Hysterosalpingo-foam sonography versus hysterosalpingography during fertility work-up: an economic evaluation alongside a randomized controlled trial.

STUDY QUESTION: What are the costs and effects of tubal patency testing by hysterosalpingo-foam sonography (HyFoSy) compared to hysterosalpingography (HSG) in infertile women during the fertility work-up? SUMMARY ANSWER: During the fertility work-up, clinical management based on the test results of HyFoSy leads to slightly lower, though not statistically significant, live birth rates, at lower costs, compared to management based on HSG results. WHAT IS KNOWN ALREADY: Traditionally, tubal patency testing during the fertility work-up is performed by HSG. The FOAM trial, formally a non-inferiority study, showed that management decisions based on the results of HyFoSy resulted in a comparable live birth rate at 12 months compared to HSG (46% versus 47%; difference -1.2%, 95% CI: -3.4% to 1.5%; P = 0.27). Compared to HSG, HyFoSy is associated with significantly less pain, it lacks ionizing radiation and exposure to iodinated contrast medium. Moreover, HyFoSy can be performed by a gynaecologist during a one-stop fertility work-up. To our knowledge, the costs of both strategies have never been compared. STUDY DESIGN, SIZE, DURATION: We performed an economic evaluation alongside the FOAM trial, a randomized multicenter study conducted in the Netherlands. Participating infertile women underwent, both HyFoSy and HSG, in a randomized order. The results of both tests were compared and women with discordant test results were randomly allocated to management based on the results of one of the tests. The follow-up period was twelve months. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied 1160 infertile women (18-41 years) scheduled for tubal patency testing. The primary outcome was ongoing pregnancy leading to live birth. The economic evaluation compared costs and effects of management based on either test within 12 months. We calculated incremental cost-effectiveness ratios (ICERs): the difference in total costs and chance of live birth. Data were analyzed using the intention to treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, 1026 of the 1160 women underwent both tubal tests and had data available: 747 women with concordant results (48% live births), 136 with inconclusive results (40% live births), and 143 with discordant results (41% had a live birth after management based on HyFoSy results versus 49% with live birth after management based on HSG results). When comparing the two strategies-management based on HyfoSy results versus HSG results-the estimated chance of live birth was 46% after HyFoSy versus 47% after HSG (difference -1.2%; 95% CI: -3.4% to 1.5%). For the procedures itself, HyFoSy cost €136 and HSG €280. When costs of additional fertility treatments were incorporated, the mean total costs per couple were €3307 for the HyFoSy strategy and €3427 for the HSG strategy (mean difference €-119; 95% CI: €-125 to €-114). So, while HyFoSy led to lower costs per couple, live birth rates were also slightly lower. The ICER was €10 042, meaning that by using HyFoSy instead of HSG we would save €10 042 per each additional live birth lost. LIMITATIONS, REASONS FOR CAUTION: When interpreting the results of this study, it needs to be considered that there was a considerable uncertainty around the ICER, and that the direct fertility enhancing effect of both tubal patency tests was not incorporated as women underwent both tubal patency tests in this study. WIDER IMPLICATION OF THE FINDINGS: Compared to clinical management based on HSG results, management guided by HyFoSy leads to slightly lower live birth rates (though not statistically significant) at lower costs, less pain, without ionizing radiation and iodinated contrast exposure. Further research on the comparison of the direct fertility-enhancing effect of both tubal patency tests is needed. STUDY FUNDING/COMPETING INTEREST(S): FOAM trial was an investigator-initiated study, funded by ZonMw, a Dutch organization for Health Research and Development (project number 837001504). IQ Medical Ventures provided the ExEm®-FOAM kits free of charge. The funders had no role in study design, collection, analysis, and interpretation of the data. K.D. reports travel-and speakers fees from Guerbet and her department received research grants from Guerbet outside the submitted work. H.R.V. received consulting-and travel fee from Ferring. A.M.v.P. reports received consulting fee from DEKRA and fee for an expert meeting from Ferring, both outside the submitted work. C.H.d.K. received travel fee from Merck. F.J.M.B. received a grant from Merck and speakers fee from Besins Healthcare. F.J.M.B. is a member of the advisory board of Merck and Ferring. J.v.D. reported speakers fee from Ferring. J.S. reports a research agreement with Takeda and consultancy for Sanofi on MR of motility outside the submitted work. M.v.W. received a travel grant from Oxford Press in the role of deputy editor for Human Reproduction and participates in a DSMB as independent methodologist in obstetrics studies in which she has no other role. B.W.M. received an investigator grant from NHMRC GNT1176437. B.W.M. reports consultancy for ObsEva, Merck, Guerbet, iGenomix, and Merck KGaA and travel support from Merck KGaA. V.M. received research grants from Guerbet, Merck, and Ferring and travel and speakers fees from Guerbet. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: International Clinical Trials Registry Platform No. NTR4746.

Oral GnRH Antagonists in Combination with Estradiol and Norethindrone Acetate for Pain Relief Associated with Endometriosis: A Review of Evidence of a Novel Class of Hormonal Agents.

Current medical treatment options for endometriosis associated pains are inadequate. Evidence on effects of nonsteroidal anti-inflammatory drugs is scarce. Around one third of patients are not responsive to oral contraceptives or progestins due to progesterone resistance. Gonadotropin-releasing hormone (GnRH) agonists can only be used for a short duration because of associated side effects. Oral GnRH antagonists, including elagolix, relugolix, and linzagolix allow oral administration, induce dose dependent reduction of estradiol levels, do not cause initial flare up of endometriosis symptoms, and allow the fast return of ovarian function and menstruation after discontinuation. Elagolix at a low dose of 150 mg once daily, or the higher dose of 200 mg twice daily, significantly increased the proportion of women achieving clinically meaningful decline of dysmenorrhea, noncyclic pelvic pain, and dyspareunia. Relugolix at an oral dose of 40 mg/day results in improvement in different forms of endometriosis related pelvic pain, with an efficacy and side effect profile similar to that of GnRH agonists. Adding 1 mg of estradiol and 0.5 mg of norethindrone to 40 mg of relugolix (relugolix combination therapy) allows extension of treatment to 24 weeks with maintained efficacy and an improved side effect profile. Linzagolix, in a dose of 75 mg/day, can be used alone to treat endometriosis associated pain. For severe pelvic pain and dyspareunia, linzagolix can be used in a high dose of 200 mg/day with hormonal add-back therapy to preserve bone health.

Spinal Cord Stimulation for Intractable Visceral Pain Originating from the Pelvic and Abdominal Region: A Narrative Review on a Possible New Indication for Patients with Therapy-Resistant Pain.

Aim: Visceral pain, characterized by pain that is diffuse and challenging to localize, occurs frequently and is difficult to treat. In cases where the pain becomes intractable despite optimal medical management, it can affect patients' Quality of Life (QoL). Spinal Cord Stimulation (SCS) has emerged as a potential solution for intractable visceral pain. Purpose: In this narrative review, we collected all evidence regarding the efficacy of SCS for visceral pain across various underlying conditions. Methods: A comprehensive literature search was conducted in PubMed, Embase, and Web of Science in which articles published from October 1st, 1963 up to March 7th, 2023 were identified. Results: Seventy articles were included in this review of which most were retrospective cohort studies, case series and case reports. The studies, often with a small number of participants, reported on SCS for chronic pancreatitis, anorectal pain and bowel disorders, gynaecological diagnoses, visceral pelvic pain, urological disorders and finally general visceral pain. They found positive effects on pain and/or symptom relief, opioid consumption, anxiety and depression and QoL. Complications occurred frequently but were often minor and reversible. Conclusion: Better screening and selection criteria need to be established to optimally evaluate eligible patients who might benefit from SCS. A positive outcome of a sympathetic nerve block appears to be a potential indicator of SCS effectiveness. Additionally, women receiving SCS for endometriosis had a better outcome compared to other indications. Finally, SCS could also relief functional symptoms such as voiding problems and gastroparesis. Complications could often be resolved with revision surgery. Since SCS is expensive and not always covered by standard health insurance, the incorporation of cost-analyses is recommended. In order to establish a comprehensive treatment plan, including selection criteria for SCS, rigorous prospective, possibly randomized and controlled studies that are diagnosis-oriented, with substantial follow-up and adequate sample sizes, are needed.

Towards comprehensive management of symptomatic endometriosis: beyond the dichotomy of medical versus surgical treatment.

Except when surgery is the only option because of organ damage, the presence of suspicious lesions, or the desire to conceive, women with endometriosis-associated pain often face a choice between medical and surgical treatment. In theory, the description of the potential benefits and potential harms of the two alternatives should be standardized, unbiased, and based on strong evidence, enabling the patient to make an informed decision. However, doctor's opinion, intellectual competing interests, local availability of specific services and (mis)information obtained from social media, and online support groups can influence the type of advice given and affect patients' choices. This is compounded by the paucity of robust data from randomized controlled trials, and the anxiety of distressed women who are eager to do anything to alleviate their disabling symptoms. Vulnerable patients are more likely to accept the suggestions of their healthcare provider, which can lead to unbalanced and physician-centred decisions, whether in favour of either medical or surgical treatment. In general, treatments should be symptom-orientated rather than lesion-orientated. Medical and surgical modalities appear to be similarly effective in reducing pain symptoms, with medications generally more successful for severe dysmenorrhoea and surgery more successful for severe deep dyspareunia caused by fibrotic lesions infiltrating the posterior compartment. Oestrogen-progestogen combinations and progestogen monotherapies are generally safe and well tolerated, provided there are no major contraindications. About three-quarters of patients with superficial peritoneal and ovarian endometriosis and two-thirds of those with infiltrating fibrotic lesions are ultimately satisfied with their medical treatment although the remainder may experience side effects, which may result in non-compliance. Surgery for superficial and ovarian endometriosis is usually safe. When fibrotic infiltrating lesions are present, morbidity varies greatly depending on the skill of the individual surgeon, the need for advanced procedures, such as bowel resection and ureteral reimplantation, and the availability of expert colorectal surgeons and urologists working together in a multidisciplinary approach. The generalizability of published results is adequate for medical treatment but very limited for surgery. Moreover, on the one hand, hormonal drugs induce disease remission but do not cure endometriosis, and symptom relapse is expected when the drugs are discontinued; on the other hand, the same drugs should be used after lesion excision, which also does not cure endometriosis, to prevent an overall cumulative symptom and lesion recurrence rate of 10% per postoperative year. Therefore, the real choice may not be between medical treatment and surgery, but between medical treatment alone and surgery plus postoperative medical treatment. The experience of pain in women with endometriosis is a complex phenomenon that is not exclusively based on nociception, although the role of peripheral and central sensitization is not fully understood. In addition, trauma, and especially sexual trauma, and pelvic floor disorders can cause or contribute to symptoms in many individuals with chronic pelvic pain, and healthcare providers should never take for granted that diagnosed or suspected endometriosis is always the real, or the sole, origin of the referred complaints. Alternative treatment modalities are available that can help address most of the additional causes contributing to symptoms. Pain management in women with endometriosis may be more than a choice between medical and surgical treatment and may require comprehensive care by a multidisciplinary team including psychologists, sexologists, physiotherapists, dieticians, and pain therapists. An often missing factor in successful treatment is empathy on the part of healthcare providers. Being heard and understood, receiving simple and clear explanations and honest communication about uncertainties, being invited to share medical decisions after receiving detailed and impartial information, and being reassured that a team member will be available should a major problem arise, can greatly increase trust in doctors and transform a lonely and frustrating experience into a guided and supported journey, during which coping with this chronic disease is gradually learned and eventually accepted. Within this broader scenario, patient-centred medicine is the priority, and whether or when to resort to surgery or choose the medical option remains the prerogative of each individual woman.

Corrigendum: Diet associations in endometriosis: a critical narrative assessment with special reference to gluten.

[This corrects the article DOI: 10.3389/fnut.2023.1166929.].

Infertility in patients with uterine fibroids: a debate about the hypothetical mechanisms.

Fibroids are benign tumours of the myometrium and are the most common gynaecologic abnormality. Although most fibroids are asymptomatic, they can cause symptoms like heavy menstrual bleeding, pelvic pain, sexual dysfunction, pressure complaints, and infertility. The association between fibroids and infertility has been debated for decades. It is generally acknowledged that the closer the fibroid is to the uterine cavity and the endometrium lining, the more unfavourable effect it might have on fertility, reducing the odds for successful implantation and gestation. Based on the limited available literature, we propose and discuss seven hypotheses on the underlying mechanism by which fibroids may reduce fertility. (i) Fibroids can cause sexual dysfunction, as fibroids can cause dyspareunia, pelvic pain, and prolonged and heavy menstrual bleeding, which could interfere with sexual arousal and as a consequence the frequency of intercourse, resulting in a reduced probability of conception. (ii) Mechanical compression by fibroids on theinterstitial part of the fallopian tubes or deformation of uterine cavity could disturb oocyte and sperm transport. (iii) Fibroids can disturb peristalsis of the junctional zone in the myometrium, which could negatively influence oocyte and sperm transport as well as implantation. In addition, fibroids could induce a detrimental environment for implantation in other ways, by: (iv) changing the vagino-uterine microbiome; (v) disturbing the levels of inflammation and autophagy; (vi) inducing molecular changes in the endometrium; and (vii) inducing aberrant angiogenesis and altering the endometrial blood supply. After the discussion of these hypotheses, the implication of the influence of fibroids on early pregnancy loss is discussed. Surgical fibroid treatment is not tailored nor focussed on the pathophysiology of the fibroid; consequently it may be accompanied by recurrence of fibroids and risks of complications. Unravelling the pathogenic mechanisms about how fibroids influence fertility is essential to evolve classic surgical fibroid treatment. Instead of treatment of fibroid-related symptoms, the research should supports development of fibroid-targeted (pharmaceutical) treatment that is compatible with an active wish to become pregnant.

Diet associations in endometriosis: a critical narrative assessment with special reference to gluten.

Endometriosis is characterized by the presence of endometrium-like tissue outside the uterus. The etiology remains largely unknown. Despite adequate treatment, patients can still experience symptoms or side effects resulting in therapy incompliance and in self-management strategies such as dietary measures is increasing. A gluten free diet is thought to be contributory in reducing endometriosis-related pain, thereby optimizing quality of life. However, data is conflicting and currently provides no evidence for causality. This narrative review aims to put the effect of dietary self-management strategies on endometriosis in a balanced perspective, especially the effect of gluten and a gluten free diet. Several studies have found a strong overlap in symptoms, metabolic and immune responses associated with endometriosis and those associated with celiac disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome and non-celiac wheat sensitivity. However, it remains unclear whether these diseases and/or disorders are causal to an increased risk of endometriosis. Some studies have found a positive effect on the risk of endometriosis, endometriosis-related symptoms and quality of life (QoL) when women either avoided certain nutrients or foods, or applied a specific nutrient supplementation. This includes the avoidance of red meat, an increasing intake of foods rich in anti-oxidants, omega-3, micronutrients and dietary fibers (e.g., fruit, vegetables) and the appliance of a gluten free diet. However, data from the available studies were generally graded of low quality and it was noted that placebo and/or nocebo effects influenced the reported positive effects. In addition, such effects were no longer seen when adjusting for confounders such as overweight, when a translation was made from in vitro to in vivo, or when the nutrients were not supplemented as isolated sources but as part of a mixed daily diet. Finally, some studies showed that long-term adherence to a gluten free diet is often associated with an impaired diet quality and nutrient intake, leading to negative health outcomes and reduced QoL. Concluding, scientific evidence on the efficacy of dietary interventions on well-defined clinical endpoints of endometriosis is lacking and recommending a gluten free diet to women solely diagnosed with endometriosis should therefore not be advised.

[Endometriosis in an episiotomy scar]. / Endometriose in een episiotomielitteken.

A 34-year-old woman had a recurrent bleu colored painful swelling in the episiotomy scar. Pathological examination showed endometriosis. Six months later, a second recurrence occurred. The lesion was again removed with a larger margin, the wound treated with argon plasma coagulation to reduce chance of recurrence.

The Effect of a Myomectomy on Myoma-related Symptoms and Quality of Life: A Retrospective Cohort Study.

STUDY OBJECTIVE: Although it is assumed that myomectomy improves uterine myoma-related symptoms such as pelvic pain and heavy menstrual bleeding (HMB), validated measures are rarely reported. This study aimed to verify the effect of myomectomy on myoma-related symptoms. DESIGN: A retrospective cohort study. SETTING: A university-affiliated hospital. PATIENTS: Our study included 241 patients with a myoma diagnosis and received a myomectomy between 2004 and 2018. Data were collected from the patient medical file and patients responded in 1 questionnaire. INTERVENTIONS: Transcervical resection of myoma (TCRM) and laparoscopic or abdominal myomectomy (LAM). MEASUREMENTS AND MAIN RESULTS: One year after TCRM, a significant number of women experienced symptom improvement for pelvic pain (79% [19/24, p = .01]) and HMB (89% [46/52, p <.001]). For other myoma-related symptoms, abdominal pressure (43%, 10/23), sexual complaints (67%, 2/3), infertility (56%, 10/18), and other complaints (83%, 5/6), improvements were not statistically significant. One year after LAM, a significant number of women experienced symptom improvement for pelvic pain (80%, 74/93), HMB (83%, 94/113), abdominal pressure (85%, 79/93), sexual complaints (77%, 36/47), and other complaints (91%, 40/44). One year after myomectomy, 47% (30/64) (TCRM) and 44% of women (78/177) (LAM) described no myoma-related symptoms. Most women (82% [172/217]) were satisfied with the postoperative result after 1 year and 53% (114/217) would have liked to receive the myomectomy earlier in life. Average quality of life (measured on a 10-point Likert scale) increased from 6.3 at baseline to 8.0 at 1 year after TCRM and from 6.2 to 8.0 1 year after LAM, resulting in a difference of 1.7 points (p <.001; 95% confidence interval, 1.1-2.3) and 1.9 points (p <.001; 95% confidence interval, 1.4-2.3), respectively. CONCLUSION: One year after myomectomy, most women have benefited from myomectomy, concluded by a significant number of women who experienced myoma-related symptom improvement, positive patient satisfaction, and a significant improvement in reported quality of life. Validation of results after conventional treatment such as myomectomy is essential in counseling patients for surgical treatment in today's evidence based practice. In addition, it is necessary to make an adequate comparison with new treatment options for myomas. To provide this, further research should preferably be conducted prospectively or by randomization.

Spontaneous haemoperitoneum in pregnancy: Nationwide surveillance and Delphi audit system.

OBJECTIVE: To evaluate the incidence, diagnostic management strategies and clinical outcomes of women with spontaneous haemoperitoneum in pregnancy (SHiP) and reassess the definition of SHiP. DESIGN: A population-based cohort study using the Netherlands Obstetric Surveillance System (NethOSS). SETTING: Nationwide, the Netherlands. POPULATION: All pregnant women between April 2016 and April 2018. METHODS: This is a case study of SHiP using the monthly registry reports of NethOSS. Complete anonymised case files were obtained. A newly introduced online Delphi audit system (DAS) was used to evaluate each case, to make recommendations on improving the management of SHiP and to propose a new definition of SHiP. MAIN OUTCOME MEASURES: Incidence and outcomes, lessons learned about clinical management and the critical appraisal of the current definition of SHiP. RESULTS: In total, 24 cases were reported. After a Delphi procedure, 14 cases were classified as SHiP. The nationwide incidence was 4.9 per 100 000 births. Endometriosis and conceiving after artificial reproductive techniques were identified as risk factors. No maternal and three perinatal deaths occurred. Based on the DAS, adequate imaging of free intra-abdominal fluid, and identifying and treating women with signs of hypovolemic shock could improve the early detection and management of SHiP. A revised definition of SHiP was proposed, excluding the need for surgical or radiological intervention. CONCLUSIONS: SHiP is a rare and easily misdiagnosed condition that is associated with high perinatal mortality. To improve care, better awareness among healthcare workers is needed. The DAS is a sufficient tool to audit maternal morbidity and mortality.

Gonadotropin-releasing hormone analogues for endometriosis.

BACKGROUND: Endometriosis is a common gynaecological condition affecting 6 to 11% of reproductive-age women and may cause dyspareunia, dysmenorrhoea, and infertility. One treatment strategy is medical therapy with gonadotrophin-releasing hormone analogues (GnRHas) to reduce pain due to endometriosis. One of the adverse effects of GnRHas is a decreased bone mineral density. In addition to assessing the effect on pain, quality of life, most troublesome symptom and patients' satisfaction, the current review also evaluated the effect on bone mineral density and risk of adverse effects in women with endometriosis who use GnRHas versus other treatment options. OBJECTIVES: To assess the effectiveness and safety of GnRH analogues (GnRHas) in the treatment of painful symptoms associated with endometriosis and to determine the effects of GnRHas on bone mineral density of women with endometriosis. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO and the trial registries in May 2022 together with reference checking and contact with study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) which compared GnRHas with other hormonal treatment options, including analgesics, danazol, intra-uterine progestogens, oral or injectable progestogens, gestrinone and also GnRHas compared with no treatment or placebo. Trials comparing GnRHas versus GnRHas in conjunction with add-back therapy (hormonal or non-hormonal) or calcium-regulation agents were also included in this review.  DATA COLLECTION AND ANALYSIS: We used standard methodology as recommended by Cochrane. Primary outcomes are relief of overall pain and the objective measurement of bone mineral density. Secondary outcomes include adverse effects, quality of life, improvement in the most troublesome symptoms and patient satisfaction.  Due to high risk of bias associated with some of the studies, primary analyses of all review outcomes were restricted to studies at low risk of selection bias. Sensitivity analysis including all studies was then performed. MAIN RESULTS: Seventy-two studies involving 7355 patients were included. The evidence was very low to low quality: the main limitations of all studies were serious risk of bias due to poor reporting of study methods, and serious imprecision.  Trials comparing GnRHas versus no treatment  We did not identify any studies. Trials comparing GnRHas versus placebo There may be a decrease in overall pain, reported as pelvic pain scores (RR 2.14; 95% CI 1.41 to 3.24, 1 RCT, n = 87, low-certainty evidence), dysmenorrhoea scores (RR 2.25; 95% CI 1.59 to 3.16, 1 RCT, n = 85, low-certainty evidence), dyspareunia scores (RR 2.21; 95% CI 1.39 to 3.54, 1 RCT, n = 59, low-certainty evidence), and pelvic tenderness scores (RR 2.28; 95% CI 1.48 to 3.50, 1 RCT, n = 85, low-certainty evidence) after three months of treatment. We are uncertain of the effect for pelvic induration, based on the results found after three months of treatment (RR 1.07; 95% CI 0.64 to 1.79, 1 RCT, n = 81, low-certainty evidence). Besides, treatment with GnRHas may be associated with a greater incidence of hot flushes at three months of treatment (RR 3.08; 95% CI 1.89 to 5.01, 1 RCT, n = 100, low-certainty evidence). Trials comparing GnRHas versus danazol For overall pain, for women treated with either GnRHas or danazol, a subdivision was made between pelvic tenderness, partly resolved and completely resolved. We are uncertain about the effect on relief of overall pain, when a subdivision was made for overall pain (MD -0.30; 95% CI -1.66 to 1.06, 1 RCT, n = 41, very low-certainty evidence), pelvic pain (MD 0.20; 95% CI -0.26 to 0.66, 1 RCT, n = 41, very low-certainty evidence), dysmenorrhoea (MD 0.10; 95% CI -0.49 to 0.69, 1 RCT, n = 41, very low-certainty evidence), dyspareunia (MD -0.20; 95% CI -0.77 to 0.37, 1 RCT, n = 41, very low-certainty evidence), pelvic induration (MD -0.10; 95% CI -0.59 to 0.39, 1 RCT, n = 41, very low-certainty evidence), and pelvic tenderness (MD -0.20; 95% CI -0.78 to 0.38, 1 RCT, n = 41, very low-certainty evidence) after three months of treatment. For pelvic pain (MD 0.50; 95% CI 0.10 to 0.90, 1 RCT, n = 41, very low-certainty evidence) and pelvic induration (MD 0.70; 95% CI 0.21 to 1.19, 1 RCT, n = 41, very low-certainty evidence), the complaints may decrease slightly after treatment with GnRHas, compared to danazol, for six months of treatment. Trials comparing GnRHas versus analgesics  We did not identify any studies. Trials comparing GnRHas versus intra-uterine progestogens We did not identify any low risk of bias studies. Trials comparing GnRHas versus GnRHas in conjunction with calcium-regulating agents There may be a slight decrease in bone mineral density (BMD) after 12 months treatment with GnRHas, compared to GnRHas in conjunction with calcium-regulating agents for anterior-posterior spine (MD -7.00; 95% CI -7.53 to -6.47, 1 RCT, n = 41, very low-certainty evidence) and lateral spine (MD -12.40; 95% CI -13.31 to -11.49, 1 RCT, n = 41, very low-certainty evidence).  AUTHORS' CONCLUSIONS: For relief of overall pain, there may be a slight decrease in favour of treatment with GnRHas compared to placebo or oral or injectable progestogens. We are uncertain about the effect when comparing GnRHas with danazol, intra-uterine progestogens or gestrinone. For BMD, there may be a slight decrease when women are treated with GnRHas, compared to gestrinone. There was a bigger decrease of BMD in favour of GnRHas, compared to GnRHas in conjunction with calcium-regulating agents. However, there may be a slight increase in adverse effects when women are treated with GnRHas, compared to placebo or gestrinone. Due to a very low to low certainty of the evidence, a wide range of outcome measures and a wide range of outcome measurement instruments, the results should be interpreted with caution.

The Relation between Patient-Centered Care and Quality of Life in Women with Endometriosis.

OBJECTIVE: The objective of this study was to examine the hypothesis that experiences with patient-centered endometriosis care are related to the endometriosis-specific quality of life dimensions "emotional well-being" and "social support." DESIGN: A secondary regression analysis of two cross-sectional studies was conducted. Participants/Materials: In total, data from 300 women were eligible for analysis. The participating women all had surgically proven endometriosis. SETTING: The study was conducted in one secondary and two tertiary endometriosis clinics in the Netherlands. Questionnaires were disseminated between 2011 and 2016. METHODS: Both included studies investigated patient-centeredness of endometriosis care and endometriosis-specific quality of life using, respectively, the ENDOCARE questionnaire (ECQ) and the Endometriosis Health Profile 30 (EHP-30). To increase power, the regression analysis focused on the previously found relation between the ten dimensions of the ECQ and the EHP-30 domains "emotional well-being" and "social support" rather than all five EHP-30 domains. After the Bonferroni correction to limit type 1 errors, the adjusted p value was 0.003 (0.05/20). RESULTS: The participating women had a mean age of 35.7 years and had predominantly been diagnosed with moderate to severe endometriosis. None of the relations between patient-centered endometriosis care and the EHP-30 domain "emotional well-being" were significant. Three dimensions of patient-centered endometriosis care proved to be significantly related to the EHP-30 domain "social support": "information, communication, and education" (p < 0.001, beta = 0.436), "coordination and integration of care" (p = 0.001, beta = 0.307), and "emotional support and alleviation of fear and anxiety" (p = 0.002, beta = 0.259). LIMITATIONS: This cross-sectional study identified relations rather than proving causality between experiencing less patient-centeredness of care and having lower quality of life. Nevertheless, it is very tangible that some causality exists, either directly or indirectly (e.g., through empowerment) and that by improving patient-centeredness, quality of life might be improved as well. CONCLUSION: "Information, communication, and education"; "coordination and integration of care"; and "emotional support and alleviation of fear and anxiety" as dimensions of patient-centered endometriosis care are related to the quality of life domain "social support" of women with endometriosis. Improving the patient-centeredness of endometriosis care was already considered an important goal, but even more so given its relation with women's quality of life, which is increasingly considered the ultimate measure of health care quality. Quality improvement projects focusing on "information, communication, and education" are expected to impact women's quality of life the most.

Endometrial Angiogenesis of Abnormal Uterine Bleeding and Infertility in Patients with Uterine Fibroids-A Systematic Review.

Uterine fibroids are the most common benign tumors in women, with abnormal uterine bleeding (AUB) as the main reported symptom. Additionally, an association between fibroids and infertility has been established, especially if the fibroid protrudes in the uterine cavity. Hormonal therapy is associated with side-effects and as well as hysterectomy, which is incompatible with a desire to conceive. To improve treatment, it is essential to unravel the etiology of fibroid-related symptoms. We aim to evaluate endometrial angiogenesis in women with fibroids, with and without AUB, and the influence of pharmaceutical therapies in these patients. Furthermore, we explore the possible role of altered angiogenesis in patients with fibroids and infertility. We performed a systematic review according to PRISMA-guidelines (PROSPERO: CRD42020169061), and included 15 eligible studies. Endometrial expression of vascular endothelial growth factor (VEGF) and adrenomedullin was increased in patients with fibroids. This suggests aberrant angiogenesis, potentially involving disturbed vessel maturation, resulting in immature and fragile vessels. Treatment with gonadotropin-releasing hormone agonist, ulipristal acetate, and continuous oral contraception pills reduced several angiogenic parameters, including VEGF. If infertile and fertile patients with fibroids were compared, a significant decreased expression of the bone morphogenetic protein/Smad-protein pathway was found, possibly caused by the increased expression of transforming growth factor-beta. For future therapeutic development, these different angiogenic pathways could be of interest as possible targets to treat fibroid-related symptoms.

A better quality of life could be achieved by applying the endometriosis diet: a cross-sectional study in Dutch endometriosis patients.

RESEARCH QUESTION: Does the endometriosis diet positively affect quality of life (QoL) in women diagnosed with endometriosis? DESIGN: A cross-sectional study was performed, recruiting women using the website and online peer platforms from the Dutch Endometriosis Society. In total, 211 women with a self-reported diagnosis of endometriosis were included in the study. They completed a questionnaire on the six QoL domains based on the conversation tool 'My Positive Health'. Women who adhered to the endometriosis diet were compared with women who did not. A distinction was made between strict (score ≥8 on a scale of 0-10) and less strict adherence to the diet. RESULTS: A significantly higher score was seen in all six QoL domains in women who adhered to the endometriosis diet (n = 90) compared with women who did not (n = 121) (range P < 0.001 to P = 0.043). Furthermore, women with strict adherence (n = 48) compared to less strict adherence (n = 42) reported significantly higher scores in all six QoL domains (range P = 0.005 to 0.05). Women diagnosed with endometriosis more than 10 years ago (n = 13) adhered to the endometriosis diet significantly less often than women that were diagnosed more recently (n = 163; range P = 0.005 to 0.046). CONCLUSION: The endometriosis diet was associated with a better QoL in Dutch women with endometriosis. Strict adherence showed higher QoL scores compared with less strict adherence. Therefore, more research is needed to clarify the mechanism of this beneficial effect and to identify facilitators and barriers to dietary adjustments in patients with endometriosis.

The link between intrauterine adhesions and impaired reproductive performance: a systematic review of the literature.

BACKGROUND: Intrauterine adhesions (IUAs) are one of the main reproductive system diseases in women worldwide. Fusion between the injured opposing walls leads to partial-to-complete obliteration of the cavity and/or cervical canal. The main clinical manifestations in case of IUAs are menstrual disturbances, cyclic pain and reproductive disorders. The reproductive outcomes of women with IUAs remain limited and inefficient compared to women without IUAs, even after adhesiolysis. An exact understanding of the underlying mechanisms and processes to explain the compromised reproductive performance and outcomes in case of IUAs are lacking. METHODS: A systematic literature review of MEDLINE-PubMed (1966 to January 2022) and EMBASE (1974 to January 2022) was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were included if they reported underlying causes, related mechanisms and processes to explain the association between IUAs and impaired reproductive performance, pregnancy and obstetric complications. RESULTS: After an extensive review of the literature, 58 articles were identified reporting underlying mechanisms to explain the association between IUAs and impaired fertility. Intrauterine scarring influences the process of fertilization, reproductive performance and ultimately reproductive outcome. IUAs can disturb the cervico-utero-tubal sperm transport and result in an avascular and unresponsive endometrium with decreased receptivity and thickness. Abnormal decidualization and abnormal trophoblastic infiltration leads to placental attachment disorders. Moreover, the risk for premature delivery, intrauterine fetal growth restriction and fetal anomalies is increased in case of IUAs. CONCLUSION: The impact of IUAs on reproductive performance, even after adhesiolysis, is becoming more apparent. The postulated mechanisms to explain the association are related to sperm transport, embryo implantation and placentation. Prevention, by preserving the basal layer of the endometrium is essential. Effective and evidence-based strategies for the prevention of endometrial injury and formation of IUAs, are urgently needed.

The effect of myomectomy on reproductive outcomes in patients with uterine fibroids: A retrospective cohort study.

RESEARCH QUESTION: What is the effect of myomectomy in women with uterine fibroids on time to live birth and other reproductive outcomes? DESIGN: This was a monocentric retrospective cohort study of 311 women with fibroids, of whom 165 eventually received myomectomy and 146 remained on expectant management. To assess the primary outcome time to live birth, a Cox proportional hazards model with a time-varying covariate for myomectomy was used. In the sensitivity analyses, this was combined with an approach to account for confounders via a cloning/censoring/weighting that aimed to emulate a randomized controlled trial. RESULTS: Notable differences in baseline characteristics between the myomectomy and expectant management group were fibroid size (fibroid >7 cm: myomectomy 48%; expectant management 15%) and whether the patient had fibroid-related complaints (myomectomy 85%, expectant management 67%). The adjusted hazard ratio for the effect of myomectomy compared with expectant management on live birth was 1.26 (95% CI 0.87-1.81). Sensitivity analyses yielded similar results, but secondary outcomes showed that women remaining on expectant management had more often received assisted reproductive technology (63%) compared with those who eventually received myomectomy (38%). CONCLUSIONS: The study did not find a significant difference in time to live birth after myomectomy compared with expectant management in women with fibroids and a wish to conceive, despite more, larger and more symptomatic fibroids in the myomectomy group. The results after myomectomy encourage the execution of a randomized controlled trial in women with large (symptomatic) fibroids not or minimally distorting the intrauterine cavity, and infertility or a desire to conceive.

What is the fertility-enhancing effect of tubal flushing? A hypothesis article.

Hysterosalpingographies (HSGs) have formed an essential part of the fertility workup for more than a century. More recently, tubal flushing, especially with oil-based contrast, has been shown to significantly improve the natural conception rates. Critically, the mechanism of this fertility-enhancing effect during tubal flushing is still unclear. This article postulates hypotheses, based on published and own research, on the potential mechanisms and root cause of tubal flushing fertility enhancement. Possible explanations for the increased fertility rates, especially with oil-based contrast, are divided into the biochemical and interfacial effects derived from the contrast properties. The biochemical effects may include the immunological response of the endometrium or peritoneum, the impact on the endometrial opioid receptors or the iodine content. The interfacial effects may include improvement of interfacial factors due to the lubricant effect or dislodgement of mucus debris within the Fallopian tubes. Impact StatementWhat is already known on this subject? Tubal flushing during hysterosalpingographies (HSGs) increases natural conception rates, and using oil-based over water-based contrast increases that effect even further. However, the underlying mechanism of the observed fertility-enhancing effect is still poorly understood.What do the results of this study add? This article postulates different hypotheses on the potential mechanisms and root cause of the fertility enhancement from tubal flushing.What are the implications of these findings for clinical practice and/or further research? We suggest additional research on the different hypotheses, intending to determine which subfertile women will benefit most from tubal flushing using oil-based contrast and at which stage of their subfertility. Furthermore, we suggest research on administering tubal flushing with oil-based contrast, besides in HSG.

Can hysterosalpingo-foam sonography replace hysterosalpingography as first-choice tubal patency test? A randomized non-inferiority trial.

STUDY QUESTION: Does hysterosalpingo-foam sonography (HyFoSy) lead to similar pregnancy outcomes, compared with hysterosalpingography (HSG), as first-choice tubal patency test in infertile couples? SUMMARY ANSWER: HyFoSy and HSG produce similar findings in a majority of patients and clinical management based on the results of either HyFoSy or HSG, leads to comparable pregnancy outcomes. HyFoSy is experienced as significantly less painful. WHAT IS KNOWN ALREADY: Traditionally, tubal patency testing during fertility work-up is performed by HSG. HyFoSy is an alternative imaging technique lacking ionizing radiation and iodinated contrast medium exposure which is less expensive than HSG. Globally, there is a shift towards the use of office-based diagnostic methods, such as HyFoSy. STUDY DESIGN, SIZE, DURATION: This multicentre, prospective, comparative study with a randomized design was conducted in 26 hospitals in The Netherlands. Participating women underwent both HyFoSy and HSG in randomized order. In case of discordant results, women were randomly allocated to either a management strategy based on HyFoSy or one based on HSG. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included infertile women between 18 and 41 years old who were scheduled for tubal patency testing during their fertility work-up. Women with anovulatory cycles not responding to ovulation induction, endometriosis, severe male infertility or a known iodine contrast allergy were excluded. The primary outcome for the comparison of the HyFoSy- and HSG-based strategies was ongoing pregnancy leading to live birth within 12 months after inclusion in an intention-to-treat analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, 1026 women underwent HyFoSy and HSG. HyFoSy was inconclusive in 97 of them (9.5%), HSG was inconclusive in 30 (2.9%) and both were inconclusive in 9 (0.9%). In 747 women (73%) conclusive tests results were concordant. Of the 143/1026 (14%) with discordant results, 105 were randomized to clinical management based on the results of either HyFoSy or HSG. In this group, 22 of the 54 women (41%) allocated to management based on HyFoSy and 25 of 51 women (49%) allocated to management based on HSG had an ongoing pregnancy leading to live birth (Difference -8%; 95% CI: -27% to 10%). In total, clinical management based on the results of HyFoSy was estimated to lead to a live birth in 474 of 1026 women (46%) versus 486 of 1026 (47%) for management based on HSG (Difference -1.2%; 95% CI: -3.4% to 1.5%). Given the pre-defined margin of -2%, statistically significant non-inferiority of HyFoSy relative to HSG could not be demonstrated (P = 0.27). The mean pain score for HyFoSy on the 1-10 Visual Analogue Scale (VAS) was 3.1 (SD 2.2) and the mean VAS pain score for HSG was 5.4 (SD 2.5; P for difference < 0.001). LIMITATIONS, REASONS FOR CAUTION: Since all women underwent both tubal patency tests, no conclusions on a direct therapeutic effect of tubal flushing could be drawn. WIDER IMPLICATIONS OF THE FINDINGS: HyFoSy or HSG produce similar tubal pathology findings in a majority of infertile couples and, where they differ, a difference in findings does not lead to substantial difference in pregnancy outcome, while HyFoSy is associated with significantly less pain. STUDY FUNDING/COMPETING INTEREST(S): The FOAM study was an investigator-initiated study funded by ZonMw, The Netherlands organization for Health Research and Development (project number 837001504). ZonMw funded the whole project. IQ Medical Ventures provided the ExEm-foam® kits free of charge. The funders had no role in study design, collection, analysis and interpretation of the data. K.D. reports travel and speaker fees from Guerbet. F.J.M.B. reports personal fees as a member of the external advisory board for Merck Serono, The Netherlands, and a research support grant from Merck Serono, outside the submitted work. C.B.L. reports speakers' fee from Ferring in the past, and his department receives research grants from Ferring, Merck and Guerbet. J.S. reports a research agreement with Takeda on MR of motility outside the submitted work. M.V.W. reports leading The Netherlands Satellite of the Cochrane Gynaecology and Fertility Group. B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.J.M. reports consultancy for Guerbet and research funding from Merck and Guerbet. V.M. reports non-financial support from IQ medicals ventures, during the conduct of the study; grants and personal fees from Guerbet, outside the submitted work. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: NTR4746/NL4587 (https://www.trialregister.nl). TRIAL REGISTRATION DATE: 19 August 2014. DATE OF FIRST PATIENT'S ENROLMENT: 7 May 2015.