Immortality Medicine

BACKGROUND

This study was designed to assess the impact of different ovarian tissue transplantation sites on the follicular pool and ovarian tissue integrity after short-term grafting, since there is no consensus in the literature as to the optimal grafting site in experimental models.

METHODS

Frozen-thawed ovarian tissue from eight patients was grafted for 1 or 3 weeks to the peritoneum, inside the ovarian bursa, under the skin and into the muscle of 16 nude mice. Assessment of follicular density and follicle classification was carried out by histological analysis. Proliferative activity was evidenced by immunostaining with anti-Ki-67 antibodies, and fibrotic areas were analyzed by morphometry on histological slides.

RESULTS

One week post-transplantation, the proportion of Ki-67-positive primordial follicles was higher (20–42%) than in controls (1.7%), demonstrating follicular activation in all four sites. Despite this activation, primordial follicles were still found 3 weeks post-grafting, (34.1–66.9% of the follicle population), most of them quiescent, as indicated by the absence of Ki-67 immunostaining. Cryopreservation and grafting resulted in extensive fibrosis in the stroma. This fibrosis was significantly less pronounced in intramuscular (IM) grafts, representing 18.8% of the surface versus 44.7–60.5% for other sites, after 3 weeks of grafting.

CONCLUSIONS

All four grafting sites equally supported early follicular growth and preserved some quiescent follicles after short-term frozen-thawed human ovarian tissue transplantation. The extensive fibrosis observed does not appear to have a major impact on early follicle development, but its long-term effects must be investigated. The graft environment may be implicated in the preservation of the stroma, as suggested by a lower degree of fibrosis in the IM site.

BACKGROUND

The aim of our research was to create a fertility status awareness tool (FertiSTAT) that would enable women to gain personalized guidance about reducing risks to their fertility and seeking timely fertility medical advice based on their own lifestyle and reproductive profile.

METHODS

Independent risk factors associated with female fertility impairment were identified. Associations between risk indicator and fertility status were examined in 1073 women who completed the Fertility Risk Factors Survey (FRFS) online or in pregnancy termination, antenatal or infertility clinics in the UK, consisting of the FertiSTAT indicators; 49.58% (n = 532) were currently pregnant (78.82% ≥12 weeks pregnant) and 15.66% (n = 168) were currently infertile (trying to conceive >12 or 6 months if >34 years of age).

RESULTS

Twenty-two risk factors were identified from the literature review and expert Delphi consultation. Prevalence of risk factors in the validation sample was similar to general population. Most risks were independently associated with fertility status in logistic regressions and in the expected direction. Discriminant analysis demonstrated that the set of FertiSTAT indicators could correctly classify whether women were currently pregnant or infertile [²(19) = 204.209, P < 0.001] with a correct classification rate for the overall sample of 85.8% (326/380), 91.0% (n = 243/267) for the currently pregnant and 73.5% (n = 83/113) for the currently infertile.

CONCLUSIONS

The main result was the generation of a self-administered, multifactorial tool that can enable women to get personalized fertility guidance. This research and the FertiSTAT provide foundational work for public health campaigns to increase awareness about fertility health.

BACKGROUND

The aim of the present study was to evaluate the implication of male factor, in terms of sperm DNA oxidation and fragmentation, and Y chromosome microdeletions in recurrent spontaneous abortion (RSA) of unknown origin in a strictly selected cohort.

METHODS

A prospective cohort study was carried out in a private university-affiliated setting. Three groups, each comprised of 30 males, were compared. The first was formed by healthy and fertile sperm donors (SD) with normal sperm parameters (control group), the second by men presenting severe oligozoospermia (SO) without RSA history, and the third by men from couples who had experienced idiopathic RSA. Frequency of Y chromosome microdeletions and mean sperm DNA fragmentation and oxidation were determined.

RESULTS

Y chromosome microdeletions were not detected in any of the males enrolled in the study. Moreover, sperm DNA oxidation measurements were not demonstrated to be relevant to RSA. Interestingly, sperm DNA fragmentation was higher in the SO group than in the RSA and the SD groups, and also higher in the RSA group compared with the SD group, but lacked an adequate predictive power to be employed as a discriminative test of RSA condition.

CONCLUSIONS

Sperm DNA features and Y chromosome microdeletions do not seem to be related to RSA of unknown origin. Other molecular features of sperm should be studied to determine their possible influence on RSA.

Clinicaltrials.gov reference: nCT00447395.

BACKGROUND

Ewing sarcoma (EWS) is a highly metastatic malignancy in young patients. Ovarian cryopreservation is often an option for fertility preservation in cancer patients of reproductive age, specifically in minors. Thus, the possibility of ovarian involvement in EWS needs to be elucidated.

METHODS

Eight patients aged 13–20 years with EWS participated in the study. Ovarian samples were fixed and prepared for light microscopy, and frozen in liquid nitrogen for RNA extraction followed by RT–PCR. Histological studies, including immunostaining for the adhesion receptor CD99, were used to detect histopathological features. Sensitive molecular methods were used to detect translocations causing the formation of tumor-specific EWS–Friend leukemia virus integration site 1 fusion gene (EWS-FLI1).

RESULTS

In seven patients, there was no evidence of EWS in the ovaries from pathological/molecular studies. However, in one patient, the RT–PCR showed the EWS translocation, although there was no pathological evidence.

CONCLUSIONS

Ovarian involvement is possible in EWS. Therefore, in patients with EWS ovarian tissue should be examined for traces of malignancy at both the pathological and molecular levels prior to the grafting of cryopreserved tissue in order to minimize the risk of reseeding the cancer.

BACKGROUND

It has been claimed that the risks to the child resulting from vitrification as compared with the slow-freezing technique, may be higher owing to the high concentrations of potentially toxic cryoprotectants. We therefore retrospectively compared the obstetric and neonatal outcomes in a cohort of children born after transfer of vitrified blastocysts, fresh blastocysts and slow-frozen early cleavage stage embryos.

METHODS

All children born after transfer of vitrified blastocysts (n = 106), fresh blastocysts (n = 207) and slow-frozen early cleavage stage embryos (n = 206) during the period January 2006 to May 2008 at Fertility Center Scandinavia were included. Data on obstetric and neonatal outcomes were obtained from medical records from the antenatal and delivery clinics.

RESULTS

For singletons, there were no significant differences between the groups in gestational age, mortality or birth defects. After adjustment for parity and BMI, birthweight was significantly higher in singletons born after transfer of vitrified blastocysts as compared with after transfer of fresh blastocysts (median 3560 versus 3510 g, P = 0.0311). More singletons born after transfer of fresh blastocysts were small for gestational age compared with singletons born after transfer of vitrified blastocysts (12.1 versus 3.0%, P = 0.0085). A higher rate of major post-partum haemorrhage was observed in the vitrified blastocyst group as compared with the other two groups (25.0 versus 6.0 and 7.5%).

CONCLUSIONS

No adverse neonatal outcomes were observed in children born after transfer of vitrified, as compared with fresh blastocysts or after transfer of slow-frozen early cleavage stage embryos.

BACKGROUND

Soluble HLA-G (sHLA-G) has been suggested as a non-invasive marker for embryo selection to improve pregnancy rates after assisted reproduction technique (ART). Our study aimed at the identification of parameters influencing the detection of sHLA-G in embryo cultures (ECs) and at the prognostic relevance of sHLA-G in a multi-centre study.

METHODS

In total 4212 EC from 2364 cycles were randomly collected from 29 German ART centres and analysed for sHLA-G by Luminex^®-based technology.

RESULTS

Among test and culture conditions, only the cleavage stage of the embryo was identified as an independent factor for sHLA-G detection (P < 0.001). Overall, sHLA-G was significantly associated with pregnancy after ART [P < 0.001; odds ratio: 2.0 (95% CI: 1.7–2.4)], suggesting that sHLA-G testing might improve the pregnancy rate from 30 to 40%. Importantly, the sHLA-G status of embryos could be associated with pregnancy after single embryo transfer [P = 0.002; odds ratio: 3.3 (95% CI: 1.5–6.8)] doubling the probability of pregnancy rate to 26% after sHLA-G testing. The patient’s age, number of transferred embryos, morphological grading [EXP(B): 4.3 (95% CI: 2.1–8.9)] of embryos and sHLA-G status [EXP(B): 2.3 (95% CI: 1.8–3.1)] were independent predictors of pregnancy, with the latter two being most powerful.

CONCLUSIONS

This study provides significant evidence that the morphological scoring system is still the best strategy for the selection of embryos but that sHLA-G might be considered as a second parameter if a choice has to be made between embryos of morphologically equal quality.

BACKGROUND

The rationale for double insemination is to create the opportunity for a longer fertilization period as follicle rupture may occur over a wide interval (~22–47 h) after hCG administration in ovarian hyperstimulation (OH) with intrauterine insemination (IUI) cycles. This randomized study evaluates the effectiveness of single versus double IUI in only OH cycles with multi-follicular development.

METHODS

We conducted a single center trial, 228 eligible patients were randomized for this study on the day of hCG. Only cycles with multi-follicular development without premature luteinization (progesterone levels >1 ng/ml on the day of hCG), were included in the study. Multi-follicular development has been defined as at least two dominant follicles reaching minimum ≥15 mm diameter in which one of them is >17 mm. OH cycles with more than five dominant follicles (>15 mm in diameter) were excluded from the study. In the single IUI group (Group 1 = 112 patients) IUI was applied 36 h after the hCG injection and in the double IUI group (Group 2 = 114 patients) the first IUI was performed 18 h after hCG administration and the second IUI was performed 40 h after hCG administration. The primary end-point is to compare live birth rates (LBRs) between single and double IUI arms.

RESULTS

LBRs were 10.7% (12/112 patients) in the single IUI group and 12.3% (14/114) in the double IUI group and the difference was not statistically significant (P = 0.835, OR = 1.16, 95% CI: 0.51–2.64). In the unexplained infertility group the LBR was 11.1% (5/45 patients) with single IUI and 18.4% (9/49) with double IUI (P = 0.393). In the mild male factor group this rate was 10.4% (7/67) and 7.7% (5/65) in the single and double IUI groups, respectively (P = 0.764).

CONCLUSION

Our study did not find any difference in LBRs between single and double IUI groups in OH cycles with multi-follicular development. To the best of our knowledge this is the first report with this kind of study design.

The study was registered at clinicaltrials.gov: NCT 00993902.

BACKGROUND

Ovulation induction treatment with metformin, either alone or in combination with clomiphene citrate (CC), remains controversial even though previous randomized trials have examined this.

METHODS

A double blinded multi-centre randomized trial was undertaken including 171 women with anovulatory or oligo-ovulatory polycystic ovary syndrome. Women with high body mass index (BMI) > 32 kg/m² received placebo (‘standard care’) or metformin; women with BMI ≤ 32 kg/m² received CC (‘standard care’), metformin or both. Treatment continued for 6 months or until pregnancy was confirmed. Primary outcomes were clinical pregnancy and live birth.

RESULTS

For women with BMI > 32 kg/m², clinical pregnancy and live birth rates were 22% (7/32) and 16% (5/32) with metformin, 15% (5/33) and 6% (2/33) with placebo. For women with BMI ≤ 32 kg/m², clinical pregnancy and live birth rates were 40% (14/35) and 29% (10/35) with metformin, 39% (14/36) and 36% (13/36) with CC, 54% (19/35) and 43% (15/35) with combination metformin plus CC.

CONCLUSIONS

There is no evidence that adding metformin to ‘standard care’ is beneficial. Pregnancy and live birth rates are low in women with BMI > 32 kg/m² whatever treatment is used, with no evidence of benefit of metformin over placebo. For women with BMI ≤ 32 kg/m² there is no evidence of significant differences in outcomes whether treated with metformin, CC or both.

ClinicalTrials.gov number NCT00795808; trial protocol accepted for publication November 2005: Johnson, Aust N Z Journal Obstet Gynaecol 2006;46:141–145.

BACKGROUND

Although female genital mutilation (FGM) does not feature in Judeo–Christian populations, it is estimated that, 100–140 million women in the world have undergone some form of FGM. Given the increasing diversity of the western populations, a review of specific complications of FGM is of paramount importance to practicing clinicians. The objective of this study is to report a case series of epidermal clitoral inclusion cysts after FGM in a Muslim population primarily from the Middle East.

METHODS

Between January 1998 and July 2009, 32 females underwent surgical removal of epidermal clitoral inclusion cysts in a tertiary referral university hospital. Data regarding age, clinical presentation, operation time, estimated blood loss, presence of intraoperative and post-operative complications, duration of admission to the hospital and long-term follow-up were extracted from the records.

RESULTS

There were 15 women (46.9%) with a definitive history of FGM, 14 (43.8%) did not know whether they had FGM or not and 3 (9.3%) had no history of FGM and were excluded from the analysis. The mean age of subjects was 28.1 years (range 5–91 years). All presented with increasing clitoral mass over a mean duration of 5.2 ± 4.1 years. The mean diameter of the cyst was 4.2 ± 2 cm. Regarding treatment, 28 subjects underwent surgical excision, and one underwent incision and drainage of a clitoral abscess. No short- or long-term complications occurred.

CONCLUSIONS

Clitoral cysts appear to be a more common complication of FGM than previously thought. Publication of studies that highlight the medical complications of FGM should be encouraged to advocate abandonment of the procedure.

Despite the advent of ICSI, cases of total fertilization failure (TFF) often lead to cycle cancellation with limited diagnostic and therapeutic strategies currently available. We report on the case of an infertile couple who failed to conceive after repeated IVF and ICSI. Sperm of the husband were morphologically normal and passed a functional test assessing their ability to activate mouse oocytes. Whether oocytes were activated artificially with calcium ionophore after injection of husband’s or with donor sperm, all oocytes failed to fertilize. Multiple polar bodies and two disorganized spindle structures were predominantly observed, pointing towards a cytoplasmic defect in the oocytes as the primary cause of the couple’s infertility. In fact, injection of husband’s sperm into donor oocytes resulted in the delivery of healthy twins. This report describes a course of action that may be applied for couples with TFF after both IVF and ICSI.

BACKGROUND

It has been identified that human epididymal protease inhibitor (EPPIN) plays a critical role in sperm function and male fertility. The aim of this study was to determine whether variants of the EPPIN gene are risk factors for idiopathic male infertility.

METHODS

All subjects, including 473 idiopathic infertile men and 198 fertile controls, underwent complete historical and physical examinations. Each subject donated 5 ml of peripheral blood for genomic DNA extraction and serum testosterone evaluation and an ejaculate for semen analysis. The semen analysis was performed by computer-assisted semen analysis system. The serum testosterone level was evaluated by radioimmunoassay. Four tagging single-nucleotide polymorphisms were analyzed by polymerase chain reaction–restriction fragment length polymorphism.

RESULTS

We have demonstrated a significant decreased risk of idiopathic infertility with abnormal semen parameters in association with the variant rs2231829, and an increased risk of idiopathic infertility with abnormal semen parameters in association with the variant rs11594. However, among men with normal semen parameters, there were no differences in risk for these genotypes. Furthermore, no significant differences were found for the other variants, rs6124715 and rs2227290, on the risk of male infertility with normal or abnormal semen parameters. Similar serum testosterone levels among different EPPIN genotypes were observed for each group.

CONCLUSIONS

These results suggest that different variants in the EPPIN gene may have different relationships with idiopathic male infertility and men carrying these variants have a decreased or increased risk of abnormal semen parameters associated with male infertility.

BACKGROUND

It has been suggested that the zona pellucida (ZP) may mediate species-specific fertilization. In human the ZP is composed of four glycoproteins: ZP1, ZP2, ZP3 and ZP4. In the present study, the expression profile of ZP1 in human oocytes and ovaries, and its role during fertilization, is presented.

METHODS

Human ZP1 (amino acid residues 26–551) was cloned and expressed in both non-glycosylated and glycosylated forms and its ability to bind to the capacitated human spermatozoa and to induce acrosomal exocytosis was studied. Monoclonal antibodies (MAbs), specific for human ZP1 and devoid of reactivity with ZP2, ZP3 and ZP4 were generated and used to localize native ZP1 in oocytes and ovarian tissues.

RESULTS

The MAbs generated against ZP1 recognized specifically the zona matrix of secondary and antral follicles, ovulated oocytes, atretic follicles and degenerating intravascular oocytes, but failed to react with the Fallopian tube, endometrium, ectocervix and kidney. Escherichia coli and baculovirus-expressed recombinant human ZP1 revealed bands of ~75 and ~85 kDa, respectively, in western blot. Lectin binding studies revealed the presence of both N- and O-linked glycosylation in baculovirus-expressed ZP1. Fluorescein isothiocyanate-labelled E. coli- and baculovirus-expressed recombinant ZP1 bound to the anterior head of capacitated spermatozoa, however, only baculovirus-expressed ZP1 induced acrosomal exocytosis in capacitated sperm suggesting the importance of glycosylation in mediating the acrosome reaction. The human ZP1-mediated acrosome reaction involved the activation of both T- and L-type voltage-operated calcium channels, but does not activate the G_i-coupled receptor pathway. Inhibition of protein kinase A and C significantly also reduced the ZP1-mediated induction of the acrosome reaction.

CONCLUSION

These studies revealed for the first time that in humans ZP1, in addition to ZP3 and ZP4, binds to capacitated spermatozoa and induces acrosomal exocytosis.

BACKGROUND

To better understand the infertility of patients with Robertsonian translocation, the biochemical and ultrastructural apoptotic characteristics of apoptosis in the sperm of patients and fertile donors were studied.

METHODS

Ejaculated sperm samples of seven Robertsonian translocation carriers and seven fertile donors were analyzed after cryopreservation. The proportion of both viable and dead spermatozoa expressing activated caspases was detected by flow cytometry through the use of different specific carboxyfluorescein-labeled caspase inhibitors. Sperm DNA fragmentation was evaluated by the TUNEL method. The percentages of intact spermatozoa or spermatozoa with ultrastructural features of apoptosis, immaturity or necrosis were estimated by electron microscopy. Meiotic segregation analysis was performed by FISH.

RESULTS

Significantly lower concentration, forward motility and normal morphology of spermatozoa were found in ejaculated samples of the Robertsonian patients than fertile donors. Compared with the control group, in Robertsonian translocation carriers: (i) the caspase assays showed a significantly increased (P < 0.05) proportion of viable spermatozoa with activated poly-caspases (57.4 versus 25.8%), caspase-3 (43.5 versus 13.4%), caspase-8 (44.4 versus 17.1%) and caspase-9 (42.4 versus 10.0%); (ii) the rate of DNA fragmentation was higher (26.3 versus 12.8%); and (iii) sperm ultrastructural examination highlighted a higher percentage of immature (28.0 versus 10.0%) and apoptotic (24.5 versus 18.5%) spermatozoa. FISH study showed predominant normal/balanced spermatozoa (78.34–85.53%).

CONCLUSIONS

These results show a predominant proportion of balanced and normal gametes and higher numbers of spermatozoa showing apoptosis and immaturity features in oligoasthenozoospermic Robertsonian translocation carriers than in fertile donors. This suggests defects in spermatogenesis and especially spermiogenesis of these infertile patients.

BACKGROUND

Semenogelin (Sg), the main protein of human semen coagulum, prevents sperm capacitation. The objective of this study was to examine the role of Sg and its mechanism of action.

METHODS AND RESULTS

Sg blocked sperm capacitation triggered by various stimuli, via inhibition of superoxide anion (O₂•–; luminescence assay) and nitric oxide (NO•; tested using diaminofluorescein) generation. Triton-soluble and -insoluble sperm fractions contained Sg and Sg peptides (immunoblotting), the level of which decreased with initiation of capacitation. This drop was prevented by superoxide dismutase and NO• synthase inhibitor and was reproduced by addition of O₂•– and NO•. Zinc (Zn²⁺) blocked and a zinc chelator (TPEN) promoted the decline in Sg levels. There was a decreased labelling of Sg on the head in capacitating spermatozoa with the two fixation techniques tested (immunocytochemistry). Reactive oxygen species (ROS) (O₂•– and NO•) caused, these changes, and zinc prevented them. Spermatozoa quickly internalized Sg upon incubation and Sg was then rapidly degraded in a zinc-inhibitable manner.

CONCLUSIONS

Sg blocked capacitation mainly via inhibition of ROS generation. Spermatozoa appeared permeable to Sg and processed Sg in a zinc-inhibitable fashion. ROS themselves could promote sperm disposal of Sg which maybe one of the mechanisms that allows initiation of capacitation.

BACKGROUND

Previous research has demonstrated an association between economic contraction at both the individual and aggregate level, and adverse health outcomes. Proposed mechanisms include increased psychosocial stress and loss of resources. The aim of this review is to assess the quantity, validity and consistency of empirical evidence examining economic contraction and birth outcomes.

METHODS

Empirical, English-language articles examining the effects of economic change at either the aggregate or individual level on birthweight, length of gestation, neonatal mortality and the secondary sex ratio were identified using PubMed and ISI Web of Knowledge. Studies were organized by level of analysis and birth outcome and evaluated for internal and external validity.

RESULTS

One individual-level study reported a strong association between individual shift to inadequate employment and decreased birthweight. Of seven aggregate-level studies on birthweight, five exhibited moderate to strong validity but reported inconsistent findings. Similarly, findings from five studies (four with moderate to strong validity) examining rates of neonatal mortality reported inconsistent findings. Three of four moderate to strong studies reported a reduced secondary sex ratio following economic contraction.

CONCLUSIONS

Associations between economic contraction and birthweight, neonatal mortality and the secondary sex ratio remain speculative. Consensus on methodology is needed to compare findings across studies. Further research on economic contraction and the secondary sex ratio, as well as individual-level birthweight and length of gestation, is warranted.

BACKGROUND

An ectopic pregnancy is a pregnancy which occurs outside of the uterine cavity, and over 98% implant in the Fallopian tube. Tubal ectopic pregnancy remains the most common cause of maternal mortality in the first trimester of pregnancy. The epidemiological risk factors for tubal ectopic pregnancy are well established and include: tubal damage as a result of surgery or infection (particularly Chlamydia trachomatis), smoking and in vitro fertilization. This review appraises the data to date researching the aetiology of tubal ectopic pregnancy.

METHODS

Scientific literature was searched for studies investigating the underlying aetiology of tubal ectopic pregnancy.

RESULTS

Existing data addressing the underlying cause of tubal ectopic pregnancy are mostly descriptive. There are currently few good animal models of tubal ectopic pregnancy. There are limited data explaining the link between risk factors and tubal implantation.

CONCLUSIONS

Current evidence supports the hypothesis that tubal ectopic pregnancy is caused by a combination of retention of the embryo within the Fallopian tube due to impaired embryo-tubal transport and alterations in the tubal environment allowing early implantation to occur. Future studies are needed that address the functional consequences of infection and smoking on Fallopian tube physiology. A greater understanding of the aetiology of tubal ectopic pregnancy is critical for the development of improved preventative measures, the advancement of diagnostic screening methods and the development of novel treatments.

In the first trimester the extravillous cytotrophoblast cells occlude the uterine spiral arterioles creating a low oxygen environment early in pregnancy, which is essential for pregnancy success. Paradoxically, shallow trophoblast invasion and defective vascular remodelling of the uterine spiral arteries in the first trimester may result in impaired placental perfusion and chronic placental ischemia and hypoxia later in gestation leading to adverse pregnancy outcomes. The hypoxia inducible factors (HIFs) are key mediators of the response to low oxygen. We aimed to elucidate mechanisms of regulation of HIFs and the role these may play in the control of placental differentiation, growth and function in both normal and pathological pregnancies. The Pubmed database was consulted for identification of the most relevant published articles. Search terms used were oxygen, placenta, trophoblast, pregnancy, HIF and hypoxia. The HIFs are able to function throughout all aspects of normal and abnormal placental differentiation, growth and function; during the first trimester (physiologically low oxygen), during mid-late gestation (where there is adequate supply of blood and oxygen to the placenta) and in pathological pregnancies complicated by placental hypoxia/ischemia. During normal pregnancy HIFs may respond to complex alterations in oxygen, hormones, cytokines and growth factors to regulate placental invasion, differentiation, transport and vascularization. In the ever-changing environment created during pregnancy, the HIFs appear to act as key mediators of placental development and function and thereby are likely to be important contributors to both normal and adverse pregnancy outcomes.

BACKGROUND

Female cancer patients are offered ‘banking’ of gametes before starting fertility-threatening cancer therapy. Transplants of fresh and frozen ovarian tissue between healthy fertile and infertile women have demonstrated the utility of the tissue banked for restoration of endocrine and fertility function. Additional methods, like follicle culture and isolated follicle transplantation, are in development.

METHODS

Specialist reproductive medicine scientists and clinicians with complementary expertise in ovarian tissue culture and transplantation presented relevant published literature in their field of expertise and also unpublished promising data for discussion. As the major aims were to identify the current gaps prohibiting advancement, to share technical experience and to orient new research, contributors were allowed to provide their opinioned expert views on future research.

RESULTS

Normal healthy children have been born in cancer survivors after orthotopic transplantation of their cryopreserved ovarian tissue. Longevity of the graft might be optimized by using new vitrification techniques and by promoting rapid revascularization of the graft. For the in vitro culture of follicles, a successive battery of culture methods including the use of defined media, growth factors and three-dimensional extracellular matrix support might overcome growth arrest of the follicles. Molecular methods and immunoassay can evaluate stage of maturation and guide adequate differentiation. Large animals, including non-human primates, are essential working models.

CONCLUSIONS

Experiments on ovarian tissue from non-human primate models and from consenting fertile and infertile patients benefit from a multidisciplinary approach. The new discipline of oncofertility requires professionalization, multidisciplinarity and mobilization of funding for basic and translational research.

BACKGROUND

Although prescription drug use is common during pregnancy, the human teratogenic risks are undetermined for more than 90% of drug treatments approved in the USA during the past decades. A particular birth defect may have its origins through multiple mechanisms and possible exposures, including medications. A specific pathogenic process may result in different outcomes depending upon factors such as embryonic age at which a drug is administered, duration and dose of exposure and genetic susceptibility. This review focuses on the teratogenic mechanisms associated with a number of medications.

METHODS

We used three methods to identify the teratogenic mechanisms of medications: the MEDLINE and EMBASE databases, two recent books on teratogenic agents and a list of drugs classified as U.S. Food and Drug Administration class D or X. Mechanisms were included only if they are associated with major structural birth defects and medications that are used relatively frequently by women of reproductive age.

RESULTS

We identified six teratogenic mechanisms associated with medication use: folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption and specific receptor- or enzyme-mediated teratogenesis. Many medications classified as class X are associated with at least one of these mechanisms.

CONCLUSIONS

Identifying teratogenic mechanisms may not only be relevant for etiologic and post-marketing research, but may also have implications for drug development and prescribing behavior for women of reproductive age, especially since combinations of seemingly unrelated prescription and over the counter medications may utilize similar teratogenic mechanisms with a resultant increased risk of birth defects.

BACKGROUND

Timing of natural menopause has great implications for fertility and women’s health. Age at natural menopause (ANM) is largely influenced by genetic factors. In the past decade, several genetic studies have been conducted to identify genes in ANM, which can help us unravel the biological pathways underlying this trait and the associated infertility and health risks. After providing an overview of the results of the genetic studies performed so far, we give recommendations for future studies in identifying genetic factors involved in determining the variation in timing of natural menopause.

METHODS

The electronic databases of Pubmed and Embase were systematically searched until September 2009 for genetic studies on ANM, using relevant keywords on the subject. Additional papers identified through hand search were also included.

RESULTS

Twenty-eight papers emerged from our literature search. A number of genetic regions and variants involved in several possible pathways underlying timing of ANM were identified, including two possible interesting regions (9q21.3 and chromosome 8 at 26 cM) in linkage analyses. Recent genome-wide association studies have identified two genomic regions (19q13.42 and 20p12.3), containing two promising candidate genes (BRKS1 and MCM). In the candidate gene association studies on ANM, very few consistent associations were found.

CONCLUSION

A number of genetic variants have been discovered in association with ANM, although the overall results have been rather disappointing. We have described possible new strategies for future genetic studies to identify more genetic loci involved in the variation in menopausal age.

BACKGROUND

Polycystic ovary syndrome (PCOS) is a common condition in reproductive-aged women associated with impaired glucose tolerance (IGT), type 2 diabetes mellitus (DM2) and the metabolic syndrome.

METHODS

A literature search was conducted (MEDLINE, CINAHL, EMBASE, clinical trial registries and hand-searching) identifying studies reporting prevalence or incidence of IGT, DM2 or metabolic syndrome in women with and without PCOS. Data were presented as odds ratio (OR) [95% confidence interval (CI)] with fixed- and random-effects meta-analysis by Mantel–Haenszel methods. Quality testing was based on Newcastle–Ottawa Scaling and The Cochrane Collaboration’s risk of bias assessment tool. Literature searching, data abstraction and quality appraisal were performed by two investigators.

RESULTS

A total of 2192 studies were reviewed and 35 were selected for final analysis. Women with PCOS had increased prevalence of IGT (OR 2.48, 95% CI 1.63, 3.77; BMI-matched studies OR 2.54, 95% CI 1.44, 4.47), DM2 (OR 4.43, 95% CI 4.06, 4.82; BMI-matched studies OR 4.00, 95% CI 1.97, 8.10) and metabolic syndrome (OR 2.88, 95% CI 2.40, 3.45; BMI-matched studies OR 2.20, 95% CI 1.36, 3.56). One study assessed IGT/DM2 incidence and reported no significant differences in DM2 incidence (OR 2.07, 95% CI 0.68, 6.30). One study assessed conversion from normal glucose tolerance to IGT/DM2 (OR 2.4, 95% CI 0.7, 8.0). No studies reported metabolic syndrome incidence.

CONCLUSIONS

Women with PCOS had an elevated prevalence of IGT, DM2 and metabolic syndrome in both BMI and non-BMI-matched studies. Few studies have determined IGT/DM2 or metabolic syndrome incidence in women with and without PCOS and further research is required.

Since Carlsen and co-workers reported in 1992 that sperm counts have decreased during the second half of the last century in Western societies, there has been widespread anxiety about the adverse effects of environmental pollutants on human fecundity. The Carlsen report was followed by several re-analyses of their data set and by many studies on time trends in sperm quality and on secular trends in fecundity. However, the results of these studies were diverse, complex, difficult to interpret and, therefore, less straightforward than the Carlsen report suggested. The claims that population fecundity is declining and that environmental pollutants are involved, can neither be confirmed nor rejected, in our opinion. However, it is of great importance to find out because the possible influence of widespread environmental pollution, which would adversely affect human reproduction, should be a matter of great concern triggering large-scale studies into its causes and possibilities for prevention. The fundamental reason we still do not know whether population fecundity is declining is the lack of an appropriate surveillance system. Is such a system possible? In our opinion, determining total sperm counts (as a measure of male reproductive health) in combination with time to pregnancy (as a measure of couple fecundity) in carefully selected populations is a feasible option for such a monitoring system. If we want to find out whether or not population fecundity will be declining within the following 20–30 years, we must start monitoring now.

BACKGROUND

The characteristics of polycystic ovary syndrome (PCOS) such as hyperandrogenism and anovulation can be highly stressful and might negatively affect psychological well-being and sexuality. The objective of this study was to evaluate the association between PCOS characteristics and psychological well-being as well as sexarche.

METHODS

Patients (n = 1148) underwent standardized clinical evaluation. Psychological well-being was investigated in 480 patients with the Rosenberg self-esteem scale (RSES), the body cathexis scale (BCS) and the fear of negative appearance evaluation scale (FNAES). Sexarche was also assessed.

RESULTS

Amenorrhoea was associated with lower self-esteem (P = 0.03), greater fear of negative appearance evaluation (P = 0.01) and earlier sexarche (P= 0.004). Hyperandrogenism and acne were associated with poorer body satisfaction (P = 0.03, 0.02, respectively). Hirsutism and BMI were negatively associated with all psychological variables (RSES, P = 0.01; BCS, P = 0.05; FNAES, P = 0.02 and RSES, P = 0.03; BCS, P = 0.001; FNAES, P = 0.03, respectively).

CONCLUSIONS

Our results suggest that menstrual irregularities might be related to sexarche. Moreover, this study stresses that the treatment of women with PCOS should notably focus on physical but also on psychological and sexual characteristics.

BACKGROUND

This study explores the differences in prenatal maternal expectations, coping resources and maternal stress between first time mothers of IVF twins and first time mothers of spontaneously conceived twins. The role of prenatal maternal expectations in the prediction of maternal stress was examined, as well as the mediating and moderating effect of coping resources on the association between pregnancy-type group and maternal stress.

METHOD

Mothers of twins from various regions in Israel were included in this prospective and cross-sectional study in which 88 mothers of IVF-conceived twins and 98 mothers of spontaneously conceived twins were interviewed twice. First, at 33–36 weeks of their pregnancy they completed a socio-demographic questionnaire and the maternal expectations questionnaire; then at 6 months after birth they completed a questionnaire regarding the delivery and medical condition of the infants, and their coping resources and maternal stress.

RESULTS

Compared with mothers who conceived spontaneously, IVF mothers had more positive prenatal maternal expectations, but poorer coping resources and higher levels of maternal stress 6 months after birth. Maternal expectations had no predictive power regarding maternal stress, although the mother’s coping resources were significantly related to maternal stress and mediated the association between pregnancy type and maternal stress.

CONCLUSIONS

IVF-pregnant women bearing twins should be considered a high-risk group. Early identification of these mothers is essential for timely psychosocial interventions in order to enhance their resources and decrease maternal stress. Further longitudinal studies are required to determine causality in more ethnically-diverse mothers of twins.

BACKGROUND

Women often enter preimplantation genetic diagnosis (PGD) treatment following traumatic reproductive and genetic histories, the detrimental psychological effects of which are known to be long lasting in some cases. In addition, attempting IVF with PGD requires an in-depth understanding of the aspects of the technology. The level of information that is required and retained by women entering treatment is important for clinicians to understand. To date, neither of these issues has been explored empirically. To address this, we assessed mood and information-seeking behavior in a sample of women entering PGD.

METHODS

Fifty women entering PGD treatment completed self-administered questionnaires that assessed anxiety, depression, knowledge of technical aspects of PGD, expectancy of establishing a pregnancy and unmet information needs.

RESULTS

Anxiety and depression rates were similar to normal population data. State anxiety was associated with degree of financial worry [β = 0.36, t = 2.60, P = 0.01, 95% confidence interval (CI): 0.03–0.23], and living in an inner metropolitan area (β = 0.30, P = 0.03, 95% CI: 0.32–10.81). Unmet information needs were positively associated with women’s education (β = 0.97, P = 0.01, 95% CI: 0.22–1.73). Lastly, expectancy of establishing a pregnancy was above that of what clinicians provide as realistic PGD pregnancy chances and, unexpectedly, was also associated with degree of financial worry (β = 0.36, P = 0.01, 95% CI: 0.07–0.56).

CONCLUSIONS

Women entering PGD are emotionally well adjusted although the financial costs associated with PGD are associated with increases in anxiety. The study is limited by its small sample size and the fact that partners were not assessed.