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The adult height of children with early onset puberty is limited by the premature maturation of hypothalamic-pituitary-gonadal axis. To evaluate the effects of gonadotropin-releasing hormone analog (GnRHa) treatment on the final height (FH) and bone maturation rate (BMR) in girls with early puberty (EP) or idiopathic central precocious puberty (ICPP), we examined data from girls who were diagnosed with EP or ICPP and underwent GnRHa (Leuplin Depot: 3.75 mg/month) at China Medical University Hospital, in Taiwan, between 2006 and 2015. Patients were observed until the achievement of FH and divided into an “EP group” (T-ep) and “ICPP group” (T-icpp) according to the age of onset of puberty. Eighty-seven patients were enrolled (T-ep, N = 44, puberty onset at 8–10 years; T-icpp, N = 43, puberty onset before 8 years). The demographic data of girls with EP or IPP was characterized. BMR, change in predicted final height (PFH) after GnRHa treatment, target height (TH) and FH were measured. After GnRHa treatment, the study groups (T-ep: 160.24±6.18 cm, T-icpp: 158.99±5.92 cm) both had higher PFH than at initiation (T-ep: 159.83±7.19 cm, T-icpp: 158.58±5.93 cm). There was deceleration of BMR in both groups (T-ep: 0.57±0.39; T-icpp: 0.97±0.97) and a significant difference between the groups (p = 0.027). The gap in FH standard deviation scores (SDS) and TH SDS had a significant difference in T-ep (p = 0.045) but not in T-icpp. Moreover, there was no difference in the gap of PFH SDS between the 1st and final treatment in both groups. We concluded that GnRHa decelerated BMR in girls with earlier puberty. Further prospective clinical studies are warranted. [ABSTRACT FROM AUTHOR]

Fertility is important to women and men with cancer. While options for fertility preservation (FP) are available, knowledge regarding the medical application of FP is lacking. Therefore we examined FP practices for cancer patients among reproductive endocrinologists (REs). A 36 item survey was sent to board-certified REs. 98% of respondents reported counseling women with cancer about FP options. Oocyte and embryo cryopreservation were universally offered by these providers, but variability was noted in reported management of these cases—particularly for women with breast cancer. 86% of the respondents reported using letrozole during controlled ovarian stimulation (COS) in patients with estrogen receptor positive (ER+) breast cancer to minimize patient exposure to estrogen. 49% of respondents who reported using letrozole in COS for patients with ER+ breast cancer reported that they would also use letrozole in COS for women with ER negative breast cancer. Variability was also noted in the management of FP for men with cancer. 83% of participants reported counseling men about sperm banking with 22% recommending against banking for men previously exposed to chemotherapy. Overall, 79% of respondents reported knowledge of American Society for Clinical Oncology FP guidelines—knowledge that was associated with providers offering gonadal tissue cryopreservation (RR 1.82, 95% CI 1.14–2.90). These findings demonstrate that RE management of FP in cancer patients varies. Although some variability may be dictated by local resources, standardization of FP practices and communication with treating oncologists may help ensure consistent recommendations and outcomes for patients seeking FP. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study is to evaluate factors predictive of outcomes in women with highest follicle-stimulating hormone (FSH) levels ≥12 IU/L on basal testing, undergoing in vitro fertilization (IVF). Methods: A prospective cohort study was conducted at Stanford University Hospital in the Reproductive Endocrinology and Infertility Center for 12 months. Women age 21 to 43 undergoing IVF with highest FSH levels on baseline testing were included. Donor/Recipient and frozen embryo cycles were excluded from this study. Prognostic factors evaluated in association with clinical pregnancy rates were type of infertility diagnosis and IVF stimulation parameters. Results: The current study found that factors associated with clinical pregnancy were: increased number of mature follicles on the day of triggering, number of oocytes retrieved, number of Metaphase II oocytes if intracytoplasmic sperm injection was done, and number of embryos developed 24 hours after retrieval. Conclusions: Our findings suggest that it would be beneficial for women with increased FSH levels to attempt a cycle of IVF. Results of ovarian stimulation, especially embryo quantity appear to be the best predictors of IVF outcomes and those can only be obtained from a cycle of IVF. Therefore, increased basal FSH levels should not discourage women from attempting a cycle of IVF. [ABSTRACT FROM AUTHOR]

Thyroid-stimulating hormone (TSH) is composed of a specific β subunit and an α subunit that is shared with the two pituitary gonadotropins. The three β subunits derive from a common ancestral gene through two genome duplications (1R and 2R) that took place before the radiation of vertebrates. Analysis of genomic data from phylogenetically relevant species allowed us to identify an additional Tshβ subunit-related gene that was generated through 2R. This gene, named Tshβ2, present in cartilaginous fish, little skate and elephant shark, and in early lobe-finned fish, coelacanth and lungfish, was lost in ray-finned fish and tetrapods. The absence of a second type of TSH receptor (Tshr) gene in these species suggests that both TSHs act through the same receptor. A novel Tshβ sister gene, named Tshβ3, was generated through the third genomic duplication (3R) that occurred early in the teleost lineage. Tshβ3 is present in most teleost groups but was lostin tedraodontiforms. The 3R also generated a second Tshr, named Tshrb. Interestingly, the new Tshrb was translocated from its original chromosomic position after the emergence of eels and was then maintained in its new position. Tshrb was lost in tetraodontiforms and in ostariophysians including zebrafish although the latter species have two TSHs, suggesting that TSHRb may be dispensable. The tissue distribution of duplicated Tshβs and Tshrs was studied in the European eel. The endocrine thyrotropic function in the eel would be essentially mediated by the classical Tshβ and Tshra, which are mainly expressed in the pituitary and thyroid, respectively. Tshβ3 and Tshrb showed a similar distribution pattern in the brain, pituitary, ovary and adipose tissue, suggesting a possible paracrine/autocrine mode of action in these non-thyroidal tissues. Further studies will be needed to determine the binding specificity of the two receptors and how these two TSH systems are interrelated. [ABSTRACT FROM AUTHOR]

Early life events induce alterations in neural function in adulthood. Although rearing in an enriched environment (EE) has a great impact on behavioral development, the effects of enriched rearing on sociosexual behavior remain unclear. In this study, we investigated the effects of rearing in an EE on male copulatory behavior and its underlying neurobiological mechanisms in Wistar-Imamichi rats. Three-week-old, recently weaned rats were continuously subjected to a standard environment (SE) or an EE comprised of a large cage with several objects, such as toys, tunnels, ladders, and a running wheel. After 6 weeks, rats reared in an EE (EE rats) showed decreased sexual activity compared with rats reared in a SE (SE rats). This included a lower number of ejaculations and longer latencies in three consecutive copulatory tests. In addition, EE rats showed decreased emotional responsiveness and less locomotor behavior in an open field. In a runway test, on the other hand, sexual motivation toward receptive females in EE males was comparable to that of SE males. Furthermore, following exposure to a female, increases in serotonin levels in the nucleus accumbens and the striatum were significantly suppressed in EE males, whereas dopaminergic responses were similar between the groups. Female-exposure-induced increases in the levels of plasma corticosterone and testosterone were also suppressed in EE rats compared to SE rats. These data suggest that rearing in an EE decreases male copulatory behavior, and serotonin and hormonal regulating systems may regulate the differences in sociosexual interactions that result from distinct rearing environments. [ABSTRACT FROM AUTHOR]

Introduction: Polycystic Ovary Syndrome (PCOS) has a strong genetic background and the majority of patients with PCOS have elevated BMI levels. The aim of this study was to determine to which extent BMI-increasing alleles contribute to risk of PCOS when contemporaneous BMI is taken into consideration. Methods: Patients with PCOS and controls were recruited from the United Kingdom (563 cases and 791 controls) and The Netherlands (510 cases and 2720 controls). Cases and controls were of similar BMI. SNPs mapping to 12 BMI-associated loci which have been extensively replicated across different ethnicities, i.e., BDNF, FAIM2, ETV5, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18, were studied in association with PCOS within each cohort using the additive genetic model followed by a combined analysis. A genetic allelic count risk score model was used to determine the risk of PCOS for individuals carrying increasing numbers of BMI-increasing alleles. Results: None of the genetic variants, including FTO and MC4R, was associated with PCOS independently of BMI in the meta-analysis. Moreover, no differences were observed between cases and controls in the number of BMI-risk alleles present and no overall trend across the risk score groups was observed. Conclusion: In this combined analysis of over 4,000 BMI-matched individuals from the United Kingdom and the Netherlands, we observed no association of BMI risk alleles with PCOS independent of BMI. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is an idiopathic multisystem disease affecting 5–7% of pregnant women. Placental oxidative stress is a characteristic feature of PE and occurs when the production of reactive oxygen species (ROS) within the placenta overwhelms the intrinsic anti-oxidant defenses. We hypothesize that excessive oxidative DNA damage at the fetal-maternal interface coupled with a defective DNA damage/repair response is causally related to PE. Here we demonstrate that γH2AX (a sensitive marker of DNA damage) is expressed in the maternal decidua but not trophoblast of normal placentas, and that expression is significantly higher in PE placental tissues in vivo. Using primary in vitro cultures of maternal decidual stromal cells (DSCs) and fetal cytotrophoblast cells (CTs), we show an increase in γH2AX foci in DSCs cultured with vs without H2O2 (70.6% vs 11.6%; P<0.0001) or under hypoxia-reperfusion vs normoxia (20- vs 3-fold; P = 0.01); no foci were seen in CTs. We further demonstrate that Base Excision Repair (BER) intermediates are significantly increased in DSCs (not CTs) under these same conditions. Our data show that DNA damage is significantly more common in PE placentas, and that this DNA damage is localized to the maternal and not fetal side of the placenta. CTs may be selectively resistant to DNA damage in an effort to protect the fetus. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies have evaluated the association between 3801T>C polymorphism of CYP1A1 gene and the risk for idiopathic male infertility, but the results are inconclusive. We aimed to derive a more precise estimation of the relationship by conducting a meta-analysis of case-control studies. Methods: This study conformed to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase and CNKI databases were searched through November 2013 to identify relevant studies. Pooled odds ratios with 95% confidence intervals were used to assess the strength of the association between CYP1A1 3801T>C polymorphism and idiopathic male infertility risk. Q-test was performed to evaluate between-study heterogeneity and publication bias was appraised using funnel plots. Sensitivity analyses were conducted to evaluate the robustness of meta-analysis findings. Results: Six studies involving 1,060 cases and 1,225 controls were included in this meta-analysis. Overall, significant associations between 3801T>C polymorphism and idiopathic male infertility risk were observed in allelic comparison (OR = 1.36, 95% CI: 1.01–1.83), homozygous model (OR = 2.18, 95% CI: 1.15–4.12), and recessive model (OR = 1.86, 95% CI: 1.09–3.20), with robust findings according to sensitivity analyses. However, subgroup analyses did not further identify the susceptibility to idiopathic male infertility in all comparisons. Funnel plot inspections did not reveal evidence of publication bias. Conclusions: The current meta-analysis provides evidence of a significant association between CYP1A1 3801T>C polymorphism and idiopathic male infertility risk. Considering the limitation inherited from the eligible studies, further confirmation in large-scale and well-designed studies is needed. [ABSTRACT FROM AUTHOR]

Vascular remodeling in the placenta is essential for normal fetal development. The previous studies have demonstrated that in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an environmental toxicant) induces the intrauterine fetal death in many species via the activation of aryl hydrocarbon receptor (AhR). In the current study, we compared the effects of 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and TCDD on the vascular remodeling of rat placentas. Pregnant rats on gestational day (GD) 15 were randomly assigned into 5 groups, and were exposed to a single dose of 1.6 and 8.0 mg/kg body weight (bw) ITE, 1.6 and 8.0 µg/kg bw TCDD, or an equivalent volume of the vehicle, respectively. The dams were sacrificed on GD20 and the placental tissues were gathered. The intrauterine fetal death was observed only in 8.0 µg/kg bw TCDD-exposed group and no significant difference was seen in either the placental weight or the fetal weight among all these groups. The immunohistochemical and histological analyses revealed that as compared with the vehicle-control, TCDD, but not ITE, suppressed the placental vascular remodeling, including reduced the ratio of the placental labyrinth zone to the basal zone thickness (at least 0.71 fold of control), inhibited the maternal sinusoids dilation and thickened the trophoblastic septa. However, no marked difference was observed in the density of fetal capillaries in the labyrinth zone among these groups, although significant differences were detected in the expression of angiogenic growth factors between ITE and TCDD-exposed groups, especially Angiopoietin-2 (Ang-2), Endoglin, Interferon-γ (IFN-γ) and placenta growth factor (PIGF). These results suggest ITE and TCDD differentially regulate the vascular remodeling of rat placentas, as well as the expression of angiogenic factors and their receptors, which in turn may alter the blood flow in the late gestation and partially resulted in intrauterine fetal death. [ABSTRACT FROM AUTHOR]

Objective: Determine whether testicular sperm extractions and pregnancy outcomes are influenced by male and female infertility diagnoses, location of surgical center and time to cryopreservation. Patients: One hundred and thirty men undergoing testicular sperm extraction and 76 couples undergoing 123 in vitro fertilization cycles with testicular sperm. Outcome Measures: Successful sperm recovery defined as 1–2 sperm/0.5 mL by diagnosis including obstructive azoospermia (n = 60), non-obstructive azoospermia (n = 39), cancer (n = 14), paralysis (n = 7) and other (n = 10). Obstructive azoospermia was analyzed as congenital absence of the vas deferens (n = 22), vasectomy or failed vasectomy reversal (n = 37) and “other”(n = 1). Sperm recovery was also evaluated by surgical site including infertility clinic (n = 54), hospital operating room (n = 67) and physician’s office (n = 11). Treatment cycles were evaluated for number of oocytes, fertilization, embryo quality, implantation rate and clinical/ongoing pregnancies as related to male diagnosis, female diagnosis, and use of fresh or cryopreserved testicular sperm. Results: Testicular sperm recovery from azoospermic males with all diagnoses was high (70 to 100%) except non-obstructive azoospermia (31%) and was not influenced by distance from surgical center to laboratory. Following in vitro fertilization, rate of fertilization was significantly lower with non-obstructive azoospermia (43%, p = <0.0001) compared to other male diagnoses (66%, p = <0.0001, 59% p = 0.015). No differences were noted in clinical pregnancy rate by male diagnosis; however, the delivery rate per cycle was significantly higher with obstructive azoospermia (38% p = 0.0371) compared to diagnoses of cancer, paralysis or other (16.7%). Women diagnosed with diminished ovarian reserve had a reduced clinical pregnancy rate (7.4% p = 0.007) compared to those with other diagnoses (44%). Conclusion: Testicular sperm extraction is a safe and effective option regardless of the etiology of the azoospermia. The type of surgical center and/or its distance from the laboratory was not related to success. Men with non-obstructive azoospermia have a lower chance of successful sperm retrieval and fertilization. [ABSTRACT FROM AUTHOR]

Background: 46,XY disorders of sex development (46,XY DSD) are genetically heterogeneous conditions. Recently, a few submicroscopic genomic rearrangements have been reported as novel genetic causes of 46,XY DSD. Methodology/Principal Findings: To clarify the role of cryptic rearrangements in the development of 46,XY DSD, we performed array-based comparative genomic hybridization analysis for 24 genetic males with genital abnormalities. Heterozygous submicroscopic deletions were identified in three cases (cases 1–3). A ∼8.5 Mb terminal deletion at 9p24.1–24.3 was detected in case 1 that presented with complete female-type external genitalia and mental retardation; a ∼2.0 Mb interstitial deletion at 20p13 was identified in case 2 with ambiguous external genitalia and short stature; and a ∼18.0 Mb interstitial deletion at 2q31.1–32 was found in case 3 with ambiguous external genitalia, mental retardation and multiple anomalies. The genital abnormalities of case 1 could be ascribed to gonadal dysgenesis caused by haploinsufficiency of DMRT1, while those of case 3 were possibly associated with perturbed organogenesis due to a deletion of the HOXD cluster. The deletion in case 2 affected 36 genes, none of which have been previously implicated in sex development. Conclusions/Significance: The results indicate that cryptic genomic rearrangements constitute an important part of the molecular bases of 46,XY DSD and that submicroscopic deletions can lead to various types of 46,XY DSD that occur as components of contiguous gene deletion syndromes. Most importantly, our data provide a novel candidate locus for 46,XY DSD at 20p13. [ABSTRACT FROM AUTHOR]

Background: Studies relating long-term exposure to persistent organochlorine pollutants (POPs) with endocrine activities (endocrine disrupting chemicals) on circulating levels of steroid hormones have been limited to a small number of hormones and reported conflicting results. Objective: We examined the relationship between serum concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulphate, androstenedione, androstenediol, testosterone, free and bioavailable testosterone, dihydrotestosterone, estrone, estrone sulphate, estradiol, sex-hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone as a function of level of exposure to three POPs known to interfere with hormone-regulated processes in different way: dichlorodiphenyl dichloroethene (DDE), polychlorinated biphenyl (PCB) congener 153, and chlordecone. Methods: We collected fasting, morning serum samples from 277 healthy, non obese, middle-aged men from the French West Indies. Steroid hormones were determined by gas chromatography-mass spectrometry, except for dehydroepiandrosterone sulphate, which was determined by immunological assay, as were the concentrations of sex-hormone binding globulin, follicle-stimulating hormone and luteinizing hormone. Associations were assessed by multiple linear regression analysis, controlling for confounding factors, in a backward elimination procedure, in multiple bootstrap samples. Results: DDE exposure was negatively associated to dihydrotestosterone level and positively associated to luteinizing hormone level. PCB 153 was positively associated to androstenedione and estrone levels. No association was found for chlordecone. Conclusions: These results suggested that the endocrine response pattern, estimated by determining blood levels of steroid hormones, varies depending on the POPs studied, possibly reflecting differences in the modes of action generally attributed to these compounds. It remains to be investigated whether this response pattern is predictive of the subsequent occurrence of disease. [ABSTRACT FROM AUTHOR]

Infant cuteness can influence adult-infant interaction and has been shown to activate reward centres in the brain. In a previous study, we found men and women to be differentially sensitive to small differences in infant facial cuteness, with reproductive hormone status as the potential underlying cause. It is unclear, however, whether reproductive hormone status impacts on the aesthetic and incentive salience of infant faces. To address this question, we conducted two interlinked studies. We used static images of the same smiling and neutral-looking infant faces in both a rating task, in which participants had to rate the cuteness of infant faces (aesthetic salience - ‘liking’), and a key-press task, in which participants could prolong or shorten viewing time of infant faces by rapid alternating key-presses (incentive salience - ‘wanting’). In a first study, we compared the performance of men, women who are taking oral contraceptives, and regularly cycling women. In this study, we found a significant correlation between cuteness ratings within and between groups, which implies that participants had the same concept of cuteness. Cuteness ratings and effort to look at faces was linked regardless of sex and reproductive hormone status, in that cute faces were looked at for longer than less cute faces. A happy facial expression contributed only marginally to the incentive salience of the face. To explore the potential impact of reproductive hormone status in more detail, we followed a subset of regularly cycling women during the menstrual, follicular and luteal phases of their cycle. The aesthetic and incentive salience of infant faces did not change across the menstrual cycle. Our findings suggest that reproductive hormone status does not modulate the aesthetic and incentive value of infant faces. [ABSTRACT FROM AUTHOR]

Background: Ovarian processes and the timing of ovulation are important predictors of both female fertility and reproductive pathology. Multiple waves of antral follicular development have been documented during the menstrual cycle in women. However, the mechanisms underlying the development of follicular waves and their clinical significance are not fully understood. The objective of this study was to examine the relationship between C-reactive protein (CRP) and follicular waves in healthy women. We wanted to determine whether follicular wave dynamics influence systemic inflammation, as ovarian activity increases local inflammatory processes and blood flow. We tested the hypothesis that women with 3 follicular waves would have higher CRP concentrations than those with 2 waves. We further hypothesized that a greater number of major waves (those with a dominant follicle) would be positively associated with CRP. Methods/Principal Findings: Thirty-nine healthy women underwent daily transvaginal ultrasound examinations for one interovulatory interval, as part of an earlier study. Serum was collected every 3 days during the interovulatory interval (IOI). Enzyme-linked immunosorbent assays were conducted to quantify serum CRP concentrations. Women with 3 waves had higher average log CRP concentrations (n = 14, −0.43±0.35) over the IOI than those with 2 waves (n = 25, −0.82±0.47, p = 02). Average log CRP concentrations were greater in women with 3 (0.30±0.31) versus 1 (−0.71±0.55) or 2 (−0.91±0.47) major waves (p = 0.03). Greater average CRP over the IOI was attributed to greater CRP in the follicular, but not the luteal phase, of the IOI. Conclusions/Significance: A greater number of total antral follicular waves, in particular major waves, corresponded to greater serum concentrations of CRP. These findings suggest that women with a greater number of follicular waves exhibit greater tissue remodeling and therefore greater local and systemic inflammation. [ABSTRACT FROM AUTHOR]

The basic component of Silastic® glue (Dow Corning) used to prepare Silastic® pellets is polydimethylsiloxane. This compound is also present in other commercial adhesives such as FASTIX® (Akapol SA) that are available in any store for that category. In the present study we developed low cost, easy to prepare handmade steroid pellets (HMSP) by mixing 17β-estradiol, progesterone or other synthetic steroids with FASTIX® adhesive. We assessed serum levels of 17β-estradiol, progesterone, prolactin and luteinizing hormone in ovariectomized mice treated for 24 and 48 h or 7, 14 and 28 days with 20 µg or 5 mg of 17β-estradiol or 5 mg progesterone HMSP. We found a time dependent and significant increase in the levels of both natural hormones, and a downregulation of serum luteinizing hormone levels, while both 17β-estradiol doses increased serum prolactin. Uterine weights at sacrifice and histological examination of the uteri and the mammary glands correlated with estrogen or progestin action. Finally, we evaluated the biological effects of HMSP compared to commercial pellets or daily injections in the stimulation or inhibition of hormone dependent mammary tumor growth, and found that HMSP were as effective as the other methods of hormone administration. These data show that HMSP represent a useful, low cost, easily accessible method for administering steroids to mice. [ABSTRACT FROM AUTHOR]

Recent studies have established that masculinization of the male reproductive tract is programmed by androgens in a critical fetal ‘masculinization programming window’ (MPW). What is peculiar to androgen action during this period is, however, unknown. Studies from 20 years ago in mice implicated prostaglandin (PG)-mediation of androgen-induced masculinization, but this has never been followed up. We therefore investigated if PGs might mediate androgen effects in the MPW by exposing pregnant rats to indomethacin (which blocks PG production by inhibiting cyclooxygenase activity) during this period and then examining if androgen production or action (masculinization) was affected. Pregnant rats were treated with indomethacin (0.8 mg/kg/day; e15.5–e18.5) to encompass the MPW. Indomethacin exposure decreased fetal bodyweight (e21.5), testis weight (e21.5) and testicular PGE2 (e17.5, e21.5), but had no effect on intratesticular testosterone (ITT; e17.5) or anogenital index (AGI; e21.5). Postnatally, AGI, testis weight and blood testosterone were unaffected by indomethacin exposure and no cryptorchidism or hypospadias occurred. Penis length was normal in indomethacin-exposed animals at Pnd25 but was reduced by 26% (p<0.001) in adulthood, an effect that is unexplained. Our results demonstrate that indomethacin can effectively decrease intra-testicular PGE2 level. However, the resulting male phenotype does not support a role for PGs in mediating androgen-induced masculinization during the MPW in rats. The contrast with previous mouse studies is unexplained but may reflect a species difference. [ABSTRACT FROM AUTHOR]

The mechanical method to isolate preantral follicle has been reported for many years. However, the culture systems in vitro are still unstable. The aim of this study was to analyze the effect of the culture system of mice preantral follicles on the follicular development in vitro. The results showed that the 96-well plate system was the most effective method for mice follicle development in vitro (volume change: 51.71%; survival rate: 89%, at day 4). Follicle-stimulating hormone (FSH) and Thyroid hormone (TH) are important for normal follicular development and dysregulation of hormones are related with impaired follicular development. To determine the effect of hormone on preantral follicular development, we cultured follicle with hormones in the 96-well plate culture system and found that FSH significantly increased preantral follicular growth on day 4. The FSH-induced growth action was markedly enhanced by T3 although T3 was ineffective alone. We also demonstrated by QRT-PCR that T3 significantly enhanced FSH-induced up-regulation of Xiap mRNA level. Meanwhile, Bad, cell death inducer, was markedly down-regulated by the combination of hormones. Moreover, QRT-PCR results were also consistent with protein regulation which detected by Western Blotting analysis. Taken together, the findings of the present study demonstrate that 96-well plate system is an effective method for preantral follicle development in vitro. Moreover, these results provide insights on the role of thyroid hormone in increasing FSH-induced preantral follicular development, which mediated by up-regulating Xiap and down-regulating Bad. [ABSTRACT FROM AUTHOR]

In mammals, carcinoembryonic antigen cell adhesion molecules (CEACAMs) and pregnancy-specific glycoproteins (PSGs) play important roles in the regulation of pathogen transmission, tumorigenesis, insulin signaling turnover, and fetal–maternal interactions. However, how these genes evolved and to what extent they diverged in humans remain to be investigated specifically. Based on syntenic mapping of chordate genomes, we reveal that diverging homologs with a prototypic CEACAM architecture–including an extracellular domain with immunoglobulin variable and constant domain-like regions, and an intracellular domain containing ITAM motif–are present from cartilaginous fish to humans, but are absent in sea lamprey, cephalochordate or urochordate. Interestingly, the CEACAM/PSG gene inventory underwent radical divergence in various vertebrate lineages: from zero in avian species to dozens in therian mammals. In addition, analyses of genetic variations in human populations showed the presence of various types of copy number variations (CNVs) at the CEACAM/PSG locus. These copy number polymorphisms have 3–80% frequency in select populations, and encompass single to more than six PSG genes. Furthermore, we found that CEACAM/PSG genes contain a significantly higher density of nonsynonymous single nucleotide polymorphism (SNP) compared to the chromosome average, and many CEACAM/PSG SNPs exhibit high population differentiation. Taken together, our study suggested that CEACAM/PSG genes have had a more dynamic evolutionary history in vertebrates than previously thought. Given that CEACAM/PSGs play important roles in maternal–fetal interaction and pathogen recognition, these data have laid the groundwork for future analysis of adaptive CEACAM/PSG genotype-phenotypic relationships in normal and complicated pregnancies as well as other etiologies. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between sex hormones and the risk of vascular disease in elderly men and to evaluate the advantages and disadvantages of testosterone replacement. Methods: A total of 337 men, aged 60 to 91 years, were enrolled in this single-center, cross-sectional study, and their sex hormone levels were assessed. Linear and logistic regression analyses were utilized to compare the sex hormone levels between patients with and without vascular disease. The nonparametric K-sample test was used for inter-group comparisons. Results: Aging and abnormal metabolism were both significantly associated with an increased risk of vascular diseases and changes in sex hormone levels. Primary linear and logistic regression analyses showed no significant differences in sex hormone concentrations between patients with and without vascular diseases after adjusting for age. Logistic regression with abnormal metabolism as categorical variable showed that free testosterone (FT) and free estradiol (FE2) had significant relationships with CEVD risk (P<0.05). In further regression with all metabolic continuous variables included, the testosterone/estradiol (T/E2) ratio replaced FT and FE2 (P<0.05). Trend line analyses showed that T/E2 actually had a binomial linear correlation with the risk of cerebrovascular disease; its best protective effect occurred at values of 0.13–0.15, with an OR value extremely close to those of FT and FE2 (0.23 vs. 0.24–0.25). Conclusion: T/E2 balance plays a key role in the relationship between sex hormones and the risk of cerebrovascular disease. The balance between T and E2 may be more important than their absolute quantities. Extremely low T/E2 and inappropriately high T/E2 ratio can both harm the brain blood vessels. Careful consideration should be given before beginning testosterone replacement treatment, and supplementing with estrogen seems to be a good way to protect blood vessels of the brain in elderly men. [ABSTRACT FROM AUTHOR]

Objective: Low grade systemic inflammation (LGSI) as well as androgen deficiency has in older men been associated with several pathologies, including cardiovascular disease (CVD). We wanted to investigate whether low testosterone levels are linked to biomarkers of LGSI already in young age, before any concurrent manifestations of CVD or other systemic diseases. Design: Nested cross-sectional study. Methods: Forty subfertile biochemically hypogonadal (n = 20) or eugonadal (n = 20) men (mean age 37 years, SD = 4.3) and 20 age-matched controls were randomly selected from an ongoing study on male subfertility. Subjects comprised male partners in infertile couples in whom also subnormal sperm concentration was present. Blood sampling, interviews, and anthropometric measures were undertaken. Serum levels of testosterone, LH, estradiol, SHBG, and 21 LGSI-markers were assessed. Results: Among 21 inflammatory markers, macrophage inflammatory protein 1-alpha (MIP1a) (ß = −0.025; p = 0.028), 1-beta (MIP1B) (ß = −0.015; p = 0.049) and tumor necrosis factor alpha (TNFa) (ß = −0.015; p = 0.040) showed negative association to total testosterone (TT) levels. MIP1a (ß = −1.95; p = 0.001) and TNFa (ß = −0.95; p = 0.014) showed negative association to calculated free testosterone (cFT) levels. Compared to men with normal TT and cFT levels, TNFa levels were higher in men with subnormal levels of TT (mean ratio 1.61; p = 0.006) and cFT (mean ratio 1.58; p = 0.007). Also, MIP1a levels were higher in men with subnormal levels of TT (mean ratio 1.84; p = 0.030). Conclusions: Subnormal testosterone may already in young age associate to LGSI, which might be a part of the mechanism underlying adverse health outcomes of male hypogonadism. [ABSTRACT FROM AUTHOR]

Cumulus cell (CC) gene expression is being explored as an additional method to morphological scoring to choose the embryo with the highest chance to pregnancy. In 47 ICSI patients with single embryo transfer (SET), from which individual CC samples had been stored, 12 genes using QPCR were retrospectively analyzed. The CC samples were at the same occasion also used to validate a previously obtained pregnancy prediction model comprising three genes (ephrin-B2 (EFNB2), calcium/calmodulin-dependent protein kinase ID, stanniocalcin 1). Latter validation yielded a correct pregnant/non-pregnant classification in 72% of the samples. Subsequently, 9 new genes were analyzed on the same samples and new prediction models were built. Out of the 12 genes analyzed a combination of the best predictive genes was obtained by stepwise multiple regression. One model retained EFNB2 in combination with glutathione S-transferase alpha 3 and 4, progesterone receptor and glutathione peroxidase 3, resulting in 93% correct predictions when 3 patient and treatment cycle characteristics were included into the model. This large patient group allowed to do an intra-patient analysis for 7 patients, an analysis mimicking the methodology that would ultimately be used in clinical routine. CC related to a SET that did not give pregnancy and CC related to their subsequent frozen/thawed embryos which ended in pregnancy were analyzed. The models obtained in the between-patient analysis were used to rank the oocytes within-patients for their chance to pregnancy and resulted in 86% of correct predictions. In conclusion, prediction models built on selected quantified transcripts in CC might help in the decision making process which is currently only based on subjective embryo morphology scoring. The validity of our current models for routine application still need prospective assessment in a larger and more diverse patient population allowing intra-patient analysis. [ABSTRACT FROM AUTHOR]

Background: While it is established that vertebrate-like steroids, particularly estrogens (estradiol, estrone) and androgens (testosterone), are present in various tissues of molluscs, it is still unclear what role these play in reproductive endocrinology in such organisms. This is despite the significant commercial shellfishery interest in several bivalve species and their decline. Methodology/Principal Findings: Using suppression subtraction hybridisation of mussel gonad samples at two stages (early and mature) of gametogenesis and (in parallel) following controlled laboratory estrogen exposure, we isolate several differentially regulated genes including testis-specific kinases, vitelline lysin and envelope sequences. Conclusions: The differentially expressed mRNAs isolated provide evidence that mussels may be impacted by exogenous estrogen exposure. [ABSTRACT FROM AUTHOR]