Efficacy of local anaesthetic infiltration via wound catheters after open hepatic surgery: a systematic review and meta-analysis.

BACKGROUND: This study analysed whether local anaesthetic wound catheter infiltration (LA-WCI) as an adjunct to intravenous patient-controlled analgesia (IV-PCA) provides superior outcomes compared to IV-PCA alone following liver resection. METHODS: A systematic review and meta-analysis was conducted for randomised control trials (RCTs) comparing LA-WCI with IV-PCA(LA-WCI group) versus IV-PCA alone (IV-PCA group). PubMed and the Cochrane Library were searched for relevant articles. RESULTS: Six RCTs with a total of 440 patients were included. Opioid use in the initial 48 h was less in the LA-WCI group [MD -21.27 mg (-39.39,-3.15), p = 0.02]. Pain scores were lower in the LA-WCI group at rest at POD0 (post-operative day 0)6-8 h (p = 0.0009), POD1AM(p = 0.01), POD1PM(p = 0.02) and POD2 (p = 0.0006), and exertion at POD0 0-2 h (p = 0.05), POD1AM(p = 0.03), POD1PM(p = 0.03), POD2 (p = 0.03) and POD3 (p = 0.01). LA-WCI group had reduced length of hospital stay [MD -1.32 days (-2.23,-0.40),p = 0.005], time to ambulation [MD -5.94 h (-8.47,-3.42),p = 0.00001] and incidence of nausea and vomiting (PONV) [OR 0.17 (0.07,0.43),p = 0.0002]. No differences were observed in length of intensive care unit (ICU) stay or incidence of surgical site infections. DISCUSSION: LA-WCI as an adjunct to opiate IV-PCA post-hepatectomy reduces opioid use, pain scores at multiple time points at rest and exertion, length of hospital stay, time to ambulation and PONV. However, LA-WCI use does not alter length of ICU stay or incidence of wound infection.

A Systematic Review and Narrative Synthesis of Risk Prediction Tools Used to Estimate Mortality, Morbidity, and Other Outcomes Following Major Lower Limb Amputation.

OBJECTIVE: The decision to undertake a major lower limb amputation can be complex. This review evaluates the performance of risk prediction tools in estimating mortality, morbidity, and other outcomes following amputation. METHODS: A systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The MEDLINE, Embase, and Cochrane databases were searched to identify studies reporting on risk prediction tools that predict outcomes following amputation. Outcome measures included the accuracy of the risk tool in predicting a range of post-operative complications, including mortality (both short and long term), peri-operative morbidity, need for re-amputation, and ambulation success. A narrative synthesis was performed in accordance with the Guidance on the Conduct of Narrative Synthesis In Systematic Reviews. RESULTS: The search identified 518 database records. Twelve observational studies, evaluating 13 risk prediction tools in a total cohort of 61 099 amputations, were included. One study performed external validation of an existing risk prediction tool, while all other studies developed novel tools or modified pre-existing generic calculators. Two studies conducted external validation of the novel/modified tools. Nine tools provided risk estimations for mortality, two tools provided predictions for post-operative morbidity, two for likelihood of ambulation, and one for re-amputation to the same or higher level. Most mortality prediction tools demonstrated acceptable discrimination performance with C statistic values ranging from 0.65 to 0.81. Tools estimating the risk of post-operative complications (0.65 - 0.74) and necessity for re-amputation (0.72) also performed acceptably. The Blatchford Allman Russell tool demonstrated outstanding discrimination for predicting functional mobility outcomes post-amputation (0.94). Overall, most studies were at high risk of bias with poor external validity. CONCLUSION: This review identified several risk prediction tools that demonstrate acceptable to outstanding discrimination for objectively predicting an array of important post-operative outcomes. However, the methodological quality of some studies was poor, external validation studies are generally lacking, and there are no tools predicting other important outcomes, especially quality of life.

The regulation and signalling of anti-Müllerian hormone in human granulosa cells: relevance to polycystic ovary syndrome.

STUDY QUESTION: What prevents the fall in anti-Müllerian hormone (AMH) levels in polycystic ovary syndrome (PCOS) and what are the consequences of this for follicle progression in these ovaries? SUMMARY ANSWER: Exposure of granulosa cells (GCs) to high levels of androgens, equivalent to that found in PCOS, prevented the fall in AMH and was associated with dysregulated AMH-SMAD signalling leading to stalled follicle progression in PCOS. WHAT IS KNOWN ALREADY: In normal ovaries, AMH exerts an inhibitory role on antral follicle development and a fall in AMH levels is a prerequisite for ovulation. Levels of AMH are high in PCOS, contributing to the dysregulated follicle growth that is a common cause of anovulatory infertility in these women. STUDY DESIGN, SIZE, DURATION: Human KGN-GC (the cell line that corresponds to immature GC from smaller antral follicles (AF)) were cultured with a range of doses of various androgens to determine the effects on AMH production. KGN-GC were also treated with PHTPP (an oestrogen receptor ß (ERß) antagonist) to examine the relationship between AMH expression and the ratio of ERα:ERß. The differential dose-related effect of AMH on gene expression and SMAD signalling was investigated in human granulosa-luteal cells (hGLC) from women with normal ovaries, with polycystic ovarian morphology (PCOM) and with PCOS. KGN-GC were also cultured for a prolonged period with AMH at different doses to assess the effect on cell proliferation and viability. PARTICIPANTS/MATERIALS, SETTING, METHODS: AMH protein production by cells exposed to androgens was measured by ELISA. The effect of PHTPP on the mRNA expression levels of AMH, ERα and ERß was assessed by real-time quantitative PCR (qPCR). The influence of AMH on the relative mRNA expression levels of aromatase, AMH and its receptor AMHRII, and the FSH and LH receptor (FSHR and LHR) in control, PCOM and PCOS hGLCs was quantified by qPCR. Western blotting was used to assess changes in levels of SMAD proteins (pSMAD-1/5/8; SMAD-4; SMAD-6 and SMAD-7) after exposure of hGLCs from healthy women and women with PCOS to AMH. The ApoTox-Glo Triplex assay was used to evaluate the effect of AMH on cell viability, cytotoxicity and apoptosis. MAIN RESULTS AND THE ROLE OF CHANCE: Testosterone reduced AMH protein secreted from KGN-GC at 10-9-10-7 M (P < 0.05; P < 0.005, multiple uncorrected comparisons Fishers least squares difference), but at equivalent hyperandrogenemic levels no change was seen in AMH levels. 5α-DHT produced a significant dose-related increase in AMH protein secreted into the media (P = 0.022, ANOVA). Increasing the mRNA ratio of ERα:ERß produced a corresponding increase in AMH mRNA expression (P = 0.015, two-way ANOVA). AMH increased mRNA levels of aromatase (P < 0.05, one-way ANOVA) and FSHR (P < 0.0001, one-way ANOVA) in hGLCs from women with PCOM, but not from normal cells or PCOS (normal n = 7, PCOM n = 5, PCOS n = 4). In contrast to hGLCs from ovulatory ovaries, in PCOS AMH reduced protein levels (cell content) of stimulatory pSMAD-1/5/8 and SMAD-4 but increased inhibitory SMAD-6 and -7 (P < 0.05, normal n = 6, PCOS n = 3). AMH at 20 and 50 ng/ml decreased KGN-GC cell proliferation but not viability after 8 days of treatment (P < 0.005, two-way ANOVA). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Luteinised GC from women undergoing IVF have a relatively low expression of AMH/AMHRII but advantageously continue to display responses inherent to the ovarian morphology from which they are collected. To compensate, we also utilised the KGN cell line which has been characterised to be at a developmental stage close to that of immature GC. The lack of flutamide influence on testosterone effects is not in itself sufficient evidence to conclude that the effect on AMH is mediated via conversion to oestrogen, and the effect of aromatase inhibitors or oestrogen-specific inhibitors should be tested. The effect of flutamide was tested on testosterone but not DHT. WIDER IMPLICATIONS OF THE FINDINGS: Normal folliculogenesis and ovulation are dependent on the timely reduction in AMH production from GC at the time of follicle selection. Our findings reveal for the first time that theca-derived androgens may play a role in this model but that this inhibitory action is lost at levels of androgens equivalent to those seen in PCOS. The AMH decline may either be a direct effect of androgens or an indirect one via conversion to oestradiol and acting through the upregulation of ERα, which is known to stimulate the AMH promoter. Interestingly, the ability of GCs to respond to this continually elevated AMH level appears to be reduced in cells from women with PCOS due to an adaptive alteration in the SMAD signalling pathway and lower expression of AMHRII, indicating a form of 'AMH resistance'. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Thomas Addison Scholarship, St Georges Hospital Trust. The authors report no conflict of interest in this work and have nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

DJ1 and microRNA-214 act synergistically to rescue myoblast cells after ischemia/reperfusion injury.

Ischemia/reperfusion injury is a tissue injury occurring post-reperfusion of tissues with pre-existing ischemia. A good blood supply to tissues aids in the survival of ischemic tissue, however, due to prolonged ischemia the levels of ATP decrease and pH declines leading to acidosis. Reduced ATP leads to an increase in the AMP/ATP ratio, causing cessation of intracellular calcium transport, hence calcium overload and cell death. In this study, we demonstrate the synergistic and antagonistic effect of DJ1 and microR-214 (miR-214) in rescuing myoblast C2C12 cells after ischemia/reperfusion in an in vitro model. Both DJ1 and miR-214 were cloned into a hypoxic inducible expression cassette and transfected into the C2C12 cells. We showed that DJ1 and miR-214 have synergistic effects in reducing intracellular lactate dehydrogenase and intracellular transient calcium levels after reoxygenation compared to control cells, in addition to reducing cell death via necrosis. Western blotting revealed a decrease in autophagosome formation in LC3II/I ratio and an increase in AKT expression in cells transfected with DJ1 and miR-214. Using quantitative real-time PCR, we demonstrated that DJ1 and miR-214 significantly reduced the expression of pro-apoptotic factors and autophagy compared to control. The results indicated DJ1 is an endogenous oxidative stress molecule and miR-214 is a potent inhibitor of the sodium calcium exchanger channel. DJ1 had the greatest effect to inhibiting mitochondrial cell death pathways by possibly acting as a modulator of autophagy. Additionally, we have concluded that miR-214 has an inhibitory effect on extrinsic cell death pathways such as necrosis and autophagy.

Editor's Choice - Direct vs. Indirect Angiosomal Revascularisation of Infrapopliteal Arteries, an Updated Systematic Review and Meta-analysis.

BACKGROUND: The importance of the angiosome concept in tibial artery revascularisation remains controversial. The aim of this review was to assess the outcomes of direct revascularisation (revascularisation to the angiosome of tissue loss; DR) versus indirect revascularisation (IR) in infrapopliteal arteries. METHODS: A previously conducted systematic review was updated according to PRISMA guidelines. Studies comparing DR with IR by both endovascular and surgical means for patients with localised tissue loss were included. Meta-analyses were performed to assess the effect of DR versus IR on wound healing (total and time to healing), limb salvage, mortality, and re-intervention rates, with multiple sensitivity analyses. Outcome data quality was determined using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. RESULTS: Seven studies (2278 limbs) were identified in the updated search, which when combined with the previous search resulted in 22 studies, comprising 4146 limbs, being included. Wound healing rates (odds ratio [OR] 0.51; 95% CI 0.39-0.68, p < 0.001), time to wound healing (standard mean difference [SMD] -1.70; 95% CI -3.34 to -0.07, p = .04) and limb salvage (OR 0.37; 95% CI 0.24-0.58, p < .0001) were significantly better with DR compared with IR. Sensitivity analyses were concordant with the primary analysis for these outcomes, with the exception of the effect of wound healing rates between DR and IR, which was lost on sensitivity analysis for bypass surgery. Mode of revascularisation had no effect on mortality or on re-intervention rates. GRADE outcomes were very low. CONCLUSION: DR of the tibial vessels appears to result in improved wound healing and limb salvage rates compared with IR, with no effect on mortality or re-intervention rates. For surgical revascularisation the importance of DR appears to be lost for wound healing. When possible, these low quality data suggests DR should be undertaken in preference to IR.

Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant.

Biallelic mutations of the alsin Rho guanine nucleotide exchange factor (ALS2) gene cause a group of overlapping autosomal recessive neurodegenerative disorders including infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS/ALS2), caused by retrograde degeneration of the upper motor neurons of the pyramidal tracts. Here, we describe 11 individuals with IAHSP, aged 2-48 years, with IAHSP from three unrelated consanguineous Iranian families carrying the homozygous c.1640+1G>A founder mutation in ALS2. Three affected siblings from one family exhibit generalized dystonia which has not been previously described in families with IAHSP and has only been reported in three unrelated consanguineous families with JALS/ALS2. We report the oldest individuals with IAHSP to date and provide evidence that these patients survive well into their late 40s with preserved cognition and normal eye movements. Our study delineates the phenotypic spectrum of IAHSP and ALS2-related disorders and provides valuable insights into the natural disease course.

Predicting Technical Success after Fistuloplasty: An Analysis of 176 Procedures.

BACKGROUND: Significant stenoses in arteriovenous fistulae (AVFs) or arteriovenous grafts (AVGs) with limitation of flow and dialysis inadequacy should prompt consideration for fistuloplasty. We sought to identify fistulae, lesions, and patient-specific variables, which predict for outcomes after fistuloplasty. METHODS: Data were extracted retrospectively from a renal access database from 2011 to 2016 of patients undergoing fistuloplasty. Demographics, comorbidities, outcomes of intervention, and flow rates documented on preintervention and postintervention duplex were collected. Secondary analysis of factors associated with postfistuloplasty flow rates of >600 mL/min, previously shown to be predictive of not requiring future intervention, was performed. RESULTS: Of 204 attempted fistuloplasties, 176 were completed. One hundred forty (79.5%) were native AVFs and 34 (19.3%), AVGs (no data for 2). Median stenosis treated was 75%, with a majority (43.8%) in the proximal outflow vein. Flow rate on duplex after fistuloplasty was significantly better in AVFs (mean improvement 189.2 mL/min) than that in AVGs (mean improvement 51.8 mL/min; P = 0.034). Greatest flow improvement occurred for needling site stenotic lesions compared with other locations (from anastomosis to central vein) but was not significant. Brachio-brachial or brachio-axillary AVGs did significantly (P < 0.05) worse than all other fistulae types. The presence of hypertension was predicted for postfistuloplasty flow rate of >600 mL/min. CONCLUSIONS: Flow rates after fistuloplasty vary depending on the type of fistula treated and the presence of hypertension. Knowledge of this can lead to better patient selection and counseling for fistuloplasty.

Niemann-Pick Diseases: The Largest Iranian Cohort with Genetic Analysis.

OBJECTIVES: Niemann-Pick diseases (NPD) is an autosomal recessive inherited lysosomal lipid storage disorder which occurs due to a defect in cellular cholesterol trafficking, leading to excess lipid accumulation in multiple organ systems such as the brain, lungs, spleen, and liver. SPMD1-associated disease includes classic infantile and visceral NPD type A and B respectively. Type C NPD is subacute or juvenile. MATERIALS & METHODS: During 2012-2016, the patients who had the clinical and biochemical signs and symptoms of different types of NPD, underwent genetic analysis. All patients were collected from five provinces in Iran (Razavi Khorasan, South Khorasan, Khozaestan, Isfahan and Tehran province). Sanger sequencing of the candidate genes for NPD was performed followed by bioinformatics analysis to confirm the types of NPD and to identify novel mutations. All patients underwent full clinical assessment. RESULTS: We present two cases with NPD type A, six cases with NPD type B, and 11 cases with type C with various enzymatic defects identified in these cases. Within these 19 patients, we present 9 previously reported mutations and 10 novel mutations causing NPD. CONCLUSION: This study is the largest Iranian study for NPD analysis ever. Our report demonstrates that NPD has a variable age of onset and can present early in life. We investigated the clinical and genetic manifestations of a large Iranian cohort. Understanding the variable presentation of NPD will allow for clinicians to have a high index of suspicion for the disease.

Epithelial mesenchymal transition Transcription Factor (TF): The structure, function and microRNA feedback loop.

Epithelial to mesenchymal transition (EMT) is a phenomenon in which epithelial cells lose their cell to cell adhesion and detach from the base of the membrane. EMT is a fundamental process which occurs during tumor progression and metastasis. Cancer genomics is a complex network which involves a variety of factors such as transcription factors (TFs), coding genes and microRNAs (miRs). Both TFs and miRs are trans-regulatory elements that crosstalk. Due to a wide range of targets, TF-miR interaction provides a feedback or feedforward loop and cross-gene regulation consequently. In this review, we focused on the structure and function of two TF families involved in EMT, zinc finger and ß helix loop helix and p53. Subsequently we analyzed recent findings on TF-miR interaction in EMT.

Potential role of gender specific effect of leptin receptor deficiency in an extended consanguineous family with severe early-onset obesity.

Congenital Leptin receptor (LEPR) deficiency is a rare genetic cause of early-onset morbid obesity characterised by severe early onset obesity, major hyperphagia, hypogonadotropic hypogonadism and immune and neuroendocrine/metabolic dysfunction. We identified a homozygous loss-of-function mutation, NM_002303.5:c.464 T > G; p.(Tyr155*), in the LEPR in an extended consanguineous family with multiple individuals affected by early-onset severe obesity and hyperphagia. Interestingly, the LEPR-deficient adult females have extremely high body mass index (BMI) with hypogonadal infertility, the BMI of the affected males began to decline around the onset of puberty (13-15 years) with fertility being preserved. These findings lead to the speculation that LEPR deficiency may have a gender-specific effect on the regulation of body weight. In order to elucidate gender-specific effects of LEPR deficiency on reproduction further investigations are needed. The limitations of this study are that our conclusion is based on observations of two males and two females. Further LEPR deficient males and females are required for comparison in order to support this finding more confidently.

Construction and Development of a Cardiac Tissue-Specific and Hypoxia-Inducible Expression Vector.

Purpose: Cardiovascular gene therapy is a sophisticated approach, thanks to the safety of vectors, stable transgene expression, delivery method, and different layers of the heart. To date, numerous expression vectors have been introduced in biotechnology and biopharmacy industries in relation to genetic manipulation. Despite the rapid growth of these modalities, they must be intelligently designed, addressing the cardiac-specific transgene expression and less side effects. Herein, we conducted a pilot project aiming to design a cardiac-specific hypoxia-inducible expression cassette. Methods: We explored a new approach to design an expression cassette containing cardiac specific enhancer, hypoxia response elements (HRE), cardiac specific promoter, internal ribosome entry site (IRES), and beta globin poly A sequence to elicit specific and inducible expression of the gene of interest. Enhanced green fluorescent protein (eGFP) was sub-cloned by BglII and NotI into the cassette. The specificity and inducible expression of the cassette was determined in both mouse myoblast C2C12 and mammary glandular tumor 4T1 as 'twin' cells. eGFP expression was evaluated by immunofluorescence microscope and flow cytometry at 520 nm emission peak. Results: Our data revealed that the designed expression cassette provided tissue specific and hypoxia inducible (O2<1%) transgene expression. Conclusion: It is suggested that cardiac-specific enhancer combined with cardiac-specific promoter are efficient for myoblast specific gene expression. As well, this is for the first time that HRE are derived from three well known hypoxia-regulated promoters. Therefore, there is no longer need to overlap PCR process for one repeated sequence just in one promoter.

Novel Homozygous Missense Mutation in RYR1 Leads to Severe Congenital Ptosis, Ophthalmoplegia, and Scoliosis in the Absence of Myopathy.

Ryanodine receptor 1 (RYR1) is an intracellular calcium receptor primarily expressed in skeletal muscle with a role in excitation contraction. Both dominant and recessive mutations in the RYR1 gene cause a range of RYR1-related myopathies and/or susceptibility to malignant hyperthermia (MH). Recently, an atypical manifestation of ptosis, variably presenting with ophthalmoplegia, facial paralysis, and scoliosis but without significant muscle weakness, has been reported in 9 cases from 4 families with bialleic variants in RYR1. Two affected children from a consanguineous family with severe congenital ptosis, ophthalmoplegia, scoliosis, and distinctive long faces but without skeletal myopathy were studied. To identify the cause of the hereditary condition, DNA from the proband was subjected to whole exome sequencing (WES). WES revealed a novel homozygous missense variant in RYR1 (c.14066T>A; p.IIe4689Asn), which segregated within the family. Although the phenotype of the affected siblings in this study was similar to previously described cases, the clinical features were more severely expressed. Our findings contribute to the expansion of phenotypes related to RYR1 dysfunction. Additionally, it supports a new RYR1-related clinical presentation without musculoskeletal involvement. It is important that individuals with RYR1 mutations are considered susceptible to MH, as 70% of the MH cases are caused by mutations in the RYR1 gene.

The physiology and clinical utility of anti-Mullerian hormone in women.

BACKGROUND The measurement of circulating anti-Müllerian hormone (AMH) has been applied to a wide array of clinical applications, mainly based on its ability to reflect the number of antral and pre-antral follicles present in the ovaries. AMH has been suggested to predict the ovarian response to hyperstimulation of the ovaries for IVF and the timing of menopause, and to indicate iatrogenic damage to the ovarian follicle reserve. It has also been proposed as a surrogate for antral follicle count (AFC) in the diagnosis of polycystic ovary syndrome (PCOS). METHODS This paper is a summary of presentations at a European Society of Human Reproduction and Embryology campus workshop on AMH, with literature cited until September 2013. Published peer-reviewed medical literature about AMH was searched through MEDLINE and was subjected to systematic review and critical assessment by the panel of authors. RESULTS Physiologically, recent data confirm that AMH is a follicular gatekeeper limiting follicle growth initiation, and subsequently estradiol production from small antral follicles prior to selection. AMH assays continue to evolve and technical issues remain; the absence of an international standard is a key issue. The dynamics of circulating AMH levels throughout life can be split into several distinct phases, with a peak in the early 20s before a decline to the menopause, with a strong and positive correlation with non-growing follicle recruitment. There is a more complex rise during childhood and adolescence, which is likely to be more reflective of different stages of follicle development. AMH shows limited short-term variability, but the influence of states such as prolonged oral contraceptive use need to be considered in clinical assessment. There are only very limited data on relationships between AMH and natural fertility at different stages of reproductive life, and while it has a relationship to age at menopause the marked variability in this needs further exploration. AMH may be useful in assessing the need for fertility preservation strategies and detecting post-chemotherapy or surgical damage to the ovarian reserve. Long-term follow-up of patients to ascertain fully the value of post-cancer serum AMH in predicting long-term ovarian function is required. There is a linear relationship between AMH and oocyte yield after ovarian stimulation, which is of value in predicting ovarian hyperstimulation. AMH can also identify 'poor responders', but it seems inappropriate at present to withhold IVF purely on this basis. Women with PCOS show markedly raised AMH levels, due to both the increased number of small antral follicles and intrinsic characteristics of those granulosa cells, and this may contribute to anovulation. The value of AMH in the diagnosis of PCOS remains controversial, but it may replace AFC in the future. CONCLUSIONS For the first time in female reproductive biology, it is possible to measure the submerged part of the iceberg of follicle growth, i.e. the intrinsic, so-called 'acyclic' ovarian activity. An international standard for AMH and improved assay validity are urgently needed to maximize the clinical utility of this very promising biomarker of ovarian function in a large array of clinical situations, both in childhood and adulthood.

Anti-Müllerian hormone reduces follicle sensitivity to follicle-stimulating hormone in human granulosa cells.

OBJECTIVE: To determine that anti-Müllerian hormone (AMH) has been shown to inhibits E(2) production in rodents and in luteinized granulosa cells (GC). We determined whether this occurs in human cells most highly expressing AMH (i.e., from small antral follicles) and whether this is an effect on aromatase promoter activity. We also investigated the effects of AMH on other factors determining FSH sensitivity. DESIGN: Granulosa cells were exposed to AMH with and without gonadotropins for 48 hours. SETTING: University laboratory. PATIENT(S): Not applicable. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Aromatase and FSH receptor messenger RNA expression measured using real time quantitative polymerase chain reaction (PCR). Aromatase promoter II activity measured using a luciferase assay. Estradiol, inhibin A and B, and vascular endothelial growth factor production were measured in the conditioned medium. RESULT(S): The AMH decreased gonadotropin-stimulated aromatase expression and decreased forskolin-stimulated aromatase in KGN cells and this effect was through a dose-dependent inhibition of promoter II. Surprisingly, AMH also reduced FSH receptor mRNA expression. High AMH doses had no effect on inhibin B, whereas a low dose stimulated production. There was no effect on inhibin A or vascular endothelial growth factor. CONCLUSION(S): The AMH inhibits factors affecting FSH sensitivity. As AMH levels decrease with follicle growth, this inhibition would be removed. The AMH overproduction in anovulatory polycystic ovaries (PCO) may therefore restrict folliculogenesis by an inhibitory effect on FSH sensitivity, thereby contributing to anovulation.