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Little is known about the role of activin B during folliculogenesis. This study investigated the expression levels of activin/inhibin subunits (βA, βB, and α), steroid enzyme, and gonadotrophin receptors in theca (TC) and granulosa cells (GC) by QPCR and activin A and B and inhibin A protein levels in follicular fluid (FF) of developing sheep follicles during estrus and anestrus. The effect of activin B on androgen production from primary TC cultures in vitro was also assessed. During folliculogenesis, in anestrus and estrus, FF activin B concentrations and thecal and GC activin βB mRNA levels decreased as follicle diameter increased from 1-3 to O6 mm regardless of estrogenic status. Estrogenic preovulatory follicles had reduced concentrations of FF activins B and A, and TC and GCs expressed higher levels of activin βA mRNA at 3-4 mm, and TCs more inhibin α mRNA at O4 mm stages of development compared with nonestrogenic follicles. Activin B decreased androstenedione production from primary TCs in vitro, an effect blocked by inhibin A. Thus, sheep follicles 1-3 mm in diameter contained high FF levels of activin B, which decreased as the follicle size increased, and, like activin A, suppressed thecal androgen production in vitro, an effect blocked by inhibin. Furthermore, the theca of large estrogenic follicles expressed high levels of inhibin α and activin βA mRNA suggesting local thecal derived inhibin A production. This would inhibit the negative effects of thecal activins B and A ensuring maximum androgen production for enhanced estradiol production by the preovulatory follicle(s). Reproduction (2012) 143 637-650 [ABSTRACT FROM AUTHOR]

Background: Many women of childbearing age with inflammatory bowel disease (IBD) require advanced therapies. While biologics are largely low risk during pregnancy, the novel small molecules tofacitinib, filgotinib, upadacitinib and ozanimod (TFUO) have shown concerning teratogenic effects, and decreased fertility in animal studies. Therefore, their use in women of childbearing age needs careful consideration., Design: RAND/University of California Los Angeles (UCLA) Appropriateness Method (RAM)., Objective: To evaluate the appropriateness of TFUO in women of childbearing age., Methods: We convened a panel of six gastroenterologists, two IBD nurses, one IBD pharmacist and three expert patients. Following a literature review, 13 statements were drafted and voted upon in 2 rounds., Results: All 13 statements were deemed appropriate. The panel concluded that women with IBD of childbearing age who wish to commence therapy with TFUO, need to use effective contraception and be counselled regarding the risk in unplanned pregnancies. For women using contraception while on Janus kinase inhibitor (JAKi) therapy, we suggest the preferred use of progesterone-only or non-hormonal long-acting contraception. TFUO are contraindicated during pregnancy and breast feeding. We recommend that women receiving TFUO cease therapy in time to establish clinical remission for at least 3 months prior to conception. Therapies other than TFUO should be considered as first-line therapy in women with IBD of childbearing age, except in select individual circumstances. TFUO may be appropriate for women of childbearing age after failure of, intolerance or contraindications to one biological agent., Conclusion: TFUO should be avoided during pregnancy and breastfeeding, and alternative therapies should be considered as first-line treatments., Summary: We provide clinical practice recommendations regarding the use of TFUO for IBD in women of childbearing age., Competing Interests: C.P.S. has received unrestricted research grants from Warner Chilcott, Janssen, Galapagos and AbbVie, has provided consultancy to Warner Chilcott, Dr Falk, AbbVie, Takeda, Fresenius Kabi, Eli Lilly, Galapagos, Ferring, Arena and Janssen, and had speaker arrangements with Warner Chilcott, Dr Falk, Galapagos, AbbVie, MSD, Pfizer, Eli Lilly, BMS, UCB, Fresenius Kabi, Celltrion and Takeda. A.K. has provided consultancy to AbbVie, Galapagos, Ferring, Warner Chilcott and Janssen and had speakers fees from AbbVie, Galapagos, Janssen, Takeda and Falk. K.K. has provided consultancy to AbbVie and Galapagos, and had speaker arrangements with AbbVie, Galapagos, Janssen and Ferring. J.L. has provided consultancy to AbbVie, Arena, BioHit, Bristol Myers Squibb, Eli Lilly, Galapagos, Janssen, Pfizer and Takeda; has received speaker fees from to AbbVie, BioHit, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Janssen, MSD, Pfizer, Takeda; and research grants from Galapagos and Takeda. A.F. has provided consultancy to Warner Chilcott, Dr Falk, AbbVie, Takeda, Allergan, Galapagos, Ferring, Pharmacosmos, UCB, Bristol Myers Sqibb and Janssen, and had speaker arrangements with Warner Chilcott, Allergan, Dr Falk, Galapagos, AbbVie, Pfizer, Ferring, Pharmacosmos, Bristol Myers Squibb, Fresenius Kabi, Celltrion and Takeda. F.R. has provided consultancy to Bristol Myers Squibb, Celltrion and Takeda and had speaker arrangements with Dr Falk, Ferring, Gilead, Intercept and Pfizer. The other authors have no conflict of interests to disclose., (© The Author(s), 2024.)

Hawke's Bay in New Zealand was impacted by Cyclone Gabrielle in 2023, experiencing intense weather conditions and rainfall. Rivers and streams surged beyond their banks, displacing large amounts of sediment. The sewage treatment plant and industries in the Waitangi catchment, south of the city of Napier, were heavily impacted, making them potential sources of contaminants. The aim of this study was to investigate the risk of displaced sediments deposited south of Napier City, using bioassays and chemical analysis methods. Sediment samples were collected across a gradient between the coastline and the Waitangi Stream. The toxicity of chemically extracted or elutriate samples was assessed by Microtox ® , mussel embryo-larval development, and aryl hydrocarbon and constitutive androstane receptor yeast two-hybrid assays. Targeted chemical analysis and automated identification and quantification system (AIQS-GC) methods were used to identify contaminants. The elutriates showed low toxicity and the yeast assays showed levels of activity like those previously reported. Chemical methods confirmed historical contamination by DDT and its metabolites DDE and DDD, as well as by plant sterols. Overall, the toxicity and chemicals detected are what would be expected from a typical agricultural soil. The risk posed by the displaced sediment in the Waitangi catchment can be considered low. Combining chemical and bioanalytical methods was an effective approach to investigate the potential risks of post-disaster contamination.

Pelvic radiotherapy can damage surrounding tissue and organs, causing chronic conditions including bowel symptoms. We systematically identified quantitative, population-based studies of patient-reported bowel symptoms following pelvic radiotherapy to synthesize evidence of symptom type, prevalence, and severity. Medline, CINAHL, EMBASE, and PsychINFO were searched from inception to September 2022. Following independent screening of titles, abstracts, and full-texts, population and study characteristics and symptom findings were extracted, and narrative synthesis was conducted. In total, 45 papers (prostate, n = 39; gynecological, n = 6) reporting 19 datasets were included. Studies were methodologically heterogeneous. Most frequently assessed was bowel function ('score', 26 papers, 'bother', 19 papers). Also assessed was urgency, diarrhea, bleeding, incontinence, abdominal pain, painful hemorrhoids, rectal wetness, constipation, mucous discharge, frequency, and gas. Prevalence ranged from 1% (bleeding) to 59% (anal bleeding for >12 months at any time since start of treatment). In total, 10 papers compared radiotherapy with non-cancer comparators and 24 with non-radiotherapy cancer patient groups. Symptom prevalence/severity was greater/worse in radiotherapy groups and symptoms more common/worse post-radiotherapy than pre-diagnosis/treatment. Symptom prevalence varied between studies and symptoms. This review confirms that many people experience chronic bowel symptoms following pelvic radiotherapy. Greater methodological consistency, and investigation of less-well-studied survivor populations, could better inform the provision of services and support.

Cryptorchidism causes spermatogenic failure and reduced serum androgen levels, as well as testicular oedema and fibrosis, which are hallmarks of inflammation. However, the role of inflammation and the effects of cryptorchidism on Sertoli cell and Leydig cell function at the molecular level remain ill-defined. Bilateral cryptorchidism was surgically induced in adult rats for 7 and 14 weeks. Testis weights decreased to 40% of normal within 7 weeks, due to loss of all developing spermatogenic cells except spermatogonia, but did not decrease further at 14 weeks. Serum FSH and LH were increased at both time points, consistent with a loss of feedback by inhibin and testosterone. This damage was accompanied by progressive accumulation of interstitial fluid and peritubular fibrosis, and a progressive decline of several critical Sertoli cell genes (Sox9, Inha (inhbin α-subunit), Cldn11 (claudin 11), Gja1 (connexin 43), and Il1a (interleukin-1α)) and the Leydig cell steroidogenic enzymes, Cyp11a1, Hsd3b1, and Hs17b3. Activin B and the activin-binding protein, follistatin, also declined, but the intratesticular concentration of activin A, which is a regulator of inflammatory responses, was largely unaffected at either time point. Expression of genes involved in inflammation (Tnf, Il10, Il1b, Mcp1) and fibrosis (Acta2, Col1a1) were considerably elevated at both time points. These data indicate that induction of experimental cryptorchidism, which causes complete failure of spermatogenesis in the adult rat, also induces chronic testicular inflammation, manifesting in oedema and fibrosis, and a progressive decline of Sertoli and Leydig cell gene expression and function., (© 2021. Society for Reproductive Investigation.)

Type 2 diabetes (T2D) manifests from inadequate glucose control due to insulin resistance, hypoinsulinemia, and deteriorating pancreatic β-cell function. The pro-inflammatory factor Activin has been implicated as a positive correlate of severity in T2D patients, and as a negative regulator of glucose uptake by skeletal muscle, and of pancreatic β-cell phenotype in mice. Accordingly, we sought to determine whether intervention with the Activin antagonist Follistatin can ameliorate the diabetic pathology. Here, we report that an intravenous Follistatin gene delivery intervention with tropism for striated muscle reduced the serum concentrations of Activin B and improved glycemic control in the db/db mouse model of T2D. Treatment reversed the hyperglycemic progression with a corresponding reduction in the percentage of glycated-hemoglobin to levels similar to lean, healthy mice. Follistatin gene delivery promoted insulinemia and abundance of insulin-positive pancreatic β-cells, even when treatment was administered to mice with advanced diabetes, supporting a mechanism for improved glycemic control associated with maintenance of functional β-cells. Our data demonstrate that single-dose intravascular Follistatin gene delivery can ameliorate the diabetic progression and improve prognostic markers of disease. These findings are consistent with other observations of Activin-mediated mechanisms exerting deleterious effects in models of obesity and diabetes, and suggest that interventions that attenuate Activin signaling could help further understanding of T2D and the development of novel T2D therapeutics., (© 2020 Federation of American Societies for Experimental Biology.)

Heat reversibly disrupts spermatogenesis, but the effects on Sertoli cell (SC) function and inhibin/activin-related proteins are less well-defined. Adult rat testis weights decreased by 40% within 2 weeks after heat-treatment (43 °C, 15 min), due to loss of pachytene spermatocytes and round spermatids. Coincident effects were reduced SC nuclear volume at one week and >50% reduction in expression of several critical SC genes (Inha, Cld11, Gja1, Tjp1, Cldn3) by 2 weeks. Leydig cell steroidogenic enzymes, Cyp11a1, Hsd3b1, were also reduced. Activin gene expression was unaffected at this time, but expression of the activin-binding protein, follistatin (Fst), increased >2-fold. At 4-8 weeks, coincident with the recovery of spermatocytes and early spermatids, but progressive loss of elongated spermatids, most SC genes had recovered; however, testicular activin A was reduced and activin B increased. At 8 weeks, serum inhibin was decreased and, consequently, serum FSH increased. Crucially, germ cell damage was not associated with a significant inflammatory response. At 14 weeks, most testicular parameters had returned to normal, but testis weights remained slightly reduced. These data indicate that, following acute heat-treatment, expression of several key Sertoli and Leydig cell genes declined in parallel with the initial loss of meiotic germ cells, whereas activins were responsive to the subsequent loss of mature spermatids, leading to an increase in testicular activin B production relative to activin A., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Patients with IBD are at risk of excess corticosteroids., Aims: To assess steroid excess in a large IBD cohort and test associations with quality improvement and prescribing., Methods: Steroid exposure was recorded for outpatients attending 19 centres and associated factors analysed. Measures taken to avoid excess were assessed., Results: Of 2385 patients, 28% received steroids in the preceding 12 months. 14.8% had steroid excess or dependency. Steroid use was significantly lower at 'intervention centres' which participated in a quality improvement programme (exposure: 23.8% vs 31.0%, P < .001; excess 11.5% vs 17.1%, P < .001). At intervention centres, steroid use fell from 2015 to 2017 (steroid exposure 30.0%-23.8%, P = .003; steroid excess 13.8%-11.5%, P = .17). Steroid excess was judged avoidable in 50.7%. Factors independently associated with reduced steroid excess in Crohn's disease included maintenance with anti-TNF agents (OR 0.61 [95% CI 0.24-0.95]), treatment in a centre with a multi-disciplinary team (OR 0.54 [95% CI 0.20-0.86]) and treatment at an intervention centre (OR 0.72 [95% CI 0.46-0.97]). Treatment with 5-ASA in CD was associated with higher rates of steroid excess (OR 1.72 [95% CI 1.24-2.09]). In ulcerative colitis (UC), thiopurine monotherapy was associated with steroid excess (OR 1.97 [95% CI 1.19-3.01]) and treatment at an intervention centre with less steroid excess (OR 0.72 [95% CI 0.45-0.95])., Conclusions: This study validates steroid assessment as a meaningful quality measure and provides a benchmark for this performance indicator in a large cohort. A programme of quality improvement was associated with lower steroid use., (© 2019 John Wiley & Sons Ltd.)

Regionalised interaction of the activins, follistatin and inhibin was investigated in the male reproductive tract of mice lacking the inhibin α-subunit (Inha -/- ). Serum and intratesticular activin B, although not activin A and follistatin, were increased in Inha -/- mice at 25 days of age, but all three proteins were elevated at 56 days. None of these proteins were altered within the epididymis and vas deferens at either age. At 25 days, histology of the epididymis and vas deferens was similar to wild-type. At 56 days, the testis contained extensive somatic cell tumours, leading to Leydig cell regression and testosterone deficiency. The epididymis and vas deferens showed epithelial regression and increased prominence of the interstitial stroma. Immunoregulatory and fibrotic gene expression in the epididymis and vas deferens were unchanged. Thus, absence of the inhibin α-subunit has marginal effects on activins in the epididymis and vas deferens, and regression of these tissues is associated with androgen deficiency., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is clinically defined and characterised by persistent disabling tiredness and exertional malaise, leading to functional impairment., Methods: This study introduces the weighted standing time (WST) as a proxy for ME/CFS severity, and investigates its behaviour in an Australian cohort. WST was calculated from standing time and subjective standing difficulty data, collected via orthostatic intolerance assessments. The distribution of WST for healthy controls and ME/CFS patients was correlated with the clinical criteria, as well as pathology and cytokine markers. Included in the WST cytokine analyses were activins A and B, cytokines causally linked to inflammation, and previously demonstrated to separate ME/CFS from healthy controls. Forty-five ME/CFS patients were recruited from the CFS Discovery Clinic (Victoria) between 2011 and 2013. Seventeen healthy controls were recruited concurrently and identically assessed., Results: WST distribution was significantly different between ME/CFS participants and controls, with six diagnostic criteria, five analytes and one cytokine also significantly different when comparing severity via WST. On direct comparison of ME/CFS to study controls, only serum activin B was significantly elevated, with no significant variation observed for a broad range of serum and urine markers, or other serum cytokines., Conclusions: The enhanced understanding of standing test behaviour to reflect orthostatic intolerance as a ME/CFS symptom, and the subsequent calculation of WST, will encourage the greater implementation of this simple test as a measure of ME/CFS diagnosis, and symptom severity, to the benefit of improved diagnosis and guidance for potential treatments.

Activin A regulates testicular and epididymal development, but the role of activin B in the epididymis and vas deferens is unknown. Mouse models with reduced activin A ( Inhba +/- and Inhba BK/+ ), or its complete absence ( Inhba BK/BK ), were investigated to identify specific roles of activins in the male reproductive tract. In 8-week-old Inhba +/- mice, serum activin A decreased by 70%, with a 50% reduction of gene expression and protein in the testis, epididymis and vas deferens. Activin B and the activin-binding protein, follistatin, were similar to wild-type. Testis weights were slightly reduced in Inhba +/- mice, but the epididymis and vas deferens were normal, while the mice were fertile. Activin A was decreased by 70% in the serum, testis, epididymis and vas deferens of Inhba BK/+ mice and was undetectable in Inhba BK/BK mice, but activin B and follistatin levels were similar to wild-type. In 6-week-old Inhba BK/BK mice, testis weights were 60% lower and epididymal weights were 50% lower than in either Inhba BK/+ or wild-type mice. The cauda epididymal epithelium showed infoldings and less intra-luminal sperm, similar to 3.5-week-old wild-type mice, but at 8 weeks, no structural differences in the testis or epididymis were noted between Inhba BK/BK and wild-type mice. Thus, Inhbb can compensate for Inhba in regulating epididymal morphology, although testis and epididymal maturation is delayed in mice lacking Inhba Crucially, reduction or absence of activin A, at least in the presence of normal activin B levels, does not lead to major defects in the adult epididymis or vas deferens., (© 2018 Society for Reproduction and Fertility.)

Type 1 diabetes (T1D) is associated with subfertility in men. We hypothesised that this results from inhibitory effects of chronic hyperglycemia on testicular function and used the Ins2 Akita+/- mouse model to investigate this. Diabetic mice exhibited progressive testicular dysfunction, with a 30% reduction in testis weight at 24 weeks of age. Diabetic mice showed significantly reduced seminiferous tubule diameters and increased spermatogenic disruption, although testes morphology appeared grossly normal. Unexpectedly, serum LH and intra-testicular testosterone were similar in all groups. Ins2 Akita+/- mice displayed elevation of the testicular inflammatory cytokines activin A and IL-6. Intratesticular activin B was downregulated, while the activin regulatory proteins, follistatin and inhibin, were unchanged. Activin signalling, measured by pSmad3 and Smad4 production, was enhanced in diabetic mice only. These results suggest that prolonged exposure to hyperglycemia in the Ins2 Akita+/- mice leads to progressive testicular disruption mediated by testicular activin activity, rather than hormonal dysregulation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Investigations of activin family proteins as serum biomarkers for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). CFS/ME is a disease with complex, wide-ranging symptoms, featuring persistent fatigue of 6 months or longer, particularly post exertion. No definitive biomarkers are available., Methods: A cross-sectional, observational study of CFS/ME patients fulfilling the 2003 Canadian Consensus Criteria, in parallel with healthy non-fatigued controls, was conducted. Comparisons with a previously defined activin reference population were also performed. For the total study cohort the age range was 18-65 years with a female: male participant ratio of greater than 3:1. All participants were assessed via a primary care community clinic. Blood samples were collected for pathology testing after physical examination and orthostatic intolerance assessment. Cytokines, activin A, activin B and follistatin were also measured in sera from these samples. All data were compared between the CFS/ME and control cohorts, with the activins and follistatin also compared with previously defined reference intervals., Results: Serum activin B levels for CFS/ME participants were significantly elevated when compared to the study controls, as well as the established reference interval. Serum activin A and follistatin were within their normal ranges. All routine and special pathology markers were within the normal laboratory reference intervals for the total study cohort, with no significant differences detected between CFS/ME and control groups. Also, no significant differences were detected for IL-2, IL-4, IL-6, IL-10, IL-17A, TNF or IFN-gamma., Conclusion: Elevated activin B levels together with normal activin A levels identified patients with the diagnostic symptoms of CFS/ME, thus providing a novel serum based test. The activins have multiple physiological roles and capture the diverse array of symptoms experienced by CFS/ME patients.

There are currently at least 2 million people in the UK living with and following a cancer diagnosis. Typically four out of every ten people with cancer will receive radiotherapy, but a large proportion of people who have pelvic radiotherapy may go on to develop gastrointestinal (GI) symptoms. This includes rectal bleeding and faecal incontinence, which can have a huge impact on quality of life. These problems often go under-reported by patients and are also under-recognised or under-treated by health professionals. Cancer survivorship is a growing topic that is likely to have a major impact on the NHS, with increasing numbers of patients presenting. A late GI effects of pelvic radiotherapy clinic was set up to address these growing needs of patients with GI symptoms following radiotherapy. This article also shares insights from a doctoral study that is underway looking at people's experiences of living with symptoms following their treatment, in order to improve awareness of the major impact that this can have.

Experimental autoimmune epididymo-orchitis (EAEO) is a model of chronic inflammation, induced by immunisation with testicular antigens, which reproduces the pathology of some types of human infertility. Activins A and B regulate spermatogenesis and steroidogenesis, but are also pro-inflammatory, pro-fibrotic cytokines. Expression of the activins and their endogenous antagonists, inhibin and follistatin, was examined in murine EAEO. Adult untreated and adjuvant-treated control mice showed no pathology. All mice immunised with testis antigens developed EAEO by 50 days, characterised by loss of germ cells, immune cell infiltration and fibrosis in the testis, similar to biopsies from human inflamed testis. An increase of total CD45+ leukocytes, comprising CD3+ T cells, CD4 + CD8- and CD4 + CD25+ T cells, and a novel population of CD4 + CD8+ double positive T cells was also detected in EAEO testes. This was accompanied by increased expression of TNF, MCP-1 and IL-10. Activin A and B and follistatin protein levels were elevated in EAEO testes, with peak activin expression during the active phase of the disease, whereas mRNA expression of the inhibin B subunits (Inha and Inhbb) and activin receptor subunits (Acvr1b and Acvr2b) were downregulated. These data suggest that activin-follistatin regulation may play a role during the development of EAEO.

Background: Activin A and its binding protein follistatin (FS) are increased in inflammatory disorders and sepsis. Overexpression of activin A in the lung causes similar histopathological changes as acute respiratory distress syndrome (ARDS). ARDS and severe respiratory failure are complications of influenza A(H1N1) infection. Interleukin 6 (IL-6), which in experimental studies increases after activin A release, is known to be related to the severity of H1N1 infection. Our aim was to evaluate the levels of activin A, activin B, FS, IL-6 and IL-10 and their association with the severity of respiratory failure in critically ill H1N1 patients., Methods: A substudy of a prospective, observational cohort of H1N1 patients in Finnish intensive care units (ICU). Clinical information was recorded during ICU treatment, and serum activin A, activin B, FS, IL-6 and IL-10 were measured at admission to ICU and on days 2 and 7., Results: Blood samples from 29 patients were analysed. At the time of admission to intensive care unit, elevated serum levels above the normal range for respective age group and sex were observed in 44% for activin A, 57% for activin B, and 39% for FS. In 13 of the 29 patients, serial samples at all time points were available and in these the highest activin A, activin B and FS were above the normal range in 85%, 100% and 46% of the patients, respectively. No difference in baseline or highest activin A or activin B was found in patients with or without acute lung injury (ALI) or ARDS (P > 0.05 for all). Peak levels of IL-6 were significantly elevated in ALI/ARDS patients. Peak activin A and activin A/FS were associated with ventilatory support free-days, severity of acute illness and length of ICU stay (P < 0.05 for all)., Conclusions: Higher than normal values of these proteins were common in patients with H1N1 infection but we found no association with the severity of their respiratory failure.

Introduction: 30 day mortality in patients with Acute Respiratory Failure (ARF) is approximately 30%, defined as patients requiring ventilator support for more than 6 hours. Novel biomarkers are needed to predict patient outcomes and to guide potential future therapies. The activins A and B, members of the Transforming Growth Factor β family of proteins, and their binding protein, follistatin, have recently been shown to be important regulators of inflammation and fibrosis but no substantial data are available concerning their roles in ARF., Methods: Specific assays for activin A, B and follistatin were used and the results analyzed according to diagnostic groups as well as according to standard measures in intensive care. Multivariable logistic regression was used to create a model to predict death at 90 days and 12 months from the onset of the ARF., Results: Serum activin A and B were significantly elevated in most patients and in most of the diagnostic groups. Patients who had activin A and/or B concentrations above the reference maximum were significantly more likely to die in the 12 months following admission [either activin A or B above reference maximum: Positive Likelihood Ratio [LR+] 1.65 [95% CI 1.28-2.12, P = 0.00013]; both activin A and B above reference maximum: LR + 2.78 [95% CI 1.96-3.95, P < 0.00001]. The predictive model at 12 months had an overall accuracy of 80.2% [95% CI 76.6-83.3%]., Conclusions: The measurement of activin A and B levels in these patients with ARF would have assisted in predicting those at greatest risk of death. Given the existing data from animal studies linking high activin A levels to significant inflammatory challenges, the results from this study suggest that approaches to modulate activin A and B bioactivity should be explored as potential therapeutic agents.

Genetic studies have identified bone morphogenetic protein-15 (BMP15) as an essential regulator of female fertility in humans and in sheep. Oocyte-derived BMP15 is a noncovalently linked dimeric growth factor mediating its effects to ovarian somatic cells in a paracrine manner. Although receptor ectodomains capable of binding BMP15 have previously been reported, no cell surface receptor complex involved in BMP15 signaling has previously been characterized. Here we have expressed and purified recombinant human BMP15 noncovalent and covalent dimer variants. The biological effects of these BMP15 variants were assessed in cultured human granulosa-luteal cells or COV434 granulosa cell tumor cells using BMP-responsive transcriptional reporter assays and an inhibin B ELISA. Biochemical characterization of ligand-receptor interactions was performed with affinity-labeling experiments using [(125)I]iodinated BMP15 variants. Both ligand variants were shown to form homodimers and to stimulate Smad1/5/8 signaling and inhibin B production in human granulosa cells in a similar manner. [(125)I]Iodination of both ligands was achieved, but only the covalent dimer variant retained receptor binding capacity. The [(125)I]BMP15(S356C) variant bound preferentially to endogenous BMP receptor 1B (BMPR1B) and BMPR2 receptors on COV434 cells. Binding experiments in COS cells with overexpression of these receptors confirmed that the [(125)I]BMP15(S356C) variant binds to BMPR1B and BMPR2 forming the BMP15 signaling complex. The results provide the first direct evidence in any species on the identification of specific cell surface receptors for a member of the GDF9/BMP15 subfamily of oocyte growth factors. The fact that BMP15 uses preferentially BMPR1B as its type I receptor suggests an important role for the BMPR1B receptor in human female fertility. The result is well in line with the demonstration of ovarian failure in a recently reported human subject with a homozygous BMPR1B loss-of-function mutant.

Recent data have indicated a relationship between placental oxygen and angiogenic protein levels in the first trimester of normal pregnancies. Our objective was to investigate if maternal serum levels of angiogenic factors Soluble vascular endothelial growth factor (VEGF) receptor 1 (sFlt-1), soluble Endoglin and placental growth factor (PlGF) are altered in women with symptoms of threatened miscarriage (TM) and if they are predictive of a subsequent miscarriage. Blood samples were collected at 6-10 weeks from women presenting with TM (n = 40), from asymptomatic controls (n = 32) and from non- pregnant women in their luteal phase (n = 14). All samples were assayed for serum level of sFLT-1, PlGF, sEndoglin and HSP70 using commercial ELISAs. Samples were analysed retrospectively on the basis of pregnancy outcome. TM group included 21 women with a normal pregnancy outcome and 19 with subsequent complete miscarriage. The latter subgroup had significantly lower mean maternal serum (MS) sFlt-1 (83%, P<0.001) and PlGF (44%, P<0.001) compared to those with a normal pregnancy outcome. Asymptomatic control pregnant women had similar MS levels of sFlt-1 and PlGF compared to the TM patients with a normal outcome. The mean MS sFlt-1 (>10 fold) and MS PlGF (∼2 fold) levels were significantly (P<0.001) higher in control pregnant women compared to the non-pregnant group in the luteal phase of the menstrual cycle. Soluble Endoglin was not altered in the normal pregnant women compared to non pregnant women, although lower in the TM subgroup with a subsequent miscarriage (∼25%, P<0.001) compared to TM with a live birth. There was no significant difference in the mean MS HSP 70 levels between the different groups. This study shows that sFlt1 and PlGF MS levels are increased by several folds in early pregnancy and that MS sFlt-1 and MS PlGF are markedly decreased in threatened miscarriage patients who subsequently have a miscarriage suggesting these proteins are sensitive predictive markers of subsequent pregnancy loss.