In 2007, I was asked by the University of Calgary to participate in a symposium called 'Pushing the Boundaries--Advances that Will Change the World in 20 Years'. My topic was oncofertility, a word I ...had just coined to describe the intersection of two disciplines--oncology and fertility--and I was thrilled to share my passion for this new field and help young women with cancer protect their future reproductive health. Fertility preservation in the cancer setting lacked a concerted effort to bridge the disciplines in an organized manner. In early 2015, I was delighted to deliver a presentation for the Society for Reproduction and Fertility titled 'Sex in Three Cities', where I gave an update on the oncofertility movement, a remarkable cross-disciplinary, global collaboration created to address the fertility preservation needs of young cancer patients. During my tour of the UK, I was impressed by the interest among the society and its members to engage colleagues outside the discipline as well as the public in a dialogue about cutting-edge reproductive science. In this invited review, I will describe the work of the Oncofertility Consortium to provide fertility preservation options in the cancer setting and accelerate the acceptance of this critical topic on a global scale. I hope that one day this word and field it created will change the world for women who had been left out of the equation for far too long.
In the central nervous system (CNS), connexin (Cx)s and pannexin (Panx)s are an integral component of homeostatic neuronal excitability and synaptic plasticity. Neuronal Cx gap junctions form ...electrical synapses across biochemically similar GABAergic networks, allowing rapid and extensive inhibition in response to principle neuron excitation. Glial Cx gap junctions link astrocytes and oligodendrocytes in the pan‐glial network that is responsible for removing excitotoxic ions and metabolites. In addition, glial gap junctions help constrain excessive excitatory activity in neurons and facilitate astrocyte Ca2+ slow wave propagation. Panxs do not form gap junctions in vivo, but Panx hemichannels participate in autocrine and paracrine gliotransmission, alongside Cx hemichannels. ATP and other gliotransmitters released by Cx and Panx hemichannels maintain physiologic glutamatergic tone by strengthening synapses and mitigating aberrant high frequency bursting. Under pathological depolarizing and inflammatory conditions, gap junctions and hemichannels become dysregulated, resulting in excessive neuronal firing and seizure. In this review, we present known contributions of Cxs and Panxs to physiologic neuronal excitation and explore how the disruption of gap junctions and hemichannels lead to abnormal glutamatergic transmission, purinergic signaling, and seizures.
Fertility preservation in women with cancer De Vos, Michel, Dr; Smitz, Johan, Prof; Woodruff, Teresa K, Prof
The Lancet,
10/2014, Letnik:
384, Številka:
9950
Journal Article
Recenzirano
Odprti dostop
Summary Enhanced long-term survival rates of young women with cancer and advances in reproductive medicine and cryobiology have culminated in an increased interest in fertility preservation methods ...in girls and young women with cancer. Present data suggest that young patients with cancer should be referred for fertility preservation counselling quickly to help with their coping process. Although the clinical application of novel developments, including oocyte vitrification and oocyte maturation in vitro, has resulted in reasonable success rates in assisted reproduction programmes, experience with these techniques in the setting of fertility preservation is in its infancy. It is hoped that these and other approaches, some of which are still regarded as experimental (eg, ovarian tissue cryopreservation, pharmacological protection against gonadotoxic agents, in-vitro follicle growth, and follicle transplantation) will be optimised and become established within the next decade. Unravelling the complex mechanisms of activation and suppression of follicle growth will not only expand the care of thousands of women diagnosed with cancer, but also inform the care of millions of women confronted with reduced reproductive fitness because of ageing.
Emerging additive manufacturing techniques enable investigation of the effects of pore geometry on cell behavior and function. Here, we 3D print microporous hydrogel scaffolds to test how varying ...pore geometry, accomplished by manipulating the advancing angle between printed layers, affects the survival of ovarian follicles. 30° and 60° scaffolds provide corners that surround follicles on multiple sides while 90° scaffolds have an open porosity that limits follicle-scaffold interaction. As the amount of scaffold interaction increases, follicle spreading is limited and survival increases. Follicle-seeded scaffolds become highly vascularized and ovarian function is fully restored when implanted in surgically sterilized mice. Moreover, pups are born through natural mating and thrive through maternal lactation. These findings present an in vivo functional ovarian implant designed with 3D printing, and indicate that scaffold pore architecture is a critical variable in additively manufactured scaffold design for functional tissue engineering.
Human ovary autotransplantation is a promising option for fertility preservation of young women and girls undergoing gonadotoxic treatments for cancer or some autoimmune diseases. Although ...experimental, it resulted in at least 42 healthy babies worldwide. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature review was performed for all relevant full-text articles published in English from 1 January 2000 to 01 October 2015 in PubMed to explore the latest clinical and research advances of human ovary autotransplantation. Human ovary autotransplantation involves ovarian tissue extraction, freezing/thawing, and transplantation back into the same patient. Three major forms of human ovary autotransplantation exist including (a) transplantation of cortical ovarian tissue, (b) transplantation of whole ovary, and (c) transplantation of ovarian follicles (artificial ovary). According to the recent guidelines, human ovary autotransplantation is still considered experimental; however, it has unique advantages in comparison to other options of female fertility preservation. Human ovary autotransplantation (i) does not need prior ovarian stimulation, (ii) allows immediate initiation of cancer therapy, (iii) can restore both endocrine and reproductive ovarian functions, and (iv) may be the only fertility preservation option suitable for prepubertal girls or for young women with estrogen-sensitive malignancies. As any other fertility preservation option, human ovary autotransplantation has both advantages and disadvantages and may not be feasible for all cases. The major challenges facing this option are how to avoid the risk of reintroducing malignant cells and how to prolong the lifespan of ovarian transplant as well as how to improve artificial ovary results.
Cancer therapy can cause off-target effects including ovarian damage, which may result in primary ovarian insufficiency in girls and premenopausal women. Loss of ovarian follicles within the ovarian ...reserve leads to ovarian endocrine dysfunction and impaired fertility. Cyclophosphamide (CPA), a commonly used chemotherapeutic and immunosuppressant agent, is a gonadotoxic agent that destroys ovarian cells by crosslinking DNA. To protect the ovary against CPA damage, we sought to precisely map the mechanism by which the ovarian reserve is depleted by CPA. We found that CPA specifically depletes primordial follicles without affecting primary and secondary follicles in three independent murine strains (CD-1, C57BL/6J and BALB/cJ) in vivo. We directly tested the effect of the active metabolite of CPA, 1 μM 4-hydroxyperoxycyclophophamide (4-HC), in vitro and confirmed the loss of primordial oocytes but no change in the number of primary and secondary follicles. We demonstrated that phospho-AKT (p-AKT) and cleaved PARP (cPARP) are present in primordial oocytes 3 days after CPA injection, consistent with the role of these markers as part of the apoptotic cascade. Interestingly, p-AKT positive primordial oocytes co-expressed cPARP. Treatment of animals with specific inhibitors of apoptotic pathway components, ETP46464 and CHK2, blocked 4-HC‒induced DNA damage in vitro. These data suggest that CPA targets primordial germ cells in the ovarian reserve by stimulating apoptosis pathways. Adjuvant therapies to protect primordial germ cells from the off-target effects of CPA may reduce the risk of POI.
Chemo- and radiation therapies used to treat cancer can have the unintended effect of making patients infertile. Clinically established fertility preservation methods, such as egg and embryo ...cryopreservation, are not applicable to all patients, which has motivated the development of strategies that involve ovarian tissue removal and cryopreservation before the first sterilizing treatment. To restore fertility at a later date, the early-stage follicles present in the tissue must be matured to produce functional oocytes, a process that is not possible using existing cell culture technologies. This review describes the application of tissue engineering principles to promote ovarian follicle maturation and produce mature oocytes through either in vitro culture or transplantation. The design principles for these engineered systems are presented, along with identification of emerging opportunities in reproductive biology.
The creation of the pool of follicles available for selection and ovulation is a multi-faceted, tightly regulated process that spans the period from embryonic development through to the first ...reproductive cycle of the organism. In mice, this development can occur in mere weeks, but in humans, it is sustained for years. Embryonic germ cell development involves the migration of primordial germs cells to the genital ridge, and the mitotic division of germ cell nuclei without complete cytokinesis to form a multi-nucleated syncytia, or germ cell nest. Through combined actions of germ cell apoptosis and somatic cell migration, the germ cell nuclei are packaged, with surrounding granulosa cells, into primordial follicles to form the initial follicle pool. Though often dismissed as quiescent and possibly uninteresting, this initial follicle pool is actually quite dynamic. In a very strictly controlled mechanism, a large portion of the initial primordial follicles formed is lost by atresia before cycling even begins. Remaining follicles can undergo alternate fates of continued dormancy or selection leading to follicular growth and differentiation. Together, the processes involved in the fate decisions of atresia, sustained dormancy, or activation carve out the follicle pool of puberty, the pool of available oocytes from which all future reproductive cycles of the female can choose. The formation of the initial and pubertal follicle pools can be predictably affected by exogenous treatment with hormones or molecules such as activin, demonstrating the ways the ovary controls the quality and quantity of germ cells maintained. Here, we review the biological processes involved in the formation of the initial follicle pool and the follicle pool of puberty, address the alternate models for regulating germ cell number and outline how the ovary quality-controls the germ cells produced.
Background Although the Revitalization Act was passed in 1993 to increase enrollment of women in clinical trials, there has been little focus on sex disparity in basic and translational research. We ...hypothesize that sex bias exists in surgical biomedical research. Methods Manuscripts from Annals of Surgery , American Journal of Surgery , JAMA Surgery , Journal of Surgical Research , and Surgery from 2011 to 2012 were reviewed. Data abstracted included study type, sex of the animal or cell studied, location, and presence of sex-based reporting of data. Results Of 2,347 articles reviewed, 618 included animals and/or cells. For animal research, 22% of the publications did not specify the sex of the animals. Of the reports that did specify the sex, 80% of publications included only males, 17% only females, and 3% both sexes. A greater disparity existed in the number of animals studied: 16,152 (84%) male and 3,173 (16%) female ( P < .0001). For cell research, 76% of the publications did not specify the sex. Of the papers that did specify the sex, 71% of publications included only males, 21% only females, and 7% both sexes. Only 7 (1%) studies reported sex-based results. For publications on female-prevalent diseases, 44% did not report the sex studied. Of those reports that specified the sex, only 12% studied female animals. More international than national (ie, United States) publications studied only males (85% vs 71%, P = .004), whereas more national publications did not specify the sex (47% vs 20%, P < .0001). A subanalysis of a single journal showed that across three decades, the number of male-only studies and usage of male animals has become more disparate over time. Conclusion Sex bias, be it overt, inadvertent, situational, financial, or ignorant, exists in surgical biomedical research. Because biomedical research serves as the foundation for subsequent clinical research and medical decision-making, it is imperative that this disparity be addressed because conclusions derived from such studies may be specific to only one sex.
Originally absent from the oncologist's consult, then placed in a ‘quality of life’ rubric, oncofertility should now be an essential part of a comprehensive cancer treatment plan in patients of ...reproductive age, including adolescents and young adults (AYAs). Oncofertility encompasses the endocrine health of the patient, as well as fertility management options. Thus, pubertal transitions in males and females, bone health, and menstrual health are all part of this discipline, enabling practitioners to work in interdisciplinary teams to solve problems in reproductive health. This review provides a summary of the essential considerations required for the assessement of reproductive risk and choice of fertility preservation options as well as considerations for developing oncofertility services for AYAs.
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