The first pregnancies and live births following in vitro fertilisation (IVF) and preimplantation genetic testing (PGT), formerly known as preimplantation genetic diagnosis, were reported in 1990, almost 30 years ago, in several couples at risk of X-linked inherited conditions, which typically only affect boys inheriting the X chromosome with the affected gene from their carrier mothers. At that time, it was only possible to identify the sex of the embryo by amplifying a Y-linked repeat sequence in single cells biopsied at cleavage stages and avoid the transfer of males, half of which would be affected. The extensive publicity surrounding these cases and the perceived risk of using IVF and PGT for desirable characteristics not related to health, such as sex selection, led to the epithet of ‘designer babies’ which continues to resonate to this day. Here, I briefly reflect on how the technology of PGT has evolved over the decades and whether it deserves this reputation. With efficient methods for whole genome amplification and the genomic revolution, we now have highly accurate universal tests that combine marker-based diagnosis of almost any monogenic disorder with the detection of aneuploidy. PGT is now clinically well established and is likely to remain a valuable alternative for couples at risk of having affected children.
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Alan H Handyside
Benjamin Fisch and Ronit Abir
Anti-cancer therapy, particularly chemotherapy, damages ovarian follicles and promotes ovarian failure. The only pharmacological means for protecting the ovaries from chemotherapy-induced injury is gonadotrophin-releasing hormone agonist, but its efficiency remains controversial; ovarian transposition is used to shield the ovary from radiation when indicated. Until the late 1990s, the only option for fertility preservation and restoration in women with cancer was embryo cryopreservation. The development of other assisted reproductive technologies such as mature oocyte cryopreservation and in vitro maturation of oocytes has contributed to fertility preservation. Treatment regimens to obtain mature oocytes/embryos have been modified to overcome various limitations of conventional ovarian stimulation protocols. In the last decades, several centres have begun cryopreserving ovarian samples containing primordial follicles from young patients before anti-cancer therapy. The first live birth following implantation of cryopreserved-thawed ovarian tissue was reported in 2004; since then, the number has risen to more than 130. Nowadays, ovarian tissue cryopreservation can be combined with in vitro maturation and vitrification of oocytes. The use of cryopreserved oocytes eliminates the risk posed by ovarian implantation of reseeding the cancer. Novel methods for enhancing follicular survival after implantation are presently being studied. In addition, researchers are currently investigating agents for ovarian protection. It is expected that the risk of reimplantation of malignant cells with ovarian grafts will be overcome with the putative development of an artificial ovary and an efficient follicle class- and species-dependent in vitro system for culturing primordial follicles.
Jens Ehmcke and Stefan Schlatt
Fertility preservation in the male is routinely focused on sperm. In clinical and veterinary settings, cryopreservation of sperm is a widely used tool. However, the goals for male fertility preservation differ between experimental models, maintenance of livestock, conservation of rare species, and fertility protection in men. Therefore very different approaches exist, which are adapted to the specialized needs for each discipline. Novel tools for male fertility preservation are explored targeting immature germ cells in embryonic or immature testes. Many options might be developed to combine germline preservation and generation of sperm ex vivo leading to interesting new perspectives. This review highlights current and future options for male fertility preservation with a special focus on animal models and a consideration of the various disciplines in need of novel tools.
R Gosden and M Nagano
Individuals may regard reproduction as optional but sufficient number of them must be productive to perpetuate the species. The reproductive system is surprisingly vulnerable and depends, among other things, on a limited endowment of oocytes, controlled proliferation of spermatogonial stem cells and the genetic integrity of both. The developmental competence of oocytes and spermatogonial stem cells is maintained by evolved mechanisms for cellular detoxification and genomic stability, and excess or damaged cells are eliminated by apoptosis. Gonadal failure as a result of germ cell depletion can occur at any age, and from the effects of chemical cytotoxicity, disease and infection as well as genetic predisposition. Among extrinsic factors, alkylating agents and ionizing radiation are important causes of iatrogenic gonadal failure in young women and men. In animal models, there is evidence that hormonal manipulation, deletion of genes involved in apoptotic pathways and dietary manipulation can protect against natural and induced germ cell loss, but evidence in humans is absent or unclear. Assisted reproductive technologies (ARTs) provide an ensemble of strategies for preserving fertility in patients and commercially valuable or endangered species. Semen cryopreservation was the first technology for preserving male fertility, but this cannot serve prepubertal boys, for whom banking of testicular biopsies may provide a future option. In sterilized rodents, cryopreserved spermatogonial stem cells can recolonize seminiferous tubules and reinitiate spermatogenesis, and subcutaneous implantation of intact tubules can generate spermatozoa for fertilization in vitro by intracytoplasmic sperm injection. Transplantation of frozen-banked ovarian tissue is well-established for restoring cyclicity and fertility and is currently undergoing clinical evaluation for cancer patients. When restoration of natural fertility is unnecessary or reimplantation is unsafe, it is desirable to culture the germ cells from thawed tissue in vitro until they reach the stage at which they can be fertilized. Low temperature banking of immature germ cells is potentially very versatile, but storage of embryos and, to a lesser extent, mature oocytes is already practised in a number of species, including humans, and is likely to remain a mainstay for fertility preservation.
B. FJÄLLBRANT and D. R. ACKERMAN
Imene Boumela, Said Assou, Abdel Aouacheria, Delphine Haouzi, Hervé Dechaud, John De Vos, Alan Handyside, and Samir Hamamah
In women, up to 99.9% of the oocyte stockpile formed during fetal life is decimated by apoptosis. Apoptotic features are also detected in human preimplantation embryos both in vivo and in vitro. Despite the important consequences of cell death processes to oocyte competence and early embryonic development, little is known about its genetic and molecular control. B cell lymphoma-2 (BCL2) family proteins are major regulators of cell death and survival. Here, we present a literature review on BCL2 family expression and protein distribution in human and animal oocytes and early embryos. Most of the studies focused on the expression of two antagonistic members: the founding and survival family member BCL2 and its proapoptotic homolog BAX. However, recent transcriptomic analyses have identified novel candidate genes related to oocyte and/or early embryonic viability (such as BCL2L10) or commitment to apoptosis (e.g. BIK). Interestingly, some BCL2 proteins appear to be differentially distributed at the subcellular level during oocyte maturation and early embryonic development, a process probably linked to the functional compartmentalization of the ooplasm and blastomere. Assessment of BCL2 family involvement in regulating the survival of human oocytes and embryos may be of particular value for diagnosis and assisted reproductive technology. We suggest that implications of not only aberrant gene expression but also abnormal subcellular protein redistribution should be established in pathological conditions resulting in infertility.
Fernando A Rivera, Luís G D Mendonça, Gláucio Lopes Jr, José E P Santos, Rolando V Perez, Marcel Amstalden, Abelardo Correa-Calderón, and Ricardo C Chebel
Fertility of lactating dairy cows is associated with reduced progesterone (P4) concentration compared with nonlactating animals. The objective of the current study was to determine whether P4 during growth of the first follicular wave (FFW) affects embryo quality. Lactating Holstein cows at 33±3 days post partum were allocated to one of three treatments. Cows in the FFW and FFW with P4 (FFWP) treatments started the superstimulation protocol on day 1 of the estrous cycle and second follicular wave (SFW) cows started the superstimulation protocol on estrous cycle day 7. Cows were superstimulated with 400 mg of NIH-FSH-P1 (FSH) given twice daily for 5 days, two prostaglandin F2α (PGF2α) injections given with the ninth and tenth injections of FSH, GNRH given 48 h after the first PGF2α injection, and timed insemination 12 and 24 h after the GNRH injection. Cows in the FFWP treatment received two intravaginal P4 inserts during the superstimulation. Embryos were recovered 6.5 days after artificial insemination and excellent/good and fair embryos were frozen and transferred. Blood was sampled daily from estrous cycle day 0 until insemination from donor cows. During the superstimulation protocol, P4 was (P<0.01) greatest for SFW cows followed by FFWP and FFW cows respectively. The percentage of embryos–oocytes from SFW and FFWP cows classified as excellent/good and fair embryos was (P=0.02) greater than those of FFW cows. Pregnancy per embryo transfer was not (P≥0.73) affected by embryo donor treatment. Reduced embryo quality of cows induced to ovulate the follicles from the first follicular wave is a consequence of reduced P4 during follicle growth.
R A Anderson, W H B Wallace, and D T Baird
Female fertility preservation provides significantly different challenges to that for the male, with the only established method being cryopreservation of embryos thus necessitating the involvement of a male. Other, experimental, options include oocyte or ovarian tissue cryopreservation. The latter has been regarded as a potential method for more than a decade, but has resulted in the birth of only five babies. It is not possible to be certain how many women have had ovarian tissue cryopreserved. Oocyte cryopreservation also remains experimental, but ∼100-fold more babies have been born through this technique over the last two decades. Ovarian tissue cryopreservation has the potential advantages of preservation of a large number of oocytes within primordial follicles, it does not require hormonal stimulation when time is short and indeed may be appropriate for the pre-pubertal. Disadvantages include the need for an invasive procedure, and the uncertain risk of ovarian contamination in haematological and other malignancies. We here review this approach in the context of our own experience of 36 women, highlighting issues of patient selection especially in the young, and uncertainties over the effects of cancer treatments on subsequent fertility. Of these 36 women, 11 have died but 5 have had spontaneous pregnancies. So far, none have requested reimplantation of their stored ovarian tissue. Ovarian cryopreservation appears to be a potentially valuable method for fertility preservation, but the indications and approaches best used remain unclear.
P. B. Farrell and R. H. Foote
Zygotes were collected from superovulated Dutch-belted rabbits 19 h after injection of LH and insemination. Oocytes that appeared to be unfertilized were discarded. The zygotes were distributed equally within each donor female across all culture treatments. Culture dishes contained 500 μl of macromolecule-free RD medium consisting of equal parts of RPMI 1640 and low glucose Dulbecco's modified Eagle's medium. Embryos were cultured at 39°C in several gas combinations of N2 plus the following: (1) 1% O2:10% CO2; (2) 5% O2:10% CO2; and (3) 20% O2:10% CO2. The control (4) was 95% air:5% CO2. The experiment was replicated with embryos from 11 donors providing 295 usable zygotes. After 84 h of culture, the percentages of blastocysts formed in treatments 1 to 4, respectively, were 13, 86, 82 and 59 (P < 0.01). The corresponding mean cell counts, including all cleaved embryos cultured (but not degenerate ones), were 55, 183, 118 and 68 (P < 0.01). These results indicate that 10% CO2 combined with 5% O2 is a more effective gas phase for culturing rabbit zygotes in a synthetic medium than is the commonly used 5% CO2, and that 5% O2 is superior to either 1% or 20% O2.
M. C. Snabes and M. J. K. Harper
Summary. Blastocysts recovered from oil- or indomethacin-treated donor rabbits between 5½ and 6 days after insemination and hCG injection were transferred to oil- or indomethacin-treated recipients between 135 and 147 h after hCG injection. Indomethacin treatment of donor rabbits (10 mg/kg s.c.) given every 6 h during the day before transfer had no effect on subsequent implantation of the blastocysts. However, indomethacin treatment of the recipients (10 mg/kg s.c. every 6 h from 120 to 168 h after hCG) prevented implantation of all transferred blastocysts, although 6 of the 8 rabbits died between Days 9 and 16 of (pseudo)pregnancy. Restriction of the indomethacin treatment of the recipients to only 3 injections of 10 mg/kg s.c. between 128 and 140 h after hCG injection had no effect on the implantation of the transferred blastocysts. It is concluded that indomethacin exerts its inhibitory influence on implantation via an action on the endometrium rather than on the blastocyst.