MEDLINE searches were done by topic (epidemiology, age and reproduction, sexual function, delayed childbearing and specific contraceptive methods). The topic summaries were presented to the Workshop Group and omissions or disagreements were resolved by discussion.

The decline in fecundity in the fifth decade is insufficient for contraceptive purposes. Thus a family planning method is needed. Sterilization is by far the most common method in several countries. Copper intrauterine devices and hormone intrauterine systems have similar effectiveness, with fewer than 1% failures in the first year of typical use. Special considerations in this age group include the frequency of menstrual irregularity, sexual problems and the possibility of menopausal symptoms, all of which may respond to hormonal methods of contraception.

Women should be advised to continue with a contraceptive method until they have reached the menopause with its natural state of sterility.

A computerized literature search in MEDLINE, EMBASE, CENTRAL and randomized controlled trial (RCT) registries was performed independently by two reviewers, aiming to identify RCTs that evaluated the following research question: does GH addition increase the probability of pregnancy in poor responders undergoing ovarian stimulation with gonadotrophin releasing hormone (GnRH) analogues and gonadotrophins for IVF?

Six relevant RCTs were identified, including a total of 169 patients. GH addition significantly increased clinical pregnancy (rate difference: +16%, 95% CI: +4 to +28; fixed effects model) (number-needed-to-treat (NNT) = 6, 95% CI: 4–25) and live birth rates (rate difference: +17%, 95% CI: +5 to +30; fixed effects model) (NNT = 6; 95% CI: 3–20). Furthermore, GH addition was associated with a significantly higher proportion of patients reaching embryo transfer (rate difference: +22%, 95% CI: +7 to +36; fixed effects model).

The present meta-analysis provides evidence that GH addition increases the probability of clinical pregnancy and live birth in poor responders undergoing ovarian stimulation with GnRH analogues and gonadotrophins for IVF. However, the total number of patients analyzed is small and thus further RCTs are warranted to prove or disprove this finding.

Articles were obtained by searching PubMed until December 2008. A first search attempted to identify genes located on the X chromosome potentially important for spermatogenesis. A second part of the study was focused on those genes for which the role has already been studied in infertile patients.

Multiple genes located on the X chromosome are expressed in testicular tissues. The function of many genes, especially the cancer–testis genes, has not been studied so far. There were striking differences between mouse and human genes. In the second part of the study, the results of mutation analyses of seven genes (AR, SOX3, USP26, NXF2, TAF7L, FATE and AKAP4) are described. Except for AR, no infertility causing mutations have, thus far, been described. It cannot be excluded that some of the observed changes should be considered as risk factors for impaired spermatogenesis.

It can be concluded that, so far, the mutation analysis of X-linked genes in humans, presumed to be crucial for spermatogenesis or sperm quality, has been disappointing. Other approaches to learn more about male infertility are necessary.

A review of monochorionic (MC) monozygotic (MZ) placentation in the pathogenesis of congenital anomalies and CP was conducted using the PubMed, MEDLINE, EMBASE and Cochrane databases.

Zygote division and MC placentation have serious implications for the development of both conceptuses. Most reports observe predominantly cerebral abnormalities in one or both conceptuses. These cerebral abnormalities often present as CP or other disabilities attributable to central nervous system impairment. In addition to the anomalies in central nervous system development, anomalies in the fetal development of a wide variety of other organs have been reported with MC MZ twinning.

CP and congenital anomalies share a common pathogenic mechanism attributable to MZ twinning. These abnormalities in singletons are coincident with very early loss of one conceptus. The quantitative contribution of monozygosity and monochorionicity to the genesis of CP and congenital anomalies needs to be made.

Relevant studies were identified by searching Pubmed up to January 2009 with English language limitation. The following key words were used: (ovarian tissue or whole ovary) AND (transplantation) AND (cryopreservation or pregnancy). Using the literature and personal experience, we examined relevant data on the different exogenous and clinical factors affecting follicular development after grafting.

Clinical factors such as the patient's age and the transplantation sites influenced the lifespan of the graft. A heterotopic transplantation site is not optimal but offers some advantages and it may also promote the hormonal environment after a combined heterotopic and orthotopic transplantation. Exogenous factors such as antioxidants, growth factors or hormones were tested to improve follicular survival; however, their efficiency regarding further follicular development and fertility potential remains to be established.

Additional evidence is required to define optimal conditions for ovarian tissue transplantation. Alternatives such as whole ovary or isolated follicles transplantations require further investigation but are likely to be successful in humans in the future.

We conducted a systematic review of randomized clinical trials of hormone therapy (i.e. oral, transdermal, i.m.) and verbal memory, distinguishing studies in younger (i.e. ≤65 years of age; n = 9) versus older (i.e. >65 years; n = 7) women and studies involving estrogen alone versus estrogen plus progestogen. Out of 32 placebo-controlled trials, 17 were included (13 had no verbal memory measures and 2 involved cholinergic manipulations). We also provide a narrative review of 25 studies of executive function (two trials), since there are insufficient clinical trial data for systematic review.

There is some evidence for a beneficial effect of estrogen alone on verbal memory in younger naturally post-menopausal women and more consistent evidence from small-n studies of surgically post-menopausal women. There is stronger evidence of a detrimental effect of conjugated equine estrogen plus medroxyprogesterone acetate on verbal memory in younger and older post-menopausal women. Observational studies and pharmacological models of menopause provide initial evidence of improvements in executive function with hormone therapy.

Future studies should include measures of executive function and should address pressing clinical questions; including what formulation of combination hormone therapy is cognitively neutral/beneficial, yet effective in treating hot flashes in the early post-menopause.

In order to quantify the association between OC use and colorectal cancer risk, we performed a systematic review and meta-analysis of studies on this issue. We identified all relevant studies published, in English, as original articles up to December 2008 through a search of the literature using PubMed and EMBASE, and by reviewing the references from the retrieved articles.

The summary relative risk of colorectal cancer for ever versus never OC use was 0.82 (95% confidence interval, CI, 0.69–0.97) from 11 case–control studies, 0.81 (95% CI, 0.75–0.89) from seven cohort studies, and 0.81 (95% CI, 0.72–0.92) from all studies combined. The results were similar for colon and rectal cancer. No difference was evident according to duration of OC use both for colon and rectal cancer, although there is an indication that the protection is stronger for more recent use (OR = 0.70, 95% CI, 0.53–0.90, on the basis of four studies).

Epidemiological data consistently indicate that OC users have a reduced risk of colorectal cancer, and that the protection is greater for recent use in the absence, however, of a duration–risk relation.

A bibliographic search of English language publications of four computerized databases was undertaken with no time restriction set for publications.

A total of 64 studies met the inclusion criteria and were included in the review. The research syntheses revealed there were distinct differences between patient and non-patient (known, commercial, volunteer and potential) donors on demographic characteristics, motives for donation, and issues relating to disclosure and attitudes towards the resultant offspring. Further, studies have found that a significant proportion of oocyte donors and women from the general population were prepared to donate their oocytes as identifiable donors. Studies which have examined the experiences of donors report positive experiences of oocyte donation. However, a number of methodological limitations relating to the oocyte donation research literature have been identified in this systematic review.

Differences between donor groups on a range of factors highlight the need for tailored psychosocial evaluation and counselling. The review has demonstrated that it is not useful to generalize across donor groups on various factors relating to oocyte donation.

A systematic review was undertaken of the published literature on Treg cells in the ovary, testes, uterus and gestational tissues in pregnancy, and their link with infertility, miscarriage and pathologies of pregnancy. An overview of current knowledge on the generation, activation and modes of action of Treg cells in controlling immune responses is provided, and strategies for manipulating regulatory T-cells for potential applications in reproductive medicine are discussed.

Studies in mouse models show that Treg cells are essential for maternal tolerance of the conceptus, and that expansion of the Treg cell pool through antigen-specific and antigen non-specific pathways allows their suppressive actions to be exerted in the critical peri-implantation phase of pregnancy. In women, Treg cells accumulate in the decidua and are elevated in maternal blood from early in the first trimester. Inadequate numbers of Treg cells or their functional deficiency are linked with infertility, miscarriage and pre-eclampsia.

The potency and wide-ranging involvement of Treg cells in immune homeostasis and disease pathology indicates the considerable potential of these cells as therapeutic agents, raising the prospect of their utility in novel treatments for reproductive pathologies.

We systematically searched the literature for papers reporting prediction models in reproductive medicine for three strategies: expectant management, intrauterine insemination (IUI) or in vitro fertilization (IVF). We evaluated which phases of development these models had passed, distinguishing between (i) model derivation, (ii) internal and/or external validation, and (iii) impact analysis. We summarized their performance at external validation in terms of discrimination and calibration.

We identified 36 papers reporting on 29 prediction models. There were 9 models for the prediction of treatment-independent pregnancy, 3 for the prediction of pregnancy after IUI and 17 for the prediction of pregnancy after IVF. All of the models had completed the phase of model derivation. For six models, the validity of the model was assessed only in the population in which it was developed (internal validation). For eight models, the validity was assessed in populations other than the one in which the model was developed (external validation), and only three of these showed good performance. One model had reached the phase of impact analysis.

Currently, there are three models with good predictive performance. These models can be used reliably as a guide for making decisions about fertility treatment, in patients similar to the development population. The effects of using these models in patient care have to be further investigated.

The scientific literature was searched for studies reporting on the several aspects of mitochondrial activity in mammalian testis, sperm, oocytes, early embryos and embryonic stem cells.

ATP synthesis and ROS production are the most discussed aspects of mitochondrial function. Metabolic shifts from mitochondria-produced ATP to glycolysis occur at several stages, notably during gametogenesis and early embryo development, either reflecting developmental switches or substrate availability. The exact role of sperm mitochondria is especially controversial. Mitochondria-generated ROS function in signalling but are mostly described when produced under pathological conditions. Mitochondria-based calcium signalling is primarily important in embryo activation and embryonic stem cell differentiation. Besides pathologically triggered apoptosis, mitochondria participate in apoptotic events related to the regulation of spermatogonial cell number, as well as gamete, embryo and embryonic stem cell quality. Interestingly, data from knock-out (KO) mice is not always straightforward in terms of expected phenotypes. Finally, recent data suggests that mitochondrial activity can modulate embryonic stem cell pluripotency as well as differentiation into distinct cellular fates.

Mitochondria-based events regulate different aspects of reproductive function, but these are not uniform throughout the several systems reviewed. Low mitochondrial activity seems a feature of ‘stemness’, being described in spermatogonia, early embryo, inner cell mass cells and embryonic stem cells.

We review changes associated with decreased fertilization rates and developmental potential of aged oocytes, and we present methods and approaches that prevent or delay oocyte aging.

Cellular and molecular abnormalities occur during oocyte aging, but prevention, delay or reversal is possible to various extents. Modifying existing culture conditions, or treatment of oocytes with agents such as caffeine, DL-dithiothreitol, nitric oxide or trichostatin A may correct molecular pathways that are affected by aging, and thus benefit and improve success rates in modern ART.

Aging of oocytes is characterized by a sequence of molecular processes that deteriorate during aging and negatively impact fertilization and development. However, oocyte aging can be delayed or reversed by various treatments to increase success rates and produce increased numbers of healthy embryos, preventing failures or abnormalities that are frequently associated with ART using aged oocytes.

Articles were identified in PubMed, Embase and PsycLIT as well as manually retrieved from literature citations for the time period from 1999 to 2008. Inclusion criteria were (i) qualitative or quantitative design, (ii) focus on patients previous to or during their reproductive lifespan and (iii) dealing with aspects such as (1) impact of fertility issues in cancer patients or (2) health professionals' and/or patients' attitudes towards fertility preservation or (3) counselling.

Twenty-four studies were identified. According to the studies on aspect (1), fertility is an important issue for cancer patients. Health professionals as well as patients and parents consider fertility preservation as an important option for young cancer patients; all parties involved, however, were noted to have knowledge and information deficits. Patients recalling counselling about the impact of cancer treatment on fertility ranged from 34% to 72%. Counselling is far from being offered globally to all patients at risk, and providing information seems to be selective.

The existing literature demonstrates the need for and the limits of current counselling. Future research should target the means to facilitate the decision-making process for patients and health professionals.

Specialist reproductive medicine clinicians and scientists delivered presentations based on published literature and ongoing research on patient work-up, ovarian stimulation and embryo quality assessment during ART. This report is based on the expert presentations and subsequent group discussions and was supplemented with publications from literature searches and the authors' knowledge.

It was agreed that single embryo transfer (SET) should be used with increasing frequency in cycles of ART. Continued improvements in cryopreservation techniques, which improve pregnancy rates using supernumerary frozen embryos, are expected to augment the global uptake of SET. Adaptation and personalization of fertility therapy may help to optimize efficacy and safety outcomes for individual patients. Prognostic modelling and personalized management strategies based on individual patient characteristics may prove to represent real progress towards improved treatment. However, at present, there is limited good-quality evidence to support the use of these individualized approaches.

Greater quality control and standardization of clinical and laboratory evaluations are required to optimize ART practices and improve individual patient outcomes. Well-designed, good-quality studies are required to drive improvements to the diagnosis and management of ART processes.

We conducted a literature review on the impact of first trimester complications in previous and index pregnancies using Medline and Cochrane databases covering the period 1980–2008.

Clinically relevant associations of adverse outcome in the subsequent pregnancy with an odds ratio (OR) > 2.0 after complications in a previous pregnancy are the risk of perinatal death after a single previous miscarriage, the risk of very preterm delivery (VPTD) after two or more miscarriages, the risk of placenta praevia, premature preterm rupture of membranes, VPTD and low birthweight (LBW) after recurrent miscarriage and the risk of VPTD after two or more termination of pregnancy. Clinically relevant associations of adverse obstetric outcome in the ongoing pregnancy with an OR > 2.0 after complications in the index pregnancy are the risk of LBW and very low birthweight (VLBW) after a threatened miscarriage, the risk of pregnancy-induced hypertension, pre-eclampsia, placental abruption, preterm delivery (PTD), small for gestational age and low 5-min Apgar score after detection of an intrauterine haematoma, the risk of VPTD and intrauterine growth restriction after a crown-rump length discrepancy, the risk of VPTD, LBW and VLBW after a vanishing twin phenomenon and the risk of PTD, LBW and low 5-min Apgar score in a pregnancy complicated by severe hyperemesis gravidarum.

Data from our literature review indicate, by finding significant associations, that specific early pregnancy events and complications are predictors for subsequent adverse obstetric and perinatal outcome. Though, some of these associations are based on limited or small uncontrolled studies. Larger population-based controlled studies are needed to confirm these findings. Nevertheless, identification of these risks will improve obstetric care.

The Cochrane Library, MEDLINE and EMBASE (plus reviews and experts) were searched to December 2007. Inclusion of randomized or residential crossover trials of soy or isoflavones for 4 or more weeks on estrogens, SHBG, FSH, LH, progesterone and thyroid hormones in women was assessed independently in duplicate. Six percent of papers assessed were included. Data concerning participants, interventions, outcomes, potential effect modifiers and trial quality characteristics were extracted independently in duplicate.

Forty-seven studies (11 of pre-, 35 of post- and 1 of perimenopausal women) were included. In premenopausal women, meta-analysis suggested that soy or isoflavone consumption did not affect primary outcomes estradiol, estrone or SHBG concentrations, but significantly reduced secondary outcomes FSH and LH [by ~20% using standardized mean difference (SMD), P = 0.01 and 0.05, respectively]. Menstrual cycle length was increased by 1.05 days (95% CI 0.13, 1.97, 10 studies). In post-menopausal women, there were no statistically significant effects on estradiol, estrone, SHBG, FSH or LH, although there was a small statistically non-significant increase in total estradiol with soy or isoflavones (~14%, SMD, P = 0.07, 21 studies).

Isoflavone-rich soy products decrease FSH and LH in premenopausal women and may increase estradiol in post-menopausal women. The clinical implications of these modest hormonal changes remain to be determined.

Publications pertaining to the recurrence of endometriosis and its related yet unaddressed issues were identified through MEDLINE. The reported recurrence rates, risk factors for recurrence, the effects of post-operative medication and causes of recurrence were reviewed and synthesized. In addition, several poorly explored issues such as time hazard function and mechanisms of recurrence were reviewed. Approaches to the development of biomarkers for recurrence and future intervention are discussed.

The reported recurrence rate was high, estimated as 21.5% at 2 years and 40–50% at 5 years. Few risk factors for recurrence have been consistently identified, and the evidence on the efficacy of the post-operative use of medication was scanty. The investigation on the patterns of recurrence may provide us with new insight into the possible mechanisms of recurrence and its control. The attempt to identify biomarkers for recurrence has started only very recently.

Much research is needed to better understand the patterns of recurrence and risk factors, and to develop biomarkers. One top priority is to develop biomarkers for recurrence, which may provide much needed clues to the possible mechanisms underlying recurrence and would allow the identification of patients with high recurrence risk, and permit for targeted intervention.

A thorough literature search was made in PubMed using the terms INSL3, as well as the older synonyms RLF and Ley-IL.

INSL3 is a major secretory product of the testicular Leydig cells in the fetus and in adult men, and in rodent models, reduction in fetal INSL3 expression is an early marker of the testicular dysgenesis syndrome. In women, it is produced in lower amounts by ovarian theca and luteal cells, and circulating levels are increased in women with polycystic ovarian syndrome. During pregnancy, there is evidence for an interaction regulating the feto-placental unit. The presence of INSL3 in amniocentesis samples taken at 12–14 weeks gestation is absolutely specific for male gender, and levels are predictive of subsequent pre-eclampsia and/or birthweight. INSL3 is also involved in adult traits, such as spermatogenesis and bone metabolism. In adult men, INSL3 is constitutively expressed and secreted into the bloodstream at a constant level, reflecting the number and/or functional capacity of the Leydig cells. In complete contrast, testosterone is highly variable within individuals, is acutely responsive to fluctuations in the hypothalamic–pituitary–gonadal axis and appears to have marginal diagnostic value. INSL3 declines consistently with age in adult men.

INSL3 promises to become an important new diagnostic tool to characterize those men with late-onset hypogonadism and to add clinical diagnostic value at amniocentesis.

We reviewed the literature on the presence of risk factors for type 2 diabetes (DM2) and cardiovascular disease (CVD) across the reproductive diagnostic phenotypes of PCOS with the aims of comparing the metabolic features of the NIH and non-NIH groups and identifying potential high metabolic risk phenotypes of PCOS.

NIH PCOS patients present with greater obesity, abdominal obesity, insulin resistance (IR) and risk factors for DM2 and CVD compared with non-NIH ovulatory and non-hyperandrogenic PCOS patients. Where differences in metabolic features exist between the phenotypes, they are generally related to the degree of total and abdominal obesity. There is emerging evidence suggesting ovulatory and non-hyperandrogenic PCOS have greater metabolic abnormalities than controls primarily linked to abdominal adiposity. There is currently no evidence that non-hyperandrogenic PCOS is associated with a less adverse metabolic profile than ovulatory PCOS.

Current metabolic evidence appears to justify the inclusion of both non-NIH PCOS groups (ovulatory and non-hyperandrogenic) as PCOS subgroups. NIH PCOS is associated with a more adverse metabolic profile including greater total and abdominal obesity, IR and risk factors for CVD and DM2 than non-NIH phenotypes.