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Taiwanese Journal of Obstetrics & Gynecology 55 (2016) 55e59

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Taiwanese Journal of Obstetrics & Gynecology


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Original Article

Low-dose add-back therapy during postoperative GnRH agonist


treatment
Hsiao-Wen Tsai a, b, c, Peng-Hui Wang b, d, Ben-Shian Huang b, c, e, Nae-Fang Twu b, d,
Ming-Shyen Yen b, d, Yi-Jen Chen b, c, d, *
a
Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
b
National Yang-Ming University, School of Medicine, Taipei, Taiwan
c
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
d
Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
e
Department of Obstetrics and Gynecology, National Yang-Ming University Hospital, Ilan, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Objective: Low-dose add-back therapy during postoperative GnRH agonist treatment could lower the
Accepted 16 April 2015 risk of add-back-induced endometriosis recurrence and reduce treatment dropout compared with a
regular dose. However, the effect of low-dose add-back therapy is still unknown. The aim of this study
Keywords: was to determine whether low-dose add-back therapy can also effectively relieve the hypoestrogenic
add-back therapy side effects and simultaneously maintain a therapeutic response of GnRH agonist treatment.
endometriosis
Materials and methods: This analysis was a prospective cohort study. During postoperative GnRH agonist
low-dose
treatment, a total of 107 women were prescribed add-back therapy [oral combination tablet; estradiol
valerate (1 mg) and medroxyprogesterone acetate (2.5 mg)] (Indivina; Orion, Espoo, Finland) for 20 weeks.
Patients in the low dose add-back therapy group were prescribed the tablet once a day, and patients in the
regular dose group were given the tablet twice a day. Hypoestrogenic side effects, such as hot flashes and
insomnia, were recorded. Patients were also questioned regarding their pelvic symptoms and pain to
evaluate the possibility of endometriosis recurrence. Lumbar spine (L2eL4) bone mineral density was
measured using dual X-ray absorptiometry. The dropout rates in both groups were also evaluated.
Results: The incidence of hypoestrogenic side effects was lower in the low dose group compared with the
regular dose group, including hot flashes (19.2% vs. 21.8%, p ¼ 0.741) and insomnia (15.4% vs. 18.2%,
p ¼ 0.699), although there were no significant difference between the groups. In addition, a higher
number of patients in the regular dose group dropped out of treatment compared to the low dose group
(14.5% and 9.6%, respectively, p ¼ 0.435). The patients in both groups had a significant loss of mean bone
mineral density during therapy (p < 0.001 and p ¼ 0.018 for the low dose and regular dose groups,
respectively).
Conclusion: Low dose add-back therapy could effectively ameliorate hypoestrogenic side effects and
simultaneously maintain the therapeutic response of GnRH agonist treatment. The treatment dropout
was lower compared with a regular dose. Therefore, low dose add-back therapy can be considered a
treatment choice during postoperative GnRH agonist treatment.
Copyright © 2016, Taiwan Association of Obstetrics & Gynecology. 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

Endometriosis is a complex disease because of the significant


diversity of clinical presentations and complicated treatment op-
tions [1,2]. Surgical intervention followed by medical treatment to
prevent endometriosis recurrence has been used as a standard
* Corresponding author. Department of Obstetrics and Gynecology, Taipei
Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. treatment for this complex disorder [3]. Postoperative medical
E-mail address: chenyj@vghtpe.gov.tw (Y.-J. Chen). treatment with a GnRH agonist can effectively prevent recurrence,

http://dx.doi.org/10.1016/j.tjog.2015.04.004
1028-4559/Copyright © 2016, Taiwan Association of Obstetrics & Gynecology. 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/).

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56 H.-W. Tsai et al. / Taiwanese Journal of Obstetrics & Gynecology 55 (2016) 55e59

but this treatment is notorious for hypoestrogenic side effects, such once a day or twice a day, beginning with the second GnRH agonist
as hot flashes, insomnia, and osteoporosis [4,5]. Therefore, to injection, for 20 weeks. To maintain a more stable therapeutic drug
relieve the hypoestrogenic side effects and reduce treatment concentration, we prescribed the therapy twice daily instead of
dropout, add-back therapy, with lowest effective hormone support, once daily.
plays an important role in postoperative GnRH agonist treatment. At the pretreatment assessment, the patients were questioned
Add-back therapy provides an alternative for patients who are regarding their pelvic symptoms (dysmenorrhea, nonmenstrual
responsive to GnRH agonist treatment but experience unwanted pelvic pain, and deep dyspareunia), and a pelvic examination was
hypoestrogenic side effects. The rationale for this approach derives performed with specific attention to pelvic tenderness and indu-
from the estrogen threshold hypothesis proposed by Barbieri [6], ration. The findings were quantified according to a modification of
which allows for patients with endometriosis to replace estrogen in the Biberoglu and Behrman scale and rated from 1 to 4 (1 ¼ no pain,
a titrated fashion, preventing hypoestrogenic side effects without 2 ¼ mild pain, 3 ¼ moderate pain, 4 ¼ severe pain) by the exam-
stimulating this estrogen-sensitive disease. However, how to titrate ining clinician and coordinator using the symptom diaries of the
the optimal dosage, the lowest effective dose of add-back therapy, patients [15]. The scores for three symptoms and two physical signs
is the most critical point of excellent add-back therapy. High-dose were summed to yield a total subjective score. In addition, the same
add-back therapy might be effective in reducing hot flashes, pelvic symptoms were assessed after the treatment period. The
insomnia, and osteoporosis, but simultaneously, in this estrogen- assessors were blinded to the patient's group allocation.
sensitive disease, it might lead to problems of pelvic pain, endo- Bone mineral density (BMD) of the lumbar spine (L2eL4) was
metriosis recurrence, and treatment dropout [7]. Therefore, deter- measured using dual X-ray absorptiometry after the initial lapa-
mining the lowest effective dose of add-back therapy continues to roscopic surgery, before the first GnRH agonist was given, and at
be investigated. the completion of 24 weeks of treatment. All measurements were
Previous studies have revealed the effects of different add-back performed using the same machine (Hologic Quantitative Digital;
regimens, including daily oral norethindrone acetate (5 mg) or daily Hologic MDM, Waltham, MA, USA) according to standardized
norethindrone acetate (5 mg) in conjunction with different doses of procedures. The results are expressed as grams per square
conjugated equine estrogens (0.625 or 1.25 mg) or estradiol (2 mg) centimeter.
only [8e13]. Although hypoestrogenic symptoms are relieved by At each visit, the patients were questioned directly regarding
add-back therapy, patient compliance is still a problem because of the presence or absence of physiologic side effects, such as hot
add-back-induced endometriosis recurrence. Because the aim of flashes and insomnia. The participants were requested to complete
add-back therapy is to relieve hypoestrogenic side effects, and not a daily diary, to record the frequency of hot flashes and to take part
to interfere with the GnRH agonist treatment, finding out the in a self-administered questionnaire survey based on the Insomnia
lowest effective dose of add-back therapy is necessary. Therefore, Severity Index to assess insomnia symptoms [16,17]. The Insomnia
we conducted a cohort study on women who received post- Severity Index is a valid and reliable self-administered instrument
operative GnRH agonist treatment with add-back therapy. We tried that measures the perception of current insomnia symptoms. In
to lower the regular dose of add-back therapy to determine addition, participants were questioned indirectly regarding the
whether low-dose add-back therapy can also effectively relieve presence of other side effects. Physical examinations were per-
hypoestrogenic side effects and simultaneously maintain a thera- formed prior to the treatment and every 4 weeks up to Week 24.
peutic response of GnRH agonist treatment. Serum E2 concentrations were measured on Day 3 of the menstrual
cycle immediately prior to the initiation of treatment and at
Materials and methods 24 weeks. Serum CA 125 was measured simultaneously. Additional
fasting serum samples were obtained to assess circulating total
This analysis was a prospective cohort study over a 24-week cholesterol, cholesterol subfractions, and triglyceride levels.
treatment period and 12-week follow-up period. The study was For the endometriosis response, BMD, endocrine effects, and
conducted at Taipei Veterans General Hospital, Taipei, Taiwan, and subjective side effects, we used the ManneWhitney U test, an un-
approved by the ethics committee and institutional review board of paired Student t test, or a chi-square test to compare the between-
the institution. From January 2009 to January 2010, a consecutive group differences at baseline and after treatment. The Wilcoxon
series of 120 patients with a history of symptomatic endometriosis, matched-pairs signed-rank test or a paired Student t test was used
which was diagnosed surgically according to the revised American to compare the within-group differences. Statistical significance
Society for Reproductive Medicine classification, agreed to partici- was defined as p < 0.05.
pate in the study [14]. No patient received any other hormonal or
medical therapies prior to study entry. In addition, all participants Results
underwent complete resection of the endometriotic lesions by
laparoscopic surgery and initiation of postoperative GnRH agonist Of the 120 patients who were assessed for eligibility, 13 patients
adjuvant treatment during the next menstruation. All patients were excluded. Seven patients did not complete the questionnaire,
provided written informed consent prior to inclusion in the study. and six patients did not come to the follow-up visit. Consequently, a
Once patients were enrolled, allocation of treatment was carried total of 107 women were enrolled in our study. Overall, 52 women
out according to a patient-centered, partially randomized design; were allocated to receive a low dose of add-back therapy, and 55
we allowed women with a preference for a particular treatment to women were assigned to receive a regular dose of add-back ther-
undergo that treatment, whereas those without a preference were apy. There were no significant differences between the two groups
randomly allocated to either one of the treatment arms. Random- in terms of age, parity, body mass index, stage of endometriosis,
ization was achieved by opening sequentially numbered, sealed, pelvic pain scores, and CA 125 levels (Table 1).
opaque envelops that were prepared by using a computer- The median changes in the overall pelvic pain scores and CA 125
generated random number list. Patients in both groups were to levels from the pretreatment baseline to the completion of GnRH
receive a depot preparation of the GnRH agonist leuprolide acetate agonist treatment for the two groups are shown in Table 2. De-
(3.75 mg) intramuscularly every 4 weeks plus either an oral com- creases in pelvic symptom scores from baseline were statistically
bination of 1 mg/2.5 mg tablet (estradiol valerate, 1 mg; medrox- significant through Week 24 of follow-up for both the low-dose and
yprogesterone acetate, 2.5 mg) (Indivina; Orion, Espoo, Finland) regular-dose groups (p < 0.001 and p < 0.001, respectively). No

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Table 1
Patient characteristics.

Characteristics Low-dose Regular-dose p


group (n ¼ 52) group (n ¼ 55)

Age (y) 35.8 ± 6.5 36.1 ± 8.3 0.834


Body mass index (kg/m2) 22.1 ± 4.0 21.8 ± 4.6 0.874
Parity, n (%) 0.988
Nulliparous 36 (69.2%) 38 (69.1%)
Parous 16 (30.8%) 17 (30.9%)
Stage of endometriosis, n (%) 0.268
Stage III 32 (61.5%) 28 (50.9%)
Stage IV 20 (38.5%) 27 (49.1%)
CA 125 (U/mL), preoperative 55.9 ± 45.0 59.9 ± 42.1 0.688
Bone mineral density (gm/cm2) 1.075 ± 0.139 1.095 ± 0.116 0.533
Baseline pelvic score 6.7 ± 1.6 7.3 ± 1.8 0.188

The data are the mean ± standard deviation or case numbers.


*p < 0.05, statistically significant.

recurrence of symptoms was noted during the additional follow-up


period after completion of therapy. In addition, decreases in CA 125
levels were statistically significant in both groups (p < 0.001 and Figure 1. Incidence of hypoestrogenic side effects in both groups after 6 months of
add-back therapy.
p < 0.001, respectively). However, there were no significant differ-
ences between the groups.
The hypoestrogenic side effects that were induced by the GnRH as the regular-dose therapy. Fortunately, according to previous
agonist, such as hot flashes and insomnia, were evaluated in both studies, the deterioration effect on BMD is transient.
groups after the 6-month add-back therapy (Figure 1). The inci-
dence of hot flashes was 19.2% and 21.8% in the low-dose and
regular-dose groups, respectively (p ¼ 0.741). The incidence of Discussion
insomnia was 15.4% and 18.2% in the low-dose and regular-dose
groups, respectively (p ¼ 0.699). The incidence of hypoestrogenic In our study, we found that low-dose add-back therapy can
side effects was higher in the regular-dose group, but no significant ameliorate hypoestrogenic side effects similar to a regular dose and
difference was found between the groups. In addition, a higher simultaneously avoid the risk of recurrent pelvic pain and treat-
number of patients who received the regular dose of add-back ment dropout while maintaining the GnRH agonist effect. There-
therapy dropped out compared to those who received the low fore, low-dose add-back therapy can be considered a treatment
dose (14.5% and 9.6%, respectively, p ¼ 0.435), but there was no choice during postoperative GnRH agonist treatment.
significant difference. The causes for dropout from the study were The benefits of GnRH agonist treatment in managing the pelvic
lack of symptom improvement, adverse events such as emotional symptoms of endometriosis and preventing its recurrence are well
change, hot flashes, and noncompliance. established [1]. Therefore, an important issue regarding treatment
The results of the analysis of total cholesterol levels, circulating with a GnRH agonist is how to effectively reduce the intolerable
cholesterol subfractions, triglycerides, and glucose during the side effects and make patients comfortable without inducing
follow-up period are listed in Table 2. There were no significant recurrent pelvic pain. A series of therapeutic trials have reported
differences in the mean changes from baseline for any of these the effectiveness and safety of add-back therapy, but the dosage
parameters between the groups (Table 3). was higher; the chance to induce recurrent pelvic pain was higher,
The mean changes in lumbar spine BMD from baseline and at too. Fernandez et al [9] demonstrated that estradiol (2 mg) plus
the end of 24 weeks of therapy for patients with follow-up data are promegestone (0.5 mg) per day as add-back therapy could effec-
shown in Figure 2. During GnRH agonist therapy, the patients all tively reduce the side effects of endometriosis symptoms without a
had a progressive and significant loss of mean BMD during therapy deleterious change in lipid parameters. In addition, Surrey and
(p < 0.001 and p ¼ 0.018 for the low-dose and regular-dose groups, Hornstein [8] also reported a relatively higher add-back dosage
respectively). However, the low-dose therapy was not as effective with conjugated equine estrogens (1.25 mg) and norethindrone

Table 2
Hormone and metabolic parameters of both groups before and after 24 weeks of treatment.

Variable Low-dose group (n ¼ 52) Regular-dose group (n ¼ 55)

Before After p Before After p

Pelvic score 6.7 (1.6) 3.2 (1.1) <0.001* 7.3 (1.8) 3.7 (1.1) <0.001*
CA 125 (U/mL) 55.9 (45.0) 9.5 (5.2) <0.001* 59.9 (42.1) 12.9 (8.9) <0.001*
E2 (pg/mL) 43.1 (27.4) 24.8 (14.6) 0.001* 38.1 (24.7) 26.6 (14.4) 0.021*
Total CHO (mg/dL) 163.4 (36.2) 166.9 (28.7) 0.303 172.2 (38.6) 173.7 (41.3) 0.659
HDL (mg/dL) 55.7 (11.4) 59.5 (13.5) 0.051 52.1 (14.3) 57.2(18.7) 0.111
LDL (mg/dL) 95.1 (32.6) 99.2 (28.4) 0.083 107.7 (30.7) 107.1 (28.3) 0.893
TG (mg/dL) 65.4 (25.5) 69.8 (46.3) 0.543 70.8 (27.4) 69.1 (43.4) 0.873
CHO/HDL ratio 3.0 (0.8) 3.1 (1.0) 0.381 3.0 (0.6) 2.9 (0.7) 0.127
Glucose (mg/dL) 86.5 (12.6) 89.5 (9.2) 0.240 100.6 (11.9) 101.8 (13.6) 0.410

The values are expressed as the mean (±standard deviation).


*p < 0.05, statistically significant.
HDL ¼ high-density lipoprotein; LDL ¼ low-density lipoprotein; TG ¼ triglycerides; Total CHO ¼ total cholesterol.

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Table 3 minimize bone loss, but they did not assess pain, extent of disease,
Changes after 24 weeks of treatment with add-back therapy in both groups. or vasomotor symptoms. However, the continuous administration
Variable Low-dose group Regular-dose group p of medroxyprogesterone acetate appears to reverse the beneficial
(n ¼ 52) (n ¼ 55) effects of GnRH agonist; moreover, norethindrone has adverse ef-
Pelvic score 3.4 ± 0.2 3.4 ± 0.3 0.884 fects on lipid profiles [22]. Vasomotor symptoms, hot flashes, and
CA 125 (U/mL) 46.3 ± 6.9 47.0 ± 6.9 0.944 vaginal dryness are all bothersome side effects and are directly
E2 (pg/mL) 18.3 ± 4.7 11.5 ± 4.5 0.317 related to the rapid drop in estrogen levels [23,24]. Therefore,
Total cholesterol (mg/dL) 3.4 ± 3.3 1.2 ± 2.7 0.622
estrogen-containing add-back therapy might be more appropriate
HDL (mg/dL) 5.4 ± 2.6 2.7 ± 2.2 0.464
LDL (mg/dL) 4.1 ± 2.3 0.6 ± 4.3 0.304 and effective in reducing vasomotor symptoms than progestin-
TG (mg/dL) 4.4 ± 7.1 1.3 ± 7.6 0.628 alone therapy and would maintain compliance and the benefits of
Cholesterol/HDL ratio 0.1 ± 0.1 0.1 ± 0.1 0.120 GnRH agonist treatment.
Glucose (mg/dL) 3.0 ± 2.3 1.2 ± 1.4 0.539
The loss of BMD is another important issue in the treatment of
The values are expressed as the mean ± standard error. endometriosis. Several investigators have demonstrated that after a
*p < 0.05, statistically significant. trend toward normalization was noted, BMD had not returned to
HDL ¼ high-density lipoprotein; LDL ¼ low-density lipoprotein; TG ¼ triglycerides.
baseline by 6 or 12 months after completion of treatment without
add-back therapy [25]. Previous study suggested that for bone
protection, a GnRH agonist should be administered to patients with
endometriosis in addition to an appropriate add-back therapy [10].
Additionally, Pierce et al [3] observed that only a small reduction of
bone loss occurred with add-back therapy. Our study of add-back
therapy revealed that BMD was reduced but remained within the
normal range. The difference in BMD loss between the two dosages
was not statistically significant; therefore, regarding BMD loss and
failure of recovery, we suggest that a GnRH agonist should not be
administered in the absence of an appropriate add-back therapy.
A limitation of the current study was the short course of treat-
ment and follow-up period. Higher doses of add-back have been
used primarily for the treatment of endometriosis in conjunction
with a GnRH agonist for up to 12 months in an effort to completely
eliminate BMD loss, which might not be the goal for a short course
of treatment. Thus, it is difficult to compare outcomes from a 12-
month study using higher doses of agents to a 6-month trial.
Therefore, there is no evidence to suggest that the add-back used in
this study can be safely used for more than 6 months. In addition,
we did not record the severity of hot flashes, which is another
important issue to assess hypoestrogenic symptoms. This lack of
quantification is a significant problem.
In conclusion, in our study, low-dose add-back therapy could
Figure 2. Mean changes in bone mineral density in both groups. *Comparison be-
tween pretherapy and end of 24 weeks of therapy for each group (p < 0.05).
effectively ameliorate hypoestrogenic side effects and simulta-
neously maintain the therapeutic response of GnRH agonist treat-
ment without recurrent pelvic pain and treatment dropout.
(5 mg), which could reduce vasomotor symptoms. However, a Therefore, low-dose add-back therapy can be considered a treat-
prospective, multicenter, randomized, double-blinded clinical trial ment choice during postoperative GnRH agonist treatment. Large,
reported a higher number of dropouts for persistent and recurrent prospective, randomized controlled studies need to be conducted
pelvic pain among those patients who received higher estrogen in the future to confirm our preliminary results.
doses, which was expected [7]. Thus, in our study, we proposed a
low dose add-back with estradiol valerate (1 mg) and medrox-
Conflict of interest
yprogesterone acetate (2.5 mg) and succeeded in reducing the
hypoestrogenic side effects and ameliorating vasomotor symptoms.
The authors have no conflicts of interest to declare.
In addition, the low dose resulted in a reduced occurrence of pa-
tients who dropped out because of persistent or recurrent pelvic
pain. Therefore, to ameliorate bothersome side effects and maintain Acknowledgments
compliance with GnRH agonist treatment, low-dose add-back
therapy might be a better and more effective choice than higher This work was supported in part by the National Science Council
doses of therapy. (NSC 101-2314-B-075-028-MY3 and NSC-102-2314-B-010-032)),
Regarding the bothersome vasomotor symptoms that are asso- Taipei Veterans General Hospital (V104B-013, VGH-104C-042,
ciated with GnRH agonist treatment, estrogen-containing add-back V103C-040, VGH-103-EA-020, and VGH-104-EA-0012), and Yen-
therapy might be a better option than progestin-alone add-back Tjing-Ling Medical Foundation (CI-104-15).
therapy [2,10,18,19]. Progestogen therapy in the form of medrox-
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