Summary: Study implicates dysregulation of epigenetic mechanisms of both DNA methylation and microRNA activity, in addition to oxytocin to hypersexuality.
Source: Taylor & Francis Group
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 characterized 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.
Funding: 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.
Taylor & Francis Group
Krystina Sihdu – Taylor & Francis Group
The image is in the public domain.
Original Research: Closed access
“Hypermethylation-associated downregulation of microRNA-4456 in hypersexual disorder with putative influence on oxytocin signalling: A DNA methylation analysis of miRNA genes”. Adrian 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
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.