Controlling the Recurrence of Pelvic Endometriosis after A Conservative Operation: Comparison between Chinese Herbal Medicine and Western Medicine
Chin J Integr Med 2013 Nov;19(11):820-825
ORIGINAL ARTICLE
Controlling the Recurrence of Pelvic Endometriosis after A
Conservative Operation: Comparison between Chinese
Herbal Medicine and Western Medicine
ZHAO Rui-hua (赵瑞华)1, HAO Zeng-ping (郝增平)2, ZHANG Yi (张 毅)3, LIAN Feng-mei (连凤梅)1,
SUN Wei-wei (孙伟伟)1, LIU Yong (刘 永)1, WANG Rui (王 蕊)4, LONG Li (龙 隶)5,
CHENG Ling (程 玲)6, DING Yong-fen (丁永芬)6, SONG Dian-rong (宋殿荣)7,
MENG Qing-wei (孟庆伟)3, and WANG Ai-ming (王蔼明)8
ABSTRACT Objective: To compare the clinical effect of Chinese medicine (CM) and Western medicine (WM)
for controlling the recurrence of pelvic endometriosis after a conservative operation. Methods: The study was a
multi-center, randomized, parallel controlled and prospective clinical trial. Patients were randomly divided into two
groups: CM group (106 cases) and WM group (102 cases). Drugs were given to patients during 1–5 days of the
fi rst menstruation after a conservative operation in both groups. Patients with stages Ⅰ and Ⅱ (revised American
Fertility Society) were treated for 3 months, while the patients with stages Ⅲ and Ⅳ were treated for 6 months.
The patients in the CM group were treated using three types of Chinese herbal medicine based on syndrome
differentiation. Patients in the WM group were treated using gonadotropin releasing hormone agonist (GnRH-a)
or gestrinone. Patients treated with GnRH-a received add-back therapy of Tibolone Tablets once a day after 4
months of treatment. Any cases of dysmenorrheal chronic pelvic pain, menstruation and any adverse reactions of
patients were recorded once a month during the preoperative and postoperative periods and once every 3 months
during the follow-up period. During the preoperative, postoperative and the follow-up periods, patients underwent
type B ultrasonography of the pelvis and measurements of serum CA125 levels, gynecologic examination, routine
evaluations of blood, urine, hepatic function (glutamate pyruvate transaminase), renal function (blood urea nitrogen)
and electrocardiograms. During the follow-up period they underwent type B pelvic ultrasonography, measurement
of serum CA125 levels and further gynecologic examinations. The two treatments were compared for clinical
recurrence rates, pregnancy rates and the incidence of adverse reactions. Results: The incidence and timing of
recurrence of endometriosis were not signifi cantly different between the two groups. The fi rst pregnancy achieved
by the patient in the CM group was signifi cantly earlier than that in the WM group (P<0.05). Moreover, the incidence
of adverse reactions in the WM group was signifi cantly
higher than in the CM group (P<0.01). Conclusions:
Treatment with Chinese herbal medicines prevented
the recurrence of endometriosis after a conservative
operation, improved the conception rate and showed
fewer and lighter adverse reactions than did treatment
with WM therapy. Treatment with Chinese herbal
medicine meets the need of patients wishing to have
a child following endometriosis and is an appropriate
form of clinical treatment.
KEYWORDS endometriosis, infertility, fertilization
in vitro, embryo transfer, recurrence rate, pregnancy
rate
©The Chinese Journal of Integrated Traditional and Western
Medicine Press and Springer-Verlag Berlin Heidelberg 2012
Supported by the Key Projects of the National Science and
Technology Pillar Program during the 11th Five-Year Plan
Period (No. 2006BA104A)
1. Department of Gynecology, Guang’anmen Hospital, China
Academy of Chinese Medical Sciences, Beijing (100053),
China; 2. Obstetrics and Gynecology Department, Beijing
Friendship Hospital, Capital Medical University, Beijing
(100050), China; 3. Department of Obstetrics and Gynecology,
Beijing Hospital, Ministry of Health, Beijing (100730), China;
4. Department of Obstetrics and Gynecology, Beijing Tiantan
Hospital Affi liated to Capital Medical University, Beijing (100050),
China; 5. Department of Gynecology, Fuxing Hospital, Capital
Medical University, Beijing (100038), China; 6. Department of
Gynecology, Wangjing Hospital of China Academy of Chinese
Medical Sciences, Beijng (100102), China; 7. Department of
Gynecology, Second Affiliated Hospital to Tianjin University
of Traditional Chinese Medicine, Tianjin (300150), China; 8.
Department of Obstetrics and Gynecology, PLA Navy General
Hospital, Beijing (100048), China
Correspondence to: Prof. ZHAO Rui-hua, Tel: 86-10-88001139,
E-mail: rhzh801@sohu.com
DOI: 10.1007/s11655-012-1247-z
Endometriosis (EMs) is an estrogen-dependent
disease that is common frequently encountered
and stubborn in women of childbearing age. In
recent years, the morbidity of EMs has increased
significantly, reaching 10% to 15% in the generalChin J Integr Med 2013 Nov;19(11):820-825 • 821 •
population and exceeding 30% among patients with
chronic pelvic pain or infertility.(1) Surgery is the first
treatment for pelvic EMs, but it is difficult to control
postoperative recurrence. Some studies reported that
the recurrence rate reached 36% by 5 years after
surgery(2) and the recurrence rate after a conservative
operation with preservation of fertility can be as high
as 50%.(3) Surgery for recurrence is difficult and
causes major bleeding; moreover, recurrence of EMs
is still possible after surgery.(4) Thus, drug treatment
after the operation is the key to eliminate or suppress
any residual lesions and to prevent recurrence. The
treatment of EMs recurrence with Chinese herbal
medicine is now an active research fi eld. To compare
the clinical effec of controlling the recurrence of pelvic
EMs after a conservative operation between Chinese
medicine (CM) and Western medicine (WM), we
ran a multi-center, randomized, parallel controlled
and prospective clinical trial. We measured the
rates of recurrence and successful pregnancy and
the incidence of adverse reactions between the two
therapies.
METHODS
Diagnostic Criteria
Methods on the Manual on the Diagnosis and
Therapy of Endometriosis(5) and Chinese Obstetrics
and Gynecology(6) were used to establish the diagnostic
criteria. The clinical stages were graded according to
the revised scheme published by the revised American
Fertility Society (r-AFS) in 1985.(6) The criteria of
symptoms and signs for syndrome differentiation were
established based on the published references(7,8) and
the clinical experience of our group.
Inclusion Criteria
Patients were included according to the following
screening criteria: (1) meet the diagnostic criteria
and CM syndrome differentiation criteria; (2) without
a history of serious drug hypersensitivity; (3) have
never undergone an open operation or laparoscopic
operation for EMs; (4) have not taken any other drugs
to treat EMs for 6 months before the operation; (5)
have no serious primary disease in the cardiovascular,
cerebrovascular, hepatic, renal or hematopoietic
systems and lacked any history of psychiatric illness;
(6) non-lactating woman aged from 18 to 45 years.
According to the above screening criteria,
patients with clinical and pathological features of
ovarian EMs and/or deep infiltrating EMs were
assigned to treatment groups during the first to fifth
days of the first menstruation after a conservative
operation. All patients signed informed consent forms.
Exclusion Criteria
Patients with EMs combined with adenomyosis
and any patients using other drugs to treat EMs after
the operation were excluded.
Patients
A total of 208 patients with pelvic EMs after a
conservative operation were recruited from outpatient
and inpatient departments of eight centers in China
from March 2008 to May 2010. The centers were
Guang’anmen Hospital; Beijing Friendship Hospital
Affiliated to Capital Medical University; Beijing
Hospital of the Ministry of Health; Beijing Tiantan
Hospital Affi liated to Capital Medical University; Fuxing
Hospital Affiliated to Capital Medical University;
Wangjing Hospital of the China Academy of Chinese
Medical Sciences; Second Affiliated Hospital to
Tianjin University of Traditional Chinese Medicine and
the PLA Navy General Hospital. The patients were
randomly assigned to two groups by randomized
blocks method. There were 106 patients in the CM
group and 102 patients in the WM group.
Treatment
Drugs began to be given to the patients during
days 1–5 of their first menstruation in both groups.
The patients with r-AFS stages Ⅰ and Ⅱ EMs were
treated for 3 months, while the patients with stages Ⅲ
and Ⅳ were treated for 6 months.
The patients in the CM group were treated using
three types of Chinese herbal medicine (Kangmei
Pharmaceutical Co., Ltd., China) treatment based
on syndrome differentiation.
The herbs were
decocted with water and given to the patients by oral
administration twice a day, with 21 days as one course.
The decoction was given again during days 1–5 of the
next menstrual period. Modified Guifu Decoction ( Radix Aconiti lateralis Preparata, 10 g; Ramulus
Cinnamomi 10 g; Radix Linderae 10 g; Rhizoma
Sparganii 10 g; Rhizoma Curcumae 10 g; Spina
Gleditsia 14 g and Radix Salviae Miltiorrhizae 25 g) was
given to patients with syndrome of cold congeal and
blood stasis to the warm meridians and dissipate cold,
activate blood and resolve stasis. Modified Danchi•
Decoction (Radix Bupleuri 10 g; Rhizoma
Cyperi 14 g; Radix Salviae Miltiorrhizae 25 g; Radix
Paeoniae rubra 15 g; Rhizoma Curcumae 10 g; Spina
Gleditsia 14 g and Rhizoma Sparganii 10 g) was
given to the patients with syndrome of qi stagnation
and blood stasis to sooth the Liver (Gan) and regulate
qi, activate blood and resolve stasis.
Modifi ed Qidan
Decoction [Astragalus membranaceus (Fisch.)
Bge. Preparata 30 g, Salvia Miltiorrhizae 25 g, Radix
Paeoniae rubra 15 g, Rhizoma Curcumae 10 g,
Poria 15 g and Rhizoma Atractylodes Macrocephala
15 g] was given to the patients with syndrome of
qi deficiency and blood stasis to invigorate Spleen
(Pi) and replenish qi, activate blood and resolve
stasis.
Drugs were added or omitted in the CM group
depending on patients’ symptoms.
Thus, the patients
with dysmenorrheal were treated by adding Rhizoma
Corydalis 10 g, Radix Linderae 10 g; the patients with
anal pain upon bearing down were treated by adding
Rhizoma et Radix Notopterygii 8 g.
The patients with
lumbago were treated by adding Radix Dipsaci 30 g
and Cortex Eucommiae 10 g.
T h e p a t i e n t s i n t h e W M g r o u p r e c e i v e d
hypodermic or intramuscular injections of 3.75 mg
GnRH-a (Triptorelin Acetate for Injection, Ipsen
Pharma-Biotech, France, No. H20030577) once
monthly or 2.5 mg oral Gestrinone (Beijing Zizhu
Pharmaceutical Co., Ltd., China, No. H19980020)
twice a week. Patients treated with gonadotropin
releasing hormone agonist (GnRH-a) received addback
therapy of 1.25 mg Tibolone Tablets (Livial,
Nanjing Organon Pharmaceutical Co., Ltd., No.
H20051085) once a day after 4 months of treatment.
February 28, 2008, it had passed the ethic
review of the 11th Five Year Plan; August 21, 2008, it
had passed the ethic review of Guang’anmen Hospital,
China Academy of Chinese Medical Sciences for
changing clinical investigation plans.
Outcome Measures
The EMs recurrence rate, the pregnancy rate
and the incidence of adverse reactions were recorded.
Evaluations of dysmenorrheal, chronic pelvic pain,
menstruation conditions and the degree of adverse
reactions were based on “Guiding principle of
clinical research on new drugs of traditional Chinese
medicine.”(9) The incidences of dysmenorrheal,
chronic pelvic pain, menstruation and any adverse
reactions were recorded once a month during the
preoperative and postoperative periods and once
every 3 months during the follow-up period. Patients
underwent preoperative, postoperative and posttreatment
evaluation of safety indices including
type B pelvic ultrasonography, measurement of
serum CA125 levels, gynecologic examinations, and
routine evaluations of blood, urine, hepatic function
[glutamate pyruvate transaminase (GPT) levels],
renal unction [blood urea nitrogen (BUN) levels]
and electrocardiograms. During the follow-up period
they underwent type B pelvic ultrasonography,
measurement of serum CA125 levels and further
gynecologic examinations.
Evaluation Criteria
The diagnosis of recurrence was made by
referring to a manual on the diagnosis and therapy of
endometriosis. These were as follows: (1) recurrence
and aggravation after postoperative symptoms had
been relieved for 3 months; (2) the pelvic signs
returned after disappearing or were aggravated to
the preoperative level; (3) after operation, the type
B ultrasound scans showed a new focus of infection
or EMs; (4) The serum CA125 level increased again
after declining and other diseases were excluded. The
patients had a diagnosis of recurrence, fi tting one of the
criteria (2–4) above with or without concomitant criteria.
The three-point scoring criteria for adverse reactions
were as follows: (1) mild (1 point): minimal reaction,
work and life activities were unaffected; (2) moderate
(2 points): light reaction, work and life activities were
affected but could be tolerated; (3) severe (3 points):
severe reaction, work and life activities were badly
affected and could not be tolerated.
Statistical Analysis
The data were analyzed using SPSS 12.0
software (SPSS Inc., Chicago, IL, USA). Comparison
of the recurrence rate between two groups was
performed using χ2 test and the relative risk (RR),
odds ratio (OR) and the 95% confidence intervals
(CI) were calculated. The difference of count data or
measurement data between groups was compared
by Student’s t-test or χ2 test, respectively. Statistical
signifi cance was assumed at P<0.05.
RESULTS
General Clinical Data
The demographic data of the patients inChin J Integr Med 2013 Nov;19(11):820-825 • 823 •
both groups was shown in Table 1. There was no
difference of the baseline characters between the two
groups.
Comparison of Recurrence Rates
There were 64 patients (60.4%) received a
3-month treatment and 42 patients (39.6%) received
a 6-month treatment in the CM group. While in the
WM group, there were 51 patients (50%) received a
3-month and a 6-month treatment, respectively. The
mean follow-up time after operation in the CM group
was 20.66±6.75 months and 20.83±6.65 months in
the WM group with no statistical difference between
groups (P>0.05). There were no statistically signifi cant
differences in the clinical recurrence rate or in the time
to recurrence of pelvic EMs between the CM and WM
groups (P>0.05, Tables 2 and 3).
Comparison of Pregnancy Rates
A comparison of the pregnancy rate between
the two groups during the follow-up period showed no
significant differences (31.1% vs . 28.4%, P =0.670).
For those diagnosed with infertility before the
operation, the pregnancy rate in the CM group [12/15
(80.0%)] was signifi cantly higher than that in the WM
group [4/15 (26.7%), P=0.003]. The mean duration to
achieving the first pregnancy after the operation for
the patients in the CM group was also significantly
less than that in the WM group (P<0.05, Table 4).•
Tables
Table 1. Demographics of Patients in the Two Groups
Item CM (106 cases) WM (102 cases) Statistics P-value
Basic material Age (x–
±s, year) 32.52±6.16 31.70±6.08 0.97 0.33
Sexual life history [Case (%)] 84 (79.2) 80 (78.4) 0.02 0.89
EMs course (x–
±s, year) 28.80±36.82 38.15±56.07 –0.40 0.69
Clinical manifestation [Case (%)] Algomenorrhea 60 (56.6) 63 (61.8) 0.57 0.45
Chronic pelvic pain 42 (39.6) 37 (36.3) 0.25 0.62
Irregular menstruation 15 (14.2) 11 (10.8) 0.54 0.46
Infertility 15 (14.2) 15 (14.7) 0.01 0.91
Pelvis positive sign 101 (95.3) 96 (94.1) 0.14 0.71
Abnormal B-Ultrasound Scan 100 (94.3) 99 (97.1) 0.93 0.33
Abnormal CA125 49 (46.2) 52 (51.0) 0.93 0.63
Postoperative diagnosis [Case (%)] Ovarian endometriosis cyst 100 (94.3) 97 (95.1) 1.37 0.50
Deep infi ltrating endometriosis 6 (5.7) 4 (3.9)
Incorporation 0 (0.0) 1 (1.0)
r-AFS staging [Case (%)] StageⅠ 13 (12.3) 8 (7.8) 6.36 0.10
StageⅡ 51 (48.1) 43 (42.2)
StageⅢ 36 (34.0) 35 (34.3)
StageⅣ 6 (5.7) 16 (15.7)
CM Syndrome differentiation [Case (%)] Cold stagnation cause qi blockage 4 (3.8) 10 (9.8) 3.92 0.14
Qi stasis cause blood stagnation 69 (65.1) 68 (66.7)
Qi defi ciency cause blood stagnation 33 (31.1) 24 (23.5)
Table 2. Comparison of the Clinical Recurrence
Rates of Pelvic Endometriosis between
the Two Groups
Group Case Recurrence
[Case (%)] χ2 P-value RR (95% CI)
CM 106 9 (8.5)
1.448 0.229 0.619
WM 102 14 (13.7) (0.280–1.366)
Table 3. Comparison of the Time to Recurrence of
Pelvic EMs between Groups
Group Case
Time to recurrence (Month)
t P-value
x–
±s Median (Range)
CM 9 8.56±4.93 6.00 (3.00–18.00)
–0.42 0.68
WM 14 7.86±3.08 6.00 (3.00–12.00)
Table 4. Comparison of the Time to First Pregnancy
between the Two Groups
Group Case
Time to fi rst pregnancy (Month)
t P-value
x–
±s Median (Range)
CM 33 5.88±4.18 4.00 (1.00–17.00)
–2.09 0.04
WM 29 8.44±5.34 6.00 (3.00–21.00)
Comparison of the Incidence of Adverse
Reactions
During the treatment period, there were
patients with adverse reactions in both groups. A
few patients in the CM group complained of mild
stomach upsets but these were relieved quickly after
adjusting the herbal medicines and dosages. Most of
the patients in the WM group showed some prolonged
adverse reactions, such as mild to moderate fever
and sweating, colpoxerosis, hypaphrodisia, acne,
weight gain, insomnia, bone pain, irregular bleeding,
headache and skin itching. There was a statistically
significant difference of adverse reactions between
the two groups [9.4% vs. 83.3%, P<0.01).
Comparison of Safety Indices
Before treatment, the safety indices and
biochemical parameters of patients in the two groups
were within normal ranges. After treatment, some of
these were outside normal ranges but there were no
statistically significant differences between the CM
and WM groups.
DISCUSSION
The pelvic pain and infertility caused by EMs
seriously affects the health and quality of life and
brings great pain and suffering to the patients.
Conservative operation is the choice of treatment for
young patients with EMs who wish to have a child, but
the recurrence rate remains persistently high. How
to delay or eliminate such recurrence is an important
research topic.
GnRH-a treatment causes a significant reduction
in the ovarian secretion of estrogen and leads to a
temporary cessation of menstruation, so it is called
reversible medical oophorectomy. At present, it is the
most effective Western medical treatment for patients
with EMs. Some authors have argued that the treatment
of EMs by combining a conservative operation with
GnRH-a therapy could reduce the recurrence rate
and increase the pregnancy rate.(10) However, others
recommended combining a conservative operation with
GnRH-a treatment for 3–6 months and following up
for 6–60 months. Comparing the above-mentioned
treatment with the expected treatment, there was
no statistically significant in the recurrence rate.(11-13)
Combined treatment with GnRH-a after operation
could increase the pregnancy rate but there was no
statistically significant difference in the pregnancy
rate.(10,14) The adverse reactions of GnRH-a treatment
mainly manifest as a low estrogen syndrome
with fevers, sweats, colpoxerosis, hypaphrodisia,
headache, insomnia, poor memory, emotional lability,
depression, debility, arthralgia, irregular vaginal
bleeding, breast haphalgesia and allergic responses.
Some patients of child-bearing age even develop
irreversible premature ovarian failure after treatment.
It is diffi cult for patients to accept these side effects. In
addition, the loss of bone mass is a serious adverse
reaction of GnRH-a, even with short-term treatments.
Because of the high-cost of GnRH-a, a
cheaper drug gestrinone has become a common
medicine to prevent the recurrence of EMs after a
conservative operation for EMs. Gestrinone inhibits
endometrial growth to control the recurrence of
EMs, and has antiestrogenic, antiprogestogenic
and antigonadotropic hormone effects. Treatments
with gestrinone and GnRH-a are both effective in
controlling recurrence and increasing the pregnancy
rate, but gestrinone induces adverse reactionsdue
to the high androgenic hormone levels.(15) The best
time for pregnancy is 6 months to 1 year after an
operation for EMs. However, during treatment with
WM, the patients cannot get pregnant, so it is easy
to miss the optimal time.(16) For those patients with
infertility before the operation, there is a need to use
assisted reproductive technologies to increase the
pregnancy rate after stopping drugs. However, this is
burdensome to the patients.
By contrast, treatment with Chinese herbal
medicines stresses prescription for the individual
patient’s syndrome pattern and attempts to adjust
the body’s physiology holistically. The recurrence
rate of EMs following treatment with CM in this study
was basically identical to treatment using WM. At
the same time, it had some advantages, such as
not interfering with the patient’s normal physical
condition. It produced a low incidence and mild
symptoms of adverse reactions and showed good
patient compliance. During treatment with CM, the
patients could also try to get pregnant. The time to
first pregnancy among the patients in the CM group
was shorter than that in the WM group, especially for
those patients diagnosed with infertility caused by
endometriosis before the operation. The effectiveness
of raising the conception rate of patients in the CM
group was obviously better than in the WM group.Chin J Integr Med 2013 Nov;19(11):820-825 • 825 •
In this study, syndrome differentiation and
treatment with CM has provided a new investigative
direction and treatment for controlling the recurrence
of EMs after a conservative operation. It also improved
the general condition of the patients, improved the
conception rate and helped them to select the best
time to get pregnant. Thus, it is appropriate for general
use in the clinical treatment of patients with EMs.
International registration number: ChiCTRTRC-
10000808
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Edited by YUAN Lin
