The polymorphism Val158Met in the COMT gene: disrupted dopamine system in fibromyalgia patients?

ABSTRACT: The single-nucleotide polymorphism (SNP) rs4680 in the catechol-O-methyltransferase gene ( COMT ) is a missense variant (Val158Met) associated with altered activity of the COMT enzyme and suggested as a predictive feature for developing some chronic pain conditions. However, there are controversial results on its role in fibromyalgia (FM). Here, the SNP Val158Met was analyzed in 294 FM patients (without comorbidities) and 209 healthy controls (without chronic pain). The concurrent impact of Val158Met genotypes and FM comorbid disorders (depression and sleep impairment) on FM risk were tested. In addition, the genotypic distribution of FM patients in relation to pain intensity was evaluated. The G allele (Val) resulted in being more represented in the FM group (57.8%) compared with the control group (48.8%; P = 0.037). Logistic regression highlighted that having the G/G (Val/Val) homozygous genotype was associated with 2 times higher risk of having FM compared with the A/A (Met/Met) carriers ( P = 0.038), whereas depression and sleep impairment increased FM risk by 12 and 8 times, respectively ( P < 0.001). However, considering only the FM patient group, the A/A homozygous genotype was significantly associated with severe pain intensity ( P = 0.007). This study highlighted associations between the SNP Val158Met and both FM and pain intensity, suggesting a link between dopaminergic dysfunction and vulnerability to chronic pain. Further studies should explore this SNP in FM patients in conjunction with COMT enzymatic activity and other symptoms connected with the dopaminergic system such as depression or sleep impairment.

Chest circumference and structural and short-term changes: a study of the Italian military call-up registers from 1881 to 1909.

The aim of this study is to demonstrate the utility of chest circumference measurements as a proxy for the socioeconomic characteristics of past populations. Our analysis is based on over 80,000 military medical examinations relating to Friuli (north-eastern Italy), recorded from 1881 to 1909. Chest circumference can be used to describe changes in standard of living, but also seasonal variations in food intakes and physical activities. The findings show the way in which these measurements are highly sensitive not only to long-term economic changes but, above all, to short-term variations in some economic and social elements, like corn prices and occupations.

Effects of a dietary intervention with Mediterranean vs lacto-ovo vegetarian diets on HDL function: Results from the CARDIVEG study.

BACKGROUND AND AIM: HDL-cholesterol efflux capacity (CEC) has been shown to be a better cardiovascular (CVD) risk marker than serum HDL concentration. Several foods and nutrients have been shown to improve HDL functions, however no effective dietetic nor pharmacological strategy is available to increase CEC. This study aims to evaluate the possible effect of Mediterranean diet (MD) and lacto-ovo-vegetarian diet (VD) on HDL function in a group of clinically healthy subjects at low-to-moderate CVD risk. METHODS AND RESULTS: Thirty apparently healthy subjects with a low-to-moderate cardiovascular risk profile (21 F; mean age: 51.3 ± 9.7 years) were randomly assigned to a 3-month MD or VD diet and then crossed. Participants on VD showed a reduction in total HDL CEC by 8.99% (p < 0.001) as well as a reduction in ABCA1 mediated-CEC by 18.62% (p < 0.001) compared to participants on MD. Regarding CEC mediated by aqueous diffusion, no significant changes were observed after treatment with either diet. Finally, a significant positive association between CEC mediated by the ABCA1 transporter and adiponectin was found (r = 0.462; p = 0.010). CONCLUSION: The results of this study suggest that HDL activity in promoting cholesterol efflux and thereby reducing the concentration of pro-atherogenic lipoproteins was more effective in participants undergoing MD than VD. Based on these findings, the MD could be considered a better therapeutic strategy for cardiovascular prevention than VD. CLINICAL TRIAL REGISTRATION URL: http://www. CLINICALTRIALS: gov. Unique identifier: NCT02641834.

Maternal nutritional status and offspring childlessness: Evidence from the late-nineteenth to early-twentieth centuries in a group of Italian populations.

The role of maternal nutrition in affecting offspring fertility, through alteration of foetal programming, has been demonstrated in animal-based experiments. However, results from human populations appear inconsistent and sometimes contradictory, likely because they have been based on single famine events. In this paper, we adopt a different approach. We combine official annual time series of daily nutrient availability with a sample of women's reproductive histories from the 1961 Italian Census to investigate the role of maternal nutritional status in pregnancy on offspring childlessness. The analysis therefore covers cohorts of females born between 1861 and 1939. Our results show a negative association between calorie availability in pregnancy and the odds of offspring childlessness, whereas no association is found between protein availability and offspring childlessness. The consequences of poor calorie intake were aggravated during the summer, likely due to the participation of pregnant women in physically demanding work.

DNA Methylation Changes in Fibromyalgia Suggest the Role of the Immune-Inflammatory Response and Central Sensitization.

Fibromyalgia (FM) has been explained as a result of gene-environment interactions. The present study aims to verify DNA methylation differences in eleven candidate genome regions previously associated to FM, evaluating DNA methylation patterns as potential disease biomarkers. DNA methylation was analyzed through bisulfite sequencing, comparing 42 FM women and their 42 healthy sisters. The associations between the level of methylation in these regions were further explored through a network analysis. Lastly, a logistic regression model investigated the regions potentially associated with FM, when controlling for sociodemographic variables and depressive symptoms. The analysis highlighted significant differences in the GCSAML region methylation between patients and controls. Moreover, seventeen single CpGs, belonging to other genes, were significantly different, however, only one cytosine related to GCSAML survived the correction for multiple comparisons. The network structure of methylation sites was different for each group; GRM2 methylation represented a central node only for FM patients. Logistic regression revealed that depressive symptoms and DNA methylation in the GRM2 region were significantly associated with FM risk. Our study encourages better exploration of GCSAML and GRM2 functions and their possible role in FM affecting immune, inflammatory response, and central sensitization of pain.

DNA methylation changes in genes involved in inflammation and depression in fibromyalgia: a pilot study.

OBJECTIVES: The present pilot study aims to investigate DNA methylation changes of genes related to fibromyalgia (FM) development and its main comorbid symptoms, including sleep impairment, inflammation, depression and other psychiatric disorders. Epigenetic modifications might trigger or perpetuate complex interplay between pain transduction/transmission, central pain processing and experienced stressors in vulnerable individuals. METHODS: We conducted DNA methylation analysis by targeted bisulfite NGS sequencing testing differential methylation in 112 genomic regions from leukocytes of eight women with FM and their eight healthy sisters as controls. RESULTS: Tests for differentially methylated regions and cytosines brought focus on the GRM2 gene, encoding the metabotropic glutamate receptor2. The slightly increased DNA methylation observed in the GRM2 region of FM patients may confirm the involvement of the glutamate pathway in this pathological condition. Logistic regression highlighted the simultaneous association of methylation levels of depression and inflammation-related genes with FM. CONCLUSIONS: Altogether, the results evidence the glutamate pathway involvement in FM and support the idea that a combination of methylated and unmethylated genes could represent a risk factor to FM or its consequence, more than single genes. Further studies on the identified biomarkers could contribute to unravel the causative underlying FM mechanisms, giving reliable directions to research, improving the diagnosis and effective therapies.

A family-based study to identify genetic biomarkers of fibromyalgia: consideration of patients' subgroups.

OBJECTIVES: Evidence from genome-wide and candidate gene association studies, familial aggregation and linkage analyses demonstrate the genetic contribution to fibromyalgia (FM) disease. This study aimed to identify genetic biomarkers of FM and its related comorbid disorders, by exploring 41 polymorphisms potentially involved in FM pathogenesis in families with at least one patient with FM. METHODS: Core symptoms were assessed, and blood samples collected from 556 patients with FM and 395 healthy relatives. For the genetic study, a final sample of 401 FM patients and 232 healthy controls was selected, discarding patients with concomitant pathologies and controls with chronic pain. A family-based approach using DFAM test (Plink) and SNPs (single nucleotide polymorphisms) combination analyses to compare FM patients vs. controls were first applied. Second, the genotypic distribution of subgroups of FM patients, stratified by severe vs. mild symptoms of pain, depression and sleep impairment, was considered. RESULTS: No evidence of associations with FM per se were detected, using either a family-based approach or SNPs combination analyses. However, considering the subgroups of FM patients, the SNP rs6454674 (CNR1, cannabinoid receptor 1 gene) was found as a potential genetic marker of FM correlated with depression (p<.001). CONCLUSIONS: No significant associations using either the family-based analysis or the SNPs combination tests dissociated FM patients and their healthy relatives. FM patients with and without depression showed a significant difference in the genotypic distribution related to the SNP rs6454674 in the cannabinoid receptor 1 gene (CNR1) indicating that FM is not a homogenous disorder.

Polymorphism rs7214723 in CAMKK1: a new genetic variant associated with cardiovascular diseases.

Cardiovascular diseases (CVDs) are the leading cause of deaths worldwide. CVDs have a complex etiology due to the several factors underlying its development including environment, lifestyle, and genetics. Given the role of calcium signal transduction in several CVDs, we investigated via PCR-restriction fragment length polymorphism (RFLP) the single nucleotide polymorphism (SNP) rs7214723 within the calcium/calmodulin-dependent kinase kinase 1 (CAMKK1) gene coding for the Ca2+/calmodulin-dependent protein kinase kinase I. The variant rs7214723 causes E375G substitution within the kinase domain of CAMKK1. A cross-sectional study was conducted on 300 cardiac patients. RFLP-PCR technique was applied, and statistical analysis was performed to evaluate genotypic and allelic frequencies and to identify an association between SNP and risk of developing specific CVD. Genotype and allele frequencies for rs7214723 were statistically different between cardiopathic and several European reference populations. A logistic regression analysis adjusted for gender, age, diabetes, hypertension, BMI and previous history of malignancy was applied on cardiopathic genotypic data and no association was found between rs7214723 polymorphism and risk of developing specific coronary artery disease (CAD) and aortic stenosis (AS). These results suggest the potential role of rs7214723 in CVD susceptibility as a possible genetic biomarker.

HDL-Mediated Cholesterol Efflux and Plasma Loading Capacities Are Altered in Subjects with Metabolically- but Not Genetically Driven Non-Alcoholic Fatty Liver Disease (NAFLD).

Background. Non-alcoholic fatty liver disease (NAFLD) increases the risk of atherosclerosis but this risk may differ between metabolically- vs. genetically-driven NAFLD. High-density lipoprotein (HDL)-mediated cholesterol efflux (CEC) and plasma loading capacity (CLC) are key factors in atherogenesis. Aims. To test whether CEC and CLC differ between metabolically- vs. genetically-determined NAFLD. Methods: CEC and CLC were measured in 19 patients with metabolic NAFLD and wild-type PNPLA3 genotype (Group M), 10 patients with genetic NAFLD carrying M148M PNPLA3 genotype (Group G), and 10 controls PNPLA3 wild-types and without NAFLD. CEC and CLC were measured ex vivo by isotopic and fluorimetric techniques using cellular models. Results: Compared with Group G, Group M showed reduced total CEC (-18.6%; p < 0.001) as well as that mediated by cholesterol transporters (-25.3% ABCA1; -16.3% ABCG1; -14.8% aqueous diffusion; all p < 0.04). No difference in CEC was found between Group G and controls. The presence of metabolic syndrome further impaired ABCG1-mediated CEC in Group M. Group M had higher plasma-induced CLC than Group G and controls (p < 0.001). Conclusions: Metabolically-, but not genetically-, driven NAFLD associates with dysfunctional HDL-meditated CEC and abnormal CLC. These data suggest that the mechanisms of anti-atherogenic protection in metabolic NAFLD are impaired.

The effects of nutrition on maternal mortality: Evidence from 19th-20th century Italy.

The role of nutrition on maternal mortality has been long debated in the historical and scientific literature. Some scholars refute any role of nutrition and diet in the decline of maternal mortality, privileging other causes such as the diffusion of professional midwifery and medical and scientific progress, while others are more open-minded about some possible nutritional effects. The present paper investigates the relationship between maternal mortality and nutrition in Italy between 1887 and 1955 with the purpose to provide new elements and new data to the knowledge of such an association. Using time-series techniques on the official data provided by the National Institute of Statistics, the analysis demonstrates that the trend of maternal mortality was affected by both long- and short-term dynamics of the average daily caloric intake of the Italian population once controlled for the economic situation, here proxied by the annual time series of the GDP per capita. The same analysis clarifies that the impact of nutrition is just one element of a complex picture in which the major role is played by medical advances and scientific progress. The introduction of sulphonamides, in the second half of the thirties of the twentieth century, emerges, in fact, as the turning point in the fight against maternal death.

Lipoprotein(a) concentration, genetic variants, apo(a) isoform size, and cellular cholesterol efflux in patients with elevated Lp(a) and coronary heart disease submitted or not to lipoprotein apheresis: An Italian case-control multicenter study on Lp(a).

BACKGROUND: Coronary artery disease (CAD) risk is greater with higher plasma lipoprotein(a)[Lp(a)] concentrations or smaller apoisoform size and putatively with increased cellular cholesterol loading capacity (CLC). The relationship between Lp(a) and CLC is not known. Information on Lp(a) polymorphisms in Italian patients is lacking. OBJECTIVE: The objective of this study was to determine relationships between Lp(a) and CLC, the impact of lipoprotein apheresis (LA), and describe the genetic profile of Lp(a). METHODS: We conducted a multicenter, observational study in Italian patients with hyperLp(a) and premature CAD with (n = 18)/without (n = 16) LA in which blood samples were analyzed for Lp(a) parameter and CLC. Genetic profiling of LPA was conducted in patient receiving LA. RESULTS: Mean macrophage CLC of the pre-LA serum was significantly higher than that of normolipidemic controls (19.7 ± 0.9 µg/mg vs 16.01 ± 0.98 µg/mg of protein, respectively). After LA, serum macrophage CLC was markedly lower relative to preapheresis (16.1 ± 0.8 µg/mg protein; P = .003) and comparable with CLC of the normolipidemic serum. LA did not significantly affect average apo(a) isoform size distribution. No anthropometric or lipid parameters studied were related to serum CLC, but there was a relationship between CLC and the Lp(a) plasma concentration (P = .035). DNA analysis revealed a range of common genetic variants. Two rare, new variants were identified: LPA exon 21, c.3269C>G, p.Pro1090Arg, and rs41259144 p.Arg990Gln, c.2969G>A CONCLUSIONS: LA reduces serum Lp(a) and also reduces macrophage CLC. Novel genetic variants of the LPA gene were identified, and geographic variations were noted. The complexity of these polymorphisms means that genetic assessment is not a predictor of CAD risk in hyperLp(a).

Genetic and Environmental Risk Factors for Cannabis Use: Preliminary Results for the Role of Parental Care Perception.

BACKGROUND: Vulnerability to cannabis use (CU) initiation and problematic use have been shown to be affected by both genetic and environmental factors, with still inconclusive and uncertain evidence. OBJECTIVE: Aim of the present study was to investigate the possible interplay between gene polymorphisms and psychosocial conditions in CU susceptibility. METHODS: Ninety-two cannabis users and ninety-three controls have been included in the study. Exclusion criteria were serious mental health disorders and severe somatic disorders, use of other drugs and alcohol abuse; control subjects were not screened to remove Reward Deficiency Syndrome (RDS) behaviors. A candidate gene association study was performed, including variants related to dopaminergic and endocannabinoids pathways. Adverse childhood experiences and quality of parental care have been retrospectively explored utilizing ACES (Adverse Children Experience Scale), CECA-q (Child Experience of Care and Abuse Questionnaire), PBI (Parental Bonding Instrument). RESULTS: Our findings evidenced a significant association between rs1800497 Taq1A of ANKK1 gene and CU. Parental care was found to be protective factor, with emotional and physical neglect specifically influencing CU. Gender also played a role in CU, with males smoking more than females. However, when tested together genotypes and psychosocial variables, the significance of observed genetic differences disappeared. CONCLUSIONS: Our results confirm a significant role of Taq1A polymorphism in CU vulnerability. A primary role of environmental factors in mediating genetic risk has been highlighted: parental care could be considered the main target to design early prevention programs and strategies.

Spanish flu in Italy: new data, new questions.

This paper proposes a new estimate for the number of victims of Spanish flu in Italy and highlights some aspects of mortality closely linked to the First World War. The sources used are official death statistics and the Albo d'oro, a roll of honor of the Italians fallen in the First World War. The new estimate of deaths from the flu is 410,000 for 1918, which should be raised to 466,000 when the numbers are taken up to 1920. Deaths from Spanish flu among the military were about 70,000. The time sequence of deaths recognizes two distinct peaks, one in October and one in November 1918. Between these two peaks, the lowest number of deaths falls in the week of the armistice between Italy and Austria-Hungary (signed 4 November 1918). This suggests links between Spanish flu and WWI that cannot be merely explained in terms of movement of people and contagion.

Gene variants and educational attainment in cannabis use: mediating role of DNA methylation.

Genetic and sociodemographic risk factors potentially associated with cannabis use (CU) were investigated in 40 cannabis users and 96 control subjects. DNA methylation analyses were also performed to explore the possibility of epigenetic changes related to CU. We conducted a candidate gene association study that included variants involved in the dopaminergic (ANKK1, NCAM1 genes) and endocannabinoid (CNR1, CNR2 gene) pathways. Sociodemographic data included gender, marital status, level of education, and body mass index. We used MeDIP-qPCR to test whether variations in DNA methylation might be associated with CU. We found a significant association between SNP rs1049353 of CNR1 gene (p = 0.01) and CU. Differences were also observed related to rs2501431 of CNR2 gene (p = 0.058). A higher education level appears to decrease the risk of CU. Interestingly, females were less likely to use cannabis than males. There was a significantly higher level of DNA methylation in cannabis users compared to controls in two of the genes tested: hypermethylation at exon 8 of DRD2 gene (p = 0.034) and at the CpG-rich region in the NCAM1 gene (p = 0.0004). Both genetic variants and educational attainment were also related to CU. The higher rate of DNA methylation, evidenced among cannabis users, may be either a marker of CU or a consequence of long-term exposure to cannabis. The identified genetic variants and the differentially methylated regions may represent biomarkers and/or potential targets for designs of pharmacological therapeutic agents. Our observations also suggest that educational programs may be useful strategies for CU prevention.

Kin and birth order effects on male child mortality: three East Asian populations, 1716-1945.

Human child survival depends on adult investment, typically from parents. However, in spite of recent research advances on kin influence and birth order effects on human infant and child mortality, studies that directly examine the interaction of kin context and birth order on sibling differences in child mortality are still rare. Our study supplements this literature with new findings from large-scale individual-level panel data for three East Asian historical populations from northeast China (1789-1909), northeast Japan (1716-1870), and north Taiwan (1906-1945), where preference for sons and first-borns is common. We examine and compare male child mortality risks by presence/absence of co-resident parents, grandparents, and other kin, as well as their interaction effects with birth order. We apply discrete-time event-history analysis on over 172,000 observations of 69,125 boys aged 1-9 years old. We find that in all three populations, while the presence of parents is important for child survival, it is more beneficial to first/early-borns than to later-borns. Effects of other co-resident kin are however null or inconsistent between populations. Our findings underscore the importance of birth order in understanding how differential parental investment may produce child survival differentials between siblings.

[Health maps of a historical population in nineteenth-century Friuli (Northeastern Italy)]. / Le mappe di salute di una popolazione storica prime indagini sul Friuli (XIX secolo).

This paper aims at presenting some health maps of a historical population. The studies on the health status of past populations are usually focused on the causes of death. Our purpose is to present some descriptive analyses on non-deadly diseases. The present work focuses on the province of Friuli (north-eastern Italy) in the second half of the nineteenth century. The used sources are military call-up records. We collected about 300,000 records relative to military recruitment that took place between 1866 and 1909 (birth cohorts 1846-1890). Our main concern was the health status of the 20-year male population, and its association with environmental, socio economic and genetic factors. Generally speaking, we observe that the northern mountain area was the most advantaged, while young adults from the eastern and western parts of the province were the most disadvantaged. A lot of factors and causes contributed to determine the spatial distribution of specific diseases in Friuli, whilst others remain unknown because simple descriptive analyses are not sufficient to highlight them all. In particular, the distribution of the thyroidal hypertrophy was almost certainly due to the water quality, while the distribution of dental caries was probably related to genetic and dietary factors.

Co-occurring Attention Deficit Hyperactivity Disorder symptoms in adults affected by heroin dependence: Patients characteristics and treatment needs.

Attention Deficit Hyperactivity Disorder (ADHD) is a risk for substance use disorders. The aim of this study was to investigate the association between adult ADHD symptoms, opioid use disorder, life dysfunction and co-occurring psychiatric symptoms. 1057 heroin dependent patients on opioid substitution treatment participated in the survey. All patients were screened for adult ADHD symptoms using the Adult ADHD Self-Report Scale (ASRS-v1.1). 19.4% of the patients screened positive for concurrent adult ADHD symptoms status and heroin dependence. Education level was lower among patients with ADHD symptoms, but not significant with respect to non-ADHD patients. Patients with greater ADHD symptoms severity were less likely to be employed. A positive association was observed between ADHD symptoms status and psychiatric symptoms. Patients with ADHD symptoms status were more likely to be smokers. Patients on methadone had a higher rate of ADHD symptoms status compared to buprenorphine. Those individuals prescribed psychoactive drugs were more likely to have ADHD symptoms. In conclusion, high rate of ADHD symptoms was found among heroin dependent patients, particularly those affected by the most severe form of addiction. These individuals had higher rates of unemployment, other co-morbid mental health conditions, heavy tobacco smoking. Additional psychopharmacological interventions targeting ADHD symptoms, other than opioid substitution, is a public health need.

Increased oxytocin levels among abstinent heroin addicts: Association with aggressiveness, psychiatric symptoms and perceived childhood neglect.

A disruption of the oxytocin system seems to affect a variety of brain functions including emotions, mood and social behavior possibly underlying severe social deficits and susceptibility for substance use and mental health disorders. Early life adversity, such as insecure attachment in childhood, has been suggested to influence oxytocin tone contributing to a condition of neurobiological vulnerability. Aim of the present study was to investigate oxytocin serum levels in abstinent heroin addicted patients, in comparison with healthy controls, and the possible correlation with co-occurring psychiatric symptoms, aggressiveness and perception of parental neglect. Eighteen (18) abstinent patients, affected by heroin use disorders, and 18 control subjects, who never used drugs or abused alcohol, were included in the study and submitted to 1) collection of a blood sample for oxytocin assay, 2) Symptoms Check List 90 for psychiatric symptoms evaluation 3) Buss Durkee Hostility Inventory to measure aggressiveness 4) Child Experience of Care and Abuse-Questionnaire to retrospectively test the perception of parental neglect. Heroin exposure extent and heroin dosages were also recorded. Oxytocin serum levels were unexpectedly significantly higher among abstinent patients affected by heroin use disorders and positively correlated with psychiatric symptoms, aggressiveness and mother neglect scores. No correlation was evidenced between oxytocin and heroin exposure extent or dosages. Our findings appear to contradict the simplistic view of oxytocin as a pro-social hormone and confirm previous evidence concerning the peptide levels direct association with aggressive behavior and mood disorders. Considering a more complex mechanism, oxytocin would increase the sensitivity to social salience cues related to contextual or inter-individual factors, promoting pro-sociality in "safe" conditions and, in contrast, inducing more defensive and "anti-social" emotions and behaviors when the social cues are interpreted as "unsafe". This latter condition is often characterizing the clinical history of addicted patients.

Perceived parental care during childhood, ACTH, cortisol and nicotine dependence in the adult.

Studies evidenced the relationship between adverse childhood experiences (ACEs) and tobacco smoking in adulthood. An appropriate parenting style has been found to be associated with children's less frequent tobacco consumption. Hypothalamus-pituitary-adrenal (HPA) axis hyperactivity could represent the potential link between ACEs, mood disorders and smoking susceptibility. We studied a sample of 50 male smokers, affected by nicotine dependence and 50 controls who never smoked. Self-reported retrospective perception of neglect (Child Experience of Care and Abuse: CECA-Q questionnaire), age of smoking onset, number of cigarette/day, psychiatric symptoms (Symptoms Check List 90 scale: SCL 90) and basal level of ACTH and cortisol have been evaluated. Total SCL-90 scores, CECA-Q values and cortisol plasma level were significantly higher among smokers. Cortisol and ACTH values showed a significant direct correlation with CECA-Q and SCL90 total score and an inverse significant correlation with the age of smoking. Cortisol and ACTH did not correlate with the number of cigarette smoked. Once controlled for SCL90 and CECA-Q with multiple regression measures, the association between smoking and hormone levels reversed, suggesting that increased cortisol and ACTH basal levels were attributable to preexisting conditions such as early-life exposure to emotional neglect, psychological problems and a predisposition to addictive behavior.

Sexual Dysfunction in Men Receiving Methadone Maintenance Treatment: Clinical History and Psychobiological Correlates.

A variety of studies evidenced a relationship between drug use disorders and sexual dysfunction. In particular, heroin and opioid agonist medications to treat heroin dependence have been found to be associated with erectile dysfunction and reduced libido. Controversial findings also indicate the possibility of factors other than the pharmacological effects of opioid drugs concurring to sexual dysfunction. With the present study, we investigated the link between sexual dysfunction and long-term exposure to opioid receptor stimulation (heroin dependence, methadone maintenance treatment, methadone dosage), the potentially related hormonal changes reflecting hypothalamus-pituitary-gonadal axis function and prolactin (PRL) pituitary release, the role of adverse childhood experiences in the clinical history and the concomitant symptoms of comorbid mental health disorders in contributing to sexual problems. Forty male patients participating in a long-term methadone treatment program were included in the present study and compared with 40 healthy control subjects who never used drugs nor abused alcohol. All patients and controls were submitted to the Arizona Sexual Experiences Scale (ASEX), Child Experiences of Care and Abuse-Questionnaire (CECA-Q) and the Symptom Check List-90 Scale. A blood sample for testosterone and PRL assays was collected. Methadone dosages were recorded among heroin-dependent patients on maintenance treatment. Methadone patients scored significantly higher than controls on the 5-item rating ASEX scale, on CECA-Q and on Symptoms Check List 90 (SCL 90) scale. Testosterone plasma levels were significantly lower and PRL levels significantly higher in methadone patients with respect to the healthy control group. ASEX scores reflecting sexual dysfunction were directly and significantly correlated with CECA-Q neglect scores and SCL 90 psychiatric symptoms total score. The linear regression model, when applied only to addicted patients, showed that methadone dosages were not significantly correlated with sexual dysfunction scores except for 'erectile dysfunction', for which an inverse association was evidenced. Testosterone values showed a significant inverse correlation with ASEX sexual dysfunction scores, CECA-Q neglect scores and psychiatric symptom at SCL 90 among methadone patients. PRL levels were directly and significantly correlated with sexual dysfunction scores, psychiatric symptoms at SCL 90 and CECA-Q neglect scores. Both testosterone and PRL did not correlate with methadone dosages. The present findings appear to support the view of childhood adversities and comorbid psychiatric symptoms contributing to sexual dysfunction and related hormonal changes among methadone patients, challenging the assumption that attributes sexual problems entirely to the direct pharmacological effects of opioid agonist medications.