Uterus transplantation is a vascularized composite allograft transplantation. It allows women who do not have a uterus to become pregnant and deliver a baby. In this paper, we analyze the first five cases of living donor uterus transplantation performed in the United States. The first three recipients lost their uterus grafts at days 14, 12, and 6, respectively, after transplant. Vascular complications, related to both inflow and outflow problems, were identified as the primary reason for the graft losses. Two recipients, at 6 and 3 mo, respectively, after transplant, have functioning grafts with regular menstrual cycles. Ultimate success will be claimed only after a live birth. This paper is an in-depth analysis of evaluation, surgical technique, and follow-up of these five living donor uterus transplants. The lessons learned were instrumental in allowing us to evolve from failure to technical and functional success. We aim to share our conclusions and build on knowledge in the evolving field of uterus transplantation.
Uterus transplantation has proven to be a successful treatment for women with absolute uterine infertility, caused either by the absence of a uterus or the presence of a nonfunctioning uterus. We report the first birth of a healthy child following uterus transplantation in the United States, from a recipient of a uterus allograft procured from an altruistic living donor. Two major modifications from the previously reported live births characterized this uterus transplant. First, the transplanted uterus relied upon and sustained the pregnancy while having only the utero-ovarian vein as venous outflow. The implication is a significantly simplified living donor surgery that paves the way for minimally invasive laparoscopic or robot-assisted techniques for the donor hysterectomy. Second, the time from transplantation to embryo transfer was significantly shortened from prior protocols, allowing for an overall shorter exposure to immunosuppression by the recipient and lowering the risk for potential adverse effects from these medications.
OBJECTIVE: To describe aggregated pregnancy outcomes after uterus transplantation from a single, experienced center. METHODS: This prospective study reports on live births among 20 women who received a uterus transplant from 2016 to 2019 at Baylor University Medical Center at Dallas. These live births occurred between November 2017 and September 2020. The main measures were live birth, maternal complications, and fetal and newborn outcomes. RESULTS: There were six graft failures (four surgical complications and two with poor perfusion postoperatively). Of the 14 technically successful transplants, at least one live birth occurred in 11 patients. Thus far, the live birth rate per attempted transplant is 55%, and the live-birth rate per technically successful transplant is 79%. Ten uteri were from nondirected living donors and one uterus was from a deceased donor. In vitro fertilization was performed to achieve pregnancy. Ten recipients delivered one neonate, and one recipient delivered two neonates. One organ rejection episode was detected during pregnancy and was resolved with steroids. The median birth weight was 2,890 g (range 1,770–3,140 g [median 68th percentile]). Maternal weight gain was higher than Institute of Medicine recommendations. Maternal medical complications were observed in five recipients (elevated creatinine level, gestational diabetes, gestational hypertension [n=2], and preeclampsia). In five recipients, maternal medical or obstetric complications led to an unplanned preterm delivery (elevated creatinine level, preeclampsia; preterm labor [n=3]). The median gestational age at delivery was 36 6/7 weeks (range 30 6/7–38 weeks). All neonates were liveborn, with Apgar scores of 8 or higher at 5 minutes. CONCLUSION: Over the first 3 years, our program experienced a live-birth rate per attempted transplant of 55% and a live-birth rate per technically successful transplant of 79%. In our experience, uterus transplantation resulted in a third-trimester live birth in all cases in which pregnancies reached 20 weeks of gestation. Maternal medical and obstetric complications can occur; however, these were manageable by applying principles of generally accepted obstetric practice. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02656550.
C19 steroids are converted to estrogens by aromatase P450 (P450arom). Aromatase expression in humans is regulated by use of tissue-specific promoters in the placenta (promoter I.1), adipose tissue (promoters I.4, I.3, and II), and gonads (promoter II). The use of each promoter gives rise to a population of P450arom messenger ribonucleic acid (mRNA) species with a unique untranslated 5'-terminus. Aromatase is not expressed in the endometrium of disease-free women. We demonstrated, however, the presence of P450arom mRNA in pelvic endometriotic implants and eutopic endometrial curettings of women with endometriosis. In the current report, aromatase activity and P450arom gene expression were investigated in cultured stromal cells derived from eutopic endometrium and ovarian endometriomas of women with pelvic endometriosis. We also investigated the hormonal regulation of aromatase expression and alternative promoter use in these cells. The effects of interleukin-1 beta (IL-1 beta), IL-2, IL-6, IL-11, oncostatin M, IL-15, tumor necrosis factor-alpha, PGE2, estradiol, R5020, dexamethasone, and dibutyryl cAMP (Bt2cAMP) on aromatase activity in endometriosis-derived stromal cells were assessed. We chose treatments with PGs and ILs because of the inflammatory nature of endometriosis. PGE2 stimulated aromatase activity in endometriosis-derived stromal cells by 19- to 44-fold (37-221 pmol/mg protein-4 h), whereas Bt2cAMP induction was 26- to 60-fold the baseline level. No stimulation was observed by estradiol or R5020 or by IL-1 beta, IL-2, IL-6, IL-11, IL-15, or TNF alpha in the presence or absence of glucocorticoids. A modest induction of aromatase activity (2-fold) was observed in dexamethasone- plus oncostatin M-treated cells. These changes in aromatase activity were accompanied by comparable changes in the levels of P450arom mRNA levels, determined by a quantitative reverse transcription-PCR method. Promoter-specific 5'-ends of P450arom transcripts in total RNA from endometriosis-derived stromal cells treated with PGE2 and Bt2cAMP were amplified employing a novel modified rapid amplification of cDNA5'-ends/Southern hybridization method using exon-specific oligonucleotide probes. The majority of P450arom transcripts in these cells contained the gonadal-type promoter II-specific sequences, whereas very few transcripts contained adipose-type promoter I.3- and I.4-specific sequences. PGE2 appears to be the most potent known stimulator of aromatase in endometriosis. Aromatase expression in PGE2-stimulated stromal cells of endometriosis is regulated primarily by the classically located promoter II, which, in turn, is regulated by cAMP. As PGE2 is known to increase intracellular cAMP levels, estrogen biosynthesis in endometriosis may be primarily regulated by PGE2 that is locally produced. Consequent local estrogen production may promote the growth of endometriotic implants.
Objective Limited data are available on the outcome of infants born after uterus transplantation. Our aim was to describe the hospital course and laboratory findings in the first 2 months of life of the 12 infants born in the Dallas UtErus Transplant Study (DUETS). Study Design Based on the trial protocol, information about infants was collected in a prospective fashion, including infant demographics, hospital course, and laboratory values. Results Twelve infants were delivered, all by cesarean section, from 11 mothers who had undergone uterus transplantation (one mother had two pregnancies and delivered two babies). All pregnancies were singleton. The mothers received immunosuppressive therapy, and one had a rejection episode that was detected during pregnancy. The rejection episode resolved after steroid treatment. The infants had a median gestational age of 366/7 weeks (range: 306/7–380/7 weeks) and median birth weight of 2,920 g (range: 1,770–3,470 g). The lowest Apgar's score at 5 minutes was 8. All infants were appropriate size for gestational age. Two infants presented with bandemia but negative blood cultures. At 2 months of age, all infants achieved the developmental and behavioral milestones outlined by the American Academy of Pediatrics. Conclusion The 12 infants born from mothers with uterus transplants had a neonatal course that reflected the gestational age at delivery. No baby was born with an identified malformation or organ dysfunction. Longer follow-up and a larger number of infants are needed to confirm these observations. Key Points
A 33-year-old, nonreproductive female gorilla was scheduled for ovariohysterectomy after diagnosing endometrioid adenocarcinoma of the right ovary; the contralateral ovary appeared small and inactive. Follicular recruitment and maturation were stimulated on the left ovary using human menopausal gonadotropin and human chorionic gonadotropin therapy. Three oocytes were recovered and inseminated using a thawed epididymal semen sample collected postmortem and cryopreserved. At 18 h postinsemination, one ovum was fertilized, the second showed evidence of polyspermia, and the third was unfertilized; no further embryonic development was observed. These results demonstrate that viable oocytes can be salvaged from a nonreproductive gorilla using a human exogenous gonadotropin treatment protocol and fertilized in vitro using cryopreservedi thawed epididymal gorilla semen. Key words: epididymal semen, exogenous human gonadotropin treat- INTRODUCTIONDemographic analysis of the captive Western Lowland gorilla population in North America has revealed several alarming trends: 1) a significant decrease in fecundity in both males and females after the animals reach 25 years of age and 2) an increasing average age of the captive population [Seal and Foose, 19883. Of 171 living, wild-born gorillas in captivity, only 106 have produced offspring. Since the breeding population is not being replaced at a rate that will maintain the population at its present size, the Gorilla Species Survival Plan committee, functioning under the auspices of the American Association of Zoological Parks and Aquariums, has made several recommendations in an effort to preserve genetic diversity from the original founder animals. These include the evaluation of all nonrepro- ment, cryopreservationReceived for publication March 13, 1989; revision accepted May 9, 1989. Reproductive technologies such as in vitro fertilization (IVF), artificial insemination (AI), and embryo transfer (ET) can offer timely conservation tools for the captive propagation of threatened species such as the gorilla by providing a means of recovering genetic material from nonreproductive individuals. Gametes or embryos may be either cryopreserved for future use or transferred directly into recipient animals. Animals that have been rendered infertile because of some pathological condition known not to be heritable, ovarian senescence, or behavioral incompatibilities may conceivably be returned to the breeding population.Pregnancy has been established in the gorilla using A1 [Gould et al., 19851. In the chimpanzee, A1 has been effective in producing offspring Matsubayashi et al., 19851. At present, information is sparse regarding oocyte retrieval, IVF, and ET in great apes. Oocyte recovery by laparoscopy and IVF have been reported in the chimpanzee [Gould, 19831; although no offspring were produced, in vitro embryonic development was reported.In humans, successful births have been reported following A1 using cryopreserved semen [Bunge and Sherman, 19531, intrafallopian tube transfer o...
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