Tommaso Falcone

Background: Uterus transplantation (UTx) is an emerging treatment for absolute uterine factor infertility. However, the use of deceased donors is limited, and donation after circulatory death (DCD) has not yet been utilized. Ischemic injury remains a major barrier, particularly compared with living donor procedures. Hypothermic oxygenated perfusion (HOPE), which has shown protective effects in heart, liver, and kidney transplantation, may offer similar benefits for uterine grafts. Methods: We report the first series applying HOPE to human uteri to improve preservation and enable metabolic injury assessment during perfusion. Six uteri (3 DBD, 3 DCD; median donor age 53 years) underwent 8 h of HOPE following procurement, while paired tissue controls were preserved using static cold storage (SCS). Perfusion was delivered using a pressure-controlled system (15 mmHg, 10 ± 1 °C, VitaSmart^®). Perfusate and tissue samples were analyzed for mitochondrial injury, inflammation, and transcriptional responses. Results: HOPE maintained stable flows (70–150 mL/min), delivered high oxygen levels (pO₂ ≈ 1000 hPa), and increased tissue ATP levels. Stratification based on perfusate flavin mononucleotide (FMN) release identified grafts with greater Complex I/II injury. HOPE was associated with lower levels of mitochondrial injury markers and inflammatory signals, preserved tissue architecture, and promoted gene expression patterns consistent with metabolic recovery compared with paired SCS tissue controls. Conclusions: These findings suggest that HOPE may serve as a preservation approach that enables metabolic and ischemic injury assessment and may facilitate broader use of deceased donor uteri for transplantation.

Advances in oncologic therapies have markedly improved survival among reproductive-age female patients, making fertility preservation an essential component of comprehensive cancer care. Gonadotoxic treatments, including chemotherapy, radiotherapy, and surgery, can disrupt ovarian and uterine endocrine function, resulting in premature ovarian insufficiency and infertility. This narrative review summarizes current and emerging surgical approaches to fertility preservation, organized by anatomic focus on the ovary, uterus, and cervix. Ovarian transposition preserves ovarian endocrine function by relocating the ovaries outside the pelvic radiation field, while ovarian tissue cryopreservation preserves primordial follicles through surgical harvesting, cryostorage, and reimplantation to restore ovarian function and fertility. Emerging uterine-preserving strategies, such as uterine transposition and uterine transplantation, demonstrate growing feasibility for restoring reproductive and endocrine uterine function. Fertility-sparing cervical procedures, including radical and simple trachelectomy, maintain favorable oncologic outcomes while preserving reproductive potential in appropriately selected patients. Across all modalities, multidisciplinary collaboration and individualized counseling are critical to optimize both oncologic and reproductive outcomes. Continued research aimed at refining surgical techniques, improve graft viability, and expanding equitable access will be key to advancing fertility preservation as a standard component of comprehensive cancer care.

With increasing cancer incidence among individuals of reproductive age, preserving fertility has become a critical aspect of cancer care. This narrative review explores the impact of contemporary cancer therapies, including immunotherapies and targeted agents, on reproductive health, highlighting clinical fertility outcomes and underlying biological mechanisms. We outline the epidemiology and treatment strategies for malignancies common in adolescents and young adults (AYAs), including breast, melanoma, lung, gynaecologic, colorectal cancers and haematologic malignancies. Basic reproductive physiology in males and females is reviewed, including the hypothalamic–pituitary–gonadal axis, ovarian follicle and oocyte development, and spermatogenesis. Clinical data related to fertility and reproductive outcomes in patients receiving immunotherapy or targeted therapy are summarised, along with proposed mechanisms of gonadotoxicity from both conventional chemotherapy and newer drug classes. Special emphasis is placed on immunotherapy, such as checkpoint inhibitors, cell-based therapies (eg, chimeric antigen receptor T cells, tumour-infiltrating lymphocytes) and monoclonal antibodies, and small-molecule inhibitors, including kinase inhibitors (eg, BRAF, MEK, epidermal growth factor receptor), poly (ADP-ribose) polymerase inhibitors, epigenetic modifiers and apoptosis promoters (eg, BCL-2 inhibitors). Despite their growing use, these therapies are poorly studied in terms of reproductive safety, with available evidence being limited, heterogeneous and often lacking baseline fertility assessments or long-term follow-up. This uncertainty complicates counselling and decision-making, requiring a precautionary approach to fertility preservation. Multidisciplinary collaboration incorporating oncology, reproductive medicine, psychology and ethics is essential for individualised, ethically sound care. Emerging technologies such as organ-on-chip systems and induced pluripotent stem cell models offer promising avenues for mechanistic insight. To advance the field, future efforts must focus on prospective cohort studies, robust preclinical models and interim clinical guidelines to support informed fertility-related care for cancer patients.

Adenomyosis is a benign gynecologic disorder that had previously not been well studied or understood. However, it is now become a more common diagnosis with long-standing implications especially for fertility. In this literature review, the pathophysiology and diagnosis along with management options for uterine preservation and fertility along with more definitive options are reviewed. While there is a better understanding of adenomyosis, there is still more research that is needed to fully elucidate the best ways of management for patients especially in those seeking fertility.

Endometriosis is a common disease among women of reproductive age in which endometrial tissue grows in ectopic localizations, primarily within the pelvic cavity. These ectopic “lesions” grow as well as migrate and invade underlying tissues. Despite the prevalence of the disease, an understanding of factors that contribute to these cellular attributes remains poorly understood. Prefoldin-5 (PFDN5) has been associated with both aberrant cell proliferation and migration, but a potential role in endometriosis is unknown. As such, the purpose of this study was to examine PFDN5 expression in endometriotic tissue. PFDN5 mRNA and protein were examined in ectopic (lesion) and eutopic endometrial tissue from women with endometriosis and in eutopic endometrium from those without endometriosis using qRT-PCR and immunohistochemistry, respectively, while function of PFDN5 in vitro was evaluated using cell count and migration assays. PFDN5 mRNA and protein were expressed in eutopic and ectopic endometrial tissue, predominantly in the glandular epithelium, but not in endometrium from control subjects. Expression of both mRNA and protein was variable among endometriotic eutopic and ectopic endometrial tissue but showed an overall net increase. Knockdown of PFDN5 by siRNA transfection of endometriotic epithelial 12Z cells was associated with reduced cell proliferation/survival and migration. PFDN5 is expressed in eutopic and ectopic glandular epithelium and may play a role in proliferation and migration of these cells contributing to disease pathophysiology.

Uterus transplantation (UTx) is a rapidly evolving treatment for uterine factor infertility. New centers offering this treatment must decide whether to utilize living donors, deceased donors, or both. Although limiting UTx to deceased donors eliminates the surgical risks for living donors, an adequate supply of suitable deceased uterus donors in the United States is an emerging concern. Previous studies describing the paucity of deceased uterus donors failed to consider key donor characteristics, potentially overestimating the available organ pool. To estimate the United States’ supply of deceased donor uteri; we extrapolated detailed clinical and demographic information from the regional donor datasets available from three organ procurement organizations to the national Organ Procurement and Transplantation Network donor pool. We estimate there are approximately 3700 possible and 400 optimal uterus donors annually in the United States. Given these projections and the number of women with uterine factor infertility in the U.S. who pursue parenthood through alternative strategies, we conclude that, as uterus transplant transitions from research to established clinical care, demand could quickly exceed the deceased donor supply. The liberalization of deceased donor selection criteria may be insufficient to address this imbalance; therefore, fulfilling the anticipated increased demand for uterus transplantation may require and justify greater use of living donors.