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In chapter one, the existing literature on ovarian ageing and fertility is reviewed. In it I (a) discuss the natural history and the potential causes of ovarian ageing (b) assess available tests of ovarian ageing and their limitations (c) discus the trends in the age of first childbirth, its causes and health service consequences. In chapter two, I explore women’s awareness of issues associated with delayed childbearing, including their social and medical implications and the limitations of available treatment. In chapter three, I surveyed IVF clinics throughout the United Kingdom, to determine (1) proportion of women aged 40 or more in each clinic (2) attitudes of clinicians towards older women and (3) clinicians’ views on an upper age limit for IVF. In chapter four, I investigated trends in the age at which women present to general infertility clinics (a step prior to IVF) in Grampian region. Women were grouped according to their age at first presentation to the infertility clinic (&lt;30, 30-34, 35-39 and ≥40 years). I tested the hypothesis that women of advanced reproductive age have a different diagnostic profile than younger women (&lt;30 years). In particular older women are more likely to be diagnosed with unexplained sub-fertility, probably due to ovarian ageing. This hypothesis was tested based on routinely collected data from a single secondary care centre. In chapter five, a systematic review of currently available dynamic tests of ovarian reserve assesses their power to predict fertility outcomes. In chapter six, I calculated the costs of achieving a live birth in different age groups (< 30, 30-34, 35-39 and ≥40 years) following IVF. In chapter seven, I summarize the results of the studies reported in this thesis and consider how they have improved our understanding of various aspects of delayed childbearing.

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La reproduction dans des mammifères est réglée par les neurones qui synthétisent et sécrètent l'hormone de gonadotropin-sortie (GnRH) et à travers l'espèce ces neurones sont présents dans peu de nombres dispersés dans l'hypothalamus. En raison de limité neurogenesis de ceux des types cellulaires neuronaux à l'extérieur du cerveau dans placode olfactif, ces neurones sont soumis au règlement serré pendant le développement embryonnaire pour atteindre leurs objectifs finaux dans l'hypothalamus, de la naissance jusqu'à la puberté pour la sécrétion minimale d'hormone et pendant des adultes pour réaliser la sécrétion pulsatile de l'hormone. La dérégulation dans n'importe lequel de ces mécanismes peut mener aux effets délétères sur la reproduction adulte et des pathologies cliniques comme l'absence de puberté, hypogonadism, la stérilité, l'aménorrhée, etc. Kallmann syndrome (KS), un d'entre ceux sévères (graves) reproducteur / Reproduction in mammals is regulated by neurons that synthesize and secrete gonadotropin-releasing hormone (GnRH) and across the species these neurons are present in few numbers scattered in the hypothalamus. Due to limited neurogenesis of these neuronal cell types outside the brain in the olfactory placode, these neurons are subjected to tight regulation during embryonic development to reach their final targets in the hypothalamus, from birth until puberty for minimal secretion of hormone and during adults to achieve pulsatile secretion of the hormone. Deregulation in any of these mechanisms may lead to deleterious effects on adult reproduction and clinical pathologies like absence of puberty, hypogonadism, sterility, amenorrhea, etc. Kallmann syndrome (KS), one of these severe reproductive pathologies is an inherited disorder and patients affected with this syndrome display anosmia (inability to smell) and hypogonadotropic hypogonadism (HH). Genetic screening of molecules in these patients lead to identification of genes like KAL1, FGFR1, FGF8, PROK2, PROKR2, WDR11 and CHD7 encoding proteins that play an important role in migration and targeting of olfactory system during embryonic development however these genes account only for 30% of KS cases emphasizing the need for further characterization and identification of other genes. While these proteins are involved in ontogenesis olfactory and GnRH system, genetic screening of molecules in patients suffering from normosmic idiopathic HH lead to identification of genes encoding for Kisspeptin receptor-GPR54, TAC-TACR3, LEP-LEPR, PCSK-1, GnRH receptor-GnRHR and GnRH-1 itself that play a crucial role in occurrence of puberty or adult reproduction. Here, for my PhD thesis, we focused on studying the role of guidance molecule Semaphorin3A (Sema3A)-Neuropilin1 (Nrp1) interactions in ontogenesis of GnRH neurons during embryonic development while in adults we first addressed the question if hypothalamic Kisspeptin neurons interact with neurons containing neuronal nitric oxide synthase (nNOS), the mutation of which causes HH in mice, and physiological significance of this interactions in regulation of GnRH neurons and neuroendocrine control of female reproduction. Finally our results demonstrate that Sema3A-Nrp1 interactions are implicated in ontogenesis of olfactory and GnRH neurons during embryonic development and nNOS neurons are important mediators of peripheral estrogens-kisspeptin signaling onto GnRH neurons and adult reproduction and propose to further study the implication of nNOS neurons in reproductive pathologies.

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Childlessness, whether voluntary, involuntary or circumstantial, is becoming more common in our society. Statistically, greater numbers of Australian women and their Western counterparts will not bear children, thereby creating a larger quantum of couple families. The unwelcome socio-economic consequences have prompted research into reproductive intentions and behaviour to address barriers to reproduction. Studying those who are childless by ‘choice’ or ‘infertile’ provides important ‘reference points’ but also creates a myopic view of the childless that often overlooks circumstantial factors or ignores the fluctuating nature of fertility intentions. Moreover, the medical discourse on infertility has conditioned our thinking and focused research on the psycho-social effects and impacts of assisted reproduction treatment and its failure. This has blurred and obscured the distinction between infertility and involuntary childlessness. Too often these are viewed through the same prism of grief and bereavement as a temporary but pervasive ‘crisis’ and as impediments to adult development in the long term. The thesis provides new insights that challenge our conventional ways of thinking particularly its findings that although infertility and childlessness are related, they are separate phenomena. This has wide-ranging implications, especially for reformulating related clinical practice and counselling. There are several important considerations. One is the finding that the grief and bereavement model has its limitations beyond the infertility stage. Another is the theoretical reconstruction that the thesis provides of the grief that the involuntary childless experience. Finally, it makes a strong case for a more appropriate alternative which the thesis argues should be based on a growth-oriented model. The time point at which the information for this study was collected has rarely ever been used before. This adds significant weight to the findings and applications that potentially derive from them. The thesis also examines gender issues including the complexities in differential experiences, amongst and across gender categories. It builds on the existing body of knowledge on the gendered experience of involuntary childlessness and offers additional explanations for the variations found, around which clinical interventions should be framed. Overall, this study makes an important contribution to our knowledge and understanding by documenting the transitional process to involuntary childlessness in broader terms than has hitherto been the case. Contrary to conventional thinking related to adult development, the findings underscore the importance of viewing involuntary childlessness as an alternative developmental pathway.

Abstract Societal expectations for procreation often result in infertile couples accessing assisted reproductive technology (ART). In the current state of this technology, the successful outcome of the birth of a child does not always occur. This study contributes to nurses' understanding of what it is like for couples to remain involuntarily and permanently childless after infertility treatment has ended, and aims to bring about change in attitudes and practice towards this group. Literature that acknowledges individuality as well as shared experience for couples who remain childless after infertility treatment is scarce. Health professionals may therefore encounter difficulties in providing this group with appropriate support. This research used a qualitative approach informed by feminist perspectives to gather stories of five couples' experiences of childlessness after accessing ART. Individual conversations with both members of the marital partnership were recorded, transcribed and analysed. The study found that due to the societal expectation of procreation, and the falsely elevated 'success rates' of ART, couples often delayed decisions about whether they should persevere with treatment, hence reducing the possibility of exploring alternative methods of parenting. As well as highlighting the ambiguity of the term 'success', the study suggests that the hope that technology brings childless couples prolongs decision making and simultaneously serves to compound the sense of failure experienced by these couples. The couples' engagement with ART, as well as their inability to conform to the normative family of parents and their biological children, also contributed to periods of isolation. Following the decision to remain childless, the participants found that setting achievable and challenging goals assisted in re-building their self-esteem, and enhanced the process of adapting to their life without children. Although participant couples expressed obvious grief at remaining childless, they also showed resilience by managing attached difficulties and stigmatisation, and by creating positive future outcomes. For these childless couples, the strength of their relationships was seen as critical in the process of overcoming adversity. This study suggests ART clinics should provide more realistic information to individual couples regarding the likelihood of taking home a baby. Further to this, independent counselling support is recommended for couples prior to and during ART treatment, and when this treatment is ceased.

Thesis (Ph.D.)--Brown University, 2008. / Vita. Advisor : Karl Jacoby. Includes bibliographical references (leaves 322-343).