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.
Early life adversity is associated with increased risk of high psychiatric disease, suicidal behavior as well as risky sexual behavior in adulthood.
Altered functioning of several neurobiological systems, like the serotonergic system and the hypothalamic-pituitary-adrenal axis associated with suicidal behavior, may stem from both genetic and developmental causes.
Adversity in early life has developmental effects on these systems that persist into adulthood. Other neuroendocrine systems such as oxytocin regulating social behavior and DHEA-S with multiple biological actions might also be implicated in suicidal behavior.
Hypersexual disorder includes features of impulsivity, addiction, sexual desire deregulation and some aspects of hypersexual behavior are also associated with more suicidality.
Neurobiological alterations in patients with hypersexual disorder are for the moment largely unknown.
The aim of this PhD project was to investigate neuroendocrine systems with focus on HPA axis, Oxytocin and DHEAS in suicide attempters and in patients with Hypersexual Disorder. Focus was on early life adversity and violent behavior in relation to neuroendocrine biomarkers.
Studies I-III: The clinical cohort consists of 28 medication free suicide attempters and 19 healthy volunteers who participated in this cross sectional and longitudinal study.
CSF and plasma basal levels of oxytocin, cortisol, DHEA-S and CSF 5-HIAA levels were assessed. Suicide intent, depressive symptoms, interpersonal violence in childhood an adult life as well as childhood emotional climate were assessed with psychometric rating scales. All patients were followed up for cause of death.
Results: Suicide attempters showed a trend for lower CSF oxytocin levels compared to healthy volunteers, CSF and plasma oxytocin was significantly negatively related to suicide intent especially in men and showed a trend for negative correlation with lifetime violent behavior. Revictimized suicide attempters had lower plasma oxytocin and a more negative childhood emotional climate compared to non revictimized suicide attempters.
Higher CSF and plasma cortisol levels were also present in suicide attempters compared to healthy volunteers, whereas CSF DHEA-S levels were higher in male suicide attempters and CSF 5-HIAA levels lower in female suicide attempters respectively. CSF cortisol/DHEAS ratio was inversely correlated with exposure to interpersonal violence as a child adjusted for age, gender and depression severity in a regression analysis.
In suicide prediction, suicide victims tended to have low CSF 5-HIAA and high CSF cortisol and suicide victims that were abused in childhood had higher CSF cortisol compared to suicide victims with low exposure to interpersonal violence as a child. Oxytocin or DHEA-S levels did not differ in suicide victims compared to survivors.
Study IV: The study includes 67 male patients with hypersexual disorder and 39 healthy male volunteers. Basal morning plasma levels of cortisol and ACTH were assessed and the dexamethasone (0.5 mg) suppression test was performed with cortisol and ACTH measured post dexamethasone administration. Multiple psychometric rating scales were used for assessing sexual behavior, depressive symptoms and early life adversity.
Results: Men with hypersexual disorder had higher DST-ACTH levels and were more often DST non-suppressors compared to healthy volunteers. Men with hypersexual disorder reported more depressive symptoms and early life adversity than healthy volunteers. Early life adversity and hypersexual behavior were negatively correlated with HPA axis measures in patients.
In the regression analyses the diagnosis of hypersexual disorder was significantly associated with both DST non-suppression and higher plasma DST-ACTH even when adjusted for childhood trauma.
Conclusion: Early life adversity, interpersonal violence and suicide intent are risk factors for suicide and oxytocin by modulating prosocial behaviors might thus be protective in individuals with high suicide risk.
The role of DHEA-S in suicidal behavior is proposed to be through the effects of early life adversity and its implication to the allostatic load while other possible mechanisms cannot be excluded. The study on male patients with hypersexual disorder reports for the first time HPA axis dysregulation.
More information: 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
