Effects of interventional fallopian tube recanalization with ozone combined with Salvia miltiorrhiza injection and Qilin pill on tubal obstructive infertility.

Fallopian tube obstructive infertility (FTOI) results from blockage of the fallopian tube – a vital organ of the female reproductive system. [ 1 ] The fallopian tube is essential for reproduction, as it facilitates the transport of spermatozoa to the fertilization site, enabling the sperm-oocyte union. [ 2 ] Obstruction of the fallopian tube prevents fertilization of the ova, resulting in infertility. Common etiological factors of FTOI include pelvic tissue infections and gynecological surgical interventions, both of which can compromise the anatomical integrity and physiological function of the fallopian tubes, thereby impairing gamete transport and fertilization. [ 3 ] Studies have indicated that tubal infertility accounts for approximately 25% to 35% of all infertility cases. [ 4 ] Pelvic tissue infections often trigger a local immune response mediated by testosterone helper 1 cells (Th1). This immune response can result in chronic inflammation and tissue fibrosis, which are primary factors responsible for tubal obstructive infertility. [ 5 ] Notably, pathological changes – such as edema, exudate accumulation, hydrops, wall thickening, fibrous adhesion, increased rigidity, and structural distortion – may develop in the fallopian tubes, ultimately resulting in complete obstruction. [ 6 ] Fallopian tube obstruction can result from various factors, including inflammation, pelvic inflammatory disease, endometriosis, sexually transmitted diseases, and previously induced abortions. [ 7 ] Currently, surgical intervention is the primary treatment modality for FTOI, with the focus involving restoration of tubal patency. [ 8 ] However, postoperative readhesion is a frequently observed complication that significantly compromises therapeutic efficacy and increases the risk of infertility. [ 9 , 10 ] Consequently, the implementation of targeted intervention techniques to minimize postoperative adhesions is vital in the effective management of tubal obstructive infertility. Interventional therapy offers several advantages – including high therapeutic efficacy, minimal invasiveness, and favorable safety profile – positioning it as a promising modality for the treatment of tubal obstructive infertility. Particularly, interventional fallopian tube recanalization with ozone (FTRO) has demonstrated high therapeutic efficacy in tubal obstructive infertility. [ 11 ] Interventional procedures for the treatment of fallopian tube pathologies have gained widespread acceptance in clinical practice due to their minimally invasive nature, reduced patient discomfort, minimal tissue damage, rapid recovery times, and significant efficacy. [ 12 ] However, postoperative readhesion persists, thereby compromising therapeutic outcomes and patient prognosis. [ 13 ] Ozone, a trioxide atom, is an unstable gas with a distinctive pungent odor under normal temperature and atmospheric pressure. [ 14 ] Ozone exhibits the following characteristics: potent oxidation capabilities, absence of permanent residue, broad-spectrum bactericidal properties, and rapid disinfection. These features render it an effective agent for the simultaneous targeting of various bacteria and viruses. [ 15 ] Furthermore, ozone triggers the overexpression of antioxidant enzymes – which neutralize excessive reactive oxygen species – and stimulates the production of antagonistic cytokines and immunosuppressive factors such as interleukin 10 and transforming growth factor-beta. [ 16 ] It also stimulates the release of endothelial-derived factors and induces vasodilation, thereby reducing local tissue hypoxia and facilitating the resolution of inflammation. [ 17 ] Administration of medical ozone to FTOI patients following interventional fallopian tube recanalization can facilitate the mechanical separation of adhesive tissues, thereby enhancing the efficacy of the procedure. [ 18 ] The interaction between ozone and bodily fluids results in dual action: it generates powerful oxidants that rapidly and efficiently eliminate bacteria and viruses; and promotes excessive secretion of antioxidant enzymes, inhibiting the release of inflammatory factors. These processes ensure therapeutic efficacy, thereby preventing readhesion and creating a favorable environment for pregnancy. [ 19 ] Additionally, the ozone performs vital functions including decomposition of toxins, stimulation of protein synthesis, enhancement of immune response, reduction of intervention-related complications, and facilitation of rapid patient recovery. [ 20 ] Consequently, interventional FTRO holds significant promise in the treatment of tubal obstructive infertility. While the FTRO method is a viable approach in the treatment of tubal obstructive infertility, it is associated with high rates of re-obstruction, contributing to low pregnancy success rates. [ 21 ] Consequently, to address this challenge, in this study, we have integrated traditional Chinese medicine (TCM) interventions to reduce the likelihood of fallopian tube re-obstruction. [ 22 ] Salvia miltiorrhiza injection – characterized by beneficial properties such as blood-activation, blood stasis resolution, qi-promotion, pain alleviation, and meridian-dredging effects [ 23 ] – has been established to improve pelvic microcirculation, regulate associated metabolic activities, resolve inflammatory responses, and prevent tubal adhesions. Ozone is a widely utilized therapeutic agent in the treatment of various gynecological infections, such as vaginitis, cervicitis, salpingitis, endometritis, and pelvic inflammation. [ 24 ] Qilin pill, a substance consisting of 15 TCM compounds – including Radix polygoni multiflori , Echinacea, Epimedium , Cuscuta chinensis , Cynomorium songaricum , Codonopsis pilosula , Curcuma, Fructus lycii , Raspberry, Chinese yam, S miltiorrhiza , Radix astragali, Radix paeoniae alba, Cortex ilicis , and Mulberry – facilitates the strengthening of the tubal wall and invigoration of qi and blood. [ 25 ] Pharmacological analysis of the Qilin pill has revealed that it exhibits a phytoestrogen-like effect, which facilitates regulation of the gonadal axis and bidirectional modulation of the expression of luteinizing hormone receptor within the ovary. [ 26 ] Notably, Qilin pill has been found to counteract oxidative stress reactions, inhibit the Bax-Caspase-9 apoptotic pathway, regulate the estrous cycle in female mice, mitigate cytotoxic drug-induced damage (such as cyclophosphamide) to ovarian function, improve sex hormone levels, increase anti-Mullerian hormone expression, and enhance fertility rates. [ 27 ] These effects are potentially attributed to the inherent ability of Qilin pill: to inhibit the ovarian tissue hypoxia-inducible factor la (HIF-la)/adenovirus E1B interaction protein 3 (Bmp3)/autophagy effector protein 1 (Beclin-1) signaling pathway; regulate the mitogen-activated protein kinase and phosphatidylinositol-3-kinase-protein kinase B (PI3K-Akt) signaling pathway; and suppress the over expression of autophagy-related proteins, such as microtubule-associated protein 1A/1B light chain 3 (LC3B-II) and P62. [ 28 ] Furthermore, Qilin pill upregulates the expression of endometrial integrin aVp3 and leukemia inhibitory factor, which promotes ovarian functional integrity, thereby improving fertility. [ 29 , 30 ] Consequently, to enhance the therapeutic efficacy of FTRO for the treatment of tubal obstructive infertility, we highly recommend the integration of TCM approaches, particularly the combined application of S miltiorrhiza injection and Qilin pill. Clinical practice research has demonstrated favorable outcomes through this integrated approach, including improved hormone levels and reduced postoperative complications.

Conceptualization: Shilin Zheng, Yun Wu. Data curation: Shilin Zheng, Yun Wu, Yiqing Tan. Formal analysis: Shengpan Jiang, Yiqing Tan. Funding acquisition: Yiqing Tan. Investigation: Shilin Zheng. Methodology: Yun Wu, Shengpan Jiang, Yiqing Tan. Resources: Shilin Zheng, Shengpan Jiang. Validation: Shilin Zheng. Writing – review & editing: Shilin Zheng, Yiqing Tan. Writing – original draft: Yun Wu.

A total of 300 patients diagnosed with tubal obstruction who underwent treatment at our hospital between March 2015 and September 2021 were enrolled in this retrospective study. The inclusion criteria were as follows: Tubal obstruction involving proximal obstruction of the interstitial region, isthmus and abdominal regions of the fallopian tube; open but morphologically uneven fallopian tubes; extremely obstructed fallopian tubes (including mild adhesion at the fimbrial end); suspected pseudo-positive obstruction of the fallopian tube (including fallopian tube development to the distal end); Absence of morphologically abnormal sperm or other reproductive organ; Absence of potential contravening symptoms resulting from Qilin pill, ozone perfusion, interventional unblocking. The exclusion criteria were as follows: Infertility due to non-fallopian tubal obstruction; Patient exhibiting comorbidities, including severe organ diseases and immune dysfunction; Patient with mental disorders and coagulation dysfunction; Presence of allergic diathesis; Patients with ozone contrasis. All participants signed an informed written consent, with the study protocol approved by the Ethics Committee of Wuhan Third Hospital (Approval No. KY2022-055). Enrolled patients were investigated to assess the effects of the various treatment methods. Patients were categorized into 3 groups: group A consisted of patients who underwent interventional FTRO alone; group B comprised patients who underwent interventional FTRO combined with S miltiorrhiza injection into the fallopian tube cavity; group C was composed of patients who underwent interventional FTRO combined with the administration of S miltiorrhiza injection into the fallopian tube cavity, and prescription of Qilin pill postoperatively. The interventional FTRO procedure applied for group A is as depicted in Figure 1 . The patient was lithotomically positioned on the Digital Subtraction Angiography examination table. Pelvic radiographic imaging was conducted using fluoroscopic guidance. The required materials, including surgical drapes, instruments, and consumables, were prepared in advance. The medical ozone generator was calibrated to a concentration of 30 μg/mL. The vulva region was sterilized under aseptic conditions, and an absorbent surgical towel was positioned to absorb excess fluids. The surgical operator wore sterilized gloves and assessed the condition of the cervix using used a vaginal speculum. A disposable water catheter was subsequently inserted into the cervical orifice up to a depth of approximately 3 to7 cm. The catheter balloon was inflated and carefully adjusted to maintain its position. It was then deflated, followed by gradual injection of 10 mL of contrast agent through the catheter, ensuring its proper positioning. Upon filling of the uterine cavity with the contrast agent, a radiographic image was obtained to serve as the reference. Hysterosalpingography showed bilateral tubal interstitial blockage, with absence of contrast agent at the distal end (Fig. 1 A). The fallopian tube recanalization kit was then assembled, followed by the insertion of an 8F catheter into the uterine cavity and a 6F catheter into the uterine horn. Additionally, a 3F microcatheter was inserted into the fallopian tube opening. Subsequently, the contrast agent was injected under controlled pressure to facilitate radiographic visualization. In cases where the fallopian tube was not visualized or only partially opacified, a 0.018-inch microguide wire was introduced through the fallopian tube catheter and advanced along the lumen toward the site of obstruction. The guide wire was then gently manipulated with minimal amplitude to traverse and dislodge the occlusion. Upon a decrease in the resistance of the guide wire decreases or the sensation of a shortened pathway, the guide wire was withdrawn. Following this, a small volume of contrast agent and medical ozone was reinjected into the tubal lumen to assess tubal patency and confirm re-opacification. Successful recanalization of the right and left fallopian tubes via interventional FTRO was confirmed radiographically, with imaging demonstrating the opening of the fimbrial end and subsequent dispersion of contrast medium into the pelvic cavity (Fig. 1 B, C, respectively). In group B, following the interventional FTRO procedure, S miltiorrhiza injection (10 mL/ampoule; Shenwei Pharmaceutical Group Co., Ltd., GYZZ Z32021076) was administered into the fallopian tube cavity. In Group C, patients underwent the same interventional FTRO, followed by intra-tubal administration of S miltiorrhiza injection, and oral administration of Qilin pill (6 g/capsule; Guangdong Tai’antang Pharmaceutical Co., Ltd., GYZZ Z10930034). The Qilin pill was prescribed at a dosage of 6 g/dose, administered twice daily, for a total duration of 3 menstrual cycles. The study protocols were approved by the Clinical Research Ethics Committee. FTRO treatment of tubal obstructive infertility. (A) Bilateral blockage of fallopian tubes; (B) FTRO treatment of right fallopian tube; and (C) FTRO treatment of left fallopian tube). FTRO = fallopian tube recanalization using ozone. Blood samples were collected to assess the levels of fallopian tube obstruction-related hormones. Following the treatments, the patency rate of the fallopian tubes, pregnancy rate, and recurrence rate of fallopian tube obstruction were determined. Additionally, the occurrence of complications following treatment was examined. Outpatient follow-up was conducted for 1 year, with the incidence of recurrence and adverse reactions recorded across the 3 groups at 6-month and 1-year intervals. Hysterosalpingography was used to precisely diagnose tubal adhesion following interventional FTRO. All data processing and analyses were conducted using Statistical Package for the Social Sciences (SPSS) (version 20.0). Continuous variables were expressed as mean ± standard deviation ( x ¯ ± s ), with comparisons between 2 groups performed using and t -test. Categorical variables were expressed as a frequency (%; n [%]), with chi-square, χ 2 , used to compare groups. A P -value of <.05 was considered statistically significant.

All the baseline characteristics – including age, body mass index, obstruction site, and fertility history – among the 3 groups were comparable ( P  > .05; Table 1 ). Demographic characteristics of the patients. The results indicated no statistically significant differences in luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradial (E2), T, and LH/FSH levels before treatment ( P  > .05). However, after treatment, the LH, E2, and LH/FSH levels across the 3 groups of patients were significantly different from those before treatment ( P  < .05). The FSH and T levels of patients in group C were statistically significant following treatment compared to those in pretreatment ( P  < .05), and the differences in hormone levels across the 3 groups were statistically significant ( P  < .05). The levels of LH, FSH, T, and LH/FSH in Group C were significantly lower compared to those in group A. Conversely, the level of E2 in group C was significantly higher compared to that in group A, as shown in Table 2 . Comparison of sex hormone levels between groups of patients (n, %). E2 = estradial, FSH = follicle-stimulating hormone, LH = luteinizing hormone, LH/FSH = luteinizing hormone/follicle-stimulating hormone, T = testosterone. P < .01. Comparison to A group, P < .05. Comparison to pretreatment, P < .05. After treatment, the tubal patency, pregnancy, and recurrent occlusion rates of patients in group C were the highest compared to the other groups ( P  < .05; Table 3 ). Tubal patency rate, pregnancy rate, recurrent occlusion rate (n, %). P  < .01. Comparison to A group, P  < .05. Following treatment, Group C exhibited the lowest incidence of complications ( P  < .05; Table 4 ). Postoperative complication rate (n, %). P  < .01. P  < .05. Comparison to A group, P  < .05.

Research has shown that FTOI is a prevalent form of infertility among women, accounting for a significant proportion of all infertility cases. Conventionally, surgical intervention is the common treatment modality for FTOI. Notably, surgical intervention focuses on restoring the patency of occluded fallopian tubes. However, this approach is characterized by a high incidence of postoperative readhesion, which poses a challenge to patient prognosis and increases the risk of infertility. Therefore, alternative intervention techniques are necessary to minimize postoperative readhesions and improve patient outcomes in the management of FTOI. In this study, we evaluated the effect of an integrated approach involving FTRO combined with S miltiorrhiza injection and administration of Qilin pill on tubal obstructive infertility. Our results demonstrate that this approach is therapeutically efficacious, underscoring its potential value and applicability in clinical practice. Fallopian tube obstruction is a common etiological factor for infertility among women of reproductive age. [ 31 ] Notably, this obstruction is attributable to various factors, with pelvic and vaginal inflammatory reactions being the most prevalent. Unregulated inflammatory response gradually disrupts the functional integrity of the fallopian tubes, specifically, it contributes to mucosal edema, vascular congestion, cellulose exudation, and fibrous adhesion. [ 32 ] These pathological alterations result in the occlusion of the fallopian tubes and subsequent infertility. However, tubal obstructions can be attributed to other factors including unprotected sexual practices, intercourse during menstruation, prolonged vaginal bleeding, abdominal surgery, and prolonged periods of sitting. [ 33 ] Fallopian tube recanalization is a therapeutically efficacious approach for resolving the fallopian tube obstruction, particularly for isthmic or interstitial obstructions. [ 34 ] This minimally invasive operation offers advantages such as minimal tissue damage, a favorable safety profile, and rapid postoperative recovery, making it a widely used alternative to traditional laparotomy. Notably, when this approach is integrated with ozone, FTRO demonstrates excellent efficacy due to the nontoxic, harmless properties of ozone. Ozone promotes the overexpression of antioxidant enzymes due to its potent oxidative ability, thereby inhibiting the release of inflammatory factors. Inhibition of the inflammatory response improves local edema and tissue hypoxia, thereby enhancing local circulation. Essentially, FTRO facilitates the repair of fallopian tube injuries and reduces the risk of recurrent obstructions. [ 35 ] Ozone has been extensively employed in the treatment of gynecological infectious diseases. It is tissue-friendly and can regulate the pH of the female genital cavity without disrupting the natural flora balance or promoting drug resistance. [ 36 ] Research findings indicate that FTRO can enhance the success rate of resolving tubal obstruction compared to conventional drug perfusion approaches. However, FTRO is limited by the common postoperative readhesion incidences that can adversely affect treatment outcomes. [ 37 ] Research has established that readhesion is etiologically attributed to the following factors: inflammatory exudation leading to re-adhesion after initial resolution; potential intraoperative injury to the fallopian tubes; and the limited duration and effectiveness of the anti-inflammatory and anti-adhesion properties associated with conventional perfusion pharmacotherapy. [ 38 ] According to TCM, tubal obstructive infertility is attributed to damp-heat stasis. The fallopian tubes are located in the pelvic cavity, subsequently, the bioavailability of the orally administered drugs at the site of the lesion is significantly reduced after undergoing liver and kidney metabolism. In contrast, TCM injections offer significant advantages. These injections can directly target the affected area, minimizing the metabolic impact on the liver and kidneys on drug bioavailability. Moreover, the administration of these injections yields rapid effects, enhances therapeutic efficacy, and mitigates inflammatory responses. [ 39 ] This study revealed that S miltiorrhiza injection offers significant therapeutic advantages. S miltiorrhiza promotes blood circulation and resolves blood stasis. Consequently, it can alleviate chronic adhesions, improve local blood circulation and supply of nutrients, and expedite the release of adherent tissues. During drug injection, the mechanical pressure exerted can facilitate the unblocking of the adherent fallopian tubes. [ 40 ] Furthermore, TCM has established that impairment in kidney function is an underlying factor contributing to infertility. In cases of kidney dysfunction, Tiangui and Chongren become imbalanced, resulting in insufficient vital energy (qi) and blood biochemistry, a deficiency of kidney-yang, and the inability to adequately warm and nourish the uterus. [ 41 ] Therefore, therapeutic strategies should emphasize promoting hematopoiesis and restoring essential physiological functions to support recovery. S miltiorrhiza injection activates blood circulation and resolves blood stasis, thereby providing calming effects and relieving pain. Notably, S miltiorrhiza is a commonly used drug clinically for the treatment of various kinds of blood stasis and poor blood circulation. It can improve the local microcirculation and tissue nutrient supply in the pelvic cavity, regulate synthetic metabolism, absorb inflammatory lesions, facilitate the mechanical separation of the tubal adhesion, reduce the incidence of reocclusion or adhesion of the fallopian tube, and promote the repair and regeneration of the tubal mucosal endothelium, improve the fertilization environment in the fallopian tube, and improve the transport of oocytes and the zygote within the tube. [ 42 ] Qilin pill is particularly relevant in this context due to its reported effects on regulating menstrual function, enhancing renal activity, replenishing vital essence, promoting hematopoiesis, and supporting overall physiological balance. Qilin pill formulation includes ingredients such as polygonum multiflorum, wolfberry fruit, raspberry fruit, and dodder seed, which provide it with the capacity to replenish qi and nourish blood, while eclipta, white peony, and mulberry are included to nourish the kidney and yin. Additionally, Epimedium and Cynomorium are traditionally used to enhance yang energy and support renal function, with reported properties that help stabilize and preserve vital essence. Astragalus , Huaishan medicine, and C pilosula contribute to the replenishing of qi and strengthening the spleen. Through the combined effects of its various components, the Qilin pill plays a significant role in regulating and enhancing physiological functioning during infertility treatment. Collectively, these findings indicate that the integrated approach involving interventional FTRO, S miltiorrhiza injection, and Qilin pill prescription yields the most favorable therapeutic outcomes for infertility patients with tubal obstruction. Despite the significant insights for the treatment of fallopian obstructive infertility, this study has several limitations. Firstly, the retrospective nature and single-center design of this study may introduce bias and limit the generalizability of the results. Consequently, further investigation involving large sample multicenter, prospective cohorts is warranted to validate our findings and establish the long-term efficacy and safety profile of this combined intervention. Secondly, it is essential to establish appropriate animal models and investigate the underlying molecular mechanisms involved. Finally, the potential liver toxicity and nephrotoxicity of S miltiorrhiza and Qilin pill warrant further investigation to establish their safety profile.

The combination of interventional FTRO, S miltiorrhiza injection, and Qilin pill shows promise in the treatment of tubal obstructive infertility. The incorporation of TCM interventions holds significant potential in improving the therapeutic outcomes of FTRO, including reducing the incidence of complications postoperatively and enhancing fertility prospects. These findings support the promotion and implementation of this combined approach in clinical practice, providing a potential therapeutic option for women with FTOI.

The authors would like to thank all the reviewers who participated in the review, as well as MJEditor ( www.mjeditor.com ) for providing English editing services during the preparation of this manuscript.