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Does increased body mass index (BMI) without an underlying metabolic issue negatively influence semen quality? Proof of concept we conducted retrospective data analysis of men (N = 84) undergoing assisted reproductive technology, who had liver function testing with fasted glucose concentrations and corresponding hormone profile (testosterone, LH, FSH and prolactin) and semen analysis. Sperm count and total concentration were only reduced in metabolically unhealthy overweight/obese men. Serum GTT was the biggest predictor of Normozoospermia and Oligospermia, with BMI having no effect. Increased BMI without an underlying metabolic condition (in particular signs of NAFLD) has no influence on semen quality.

The prevailing legal position and opinion of professional societies such as the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine is that posthumous sperm conception should only occur in the presence of explicit written consent from the deceased man. However, in our opinion this is an impractical approach as the majority of deaths of reproductive-age men are sudden and unexpected, thereby precluding explicit consent. Previously in this journal we have outlined arguments supporting a move to a standard of presumed consent for posthumous conception, with provisions for men to 'opt out' and safeguards to protect the welfare of the prospective mother and her child. In a recent commentary in this journal, Kroon outlines arguments against our position of presumed consent as an unacceptable violation of the deceased's autonomy. However, such arguments on the primacy of the rights of the dead are in our opinion not paramount, especially since this position blocks access to posthumous conception for the majority who support its use. The objective of this commentary is to provide a rebuttal to the concerns raised by Kroon and hopefully reorientate the discussion towards the rights and welfare of the living (widow, prospective child), not the dead.

Summary Aim Abnormally functioning immunocompetent cells in the endometrium are thought to be responsible for at least some cases of recurrent reproductive failure [recurrent miscarriage or recurrent in vitro fertilisation (IVF) failure], but their detailed investigation has been hampered by a lack of a standardised protocol of counting such cells in study or control patients. The purpose of this study is to use a standardised protocol for the assessment of immune cells in the endometrial biopsies of a large cohort of women with recurrent reproductive failure and establish relevant reference ranges. Method In a recent study, we reported the presence and distribution of selected immune cells and macrophages in the endometria from 222 women who had a routine endometrial biopsy for investigation of recurrent miscarriage or IVF failure. Since the completion of that study, a further 1767 cases have been examined, using the same assessment parameters of the earlier study. Results This updated analysis of 1989 endometrial biopsies provides reference ranges for CD8 + , CD163 + , CD56 + and CD57 + cells for individual ‘days’ of a normalised menstrual cycle. CD8 + T-cells displayed a modest (50%) increase in numbers in the luteal phase and periglandular aggregation was a useful indicator of a subtle focal endometritis, possibly of infective origin, and generally not identified in H&E sections. A rapid accumulation of CD163 + macrophages occurs in the superficial stroma after day 22 of the cycle, while a significant number of cases displayed single or clustered macrophages within glandular lumens of the superficial endometrium in luteal phase, especially after day 20 of the cycle. The significance of this change is unclear but may relate to a macrophage response to abnormal glandular secretion or to bleeding occurring at the time of ovulation. CD56 + uterine natural killer (uNK) cells show such a dramatic rise in both absolute numbers and percentage of stromal cells from day 22 of the standardised 28 day cycle that this needs to be taken into account in all clinical studies or individual assessments of endometrial biopsies. CD57 + NK cells are seen in small numbers in most cases and cell counts of greater than 10 per mm 2 are regarded as abnormal. Conclusions This large database provides a daily range which is the most accurate survey yet of uNK cell numbers. Co-location of CD8 + T-cells and CD56 + uNK cells in perviascular aggregates has been demonstrated.

Adenomyosis, a condition usually associated with multiparity, is not generally seen as a cause of infertility. However, recent studies have reported a reduction in IVF implantation rates and a link with miscarriage, suggesting that adenomyosis may interfere with successful implantation. To investigate this hypothesis, the clinical records and laboratory results, which routinely include immunohistochemical examination of a late luteal phase endometrial biopsy for leukocytes, were retrospectively reviewed for 64 women with implantation failure and who previously had been screened for the presence of adenomyosis by pelvic MRI. The presence of either diffuse or "adenomyoma" type of adenomyosis was associated with a marked increase (p=0.004) in the density of macrophages and natural killer cells in the endometrial stroma, compared to those women with mild focal adenomyosis or no disease. These findings point to an immunological mechanism by which adenomyosis might interfere with successful embryo implantation.

Recurrent miscarriage affects approximately 1% of the population and in half of these cases no cause is found. Abnormally functioning immunocompetent cells, including natural killer (NK) cells, in the endometrium, are thought to be responsible for many such cases and treatment trials including oral prednisolone and intravenous immunoglobulins are now underway. Despite these encouraging developments, there is neither adequate standardization of counting uterine NK cells nor consensus as to what constitutes an abnormal level. To address this issue, immunohistochemistry was used to examine the presence and distribution of selected immune cells and macrophages in the endometrium from 222 women who had a routine endometrial biopsy for investigation of recurrent miscarriage or IVF failure, at various stages of the menstrual cycle, and accessioned prospectively over a 7-month period. Biopsies were examined by H+E and immunostained for CD8(+) T-cells, CD163(+) macrophages, CD56(+) NK cells, and CD57(+) cells. Cell numbers (expressed as immunopositive cells per mm(2)) were determined in the stroma of the functional layer of endometrium and the relative concentrations of some cell types (CD163(+) macrophages, CD56(+) NK cells) were expressed as a percentage of all stromal cells. Routine H+E sections revealed 12 patients with focal "endometritis" without plasma cells. CD8(+) T-cells showed focal perivascular aggregates in most instances, and non-random but scattered cells in all cases, with a twofold increase in the luteal phase. CD163(+) cells were distributed evenly throughout the superficial endometrial stroma and also present as single or clustered macrophages within the lumens of superficial glands, mostly in the luteal phase. CD56(+) NK cells showed "diffuse" but variable distribution throughout the functional layer and perivascular aggregates of various sizes in two thirds of cases. Raw cell counts were low and relatively stable in the proliferative phase, but increased somewhat during the first half of the secretory phase, while in the second half of secretory phase they increased six to tenfold. Percentage counts rose from approximately 5% of stromal cells in the early part of the secretory phase of the cycle to over 35% in premenstrual endometrium. CD57(+) cells were present in very low numbers in most cases. The study illustrates the complexity and variability of immune cell infiltration of endometrium. We stress the need for strict counting protocols and attention to histological criteria if any immunological perturbations potentially responsible for recurrent reproductive failure are to be identified. Reference ranges for individual cell types are only valid for individual "days" of a normalized menstrual cycle.

Serum anti-Mullerian hormone (AMH) concentration and antral follicle count (AFC) are two increasingly popular static measures used to predict ovarian reserve prior to IVF treatment. While they have been shown to be good predictors of oocyte yield during ovarian stimulation, their status as indicators of oocyte quality and pregnancy rates is currently uncertain. The present study measured baseline concentrations of serum AMH and FSH, and AFC from 126 women undergoing IVF treatment. These data were then related to IVF outcomes. As expected, patients with lower serum AMH and AFC produced a significantly (P < 0.001) lower number of oocytes compared with patients with higher serum AMH/AFC. Fertilization rates in patients with lower serum AMH were significantly inferior compared with patients with higher serum AMH, irrespective of whether IVF (P = 0.043) or intracytoplasmic sperm injection (P = 0.006) was used to achieve fertilization. These low AMH patients yielded fewer oocytes, had lower fertilization rates, generated fewer embryos, and had a higher incidence of miscarriage during fresh transfers, ultimately culminating in a halving of the pregnancy rate per IVF cycle compared with the high AMH group.

Conventional belief holds that an immune response to ejaculate antigens should interfere with fertilisation and establishment of pregnancy. However, emerging evidence now supports the opposing view—that insemination acts to activate maternal immune mechanisms exerting a positive effect on reproductive events. In a response well documented in rodents, semen triggers an influx of antigen-presenting cells into the female reproductive tract which process and present paternal ejaculate antigens to elicit activation of lymphocytes in the adaptive immune compartment. Transforming growth factor beta (TGFβ), a cytokine present in abundance in seminal plasma, initiates this inflammatory response by stimulating the synthesis of pro-inflammatory cytokines and chemokines in uterine tissues. Lymphocyte activation is evident in lymph nodes draining the uterus and leads to hypo-responsiveness in T-cells reactive with paternal alloantigens. TGFβ has potent immune-deviating effects and is likely to be the key agent in skewing the immune response against a Type-1 bias. Prior exposure to semen in the context of TGFβ can be shown to be associated with enhanced fetal–placental development late in gestation. In this paper, we review the experimental basis for these claims and propose the hypothesis that, in women, the partner-specific protective effect of insemination in pre-eclampsia might be explained by induction of immunological hypo-responsiveness conferring tolerance to histocompatibility antigens present in the ejaculate and shared by the conceptus.

TGFbeta is a potent immune deviating agent, driving active forms of immune tolerance in peripheral tissues through effects on the induction and resolution of inflammatory responses and phenotype skewing in antigen-presenting cells and lymphocytes. The TGFbeta content of seminal plasma from human, rodent and livestock species is amongst the highest measured in biological fluids. The seminal vesicle gland is the principal source of TGFbeta in the semen of mice, where its synthesis is regulated by testosterone. At insemination, seminal TGFbeta is deposited in the female tract and is activated by acidic vaginal pH, enzymes of male or female tract origin, or through cleavage-independent processes involving conformational change after interaction with epithelial cell docking proteins. Seminal TGFbeta has been shown to be a principal stimulating agent in the post-coital inflammatory response, and is likely to be essential for induction of immune tolerance to seminal antigens. As well as preventing aberrant immunity to spermatozoa, these events are implicated in priming an appropriate female immune response to embryo implantation, since many seminal antigens are shared by the conceptus. The cascade of immunological events elicited by seminal TGFbeta may therefore explain epidemiological observations linking acute and cumulative exposure to semen with successful placental development and pregnancy outcome. Depending on whether the female tract has evolved mechanisms to discriminate seminal antigens from opportunistic pathogens, there may be a detrimental cost of seminal TGFbeta in inhibiting protective immunity to agents of sexually transmitted disease including HIV. A better understanding of the significance and role of TGFbeta in semen will facilitate development of novel therapies for immune-based infertility disorders.

OBJECTIVE: To evaluate a new fully automated assay measuring antimüllerian hormone (AMH; Roche Elecsys) against antral follicle count in women of reproductive age.DESIGN: Prospective cohort study.SETTING: Hospital infertility clinics and academic centers.PATIENT(S): Four hundred fifty-one women aged 18 to 44 years, with regular menstrual cycles.INTERVENTION(S): None.MAIN OUTCOME MEASURE(S): AMH and antral follicle count (AFC) determined at a single visit on day 2-4 of the menstrual cycle.RESULT(S): There was a statistically significant variance in AFC but not in AMH between centers. Both AFC and AMH varied by age (overall Spearman rho -0.50 for AFC and -0.47 for AMH), but there was also significant between-center variation in the relationship between AFC and age but not for AMH. There was a strong positive correlation between AMH and AFC (overall spearman rho 0.68), which varied from 0.49 to 0.87 between centers. An agreement table using AFC cutoffs of 7 and 15 showed classification agreement in 63.2%, 56.9% and 74.5% of women for low, medium, and high groups, respectively.CONCLUSION(S): The novel fully automated Elecsys AMH assay shows good correlations with age and AFC in women of reproductive age, providing a reproducible measure of the growing follicle pool.