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Hepatotoxicity induced by cyproterone acetate: A report of three cases

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Cyproterone acetate (CPA) is a steroidal synthetic progestagen and anti-androgenic compound widely administered in prostate cancer which has been evidentially correlated with a severe hepatotoxic potency. Three male patients aged 78-83 years are presented, in whom severe hepatotoxic reactions emerged after CPA administration. Patients were treated with CPA at the doses of 200-300 mg/d for malignant prostate disease for 3-12 mo prior to the acute manifestation of the hepatic disease. Clinical features compatible with mixed hepatocellular and cholestatic liver disease including jaundice, white stools and dark urine, manifested in all three cases whereas encephalopathy and ascites were present in two of the patients. Other primary causes of hepatotoxicity (alcohol consumption and viral hepatitis) were also verified in two cases, and in those patients biopsy findings revealed the presence of cirrhotic lesions in liver parenchyma. Discontinuation of the therapeutic agent led to the amelioration of the clinical profile in all the patients whereas a patient died 40 d after hospital admission due to sepsis, despite acute liver disease improvement. The current article highlights the hepatotoxic potency of a widely administered therapeutic agent and illustrates the importance of clinical surveillance especially in patients with previous hepatic diseases. Three relevant cases are reported and a review of the published literature is made.
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PO Box 2345, Beijing 100023, China World J Gastroenterol 2006 December 14; 12(46): 7551-7555
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World Journal of Gastroenterology
ISSN 1007-9327
wjg@wjgnet.com © 2006 The WJG Press. All rights reserved.
Hepatotoxicity induced by cyproterone acetate: A report of
three cases
Ioanna Savidou, Melanie Deutsch, Aspasia S Soultati, Dimitrios Koudouras, Georgia Ka ri, Spyridon P Dourakis
CASE REPORT
Ioanna Savidou, Melanie Deutsch, Aspasia S Soultati,
Dimitrios Koudouras, Spyridon P Dourakis
, 2nd Department
of Medicine, University of Athens Medical School, Hippokration
General Hospital, 114 Vas So as Avenues, 11527, Athens, Greece
Georgia Ka ri
, Department of Pathology, Hippokration General
Hospital, Greece
Correspondence to:
Spyridon P Dourakis, 28 Achaias st, 11523
Athens, Greece. spdour@med.uoa.gr
Telephone:
+30-693-2272 477
Fax:
+30-210-6993 693
Received:
2005-11-17
Accepted:
2005-12-07
Abstract
Cyproterone acetate (CPA) is a steroidal synthetic
progestagen and anti-androgenic compound widely
administered in prostate cancer which has been
evidentially correlated with a severe hepatotoxic potency.
Three male patients aged 78-83 years are presented, in
whom severe hepatotoxic reactions emerged after CPA
administration. Patients were treated with CPA at the
doses of 200-300 mg/d for malignant prostate disease
for 3-12 mo prior to the acute manifestation of the
hepatic disease. Clinical features compatible with mixed
hepatocellular and cholestatic liver disease including
jaundice, white stools and dark urine, manifested in all
three cases whereas encephalopathy and ascites were
present in two of the patients. Other primary causes of
hepatotoxicity (alcohol consumption and viral hepatitis)
were also verified in two cases, and in those patients
biopsy ndings revealed the presence of cirrhotic lesions
in liver parenchyma. Discontinuation of the therapeutic
agent led to the amelioration of the clinical profile
in all the patients whereas a patient died 40 d after
hospital admission due to sepsis, despite acute liver
disease improvement. The current article highlights the
hepatotoxic potency of a widely administered therapeutic
agent and illustrates the importance of clinical
surveillance especially in patients with previous hepatic
diseases. Three relevant cases are reported and a review
of the published literature is made.
© 2006 The WJG Press. All rights reserved.
Key words:
Cyproterone acetate; Drug induced
hepatotoxicity; Prostate cancer; Idiosyncratic drug
reaction; Hepatomitogen action
Savidou I, Deutsch M, Soultati AS, Koudouras D, Ka ri G,
Dourakis SP. Hepatotoxicity induced by cyproterone acetate:
A report of three cases.
World J Gastroenterol
2006; 12(46):
www.wjgnet.com
7551-7555
http://www.wjgnet.com/1007-9327/12/7551.asp
INTRODUCTION
Androgen deprivation therapy in the form of either
orchiectomy or treatment with endogenous estrogens
or luteinizing hormone releasing hormone (LHRH)
analogues alone or coupled with antiandrogens, produces
regression of prostate cancer cells through suppression of
serum testosterone levels, and is on that ground regarded
as an effective adjuvant therapeutic option. Cyproterone
acetate (CPA) is a steroidal synthetic progestagen and
antiandrogenic compound widely administered not only
in prostate cancer but also in breast cancer, severe acne,
female hirsutism, precocious puberty, hyper sexuality and
sexual deviation in men. CPA inhibits the peripheral actions
of testosterone and suppresses gonadotropin secretion
by maintaining the negative feedback on the pituitary.
Hepatotoxicity is a serious adverse reaction potentially
induced by both steroidal and nonsteroidal antiandrogens.
The first case of CPA-induced fulminant hepatitis with
a fatal outcome was described in 1989
[1]
. A variety of
hepatotoxic reactions have been documented in the
literature including immunoallergic cytotoxic reactions
[2]
,
cholestasis, autoimmune hepatitis
[3]
, acute hepatitis
[4-10]
fulminant hepatic failure
[1,2,11-17]
cirrhosis
[18]
and nally CPA
has been attributed a hepatocellular mutagenic potency
leading to hepatocarcinogenesis
[8,19-27]
. Clinical features
include jaundice, fatigue, nausea, elevated serum levels
of liver enzymes, different types of necrosis (bridging,
confluent, and centrilobular), inflammation and features
of hepatic decompensation
[19]
. This article highlights the
hepatotoxic potency of a widely administered therapeutic
agent and illustrates the importance of clinical surveillance.
Three relevant cases are presented and a review of the
published literature is made.
We searched the database PubMed (1995-2005)
using the following key words: “cyproterone acetate
hepatotoxicity”, “drug induced hepatotoxicity”. We also
included review articles, book chapters, or commonly
referenced publications. We reviewed the reference lists of
articles identi ed by the search strategy and selected those
we judged relevant. The search was restricted to papers
published in English.
CASE REPORT
Three male patients aged 78-83 years with clinical features
compatible with mixed hepatocellular and cholestatic
liver diseases, including jaundice, white stools and
dark urine were admitted to Hippocration University
Hospital of Athens. Clinical manifestations including
encephalopathy (Case 2) and ascites were documented
in two of the patients (Case 1 and 2) (Table 1). The
main characteristics of patients, as well as the values of
bilirubin, aspartate (AST) and alanine aminotransferase
(ALT), International Normalized Ratio (INR), albumin,
and alkaline phosphatase (ALP) at the time of admission
are depicted in Table 1. All three patients had been
administered cyproterone acetate for 3-12 mo for prostate
cancer without metastasis, at a dose ranging from 200-300
mg/d. Extensive clinical evaluation and exclusion of
other potential hepatotoxic causes were performed. No
serological evidence of recent acute viral hepatic infection
was verified whereas in Case 3, pre-existing chronic
inactive hepatitis B virus infection was justi ed based on
compatible serological ndings (hepatitis B virus surface
(HBs) antigen was positive and hepatitis B virus DNA
negative by hybridization assay). In addition, a history
of excessive alcohol consumption was documented in
Case 1. Autoimmunity markers were negative and no
evidence of tumor in the liver or pelvis was seen on the
computer tomography scan. Yet the presence of cirrhotic
lesions was verified in Cases 1 and 3 on tomography.
Liver biopsy was performed in all three Cases (Figure 1).
In Cases 1 and 3, cirrhosis with brosis and loss of the
normal lobular architecture were revealed and attributed
to chronic hepatitis B and alcohol consumption. In all
three cases, hepatocellular degeneration with ballooning
of hepatocytes, portal and lobular inflammation and
marked cholestasis with bile plugs were also demonstrated.
Discontinuation of the therapeutic agent led to the
restoration of the pathological clinical pro le in Cases 1
and 3 whereas this was not accomplished in the second
patient who died 40 d after hospital admission, due to
sepsis, despite acute liver disease improvement. (Figures 2
and 3).
Table 1 Patients’ laboratory values
Case Age (yr) Use of
cyproterone
acetate (mo)
Daily
dose
(mg)
Bilirubin
(total/direct,
g/L)
1
AST/ALT
(IU/L)
2
Alkaline
phospatase
(IU/L)
3
Albumin
(g/L)
4
INR
5
1 82 12 200 29.5/18.4 935/535 300 3.9 1.4
2 83 7 300 10.1/9.2 721/283 350 4 2.24
3 78 3 300 30.0/25.3 505/320 380 4.2 1.2
1
Normal values (total) < 1.2 g/L, normal values (direct) < 0.4 g/L;
2
Normal values < 40 IU/L;
3
Normal values < 133
IU/L;
4
Normal values > 3.5 g/L;
5
Normal values < 1.2
Figure 1 Hepatocellular degeneration, with ballooning of hepatocytes, portal and
lobular in ammation and marked cholestasis with bile plugs were demonstrated in
liver biopsy ndings (liver biopsy from case 2).
0 10 20 30 40 (d)
1000
900
800
700
600
500
400
300
200
100
0
AST (IU/L)
Figure 2: Serum aspartate aminotransferase levels following withdrawal of
cyproterone acetate.
35
30
25
20
15
10
5
0
Bilirubin (g/L)
0 10 20 30 40 (d)
Case 1
Case 2
Case 3
Figure 3 Serum total bilirubin levels following withdrawal of cyproterone acetate.
7552 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol December 14, 2006 Volume 12 Number 46
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DISCUSSION
The diagnosis of drug-induced hepatotoxicity is usually
based on exclusion of other possible causes of hepatic
dysfunction and on the temporal association between
drug administration and the onset of liver disease while
liver biopsy may allow a correct diagnosis
[28,29]
. Toxic
hepatitis in our patients appeared to be causally related
to the administration of cyproterone acetate based on a
temporal relationship, negative serology for acute viral
infection, negative autoantibody markers and exclusion
of drugs or other potentially hepatotoxic agents. Proof is
not possible in the absence of the rechallenge for ethical
reasons. Pathophysiology of CPA-induced hepatotoxicity
remains largely hypothetical. The histological features
fit with an idiosyncratic reaction to the drug or its
metabolites, or possibly an immunologically mediated
reaction
[2]
. In many cases, a direct drug or metabolite
effect is implied attributed to the hepatomitogen action
of cyproterone, causing an increase of hepatocytes
expressing placental glutathione S-transferase, which are
considered preneoplastic elements
[30-31]
. The combination
of Transforming Growth Factor-beta 1 (TGF) expression
coupled with a strikingly enhanced sensitivity to the
induction of apoptosis might be responsible for both
the liver damage and the development of liver tumors
observed after CPA supplementation since CPA shortens
the lag phase of induction of apoptosis by shifting
hepatocytes to a point before S phase, where they are
highly susceptible to TGF-beta 1-induced apoptosis
[19,32]
.
Hinkel
et al
[33]
have conducted a retroprospective
analysis of 89 patients who received cyproterone acetate
for 4 years (50mg/d po range, 2-152 mo) for prostate
cancer. Elevated liver enzymes were documented in
28.2% of the patients, yet CPA-induced liver toxicity
and carcinogenesis were implied to be totally irrelevant
considering the life expectancy of patients with advanced
prostate cancer and the high-dose exposure of CPA
required to possibly induce liver malignancies. Since then
several large series have assessed the same issue with yet
controversial results. In 1996, a retrospective study was
conducted in 2506 patients receiving CPA (18-136 mg/d
for less than 47.5 mo/patient) and a correlation with
hepatocarcinogenesis could not be established. And 9.6%
of the patients eventually presented with pathological liver
profile, yet discontinuation of the therapeutic agent was
not regarded necessary in any case
[8]
. Lin
et al
[34]
assessed
229 patients by retrospective chart review submitted in
orchiectomy or LHRH analogues plus antiandrogen for
prostate cancer. In 105 patients administered with CPA
(150 mg/d), hepatotoxity rates were 9.5%. Serious hepatic
injury was documented in 3.8% (4/105) of the patients,
mean latency period of hepatotoxity was estimated to be
5.8 ± 1.9 mo and in 9 out of 10 patients CPA-induced
hepatotoxity got self resolution after discontinuation of
the antiandrogen in an average period of 6.3 ± 4.7 mo
[34]
.
In another study, patients with a preexisting chronic
viral hepatitis were recognized as having a higher risk of
developing antiandrogen hepatotoxicity
[35]
. Finally in a
series assessing predictive utility of several clinical features,
both age and therapeutic indication or the dose prescribed
failed to depict with signi cant accuracy, those patients at
risk for presenting hepatic disorders
[36]
.
In the three cases of severe CPA-induced hepatotoxi-
city presented in this article patients were administered
with CPA at the doses of 200-300 mg/d for malignant
prostate disease for 3-12 mo prior to the manifestation
of hepatic disease. In two of the patients, other primary
causes of hepatotoxicity (excessive alcohol consumption
and viral hepatitis) were also veri ed and in those patients,
biopsy ndings revealed the presence of cirrhotic lesions
in liver parenchyma along with acute cholestatic hepatitis.
Discontinuation of the therapeutic agent resulted in
the amelioration of the hepatic injury in all the patients
whereas Case 2 died 40 d after hospital admission from
sepsis.
Eleven cases assessing CPA-induced fulminant hepatic
failure are presented in the literature
[1,2,11-17]
. According
to Friedman
et al
[13]
adverse hepatic reactions occurred
more commonly in elderly patients (range, 65-92 years)
with malignant diseases who were treated with high doses
(range, 100-300 mg) for a prolonged period. Fulminant
hepatic failure developed a few weeks to several months
after initiation of therapy (range, 2-15 mo). On admission,
aminotransferases were 3-27 times that of normal,
and a markedly elevated bilirubin of 9-30 times higher
than normal were also documented, but the ALP was
usually 2 times lower than normal. Clinical features of
hepatotoxicity initially included nausea, anorexia and
malaise; however, a progressive jaundice eventually ensued.
The duration from the onset of jaundice to death was
2-7 wk
[13]
. Beside acute liver failure, a less severe hepatic
reaction can emerge on the ground of CPA-administration.
Eight cases of acute hepatitis complicating CPA-treatment
have been documented in the literature
[4-10]
. Doses of
100-150 mg/d are correlated with mild hepatotoxic
reactions, mainly elevated transaminase levels, whereas an
association between the duration of CPA-treatment and
the prevalence of liver enzymes could not be established
[8]
.
Latency before the onset of hepatocellular carcinoma and
cirrhosis after CPA therapy is estimated up to several years.
Preexisting viral, metabolic, drug-induced or alcoholic liver
diseases are found correlated with the development of
more severe hepatotoxic reactions. Discontinuation of the
antiandrogens results in the resolution of hepatotoxicity.
A change to other antiandrogen may be the alternative
strategy to CPA-induced hepatic injury although
controversy exists upon that issue
[9]
. After the withdrawal
of the causative agent, hepatocellular recovery is achieved
within 2-3 mo
[19]
. Fourteen case reports involving CPA-
induced hepatotoxicity are reviewed with regard to the
patient’s age, dose of CPA, latency before the onset of
jaundice and duration between onset of jaundice and
death
[13,36]
(Table 2). Descriptive statistics including means,
medians and standard deviations were calculated, and are
displayed in Table 2. Age and CPA doses were plotted in
correlation with mortality (Figure 4). Relevant statistics
were calculated and no statistically signi cant correlation
was demonstrated between age and doses of CPA and the
clinical outcome (death or survival) (
P
= 0.241 and
P
=
0.789 for CPA doses and age, respectively; not signi cant).
In conclusion
the aim of this report and review of
Savidou I
et al
. Cyproterone acetate induced hepatotoxicity 7553
www.wjgnet.com
the literature is to underline the potential hepatotoxicity
effect of CPA, which may prove fatal in some cases.
Close monitoring of liver function tests is recommended,
particularly on the setting of a pre-existing liver disease for
which increased risk rate has been implied.
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Table 2 CPA-induced hepatotoxicity: review of 14 cases
Reference Age
(yr)
Liver
injury
Doses (mg) Latency (mo) Duration
1
(wk)
Levesque
[1]
78 ALF 200 6 2
Parys
[11]
65 ALF 300 12 7
Parys
[11]
83 ALF 300 15 2
Bressollette
[16]
79 ALF 300 10 2
Hirsch
[14]
92 ALF 100 4 5
Murphy
[2]
73 ALF 100 4 Alive
Lombardi
[15]
84 ALF 1
Friedmann
[13]
81 ALF 300 6 7
Friedmann
[13]
66 ALF 300 2 4
Giordano
[10]
87 AH 300 Alive
Manolakopoulos
[9]
76 AH 150 7 Alive
Savidou 82 AH 200 12 Alive
Savidou 83 AH 300 7 6
Savidou 78 AH 300 3 Alive
Mean 79.1 242.3 7.3 4
Median 80 300 6.5 4
SD 7.4 81.2 4 2.3
1
Duration between onset of jaundice and death; ALF: Acute liver failure; AH:
Acute hepatitis.
400
300
200
100
0
60 70 80 90 100
Age/yr
Doses/mg
Outcome
Died
Alive
Figure 4 Scatter plot graphed for patient death events in correlation with patient’s
age and CPA-doses administered (Table 2).
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S- Editor
Wang J
L- Editor
Ma JY
E- Editor
Lu W
Savidou I
et al
. Cyproterone acetate induced hepatotoxicity 7555
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... Mild and transient elevation in levels of liver enzymes is reported in 10-30% of patients, and acute liver failure (ALF) is uncommon. CPA induced ALF has been reported only in 14 cases, either as case reports or case series, to the best of our knowledge of studies published in English [2][3][4][5][6][7][8][9][10][11] (Table 2). Here, we report the first case of ALF due to CPA in a young woman from the Indian subcontinent. ...
... Preliminary studies have shown that the combination of enhanced expression of transforming growth factor b1 and increased sensitivity to induction of apoptosis in hepatocytes by CPA could be responsible for liver injury. 3,4,12 Idiosyncratic DILI is caused by the interaction of the drug with various environmental and host factors. It has a long latency period ranging from few days to months and usually occurs at a dose of >50-100 mg per day, which varies among individuals. ...
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Cyproterone acetate (CPA), a hydroxyprogesterone derivative, is used to treat advanced prostate cancer and infrequently in females for acne, breast cancer, and hirsutism. Transient mild liver enzymes' elevation is reported in 10% -30% of patients, and acute liver failure (ALF) is uncommon. Here we discuss the first case of CPA-induced ALF from India and the available literature.
... However, adverse effects are reported during CPA administration such as weight gain, hepatotoxicity, dosedependent sedative effects and depression (2,6). Episodes of hepatotoxicity have been documented but after higher doses of CPA (100-300 mg) in elderly treated for cancer for long periods (7). Transgenders are a different population, with their own characteristics and risk factors to which is difficult to apply these data. ...
Article
Objective: The impact of different combinations of long-term gender-affirming hormone therapy (GAHT) in transwomen (TW) is largely unknown. To assess the effects of 5-year administration of cyproterone acetate (CPA) or leuprolide acetate (Leu) plus transdermal or oral estradiol (E). Design: Cohort study based on prospectively collected data. Fifty TW received 50 mg CPA daily orally (n = 25; CPA+E group) or 3.75 mg Leu i.m. monthly (n = 25; Leu+E group) with 1 or 2 mg E daily for 5 years. Reproductive hormones, biochemical and anthropometric parameters, body composition and bone mineral density (BMD) were assessed. Results: LH, FSH and total testosterone levels were similarly and significantly suppressed in both groups. Prolactin increased only in the CPA+E group (P = 0.002). Fasting insulin resistance and glucose progressively increased in the CPA+E group only (treatment × time effect P = 0.002 and P = 0.043, respectively). Total cholesterol increased more in the Leu+E group than in the CPA+E group and HDL-cholesterol decreased in the CPA+E group (time × treatment interaction effect, P = 0.007). Lumbar and total body BMD increased in both groups after 3 years. No serious adverse events were recorded. Conclusions: Both regimens were effective in suppression of T production. CPA+E worsened the metabolic profile with a slight increase in PRL levels. All subjects presented an increase in BMD regardless of treatment. These preliminary data could have clinical implications in the choice of GAHT, in particular for those TW not requiring gender-affirming surgery.
... Supporting our findings, a recently published US retrospective audit of 98 transfeminine individuals found only a quarter of those on spironolactone achieved total testosterone concentrations in the female reference range 8 . Notably, although cyproterone has been used internationally for many years, it is not available in the US due to rare case reports of hepatotoxicity in men receiving high doses for prostate cancer 9 . Reasons for the variable effects of spironolactone and cyproterone on serum testosterone concentrations may well be related to differing mechanisms of action. ...
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Background: Estradiol with or without an antiandrogen (cyproterone acetate or spironolactone) is commonly prescribed in transfeminine individuals who have not had orchidectomy, however there is no evidence to guide optimal treatment choice. Objective: We aimed to compare add-on cyproterone acetate versus spironolactone in lowering endogenous testosterone concentrations in transfeminine individuals. Design: Retrospective cross-sectional study. Methods: We analysed 114 transfeminine individuals who had been on estradiol therapy for >6 months in two gender clinics in Melbourne, Australia. Total testosterone concentrations were compared between three groups; estradiol alone (n=21), estradiol plus cyproterone acetate (n=21) and estradiol plus spironolactone (n=38). Secondary outcomes included serum estradiol concentration, estradiol valerate dose, blood pressure, serum potassium, urea and creatinine. Results: Median age was 27.0 years (22.5, 45.1) and median duration of hormone therapy was 1.5 years (0.9, 2.6), which was not different between groups. On univariate analysis, the cyproterone group had significantly lower total testosterone concentrations (0.8nmol/L (0.6, 1.20)) compared with the spironolactone group (2.0nmol/L (0.9, 9.4), p=0.037) and estradiol alone group (10.5nmol/L (4.9, 17.2), p<0.001), which remained significant (p=0.005) after adjustments for estradiol concentration, dose and age. Serum urea was higher in the spironolactone group compared with the cyproterone group. No differences were observed in total daily estradiol dose, blood pressure, serum estradiol, potassium or creatinine. Conclusions: The cyproterone group achieved serum total testosterone concentrations in the female reference range. As spironolactone may cause feminisation without inhibition of steroidogenesis, it is unclear which anti-androgen is more effective at feminisation. Further prospective studies are required.
... However, severe drawbacks like hepatotoxicity, cardiovascular toxicity (4-40% for CPA), and hypertension had limited their clinical utilization (Reilly et al., 2000;Savidou et al., 2006;Mottet et al., 2015). ...
Article
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Objectives Investigation the cytogenetic activity and antioxidant role of methanolic extract of flaxseeds in male albino rats treated with cyproterone acetate. Methods The first part contains a phytochemical analysis of flaxseeds 20% methanolic extract include: Thin layer chromatography (TLC), determination of active compounds, and antioxidant activity of flaxseeds extract. The second part was experimental groups include 35 rats divided randomly into 7 groups: first and second groups treated with distilled water (D.W) and corn oil respectively as control groups, cyproterone acetate (CPA) (10 mg/kg/day) group, flaxseeds extract (250 and 500 mg/kg/day) respectively, and groups treated both CPA with flaxseeds extract with the same doses above respectively. After 50 days, the cytogenetic study including mitotic index (MI) and chromosomal aberrations (CA) of bone marrow cells in addition to the levels of DNA fragmentation in both white blood cells (WBC) and testes tissues was assessed. Results Presence of some phytochemical and antioxidant compounds in 20% methanolic extract of flaxseeds. CPA group had a significant increase (P≤0.05) in MI and CA compared to both D.W and corn oil control groups and has a high level of DNA fragmentation in both WBC and testes tissue. In contrast, flaxseeds extract alone or with CPA did not induce a significant difference in MI and CA but it considered as significant decreasing (P≤0.05) when compared with CPA group. Furthermore, both groups treated with flaxseeds 250 and 500 mg/kg/day alone did not record any fragmentation of DNA of WBC but caused fragmentation of DNA of testes tissue. While a decreased level of DNA fragmentation of WBC and testes tissue was noted in CPA with flaxseeds treated groups when compared with the CPA group. Conclusions The methanolic extract of flaxseeds had a cytogenetic activity to suppresses mitogenic and genotoxic effects of CPA via its antioxidant properties.
... It works by blocking androgen receptors. Although good efficacy has been shown in the treatment of acne [106,107], there are serious risks of hepatotoxicity [108,109] and for this reason, it should not be used in the treatment of acne. ...
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Purpose of review: Acne vulgaris is a global disease with increasing prevalence in adolescents. It has a profound impact on their quality of life, especially when endocrine disorders are also involved. Recent concerns regarding antibiotic stewardship, failures with antibiotic usage, and the development of antibiotic-resistant Propionibacterium acnes have led clinicians to consider other therapeutic options for acne treatment. The present review explores hormonal therapies for the treatment of acne vulgaris. Recent findings: There are now four different combined oral contraceptive pills that are FDA approved for the treatment of acne since its first introduction in 1960. Recent literature has provided more information on the efficacy of different generations of combined oral contraceptive pills, their side-effects, and cancer risks. Furthermore, spironolactone has been gaining wider use among dermatologists in adolescents with endocrine dysfunction. New diagnostic guidelines and treatment recommendations have also been suggested. Summary: Hormonal therapies are effective and well tolerated options for the treatment of acne vulgaris in adolescents with and without endocrine disorders. They can be used as monotherapy or in conjunction with benzoyl peroxide, topical retinoic acid, or antibiotics.
Article
The effects of chemosterilizing agents on the testes and sperm production and maturation are much less understood than their effects on the ovaries and oogenesis. It was discovered that sterilising male insects with ionising radiation caused the emergence of chromosome-wide or chromatid-specific dominant lethal mutations, which led to the development of the classical male castration techniques1, 2. It was discovered in those investigations that alterations were not frequently found on spermatozoa, but that they were commonly visible in anomalies during the division of the zygote in the fertilised egg2, 3. Dominant lethal mutation in the screw-worm, Cochliomyia hominivorax, were first discussed vividly by LaChance & Riemann (1964)3 and LaChance & Crystal (1965)4, in the most classic experiments ever conducted. Detailed information on and complications related to dominant lethal mutations in insects caused by irradiation and sterilizing agents have been enumerated by LaChance (1967), who has also incorporated a detailed references containing research that dispensed this arena long before the era when chemosterilizing agents were introduced into the scientific community5.
Article
Background Spironolactone and cyproterone acetate are commonly used in feminizing hormone therapy to achieve the goal of female range testosterone level; however, the data on the efficacy comparing between these two anti-androgens are scarce. Aim To compare the anti-androgenic effects between spironolactone and cyproterone acetate as the component of feminizing hormone therapy among transgender women population. Methods The study was single-blinded randomized controlled trial involved 52 transgender women from two transgender health clinics. Each participant received oral estradiol valerate 4 mg/day combined with anti-androgen, spironolactone 100 mg/day or cyproterone acetate 25 mg/day, depending on which group they were randomized to. Clinical and biochemical variables were obtained at baseline and at 12 weeks of feminizing hormone therapy. Main Outcome Measures The change of testosterone level from baseline. Other changes including free testosterone, estradiol, prolactin and lipid profile after the therapy. Results After a 12 weeks of feminizing hormone therapy, the change of testosterone level in the cyproterone acetate group [558.0 ng/dL (IQR 352.0 to 783.3)] was significantly higher than the spironolactone group [226.2 ng/dL (IQR,-4.3 to 480.1)](p value <0.001). Testosterone and calculated free testosterone in the cyproterone acetate group were significantly lower than the spironolactone group. Consequently, a proportion of the participants who achieved the female range testosterone (<50 ng/dL) was significantly higher in cyproterone acetate group (90%) compared to the spironolactone group (19%). Serious adverse effects observed in cyproterone acetate users were drug-induced liver injury and asymptomatic hyperprolactinemia. Clinical Implications The data on the differences between the two anti-androgen could be benefit for the transgender health-care providers in medication selection and adverse-effects counseling. Strengths & Limitations The study design was randomized controlled trial and controlled the estrogen component by prescribed the same type and dose for each participant. However, the study was suffered from the confound feminizing effects from previous hormone therapy and the high drop-out rate. Conclusion For feminizing hormone therapy, cyproterone acetate had a higher testosterone suppression efficacy than spironolactone. Burinkul S, Panyakhamlerd K, Suwan A, et al. Anti-Andorgenic Effects Comparison Between Cyproterone Acetate and Spironolactone in Transgender Women: A Randomized Controlled Trial. J Sex Med 2021;18:1299–1307.
Article
Background: Transgender women with intact gonads receive lifelong hormonal treatment to suppress physiologic androgen production, the optimal efficacious and safe cyproterone acetate (CPA) dose has not been established. Aim: To assess the effectiveness and safety of low-dose (10-20 mg/day) compared with high-dose (50-100 mg/day) CPA treatment. Methods: We conducted a historical cohort study of transgender women treated at a tertiary center for transgender health. Outcome measures: Serum levels of testosterone, estradiol, prolactin, gonadotrophins, liver enzymes, and lipids. Results: There were 38 transgender women in the low-dose group and 26 in the high-dose group. Age (median 24.9 years, interquartile range [IQR] 21-30 vs 25 years, IQR 19-35) and follow-up time (median 12 months, IQR 6-23 vs 15 months, IQR 12-36) were similar in the low- and high-dose groups, respectively. Serum gonadotropins and testosterone were suppressed to a similar level at all time points in both groups. Prolactin levels increased significantly in both groups, however, with a more substantial increase in the high- vs the low-dose group (804 ± 121 vs 398 ± 69 mIU/ml at 12 months, respectively, P = .004). Total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels were not significantly affected by the dose. Clinical implications: We suggest an adjustment of current clinical practice guidelines to recommend lower doses of CPA for the treatment of transgender women. Strengths & limitations: This is the first demonstration that low-dose CPA treatment of transgender women is effective. Limitations include a relatively small sample and retrospective study design. Conclusion: Low-dose CPA treatment of transgender women is as effective as high-dose treatment and possibly safer. Zohar NE, Sofer Y, Yaish I, et al. Low-Dose Cyproterone Acetate Treatment for Transgender Women. J Sex Med 2021;XX:XXX-XXX.
Article
Introduction The efficacy of clascoterone cream was demonstrated in two phase three vehicle-controlled clinical trials that enrolled over 1,400 subjects. Its safety profile allowed it to be approved for treating patients as young as 12 years old. During clinical trials, the occurrence of local skin reactions (edema, erythema, pruritus, dryness) was similar to treatment with vehicle alone. Areas covered All publications describing the clinical development of clascoterone cream (cortexolone 17α-propionate) are reviewed and discussed in relation to with existing topical and systemic therapies for acne vulgaris. Expert opinion Clascoterone 1% cream is a novel first-in-class topical androgen receptor inhibitor for the treatment of acne vulgaris. Topical clascoterone 1% cream represents the first new type of therapy for acne treatment in almost 40 years and may become first-line therapy.
Chapter
In adult gender dysphoric natal males, where full development of male secondary sexual characteristics has already taken place, the goal of cross-sex hormonal therapy is the suppression of testosterone secretion to achieve regression of male characteristics and the development of feminine secondary sexual characteristics. For this reason, in transwomen an almost complete suppression of endogenous androgen production and action with combined administration of estrogens is required. The aim of therapy is to maintain hormone levels within the normal physiological range for the individual’s desired gender. Practice guidelines describe eligibility for puberty suppression in adolescents that have met the criteria for gender dysphoria and that have experienced at least Tanner stage 2 puberty. In these subjects if dysphoria persists, cross-hormonal therapy is generally started after 16 years of age.
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To study growth regulation in the beginning of carcinogenesis, we established a novel ex vivo model for co-cultivation of normal and putatively initiated hepatocytes. Rats received the genotoxic hepatocarcinogen N-nitrosomorpholine (NNM). This led to the appearance of hepatocytes expressing placental glutathione S-transferase (G(+) cells). These cells exhibited elevated rates of cell replication and apoptosis, as known from further advanced preneoplasia; G(+) cells were considered initiated. At days 20-22 post-NNM treatment their frequency was maximal (1-2%); approximately 40% were still single and 60% were arranged in mini foci. At this time-point liver cells were isolated by collagenase perfusion and cultivated. G(+) cells, identified by immunostaining of the culture-plates, were present at the same percentage as in vivo, excluding selective loss, enrichment or spontaneous expression of the G(+) phenotype. In untreated cultures G(+) hepatocytes showed significantly higher rates of replicative DNA synthesis than normal G(-) cells. Application of the hepatomitogen cyproterone acetate (CPA) elevated DNA replication preferentially in G(+) cells. Transforming growth factor beta1 (TGF-beta1) suppressed replicative DNA synthesis which was more pronounced in G(+) than in G(-) hepatocytes. Combined treatment with CPA and TGF-beta1 had no effect on G- cells, but considerably inhibited DNA replication in G(+) cells. This suggests that the effects of TGF-beta1 predominated in G(+) hepatocytes. We conclude that putatively initiated G(+) hepatocytes, both in vivo and in culture, exhibit higher basal rates of DNA replication than normal G(-) hepatocytes and an over-response to mitogens and growth inhibitors. Therefore, G(+) cells show (i) nearly identical behaviour in intact liver and in primary culture and (ii) inherent defects in growth control that are principally similar although somewhat less pronounced than in later stages of carcinogenesis. The present ex vivo system thus provides a novel and useful tool to elucidate biological and molecular changes during initiation of carcinogenesis.
Article
To study growth regulation in the beginning of carcinogenesis, we established a novel ex vivo model for co-cultivation of normal and putatively initiated hepatocytes. Rats received the genotoxic hepatocarcinogen N-nitrosomorpholine (NNM). This led to the appearance of hepatocytes expressing placental glutathione S-transferase (G + cells). These cells exhibited elevated rates of cell replication and apoptosis, as known from further advanced preneoplasia; G + cells were considered initiated. At days 20-22 post-NNM treatment their frequency was maximal (1-2%); ∼40% were still single and 60% were arranged in mini foci. At this time-point liver cells were isolated by collagenase perfusion and cultivated. G + cells, identified by immunostaining of the culture-plates, were present at the same percentage as in vivo, excluding selective loss, enrichment or spontaneous expression of the G + phenotype. In untreated cultures G + hepatocytes showed significantly higher rates of replicative DNA synthesis than normal G- cells. Application of the hepatomitogen cyproterone acetate (CPA) elevated DNA replication preferentially in G + cells. Transforming growth factor β1 (TGF-β1) suppressed replicative DNA synthesis which was more pronounced in G + than in G - hepatocytes. Combined treatment with CPA and TGF-β1 had no effect on G- cells, but considerably inhibited DNA replication in G + cells. This suggests that the effects of TGF-β1 predominated in G + hepatocytes. We conclude that putatively initiated G + hepatocytes, both in vivo and in culture, exhibit higher basal rates of DNA replication than normal G- hepatocytes and an overresponse to mitogens and growth inhibitors. Therefore, G + cells show (i) nearly identical behaviour in intact liver and in primary culture and (ii) inherent defects in growth control that are principally similar although somewhat less pronounced than in later stages of carcinogenesis. The present ex vivo system thus provides a novel and useful tool to elucidate biological and molecular changes during initiation of carcinogenesis.
Article
Recently, cases of liver damage and liver tumors have been reported after treatment of prostate cancer patients with the antiandrogen cyproterone acetate (CPA). In rat liver, CPA initiates a wave of DNA synthesis that is accompanied by apoptosis. In apoptotic hepatocytes, a latent form of transforming growth factor beta 1 (TGF-beta 1) is detectable by immunohistochemistry. Injection of a single dose of TGF- beta 1 induces apoptosis in the liver of animals pretreated with CPA but has an insignificant effect in untreated animals. In this study, we show by Northern analysis that there is increased expression of TGF-beta 1 in the liver after CPA treatment. Detection of TGF-beta 1 with in situ hybridization showed that TGF-beta 1 was synthesized in the parenchymal cells. Time course and dose-response experiments performed 48 hours after the last application of CPA showed that apoptotic nuclei with chromatin condensed at the nuclear periphery (AN) were already visible 2 hours after injection (0.13%), and apoptotic bodies (ABs) increased 2 to 9 hours after the injection (from 1.28% to 6.67%) after 25 micrograms TGF-beta 1/kg. At 4.5 hours after injection, an induction of apoptosis could be detected with 0.25 microgram TGF-beta 1/kg and after the maximum dose (250 micrograms TGF-beta 1/kg) ANs (0.24%) and ABs (16.74%) were homogeneously distributed throughout the liver lobe. Irrespective of the dose or time after injection of TGF-beta 1, 82% of the ABs were localized within hepatocytes. Liver enzymes were detected in high amounts in the serum (eightfold elevation of glutamate dehydrogenase, fivefold elevation of alanine transaminase [ALT]) 7 hours after the first visible sign of apoptosis. After an additional 20 hours, the liver contained many necrotic figures. These results suggest that the combination of TGF-beta 1 expression coupled with a strikingly enhanced sensitivity to the induction of apoptosis could be responsible both for the liver damage and the development of liver tumors observed after treatment with CPA. (Hepatology 1996 Feb;23(2):329-37)
Article
Cyproterone acetate (CPA) is an antiandrogenic drug that has been used in the treatment of hirsutism, precocious puberty, acne, and breast cancer. Recent widespread use of this drug has occurred as a result of its success as an adjuvant therapy for prostate cancer. Despite over two decades of CPA use, there are very few reports of hepatotoxicity in the literature (1± 7). Although CPA is usually a well-tolerated medication, acute hepatitis has been described and a review of the literature revealed ® ve reports of fatal hepatitis due to cyproterone acetate (3± 6). We describe a further two cases of fulminant hepatitis due to cyproterone acetate with fatal consequences.
Article
Concern about a potentially increased risk of liver cancer associated to cyproterone acetate (CPA) treatment led to a postmarketing long-term surveillance study with historic accural of four groups of patients with sexual-hormonal disorders under treatment with CPA.The aim of the study was to provide a description of potential ADRs under CPA treatment with special emphasis on liver cancer. A long-term follow-up of 2506 patients was conducted. Six hundred and two persons were followed up retrospectively for longer than 10 years.In 16,721 patient-years of observation after the first CPA dose no malignant liver tumour was observed, whereas six would have been expected in this cohort. Seven incident, non-fatal benign liver tumours were found. Altogether 9.6% of a subset of 1685 patients with reported liver tests had, at some time, elevated liver enzymes. No cases were reported where CPA therapy had been discontinued due to severe liver disorder.We concluded from this active surveillance project, that CPA treatment is probably safe in the groups of patients followed up. Even though there was not a single case of liver cancer detected, the hypothesis of an elevated risk is being tested in an ongoing collaborative European case–control study which is examining the association of CPA use and primary hepatocellular cancer. © John Wiley & Sons, Ltd.
Article
Cyproterone acetate (CPA) is a widely used drug in the treatment of advanced prostatic carcinoma. Although it is generally well tolerated, liver toxicity has been recognised as a complication of long-term use. We report 3 patients with severe hepatocellular damage due to CPA therapy, 2 with fatal fulminant hepatitis.