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Vaginal progesterone via capsule, gel or tablet is the most common route for luteal phase support (LPS) in Europe. Although there is a wealth of data comparing products used at other stages of assisted reproductive technology cycles, there is a lack of systematically identified evidence comparing the wide range of vaginal progesterone products. This systematic review queried the MEDLINE, Embase and Cochrane Library databases on 30 June 2016 to identify head-to-head randomized controlled trials (RCTs) comparing the efficacy or safety of vaginal progesterone preparations (Crinone, Cyclogest, Lutigest or Utrogestan Vaginal) for LPS in assisted reproductive technology cycles. Of 1914 results, 18 RCTs were included. No significant difference in clinical pregnancy rate was identified in comparisons of Utrogestan Vaginal with Crinone. Utrogestan Vaginal and Lutigest were non-inferior to Crinone in ongoing pregnancy rate comparisons. Differences in patient-reported perineal irritation with Crinone and Lutigest were not significantly different to Cyclogest. In studies comparing varying timing or dosage of Utrogestan Vaginal or Crinone, no significant differences were observed. These results suggest Crinone, Cyclogest, Lutigest and Utrogestan Vaginal represent equally safe and effective choices of vaginal progesterone for LPS in assisted reproductive technology cycles. Future quantitative analyses could provide further support for these findings., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: In vitro maturation (IVM) is a fertility treatment that involves the transvaginal retrieval of immature oocytes, and their subsequent maturation and fertilisation. Although the live birth rate is lower than conventional in vitro fertilisation (IVF) with ovarian stimulation, it is a useful treatment, as it avoids the risk of ovarian hyperstimulation syndrome (OHSS). Women with polycystic ovaries (PCO) or polycystic ovarian syndrome (PCOS) are at an increased risk of OHSS. Thus, IVM may be a more useful treatment in this patient group.Strategies to maximise the maturation rates of the immature oocytes are important. This review focuses on the administration of human chorionic gonadotrophin (hCG) prior to immature oocyte retrieval., Objectives: To determine the effectiveness and safety of hCG priming in subfertile women who are undergoing IVM treatment in the context of assisted reproduction., Search Methods: We searched the following electronic databases up to 29 August 2016: Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL. We also searched the trial registries ClinicalTrials.gov and WHO ICTPR to identify ongoing and registered trials. We sought recently published papers not yet indexed in the major databases, and reviewed the reference lists of reviews and retrieved studies as sources of potentially relevant studies. There were no language restrictions., Selection Criteria: We included randomised controlled trials (RCTs) that compared hCG priming with placebo or no priming in women undergoing IVM. We also included RCTs that compared different doses of hCG, or the timing of oocyte retrieval. The primary outcomes were live birth rate and miscarriage rate per woman randomised., Data Collection and Analysis: Two review authors independently selected studies for inclusion, and with a third author, assessed risk of bias and extracted data. We contacted the original authors where data were missing. For dichotomous outcomes, we used the Mantel-Haenszel method to calculate odds ratios (OR). For continuous outcomes, we calculated the mean differences (MD) between treatment groups. We assessed statistical heterogeneity using the I² statistic. We assessed the overall quality of the evidence using GRADE methods., Main Results: We included four studies, with a total of 522 women, in the review. One of these studies did not report outcomes per woman randomised, and so was not included in formal analysis. Three studies investigated 10,000 units hCG priming compared to no priming. One study investigated 20,000 units hCG compared to 10,000 units hCG priming. Three studies only included women with PCOS (N = 122), while this was an exclusion criteria in the fourth study (N = 400).We rated all four studies as having an unclear risk of bias in more than one of the seven domains assessed. The quality of the evidence was low, the main limitations being lack of blinding and imprecision.When 10,000 units hCG priming was compared to no priming, we found no evidence of a difference in the live birth rates per woman randomised (OR 0.65, 95% confidence intervals (CI) 0.24 to 1.74; one RCT; N = 82; low quality evidence); miscarriage rate (OR 0.60, 95% CI 0.21 to 1.72; two RCTs; N = 282; I² statistic = 21%; low quality evidence), or clinical pregnancy rate (OR 0.52, 95% CI 0.26 to 1.03; two RCTs, N = 282, I² statistic = 0%, low quality evidence). Though inconclusive, our findings suggested that hCG may be associated with a reduction in clinical pregnancy rates; 22% of women who received no priming achieved pregnancy, while between 7% and 23% of women who received hCG priming did so.The study comparing 20,000 units hCG with 10,000 units hCG did not report sufficient data to enable us to calculate odds ratios.No studies reported on adverse events (other than miscarriage) or drug reactions., Authors' Conclusions: This review found no conclusive evidence that hCG priming had an effect on live birth, pregnancy, or miscarriage rates in IVM. There was low quality evidence that suggested that hCG priming may reduce clinical pregnancy rates, however, these findings were limited by the small number of data included. As no data were available on adverse events (other than miscarriage) or on drug reactions, we could not adequately assess the safety of hCG priming. We need further evidence from well-designed RCTs before we can come to definitive conclusions about the role of hCG priming, and the optimal dose and timing.

One in 400 people has a maternally inherited mutation in mtDNA potentially causing incurable disease. In so-called heteroplasmic disease, mutant and normal mtDNA co-exist in the cells of carrier women. Disease severity depends on the proportion of inherited abnormal mtDNA molecules. Families who have had a child die of severe, maternally inherited mtDNA disease need reliable information on the risk of recurrence in future pregnancies. However, prenatal diagnosis and even estimates of risk are fraught with uncertainty because of the complex and stochastic dynamics of heteroplasmy. These complications include an mtDNA bottleneck, whereby hard-to-predict fluctuations in the proportions of mutant and normal mtDNA may arise between generations. In 'mitochondrial replacement therapy' (MRT), damaged mitochondria are replaced with healthy ones in early human development, using nuclear transfer. We are developing non-invasive alternatives, notably activating autophagy, a cellular quality control mechanism, in which damaged cellular components are engulfed by autophagosomes. This approach could be used in combination with MRT or with the regular management, pre-implantation genetic diagnosis (PGD). Mathematical theory, supported by recent experiments, suggests that this strategy may be fruitful in controlling heteroplasmy. Using mice that are transgenic for fluorescent LC3 (the hallmark of autophagy) we quantified autophagosomes in cleavage stage embryos. We confirmed that the autophagosome count peaks in four-cell embryos and this correlates with a drop in the mtDNA content of the whole embryo. This suggests removal by mitophagy (mitochondria-specific autophagy). We suggest that modulating heteroplasmy by activating mitophagy may be a useful complement to mitochondrial replacement therapy., (© 2016 The Author(s).)

Socio-economic factors have led to an increasing trend for couples to delay parenthood. However, advancing age exerts detrimental effects upon gametes which can have serious consequences upon embryo viability. While such effects are well documented for the oocyte, relatively little is known with regard to the sperm. One fundamental role of sperm is to activate the oocyte at fertilisation, a process initiated by phospholipase C zeta (PLCζ), a sperm-specific protein. While PLCζ deficiency can lead to oocyte activation deficiency and infertility, it is currently unknown whether the expression or function of PLCζ is compromised by advancing male age. Here, we evaluate sperm motility and the proportion of sperm expressing PLCζ in 71 males (22-54 years; 44 fertile controls and 27 infertile patients), along with total levels and localisation patterns of PLCζ within the sperm head. Three different statistical approaches were deployed with male age considered both as a categorical and a continuous factor. While progressive motility was negatively correlated with male age, all three statistical models concurred that no PLCζ-related parameter was associated with male age, suggesting that advancing male age is unlikely to cause problems in terms of the sperm's fundamental ability to activate an oocyte.

The use of in vitro fertilization (IVF) has revolutionized the treatment of infertility and is now responsible for 1-5% of all births in industrialized countries. During IVF, it is typical for patients to generate multiple embryos. However, only a small proportion of them possess the genetic and metabolic requirements needed in order to produce a healthy pregnancy. The identification of the embryo with the greatest developmental capacity represents a major challenge for fertility clinics. Current methods for the assessment of embryo competence are proven inefficient, and the inadvertent transfer of non-viable embryos is the principal reason why most IVF treatments (approximately two-thirds) end in failure. In this study, we investigate how the application of proteomic measurements could improve success rates in clinical embryology. We describe a procedure that allows the identification and quantification of proteins of embryonic origin, present in attomole concentrations in the blastocoel, the enclosed fluid-filled cavity that forms within 5-day-old human embryos. By using targeted proteomics, we demonstrate the feasibility of quantifying multiple proteins in samples derived from single blastocoels and that such measurements correlate with aspects of embryo viability, such as chromosomal (ploidy) status. This study illustrates the potential of high-sensitivity proteomics to measure clinically relevant biomarkers in minute samples and, more specifically, suggests that key aspects of embryo competence could be measured using a proteomic-based strategy, with negligible risk of harm to the living embryo. Our work paves the way for the development of "next-generation" embryo competence assessment strategies, based on functional proteomics., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)

Ehlers-Danlos syndrome (EDS) is an autosomal dominant connective tissue disorder with one of the highest maternal mortality rates of any condition. Patients with the vascular type of EDS are prone to spontaneous arterial and visceral ruptures. The occurrence of these severe and life-threatening complications is increased in pregnancy. Moreover, these patients carry a 50% risk of having an affected child. However, little is known about the risks of assisted conception treatments on these patients. We present the case of a 33-year-old woman suffering from EDS with a history of repeated ruptures of arterial aneurysms and a recently ruptured aneurysm of the splenic artery during her first intracytoplasmic sperm injection (ICSI) cycle who was then advised to undergo only unstimulated cycles. After a few natural ICSI cycles, the patient safely underwent two in vitro maturation cycles with pre-implantation genetic diagnosis in our unit. An unaffected blastocyst was transferred into a surrogate host. To our knowledge, this is the first case of EDS in assisted reproduction technologies including pre-implantation genetic diagnosis to be reported in the medical literature. This case has shown that unstimulated in vitro maturation and pre-implantation genetic diagnosis can safely be offered for vascular-type Ehlers-Danlos patients.

Breast cancer is one of the hormone-dependent cancers that may be adversely affected by elevated oestrogen or progesterone concentrations, particularly the endocrine active (hormone receptor positive) breast cancers. Treatment for breast cancer patients aimed at fertility preservation, includes ovarian hyperstimulation, the harvest of oocytes, and subsequent cryopreservation of oocytes or embryos. Classically, gonadotrophins have been used effectively for ovulation induction, a treatment often accompanied by high blood oestrogen concentrations produced by the hyperstimulated granulosa cells. Despite the uncertainty which surrounds this issue and the lack of clear-cut clinical evidence, it is still of major concern that these ensuing high hormone levels might be associated with a high risk of recurrence of the cancer. A growing number of clinical studies have strongly suggested the benefits of using aromatase inhibitors in infertility treatment, both as single agents or as adjuncts to FSH-containing ovulation induction regimes in reproductive medicine. Combining gonadotrophins with aromatase inhibitors would augment the stimulation effect, with a reduced increase in serum concentrations of estradiol. We propose to open a debate over the use of aromatase inhibitors in combination with FSH in ovulation induction treatment of breast cancer oncofertility patients. As the safety of aromatase inhibitors such as letrozole has recently been demonstrated in several studies, and there is growing concern over the possible detrimental effects of high estradiol levels on breast cancer cells (at least in mouse models), the co-administration of letrozole in these patients would reduce both the high supraphysiologic serum levels of estradiol and the intratumoral in situ production of oestrogen. However, since it is unlikely that a well-founded evidence-based justification of this treatment will be formulated in the near future, based on well-designed prospective randomised controlled trials, we advocate a wider use of aromatase inhibitors in combination with gonadotrophins in breast cancer patients, especially those with hormone-receptor-positive tumours.

Follicular fluid (FF) contains various cytokines that are involved with folliculogenesis, some of which have been shown to be associated with oocyte quality and the implantation potential of a resulting embryo. Several IL-1 family members have previously been identified in FF. This study investigates a newly identified member of the family, IL-33, and its receptor ST2, comparing values to those of FF Granulocyte-Colony Stimulating Factor (G-CSF)--a known predictor of Assisted Reproductive Technology (ART) success. FF was collected from patients undergoing in vitro fertilisation/intra-cytoplasmic sperm injection (IVF/ICSI) at oocyte retrieval to analyse IL-33 and sST2 expression in human follicles. sST2, but not IL-33, is highly increased in the FF compared to plasma levels (up to 7.9-fold), with higher levels in larger follicles (p<0.05). Furthermore, we identify that human luteinised granulosa cells are one possible source of the FF sST2, as these cells express and secrete sST2 when cultured ex vivo. FF associated with oocytes which when fertilised develop into good quality embryos have higher sST2 levels than those which are graded average (p<0.01). These embryos were transferred to the patient and levels of FF sST2 compared between successful and unsuccessful ICSI cycles. However unlike G-CSF, sST2 levels cannot be used to predict cycle outcome.

A diagnostic test to confirm pre-eclampsia would be beneficial for the clinical management of the syndrome. The Triage PlGF test is able to confirm pre-eclampsia with high accuracy, with the greatest efficacy at <35weeks gestation. We recently found that the anti-inflammatory protein sST2 is elevated in the plasma of pre-eclamptic women compared to normal controls. Here sST2 and PlGF are compared in early-onset and late-onset pre-eclamptic women. sST2 was found to be an equally good diagnostic tool for early-onset (sST2 AUC 0.944 versus PlGF AUC 0.995; not significant) but not late-onset disease., (Copyright © 2013 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

The main causes of infertility are female factor (anovulation, tubal damage, endometriosis and ovarian failure), male factor (low or absent numbers of motile sperm in the ejaculate, and erectile dysfunction), or unexplained infertility. More than 80% of couples will conceive within one year if the woman is aged under 40 and they have regular sexual intercourse. Of those who fail to conceive in the first year, around half will do so in the second year, giving a cumulative pregnancy rate > 90%. A woman of reproductive age who has not conceived after a year of regular sexual intercourse, and has no known cause of infertility, should be offered referral for further clinical assessment and investigation with her partner. Women who have a BMI > or = 30 are likely to take longer to conceive. Those with a BMI < 19 who have irregular or absent menstruation should be advised that putting on weight is likely to improve their chance of conception. The best test of ovulation is an appropriately timed mid-luteal serum progesterone level. Women with irregular or absent menstrual cycles should be offered a blood test to measure serum gonadotrophin levels (FSH and LH). Women with no known comorbidities should be screened for tubal occlusion. Those who are thought to have comorbidities should be offered laparoscopy and dye testing.

Assisted reproductive technology (ART) has resulted in more than 5 million births worldwide. However, mainstream ART techniques are not always successful for an estimated 30% of infertile patients in whom gametes are nonviable. Most patients would clearly prefer genetic parenthood, currently possible only via the use of donated gametes or, in future, via the clinical use of artificial gametes (AGs) incorporating parental DNA. Despite much recent progress in the derivation of AGs, significant obstacles remain. Although it is possible to create artificial cells exhibiting some of the molecular and physiological traits of human gametes, they do not yet exhibit the same level of functionality as their in vivo counterparts. Most current effort pays scant attention to confirmation of molecular integrity and clinical applicability of AGs. Here we discuss the various clinical parameters used to assess gamete and embryo viability and discuss markers of gamete function that may be used within future studies attempting to derive AGs. The use of AGs may prove controversial to some members of the general public, and, as such, there is significant need for an appropriate ethical and legal framework governing the clinical use of such cells. However, provided these issues can be successfully overcome, it is highly likely that AGs will represent powerful biological tools for reproductive science, a valuable training resource for embryologists and for potential use in the clinical treatment of human infertility.

Normal pregnancy is associated with a mild systemic inflammatory response and an immune bias towards type 2 cytokine production, whereas pre-eclampsia is characterized by a more intense inflammatory response, associated with endothelial dysfunction and a type 1 cytokine dominance. Interleukin (IL)-33 is a newly described member of the IL-1 family, which binds its receptor ST2L to induce type 2 cytokines. A soluble variant of ST2 (sST2) acts as a decoy receptor to regulate the activity of IL-33. In this study circulating IL-33 and sST2 were measured in each trimester of normal pregnancy and in women with pre-eclampsia. While IL-33 did not change throughout normal pregnancy, or between non-pregnant, normal pregnant or pre-eclamptic women, sST2 was significantly altered. sST2 was increased in the third trimester of normal pregnancy (p<0.001) and was further increased in pre-eclampsia (p<0.001). This increase was seen prior to the onset of disease (p<0.01). Pre-eclampsia is a disease caused by placental derived factors, and we show that IL-33 and ST2 can be detected in lysates from both normal and pre-eclampsia placentas. ST2, but not IL-33, was identified on the syncytiotrophoblast layer, whereas IL-33 was expressed on perivascular tissue. In an in vitro placental perfusion model, sST2 was secreted by the placenta into the 'maternal' eluate, and placental explants treated with pro-inflammatory cytokines or subjected to hypoxia/reperfusion injury release more sST2, suggesting the origin of at least some of the increased amounts of circulating sST2 in pre-eclamptic women is the placenta. These results suggest that sST2 may play a significant role in pregnancies complicated by pre-eclampsia and increased sST2 could contribute to the type 1 bias seen in this disorder.

Objective: To examine the outcome of IVF in women who have normal ovaries, ovulatory PCO or PCOS., Study Design: Analysis of a prospectively collected database in an assisted conception unit in a university teaching hospital including 290 women <37 years of age undergoing their first IVF cycle. The main outcome measure was severe OHSS requiring hospitalization., Results: Severe OHSS rates were significantly higher in women with PCO (12.6%) and PCOS (15.4%) compared to those with normal ovaries (2.7%). Coasting was used significantly more often. Live birth rates per cycle started are similar among women with PCO (38%), PCOS (37%) and normal ovaries (40%)., Conclusion: Women with ovaries of polycystic morphology are at increased risk of developing severe OHSS and of requiring avoidance techniques such as coasting, regardless of ovulatory status. However, live birth rates per cycle are similar to women with normal ovaries., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Open ileal pouch surgery leads to high rates of adhesive small-bowel obstruction (SBO). A laparoscopic approach may reduce these complications. We aimed to review the incidence of adhesive SBO-related complications after open pouch surgery and to model the potential financial impact of a laparoscopic approach purely as an adhesion prevention strategy., Materials and Methods: We reviewed cases of open ileal pouch patients kept on a database and examined annually. Case notes were studied for episodes of adhesive SBO requiring admission or reoperation. Similar parameters were studied in a small series undergoing laparoscopic pouch surgery. The financial burden of the open access complications was estimated and potential financial impact of a laparoscopic approach modeled., Results: Two hundred seventy-six patients were followed up after open surgery (median, 6.3; range, 0.2-20.1 years). There were 76 (28%) readmissions (median length of stay, 7.4 days) in 53 patients (19%) and 28 (10%) reoperations (43% within 1 year). Laparoscopic patients required less adhesiolysis at second-stage surgery (0% vs 36%, p < 0.0001) and had less SBO episodes within 12 months of surgery (0% vs 14%, p < 0.0001) than open patients. Modeling a laparoscopic approach cost $1,450 and saved $3,282, thus netting $1,832 per pouch constructed., Conclusion: Open ileal pouch surgery results in significant cumulative long-term access-related complications, particularly adhesions. These impose a large medical burden on patients and financial burden on health-care systems, all of which may be recouped by a laparoscopic approach, despite higher theater costs.

A mechanistic understanding of factors influencing the dispersal behavior of metamorph cane toads (Bufo marinus) has direct conservation relevance in Australia. These invasive anurans are toxic to native predators, and if we can predict their distribution across the landscape, we can also predict (and perhaps, manage) the scale of their impact. We propose that the major drivers of metamorph distribution are the risk of dehydration (restricting the young toads to moist substrates near pond margins) and biotic advantages to dispersal away from the pond (especially, less risk of cannibalism). To test this model, we investigated the influence of abiotic and biotic cues on the behavior of individual toads in the laboratory. Substrate moisture levels strongly influenced metamorph activity levels and habitat selection: dry substrates induced most metamorphs to remain near water. The only biotic cue to influence metamorph dispersal was proximity of a larger (cannibalistic) conspecific; a cannibal's presence at the pond margin caused most metamorphs to spend less time there, and as a consequence, to dehydrate more rapidly. Our results suggest that the spatial and temporal distribution of metamorph cane toads reflects a trade-off between competing risks: the danger of desiccation tends to keep young toads close to the pond margin in dry conditions, whereas the danger of cannibalism stimulates dispersal.

Objectives: To report the short- and medium-term complications of laparoscopic laser excisional surgery for rectovaginal endometriosis., Design: Retrospective cohort study., Setting: University teaching hospital, UK., Population: A total of 128 women with histologically confirmed rectovaginal endometriosis who underwent laparoscopic laser surgery between May 1999 and September 2006., Methods: Women were identified from operative database, and a case note review was performed. Data for surgical outcome and surgical complications were collected., Main Outcome Measures: Rates of urinary tract and colorectal complications., Results: A total of 128 women underwent surgery. Of these, 32 required intraoperative closure of a rectal wall defect, including 3 segmental rectosigmoid resections. There were three rectovaginal fistulae and one ureterovaginal fistula. Ureteric damage occurred in two women, and five women suffered postoperative urinary retention. The risk of intraoperative bowel intervention was increased in women who complained of cyclical rectal bleeding., Conclusion: Laparoscopic laser excision of rectovaginal endometriosis is a safe procedure with similar, if not lower, complication rates to other published surgical series.

Objective: Some men with azoospermia on general laboratory testing have low quantities of sperm in the ejaculate that can only be identified through sample centrifugation and careful examination of the pellet droplets (extended sperm preparation [ESP]). Such sperm can be used for IVF-ICSI as an alternative to either surgical sperm retrieval (SSR) or donor sperm. The aims of the present study were to: 1) assess UK IVF clinic practice with regard to ESP in men with azoospermia; and 2) to analyze the outcome of ESP and SSR in azoospermic men attending the Oxford Fertility Unit., Design: National survey of all 70 IVF units plus chart review., Setting: Assisted conception unit., Patient(s): One hundred twenty-two azoospermic men referred to the Oxford Fertility Unit., Main Outcome Measure(s): Proportions of UK IVF clinics performing ESP for azoospermia. Proportions of azoospermic men in Oxford with sperm identified at ESP and, if necessary, SSR. Relationship between serum FSH and outcome., Result(s): In part 1 of the study, 55 (79%) of the 70 UK IVF clinics returned completed questionnaires. Fifty clinics (91%) routinely performed ESP for men with azoospermia on general laboratory testing, four clinics (7%) proceeded straight to SSR without prior ESP, and one clinic varied in their approach. When clinics were asked whether they used serum FSH levels when considering whether to proceed to SSR 28 (51%) did, 9 (16%) did not, and 18 (33%) varied in their approach. The value placed on testicular volume similarly varied. Part 2 of the study included 122 men referred to the Oxford Fertility Unit with azoospermia on general laboratory testing. Eighty-seven men underwent ESP. Motile sperm was found, cryopreserved, and later used during IVF-ICSI treatment in 19 men (22%). Eighty-one men underwent SSR (after either a negative ESP or declining ESP). Viable sperm was found in 66 men undergoing SSR (81%). There was a statistically significant relationship between serum FSH and the chance of retrieving sperm with SSR (P=0.002) but not with ESP., Conclusion(s): The majority (91%) of IVF clinics in the UK routinely perform ESP in men with azoospermia on general testing. Only half routinely used serum FSH levels as predictors of SSR outcome. The value of ESP is confirmed by our findings in Oxford. Twenty-two percent of men with azoospermia on general laboratory testing had sufficient sperm found at ESP to proceed to IVF-ICSI without resorting to the use of either SSR or donor sperm. Serum FSH levels were not related to the chance of finding sperm during ESP but were related to the outcome of SSR. Our results suggest that ESP should be considered for all men with azoospermia and no apparent obstruction.

Polycystic ovary syndrome (PCOS) is a common syndrome among young women. It is associated with fertility problems, clinical manifestations of hyperandrogenism and metabolic disturbance, particularly insulin resistance. The long-term consequences of PCOS have not been fully determined, but there is an increased risk of progression to diabetes and an increase in cardiovascular risk factors. The extent to which PCOS is present in postmenopausal women and the degree to which it increases various risk factors in addition to the known risk of the postmenopausal period are not yet known. This paper reviews the pathophysiology of PCOS and its long-term consequences and considers the evidence to date that is applicable to the postmenopausal woman.

Female fertility rates are inherently linked to a woman's age, which is in turn related to ovarian function. Reproductive potential declines gradually until 37-38 years of age, from when the rate of decline hastens. Approximately 1% of women suffer from premature ovarian ageing, and many may not have completed their families. This paper reviews the physiology and fertility consequences of ovarian ageing, premature ovarian failure, measures of ovarian reserve and methods of fertility preservation.

Immunocytochemistry was used to demonstrate the presence of beta-endorphin and alpha-MSH, and in situ hybridisation was used to study the presence of pro-opiomelanocortin (POMC) mRNA, in spinal motoneurones, up to 8 days following the administration of a single dose of acrylamide in mice. The proportions of POMC-mRNA positive neurones, beta-endorphin-immunoreactive neurones and alpha-MSH-immunoreactive neurones were significantly increased in the treated animals compared to controls. It seems likely that upregulation of the POMC gene precedes acrylamide-induced neuropathy.

Endometriosis, which may be defined as the presence and proliferation of endometrial tissue outside the uterine cavity, causes pain and infertility for millions of women worldwide. Studies suggest a prevalence of 0.5 to 5% in fertile and 25 to 40% in infertile women. The most widely accepted aetiological theory is that retrograde flow of menstrual fluid through the Fallopian tubes deposits viable endometrial tissue, which implants on the peritoneal surface. Increasingly, the aetiology of endometriosis is being studied at the immunological and genetic levels. The aim of treatment of endometriosis is to remove or diminish disease deposits. This may be attempted through medical or surgical means. It has long been recognised that endometriotic glands are hormonally sensitive. Medical therapies work by inducing a hypoestrogenic, anovulatory state to induce atrophy within the glandular tissue. Conception is generally not possible during medical therapy and has not been demonstrated to increase afterwards. Medical treatment of endometriosis should be discouraged when infertility is the primary problem. In this situation surgery or an assisted reproduction treatment such as in vitro fertilisation may be more appropriate. Medical treatment of pain caused by endometriosis is generally effective. There is little difference in efficacy between the different medications but their adverse effect profiles differ greatly. It appears that gonadotropin-releasing hormone agonists, particularly when used with add-back estrogen, may be more acceptable to women than other treatments. Laparoscopic surgical treatment of minimal and mild endometriosis has been demonstrated to increase fecundity. Surgical treatment has also been shown to decrease pain scores compared with expectant management. Ongoing and future research examining the aetiology of endometriosis at the immunological and genetic levels should usher in new treatments directed at the actual cause of the disease. More randomised trials examining the role of surgery, and comparing surgical and medical treatments, are also required and are necessary if we are to continue in our attempts to adopt an evidence-based approach to treatment.

All assisted conception techniques are associated with an increase in the multiple pregnancy rate. Iatrogenic multiple births are increasing as the use of these technologies expands. The cornerstone of safe ovulation induction is careful ultrasound monitoring, with cancellation of cycles if excessive ovulation is expected. In in vitro fertilization (IVF) cycles, the main determinant of multiple pregnancy risk is the number of embryos replaced. The current move in IVF clinics is to reduce the risk of multiple pregnancy by reducing the number of embryos transferred. We would suggest a maximum of two embryos transferred to women under, for example, 39 years of age. Women of 39 years or over have a reduced chance of embryo implantation; they should be allowed the transfer of up to three embryos (the UK legal maximum).

This study examines a form of masking that can take place when the signal and masker are widely separated in frequency and cannot be explained in terms of the traditional concept of the auditory filter or critical band. We refer to this as across-channel masking. The task of the subject was to detect an increment in modulation depth of a 1000-Hz sinusoidal carrier. The carrier could either be sinusoidally amplitude modulated or sinusoidally frequency modulated at a 10-Hz rate. Modulation increment thresholds of this "target" signal were measured for the target alone, and in the presence of two interfering sounds with carrier frequencies of 230 and 3300 Hz. When the interfering sounds were unmodulated, they had no effect on modulation increment thresholds. When the interfering sounds were either amplitude or frequency modulated, thresholds increased. Amplitude modulation (AM) increment thresholds were affected by both amplitude-modulated and frequency-modulated interference. Similarly, frequency modulation (FM) increment thresholds were affected by both amplitude-modulated and frequency-modulated interference. For both types of signal, the interference was tuned for modulation rate; across-channel masking was greatest when the interfering sounds were modulated at rates close to 10 Hz, and declined for higher or lower rates. However, the tuning was rather broad. When the target and interfering sounds were modulated at the same rate, there was no effect of the relative phase of the modulators. Two possible explanations for the results are discussed. One is based on the idea that carriers that are modulated in a similar way tend to be perceptually "grouped". The other is based on the idea that there are "channels" in the auditory system tuned for AM and FM rate. Neither explanation appears completely satisfactory.