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Objective: To assess the adequate ovarian follicular development and oocyte recovery between ovarian potential (antral follicle count [AFC]) before the start of ovarian stimulation (OS) and oocyte quantity and quality at oocyte retrieval. A holistic overview of the current key performance indicators (KPIs) was applied to identify the complementary strengths and identify where the current repertoire can be expanded., Design: Expert opinion., Setting: Not applicable., Patient(s): Not applicable., Intervention(s): None., Main Outcome Measure(s): To formulate a proposal for a refined and expanded repertoire of KPIs for individualized OS for assisted reproductive technology., Result(s): The performance and outcomes of OS on ovarian follicular development can be evaluated through the application of defined KPIs. Current KPIs for OS are the ovarian sensitivity index, follicular output rate (FORT), oocyte retrieval rate, and follicle-to-oocyte index (FOI). Notably, there are no specific KPIs dedicated to the assessment of follicular development (i.e., recruitment, selection, growth, and dominance). In light of this, we recommend expanding the current KPIs for OS to include "early FORT" (accounting for the number of follicles measuring ≥10 to 11 mm on day 5/6 of OS relative to AFC) and "modified FORT" (the ratio between the number of follicles measuring ≥12 mm at the time of oocyte maturation triggering and AFC); the extension of oocyte retrieval rate to include two discrete categories at oocyte retrieval-follicles measuring ≥12 mm and ≥16 mm-to ensure that all responsive follicles are accounted for; and FOI to be measured at oocyte maturation triggering and oocyte retrieval ("advanced FOI")., Conclusion(s): Once validated and adopted in clinical practice, we envisage that the proposed expanded KPIs measuring the effect of OS on follicular development (recruitment, selection, growth, and dominance) will increase the understanding of the relationship between ovarian reserve, measured by AFC, and oocyte quantity and quality at oocyte retrieval. This understanding will enable physicians to better evaluate the direct effect of different gonadotropins and doses on ovarian response, leading to a more personalized approach to OS in the context of assisted reproductive technology treatment., Competing Interests: Declaration of Interests S.K.S. reports receipt of payment or honoraria for nonpromotional educational lectures from Merck, Ferring, and MSD. J.-E.S. is an employee of Merck Healthcare KGaA, Darmstadt, Germany. R.O. reports receipt of consulting fees from Merck and Ferring and payment or honoraria for lectures from Merck and Ferring. RF has received honoraria for lectures from Merck Healthcare KGaA, Medea and Event Planet. M.H.D. has nothing to disclose. S.C.E. has received unrestricted research grants from Merck KGaA and consulting fees from Merck, Medea, and Event Planet; payment or honoraria for lecture fees from Merck, Sanitanova, Medea, and Event Planet; has a patent on the ART calculator; and is an advisory board member for Nature Reviews Urology (unpaid), Head of the Andrology Committee of the Brazilian Society of Human Reproduction (unpaid), and Co-chair of the Male Infertility Group, WHO Infertility Guidelines (unpaid). M.L. is an employee of Merck Healthcare KGaA, Darmstadt, Germany. T.D. is an employee of Merck Healthcare KGaA, Darmstadt, Germany. C.A. declares receipt of personal fees from Merck, Medea, Event Planet, IBSA, Ely Lilly, and Biogen and payment or honoraria from Merck, Medea, Event Planet, IBSA, and Ferring., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: The clinical management of women with diminished ovarian reserve (DOR) is a challenge in the field of medically assisted reproduction. Several therapeutic strategies have been proposed, but with mixed results, mainly because the definition of DOR used was inconsistent among trials., Objective: To investigate adjuvant treatments and protocols involving only women with DOR according to POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) criteria., Data Sources: We conducted a systematic search using the MEDLINE (PubMed), EMBASE, and ISI Web of Knowledge databases to identify relevant studies published up to June 2024.The review protocol was registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number: CRD42022346117)., Study Selection and Synthesis: After duplication removal, the titles and abstracts of 4,806 articles were scrutinized, and 124 full-text articles were assessed for eligibility. In total, 38 randomized controlled trials were included in the qualitative/quantitative analysis. The following interventions were evaluated: dehydroepiandrosterone (n = 1,336); testosterone (n = 418); high- vs. low-dose gonadotropin (n = 957); delayed-start protocol with gonadotropin hormone-releasing hormone antagonist (n = 398); letrozole (n = 612); clomiphene citrate (1,113); growth hormone (311); luteal phase stimulation (n = 57); dual triggering (n = 139); dual stimulation (168); luteinizing hormone (979); oestradiol pretreatment (n = 552); and corifollitropin alfa (n = 561)., Main Outcomes: The primary outcome was live birth rate or ongoing pregnancy if data on live birth were unavailable. Secondary outcomes were number of oocytes retrieved, number of metaphase II oocytes, clinical pregnancy rate and miscarriage rate., Results: Testosterone supplementation is associated with higher live birth rates compared with nonsupplemented women among all interventions evaluated (odds ratio: 2.19, 95% confidence interval [CI]: 1.11-4.32, four studies, 368 patients). Testosterone (weighted mean difference [WMD] 0.88, 95% CI: 0.03-1.72; 4 studies, n = 368 patients), dehydroepiandrosterone (WMD 0.60, 95% CI: 0.07-1.13; 4 studies, n = 418 patients), and delayed started protocol (WMD 1.32, 95% CI: 0.74 to 1.89; 3 studies, n = 398 patients) significantly improved the total number of eggs collected. Lower number of oocytes retrieved is achieved in women undergoing low dose gonadotropin regimen vs high dose (WMD: -1.57, 95% CI: -2.12 to -1.17; 2 studies, n = 905 patients), The other interventions did not produce significant improvements., Conclusion and Relevance: Specific interventions such as testosterone seem to correlate with a better live birth rate in women with DOR; these findings should be further explored in randomized trials., Competing Interests: Declaration of Interests C.A. reports honoraria from Merck, Serono, Medea, Event Planet, and IBSA outside the submitted work. D.C. reports honoraria from IBSA, Merck KGaA, Organon, and Fairtility; leadership, positions: ESHRE SIG implantation and Early Pregnancy, SIERR, Associate Editor Human Reproduction Update outside the submitted work. A.C. reports honoraria from Merck, Serono, Medea, and Event Planet outside the submitted work. S.C.E. reports honoraria from Merck outside the submitted work. L.R. reports honoraria from Merck KGaA, MSD, Ferring, IBSA, Gedeon Richter, Cooper Surgical, and Cook; leadership positions: Nterilizer and Editor of Reproductive BioMedicine Online outside the submitted work. F.M.U. reports honoraria from Merck KGaA, MSD, Ferring, IBSA, Gedeon Richter, Cooper Surgical, and Cook; President of SIFES-MR outside the submitted work. A.V. reports honoraria from Meck, MSD- Organon, Gedeon Richer, and Ferring; travel support from Ferring, Theramex, and Merck; advisory board Scientific Seminars outside the submitted work. A.C., F.M.U., L.R., A.V., S.C.E., and C.A. report personal fees and honoraria outside the submitted work. S.L. is Senior Medical Director Fertility, Clinical Development, Merck KGaA, Darmstadt, Germany. T.D.H. is Vice President and Head of Global Medical Affairs Fertility, Research and Development, Merck Healthcare KGaA, Darmstadt, Germany. L.C. has nothing to disclose. R.D.G. has nothing to disclose. G.G.I. has nothing to disclose. M.G. has nothing to disclose. M.R.C. has nothing to disclose. C.R. has nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Randomized controlled trials (RCTs) are the cornerstone of evidence-based medicine. In this series in Fertility and Sterility, several aspects of RCTs are discussed, with contributions on multicenter RCTs, different international settings, and integrity of RCTs. The present contribution deals with methodologic issues. We discuss different types of RCTs based on null hypothesis (superiority vs. noninferiority vs. equivalence) as well as frequentist versus Bayesian interpretation. We also discuss the use of RCTs in the era of personalized medicine and RCTs to address diagnostic and prognostic questions. Finally, we address the use of big data compared with the use of RCTs., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Although most medical treatments are designed for the average patient with a one-size-fits-all-approach, they may not benefit all. Better understanding of the function of genes, proteins, and metabolite, and of personal and environmental factors has led to a call for personalized medicine. Personalized reproductive medicine is still in its infancy, without clear guidance on treatment aspects that could be personalized and on trial design to evaluate personalized treatment effect and benefit-harm balance. While the rationale for a personalized approach often relies on retrospective analyses of large observational studies or real-world data, solid evidence of superiority of a personalized approach will come from randomized trials comparing outcomes and safety between a personalized and one-size-fits-all strategy. A more efficient, targeted randomized trial design may recruit only patients or couples for which the personalized approach would differ from the previous, standard approach. Multiple monocenter studies using the same study protocol (allowing future meta-analysis) might reduce the major center effect associated with multicenter studies. In certain cases, single-arm observational studies can generate the necessary evidence for a personalized approach. This review describes each of the main segments of patient care in assisted reproductive technologies treatment, addressing which aspects could be personalized, emphasizing current evidence and relevant study design., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of luteal phase support (LPS) in intrauterine insemination (IUI) cycles stimulated with gonadotropins., Design: Randomized multicenter trial., Setting: Academic tertiary care centers and affiliated secondary care centers., Patient(s): Three hundred and ninety-three normo-ovulatory patients, <43 years, with body mass index ≤30 kg/m 2 , in their first IUI cycle, with at least one patent tube, a normal uterine cavity, and a male partner with total motile sperm count ≥5 million after capacitation., Intervention(s): Gonadotropin stimulation, IUI, randomization to LPS using vaginal progesterone gel (n = 202) or no LPS (n = 191)., Main Outcome Measure(s): Clinical pregnancy rate, live-birth rate, miscarriage rate, and duration of the luteal phase., Result(s): The primary outcome, the clinical pregnancy rate, was not statistically different between the treatment group (16.8%) and the control group (11%) (relative risk [RR] 1.54; 95% confidence interval [CI], 0.89-2.67). Similarly, the secondary outcome, the live-birth rate, was 14.9% in the treatment group and 9.4% in the control group (RR 1.60; 95% CI, 0.89-2.87). The mean duration of the luteal phase was about 2 days longer in the treatment group (16.6 ± 2.2 days) compared with the control group (14.6 ± 2.5 days) (mean difference 2.07; 95% CI, 1.58-2.56)., Conclusion(s): Although a trend toward a higher clinical pregnancy rate as well as live-birth rate was observed in the treatment group, the difference with the control group was not statistically significant., Clinical Trial Registration Number: NCT01826747., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To study single nucleotide polymorphisms (SNPs) involved in angiogenesis (VEGF, PLGF, VEGFR1, VEGFR2, HIF-1α) and plasma levels of the corresponding proteins (VEGF, PLGF, sVEGFR1, sVEGFR2) in women with and without endometriosis., Design: Allele frequencies of vascular endothelial growth factor (VEGF) pathway SNPs and plasma levels of the corresponding proteins were investigated in patients with endometriosis and in controls., Setting: University hospital., Patient(s): Samples of DNA from 1,931 Caucasian patients were included (1,109 patients with endometriosis and 822 controls). An additional study group included 973 DNA samples from volunteers, self-reported to be healthy without laparoscopic evaluation., Intervention(s): Women who underwent a laparoscopy for subfertility and/or pain and healthy volunteers without laparoscopic evaluation., Main Outcome Measure(s): Functional SNPs of the VEGF, VEGFR1, VEGFR2, HIF-1α genes and Hap Map tagging SNPs of the PLGF gene were genotyped by using iPLEX technology on a Sequenom MassArray and TaqMan SNP Genotyping Assay. The VEGF levels were determined in ethylenediaminetetraacetic acid plasma samples by using Bio-Plex Protein Array System. PLGF, sVEGFR1, and sVEGFR2 levels were measured in ethylenediaminetetraacetic acid plasma samples by using ELISA Quantikine kits., Result(s): A significant association was found between the rs2268613 polymorphism in the PLGF gene and PLGF plasma levels. In all study subjects, women with the AA variant of the rs2268613 PLGF gene had significantly lower PLGF plasma levels (median [interquartile range] 9.36 [8.19-10.43] pg/mL) than those with the AG variant (12.1 [11.81-20.84] pg/mL; P(a)=.0085, P(b)=.04), both before and after multiple testing. Plasma levels of VEGF were elevated in endometriosis patients (especially in minimal-mild endometriosis during the menstrual cycle phase) compared with laparoscopic controls but had a moderate diagnostic performance (area under the curve, 0.73) in this discovery dataset. At a cut-off plasma level of VEGF >3.88 pg/mL, minimal-mild stages of endometriosis were diagnosed with a sensitivity of 74% and a specificity of 80% during the menstrual phase of cycle. The associations between the presence of endometriosis and SNPs in PLGF (rs2268614), HIF-1α (rs11549465), and VEGFR1 (rs9582036) genes lost statistical significance after multiple testing., Conclusion(s): Genetic variants in the PLGF rs2268613 gene may influence plasma levels of the corresponding protein. Plasma levels of VEGF were elevated in endometriosis patients compared with controls. The associations between the presence of endometriosis and SNPs in PLGF (rs2268614), HIF-1α (rs11549465), and VEGFR1 (rs9582036) genes lost statistical significance after multiple testing., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

A noninvasive test for endometriosis would be useful for the early detection of endometriosis in symptomatic women who have pelvic pain and/or subfertility with normal ultrasound results. This would include nearly all cases of minimal-to-mild endometriosis, some cases of moderate-to-severe endometriosis without a clearly visible ovarian endometrioma, and cases with pelvic adhesions and/or other pelvic pathology that might benefit from surgery to improve pelvic pain and/or subfertility. This overview discusses the diagnostic performance of noninvasive or semi-invasive tests for endometriosis, including panels of known peripheral blood biomarkers, protein/peptide markers discovered by proteomics, miRNA, and endometrial nerve fiber density. Tests with high sensitivity and acceptable specificity have been developed; some have been validated in independent populations and are therefore promising. To make real progress, international agreement on biobank development is needed for standard operating procedures for the collection, treatment, storage, and analysis of tissue samples and for detailed clinical phenotyping of these samples. Furthermore, it is necessary to validate the diagnostic accuracy of any promising test prospectively in an independent symptomatic patient population with subfertility and/or pain without clear ultrasound evidence of endometriosis and with a clinical indication for surgery, divided into cases with laparoscopically and histologically confirmed endometriosis and controls with laparoscopically confirmed absence of endometriosis., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

This study indicates that the immunobiology of macroscopically normal peritoneum is relevant to understand the pathogenesis of endometriosis. Peritoneal interleukin 6, interleukin 12, and ferritin were differentially expressed in women with and without endometriosis., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the impact of endometriosis on health-related quality of life (HRQoL) and work productivity., Design: Multicenter cross-sectional study with prospective recruitment., Setting: Sixteen clinical centers in ten countries., Patient(s): A total of 1,418 premenopausal women, aged 18-45 years, without a previous surgical diagnosis of endometriosis, having laparoscopy to investigate symptoms or to be sterilized., Intervention(s): None., Main Outcome Measure(s): Diagnostic delay, HRQoL, and work productivity., Result(s): There was a delay of 6.7 years, principally in primary care, between onset of symptoms and a surgical diagnosis of endometriosis, which was longer in centers where women received predominantly state-funded health care (8.3 vs. 5.5 years). Delay was positively associated with the number of pelvic symptoms (chronic pelvic pain, dysmenorrhoea, dyspareunia, and heavy periods) and a higher body mass index. Physical HRQoL was significantly reduced in affected women compared with those with similar symptoms and no endometriosis. Each affected woman lost on average 10.8 hours (SD 12.2) of work weekly, mainly owing to reduced effectiveness while working. Loss of work productivity translated into significant costs per woman/week, from US$4 in Nigeria to US$456 in Italy., Conclusion(s): Endometriosis impairs HRQoL and work productivity across countries and ethnicities, yet women continue to experience diagnostic delays in primary care. A higher index of suspicion is needed to expedite specialist assessment of symptomatic women. Future research should seek to clarify pain mechanisms in relation to endometriosis severity., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine [1] expression levels of both DNA methyltransferases (DNMTs) and methyl-CpG-binding domain proteins (MBDs) in human endometrium throughout the menstrual cycle and in eutopic and ectopic endometrium of patients with endometriosis and [2] hormone responsiveness of DNMT and MBD expression in explant cultures of proliferative phase endometrium., Design: In vitro study., Setting: Academic medical center., Patient(s): Premenopausal women with and without endometriosis., Intervention(s): Explant cultures of proliferative phase endometrium were treated with vehicle, 17β-E(2), or a combination of E(2) and P (E(2) + P) for 24 hours., Main Outcome Measure(s): Expression levels of DNMT1, DNMT2, and DNMT3B and MBD1, MBD2, and MeCP2 with use of real-time quantitative polymerase chain reaction., Result(s): Expression levels of DNMT1 and MBD2 were significantly higher in secretory-phase endometrium compared with proliferative endometrium and menstrual endometrium. In explant cultures, treatment with E(2) + P resulted in significant up-regulation of DNMT1 and MBD2. Expression levels of several DNMTs and MBDs were significantly lower in endometriotic lesions compared with eutopic endometrium of women with endometriosis and disease-free controls., Conclusion(s): These findings suggest a role for DNMTs and MBDs in the growth and differentiation of the human endometrium and support the notion that endometriosis may be an epigenetic disease., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To report a case of lower limb compartment syndrome (LLCS) during long duration laparoscopic interventions for resection of extensive endometriosis, and evaluate the efficiency of a novel patient positioning method to reduce its prevalence., Design: Case report and observational study., Setting: University Hospitals, Belgium., Patient(s): Thirty-year-old woman undergoing a long duration laparoscopic intervention for resection of stage IV pelvic endometriosis., Intervention(s): Laparoscopic intervention for resection of stage IV pelvic endometriosis., Main Outcome Measure(s): The occurrence of LLCS after laparoscopic surgery for extensive endometriosis, in this case, and the prevention of subsequent LLCS after the application of a novel patient positioning method including the following steps: maximal avoidance of the lithotomy position, patient positioning in a modified supine position, mobilization of the legs of the patient in between different surgical phases, and application of intermittent compression stockings., Result(s): The prevalence of lower limb compartment syndrome has been reduced to 0 since the application of the new patient positioning method., Conclusion(s): Lower limb compartment syndrome can be prevented in patients undergoing long duration multidisciplinary laparoscopic resection of extensive endometriosis by a novel sequential positioning method of patients before and during surgery.

Objective: To determine the prevalence of histologically proven endometriosis in a subset of infertile women., Design: Retrospective case series with electronic file search and multivariable logistic regression analysis., Setting: Tertiary academic fertility center., Patient(s): Two hundred twenty-one infertile women without previous surgical diagnosis for infertility with regular cycles (variation, 21-35 days) whose partners have a normal semen analysis., Intervention(s): Diagnostic laparoscopy and, if necessary, operative laparoscopy with CO(2) laser excision., Main Outcome Measurement(s): The prevalence of endometriosis and of fertility-reducing nonendometriotic tubal and/or uterine pathology., Result(s): The prevalence of endometriosis was 47% (104/221), including stage I (39%, 41/104), stage II (24%, 25/104), stage III (14%, 15/104), and stage IV (23%, 23/104) endometriosis, and was comparable in patients with (54%, 61/113) and without (40%, 43/108) pelvic pain. The prevalence of fertility-reducing nonendometriotic tubal and/or uterine pathology was 29% in all patients (15% in women with and 40% in women without endometriosis). A multivariate logistic regression model including pain, ultrasound data, age, duration of infertility, and type of fertility was not or not sufficiently reliable for the prediction of endometriosis according to the revised American Fertility Society (rAFS) classifications I-II and rAFS III-IV, respectively., Conclusion(s): Reproductive surgery is indicated in infertile women belonging to the study population, regardless of pain symptoms or transvaginal ultrasound results, since half of them have endometriosis and 40% of those without endometriosis have fertility-reducing pelvic pathology.

Objective: To extend existing research on the psychological impact of IVF by studying the association between the psychosocial factors of self-criticism and dependency, and romantic attachment, with the well-being and relationship satisfaction of couples across the different phases of IVF/intracytoplasmic sperm injection (ICSI) treatment., Design: Prospective, three-wave study (i.e., from start of IVF/ICSI treatment, to 3- and 6-month follow-up)., Setting: University hospital., Patient(s): Seventy couples in IVF/ICSI treatment., Intervention(s): Psychometric tests were administered at first visit of IVF/ICSI treatment, and at 3- and 6-month follow-up., Main Outcome Measure(s): Psychological well-being, relationship satisfaction., Result(s): Results demonstrated that preexisting psychosocial factors such as self-criticism, dependency, and romantic attachment are more important factors for psychological well-being and relationship satisfaction during IVF/ICSI than gender and treatment-related factors such as duration of fertility problems. In addition, multilevel analysis, a statistical method that is required for the analysis of longitudinal couple data and decomposes variation in three levels (i.e., time, individuals, and couples), showed more variation in psychological well-being and relationship satisfaction between couples, than between individuals and different time measurements., Conclusion(s): Preexisting personality factors and being embedded within a certain couple relationship are important factors for the psychological well-being and relationship satisfaction during IVF/ICSI.

Objective: To determine the effects of a thiazolidinedione (TZD) agonist of peroxisome proliferator-activated receptor (PPAR)-gamma, rosiglitazone, in a baboon model of established endometriosis., Design: Prospective, randomized, placebo-controlled study., Setting: Experimental surgery laboratory at the Institute of Primate Research in Nairobi, Kenya., Animal(s): Endometriosis was induced using intrapelvic injection of eutopic menstrual endometrium in 12 female baboons with a normal pelvis that had undergone at least one menstrual cycle since the time of captivity., Intervention(s): Induction of endometriosis by laparoscopy was performed in 12 baboons with a normal pelvis. Endometrial tissue was extracted from each baboon by curettage, and a standard amount of endometrium was then seeded onto several peritoneal sites. About 34-68 days after the induction of laparoscopy, a pretreatment laparoscopy (baseline disease assessment) was performed in the baboons to record the extent of endometriotic lesions. The 12 baboons were randomized into three groups and treated from the day after the staging laparoscopy for a total duration of 30 days. They received phosphate-buffered saline tablets (n = 4, placebo control; placebo tablets once a day by mouth for 30 days), GnRH-antagonists (n = 4, active control; ganirelix acetate 125 microg/day for 30 days), or rosiglitazone (n = 4, test drug, 2 mg by mouth each day for 30 days). A third and final laparoscopy on day 30 after the start of treatment was performed to record the extent of endometriosis. The type of lesion (typical, red, white, or suspicious) was recorded. Biopsies were obtained to confirm the histological presence of endometriosis., Main Outcome Measure(s): A videolaparoscopy was performed 30 days after treatment to document the number and surface area of endometriotic lesions as well as to calculate the revised American Society for Reproductive Medicine score and stage., Result(s): The surface area of endometriotic lesions was statistically significantly lower in rosiglitazone-treated baboons when compared with the placebo group. Baboons treated with rosiglitazone or ganirelix had a greater negative relative change in surface area of peritoneal endometriotic lesions than controls. The overall weighted appearance of the lesion types suggests that rosiglitazone may deter the development of newer endometriotic lesions., Conclusion(s): A PPAR-gamma ligand, rosiglitazone, effectively diminishes the burden of endometriosis disease in a baboon endometriosis model. This animal model holds promise that a TZD drug may be helpful in women with endometriosis.

Objective: The association between infertility and minimal to mild endometriosis is controversial and poorly understood. The clinical pregnancy rate (PR) per cycle after controlled ovarian hyperstimulation (COH) with or without intrauterine insemination (IUI) is reportedly lower in women with surgically untreated minimal to mild endometriosis than in women with unexplained infertility. It is possible that prior laparoscopic removal of endometriosis has a positive effect on the clinical PR after COH and IUI. Therefore, we tested the hypothesis that after COH and IUI the PR per cycle and the cumulative live-birth rate (CLBR) are equal or higher in women with recently surgically treated minimal to mild endometriosis when compared with women with unexplained infertility., Design: A retrospective, controlled cohort study., Setting: Leuven University Fertility Centre, a tertiary academic referral center., Patient(s): One hundred seven women treated during 259 cycles with COH and IUI including patients with endometriosis (n = 58, 137 cycles) and unexplained infertility (n = 49, 122 cycles). All patients with endometriosis had minimal (n = 41, 100 cycles) or mild (n = 17, 37 cycles) disease that had been laparoscopically removed within 7 months before the onset of treatment with COH and IUI., Intervention(s): Controlled ovarian hyperstimulation using clomiphene citrate (23 cycles) or gonadotrophins (236 cycles) in combination with IUI., Main Outcome Measure(s): Clinical PR per cycle and CLBR within four cycles of treatment with COH and IUI., Result(s): The clinical PR per cycle was comparable in women with minimal or mild endometriosis (21% or 18.9%, respectively) and in women with unexplained infertility (20.5%). The CLBR within four cycles of COH and IUI was also comparable in women with minimal endometriosis, mild endometriosis, and unexplained infertility (70.2%, 68.2 %, 66.5%, respectively)., Conclusion(s): The data from our study suggest that COH and IUI shortly after laparoscopic excision of endometriosis is as effective as COH and IUI in patients with unexplained subfertility.

Objective: This study tests the hypothesis that IUI treatment in cases with isolated teratozoospermia (<10% normal forms using strict criteria, normal motility and normal count), results in a lower cumulative live birth rate compared to cases with normozoospermia., Design: A retrospective cohort study., Setting: An academic fertility center., Patient(s): Eight hundred seventy-two IUI cycles in 440 couples were analyzed., Intervention(s): Couples (n = 440) were classified in three groups: normozoospermia (n = 213), isolated teratozoospermia (n = 104), and male factor infertility (n = 123)., Main Outcome Measure(s): Live birth rate per cycle and cumulative live birth rate (CLBR)., Result(s): The three groups were similar with regard to female age, female infertility factors, and ovarian response after hormonal stimulation. The overall CLBR after four cycles was 41.5%, and was significantly increased in the normozoospermic group (52.8%) when compared to the isolated teratozoospermia group (33.4%) and the male factor infertility group (31.4%)., Conclusion(s): This study documents for the first time that the CLBR after four IUI cycles is significantly and similarly reduced in couples with isolated teratozoospermia as in couples with other sperm defects, when compared to couples with normozoospermia. As with couples with male factor infertility, couples with isolated teratozoospermia should be counseled about other treatment options such as IVF, as the CLBR after three IVF cycles is 70%-80% in our program.

Objective: To determine the prevalence of chromosomal abnormalities in female partners of couples undergoing IVF or intracytoplasmic sperm injection (ICSI)., Design: Prospective study., Setting: Leuven University Fertility Center., Patient(s): Female candidates for IVF or ICSI., Intervention(s): An initial cytogenetic study was performed on peripheral blood lymphocyte cultures using G- and R-banding. In all patients, > or =25 metaphases were examined. If a chromosomal aberration was detected, additional cytogenetic studies were performed for precise identification., Main Outcome Measure(s): Abnormal female karyotypes in comparison with the general female population., Result(s): Cytogenetic analysis was performed in 263 female partners of couples before entering an IVF or ICSI program. The prevalence of autosomal reciprocal balanced translocations was seven times higher in the study group (1.14%) than in the general population (0.16%). All abnormal karyotypes were found in the IVF group with male factor infertility., Conclusion(s): Chromosomal abnormalities are more frequent in the female partners of couples seeking fertility treatment. We recommend chromosomal analysis in women before starting IVF or ICSI treatment, even in the presence of male factor infertility.

Objective: To test the hypothesis that diagnostic laparoscopy can cause pelviperitoneal inflammation., Design: Retrospective analysis of data collected during a prospective controlled study in baboons., Setting: An academic research environment., Animal(s): Samples were collected during laparoscopies in female baboons at the Institute of Primate Research, Kenya., Intervention(s): In the first part of the study, 44 laparoscopies were performed in 16 baboons (5 with a normal pelvis, 11 with endometriosis) during the luteal phase, with a time interval of 1 month. In the second part of the study, 53 laparoscopies were performed in 15 baboons (6 with a normal pelvis, 9 with endometriosis) during the late follicular and luteal phases of one cycle, with a median time of 3-4 days between each laparoscopy., Main Outcome Measure(s): Peritoneal fluid (PF) was measured and analyzed for white blood cell (WBC) concentrations and, in the second part of the study, for the distribution of lymphocyte subsets (CD3, CD4, CD8, and CD20) and for the presence of cytokines transforming growth factor-beta1, interleukin (IL)-6, and IL-10., Result(s): In the first part of the study, PF volumes and WBC concentrations were comparable at the baseline and follow-up laparoscopies. In the second part of the study, PF obtained at the second laparoscopy showed a 10-fold increase in volume, a 3-fold increase in WBC concentration, a 10-fold increase in IL-6 concentration, and a 2-fold increase in transforming growth factor-beta1 concentration when compared with PF obtained at the first laparoscopy. The PF subset of granulocytes and CD3-positive cells was higher and the PF subset of macrophages was lower at follow-up laparoscopies than at the baseline laparoscopy., Conclusion(s): Diagnostic laparoscopy can cause peritoneal inflammation in baboons.

Objective: To examine the influence of depression levels and coping on IVF outcome in women, taking into account the cause of infertility., Design: Prospective clinical study., Setting: A university hospital., Patient(s): Ninety-eight women undergoing IVF treatment., Intervention(s): Psychometric tests were administered at the first visit (day 3) of the investigated treatment cycle., Main Outcome Measure(s): Achievement of pregnancy., Results: The nonpregnant group reported increased expression of negative emotions. In the subgroup with a female indication for IVF, increased depressive symptomatology (correlated with increased expression of negative emotions) was associated with lower pregnancy rates (PRs), whereas in the subgroup with a male indication for IVF, increased depressive symptomatology (correlated with decreased expression of negative emotions) was associated with higher PRs., Conclusion(s): Expression of negative emotions predicts depression levels and outcome in IVF. The cause of infertility should be taken into account when investigating the relation between psychologic functioning and outcome in IVF.

Objective: To test the hypothesis that alpha-glycosidase activity in seminal plasma can predict the outcome of both IUI and IVF., Design: A retrospective cohort study., Setting: Tertiary fertility center in a university hospital., Patient(s): Eighty-three subfertile couples who underwent IUI and 125 subfertile couples who underwent IVF., Intervention: None., Main Outcome Measure(s): Determination of the alpha-glycosidase activity in seminal plasma before an IUI or IVF attempt, correlation of alpha-glycosidase activity and other semen parameters, and prediction of pregnancy using alpha-glycosidase activity in seminal plasma., Result(s): Alpha-glycosidase activity correlated with sperm count. In the IUI group, alpha-glycosidase activity of >23.9 mU/mL predicted pregnancy with a sensitivity of 100% and a specificity of 55.2%. In the IVF group, the outcome could not be predicted with use of any of the semen parameters., Conclusion(s): Alpha-glycosidase activity measured in mU/mL probably can be used as a predictor for IVF and pregnancy in an IUI program but has no predictive value with regard to pregnancy rate in an IVF program.

Objective: To review the value of the baboon as a model for the study of endometriosis., Data Identification and Selection: Studies performed at the Institute of Primate Research in Nairobi, Kenya (1990-1994), and published in peer-reviewed journals., Result(s): Spontaneous endometriosis was found in about 25% of the baboons, and its prevalence increased with the duration of captivity. The laparoscopic appearance, pelvic localization, and microscopic aspects of the disease were similar to endometriosis in women. Microscopic endometriosis in macroscopically normal peritoneum was rare. Sampson's hypothesis (i.e., retrograde menstruation causes endometriosis) was supported by the increased incidence of retrograde menstruation in baboons with spontaneous endometriosis, the observation that cervical occlusion could cause retrograde menstruation and endometriosis, and the finding that intrapelvic injection of menstrual endometrium caused experimental moderate to severe endometriosis similar to the spontaneous disease. During follow-up of more than 2 years, endometriosis in baboons appeared to be a progressive disease, with active remodeling between several types of lesions. Progression was stimulated by high-dose immunosuppression. Fertility was normal in baboons with minimal disease but was reduced in baboons with mild, moderate, or severe endometriosis, possibly related to an increased incidence and recurrence of the luteinized unruptured follicle syndrome., Conclusion(s): The baboon is a good model for the study of endometriosis.

Objectives: To test the hypothesis that fertility is reduced in baboons with endometriosis., Design: Prospective controlled follow-up study., Setting: Institute of Primate Research, Nairobi Kenya., Subjects: Seventy-one baboons, including 34 controls (normal pelvis) and 37 animals with histologically proven endometriosis (16 spontaneous and 21 induced). Baboons with endometriosis had minimal (n = 9), mild (n = 14), moderate (n = 7), or severe (n = 7) disease., Interventions: Seventy-one baboons were mated during 286 cycles., Main Outcome Measures: Cycle fecundity rate, cycle pregnancy rate, cycle abortion rate., Results: Cycle pregnancy rate (excluding spontaneous abortions) was 15% (44/286) and was comparable between controls (19%, 20/104) and baboons with endometriosis (13%, 24/182). The cycle pregnancy rates were 24%, 10%, 7.5%, and 12.5% in animals with minimal, mild, moderate, and severe endometriosis, respectively. The cycle pregnancy rate was significantly lower in baboons with stage III-IV endometriosis (9%, 6/64) and with stage II disease (10%, 7/73) than in animals with stage I endometriosis (24%, 11/45) or in controls with a normal pelvis (19%)., Conclusion: The normal cycle pregnancy rate in baboons with stage I endometriosis and the decreased cycle pregnancy rate in baboons with stage II and stage III-IV disease suggest that fertility decreases with the stage of endometriosis in baboons.

Objective: To investigate how long an ovulation stigma remains visible as determined by serial laparoscopies performed during the luteal phase in baboons., Subjects and Setting: Sixteen female baboons with a normal pelvis (n = 6) and with endometriosis (n = 10) housed at the Institute of Primate Research, Nairobi, Kenya., Interventions: Fifty-six laparoscopies were carried out before ovulation (n = 7) and serially during the luteal phase (n = 49; 3 +/- 1 per baboon): 1 to 2 days (n = 2), 4 to 5 days (n = 15), 8 to 9 days (n = 11), 12 to 13 days (n = 12), and 16 to 17 days (n = 9) after ovulation., Main Outcome Measure: During each laparoscopy the ovaries were screened systematically for the presence and size of an ovulation stigma and/or corpus luteum (CL)., Results: When the laparoscopy was done within 5 days after ovulation, a fresh ovulation stigma was observed in all nine baboons with a normal pelvis or minimal endometriosis, but only in four of seven animals with mild to severe disease. If a fresh ovulation stigma had been observed within 5 days after ovulation (n = 13), it gradually became smaller but remained visible 8 to 9 days after ovulation in 91%, at 12 to 13 days after ovulation in 75%, and at 16 to 17 days after ovulation in 50% of the primates., Conclusion: If a fresh ovulation stigma was observed in baboons within 5 days after ovulation, it diminished in size but remained visible up to 8, 12, and 16 days after ovulation in 91%, 75%, and 50% of animals, respectively. Therefore, diagnostic laparoscopies for the detection of an ovulation stigma in baboons should be performed in the early luteal phase.

Objective: To test the hypothesis that spontaneous endometriosis is a progressive disease in baboons., Design and Setting: Prospective cohort study, Institute of Primate Research, Nairobi, Kenya., Participants: Twelve baboons with histologically proven spontaneous endometriosis., Interventions: Fifty-four serial laparoscopies (4.2 +/- 1.9 per animal, range 1 to 7) were performed after 1 to 3 months (n = 2), 4 to 6 months (n = 1), 7 to 9 months (n = 6), 10 to 12 months (n = 17), 13 to 15 months (n = 7), 16 to 18 months (n = 1), 19 to 21 months (n = 8), 22 to 24 months (n = 8), 25 to 27 months (n = 2), and 30 to 32 months (n = 2)., Main Outcome Measure: During each laparoscopy the pelvis was examined for the presence of endometriosis. The number, size, and type of endometriotic implants were noted on a pelvic map and both endometriosis score and stage were calculated. Remodeling was defined as a change in laparoscopic appearance (typical, subtle, suspicious) of an individual endometriotic lesion. Data were analyzed by a signed rank test., Results: Endometriosis was progressive as shown by the significant increase in the number and surface of lesions and in endometriosis scores after 24 months. The total number of endometriotic lesions after 24 months consisted of 69% new (and mostly subtle) implants, 10% remodeled lesions, and 21% unchanged implants., Conclusions: This study demonstrated that endometriosis in captive baboons undergoing repeated laparoscopies is a dynamic and moderately progressive disease with periods of development and regression and active remodeling between different types of lesions.

Objective: To test the hypothesis that immunosuppression increases the development and progression of endometriosis in baboons., Design: Experimental controlled study., Setting: Institute of Primate Research, Nairobi, Kenya., Participants: Thirty-two baboons (8 with normal pelvis, 10 with spontaneous endometriosis, and 14 with endometriosis induced by intraperitoneal seeding of menstrual endometrium)., Intervention: Daily injection of 0.8 mg/kg IM methylprednisolone and 2 mg/kg azathioprine for 3 months in 16 baboons (4 with normal pelvis, 5 with spontaneous endometriosis, and 7 with induced endometriosis). No treatment was given to the remaining 16 primates., Main Outcome Measures: The change in number and surface area (mm2) of endometriotic lesions was evaluated by laparoscopy in all baboons after 3 months, in 8 animals with induced endometriosis and in 9 primates with spontaneous disease after 7 and 12 months, respectively., Results: Immunosuppressed baboons with spontaneous endometriosis had a significantly higher number and larger surface area of endometriotic lesions than nontreated animals. However, immunosuppressed and nontreated primates with induced endometriosis were comparable with respect to both number and surface area of implants. A transient decrease in typical lesions was noted during immunosuppression. Immunosuppression did not cause the development of endometriosis in baboons with previously documented normal pelvis., Conclusion: Immunosuppression may increase the progression of endometriosis in baboons with spontaneous disease.

Objectives: To determine if microscopic endometriosis exists in visually normal pelvic peritoneum from baboons with and without endometriosis., Design: Observational histologic study at Institute of Primate Research, Nairobi, Kenya., Subjects: Seventeen baboons including 13 adult females (5 with histologically proven endometriosis, 8 with a normal pelvis) and 4 juveniles (1 female and 3 males)., Interventions: Diagnostic laparoscopy with identification of visually normal pelvic peritoneum before euthanasia, followed by laparotomy with excision of a large area (at least 4 x 6 cm or 24 cm2 per animal, 408 cm2 surface in all baboons) of this visually normal-appearing peritoneum., Main Outcome Measure: Presence of microscopic endometriosis (endometrial glands and stroma) in serial sections of visually normal pelvic peritoneum., Results: Two adjacent glandular structures compatible with endometriosis were found in normal peritoneum obtained during menses from one female baboon without macroscopic disease. Microscopic endometriosis was not detected in the other female primates with or without macroscopic disease or in male animals., Conclusion: Microscopic endometriosis was found in only 1 of 14 female baboons (prevalence 7%; 95% confidence interval 0% to 33%) with visually normal pelvic peritoneum. These findings suggest that, with the paucity of human data available, more studies are needed before concluding that massive microscopic disease exists in visually normal-appearing peritoneum of women.

To document the spontaneous evolution of endometriosis, a repeat laparoscopy was performed in 11 baboons after 10 and/or 12 months. The mean number of endometriotic lesions had increased significantly after 10 months (P less than 0.02) because of a high proportion of new lesions (82%). These implants were mainly subtle (67%) and localized on the uterine peritoneum (58%). Progression of endometriosis did not go beyond revised AFS stage I. Additionally, repeat laparoscopy in 10 baboons with an initially normal pelvis showed an endometriosis incidence of 70% after 10 to 12 months. Remodeling of the lesions was apparent in both groups after 12 months. These results suggest that endometriosis is moderately progressive in the baboon. It is possible that multiple laparoscopies could favor the development of endometriosis.