Michael S. Neal

Effectiveness of Sperm Banking in Adolescents and Young Adults With Cancer A Regional Experience

Improving success in the treatment of cancer has resulted in an increasing number of survivors. An important quality of life issue among younger survivors is the ability to have a family. Current gonadotoxic treatments for cancer pose a challenge to future fertility. Preservation of fertility after gonadotoxic therapy is an important consideration for these patients. In a regional center, the authors evaluated efficacy and utilization of sperm banking for preservation of male fertility in adolescents and young adults (AYA) with cancer.

Environmental contaminants and human infertility: hypothesis or cause for concern?

Throughout the 1980s and 1990s the crude human birth rate (live births per 1000 population) declined, indicating reduced fertility and suggesting a potential decline in fecundity (the potential to conceive). Detection of environmental contaminants in human tissues, together with reports of a global decline in semen quality, further fueled speculation that human infertility rates are increasing and environmental toxicants are potentially important causal agents associated with this change. However, there is little compelling evidence to suggest that infertility rates amongst the general population have changed over time. Moreover, recent studies suggest a rise in the fertility rates. While several studies documented increased time to pregnancy (TTP) in exposed study populations, other investigators were not able to replicate these findings. Nevertheless, studies involving occupational exposure together with results from animal experiments lend support to the conclusion that environmental contaminants potentially adversely affect fertility. Consequently, the impact of exposure to environmental contaminants on human fertility remains controversial. To test the hypothesis that environmental contaminant exposure was associated with enhanced risk of infertility, data concerning trends in fertility and infertility rates were examined to assess the impact of exposure of developing gametes to environmental contaminants. The relationship between exposure and reproductive outcomes was then examined to illustrate the range of adverse effects for reproductive toxicants with data sets of divergent depth and reliability. Data showed that only a weak association between exposure to environmental contaminants and adverse effects on human fertility exists. However, it is postulated that evidence of chemical exposure and potential health consequences of these exposures highlight the need for further research in this area.

Bisphenol A concentration-dependently increases human granulosa-lutein cell matrix metalloproteinase-9 (MMP-9) enzyme output.

Bisphenol A (BPA) is an estrogenic contaminant that has been quantified at higher levels in the follicular fluid of women with polycystic ovarian syndrome (PCOS) compared to healthy fertile controls. However, the effect of BPA on granulosa cell function is unknown. Therefore, the objective of the present study was to quantify the effect of BPA on granulosa cell progesterone (P4) output and matrix metalloproteinase (MMP)-2, and -9 output and activity. Granulosa-lutein cells (GLCs) were collected from women undergoing oocyte retrieval in an academic in vitro fertilization (IVF) program. Granulosa-lutein cells were treated with increasing log concentrations of BPA (1-10,000 ng/ml) or 17beta-estradiol (E2, 272 pg/ml or 1.0 nM) and treatment effects on MMP-2 and -9 activity and output, cell viability and cell proliferation were measured by commercial gelatin zymography, MMP-ELISA, MTS and BrdU incorporation assays, respectively. Granulosa-lutein cells in culture secrete MMP-2 and MMP-9. Bisphenol A treatment concentration-dependently increased MMP-9 output by GLCs with a maximal effect observed at 1000 ng/ml. Cell viability/proliferation was unaffected by BPA treatment at concentrations<or=100 ng/ml; however, higher concentrations of BPA were cytotoxic. Progesterone output by the GLCs was unaffected by increasing BPA concentrations in the media. In conclusion, GLCs in culture secrete MMP-2 and MMP-9. At lower concentrations, compatible with human exposure levels (100-1000 ng/ml), BPA stimulates GLC MMP-9 output; however, higher concentrations are cytotoxic. Our findings suggest that BPA treatment can modulate ovarian extracellular matrix stability.

Using Plain Language Skills to Create an Educational Brochure About Sperm Banking for Adolescent and Young Adult Males With Cancer

Writing in plain language makes it easier for patients to read, understand, and make informed decisions about sperm banking. Greater attention to the issue and properly designed educational brochures for use by nurses in oncology and reproductive health is of evident importance but of unknown impact. A multidisciplinary clinical team followed an evidence-based, patient-centered approach to develop “plain language” patient education materials about sperm banking for adolescent and young adult (AYA) males with cancer. A patient education booklet was produced and implemented as part of the planned patient education for AYA male oncology patients at McMaster Childrens Hospital, Hamilton Health Sciences, in Hamilton, Ontario, Canada. The patient education booklet for use by health professionals as a teaching tool to facilitate discussion with AYA males has been produced with the hope that it will contribute to better informed decision making regarding sperm banking and increased use of this technology for fertility preservation.

Collaborative multidisciplinary team approach to fertility issues among adolescent and young adult cancer patients

Cancer treatment and the field of reproductive technology have each made impressive advancements in the last decade. Improved cancer treatment and survival rates have increased the number of cancer survivors, who might benefit from an array of fertility preservation strategies provided by emerging and advanced assisted conception technology. The challenge becomes bridging the gap between these two separate disciplines to ultimately improve the quality of life for cancer survivors. This paper discusses the issues and process involved with bringing these two teams of health-care professionals together. This model provides a framework for coordinating efforts in providing fertility preservation options to patients undergoing treatment for cancer. Effective multidisciplinary teams that include: oncologists, nurses in the specialties of oncology and infertility, social workers, reproductive endocrinology and infertility specialists, andrologists, and embryologists are required to work together in order to achieve success. The result of this unique team approach is not only a cancer survivor, but one whose quality of life might be enhanced by being able to have a child of his or her own in the future.

Cytogenetic evaluation of human oocytes that failed to complete meiotic maturation in vitro

OBJECTIVE To determine the cause of infertility in a couple whose oocytes failed to mature in two consecutive fertility treatments. DESIGN Case report. SETTING University-based IVF program. PATIENT(S) A 32-year-old woman with unexplained infertility. INTERVENTION(S) Cytogenetic evaluation of oocytes that failed to reach meiotic metaphase II stage of maturation. MAIN OUTCOME MEASURE(S) Observation of oocyte maturity and chromosome composition after fixing and staining with Orcein stain. RESULT(S) Cytogenetic analysis revealed that the oocytes had successfully resumed meiosis. Germinal vesicle breakdown was also indicated, and chromosomes were at metaphase II stage of development. However, meiotic reduction of those chromosomes failed. CONCLUSION(S) Infertility in this couple seems to be attributed to the failure of the chromosomes to complete the reduction phase of metaphase II of meiosis.

Neurotrophins (BDNF and NGF) in follicular fluid of women with different infertility diagnoses.

Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are intra-ovarian signalling peptides that are important in follicle development and oocyte maturation. In the ovary, neurotrophin expression is regulated by gonadotrophins. Therefore, this study postulates that aetiology of infertility will affect follicular-fluid BDNF and NGF concentrations. Follicular fluid from the first follicle aspirated from 190 infertile women attending a university-affiliated fertility programme (McMaster University and ONE Fertility, Burlington, Ontario) was collected between February 2004 and November 2010. The relationship between follicular-fluid BDNF and NGF concentration and age, day-3 FSH and peak serum oestradiol concentrations and antral follicle count was determined. Participants were aged between 24 and 44 years (mean±SEM, 35.2±0.3years) of age. The median concentrations of BDNF and NGF in the follicular fluid was 19.4pg/ml and 344.6ng/ml, respectively. The concentrations of BDNF and NGF were significantly related (P=0.028) but only the BDNF concentration was significantly higher (P<0.05) in women with unexplained infertility compared with other causes of infertility. It is concluded that, apart from unexplained infertility, the underlying cause of infertility did not affect ovarian output of BDNF and NGF in response to ovulation induction.

Brain-derived neurotrophic factor expression in granulosa lutein cells

Brain-derived neurotrophic factor (BDNF) is thought to play a role in follicle activation and oocyte maturation. It is postulated that BDNF and its receptor, tyrosine kinase receptor B (TrkB), may also play a role in maintaining the corpus luteum. Therefore,human granulosa lutein cells (GLC) were obtained from women undergoing ovulation induction and treated with increasing concentrations of cAMP (0, 125, 500 and 1000 μmol/l). BDNF and progesterone concentrations were quantified by enzyme-linked immunosorbent assay. cAMP treatment significantly increased progesterone output but had no effect on BDNF concentration in the spent media. However, the BDNF concentration was significantly increased in GLC lysates. To assess the expression of BDNF and TrkB in active versus regressing corpora lutea, ovaries from adult female BALBc mice (n = 4) from each day of the oestrous cycle were processed for immunohistochemistry. Two markers of luteal activity were used (3b-hydroxysteroid dehydrogenase and tenascin-X). There was a trend towards higher BDNF and TrkB H-scores in active versus regressing corpus lutea. In conclusion, intracellular BNDF concentrations were dose-dependently increased by cAMP but treatments had no effect on BDNF output. It is speculated that BDNF contributes in an autocrine manner to GLC survival in the active corpus luteum.

Ovulation suppression to protect against chemotherapy-induced ovarian toxicity: helpful or just hopeful?

For many years, young men with cancer have successfully stored sperm for assisted conception after curative treatment. It is now increasingly common for young women to seek fertility care before embarking on potentially gonadotoxic chemotherapy or irradiation treatment. The two reviews reported in this issue of Human Reproduction Update ask primarily whether, for these women, ovarian suppression with gonadotrophin-releasing hormone analogues (GnRHa) improves the prognosis for future fertility (Beck-Fruchter et al., 2008; Blumenfeld and von Wolff, 2008). The options for fertility preservation in female cancer patients currently include ovulation suppression and cryopreservation of reproductive tissue. The most reliable choice remains embryo freezing after conventional IVF. Although the chance of pregnancy is relatively high following this approach, there are several drawbacks. The need for sperm from a donor may create personal, legal and ethical problems for the woman; the time associated with the ovarian stimulation and oocyte recovery procedures may delay the start of cancer treatment; and ovarian stimulation may be harmful in the presence of estrogen sensitive tumours. Oocyte freezing would at least resolve the first of these problems. However, its success is currently limited (Gook and Edgar, 2007). Oocytes are much more vulnerable to cryopreservation damage than sperm. Moreover, a successful oocyte retrieval results in perhaps 10 oocytes, compared with the millions of sperm from a single ejaculate. Cell damage and loss due to freezing are much greater concerns when dealing with female gametes. Nevertheless, the methods of oocyte freezing (both slow-cooling and vitrification) continue to evolve with improving success. The rate of implantation per oocyte retrieved currently ranges from 2% to 5% (Borini et al., 2008). Less is known about the therapeutic value of ovarian tissue freezing, since few women have had frozen tissue replaced, but again this strategy is under scrutiny (Wallace et al., 2004). One advantage with ovarian tissue freezing is its potential for use in pre-pubertal girls. The simplest and most commonly used approach to fertility preservation in women of reproductive age remains suppression of ovulation with GnRHa before and during chemotherapy. There is certainly biological plausibility for this strategy: in women who receive chemotherapy before puberty, ovarian function is more frequently retained in young adulthood. GnRHa may create a ‘pre-pubertal’ ovarian milieu, reducing ovarian vulnerability to cell damage. Despite this rationale, the question remains, does the available evidence demonstrate a protective effect? In their review of this question, Beck-Fruchter et al. (2008) included two randomized controlled trials (RCT), seven casecontrolled studies and three case series. They conclude that the evidence is insufficient to claim an effect exists. Blumenfeld and von Wolff (2008) included one RCT and eight human ‘controlled studies’ and reached a different conclusion: that treatment reduces the incidence of premature ovarian failure and the risk of abnormal bleeding associated with the haematological effects of chemotherapy. Both author groups agree that larger RCTs are needed to ‘prove’ a benefit if one exists. How should readers respond to these reviews, which draw somewhat different conclusions? Jadad et al. (1997) suggest that such differences stem from the choice and validity of included studies. In this case, seven studies are common to both reviews, but almost all data are observational, rather than experimental. Important differences in prognostic variables between groups in the observational studies may thus be responsible for apparent treatment effects. Such differences include age at treatment, intensity of chemotherapy and length of follow-up. Imbalance of these and other variables is expected when physicians and patients make choices around who should and should not receive treatment. The choice and measurement of clinically important outcomes is also a key point. Differences in definition of ‘ovarian failure’ and limited data on live birth make studies hard to interpret. In any systematic review combining observational with experimental data, RCT results are worth looking at in isolation. Two trials are available here. However, they include only 47 women and although they show no statistically significant difference in return of menstruation or in live birth, their combined power is insufficient to allow acceptance of the null hypothesis. How should a young female cancer patient respond to this uncertainty? Her primary concern should be the balance of risks, costs and potential benefits of GnRHa co-treatment. The financial

Fertility Preservation for Young Women with Cancer: Hope for the Future

Advances in the diagnosis and successful treatment of childhood, adolescent, and adult cancers have allowed many young women to lead healthy lives after overcoming their disease. However, life-saving cancer treatment often impairs fertility. Chemotherapy and/or radiation may irreversibly damage the reproductive system. The maturing field of assisted conception, and specifically cryopreservation, has created a unique partnership between oncologists and fertility specialists. Improving assisted conception success and fertility sparing strategies provide options for young women who would like to have children of their own after cancer treatment. This review article focuses on the current practices and developing opportunities for women who wish to preserve their fertility when faced with gonadotoxic cancer treatment.