"Genome-Wide Linkage in a Highly Consanguineous Pedigree Reveals Two Novel Loci on Chromosome 7 for Non-Syndromic Familial Premature Ovarian Failure"

Background: The human condition known as Premature Ovarian Failure (POF) is characterized by loss of ovarian function before the age of 40. A majority of POF cases are sporadic, but 10–15% are familial, suggesting a genetic origin of the disease. Although several causal mutations have been identified, the etiology of POF is still unknown for about 90% of the patients. Methodology/Principal Findings: We report a genome-wide linkage and homozygosity analysis in one large consanguineous Middle-Eastern POF-affected family presenting an autosomal recessive pattern of inheritance. We identified two regions with a LODmax of 3.26 on chromosome 7p21.1-15.3 and 7q21.3-22.2, which are supported as candidate regions by homozygosity mapping. Sequencing of the coding exons and known regulatory sequences of three candidate genes (DLX5, DLX6 and DSS1) included within the largest region did not reveal any causal mutations. Conclusions/Significance: We detect two novel POF-associated loci on human chromosome 7, opening the way to the identification of new genes involved in the control of ovarian development and function.

Prevalence of Premature Ovarian Failure in Women with Tuberous Sclerosis

Tuberous Sclerosis Complex (TSC) is an autosomal dominant tumor suppressor disorder characterized by hamartomas, or benign growths, in various organ systems. Inactivating mutations in either the TSC1 or the TSC2 gene cause most cases of TSC. Recently, the use of ovarian specific conditional knock-out mouse models has demonstrated a crucial role of the TSC genes in ovarian function. Mice with complete deletion of Tsc1 or Tsc2 showed accelerated ovarian follicle activation and subsequent premature follicular depletion, consistent with the human condition premature ovarian failure (POF). POF is defined in women as the cessation of menses before the age of 40 and elevated levels of follicle stimulating hormone (FSH). The prevalence of POF is estimated to be 1%, affecting a substantial number of women in the general population. Nonetheless, the etiology of most cases of POF remains unknown. Based on the mouse model results, we hypothesized that the human TSC1 and TSC2 genes are likely to be crucial for ovarian development and function. Moreover, since women with TSC already have one inactivated TSC gene, we further hypothesized that they may show a higher prevalence of POF. To test this hypothesis, we surveyed 1000 women with TSC belonging to the Tuberous Sclerosis Alliance, a national support organization. 182 questionnaires were analyzed for information on menstrual and reproductive function, as well as TSC. This self-reported data revealed 8 women (4.4%) with possible POF, as determined by menstrual history report and additional supportive data. This prevalence is much higher than 1% in the general population. Data from all women suggested other reproductive pathology associated with TSC such as a high rate of miscarriage (41.2%) and menstrual irregularity of any kind (31.2%). These results establish a previously unappreciated effect of TSC on women’s reproductive health. Moreover, these data suggest that perturbations in the cellular pathways regulated by the TSC genes may play an important role in reproductive function.

Novel NR5A1 Missense Mutation in Premature Ovarian Failure: Detection in Han Chinese Indicates Causation in Different Ethnic Groups

Background The etiology of most premature ovarian failure (POF) cases is usually elusive. Although genetic causes clearly exist and a likely susceptible region of 8q22.3 has been discovered, no predominant explanation exists for POF. More recently, evidences have indicated that mutations in NR5A1 gene could be causative for POF. We therefore screened for mutations in the NR5A1 gene in a large cohort of Chinese women with non-syndromic POF. Methods Mutation screening of NR5A1 gene was performed in 400 Han Chinese women with well-defined 46,XX idiopathic non-syndromic POF and 400 controls. Subsequently, functional characterization of the novel mutation identified was evaluated in vitro. Results A novel heterozygous missense mutation [c.13T>G (p.Tyr5Asp)] in NR5A1 was identified in 1 of 384 patients (0.26%). This mutation impaired transcriptional activation on Amh, Inhibin-a, Cyp11a1and Cyp19a1 gene, as shown by transactivation assays. However, no dominant negative effect was observed, nor was there impact on protein expression and nuclear localization. Conclusions This novel mutation p.Tyr5Asp, in a novel non-domain region, is presumed to result in haploinsufficiency. Irrespectively, perturbation in NR5A1 is not a common explanation for POF in Chinese.

Novel variants in growth differentiation factor 9 in mothers of dizygotic twins

Context: Genes from the ovarian bone morphogenetic signaling pathway (GDF9 and BMP15) are critical for normal human fertility. We previously identified a deletion mutation in GDF9 in sisters with spontaneous dizygotic (DZ) twins, but the prevalence of rare GDF9 variants in twinning families is unknown. Objective: The objective was to evaluate the frequency of rare variants in GDF9 in families with a history of DZ twinning. Design and Subjects: We recruited 3450 individuals from 915 DZ twinning families (1693 mothers of twins) and 1512 controls of Caucasian origin. One mother of DZ twins was selected from 279 of the 915 families, and a DNA sample was screened for rare variants in GDF9 using denaturant HPLC. Variants were confirmed by DNA sequencing and genotyped in the entire sample by matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry. Results: We found two novel insertion/deletions (c.392-393insT, c.1268-1269delAA) and four missense alterations in the GDF9 sequence in mothers of twins. Two of the missense variants (c.307C > T, p.Pro103Ser and c.362C > T, p.Thr121Leu) were located in the proregion of GDF9 and two (c.1121C > T, p.Pro374Leu and c.1360C > T, p.Arg454Cys) in the mature protein region. For each variant, the frequencies were higher in cases compared with controls. The proportion of mothers of DZ twins carrying any variant (4.12%) was significantly higher (P < 0.0001) than the proportion of carriers in controls (2.29%). Conclusion: We describe new variants in the GDF9 gene that are significantly more common in mothers of DZ twins than controls, suggesting that rare GDF9 variants contribute to the likelihood of DZ twinning.

Premature ovarian aging in mice deficient for Gpr3

After becoming competent for resuming meiosis, fully developed mammalian oocytes are maintained arrested in prophase I until ovulation is triggered by the luteotropin surge. Meiotic pause has been shown to depend critically on maintenance of cAMP level in the oocyte and was recently attributed to the constitutive Gs (the heterotrimeric GTP-binding protein that activates adenylyl cyclase) signaling activity of the G protein-coupled receptor GPR3. Here we show that mice deficient for Gpr3 are unexpectedly fertile but display progressive reduction in litter size despite stable age-independent alteration of meiotic pause. Detailed analysis of the phenotype confirms premature resumption of meiosis, in vivo, in about one-third of antral follicles from Gpr3-/- females, independently of their age. In contrast, in aging mice, absence of GPR3 leads to severe reduction of fertility, which manifests by production of an increasing number of nondeveloping early embryos upon spontaneous ovulation and massive amounts of fragmented oocytes after superovulation. Severe worsening of the phenotype in older animals points to an additional role of GPR3 related to protection (or rescue) of oocytes from aging. Gpr3-defective mice may constitute a relevant model of premature ovarian failure due to early oocyte aging.

Birth weight and age at menopause in Australian female twin pairs: exploration of the fetal origin hypothesis

In a twin sample where duration of gestation can be controlled, a specific example of the fetal origins hypothesis concerning association between low birth weight and early age at menopause is explored. The hypothesis is based on the physiologically plausible path from intrauterine growth retardation and reduced numbers of primary follicles to an earlier menopause. The sample comprised 323 Australian female twin pairs where both co-twins had reached menopause naturally and reported on their weight at birth. Regression analysis showed no linear association between the two variables (P = 0.371, r(2) = 0.0009). Intra-pair differences in age at menopause were investigated in the context of relative birth weight of co-twins. In 265 pairs an intra-pair birth a eight difference was reported. In monozygotic (MZ) pairs (n = 168) this allowed for control of genetic effects as well as gestation duration. No significant differences dependent on birth weight relative to co-twin were found for age at natural menopause in either MZ or dizygotic (DZ) twin pairs, even in pairs whose birth weights differed markedly. There was some indication that twins with premature ovarian failure were heavier at birth than twins with normal or later menopausal age. We conclude that the hypothesis that lower birth weight is associated with earlier menopause is not supported by our data.

Comparison of fractional and geodesic anisotropy in diffusion tensor images of 90 monozygotic and dizygotic twins

We used diffusion tensor magnetic resonance imaging (DTI) to reveal the extent of genetic effects on brain fiber microstructure, based on tensor-derived measures, in 22 pairs of monozygotic (MZ) twins and 23 pairs of dizygotic (DZ) twins (90 scans). After Log-Euclidean denoising to remove rank-deficient tensors, DTI volumes were fluidly registered by high-dimensional mapping of co-registered MP-RAGE scans to a geometrically-centered mean neuroanatomical template. After tensor reorientation using the strain of the 3D fluid transformation, we computed two widely used scalar measures of fiber integrity: fractional anisotropy (FA), and geodesic anisotropy (GA), which measures the geodesic distance between tensors in the symmetric positive-definite tensor manifold. Spatial maps of intraclass correlations (r) between MZ and DZ twins were compared to compute maps of Falconer's heritability statistics, i.e. the proportion of population variance explainable by genetic differences among individuals. Cumulative distribution plots (CDF) of effect sizes showed that the manifold measure, GA, comparably the Euclidean measure, FA, in detecting genetic correlations. While maps were relatively noisy, the CDFs showed promise for detecting genetic influences on brain fiber integrity as the current sample expands.

On the probability of dizygotic twins being concordant for two alleles at multiple polymorphic loci

Accurate determination of same-sex twin zygosity is important for medical, scientific and personal reasons. Determination may be based upon questionnaire data, blood group, enzyme isoforms and fetal membrane examination, but assignment of zygosity must ultimately be confirmed by genotypic data. Here methods are reviewed for calculating average probabilities of correctly concluding a twin pair is monozygotic, given they share the same genotypes across all loci for commonly utilized multiplex short tandem repeat (STR) kits.

A genome wide linkage scan for dizygotic twinning in 525 families of mothers of dizygotic twins

BACKGROUND: The tendency to conceive dizygotic (DZ) twins is a complex trait influenced by genetic and environmental factors. To search for new candidate loci for twinning, we conducted a genome-wide linkage scan in 525 families using microsatellite and single nucleotide polymorphism marker panels. METHODS AND RESULTS: Non-parametric linkage analyses, including 523 families containing a total of 1115 mothers of DZ twins (MODZT) from Australia and New Zealand (ANZ) and The Netherlands (NL), produced four linkage peaks above the threshold for suggestive linkage, including a highly suggestive peak at the extreme telomeric end of chromosome 6 with an exponential logarithm of odds \[(exp)LOD] score of 2.813 (P = 0.0002). Since the DZ twinning rate increases steeply with maternal age independent of genetic effects, we also investigated linkage including only families where at least one MODZT gave birth to her first set of twins before the age of 30. These analyses produced a maximum expLOD score of 2.718 (P = 0.0002), largely due to linkage signal from the ANZ cohort, however, ordered subset analyses indicated this result is most likely a chance finding in the combined dataset. Linkage analyses were also performed for two large DZ twinning families from the USA, one of which produced a peak on chromosome 2 in the region of two potential candidate genes. Sequencing of FSHR and FIGLA, along with INHBB in MODZTs from two large NL families with family specific linkage peaks directly over this gene, revealed a potentially functional variant in the 5' untranslated region of FSHR that segregated with the DZ twinning phenotype in the Utah family. CONCLUSION: Our data provide further evidence for complex inheritance of familial DZ twinning.

HLA and Genomewide Allele Sharing in Dizygotic Twins

Gametic selection during fertilization or the effects of specific genotypes on the viability of embryos may cause a skewed transmission of chromosomes to surviving offspring. A recent analysis of transmission distortion in humans reported significant excess sharing among full siblings. Dizygotic (DZ) twin pairs are a special case of the simultaneous survival of two genotypes, and there have been reports of DZ pairs with excess allele sharing around the HLA locus, a candidate locus for embryo survival. We performed an allele-sharing study of 1,592 DZ twin pairs from two independent Australian cohorts, of which 1,561 pairs were informative for linkage on chromosome 6. We also analyzed allele sharing in 336 DZ twin pairs from The Netherlands. We found no evidence of excess allele sharing, either at the HLA locus or in the rest of the genome. In contrast, we found evidence of a small but significant (P = .003 for the Australian sample) genomewide deficit in the proportion of two alleles shared identical by descent among DZ twin pairs. We reconciled conflicting evidence in the literature for excess genomewide allele sharing by performing a simulation study that shows how undetected genotyping errors can lead to an apparent deficit or excess of allele sharing among sibling pairs, dependent on whether parental genotypes are known. Our results imply that gene-mapping studies based on affected sibling pairs that include DZ pairs will not suffer from false-positive results due to loci involved in embryo survival.

Changing bodies, changing discourses : women's experiences of early menopause

Early menopause has been constructed by discourses of biological determinism as an untimely, but natural, failure of the female body. Medical discourses in particular have interpreted early menopause as a congenital irregularity and a rare anomaly of menopause at midlife. In this thesis I challenge the notion that early menopause is an innate imperfection related only to women’s age. I propose that early menopause is dependent upon the cultural interpretations of individual women and is constituted through the mercurial and multiple discourses of women who have this embodied experience. Moreover, I reveal that early menopause is a contemporary condition and that its location in history is inextricably bound to discourses of risk, naturalism and the self. Further I make the assumption that having an early menopause both affects and is an effect of women’s fertility, sexuality and subjectivity. I have drawn upon a broad range of sources to provide a sociological analysis of early menopause. Literature on early menopause is dominated by positivist discourses, yet many alternate discourses negotiate these influential constructions. I suggest here that the perception of early menopause as a natural fault is merely a construction by medical discourses and does not incorporate the dynamic discourses of early-menopausal women. Moreover, the restriction of early menopause to a genetic female failure excludes the majority of women who have an early menopause through iatrogenisis. This omission occurs through the failure of positivist discourses to accommodate diversity in discourses. Recent sociological and feminist studies have vindicated menopausal women. They have reconstructed menopause through notions of embodiment and have removed the veil of negativity used by the medical sciences to contain menopausal women (Komesaroff, Rothfield and Daly 1997). The visibility of menopausal women, however, remains connected to age. Menopause has been created as a predictable consequence of aging and as such has come to be synonymous with middle age. Nowadays, even men are said to experience menopause at midlife (Carruthers 1996). But early menopause is constituted within the discourses of women who have this experience. Medico-scientific discourses, based upon theories of genetic inevitability, disregard this perspective. Consequently early menopause is subsumed by naturalistic discourses that relate menopause to midlife. Such restraint reflects the unease created by menopause that does not coincide with prescribed life stages. Women's experiences of their changing bodies are largely unheard. Thus, women who have an early menopause are faced with a chasm of ‘cultural non-recognition’ (Fraser 1997). Conjointly with this discursive repression early-menopausal women face social imbalances that are transacted as both cause and consequence of early menopause. In particular the contemporary creation of early menopause is bound to the social and historical location of women as a group. Women are exploited by the institution of medicine, ‘exposure to environmental toxicity’ (Fraser 1997: 11) and commercialization as causes of early menopause. Yet the corporeal effects of practices of risk avoidance (Beck 1993), social practices (Shilling 1993) and Western consumerism (Lupton 1994) fail to be recognized. I address these problematics through a poststructural and feminist critique that assumes moments of commonality among women, while at the same time recognizes shifting and multiple differences (Nicholson 1999). I suggest here that early menopause falls into cultural misrecognition in Fraser's (1997) terms and argue that it is united concurrently with the gender injustice of androcentrism (Fraser 1997: 21). Fraser (1997: 16) suggests that it is only by relating these dual problematics that we are able to make sense of current dilemmas. Thus I have critiqued early menopause through a connection between individual embodied experiences of early menopause and early menopause as a modern phenomenon that is specific to women. I have attempted to unravel these arguments that simultaneously call to ‘... abolish gender differentiation and to valorize gender specificity’ (Fraser 1997: 21) while at the same time acknowledging their interconnectedness. An approach of merely combining women’s discourses with overarching social issues would be inadequate as not only do these problematics intersect but they also can be opposed. As Fraser (1997: 25) notes with her theory, redressing one aspect of cultural or social analysis can further imbalance another. For instance making visible the diversity and uniqueness of individual experiences of early menopause could detract from acknowledging the contemporary construction of early menopause through social inequality. Crucial to this understanding is a destabilizing of the binary construction of differences between the sexes that makes way for a reconstruction of early menopause through ‘sexual slippage’ (Matus 1995). In this thesis I look for a subtlety between the particular and the collective that views early menopause as concurrently a singular and changeable experience as well as imbedded in social practice. I suggest that these concepts are entwined as interactive effects of early menopause. Thus I have analyzed the bivalent problematics of the embodiment and social location of early menopause as imbricated, dynamic and unending discourses. From this perspective I reviewed the literature that was available on early menopause. In Chapter One I look to descriptions of early menopause and note that it has disappeared into a conglomeration of disparate, mostly medical, discourses that are contradictory. Nevertheless medical discourses offer ‘conclusive’ definitions of early menopause that are based on naturalistic views of the body (Shilling 1994). The determinants used are inconsistent and do not include women's discourses of early menopause. Thus, dominant medical discourses obscure women’s embodied experiences of early menopause and ignore the contemporary causes of early menopause. In Chapter Two I examine the causes of early menopause as a way of explaining the disparity between medical discourses and my anecdotal observations of early menopause as a fairly common contemporary occurrence. The relatively recent escalation in gynaecological surgery, especially hysterectomy, appears to account almost single-handedly for early menopause as a current phenomenon. Moreover, the extraordinary number of women who have their uterus removed at hysterectomy can be interpreted as a modern implementation of ancient anxieties. Women's sexuality has been constructed throughout history as problematic and this unease has been translated through women's bodies as dangerous and in need of control (Greer 1992). Thus social concerns which have evolved historically have emerged through the representation of a woman's uterus as an unseen, dark and mysterious risk (Beck 1993). Medical discourses define this risk and are able to negate the so-called dangers of women's sexuality through the surgical removal of their organs. Widespread negotiation of medical discourses is apparent, as hysterectomy in the modern Western world is the most common of all surgical operations (Hufnagel 1989). It is overwhelmingly the most common cause of early menopause as well. I examine also the historical condemnation of infertile women and how this anxiety has been transposed to the modern world through the commercialization of reproduction. Transactions of this social unease can cause early menopause. For instance the medical technology of in-vitro fertilization (I.V.F.) has been offered as a panacea for the infertility of early menopause but, paradoxically, can cause early menopause as well. Conception through technology has been normalized as a viable option for women who are unable to conceive and understandings of I.V.F. have moved into everyday discourse. Medical discourses have constructed fertility as a saleable item and infertile women expect that they can purchase this merchandise. Human eggs have become lucrative commodities that now are available in the market place. Egg ‘donation’ for I.V.F. programs can hasten the attrition rate of eggs and can cause early menopause in some pre-menopausal women (Rowland 1992: 24). Even the recycling of a woman’s uterus supposedly has become a possibility through the transferring of this ‘used’ organ at hysterectomy to a recipient woman who can use the other woman’s uterus as a ‘gestational garage’ (Rogers 1998). In this way women have been disembodied as mechanical systems with inter-changeable body parts and the potentially detrimental consequences of these commercial transactions are ignored. In addition I show how early menopause can be caused by the connection between the self and the social structure. Women's subjectivity is constituted through the cultural discourses available to them and these discourses affect social behaviour (Lupton 1995). For instance smoking and dieting have been identified as causes of early menopause. These activities have been related to the creation of women’s bodies as hetero-sexually desirable and are endemic to young women (Evans-Young 1995). This suggests that cultural causes of early menopause are transactions of sexual politics. Yet there is a paucity of literature that acknowledges the relationship between women’s subjectivity and early menopause. Thus the second chapter exposes a link between sexual politics and causes of early menopause through women's relationships with risk, naturalism and the self. In Chapter Three I deconstruct early menopause through theoretical considerations. I rely on an overarching poststructuralism that embraces the concept of fragmented plural discourses and the subjectivity of menopausal women as a continuous process (Komesaroff 1997: 61). I have woven these variables through broad feminist critiques (Leonard 1997). Through this eclectic approach I hoped to find some loose alignment between the corporeal, ontological and embodied dimensions of early menopause. The recurring themes of sexuality, fertility and subjectivity emerge through deconstructing discourses of sexual difference as immutable and non-negotiable; exposing ‘premature ovarian failure’ as a discursive construction that censures early-menopausal women; and acknowledging the discourses of individual women as unique, diverse and dynamic. I looked to a method of exposing some of these individual discourses and in Chapter Four I describe a critical research process aimed at understanding early menopause as a lived experience. In the remaining chapters I align these ontological arguments with an analysis of the discourses of women who had experienced or were experiencing an early menopause. This section partly relieves the ‘cultural non-recognition’ of the discourses of early-menopausal women. I recorded the narratives of fifty early-menopausal women through in-depth interviews and used this empirical data to direct the study. This data provides the opportunity to understand early menopause as an assortment of embodied experiences. For instance women’s experiences of age at commencement of menopause spanned over three and half decades. They did not reflect the age specifications prescribed by medical discourses. Rather women interpreted their experiences within their own discourses and determined their menopause as early based upon the expectations of their cultural context. Many of the women experienced changes attributed to menopause at midlife. It was not these changes that were significant to early-menopausal women it was how each woman translated these changes that provided meanings of early menopause. In Chapter Five I introduce the women through a table that connects the varying experiences of each woman. This profile shows that, in the main, the women’s experiences of early menopause were unexpected. I suggest that this is due to the disparity between early-menopausal women’s experiences and the current age and social norms of menopause. By bracketing the women into cohorts patterns emerged displaying differences between women who had menopause in their teens, twenties, thirties and forties. Adolescent women had intense feelings of abnormality and despair. Women who were in their twenties were less devastated by menopause than the younger women but described their sexuality and self-identity as changing. And although some women in their thirties were shocked or dismayed to have an early menopause others were ambivalent or happy. These women also described their sexuality and self-identity through changing discourses. A number of the women who were in their forties said that they were ‘too young for the menopause’ but were far less despondent than the younger women. It seemed that the greater the distance between age norms and social norms the more negatively women responded. Age norms that determine the social norms of women's lives through a ‘biological clock’ are constructed to reflect social values. But age is a social construction that changes over time. Thus it would appear that women’s changing bodies and changing discourses of early menopause are in the process of recreating age and social norms around menopause. In Chapter Six I draw upon women’s narratives that describe a connection between early menopause and sexuality. Yet the respondents were not unified in their constructions of sexuality. For instance a number of the women rejected the containment of their sexuality as absolute and defined in terms of bi-lateral hetero-sexual opposition. The discourses of these women constructed their sexuality as continuously flexible. Some early-menopausal women described this sexual mobility as an equivocal relationship between their sexuality, reproductive capacity and female organs. Other women articulated their sexuality as vacillating, ambiguous and unrepresentative of the so-called ‘true woman’. Several felt that they were not meant to have female reproductive organs at all. Nearly one third of the women had had their uterus removed at hysterectomy and the reproductive organs of two women were rudimentary. Women’s narratives showed that the social value of fertility influences constructions of early menopause. In Chapter Seven I record the contrast between the poignant responses of women who wished to have a baby of their own and other women who resisted discourses that entwine reproductivity with being a woman. For instance some women negotiated fertility through economic discourses of consumerism with the expectation that they could purchase conception as a commodity. Other women welcomed their early menopause as freedom from contraceptive concerns and others had no interest in reproduction at all. Thus discord arose through discourses that problematize early-menopausal women as non-reproductive and discourses that value variability. In addition many of the women’s accounts constructed their subjectivity as mobile, challenging the notion that discourses of the self are immutable. Chapter Eight presents narratives which suggest that the subjectivity of many women was altered continuously by early menopause. Yet some of the women rejected the construction of their subjectivity as unfluctuating. These contradictions reflect the uncertainties of the contemporary world. Nevertheless most respondents found that the tethering of menopause to constructions of midlife was incongruous with their own experiences. Many women refused to accept the label of social redundancy attached to middle-aged women. They moved their subjectivity beyond the reproductive body to a shifting and tractable identity of the self. This thesis demonstrates that the medical construction of early menopause as a rare and natural female flaw varies from women's experiences which suggest that early menopause is common and discursively constructed. This disparity has occurred through the privilege placed upon the construction of bodies as immutable and sexually static. This privileging has obscured the multi-dimensional causes of early menopause and given preference to a mono-causal theory. By exposing the variety of causes of early menopause the medical construction of women through a universal and unalterable body of reproduction is challenged. Moreover, women's discourses of early menopause demonstrate that the medical reduction of early menopause to a spontaneous bio-chemical malfunction has ignored the volatility of women’s embodied experiences. Women experience early menopause variously and through mercurial discourses. I suggest here that women's discourses of their experiences of early menopause reflect recurring and restructuring philosophical quandaries of fertility, sexuality and subjectivity. While there can be no representative claims made from this thesis it contributes to an understanding of the embodied experiences of early menopause. It provides an understanding of the creation of early menopause through social practices and goes part way to redressing the problematics of what Fraser terms ‘cultural non-recognition’. But, more importantly, it acknowledges early menopause as a variety of experiences where women interpret their changing bodies through changing discourses.

Fertility preservation: Successful transplantation of cryopreserved ovarian tissue in a young patient previously treated for Hodgkin's disease

Cryopreservation of ovarian tissue is now offered as an experimental procedure to preserve the fertility of young patients with a high risk for premature ovarian failure resulting from cancer therapy. This is the only available option to preserve the fertility of prepubertal patients treated with gonadotoxic chemotherapy. At present, thousands of patients all over the world have undergone this procedure with the hope of later restoring their fertility. Although the efficiency of the transplantation of cryopreserved ovarian tissue to restore ovarian function has been established, reports of pregnancy are still very scarce. Here, we describe the second published full-term spontaneous pregnancy after an orthotopic and heterotopic transplantation of cryopreserved ovarian tissue in a 31-year-old woman previously treated by conditioning therapy for bone marrow transplantation for Hodgkin's disease. This birth gives compelling evidence for the graft origin of the gamete and confirms the efficacy of ovarian tissue transplantation in restoring human natural fertility after oncological treatment. This case report stresses the importance of proposing the ovarian tissue cryopreservation procedure to all young patients who require potentially sterilizing treatment, with all alternative options to preserve fertility being duly taken into consideration.