) and
in the one with MELD e” 18 (p = 0.005), being more
pronounced in the group with Meld e” 18 (p = 0.006) (Fi-
gure 3). There was a reduction in serum prolactin levels in
the MELD group <18 (p = 0.03) and MELD e” 18 (p =
0.005), with no statistically significant difference (p = 0.07)
(Figure 4).
DISCUSSIONDISCUSSION
DISCUSSIONDISCUSSION
DISCUSSION
Male patients with cirrhosis have a number of
changes in the regulation of their sex hormones, resulting
in hypogonadism and feminization. End-stage liver disease
causes dysfunction in the hypothalamic-pituitary-gonadal
axis and hormonal peripheral metabolism 1,2,11,12, resulting
in a significant deterioration in quality of life 3-10.
Our prospective study showed that cirrhotic men
have significant alterations in the pituitary regulatory
functions, and that these disorders are completely reversed
after liver transplantation.
The FSH and HL were at levels within their
reference values, and increased after OLT 13. These data
confirm the results of previous studies. However, it is
important to note that serum levels of these hormones were
inappropriately low, given the androgen failure evidenced
in these patients 7,14,15. In fact, one would expect them to
suffer a compensatory increase due to low serum
testosterone levels. Our results showed that six months after
transplantation the values of FSH and HL showed a
Figure 4 -Figure 4 -
Figure 4 -Figure 4 -
Figure 4 - Liver Transplantation Orthotopic (OLT); prolactin (PRL).
Reduction in levels of PRL in the MELD groups <18 (p
= 0.03) and e” 18 (p = 0.005), with no difference
between them (p = 0.07).
Figure 3 Figure 3
Figure 3 Figure 3
Figure 3 -Orthotopic Liver Transplantation (OLT); estradiol (E2).
Reduction in E2 levels in groups MELD <18 (p = 0.05)
and MELD score e” 18 (p = 0.005), more pronounced
in the MELD group e” 18 (p = 0.01).
Figure 2 -Figure 2 -
Figure 2 -Figure 2 -
Figure 2 - Orthotopic liver transplantation (OLT); luteinizing
hormone (LH). Increases in serum LH levels in the MELD
group <18 (p = 0.01), not observed in the MELD group
e” 18 (p = 0.26), with no difference between them (p
= 0.89).
Figure 1 -Figure 1 -
Figure 1 -Figure 1 -
Figure 1 - Orthotopic liver transplantation (OLT); follicle
stimulating hormone (FSH). Increased serum FSH levels
in both groups MELD <18 and MELD e” 18 (p = 0.04),
with no difference between them (p = 0.89).
Before OLT6 months after OLTBefore OLT6 months after OLT
Before OLT6 months after OLT
Before OLT6 months after OLT

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Hypothalamic-pituitary-gonadal function in men with liver cirrhosis before and after liver transplantation
significant increase, suggesting that the liver disease had a
direct influence on this abnormality, which is consistent with
the available literature on the subject 3,12,13 16.
The exact cause of this central dysfunction has
not been clearly elucidated. It is speculated that liver cirrhosis
alone can cause a malfunction of the hypothalamic-
pituitary-gonadal axis1,3,10. Furthermore, high circulating
levels of estradiol and prolactin also contribute to
hypogonadism2,3, either by regulatory suppression or by
direct inhibition of the testicular function10. The results also
showed that both the PRL and E2 were at levels above
normal in patients with end-stage liver disease, with
normalization after OLT, in line with previous studies 1,17,18.
The increase in serum levels of E2 is primarily due to
increased peripheral conversion of androgens into estrogens
and reduction in liver clearing function 5,7. Portal hypertension
can lead to a diversion of blood flow from the liver to
peripheral tissues, resulting in a further increase in the
conversion of steroids into estrogens8. Although some studies
2,19,20 have established a correlation between increased PRL
in cirrhosis and hyperestrogenemia, the mechanism that
leads to hyperprolactinemia is not yet clear.
Another important finding of our study is the
correction between these hormonal changes and the MELD
score at the time of transplantation. It was found that the
severity of liver disease has no influence on changes in
FSH, LH and PRL (p = 0.89, p = 0.89 and p = 0.07,
respectively) after OLT. This may be due to the limited
number of patients included in this analysis.
However, E2 values decreased after liver
transplantation in direct proportion with the worst liver
function (p = 0.01). Furthermore, the higher the value of
MELD at the time of OLT, the more significant the
normalization of estradiol (p = 0.006).
Finally, after the evaluation of the impact of liver
transplantation in the hypothalamic-pituitary-gonadal
dysfunction in male cirrhotic patients, we observed that all
hormone levels are normal six months after transplantation.
This conclusion is consistent with the literature 3,7,10,13,16-18.
Seehofer
et al
, after a five-year follow-up of their patients,
found that this improvement is persistent 12.
The present study demonstrated that male
patients with end-stage liver disease have inappropriately
low levels of FSH and LH due to androgenic failure, and
elevated serum E2 and PRL. After liver transplantation, FSH
and LH values increased, while E2 and PRL returned to
normal. Changes in estradiol are more pronounced in
patients with higher MELD (MELD e” 18). Changes of FSH,
PRL and LH did not vary according to the severity of liver
disease.
RESUMORESUMO
RESUMORESUMO
RESUMO
Objetivo: Objetivo:
Objetivo: Objetivo:
Objetivo: avaliar a influência da doença hepática terminal e do transplante hepático ortotópico na função hipofisária e no
metabolismo hormonal através da aferição dos níveis séricos dos hormônios folículo estimulante (FSH), hormônio luteinizante (HL),
estradiol (E2) e prolactina (PRL) antes e após o transplante hepático. Métodos: Métodos:
Métodos: Métodos:
Métodos: em um estudo prospectivo, níveis séricos dos
hormônios folículo estimulante (FSH), hormônio luteinizante (HL), estradiol (E2) e prolactina (PRL) de 30 paciente masculinos com
cirrose foram determinados duas a quatro horas antes e seis meses após o transplante hepático. Os resultados foram comparados
de acordo com o
Model for End-stage Liver Disease
(MELD). Resultados: pResultados: p
Resultados: pResultados: p
Resultados: pacientes masculinos com cirrose hepática apresentam
hipogonadismo. O FSH encontravam-se normais, porém inapropriadamente baixos devido à falência androgênica; já o E2 e o PRL
estavam elevados. Após o transplante hepático, os níveis de FHS e HL aumentaram (p < 0,05), enquanto o E2 e o PRL normalizaram
(p < 0,05). O MELD não influenciou as alterações no FSH, HL ou PRL, todavia, quanto mais grave a cirrose, mais significante foi a
normalização do E2 (p=0,01). Conclusão: Conclusão:
Conclusão: Conclusão:
Conclusão: pacientes masculinos com cirrose e hipogonadismo apresentam níveis inapropriadamente
normais de FSH e HL, associados com elevação do E2 e PRL. Após o transplante hepático, FSH e HL aumentaram, enquanto E2 e PRL
retornaram aos valores normais. As alterações nos níveis de E2 foram mais pronunciadas em pacientes com MELD > 18. A gravidade
da cirrose não teve influência no FSH, HL e PRL.
DescritoresDescritores
DescritoresDescritores
Descritores: Transplante de Fígado, Cirrose Hepática, Hipófise, Hipogonadismo.
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Received 16/01/2014
Accepted for publication 20/03/2014
Conflict of interest: none.
Source of funding: none.
Mailing address:Mailing address:
Mailing address:Mailing address:
Mailing address:
Bruno T. Zacharias
E-mail: brunozacharias@hotmail.com