Evaluation of Using Dienogest and N-Acetyl Cysteine on the Volume of Uterine Leiomyoma
Phase: PHASE2
Conditions: Uterine Leiomyoma
Sponsor: Ain Shams University

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NCT06115408
Evaluation of Using Dienogest and N-
Acetyl
Cysteine
on
the
Volume
of
Uterine Leiomyoma
Faculty of Medicine
Ain Shams University
2023- 2024

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What is already known on this subject? AND
What does this study add?
Apart from surgical procedures, there are numerous hormonal and non-
hormonal drugs for management of leiomyoma. One of the non-hormonal drugs is
N-acetyl cysteine (NAC), but its use for this indication is poorly understood
(Aghaamoo et al., 2021)
This randomized controlled comparative clinical trial will assess the impact
of Dienogest versus N-Acetyl Cysteine in management of women with uterine
leiomyoma.
1.INTRODUCTION/ REVIEW
Leiomyoma is a relatively common benign tumor. It is the most common
cause of abnormal uterine bleeding and pelvic pain (Ali et al., 2018).
Leiomyoma originates from the smooth muscle of the uterus and its incidence
is 4.5%–68.6%. In black women, the prevalence is doubled and they have higher
numbers of leiomyoma and more severe symptoms than white women (Vercellini
and Frattaruolo, 2017)
Leiomyoma is symptomatic in patients and there are numerous clinical
presentations, for instance, pressure on adjacent organs, infertility, abnormal uterine
bleeding, and obstetric complications (Stewart et al., 2017)
Leiomyoma is considered the most common cause of gynecologic surgery
worldwide (Yuan et al., 2021)
Recent research has succeeded in stemming the leiomyoma and found a
multi-factorial inheritance pattern, but leiomyoma is still a matter of debate by
experts and poses tremendous challenges (Ayakannu et al., 2019)
More than 100 gene abnormalities are identified in leiomyoma, in the genes
for estrogen receptors, progesterone receptors, growth factors, prolactin receptors,
extracellular matrix, and collagens (Sogoyan et al., 2020)

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Apart from surgical procedures, there are numerous hormonal drugs for
leiomyoma. Dienogest is a selective progestin that combines the pharmacologic
properties of 19-norprogestins and progesterone derivatives, offering potent
progestogenic effects without androgenic, mineral corticoid, or glucocorticoid
activity (Caruso et al., 2019)
Previous trials demonstrated that dienogest provides effective reductions in
endometriosis-associated pelvic pain and laparoscopic measures of pathology
(Taylor et al., 2021)
Recently, the new progesterone 2 mg daily demonstrated equivalent efficacy
to GnRHa (e.g., buserelin acetate and leuprolide acetate) for relieving the pain of
endometriosis in two 24 week randomized studies (Marquardt et al., 2019)
Because uterine myomas and endometriosis have many common features, these
successful trials on endometriosis support that the use of dienogest inhibits myoma
growth. While evaluating superiority of dienogest in women with endometriosis,
significant shrinkage of myoma nodes was found coexisting with endometriosis over
several months during an administration of dienogest (Pritts et al., 2015)
One of the non-hormonal drugs suggested for management of leiomyoma is
N-acetyl cysteine (NAC), but its use for this indication is poorly understood. NAC is
a medication that was used to treat paracetamol overdose, and in chronic obstructive
pulmonary disease (Aghaamoo et al., 2021)
It can be prescribed intravenously, orally, or inhaled as a mist. However, in
leiomyoma, NAC is based on a simple premise. It is an anti-oxidative drug that
inhibits free oxidative radicals and consequently neutralizes the proliferation of the
tumor cells (Izadi et al., 2014)
Adverse effects have been reported for NAC, including stomatitis, nausea,
vomiting,
fever,
rhinorrhea,
drowsiness,
fatigue,
chest
tightness,
and
bronchoconstriction. NAC-induced bronchospasm occurs clinically rarely and
unpredictably, even in patients with asthma bronchitis or bronchitis that complicates
bronchial asthma (Farris et al., 2019)
Acquired
hypersensitivity
to
NAC
has
been
reported,
also
rarely.
Sensitization reports in patients with patch testing have not been confirmed.

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Sensitivity has been confirmed by several inhalation therapists who have reported a
history of skin eruption after repeated and prolonged contact with NAC (Timuroğlu
et al., 2018)
There is a consensus of opinion concerning the anti-oxidative effect of NAC,
but it is difficult to assess its effectiveness in leiomyoma. Not only would using
NAC avoid some of the adverse effects of hormonal drugs, but NAC is also cheaper
than the hormonal alternatives. This spurs efforts to develop non-hormonal therapies
in leiomyoma (Aghaamoo et al., 2021)
Experts have suggested several hormonal drugs, according to steroid receptors
identified in leiomyoma tissue. Given the majority of previous and current research that
has been carried out in medical treatment for leiomyoma, oral non-hormonal drugs may
be on track to overtake other treatment options. Evidence suggests that anti-oxidative
mechanisms may lead to a reduction in leiomyoma volume. The administration of
NAC as an anti-oxidant reduces oxidative stress by inhibiting free radicals and
glutathione synthesis, but its protection is incomplete. As a result, it prevents the
peroxidation of membrane lipids and prevents their release (Tahmasebi et al., 2020)
The present study is a randomized control trial that aims to assess the impact
of NAC versus Dienogest on the volume of uterine leiomyoma.
2.AIM / OBJECTIVES
This study aims to assess the effect of Dienogest and NAC on the volume of
uterine leiomyoma in women previously diagnosed with leiomyoma.
Research hypothesis: In women with leiomyoma, the use of NAC as a non-
hormonal drug in the treatment of leiomyoma of the uterus is more feasible and
effective in the reduction of leiomyoma volume with no hormonal side effects
compared with Dienogest.
Research question: In women with leiomyoma, is the use of NAC as a non-
hormonal drug in the treatment of leiomyoma of the uterus more feasible and
effective in the reduction of leiomyoma volume with no hormonal side effects
compared with Dienogest?

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3.METHODOLOGY:
Patients and Methods/ Subjects and Methods/ Material and Methods
Type of Study:
A Randomized Controlled Trial
Study Setting:
The study will be conducted at Ain Shams University Maternity Hospital
(ASUMH) “outpatient gynaecology clinic”
Study duration:
After protocol approval till completing of required sample size
Study Population:
Women attending outpatient gynaecology clinic at Ain Shams University Maternity
Hospital with the following criteria:
Inclusion criteria:
1. Age: 20-45 years.
2. Women with uterine leiomyoma (sub-mucous, sub-serous or intramural)
based on transvaginal sonography criteria. Uterine fibroids most often appear
as concentric, solid, hypoechoic masses. This appearance results from the
prevailing muscle, which is observed at histologic examination. These solid
masses absorb sound waves and therefore cause a variable amount of
acoustic shadowing.
Exclusion criteria:
1. Pregnant or menopausal women.
2. History of malignancies, metabolic, hematologic, cardiac, thromboembolism,
diabetes, renal or hepatic diseases.
3. History of hormonal drug use or treatment for leiomyoma in the past 3
months.
Sampling Method:
simple random sample

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Sample Size:
The study will be conducted on 40 women; they will be subdivided into 2 equal
groups.
Group (A): women will receive Dienogest, with brand name GYNOPROGEST,
2mg pills daily for 3 months (20 cases) (Ichigo et al., 2011)
Group (B): women will receive NAC, with brand name GEMACYSTEINE, orally
at a dose of 600 mg/day for 3 months ( 20 cases) (Aghaamoo et al., 2021)
Sample size Justification:
Assuming an effect size of 1.0 reflecting the percentage change (reduction) in the
volume of uterine leiomyoma, a sample of 12 patients in each group will be enough
to detect such rate, if true, at 0.01 α error and 0.90 power of the test. We will
increase the sample to 20 cases in each group to maximize the power of the study.
Randomization:
It will be done using computer generated randomization sheet.
Allocation and concealment:
It will be done by use of sealed opaque packages that will be given to a third person
(nurse) who will assign the packages to study groups. Each woman will be invited
to pull out a package. According to the number inside her package, women will be
allocated to either group A or B according to a computer- generated random list.
Blinding:
The tablets will be enclosed in an opaque packages labelled according to a
computer- generated random list. Each woman will be invited to pull out a package.
The tablets will be administered anonymously with coding with no knowledge of
the codes. Final assessment will be performed by another colleague who will have
no information about the groups. Patients and assessor will be blinded to the
groups.
Ethical and Safety Consideration:
This study will be done after approval of the Ethical Committee of the Department
of Obstetrics and Gynecology, Faculty of Medicine, Ain Shams University.
Informed consent will be taken from all participants before recruitment in the study,

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and after explaining the purpose and procedures of the study. The investigator will
obtain the written, signed informed consent of each subject prior to performing any
study specific procedures on the subject. The investigator will retain the original
signed informed consent form. All data will be collected confidentially. All cases
will be counseled about the side effects associated with study medications. The
study will be based on the investigator self-funding.
Study procedures and interventions:
1. After approval of study protocol, women will be enrolled into the study
according to inclusion and exclusion criteria.
2. Eligible patients will be randomized using a computer-generated sequence
1:1 either to
3. Intervention:
o Group
(A):
women
will
receive
Dienogest,
with
brand
name
GYNOPROGEST, 2mg pills daily for 3 months (20 cases) (Ichigo et al.,
2011)
o Group
(B):
women
will
receive
NAC,
with
brand
name
GEMACYSTEINE, orally at a dose of 600 mg/day for 3 months ( 20
cases) (Aghaamoo et al., 2021)
4. Methodology: All cases will be subjected to:
o Full history taking: with special emphasis to age, parity, BMI, age of
menarche, obstetric history, drug history as well as presence of any
medical disease.
o Full general examination: for pallor, fatigue.
o Abdominal examination: to assess the leiomyoma size, surface, contour
and consistency.
o Bimanual vaginal examination(for uterus <12 weeks): to confirm its
uterine origin.
o Vaginal
Ultrasound
examination
with
the
addition
of
a
transabdominal approach if needed to diagnose and assess the
leiomyoma (size and number).

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Ultrasound will be done using the same machine.
The principal investigator will hold regular meetings with the research
team to assess data and adverse events.
Serious adverse events will be reported to the research ethics committee,
Faculty of medicine, Ain Shams university within 24 hours.
Outcomes:

Primary outcome:
Leiomyoma volume: Size of myoma will be measured at three
diameters
of myomas (transverse, vertical and anterior–posterior). These
measurements will be repeated after 3 months of therapy by the same
sonographer.

Secondary outcomes:
o Dysmenorrhea:
according to the visual analog scale (VAS) is a
validated, subjective measure for acute and chronic pain. The scale is
composed of 0 (no pain at all) to 10 (worst imaginable pain).
o Heavy menstrual bleeding (HMB).
1.Actual blood loss per menstrual period: according to PBAC score is seen
in Figure 1,also defined by FIGO System is seen in Figure 2 according to
frequency, duration, regularity and flow volume.
2.using the measurement of hemoglobin.

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FIGURE 1 The PBAC scoring system; pictorial blood loss assessment chart (PBAC)
semi
objective assessment
blood loss has variable accuracy
80% -90% sensitivity but variable
specificity and PPV &NPV 60% (score >100 = HMB) (Magnay et al., 2020)
FIGURE 2 The FIGO AUB System (Munro et al., 2018)

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the
volume
of
uterine
leiomyoma:
A randomized clinical
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