COMMENTS: Study on subjects with hypersexuality (porn/sex addiction) reports epigenetic changes mirroring those occurring in alcoholics. The epigenetic changes occurred in genes associated with the oxytocin system (which is important in love, bonding, addiction, stress, etc.). Highlights:
- Sex/porn addict’s epigenetic markers for the brain’s oxytocin system looks similar to alcoholics
- Study’s findings aligns with Kuhn & Gallinat, 2014 (famous fMRI study on porn users)
- Findings could indicate a dysfunctional stress system (which is a key change in addiction)
- Alteration in oxytocin genes could affect bonding, stress, sexual functioning, etc.
For more, read this rather technical lay article: Scientists identify hormone potentially linked to hypersexual disorder
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Adrian E. Boström, Andreas Chatzittofis, Diana-Maria Ciuculete, John N. Flanagan, Regina Krattinger, Marcus Bandstein, Jessica Mwinyi, Gerd A. Kullak-Ublick, Katarina Görts Öberg, Stefan Arver, Helgi B. Schiöth & Jussi Jokinen (2019)
Epigenetics, DOI: https://doi.org/10.1080/15592294.2019.1656157
Abstract
Hypersexual disorder (HD) was proposed as a diagnosis in the DSM-5 and the classification ‘Compulsive Sexual Behavior Disorder’ is now presented as an impulse-control disorder in ICD-11. HD incorporates several pathophysiological mechanisms; including impulsivity, compulsivity, sexual desire dysregulation and sexual addiction. No previous study investigated HD in a methylation analysis limited to microRNA (miRNA) associated CpG-sites. The genome wide methylation pattern was measured in whole blood from 60 subjects with HD and 33 healthy volunteers using the Illumina EPIC BeadChip. 8,852 miRNA associated CpG-sites were investigated in multiple linear regression analyses of methylation M-values to a binary independent variable of disease state (HD or healthy volunteer), adjusting for optimally determined covariates. Expression levels of candidate miRNAs were investigated in the same individuals for differential expression analysis. Candidate methylation loci were further studied for an association with alcohol dependence in an independent cohort of 107 subjects. Two CpG-sites were borderline significant in HD – cg18222192 (MIR708)(p < 10E-05,pFDR = 5.81E-02) and cg01299774 (MIR4456)(p < 10E-06, pFDR = 5.81E-02). MIR4456 was significantly lower expressed in HD in both univariate (p < 0.0001) and multivariate (p < 0.05) analyses. Cg01299774 methylation levels were inversely correlated with expression levels of MIR4456 (p < 0.01) and were also differentially methylated in alcohol dependence (p = 0.026). Gene target prediction and pathway analysis revealed that MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signalling pathway. In summary, our study implicates a potential contribution of MIR4456 in the pathophysiology of HD by putatively influencing oxytocin signalling.
FROM DISCUSSION SECTION
In a DNA methylation association analysis in peripheral blood, we identify distinct CpG-sites associated with MIR708 and MIR4456 that are significantly differentially methylated in HD patients. Additionally, we demonstrate that hsamiR- 4456 associated methylation locus cg01299774 is differentially methylated in alcohol dependence, suggesting that it may be primarily associated with the addictive component observed in HD.
To our knowledge, no previous paper described the importance of MIR4456 in a context of psychopathologies. We identify that this miRNA is evolutionarily conserved with regard to primary sequence composition and predicted hairpin secondary structures from the advent of primates. In addition, we provide evidence that putative mRNA targets of MIR4456 are preferentially expressed in amygdala and hippocampus, two brain regions suggested by Kühn et al. to be implicated in the pathophysiology of HD [5].
The involvement of the oxytocin signaling pathway identified in this study appears to be significantly implicated in many of the characteristics defining HD as proposed by Kafka et al. [1], such as sexual desire dysregulation, compulsivity, impulsivity and (sexual) addiction. Mainly produced by the paraventricular nucleus of the hypothalamus and released by the posterior pituitary, oxytocin plays an important role in social bonding and sexual reproduction in both males and females [59]. Murphy et al. described elevated levels during sexual arousal [60]. Burri et al. found that intranasal oxytocin application in men resulted in an increase in epinephrine plasma levels during sexual activity and an altered perception of arousal [61]. Additionally, oxytocin has been proposed to inhibit the activity of the hypothalamic-pituitary-adrenal (HPA) axis during stress. Jurek et al. observed that oxytocin receptormediated intracellular mechanisms postpone the transcription of corticotropin-releasing factor (Crf) in the paraventricular nucleus, a gene strongly associated with the stress response [62].
Alterations in the oxytocin signalling pathway could explain findings by Chatzittofis et al., who observed HPA axis dysregulation in men with hypersexual disorder [3]. Furthermore, studies indicate that oxytocin may be involved in the pathophysiology of obsessive-compulsive disorder [63]. The interaction of oxytocin with the dopamine system, the HPA-axis and the immune system led to the postulation that individual differences in oxytocin levels are impacting addiction vulnerability [64]. While oxytocin has been previously associated with the regulation of social and aggressive behaviour, Johansson et al. further demonstrated that genetic variation in the oxytocin receptor gene (OXTR) impacted on the tendency to react to situations with elevated levels of anger under the influence of alcohol [65]. Lastly, Brüne et al. concluded that genetic variation in OXTR may contribute to explaining the pathophysiology of borderline personality disorder [66], a personality pathology characterized by severe impulsivity dysregulation [66].
MIR4456may have an additional regulatory function in HD that was not revealed in the current study. In line with our findings, previous studies have reported associations of aberrant male sexual behaviour and genes involved in glutamatergic system in depressed individuals [67]. Furthermore, a potential role of the 3ʹ-5ʹ-cyclic adenosine mono phosphate (cAMP) levels in sexual receptivity was shown in female rats, by modulating the phosphoprotein- 32 and leading to alterations of progestin receptors [68]. Interestingly, cAMP also regulates molecules associated with axon guidance [69], such as the B3gnt1 gene, which was associated with impaired sexual behaviour in male mice
FIRST ARTICLE ABOUT THE STUDY:
Scientists identify hormone potentially linked to hypersexual disorder
A new study of men and women with hypersexual disorder has revealed a possible role of the hormone oxytocin, according to results published in the journal Epigenetics. The finding could potentially open the door to treating the disorder by engineering a way to suppress its activity.
Hypersexual disorder, or an overactive sex drive, is recognized as a compulsive sexual behaviour disorder, listed as an impulse-control disorder by the World Health Organisation. It can be characterised by obsessive thoughts of sex, a compulsion to perform sexual acts, a loss of control, or sexual habits that carry potential problems or risks. While prevalence estimates vary, literature indicates that hypersexual disorder affects 3-6% of population.
Controversy surrounds diagnosis because it often occurs alongside other mental health issues, suggesting it could be an extension or manifestation of an existing mental disorder. Little is known about the neurobiology behind it.
“We set out to investigate the epigenetic regulatory mechanisms behind hypersexual disorder so we could determine whether it has any hallmarks that make it distinct from other health issues,” says lead author Adrian Boström from the Department of Neuroscience at Uppsala University, Sweden who conducted the study with researchers from the Andrology/Sexual Medicine Group (ANOVA) at Karolinska Institutet, Stockholm, Sweden.
“To our knowledge, our study is the first to implicate dysregulated epigenetic mechanisms of both DNA methylation and microRNA activity and the involvement of oxytocin in the brain among patients seeking treatment for hypersexuality.”
The scientists measured DNA methylation patterns in the blood from 60 patients with hypersexual disorder and compared them to samples from 33 healthy volunteers.
They investigated 8,852 regions of DNA methylation associated to nearby microRNAs to identify any variations between samples. DNA methylation can affect gene expression and the function of genes, typically acting to reduce their activity. Where changes in DNA methylation were detected, the researchers investigated levels of gene expression of the associated microRNA. MicroRNAs are particularly interesting as they can pass the blood-brain-barrier and modulate or degrade the expression of up to several hundred different genes in brain and other tissues.
They also compared their findings to samples from 107 subjects, 24 of whom were alcohol-dependent, to explore an association with addictive behaviour.
Results identified two regions of DNA that were altered in hypersexual disorder patients. Normal function of DNA methylation was disrupted and an associated microRNA, involved in gene silencing, was found to be under-expressed. Analysis revealed that the microRNA identified, microRNA-4456, targets genes that are normally expressed at particularly high levels in the brain and that are involved in the regulation of the hormone oxytocin. With gene silencing reduced, oxytocin may be expected to be at elevated levels, although the current study does not confirm this.
It has been seen in specific vole and primate species the neuropeptide oxytocin plays a central role in the regulation of pair-bonding behaviour. Previous studies have demonstrated that oxytocin is associated with the regulation of social and pair-bonding, sexual reproduction and aggressive behaviour in both men and women. The comparison with alcohol-dependent subjects revealed the same DNA region to be significantly under-methylated, suggesting that it may be primarily associated with the addictive components of hypersexual disorder, such as sex addiction, dysregulated sexual desire, compulsivity and impulsivity.
“Further research will be needed to investigate the role of microRNA-4456 and oxytocin in hypersexual disorder, but our results suggest it could be worthwhile to examine the benefits of drug and psychotherapy to reduce the activity of oxytocin,” says Professor Jussi Jokinen from Umeå University, Sweden.
The authors note that a limitation of the study is that the mean difference in DNA methylation between hypersexual disorder patients and healthy volunteers was only around 2.6%, so the impact on physiological changes might be called into question. However, a growing body of evidence suggestions that just subtle methylation changes can have wide-ranging consequences for complex conditions such as depression or schizophrenia.
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The study was funded through a regional agreement between Umeå University and Västerbotten County Council (ALF) and by grants provided by the Stockholm County Council as well as by the Swedish Research Foundation, the Åhlens Foundation, the Novo Nordisk Foundation, and the Swedish Brain Research Foundation.
SECOND ARTICLE ABOUT THE STUDY:
Epigenetic Changes Linked to Hypersexual Disorder and Addictive Behaviors
MedicalResearch.com Interview with: Adrian E. Boström MD, on behalf of the authors
Department of Neuroscience, Uppsala University, Sweden
MedicalResearch.com: What is the background for this study?
Response: While prevalence estimates vary, literature indicates that hypersexual disorder (HD) affects 3-6% of the population. However, controversy surrounds the diagnosis and little is known about the neurobiology behind it.
Hypersexual disorder has not previously been investigated with regards to epigenomic and transcriptomics in a hypothesis-free study approach and little is known about the neurobiology behind this disorder. We investigated whether there were any epigenetic changes that affect gene activity and expression in hypersexual disorder (HD) patients and identified a dysregulated microRNA that is believed to influence the mechanism of action of the hormone oxytocin in brain.
Oxytocin is known to have wide-ranging behavioral influences. To the best of our knowledge, no previous study provided evidence for an association between DNA methylation, microRNA activity and oxytocin in hypersexual disorder. Our findings merits further research in the role of MIR4456 and especially Oxytocin in hypersexual disorder. Further studies are needed to confirm the role of Oxytocin in HD and to investigate whether treatment with oxytocin antagonist drug therapy could have beneficial effects for patients suffering from hypersexual disorder.
MedicalResearch.com: What are the main findings?
Response: – In this study we investigated over 8000 different DNA methylation sequenced in a hypothesis-free and thereby unbiased manner. Therefore, we were intrigued and surprised to identify a strongly dysregulated microRNA targeting genes primarily expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for hypersexual disorder, e.g. the oxytocin signaling pathway. This microRNA also appears to be evolutionary conserved throughout primates, which is also an interesting and unexpected finding.
MedicalResearch.com: What should readers take away from your report?
Response: Hypersexual disorder incorporates different pathophysiological mechanisms including impulsivity, compulsivity, sexual desire dysregulation and sexual addiction. This can be interpreted such that hypersexual disorder contains addictive elements, but is not to be seen as exclusively an addiction. Our findings, in light of the crossover with alcohol dependence, suggest that MIR4456 and the oxytocin signaling pathway may be primarily involved with the addictive component of hypersexual disorder. Further studies are needed to fully confirm this.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Our results motivates further research in the efficacy of, for example, oxytocin regulating drug therapy in hypersexual disorder which could contribute to novel treatment options to improve the clinical outcome of those affected. In addition, we identify a specific microRNA (miRNA) for which future potential miRNA regulating drugs could be tested in hypersexual disorder.
MedicalResearch.com: Is there anything else you would like to add?
Response: Our DNA is genetic code for genes that translate into different sequences of amino acids called proteins. Proteins, in turn, constitute a main defining element of all living things. Our DNA is inherited and does not change over time. This study, however, pertained to epigenetics, which are changes that affect gene activity and expression. These epigenetic activities change over time and can be dysregulated in certain ailments. There are different epigenetic mechanisms.
In this study, we studied DNA methylation (a process known to influence gene expression, that is, the quantity of a gene that is translated into a protein) and microRNA activity (short non-coding gene segments that can influence the translation of several hundred different genes).
Comparing patients with hypersexual disorder to healthy volunteers, we identified a DNA methylation sequence to be significantly altered in hypersexual disorder. To ascertain the significance of this finding, the same DNA sequence was further demonstrated to be dysregulated in subjects with alcohol dependence, suggesting it could be primarily associated with the addictive component of hypersexual disorder. The identified DNA methylation sequence was associated to a microRNA called (microRNA 4456; MIR4456), and further analysis showed that this DNA methylation sequence influence the quantity of MIR4456 that is produced. Furthermore, in the same study group, we demonstrate that MIR4456 exists in significantly lower quantity in hypersexual disorder as compared to healthy volunteers, strongly suggesting that altered DNA methylation patterns in hypersexual disorder influence and contributes to explaining the observed dysregulation of MIR4456. As microRNA:s theoretically are able to target several hundred different genes, we used computer algorithms to reveal that MIR4456 targets genes that are preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signaling pathway. Our findings merits further research in the role of MIR4456 and especially Oxytocin in hypersexual disorder. Further studies are needed to confirm the role of Oxytocin in HD and to investigate whether treatment with oxytocin antagonist drug therapy could have beneficial effects for patients suffering from hypersexual disorder.
Yet unpublished data intended for a separate follow-up study show a highly significant increase in Oxytocin levels in patients with hypersexual disorder as compared to controls, and a significant reduction in oxytocin levels after Cognitive Behavior Therapy treatment, strongly implying a causal role of Oxytocin in hypersexual disorder and making the claims presented in this study much stronger. These preliminary results have been presented as a late breaking poster in Society of Biological Psychiatry meeting in May 2019 and also submitted as a poster in ACNP in December 2019.
Citation:
Adrian E. Boström et al, Hypermethylation-associated downregulation of microRNA-4456 in hypersexual disorder with putative influence on oxytocin signalling: A DNA methylation analysis of miRNA genes, Epigenetics (2019). DOI: 10.1080/15592294.2019.1656157
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