RESUMEN
BACKGROUND: Uterus transplantation (UTx) is an emerging therapy for women with uterine infertility. However, critical questions remain with this procedure including the mechanisms involved in graft rejection. METHODS: In this study, we analyzed the immune profile of ectocervical biopsies from 5 patients after UTx before and during their first episode of rejection using RNA sequencing, quantitative polymerase chain reaction, and imaging mass cytometry. RESULTS: We identified 530 upregulated and 207 downregulated genes associated with graft rejection. Enrichment databases revealed abnormalities of skin-associated genes and the immune system, in particular activation of T and B lymphocytes, and macrophages. Imaging mass cytometry confirmed these observations; in cervical biopsies of 3 women, rejection was associated with the presence of B-cell structures linked to tertiary lymphoid structures, and 2 biopsies from 1 woman with severe rejection episodes and poor prognosis of graft function (repeated miscarriage and implantation failures) were associated with an accumulation of HLA-DR- macrophages, producing granzyme B at the surface of the epithelium. CONCLUSIONS: We showed that rejection of a UTx graft was associated with major alterations of immune markers including the involvement of tertiary lymphoid structures, the most organized of which may be a sign of chronic rejection, and with an increase in HLA-DR- macrophages expressing granzyme B in the case of grade 3 rejection episodes according Mölne's classification. We identified potential emerging biomarkers to predict or diagnose graft rejection (Keratin 1 granzyme B, IL1ß). These findings could lead to development of improved strategies for the identification, prevention, and/or treatment of uterus graft rejection.
RESUMEN
Women suffering from absolute uterine factor infertility (AUFI), due to either lack of a uterus or one unable to sustain neonatal viability, presented as one of the last frontiers in conquering infertility. Following systematic animal research for over a decade, uterus transplantation was tested as a treatment for AUFI in 2012, which culminated in the first human live birth in 2014. The development of uterus transplantation from mouse to human has followed both the Moore Criteria for introduction of a surgical innovation and the IDEAL concept for evaluation of a novel major surgical procedure. In this article we review the important pre-clinical animal and human studies that paved the way for the successful introduction of human uterus transplantation a decade ago. We discuss this in the context of the Moore Criteria and describe the different procedures of preparation, surgeries, post-operative monitoring, and use of assisted reproduction in human uterus transplantation. We review the world-wide activities and associated results in the context of the IDEAL concept for evaluation of surgical innovation and appraise the ethical considerations relevant to uterus transplantation. We conclude that rigorous application of the Moore Criteria and strict alignment with the IDEAL concept has resulted in the establishment of uterus transplantation as a novel, safe and effective infertility therapy that is now being used worldwide for the treatment of women suffering from AUFI.
RESUMEN
AIM: Uterus transplantation (UTx) is an emerging treatment option for women with uterine factor infertility (UFI) or the absence of a functional uterus. This is the study protocol for the first human UTx clinical trial in Australia. MATERIALS AND METHODS: This protocol outlines the approved training program used to plan, diagnose, screen, and treat patients who may be eligible for UTx using living and deceased donors. This multi-site clinical research study includes three tertiary hospital sites within New South Wales (NSW), Australia - Prince of Wales, Royal Hospital for Women and Westmead Hospitals. Our UTx protocol is based on that used by our collaborative partner, the inaugural UTx team in Gothenburg, Sweden. The Swedish UTx team provides ongoing preceptorship for the Australian UTx team. Ethics approval for six UTx procedures using living or deceased donors (Western Sydney Local Health District Human Research Ethics Committee: 2019/ETH138038) was granted in 2020. RESULTS: Results from surgeries and live births will be published. Data will be prospectively entered into the registry of the International Society of Uterus Transplantation (ISUTx), a sub-section of The Transplantation Society (TTS). TRIAL ID: ACTRN12622000917730. DISCUSSION: A multidisciplinary research team has been formed between three tertiary hospitals in Sydney - The Royal Hospital for Women, Prince of Wales and Westmead Hospitals; and with the Swedish UTx, University of Gothenburg. The Swedish team pioneered animal and human UTx studies since 1998, including publishing the first live birth after UTx. (1) This Australian trial commenced in January 2023. CONCLUSION: Uterus transplantation gives women with UFI the opportunity to be gestational and genetic mothers. It is a complex procedure for both the donor and recipient, with medical and surgical risks. An extensive multidisciplinary approach is required to optimise patient safety and graft outcomes. This protocol outlines our Australian UTx team strategy for screening, recruitment, surgical approach, and clinical management of UTx recipients and donors.
Asunto(s)
Infertilidad Femenina , Útero , Humanos , Femenino , Útero/trasplante , Infertilidad Femenina/cirugía , Infertilidad Femenina/terapia , Embarazo , Trasplante de Órganos , Donadores Vivos , Australia , Adulto , Donantes de TejidosRESUMEN
Innovative bioengineering strategies utilizing extracellular matrix (ECM) based scaffolds derived from decellularized tissue offer new prospects for restoring damaged uterine tissue. Despite successful fertility restoration in small animal models, the translation to larger and more clinically relevant models have not yet been assessed. Thus, our study investigated the feasibility to use a 6 cm2 graft constructed from decellularized sheep uterine tissue, mimicking a future application to repair a uterine defect in women. Some grafts were also recellularized with fetal sheep bone marrow-derived mesenchymal stem cells (SF-MSCs). The animals were followed for six weeks post-surgery during which blood samples were collected to assess the systemic immune cell activation by fluorescence-activated cell sorting (FACS) analysis. Tissue regeneration was assessed by histology, immunohistochemistry, and gene expression analyses. There was a large intra-group variance which prompted us to implement a novel scoring system to comprehensively evaluate the regenerative outcomes. Based on the regenerative score each graft received, we focused our analysis to map potential differences that may have played a role in the success or failure of tissue repair following the transplantation therapy. Notably, three out of 15 grafts exhibited major regeneration that resembled native uterine tissue, and an additional three grafts showed substantial regenerative outcomes. For the better regenerated grafts, it was observed that the systemic T-cell subgroups were significantly different compared with the failing grafts. Hence, our data suggest that the T-cell response play an important role for determining the uterus tissue regeneration outcomes. The remarkable regeneration seen in the best-performing grafts after just six weeks following transplantation provides compelling evidence that decellularized tissue for uterine bioengineering holds great promise for clinically relevant applications.
Asunto(s)
Células Madre Mesenquimatosas , Ingeniería de Tejidos , Humanos , Femenino , Animales , Ovinos , Útero , Bioingeniería , Células Madre Mesenquimatosas/metabolismo , Matriz Extracelular/metabolismo , Andamios del TejidoRESUMEN
Gynecological cancer diagnosed during pregnancy requires accurate diagnosis and staging to determine optimal treatment based on gestational age. Cervical and ovarian cancers are the most common and multidisciplinary team collaboration is pivotal. Magnetic resonance imaging and ultrasound can be used without causing fetal harm. In cervical cancer, early-stage treatments can often be delayed until fetal lung maturation and cesarean section is recommended if disease prevails, in combination with a simple/radical hysterectomy and lymphadenectomy. Chemoradiotherapy, the recommended treatment for advanced stages, is not compatible with pregnancy preservation. Most gestational ovarian cancers are diagnosed at an early stage and consist of nonepithelial cancers or borderline tumors. Removal of the affected adnexa during pregnancy is often necessary for diagnosis, though staging can be performed after delivery. In selected cases of advanced cervical and ovarian cancers, neoadjuvant chemotherapy may be an option to allow gestational advancement but only after thorough multidisciplinary discussions and counseling.
Asunto(s)
Neoplasias de los Genitales Femeninos , Neoplasias Ováricas , Complicaciones Neoplásicas del Embarazo , Neoplasias del Cuello Uterino , Embarazo , Femenino , Humanos , Cesárea , Neoplasias del Cuello Uterino/patología , Neoplasias de los Genitales Femeninos/cirugía , Neoplasias Ováricas/patología , Escisión del Ganglio Linfático , Complicaciones Neoplásicas del Embarazo/diagnóstico por imagen , Complicaciones Neoplásicas del Embarazo/terapia , Complicaciones Neoplásicas del Embarazo/patología , Estadificación de Neoplasias , HisterectomíaRESUMEN
STUDY QUESTION: What are the outcomes regarding health-related quality-of-life, mood, and marital relationship of recipients and donors 5 years after uterus transplantation (UTx) and uterus donation? SUMMARY ANSWER: Both recipients and donors generally demonstrated long-term stability regarding psychosocial outcomes but with negative deviations associated with unsuccessful outcomes. WHAT IS KNOWN ALREADY: UTx is the first infertility treatment for women with absolute uterine factor infertility. The procedure can be performed with either a uterus donation from a live donor (LD), typically a close relative, or from a deceased, multi-organ donor. There are many potential stressful events over several years after UTx both for recipients and for LDs and these events may have impacts on quality-of-life and mental well-being. STUDY DESIGN, SIZE, DURATION: This, prospective observational cohort study includes the nine recipients and LDs of the first human UTx trial. They were assessed in 2017-2018 by questionnaires 5 years after UTx. PARTICIPANTS/MATERIALS, SETTING, METHODS: The nine recipients (ages 32-43 years) and their respective LDs (ages 44-67 years) were either related (n = 8) or friends (n = 1). Eight recipients had congenital uterine absence and one was hysterectomized due to cervical cancer. For two recipients, UTx resulted in early graft failures, while six of the other seven recipients gave birth to a total of eight babies over the following 5 years. Physical and mental component summaries of health-related quality-of-life were measured with the SF-36 questionnaire. Mood was assessed by the Hospital Anxiety and Depression Scale. Relationship with partner was measured with the Dyadic Adjustment Scale. Comparisons were made between the values after 5 years and the values before uterus donation/transplantation. MAIN RESULTS AND THE ROLE OF CHANCE: Five years after primary UTx, the majority of recipients scored above the predicted value of the general population on quality-of-life, except for two women, one of whom had a viable graft but no live birth and one recipient who was strained by quality-of-life changes, possibly related to parenthood transitions. Regarding mood, only one value (anxiety) was above the threshold for further clinical assessment. Recipients showed declining satisfaction with their marital relationships, but all reported scores above the 'at risk for divorce' threshold at the time of the final assessment in our study. The LDs were all found to be stable and above the predicted value of the general population regarding mental components of quality-of-life. Three LDs showed declined physical components, possibly related to older age. Only one LD reported a value in mood (anxiety) that would need further assessment. The marital satisfaction of LDs remained stable and unchanged compared to baseline values. Notably, the two recipients with early graft failures, and their related LDs, regained their mental well-being during the first years after graft failure and remained stable after 5 years. LIMITATIONS, REASONS FOR CAUTION: The restricted sample size and the single-centre study-design are limitations of this study. Additionally the study was limited to LD UTx, as opposed to deceased donor UTx. WIDER IMPLICATIONS OF THE FINDINGS: Our study shows that both LDs and recipients had acceptable or favourable quality-of-life outcomes, including mood assessment, at the 5-year follow-up mark, and that failure to achieve a live birth negatively affected these modalities both for LDs and recipients. Moreover, an important finding was that LDs and recipients are not reacting with depression after hysterectomy, which is common after hysterectomy in the general population. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the Jane and Dan Olsson Foundation for Science, Knut and Alice Wallenberg Foundation, Handlanden Hjalmar Svensson Foundation, Swedish Governmental ALF Grant, and Swedish Research Council. There are no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: NCT01844362.
Asunto(s)
Infertilidad Femenina , Humanos , Femenino , Estudios de Seguimiento , Estudios Prospectivos , Infertilidad Femenina/terapia , Útero/anomalías , Donadores Vivos/psicología , Calidad de VidaRESUMEN
Background: Chronic kidney disease is common after non-renal solid organ transplantation, mainly secondary to calcineurin inhibitors toxicity. Uterus transplantation (UTx) is an innovative treatment for women with absolute uterine factor infertility. UTx is exclusive because it is transient with the absence of lifelong immunosuppression and is performed in young healthy participants. Therefore, UTx provides a unique setting for evaluating the effect of time-limited calcineurin inhibitors treatment on recipients' kidney function. Methods: In the first UTx cohort worldwide, we studied kidney function using estimated glomerular filtration rate (eGFR) in 7 women over a median follow-up of 121 (119-126) mo. Results: Median eGFR (mL/min/1.73 m2) of the cohort was 113 at UTx, which declined to 74 during month 3, 71 at months 10-12, 76 at hysterectomy (HE), and 83 at last follow-up. Median duration of tacrolimus exposure was 52 (22-83) mo, and median trough levels (µg/L) were 10 during month 3 and 5.8 at HE. Between UTx and month 3, decline in kidney function was observed in all 7 participants with a median eGFR slope for the whole cohort of -24 mL/min/1.73 m2, which declined further by -4 mL/min/1.73 m2 until months 10-12. Thereafter, eGFR slope improved in 3 participants, remained stable in 3, and worsened in 1 until HE/tacrolimus discontinuation, after which it improved in 2. Eventually, between UTx and last follow-up, 4 of 7 participants had a decline in their eGFR, the median annual eGFR slope being negative at -1.9 mL/min/1.73 m2/y for the whole group. Conclusions: Kidney function declined in all recipients early after UTx followed by a persistent long-term decrease in majority, despite transplantectomy and discontinuation of immunosuppression. Thus, UTx may incur an increased risk of chronic kidney disease even in this young and healthy population, highlighting the importance of close surveillance of kidney function and minimization of tacrolimus exposure.
RESUMEN
Background: Diagnosis of rejection after uterus transplantation is based on histopathological examination of ectocervical biopsies. Inflammation at the stromal-epithelial interface is the backbone of the histopathological classification proposed by our group in 2017. However, the reproducibility of this grading scheme has not been tested, and it is unclear whether it covers the full morphological spectrum of rejection. Methods: We present a multicenter study in which 5 pathologists from 4 uterus transplantation centers performed 2 rounds of grading on 145 and 48 cervical biopsies, respectively. Three of the centers provided biopsies. Additionally, the presence of perivascular stromal inflammation was recorded. During discussions after the first round, further histological lesions (venous endothelial inflammation and apoptosis) were identified for closer evaluation and added to the panel of lesions to score in the second round. All participants completed a questionnaire to explore current practices in handling and reporting uterus transplant biopsies. Results: Cervical biopsies were commonly performed in all centers to monitor rejection. Intraobserver reproducibility of rejection grading (performed by 1 rater) was excellent, whereas interobserver reproducibility was moderate and did not improve in the second round. Reproducibility of perivascular stromal inflammation was moderate but unsatisfactory for venous endothelial inflammation and apoptosis. All lesions were more frequent in, but not restricted to, biopsies with rejection patterns. Conclusions: Grading of rejection in cervical biopsies is reproducible and applicable to biopsies from different centers. Diagnosis of rejection may be improved by adding further histological lesions to the grading system; however, lesions require rigorous consensus definition.
RESUMEN
Pregnancy-related problems have been linked to impairments in maternal uterine spiral artery (SpA) remodeling. The mechanisms underlying this association are still unclear. It is also unclear whether hyperandrogenism and insulin resistance, the two common manifestations of polycystic ovary syndrome, affect uterine SpA remodeling. We verified previous work in which exposure to 5-dihydrotestosterone (DHT) and insulin (INS) in rats during pregnancy resulted in hyperandrogenism, insulin intolerance, and higher fetal mortality. Exposure to DHT and INS dysregulated the expression of angiogenesis-related genes in the uterus and placenta and also decreased expression of endothelial nitric oxide synthase and matrix metallopeptidases 2 and 9, increased fibrotic collagen deposits in the uterus, and reduced expression of marker genes for SpA-associated trophoblast giant cells. These changes were related to a greater proportion of unremodeled uterine SpAs and a smaller proportion of highly remodeled arteries in DHT + INS-exposed rats. Placentas from DHT + INS-exposed rats exhibited decreased basal and labyrinth zone regions, reduced maternal blood spaces, diminished labyrinth vascularity, and an imbalance in the abundance of vascular and smooth muscle proteins. Furthermore, placentas from DHT + INS-exposed rats showed expression of placental insufficiency markers and a significant increase in cell senescence-associated protein levels. Altogether, this work demonstrates that increased pregnancy complications in polycystic ovary syndrome may be mediated by problems with uterine SpA remodeling, placental functionality, and placental senescence.
Asunto(s)
Hiperandrogenismo , Síndrome del Ovario Poliquístico , Humanos , Ratas , Embarazo , Femenino , Animales , Placenta/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Hiperandrogenismo/metabolismo , Útero/metabolismo , Arterias , Dihidrotestosterona/metabolismo , Insulina , Arteria Uterina/metabolismoRESUMEN
Hysterectomy, most often performed because of bleeding disorders or uterine leiomyoma, is one of the most common major surgical procedures in women and is usually performed during the perimenopausal period on ages 45-55 years. Hysterectomy may be combined with bilateral salpingo-oophorectomy, as a risk-reducing procedure to minimize the risk of ovarian cancer. An open question is whether concomitant oophorectomy, with cessation of ovarian androgen secretion, has any long-term effects on sexual function. In the present prospective cohort study of women undergoing benign hysterectomy, the long-term (10-12 years) effects on sexual function and changes in sex hormone levels were investigated in women having undergone perimenopausal hysterectomy, with or without concomitant bilateral salpingo-oophorectomy. Originally, 491 women (mean age around 50 years) were operated with (patient preference) either only hysterectomy (HYST) or hysterectomy plus bilateral salpingo-oophorectomy (HYST + BSO), and 441 women (90%; HYST; n = 271 and HYST + BSO; n = 170) completed a one-year survey. In the present study, 185 women (42%) of the cohort with one-year follow up participated in the long-term follow up after 10-12 years. Follow-up was with the 10-item McCoy Female Sex Questionnaire and blood analysis of levels of testosterone, estradiol and sexual-hormone-binding globulin. The results showed that specific aspects of sexual function were lower after HYST + BSO compared to HYST 10-12 years after surgery. These lowered items were frequency of sexual fantasies, enjoyment of sexual activity, sexual arousal, and orgasmic frequency. No long-term differences in sex hormone levels were found between the two groups. In conclusion, some items related to sexual function were lower after HYST + BSO in a long-term perspective study, although the levels of testosterone were unaltered. This finding may have implications for clinical recommendations concerning prophylactic salpingo-oophorectomy or for hysterectomy during the perimenopausal age.
RESUMEN
BACKGROUND: Uterus transplantation is an emerging treatment option for uterine factor infertility. Most uterus transplantation research programs use living donors, although this comes with considerable surgical and psychological risks and not all women desiring uterus transplantation will have an available living donor. A deceased donor program eliminates donor risks; however, the availability of deceased uterus donors is currently unknown in Australia. AIMS: To establish the feasibility of a deceased donor uterus transplantation program in Australia and consider expanded inclusion criteria for this model. MATERIALS AND METHODS: A retrospective review of the New South Wales (NSW) Organ and Tissue Donation Service database was undertaken to identify potential deceased uterus donors, with comparison to the broad deceased donor inclusion criteria from three international uterus transplantation trials including female, brain-dead, multi-organ donation, no major abdominal surgery, and <60 years of age. RESULTS: Between January 1, 2018, and December 31, 2022, 648 deceased donors were available in NSW. Of these, 43% (279/648) were female and 67% of the women (187/279) were also multi-organ donors. When the brain-dead donor-only and age criteria (<60 years) were applied, a total of 107 deceased donors met the available criteria for uterus transplantation, with an average of 21 deceased donors per year in NSW. CONCLUSIONS: There appears to be adequate deceased donor organ availability to establish a deceased uterus transplantation program in NSW, Australia. Should interest in uterus transplantation increase, including criteria such as older and nulliparous donors could increase organ availability for a uterus transplantation program.
Asunto(s)
Infertilidad Femenina , Obtención de Tejidos y Órganos , Femenino , Humanos , Persona de Mediana Edad , Masculino , Infertilidad Femenina/cirugía , Útero/cirugía , Donadores Vivos , AustraliaRESUMEN
Women suffering from absolute uterine factor infertility (AUFI) had no hope of childbearing until clinical feasibility of uterus transplantation (UTx) was documented in 2014 with the birth of a healthy baby. This landmark accomplishment followed extensive foundational work with a wide range of animal species including higher primates. In the present review, we provide a summary of the animal research and describe the results of cases and clinical trials on UTx. Surgical advances for graft removal from live donors and transplantation to recipients are improving, with a recent trend away from laparotomy to robotic approaches, although challenges persist regarding optimum immunosuppressive therapies and tests for graft rejection. Because UTx does not involve transplantation of the Fallopian tubes, IVF is required as part of the UTx process. We provide a unique focus on the intersection between these two processes, with consideration of when oocyte retrieval should be performed, whether, and for whom, preimplantation genetic testing for aneuploidy should be used, whether oocytes or embryos should be frozen and when the first embryo transfer should be performed post-UTx. We also address the utility of an international society UTx (ISUTx) registry for assessing overall UTx success rates, complications, and live births. The long-term health outcomes of all parties involved-the uterus donor (if live donor), the recipient, her partner and any children born from the transplanted graft-are also reviewed. Unlike traditional solid organ transplantation procedures, UTx is not lifesaving, but is life-giving, although as with traditional types of transplantation, costs, and ethical considerations are inevitable. We discuss the likelihood that costs will decrease as efficiency and efficacy improve, and that ethical complexities for and against acceptability of the procedure sharpen the distinctions between genetic, gestational, and social parenthood. As more programs wish to offer the procedure, we suggest a scheme for setting up a UTx program as well as future directions of this rapidly evolving field. In our 2010 review, we described the future of clinical UTx based on development of the procedure in animal models. This Grand Theme Review offers a closing loop to this previous review of more than a decade ago. The clinical feasibility of UTx has now been proved. Advancements include widening the criteria for acceptance of donors and recipients, improving surgery, shortening time to pregnancy, and improving post-UTx management. Together, these improvements catalyze the transition of UTx from experimental into mainstream clinical practice. The procedure will then represent a realistic and accessible alternative to gestational surrogacy for the treatment of AUFI and should become part of the armamentarium of reproductive specialists worldwide.
Asunto(s)
Infertilidad Femenina , Embarazo , Animales , Niño , Humanos , Femenino , Infertilidad Femenina/cirugía , Infertilidad Femenina/etiología , Útero/trasplante , Donadores Vivos , Transferencia de Embrión/efectos adversos , Nacimiento VivoAsunto(s)
Experimentación Animal , Infertilidad Femenina , Humanos , Masculino , Femenino , Animales , Útero/trasplante , Infertilidad Femenina/cirugíaRESUMEN
AIMS: The aim is to report the results of Australia's first uterus transplantation (UTx). METHODS: Following long-standing collaboration between the Swedish and Australian teams, Human Research Ethics approval was obtained to perform six UTx procedures in a collaborative multi-site research study (Western Sydney Local District Health 2019/ETH13038), including Royal Hospital for Women, Prince of Wales Hospital, and Westmead Hospital in New Souh Wales. Surgeries were approved in both the live donor (LD) and deceased donor models in collaboration with the inaugural Swedish UTx team. RESULTS: This is the first UTx procedure to occur in Australia, involving a mother donating her uterus to her daughter. The total operative time for the donor was 9 h 54 min. Concurrently, recipient surgery was synchronised to minimise graft ischaemic time, and the total operative time for the recipient was 6 h 12 min. Surgery was by laparotomy in the LD and recipient. The total warm ischaemic time of the graft was 1 h 53 min, and the cold ischaemic time was 2 h 17 min (total ischaemic time 4 h 10 min). The patient's first menstruation occurred 33 days after the UTx procedure. CONCLUSION: Twenty-five years of Swedish and Australian collaboration has led to Australia's first successfully performed UTx surgery at The Royal Hospital for Women, Sydney, Australia.
Asunto(s)
Infertilidad Femenina , Femenino , Humanos , Suecia , Infertilidad Femenina/cirugía , Australia , Útero/trasplante , Donadores VivosRESUMEN
OBJECTIVE: Polycystic ovary syndrome (PCOS), affecting more than every 10th woman of reproductive age, is associated with increased risk factors for cardiovascular disease (CVD). Most knowledge regarding longtime consequences concerning morbidity is based on women where ovarian wedge resection (WR) was used as a surgical treatment, a method not used today. The aim of this study was to compare women with PCOS who had and had not undergone WR, regarding risk factors for CVD. The hypothesis was that women who had undergone WR had a more severe PCOS phenotype, and that this cohort thus had more associated CVD risk factors compared with women diagnosed through non-invasive methods. STUDY DESIGN: A cross-sectional study was performed. A PCOS cohort who underwent WR in the 1950-60 s (n = 27) were compared with a PCOS cohort diagnosed by NIH-criterions in the 1990s without WR (n = 32). Both cohorts were examined at perimenopausal age. RESULTS: No differences were seen in prevalence of hypertension, obesity or type 2 diabetes mellitus (T2DM) between the women with PCOS with or without WR, respectively. The results were persistent irrespective of the lower mean BMI in the WR group, 26.4 vs. 30.7 kg/m2, p = 0.01. In the stratified group of overweight and obese, there was no difference in T2DM 27% vs 25% or hypertension 27% vs 25%, in WR and non-WR women with PCOS, respectively. The cohort diagnosed through WR had higher free androgen index (6.3 vs. 2.1, p < 0.01) and total testosterone (2.20 vs. 0.99 nmol/L, p < 0.01). CONCLUSION: No differences in CVD risk factors were found in perimenopausal women with PCOS with or without a previous WR, and irrespective of body weight. The results indicate that CVD morbidity and mortality from studies in women with PCOS who have undergone WR are generalizable to women with PCOS who have not undergone WR.
Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipertensión , Síndrome del Ovario Poliquístico , Femenino , Humanos , Masculino , Diabetes Mellitus Tipo 2/complicaciones , Estudios Transversales , Perimenopausia , Obesidad/epidemiología , Morbilidad , Hipertensión/complicaciones , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Índice de Masa CorporalRESUMEN
Leukocytes are in situ regulators critical for ovarian function. However, little is known about leukocyte subpopulations and their interaction with follicular cells in ovulatory follicles, especially in humans. Single-cell RNA sequencing (scRNA-seq) was performed using follicular aspirates obtained from four IVF patients and identified 13 cell groups: one granulosa cell group, one thecal cell group, 10 subsets of leukocytes, and one group of RBC/platelet. RNA velocity analyses on five granulosa cell populations predicted developmental dynamics denoting two projections of differentiation states. The cell type-specific transcriptomic profiling analyses revealed the presence of a diverse array of leukocyte-derived factors that can directly impact granulosa cell function by activating their receptors (e.g., cytokines and secretory ligands) and are involved in tissue remodeling (e.g., MMPs, ADAMs, ADAMTSs, and TIMPs) and angiogenesis (e.g., VEGFs, PGF, FGF, IGF, and THBS1) in ovulatory follicles. Consistent with the findings from the scRNA-seq data, the leukocyte-specific expression of CD68, IL1B, and MMP9 was verified in follicle tissues collected before and at defined hours after hCG administration from regularly cycling women. Collectively, this study demonstrates that this data can be used as an invaluable resource for identifying important leukocyte-derived factors that promote follicular cell function, thereby facilitating ovulation and luteinization in women.
Asunto(s)
Folículo Ovárico , Comunicación Paracrina , Humanos , Femenino , Folículo Ovárico/metabolismo , Células de la Granulosa/metabolismo , Ovulación , Expresión Génica , LeucocitosRESUMEN
High-mobility group box 1 (HMGB1) is critical for inflammatory homeostasis and successful pregnancy, and there is a strong association among elevated levels of HMGB1, polycystic ovary syndrome (PCOS), chronic inflammation and pregnancy loss. However, the mechanisms responsible for PCOS-driven regulation of uterine HMGB1 and its candidate receptors [toll-like receptor (TLR) 2 and 4] and inflammatory responses during pregnancy remain unclear. In this study, we found a gestational stage-dependent decrease in uterine HMGB1 and TLR4 protein abundance in rats during normal pregnancy. We demonstrated that increased expression of HMGB1, TLR2 and TLR4 proteins was associated with activation of inflammation-related signalling pathways in the gravid uterus exposed to 5α-dihydrotestosterone and insulin, mimicking the clinical features (hyperandrogenism and insulin resistance) of PCOS and this elevation was completely inhibited by treatment with the androgen receptor (AR) antagonist flutamide. Interestingly, acute exposure to lipopolysaccharide suppressed HMGB1, TLR4 and inflammation-related protein abundance but did not affect androgen levels or AR expression in the gravid uterus with viable fetuses. Furthermore, immunohistochemical analysis revealed that, in addition to being localized predominately in the nuclear compartment, HMGB1 immunoreactivity was also detected in the cytoplasm in the PCOS-like rat uterus, PCOS endometrium and pregnant rat uterus with haemorrhagic and resorbed fetuses, possibly via activation of nuclear factor κB signalling. These results suggest that both AR-dependent and AR-independent mechanisms contribute to the modulation of HMGB1/TLR2/TLR4-mediated uterine inflammation. We propose that the elevation of HMGB1 and its receptors and disruption of the pro-/anti-inflammatory balance in the gravid uterus may participate in the pathophysiology of PCOS-associated pregnancy loss.
Asunto(s)
Proteína HMGB1 , Síndrome del Ovario Poliquístico , Animales , Femenino , Embarazo , Ratas , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Inflamación/genética , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/terapia , Receptor Toll-Like 2/genética , Receptor Toll-Like 4/genéticaRESUMEN
BACKGROUND: Uterus transplantation (UTx) is a novel type of transplantation to treat infertility in women with an absent or nonfunctioning uterus. The International Society of Uterus Transplantation (ISUTx) has developed a registry to monitor worldwide UTx activities while serving as a repository for specific research questions. METHODS: The web-based registry has separate data fields for donor, recipient, surgeries, immunosuppression, rejections, pregnancies with live birth(s), and transplant hysterectomies. Data are prospectively registered. RESULTS: A total of 45 UTx procedures have been registered; the majority (78%) of those procedures were live donor (LD) transplants. Median age of the LDs, deceased donors, and recipients were 50 y (range 32-62), 38.5 y (19-57), and 29 y (22-38), respectively. The duration of LD surgery was approximately twice as long as the recipient surgery. Postoperative complications of any Clavien-Dindo grade were registered in 20% of LDs and 24% of recipients. Rejection episodes were more frequent (33%) early after transplantation (months 1-5) compared with later time points (months 6-10; 21%). Healthy neonates were delivered by 16 recipients, with 3 women giving birth twice. The total live birth rate per embryo transfer was 35.8%. Median length of pregnancy was 35 gestational weeks. Twelve uteri were removed without childbirth, with 9 transplant hysterectomies occurring during the initial 7 mo post-UTx. CONCLUSIONS: A mandatory registry is critical to determine quality and process improvement for any novel transplantation. This registry provides a detailed analysis of 45 UTx procedures performed worldwide with a thorough analysis of outcomes and complications.