Table 4.

Critical evaluation of various options available to tackle infertility

Various approaches	Current status
Making Artificial Gametes from ES/iPS Cells	• Protocols are not yet available to convert human ES/iPS cells into PGCLCs. Obtaining gametes from mouse ES/iPS cells is successful but still inefficient and has associated epigenetic concerns. • Human ES cells exist in primed state and have to be converted to naïve state for further differentiation • Gametes obtained from human ES cells will not ensure biological parenthood unless and until the hES cells are derived by somatic cell nuclear transfer (therapeutic cloning). However, despite recent success in the field [130], this may also not be a practical solution since the hES cells derived by this method will have to be first converted into PGCLCs which is a road-block at present. • Serious concern exists with the use of iPS cells to make gametes. They exhibit genomic [131, 132] and mitochondrial [133] DNA mutations which seriously limit their clinical utility [134]. They also retain residual epigenetic memory of the somatic cell from which they are derived [135, 136]. Even for other clinical conditions, it is being advocated to use allogeneic over autologus iPS cells as it is more practical and safe. The first clinical trial for macular degeneration using autologus iPS cells was suspended due to safety concerns [137]. But use of allogeneic iPS cells to make gametes will not ensure biological parenthood. • Gametes obtained from hES/iPS cells will require use of assisted reproductive technology to have a baby. But this approach is expensive and inefficient.
Restoring Fertility by Targeting Endogenous, Resident Stem Cells (VSELs)	• Major advantage of VSELs compared to hES/iPS cells is that they are equivalent to PGCs. Developmentally they are obtained from epiblast-stage embryo and thus relatively more mature compared to ES cells obtained from the inner cell mass of blastocyst stage embryo. • Being equivalent to PGCs (natural precursors to gametes), VSELs spontaneously differentiate into sperm & oocytes in vitro • VSELs survive oncotherapy in the gonads and transplanting niche cells (autologus mesenchymal cells from any source) can regenerate non-functional, azoospermic testis and POF ovary. This approach will ensure restoration of normal fertility. If mesenchymal cells are transplanted in pediatric cancer survivors, the gonads could serve as a source of hormones for secondary sexual development and later on in life will also be a source of gametes. • This approach could circumvent all associated safety and epigenetic concerns that invariably creep in when cells are cultured in vitro. Normal fertility will be restored and there will be no need of use of assisted reproductive technology. This approach is more feasible and less expensive. Most importantly, this approach could obviate the need to cryopreserve gonadal tissue prior to oncotherapy.
Other Available Options	• All the below mentioned alternatives are still being researched upon and are not yet ready for the clinics • In vitro follicle culture • Artificial ovary • Entire ovary cryopreservation • Use of feto-protective agents • In vitro culture of OSCs and SSCs • Transplantation of cryopreserved cortical tissue pieces has given promising results. However, it is an invasive and expensive procedure. • Only option available is semen banking for men. Use of cryopreserved testicular tissue is not yet available in the clinics