Forty years of IVF

Study question Do different chemotherapy drugs exert the same magnitude of cytotoxicity on dormant primordial follicles and the growing follicle fraction in the ovary in vivo and on mitotic non-luteinized and non-mitotic luteinized granulosa cells in vitro? Summary answer Cyclophosphamide (alkylating agent) and cisplatin (alkylating like) impacted both primordial and pre-antral/antral follicles and both mitotic and non-mitotic granulosa cells, whereas the anti-metabolite cancer drug gemcitabine was detrimental only to pre-antral/antral follicles and mitotic non-luteinized granulosa cells. What is known already It is already known that anti-metabolite cancer drugs are less detrimental to the ovary than alkylating and alkylating like agents, such as cyclophosphamide and cisplatin. This assumption is largely based on the results of clinical reports showing lower rates of amenorrhea in women receiving anti-metabolite agent-based regimens compared with those treated with the protocols containing an alkylating drug or a platinum compound. But a quantitative comparison of gonadotoxicity with a histomorphometric proof of evidence has not been available for many chemotherapy drugs. Therefore, we combined in this study in vivo and in vitro models of human and rat origin that allows a comparative analysis of the impact of different chemotherapy agents on the ovary and granulosa cells using real-time quantitative cell indices, histomorphometry, steroidogenesis assays, and DNA damage and cell death/viability markers. We also aimed to investigate if there is a difference between mitotic and non-mitotic granulosa cells in terms of their sensitivity to the cytotoxic actions of chemotherapy drugs with different mechanisms of action. This issue has not been addressed previously. Study design, size, duration This translational research study involved in vivo analyses of ovaries in rats and in vitro analyses of granulosa cells of human and rat origin. Participants/materials, setting, methods For the in vivo assays, 54 4- to 6-week old Sprague-Dawley young female rats were randomly allocated into four groups of 13 to receive a single IP injection of: saline (control), gemcitabine (200 mg/kg), cisplatin (50 mg/kg) or cyclophosphamide (200 mg/kg). The animals were euthanized 72 h later. Follicle counts and serum AMH levels were compared between the groups. In vitro cytotoxicity studies were performed using mitotic non-luteinized rat (SIGC) and human (COV434, HGrC1) granulosa cells, and non-mitotic luteinized human (HLGC) granulosa cells. The cells were plated at a density of 5000 cells/well using DMEM-F12 culture media supplemented with 10% FBS. Chemotherapy agents were used at their therapeutic blood concentrations. The growth of mitotic granulosa cells was monitored real-time using xCelligence system. Live/dead cell and apoptosis assays were also carried out using intravital Yo-Pro-1 staining and cleaved caspase-3 expression, respectively. Estradiol (E2), progesterone (P) and anti-Mullerian hormone (AMH) levels were assayed with ELISA. Main results and the role of chance Cyclophosphamide and cisplatin caused massive atresia of both primordials and growing follicles in the rat ovary whereas gemcitabine impacted pre-antral/antral follicles only. Cyclophosphamide and cisplatin induced apoptosis of both mitotic non-luteinized and non-mitotic luteinized granulosa cells in vitro. By contrast, cytotoxicity of gemcitabine was confined to mitotic non-luteinized granulosa cells. Limitations, reasons for caution This study tested only three chemotherapeutic agents. The experimental methodology described here could be applied to other drugs for detailed analysis of their ovarian cytotoxicity. Wider implications of the findings These findings indicate that in vivo and in vitro cytotoxic actions of chemotherapy drugs on the ovarian follicles and granulosa cells vary depending upon the their mechanism of action and the nature of the granulosa cells.

/pdf/the-magnitude-of-gonadotoxicity-of-chemotherapy-drugs-on-46585lpux4.pdf

The magnitude of gonadotoxicity of chemotherapy drugs on ovarian follicles and granulosa cells varies depending upon the category of the drugs and the type of granulosa cells

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding a peroxisomal ABC transporter. In this review, we compare estimates of incidence derived from different populations in order to provide an overview of the worldwide incidence of X-ALD. X-ALD presents with heterogeneous phenotypes ranging from adrenomyeloneuropathy (AMN) to inflammatory demyelinating cerebral ALD (CALD). A large number of different mutations has been described, providing a unique opportunity for analysis of functional domains within ABC transporters. Yet the molecular basis for the heterogeneity of clinical symptoms is still largely unresolved, as no correlation between genotype and phenotype exists in X-ALD. Beyond ABCD1, environmental triggers and other genetic factors have been suggested as modi- fiers of the disease course. Here, we summarize the findings of numerous reports that aimed at identifying modifier genes in X-ALD and discuss potential problems and future approaches to address this issue. Different options for prenatal diagnosis are summarized, and potential pitfalls when applying next-generation sequencing approaches are discussed. Recently, the measurement of very long-chain fatty acids in lysophosphatidylcholine for the identification of peroxisomal disorders was included in newborn screening programs.

https://dash.harvard.edu/bitstream/handle/1/16121005/4427263.pdf?sequence=1

The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis.

Wiskott-Aldrich syndrome is a life-threatening primary immunodeficiency associated with a bleeding tendency, eczema and a high incidence of autoimmunity and malignancy. Stem cell transplantation offers the opportunity of cure for all these complications, and over the past 35 years there has been a remarkable improvement in survival following this treatment. Here, we review advances in management of clinical complications pre- and post-transplant, as well as discuss the morbidity Wiskott-Aldrich syndrome patients experience following treatment. For patients with a poorly matched stem cell donor, recent gene therapy trials demonstrate encouraging results and the potential of low-toxicity therapy for all patients.

Current and emerging treatment options for Wiskott-Aldrich syndrome.

For many decades, the dogma prevailed that female mammals had a finite pool of oocytes at birth and this was gradually exhausted during a lifetime of reproductive function. However, in 2004, a new era began in the field of female oogenesis. A study was published that appeared to detect oocyte-stem cells capable of generating new eggs within mouse ovaries. This study was highly controversial and the years since this initial finding have produced extensive research and even more extensive debate into their possibility. Unequivocal evidence testifying to the existence of oocyte-stem cells (OSCs) has yet to be produced, meanwhile the spectrum of views from both sides of the debate are wide-ranging and surprisingly passionate. Although recent studies have presented some convincing results that germ cells exist and are capable of creating new oocytes, many questions remain. Are these cells present in humans? Do they exist in physiological conditions in a dormant state? This comprehensive review first examines where and how the dogma of a finite pool was established, how this has been challenged over the years and addresses the most pertinent questions as to the current status of their existence, their role in female fertility, and perhaps most importantly, if they do exist, how can we harness these cells to improve a woman's oocyte reserve and treat conditions such as premature ovarian insufficiency (POI: also known as premature ovarian failure, POF).

/pdf/oocyte-stem-cells-fact-or-fantasy-24och2192w.pdf

Oocyte stem cells: fact or fantasy?

Haematopoietic stem cell transplantation (HSCT) remains the best therapeutic option for many acquired and inherited paediatric haematological disorders. Unfortunately, the probability of finding an HLA matched donor is limited. An alternative technique is PGD combined with HLA matching, which offers the possibility of selecting unaffected embryos that are HLA compatible with the sick child, with the aim of possible use of stem cells from the resulting baby in future. Since the first successful report for Fanconi anaemia a decade ago, the therapeutic success of this technique was reported in a few cases and for a limited number of disorders. Here, we report full recovery of 44 sick children who received HSCT from healthy infants conceived after pre-implantation HLA matching for the following 10 indications; beta-thalassaemia, Wiskott–Aldrich syndrome, Fanconi anaemia, sickle cell anaemia, acute myeloid leukaemia, acute lymphoblastic leukaemia, Glanzmann's thrombasthaenia, Diamond–Blackfan anaemia, X-linked adrenoleukodystrophy and mucopolysaccharidosis type I. No serious complications were observed among recipients and donors. Graft failure occurred in four children with beta-thalassaemia where a second HSCT was planned. Preimplantation HLA matching is a reliable technique and provides a realistic option for couples seeking treatment for an affected child when no HLA-matched donor is available.

Successful haematopoietic stem cell transplantation in 44 children from healthy siblings conceived after preimplantation HLA matching

Session 32: Stem cells and translational research

Preimplantation genetic diagnosis (PGD) gives couples who are at risk of having a child with an inherited genetic disorder or chromosome abnormality, a chance to have an unaffected child without undergoing termination or miscarriage of an affected pregnancy. Embryos obtained from in-vitro fertilisation (IVF) with or without intracytoplasmic sperm injection are tested genetically prior to selective transfer of unaffected ones into the uterus. The physical and psychological complications of a termination or miscarriage, especially in repeated situations, should not be underestimated. In PGD, DNA can be obtained by blastomere biopsy at the cleavage stage, trophectoderm cell biopsy when an embryo has developed to the blastocyst stage or biopsy of one or both polar bodies. Compared with cleavage stage biopsy, trophectoderm biopsy does not adversely impact the embryo, although vitrification and cryopreservation of the embryo may be required to allow time for genetic analysis.1 Although polar body biopsy is less invasive, it is less predictive of actual clinical outcome than direct embryo assessment.2 Genetic laboratories have developed their own protocols to perform different molecular tests on the limited amount of DNA obtained from biopsy. Traditionally, fluorescent in-situ hybridisation is used for cytogenetic diagnosis, and polymerase chain reaction for molecular diagnosis. New technologies, including array comparative genomic hybridisation (CGH) and single nucleotide polymorphism (SNP) microarrays, can improve diagnostic accuracy.3,4 The single-cell whole genome amplification (WGA) method allows subsequent mutation study, directly by minisequencing and/or indirectly by linkage analysis alongside the mutation test. It also allows simultaneous PGD for more than one indication.5 The indications for PGD are increasing. Common ones include single-gene disorders, X-linked diseases, and inherited chromosome abnormalities. Preimplantation genetic diagnosis of predisposition to inherited cancer such as breast cancer (BRCA mutation) is also emerging.6 Nonetheless, social sexing is prohibited in Hong Kong and Europe. Legislation and regulation of PGD also vary among different countries. Aneuploidy is the most common cause of repeated implantation failure and recurrent Hong Kong Med J 2015;21:296–7 DOI: 10.12809/hkmj154638 KY Leung*, MD, FHKAM (Obstetrics and Gynaecology)

https://www.dovepress.com/getfile.php?fileID=24674

Recent advances in preimplantation genetic diagnosis

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Successful haematopoietic stem cell transplantation in 44 children from healthy siblings conceived after preimplantation HLA matching

Session 32: Stem cells and translational research

Recent advances in preimplantation genetic diagnosis