Speakers' Overviews
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Richard Anderson, UK
CANCER INDUCED CHANGES IN THE TESTIS AND SPERMATOZOA
Spermatogonial stem cells in the testis are damaged by exposure to chemotherapy agents and radiotherapy. Thus anti-cancer treatments may render the patient sterile, and a key issue is accurate assessment of risk. This depends on the agents used, and their cumulative dose, but there may well also be variations in susceptibility. An additional consideration is that some men may well already have damaged spermatogenesis at presentation, due to their illness. These issues will all be discussed in this talk.
Pedro N Barri, Spain
FERTILITY SPARING STRATEGIES IN ENDOMETRIAL CANCER
Endometrial cancer is the most common malignancy of the female genital tract and 10% of patients with endometrial cancer are afflicted by the disease during the reproductive period of their lives. A majority of cases of endometrial cancer in young patients are of early stage and low grade tumours, thus associated with an excellent outcome.
We must select the criteria to be applied in the identification of the appropriate candidates for this kind of treatment and we now know that the requisites are:
a) Grade 1 well differentiated tumour
b) Absence of lymph vascular space invasion (LVSI)
c) No evidence of myometrial invasion on MRI
d) No evidence of metastatic disease on CT scan
e) No evidence of adnexal pathology on CT scan or pelvic ultrasound
f) Strong and diffuse expression of progesterone receptors on immunohistochemistry staining of the endometrial biopsy.
Despite a large number of pooled papers, the total number of patients treated with these protocols remains low. Of all women attempting to conceive, in the literature we have found a 47% live birth rate and a remission rate of 81% with a relapse rate of 28%. A total of 18% of patients failed up front hormonal therapy and required hysterectomy.
Mats Brännström, SWEDEN
UTERINE TRANSPLANTATION
Uterine transplantation is developed towards clinical introduction as a treatment for absolute uterine infertility. After extensive animal experimentation during the last decade, we conducted a series of 9 live donor human uterine transplantaations in Gothenburg, during the fall of 2012 and spring of 2013. The outcome of these transplantations will be presented.
Ri-Cheng Chian, CANADA
NATURAL CYCLE IVF/IVM
It has been attempted using in vitro maturation (IVM) technology to treat patients with normal menstrual cycle and intact ovaries. As protocols, the patients were administrated 10,000 IU human chorionic gonadotropin (HCG) 36 h before oocyte retrieval in natural cycle when the leading follicle reached to 12-14 mm in diameter. The results indicate that mature oocytes can be retrieved when the leading follicles reached 12-14 mm in diameter after HCG administration. It is important to identify the mature oocytes at egg collection. Following transfer the resulted embryos, the clinical pregnancy and implantation rates are approximately 45% and 25% respectively. This new technology has to be defined as natural cycle IVF combined with IVM, namely Natural cycle IVF/M, in order to distinguish with traditional concept of IVM treatment. Recently it has been reported that natural cycle IVF/M together with IVM treatment can offer more than 50% of total infertile women with acceptable pregnancy and implantations rates. Therefore, natural cycle IVF/IVM can be considered as an option for fertility preservation.
Ana Cobo, Spain
OOCYTE VITRIFICATION FOR FERTILITY PRESERVATION: HAS IT COME TO AGE?
Owing to the increasing number of young women that fully recover from cancer due to improved and modern therapies, their future fertility has become a very relevant issue. The advent of vitrification as means of fertility preservation (FP) has opened a window of opportunity for many cancer patients to be a mother after having overcome the disease. Oocyte vitrification has also been an effective strategy for treatment in other medical conditions that may compromise fertility as endometriosis, Turner's syndrome, early ovarian failure etc., where an intervention as safeguarding gametes for future use is required to uphold fertility potential. Additionally, elective oocyte vitrification is being increasingly applied as an option to delay motherhood when modern life forces women to delay the age to conceive. So far, six healthy babies have been born in our institution as a consequence of applying oocyte vitrification for FP due to either oncological or non-oncological reasons.
César Diaz, SPAIN
THERE A PLACE FOR ANTI--‐LEUKEMIC IN--‐VITRO TREATMENT OF OVARIAN CORTEX PRIOR TO TRANSPLANTATION?
Corticoids have been proven to be effective treatment for leukemic cells in--‐vitro. Ovarian cortex from leukemic patients was treated in--‐vitro prior to reimplantation in a SCID mouse model. Potential transmission of malignant disease was evaluated.
Maria Madeleine Dolmans, BELGIUM
RISK OF TRANSPLANTATION OF MALIGNANT CELLS IN FERTILITY PRESERVATION
Ovarian tissue cryopreservation and transplantation is a promising technique to restore fertility in prepubertal cancer survivors or those requiring immediate chemotherapy. Twenty-four live births have been reported using this technique so far. Nevertheless, concerns linger over the risk of retransplanting malignant cells potentially present in the ovaries. This risk is particularly serious for hematologic cancers and advanced-stage breast cancer. It is therefore of utmost importance to identify minimal residual disease before transplantation, and only go ahead with the procedure after pluridisciplinary discussion and consensus.
CURRENT METHODS OF FERTILITY PRESERVATION
Jacques Donnez,
Belgium
Aggressive chemotherapy and/or radiotherapy and BMT can cure >90% of girls and young women affected by diseases requiring such treatment. Nevertheless, the risk of impairing gonadal function is high, particularly when gonadotoxic drugs (especially alkylating agents) are used.
Embryo and oocyte cryopreservation are the options of choice if chemotherapy can be delayed, giving patients with cancer the hope of a successful pregnancy when they have overcome their disease. In prepubertal girls and patients for whom immediate treatment is required, ovarian tissue cryopreservation is the only available method.
Tommaso Falcone, USA
SURGICAL TECHNIQUES IN TISSUE TRANSPLANTATION FOR FP
Several techniques have been proposed for autologous ovarian tissue transplantation that have been broadly divided into two- heterotopic and orthotopic. No pregnancies have been reported with heterotopic transplants that can be directly attributed to the transplant. Since Ovarian tissue transplantation is an avascular transplant the main limitation of the technique is tissue ischemia. Several surgical techniques have been proposed to improve tissue reperfusion.
Kate Hardy, UK
ACTIVATION OF DORMANT FOLLICLES
Female mammals are born with a lifetime's supply of follicles, the majority of which are small, immature and quiescent. The signals that stimulate specific follicles to start growing are unclear. An increased understanding of the cell biology of early follicle growth will allow identification of the nature of the activation signal, and hence bring us closer to identifying the signal or signals that trigger the transition from quiescence to growth.
Outi Hovatta, SWEDEN
SLOW FREEZING VS VITRIFICATION OF HUMAN OVARIAN TISSUE
Slow freezing of human ovarian tissue has been practiced since 1996 (Hovatta et al. Human Reproduction). It has proven a viable method for fertility preservation, with many healthy children born after transplantation of thawed tissue. The structure of the ovarian stroma, has not been optimal after slow freezing. In our comparative study, the stroma had survived significantly better after vitrification than after slow freezing, as demonstrated by electron microscopy and tissue culture. We have developed a clinically feasible closed vitrification method using only ethylene glycol as a permeating cryoprotectant.
S. Samuel Kim, USA
DOES OOCYTE INTEGRITY MATTER WITH CRYOPRESERVATION OF OVARIAN TISSUE?
Cryopreservation can cause DNA damages which may eventually affect the survival and function of cells. Thus, it is important to investigate the integrity of oocytes after cryopreservation of ovarian tissue.
CRYOPRESERVATION OF ISOLATED HUMAN PREANTRAL FOLLICLES FOR FERTILITY PRESERVATION: A NEW OPTION
Stine Gry Kristensen,
Denmark
Nowadays, the available methods for fertility preservation in women
have different advantages and limitations. Succesfull experiments in
mice have now shown that cryopreservation of isolated preantral
follicles holds huge potential as a new method for preserving fertility
in cancer patients. Preantral stage follicles constitute the vast
majority of follicles in the ovary and we have shown that murine
preantral follicles can be isolated, vitrified, thawed, re-transplanted
and grown to large antral stages. More importantly, by isolating the
preantral follicles the presence of malignant cells which could
potentially reintroduce cancer is eliminatede which gives us an
improved opportunity to restore fertility in patients with blood born cancers.
Dror Meirow, Israel
MEDICAL PROTECTION OF GONADAL DAMAGE
The ovarian follicle reserve is maintained in a delicate state of homeostasis aimed at preserving the majority of follicles in a dormant state. Disturbance of ovarian homeostasis has been shown to be a mechanism of follicle loss in the case of iatrogenic ovo-toxicity. Cyclophosphamide , triggers upregulation of the PI3K pathway, initiating a wave of follicle recruitment and growth, and ultimately burn-out of the ovarian follicle reserve. Cyclophosphamide also induced apoptosis in growing follicles within 24 hours of exposure. Co-treatment with immunomodulator, AS101, reduced both apoptosis of growing follicles and activation of the PI3K/PTEN/Akt pathway, thereby reducing follicle activation and loss.
Philippe Morice, France
BORDERLINE OVARIAN CANCER
Conservative treatment gives good results on fertility and does not affect the survival of patients with early stage borderline ovarian tumor. It must be considered for young women with a desire of fertility. In case of infertility, medically assisted procreation techniques may be proposed to patients with stage I BOT with a limited number of stimulation cycles.
Kutluk Oktay, USA
OVARIAN STIMULATION IN CANCER PATIENTS
Ovarian stimulation and fertility preservation requires attention to special details in cancer patients due to their complex medical needs. In breast cancer patients ovarian stimulation can be accomplished with the aid of an aromatase inhibitor, letrozole, to maintain estrogen levels at the lowest possible. GnRHa trigger is recommended to minimize the risk of OHSS. A measured rather then an aggressive approach is recommended to avoid creating new medical issues for the patient and unnecessarily delaying the chemotherapy. Before proceeding with the pregnancy attempt, chemotherapy-induced vital organ dysfunction such as cardiomyopathy should be ruled out based on the type of cancer drugs received.
Pasquale Patrizio, USA
NEW STRATEGIES IN FERTILITY PRESERVATION: FREEZE/DRY AND IN VITRO PERFUSION
Storage of cryopreserved reproductive cells and tissues (and stem cells) in liquid nitrogen is very demanding in terms of maintenance, storage space, equipment and costs. In addition, ovarian cortical tissue preservation cannot be proposed to patients with leukemia given the risk of ovarian leukemic colonization. To solve these issues we are seeking alternative strategies and will discuss preliminary results on lyophilization of oocytes, chromosomes, stem cells and in vitro folliculogenesis by continuous perfusion of whole ovaries.
Helen Picton, UK
THE ROLE OF IN VITRO MATURATION OF OOCYTES: PRESENTATION SYNOPSIS
This presentation will provide an overview of the recent consensus in the development of strategies used for the in vitro growth and maturation of oocytes in large animals and humans. It will provide insights into the use of follicle and oocyte culture as a vehicle to restore fertility, to test the ovarian toxicity of chemotherapy agents and drug combinations, and to audit and improve the efficacy of ovarian cryopreservation protocols.
Michel Roy, CANADA
CERVICAL CANCER AND PRESERVATION OF FERTILITY
Cervical cancer is the 3rd most common cancer in women aged less than 40. According to the SEER data, up to 42 percent of all cervical cancers are diagnosed in women prior to the age of 45. In this group of patients fertility preservation is very important. Classically, the only available treatment for early-stage cervical cancer was a radical hysterectomy and lymph node dissection, and loss of fertility.
Data on the radical trachelectomy procedure, proposed by the late Professor Daniel Dargent in the early ‘90s, have showed that fertility preservation was possible, without affecting recurrence rate and the chances of cure. This procedure has revolutionized the management of early-stage cervical cancer. Today, the classical radical hysterectomy is no longer the "gold standard” for young women with small lesions. Even more conservative surgery in carefully selected patients is studied world-wide.
Jane Ruman, USA
OPTIMIZING PATIENT ACCESS TO FERTILITY PRESERVATION
Advances in the field of fertility preservation coupled with the improved detection and treatment of cancer in reproductive-age individuals generates a large patient population that should be eligible to benefit from available fertility preservation options. However, studies indicate that only a small fraction of these eligible patients actually undergo fertility preservation prior to their cancer treatment. Financial, educational, and structural barriers exist for these patients, but can be overcome by improved interdisciplinary communication, expeditious financial assistance and access to accurate information from reliable sources.
Gerald Schatten, USA
SCIENCE FICTION OR REALITY? PRODUCING GAMETES FROM STEM CELLS AND SOMATIC CELLS
The 2012 Nobel Prizes to Sir John Gurdon and Shinya Yamanaka for their seminal work in nuclear transfer and induced pluripotency, coupled with the 2010 Nobel Prize to Bob Edwards for pioneering In Vitro Fertilization in humans, attests to the contemporary importance of stem cells and regenerative medicine for ART. This lecture will consider pluripotent stem cells, their differentiation into both sperm and oocytes, as well as their role of PSCs in cancers and epigenetics.
Kirsten T. Schmidt, DENMARK
SPONTANEOUS RECOVERY OF FERTILITY AND OVARIAN FUNCTION
Despite chemotherapy some women regain their ovarian function after treatment, ususally after a few months. We have shown that a lot of these women have an intact fertility and succeed in their wish to start a family, as quickly and easily as other women. The chance of a spontaneous recovery depends on the type and dose of drugs used in the treatment of their cancer.
Sherman Silber, USA
IN VIVO POST-GRAFTING RECOVERY OF FOLLICULOGENESIS AND OVULATION
"The time for resting follicles to reach the menstrual cycle and ovulate is consistently 4.5 months. The recruitment of resting follicles is controlled by pressure. The fetal female sex cords (once meiosis is initiated by retinoic acid) must invade the tough stroma of the tunica albuginea, to prevent a massive sudden release of eggs by arrest in prophase. Likewise, when a thin ovary transplant begins to function, there is a massive release of eggs from the resting phase. Later the remaining eggs undergo a slower compensatory decrease in recruitment as their number diminishes."
Norah Spears, UK
MECHANISMS OF CHEMOTHERAPY-INDUCED LOSS OF FOLLICLES
It has long been recognised that chemotherapy treatment can result in fertility problems in patients, leading to premature ovarian failure in premenopausal females. The precise manner by which the drugs damage the gonads is, however, much less clear, yet without that information, protective treatments will be difficult to develop. We are using mouse gonadal tissue culture techniques to examine the effect of drugs commonly administered to younger cancer patients, with the work showing that each drug leads to a very different pattern of damage, acting through different cellular mechanisms. This may in turn mean that any treatments designed to protect the ovary from chemotherapy-induced damage have to be tailored to the specific drug regimens used.
Herman Tournaye, BELGIUM
FERTILITY PRESERVATION IN MALE PATIENTS
Cryopreservation of ejaculated sperm and surgically retrieved sperm are routine practice in most fertility centres. Banking of sperm or testicular tissue in adolescents, however, is less common but emerging since cancer treatments are becoming more successful and the focus now shifts towards quality of life. Banking of testicular tissue in prepubertal boys is still in an experimental phase, however, given the promising results in animal models, the preservation of spermatogonial stem cells is now being introduced in more and more centres worldwide
Hamish Wallace, UK
WHICH YOUNG FEMALE PATIENTS WITH CANCER MAY BENEFIT FROM FERTILITY PRESERVATION?
For young females without a partner fertility preservation provides significantly different challenges to that for the male. Cryopreservation of embryos and or oocytes are not generally possible for children and ovarian tissue cryopreservation remains experimental and invasive. With the live birth of increasing numbers of children after reimplantation of frozen thawed ovarian tissue in successfully treated cancer patients it remains important to establish who may benefit from this technique. In this lecture I will present our 16 year experience of ovarian tissue cryopreservation in young females and discuss the potential role for the assessment of ovarian reserve and AMH in patient selection.
Claus Yding Andersen, Denmark
USE OF FROZEN/THAWED OVARIAN TISSUE FOR HORMONE REPLACEMENT
In contrast to freezing mature oocytes or embryos, cryopreservation of ovarian tissue preserves the functional unit of the ovary, the follicle. Transplantation of ovarian tissue therefore restores not only fertility but also a natural hormonal environment including cycling levels of oestradiol and progesterone. More than 99 % of all ovarian follicles undergo atresia although they do possess the capacity to produce hormones. The presentation will focus on whether it is possible to enhance utilisation of these follicles possibly to prolong the period with cyclic variations in hormone levels.