The Need for Animal Research in the Field of Uterus Transplantation in Males

In the current issue of Transplantation, the first ever publication on uterus transplantation (UTx) in males is published.1 The report marks a start for a very important area of research within the fields of transplantation and infertility. In 2012, the Swedish team at the University of Gothenburg started the first clinical trial of UTx as a possible treatment for absolute uterine factor infertility (AUFI) in women.2 Women with AUFI have either congenital/surgical uterine absence or any abnormality (anatomic/functional) that impedes pregnancy. The proof-of-concept of UTx as an infertility treatment for women with AUFI came with the first live birth after UTx, which occurred in Sweden in September 2014.3 In that case, a 35-y-old woman with congenital uterine absence, as part of the Mayer-Rokitansky-Küster-Hauser syndrome, had been transplanted the year before with a uterus from a 61-y-old friend. A total of 9 live births, from 6 transplanted women, occurred from this Swedish live donor (LD) UTx trial of 2012–2013, which included 9 LD-UTx procedures.2 Already for this initial UTx introduction, the reproductive efficacy of the procedure proved to be high, with a 100% cumulative clinical pregnancy rate and 86% cumulative take-home-baby rate, among the study participants that underwent pregnancy attempts.4 Today, >90 UTx procedures have been performed worldwide, with >50 live births achieved.5,6 The great clinical success of female UTx within the initial clinical trial2 and in following clinical trials of both LD and deceased donor UTx procedures5,6 is most likely due to the meticulous and long-term research preparations before the commencement of the first clinical UTx. The Swedish team started already in 1999 an animal-based research project on UTx, initially in rodents but later also including large domestic species and nonhuman primates.7 This was to optimize and safeguard the procedure before introduction in 20122,4 as an experimental surgical procedure for female AUFI. The UTx was initially intended as an infertility treatment for female AUFI, with the potentially largest groups being those with congenital uterine absence, as part of Mayer-Rokitansky-Küster-Hauser syndrome, or women of fertile age that had undergone hysterectomy due to cervical cancer, postpartum bleeding, or leiomyoma. However, the panorama of possible patient groups that may benefit from UTx has expanded and today also includes 2 distinct groups of women, with male (XY) genetic setups. Women of these groups have expressed interest in UTx as a possibility to gestational motherhood both by personal contacts to teams undertaking UTx trials and also with the interest documented in scientific publications.8,9 These 2 potential UTx groups with male chromosomes are women with complete androgen insensitivity syndrome (CAIS) and transsexual women that have undergone male-to-female (MTF) gender affirmation treatment. The CAIS condition is rare (<1:20 000) and occurs because of complete resistance to the action of androgens due to mutation(s) in the androgen receptor, causing the fetus and child to develop with normal external female phenotype but with absent internal genitalia and presence of testes.10 At puberty, there will typically be normal female breast and female distribution of adipose tissues, but estrogen treatment is needed for the full development of secondary sexual sex characteristics, such as pubic hair. Later on, vaginal dilatation and orchidectomy, because of the risk of malignant transformation of the gonads, may be needed. Concerning transsexual MTF, feminizing hormone therapy (antiandrogens and estrogen) will usually be started well before gender affirmation surgery, including breast augmentation, penilectomy, orchidectomy, and construction of vagina and labia.11 In many MTF women, sperm cryopreservation may occur before orchidectomy. A UTx procedure in a transwoman would provide the possibility for gestational motherhood and for genetic motherhood, the latter in the event that her cryopreserved sperms are used in the in vitro fertilization procedure, with donor oocytes or oocytes from a female partner. The article by Yang and colleagues1 is a very good start for expectantly long-term research interest, by the Chinese group and other research teams, to investigate the feasibility of UTx in various male animal models toward human experimental clinical trials in transwomen or women with CAIS. My prediction is that there will be a 5- to 10-y research period before we are ready for human experimental trials in this area of UTx-in-male or before the research findings have found that it is not advisable to test this in humans. The research pioneers of male UTx from Xi’an, China,1 used a rat model with transplantation from Spraque-Dawley female rats into the groin area of orchidectomized male rats of the same inbred strain. The UTx method, with retrieval including excision of 1 uterine horn and creation of unilateral vascular pedicles of the common iliac, was adopted from our studies in the mouse and rat for female UTx.12,13 In the latter female animal models, the uterus was positioned intraabdominally with end-to-side anastomoses to the aorta/vena cava and common iliac in the mouse and rat, respectively. In the study by Chang and coworkers,1 anastomoses were on the femoral vessels. In this initial report, there was high-perioperative/postoperative mortality, and only 6 of 13 transplanted rats survived for evaluation 30 d after UTx. This shows that further improvements are needed in the surgical approach used and in postoperative management. Importantly, this methodological article1 showed that the histology of the uterine grafts was normal and thus demonstrated that this unilateral UTx surgical method, or modifications of this, can be used in further studies on UTx in males. The authors also conclude that the results may provide a reference for further studies of transsexual UTx in animals. Human UTx in males may raise both ethical concerns and may involve challenges relating to the anatomical, physiological, and genetical differences between females and males. Concerning ethics, we have to weigh the potential benefits of a UTx-in-male intervention against its biophysical risks. However, it should be ethically apparent that the reproductive goals of MTF transgender women warrant equal consideration to those assigned cis females, as described as “that the principle of autonomy is not sex-specific” in the Montreal Ethics Criteria of UTx.14 It should be pointed out that in the event that UTx-in-male research in animals and humans is successful and that UTx-in-female before that develops into a clinically accepted treatment for female AUFI, refusal to perform the UTx procedure based on the presence of XY chromosomes may face legal and moral obstacles. As mentioned above, there are differences between males and females, which may present difficulties in the development of male UTx. There is a difference in the shape of the female gynecoid pelvis compared with the narrower male android pelvis. This may influence the risk for abnormal fetal positioning during pregnancy in a male, as well as make the embryo transfer procedure, to achieve pregnancy, more difficult. Moreover, the transplanted uterus in a female pelvis would be supported with attachment to the round ligaments and sacrouterine ligaments, which are not present in a male pelvis. An obvious fact is that orchidectomy should occur before any pregnancy attempt in an MTF transwoman, because antiandrogen treatment will increase the risk for genital birth defects, and in CAIS, because the fetus will have functional androgen receptors. Also, the effects of long-term androgen treatment on the uterus and its vasculature have to be taken into account in the event that the donor uterus to an MTF woman is from donor-hysterectomy in a female-to-male man. One of the most challenging issues in male UTx would be possible negative influence by the type of vagina. A neovagina created in a male would not be lined by the normal vaginal epithelium because the vagina would be either an intestinal vagina, a split-skin-graft McIndoe vagina, or a vagina created by inversion of the skin after penilectomy. The altered vaginal microbiome, caused by the milieu of the abnormal vaginal epithelium, may negatively influence implantation after embryo transfer and may also lead to increased risks for ascending infections and septic abortions in the immunosuppressed uterus recipient. It should be emphasized that pregnancies in a male will most likely have an unphysiological epigenetic influence on the fetus, and this may cause negative effects on development and health during childhood and adulthood. Thus, this important issue has to be thoroughly studied in animal models. Taken together, because of anatomical, hormonal, fertility, obstetrical, and genetic complexity involvements, it is strongly recommended that any UTx attempt in genetically XY humans should be preceded by systematic animal research to maximize safety and efficacy, as was performed for genetically XX females. The article by Yang and colleagues1 is a first step in that direction.

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