Background: Effective management of endometriosis necessitates a comprehensive, multidisciplinary approach. Networks or centres of expertise play a pivotal role in enhancing clinical care, fostering collaboration, and promoting innovative research, knowledge dissemination, and healthcare professional training. Despite the established benefits of structured care systems, there remains no global consensus on the essential components of an endometriosis network of expertise. This study aims to define key elements for such networks, with a particular focus on improving care structures in the Asia-Pacific region. Methods: A three-stage consensus process was conducted by Asia Pacific Initiative on Reproduction (ASPIRE), incorporating literature review, modified Delphi surveys, and face-to-face and virtual consensus meetings. The process involved multidisciplinary stakeholders, including medical and paramedical professionals, researchers, patients and patient advocates. Two rounds of Delphi surveys refined key features based on stakeholder input, followed by consensus refinement through a face-to-face consensus development meeting at the ASPIRE Auckland Endometriosis Masterclass 2024, a subsequent Zoom meeting, then specific patient and patient advocate input to finalise the key features. Results: Consensus was reached on 38 key features, categorised into five domains: network importance, organisational structure, clinical services, training and research. The study highlights the strength of a multidisciplinary approach, ensuring accessibility to specialised surgical, pain management and fertility services, with the person with endometriosis at the centre of this structure. The inclusion of experts in acupuncture, nutrition, psychology, physiotherapy and other allied health fields enhances patient care through a multidisciplinary holistic care approach, addressing the diverse needs of individuals with endometriosis. Conclusions: Consensus has been reached on key features of an endometriosis network of expertise, incorporating the perspectives of those with lived experience and their advocates, to improve endometriosis care across the Asia-Pacific region. This framework serves as a reference for global discussions. It has the potential to become an audit accreditation standard in Asia-Pacific.

Endometriosis and chronic pelvic pain (CPP) impose substantial economic burden in New Zealand, yet no national cost-of-illness (COI) model currently exists. This study provides the first nationwide estimate using a modified World-Endometriosis-Research-Foundation (WERF) EndoCost protocol incorporating direct healthcare, productivity, and carer costs. An attribution correction model was applied to account for diagnostic overlap, assigning 43.4% of CPP cases to endometriosis. Attribution-adjusted annual per capita costs were INT 97,497 (NZD 174,130) for endometriosis and INT 33,262 (NZD 59,406) for CPP. Macroeconomic costs ranged from INT 12.7B to 17.7B (NZD 22.6B–31.7B) per annum, depending on prevalence. Productivity losses were the primary cost driver, accounting for 65% of endometriosis and 75% of CPP cost. The unattributed lifetime burden was INT 1.96M (NZD 3.50M) per person for endometriosis and INT 1.54M (NZD 2.74M) per person with CPP. This reflects total economic burden over a 34.5-year working lifespan, adjusted for labor-force participation. Diagnostic delays and health system inefficiencies such as poor healthcare access and suboptimal symptom management are likely to be the most significant modifiable contributor to this burden. Addressing this will require investment in healthcare provision and symptom management alongside equitable access to fertility care.

Fertility & ReproductionVol. 06, No. 02, pp. 61-63 (2024) REVIEWOpen AccessIs the Paradigm Shift in Treating Endometriosis and Endometriomas Evidence-Based?Neil P. JohnsonNeil P. JohnsonFlinders University, Adelaide, AustraliaThe Robinson Research Institute, University of Adelaide, AustraliaFlinders Fertility, Adelaide, AustraliaAuckland Gynaecology Group and Repromed Auckland, New ZealandE-mail Address: [email protected]Corresponding author: Neil P. Johnson, Repromed and Auckland Gynaecology Group, 105 Remuera Road, Remuera, Auckland 1050, New Zealand.https://doi.org/10.1142/S2661318224300022Cited by:0 (Source: Crossref) Next AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsRecommend to Librarian ShareShare onFacebookTwitterLinked InRedditEmail INVITED EDITORIAL The management of ovarian endometriomas has been the subject of much conjecture in the literature over the past decade – and the systematic review and meta-analysis of randomised and non-randomised studies examining medical treatment for those with endometriomas from Lim et al., 2024 in the current edition of Fertility and Reproduction is a useful addition to this evidence base. It is perhaps another means by which 'surgery can be avoided to minimise the risk of damage to the ovarian reserve'. Traditional evidence suggested that surgery was the most favourable treatment approach to endometriomas, with complete surgical removal of an endometrioma promoted by randomised controlled trial (RCT) evidence showing the benefit of this approach (compared to more conservative surgery) to minimise pain recurrence, endometrioma recurrence and improve fertility in the short-term (Hart et al., 2008). There has recently been tension between the findings from these traditional RCTs and new evidence, enlightening us that more conservative approaches are preferable to retain ovarian reserve and, therefore, fertility longevity. This includes not only more conservative approaches to surgery involving less ovarian electrosurgery, but now also medical treatment, as outlined by Lim et al., 2024. Over the past decade, there has been an average of approximately one RCT per month published in peer-reviewed literature that assesses treatment interventions for those with endometriosis. While we have traditionally regarded RCTs examining surgical interventions as difficult to undertake for a host of reasons (Johnson, 2009), in fact, a reasonable proportion of these trials (around one-third) have directly assessed surgical treatment interventions. Almost half of all published endometriosis surgical technique RCTs have studied interventions for endometriomas. There have been no fewer than eight studies published in F&R since the inauguration of the journal whose titles reflect the study of endometriomas or chocolate cysts (Choi et al., 2023; Dewanto et al., 2023; Kathuria, 2023; Piessens, 2023; Sari et al., 2023; Sen et al., 2020; Shume et al., 2021; Zhao et al., 2023). Hence, there has been an enlightenment in managing endometriomas and the paramount importance of respecting ovarian reserve when so doing. If laparoscopic surgery is to be undertaken for endometriomas, more recent RCTs have underscored the following important principles. First, a reminder that laparoscopic excision versus ablation significantly reduces the endometrioma recurrence rate (Carmona et al., 2011), but highlighting that the negative impact on ovarian reserve (evidenced by a substantial drop in serum anti-Mullerian hormone [AMH] level) is unacceptable when endometriomas are excised (Candiani et al., 2018), especially if the endometrioma is 5cm in diameter or bigger (Giampaolino et al., 2015). Vasopressin injection during excisional cystectomy reduces the need for haemostasis techniques (Ghafarnejad et al., 2014; Qiong-Zhen et al., 2014). Laparoscopic suturing (Asgari et al., 2016; Coric et al., 2011) or haemostatic matrix (Sönmezer et al., 2013) have been shown to be preferable to electrosurgical cautery to maintain AMH and antral follicle count (AFC) – although this has not been demonstrable in all RCTs (Ferrero et al., 2012; Tanprasertkul et al., 2014). Laparoscopic suturing is facilitated with the use of barbed suture (Fouda et al., 2016). Insertion of absorbable haemostat (oxidised regenerated cellulose) to the endometrioma bed in the ovary at the time of surgical intervention significantly reduces endometrioma recurrence risk (Shaltout et al., 2019). Alcohol sclerotherapy is another treatment option that has featured in only two RCTs to date, and which requires more evaluation (Ronsini et al., 2023). But what of medical treatment for endometriomas? Is ovarian reserve yet safer with no surgery at all? While pooling of RCTs with non-randomised studies, as undertaken by Lim et al., 2024 can be questioned, nonetheless this meta-analysis suggests an endometrioma size reduction (particularly with the progestin dienogest) and a reduction in pain (Lim et al., 2024). Whether pain reduction is consequent upon endometrioma size reduction remains moot, as we recognise medical hormonal treatment as effective for treating endometriosis-related pain (as well as adenomyosis-related pain) irrespective of the presence of an endometrioma. If medical treatment can avoid surgical treatment for endometriomas, ovarian reserve will surely be another beneficiary. While our traditional thinking has been that hormonal medical treatment is not advised amongst those endeavouring to become pregnant, indeed its contraceptive efficacy was always considered a hindrance to fertility and, therefore, that medical treatment was essentially contraindicated in those endeavouring to become pregnant, even that paradigm is being challenged. New data synthesis, including network meta-analysis, is suggesting that medical treatment alone, such as gonadotrophin-releasing hormone agonists (GnRHa) and the progestin dydrogesterone (particularly if used cyclically in the luteal phase), might well improve fertility (Hodgson et al., 2020). Aromatase inhibitors have been recommended for pain, but their role in empirical treatment for endometriosis-related infertility needs more data (Johnson, 2023). These inferences, along with the dramatic fertility improvement seen with use of oil-based contrast to perform uterine bathing and tubal flushing (Hodgson et al., 2020), demonstrate that fertility treatment for endometriosis-related infertility is far from a straight choice between medically assisted reproduction and laparoscopic surgery as suggested in the ESHRE 2022 guideline (Becker et al., 2022). The myriad of evidence-based treatment choices for those with endometriosis continues to grow.FUNDING No external funding was received for this invited editorial.CONFLICT OF INTEREST NPJ has received grants and, speaker and conference fees from Guerbet, Abbott, Myovant Sciences, Organon and Gedeon Richter.ORCID Neil P. Johnson https://orcid.org/0009-0000-2119-9942 References Asgari Z, Rouholamin S, Hosseini R, Sepidarkish M, Hafizi L, Javaheri A . Comparing ovarian reserve after laparoscopic excision of endometriotic cysts and hemostasis achieved either by bipolar coagulation or suturing: a randomized clinical trial. Arch Gynecol Obstet. 2016; 293 :1015–22. https://doi.org/10.1007/s00404-015-3918-4. Epub 2015 Oct 22. PMID: 26493551. Crossref, Google Scholar Becker CM, Bokor A, Heikinheimo O, et al. ESHRE guideline: endometriosis. Hum Reprod Open. 2022; 2 :hoac009. https://doi.org/10.1093/hropen/hoac009 Crossref, Google Scholar Candiani M, Ottolina J, Posadzka E, et al. 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BackgroundFluoroscopic hysterosalpingography (HSG) with Lipiodol (R) is safe and has a therapeutic effect on fertility: transient in endometriosis-related infertility and sustained in unexplained infertility. Ultrasound is replacing fluoroscopy as the preferred imaging modality for HSG due to comfort and radiation safety (no ionising radiation). The safety of ultrasound-guided Lipiodol (R) HSG is uncertain.AimsProspectively observe pregnancy and complication rates after ultrasound-guided Lipiodol (R) HSG.Materials and MethodsA single-centre prospective study of women with unexplained infertility undergoing ultrasound-guided Lipiodol (R) uterine bathing and tubal flushing after tubal patency confirmed with ExEm (R) Foam HyFoSy (hysterosalpingo-foam-sonography). Pregnancy outcomes at six months and serum and urinary thyroid function at one, three and eight weeks were recorded. Pain scores were recorded during and immediately after HSG. Descriptive statistics are reported.ResultsFifty-two participants were enrolled between July 2019 and April 2021, median age 33 years (range 21-45). Only 45 (87%, 45/52) completed the Lipiodol (R) HSG; 5/7 experienced intravasation during initial HyFoSy. Of 30 women at follow-up, 57% had biochemical (17/30, 95% CI 37%-75%), 53% clinical (16/30 95% CI 34%-72%) and 35% ongoing pregnancies (11/30, 95% CI 20%-56%). The rate of subclinical hypothyroidism (SCH) at two months was 41% (7/17). One intravasation event occurred during Lipiodol (R) HSG (2%, 1/45). Median pain score was 5/10 (range 0-9, interquartile range 2.5-7). No anaphylaxis, infection or oil embolism was observed.ConclusionOutpatient ultrasound-guided Lipiodol (R) HSG was safe, with pregnancy rates comparable to previous studies of fluoroscopic guidance. Rates of intravasation and SCH were also similar, confirming the need to monitor thyroid function.

Background and Aims: Numerous endometriosis treatments exist, ranging from surgical to traditional medications to complementary and alternative medicines (CAMs). The ranking of treatments across management categories remains unknown. To address this research gap, this network meta-analysis (NMA) aims to rank endometriosis treatments in terms of efficacy and safety for endometriosis-related pain and quality of life. Method: A systematic literature search and fixed effects NMA was conducted. Eight databases were searched from inception to August 2022. All randomised control trials (RCTs) in women with surgically confirmed endometriosis were considered. Results: After screening 8,668 studies, 165 RCTs were included, consisting of 26,762 participants, investigating 48 medical, 13 CAMs and 16 surgical interventions. Preliminary analysis of the CAMs interventions (9 RCTs, n=522) suggested acupuncture (SMD -1.96; 95%CI: -2.63, -1.29), olive oil (SMD -1.68; 95%CI: -2.69, -0.67), fatty acid supplements (SMD -1.48; 95% CI: -2.15, -0.81), contraception + Chinese medicines (SMD -1.28; 95%CI: -2.39, -0.16), Chinese medicine (SMD -0.91, 95%CI: -1.78, -0.04) and vitamin C&E (SMD -0.38; 95%CI -0.89, 0.13) demonstrated a reduction in pain compared to placebo. There was insufficient evidence to detect a difference in pain using Vitamin D compared to placebo (SMD 0.09 95% CI: -0.55, 0.73). Complete results, including the individual and combined categories within a Bayesian framework and intervention ranking, will be available for ASPIRE 2023. Conclusion: This is the first NMA to compare the evidence of all endometriosis treatments. The findings have the potential to guide treatment decisions and guideline development.

WHAT IS THIS SUMMARY ABOUT?:This is a summary of research studies (known as clinical trials) called SPIRIT 1 and SPIRIT 2. The SPIRIT 1 and SPIRIT 2 studies compared how well a medicine called relugolix combination therapy worked in relieving pain in women with moderate to severe endometriosis compared to a placebo, a pill with no active medication. Endometriosis occurs when tissue similar to what normally lines the uterus grows in other places, such as the ovaries, fallopian tubes, and bowels. WHAT WERE THE RESULTS?:Researchers looked at 1261 adult women with moderate to severe endometriosis. Randomly, 420 (33%) of these women were assigned to relugolix combination therapy, 420 (33%) were assigned to delayed relugolix combination therapy (relugolix alone first and then relugolix combination therapy for the remainder of the study), and 421 (33%) were assigned to placebo. The SPIRIT 1 and SPIRIT 2 studies showed that more women taking relugolix combination therapy (75% from SPIRIT 1 and 75% from SPIRIT 2) for 24 weeks had both less pelvic or groin pain during menstrual periods from endometriosis and no need for more pain medicines than women who took placebo (27% from SPIRIT 1 and 30% from SPIRIT 2). The SPIRIT 1 and SPIRIT 2 studies also showed that more women taking relugolix combination therapy (59% from SPIRIT 1 and 66% from SPIRIT 2) for 24 weeks had both less pelvic or groin pain between menstrual periods from endometriosis and no need for more pain medicines than women who took placebo (40% from SPIRIT 1 and 43% from SPIRIT 2). Women taking relugolix combination therapy had less pelvic or groin pain during and between menstrual periods within 4 weeks of starting the medicine. The most common side effects were headaches, the common cold, and hot flushes or feeling hot among women taking relugolix combination therapy, delayed relugolix combination therapy, and placebo. Relugolix combination therapy was considered safe for those with no major medical problems. Women taking relugolix combination therapy had little to no loss of bone mineral density (a way of knowing how strong bones are) after 24 weeks of treatment. WHAT DO THE RESULTS OF THESE STUDIES TELL US?:Women with moderate to severe endometriosis taking relugolix combination therapy had much less pain from endometriosis than women taking placebo. Clinical Trial Registration: NCT03204318 (SPIRIT-1); NCT03204331 (SPIRIT-2) (ClinicalTrials.gov).

INTRODUCTION: Relugolix combination therapy (Relugolix-CT: relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) significantly improved endometriosis-associated pain versus placebo in the SPIRIT 1&2 studies. Efficacy was maintained over 104 weeks in the long-term extension (LTE) study. Bleeding patterns in women treated up to 104 weeks with Relugolix-CT are reported. METHODS: SPIRIT 1&2 were IRB-approved phase 3, 24-week, randomized studies of Relugolix-CT, delayed Relugolix-CT (relugolix 40 mg monotherapy followed by Relugolix-CT; 12 weeks each), or placebo in premenopausal women (age 18–50 years) with moderate-to-severe endometriosis-associated pain. Eligible women completing SPIRIT 1&2 could enroll in the open-label LTE with once-daily Relugolix-CT. Bleeding days per cycle and bleeding patterns were recorded on eDiaries. Amenorrhea was defined as no bleeding over 28 consecutive days. RESULTS: Of 1,261 women originally randomized, 501 completed week 104. Baseline demographics and characteristics were balanced across treatment groups. The proportion of women achieving amenorrhea increased over time: 74.4% (95% CI 68.8–79.4) at week 24, and 82.3% (95% CI 74.6–88.4) at week 104. The average number of bleeding days per cycle (standard deviation) decreased over time from 5.8 (2.4) at baseline to 1.2 (3.3) at week 104. The number of heavy or extremely heavy bleeding days decreased from 1.9 at baseline to 0.0 at week 104. CONCLUSION: Treatment with Relugolix-CT in women with endometriosis-associated pain resulted in high rates of amenorrhea and complete elimination of heavy bleeding, thus demonstrating sustained benefit through 2 years. Findings may support patient counseling.

Background and Aims: Although opposing risk factors have been proposed for mate kirikōpū/endometriosis (oestrogen-dependence) and huahua hua kūao/polycystic ovary syndrome (PCOS; androgen dependence), there is a cohort of individuals with both endometriosis and PCOS. We propose that disease comorbidity will alter symptom profiles in comparison to those with only one disease, and that analysis of these differential profiles may hint at underlying mechanisms of disease pathology. Methods: An anonymous online survey was distributed via social media (NZ residents, >18 years) and included questions related to diagnosis, symptoms, treatment and management of endometriosis and/or PCOS. Results: In total, 1323 responses (median [range] = 31 years [18–72]) were received within a two-week period (endometriosis only: n=615, 48%; PCOS only: n=459, 35%; both diseases: n=247, 19%). When asked about symptoms ‘ever experienced’, comorbid individuals report both symptoms commonly ascribed to endometriosis (e.g, dysmenorrhea) as well as those ascribed to PCOS (e.g., irregular periods) thereby exacerbating impacts on quality of life. An exception, the proportion of individuals reporting absent menstrual periods was increased in cormobid individuals (45%) relative to those with endometriosis only (21%), but decreased relative to those with PCOS only (67%), suggesting a more complex interaction between the two diseases. Conclusions: These data highlight the heterogenity of disease phenotype in individuals with endometriosis and/or PCOS. We suggest that an understanding of the intersection of these two common diseases, and a recognition of the associated phenotypic diversity, will provide avenues of research to better understand the pathophysiology of both endometriosis and PCOS.

This presentation will focus on the following innovative areas in medical treatments for endometriosis. Where were we, say, a decade ago compared to where we are now? What diagnostic techniques should we employ to define the population we should treat? Does gold standard surgical treatment help patients avoid unwanted medical treatment - or should it now be the other way round? Do we still believe that medical treatment is not indicated for infertility related to endometriosis? What are the genuinely evidence-based innovative medical treatments for endometriosis? Consensus statements and guidelines represent a clear line in the sand of what may be considered gold standard practice of the time – the World Endometriosis Society’s consensus on current management of endometriosis (2013)1 provides a good perspective on where we were around a decade ago; the ESHRE Guideline (2022)2 reflects best practice today. There is growing consensus that a laparoscopic (+/- histological) diagnosis is no longer practical, or indeed needed, in most cases to implement the whole gamut of medical treatment, even though the entire evidence base for treating endometriosis hinges on laparoscopic diagnosis. Hence, “in 2023, there is a strong case for treatment of endometriosis to be based on a clinical diagnosis of ‘likely endometriosis’ supported by imaging findings, when appropriate, in lieu of a traditional diagnosis by laparoscopy +/- histology”. Following laparoscopic surgery, those not intending to conceive should consider the levonorgestrel intrauterine system or combined oral contraceptive pill for at least 18-24 months to reduce the recurrence of endometriosis-related pain symptoms;2 following surgery for either endometriomas or deep endometriosis, long term hormone therapy should be considered to reduce the chance of recurrence.2 Given the respective evidence bases, progestin hormone therapy may be preferable to the combined oral contraceptive pill to turn the tide of increasing prevalence of endometriosis.3 While medical treatment has not been recommended to improve fertility, indeed a delaying effect on fertility through medical treatment has traditionally been highlighted, innovative analysis methods, including network meta-analysis, have raised the question whether some medical treatments (dydrogesterone and GnRH agonists) might benefit fertility – and this is merit-worthy of further investigation. GnRH antagonists and aromatase inhibitors are the innovative medical treatments that have shifted from ‘showing potential’ to ‘recommended’, so we will delve into the data supporting this to discover that, for aromatase inhibitors, this remains far from convincing, but for GnRH antagonists, these present a genuine innovative medical treatment option for those suffering from endometriosis.

Relugolix combination therapy (Rel-CT [once-daily relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg]) is being developed to treat heavy menstrual bleeding associated with uterine fibroids (UF), and endometriosis-associated pain (EM). In the Phase 3 LIBERTY 1/2 trials and long-term extension (LTE) study for UF, Rel-CT maintained BMD through 52 weeks. In the SPIRIT 1/2 trials and LTE study for EM, Rel-CT minimized BMD loss through 24 weeks, after which BMD plateaued up to 52 weeks. Since the mean age of women in the UF studies was higher than that in the EM studies, a pooled population assessment was undertaken to determine if a single BMD profile with a full range of ages could be developed for Rel-CT. A 52-week observational study in a group of contemporaneous age-matched women with UF or EM (Natural History Study [NHS], N=714) was used to benchmark BMD data from the pivotal and LTE studies. Percent change in BMD from baseline with 95% CI was summarized by treatment group and anatomical location using descriptive statistics: mean, 95% CI (Table). There were 2019 women included in pooled data from the 24-week LIBERTY and SPIRIT studies and associated 28-week LTE studies. Percent change from baseline in pooled BMD was consistent with trends in the separate UF and EM populations. Specifically, at the lumbar spine at Week 12, there was a –0.56% change in BMD with Rel-CT that was not clinically significant and likely reflected adjustment from endogenous to exogenous estradiol in the context of Rel-CT. This timepoint marked the beginning of a plateau. At Week 52, the change from baseline was –0.66% in women treated with Rel-CT compared with 0.19% in women in the NHS (Table). Women initially treated with relugolix monotherapy experienced a larger change in BMD from baseline to Week 12 (–1.84%) that plateaued after transition to Rel-CT with change from baseline to Week 52 of –1.31%.TablePercent change from baseline in lumbar spine BMDNHS (mean, 95% CI)N=714Pooled SPIRIT and LIBERTYRel-CT (mean, 95% CI)N=672Delayed Rel-CT* (mean, 95% CI)N=675Week 12––0.56% (–0.76, –0.36)–1.84% (–2.03, –1.64)Week 240.26% (0.07, 0.44)–0.57% (–0.78, –0.36)–2.00% (–2.23, –1.77)Week 36––0.61% (–0.88, –0.34)–1.67% (–1.94, –1.40)Week 520.19% (–0.04, 0.42)–0.66% (–0.97, –0.35)–1.31% (–1.62, –1.01)*Relugolix monotherapy for 12 weeks then Rel-CT for 40 weeks. Open table in a new tab *Relugolix monotherapy for 12 weeks then Rel-CT for 40 weeks. In premenopausal women with UF or EM, treatment with Rel-CT lead to an initial insignificant decline in BMD followed by a plateau through the 52 weeks of the study.

To evaluate bone mineral density (BMD) changes in women with endometriosis (EM)-associated pain treated with relugolix combination therapy (Rel-CT: relugolix 40 mg, estradiol 1 mg and norethindrone acetate 0.5 mg) in the SPIRIT long-term extension (LTE) study through 104 weeks and post-treatment follow-up (PTFU) for 12 months. In the pivotal SPIRIT 1 and 2 studies, premenopausal women (aged 18–50 years) with moderate-to-severe EM-associated pain were randomized 1:1:1 to receive once-daily Rel-CT, placebo or delayed Rel-CT (relugolix 40 mg monotherapy followed by Rel-CT, 12 weeks each) for 24 weeks. Women who completed SPIRIT 1 or 2 could enroll in the 80-week SPIRIT LTE and receive open-label Rel-CT up to 104 weeks. The study was amended at Week 104 to include PTFU at Month 6 (M6) and 12 (M12) after treatment cessation in all women, regardless of whether they met protocol-specified BMD loss criteria compared with pivotal study baseline. Least squares (LS) mean percent change from pivotal study baseline to Week 104 and M6 and M12 PTFU were summarized on the Week 104 completers using a mixed-effects model to account for patient attrition during the PTFU period. Mean percent changes were derived using last-observation-carried-forward (LOCF) to assess robustness of the model-based analysis. In SPIRIT 1 and 2, 1261 women were randomized and 1041 completed Week 24 of treatment. Of 802 (77%) women who entered the SPIRIT LTE, 501 (62%) women completed Week 104 of treatment. In the LTE safety population at lumbar spine, a small but not clinically meaningful BMD decline (<1%) was observed in women receiving Rel-CT at Week 12 that subsequently plateaued starting at Week 36 and was sustained for the duration of treatment of 104 weeks. For women treated with Rel-CT who completed 104 weeks of treatment (n=172), there were 43 and 55 women who had PTFU performed at M6 and M12, respectively. LS mean percent changes in BMD from baseline at Week 104, M6 and M12 PTFU at the lumbar spine were -0.41% (95% CI: –1.07, 0.26), 0.30% (95% CI: –0.52, 1.13) and 0.55% (95% CI: –0.25, 1.35), respectively. When analyzed by LOCF, mean percent changes from baseline at the lumbar spine were –0.18% (95% CI: –0.77, 0.41), –0.03% (95% CI: –0.58, 0.52) and 0.01% (95% CI: –0.54, 0.55), respectively. In women with EM-associated pain treated with Rel-CT whose changes in BMD were evaluated after treatment cessation, there was evidence of recovery, regardless of whether they maintained or lost BMD after two years of treatment.

BACKGROUND:Currently, there are five major approaches to hysterectomy for benign gynaecological disease: abdominal hysterectomy (AH), vaginal hysterectomy (VH), laparoscopic hysterectomy (LH), robotic-assisted hysterectomy (RH) and vaginal natural orifice hysterectomy (V-NOTES). Within the LH category we further differentiate the laparoscopic-assisted vaginal hysterectomy (LAVH) from the total laparoscopic hysterectomy (TLH) and single-port laparoscopic hysterectomy (SP-LH).OBJECTIVES:To assess the effectiveness and safety of different surgical approaches to hysterectomy for women with benign gynaecological conditions.SEARCH METHODS:We searched the following databases (from their inception to December 2022): the Cochrane Gynaecology and Fertility Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase, CINAHL and PsycINFO. We also searched the trial registries and relevant reference lists, and communicated with experts in the field for any additional trials.SELECTION CRITERIA:We included randomised controlled trials (RCTs) in which clinical outcomes were compared between one surgical approach to hysterectomy and another.DATA COLLECTION AND ANALYSIS:At least two review authors independently selected trials, assessed risk of bias and performed data extraction. Our primary outcomes were return to normal activities, satisfaction and quality of life, intraoperative visceral injury and major long-term complications (i.e. fistula, pelvic-abdominal pain, urinary dysfunction, bowel dysfunction, pelvic floor condition and sexual dysfunction).MAIN RESULTS:We included 63 studies with 6811 women. The evidence for most comparisons was of low or moderate certainty. The main limitations were poor reporting and imprecision. Vaginal hysterectomy (VH) versus abdominal hysterectomy (AH) (12 RCTs, 1046 women) Return to normal activities was probably faster in the VH group (mean difference (MD) -10.91 days, 95% confidence interval (CI) -17.95 to -3.87; 4 RCTs, 274 women; I2 = 67%; moderate-certainty evidence). This suggests that if the return to normal activities after AH is assumed to be 42 days, then after VH it would be between 24 and 38 days. We are uncertain whether there is a difference between the groups for the other primary outcomes. Laparoscopic hysterectomy (LH) versus AH (28 RCTs, 3431 women) Return to normal activities may be sooner in the LH group (MD -13.01 days, 95% CI -16.47 to -9.56; 7 RCTs, 618 women; I2 = 68%, low-certainty evidence), but there may be more urinary tract injuries in the LH group (odds ratio (OR) 2.16, 95% CI 1.19 to 3.93; 18 RCTs, 2594 women; I2 = 0%; moderate-certainty evidence). This suggests that if the return to normal activities after abdominal hysterectomy is assumed to be 37 days, then after laparoscopic hysterectomy it would be between 22 and 25 days. It also suggests that if the rate of ureter injury during abdominal hysterectomy is assumed to be 0.2%, then during laparoscopic hysterectomy it would be between 0.2% and 2%. We are uncertain whether there is a difference between the groups for the other primary outcomes. LH versus VH (22 RCTs, 2135 women) We are uncertain whether there is a difference between the groups for any of our primary outcomes. Both short- and long-term complications were rare in both groups. Robotic-assisted hysterectomy (RH) versus LH (three RCTs, 296 women) None of the studies reported satisfaction rates or quality of life. We are uncertain whether there is a difference between the groups for our other primary outcomes. Single-port laparoscopic hysterectomy (SP-LH) versus LH (seven RCTs, 621 women) None of the studies reported satisfaction rates, quality of life or major long-term complications. We are uncertain whether there is a difference between the groups for rates of intraoperative visceral injury. Total laparoscopic hysterectomy (TLH) versus laparoscopic-assisted vaginal hysterectomy (LAVH) (three RCTs, 233 women) None of the studies reported satisfaction rates or quality of life. We are uncertain whether there is a difference between the groups for rates of intraoperative visceral injury or major long-term complications. Transvaginal natural orifice transluminal endoscopic surgery (V-NOTES) versus LH (two RCTs, 96 women) We are uncertain whether there is a difference between the groups for rates of bladder injury. Our other primary outcomes were not reported. Overall, adverse events were rare in the included studies.AUTHORS' CONCLUSIONS:Among women undergoing hysterectomy for benign disease, VH appears to be superior to AH. When technically feasible, VH should be performed in preference to AH because it is associated with faster return to normal activities, fewer wound/abdominal wall infections and shorter hospital stay. Where VH is not possible, LH has advantages over AH including faster return to normal activities, shorter hospital stay, and decreased risk of wound/abdominal wall infection, febrile episodes or unspecified infection, and transfusion. These advantages must be balanced against the increased risk of ureteric injury and longer operative time. When compared to LH, VH was associated with no difference in time to return to normal activities but shorter operative time and shorter hospital stay. RH and V-NOTES require further evaluation since there is a lack of evidence of any patient benefit over conventional LH. Overall, the evidence in this review has to be interpreted with caution as adverse event rates were low, resulting in low power for these comparisons. The surgical approach to hysterectomy should be discussed with the patient and decided in the light of the relative benefits and hazards. Surgical expertise is difficult to quantify and poorly reported in the available studies and this may influence outcomes in ways that cannot be accounted for in this review. In conclusion, when VH is not feasible, LH has multiple advantages over AH, but at the cost of more ureteric injuries. Evidence is limited for RH and V-NOTES.

Once-daily relugolix combination therapy (Rel-CT; relugolix 40 mg, estradiol [E2] 1 mg, norethindrone acetate [NETA] 0.5 mg) in women with endometriosis-associated pain was associated with maintained efficacy on dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) through 104 weeks (Becker, ESHRE 2022). Here, the effect of Rel-CT on BMD was assessed for up to 104 weeks (wks) in the SPIRIT LTE study.

Objective . Hysterosalpingography (HSG) with oil-soluble contrast medium (OSCM) improves pregnancy rates in women with idiopathic infertility. However, OSCM has high iodine content and slow clearance resulting in potential iodine excess. If pregnancy occurs, this could impact fetal thyroid gland development and function. We aim to determine the effect of a preconceptional OSCM HSG on the thyroid function of the neonate. Design and Patients . This was a retrospective analysis of newborn TSH data for a cohort of neonates conceived within six months of an OSCM HSG in the Auckland region, New Zealand, from the years 2000 to 2019. Thyroid-stimulating hormone (TSH) levels of these newborns were obtained from newborn screening, which is routinely performed for all children at 48–72 hours of life. The primary outcome was the incidence of permanent or transient congenital hypothyroidism in this cohort. Results . Of 146 babies included, all had normal TSH levels with values ranging from 1 to 7 mIU/L on the whole blood analysis of a capillary heel sample using the Perkin–Elmer AutoDelfia assay. Conception during the first 3 cycles following an OSCM HSG was 76%; however, TSH levels in this group were not higher than those conceived in later cycles. Conclusion . Preconceptional OSCM HSG did not increase the risk of congenital hypothyroidism in the New Zealand scenario.

Chronic pelvic pain (CPP) causes important negative effects on quality of life. Endometriosis is the most common cause of CPP in females, and diagnostic delay is over six years internationally. Data remain scarce for CPP impact or diagnostic delay in Aotearoa New Zealand. This study used an online survey to explore the impact of CPP on various life domains for those aged over 18. Additionally, for those with an endometriosis diagnosis, diagnostic delay and factors affecting this over time were explored. There were 800 respondent (620 with self-reported endometriosis). CPP symptoms, irrespective of final diagnosis, started prior to age 20 and negatively impacted multiple life domains including employment, education, and relationships. Mean diagnostic delay for those with endometriosis was 8.7 years, including 2.9 years between symptom onset and first presentation and 5.8 years between first presentation and diagnosis. Five doctors on average were seen prior to diagnosis. However, there was a reduction in the interval between first presentation and diagnosis over time, from 8.4 years for those presenting before 2005, to two years for those presenting after 2012. While diagnostic delay is decreasing, CPP, irrespective of aetiology, continues to have a significant negative impact on the lives of those affected.

Chronic pelvic pain (CPP) causes important negative effects on quality of life. Endometriosis is the most common cause of CPP in females, and diagnostic delay is over six years internationally. Data remain scarce for CPP impact or diagnostic delay in Aotearoa New Zealand. This study used an online survey to explore the impact of CPP on various life domains for those aged over 18. Additionally, for those with an endometriosis diagnosis, diagnostic delay and factors affecting this over time were explored. There were 800 respondent (620 with self-reported endometriosis). CPP symptoms, irrespective of final diagnosis, started prior to age 20 and negatively impacted multiple life domains including employment, education, and relationships. Mean diagnostic delay for those with endometriosis was 8.7 years, including 2.9 years between symptom onset and first presentation and 5.8 years between first presentation and diagnosis. Five doctors on average were seen prior to diagnosis. However, there was a reduction in the interval between first presentation and diagnosis over time, from 8.4 years for those presenting before 2005, to two years for those presenting after 2012. While diagnostic delay is decreasing, CPP, irrespective of aetiology, continues to have a significant negative impact on the lives of those affected.

Abstract Study question To assess the long-term efficacy and safety of once-daily Relugolix combination therapy (Relugolix-CT) in the treatment of endometriosis-associated pain over two years. Summary answer Relugolix-CT previously demonstrated sustained improvement of endometriosis-associated pain and was generally well tolerated over 52 weeks. Research is ongoing: two-year results will be reported. What is known already SPIRIT 1&2 were international, Phase 3, replicate, randomized, double-blind, placebo-controlled studies of Relugolix-CT (relugolix 40mg, estradiol 1mg, norethisterone acetate 0.5mg) in premenopausal women with moderate-to-severe endometriosis-associated pain, which were followed by the open-label, 80-week, long-term extension. 52-week results showed sustained improvement in dysmenorrhea and non-menstrual pelvic pain (NMPP) with 84.8% and 73.3% of responders, respectively. Efficacy was evidenced by reductions in dysmenorrhea (82.8%,) NMPP (62.9%,) proportion of women using opioids, and improvements in function. Relugolix-CT was generally well tolerated. Bone mineral density (BMD) assessment showed minimal initial decline (<1%) from baseline followed by stabilization from Week 24 to 52. Study design, size, duration Women who completed the 24-week pivotal studies (SPIRIT 1&2) were eligible to enroll in an 80-week open-label, single-arm, long-term extension study of safety and efficacy, representing up to 104 weeks of treatment in total. All women enrolled in the long-term extension study received once-daily oral Relugolix-CT. Analyses were performed based on the initial randomized treatment groups in pivotal studies: Relugolix-CT, delayed Relugolix-CT (relugolix 40mg alone for 12 weeks, then Relugolix-CT for 12 weeks), or placebo. Participants/materials, setting, methods Primary endpoints are proportion of dysmenorrhea and NMPP responders at Weeks 52 and 104 based on daily Numerical Rating Scale (NRS) scores (0=no pain, 10=worst pain imaginable) and analgesic use. Responders are women who achieved a predefined, clinically meaningful reduction from baseline in NRS score and no increase in analgesic use. Secondary efficacy endpoints include change in Endometriosis Health Profile-30 pain domain scores, use of opioids/analgesics. Safety endpoints include adverse events and BMD (percent change). Main results and the role of chance Of 1251 randomized patients in SPIRIT 1&2, 1044 (83.4%) completed the pivotal studies; 802 (76.8%) enrolled in the long-term extension, and 681 (84.9%) completed 52 weeks of treatment. Baseline demographics and clinical characteristics of the long-term extension population were consistent with those of the pivotal study population. The study remains ongoing at the time of writing. Efficacy and safety data with Relugolix-CT for up to Week 104, will be presented at the scientific session of the 2022 congress. Limitations, reasons for caution The study was conducted as an open-label study without a control group over the 80 weeks of the extension period. Wider implications of the findings Through 52 weeks of treatment, Relugolix-CT demonstrated sustained improvement of dysmenorrhea, NMPP, function, and reduced need for opiates in women with endometriosis-associated pain. No new safety concerns were identified, and treatment was associated with BMD loss <1%. Data from 104 weeks of treatment will be presented at the 2022 congress. Trial registration number NCT03654274