Modified laparoscopic uterine-sparing surgery combined with gonadotropin-releasing hormone agonist therapy for focal uterine adenomyosis

doi:10.21203/rs.3.rs-1435202/v1

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Modified laparoscopic uterine-sparing surgery combined with gonadotropin-releasing hormone agonist therapy for focal uterine adenomyosis

https://doi.org/10.21203/rs.3.rs-1435202/v1

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Objectives

To evaluate the outcomes of women with uterine adenomyoma treated with combined modified laparoscopic adenomyomectomy and gonadotropin-releasing hormone (GnRH) agonists.

Methods

Between 2012 and 2016, 141 women with adenomyoma were admitted to The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University in a retrospective study. All 141 patients were treated with laparoscopic adenomyomectomy combined with GnRH agonists. We used a modified laparoscopic adenomyomectomy technique that involved the insertion of two fingers into the vagina to elevate the uterus, while one finger of the other hand was inserted into the abdomen through a suprapubic 15-mm trocar port for systematic palpation of the uterus. The integrity of the endometrium was preserved for 21 patients who had fertility requirements; for the remaining 120 patients, who did not have fertility requirements, the adenomyosis tissue and the endometrium under the adenomyosis tissue were both resected. We assessed the degree of postoperative clinical improvement, pregnancy outcomes, and possible recurrences. All patients were followed up for at least 24 months.

Results

Combined surgical-medical treatment significantly improved the serum cancer antigen 125 level, hemoglobin level, dysmenorrhea (as indicated by visual analogue scale scores), and menorrhagia (p < 0.05 for all). Of the 23 patients not using contraceptives, 12 (52%) had 14 clinical pregnancies during a 48-month follow-up period. Among the women with fertility requirements, 38.9% of patients had a clinical pregnancy during 48 months of postoperative follow-up. Of the 21 patients with fertility requirements, 4 (19.0%) patients relapsed, and of the 120 patients without fertility requirements, 3 (2.5%) patients relapsed (identified through ultrasound examination).

Conclusion

Laparoscopic adenomyomectomy combined with GnRH agonists can be used to effectively treat adenomyoma. In patients with no fertility requirements, complete resection of the adenomyosis tissue can significantly decrease the relapse risk.

focal adenomyosis

gonadotropin-releasing hormone agonist

laparoscopic uterine-sparing surgery

Uterine adenomyosis is characterized by the encroachment of endometrial tissue, both the stroma and glands, into the myometrium to a minimum depth of 2.5 mm beneath the endometrial/myometrial junction and even throughout the thickness of the uterine myometrium¹. Adenomyosis can be diagnosed with relative ease using sonohysterography in selected patients (as endometrial pseudo-thickening can be identified on sonography). In addition, magnetic resonance imaging (MRI) can be used to confirm the diagnosis and explore possible comorbid conditions². Focal uterine adenomyosis is termed uterine adenomyoma, and can be differentiated from uterine adenomyosis on diagnostic tests.

The symptomatology of uterine adenomyosis/adenomyoma includes menorrhagia, dysmenorrhea, chronic pelvic pain, and possibly, fertility issues^3–5. Compared to pelvic ultrasonography, MRI⁶ can provide more distinguishing details because it can differentiate between adenomyosis and leiomyomas with relative ease as well as depict diffuse/focal adenomyosis with a higher resolution (providing better contrast between low-intensity lesions and adjacent tissues). However, MRI is considerably costlier than ultrasonography.

One radical, though highly effective, treatment for most uterine-based pathologies is hysterectomy. However, conditions such as adenomyosis usually develop during this later age demographic (30–45 years), rendering fertility maintenance more challenging. Presently, there are no established protocols for the ideal treatment strategies for clinically symptomatic uterine adenomyosis in patients who do not wish to undergo hysterectomy. Conservative treatment typically revolves around the clinical management of pain-related/hemorrhagic symptoms rather than surgery. This involves the administration of oral contraceptive pills, prostaglandin inhibitors, progestogens, danazol, dialogist, and gestrinone, together with gonadotropin-releasing hormone (GnRH) agonists⁷. However, the major drawback of such drug treatments is that they do not provide a permanent cure, as the pharmacological effects are of a transient nature. Consequently, issues such as low patient compliance can easily allow for the re-development of adenomyoma-related clinical symptoms, especially, the muscle pain component. Stemming from this, nearly all patients with adenomyoma are typically in dire need of treatment options that allow for fertility preservation through the adoption of novel, conservative ‘keyhole’ or uterus-sparing surgical interventions that can cure or at least control their condition.

While multiple uterus-sparing surgical techniques exist for adenomyosis, the most highly regarded, feasible, and effective surgical option is adenomyomectomy. This surgical intervention is also particularly apt for the treatment of focal adenomyosis, which renders it the preferred surgical treatment recommended to patients. However, one major challenge lies in the determination of the extent of adenomyosis tissue present and if such tissue has developed into an adenomyoma. Indeed, conservative surgical interventions have been demonstrated to be effective in only approximately 50% of cases⁸.

Since currently, neither medical management nor surgical intervention alone can comprehensively and effectively treat uterine adenomyoma-related symptoms, the development of combination therapies using both these treatment options is being explored. In essence, a combination therapy includes conservative surgical procedures coupled with GnRH agonist therapy, and the initial clinical outcomes show good potential⁹. Therefore, the aim of this study was to analyze patient outcomes, namely, fertility preservation and symptomatic relief, following such novel combination treatments for uterine adenomyoma.

2.1. Patients

This study was approved by the institutional review board of The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University. The study aim was described in detail to all potential participants, after which each willing patient provided written, informed consent. The study retrospectively compiled the clinical data of 141 patients who were willing to undergo uterus-sparing surgery for the treatment of uterine focal adenomyosis. The study was conducted from January 2012 to December 2016 at the Department of Gynecology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University.

Of the 141 patients, 21 patients had fertility requirements, and the integrity of the endometrium was preserved in these patients. The remaining 120 patients did not have fertility requirements, and the adenomyosis tissue and the endometrium under the adenomyosis tissue were both resected in these patients. Patients were eligible to participate in the study if they presented with severe dysmenorrhea/menorrhagia and an enlarged, firm uterus. In all such patients, a tentative diagnosis of uterine adenomyoma was made, and the postoperative histological examination subsequently confirmed adenomyoma in all 141 study participants.

The inclusion criteria for this study were as follows: patients with aggressive dysmenorrhea or menorrhagia (hypermenorrhea), with failure to respond to drug therapies such as GnRH agonists, Mirena^®, and oral contraceptive pills; patients who specifically requested uterus preservation; and patients for whom focal adenomyosis (adenomyoma) was preoperatively confirmed through diagnostic ultrasonography or MRI, according to previously reported diagnostic criteria^{10, 11}. The exclusion criteria for this study were as follows: patients with a clear contraindication to laparoscopy due to previous medical conditions and patients with a uterine size indicating > 12 weeks of gestation.

In all patients, the following preoperative evaluations were performed: routine biochemistry analyses, including cancer antigen 125 (CA125) in the luteal phase, complete blood count, and ultrasound/MRI examinations.

2.2. Magnetic resonance imaging

All patients underwent pelvic ultrasound or MRI examination (Magnetom Impact 1.0 T^®: Siemens AG, Erlangen, Germany). The MRI procedure involved routine scanning of axial, longitudinal, and oblique sections, and was completed within 30–45 min. Diagnostic confirmation of adenomyosis depended mainly on the degree of endometrial thickness and uniformity in the junctional zone. Endometrial thickness was measured in both the anterior and posterior walls at the thickest regions. A thickness of at least 12 mm, together with focal, non-demarcated areas of endometrial tissue in the myometrium, and a non-uniform junctional zone indicated a diagnosis of adenomyosis⁶. In addition, the margin between the tumor tissue and the healthy myometrium was determined on the preoperative pelvic MRI examination (Fig. 1A and Fig. 1B).

2.3. Surgical procedure

Laparoscopy was performed for all the study patients. In the 21 patients with fertility requirements, the basic principles of reproductive surgery were strictly abided with to minimize trauma to the healthy uterine tissue and preserve endometrial integrity throughout the surgical procedure (Fig. 1C). For the 120 patients who had no specific fertility requirements, we performed laparoscopic adenomyomectomy, which entailed the complete resection of the adenomyosis tissue, including part of the endometrium (Fig. 1D). We used a modified laparoscopic adenomyomectomy technique that involved the insertion of two fingers into the vagina to elevate the uterus, while one finger of the other hand was inserted into the abdomen through a suprapubic 15-mm trocar port for systematic palpation of the uterus¹², especially in patients with multiple foci of adenomyosis or suspicious lesions.

The boundaries of the lesions were determined using comprehensive and systematic palpation of the uterus. We ensured that no macroscopic residual lesions were present, and that the residual myometrium was soft.

Four-port laparoscopic surgery was performed with the patients under general anesthesia and in the lithotomy position. A Veress needle was inserted through an incision in the umbilicus to establish pneumoperitoneum with carbon dioxide gas. The intra-abdominal pressure was maintained at 13 mm Hg. Once the pneumoperitoneum had been established, videolaparoscopy (laparoscopic camera provided by Storz, Germany) was performed using a 10-mm trocar introduced through the umbilicus. Another three trocars were needed for the operation. Two 5-mm trocars were placed on the left and right sides of the lower abdomen, and a 10-mm trocar was introduced through the paramedian line, just above the pubic hairline. These ports were used for the introduction of surgical instruments.

To reduce bleeding, a local injection of diluted vasopressin (1 U/mL, 5–10 mL) was routinely administered at the site of the adenomyoma. Adenomyomectomy was preferred in cases of localized adenomyosis (adenomyoma). Following enucleation of the adenomyoma, which could be identified through the laparoscopic visual field, the suprapubic 10-mm trocar was replaced with a 15-mm trocar, followed by manual uterine elevation to allow uterine palpation by the surgeon¹². Once the adenomyotic lesions were identified, they were dissected and carefully removed through systematic and thorough uterine palpation.

The use of adenomyomectomy surgery for the excision of focal (localized) adenomyosis presents few challenges to the experienced surgeon. In addition, this surgical procedure can be adeptly used to avoid widespread uterine cavity trauma in patients who require preservation of the reproductive functionality of the uterus.

2.4 Menorrhagia score

Menorrhagia score was defined as a bleeding episode persisting for > 7 days in each cycle, and a hemoglobin level < 10 g/dL without any other cause of anemia. The severity of menorrhagia was scored according to the duration of menses and degree of anemia as follows: no anemia and menses lasting for < 4 days, 0 points; no anemia and menses lasting for 4–7 days, 1 point; no anemia and menses lasting for > 1 week, 2 points; anemia and menses lasting for < 4 days, 3 points; anemia and menses lasting for 4–7 days, 4 points; and anemia and menses lasting for > 7 days, 5 points.

2.5 VAS score

The severity of dysmenorrhea was documented using a standardized questionnaire with a Visual Analogue Scale (VAS)¹³.

The patients were asked to rate their pain on a scale from 0 to 5, where 0 represented “no pain” and 5 “the worst pain possible”, using whole numbers (6 integers including zero)

2.6 Statistical analysis

Continuous data are shown as mean ± standard deviation (SD) and compared by paired-samples t test. Statistical significance was considered with a P < 0.05. All analyses were performed in SPSS 20.0 (SPSS, IBM, New York, USA).

3.1. Clinical outcomes

Serum CA125 and blood hemoglobin levels, pain scores, and menorrhagia were again assessed at 24 months after the operation. The postoperative values of the above parameters were significantly lower than their preoperative values (P < 0.05, Table 1).

Table 1

Changes in serum CA125 level, hemoglobin level, pain scores, and menorrhagia after surgery
Parameter	Before surgery	After surgery	P value
Serum CA125 (U/mL)	64.50 ± 55.27	26.13 ± 23.94	0.00
Hemoglobin	111.22 ± 18.66	122.66 ± 14.63	0.00
menorrhagia score	1.92 ± 1.38	0.56 ± 0.81	0.00
VAS score^$	5.07 ± 3.64	1.23 ± 1.68	0.00
Data are presented as mean ± standard deviation.
CA125: cancer antigen 125; VAS score, visual analogue scale score.
^$The severity of dysmenorrhea was documented using a standardized questionnaire with a VAS¹³.
Menorrhagia score was defined as a bleeding episode persisting for > 7 days in each cycle, and a hemoglobin level < 10 g/dL without any other cause of anemia. The severity of menorrhagia was scored according to the duration of menses and degree of anemia as follows: no anemia and menses lasting for < 4 days, 0 points; no anemia and menses lasting for 4–7 days, 1 point; no anemia and menses lasting for > 1 week, 2 points; anemia and menses lasting for < 4 days, 3 points; anemia and menses lasting for 4–7 days, 4 points; and anemia and menses lasting for > 7 days, 5 points.

For example, the VAS score significantly reduced from a baseline value of 5.07 ± 3.64 to 1.23 ± 1.68 at 24 months after the surgery (P = 0.00), and the menorrhagia score decreased from 1.92 ± 1.38 at the baseline to 0.56 ± 0.81 at 24 months (P = 0.00).

3.2. Pregnancy outcomes

Among the 21 patients with fertility requirements, 3 patients were treated with a levonorgestrel-releasing intrauterine system (LNG-IUS) since they had no short-term fertility requirements. Of the remaining 18 infertile women, 7 (38.9%) succeeded in conceiving after the operation. Among the 120 patients with no fertility requirements, 5 patients had 5 clinical pregnancies due to contraceptive failure (or due to not using contraceptive measures). All 5 patients opted for elective termination under hysteroscopy because they had no fertility requirements and because the endometrial defect increased the risk of metrorrhexis (Table 2).

Table 2

Pregnancy outcomes following combined surgical and medical treatment of adenomyoma in patients not using contraception (n = 23) at various follow-up intervals
Outcome	1 year	2 years	3 years	4 years	Total
Term delivery Preterm delivery Spontaneous abortion Elective termination Ectopic pregnancy Pregnancy	1 0 1 2 1 5	0 0 1 3 - 4	1 0 - 1 1 3	2 0 - - - 2	4 0 2 6 2 14

Of the 23 patients not using contraception in our study, 12 patients (52%) had a total of 14 clinical pregnancies during 48 months of postoperative follow-up. The pregnancy outcomes in these patients included 4 term deliveries, 2 spontaneous abortions, 6 elective terminations, and 2 ectopic pregnancies.

3.3. Relapses

Of the 21 patients with fertility requirements, 4 (19.0%) patients relapsed (identified through ultrasound examination), and consequently, underwent a second surgical procedure. One patient elected to undergo laparoscopic hysterectomy, and the remaining three patients opted to again undergo laparoscopic adenomyomectomy. Of the 120 patients without fertility requirements, 3 (2.5%) patients relapsed. Two of these patients underwent laparoscopic hysterectomy, and the third patient opted for conservative treatment.

Even though uterine-sparing surgery is being increasingly recommended as a mainstay treatment for adenomyoma^14–16, conservative surgical interventions cannot be the sole therapeutic measure for adenomyoma, especially since it can prove a challenge to excise all the ectopic uterine tissue. Adenomyotic tissue has the pathological propensity to invade the uterine muscle layer without leaving clear lesion border markings, so we believe that resection of adenomyosis tissue should be as complete as possible, and that comprehensive therapy is essential to achieve a clinically successful outcome for the patient.

In the current study, 4 of the 21 patients with fertility requirements and 3 of the 120 patients without fertility requirements were found to have a relapse on ultrasound examination. At 48 months after the operation, only 19.0% of patients with fertility requirements and 2.5% of patients without fertility requirements were found to have relapses. This indicates that laparoscopic adenomyomectomy with complete resection of adenomyosis, including part of the endometrium, can be expected to produce a significant decline in the relapse rate.

The results of the present study demonstrated a marked reduction in VAS scores, menorrhagia, and serum CA125 levels, together with a rise in blood hemoglobin level, after the surgery. Dysmenorrhea and menorrhagia are both hallmark symptoms of adenomyosis, and their degree of severity is directly related to the surgical efficacy of laparoscopic adenomyomectomy¹⁷. Serum CA125 level is deemed to be a reliable diagnostic biomarker and is suitable for monitoring the efficacy of adenomyosis therapies and detecting possible recurrences^{2, 17}. It is apparent that laparoscopic adenomyomectomy combined with GnRH agonists can effectively treat adenomyoma patients.

Our group has already reported the advantage of modified laparoscopic myomectomy using manual assistance for the comprehensive and systematic palpation of the uterus for multiple uterine myomas¹². In the current study, this method was used to perform adenomyomectomy for patients with multiple foci of adenomyosis or suspicious lesions.

The 23 patients who did not use contraception in our study included 5 patients without preservation of endometrial integrity and 18 patients with preservation of endometrial integrity. Among these patients, 12 patients (52%) had a total of 14 clinical pregnancies during 48 months of postoperative follow-up. Among the 18 patients with preserved endometrial integrity, 7 patients had 9 clinical pregnancies; 7 of the 18 infertile women (38.9%) succeeded in conceiving after the operation, but 1 of them underwent elective termination because she no longer had any fertility requirements. None of the patients had another pregnancy during the rest of the follow-up period. The 5 patients without preserved endometrial integrity who became pregnant also opted for elective termination under hysteroscopy because they had no fertility requirements. Thus, if the patient has no fertility requirements, contraception should be used after this procedure. This study had no uterine rupture. In infertile women, if a pregnancy fails to result after conservative therapy, laparoscopic adenomyoma resection may be considered.

Research has proved that the high-intensity-focused ultrasound method (HIFU) and combined treatment before assisted reproductive techniques can prove beneficial in adenomyosis patients¹⁸.

Of the 21 patients with fertility requirements, 3 patients were treated with an LNG-IUS, as they had no short-term fertility requirements. Indeed, for some patients with no desire for fertility, laparoscopic adenomyoma resection can be followed by combined treatment with the LNG-IUS and GnRH agonists. Research has proved that laparoscopic adenomyoma resection and GnRH agonist treatment can be of great therapeutic benefit in symptomatic adenomyoma and that the LNG-IUS can improve the efficacy of this novel combination therapy¹⁴.

However, the number of patients with fertility requirements was limited and the study lacked a control group. Further studies are needed to investigate the pregnancy outcomes and relapses.

Laparoscopic adenomyomectomy combined with GnRH agonist therapy can effectively treat uterine adenomyoma. In the case of patients with no fertility requirements, complete resection of the adenomyosis tissue (including part of the endometrium) can be expected to result in a significant decline in the relapse rate.

GnRH

gonadotropin-releasing hormone

MRI

magnetic resonance imaging

CA125

cancer antigen 125

VAS

Visual Analogue Scale

standard deviation LNG-IUS:levonorgestrel-releasing intrauterine system

HIFU

the high-intensity-focused ultrasound method.

Acknowledgements

Not applicable.

Authors’ contributions

Weiwei wei and Shoufeng Zhang contributed to the follow-up of patients, data collection and analysis, and manuscript writing; Ru-xia Shi contributed to the follow-up of patients; Jiming Chen contributed to data collection; Hong Zheng contributed to the design of the study; All authors read and approved the final manuscript.

Funding

This work was supported by grants from the Changzhou Science & Technology Program (QN201931), the maternal and child health research project of Jiangsu Province（F202138）, the Scientific Research Support Program for Postdoctoral of Jiangsu Province(2019K064), and the Scientific Research Support Program for "333 Project" of Jiangsu Province（BRA2019161）.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The study protocol was approved by the institutional review board (Clinical Medical Technical Ethics Committee) of The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University (protocol code: [2019] BYL70; date of approval: 24 November 2019). All methods were performed in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all subjects involved in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.

Author details

¹Department of Gynecology, The Affiliated Changzhou No. 2People's Hospital of Nanjing Medical University, NO.29 Xinglong Road, Changzhou 213000, Jiangsu, China. ²Dalian Medical University, Dalian 116000, China.

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No competing interests reported.

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Version 1

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You are reading this latest preprint version

Modified laparoscopic uterine-sparing surgery combined with gonadotropin-releasing hormone agonist therapy for focal uterine adenomyosis

Status:

Version 1

Abstract

Objectives

Methods

Results

Conclusion

Figures

1. Introduction

2. Materials And Methods

2.1. Patients

2.2. Magnetic resonance imaging

2.3. Surgical procedure

2.4 Menorrhagia score

2.5 VAS score

2.6 Statistical analysis

3. Results

3.1. Clinical outcomes

3.2. Pregnancy outcomes

3.3. Relapses

4. Discussion

Abbreviations

Declarations

References

Additional Declarations

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