Low-pressure pneumoperitoneum reduces influence on ovarian hormones in infertile women: a randomised trial

Introduction

In recent years, laparoscopic surgery has become one of the most important diagnostic and therapeutic approaches in gynecological surgery. The surgery can improve the efficiency and maintain hemodynamic stability in laparoscopy for gynecological diseases (1). This minimally invasive therapy requires pneumoperitoneum for adequate visualization and operative manipulation. Carbon dioxide (CO₂) is the most commonly used gas to inflate the peritoneum, because of its high diffusibility and rapid absorption and excretion. Compared with open surgical procedures, this technique potentially offers shorter operative time and hospital stay, earlier recovery, and less pain and pelvic adhesions (2,3).

However, insufflation of CO₂ into the peritoneum may lead to alterations in the acid-base balance, and cardiovascular and pulmonary physiology. Mastroyannis et al. reported the effects of CO₂ pneumoperitoneum pressure on rabbit follicular oocytes and early embryonic development using the animal model of pneumoperitoneum. They found that the duration of pneumoperitoneum, irrespective of type of gas used, was negatively correlated with success of embryonic development (4).

There are many reports on the safety of low CO₂ pneumoperitoneum pressure (5,6). The benefits of laparoscopic surgery include reduced blood loss, fewer transfusions, and shorter hospital stay. Peng et al. found that CO₂ pneumoperitoneum did not raise the incidence rate of bacterial translocation under laparoscopy surgery (7). Chen et al. showed that CO₂ pneumoperitoneum did not affect expression of the cellular proliferation marker Ki67 in an orthotropic xenograft nude mouse model of human renal cell carcinoma (8). Contrastingly, high pressure CO₂ pneumoperitoneum was found to induce oxidative damage and apoptosis in rabbit kidneys with severe hydronephrosis (9). However, there has been little exploration of the clinical effects of low CO₂ pneumoperitoneum pressure in post obstetric surgery patients. Akdemir et al. demonstrated that CO₂ pneumoperitoneum does not cause ischemia-reperfusion injury in premenopausal human ovaries at clinically safe levels of intra-abdominal pressure (14 mmHg) (10). However, the effect of different CO₂ pneumoperitoneum pressure on ovarian function in laparoscopy has not been reported. Therefore, it is very important for gynecologists to fathom the effect of pneumoperitoneum pressure on reproductive-age patients.

The purpose of our study was to evaluate the effect of CO₂ pneumoperitoneum pressure on ovarian hormones in infertile women. The findings were intended to contribute to the development of a standard of CO₂ pneumoperitoneum pressure for infertile women undergoing laparoscopic surgery and reduce the adverse effects of the surgery.

We present the following article in accordance with the CONSORT reporting checklist (available at http://dx.doi.org/10.21037/apm-21-476).

Methods

Participants

From April 2009 to May 2013, a total of 424 women diagnosed infertile at the Institute of Obstetrics and Gynecology were screened for this study (Figure 1). Patients were included if their infertility was caused by pelvic adhesions, tubal factors, or unexplained, and were followed up for 3 menstrual cycles following surgery.

Figure 1 Study profile.

Patients with endocrine-related diseases, such as endometriosis and polycystic ovary syndrome (PCOS), were excluded. Participants who dropped out during the course of study were also excluded. The excluded cases were as follows: 106 were diagnosed with endometriosis upon surgery; 80 were diagnosed with PCOS, 50 had ovarian cysts detected during surgery (ovarian endometrial cyst, 26 cases; teratoma, 18 cases; corpus luteum cyst, 6 cases). A total of 120 cases were excluded who did not undergo blood draw or ultrasound examination.

A total of 118 patients (aged 18–39 years) met the inclusion criteria and were retrospectively analyzed. Among them, 70 participants underwent laparoscopic surgery for pelvic adhesions, 20 underwent tubal colostomy, 6 underwent tubal fimbria angioplasty, and 22 underwent laparoscopic surgery for detection. According to the CO₂ pressure applied in laparoscopic surgery, and the volume of insufflation of CO₂ was determined by pneumoperitoneum pressure indicator (Olympus UHI-4; Japan), participants were divided into 4 groups [A, 10 mmHg (n=35), B, 11–12 mmHg (n=31), C, 13–14 mmHg (n=28), and D, 15–16 mmHg (n=24), respectively] (Figure 1). All surgical procedures were performed by the same surgeons. Written informed consent was provided by every participant and the study protocols were approved by the Ethics Committee and Institutional Review Board of the Maternal and Child Hospital (No. 81), Guiyang. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013).

Ovarian hormone evaluation

The ovarian hormones estradiol (E₂), progesterone (P), luteinizing hormone (LH), testosterone (T), and follicle-stimulating hormone (FSH) were detected by radioimmunoassay. These hormones were assessed before and on days 3 and 5 of the first and third menstrual cycles after surgery.

Ultrasound monitoring

Uterus and bilateral annexes were detected via vaginal examination on the first 3–5 days of menstruation before and after surgery. A 6.0 MHz vaginal probe of B-mode ultrasound (Sonolayer SSA-220A, Toshiba, Tokyo, Japan) was used for examination. The number and diameter of follicles and diameter of ovaries were measured at 3 time points (T0, before operation; T1, 1 month after operation; T2, 3 months after operation). Ovarian volume was calculated as previously described (11). Ovarian function was also evaluated using mean ovarian volume (MOV, the average volume of both ovaries), maximal ovarian volume (MaxOV, the volume of the largest ovary), mean follicle number (MFN, the mean number of bilateral ovarian follicles), and maximal follicle diameter (MFD, the dominant follicle diameter).

Statistical methods

Measurements were expressed as means ± SD and/or median and range. Means were compared using the Student’s t-test or 2-way analysis of variance (ANOVA) with the corresponding post-test. All statistical tests were 2-tailed and P value <0.05 was considered statistically significant. All data were analyzed using the software SPSS 19.0 (SPSS, Inc., IBM, Chicago, IL, USA).

Results

Participants and surgical complications

A total of 118 patients were included in this study. The mean age of the participants was 27.2±4.6 years (18–36 years). The mean surgery time was 89±16 min (35–120 min). The total numbers of participants were 35, 31, 28, and 24 in groups A, B, C, and D, respectively. Length of hospital stay was not different among the 4 groups (P>0.05). Group D had the longest surgical time, and also had the highest frequency of pelvic adhesion (37.5%, Table 1).

Table1 Baseline characteristics of the study sample
Full table

Surgical complications were graded according to the Accordion Severity Grading System (12) and the results are summarized in Table 2, including pneumohypoderma, shoulder pain, delayed wound healing, and postoperative nausea and vomiting. The incidences of complications in group A, B, C, and D were 2.86%, 12.9%, 28.6%, and 50%, respectively, and were significantly higher in group C and D than in group A (P<0.05). No severe complications were observed in all groups, such as severe infection or damage to adjacent organs and blood vessels.

Table 2 Surgery related complications in four groups
Full table

Ovarian hormones E², FSH, LH, P, and T

Preoperative levels of ovarian hormones were within the normal range and were similar among the 4 groups. The E₂ decreased significantly in the first menstrual period following surgery as compared with before surgery (P<0.05) and returned to the preoperative levels in the third menstrual period (Figure 2A). It trended to decrease with increasing CO₂ pressure. After surgery, serum E₂ was the lowest in group D, although it was not significantly different among the 4 groups (P>0.05, Figure 2A).

Figure 2 The levels of ovarian hormones before and after surgery under different CO₂ pneumoperitoneum pressures. (A) Estradiol; (B) luteinizing hormone; (C) follicle-stimulating hormone; (D) progesterone; and (E) testosterone. T0, before operation; T1–2, one and three months after operation. CO₂, carbon dioxide.

Levels of LH and FSH were higher at the first menstrual period after surgery than before surgery (P<0.05). Both had returned to normal range at the third menstrual period (Figure 2B,C). The concentrations of LH and FSH showed an increasing tendency with increasing CO₂ pressure, especially in group D, where they were statistically higher than in the other 3 groups (P<0.05) (Figure 2B,C). The levels of P and T did not show significant change after surgery and CO₂ pressure did not affect the levels of these hormones (P>0.05, Figure 2D,E).

MOV, MFN, and MFD

We then surveyed the change of ovarian structures with B-mode ultrasound at day 5 of the menstrual cycle. The MOV, MFD, and MFN remained unchanged after surgery (Figure 3A,B,C, P>0.05), although MFN in group D showed a statistically insignificant decrease at 1 month (P>0.05, Figure 3C).

Figure 3 The MOV, MFN, MFD, and menstrual period before and after surgery under different carbon dioxide pneumoperitoneum pressures. (A) Mean ovarian volume; (B) mean follicle diameter; (C) mean follicle number; (D) menstrual period (day). T0, before operation; T1–2, 1 or 3 months after operation. MOV, mean ovarian volume; MFN, mean follicle diameter; MFD, mean follicle diameter.

Length of menstrual cycle

We followed up the menstrual cycle after surgery and found that the menstrual period of participants in group D were delayed at 1 month post operation (P<0.05, Figure 3D). However, it had recovered to normal range at the third menstrual period. Within 1 year, 46 participants were successfully pregnant after surgery.

Discussion

Increased intra-abdominal pressure used in laparoscopy resulting from pneumoperitoneum may lead to systemic effects, such as acid-base imbalance, blood gas alterations, and pulmonary disease, cardiovascular disease, pneumothorax, mediastinal emphysema, air embolism, and acute respiratory distress syndrome (ARDS) (13,14). We reviewed the literature for clinical and laboratory studies on the currently used laparoscopic insufflation gases, and CO₂ showed adverse effects on respiration and circulation (15).

Eleftheriadis et al. found when pneumoperitoneum pressure was up to 15 mmHg, bacteria could diffuse to other organs in the abdominal cavity (16). Marana et al. confirmed that CO₂ pneumoperitoneum pressure affected stress-related neuroendocrine hormones after comparing the level of stress hormones, plasma epinephrine, norepinephrine, and epinephrine after laparoscopy, mini laparotomy, and laparotomy (17). However, the range of pneumoperitoneum pressure that is safe for ovarian function has not been well defined. Bogani et al. compared low (LPP 8 mmHg) vs. standard pneumoperitoneum pressure (SPP 12 mmHg) during mini-laparoscopic hysterectomy (MLH), and found there was less shoulder-tip pain in LPP (18). In our study, low CO₂ pneumoperitoneum pressure was found to be safer and feasible for surgery. No severe complications, such as infection, adjacent organ damage, abdominal vascular injury, and drain off into the abdominals, occurred at low pressure. Conversely, under high pressure (15–16 mmHg), more complications were observed, which was similar to earlier works (18).

Our analysis showed that CO₂ pressure of CO₂ has some effects on ovarian hormones, especially in the first postoperative menstrual period. When the pressure applied exceeded 15 mmHg, the serum LH and FSH increased significantly in the first menstrual period. At the highest pressure, patients’ menstrual cycles were extended. Recently, a prospective study showed that CO₂ pneumoperitoneum caused acute injury to the retained kidney after laparoscopic donor nephrectomy (19). Our data showed that Group D had the longest surgical time, and the highest incidence of pelvic adhesion (37.5%). We speculate that high pressure may reduce ovarian blood supply during operation, and this adverse effect would prolong surgical time and increase surgical difficulty.

Meanwhile, we also found that increased pneumoperitoneum pressure might result in reduced follicle numbers. These clinical observations and laboratory data suggest that high pneumoperitoneum pressure may adversely affect follicular development during the cycle.

Measurement of FSH and LH during the cycle can reflect ovarian reserve (20). Based on the recent result that high CO₂ pneumoperitoneum pressure reduced splanchnic blood (19,21), it is likely that when CO₂ pneumoperitoneum pressure exceeds 16 mmHg, it might affect the ovarian blood supply and cause a transient ischemia-reperfusion, affecting follicular development and leading to temporary follicular dysplasia. However, this impact is likely short-lived and would vanish soon after surgery. As a consequence, we observed that the ovarian hormone levels had returned to previous levels by the third menstrual period.

Previously, ovarian surgery was found to have various impacts on the menstrual cycle and ovarian function. For example, Sayegh et al. reported on 87 reproductive-aged women who had undergone pelvic surgery for indications including endometriosis, infertility, and pelvic pain; the result showed conservational ovarian surgery had no significant effects on ovulatory and menstrual function over a prolonged follow-up period (22). Zhang et al. found that ovarian biopsy/scratch could promote follicle development in vivo (23). In addition, surgical excision of endometriomas acutely impairs ovarian function (24) and hemostatic methods during surgery affect ovarian function (25).

We further analyzed the characteristics of participants in group D. Since frequent intraoperative adhesions occurred in the group, it is likely that the ovarian function affected by high CO₂ pneumoperitoneum pressure resulted from the adhesions as well as from adhesion-induced release of inflammatory factors. Therefore, for patients with severe adhesions, factors other than pneumoperitoneum pressure should be taken into consideration. Based on our data, it is reasonable to interpret that CO₂ pneumoperitoneum pressure below 16 mmHg is safer for preservation of ovarian function. Base on the reported researches (15,26), N₂O (nitrous oxide) has only weak hemodynamic effects. It seems to be the alternative gas for insufflation into the peritoneum. Other gases such as helium, air, nitrogen and argon, which have no significant advantage over CO₂ or N₂O. Menes T reviewed previous studies and concluded the effect of CO₂ insufflation on acid-base changes usually are mild (15).

However, further exploration is required on the impact of CO₂ pneumoperitoneum pressure on acid-base changes and blood supplying the ovaries, oocyte quality, subsequent pregnancy in multi-center, large-cohort studies.

Conclusions

Our work demonstrated that low-pressure pneumoperitoneum in laparoscopic operation has less adverse impacts on ovarian function and a lower complication rate, suggesting that CO₂ pressure below 16 mmHg during laparoscopy for infertility patients is worthy of recommendation. However, this was a single center-, small-scale retrospective study, and the conclusions need to be validated in multi-center, large scale, and prospectively designed studies.

Acknowledgments

Funding: This study was supported by Guiyang Health Science and education foundation [2008] No.40.

Footnote

Trial Protocol: Available at http://dx.doi.org/10.21037/apm-21-476

Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at http://dx.doi.org/10.21037/apm-21-476

Data Sharing Statement: Available at http://dx.doi.org/10.21037/apm-21-476

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/apm-21-476). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Ethics Committee and Institutional Review Board of Maternal and Child Hospital (No. 81), Guiyang and written consent was provided by every participant. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Jones)