Peritoneal fluid progesterone and progesterone resistance in superficial endometriosis lesions.

Peritoneal fluid in ovulatory women is an ovarian exudate with higher estrogen and progesterone concentrations than in plasma. In the follicular phase, progesterone concentrations are as high as plasma concentrations in the luteal phase. After ovulation, estrogen and progesterone concentrations in the peritoneal fluid are 5-10 times higher than in plasma, both in women with and without endometriosis. The histologically proliferative aspect without secretory changes of most superficial subtle lesions is not compatible with the progesterone concentrations in the peritoneal fluid. Therefore, we have to postulate a strong progesterone resistance in these lesions. The mechanism is unclear and might be a peritoneal fluid effect in women with predisposing defects in the endometrium, or isolated endometrial glands with progesterone resistance, or subtle lesions originating from the basal endometrium: the latter hypothesis is attractive since in basal endometrium progesterone does not induce secretory changes while progesterone withdrawal, not occurring in peritoneal fluid, is required to resume mitotic activity and proliferation. Hormone concentrations in the peritoneal fluid are an important factor in understanding the medical therapy of endometriosis. The effect of oestro-progestin therapy on superficial endometriosis lesions seems to be a consequence of the decreased estrogen concentrations rather than a direct progestin effect. In conclusion, the peritoneal fluid, being a secretion product of the ovarian follicule, deserves more attention in the pathophysiology and treatment of endometriosis.

From laparotomy to laparoscopy to in vitro fertilization.

Before the modern era of in vitro fertilization, reproductive surgery to deal with pelvic disease was the key intervention in the management of infertility. A series of clinical observations and animal experiments led to the development of microsurgical principles, which were applicable to all forms of gynecologic surgery. The evolution of endoscopy permitted minimally invasive approaches to most pelvic pathology. Assisted reproductive techniques now have primacy in the management of infertility, but women deserve to have fertility-enhancing or fertility-sparing surgery performed by a surgeon with relevant training. Thus, we have an obligation to maintain formal training programs in reproductive surgery.

A Novel Treatment for Cervical and Cesarean Section Scar Pregnancies by Transvaginal Injection of Absolute Ethanol to Trophoblasts: Efficacy in 19 Cases.

STUDY OBJECTIVE: To evaluate the efficacy of a nonsurgical treatment for cervical pregnancy (CP) and cesarean section scar pregnancy (CSP). DESIGN: Retrospective clinical study (Canadian Task Force classification III). SETTING: Private assisted reproductive technology practice. PATIENTS: Nineteen women with CP (n = 16) or CSP (n = 3), including 6 patients with positive fetal heartbeat. INTERVENTION: Transvaginal local injection of absolute ethanol (AE) into the hyperechoic ring (lacunar space) around the gestational sac under ultrasound guidance. MEASUREMENTS AND MAIN RESULTS: Serum beta-human chorionic gonadotropin (ß-hCG) was measured at frequent intervals, and ultrasound and/or magnetic resonance imaging was used to observe the gestational sac. In 9 patients, the serum ß-hCG level was effectively reduced with a single AE injection at 2 hours. In the remaining 10 patients, the level decreased but then increased in 4 and slowly decreased in the other 6; all of these 10 patients required 2 to 5 repeat AE injections. In all patients, serum ß-hCG level was reduced by 50% within 3 days and decreased to <10% of the initial level within 14 days. In 18 patients (95%), the level was decreased to 1.0 mIU/mL within 40 days. Seven patients were treated on an outpatient basis. Twelve patients received no anesthesia. Five patients subsequently became pregnant, and each had a live birth. There was no recurrent CP or CSP. The procedure was successful in all 19 patients. CONCLUSION: This procedure is an effective treatment for CP or CSP that could be used in place of conventional surgical interventions and medical treatment using MTX.

Uterus preservation is superior to hysterectomy when performing laparoscopic lateral suspension with mesh.

INTRODUCTION AND HYPOTHESIS: We aimed to compare differences between laparoscopic lateral suspension with mesh (LLS) performed with supracervical hysterectomy (LLSHE) and without hysterectomy (LLSUP). METHODS: We retrospectively collected data from women operated by a single surgeon between 2003 and 2011. From a total of 339 women with symptomatic anterior and/or apical pelvic organ prolapse (POP) and an intact uterus, 224 had LLSUP (70.4%) and 94 had LLSHE (29.6%). Three hundred and sixteen patients were examined at 1 year. Primary outcomes were objective and subjective success at 1 year during clinical evaluation. Secondary outcomes were complications (Clavien-Dindo scale) and mesh exposure. Patient satisfaction was evaluated by telephone interview using a 10-point scale and the Patient Global Impression of Improvement Scale (PGI-I). RESULTS: LLSUP and LLSHE did not differ for age (mean 57 and 55 years, respectively), preoperative status, complications, and participation at the interview (52 vs 53%). LLSHE is associated with higher mesh exposure (6.5 vs 1.3%, p = 0.014) and more frequent use of Mersilene. Titanium-coated and noncoated polypropylene was more frequently used in LLSUP. At 1 year, both anatomic success rate for the anterior compartment (98.7 vs 94.6%, p = 0.021) and subjective success rate (83.5 vs 72.8%, p = 0.035) were higher for LLSUP. Without hysterectomy, patients more often improved (90.5 vs 76.5%, p = 0.013) and would more frequently recommend the procedure (94.5 vs 80.4%, p = 0.004). CONCLUSIONS: LLS with or without hysterectomy is a safe technique with high patient satisfaction. The uterus-preserving approach appears to result in better anatomic outcome for the anterior compartment, better subjective outcome, and higher patient satisfaction.

Pathogenesis of endometriosis: the genetic/epigenetic theory.

OBJECTIVE: To study the pathophysiology of endometriosis. DESIGN: Overview of observations on endometriosis. SETTING: Not applicable. PATIENT(S): None. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): The hypothesis is compatible with all observations. RESULT(S): Endometriosis, endometrium-like tissue outside the uterus, has a variable macroscopic appearance and a poorly understood natural history. It is a hereditary and heterogeneous disease with many biochemical changes in the lesions, which are clonal in origin. It is associated with pain, infertility, adenomyosis, and changes in the junctional zone, placentation, immunology, plasma, peritoneal fluid, and chronic inflammation of the peritoneal cavity. The Sampson hypothesis of implanted endometrial cells following retrograde menstruation, angiogenic spread, lymphogenic spread, or the metaplasia theory cannot explain all observations if metaplasia is defined as cells with reversible changes and an abnormal behavior/morphology due to the abnormal environment. We propose a polygenetic/polyepigenetic mechanism. The set of genetic and epigenetic incidents transmitted at birth could explain the hereditary aspects, the predisposition, and the endometriosis-associated changes in the endometrium, immunology, and placentation. To develop typical, cystic ovarian or deep endometriosis lesions, a variable series of additional transmissible genetic and epigenetic incidents are required to occur in a cell which may vary from endometrial to stem cells. Subtle lesions are viewed as endometrium in a different environment until additional incidents occur. Typical cystic ovarian or deep endometriosis lesions are heterogeneous and represent three different diseases. CONCLUSION(S): The genetic epigenetic theory is compatible with all observations on endometriosis. Implications for treatment and prevention are discussed.

N2O strongly prevents adhesion formation and postoperative pain in open surgery through a drug-like effect.

BACKGROUND: Microsurgical tenets and peritoneal conditioning during laparoscopic surgery (LS) decrease postoperative adhesions and pain. For a trial in human, the strong beneficial effects of N2O needed to be confirmed in open surgery (OS). RESULTS: In a mouse model for OS, the effect of the gas environment upon adhesions was evaluated. Experiment I evaluated desiccation and the duration of exposure to CO2, N2O or CO2 + 4%O2. Experiment II evaluated the dose-response curve of adding N2O to CO2. Experiment III compared humidified CO2 + 10% N2O during LS and OS.In OS, 30- and 60-min exposure to non-humidified CO2 caused mortality of 33 and 100%, respectively. Mortality was prevented by humidification, by dry N2O or dry CO2 + 4%O2. Adhesions increased with the duration of exposure to CO2 (p < 0.0001) and decreased slightly by humidification or by the addition of 4% O2. N2O strongly decreased adhesions at concentrations of 5% or greater. With humidified CO2 + 10% N2O, adhesion formation was similar in OS and LS. CONCLUSIONS: The drug-like and strong beneficial effect of low concentrations of N2O is confirmed in OS.

Microsurgical principles and postoperative adhesions: lessons from the past.

"Microsurgery" is a set of principles developed to improve fertility surgery outcomes. These principles were developed progressively based on common sense and available evidence, under control of clinical feedback obtained with the use of second-look laparoscopy. Fertility outcome was the end point; significant improvement in fertility rates validated the concept clinically. Postoperative adhesion formation being a major cause of failure in fertility surgery, the concept of microsurgery predominantly addresses prevention of postoperative adhesions. In this concept, magnification with a microscope or laparoscope plays a minor role as technical facilitator. Not surprisingly, the principles to prevent adhesion formation are strikingly similar to our actual understanding: gentle tissue handling, avoiding desiccation, irrigation at room temperature, shielding abdominal contents from ambient air, meticulous hemostasis and lavage, avoiding foreign body contamination and infection, administration of dexamethasone postoperatively, and even the concept of keeping denuded areas separated by temporary adnexal or ovarian suspension. The actual concepts of peritoneal conditioning during surgery and use of dexamethasone and a barrier at the end of surgery thus confirm without exception the tenets of microsurgery. Although recent research helped to clarify the pathophysiology of adhesion formation, refined its prevention and the relative importance of each factor, the clinical end point of improvement of fertility rates remains demonstrated for only the microsurgical tenets as a whole. In conclusion, the principles of microsurgery remain fully valid as the cornerstones of reproductive microsurgery, whether performed by means of open access or laparoscopy.

Role of the peritoneal cavity in the prevention of postoperative adhesions, pain, and fatigue.

A surgical trauma results within minutes in exudation, platelets, and fibrin deposition. Within hours, the denuded area is covered by tissue repair cells/macrophages, starting a cascade of events. Epithelial repair starts on day 1 and is terminated by day 3. If repair is delayed by decreased fibrinolysis, local inflammation, or factors in peritoneal fluid, fibroblast growth starting on day 3 and angiogenesis starting on day 5 results in adhesion formation. For adhesion formation, quantitatively more important are factors released into the peritoneal fluid after retraction of the fragile mesothelial cells and acute inflammation of the entire peritoneal cavity. This is caused by mechanical trauma, hypoxia (e.g., CO2 pneumoperitoneum), reactive oxygen species (ROS; e.g., open surgery), desiccation, or presence of blood, and this is more severe at higher temperatures. The inflammation at trauma sites is delayed by necrotic tissue, resorbable sutures, vascularization damage, and oxidative stress. Prevention of adhesion formation therefore consists of the prevention of acute inflammation in the peritoneal cavity by means of gentle tissue handling, the addition of more than 5% N2O to the CO2 pneumoperitoneum, cooling the abdomen to 30°C, prevention of desiccation, a short duration of surgery, and, at the end of surgery, meticulous hemostasis, thorough lavage, application of a barrier to injury sites, and administration of dexamethasone. With this combined therapy, nearly adhesion-free surgery can be performed today. Conditioning alone results in some 85% adhesion prevention, barriers alone in 40%-50%.

Introduction: Quality of pelvic surgery and postoperative adhesions.

The health care and the emotional cost of postoperative adhesions that frequently cause chronic pain, infertility, bowel obstruction, and repeat surgery are well known. Our understanding of the pathophysiology of adhesion formation and of its prevention has evolved from good surgical practice based on microsurgical principles, barriers to keep denuded areas separated to the prevention of mesothelial cell damage and of acute inflammation in the entire peritoneal cavity. Oxidative stress, in the surgical lesions and in the peritoneal cavity has an important role in adhesion formation by slowing down repair. This has resulted in virtually adhesion-free surgery, in addition with less CO2 resorption, less postoperative pain, and a faster recovery. The clinical efficacy had been demonstrated by higher pregnancy rates (PRs) using microsurgical tenets.

The place of reconstructive tubal surgery in the era of assisted reproductive techniques.

Assisted reproductive techniques yield high rates of success for women with tubal factor infertility. Because they are potentially effective for all categories of infertility, for two decades, clinical and basic research in infertility has been focused on IVF techniques and outcomes, rather than developing surgical techniques or training infertility subspecialists in tubal microsurgery. Nonetheless, in comparison with IVF, reconstructive tubal surgery is inexpensive and offers multiple opportunities to attempt conception. Performing laparoscopic salpingostomy prior to IVF in women with good prognosis tubal disease may improve the outcome of subsequent IVF, while offering the potential for spontaneous conception. Tubo-tubal anastomosis for reversal of tubal ligation, performed either by a microsurgical technique through a mini-laparotomy or by laparoscopy, is preferable to IVF in younger women with no other fertility factors, because it offers potentially higher cumulative pregnancy rates. Surgery is the only alternative for women with tubal factor infertility who for personal or other reasons are unable to undergo assisted reproductive techniques. Tubal reconstructive surgery and assisted reproductive techniques must be considered complementary forms of treatment for women with tubal factor infertility, and training in tubal reconstructive surgery should be an integral part of subspecialty training in reproductive endocrinology and infertility.

The effectiveness of hysteroscopy in improving pregnancy rates in subfertile women without other gynaecological symptoms: a systematic review.

BACKGROUND: Although hysteroscopy is frequently used in the management of subfertile women, a systematic review of the evidence on this subject is lacking. METHODS: We summarized and appraised the evidence for the benefit yielded by this procedure. Our systematic search was limited to randomized and controlled studies. The QUOROM and MOOSE guidelines were followed. Language restrictions were not applied. RESULTS: We identified 30 relevant publications. Hysteroscopic removal of endometrial polyps with a mean diameter of 16 mm detected by ultrasound doubles the pregnancy rate when compared with diagnostic hysteroscopy and polyp biopsy in patients undergoing intrauterine insemination, starting 3 months after the surgical intervention [relative risk (RR) = 2.3; 95% confidence interval (CI): 1.6-3.2]. In patients with one fibroid structure smaller than 4 cm, there was a marginally significant benefit from myomectomy when compared with expectant management (RR = 1.9; 95% CI: 1.0-3.7). Hysteroscopic metroplasty for septate uterus resulted in fewer pregnancies in patients with subfertility when compared with those with recurrent pregnancy loss (RR = 0.7; 95% CI: 0.5-0.9). Randomized controlled studies on hysteroscopic treatment of intrauterine adhesions are lacking. Hysteroscopy in the cycle preceding a subsequent IVF attempt nearly doubles the pregnancy rate in patients with at least two failed IVF attempts compared with starting IVF immediately (RR = 1.7; 95% CI: 1.5-2.0). CONCLUSIONS: Scarce evidence on the effectiveness of hysteroscopic surgery in subfertile women with polyps, fibroids, septate uterus or intrauterine adhesions indicates a potential benefit. More randomized controlled trials are needed before widespread use of hysteroscopic surgery in the general subfertile population can be justified.

The uterus and fertility.

OBJECTIVE: To review the current understanding of the role the uterus plays in embryo implantation and to outline congenital anomalies and acquired diseases that impact normal uterine function. DESIGN: The publications related to the embryo implantation, Mullerian anomalies, uterine polyps, uterine synechiae, and myomas were identified through Medline and reviewed. CONCLUSION(S): Congenital anomalies and acquired diseases of the uterus may negatively impact on the complex processes of embryo implantation. Hysteroscopic surgery to correct uterine septa, intrauterine synechiae, and myomas that distort the uterine cavity may benefit women with infertility or recurrent pregnancy loss. The effect of endometrial polyps on fertility is uncertain, but their removal, once identified, is justifiable. Complex congenital anomalies such as unicornuate uterus and uterus didelphys may negatively affect fertility and pregnancy outcome, and surgical treatment may benefit select patients.

Reversal of tubal sterilization versus IVF in the era of assisted reproductive technology: a clinical dilemma.

Two treatment options are available to women who wish to become pregnant after having had tubal sterilization: microsurgical reversal or IVF. The first approach is designed to restore tubal function, whereas the second replaces it. The first, to be successful, requires the presence of sufficient tubal length and normal or treatable fertility parameters. Treatment should therefore be individualized, based upon the findings of the couple's investigation, their wishes and the costs involved. The age of the female is the most important factor that affects the outcome with both treatment options. The live birth rate per cycle with IVF is 28%, but only 65.8% are singletons; 31.0% are twins and 3.2% triplets or more. Microsurgical tubal anastomosis yields a birth rate that exceeds 55%, without increased risk of multiple pregnancy. It offers the couple multiple cycles in which to achieve conception naturally, and the opportunity to have more than one pregnancy from a single intervention. The real dilemma lies with the 'industrialization' of IVF, and its frequent use as primary treatment for infertility. The dilemma is heightened by the fact that reconstructive tubal microsurgery is being taught and practised less and less, thereby eliminating this credible surgical option in most centres.