Recurrence-Free Survival after Postoperative Hormone Therapy for Catamenial Pneumothorax

Catamenial pneumothorax (CP) is a rare condition that predominantly affects women of reproductive age during the perimenstrual period, which is 72 to 96 hours before or after the onset of the menstrual cycle [ 1 ]. This condition is characterized by diaphragmatic defects and the presence of endometrial implants [ 2 ]. Treatment for CP is focused on managing the condition and preventing its recurrence [ 3 ]. Over the past decade, surgical interventions for pneumothorax have shifted toward minimally invasive thoracoscopic approaches. These procedures typically involve the excision of alveolar or endometrial nodules and the application of oxidized regenerated cellulose to achieve complete pleural coverage, which minimizes recurrence [ 4 ]. Additionally, surgeons must address diaphragmatic pores by performing diaphragmatic resection, given the distinctive presence of endometrial deposits or perforations associated with this type of pneumothorax. Postoperative hormone therapy has been repeatedly identified as an adjunctive treatment to surgery for CP [ 5 ]. Administered for 6 to 12 months postoperatively, this therapy has been considered essential for preventing recurrence. Hormone therapy induces hypogonadotropic hypogonadism and amenorrhea, allowing the ovaries to rest and suppressing the activity of ectopic endometrial tissue [ 6 ]. Additionally, these medications may help prevent pneumothorax caused by cyclic hormonal fluctuations [ 6 ]. However, the current literature reveals inconsistent results regarding the efficacy of adjunctive hormone therapy for CP, which can be attributed to the low incidence of this condition and the scarcity of available studies. Therefore, we sought to identify risk factors associated with the recurrence of CP and to explore the clinical implications of postoperative hormone treatment in patients with this condition.

From November 2009 to February 2023, 41 patients with CP at Gangnam Severance Hospital received surgical treatment and hormone therapy. Clinically, CP was suspected when chest pain or pneumothorax was detected on chest radiography, coinciding with or preceding menstruation, and when the pain or extent of the pneumothorax spontaneously subsided after menstruation. Prior to surgery, all patients with suspected menstrual pneumothorax underwent pelvic examination and ultrasonography. Postoperatively, the resected lung and diaphragm tissues were stained with hematoxylin and eosin. A diagnosis of CP was confirmed if endometrial glands and stroma were identified. If confirmation of endometrial tissue was difficult, CD10 staining was used to facilitate the process. The study protocol was approved by the institutional review board (IRB) of Severance Hospital, Yonsei University Health System (IRB approval no., 3-2022-0061; approval date: April 15, 2022). Informed consent was obtained from all individual participants included in the study. All patients underwent video-assisted thoracoscopic surgery (VATS). A 12-mm camera port was inserted through the seventh intercostal space (ICS) at the anterior axillary line, a 5-mm working port through the seventh ICS at the posterior axillary line, and a wound retractor through the ninth ICS at the posterior axillary line. When endometrial tissues were identified around the lungs, wedge resection of the lung and total pleural coverage were performed ( Fig. 1 ). Total pleural coverage involved wrapping the entire visceral pleura with sheets of oxidized regenerated cellulose mesh, reinforcing the affected pleura and helping to prevent recurrence [ 7 ]. Additionally, when diaphragmatic defects were present, diaphragm resection and plication were conducted, followed by the removal of intraperitoneal endometrial tissue. The tendon of the diaphragm was resected using 2 or 3 tri-staples from an Endo GIA endoscopic linear stapler (Medtronic, Minneapolis, MN, USA). After resection, the stapled area of the diaphragm was reinforced with deep bite sutures using V-Loc 1-0 thread (Covidien, Mansfield, MA, USA) [ 8 ]. Following surgery, a 28F chest tube was inserted. The chest tube was removed on postoperative day 2, and patients were discharged on the same day. One week after discharge, patients underwent a follow-up chest X-ray examination and had their stitches removed. Hormone therapy, primarily consisting of oral progesterone, was initiated to prevent recurrence. However, patients who experienced side effects of continuous medication, such as weight gain, depression, nausea, bruising, or discomfort, had the option to switch to monthly gonadotropin-releasing hormone (GnRH) agonist injections. Continuous variables are presented as medians with interquartile ranges. Cox proportional hazards analysis was employed to identify risk factors associated with recurrence-free survival, and survival curves were generated using the Kaplan-Meier log-rank test. Statistical analyses were performed using R ver. 4.0.4 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria). A 2-tailed p-value of less than 0.05 was considered to indicate statistical significance.

A total of 41 patients were clinically diagnosed with CP and subsequently received surgical intervention. The mean age of the patients was 38.4 years ( Table 1 ). Pneumothorax was predominantly observed on the right side (39/41, 95%). All patients underwent thoracoscopic surgery ( Table 2 ), and wedge resection was performed in 34 of the 41 patients (83%). Diaphragm resection was conducted in 39 patients (95%) and was followed by diaphragmatic reinforcement. Total pleural coverage was achieved in 28 patients (68%), while partial pleural coverage was performed in 6 (15%). Among the 41 patients, 28 (68%) underwent a comprehensive surgical approach that included wedge resection, diaphragm resection, and total pleural coverage. These patients were discharged after an average of approximately 4 days postoperatively without any complications. Notably, within the first 6 months after surgery, 29 of the 41 patients (71%) experienced no recurrence. Of these individuals without recurrence, 21 (72%) had received hormone therapy. Following surgery, 27 patients underwent postoperative hormone therapy. Among them, 9 selected oral progesterone, while 16 opted for agonist therapy. However, oral progesterone can result in complications such as weight gain, depression, nausea, and bruising. Those who exhibited these side effects or experienced discomfort with continuous medication use were transitioned to GnRH injections. The side effects of oral progesterone were depression in 3 patients, weight gain in 2, bruising in 1, and breast pain in 1. In comparison, the side effects reported from GnRH agonist injections were insomnia in 3 patients, headache in 1, amnesia in 1, and sweating in 1. The group receiving postoperative hormone therapy demonstrated a lower recurrence rate than the patients who did not receive this therapy, as indicated by Kaplan- Meier analysis ( Fig. 2 ). However, this finding did not achieve statistical significance (p=0.117), which may be attributed to the limited number of cases. Analysis of risk factors for postoperative recurrence identified diaphragm resection as a protective factor against recurrence (hazard ratio, 0.16; 95% confidence interval, 0.03–0.77; p=0.022) ( Table 3 , Fig. 3 ).

Thoracic endometriosis syndrome is a rare condition characterized by the presence of ectopic endometrial tissue within the thoracic cavity. It typically manifests as spontaneous pneumothorax, with symptoms that may include chest pain, dyspnea, and cough. A high degree of clinical suspicion and a thorough gynecological history are essential for diagnosis. Although imaging studies can be helpful, VATS is considered the gold-standard diagnostic tool. Surgical intervention, followed by at least 6 months of hormone therapy, has been shown to improve the prognosis and reduce the recurrence rate of this condition [ 9 ]. In general, recurrence represents the most common complication after surgery for CP. The general recurrence rate after VATS for spontaneous pneumothorax ranges from 10% to 20% [ 10 ], but for CP, it is markedly higher, between 20% and 40% [ 1 ]. Therefore, minimizing recurrence should be a primary focus of all post-thoracic surgical interventions. In cases of CP, endometrial tissues migrate from the abdominal cavity to the thoracic cavity through an opening in the diaphragm. Since 2021, laparoscopy has been performed for all patients with CP at our institution in collaboration with gynecological surgeons, enabling the diagnosis of pelvic endometriosis. Considering the systemic nature of CP, exclusive reliance on localized treatments, such as wedge resection similar to that used for spontaneous pneumothorax, is associated with an increased rate of recurrence. In one systematic review and meta-analysis, the recurrence rate among patients who received postoperative hormone therapy was 17.3%, compared to a 53% rate in those who did not receive such therapy [ 1 ]. Notably, this meta-analysis indicated inconsistency in the surgical approaches and hormone therapy protocols used. At our center, recurrence was observed in 6 of 27 patients (22.2%) who received hormone therapy and in 6 of 14 patients who did not. Currently, in the landscape of CP surgical treatments, growing emphasis is placed on procedures such as diaphragm resection, excision of parietal pleural endometrial tissue, and total pleural coverage. As surgical treatments continue to evolve, the role of postoperative hormone therapy is expected to become increasingly vital in reducing the recurrence rate. The analysis identified diaphragm resection as a significant factor that may influence recurrence. When CP is suspected, a thorough examination of the diaphragm during surgery is crucial. At our center, we have found that diaphragm resection, followed by muscular layer reinforcement with barbed suture, is an effective technique to minimize operative time. In cases of re-exploratory thoracoscopy due to recurrence, diaphragmatic examination revealed no abnormalities. We expect improved outcomes to be realized with continuous follow-up and hormone therapy in patients who have undergone this standardized surgical approach. Despite not achieving statistical significance regarding postoperative hormone therapy, this retrospective study holds value as the largest single-center evaluation of CP to date, including 41 patients under continuous follow-up. Furthermore, since November 2020, our center has adopted a standardized surgical approach. This includes wedge resection, diaphragm resection and plication, and total pleural coverage, complemented by postoperative hormone therapy administered by 2 specialized thoracic surgeons. With a sufficiently large sample size, we anticipate obtaining statistically significant results with the established treatment protocols at our center. CP remains a substantial challenge for clinicians. Among women of reproductive age who present with chest pain, dyspnea, or pneumothorax, the potential for diaphragmatic or thoracic endometriosis should be a key consideration. An integrated approach that includes both hormone therapy and surgery should be recognized as the optimal strategy for managing patients with thoracic endometriosis.