Autologous stem cell ovarian transplantation to increase reproductive potential in patients who are poor responders.

Objective: To evaluate effects of autologous stem cell ovarian transplant (ASCOT) on ovarian reserve and IVF outcomes of women who arc poor responders with very poor prognosis. Design: Prospective observational pilot study. Setting: University hospital. Patient(s): Seventeen women who are poor responders. Intervention(s): Ovarian infusion of bone marrow-derived stem cells. Main Outcome Measure(s): Serum antimullerian hormone levels and antral follicular count (AFC), punctured follicles, and oocytes retrieved after stimulation (controlled ovarian stimulation) were measred. Apheresis was analyzed for growth factor concentrations. Result(s): The ASCOT resulted in a significant improvement in A…

Human uterus transplantation in focus.

Introduction Uterus transplantation (UTx) is introduced as the first treatment for absolute uterine factor infertility (AUFI), affecting 1:500 fertile aged women. This review presents potential patients, research and human UTx cases. Sources of data Published articles and our research experience. Areas of agreement The first UTx live births in 2014 established UTx as a possible treatment for AUFI. This was proceeded by 15 years of systematic research. Areas of controversy Is a deceased donor UTx as effective as the proven successful live donor UTx?. Growing points Human UTx trials will accumulate data on risks, effectiveness and long-term consequences for donors, recipients and children. Th…

The effect of warm ischemia at uterus transplantation in a rat model

Objective Uterus transplantation (UTx) has been proposed as a method to treat women with absolute uterine factor infertility. The aim of this study was to evaluate the viability of the transplanted rat uterus after exposure to long warm ischemic times, in order to mimic a time frame likely to occur in a human situation during complicated pelvic vascular anastomosis surgery. Design Experimental study. Setting Obstetrics and Gynecology Department. Population Female Lewis rats. Methods. Pseudopregnant rats were randomly allocated into two intervention groups, a standardized syngeneic UTx procedure (control; n = 10) and a modified UTx protocol with a four hour extended period of warm ischemia (…

Uterus transplantation in a non-human primate: long-term follow-up after autologous transplantation

BACKGROUND Uterus transplantation (UTx) may provide the first available treatment for women affected by uterine infertility. The present study aimed to further develop a surgical technique for autologous UTx in a non-human primate species and to assess long-term function. METHODS Female baboons (n= 16) underwent autologous transplantation of the uterus with the Fallopian tubes and ovaries, performed with a previously published surgical technique (n= 6, Group 1) or using a modified technique (n= 10; Group 2). The uterine arteries were dissected to the proximal end of the anterior branch (Group 1) or the entire (Group 2) internal iliac artery, and the ovarian veins were dissected to the cross…

First report on fertility after allogeneic uterus transplantation

Uterus transplantation may become the first available treatment for uterine factor infertility, which is due to the absence or malfunction of the uterus. Here we describe for the first time pregnancy after allogeneic uterus transplantation, as a proof of concept of uterine function in a transplanted uterus in a standardized animal model (rat) under immunosuppression.

New methods to improve the safety assessment of cryopreserved ovarian tissue for fertility preservation in breast cancer patients

Objective To develop a novel molecular panel of markers to detect breast cancer (BC) disseminated malignant cells in ovarian tissue, and to improve the safety of ovarian tissue transplantation. Design Experimental study. Setting University hospital. Patient(s) Ten ovarian biopsies from healthy patients, 13 biopsies with diagnosed BC metastasis, and 4 biopsies from primary BC tumor for designing a diagnostic panel of BC cell contamination; 60 ovarian biopsies from BC patients undergoing fertility preservation for validating the panel. Animal(s) Female nude mice. Intervention(s) A novel panel for BC malignant cell detection by reverse-transcription polymerase chain reaction (RT-PCR), inmmunoh…

Livebirth after uterus transplantation.

Uterus transplantation is the first available treatment for absolute uterine infertility, which is caused by absence of the uterus or the presence of a non-functional uterus. Eleven human uterus transplantation attempts have been done worldwide but no livebirth has yet been reported.In 2013, a 35-year-old woman with congenital absence of the uterus (Rokitansky syndrome) underwent transplantation of the uterus in Sahlgrenska University Hospital, Gothenburg, Sweden. The uterus was donated from a living, 61-year-old, two-parous woman. In-vitro fertilisation treatment of the recipient and her partner had been done before transplantation, from which 11 embryos were cryopreserved.The recipient an…

Viability and function of the cryopreserved whole rat ovary: comparison between slow-freezing and vitrification

Objective To investigate four different protocols for cryopreservation of the whole rat ovary with intact vasculature to evaluate whether differences exist in post-thawing viability of the ovary after either vitrification or slow freezing. Design Experimental study. Setting Obstetrics and gynecology department. Animal(s) Immature Sprague-Dawley female rats. Intervention(s) Ovaries were isolated with the vascular tree intact up to the bifurcation of the abdominal aorta and were subsequently cannulated. The ovaries were flushed with increasing concentrations of the cryoprotectant dimethyl sulfoxide (DMSO) to either 1.5 or 7 M. The ovaries underwent cryopreservation by vitrification or passive…

Obstetric and Neonatal Outcome of Pregnancies Fathered by Males on Immunosuppression After Solid Organ Transplantation

Immunosuppressive drugs may influence spermatogenesis, but little is known about outcome of pregnancies fathered by transplanted males. We estimated risk of adverse outcomes in pregnancies (with data after the first trimester) fathered by males that had undergone organ transplantation and were treated with immunosuppression. A population-based study, linking data from the Norwegian transplant registry and the Medical Birth Registry of Norway during 1967-2009 was designed. All Norwegian men undergoing solid organ transplantation were included. Odds ratios for major malformations, preeclampsia, preterm delivery (<37 weeks) and small-for-gestational-age were obtained using logistic regression.…

[Fertility preservation in the oncology patient].

In recent years, medical advances have substantially improved survival of cancer patients, generating growing concern about the quality of life of the survivors. Increased attention has been paid to reproductive problems after oncological treatments. International guidelines on fertility preservation in cancer patients require that healthcare teams discuss, as early as possible, the impact of cancer treatments on fertility and encourage access to fertility preservation techniques. The development of these techniques in women is a recent effort and many patients and health care providers are not familiar with their rapid expansion. This article discusses indications, results, and risks of th…

Uterus Transplantation

Uterus transplantation (UTx) has been successfully introduced as a treatment option for women with absolute uterine factor infertility (AUFI). AUFI representing approximately 3% to 5% of the female general population is linked to either congenital uterine agenesis (Mayer-Rokitansky-Küster-Hauser syndrome), major congenital uterine malformation (hypoplastic uterus, fraction of bicornuate/unicornuate uterus), a surgically absent uterus, or an acquired condition (intrauterine adhesions, leiomyoma) linked to uterine malfunction that causes implantation failure or defect placentation. The world's first clinical uterus transplant was performed in 2000. However, a hysterectomy became necessary sho…

Live Birth After Uterus Transplantation

ABSTRACTIn the 3 decades since the birth of the first in vitro fertilization baby in 1978, there have been remarkable advances in infertility treatment. Until now, however, absolute uterine factor infertility remained the only major type of female infertility viewed as untreatable. Absolute uterine

Uterus transplantation: animal research and human possibilities

Uterus transplantation research has been conducted toward its introduction in the human as a treatment of absolute uterine-factor infertility, which is considered to be the last frontier to conquer for infertility research. In this review we describe the patient populations that may benefit from uterus transplantation. The animal research on uterus transplantation conducted during the past two decades is summarized, and we describe our views regarding a future research-based human attempt.

Allogeneic Uterus Transplantation in Baboons

Uterine transplantation: one human case followed by a decade of experimental research in animal models

Uterine transplantation (UTx) aims to treat unconditional uterine factor infertility by replacing a non-functioning or non-existing uterus. After one attempt of UTx in the human 10 years ago, intensive research has been performed. The results of these specific studies on surgical technique, ischaemia-reperfusion injury, immunosuppression and fertility are discussed.

Pregnancy after syngeneic uterus transplantation and spontaneous mating in the rat.

BACKGROUND: Uterus transplantation (UTx) research aims towards the introduction of UTx as a treatment for uterine factor infertility. The rat model is the principal rodent model used and this study aims to assess the potential for pregnancy and to assess effects on pregnancy outcome. METHODS: Female Lewis rats underwent hysterectomy and received syngeneic uterine transplants (with one horn removed) by end-to-side anastomosis between the common iliac vessels of the recipient and the graft. The graft was placed in an orthotopic position with anastomosis to the upper part of the native uterine horn and vagina to allow for pregnancy by mating. Controls had only one uterine horn removed. Mating …

Uterine rejection after allogeneic uterus transplantation in the rat is effectively suppressed by tacrolimus

Objective To evaluate the effects of the immunosuppressant tacrolimus on rejection of a transplanted uterus and on uterine expression of markers of inflammation and implantation. Design Experimental study. Setting University laboratory. Animal(s) Female rats. Intervention(s) Uteri from brown Norway rats were transplanted to Lewis rats, receiving either tacrolimus or no treatment. Sham groups underwent either hemihysterectomy or tacrolimus treatment. Main Outcome Measure(s) Gross morphology, histology, density of T-lymphocytes by immunohistochemistry, and mRNA levels of interleukin (IL)-1α, leukemia inhibitory factor (LIF), galectin-1, CD200, IL-15, interferon-inducible protein-10 (IP-10), a…

Survey of Fertility Preservation Options Available to Patients With Cancer Around the Globe

Purpose Oncofertility focuses on providing fertility and endocrine-sparing options to patients who undergo life-preserving but gonadotoxic cancer treatment. The resources needed to meet patient demand often are fragmented along disciplinary lines. We quantify assets and gaps in oncofertility care on a global scale. Methods Survey-based questionnaires were provided to 191 members of the Oncofertility Consortium Global Partners Network, a National Institutes of Health–funded organization. Responses were analyzed to measure trends and regional subtleties about patient oncofertility experiences and to analyze barriers to care at sites that provide oncofertility services. Results Sixty-three res…

Uterus transplantation trial: 1-year outcome

Objective To report the 12-month outcome of seven patients with viable uteri after uterus transplantation (UTx). Design Prospective observational study. Setting University hospital. Patient(s) Seven patients with absolute uterine infertility and viable uteri for 12 months after live-donor UTx. Intervention(s) Predetermined immunosuppression was with tacrolimus and mychophenolate mofetil (MMF) during 6 months, whereupon MMF should be withdrawn. Frequent ultrasound examinations were performed to assess uterine appearance and uterine artery blood flow. Cervical biopsies (for histological detection of rejection) were obtained at preset time points, with temporary adjustments of immunosuppressio…

Oocyte vitrification versus ovarian cortex transplantation in fertility preservation for adult women undergoing gonadotoxic treatments: a prospective cohort study

Objective To compare the efficacy of oocyte vitrification (OV) with that of ovarian cortex cryopreservation and transplantation (OCT) in women undergoing gonadotoxic treatments. Design Prospective observational cohort study. Setting Not applicable. Patient(s) Candidates for chemo-/radiotherapy who joined our fertility preservation (FP) program were included in this study between 2005 and 2015. One cohort included 1,024 patients undergoing OV; the other cohort included 800 patients undergoing OCT. Intervention(s) OV using the cryotop device and OCT using a slow freezing protocol. Main Outcome Measure(s) Live-birth rate (LBR) and clinical pregnancy rate (CPR). Result(s) Basal antimullerian ho…

First clinical uterus transplantation trial: a six-month report.

Objective To report the 6-month results of the first clinical uterus transplantation (UTx) trial. This type of transplantation may become a treatment of absolute uterine-factor infertility (AUFI). Design Prospective observational study. Setting University hospital. Patient(s) Nine AUFI women and their live uterine donors, the majority being mothers. Intervention(s) Live-donor UTx and low-dose induction immunosuppression. Main Outcome Measure(s) Data from preoperative investigations, surgery and follow-up for 6 months. Result(s) Durations of donor and recipient surgery ranged from 10 to 13 hours and from 4 to 6 hours, respectively. No immediate perioperative complications occurred in any of …

The history behind successful uterine transplantation in humans

This paper aimed to describe the basic aspects of uterine transplant (UTx) research in humans, including preliminary experiences in rodents and domestic species. Studies in rats, domestic species, and non-human primates validated and optimized the UTx procedure in terms of its surgical aspects, immunosuppression, rejection diagnosis, peculiarities of pregnancy in immunosuppressed patients, and patients with special uterine conditions. In animal species, the first live birth from UTx was achieved in a syngeneic mouse model in 2003. Twenty-five UTx procedures have been performed in humans. The first two cases were unsuccessful, but established the need for rigorous research to improve success…

Preclinical report on allogeneic uterus transplantation in non-human primates

Study question Is it possible to perform allogeneic uterus transplantation (UTx) with a donation from a live donor in a non-human primate species and what immunosuppression is needed to prevent rejection? Summary answer Allogeneic UTx in the baboon is a donor- and recipient-safe surgical procedure; immunosuppression with induction therapy and a triple protocol should be used. What is known already UTx may become a treatment for absolute uterine factor infertility. Autologous UTx models have been developed in non-human primates with reports on long-term survival of the uterine grafts. STUDY DESIGN, SIZEAND DURATION: This experimental study included 18 female baboons as uterus donors and 18 f…

Ethics of uterus transplantation with live donors.

Inter-cycle and inter-observer variability of the antral follicle count in routine clinical practice

Antral follicle count (AFC) is a reliable predictor of ovarian response to stimulation and its inter-cycle and inter-observer variability has been extensively studied on in vitro fertilization (IVF), mostly in highly selected populations within studies not originally designed for this purpose. In this retrospective cohort study, we assess the inter-cycle variation of AFC in a setting similar to that of the daily practice. We included only patients undergoing mild stimulation for intrauterine insemination (IUI). One hundred and forty-eight patients had two (62 patients, group A), three (49 patients, group B) or four (37 patients, group C) IUI cycles and AFC was measured on early follicular p…

Pregnancy after allogeneic uterus transplantation in the rat: perinatal outcome and growth trajectory

Objective To investigate whether allogeneic uterine grafts in a rat model, with tacrolimus immunosuppression, can harbor pregnancies that result in offspring with normal postnatal growth. Design Experimental animal study. Setting University hospital. Animal(s) Lewis rats as uterus donors and Piebald-Virol-Glaxo rats as recipients. Intervention(s) Animals were allocated to one of the following three groups: allogeneic uterus transplantation with end-to-side anastomosis to the external iliac vessels and immunosuppression with tacrolimus (UT+Tac; n=10); sham surgery and immunosuppression with tacrolimus (Sham+Tac; n=10); or sham surgery (Sham; n=10). The rats were subsequently introduced to ma…

Reproductive medicine and inheritance of infertility by offspring: the role of fetal programming.

Objective To summarize the molecular processes involved in fetal programming, to describe how assisted reproduction technologies (ART) may affect the epigenetic pattern of the embryo, and to highlight the current knowledge of the role of perinatal events in the subsequent development of reproductive pathology affecting infertile patients. Design A literature review of fetal programming of adulthood gynecologic diseases and ART. A Medline search was performed with the following keywords: (fetal programming OR epigenetics OR methylation OR acetylation) AND (IVF OR ART) AND (gynecology). Articles up to October 2010 were selected. Articles and recent reviews were classified by human and animals…

722: Maternal solid organ transplantation and pregnancy outcome; a national population-based cohort study

outcome; a national population-based cohort study Nils-Halvdan Morken, Cesar Diaz-Garcia, Mats Brannstrom University of Bergen, Public Health and Primary Health care, Bergen, Norway, University of Valencia, Gynecology and Obstetrics, Valencia, Spain, University of Gothenburg, Obstetrics and Gynecology, Valencia, Sweden OBJECTIVE: The first pregnancy with a live birth after solid organ transplantation in the human occurred more than 50 years ago. Still, knowledge about this very special patient group is limited. The objective was to assess the risk of adverse pregnancy outcome after transplant compared to pregnancies before transplant in females. We also compared the risk after transplant wi…

One uterus bridging three generations: first live birth after mother-to-daughter uterus transplantation

Objective To determine whether a uterus from the mother of a woman with absolute uterine factor infertility can be transplanted to daughter and carry a pregnancy with delivery of a healthy child. Design Part of an observational study. Setting University teaching hospital. Patient(s) Twenty eight-year-old woman with uterine agenesis, her male partner, and her 50-year-old mother. Intervention(s) In vitro fertilization with embryo cryopreservation before live donor uterus transplantation (UTx). Induction immunosuppression. Embryo transfer 12 months after UTx, pregnancy controls, delivery, and hysterectomy. Main Outcome Measure(s) Results of IVF-ET, parameters of pregnancy/birth, and surgical d…

Uterus transplantation from a deceased donor

Antral Follicle Priming Before Intracytoplasmic Sperm Injection in Previously Diagnosed Low Responders: A Randomized Controlled Trial (FOLLPRIM).

A low response to controlled ovarian hyperstimulation implies a reduced number of embryos and impaired pregnancy rate. Follicular priming with steroids before controlled ovarian hyperstimulation has been suggested to improve the subsequent ovarian response.The purpose of this study was to determine the best follicular priming protocol in low responders and to investigate the intrafollicular mechanisms triggered by steroid hormone priming.This was a single-center, randomized, parallel, open-label, controlled trial, in two phases.The setting was a university-based in vitro fertilization unit.Potential low responders (n = 99) underwent a first intracytoplasmic sperm injection cycle. Confirmed …

Survey of third-party parenting options associated with fertility preservation available to patients with cancer around the globe

Purpose In the accompanying article, “Survey of Fertility Preservation Options Available to Patients With Cancer Around the Globe,” we showed that specific fertility preservation services may not be offered at various sites around the world because of cultural and legal barriers. We assessed global and regional experiences as well as the legal status of third-party reproduction and adoption to serve as a comprehensive international data set and resource for groups that wish to begin oncofertility interventions. Methods We provide data on the legalities of third-party assisted reproductive technologies and other family-building options in the 28 oncofertility-practicing countries surveyed. R…