Effects of acitretin on semen quality and reproductive hormone levels in patients with psoriasis vulgaris lable at ScienceDirect DERMATOLOGICA SINICA xxx (2016) 1e4 Contents lists avai Dermatologica S[.]
Trang 1ORIGINAL ARTICLE
Effects of acitretin on semen quality and reproductive hormone levels
in patients with psoriasis vulgaris
Hui Liu*, Jie Li, Li Yu
Department of Dermatology, 210 Hospital of People's Liberation Army, Dalian 116021, Liaoning, China
a r t i c l e i n f o
Article history:
Received: Aug 5, 2016
Revised: Sep 21, 2016
Accepted: Oct 31, 2016
Keywords:
acitretin
erythrocyte
innate immune
psoriasis
semen quality
sperm
a b s t r a c t Background: The aim of this study was to investigate the effect of different doses of acitretin (ACI) on the main parameters of semen, sperm morphology, and reproductive hormone levels in patients with psoriasis vulgaris
Methods: The main parameters of semen and the sperm morphology of 31 psoriatic patients were analyzed before and after treatment with different doses of ACI, and the changes in reproductive hormone levels were measured and compared with those of 14 healthy control individuals
Results: At treatment doses of 20 mg/d (n¼ 15) and 30 mg/d (n ¼ 16) of ACI, the semen volume, sperm motility, viability, concentration, and normal appearance percentage, and the serum reproductive hor-mone levels in the psoriatic patients showed no significant difference from those in healthy control individuals (n¼ 14) after 1 month and 3 months of treatment, as well as after withdrawing the treatment for 3 months (p> 0.05)
Conclusion: Different doses of ACI did not significantly affect semen quality in psoriatic patients at different treatment stages
Copyright© 2016, Taiwanese Dermatological Association Published by Elsevier Taiwan LLC This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/)
Introduction
Retinoids are a group of compounds that have similar structure and
biological activity as vitamin A Their bioactive isomers include
all-trans retinoid and 9-cis retinoid, which regulate cell proliferation
and differentiation, thus exhibiting bioactivities such as
keratosis, proliferation inhibition, antisebum synthesis,
anti-inflammation, and immunomodulation.1 Their molecular
struc-ture is composed of one cyclic group, one polyene side chain, and
one terminal polar group The change in any of the three parts could
result in compounds with different bioactivities Among the three
generations of retinoids,2acitretin (ACI) is the second-generation
derivative, and is suitable for treatment of all types of psoriasis
and keratosis Previously, the treatments of psoriasis with retinoids
were mostly focused on severe erythrodermic psoriasis and
pus-tular psoriasis,3,4which are types of psoriasis with significant side
effects Their indications kept on expanding, and low dose long-term treatment protocols were more widely used for psoriasis vulgaris, with satisfactory results and minimal side effects.5 Currently, it has been established that the major side effects of retinoids mainly manifest in muscle and bone, the central nervous system, liver, blood lipids, skin, and mucous membranes They have particularly potent teratogenic effects in women and female ani-mals, and women of childbearing age must use contraception during retinoid use and for at least 2 years after the withdrawal of retinoids.6 The specific effects of retinoids occur mainly in the cardiovascular system, central nervous system, and auditory sys-tem, and the occurrence rate could be as high as approximately 30% The embryotoxicity manifests as a high proportion of still-births and miscarriages, and the teratogenicity is still high a long time after withdrawal.6Thus, a consensus has been formed by to-day’s medical community that women of childbearing age must strictly use contraception during retinoid use The combination of sperm and egg, formation of a fertilized egg, and fetal development are all carried out in utero, so the effect of maternal factors on fetal development is self-evident Sperm cells are one of the most active and damage-susceptible cells in humans The father’s sperm qual-ity, especially the sperm concentration, mobilqual-ity, and morphology, affects the formation and development of the fertilized egg and the
Conflicts of interest: The authors declare that they have no financial or
non-financial conflicts of interest related to the subject matter or materials
discussed in this article.
* Corresponding author Department of Dermatology, 210 Hospital of People's
Liberation Army, Dalian 116021, Liaoning, China.
E-mail address: huiliudoc@126.com (H Liu).
Contents lists available atScienceDirect Dermatologica Sinica
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http://dx.doi.org/10.1016/j.dsi.2016.10.005
1027-8117/Copyright © 2016, Taiwanese Dermatological Association Published by Elsevier Taiwan LLC This is an open access article under the CC BY-NC-ND license ( http:// creativecommons.org/licenses/by-nc-nd/4.0/ ).
DERMATOLOGICA SINICA xxx (2016) 1e4
Trang 2fetus It was reported that infertility caused by male factors
accounted for about half of the total number of cases of infertility.7
Thus, we must determine whether the increasingly widespread
usage of retinoids influences the reproductive system of male
pa-tients This has not received enough attention for a long time, and
the effect of retinoids on the semen quality and genital safety in
male psoriatic patients of childbearing age in China and abroad is
rarely reported Reproductive safety-targeted research wasfirstly
done by Parsch et al8in 1990, who used a manual method to detect
the semen quality changes in five patients after one retinoid
treatment (50 mg/d, 3e4 months) and concluded that retinoids had
no impact on sperm quality However, it is concerning that the
majority of the literature on the effects of retinoids on male genital
safety thereafter cited this report In recent years, foreign scholars
have begun to focus on the issue of retinoids’ application toward
male genital safety Because of ethical reasons, direct intervention
studies of ACI on the human male reproductive system in psoriatic
patients are very difficult Choosing animal models to obtain
tera-togenicity data and referring to the results of oral administration of
vitamin A and its major metabolites in the volunteers are the new
methods being used by certain research institutes to solve this
problem; however, the conclusions were different.9,10Using in vitro
tests, Pilkington and Brogden11found that high concentrations of
ACI could inhibit the fructose decomposition inside sperm,
signif-icantly decreasing the contents of lactic acid and CO2 Sigg et al12
conducted a small study on the effect of ACI on eight male
pa-tients, and reported no change in sperm concentration Although it
is still unknown whether ACI has residual effects in the semen of
male patients taking ACI during or after the treatment, it would not
constitute a risk to the fetus The maximum concentration of ACI
observed in human semen after taking ACI or etretinate was
12.5 ng/mL, namely about 125 ng/10 mL in semen However, there
is a warning that women of childbearing age and their spouses
must use contraception for at least 3 months before or after taking
isotretinoin in its package inserts Therefore, the aim of this study
was to investigate the changes of semen quality in 31 psoriatic
patients of childbearing age before and after treatment with
different doses of ACI Parameters analyzed included sperm
con-centration, motility, viability, and morphology, as well as levels of
three serum reproductive hormones: luteinizing hormone (LH),
follicle stimulating hormone (FSH), and serum testosterone (T) The
aim was to preliminarily explore the reproductive safety issues in
male patients using this kind of drug In this study, the detection of
physical indicators and parameters was done using a manual
method, and the sperm concentration and motility were analyzed
using a computerized automatic semen analysis system
Methods
General information
Thirty-one psoriatic patients were recruited from the in-patient
department of our hospital All were: young soldiers, aged 18e24
years, without any history of contact with radar or nuclear
radia-tion; unmarried with no children; with their primary disease as
psoriasis without orchitis, prostatitis, or varicocele; without
infec-tious diseases (such as hepatitis B, hepatitis C, or human
immu-nodeficiency virus); without endocrine or genetic diseases;
without familial high incidence of cancer; with a disease duration
of 3e48 months; and with a Psoriasis Area and Severity Index
(PASI) score of over eight points All of the patients were in the
progressive or stationary phase when semen examination was
performed The 31 patients were randomly divided into two groups
according to the doses of ACI The major parameters of semen
[sperm morphology and serum reproductive hormone levels (T,
FSH, and LH)] were observed before the treatment, 1 month after the treatment, 3 months after the treatment, and 3 months after withdrawal Group A: 15 cases, orally administered 20 mg once a day; Group B: 16 cases, orally administered 30 mg once a day The PASI score, age, disease duration, and body weight of the two groups showed no statistically significant difference (p > 0.05) All
of the patients were prohibited from undergoing any treatment during the withdrawal, except for external ointment therapy such
as tazarotene or mometasone The 14 healthy volunteers in the control group were young soldiers recruited from the surrounding area All were unmarried, without children, healthy, and aged 20e25 years All of the patients and volunteers were familiar with the study contents and gave informed consent
Semen tests All participants were asked to abstain from sexual activity for 2e7 days before the semen collection During the sampling, benzalko-nium bromide solution and saline were used to swab the urethra and surrounding skin Then, the semen was obtained in a sterile wide-mouth glass bottle by masturbation so as to avoid contami-nation and leakage The semen was liquefied, and the sperm count, motility, and morphological analyses were measured according to the standards described in the Laboratory Manual of WHO human semen and spermdcervical mucus interactions (fifth edition).13 The semen volume was measured, and the color, sticky degree,
or liquefaction were observed The pH was determined using pH test strips after the semen was liquefied A sperm quality automatic analyzer (SCA 5.2; Microptic, Barcelona, Spain) was used to mea-sure the sperm concentration, viability, and motility.14
Sperm morphology observations The results of sperm morphology observations were manually counted using the Diff-Quik method.15
Detection of sperm nuclear DNA fragments Sperm nuclear DNA fragments were detected usingflow cytometry (Accuri C6; Becton Dickinson Immunocytometry Systems, San Jose,
CA, USA).16 Detection of reproductive hormones by radioimmunoassay The levels of T, FSH, and LH were detected using the BHP9507 chemiluminescence immunoassay analyzer and kit (Yamasa Shoyu Co., Ltd., Chiba, Japan),17with the intrabatch error< 5%
Statistical analysis The comparison between different ACI dose groups, different treatment period groups, and the control group was performed using the t test The measurement data were expressed as x±SD, and all the data were processed using SPSS13.0 statistical package (SPSS Company, Chicago, Illinois, USA), witha¼ 0.05 set as the test level
Ethical approval This study was conducted in accordance with the declaration of Helsinki This study was conducted with approval from the Ethics Committee of 210 Hospital of People's Liberation Army Written informed consent was obtained from all participants
H Liu et al / Dermatologica Sinica xxx (2016) 1e4
Trang 3Comparison of routine semen tests
The concentration, motility, viability, and morphology of sperm, the
semen volume, and the pH in Groups A and B showed no significant
difference compared with those in the control group before the
treatment or 1 month and 3 months after the treatment (p> 0.05,
Table 1)
Comparison of sperm nuclear DNA fragments
The redfluorescence intensity (FL1-H) and red fluorescence
in-tensity/totalfluorescence intensity (at) in Groups A and B showed
no significant difference compared with those in the control group
before the treatment or 1 month and 3 months after the treatment
(p> 0.05,Table 2)
Comparison of reproductive hormone levels
The levels of T, FSH, and LH in Groups A and B showed no significant
difference compared with those in the control group before the
treatment or 1 month and 3 months after the treatment (all
p> 0.05,Table 3)
Comparison of semen quality and reproductive hormone levels
The semen quality indexes and levels of T, FSH, and LH in Groups A
and B showed no significant difference compared with those in the
control Group 3 months after withdrawal (p> 0.05,Table 4)
Discussion
It has been confirmed that ACI has strong teratogenic effects in
humans and animals Thus, women of childbearing age must use
contraception for at least 2 years after the withdrawal of
treat-ment.6There is a large number of studies on the teratogenicity and
embryotoxicity of retinoids after their oral and topical
adminis-tration in animals, but retinoid risk assessments in humans mainly
include indirect data of pharmacokinetic analysis in animals and
humans after systematic administration experiments and topical
retinoid application in humans, which also referred to the results of
in vitro teratogenic tests in animals and humans.18e20 The most
direct determinants of teratogenic effects depend on the
concentration-time relationship of drugs in target tissues, the
drugs’ physicochemical and structure-activity properties, and their
concentration and affinity in the terminal target organs.21Although
pharmacological and pharmacokinetic preventive measures have
been proposed, they are still widely used clinically because of their
efficacy.22Currently, there are few studies on the effects of retinoids
on the male reproductive system These studies are based on tests and literature, and most of them consider retinoid treatment to be safe from the viewpoint of andrology Given the wide clinical usage
of retinoids, clarification of whether retinoids affect the reproduc-tive system in male patients of childbearing age is urgently needed
Table 1 Comparison of semen quality between psoriatic patients and normal controls in different periods ðx±sÞ.
Group Course (mo) Semen volume
(mL)
pH Total motility
(PRþNP) (%)
Ratio of live sperm (%)
Sperm concentration (10 6 /mL)
Percentage of sperm with normal morphology (%) A
(20 mg/d, n ¼ 15)
0 3.4 ± 0.4 7.5 ± 0.1 63.1 ± 3.8 79.8 ± 13.6 46.9 ± 10.2 3.9 ± 0.7
1 3.3 ± 0.5 7.4 ± 0.3 64.1 ± 4.0 81.1 ± 14.1 48.1 ± 11.0 3.8 ± 0.3
3 3.4 ± 0.2 7.5 ± 0.1 63.9 ± 2.7 79.6 ± 12.7 47.5 ± 9.8 3.8 ± 0.2 B
(30 mg/d, n ¼ 16)
0 3.3 ± 0.6 7.4 ± 0.2 64.0 ± 2.9 80.1 ± 11.7 48.0 ± 9.9 3.8 ± 0.4
1 3.4 ± 0.1 7.6 ± 0.1 63.7 ± 3.1 81.4 ± 12.9 46.9 ± 8.9 3.7 ± 0.6
3 3.4 ± 0.2 7.5 ± 0.3 63.1 ± 4.1 79.2 ± 14.0 47.1 ± 11.3 3.9 ± 0.5 Control
(n ¼ 14)
0 3.4 ± 0.3 7.5 ± 0.2 63.8 ± 3.6 80.4 ± 12.2 47.6 ± 10.9 3.8 ± 0.5
NP ¼ nonprogressive sperm; PR ¼ progressive sperm.
Table 2 The variety of DNA fragments determination of sperm nuclear for men between psoriatic patients and normal controls in different periods ðx±sÞ Group Course (mo) Red fluorescence
intensity (FL1-H)
Red fluorescence intensity/total fluorescence intensity (at )
A (20 mg/d, n ¼ 15) 0 13.92 ± 1.03 9.92 ± 3.05
1 13.77 ± 0.90 10.26 ± 3.90
3 14.18 ± 1.16 9.90 ± 2.37
B (30 mg/d, n ¼ 16) 0 14.47 ± 1.40 10.77 ± 4.01
1 13.92 ± 1.07 9.89 ± 2.64
3 13.82 ± 1.01 9.90 ± 6.31 Control (n ¼ 14) 0 14.13 ± 1.48 10.10 ± 5.61
Table 3 The variety of the genital hormone for men between psoriatic patients and normal controls in different treatment stage ðx±sÞ.
Group Course (mo) T (ng/mL) FSH (ng/mL) LH (ng/mL)
A (20 mg/d, n ¼ 15) 0 744 ± 189 7.2 ± 1.4 2.7 ± 1.1
1 746 ± 240 7.3 ± 1.5 2.8 ± 1.7
3 739 ± 171 7.3 ± 0.9 2.7 ± 1.6
B (30 mg/d, n ¼ 16) 0 751 ± 201 7.3 ± 1.0 2.8 ± 1.3
1 737 ± 223 7.3 ± 0.9 2.7 ± 1.4
3 742 ± 193 7.4 ± 1.3 2.9 ± 1.9 Control (n ¼ 14) 0 740 ± 235 7.3 ± 1.6 2.8 ± 1.8 FSH ¼ follicle stimulating hormone; LH ¼ luteinizing hormone; T ¼ testosterone.
Table 4 Comparison of semen quality and genital hormone between psoriatic pa-tients and normal controls after 3 months of withdrawal ðx±sÞ Index A (20 mg/d,
n ¼ 14)
B (30 mg/d,
n ¼ 13)
Control (n ¼ 14) Semen volume (mL) 3.3 ± 0.4 3.4 ± 0.2 3.4 ± 0.3
pH 7.4 ± 0.2 7.3 ± 0.3 7.5 ± 0.2 Total mobility (PR þ NP) (%) 63.7 ± 2.7 62.8 ± 3.1 63.8 ± 3.6 Ratio of live sperm (%) 81.1 ± 11.3 80.9 ± 12.9 80.4 ± 12.2 Sperm concentration ( 10 6 /L) 48.6 ± 9.9 47.1 ± 10.2 47.6 ± 10.9 Ratio of sperm with normal
morphology (%)
3.8 ± 0.3 3.7 ± 0.6 3.8 ± 0.5
T (ng/mL) 737 ± 179 743 ± 201 740 ± 235 FSH (ng/mL) 7.3 ± 1.3 7.4 ± 0.6 7.3 ± 1.6
LH (ng/mL) 2.7 ± 1.6 2.8 ± 1.3 2.8 ± 1.8 Red fluorescence intensity 14.60 ± 1.45 13.93 ± 1.36 14.13 ± 1.48 Red fluorescence intensity/total
fluorescence intensity
9.94 ± 5.61 10.30 ± 3.44 10.10 ± 5.61
FSH ¼ follicle stimulating hormone; LH ¼ luteinizing hormone; NP ¼ nonprog-ressive sperm; PR ¼ progressive sperm; T ¼ testosterone.
H Liu et al / Dermatologica Sinica xxx (2016) 1e4
Trang 4As one of the most active and damage-susceptible cells in vivo,
the development and maturation of sperm cells are complex These
processes mainly occur in testes and seminiferous tubes, and
consist of three phases that together last 2e3 months: the
prolif-eration and division of spermatogonia, reduction division of
sper-matocytes, and spermatogenesis.7 Routine tests and analysis of
semen and sperm are a direct and objective experimental method
in clinical practice The comprehensive assessment of semen
vol-ume and liquefaction time, as well as sperm concentration, motility,
viability, morphology, and other indexes could be used as an
important basis for understanding male fertility The male
repro-ductive hormone levels depend on the
hypothalamic-pituitary-gonadal axis, and changes to this axis are directly related to
changes in sperm concentration, motility, and morphology seen in
semen analysis
To understand the effects of different doses of ACI on sperm, we
compared the semen volume, motility, survival ratio, sperm
con-centration, percentage of sperm with normal morphology,
damaged DNA fragment index, and certain genital hormones
among 15 psoriatic patients administered 20 mg of ACI/d, 16
pso-riatic patients administered 30 mg of ACI/d, and 14 healthy
vol-unteers before the treatment and 1 month and 3 months after
treatment The results showed that ACI can improve the clinical
symptoms of psoriatic patients, but different doses of ACI did not
cause significant changes in sperm concentration, sperm
morphology, total sperm count, sperm motility, or reproductive
hormone levels 1 month or 3 months after treatment Three
months after withdrawal of treatment (one period of
spermato-genesis), we rechecked the semen quality and reproductive
hor-mone levels of 27 patients (3 patients retired from active military
service, and 1 patient quit) The results did not reveal any
abnor-malities, indicating that long-term oral treatment with ACI did not
affect spermatogenesis and that ACI did not affect sperm
concen-tration, reduce sperm motility, or affect sperm morphology ACI had
no significant effect on the male hypothalamic-pituitary-gonadal
axis or its regulated reproductive hormone levels during or after
treatment Compared with the previous experiments,8the patients
in this study were younger and the volunteers were young soldiers
without psoriasis; therefore, the study samples were easily
managed and followed up, and their compliance was better The
sample size was larger than in previous studies, the treatment
protocol used conventional doses (no more than 30 mg/d), and the
conclusions obtained were consistent Therefore, the study
confirmed that long-term treatment with therapeutic doses of
retinoids has no adverse effects on reproductive function in
pso-riatic male patients
ACI has confirmed efficacy in the treatment of psoriasis, and
despite its relatively many side effects, it shows no adverse effects
in the reproductive system of male patients of childbearing age
during treatment Many issues regarding the use of ACI have not
been completely understood, such as post-treatment long-term
follow-up and reproductive safety issues of other drugs used
concomitantly with ACI (such as isotretinoin) in male patients of
childbearing age Confirming whether ACI affects the reproductive
system of male psoriatic patients of childbearing age is an impor-tant public health problem that requires urgent solutions Answering this question would provide a strong theoretical basis for clinical and scientific application and safety assessment of retinoids
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