J Endocrinol Invest
DOI 10.1007/s40618-015-0383-7
ORIGINAL ARTICLE
Quality of life and sexual function of women affected
by endometriosis‑associated pelvic pain when treated
with dienogest
S. Caruso1,2 · M. Iraci1 · S. Cianci1 · E. Casella1 · V. Fava1 · A. Cianci1,2
Received: 25 April 2015 / Accepted: 18 August 2015
© Italian Society of Endocrinology (SIE) 2015
Abstract
Purpose The aim of the study was to evaluate the effects
of dienogest (DNG) on quality of life (QoL) and sexual
function of women affected by endometriosis pain.
Methods Fifty-four women constituted the study group
and were given 2 mg/daily DNG; 48 women were given
non-steroidal anti-inflammatory drugs and constituted the
control group. To define the endometriosis-associated pel-
vic pain, the Visual Analogic Scale (VAS) was used. The
Short Form-36 (SF-36), the Female Sexual Function Index
(FSFI) and the Female Sexual Distress Scale (FSDS) were
used to assess the QoL, the sexual function and the sexual
distress, respectively. The study included two follow-ups at
3 and 6 months.
Results Pain improvement was observed in the study
group at 3 (p < 0.05) and 6 months (p < 0.001) of treatment.
At the 1st follow-up, women reported QoL improvements
in some functions (p < 0.05); at the 2nd follow-up, they
reported improvement in all categories (p < 0.001). The
FSFI score did not change at the 1st follow-up (p = NS).
On the contrary, at the 2nd follow-up, it improved with
respect to the baseline (p < 0.05). At the 2nd follow-up,
the FSFI score had risen to 27.8 (p < 0.001) and the FSDS
score had dropped to 11.3 (p < 0.001). No change was
observed in the control group (p = NS).
Conclusions The progressive reduction of the pain syn-
drome reported by women over the treatment period could
* S. Caruso
scaruso@unict.it
1
Department of General Surgery and Medical Surgical
Specialties, Gynecological Clinic of the Policlinico
Universitario, Via S.Sofia 78, 95124 Catania, Italy
2
Research Group for Sexology, Catania, Italy
contribute to improve the QoL and sexual life of women on
DNG.
Keywords Dienogest · Dyspareunia · Endometriosis ·
Chronic pelvic pain · Quality of life · Sexual life
Introduction
Endometriosis is the most common reproductive tract dis-
order causing chronic pelvic pain and is defined by the
presence of endometrium-like tissue developing outside the
uterus [1]. Women with endometriosis refer chronic pelvic
pain [2], a disabling condition that affects approximately
10 % of women of reproductive age, with a peak incidence
in the age range of 25–30 years [3]. The development of
endometriotic lesions induces a chronic inflammatory
reaction that typically causes painful symptoms [4]. Signs
and symptoms associated with endometriosis are severe
dysmenorrhea, pelvic pain, deep dyspareunia, ovulation
pain, cyclical or peri-menstrual symptoms, with or without
abnormal bleeding or pains, dyschezia, fatigue/weariness
and infertility [5, 6].
Quality of life (QoL) studies show that symptoms of
endometriosis impact on many aspects of a woman’s life,
including work, education, relationships, and social func-
tioning. As symptoms become more severe, QoL is reduced
further [7, 8]. In a recent international survey, women
with endometriosis reported a substantial 38 % reduction
in work productivity, which was attributable primarily to
reduced work effectiveness in the presence of pelvic pain
[9]. Endometriosis also impacts on mental health, with one
study showing that 87 % of the women investigated had
depressive symptoms and 88 % had anxiety. The severity
of anxiety symptoms correlated with the intensity of pain
13

[10]. Furthermore, women also refer sexual discomfort,
principally dyspareunia, either spontaneously or more often
as a result of medical counseling [11].
There is no permanent cure for endometriosis. Proges-
tins have been used to treat endometriosis for decades, but
most have not been developed for the treatment of endo-
metriosis, and the acceptance of many of these agents as
an effective therapy is based on clinical experience without
supportive evidence from controlled trials. The scarcity of
clinical data also hampers the selection of one progestin
over another [12, 13].
Dienogest (DNG) is a synthetic steroid that is cur-
rently used for clinical treatment of endometriosis [15],
and DNG is used both in combined and multiphasic pills
[14, 16]. Research demonstrated that this medication at
a dose of 2 mg daily for 12 weeks could be significantly
more effective than placebo for reducing endometriosis-
associated pain [17]. It exhibits highly selective binding to
the progesterone receptor and has high progestational and
significant antiandrogenic activity, but only moderate anti-
gonadotrophic activity. In the current study, we used DNG
because, in addition to the estradiol-mediated effects, the
steroid also has direct antiproliferative, immunologic and
antiangiogenic activities that contribute to the reduction of
endometriosis-associated symptoms [18, 19].
The aim of the study was to evaluate the effects of 2 mg/
daily DNG for 6 months on QoL and sexual function of
women affected by endometriosis.
Materials and methods
Our departmental institutional review board approved the
study. The study protocol conformed to the ethical guide-
lines of the 1975 Helsinki Declaration. Informed written
consent was obtained from each woman before entering the
study, and they did not receive payment of any kind.
Ninety-two women aged 18–37 years (mean age
28 ± 8), affected by chronic pelvic pain, avoiding surgery,
were enrolled. After having received counseling on the
effects and benefits of DNG, 38 (41.3 %) women refused
the use of the hormonal treatment, choosing to continue
using their previous on-demand non-steroidal anti-inflam-
matory drugs. They were enrolled as the control group after
having signed a new informed consent.
At enrollment, physical and gynecological examina-
tions, and transvaginal ultrasound (TVS) were performed.
Moreover, medical, surgical and medication histories were
assessed to ensure study eligibility. On the basis of ESHRE
guidelines [5], women affected by chronic pelvic pain with
a clinical diagnosis of endometriosis (dysmenorrhea, non-
cyclical chronic pelvic pain, deep dyspareunia, and dys-
chezia), had undergone TVS to identify or rule out rectal
13
J Endocrinol Invest
endometriosis, deep endometriosis, ovarian endometrioma,
or adenomyosis [20] were enrolled. Moreover, sexually
active women having at least one sexual activity during the
month before the counseling were included. Women with a
history of non-organic sexual dysfunction, or having a part-
ner affected by sexual dysfunction, or under GnRH analog
treatment for less than 6 months or hormonal contraceptive
treatment for less than 3 months were excluded.
Instruments
To define the endometriosis-associated pelvic pain, the
Visual Analogic Scale (VAS) was used [21]. Women were
instructed to place a mark on 0–100 scale, 0 representing
absence of pain and 100 indicating unbearable pain.
The Short Form-36 (SF-36) questionnaire was used to
assess QoL [22]. The questionnaire contains 36 questions
which are grouped into eight categories: physical function-
ing (10 items), physical role functioning (4 items), bodily
pain (2 items), general health (6 items), vitality (4 items),
social functioning (2 items), emotional role functioning (3
items) and mental health (5 items). Women were instructed
to place a mark on a 0–100 scale for each item that best
corresponded to their feelings, from the lowest to the high-
est score of a given category of the QoL questionnaire.
Thereafter, the sum of all items of each category was per-
formed. Mean values were calculated on the basis of indi-
vidual items within a given category. Consequently, eight
scale scores were obtained, with higher scores indicating
better functioning.
Each woman underwent a sexual history interview
before starting treatment. To define female sexual dysfunc-
tion (FSD), the revised definition and classification of the
international consensus development conference on FSD
were used [23].
Sexual behavior was assessed using the self-adminis-
tered Female Sexual Function Index (FSFI) validated in the
Italian gynecological population [24]. The FSFI consists
of six domains, which include desire (two items), arousal
(four items), lubrication (four items), orgasm (three items),
satisfaction (three items), and pain (three items), answered
on a five point Likert scale, ranging from 0 (no sexual activ-
ity) or 1 (never/very low) to 5 (always/very high). A score
is calculated for each of the six domains and the total score
is obtained summing all the items. The total score range is
2–36. A cutoff of ≤26.55 is usually accepted for diagnosis
of sexual dysfunction in women within a wide age range.
Moreover, for diagnosis of sexual dysfunction, an essen-
tial element is the requirement that the condition causes
significant personal distress for the woman. Therefore, the
Female Sexual Distress Scale (FSDS) was used [25]. The
FSDS consists of 12 items. The maximum score is 48. An
FSDS score of ≥15 corresponds to clinically significant
J Endocrinol Invest

distress. We considered women with an FSFI score of less Results

than 26.55 to be affected by sexual dysfunction if they also
had an FSDS score of 15 or greater.
After the baseline evaluation, each woman meeting
the inclusion criteria was prescribed 2 mg/daily DNG for
6 months. The study included two follow-ups at 3 and
6 months. All questionnaires were administered to both
the study and control groups at baseline evaluation, and at
both the follow-ups. Furthermore, each woman received a
diary to record daily sexual events as well as adverse events
before and during treatment.
Statistical analysis
Paired Student’s t test was used to compare the values
obtained at baseline with those of both follow-ups from the
SF-36 domains and VAS. ANOVA was used to compare the
demographic and clinical data between the two groups. The
difference was estimated with a 95 % confidence interval
(CI). For comparisons of the values obtained from the FSFI
items between baseline and both the follow-ups, the non-
parametric Wilcoxon rank-sum test with z values was used.
Scores are presented as mean ± SD. The result was sta-
tistically significant when p < 0.05. Statistical analysis was
carried out using the Primer of Biostatistics statistical com-
puter package (Glantz SA, New York, USA: McGraw-Hill,
Inc.1997).
After having received the baseline counseling on the effects
and efficacy of DNG, 38 (41.3 %) women refused the hor-
monal treatment; 8 (21.1 %) of them accepted to undergo
surgical treatment, and 30 (78.9 %) chose to continue using
their previous on-demand non-steroidal anti-inflammatory
drugs. They were enrolled as the control group after having
signed a new informed consent. Consequently, 54 (60.7 %)
Caucasian women constituted the study group.
Table 1 shows the demographic characteristics of the
study group and the control group at baseline. At the 1st
and the 2nd follow-ups, 3 (5.6 %) and 2 (3.7 %) women,
respectively, discontinued treatment due to spotting.
Therefore, 49 (90.7 %) women completed the study.
Moreover, women reported mild adverse events at the 1st
follow-up that did not provoke discontinuation, namely
spotting (9 = 18.3 %), nausea (7 = 14.3 %) or breast ten-
derness (8 = 16.3 %). At the 1st and the 2nd follow-ups, 10
(20.4 %) and 39 (79.6 %) women underwent amenorrhea,
respectively. The women in the control group reported
mainly headache [12, (31.6 %)] and nausea [23, (60.5 %)]
during the usage of on-demand non-steroidal anti-inflam-
matory drugs; finally, the dropout rate was 8 (21.1 %).
Figure 1 shows the improvement of the pelvic pain by
VAS after 3 (p < 0.05) and 6 months (p < 0.001) of pro-
gestogen usage, and no change of control group.

Table 1  Demographic Treated group (n = 54) Control group (n = 38) p

characteristics
Age range (years) 18–36 18–34 NS
Mean age 29.4 ± 9.2 27.4 ± 8.3 NS
BMI kg/m2 23.2 ± 4.8 24.1 ± 3.5 NS
Age at menarche 12.4 ± 2.4 12.6 ± 3.1 NS
Menstrual cycle length (days) 25–31 26–33
Duration of menses (days) 4.1 ± 2.2 3.4 ± 1.8 NS
Chronic pelvic pain 51 (100 %) 38 (100 %) NS
Dysmenorrhea 40 (78.4 %) 29 (76.3 %) NS
Dyspareunia 35 (68.6 %) 27 (71.1 %) NS
Parity
Nulliparous 40 (78.4 %) 29 (76.3 %) NS
One or more children 11 (21.6 %) 9 (23.7 %) NS
Cigarette smoking
Non-smoker 41 (80.4 %) 30 (78.9 %) NS
Current smoker 10 (19.6 %) 8 (21.1 %) NS
Daily cigarettes 12.3 ± 4.8 13.1 ± 5.3 NS
Current coffee drinker 48 (94.1 %) 36 (94.7 %) NS
Daily cups of coffee 2.7 ± 2.1 2.5 ± 1.8 NS
Systolic blood pressure (mmHg) 107.5 ± 10.5 112.4 ± 9.7 0.02
Diastolic blood pressure (mmHg) 68.4 ± 6.8 66.4 ± 9.5 NS
Heart rate (×min) 69.5 ± 8.5 65.6 ± 7.8 0.03

13

Fig. 1  Visual Analog Scale
score of women affected by
endometriosis-associated pelvic
pain before and during treat-
ment with dienogest 2 mg/die
Fig. 2  Improvement of pain syndromes of women with endometrio-
sis-associated pelvic pain before and during treatment with dienogest
2 mg/die
Figure 2 shows the changes of the subjective symp-
toms referred by the study group. Chronic pelvic pain was
reduced by 30 and 89 %, dysmenorrhea by 50 and 74 %
and dyspareunia by 55 and 73 % when compared with the
1st and 2nd follow-up values with baseline, respectively.
Figure 3 shows the changes of QoL of the study group.
At the 1st follow-up, women reported QoL improvement in
physical function, physical role, body pain, general health,
social function and emotional role categories (p < 0.05); at
the 2nd follow-up, they reported improvement in all cate-
gories (p < 0.001).
Table 2 shows the intergroup statistical comparison anal-
ysis of QoL between baseline, 1st and 2nd follow-up val-
ues. At baseline, no difference was observed between the
study group and the control group scores (p = NS). Except
vitality, mental health and emotional role scores (p = NS),
at the 1st follow-up the comparison between the study
group and the control group was statistically significant
(p ≤ 0.01). Finally, at the 2nd follow-up, the intergroup
13
J Endocrinol Invest
difference was statistically significant in all SF-36 catego-
ries (p < 0.001).
Table 3 shows the statistical comparisons of the FSFI
and FSDS scores obtained at baseline and at the 1st and
the 2nd follow-ups of the study group. At the 1st follow-
up, the sexual desire score detected a worsening (p < 0.05);
all the other items did not change with respect to baseline
scores (p = NS). On the contrary, the scores observed at the
2nd follow-up improved with respect to the baseline val-
ues (p < 0.05). The total FSFI score at baseline was 23.6
and the FSDS score was 18.4; at the 1st follow-up, the total
FSFI score and the FSDS score were 23.9 and 17.5, respec-
tively (NS). At the 2nd follow-up, FSFI score had risen to
27.8 (p < 0.001) and the FSDS score had dropped to 11.3
(p < 0.001).
Table 4 shows the intergroup statistical comparison
analysis of sexual function index and sexual distress scale
between baseline, 1st and 2nd follow-up scores. At base-
line and at the 1st follow-up, no difference was observed
between the Study group and the Control group (p = NS),
except for dyspareunia (p < 0.002). At the 2nd follow-
up, the intergroup difference was statistically significant;
the study group showed improvement in all FSFI items
(p < 0.02), in FSFI total score (p < 0.001) and in FSDS
score (p < 0.001) with respect to the control group scores.
Finally, the monthly frequency of the sexual activity
improved over the 6 months in women on steroid intake,
from 2.1 (baseline) to 4.2 (2nd follow-up) (p < 0.001). On
the contrary, the control group did not have any change
(p = NS).
Discussion
We investigated the QoL and the sexual function of women
with clinical diagnosis of endometriosis over 6 months in
two groups; the first (study group) and the second (control
J Endocrinol Invest

Fig. 3  Quality of life of women

affected by endometriosis-asso-
ciated pelvic pain before and
during treatment with dienogest
2 mg/die

Table 2  Intergroup quality of life statistical comparison analysis between baseline, 3- and 6-months values
SF 36-Scores Baseline 1st follow-up 2nd follow-up
Study group vs. control group Study group vs. control group Study group vs. control group
t 95 % CI p t 95 % CI p t 95 % CI p

Physical function −1.73 −4.33 to −0.33 NS 2.53 0.64 to − 5.35 0.01 4.16 3.07 to −6.92 0.001
Physical role −1.58 −4.50 to 0.50 NS 3.14 1.46 to −6.53 0.002 15.91 13.13 to −16.8 0.001
Body pain −1.10 −2.79 to 0.79 NS 4.38 −5.81 to −2.18 0.001 27.21 24.1 to −27.9 0.001
General health 1.70 −0.33 to 4.33 NS 5.56 3.21 to −6.78 0.001 23.31 23.78 to −28.22 0.001
Vitality 1.31 −1.02 to 5.02 NS 0.71 −1.77 to −3.77 NS 3.99 2.51 to −7.48 0.001
Mental health 1.03 −0.91 to 2.91 NS 1.49 −0.66 to −4.66 NS 11.97 10.01 to −13.99 0.001
Social function −1.84 −4.15 to 0.15 NS 4.38 3.27 to −8.72 0.001 8.96 7.78 to −12.22 0.001
Emotional role 0.92 −1.15 to 3.15 NS 0.67 −1.92 to −3.92 NS 10.98 9.009 to −12.99 0.001

Degrees of freedom = 87
t two-sided t test, CI confidence interval, NS not significant

Table 3  Female Sexual FSFI items Baseline 51 1st follow-up 48 2th follow-up 46 p value ∗ 1st p-value ∗ 2nd
Function Index (FSFI) and follow-up vs. follow-up vs.
Female Sexual Distress Scale baseline baseline
(FSDS) scores at baseline and
at the 1st and 2nd follow-ups of Desire 3.4 ± 1.3 3.1 ± 1.2 3.8 ± 1.1 0.05 0.01
women with endometriosis on
Arousal 4.1 ± 1.1 4.1 ± 1.2 4.6 ± 1.2 NS 0.03
2 mg/daily dienogest
Lubrication 4.1 ± 1.2 4.2 ± 1.1 4.5 ± 1.3 NS 0.05
Orgasm 3.9 ± 1.1 4.1 ± 1.3 4.8 ± 1.2 NS 0.01
Satisfaction 3.8 ± 1.1 4.1 ± 1.4 4.6 ± 1.1 NS 0.02
Dyspareunia 4.4 ± 1.2 4.7 ± 1.2 5.5 ± 1.3 NS 0.03
FSFI Total score 23.6 ± 1.3 23.9 ± 1.3 27.8 ± 1.3 NS 0.001
FSDS score 18.4 ± 1.3 17.5 ± 1.8 11.3 ± 1.4 NS 0.001

Values are mean ± SD

NS not significant
∗ p values determined by non-parametric Wilcoxon rank-sum test

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 J Endocrinol Invest

Table 4  Intergroup Female Sexual Function Index and Female Sexual Distress Scale statistical comparison analysis between baseline, 3- and
6-month values
FSFI items Baseline 1st follow-up 2nd follow-up
Study group vs. control group Study group vs. control group Study group vs. control group
t 95 % CI p t 95 % CI p t 95 % CI p

Desire 0.33 −0.49 to 0.69 NS −1.21 −0.079 to 0.19 NS 2.30 0.08 to 1.11 0.02
Arousal 0.72 −0.34 to 0.74 NS 0.37 −0.43 to 0.63 NS 2.35 0.09 to 1.10 0.02
Lubrication 0.69 −0.37 to 0.77 NS 0.83 −0.27 to 0.67 NS 2.07 0.01 to 0.98 0.04
Orgasm −0.36 −0.64 to 0.44 NS 1.12 −0.22 to 0.82 NS 2.93 0.25 to 1.34 0.004
Satisfaction 0.39 −0.40 to 0.60 NS 0.75 −0.32 to 0.72 NS 3.07 0.28 to 1.31 0.003
Dyspareunia 0.37 −0.43 to 0.63 NS 3.17 0.29 to 1.30 0.002 3.97 0.54 to 1.65 0.001
FSFI total score 1.33 −0.19 to 0.99 NS 1.12 −0.22 to 0.82 NS 13.73 3.25 to 4.35 0.001
FSDS score −1.77 −1.27 to 0.07 NS −1.28 −1.27 to 0.27 NS −24.08 −8.01 to −6.78 0.001

Degrees of freedom = 87
t two-sided t test, CI confidence interval, NS not significant

group) included women treated with 2 mg/daily DNG and
nonsteroidal anti-inflammatory drugs, respectively. The
efficacy of the drugs was evaluated at 3 (1st follow-up) and
6 (2nd follow-up) months. The study group experienced
an improvement in pain syndrome and QoL at the 1st fol-
low-up, and in sexual life at the 2nd follow-up of steroid
usage, than the control group. The progressive reduction of
the pain syndrome reported by women over the treatment
period could have contributed to improve further their QoL
and their sexual life. Interestingly, the frequency of sex-
ual activity improved at the 2nd follow-up. This could be
mainly due to the reduction of dyspareunia and pelvic pain.
Assessment of the QoL is a crucial parameter to take
into account before concluding on the efficacy of a treat-
ment. Our study showed an improvement in some cat-
egories of the SF-36 during the 1st follow-up, mainly
those related to the physical aspects. However, at the 2nd
follow-up all categories improved. We considered the
first 3 months of our investigation the time during which
a series of objective and subjective adjustments could be
initiated. A recent study showed that the QoL and sexual-
ity, particularly libido and pain, improve after 6 months of
DNG treatment of women with endometriosis [26]. Several
recent studies investigated the effects of a quadriphasic pill
containing DNG in women with endometriosis, confirming
decreased pelvic pain and improvement of QoL [27, 28].
The mean VAS score in the study group decreased pro-
gressively over all the treatment period. Reduction of pel-
vic pain without a relevant increase of concomitant pain
medication was achieved in women on DNG. Our study
cannot clinically confirm that DNG reduces endometriosis
lesions, because laparoscopy was not used; however, we
hypothesize the increased apoptotic rates seen in preclini-
cal models during DNG treatment [29].
Chronic pelvic pain is the pain lasting more than
6 months and is estimated to occur in 15 % of women.
Apart from gynecological disorders, urologic, gastroenter-
ological, and musculoskeletal disorders can cause chronic
pelvic pain [30]. The multidisciplinary nature of chronic
pelvic pain may cause confusion for a correct diagnosis and
treatment. To avoid this, women affected by chronic pelvic
pain with dysmenorrhea and dyspareunia were enrolled in
our current study.
The majority of women affected by pelvic pain report
symptoms beginning during adolescence, also reporting a
longer time and worse experience while obtaining a diag-
nosis; thus treatment is often started several years after
[31]. Frequently, women and adolescents with endometrio-
sis use non-steroidal anti-inflammatory symptomatic drugs
[13], delaying proper treatment and often not restricting the
progression of endometriosis. Early diagnosis is essential
to decrease pain and hopefully prevent disease progression
and preserve future fertility [32]. In fact, 77.2 % women
of our control group were delaying a correct treatment for
their chronic pelvic pain. On the other hand, 41.3 % of
enrolled women refused to use hormonal treatment, choos-
ing to continue using their previous on-demand non-steroi-
dal anti-inflammatory drugs, participating in the study as
the control group.
When given continuously, DNG leads to a hyperpro-
gestogenic and moderately hypoestrogenic endocrine envi-
ronment causing decidualization of endometrial tissue. In
addition to the estradiol-mediated effects, the steroid also
has direct antiproliferative, immunologic and antiangio-
genic effects that contribute to the reduction of endometrio-
sis-associated symptoms [18, 19]. Ovulation is inhibited at
a daily dose of 2 mg but ovarian activity is not completely
suppressed. Consequently, circulating estradiol levels

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J Endocrinol Invest
during treatment with 2 mg daily DNG are similar to those
in the early follicular phase of the menstrual cycle [33].
The moderate suppression of estradiol with dienogest
may represent a potential advantage over other therapies,
such as GnRH agonists, which require estrogen add-back if
used for more than 6 months [34].
Today, the gold standard investigation to a definitive
diagnosis of the most forms of endometriosis is laparos-
copy for women presenting symptoms suggestive of endo-
metriosis. However, pain symptoms suggestive of the dis-
ease can be treated without a definitive diagnosis using a
therapeutic trial of a hormonal drug to reduce menstrual
flow [4, 35]. On the other hand, no single treatment is
ideal for all patients and the management approach chosen
should be directed to the individual needs of each patient
[1, 5]. Recent data suggest that low Vitamin D status could
be associated with impaired endometriosis [36]. DNG rep-
resents a promising new medication for the long-term man-
agement of endometriosis.
Probably, a longer period without pelvic pain could lead
to a greater awareness of being able to live their sexuality
without discomfort, and improve their QoL.
The current study has some limitations: one is the lack
of randomization; however, future investigations are pro-
posed to address this. One other limit is the lack of laparos-
copy to confirm endometriosis.
Acknowledgments The authors wish to thank The Scientific
Bureau of the University of Catania, Italy, for language support.
Compliance with ethical standards
Conflict of interest None.
Ethical approval I declare that this study was approved by the Insti-
tutional Review Board (IRB) of our Department.
Informed consent Informed consent was obtained from all individ-
ual participants included in the study.
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