{"paper_id":"0008f3d8-641d-4a01-992d-94b353592fab","body_text":"The differences in the respiratory system between women and men begin in utero. As discussed elsewhere in this issue, biologic sex plays a critical role in fetal development, airway anatomy, inhalational exposures, and inhaled particle deposition of the respiratory system, thus leading to differences in risk for disease, as well as clinical manifestations, morbidity and mortality. In this article, we focus on those respiratory diseases unique to females: lymphangioleomyomatosis (LAM) and thoracic endometriosis syndrome (TES).\n\nLAM is a rare, diffuse cystic lung disease seen nearly exclusively in women (5 per million). 1 – 3  In addition to cystic destruction of the lung parenchyma, LAM can also cause axial lymphatic cystic masses called lymphangioleiomyomas (39%) and/or benign abdominal tumors called angiomyolipomas (40%–80%), typically found in the kidneys. 1 , 2 , 4 – 6  Management includes mammalian target of rapamycin (mTOR) inhibitors, which stabilize lung function and improve survival in transplant and nontransplanted patient, supportive care in the form of oxygen therapy, pulmonary rehabilitation, and/or bronchodilators, and lung transplantation for progressive and debilitating disease. 7 – 10  This review explores the epidemiology, pathophysiology, clinical presentation, current treatment recommendations, and ongoing and future studies for LAM.\nLAM can either occur secondary to tuberous sclerosis complex (TSC), an autosomal-dominant condition associated with cerebral calcifications, cognitive impairment, seizures, and hamartomatous lesions in several organs, or can occur sporadically. 1  Sporadic LAM affects roughly 5 in 1 million adults; secondary LAM occurs about one-third of women with TSC. 2 , 3 , 11  The average age at diagnosis is 35 years. 1 , 2 , 4  Sporadic LAM is rarely seen in men, but ranges from 13% to 38% in TSC-associated LAM. 4  Children are rarely affected. 2\nBoth sporadic and TSC-associated LAM are secondary to mutations in the tuberous sclerosis gene  TSC1 , which leads to functional loss of the protein product hamartin, or in  TSC2 , leading to functional loss of tuberin. 1  The mutations in TSC-associated LAM are autosomal dominant, whereas the mutations in sporadic LAM occur somatically. 12\nMutations in the hamartin/tuberin heterotrimer leads to continuous activation of the mTOR signaling pathway, resulting in continuous cell growth and proliferation of migrating abnormal smooth-muscle like cells, known as LAM cells. 1 , 13  These LAM cells lead to cystic destruction in the lung parenchyma and infiltrate lymphatic channels, lymph nodes, and the thoracic duct, resulting in lymphangioleiomyomas and chylous fluid in the pleural and peritoneal spaces. 14\nPatients on average have respiratory symptoms for 2 to 6 years and experience 2.2 pneumothoraces before a definitive LAM diagnosis. 4 , 11  Most common symptoms include progressive dyspnea with daily activities (>70%), recurrent pneumothoraces (50%), chylous pleural effusions, hemoptysis, and hypoxia requiring supplemental oxygen. 1 – 5  Rarely, patients present may also present with bleeding angiomyolipomas. 15  Angiomyolipomas are more common in TSC-LAM (95.7%) than in sporadic LAM (41.3%), whereas lymphangioleiomyomas and chylous effusions are more common in sporadic LAM (38% and 20%, respectively) than in TSC-LAM (12.8% and 13.8%, respectively). 16\nDepending on a patients’ degree of disease, pulmonary function studies may be normal or show obstruction and/or reduced diffusion capacity for carbon monoxide (DLCO). 3 , 8 , 17  The DLCO may be a more sensitive indicator of early disease because it is often abnormal before the forced expiratory volume in 1 second (FEV 1 ) decreases. 7\nThere are 3 main pillars for definite clinical LAM diagnosis, which include typical clinical history, characteristic high-resolution computed tomography (HRCT) scan findings in the chest, and 1 or more of various supporting characteristics, from laboratory, histopathology, and additional clinical manifestations. 17\nThe clinical history should include young to middle-aged women with dyspnea, pneumothorax, and/or chylothorax. 17  A patient being considered for a LAM diagnosis should not have clinical characteristics and/or manifestations that are compatible with other diffuse cystic lung diseases, such as history of significant smoking, sicca symptoms, connective tissue disease, and personal or family history of non–TSC-related facial skin lesions and/or renal tumors. 7 , 17\nFeatures on HRCT chest compatible with LAM include thin-walled, air-filled round cysts of more than 10 in number, uniform in shape, and diffusely distributed throughout the lungs. Outside of these characteristic cystic changes, the lung parenchyma is typically normal. 17 , 18  Expert radiologists have demonstrated an ability to recognize LAM on HRCT in the absence of additional clinical data. In a retrospective review of 89 patients referred to the LAM Foundation Clinics at the University of Cincinnati, expert radiologists identified LAM upon review of HRCT alone in 91% of patients with LAM and were able to exclude LAM in 98% of patients without LAM. These numbers decreased when HRCTs were reviewed by expert pulmonologists, pulmonary fellows, and general pulmonologists. The data suggest that HRCT can diagnose LAM accurately 72% to 91% of the time. 19 – 21  As a result, despite the capability of expert radiologists and appeal of noninvasive expedient diagnostic testing, the American Thoracic Society (ATS) does not recommend use of HRCT alone for LAM diagnosis. 17\nIn addition to supporting clinical history and HRCT chest, LAM diagnosis requires 1 or more of the following findings: (1) TSC diagnosis, (2) renal angiomyolipoma(s), (3) lymphangioleiomyomas, (4) a serum vascular endothelial growth factor-D (VEGF-D) of greater than or equal to 800 pg/mL, (5) chylous pleural and/or ascites effusions, (6) the presence of LAM cells and/or cell clusters on cytologic examination of effusions and/or lymph nodes, and/or (7) biopsy of lung or retroperitoneal and/or pelvic masses showing histopathologic evidence of LAM. 17\nIn the absence of TSC and pleural/ascitic fluid, serologic evaluation with VEGF-D level is commonly performed first owing to the noninvasive nature of sampling. VEGF-D is a lymphangiogenic growth factor expressed by LAM cells that forms lymphatic vessels and is involved in the spread of tumor cells to lymph nodes. 1 , 2  It is now used as a diagnostic serum biomarker because levels of 574 pg/mL or greater are associated with LAM diagnosis with a specificity of 91% and sensitivity of 86%. The current cut-off value for LAM diagnosis must be 800 pg/mL or greater. 17  If VEGF-D is unrevealing, a noncontrast CT or MRI of the abdomen/pelvis can be used to assess for renal angiomyolipomas or lymphangioleiomyomas.\nAsymptomatic patients with compatible clinical history and HRCT findings of mild cystic changes can be considered probable LAM and do not require further invasive diagnostic testing, given that a definitive LAM diagnosis will not impact management. 5  Instead, these patients are monitored with repeat pulmonary function tests every 3 to 12 months, with the frequency depending on whether there are changes concerning for disease progression. 5 , 17  Patients who become symptomatic or demonstrate disease progression on surveillance pulmonary function tests should undergo further workup to definitively confirm or exclude LAM diagnosis. 17  If abdominopelvic imaging, VEGF-D testing, and/or aspirates of chylous fluid, lymph nodes, or abdominopelvic masses are indeterminate or not applicable, then a lung biopsy should be pursued. 17  Despite a diagnostic yield of only about 50%, a transbronchial lung biopsy should be considered before -assisted thoracoscopic surgery (VATS)–guided lung biopsy because a transbronchial lung biopsy is minimally invasive with a lower complication rate and cost. 17\nSignificant progress has been made for LAM treatment in the past decade, with the US Food and Drug Administration (FDA) approving sirolimus, otherwise known as rapamycin, in 2015 as the first FDA-approved LAM therapy. 22  Sirolimus is an mTOR inhibitor, which in turn blocks activation of downstream kinases, restoring normal cellular processes, such as growth, motility, and survival in cells with TSC mutations. 2 , 7  Support for sirolimus is largely the result of the Multicenter International LAM Efficacy of Sirolimus (MILES) trial, which was a 2011 double-blinded, randomized, placebo-controlled, parallel group trial that evaluated 12 months of oral sirolimus 2 mg/d or matched placebo in adult women with LAM with an FEV 1  of 70% or less of predicted (n = 89), with an additional 12-month off-treatment observation period. 7  More patients treated with sirolimus demonstrated improvements in their FEV 1  from baseline to 12 months (46% sirolimus vs 12% in placebo group;  P <.001). 7  Furthermore, the sirolimus group had stabilization of lung function during treatment whereas the control group had continued monthly lung function decline (FEV 1  1 ± 2 mL/mo for sirolimus vs −12 ± 2 mL/mo for placebo [ P <.001]; FVC 8 ± 3 mL/mo for sirolimus vs −11 ± 3 mL/mo for placebo [ P <.001]). 7  After 12 months of treatment, participants treated with sirolimus had an average FEV 1  that was 152 mL higher than those treated with placebo ( P <.001). Twelve months after treatment was withdrawn, the decrease in FEV 1  in the sirolimus arm was similar to the placebo arm (8 ± 2 mL/mo vs 14 ± 3 mL/mo, respectively [ P  =.08]). 7\nSirolimus also significantly improved quality of life and self-reported functional performance, and significantly lowered mean VEGF-D levels at 6 and 12 months, as compared with the placebo group. 7  Adverse events during the treatment period, including mucositis, diarrhea, nausea, elevated cholesterol, acneiform rash, and lower extremity swelling, were more common in the sirolimus arm than placebo; however, serious adverse events were similar between the 2 arms. 7  Because of the outcomes of this study, the ATS/ERC issued a 1A recommendation in 2016 for sirolimus initiation in patients with LAM with an FEV 1  of less than 70% predicted. 2\nSirolimus is also recommended by the ATS/ERS for patients with LAM with chylous effusions or ascites based on a 2011 observational study in which 12 patients with LAM had chylous effusions, including pleural and/or ascitic, and were observed for 2.5 years without sirolimus and then a subsequent 2.6 years with sirolimus. 7 , 13  After a range of 131 to 410 ± 61 to 111 days of sirolimus therapy, all 12 patients had either decreases in effusion size or complete resolution. 13  Therefore, the ATS/ERS recommend that mTOR inhibitors be used before pursuing invasive therapeutic fluid drainage. 2  Taveira-DaSilva et al 13  also observed that 11 of their patients with LAM with lymphangioleiomyomas had either complete resolution or size reductions; however, the ATS/JRS do not specifically recommend mTOR inhibitor initiation for this indication. 2\nAn alternative mTOR inhibitor recommended by the ATS/JRS is everolimus, based on a 2015 phase IIA multicenter, open-label trial that enrolled 24 patients with LAM with an FEV 1  of 80% or less than predicted or an FEV 1  of less than 90% and a DLCO of less than 80%. 23  Goldberg and colleagues 23  found improvements in FEV 1  and 6-minute walk distance (mean change of 114 mL and 47 m, respectively), stabilization of FVC (mean change of 10 mL), and a decrease in serum VEGF-D levels with similar adverse events and rates to sirolimus compared with baseline after 6 months of therapy.\nThe efficacy of lower dose sirolimus (blood trough level of ≤5 ng/mL), rather than the conventional dose (5–15 ng/mL) used in the MILES trial, 7 , 24  has been evaluated in several observational studies. A Japanese retrospective, observational study of 15 patients with LAM treated with lower dose sirolimus for at least 6 months found resolution of chylous effusions in 6 of the 7 patients with effusions and significant improvement in annual change of FEV 1  and FVC in 9 of their patients without chylous effusions (FEV 1  before sirolimus, −115 ± 86 mL vs on sirolimus, 128 ± 290 mL [ P  = .015]; FVC before sirolimus, −101.0 ± 314 mL vs on sirolimus, 190 ± 246 mL [ P  = .046]). 24  This outcome is similar to the MILES trial, with the FEV 1  increasing by 19 ± 124 mL ( P <.001) and the FVC increasing by 97 ± 260 ( P  = .001) after 12 months of conventional-dose sirolimus. 7\nHowever, a 2018 South Korean 5-year retrospective study compared lung function between 20 patients with LAM treated with low-dose sirolimus with 19 patients LAM treated with conventional dose sirolimus. 25  These authors observed significant monthly rate of FEV 1  improvement in the conventionally dosed sirolimus group but no change in FEV 1  in the low-dose sirolimus group (FEV 1  on low-dose therapy: before sirolimus, −0.08 ± 0.38 vs on sirolimus, 0.19 ± 0.51 [ P  = .264]; FEV 1  on conventional dose: before sirolimus, −0.26 ± 0.54 vs on sirolimus, 0.22 ± 0.38 [ P  = .024]). 25  Adverse event rates were similar between the 2 treatment groups. 25  This more recent study, albeit small and nonrandomized, suggests that lower dose sirolimus is inferior to the conventional dose for lung function improvement. 25  A definitive randomized controlled trial, the Multicenter Interventional Lymphangioleiomyomatosis Early Disease Trial (MILED) is being conducted to determine whether lower dose sirolimus can achieve similar efficacy to conventional dosing in patients with LAM ( NCT03150914 ).\nBased on resumption of FEV 1  decline in the sirolimus arm that paralleled the control group during the withdrawal period in the MILES trial, it is thought that sirolimus suppresses LAM and does not lead to remission, suggesting that sirolimus may need to be a lifelong therapy. 7 , 26  To better understand whether long-term mTOR inhibitor therapy is safe and effective, a subanalysis of 12 patients with LAM enrolled in a 2014 observational study were followed for 5.5 ± 3.3 years before sirolimus initiation and then followed for an additional 4.6 ± 1.8 years while on sirolimus. 15  Yao and colleagues 15  found significant yearly FEV 1  decrease over a 5-year period while patients were on sirolimus, compared with no therapy (FEV 1 , 0.3 ± 0.4 on sirolimus vs FEV 1 , −1.4 ± 0.2 before therapy initiation [ P  = .025]). The adverse effects of sirolimus therapy were similar to those reported by McCormack and colleagues 7  and Taveira-DaSilva et al, 13 , 15  and thought to be manageable.\nDoxycycline and hormonal therapies have been explored in the past, but are not recommended for LAM. 2  Patients with LAM have increased levels of matrix metalloproteinases 2 and 9, which are proteolytic enzymes that degrade the extracellular matrix and are thought to induce lung cyst formation because they are particularly positioned near these cysts. Therefore, it was hypothesized that doxycycline, which is a tetracycline antibiotic that inhibits matrix metalloproteinase production and activity, may decrease lung parenchymal destruction in LAM. 27  However, a 2-year randomized placebo-controlled trial comparing 12 patients receiving doxycycline with 11 patients receiving placebo found no significant difference in mean FEV 1  (FEV 1  of −123 ± 246 mL/y in doxycycline vs FEV 1  of −90 ± 154 mL/y in placebo [ P  = .35]), FVC, DLCO, and quality of life. 27\nThere are no randomized controlled trials evaluating hormonal therapies. However, there have been numerous case reports, case series, and observational trials studying serum estrogen response modulators, progesterone, gonadotropin-releasing hormone (GnRH) agonists, combination hormonal therapy, and oophorectomy because, anecdotally, LAM tends to worsen during pregnancy, menstruation, and after exposure to estrogen-containing drugs, but stabilize in the post-menopausal period. 2  Based on the existing data, hormonal therapy is not recommended for patients with LAM. 2\nBronchodilators are recommended for patients with LAM with reversible obstruction on pulmonary function tests. 5 , 8  Furthermore, patients should be prescribed supplemental oxygen if they have evidence of resting and/or exertional desaturations. 8  Pulmonary rehabilitation is an important program for patients with LAM to participate in, particularly because their most common cause of death is respiratory failure. 11  Pulmonary rehabilitation in patients with LAM is associated with significant improvements in dyspnea, exercise capacity, muscle strength, and quality of life and should be considered in patients once demonstrating diminished physical activity. 9\nGiven that angiomyolipomas can lead to spontaneous hemorrhage, patients with known angiomyolipoma are generally periodically monitored with CT scans or MRI and considered for treatment if angiomyolipoma size is 4 cm or greater. 5  Treatment with embolization or nephron-sparing surgery is generally considered.\nSpontaneous pneumothorax is a common initial presentation of LAM. A pooled analysis of case series and observational studies by the ATS/JRS in 2017 found a 57% pneumothorax rate in patients with LAM, with recurrence rate ranging from 29% to 81%, and the recurrence rate per patient ranged from 3.2% to 5.0%. 17  The recurrence rate was decreased from about 65% for patients managed conservatively to 18% to 32% for patients managed with pleurodesis after initial pneumothorax. 17  Owing to this high risk for recurrence and the risk reduction with pleurodesis, ipsilateral pleurodesis after first pneumothorax is recommended for the management of pneumothorax in LAM. 17  Pleurodesis, as well as pleurectomy, are not contraindications to lung transplantation. 9\nPatients with an FEV 1  of 30% or less, a New York Heart Association functional class of III or IV with resting hypoxemia, or severe exercise capacity impairment should be referred for lung transplant evaluation. 5 , 28  A recent review of 138 patients with LAM who underwent lung transplant in the United States between 2003 and 2017 reported a 12-year median survival after lung transplantation and 1-, 5-, and 10-year survival rates at 94%, 73%, and 56%, respectively. 28  Although 81% of the patients underwent bilateral lung transplantation, there was no significant difference in the survival rate for single compared with bilateral transplantation. 28  In a retrospective cohort study of 410 patients with LAM with 10.4-year median observation time, independent predictors of decreased time to death or transplant were younger age at diagnosis, supplemental oxygen use, and increased weight loss. 11\nThe most frequent causes of death within 1 year after transplantation were infection and graft failure (43%) and after 1 year after transplantation was bronchiolitis obliterans syndrome (27.2%), which are similar complications and complication rates compared with the general lung transplant population. 28\nThe recurrence rate of LAM after transplantation is not well-studied, but thought to be rare. 5 , 10  In a 2019 retrospective analysis of 183 patients with LAM who underwent lung transplantation in the United States from 2003 to 2017, recurrent LAM occurred in 1 patient (0.72%). 28  The European Respiratory Society recommends against post-transplant LAM recurrence surveillance with biopsy owing to its low recurrence rate. 5\nObservational and registry data suggest the annual decrease in FEV 1  in untreated patients with LAM ranges from roughly 40 to 120 mL/y. 29 – 32  In randomized studies of doxycycline and sirolimus, the placebo groups experienced decline in the 90 to 134 mL/y range. The National Heart, Lung, and Blood Institute LAM registry reports an annual rate of decline of 89 mL/y. 33  Although early studies suggested the median survival was between 8 and 10 years from diagnosis, more recent data suggest that survival is likely longer. In the National Heart, Lung, and Blood Institute longitudinal LAM registry, the estimated 5-, 10-, 15- and 20-year transplant-free survival rates were 95%, 85%, 75%, and 64%, respectively. 33\nSignificant progress has been made in the treatment of LAM over the past decade since the introduction of mTOR inhibitors. However, more data are still needed on the long-term impact of mTOR inhibitor therapy. The Multicenter International Durability and Safety of Sirolimus in LAM (MIDAS) trial is a longitudinal observational registry currently being conducted with the goal to enroll 600 patients with LAM who are either currently on or previously took mTOR inhibitors (either sirolimus or everolimus). 26  Enrolled patients are being observed for a 2-year period with particular attention focused on lung function test results and adverse events. 26  A recent study examining Reservatrol and Sirolimus in Lymphangioleiomyomatosis (RESULT) recently completed enrolling, but results are still pending ( NCT03253913 ).\nImmunotherapy in LAM represents a novel therapeutic approach that is under investigation. Human lung tissue from patients with LAM have increased expression of programmed death-ligand 1, which is a protein that leads to immune cell inactivation and thus can cause tumor proliferation. 34  Using murine models of LAM, in vivo treatment with anti–programmed death 1 antibody showed significant survival benefit with about 70% of anti–programmed death 1 treated mice surviving compared with about 30% of control iso-type antibody mice surviving at day 55 ( P <.0001). 34  Although no in vivo studies with immune checkpoint inhibitors have yet to be conducted on patients with LAM, these promising murine data suggest a future role for immunotherapy in LAM management.\nAlthough a rare disease, significant research attention to LAM has led to improved prognosis and survival over the past decade, and the future for LAM management remains promising with the many active registries and studies devoted to better understanding the natural history of LAM, doses, and durations of mTOR inhibitors, as well as the role of novel immunotherapy.\n\nEndometriosis is defined by the presence of endometrial-like tissue outside the uterine cavity. 35  It is estimated to involve 5% to 10% of women in their reproductive age 36 ; however, it is reported to be underdiagnosed. 37  It most commonly involves the pelvic peritoneum, ovaries, and rectovaginal septum. 38  TES is a collection of clinical diseases related to ectopic endometrial tissue in the thoracic cavity; it includes catamenial hemothorax, catamenial pneumothorax, catamenial hemoptysis, and endometriotic lung nodules. Catamenial pneumothorax is the most common presentation of TES. 39  The peak incidence of TES is believed to be 5 years after the peak incidence of pelvic endometriosis. 40 , 41\nThe pathogenesis of TES remains poorly understood. TES likely has a multifactorial etiology, because none of the theories can solely explain all of the clinical manifestations of the disease. 40  Sampson’s theory of retrograde menstruation is the most accepted theory to explain TES, and is further validated because TES was found to be 9 times more likely to occur on the right than on the left hemidiaphragm. 42  It presumes that endometrial cells travel retrograde through the fallopian tubes and into the peritoneal cavity where an impaired clearance mechanism at the peritoneal level allows the survival, implantation, and proliferation of the endometrial tissue on peritoneal surfaces. 42  The peritoneal fluid containing the endometrial cells is presumed to follow a distinct pattern of movement within the peritoneal cavity. The falciform and phrenicocolic ligaments impose an obstruction of flow through the left hemidiaphragm, which results in a preferential flow of the cells from the pelvis through the right paracolic gutter via the right hemidiaphragm. 42  Once reaching the right subdiaphragmatic area, endometrial cells implant on the diaphragmatic surface or undergo transperitoneal–transdiaphragmatic migration to the pleural cavity where it may colonize the diaphragm or the pleural space. This migration is made possible through congenital diaphragmatic defects or acquired defects of the diaphragm called fenestrations. 42\nAnother theory for the pathogenesis of TES hypothesizes that estrogen and other physiologic stimuli results in metaplasia of mesothelial cells into endometrial tissue. 43  This theory does not explain bronchopulmonary TES. Benign metastasis is another theory that might explain bronchopulmonary TES and is based on hematogenous or lymphatic dissemination of the endometrial tissue. 44 , 45\nTES has a wide range of presentations, from being asymptomatic to life-threatening hemoptysis. Catamenial pneumothorax is the most common presentation of TES. In a retrospective series of 112 patients, Joseph and colleagues 41  reported that 73% of the cases presented with catamenial pneumothorax, whereas 14% presented with hemothorax, 7% with hemoptysis, and 6% with lung nodules. The timing of these presentations is related to the onset of menses; it occurs between 24 hours before and 72 hours after the onset of menses, but not every menstrual cycle coincides with symptoms. 39 , 46  A patient’s clinical presentation depends on the anatomic location of the disease; pleural disease can result in catamenial pneumothorax or hemothorax, and both can present with pleuritic chest pain, cough, and shortness of breath. In contrast, parenchymal disease can present with hemoptysis and lung nodules. The majority of these clinical manifestations are right sided, but left-sided and bilateral disease have been reported in the literature. 47 – 50  The temporal relationship with menses is what differentiates TES from other etiologies that presents in similar clinical manifestations. Other less common presentations have been proposed to be included under the umbrella of TES; Bobbio and colleagues 51  reported that catamenial chest pain, endometriosis-related diaphragmatic hernia, and endometriosis-related pleural effusion can be added to the classical manifestations of TES.\nThe diagnosis of TES is often challenging. Noninvasive imaging modalities including chest radiograph, CT scan, and MRI offer nonspecific findings that can be useful for the diagnosis of TES, only when based on high clinical suspicious. 47 , 52 , 53  Invasive modalities including VATS and laparoscopy offer a superior assessment of the disease. 40 , 54\nA chest radiograph is the best initial imaging modality for most thoracic pathology. In TES, the chest radiograph can be normal, but common findings include pneumothorax, pleural effusion, pneumomediastinum, and, to a lesser extent, lung nodules. 47  In addition to the findings detected by a chest radiograph, a chest CT can detect ground glass opacities, parenchymal thin-walled cavities, and bullous formation. 52 , 55  MRI is beneficial for detecting diaphragmatic disease with a sensitivity of up to 83%. 56\nBronchoscopy is mainly helpful in bronchopulmonary disease, and has the highest detection rate when performed at the time of menses. Bronchoscopic findings vary from normal airway appearance to the detection of red submucosal patches and white cystic lesions. 47 , 57 , 58  The yield of bronchoscopic biopsies and cytologic washing vary and is also related to the timing of menses. Brush cytology has a higher detection rate of ectopic endometrial cells than bronchoscopic biopsies. 59\nVATS is considered the gold standard modality for the diagnosis of TES, whereas laparoscopy is preferred for the diagnosis of diaphragmatic disease in TES. 39 , 40  VATS offers a superior visual detection and assessment of the lesions and is preferred over open thoracotomy because of lower rate of postoperative complications. 60 – 62\nTES is a complex disease that require a multidisciplinary approach. Medical management is considered the initial therapy in TES and is similar to pelvic endometriosis. 40 , 47  It is based on the inhibition of endometrial tissue growth in the thorax. Different types of agents are available; the most common are the GnRH agonists. 40 , 63  Physiologically, GnRH binds to its receptors in the pituitary, which results in the release of gonadotropins; subsequently, estrogen release and endometrial tissue growth. 64  The long-term use of the long-acting GnRH agonists results in downregulating the GnRH receptors and pituitary desensitization, which results in a decreased production of estrogen and the inhibition of pelvic and ectopic endometrial tissue growth. 65  Three GnRH agonists are approved for endometriosis in the United States, namely, leuprolide, goserelin, and nafarelin. Treatment with GnRH agonists results in a hypoestrogen state and menopausal-like symptoms, including hot flashes, vaginal atrophy, decreased libido, osteoporosis, and, most important, infertility. 65  GnRH antagonists, the oral contraceptive danazol, and aromatase inhibitors are additional therapeutic options that have a similar efficacy to long-acting GnRH agonists. 40 , 65  Infertility, high cost, patient preference, and disease recurrence after stopping the medications are the limiting factors to medical therapy in TES.\nSurgical management is indicated in recurrent disease, failed medical management, and intolerance to medical therapy. A VATS procedure is considered the gold standard treatment modality of TES. 66 – 68  Superficial thoracic endometrial disease can be excised using different types of laser therapy, 40 , 69  whereas deep parenchymal nodules might require subsegmentectomy or lobectomy. 70 , 71  To prevent recurrence, concomitant medical therapy for 6 to 12 months after surgical treatment is recommended. 39  Pleurodesis is an alternative procedure for catamenial pneumothorax. 40  Bricelj and colleagues 39  reported that pleurodesis is the most common procedure performed for the treatment of catamenial pneumothorax. It can be performed using mechanical pleural abrasion with gauze, or chemically using talc, or tetracyclines derivates. 72  In cases were diaphragmatic endometrial lesions present, a VATS procedure combined with laparoscopy can be performed. 73  laparoscopy allows the visualization of the diaphragm, resection of the lesions, and repairing the diaphragm. Diaphragmatic repair can be done using endoscopic stapler for small defects, or synthetic mesh for larger lesions. 54 ,67\n\nLung diseases specific to women are rare, complex diseases. There have been significant achievements in the understanding and treatment of LAM since its first introduction to the medical literature in 1937. 74  Diagnosis is no longer as invasive as in the past, with lung biopsies only indicated if noninvasive means, including serum VEGF-D levels, are nondiagnostic. The discovery of mTOR inhibitors and their use in LAM was a monumental achievement for the LAM community because it was the first ever FDA-approved therapy for this condition. TES is a poorly understood disease that requires a high clinical suspicion of temporal relationship of symptoms with menses. Diagnosis is difficult and invasive modalities like VATS are often required for diagnosis and treatment. Medical management is widely available, but has limitations owing to cost and side effects.","source_license":"public-domain-us","license_restricted":false}