Impact on Ovarian Reserve after Minimally Invasive Single-Port Laparoscopic Ovarian Cystectomy in Patients with Benign Ovarian Cysts: A Review of the Literature
The goal of this article is to review the published literature on single-port laparoscopy (SPL) in ovarian cystectomy and to evaluate whether the reduced port number affects the ovarian reserve with comparison to the conventional multiport laparoscopy (MPL).
Serum Anti-Müllerian hormone (AMH) had been proposed as the most accurate marker of ovarian reserve. A review of the current literature on the comparison of the preoperative and postoperative AMH after single-port laparoscopic and multi-port laparoscopic ovarian cystectomy in adult patients with benign ovarian cysts was performed. The review revealed 4 relative articles published between 2014 and 2019 including 336 patients of which 143 underwent SPL and 193 MPL. Two of them were retrospective case-control studies, one of them was randomized controlled trial and the other was non-randomized concurrent control trial.
As single-port laparoscopy surgery is relatively novel, the current literature on the impact of this technique in ovarian reserve after the excision of benign ovarian cysts is somewhat limited. However, it seems that SPL doesn't have a statistically significant negative influence in postoperative AMH compared to MPL. Additionally, patients who underwent SPL reported lower postoperative pain and less postoperative analgesics when compared with patients who underwent MPL.
SPL surgery provides another option in the arena of minimally invasive gynecologic surgery in treatment of benign ovarian cyst. Further studies with larger sample sizes are required to demonstrate the short and long-term impact of SPL to ovarian reserve and others co-factors who increase the risk of ovarian damage.
Single-port laparoscopy, Anti-Müllerian hormone, Benign ovarian cysts, Ovarian cystectomy, Ovarian reserve
Benign ovarian cysts are very common in women of reproductive age and often require surgical excision, particularly when they are symptomatic . However, there has been a growing concern over the possible damaging effect of this surgery on ovarian reserve [2,3]. In recent years, with continuous development of technology and minimally invasive techniques, laparoscopic cystectomy should be considered the first-line treatment in benign ovarian tumor, such as symptomatic endometrioma, dermoid cyst, and serous cystadenoma . Due to better surgical outcomes, fewer complications, less pain, and improved cosmetic results laparoscopic cystectomy has almost replaced open surgery . Many studies have indicated that laparoscopic ovarian cystectomy is associated with a decreased ovarian reserve and for this reason there has been a big concern to investigate the better laparoscopic approach in order to have the less damage in ovarian reserve after surgery [6-9].
A recent advancement in the field of minimally invasive gynecology is transumbilical single-port laparoscopy (SPL). This minimally invasive approach to surgery requires only one entry point, typically in the umbilical region. In particular, the use of SPL in adnexal disease, as well as in endometrioma excision has been proposed . There are studies that shown that a limited operative space in SPL causes unstable camera motion and interference between instruments, which may increase the difficulty and risk of surgery [11,12]. Yoon, et al. , Huang, et al.  and Wang, et al.  found that the ovarian reserve did not statistically differ between single-port laparoscopic cystectomy (SPL) and conventional multiport laparoscopic cystectomy (MPL). However, Angioni, et al.  found that the mean AMH concentration significantly decreased in their SPL group at the four to six-week and three-month follow-ups compared with that in their MPL group.
Compared with other traditional biologic indicators, the Anti-Mullerian hormone (AMH) is the most accurate biomarker of ovarian reserve. AMH reflects the decreasing ovarian reserve earlier than the other hormones such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and other ovarian indicators such as inhibin B, and antral follicle count (AFC) [17-19]. The aim of our review was to evaluate the impact of surgical technique on the ovarian reserve by comparing the preoperative and postoperative AMH of patients who underwent SPL and MPL.
Materials and Methods
A literature search was conducted in order to identify studies comparing SPL to MPL for ovarian benign cysts excluding diseases related to pregnancy. Pubmed, Embase and Medline were consulted in order to identify publications in English published between 1975 and 2019. The references were exported to a reference management software, Endnote, and duplicates were deleted. The literature was reviewed for terms "single-port laparoscopic cystectomy" and/or "ovarian reserve", "laparoscopic cystectomy", "laparoscopy", "endometrioma", "AMH". Primary endpoints were the age at surgery (> 18 years and < 45 years), type of performed laparoscopic and surgical technique, unilateral or bilateral ovarian cysts presumed as benign (endometrioma, dermoid cysts, simple cysts, serous cystadenomas, mucinous cystadenomas) on ultrasonography, size 3-20 cm, regular menstrual cycle (21-35 days), absence of endocrine disorders, no use of any medications such as oral contraceptive pills or other hormonal agents within 3 months before study enrollment, no previous history of ovarian cyst surgery, radiotherapy or chemotherapy. All patients underwent the surgery under general anesthesia with endotracheal intubation and were placed in the Trendelenburg position. Initially the research strategy identified 17 studies published the last ten years. Other databases were searched and no additional studies were identified. Thirteen articles were excluded on the basis that they failed to meet inclusion criteria. Finally the search revealed 4 relative articles published between 2014 and 2019 and offered 336 patients for this analysis, of which 143 underwent SPL and 193 MPL (Figure 1). Two of them were retrospective case-control studies [14,16], one of them was randomized controlled trial  and the other was non-randomized concurrent control trial . All of them used the same surgical technique with a few variants and the same biomarker (AMH) to evaluate postoperative ovarian function (Table 1). Additional they evaluated secondary outcomes, which were operative outcomes, including operating time, estimated blood loss (EBL), hemoglobin (Hb) drop, adhesiolysis, rupture of cyst, operative complications, conversion rate and postoperative outcomes such as parental analgesic use, postoperative lower abdominal wound pain and length of hospital stay.
Development of single-port laparoscopy access in gynecology
The idea of single-port minimally invasive surgery in gynecology dates to 1969, when Wheeless  reported single-incision laparoscopy for female sterilization. And although gynecologic surgeons performed pelvic laparoscopy to conduct tubal ligation through a single umbilical incision in the 1970's, more advanced procedures were reported years later, with the first single-port hysterectomy reported by Pelosi, et al.  in 1991 and the first single-port ovarian cystectomy reported by Kosumi, et al. in 2001 [22,23]. In 2005, Ghezzi, et al.  reported a novel single-port technique for treatment of tubal pregnancy and 2009 Lim, et al.  reported a series of 12 patients who underwent single-port laparoscopic surgery for treatment of benign adnexal masses. Also in 2009, Kim, et al.  published a series of 24 patients who underwent adnexal surgery performed through a single port. Langebrekke, et al.  in 2009 reported the first total laparoscopic hysterectomy through a single incision. The studies that followed, showed that SPL improves cosmetic results, decreases hospital stay, and facilitates faster recovery. Less ports also means reduction in port-associated complications such as hernias, vascular and soft-tissue traumatic injuries during trocar insertion, less blood loss and nerve injuries but the ovarian reserve constitute controversial subject [28,29].
Technical limits of single-port laparoscopic surgery
Despite the development of new instruments and access ports, several technical challenges in operating through a single port remain. The intrinsic limit of this new approach is the reduced freedom of movement between the instruments, which may limit the surgeon's movements, surgical ergonomy, and increase operating time. Triangulation is a necessity in traditional laparoscopy. In SPL with a single incision accommodating both the camera and the instruments, there is loss of triangulation, reduced visualization, and interference between instruments [22,30]. Moreover single-port surgery might not be so easy to learn, given the high level of skill and technical ability required to overcome many of the obstacles. This may lead to a difficult and long learning curve, and it is imperative that surgeons who attempt this new surgical approach be at least highly proficient in traditional laparoscopy [31,32]. If we really know the technical limits of this new surgical approach, maybe we can find ways to overcome these and minimalize the operative and post-operative complications, such as the postoperatively reduction of AMH.
Assessment of ovarian reserve
Ovarian reserve is defined as the functional potential of the ovary, and reflects the number and quality of the follicles left in the ovary at any given time. There are no definite estimates to measure of the quantitative ovarian reserve in reproductive age. Although recent progresses have been achieved in this field, the ideal test reflecting ovarian reserve has remained the evaluation of the response to ovarian stimulation. Various tests and markers of the ovarian reserve have been reported. Hormonal tests, such as follicle stimulating hormone (FSH), estradiol, luteinizing hormone (LH), AMH or inhibin-b and sonographic measurements, such as ovarian volume, antral follicular count (AFC), or ovarian blood flow, have been proposed. Among these factors, AMH is produced by the granulosa cells of the recruited follicles until they become sensitive to FSH, and has been identified as a regulator of recruitment for preventing depletion of the entire primordial follicle pool at once [33,34]. Serum AMH levels appears to correspond well with AFCs and ovarian response hyperstimulation in IVF. It has been found to decline with age in females, and suggested as a predictor of ovarian response and menopausal transition. Moreover, AMH is the only marker of ovarian reserve while being menstrual cycle independent and easily measurable, although the threshold levels in follicular and luteal phases need to be standardized. The measurement of serum AMH levels is more convenient than ovarian response to hyperstimulation for predicting the ovarian reserve . It is worthy to elucidate the change of ovarian reserve serially measured by serum AMH, which reflect the count of primordial follicles after ovarian surgery.
Variability of AMH
Several studies have reported that serum AMH levels are more decreased in endometriomas than other ovarian tumors, and severely declined as the endometriosis is severe and bilateral . Iwase, et al. reported that decrease AMH levels were found after laparoscopic excision of endometriomas and non-endometriotic cysts, but the decrease was more profound in endometriomas than in non-endometriomas. Hirokawa, et al. also reported that the rate of decline of the serum AMH level was significantly higher in the bilateral group than the unilateral group, and was correlated with the revised American Society for Reproductive Medicine (rASRM) score . Laparoscopic cystectomy further exerted a significant negative impact on ovarian reserve measured by serum AMH levels in both short and long term observations [37,38]. Tsolakidis, et al.  reported that the mean serum AMH level was significantly reduced 6 months after surgery. Chang, et al.  also observed a significant decrease in serum AMH levels 3 months after laparoscopic cystectomy. During cystectomy, it is not always easy to identify and separate the cleavage plane between the cyst wall and adjacent ovarian cortex tissue due to fibrotic adhesion. Cystectomy using the stripping technique usually leads to removal of normal primary follicles and damage of ovarian reserve. Furthermore, bipolar coagulation at seriously bleeding sites close to ovarian hilus also leads to destruction of the ovarian blood supply and reduced ovarian reserve .
In all these 4 relative articles we studied, there were no statistically significant differences regarding baseline characteristics (age, BMI, histologic findings, cyst size, cyst position) among the patients groups. According to the surgical outcomes none of the cases converted to a different surgical approach, and no complication occurred during the perioperative period. Yoon, et al. , Huang, et al.  and Wang, et al.  found AMH levels decreased during follow-up in SPL and MPL group, but there is no significantly difference between two groups. Moreover there were no significant differences in the other surgical outcomes. Angioni, et al. , however, found that in SPL group AMH levels were significantly lower (p < 0.01), operative time was significantly longer (p < 0.01) and blood loss was significantly higher in the SPL group (p < 0.001) compared with MPL group. We should mention that in the study by Angioni, et al. all patients (in both groups) had only endometriotic cysts, and haemostasis was achieved by bipolar forceps applied to the ovarian parenchyma. This is by itself a negative factor for the initial preoperative AMH level because the mean serum AMH level in patients with ovarian endometrioma per se is associated with reduced ovarian reserve [41,42]. Moreover laparoscopic stripping of ovarian endometriomas may further worsen ovarian reserve through many ways [38,43] (Figure 2).
Single-port laparoscopic ovarian cystectomy seems to be a promising surgical minimal invasive technique because of the advantages of fast recovery, less trauma, and superior cosmetic outcome. From the other side, the safety of this technique with respect to aspects of damage to ovarian reserve has been questioned. Until now, this relevant issue has been poorly investigated, because of difficulties in assessing ovarian reserve after this surgery in combination with the small number of study subjects and short follow-up intervals.
The presence of an ovarian cyst may distort and damage the adjacent healthy ovarian tissue but the laparoscopic stripping of ovarian cysts may further worsen ovarian reserve, even if performed by experienced surgeons, through at least three ways: (i) The accidental removal of healthy ovarian cortex near the cyst's capsule (ii) The thermal effect of diathermy coagulation of small bleeding vessels on the stripping area with consequent vascular compromise and (iii) A surgery-related local inflammation [37,44].
In single-port laparoscopy (SPL) the surgeons often experienced difficulties in handling their instruments, due to the unsatisfactory surgical plane . All instruments were placed in parallel, bumped each other for targeting procedures, and also were in line with the vision. Maybe these limitations make the procedure difficult, and cause more negative impact on preserving of the ovarian function in laparoscopic ovarian cystectomy. The majority of studies did not display a remarkable difference in reduction of postoperative AMH between SPL ovarian cystectomy and conventional multiport laparoscopic approach.
It seems that besides the number of laparoscopic ports there are more factors like histological type of cyst (endometriotic cysts or non-endometriotic cysts), the hemostatic approach (coagulation, suturing), the location of cyst (unilateral or bilateral), the cyst size, that affects postoperatively in ovarian function. Further studies with larger sample sizes are required to demonstrate in which degree all these factors contribute to the loss of the ovarian reserve.
Studies with a long-term follow-up of the ovarian reserve after surgery are lacking. The most accurate marker to evaluate the ovarian reserve changes after laparoscopic cystectomy is AMH. Several mechanisms about the recovery of serum AMH levels have been postulated, however most studies with laparoscopic cystectomies (SPL or MPL) have short term postoperative measurements of AMH . In Chang, et al. study  there was a significant reduction of AMH levels postoperatively (7th day) and then serum AMH levels had been increased gradually and recovered about 65% of the preoperative level 3 months later. The question is, if single-port laparoscopy can be an alternative method to conventional laparoscopy in the treatment of benign ovarian cyst. For women with fertility problems, it is crucial for surgeons to select the best surgical technique that would allow the ovarian reserve to recover within a short period.
The laparoscopic ovarian cystectomy with reduced port number seems that does not affect the serial change of ovarian reserve. The simple port laparoscopy may be the alternative minimal invasive method to conventional laparoscopy in terms of ovarian reserve.
Disclosure of Interest
The authors confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
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Eleni Tsiampa, 2nd Department of Obstetrics and Gynecology, General & Maternity Hospital Helena Venizelou; Hellenic Minimally Invasive and Robotic Surgery (MIRS) Study Group, National and Kapodistrian University of Athens, Athens Medical School, Athens, Greece.
© 2020 Tsiampa E, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.