Male fertility restoration: in vivo and in vitro stem cell–based strategies using cryopreserved testis tissue
Childhood cancer survival rates have increased substantially
in the past few decades, with over 80% of survivors reaching adulthood thanks
to modern treatment regimens. Many prepubertal patients with cancer are facing
gonadotoxic treatments such as chemotherapy or gonadal radiation, which poses a
significant threat to their future fertility. Prepubertal males have no option
to preserve fertility by traditional sperm cryopreservation; for these
patients, the only fertility preservation strategy is cryopreservation of immature
testis tissue (ITT). Fertility restoration is increasingly becoming a concern,
with the focus shifting toward continuation of care after successful cancer
treatment and securing quality of life for childhood cancer survivors who wish
to become biologic parents in adulthood. Some centers also offer testis tissue
cryopreservation for selected young boys with cryptorchidism who have a high
risk of infertility. A growing number of centers worldwide now offer routine
cryopreservation of ITT with the aim of advancing spermatogonial stem cell
(SSC)–based treatments to a clinical stage to provide opportunities for
fertility restoration.
Fertility has a profound impact on our quality of life. Male
fertility restoration is currently a dynamically evolving field including a
broad range of strategies such as surgical and in vitro approaches to achieve
restoration of fertility from prepubertally cryopreserved testis tissue.
Meanwhile, the current evidence for fertility restoration strategies has not yet
been systematically synthesized, leading to a potential lack of structured
research cooperation across different disciplines. Thus, this topic lends
itself to a scoping approach to map and assess the extent of the evolving
heterogeneous literature and identify gaps in knowledge. This review aimed to
examine the current evidence and clinical applicability of the different
strategies for fertility restoration using ITT as well as identify future
research questions that will accelerate the expected implementation of therapy
options in clinical medicine. Furthermore, potential barriers in the
development of clinically relevant therapies are identified.
The review was conducted after the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses extension for Scoping Reviews criteria
and previously published guidelines and examined studies using human testis
tissue of prepubertal boys or healthy male adults. A literature search in
PubMed was conducted, and 72 relevant studies were identified, including in
vivo and in vitro approaches.
In vivo strategies, such as testis tissue engraftment and
spermatogonial stem cell transplantation, hold promise for promoting cell
survival and differentiation. Yet, complete spermatogenesis has not been
achieved. In vitro approaches focus on the generation of male germ cells from
direct germ cell maturation in various culture systems, alongside human induced
pluripotent stem cells and embryonic stem cells. These approaches mark
significant advancements in understanding and promoting spermatogenesis, but
achieving fully functional spermatozoa in vitro remains a challenge. Barriers
to clinical implementation include the risk of reintroducing malignant cells
and introduction of epigenetic changes.
Male fertility restoration is a rapidly transforming field
with new evolving technologies and a recent substantial advancement with the
first proof-of-principle study of testis tissue engraftment in a human male. A
broad range of studies on in vitro and in vivo stem cell–based strategies for
male fertility restoration demonstrated significant advancements. However, lack
of standardized outcomes and reporting tools, heterogeneous source tissue
material, risk of reintroduction of malignant cells, and unresolved challenge
of definite identification of SSCs in vitro are still challenging clinical
implementation. After assessment of the currently available reports, autologous
engraftment of cryopreserved and thawed testis tissue appears to be the most
promising strategy for male fertility restoration and is likely close to the
first human experimental clinical trials. Testis tissue has been cryopreserved
from >3,000 boys aged <18 years worldwide, and it is now a collective
task to team up, improve interdisciplinary efforts, and share knowledge across
countries for establishing evidence-based robust guidelines for clinical male
fertility preservation and restoration.
Source: Elena von Rohden, M.D.,a,b,h Christian Fuglesang S.
Jensen, M.D., Ph.D.,a Claus Yding Andersen; Fertil Steril® Vol. 122, No. 5,
November 2024 0015-0282
https://doi.org/10.1016/j.fertnstert.2024.07.010
