- Email: [email protected]
The Efficacy of Postoperative Cyclic Oral Contraceptives after Gonadotropin-Releasing Hormone Agonist Therapy to Prevent Endometrioma Recurrence in Adolescents
Accepted Manuscript The Efficacy of Postoperative Cyclic Oral Contraceptives after GonadotropinReleasing Hormone Agonist Therapy to Prevent Endometrioma Recurrence in Adolescents Jong-Wook Seo, MD, Dong-Yun Lee, MD, PhD, Byung-Koo Yoon, MD, PhD, DooSeok Choi PII:
S1083-3188(16)30218-2
DOI:
10.1016/j.jpag.2016.10.004
Reference:
PEDADO 2054
To appear in:
Journal of Pediatric and Adolescent Gynecology
Received Date: 12 May 2016 Revised Date:
31 August 2016
Accepted Date: 4 October 2016
Please cite this article as: Seo J-W, Lee D-Y, Yoon B-K, Choi D, The Efficacy of Postoperative Cyclic Oral Contraceptives after Gonadotropin-Releasing Hormone Agonist Therapy to Prevent Endometrioma Recurrence in Adolescents, Journal of Pediatric and Adolescent Gynecology (2016), doi: 10.1016/ j.jpag.2016.10.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
The Efficacy of Postoperative Cyclic Oral Contraceptives after Gonadotropin-Releasing Hormone Agonist Therapy to Prevent
RI PT
Endometrioma Recurrence in Adolescents
Jong-Wook Seo*, MD, Dong-Yun Lee*, MD, PhD, Byung-Koo Yoon, MD, PhD,
SC
DooSeok Choi†
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan
M AN U
University School of Medicine, Seoul, Korea
*The first two authors contributed equally to this work.
Address for correspondence:
TE D
†
DooSeok Choi, MD, PhD
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan
EP
University School of Medicine, 81 Irwon-ro, Gangnam-Gu, Seoul 06351, Korea Telephone: 82-2-3410-3514, Fax: 82-2-3410-0630
AC C
E-mail address: [email protected]
1
ACCEPTED MANUSCRIPT ABSTRACT Study Objective: Young age is a possible risk factor of endometriosis recurrence after surgery. However, the efficacy of postoperative medical treatment has not been well
RI PT
addressed in adolescents. The purpose of this study was to evaluate whether postoperative medical treatment is as effective in adolescents as it is in adults in the prevention of endometrioma recurrence.
Setting: Samsung Medical Center, Seoul, Korea.
SC
Design: A retrospective cohort study
M AN U
Participants: This study included 176 reproductive-aged women who underwent conservative laparoscopic surgery for pathology-confirmed endometrioma. Women were classified into two groups according to age: adolescents (≤20 years, n = 34; group I) and reproductive-aged women (25-35 years, n = 142; group II).
TE D
Interventions: The same surgeon performed all the operations for uniformity. Postoperatively, patients were treated monthly with GnRH agonist depot for three to six months, followed by cyclic OCs. Outcome
Measure:
Endometrioma
recurrence
was
determined
using
EP
Main
ultrasonography. The recurrence rate of endometrioma was compared between the two
AC C
groups.
Results: During the treatment period (median: 41.0 months, range: 6-159 months), recurrence was noted in 8 cases (4.5%). After adjusting for confounders (which were statistically different between the groups), the cumulative proportion of recurrent endometriomas after 60 months was comparable between the two groups (5.3% in group I and 8.5% in group II).
2
ACCEPTED MANUSCRIPT Conclusion: Long-term postoperative medical treatment with cyclic OCs after GnRH agonist can be as effective in adolescents as it is in adults in the prevention of
RI PT
endometrioma recurrence.
AC C
EP
TE D
M AN U
SC
Key Words: Postoperative medical treatment, Endometrioma recurrence, Adolescent
3
ACCEPTED MANUSCRIPT
Introduction Endometriosis is an estrogen-dependent inflammatory disease characterized by the ectopic growth of endometrial stroma and glands.1 Its incidence is estimated to be
RI PT
approximately 5-15% of reproductive-aged women.1 One of the most common manifestations of endometriosis is an ovarian endometrioma, or chocolate cyst, which occur in 17-44% of patients.2 Conservative laparoscopic surgery is
SC
the gold standard of treatment for endometrioma.3,4 Unfortunately, endometriomas can recur after surgery and will continue to progress with time.5-7
M AN U
It is well known that younger age at the time of surgery is a risk factor of recurrence.8,9 Unfortunately, repeated ovarian surgeries to address recurrences can significantly decrease the reproductive potential of young patients.10-14 Therefore, it is essential to prevent endometrioma recurrence after conservative surgery in order to maintain the reproductive
TE D
potential. Postoperative medical treatment is one way of preventing endometrioma recurrence in adolescents and adults. However, due to the low incidence of endometrioma,15-17 there are limited data regarding postoperative medical treatments and
EP
their efficacy in adolescent patients with ovarian endometrioma. Therefore, many current treatment strategies for adolescents have been extrapolated from the adult literature.
AC C
In reproductive-aged women who do not wish to conceive in the near future, postoperative gonadotropin-releasing hormone agonist (GnRHa) treatment followed by cyclic OCs effectively reduces endometrioma recurrence.18 Therefore, this study was conducted to determine whether this postoperative medical treatment regimen (GnRHa with add back and cyclic OCs) is as effective in adolescents as it is in adults in the prevention of endometrioma recurrence.
4
ACCEPTED MANUSCRIPT
Materials and Methods Patients All adolescent and adult reproductive-aged women who underwent conservative
RI PT
laparoscopic surgery for ovarian endometrioma and were followed at Samsung Medical Center between May 1996 and December 2013 were considered for inclusion in this retrospective study.
SC
The inclusion criteria were as follows: (i) women between 15-20 years or 25-35 years old who underwent conservative laparoscopic ovarian surgery for pathology-confirmed
M AN U
endometrioma; (ii) postoperative GnRHa injections every 28 days for three to six cycles with add-back therapy; (iii) subsequent OC treatment after completion of GnRHa injections; and (iv) women who were not pregnant at the final follow-up.
Patients were excluded if they (i) underwent hysterectomy; (ii) underwent >6 cycles of
TE D
GnRHa injections; (iii) were treated with other types of postoperative medical treatment (progestins or an intrauterine device); (iv) had a history of pelvic surgery for endometriosis; (v) had a history of preoperative hormonal treatment; (vi) had contraindications for OCs;
EP
and (vii) were identified as having ovarian endometriomas at their first postoperative ultrasonography.
AC C
A total of 34 adolescents between 15 and 20 years of age (group I) and 142 adult reproductive-aged women between 25 and 35 years of age (group II) were included. This study was approved by the Institutional Review Board at Samsung Medical Center.
Treatment and Measurement At the physician’s discretion, patients were offered between three and six cycles of postoperative GnRHa treatment with add-back therapy (estradiol 1 mg or equivalent with
5
ACCEPTED MANUSCRIPT progestogen). Patients were then offered cyclic, low-dose, monophasic OCs. Endometrioma recurrence was determined using ultrasonography. Recurrence was defined as the presence of an ovarian cyst with a wall (with a diameter of at least 2 cm), regular margins, and a
RI PT
homogenous low echogenic fluid content with scattered internal echoes but no papillary projections.19 Patients attended follow-up visits every 3-6 months. Pelvic ultrasounds were performed every 6-12 months. During the postoperative cyclic OC treatment, bone mineral
SC
density (BMD) was measured using dual-energy X-ray absorptiometry.
M AN U
Surgery
On the basis of the management guidelines for endometriosis,20 laparoscopic ovarian cystectomy was performed on all patients with ovarian endometriomas
3 cm by the
same surgeon. First, adhesions were dissected using laparoscopic scissors. Both ovaries
TE D
were then completely mobilized. Atraumatic forceps were used to strip and enucleate the endometriomas. Hemostasis was achieved by the selective application of bipolar coagulation. After all endometriomas were removed, deep infiltrating endometriosis was
EP
treated with excision and superficial endometriotic lesions were treated with fulguration, if indicated. Anatomical restoration was then achieved. Endometriosis staging was performed
AC C
according to the classification of the American Society of Reproductive Medicine.21
Statistical Analyses
Statistical analyses were performed using the Statistics Package for Social Sciences Version 20.0 (SPSS Inc., Chicago, IL, USA). The baseline characteristics and rates of endometrioma recurrence were compared between the two groups. Quantitative variables were compared using t-tests. Fisher’s exact or Chi-square tests were used to analyze
6
ACCEPTED MANUSCRIPT qualitative variables. After adjusting for statistically different confounders, the KaplanMeier method was used to calculate the cumulative probability of endometrioma recurrence. The curves were compared by using Z – test at 60 months follow-up. P-values <0.05 were
RI PT
considered statistically significant.
SC
Results
The baseline patient characteristics are shown in Table 1. At the time of surgery, the
M AN U
mean age of group I was 19.1 years, while that of group II was 28.4 years. The largest cyst diameter in group I (6.2 ± 2.4 cm) was significantly larger than that in group II (5.3 ± 1.3 cm). The durations of follow-up (53.9 months) and OC use (47.9 months) in group I were both significantly longer than they were in group II (39.5 and 31.7 months, respectively).
TE D
No other variables differed significantly between the two groups.
During the treatment period (median: 41.0 months, range: 6-159 months), there were a total of 8 recurrences (4.5%). Seven of these recurrences were unilateral, and one was
EP
bilateral. All of the patients with recurrence underwent a second surgery. The crude recurrence rate was 5.8% (2/34) in group I and 4.2% (6/142) in group II. After adjusting for
AC C
parity, cyst size, number of GnRHa injections, and duration of OC use, the cumulative proportion of recurrent endometrioma after 60 months was comparable between the two groups (5.3% in group I and 8.5% in group II) (Fig. 1). The median time to recurrence was 42 months (range: 13-86 months) and the median size of recurrent endometrioma was 3.9 cm (range: 2.0-5.1 cm). Four patients underwent a second surgery, and main indication for the surgery was an increase in size of the ovarian endometrioma. Another four patients who had no change in size of
7
ACCEPTED MANUSCRIPT endometrioma and pain symptoms did not undergo a second surgery. Following postoperative medical treatment, the BMD was measured at the lumbar spine and hip (mean: 34.0 months) in order to identify the effects of long-term medical treatment
RI PT
on bone mass during the adolescent period. The mean age at measurement was 22.9 years. The Z-scores in the adolescent group were -0.2 at the lumbar spine, 0.3 at the femur neck,
SC
and 0.2 at the total hip (Table 2).
M AN U
Discussion
This study evaluated the efficacy of postoperative GnRHa and cyclic OCs on the prevention of endometrioma recurrence in adolescents compared to that in adults. Our results demonstrate that the cumulative proportion of recurrent endometrioma after 60
TE D
months is comparable between adolescent- and women of reproductive-age. In the current study, we have included patients up to 20 years of age as adolescents. Those between 21 and 24 years were excluded in order to maximize the comparability.
EP
Individuals between 21 and 24 years could have clinically different characteristics from those of adults as they are in the transition to adulthood. We also selected adult
AC C
reproductive-aged women as those between 25 and 35 years as a comparison, because they who belong to the peak incidence age of endometriosis demonstrate general features of disease.20,22
The 60-month cumulative proportion of endometrioma recurrence with long-term postoperative medical treatment was 8.5% in adults. Despite differences in age, definition of ovarian endometrioma recurrence, and follow-up duration, the recurrence rate of ovarian endometrioma after conservative laparoscopic surgery has been reported to be 29-56% at 2
8
ACCEPTED MANUSCRIPT years and 43% at 5 years.18,23-25 One review estimated that the recurrence rate among different published studies was 21.5% at 2 years and 40-50% at 5 years.5 When postoperative medical treatment was introduced, the endometrioma recurrence rate
RI PT
substantially declined to 3-11% at 2 years and 6% at 5 years, according to the treatment modality.18,23-25 In one meta-analysis, endometrioma recurrence was identified in 8% of patients; compared to those treated by expectant management, the pooled odds ratio was
SC
0.12 in OC users.26 These values are in agreement with our results. However, most previous studies concerning endometrioma recurrence after surgery have focused on adults. Up to
M AN U
date, the premise for investigating adolescent endometriosis was based on the concept that in certain patients, endometriosis is a progressive disease,27 and two studies have addressed the definite topic of endometrioma recurrence in adolescents without genital malformation. One study identified a crude recurrence rate of 36.8% over a mean of 97 months in patients with no postoperative medications; this rate was as high as that in adults
TE D
with endometrioma.15 Another study of the use of postoperative medications reported that the cumulative recurrence rate was 19.9% at 60 months after surgery.28 In the current study,
EP
the 60-month cumulative recurrence rate in adolescents was 5.3%. The lower recurrence rate in this study compared to that in the prior study might be due to the use of continuous
AC C
postoperative medication during the follow-up period. Also, compared to adults, the recurrence rate in adolescents was low in the present study. Taken together, these results suggest that postoperative continuous medical treatment in adolescents seems to play a pivotal role in the prevention of endometrioma recurrence as expected, although current treatment for adolescents have been extrapolated and adapted from the literature of adult cases of endometriosis. In addition, for these reasons, the ACOG Committee Opinion on Adolescent Endometriosis states that
after surgery, all adolescents who have
9
ACCEPTED MANUSCRIPT endometriosis should be treated with medical therapy until they have completed child bearing”.27 In this study, after long-term postoperative medical treatment (mean: 34 months), the
RI PT
BMDs of treated adolescents did not deviate from those of the reference populations at any sites. Oral contraceptives suppress the hypothalamic-pituitary-ovarian axis and can interfere with bone accrual in adolescents who have not yet achieved peak bone mass.29,30 Therefore,
SC
there has been some concern regarding the long-term use of OCs on BMD during the adolescent period. However, despite the controversial effect of long-term OC use on BMD
M AN U
during the adolescent period, several randomized and large cohort studies have demonstrated no significant difference in BMDs between OC users and controls.31-38 Our findings also suggest that there is no detrimental effect on BMD related to long-term OC use in adolescents with endometriosis. In addition, hormonal add-back therapy for
TE D
adolescents treated with GnRHa appears to minimize the adverse effects on bone.39 Therefore, using this regimen postoperatively might play an essential role in preventing the more serious complications caused by endometrioma recurrence during adolescence.
EP
This is the first study which addresses endometrioma recurrence after long-term postoperative cyclic OCs after GnRHa therapy for the prevention of endometrioma
AC C
recurrence in adolescents. Since ovarian endometrioma is not common in adolescents, there have been limited studies focusing on the postoperative treatment regimen during the adolescence period.
However, this study has several limitations. First, it was a retrospective study and follow-up duration is different between adolescents and adults, although all consecutive patients were selected during the study period. A potential problem regarding different follow-up duration could be minimized as statistically making use of the Kaplan-Meier
10
ACCEPTED MANUSCRIPT method and Z-test. Second, although ovarian endometriomas are not common during adolescence, there was no age-matched control group. This may have obscured necessity of postoperative medical treatment in adolescents. However, since addressing its
RI PT
necessity was not a goal of current study, which was to evaluate whether postoperative medical treatment was effective to a certain degree in adolescents of reproductive agedwomen, we compared postoperative recurrence rate to that of adult reproductive-aged
SC
women in peak incidence. Finally, the long-term effects of OC on BMDs were not precisely evaluated given the lack of baseline measurements, but we could compare BMDs after
M AN U
postoperative medical treatment with age-matched reference populations and therefore BMDs were assessed as either below or within expected range of age. In conclusion, long-term postoperative medical treatment with cyclic OCs after GnRHa can be as effective in adolescents as it is in adults in the prevention of endometrioma
AC C
EP
TE D
recurrence. A large-scale, prospective study is warranted to substantiate these findings.
11
ACCEPTED MANUSCRIPT
References 1.
Bulun SE: Endometriosis. N Engl J Med 2009; 360:268
2.
Busacca M, Vignali M: Ovarian endometriosis: from pathogenesis to surgical
3.
RI PT
treatment. Curr Opin Obstet Gynecol 2003; 15:321 Chapron C, Vercellini P, Barakat H, et al: Management of ovarian endometriomas. Hum Reprod Update 2002; 8:591
Hart RJ, Hickey M, Maouris P, et al: Excisional surgery versus ablative surgery
SC
4.
for ovarian endometriomata. Cochrane Database Syst Rev 2008:Cd004992 Guo SW: Recurrence of endometriosis and its control. Hum Reprod Update 2009;
M AN U
5.
15:441 6.
Hayasaka S, Ugajin T, Fujii O, et al: Risk factors for recurrence and re-recurrence of ovarian endometriomas after laparoscopic excision. J Obstet Gynaecol Res
7.
TE D
2011; 37:581
Kim ML, Kim JM, Seong SJ, et al: Recurrence of ovarian endometrioma after second-line, conservative, laparoscopic cyst enucleation. Am J Obstet Gynecol
8.
EP
2014; 210:216.e1
Ouchi N, Akira S, Mine K, et al: Recurrence of ovarian endometrioma after
AC C
laparoscopic excision: risk factors and prevention. J Obstet Gynaecol Res 2014; 40:230
9.
Sengoku K, Miyamoto T, Horikawa M, et al: Clinicopathologic risk factors for
recurrence of ovarian endometrioma following laparoscopic cystectomy. Acta Obstet Gynecol Scand 2013; 92:278
10.
Vercellini P, Somigliana E, Daguati R, et al: The second time around: reproductive performance after repetitive versus primary surgery for endometriosis. Fertil Steril
12
ACCEPTED MANUSCRIPT 2009; 92:1253 11.
Vercellini P, Somigliana E, Vigano P, et al: The effect of second-line surgery on reproductive performance of women with recurrent endometriosis: a systematic
12.
RI PT
review. Acta Obstet Gynecol Scand 2009; 88:1074 Kuroda M, Kuroda K, Arakawa A, et al: Histological assessment of impact of ovarian endometrioma and laparoscopic cystectomy on ovarian reserve. J Obstet
13.
SC
Gynaecol Res 2012; 38:1187
Muzii L, Achilli C, Lecce F, et al: Second surgery for recurrent endometriomas is
Fertil Steril 2015; 103:738 14.
M AN U
more harmful to healthy ovarian tissue and ovarian reserve than first surgery.
Ferrero S, Scala C, Racca A, et al: Second surgery for recurrent unilateral endometriomas and impact on ovarian reserve: a case-control study. Fertil Steril
15.
TE D
2015; 103:1236
Audebert A, Lecointre L, Afors K, et al: Adolescent Endometriosis: Report of a Series of 55 Cases With a Focus on Clinical Presentation and Long-Term Issues. J
16.
EP
Minim Invasive Gynecol 2015; 22:834 Vicino M, Parazzini F, Cipriani S, et al: Endometriosis in young women: the
17.
AC C
experience of GISE. J Pediatr Adolesc Gynecol 2010; 23:223 Yang Y, Wang Y, Yang J, et al: Adolescent endometriosis in China: a retrospective analysis of 63 cases. J Pediatr Adolesc Gynecol 2012; 25:295
18.
Lee DY, Bae DS, Yoon BK, et al: Post-operative cyclic oral contraceptive use after gonadotrophin-releasing hormone agonist treatment effectively prevents endometrioma recurrence. Hum Reprod 2010; 25:3050
19.
Exacoustos C, Zupi E, Carusotti C, et al: Staging of pelvic endometriosis: role of
13
ACCEPTED MANUSCRIPT sonographic appearance in determining extension of disease and modulating surgical approach. J Am Assoc Gynecol Laparosc 2003; 10:378 20.
Kennedy S, Bergqvist A, Chapron C, et al: ESHRE guideline for the diagnosis and
21.
RI PT
treatment of endometriosis. Hum Reprod 2005; 20:2698 Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67:817
Rogers PA, D'Hooghe TM, Fazleabas A, et al: Priorities for endometriosis
SC
22.
research: recommendations from an international consensus workshop. Reprod
23.
M AN U
Sci 2009; 16:335
Seracchioli R, Mabrouk M, Frasca C, et al: Long-term cyclic and continuous oral contraceptive therapy and endometrioma recurrence: a randomized controlled trial. Fertil Steril 2010; 93:52
Takamura M, Koga K, Osuga Y, et al: Post-operative oral contraceptive use
TE D
24.
reduces the risk of ovarian endometrioma recurrence after laparoscopic excision. Hum Reprod 2009; 24:3042
Vercellini P, Somigliana E, Daguati R, et al: Postoperative oral contraceptive
EP
25.
exposure and risk of endometrioma recurrence. Am J Obstet Gynecol 2008;
26.
AC C
198:504.e1
Vercellini P, S DEM, Somigliana E, et al: Long-term adjuvant therapy for the prevention of postoperative endometrioma recurrence: a systematic review and meta-analysis. Acta Obstet Gynecol Scand 2013; 92:8
27.
American College of O, Gynecologists: ACOG Committee Opinion. Number 310, April 2005. Endometriosis in adolescents. Obstet Gynecol 2005; 105:921
28.
Lee SY, Kim ML, Seong SJ, et al: Recurrence of ovarian endometrioma in
14
ACCEPTED MANUSCRIPT adolescents after conservative, laparoscopic cyst enucleation. J Pediatr Adolesc Gynecol 2015 29.
Nappi C, Bifulco G, Tommaselli GA, et al: Hormonal contraception and bone
30.
RI PT
metabolism: a systematic review. Contraception 2012; 86:606 Ziglar S, Hunter TS: The effect of hormonal oral contraception on acquisition of peak bone mineral density of adolescents and young women. J Pharm Pract 2012;
31.
SC
25:331
Cobb KL, Kelsey JL, Sidney S, et al: Oral contraceptives and bone mineral
M AN U
density in white and black women in CARDIA. Coronary Risk Development in Young Adults. Osteoporos Int 2002; 13:893 32.
Endrikat J, Mih E, Dusterberg B, et al: A 3-year double-blind, randomized, controlled study on the influence of two oral contraceptives containing either 20
TE D
microg or 30 microg ethinylestradiol in combination with levonorgestrel on bone mineral density. Contraception 2004; 69:179 33.
Gargano V, Massaro M, Morra I, et al: Effects of two low-dose combined oral
EP
contraceptives containing drospirenone on bone turnover and bone mineral density in young fertile women: a prospective controlled randomized study.
34.
AC C
Contraception 2008; 78:10 Hawker GA, Forsmo S, Cadarette SM, et al: Correlates of forearm bone mineral density in young Norwegian women: the Nord-Trondelag Health Study. Am J
Epidemiol 2002; 156:418
35.
Murphy S, Khaw KT, Compston JE: Lack of relationship between hip and spine bone mineral density and oral contraceptive use. Eur J Clin Invest 1993; 23:108
36.
Nappi C, Di Spiezio Sardo A, Acunzo G, et al: Effects of a low-dose and ultra-
15
ACCEPTED MANUSCRIPT low-dose combined oral contraceptive use on bone turnover and bone mineral density in young fertile women: a prospective controlled randomized study. Contraception 2003; 67:355 Nappi C, Di Spiezio Sardo A, Greco E, et al: Effects of an oral contraceptive
RI PT
37.
containing drospirenone on bone turnover and bone mineral density. Obstet Gynecol 2005; 105:53
Petitti DB, Piaggio G, Mehta S, et al: Steroid hormone contraception and bone
SC
38.
mineral density: a cross-sectional study in an international population. The WHO
DiVasta AD, Feldman HA, Sadler Gallagher J, et al: Hormonal Add-Back Therapy for Females Treated With Gonadotropin-Releasing Hormone Agonist for
EP
TE D
Endometriosis: A Randomized Controlled Trial. Obstet Gynecol 2015; 126:617
AC C
39.
M AN U
Study of Hormonal Contraception and Bone Health. Obstet Gynecol 2000; 95:736
16
ACCEPTED MANUSCRIPT Table 1. Patient Characteristics According to Age Group I (n = 34) 19.1±1.3
28.4±2.8
< .001
0
0.1±0.4
.003
Parity (n)* Largest cyst diameter (cm)*
RI PT
Age at surgery (years)*
Group II (n = 142) P-value
6.2±2.4
5.3±1.9
ASRM stage (n, %)
.029
.177
IV
18 (52.9%)
Laterality (n, %) Unilateral Bilateral No. of GnRHa injections (n)*
Duration of follow-up (months)*
57 (40.1%) .749
19 (55.9%)
74 (52.5%)
15 (44.1%)
67 (47.5%)
5.4±1.2
5.8±0.7
.041
47.9±29.3
31.7±28.5
.003
38.1 (6-159)
.004
TE D
Duration of OC use (month)*
85 (59.9%)
SC
16 (47.1%)
M AN U
III
53.9 (8-114)
Values are presented as mean ± SD or number (percentage).
EP
* P < .05 between the two groups.
AC C
OC: oral contraceptive; GnRHa: gonadotropin-releasing hormone agonist; ASRM: Revised American Society for Reproductive Medicine classification of endometriosis
17
ACCEPTED MANUSCRIPT Table 2. BMD after Postoperative Medical Treatment in Adolescents
Lumbar Spine Z-score (g/cm2)
Femur Neck (g/cm2)
Z-score
Total Hip (g/cm2)
0.952±0.114
0.804±0.100
0.3±1.0
0.879±0.086 0.2±0.7
AC C
EP
TE D
M AN U
SC
Values are presented as mean ± SD.
RI PT
-0.2±1.1
18
Z-score
ACCEPTED MANUSCRIPT
Figure legend Fig. 1. Cumulative recurrence-free survival according to age group. The cumulative proportion of recurrent endometrioma after 60 months was not significantly different
AC C
EP
TE D
M AN U
SC
RI PT
between the adolescent and adult groups (5.3% versus 8.5%, respectively).
19
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1083-3188(16)30218-2
DOI:
10.1016/j.jpag.2016.10.004
Reference:
PEDADO 2054
To appear in:
Journal of Pediatric and Adolescent Gynecology
Received Date: 12 May 2016 Revised Date:
31 August 2016
Accepted Date: 4 October 2016
Please cite this article as: Seo J-W, Lee D-Y, Yoon B-K, Choi D, The Efficacy of Postoperative Cyclic Oral Contraceptives after Gonadotropin-Releasing Hormone Agonist Therapy to Prevent Endometrioma Recurrence in Adolescents, Journal of Pediatric and Adolescent Gynecology (2016), doi: 10.1016/ j.jpag.2016.10.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
The Efficacy of Postoperative Cyclic Oral Contraceptives after Gonadotropin-Releasing Hormone Agonist Therapy to Prevent
RI PT
Endometrioma Recurrence in Adolescents
Jong-Wook Seo*, MD, Dong-Yun Lee*, MD, PhD, Byung-Koo Yoon, MD, PhD,
SC
DooSeok Choi†
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan
M AN U
University School of Medicine, Seoul, Korea
*The first two authors contributed equally to this work.
Address for correspondence:
TE D
†
DooSeok Choi, MD, PhD
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan
EP
University School of Medicine, 81 Irwon-ro, Gangnam-Gu, Seoul 06351, Korea Telephone: 82-2-3410-3514, Fax: 82-2-3410-0630
AC C
E-mail address: [email protected]
1
ACCEPTED MANUSCRIPT ABSTRACT Study Objective: Young age is a possible risk factor of endometriosis recurrence after surgery. However, the efficacy of postoperative medical treatment has not been well
RI PT
addressed in adolescents. The purpose of this study was to evaluate whether postoperative medical treatment is as effective in adolescents as it is in adults in the prevention of endometrioma recurrence.
Setting: Samsung Medical Center, Seoul, Korea.
SC
Design: A retrospective cohort study
M AN U
Participants: This study included 176 reproductive-aged women who underwent conservative laparoscopic surgery for pathology-confirmed endometrioma. Women were classified into two groups according to age: adolescents (≤20 years, n = 34; group I) and reproductive-aged women (25-35 years, n = 142; group II).
TE D
Interventions: The same surgeon performed all the operations for uniformity. Postoperatively, patients were treated monthly with GnRH agonist depot for three to six months, followed by cyclic OCs. Outcome
Measure:
Endometrioma
recurrence
was
determined
using
EP
Main
ultrasonography. The recurrence rate of endometrioma was compared between the two
AC C
groups.
Results: During the treatment period (median: 41.0 months, range: 6-159 months), recurrence was noted in 8 cases (4.5%). After adjusting for confounders (which were statistically different between the groups), the cumulative proportion of recurrent endometriomas after 60 months was comparable between the two groups (5.3% in group I and 8.5% in group II).
2
ACCEPTED MANUSCRIPT Conclusion: Long-term postoperative medical treatment with cyclic OCs after GnRH agonist can be as effective in adolescents as it is in adults in the prevention of
RI PT
endometrioma recurrence.
AC C
EP
TE D
M AN U
SC
Key Words: Postoperative medical treatment, Endometrioma recurrence, Adolescent
3
ACCEPTED MANUSCRIPT
Introduction Endometriosis is an estrogen-dependent inflammatory disease characterized by the ectopic growth of endometrial stroma and glands.1 Its incidence is estimated to be
RI PT
approximately 5-15% of reproductive-aged women.1 One of the most common manifestations of endometriosis is an ovarian endometrioma, or chocolate cyst, which occur in 17-44% of patients.2 Conservative laparoscopic surgery is
SC
the gold standard of treatment for endometrioma.3,4 Unfortunately, endometriomas can recur after surgery and will continue to progress with time.5-7
M AN U
It is well known that younger age at the time of surgery is a risk factor of recurrence.8,9 Unfortunately, repeated ovarian surgeries to address recurrences can significantly decrease the reproductive potential of young patients.10-14 Therefore, it is essential to prevent endometrioma recurrence after conservative surgery in order to maintain the reproductive
TE D
potential. Postoperative medical treatment is one way of preventing endometrioma recurrence in adolescents and adults. However, due to the low incidence of endometrioma,15-17 there are limited data regarding postoperative medical treatments and
EP
their efficacy in adolescent patients with ovarian endometrioma. Therefore, many current treatment strategies for adolescents have been extrapolated from the adult literature.
AC C
In reproductive-aged women who do not wish to conceive in the near future, postoperative gonadotropin-releasing hormone agonist (GnRHa) treatment followed by cyclic OCs effectively reduces endometrioma recurrence.18 Therefore, this study was conducted to determine whether this postoperative medical treatment regimen (GnRHa with add back and cyclic OCs) is as effective in adolescents as it is in adults in the prevention of endometrioma recurrence.
4
ACCEPTED MANUSCRIPT
Materials and Methods Patients All adolescent and adult reproductive-aged women who underwent conservative
RI PT
laparoscopic surgery for ovarian endometrioma and were followed at Samsung Medical Center between May 1996 and December 2013 were considered for inclusion in this retrospective study.
SC
The inclusion criteria were as follows: (i) women between 15-20 years or 25-35 years old who underwent conservative laparoscopic ovarian surgery for pathology-confirmed
M AN U
endometrioma; (ii) postoperative GnRHa injections every 28 days for three to six cycles with add-back therapy; (iii) subsequent OC treatment after completion of GnRHa injections; and (iv) women who were not pregnant at the final follow-up.
Patients were excluded if they (i) underwent hysterectomy; (ii) underwent >6 cycles of
TE D
GnRHa injections; (iii) were treated with other types of postoperative medical treatment (progestins or an intrauterine device); (iv) had a history of pelvic surgery for endometriosis; (v) had a history of preoperative hormonal treatment; (vi) had contraindications for OCs;
EP
and (vii) were identified as having ovarian endometriomas at their first postoperative ultrasonography.
AC C
A total of 34 adolescents between 15 and 20 years of age (group I) and 142 adult reproductive-aged women between 25 and 35 years of age (group II) were included. This study was approved by the Institutional Review Board at Samsung Medical Center.
Treatment and Measurement At the physician’s discretion, patients were offered between three and six cycles of postoperative GnRHa treatment with add-back therapy (estradiol 1 mg or equivalent with
5
ACCEPTED MANUSCRIPT progestogen). Patients were then offered cyclic, low-dose, monophasic OCs. Endometrioma recurrence was determined using ultrasonography. Recurrence was defined as the presence of an ovarian cyst with a wall (with a diameter of at least 2 cm), regular margins, and a
RI PT
homogenous low echogenic fluid content with scattered internal echoes but no papillary projections.19 Patients attended follow-up visits every 3-6 months. Pelvic ultrasounds were performed every 6-12 months. During the postoperative cyclic OC treatment, bone mineral
SC
density (BMD) was measured using dual-energy X-ray absorptiometry.
M AN U
Surgery
On the basis of the management guidelines for endometriosis,20 laparoscopic ovarian cystectomy was performed on all patients with ovarian endometriomas
3 cm by the
same surgeon. First, adhesions were dissected using laparoscopic scissors. Both ovaries
TE D
were then completely mobilized. Atraumatic forceps were used to strip and enucleate the endometriomas. Hemostasis was achieved by the selective application of bipolar coagulation. After all endometriomas were removed, deep infiltrating endometriosis was
EP
treated with excision and superficial endometriotic lesions were treated with fulguration, if indicated. Anatomical restoration was then achieved. Endometriosis staging was performed
AC C
according to the classification of the American Society of Reproductive Medicine.21
Statistical Analyses
Statistical analyses were performed using the Statistics Package for Social Sciences Version 20.0 (SPSS Inc., Chicago, IL, USA). The baseline characteristics and rates of endometrioma recurrence were compared between the two groups. Quantitative variables were compared using t-tests. Fisher’s exact or Chi-square tests were used to analyze
6
ACCEPTED MANUSCRIPT qualitative variables. After adjusting for statistically different confounders, the KaplanMeier method was used to calculate the cumulative probability of endometrioma recurrence. The curves were compared by using Z – test at 60 months follow-up. P-values <0.05 were
RI PT
considered statistically significant.
SC
Results
The baseline patient characteristics are shown in Table 1. At the time of surgery, the
M AN U
mean age of group I was 19.1 years, while that of group II was 28.4 years. The largest cyst diameter in group I (6.2 ± 2.4 cm) was significantly larger than that in group II (5.3 ± 1.3 cm). The durations of follow-up (53.9 months) and OC use (47.9 months) in group I were both significantly longer than they were in group II (39.5 and 31.7 months, respectively).
TE D
No other variables differed significantly between the two groups.
During the treatment period (median: 41.0 months, range: 6-159 months), there were a total of 8 recurrences (4.5%). Seven of these recurrences were unilateral, and one was
EP
bilateral. All of the patients with recurrence underwent a second surgery. The crude recurrence rate was 5.8% (2/34) in group I and 4.2% (6/142) in group II. After adjusting for
AC C
parity, cyst size, number of GnRHa injections, and duration of OC use, the cumulative proportion of recurrent endometrioma after 60 months was comparable between the two groups (5.3% in group I and 8.5% in group II) (Fig. 1). The median time to recurrence was 42 months (range: 13-86 months) and the median size of recurrent endometrioma was 3.9 cm (range: 2.0-5.1 cm). Four patients underwent a second surgery, and main indication for the surgery was an increase in size of the ovarian endometrioma. Another four patients who had no change in size of
7
ACCEPTED MANUSCRIPT endometrioma and pain symptoms did not undergo a second surgery. Following postoperative medical treatment, the BMD was measured at the lumbar spine and hip (mean: 34.0 months) in order to identify the effects of long-term medical treatment
RI PT
on bone mass during the adolescent period. The mean age at measurement was 22.9 years. The Z-scores in the adolescent group were -0.2 at the lumbar spine, 0.3 at the femur neck,
SC
and 0.2 at the total hip (Table 2).
M AN U
Discussion
This study evaluated the efficacy of postoperative GnRHa and cyclic OCs on the prevention of endometrioma recurrence in adolescents compared to that in adults. Our results demonstrate that the cumulative proportion of recurrent endometrioma after 60
TE D
months is comparable between adolescent- and women of reproductive-age. In the current study, we have included patients up to 20 years of age as adolescents. Those between 21 and 24 years were excluded in order to maximize the comparability.
EP
Individuals between 21 and 24 years could have clinically different characteristics from those of adults as they are in the transition to adulthood. We also selected adult
AC C
reproductive-aged women as those between 25 and 35 years as a comparison, because they who belong to the peak incidence age of endometriosis demonstrate general features of disease.20,22
The 60-month cumulative proportion of endometrioma recurrence with long-term postoperative medical treatment was 8.5% in adults. Despite differences in age, definition of ovarian endometrioma recurrence, and follow-up duration, the recurrence rate of ovarian endometrioma after conservative laparoscopic surgery has been reported to be 29-56% at 2
8
ACCEPTED MANUSCRIPT years and 43% at 5 years.18,23-25 One review estimated that the recurrence rate among different published studies was 21.5% at 2 years and 40-50% at 5 years.5 When postoperative medical treatment was introduced, the endometrioma recurrence rate
RI PT
substantially declined to 3-11% at 2 years and 6% at 5 years, according to the treatment modality.18,23-25 In one meta-analysis, endometrioma recurrence was identified in 8% of patients; compared to those treated by expectant management, the pooled odds ratio was
SC
0.12 in OC users.26 These values are in agreement with our results. However, most previous studies concerning endometrioma recurrence after surgery have focused on adults. Up to
M AN U
date, the premise for investigating adolescent endometriosis was based on the concept that in certain patients, endometriosis is a progressive disease,27 and two studies have addressed the definite topic of endometrioma recurrence in adolescents without genital malformation. One study identified a crude recurrence rate of 36.8% over a mean of 97 months in patients with no postoperative medications; this rate was as high as that in adults
TE D
with endometrioma.15 Another study of the use of postoperative medications reported that the cumulative recurrence rate was 19.9% at 60 months after surgery.28 In the current study,
EP
the 60-month cumulative recurrence rate in adolescents was 5.3%. The lower recurrence rate in this study compared to that in the prior study might be due to the use of continuous
AC C
postoperative medication during the follow-up period. Also, compared to adults, the recurrence rate in adolescents was low in the present study. Taken together, these results suggest that postoperative continuous medical treatment in adolescents seems to play a pivotal role in the prevention of endometrioma recurrence as expected, although current treatment for adolescents have been extrapolated and adapted from the literature of adult cases of endometriosis. In addition, for these reasons, the ACOG Committee Opinion on Adolescent Endometriosis states that
after surgery, all adolescents who have
9
ACCEPTED MANUSCRIPT endometriosis should be treated with medical therapy until they have completed child bearing”.27 In this study, after long-term postoperative medical treatment (mean: 34 months), the
RI PT
BMDs of treated adolescents did not deviate from those of the reference populations at any sites. Oral contraceptives suppress the hypothalamic-pituitary-ovarian axis and can interfere with bone accrual in adolescents who have not yet achieved peak bone mass.29,30 Therefore,
SC
there has been some concern regarding the long-term use of OCs on BMD during the adolescent period. However, despite the controversial effect of long-term OC use on BMD
M AN U
during the adolescent period, several randomized and large cohort studies have demonstrated no significant difference in BMDs between OC users and controls.31-38 Our findings also suggest that there is no detrimental effect on BMD related to long-term OC use in adolescents with endometriosis. In addition, hormonal add-back therapy for
TE D
adolescents treated with GnRHa appears to minimize the adverse effects on bone.39 Therefore, using this regimen postoperatively might play an essential role in preventing the more serious complications caused by endometrioma recurrence during adolescence.
EP
This is the first study which addresses endometrioma recurrence after long-term postoperative cyclic OCs after GnRHa therapy for the prevention of endometrioma
AC C
recurrence in adolescents. Since ovarian endometrioma is not common in adolescents, there have been limited studies focusing on the postoperative treatment regimen during the adolescence period.
However, this study has several limitations. First, it was a retrospective study and follow-up duration is different between adolescents and adults, although all consecutive patients were selected during the study period. A potential problem regarding different follow-up duration could be minimized as statistically making use of the Kaplan-Meier
10
ACCEPTED MANUSCRIPT method and Z-test. Second, although ovarian endometriomas are not common during adolescence, there was no age-matched control group. This may have obscured necessity of postoperative medical treatment in adolescents. However, since addressing its
RI PT
necessity was not a goal of current study, which was to evaluate whether postoperative medical treatment was effective to a certain degree in adolescents of reproductive agedwomen, we compared postoperative recurrence rate to that of adult reproductive-aged
SC
women in peak incidence. Finally, the long-term effects of OC on BMDs were not precisely evaluated given the lack of baseline measurements, but we could compare BMDs after
M AN U
postoperative medical treatment with age-matched reference populations and therefore BMDs were assessed as either below or within expected range of age. In conclusion, long-term postoperative medical treatment with cyclic OCs after GnRHa can be as effective in adolescents as it is in adults in the prevention of endometrioma
AC C
EP
TE D
recurrence. A large-scale, prospective study is warranted to substantiate these findings.
11
ACCEPTED MANUSCRIPT
References 1.
Bulun SE: Endometriosis. N Engl J Med 2009; 360:268
2.
Busacca M, Vignali M: Ovarian endometriosis: from pathogenesis to surgical
3.
RI PT
treatment. Curr Opin Obstet Gynecol 2003; 15:321 Chapron C, Vercellini P, Barakat H, et al: Management of ovarian endometriomas. Hum Reprod Update 2002; 8:591
Hart RJ, Hickey M, Maouris P, et al: Excisional surgery versus ablative surgery
SC
4.
for ovarian endometriomata. Cochrane Database Syst Rev 2008:Cd004992 Guo SW: Recurrence of endometriosis and its control. Hum Reprod Update 2009;
M AN U
5.
15:441 6.
Hayasaka S, Ugajin T, Fujii O, et al: Risk factors for recurrence and re-recurrence of ovarian endometriomas after laparoscopic excision. J Obstet Gynaecol Res
7.
TE D
2011; 37:581
Kim ML, Kim JM, Seong SJ, et al: Recurrence of ovarian endometrioma after second-line, conservative, laparoscopic cyst enucleation. Am J Obstet Gynecol
8.
EP
2014; 210:216.e1
Ouchi N, Akira S, Mine K, et al: Recurrence of ovarian endometrioma after
AC C
laparoscopic excision: risk factors and prevention. J Obstet Gynaecol Res 2014; 40:230
9.
Sengoku K, Miyamoto T, Horikawa M, et al: Clinicopathologic risk factors for
recurrence of ovarian endometrioma following laparoscopic cystectomy. Acta Obstet Gynecol Scand 2013; 92:278
10.
Vercellini P, Somigliana E, Daguati R, et al: The second time around: reproductive performance after repetitive versus primary surgery for endometriosis. Fertil Steril
12
ACCEPTED MANUSCRIPT 2009; 92:1253 11.
Vercellini P, Somigliana E, Vigano P, et al: The effect of second-line surgery on reproductive performance of women with recurrent endometriosis: a systematic
12.
RI PT
review. Acta Obstet Gynecol Scand 2009; 88:1074 Kuroda M, Kuroda K, Arakawa A, et al: Histological assessment of impact of ovarian endometrioma and laparoscopic cystectomy on ovarian reserve. J Obstet
13.
SC
Gynaecol Res 2012; 38:1187
Muzii L, Achilli C, Lecce F, et al: Second surgery for recurrent endometriomas is
Fertil Steril 2015; 103:738 14.
M AN U
more harmful to healthy ovarian tissue and ovarian reserve than first surgery.
Ferrero S, Scala C, Racca A, et al: Second surgery for recurrent unilateral endometriomas and impact on ovarian reserve: a case-control study. Fertil Steril
15.
TE D
2015; 103:1236
Audebert A, Lecointre L, Afors K, et al: Adolescent Endometriosis: Report of a Series of 55 Cases With a Focus on Clinical Presentation and Long-Term Issues. J
16.
EP
Minim Invasive Gynecol 2015; 22:834 Vicino M, Parazzini F, Cipriani S, et al: Endometriosis in young women: the
17.
AC C
experience of GISE. J Pediatr Adolesc Gynecol 2010; 23:223 Yang Y, Wang Y, Yang J, et al: Adolescent endometriosis in China: a retrospective analysis of 63 cases. J Pediatr Adolesc Gynecol 2012; 25:295
18.
Lee DY, Bae DS, Yoon BK, et al: Post-operative cyclic oral contraceptive use after gonadotrophin-releasing hormone agonist treatment effectively prevents endometrioma recurrence. Hum Reprod 2010; 25:3050
19.
Exacoustos C, Zupi E, Carusotti C, et al: Staging of pelvic endometriosis: role of
13
ACCEPTED MANUSCRIPT sonographic appearance in determining extension of disease and modulating surgical approach. J Am Assoc Gynecol Laparosc 2003; 10:378 20.
Kennedy S, Bergqvist A, Chapron C, et al: ESHRE guideline for the diagnosis and
21.
RI PT
treatment of endometriosis. Hum Reprod 2005; 20:2698 Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67:817
Rogers PA, D'Hooghe TM, Fazleabas A, et al: Priorities for endometriosis
SC
22.
research: recommendations from an international consensus workshop. Reprod
23.
M AN U
Sci 2009; 16:335
Seracchioli R, Mabrouk M, Frasca C, et al: Long-term cyclic and continuous oral contraceptive therapy and endometrioma recurrence: a randomized controlled trial. Fertil Steril 2010; 93:52
Takamura M, Koga K, Osuga Y, et al: Post-operative oral contraceptive use
TE D
24.
reduces the risk of ovarian endometrioma recurrence after laparoscopic excision. Hum Reprod 2009; 24:3042
Vercellini P, Somigliana E, Daguati R, et al: Postoperative oral contraceptive
EP
25.
exposure and risk of endometrioma recurrence. Am J Obstet Gynecol 2008;
26.
AC C
198:504.e1
Vercellini P, S DEM, Somigliana E, et al: Long-term adjuvant therapy for the prevention of postoperative endometrioma recurrence: a systematic review and meta-analysis. Acta Obstet Gynecol Scand 2013; 92:8
27.
American College of O, Gynecologists: ACOG Committee Opinion. Number 310, April 2005. Endometriosis in adolescents. Obstet Gynecol 2005; 105:921
28.
Lee SY, Kim ML, Seong SJ, et al: Recurrence of ovarian endometrioma in
14
ACCEPTED MANUSCRIPT adolescents after conservative, laparoscopic cyst enucleation. J Pediatr Adolesc Gynecol 2015 29.
Nappi C, Bifulco G, Tommaselli GA, et al: Hormonal contraception and bone
30.
RI PT
metabolism: a systematic review. Contraception 2012; 86:606 Ziglar S, Hunter TS: The effect of hormonal oral contraception on acquisition of peak bone mineral density of adolescents and young women. J Pharm Pract 2012;
31.
SC
25:331
Cobb KL, Kelsey JL, Sidney S, et al: Oral contraceptives and bone mineral
M AN U
density in white and black women in CARDIA. Coronary Risk Development in Young Adults. Osteoporos Int 2002; 13:893 32.
Endrikat J, Mih E, Dusterberg B, et al: A 3-year double-blind, randomized, controlled study on the influence of two oral contraceptives containing either 20
TE D
microg or 30 microg ethinylestradiol in combination with levonorgestrel on bone mineral density. Contraception 2004; 69:179 33.
Gargano V, Massaro M, Morra I, et al: Effects of two low-dose combined oral
EP
contraceptives containing drospirenone on bone turnover and bone mineral density in young fertile women: a prospective controlled randomized study.
34.
AC C
Contraception 2008; 78:10 Hawker GA, Forsmo S, Cadarette SM, et al: Correlates of forearm bone mineral density in young Norwegian women: the Nord-Trondelag Health Study. Am J
Epidemiol 2002; 156:418
35.
Murphy S, Khaw KT, Compston JE: Lack of relationship between hip and spine bone mineral density and oral contraceptive use. Eur J Clin Invest 1993; 23:108
36.
Nappi C, Di Spiezio Sardo A, Acunzo G, et al: Effects of a low-dose and ultra-
15
ACCEPTED MANUSCRIPT low-dose combined oral contraceptive use on bone turnover and bone mineral density in young fertile women: a prospective controlled randomized study. Contraception 2003; 67:355 Nappi C, Di Spiezio Sardo A, Greco E, et al: Effects of an oral contraceptive
RI PT
37.
containing drospirenone on bone turnover and bone mineral density. Obstet Gynecol 2005; 105:53
Petitti DB, Piaggio G, Mehta S, et al: Steroid hormone contraception and bone
SC
38.
mineral density: a cross-sectional study in an international population. The WHO
DiVasta AD, Feldman HA, Sadler Gallagher J, et al: Hormonal Add-Back Therapy for Females Treated With Gonadotropin-Releasing Hormone Agonist for
EP
TE D
Endometriosis: A Randomized Controlled Trial. Obstet Gynecol 2015; 126:617
AC C
39.
M AN U
Study of Hormonal Contraception and Bone Health. Obstet Gynecol 2000; 95:736
16
ACCEPTED MANUSCRIPT Table 1. Patient Characteristics According to Age Group I (n = 34) 19.1±1.3
28.4±2.8
< .001
0
0.1±0.4
.003
Parity (n)* Largest cyst diameter (cm)*
RI PT
Age at surgery (years)*
Group II (n = 142) P-value
6.2±2.4
5.3±1.9
ASRM stage (n, %)
.029
.177
IV
18 (52.9%)
Laterality (n, %) Unilateral Bilateral No. of GnRHa injections (n)*
Duration of follow-up (months)*
57 (40.1%) .749
19 (55.9%)
74 (52.5%)
15 (44.1%)
67 (47.5%)
5.4±1.2
5.8±0.7
.041
47.9±29.3
31.7±28.5
.003
38.1 (6-159)
.004
TE D
Duration of OC use (month)*
85 (59.9%)
SC
16 (47.1%)
M AN U
III
53.9 (8-114)
Values are presented as mean ± SD or number (percentage).
EP
* P < .05 between the two groups.
AC C
OC: oral contraceptive; GnRHa: gonadotropin-releasing hormone agonist; ASRM: Revised American Society for Reproductive Medicine classification of endometriosis
17
ACCEPTED MANUSCRIPT Table 2. BMD after Postoperative Medical Treatment in Adolescents
Lumbar Spine Z-score (g/cm2)
Femur Neck (g/cm2)
Z-score
Total Hip (g/cm2)
0.952±0.114
0.804±0.100
0.3±1.0
0.879±0.086 0.2±0.7
AC C
EP
TE D
M AN U
SC
Values are presented as mean ± SD.
RI PT
-0.2±1.1
18
Z-score
ACCEPTED MANUSCRIPT
Figure legend Fig. 1. Cumulative recurrence-free survival according to age group. The cumulative proportion of recurrent endometrioma after 60 months was not significantly different
AC C
EP
TE D
M AN U
SC
RI PT
between the adolescent and adult groups (5.3% versus 8.5%, respectively).
19
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT