Clinical prediction models to inform individualized decision-making in subfertile couples : a stratified medicine approach

Funding This work was supported by a Chief Scientist Office Postdoctoral Training Fellowship in Health Services Research and Health of the Public Research (Ref PDF/12/06). The views expressed in this paper represent the views of the authors and not necessarily the views of the funding body.Peer reviewedPostprin

Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities

Background : Observational studies suggest higher pregnancy rates after the hysteroscopic removal of endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions, which are detectable in 10% to 15% of women seeking treatment for subfertility. Objectives : To assess the effects of the hysteroscopic removal of endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions suspected on ultrasound, hysterosalpingography, diagnostic hysteroscopy or any combination of thesemethods inwomenwith otherwise unexplained subfertility or prior to intrauterine insemination (IUI), in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). Search methods : We searched theCochraneMenstrualDisorders and Subfertility SpecialisedRegister (8 September 2014), theCochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 9), MEDLINE (1950 to 12 October 2014), EMBASE (inception to 12 October 2014), CINAHL (inception to 11 October 2014) and other electronic sources of trials including trial registers, sources of unpublished literature and reference lists. We handsearched the American Society for Reproductive Medicine (ASRM) conference abstracts and proceedings (from January 2013 to October 2014) and we contacted experts in the field. Selection criteria : Randomised comparisons between operative hysteroscopy versus control in women with otherwise unexplained subfertility or undergoing IUI, IVF or ICSI and suspected major uterine cavity abnormalities diagnosed by ultrasonography, saline infusion/ gel instillation sonography, hysterosalpingography, diagnostic hysteroscopy or any combination of these methods. Primary outcomes were live birth and hysteroscopy complications. Secondary outcomes were pregnancy and miscarriage. Data collection and analysis : Two review authors independently assessed studies for inclusion and risk of bias, and extracted data. We contacted study authors for additional information. Main results : We retrieved 12 randomised trials possibly addressing the research questions. Only two studies (309 women) met the inclusion criteria. Neither reported the primary outcomes of live birth or procedure related complications. In women with otherwise unexplained subfertility and submucous fibroids there was no conclusive evidence of a difference between the intervention group treated with hysteroscopic myomectomy and the control group having regular fertility-oriented intercourse during 12 months for the outcome of clinical pregnancy. A large clinical benefit with hysteroscopic myomectomy cannot be excluded: if 21% of women with fibroids achieve a clinical pregnancy having timed intercourse only, the evidence suggests that 39% of women (95% CI 21% to 58%) will achieve a successful outcome following the hysteroscopic removal of the fibroids (odds ratio (OR) 2.44, 95% confidence interval (CI) 0.97 to 6.17, P = 0.06, 94 women, very low quality evidence). There is no evidence of a difference between the comparison groups for the outcome of miscarriage (OR 0.58, 95% CI 0.12 to 2.85, P = 0.50, 30 clinical pregnancies in 94 women, very low quality evidence). The hysteroscopic removal of polyps prior to IUI can increase the chance of a clinical pregnancy compared to simple diagnostic hysteroscopy and polyp biopsy: if 28% of women achieve a clinical pregnancy with a simple diagnostic hysteroscopy, the evidence suggests that 63% of women (95% CI 50% to 76%) will achieve a clinical pregnancy after the hysteroscopic removal of the endometrial polyps (OR 4.41, 95% CI 2.45 to 7.96, P < 0.00001, 204 women, moderate quality evidence). Authors' conclusions : A large benefit with the hysteroscopic removal of submucous fibroids for improving the chance of clinical pregnancy in women with otherwise unexplained subfertility cannot be excluded. The hysteroscopic removal of endometrial polyps suspected on ultrasound in women prior to IUI may increase the clinical pregnancy rate. More randomised studies are needed to substantiate the effectiveness of the hysteroscopic removal of suspected endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions in women with unexplained subfertility or prior to IUI, IVF or ICSI

Expression of a catalytically inactive mutant form of glutathione peroxidase 4 (Gpx4) confers a dominant-negative effect in male fertility.

The selenoenzyme Gpx4 is essential for early embryogenesis and cell viability for its unique function to prevent phospholipid oxidation. Recently, the cytosolic form of Gpx4 was identified as an upstream regulator of a novel form of non-apoptotic cell death, called ferroptosis, whereas the mitochondrial isoform of Gpx4 (mGpx4) was previously shown to be crucial for male fertility. Here, we generated and analyzed mice with targeted mutation of the active site selenocysteine (Sec) of Gpx4 (Gpx4_U46S). Mice homozygous for Gpx4_U46S died at the same embryonic stage (E7.5) as Gpx4-/- embryos as expected. Surprisingly, male mice heterozygous for Gpx4_U46S presented subfertility. Subfertility was manifested in a reduced number of litters from heterozygous breedings and an impairment of spermatozoa to fertilize oocytes in vitro. Morphologically, sperm isolated from heterozygous Gpx4_U46S mice revealed many structural abnormalities particularly in the spermatozoan midpiece due to improper oxidation and polymerization of sperm capsular proteins and malformation of the mitochondrial capsule surrounding and stabilizing sperm mitochondria. These findings are reminiscent of sperm isolated from selenium-deprived rodents or from mice specifically lacking mGpx4. Due to a strongly facilitated incorporation of Ser in the polypeptide chain as compared to Sec at the UGA codon, expression of the catalytically inactive Gpx4_U46S was found to be strongly increased. Since the stability of the mitochondrial capsule of mature spermatozoa depends on the moonlighting function of Gpx4 both as an enzyme oxidizing capsular protein thiols and being a structural protein, tightly controlled expression of functional Gpx4 emerges being key for full male fertility

A small population of hypothalamic neurons govern fertility: the critical role of VAX1 in GnRH neuron development and fertility maintenance.

Fertility depends on the correct maturation and function of approximately 800 gonadotropin-releasing hormone (GnRH) neurons in the brain. GnRH neurons are at the apex of the hypothalamic-pituitary-gonadal axis that regulates fertility. In adulthood, GnRH neurons are scattered throughout the anterior hypothalamic area and project to the median eminence, where GnRH is released into the portal vasculature to stimulate release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. LH and FSH then regulate gonadal steroidogenesis and gametogenesis. Absence of GnRH neurons or inappropriate GnRH release leads to infertility. Despite the critical role of GnRH neurons in fertility, we still have a limited understanding of the genes responsible for proper GnRH neuron development and function in adulthood. GnRH neurons originate in the olfactory placode then migrate into the brain. Homeodomain transcription factors expressed within GnRH neurons or along their migratory path are candidate genes for inherited infertility. Using a combined in vitro and in vivo approach, we have identified Ventral Anterior Homeobox 1 (Vax1) as a novel homeodomain transcription factor responsible for GnRH neuron maturation and fertility. GnRH neuron counts in Vax1 knock-out embryos revealed Vax1 to be required for the presence of GnRH-expressing cells at embryonic day 17.5 (E17.5), but not at E13.5. To localize the effects of Vax1 on fertility, we generated Vax1flox mice and crossed them with Gnrhcre mice to specifically delete Vax1 within GnRH neurons. GnRH staining in Vax1flox/flox:GnRHcre mice show a total absence of GnRH expression in the adult. We performed lineage tracing in Vax1flox/flox:GnRHcre:RosaLacZ mice which proved GnRH neurons to be alive, but incapable of expressing GnRH. The absence of GnRH leads to delayed puberty, hypogonadism and complete infertility in both sexes. Finally, using the immortalized model GnRH neuron cell lines, GN11 and GT1-7, we show that VAX1 is a direct regulator of Gnrh1 transcription by binding key ATTA sites within the Gnrh1 promoter. This study identifies VAX1 as a key transcription factor regulating GnRH expression and establishes VAX1 as a novel candidate gene implicated in heritable infertility

Breast Cancer Risk After Ovarian Stimulation for In Vitro Fertilization

The study by Dr van den Belt-Dusebout and colleagues1 investigated a debated aspect of reproductive medicine: breast cancer risk following ovarian stimulation for in vitro fertilization (IVF).2-5 The authors concluded that “these findings are consistent with absence of a significant increase in long-term risk of breast cancer among IVF-treated women”.1 However, some important points should be discussed. For about 23 % of women, sub-fertility diagnosis and number of IVF cycles were collected using a questionnaire since medical records were not available. This high rate threatens the reliability of results. It is not possible to compare a detailed report of official medical records with data deriving from subjective memory of treatments received many years before. This may be a strong bias, because reproductive medicine, IVF strategies and the pharmacological protocols have changed rapidly in the last decades. Dates of diagnosis and histology were reported but unfortunately not disease staging. It would be interesting to investigate if ovarian stimulation with the use of IVF techniques can promote the occurrence of biologically different types of breast cancer, as in the case of tamoxifen-related endometrial cancer, a neoplasia with better prognostic profile and outcome. Also, the authors reported that breast cancer risk decreased with more IVF cycles (7 or more compared with 1-2). They suggested as potential explanations that women treated with more IVF cycles received more hCG or had longer periods of down-regulation with low estradiol and progesterone levels, or the women requiring more IVF cycles were inherently different. It is difficult to provide a definitive conclusion since the clinical outcomes of IVF cycles were not reported. The decreased risk in women treated with many IVF cycles also could be related to the improvement of ovarian function after repeated endocrine stimulations. Infertility and infertility-related nulliparity must be considered as risk factors for breast cancer, and prolonged treatment of anovulatory or poor ovulatory cycles could be one approach for restoring normal ovarian activity and reducing breast cancer risk

Validity of self-reported causes of subfertility

The authors assessed the accuracy of cause(s) of subfertility as reported by women in a self-administered questionnaire in comparison with medical record information, in a nationwide cohort study of women receiving in vitro fertilization treatment in the Netherlands (n = 9,164) between 1983 and 1995. Validity was expressed as sensitivity and specificity, and reliability was expressed by the kappa statistic and overall agreement between self-reports and medical records for various subfertility categories. The sensitivity for subfertility attributed to tubal, male, hormonal, cervical, uterine, and idiopathic factors and for endometriosis was 84%, 78%, 65%, 40%, 46%, 59%, and 83%, respectively. The corresponding kappas were 0.79, 0.71, 0.38, 0.34, 0.13, 0.50, and 0.52, respectively. For 54% of all women who reported two or more causes of subfertility, the medical record revealed only one major factor. Conversely, for 43% of all women whose subfertility was attributed to two or more major factors in the record, only one factor was reported by the women. Older age at the time of filling out the questionnaire, low educational level, long duration of subfertility, and pre-in vitro fertilization treatment were associated with less accurate reporting. The results indicate that the validity of self-reports for tubal and male subfertility is satisfactory. For unexplained subfertility, the validity is moderate; for other causes of subfertility and when two causes of subfertility play a role, the validity is low. Copyrigh

Estrous behavior in dairy cows: identification of underlying mechanisms and gene functions

Selection in dairy cattle for a higher milk yield has coincided with declined fertility. One of the factors is reduced expression of estrous behavior. Changes in systems that regulate the estrous behavior could be manifested by altered gene expression. This literature review describes the current knowledge on mechanisms and genes involved in the regulation of estrous behavior. The endocrinological regulation of the estrous cycle in dairy cows is well described. Estradiol (E2) is assumed to be the key regulator that synchronizes endocrine and behavioral events. Other pivotal hormones are, for example, progesterone, gonadotropin releasing hormone and insulin-like growth factor-1. Interactions between the latter and E2 may play a role in the unfavorable effects of milk yield-related metabolic stress on fertility in high milk-producing dairy cows. However, a clear understanding of how endocrine mechanisms are tied to estrous behavior in cows is only starting to emerge. Recent studies on gene expression and signaling pathways in rodents and other animals contribute to our understanding of genes and mechanisms involved in estrous behavior. Studies in rodents, for example, show that estrogen-induced gene expression in specific brain areas such as the hypothalamus play an important role. Through these estrogen-induced gene expressions, E2 alters the functioning of neuronal networks that underlie estrous behavior, by affecting dendritic connections between cells, receptor populations and neurotransmitter releases. To improve the understanding of complex biological networks, like estrus regulation, and to deal with the increasing amount of genomic information that becomes available, mathematical models can be helpful. Systems biology combines physiological and genomic data with mathematical modeling. Possible applications of systems biology approaches in the field of female fertility and estrous behavior are discusse

Are we overusing IVF?

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Time to pregnancy : a computational method for using the duration of non-conception for predicting conception

An important problem in reproductive medicine is deciding when people who have failed to become pregnant without medical assistance should begin investigation and treatment. This study describes a computational approach to determining what can be deduced about a couple's future chances of pregnancy from the number of menstrual cycles over which they have been trying to conceive. The starting point is that a couple's fertility is inherently uncertain. This uncertainty is modelled as a probability distribution for the chance of conceiving in each menstrual cycle. We have developed a general numerical computational method, which uses Bayes' theorem to generate a posterior distribution for a couple's chance of conceiving in each cycle, conditional on the number of previous cycles of attempted conception. When various metrics of a couple's expected chances of pregnancy were computed as a function of the number of cycles over which they had been trying to conceive, we found good fits to observed data on time to pregnancy for different populations. The commonly-used standard of 12 cycles of non-conception as an indicator of subfertility was found to be reasonably robust, though a larger or smaller number of cycles may be more appropriate depending on the population from which a couple is drawn and the precise subfertility metric which is most relevant, for example the probability of conception in the next cycle or the next 12 cycles. We have also applied our computational method to model the impact of female reproductive ageing. Results indicate that, for women over the age of 35, it may be appropriate to start investigation and treatment more quickly than for younger women. Ignoring reproductive decline during the period of attempted conception added up to two cycles to the computed number of cycles before reaching a metric of subfertility