Study on the value of Inhibin B in the diagnosis of nasopharyngeal carcinoma and its correlation with traditional Chinese medicine syndromes: An observational study.

To investigate the expression of Inhibin B between various clinical stages, Chinese medicine dialectic typing, and in nasopharyngeal carcinoma (NPC) tissues and serum, and to evaluate the potential of Inhibin B as a new biomarker for NPC. Paraffin specimens of pathologically confirmed NPC tissues and paracancerous tissues were retrospectively collected, and the expression of Inhibin α (INHA) and Inhibin ßB (INHBB) was detected by SP method, and their relationship with clinicopathological indexes was analyzed; in addition, patients with NPC who had received radiotherapy were included as the study subjects, and Epstein-Barr virus DNA (EBV-DNA), INHA, and INHBB in patients were detected by using the fluorescence quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and chemiluminescent immuno-sandwiching method, respectively. EBV-DNA, EBV-viral capsid antigen-immunoglobulin A (VCA IgA), INHA, and INHBB were detected in the patients, respectively, and their relationships with traditional Chinese medicine (TCM) patterns were also analyzed. The expression of INHA and INHBB in NPC tissues was lower than that in paracancerous tissues, and the expression of INHA in NPC patients was correlated with lymphatic metastasis, clinical staging, and TCM staging; the levels of EBV-DNA and VCA IgA were higher than that of healthy populations in NPC patients and were higher than that of patients with stage III + IV than that of patients with stage I + II, and the levels of INHA and INHBB were lower than those of healthy populations and were lower than those of patients with stage III + IV than that of patients with stage I + II. The levels of INHA and INHBB in nasopharyngeal cancer patients were lower than those in healthy people, and the levels in stage III + IV patients were lower than those in stage I + II patients. The levels of EBV-DNA and VCA IgA in nasopharyngeal cancer patients were correlated with the Chinese medicine patterns, and had different patterns. The expression of Inhibin B may be related to the progression of NPC, and it has certain typing significance for different TCM syndromes of NPC, which is helpful for TCM typing diagnosis.

Potential of Activin B as a Clinical Biomarker in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Reliable serum biomarkers are of immense need for diagnostic purposes of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-a disabling and complex disease for which diagnosis is mainly based on clinical symptoms. The aim of this study was to evaluate a possible diagnostic potential of activin B by directly comparing 134 cases of ME/CFS with 54 healthy controls. Analyses of human activin B level in plasma samples were performed using a validated human activin B ELISA assay. The results of the study show that activin B levels did not differ statistically significantly between ME/CFS patients and healthy controls (p = 0.6511). No gender or age-related differences in activin B levels were observed in the ME/CFS group and healthy controls. The level of activin B tended to decrease with increasing visual analogue scale score (r = -0.2004; p = 0.5085) nevertheless the results obtained so far does not support the clinical utility of activin B as a biomarker for ME/CFS.

Identification of genomic imbalances (CNVs as well as LOH) in sertoli cell only syndrome cases through cytoscan microarray.

Sertoli cell only syndrome (SCOS) is characterized by complete absence of germ cells in seminiferous tubules of testis. SCOS is multifactorial but genetic factors play a major role in pathogenesis of the disorder with idiopathic origin. Genetic factors majorly include sex chromosomal aneuploidy and Yq Microdeletion. But a large number of cases are still idiopathic. The study aimed to evaluate the genomic imbalances (CNVs and LOH) in idiopathic SCOS patients. The study is based on 28 apparent idiopathic SCOS cases and 10 controls. Molecular cytogenetic techniques viz., FISH, STS-Multiplex PCR and Affymetrix cytoscan microarray (750 K) were used. The microarray screened whole genomic imbalances in DNA from peripheral blood of 25 cases (excluded Klinefelter syndrome patients) and testicular FNAC sample of 2 cases. High FSH and low Inhibin B were observed in cases as compared to control controls groups. Four cases of sex chromosomal abnormality (i.e., three non-mosaic 47, XXY males and one non-mosaic 46, XX male) as well as four cases of Yq microdeletion (i.e., three cases with AZFc deletion and one case with complete AZFa, b and c deletion) were identified. Microarray detected unbalanced translocation of two segments of Y-chromosome i.e., Yp11.31-p11.2 (~4.o mb region, involving SRY) and Yp11.2 (~2.5 mb region) on X-chromosome in XX male. Also, loss of segment on same X-chromosome involving PAR1 region was identified. We have identified both autosomal and sex chromosomal CNVs (recurrent as well as private) involving candidate genes like SYCE1, ZFPM2, SRPK1, DAZ1, BPY2, HSFY1, VCY1 etc. All these CNVs are possibly associated with SCOS pathogenesis. CNVs identified in cases were already reported as pathogenic variant in clinical database DECIPHER. Microarray also detected many LOH (all autosomal, >3.0 mb size) that covered genes with spermatogenesis related function. The mechanism of action of LOH in pathogenesis of SCOS still remains unravelled. CNVs and LOH related to spermatogenesis identified from two different sample types (blood vs. testicular tissue) were discordant. This study should be extended for larger cohort of patients.

FSH-stimulated Inhibin B (FSH-iB): A Novel Marker for the Accurate Prediction of Pubertal Outcome in Delayed Puberty.

BACKGROUND: Clinicians have long been struggling to find an effective tool to predict onset of puberty. OBJECTIVE: To explore stimulability of inhibin B after exogenous FSH and its potential role for prediction of onset of puberty. DESIGN AND PARTICIPANTS: Study subjects were enrolled into "exploratory cohort" (n = 42) and "validation cohort" (n = 19). The exploratory cohort was further divided into group 1 (healthy children with spontaneous puberty [SP], n = 26) and group 2 (patients with hypogonadotropic hypogonadism [HH], n = 16). The validation cohort included children who presented with complaints of delayed puberty. INTERVENTION AND OUTCOME: Participants were subjected to FSH stimulation test and GnRH analogue stimulation test. Cutoffs derived from the exploratory cohort for basal and FSH stimulated inhibin B (FSH-iB) were applied on the validation cohort. Basal LH, GnRH analogue-stimulated LH, basal inhibin B, and FSH-iB were compared with clinical outcomes on a prospective follow-up for prediction of onset of puberty. RESULTS: There was statistically significant increment in inhibin B after exogenous FSH in group 1 (SP) in both male (188.8 pg/mL; P = 0.002) and female (1065 pg/mL; P = 0.023) subjects. The increment was not statistically significant in group 2 (HH) in both sexes. FSH-iB at a cutoff of 116.14 pg/mL in males and 116.50 pg/mL in females had 100% sensitivity and specificity for labelling entry into puberty. On application of these cutoffs on the validation cohort, FSH-iB had 100% positive predictive value, negative predictive value, and diagnostic accuracy for prediction of pubertal onset. CONCLUSION: Inhibin B was stimulable in both male and female subjects. FSH-iB can be considered a novel and promising investigation for prediction of onset of puberty. Future studies are required for further validation.

The impact of metabolically healthy obesity in primary infertile men: Results from a cross-sectional study.

BACKGROUND: A number of studies showed that obesity may negatively impact on sperm quality and consequently couple's fertility. Recently, specific attention was given to a clinical condition known as metabolically healthy obesity (MHO). OBJECTIVES: To evaluate the effects of MHO on semen and hormonal parameters of men presenting for primary couple's infertility associated with pure male factor infertility (MFI). MATERIALS AND METHODS: Data from a homogenous cohort of 512 white-European primary infertile men belonging to couples with pure MFI have been cross-sectionally analyzed. Semen analysis was based on 2010 WHO reference criteria. Patients were segregated into eugonadal, secondary hypogonadal, primary hypogonadal, and compensated hypogonadal. The Harmonized International Diabetes Federation criteria were used to define metabolic syndrome (MetS). Based on BMI and MetS, patients were further segregated into the following: (a) metabolically healthy non-obese (MHNO); (b) metabolically unhealthy non-obese (MUNO) (c) metabolically healthy obesity (MHO); and, (d) metabolically unhealthy obesity (MUHO). Main outcome measures were the prevalence of MHO and the impact of MHO on semen and hormonal parameters in this cohort of MFI primary infertile men. RESULTS: Overall, MHNO, MUNO, MHO, and MUHO were found in 462 (90%), 13 (2.5%), 27 (5.2%), and 10 (1.9%) men, respectively. MHO patients had lower total testosterone and SHBG levels (all P < .05) but higher E2 values (P < .005) compared with MHNO men. Groups did not differ in terms of semen parameters. At multivariable logistic regression, analysis MHO was associated with an increased risk of primary and secondary hypogonadism (all P ≤ .02) compared with MHNO, after accounting for age and comorbid conditions. DISCUSSION AND CONCLUSIONS: Metabolically healthy obesity is threefold more prevalent than unhealthy obesity in primary infertile men. Despite semen parameters are comparable among groups, MHO patients show worse endocrine parameters and a higher risk of primary and secondary hypogonadism compared with metabolically healthy normal infertile men.

Short-term treatment with high dose liraglutide improves lipid and lipoprotein profile and changes hormonal mediators of lipid metabolism in obese patients with no overt type 2 diabetes mellitus: a randomized, placebo-controlled, cross-over, double-blind clinical trial.

OBJECTIVE: Long-term treatment with up to 1.8 mg liraglutide improves cardiovascular and all-cause mortality in patients with type 2 diabetes at high risk for cardiovascular disease (CVD) and is currently under investigation in subjects without diabetes. Aim of our study was to investigate whether high dose (3 mg) short-term (5 weeks) treatment with liraglutide in obese patients with no overt type 2 diabetes affects metabolites, lipid and lipoprotein profile and components of activin-follistatin axis in cardiovascular beneficial or detrimental way. RESEARCH DESIGN AND METHODS: Twenty obese patients participated in a randomized, placebo-controlled, cross-over, double-blind study and were administrated liraglutide 3 mg or placebo for 5 weeks. Metabolites, fatty acids, lipid-lipoprotein profile and concentrations of activins and follistatins (250 parameters) were assessed in serum at start and completion of each treatment. RESULTS: Concentrations of important cardiovascular markers such as total, free and remnant cholesterol were reduced with liraglutide before and after adjusting for weight loss. Similarly, reductions in number of small and medium size LDL particles and in their total lipid concentration were observed with liraglutide and partially weight-loss related. Tyrosine levels were reduced and behenic acid levels were increased whereas only minor changes were observed in HDL, VLDL and IDL. Concentrations of activin AB and follistatin were significantly reduced in liraglutide-treated group. CONCLUSIONS: Treatment of obese patients without overt type 2 diabetes with high dose of liraglutide for a short period of time induces changes in lipid-lipoprotein and hormonal profile that are suggestive of lower risk of atherosclerosis and CVD. Trial registration ClinicalTrials.gov Identifier: NCT02944500. Study ID Number 2015P000327. Registered November 2016.

Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle.

BACKGROUND: Skeletal muscle wasting is often associated with insulin resistance. A major regulator of muscle mass is the transforming growth factor ß (TGF-ß) superfamily, including activin A, which causes atrophy. TGF-ß superfamily ligands also negatively regulate insulin-sensitive proteins, but whether this pathway contributes to insulin action remains to be determined. METHODS: To elucidate if TGF-ß superfamily ligands regulate insulin action, we used an adeno-associated virus gene editing approach to overexpress an activin A inhibitor, follistatin (Fst288), in mouse muscle of lean and diet-induced obese mice. We determined basal and insulin-stimulated 2-deoxy-glucose uptake using isotopic tracers in vivo. Furthermore, to evaluate whether circulating Fst and activin A concentrations are associated with obesity, insulin resistance, and weight loss in humans, we analysed serum from morbidly obese subjects before, 1 week, and 1 year after Roux-en-Y gastric bypass (RYGB). RESULTS: Fst288 muscle overexpression markedly increased in vivo insulin-stimulated (but not basal) glucose uptake (+75%, P < 0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, pyruvate dehydrogenase-E1α, and p70S6K, while decreasing TBC1D1 signaling (P < 0.05). Fst288 increased both basal and insulin-stimulated protein synthesis, but no correlation was observed between the Fst288-driven hypertrophy and the increase in insulin-stimulated glucose uptake. Importantly, Fst288 completely normalized muscle glucose uptake in insulin-resistant diet-induced obese mice. RYGB surgery doubled circulating Fst and reduced activin A (-24%, P < 0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations. CONCLUSIONS: We here present evidence that Fst is a potent regulator of insulin action in muscle, and in addition to AKT and p70S6K, we identify TBC1D1, TBC1D4, pyruvate dehydrogenase-E1α, and PAK1 as Fst targets. Circulating Fst more than doubled post-RYGB surgery, a treatment that markedly improved insulin sensitivity, suggesting a role for Fst in regulating glycaemic control. These findings demonstrate the therapeutic potential of inhibiting TGF-ß superfamily ligands to improve insulin action and Fst's relevance to muscle wasting-associated insulin-resistant conditions in mice and humans.

Activin A regulates activities of peripheral blood natural killer cells of mouse in an autocrine and paracrine manner.

Activin A, a multifunctional cytokine of transforming growth factor-ß (TGF-ß) superfamily, can be produced by the diverse immune cells. NK cells in peripheral blood are one of the major immune cells applied to cancer therapy in recent years. However, whether activin A can be produced by natural killer (NK) cells and be involved in regulation of peripheral blood NK cells activities of mouse are not well characterized. Here, we found that activin type IIA and IIB receptors and signaling molecules Smad2, 3 were expressed in peripheral blood NK cells of mouse by flow cytometry and RT-PCR. The cultured blood NK cells of mouse not only produced activin ßA chain protein by intracellular cytokine staining, but also secreted mature activin A protein by enzyme-linked immunosorbent assay (ELISA), and the production was promoted by IL-2. In addition, IL-2 as a positive control obviously promoted IFNγ production of mouse blood NK cells in vitro. However, activin A suppressed IFNγ production, but enhanced IL-2 synthesis and did not alter IL-10 production. Moreover, we found that activin A significantly suppressed the ability of NK cells to lyse target cells. These data revealed that blood NK cells of mouse were not only the target cells in response to activin A, but also the source of activin A, suggesting that activin A may play an important role in regulation of NK cells activities of mouse in an autocrine / paracrine manner.

Is ovarian reserve associated with body mass index and obesity in reproductive aged women? A meta-analysis.

OBJECTIVE: The associations of body mass index (BMI) and obesity with ovarian reserve are controversial. This systematic review and meta-analysis was conducted to investigate the associations in reproductive-aged women. METHODS: PubMed and Scopus were searched up to December, 2016. Original studies on the association of BMI with ovarian reserve markers, anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), inhibin ß, and antral follicle count (AFC), either according to BMI categories or a continuous variable, were selected. Analyses were stratified into three groups based on polycystic ovary syndrome (PCOS) and fertility status of women. RESULTS: Of 4,055 records identified, 45 studies were eligible for inclusion. Comparing the obese with nonobese, the pooled mean differences (MDs) and 95% confidence intervals (CIs) were -1.08 (95% CIs -1.52, -0.63) ng/mL for AMH, -0.22 (95% CIs -0.39, -0.06) mIU/mL for FSH, -0.09 (95% CIs -0.60, 0.42) for AFC, and -21.06 (95% CIs -41.18, -0.85) pg/mL for inhibin ß in overall populations. The MDs were significant for AMH in fertile non-PCOS and PCOS women, and for FSH only in PCOS women. Fisher's Z showed significant correlations of BMI with AMH in the overall populations (-0.15 [95% CIs -0.20, -0.11]) and in all subgroups, and with FSH in the fertile non-PCOS women (-0.16 [95% CIs -0.28, -0.04]). CONCLUSION: Ovarian reserve markers of AMH and FSH are significantly lower in obese than in nonobese women, and BMI is negatively correlated with AMH in all study populations, and with FSH in fertile non-PCOS subgroups. PCOS and fertility status do not appear to affect the associations.

Comparison between two inhibin B ELISA assays in 46,XY testicular disorders of sex development (DSD) with normal testosterone secretion.

BACKGROUND: Inhibin B is a hormone produced by the Sertoli cells that can provide important information for the investigation of disorders of sex development (DSD) with 46,XY karyotype. The aim of this study is to compare two enzyme-linked immunosorbent assay (ELISA) assays for dosage of serum inhibin B in patients with 46,XY DSD with normal testosterone secretion. METHODS: Twenty-nine patients with 46,XY DSD and normal testosterone secretion (partial androgen insensitivity syndrome [PAIS] [n=8]; 5α-reductase deficiency [n=7] and idiopathic 46,XY DSD [n=14]) were included. Molecular analysis of the AR and SRD5A2 genes were performed in all patients and the NR5A1 gene analysis in the idiopathic group. Measurements of inhibin B were performed by two second-generation ELISA assays (Beckman-Coulter and AnshLabs). Assays were compared using the interclass correlation coefficient (ICC) and the Bland-Altman method. RESULTS: ICC was 0.915 [95% confidence interval (CI): 0.828-0.959], however, a discrepancy was observed between trials, which is more evident among higher values when analyzed by the Bland-Altman method. CONCLUSIONS: It is recommended to perform the inhibin B measurement always using the same ELISA kit when several evaluations are required for a specific patient.

The Association Between Serum Activin A Levels and Hypertension in the Elderly: A Cross-Sectional Analysis From I-Lan Longitudinal Aging Study.

BACKGROUND: Hypertension is an important risk factor for cardiovascular disease. Activin A, a member of the transforming growth factor-ß cytokine family, has been shown to regulate blood pressure through the renin-angiotensin system. However, the relationship between activin A and blood pressure remains uncertain. The objective of this study was to determine whether serum activin A levels are associated with blood pressure. METHOD: A total of 470 participants of I-Lan longitudinal Aging Study (ILAS) were eligible for this study. Serum levels of activin A were assessed by enzyme-linked immunosorbent assay. Cross-sectional analyses were performed, including comparisons of demographic characteristics, hypertensive status, and activin A levels. RESULTS: Among the study participants (50% men, mean age, 69 years), 236 (50.2%) were hypertensive and 234 (49.8%) were normotensive. Hypertensive patients had significantly higher serum activin A levels than normotensives (normotensive vs. hypertensive: 507 ± 169 vs. 554 ± 176 pg/ml, mean ± SD, P < 0.001). All subjects were divided into 3 tertiles on the basis of serum activin A levels. Increasing tertiles of activin A were associated with higher systolic blood pressure (SBP), diastolic blood pressure and pulse pressure (PP) (all P < 0.001). After adjusting for all the potential confounding factors, serum activin A concentration was still significantly associated with SBP (P = 0.02) and PP (P = 0.03). CONCLUSIONS: Serum activin A level was associated with SBP and PP. Further studies are required to assess their causal relationship and the clinical relevance.

Klotho and activin A in kidney injury: plasma Klotho is maintained in unilateral obstruction despite no upregulation of Klotho biosynthesis in the contralateral kidney.

In a new paradigm of etiology related to chronic kidney disease-mineral and bone disorder (CKD-MBD), kidney injury may cause induction of factors in the injured kidney that are released into the circulation and thereby initiate and maintain renal fibrosis and CKD-MBD. Klotho is believed to ameliorate renal fibrosis and CKD-MBD, while activin A might have detrimental effects. The unilateral ureter obstruction (UUO) model is used here to examine this concept by investigating early changes related to renal fibrosis in the obstructed kidney, untouched contralateral kidney, and vasculature which might be affected by secreted factors from the obstructed kidney, and comparing with unilateral nephrectomized controls (UNX). Obstructed kidneys showed early Klotho gene and protein depletion, whereas plasma Klotho increased in both UUO and UNX rats, indicating an altered metabolism of Klotho. Contralateral kidneys had no compensatory upregulation of Klotho and maintained normal expression of the examined fibrosis-related genes, as did remnant UNX kidneys. UUO caused upregulation of transforming growth factor-ß and induction of periostin and activin A in obstructed kidneys without changes in the contralateral kidneys. Plasma activin A doubled in UUO rats after 10 days while no changes were seen in UNX rats, suggesting secretion of activin A from the obstructed kidney with potentially systemic effects on CKD-MBD. As such, increased aortic sclerostin was observed in UUO rats compared with UNX and normal controls. The present results are in line with the new paradigm and show very early vascular effects of unilateral kidney fibrosis, supporting the existence of a new kidney-vasculature axis.

Circulating anti-Müllerian hormone (AMH) associates with the maturity of boys' drawings: Does AMH slow cognitive development in males?

PURPOSE: High levels of circulating anti-Müllerian hormone are unique to developing males, but the function of anti-Müllerian hormone in boys is unknown. In mice, anti-Müllerian hormone contributes to the male biases in the brain, but its receptors are present throughout non-sexually dimorphic portions of the brain. In humans, the speed of maturation is the most overt difference between girls and boys. We postulate that this is because anti-Müllerian hormone slows the maturation of the male human brain. METHODS: One hundred and fourty three 5-year or 6-year-old boys and 38 age-matched girls drew a person and donated a blood sample. The children's drawings were blind-scored to generate a maturity index. The level of anti-Müllerian hormone and the other Sertoli cell hormone, inhibin B, were measured by ELISA. The relationship between the children's age, hormones and maturity index were examined by linear regression analysis. RESULTS: The girls drew more complex and realistic person than the boys (32%, p = 0.001), with their drawings also being larger (39%, p = 0.037) and more coloured-in (235%, p = 0.0005). The maturity index in boys correlated with age (+r = 0.43, p < 0.0005) and anti-Müllerian hormone level (-r = -0.29, p < 0.0005). The association between maturity index and anti-Müllerian hormone level persisted when corrected for age and for inhibin B (r = -0.24, p = 0.0005). The calculated effect of the median level of anti-Müllerian hormone (1 nM) was equal to 0.81 months of development. The size and colouring of the drawings did not correlate with the boys' age, anti-Müllerian hormone or inhibin B. CONCLUSIONS: This exploratory study provides the first indicative evidence that circulating anti-Müllerian hormone may influence the development of the human brain.

[Testicular artery-sparing microscopic varicocelectomy combined with Qilin Pills for bilateral varicocele-induced oligoasthenospermia].

OBJECTIVE: To explore the clinical effect of testicular artery-sparing microscopic varicocelectomy (MV) in combination with Qilin Pills (QL) in the treatment of bilateral varicocele-induced oligoasthenospermia. METHODS: Sixty patients with bilateral varicocele-induced oligoasthenospermia were randomly assigned to receive MV (n=30) or MV+QL (n=30), those in the latter group treated with oral QL for 12 weeks postoperatively. At 4, 8, and 12 weeks after operation, we compared the semen volume, sperm concentration, sperm motility, the levels of serum Inh B, luteinizing hormone (LH) and total testosterone (TT), and the testosterone secretion index (TSI) between the two groups. RESULTS: After surgery, all the patients showed disappearance of varicocele symptoms, remarkably improved semen volume, sperm concentration, sperm motility, serum Inh B and TT levels, TSI, decreased LH and FSH (P<0.01). At 12 weeks after treatment, statistically significant differences were found between the MV and MV+QL groups in Inh B (138.96±22.26 vs 129.54±22.23) ng/L, LH (3.17±0.12 vs 3.59±0.11) IU/L, TT (13.98±3.02 vs 12.68±3.12) nmol/L, and TSI (4.41±0.53 vs 3.53±0.51) nmol/ IU (P<0.05). The pregnancy rate was significantly higher in the MV+QL than in the MV group (73.4% vs 36.6%, P<0.05). CONCLUSIONS: Testicular artery-sparing microscopic varicocelectomy combined with Qilin Pills is an effective strategy for the treatment of bilateral varicocele-induced oligoasthenospermia by significantly improving the semen quality of the patient.

Change in the Gastro-Intestinal Tract by Overexpressed Activin Beta A.

Originally, activins were identified as stimulators of FSH release in reproduction. Other activities, including secondary axis formation in development, have since been revealed. Here, we investigated the influence of activin ßA on the body, including the gastro-intestinal (GI) tract. Initially, the activin ßA protein was detected in the serum proportional to the amount of pCMV-rAct plasmid injected. The induced level of activin ßA in muscle was higher in female than male mice. Subsequent results revealed that stomach and intestine were severely damaged in pCMV-rAct-injected mice. At the cellular level, loss of parietal cells was observed, resulting in increased pH within the stomach. This phenomenon was more severe in male than female mice. Consistent with damage of the stomach and intestine, activin ßA often led to necrosis in the tip of the tail or foot, and loss of body weight was observed in pCMV-rAct-injected male but not female mice. Finally, in pCMV-rAct-injected mice, circulating activin ßA led to death at supraphysiological doses, and this was dependent on the strain of mice used. Taken together, these results indicate that activin ßA has an important role outside of reproduction and development, specifically in digestion. These data also indicate that activin ßA must be controlled within a narrow range because of latent lethal activity. In addition, our approach can be used effectively for functional analysis of secreted proteins.

Anti-Müllerian Hormone Is a Marker for Chemotherapy-Induced Testicular Toxicity.

Due to increased numbers of young cancer patients and improved survival, the impact of anticancer treatments on fertility has become a major health concern. Despite mounting research on ovarian toxicity, there is paucity of data regarding reliable biomarkers of testicular toxicity. Our aim was to evaluate anti-Müllerian hormone (AMH) as a marker for chemotherapy-induced testicular toxicity. Serum AMH and a panel of gonadal hormones were measured in male cancer patients at baseline and after chemotherapy. In the preclinical setting, mice were injected with diverse chemotherapies and were killed 1 week or 1, 3, or 6 months later. We evaluated spermatogenesis by AMH as well as qualitative and quantitative sperm parameters. Nineteen patients were enrolled, the median age was 38 years (21-44 y). Serum AMH was correlated with increased FSH and T and decreased inhibin-B in gonadotoxic protocols (cisplatin or busulfan) and remained unchanged in nongonadotoxic protocols (capecitabine). AMH expression had the same pattern in mice serum and testes; it was negatively correlated with testicular/epididymal weight and sperm motility. The increase in testicular AMH expression was also correlated with elevated apoptosis (terminal transferase-mediated deoxyuridine 5-triphosphate nick-end labeling) and reduced proliferation (Ki67, proliferating cell nuclear antigen; all seminiferous tubules cells were analyzed). Severely damaged mice testes demonstrated a marked costaining of AMH and GATA-4, a Sertoli cell marker; staining that resembled the pattern of the Sertoli cell-only condition. Our study indicates that the pattern of serum AMH expression, in combination with other hormones, can delineate testicular damage, as determined in both experimental settings. Future large-scale clinical studies are warranted to further define the role of AMH as a biomarker for testicular toxicity.

The effects of pegylated interferon-α and ribavirin on liver and serum concentrations of activin-A and follistatin in normal Wistar rat: a preliminary report.

BACKGROUND: Activin-A and follistatin regulate the liver and the immune system. AIMS: To measure the effects of treatment with pegylated-interferon-α (Peg-IFN-α) and ribavirin on the concentrations of mature activin-A and follistatin in serum and liver tissue homogenates in rats. METHODS: A total of 28 male Wistar rats were divided equally into four groups as follow: 'Control group' (n = 7), 'PEG only group' consisted of those that only received a weekly injection of Peg-IFN-α (6 µg/rat) for 4 weeks, 'RBV only group' received ribavirin only (4 mg/rat/day) orally for 35 days and the last group received both Peg-IFN-α and ribavirin 'PEG & RBV group'. The concentrations of candidate proteins in serum and liver samples were measured using ELISA. RESULTS: Pegylated-interferon-α decreased activin-A and increased follistatin significantly in serum and liver of 'PEG only' and 'PEG & RBV' groups compared with the 'Control' and 'RBV only' groups (P < 0.05). There was no significant difference between the 'RBV only' and 'Control' groups (P > 0.05) in the concentrations of candidate proteins. A significant positive correlations between serum and liver activin-A (r = 0.727; P = 0.02 × 10(-3)) and follistatin (r = 0.540; P = 0.01) was also detected. CONCLUSION: Pegylated-interferon-α modulates the production of activin-A and follistatin by the liver, which is reflected and can be detected at the serum level. Further studies are needed to explore the role of Peg-IFN-α based therapy on the production of activins and follistatin by the liver and immune cells.

Effects of conservative laparoscopic endometrial cystectomy and use of kidney-reinforcing and blood activating traditional Chinese medicine on ovarian functions.

This study investigated functional changes in the ovaries of women who have had conservative laparoscopic endometrial cystectomy and the effects of traditional kidney-reinforcing and blood-activating Traditional Chinese Medicine (TCM) on ovarian function. Seventy female patients who underwent laparoscopic endometrial cystectomy were randomized into two groups: TCM group receiving kidney-reinforcing and blood-activating Chinese medicine (N = 35) and control group receiving only routine follow-up (N = 35). The serum levels of all study participants were measured for follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and inhibin B (INHB) prior to and after endometrial surgery. Postoperative menstruation conditions were also assessed. Compared to preoperative conditions, both LH and FSH levels during the postoperative 1st month increased in both groups, while E2 and INHB levels decreased (P < 0.05). In the TCM group, in contrast to the control group and the postoperative 1st month, we observed a decrease in LH and FSH levels during the postoperative 4th month, while E2 and INHB levels increased (P < 0.05). In this study, we found that certain TCM prescriptions lowered postoperative serum FSH and LH levels and increased the serum INHB and basal E2 levels, thereby improving the ovarian reserve.

[Study on the association between maternal urinary phthalate metabolites and testicular steroid hormones in the cord blood in a Chinese population].

OBJECTIVE: The purposes of our study were to investigate the association between maternal urinary phthalate metabolites and the levels of inhibin B (INHB) and insulin-like factor 3 (INSL3) in the cord blood in a Chinese pregnant population. METHODS: Maternal urine samples in the third trimester of pregnancy of 69 participants were collected and stored, and the samples of cord blood (10 ml) were collected at delivery between June 2011 and September 2012 in a comprehensive hospital of gynecology and obstetrics in Tianjin, China.Four phthalate metabolites, monomethyl phthalate (MMP), monoethyl phthalate (MEP), monobutyl phthalate (MBP), and mono-2-ethylhexyl phthalate (MEHP) were measured in the urine samples using liquid chromatography-tandem mass spectrometry. The levels of INHB, INSL3 in the cord blood were tested by ELISA. Associations of phthalate exposure with INHB and INSL3 levels were determined by spearman correlation and multiple regression model analysis. RESULTS: The median concentrations of observed metabolites in descending order were 49.74 µg/L for MMP, 24.96 µg/L for MEHP, 19.52 µg/L for MEP and 17.73 µg/L for MBP. The median concentrations of INHB and INSL3 were 89.09 and 106.21 ng/L.Significant negative associations between INHB and MMP(ß' = -0.252), MEP(ß' = -0.363) or the sum value (∑PAEs) (ß' = -0.346) were found by the multiple regression model analysis. For INSL3, only the sum value (ß' = -0.313) was inversely significantly associated with the levels of INSL3 in the cord blood. CONCLUSIONS: Maternal urinary phthalate metabolites were associated with INHB and INSL3 in the cord blood in a Chinese population.

Association between GH receptor polymorphism (exon 3 deletion), serum IGF1, semen quality, and reproductive hormone levels in 838 healthy young men.

INTRODUCTION: GH activity may be involved in male reproductive function. A common genetic polymorphism in the gene encoding the GH receptor (GHR) results in deletion of the entire exon 3 sequence (GHRd3 isoform). The short GHRd3/d3 isoform seems more sensitive compared with full-length receptors (GHRfl/fl). AIM: TO INVESTIGATE THE ASSOCIATIONS BETWEEN GH ACTIVITY, EVALUATED BY EXON 3 GHR POLYMORPHISM, AND SERUM IGF1 VS REPRODUCTIVE HORMONES, SEMEN QUALITY, AND PRE- AND POSTNATAL GROWTH IN HEALTHY YOUNG MALES (N=838, MEAN AGE: 19.4 years). RESULTS: Compared with GHRfl/fl homozygous individuals (n=467) GHRd3/d3 homozygous individuals (n=69) tended to have larger semen volume (3.2 (2.4-4.3) vs 3.6 (2.6-4.7) ml, P=0.053) and higher serum inhibin-B levels (208 pg/ml (158-257) vs 227 pg/ml (185-264), P=0.050). Semen quality, levels of gonadotropins, testosterone, estradiol, sex hormone-binding globulin, and IGF1 were not associated with GHRd3 genotype. A twofold increase in serum IGF1 was associated with a 13% (4-23) increase in calculated free testosterone (P=0.004). By contrast IGF1 was inversely associated with serum inhibin-B (P=0.027), but showed no associations to semen quality. GHR genotype and serum IGF1 were not associated with size at birth or final height. CONCLUSIONS: GHRd3 polymorphism seemed only to have a weak influence on male reproductive function of borderline significance. The sensitive GHRd3/d3 genotype may slightly increase testicular function, as evaluated by semen volume and levels of inhibin-B, but does not seem to influence Leydig cell steroidogenesis. GHR genotype did not influence pre- and postnatal growth.