Phytoestrogens are plant-derived compounds with oestrogenic activity. They are common in both human and animal diets, particularly through soy-based foods. This study assessed whether the reproductive function of male rats is affected by exposure to a high phytoestrogen diet during adulthood and examined possible mechanisms through which phytoestrogens may disrupt reproductive function. Experiments focused on the epididymis, a steroid-regulated organ responsible for the maturation, transport, and storage of sperm. Adult male rats, bred and raised on a low phytoestrogen diet, were either transferred to a high phytoestrogen diet (experimental), or remained on the low phytoestrogen diet (control). Litter size is a measure of fecundity and after 3 days on the high phytoestrogen diet litter size was reduced. This effect on fecundity was transient as litter sizes returned to control levels by day 12. The reduced fecundity at day 3 could not be explained by changes in sperm concentration. Plasma gonadotrophin levels and testicular testosterone levels were not affected by phytoestrogen exposure, however, the expression of steroid hormone receptors in the epididymis was affected, coincidental with reduced fecundity. The gene expression of oestrogen receptor alpha and androgen receptor was increased in the initial segment of the epididymis and decreased in the cauda epididymis. Additionally, lipid peroxidation of epididymal sperm was significantly increased in rats fed the high phytoestrogen diet for 3 days. It is concluded that acute exposure to the high phytoestrogen diet disrupts the steroid regulation of the epididymis, disrupting its normal function. This results in decreased sperm quality, thereby reducing fecundity.

Circadian rhythms are the endogenous cycling of hormones, activity patterns and gene expression that occur across 24 hours. Disruption of circadian rhythms has been associated with multiple health complications, including reduction of fertility. The bmal1 mouse provides an animal model for central and peripheral loss of rhythmicity. Herein the reproductive function and postnatal development in the bmal1 knockout mouse has been evaluated. The reproductive capability of the heterozygous breeding colony was investigated, with around 50% of the female breeder mice becoming pregnant within one estrus cycle. The offspring of the colony had a higher than expected level of perinatal mortality while the knockout and heterozygous genotype was under represented among the offspring surviving to weaning, suggesting high knockout embryo or perinatal losses. The circadian phenotype of this mouse model was confirmed, identifying the severe disruption of circadian behavioural rhythms. Further, the growth of the bmal1 knockout mice was retarded compared with their heterozygous and wild type littermates from weaning to 9 months of age. The reproductive function of the homozygous male bmal1 knockout mouse was evaluated. They showed poor fertility, poorly developed secondary sexual organs, reduced sperm count and reduced sperm motility. Female bmal1 knockout mice had delayed vaginal opening, delayed onset of first estrus, disrupted estrus cyclicity as well as impaired reproductive and mammary tissue development. Steroid hormone synthesis was compromised in both males (testosterone) and females (progesterone) and ovarian morphology revealed reduced corpora lutea formation and structural abnormalities. Female bmal1 knockout mice also evidenced profound infertility, which was caused by a continuum of reproductive insufficiencies including reduced ovulation of oocytes, poorer progression of the preimplantation embryo and failure to successfully implant in the uterus. While the ovaries of bmal1 knockout females were able to respond to exogenous stimulation, the number of ovulated oocytes was reduced, the fertilised oocytes were of reduced quality, progressed poorly to mature blastocyst and once again failed to implant. A bioinformatical evaluation of a panel of genes closely involved in reproduction and ovarian function was analysed for the presence of circadian enhancer regions (E-box sequences) or RORA response elements (RRE) in their promoter regions. It was revealed that many of the genes investigated contained one or more circadian E-box and RRE sequence, providing a mechanism for the disruption of circadian gene expression within the ovary to cause detrimental changes in gene expression. Further to this, the gene expression profile of these functional genes and clock genes were evaluated in ovarian tissues from wild type and knockout mice across the estrus cycles and across 24 hours. It was shown that the murine ovary rhythmically expressed the genes involved with the molecular clock across 24 hours, as well as several other genes previously associated with rhythmicity in peripheral tissues. Further, the loss of functional bmal1 gene expression resulted in up or down regulation of over 75% of the functional genes investigated, including steroidogenic acute regulatory protein (the rate limiting enzyme for progesterone synthesis). In conclusion, the bmal1 knockout mouse shows a significant multi-factorial loss in fertility in both males and females. This loss occurs across a range of tissues and results in heavily reduced fertility in the male and complete infertility in the female. Further research could identify in greater detail the precise molecular mechanisms underpinning of this disruption. / Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2008

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 129-133).

Thesis (Ph. D.)--University of Texas at Austin, 2005. / Supervisor: Robert A. Hummer. Vita. Includes bibliographical references.

Thesis (M.Soc.Sc.)--University of Hong Kong, 1989. / Also available in print.

Thesis (Ph.D.)--Brown University, 2005. / Vita. Thesis advisor: Andrew Foster. Includes bibliographical references (leaves 120-127). Also available online.

BACKGROUND: Gliomas are the most common primary brain malignancy, with more than 16,000 patients diagnosed every year (Ostrom, et al., 2015). Outcomes vary widely depending on tumor grade and treatment, and have been steadily improving with the advent of new therapeutics. Glioma patients frequently undergo chemotherapy to remove residual tumor after surgery, and many of these cytotoxic therapies are known to affect rapidly dividing cells such as ovarian follicles (Vassilakopoulou et al., 2016). The negative effects of chemotherapy on fertility have been demonstrated in patients with breast and colorectal cancer (Bines, et al., 1996; Avastin Prescribing Information). Additionally, infertility has been linked with decreased quality of life, primarily in women (O’Moore et al., 1983; Greil, 1997). Fertility treatments are available for women undergoing cancer treatment, however it is unknown whether these treatments are routinely discussed with glioma patients before initiating chemotherapy. OBJECTIVE: The primary goal of this study was to assess whether female glioma patients are being effectively counselled on their possible loss of fertility and their choices for fertility treatment prior to beginning chemotherapy. To this end, it was also important to understand the barriers preventing patients from obtaining information related to their fertility. Another principle goal of this study was to describe the effects of chemotherapy on a sample of women with glioma. Finally, this study sought to understand the priorities of women with glioma in regards to family planning, and to address these priorities in the context of a comprehensive fertility preservation discussion. METHODS: To assess these endpoints, a survey was designed and delivered to patients being treated at the Neuro-oncology clinic of the University of California, San Francisco. Eligible candidates were identified prior to a clinic visit, and patients were asked whether they would like to participate in the survey. Consenting patients then completed the survey at home or in the clinic. Seventy two women completed the survey. Data was analyzed using STATA Software Version 10.0. RESULTS: Analysis of the survey results showed that only 35% of women receiving chemotherapy reported having a discussion regarding fertility preservation prior to beginning treatment. Of those who reported having this discussion, only 80% were aware that chemotherapy could negatively affect their fertility. Many women reported that while fertility preservation was not important to them at the time of diagnosis, it was a priority for them at the time of survey completion. Most women surveyed expressed a desire to have a fertility preservation discussion with a reproductive specialist. CONCLUSIONS: The data obtained in this study suggest a lack of understanding of the negative effects of chemotherapy which may be addressed with a more comprehensive fertility discussion with glioma patients prior to beginning treatment. Although interest in having children tends to decrease after cancer treatment, the majority of respondents still report wanting a child after treatment. The priorities of women in the study reflect a concern for the health of their future offspring which may be best addressed prior to beginning treatment in order to increase their chances of conceiving at a later date.

Call number: LD2668 .T4 1959 Y38

Call number: LD2668 .T4 1953 L45 / Master of Science

Call number: LD2668 .T4 1955 H41 / Master of Science