Both reduced ovarian reserve and severe semen alterations are overrepresented in couples seeking assisted reproductive technology treatment for the first time: a cross-sectional study.

BACKGROUND: Once a mate choice decision has been made, couples that fail to reach a live birth in natural and/or intrauterine insemination (IUI) cycles will likely visit fertility clinics seeking assisted reproductive technology (ART) treatment. During the more or less prolonged period of infertility experienced, those couples with mild/moderate reproductive anomalies would have advantage over couples displaying more severe reproductive alterations in achieving a natural or IUI conception. Thus, we can expect to find a progressive increase in the proportion of couples with more severe reproductive anomalies as duration of infertility rises. In this study, we aim to ascertain whether there is an association between male and female infertility diagnoses and duration of infertility in couples seeking ART treatment for the first time. METHODS: A cross-sectional analysis of 1383 infertile couples that sought ART treatment for the first time. Forward-stepwise binary logistic regression analyses were applied to calculate exponentiated regression coefficients. RESULTS: Men suffering from any combination of oligo-, astheno-, and teratozoospermia (ACOAT) exhibited higher odds of having a duration of infertility > 2 years compared with non-ACOAT men [odds ratio (95% confidence interval): 1.340 (1.030-1.744)]. Women from ACOAT couples displaying a duration of infertility > 2 years presented shorter menstrual cycles (P ≤ 0.047) and lower antral follicular count (AFC) values (P ≤ 0.008) and serum anti-Müllerian hormone (AMH) levels (P ≤ 0.007) than women from non-ACOAT couples exhibiting > 2 years of infertility. Likewise, AFC values (P ≤ 0.013) and serum AMH levels (P ≤ 0.001) were decreased when compared with women from ACOAT couples displaying ≤ 2 years of infertility. A relative low but significant percentage of ACOAT couples displaying > 2 years of infertility stood out for their smoking habits. CONCLUSIONS: Couples consisting of ACOAT men and women with a relative low ovarian reserve are overrepresented in couples seeking ART treatment for the first time after experiencing > 2 years of infertility. This outcome leads us to develop a general hypothesis proposing that the origin of couple's infertility is a consequence of a process of positive assortative mating shaped by sexual selection forces.

A predictive model for women's assisted fecundity before starting the first IVF/ICSI treatment cycle.

PURPOSE: To introduce a prognostic model for women's assisted fecundity before starting the first IVF/ICSI treatment cycle. METHODS: In contrast to previous predictive models, we analyze two groups of women at the extremes of prognosis. Specifically, 708 infertile women that had either a live birth (LB) event in the first autologous IVF/ICSI cycle ("high-assisted-fecundity women", n = 458) or did not succeed in having a LB event after completing three autologous IVF/ICSI cycles ("low-assisted-fecundity women", n = 250). The initial sample of 708 women was split into two sets in order to develop (n = 531) and internally validate (n = 177) a predictive logistic regression model using a forward-stepwise variable selection. RESULTS: Seven out of 32 initially selected potential predictors were included into the model: women's age, presence of multiple female infertility factors, number of antral follicles, women's tobacco smoking, occurrence of irregular menstrual cycles, and basal levels of prolactin and LH. The value of the c-statistic was 0.718 (asymptotic 95% CI 0.672-0.763) in the development set and 0.649 (asymptotic 95% CI: 0.560-0.738) in the validation set. The model adequately fitted the data with no significant over or underestimation of predictor effects. CONCLUSION: Women's assisted fecundity may be predicted using a relatively small number of predictors. This approach may complement the traditional procedure of estimating cumulative and cycle-specific probabilities of LB across multiple complete IVF/ICSI cycles. In addition, it provides an easy-to-apply methodology for fertility clinics to develop and actualize their own predictive models.

Obstetric and offspring risks of women's morbid conditions linked to prior anticancer treatments.

BACKGROUND: Literature shows the effects of type of cancer and/or anticancer treatment on live birth percentages and/or pregnancy and neonatal complications in female cancer survivors. However, studies analyzing the obstetric and offspring risks of the morbid conditions associated with previous anti-cancer treatments are missing. The present review aims to uncover these risks. METHODS: A literature search based on publications up to March 2016 identified by PubMed and references cited in relevant articles. RESULTS: The morbid conditions associated with prior anticancer treatments including chemotherapy, radiotherapy, surgery, and/or hematopoietic stem-cell transplant may induce not only obstetric and neonatal complications but also long-term effects on offspring. Whereas some risks are predominantly evidenced in untreated women others are observed in both treated and untreated women. These risks may be superimposed on those induced by the current women's trend in Western societies to postpone maternity. CONCLUSIONS: Medical professionals should be aware and inform female cancer survivors wishing to have a child not only of the short- and long-term risks to themselves and their prospective offspring of previous anticancer treatments, fertility-preservation technologies, and pregnancy itself, but also of those risks linked to the morbid conditions induced by prior anticancer treatments. Once female cancer survivors wishing to have a child have been properly informed about the risks of reproduction, they will be best placed to make decisions of whether or not to have a biological or donor-conceived child. In addition, when medical professionals be aware of these risks, they will be also best placed to provide appropriate treatments before/during pregnancy in order to prevent or alleviate the impact of these morbid conditions on maternal and offspring health.

Deficiencies in reporting results of lesbians and gays after donor intrauterine insemination and assisted reproductive technology treatments: a review of the first emerging studies.

At a time when increasing numbers of lesbians and gays consider parenthood using reproductive assistance in infertility centers, the present review aims to summarize the results obtained so far by lesbians after intrauterine insemination (IUI) and in-vitro fertilization (IVF) using donor spermatozoa (D-IUI and D-IVF, respectively) and gays entering into gestational-surrogacy programs. Data show that gays display normal semen parameters and lesbians exhibit no specific causes of female infertility except perhaps for polycystic ovary syndrome (PCOS) and some PCOS-related factors. Pair-bonded lesbians entering into D-IUI programs, tend to have higher pregnancy and delivery percentages following spontaneous or induced ovulation than single or pair-bound heterosexual women. The only single study reporting success percentages of lesbians after D-IVF provides, however, puzzling results. In particular, pair-bonded lesbians have lower pregnancy and live-birth percentages than pair-bonded heterosexual women in fresh D-IVF cycles but percentages are similar in frozen/thawed D-IVF cycles. Like in lesbians after D-IUI, surrogate women recruited by pair-bonded gays/single men tend to have higher pregnancy percentages and lower miscarriage percentages than surrogate women recruited by heterosexual couples. Notably, all the reports reviewed in the present study are methodologically flawed because of sampling bias, small sample sizes and inadequate use of statistical methods to control for the effects of influential covariates including age, smoking habits, previous gynecological problems, hormonal stimulation type and protocol, and number of prior treatment types and pregnancies/deliveries. Clinicians, reproductive biologists and editors of fertility/infertility journals should make efforts to prevent these deficiencies in future data reporting.

Infertility etiologies are genetically and clinically linked with other diseases in single meta-diseases.

The present review aims to ascertain whether different infertility etiologies share particular genes and/or molecular pathways with other pathologies and are associated with distinct and particular risks of later-life morbidity and mortality. In order to reach this aim, we use two different sources of information: (1) a public web server named DiseaseConnect ( http://disease-connect.org ) focused on the analysis of common genes and molecular mechanisms shared by diseases by integrating comprehensive omics and literature data; and (2) a literature search directed to find clinical comorbid relationships of infertility etiologies with only those diseases appearing after infertility is manifested. This literature search is performed because DiseaseConnect web server does not discriminate between pathologies emerging before, concomitantly or after infertility is manifested. Data show that different infertility etiologies not only share particular genes and/or molecular pathways with other pathologies but they have distinct clinical relationships with other diseases appearing after infertility is manifested. In particular, (1) testicular and high-grade prostate cancer in male infertility; (2) non-fatal stroke and endometrial cancer, and likely non-fatal coronary heart disease and ovarian cancer in polycystic ovary syndrome; (3) osteoporosis, psychosexual dysfunction, mood disorders and dementia in premature ovarian failure; (4) breast and ovarian cancer in carriers of BRCA1/2 mutations in diminished ovarian reserve; (5) clear cell and endometrioid histologic subtypes of invasive ovarian cancer, and likely low-grade serous invasive ovarian cancer, melanoma and non-Hodgkin lymphoma in endometriosis; and (6) endometrial and ovarian cancer in idiopathic infertility. The present data endorse the principle that the occurrence of a disease (in our case infertility) is non-random in the population and suggest that different infertility etiologies are genetically and clinically linked with other diseases in single meta-diseases. This finding opens new insights for clinicians and reproductive biologists to treat infertility problems using a phenomic approach instead of considering infertility as an isolated and exclusive disease of the reproductive system/hypothalamic-pituitary-gonadal axis. In agreement with a previous validation analysis of the utility of DiseaseConnect web server, the present study does not show a univocal correspondence between common gene expression and clinical comorbid relationship. Further work is needed to untangle the potential genetic, epigenetic and phenotypic relationships that may be present among different infertility etiologies, morbid conditions and physical/cognitive traits.

Assisted reproductive technology results: why are live-birth percentages so low?

The present bioessay aims to analyze the impact of parental age, cause of infertility, embryo chromosomal anomalies, assisted reproduction technology (ART) treatments, and environmental and occupational exposures to xenobiotics on ART results, particularly on live-birth percentages per transfer. Special attention is paid to analyzing the effects of these factors on the mitochondrial, genetic, and epigenetic traits of gametes and embryos to ascertain the molecular/cellular mechanisms responsible for the relatively low percentages of live births reported year after year in ART cycles. The bias of age distribution of women attending fertility clinics toward the late thirties and beyond and the high incidence of mosaicism found in pre-implantation embryos emerge as the two biggest players in this scenario. Parental reproductive aging and some causes of infertility are associated with mitochondrial, genetic, and epigenetic alterations to gametes. ART treatments such as ovarian stimulation, gamete/embryo cryopreservation, oocyte in vitro maturation, intracytoplasmic sperm injection, in vitro culture system, and embryo biopsy may also induce epigenetic changes in gametes and/or pre-implantation embryos. Finally, exposure to numerous environmental chemicals is linked to sperm genetic and epigenetic defects. Whereas the selective transfer of euploid blastocysts may improve implantation and pregnancy percentages, especially in reproductively older women, it does not guarantee the total absence of mitochondrial and/or epigenetic defects in embryos. The presence of induced and/or inherited DNA epigenetic disturbances in ART offspring is unlikely to be prevented, even by replacing the whole cytoplasm of oocytes using nuclear-genome-transfer technology.

Endocrinology and physiology of pseudocyesis.

This literature review on pseudocyesis or false pregnancy aims to find epidemiological, psychiatric/psychologic, gynecological and endocrine traits associated with this condition in order to propose neuroendocrine/endocrine mechanisms leading to the emergence of pseudocyetic traits. Ten women from 5 selected studies were analyzed after applying stringent criteria to discriminate between cases of true pseudocyesis (pseudocyesis vera) versus delusional, simulated or erroneous pseudocyesis. The analysis of the reviewed studies evidenced that pseudocyesis shares many endocrine traits with both polycystic ovarian syndrome and major depressive disorder, although the endocrine traits are more akin to polycystic ovarian syndrome than to major depressive disorder. Data support the notion that pseudocyetic women may have increased sympathetic nervous system activity, dysfunction of central nervous system catecholaminergic pathways and decreased steroid feedback inhibition of gonadotropin-releasing hormone. Although other neuroendocrine/endocrine pathways may be involved, the neuroendocrine/endocrine mechanisms proposed in this review may lead to the development of pseudocyetic traits including hypomenorrhea or amenorrhea, galactorrhea, diurnal and/or nocturnal hyperprolactinemia, abdominal distension and apparent fetal movements and labor pains at the expected date of delivery.

Unpredicted ovulations and conceptions during early pregnancy: an explanatory mechanism of human superfetation.

In this bioessay, a literature review on human superfetation was performed in order to find epidemiological variables associated with this phenomenon. Thereafter, an explanatory mechanism of superfetation compatible with the endocrinological, histological and physiological changes undergone by women during early pregnancy is proposed. Superfetation can be defined as the ovulation, fertilisation and implantation of a second or additional embryo(s) during pregnancy. The literature review evidences a small discordance in gestational age between dizygotic twins in humans (range: 2-4 weeks; mean ± s.e.m.: 3.3 ± 0.3 weeks). This difference is compatible with a luteal out-of-phase (LOOP; i.e. atypical increase in E2 levels in the mid-luteal phase)-like event occurring between 1 and 3 weeks after the ovulation that allowed the first pregnancy to take place. The LOOP-like event may allow passive sperm transport from the vaginal fornix to the Fallopian tube ipsilateral to the ovulatory ovary and trigger a LH peak and ovulation. Furthermore, during very early pregnancy, the decidual reaction is not yet completed and at least one proximal Fallopian ostium may be opened, allowing the passage of the spermatozoa ascending to the fertilisation site and the extra embryo(s) descending to the implantation site(s).

Nuclear receptor NR5A2 and bone: gene expression and association with bone mineral density.

OBJECTIVE: There is growing evidence for a link between energy and bone metabolism. The nuclear receptor subfamily 5 member A2 (NR5A2) is involved in lipid metabolism and modulates the expression of estrogen-related genes in some tissues. The objective of this study was to explore the influence of NR5A2 on bone cells and to determine whether its allelic variations are associated with bone mineral density (BMD). DESIGN: Analyses of gene expression by quantitative PCR and inhibition of NR5A2 expression by siRNAs were used to explore the effects of NR5A2 in osteoblasts. Femoral neck BMD and 30 single nucleotide polymorphisms (SNPs) were first analyzed in 935 postmenopausal women and the association of NR5A2 genetic variants with BMD was explored in other 1284 women in replication cohorts. RESULTS: NR5A2 was highly expressed in bone. The inhibition of NR5A2 confirmed that it modulates the expression of osteocalcin, osteoprotegerin, and podoplanin in osteoblasts. Two SNPs were associated with BMD in the Spanish discovery cohort (rs6663479, P=0.0014, and rs2816948, P=0.0012). A similar trend was observed in another Spanish cohort, with statistically significant differences across genotypes in the combined analysis (P=0.03). However, the association in a cohort from the United States was rather weak. Electrophoretic mobility assays and studies with luciferase reporter vectors confirmed the existence of differences in the binding of nuclear proteins and the transcriptional activity of rs2816948 alleles. CONCLUSIONS: NR5A2 modulates gene expression in osteoblasts and some allelic variants are associated with bone mass in Spanish postmenopausal women.

Randomized study comparing two tongue base surgeries for moderate to severe obstructive sleep apnea syndrome.

OBJECTIVE: To compare the effectiveness and morbidity of the tongue base radiofrequency and tongue base suspension techniques combined with uvulopalatopharyngoplasty for moderate to severe obstructive sleep apnea. STUDY DESIGN AND SETTING: Prospective and randomized surgical trial at a university hospital. METHODS: In total, 57 patients received either tongue base radiofrequency reduction (n = 29) or tongue base suspension (n = 28). Apnea-hypopnea index, lowest oxygen saturation (polysomnography), Epworth score, and side effects were assessed. Success was defined as a > or =50 percent reduction and final apneahypopnea index < 15/h, and an Epworth score < 11. RESULTS: The success rates of the two procedures were 57.1 percent and 51.7 percent, respectively (P = 0.79), but only 12.5 percent and 10 percent, respectively (P = 0.87), in obese patients. Body mass index (P = 0.0002) was the main predictor of success in a logistic regression analysis. Tongue base suspension demonstrated higher morbidity (P < 0.05). CONCLUSIONS: The effectiveness of tongue base suspension was similar to that of tongue base radiofrequency reduction, although with significantly higher morbidity, for moderate to severe obstructive sleep apnea. The effectiveness of both techniques was lower in obese patients. SIGNIFICANCE: Neither technique should be used in obese patients who have moderate to severe obstructive sleep apnea.

Delayed fatherhood in mice decreases reproductive fitness and longevity of offspring.

This study aims to analyze, in mice, the long-term effects of delayed fatherhood on reproductive fitness and longevity of offspring. Hybrid parental-generation (F(0)) males, at the age of 12, 70, 100, and 120 wk, were individually housed with a randomly selected 12-wk-old hybrid female. The reproductive fitness of first-generation (F(1)) females was tested from the age of 25 wk until the end of their reproductive life. In F(1) males, the testing period ranged from the age of 52 wk until death. Breeding F(1) females from the 120-wk group displayed interbirth intervals longer than females from the 12-, 70-, and 100-wk groups. Furthermore, F(2) pups begotten by F(1) studs exhibited weaning weights lower than pups from the 12- and 70-wk groups. Offspring from the 120-wk group exhibited shorter survival times associated with lower incidence of tumorigenesis and higher loss of body weight when approaching death when compared to F(1) offspring from younger age-groups. The results indicate that advanced paternal age at conception has negative long-term effects on reproductive fitness and longevity of offspring in the mouse model.

Mutations of CD40 ligand in two patients with hyper-IgM syndrome.

Two patients with the X-linked form of the hyper-IgM syndrome have been studied. Both patients present: 1. Mutations in the CD40L gene (a nonsense point mutation that introduces a termination codon at the extracellular domain of the protein, and a deletion that eliminates exon 4 as consequence of an abnormal splicing). 2. Lack of CD40L expression on the lymphocyte surface after stimulation with ionomycin and PMA. 3. Altered lymphocytic proliferation in response to anti-CD3. 4. Hyper IgM, low IgG and IgA levels and neutropenia. One of the patients shows, in addition, low Natural Killer cell numbers and severe herpetic infections, which distinguishes this case from the common hyper-IgM syndrome phenotype. Finally, a hyper-IgM stable phenotype has been immortalized by Herpes virus Saimiri for the first time.