Methylation of HPA axis related genes in men with hypersexual disorder
Introduction
Hypersexual Disorder (HD) defined as non-paraphilic sexual desire disorder with components of impulsivity, compulsivity and behavioral addiction, was proposed as a diagnosis for the DSM 5 (Kafka, 2010). Even though limited, recent research demonstrated some overlapping features between HD and substance use disorders, including common neurotransmitter systems and dysregulated hypothalamic-pituitary-adrenal (HPA) axis function (Kraus et al., 2016, Chatzittofis et al., 2016). While the neurobiological underpinnings of hypersexual disorder largely remain to be elucidated, it has been proposed that HD may share characteristics with addictive behaviors with a reward deficiency component, in turn partly affected by both genetic and epigenetic factors (Blum et al., 2015).
Increasing evidence suggests that DNA methylation is implicated in the pathophysiology of most psychiatric disorders (Menke and Binder, 2014, Mill et al., 2008) and alterations in epigenetic patterns have an effect on brain functions (Ma et al., 2009). Variations in DNA methylation (the addition of a methyl group to the 5′-position of the cytosine pyrimidine ring) modify gene expression by inhibiting transcription or by recruiting specific proteins that alter the chromatin state. Epigenetic modifications, including DNA methylation and histone acetylation (involved in chromatin remodeling), are involved not only in brain functioning but also in sexual behavior. In animal models, epigenetic modifications have been shown to affect sexual behavior, influencing sociosexual behavior, partner preference and post-copulatory sexual selection (Matsuda, 2014, Zeh and Zeh, 2008, Wang et al., 2013). Direct evidence of epigenetic mechanisms in human sexual behavior is sparse and research has mainly focused on the role of epigenetics in sexual orientation (Ngun and Vilain, 2014). To our knowledge, no studies thus far have investigated epigenetic changes in hypersexual disorder.
Substantial translational evidence implicates impairments in glucocorticoid signaling in stress related psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Early life adversity increases risk for developing psychopathology (Teicher and Samson, 2013) through epigenetic modification of stress reactivity genes (Turecki and Meaney, 2016). We have previously reported that hypersexual disorder was associated to hyperactive HPA axis in male patients, irrespective of early life adversity (Chatzittofis et al., 2016) and men with HD had higher TNFα levels compared to healthy male volunteers (Jokinen et al., 2016).
In this study, we aimed to identify HPA-axis coupled CpG-sites, in which modifications of the epigenetic profile are associated with hypersexual disorder. Further, associations of methylation to gene expression were tested in an independent sample of healthy controls.
Section snippets
Ethics
The study protocols were approved by the Regional Ethical Review Board in Stockholm (Dnrs: 2013/1335-31/2) and the participants gave their written informed consent to the study.
Patients
The study population has been described previously in detail (Chatzittofis et al., 2016). Sixty-seven male patients with hypersexual disorder seeking psychotherapeutic treatment were recruited to the study at the Center for Andrology and Sexual Medicine (CASM) at the Karolinska University Hospital, a multidisciplinary
Behavior of the clinical outcome variables
In this study, comprising 54 patients diagnosed with hypersexual disorder and 33 healthy volunteers, we initially aimed to identify HPA-axis coupled CpG-sites, in which modifications of the epigenetic profile are associated with hypersexual disorder. The study group included only male subjects. Patients with HD scored significantly higher on the CTQ (p < 0.001) and had higher levels of plasma DST ACTH (p < 0.01) and TNF-alpha (p < 0.0001), and lower levels of plasma IL-6 (p < 0.01). In addition, HD
Discussion
In this study, we found that male patients with hypersexual disorder had reduced levels of methylation in a methylation locus (cg23409074) site located 48 bp upstream of the transcription start site of the CRH gene. Furthermore, this methylation locus was significantly positively correlated with CRH gene expression in an independent cohort of healthy male subjects. To our knowledge, this is the first report on epigenetic changes related to hypersexual disorder. We used genome-wide methylation
Role of funding source
Funding for this study was provided by the Swedish Research Council and the Swedish Brain Research Foundation (Helgi Schiöth) and through a regional agreement between Umeå University and Västerbotten County Council (ALF) and by grants provided by the Stockholm County Council (ALF) (Jussi Jokinen).
Acknowledgements
Methylation profiling was performed by the SNP&SEQ Technology Platform in Uppsala (www.genotyping.se). The facility is part of the National Genomics Infrastructure (NGI) Sweden and Science for Life Laboratory. The SNP&SEQ Platform is also supported by the Swedish Research Council and the Knut and Alice Wallenberg Foundation. DNA extraction was performed by Latvian BMC, funded by the Latvian Council of Science European Social Fund and European Regional Development Fund.
References (49)
- et al.
HPA axis dysregulation in men with hypersexual disorder
Psychoneuroendocrinology
(2016) - et al.
The link between childhood trauma and depression: insights from HPA axis studies in humans
Psychoneuroendocrinology
(2008) - et al.
The role of neuroinflammation in the pathophysiology of hypersexual disorder
Psychoneuroendocrinology
(2016) - et al.
Mood and neuroendocrine response to a chemical stressor, metyrapone, in buprenorphine-maintained heroin dependence
Biol. Psychiatry
(2008) - et al.
Addiction as a stress surfeit disorder
Neuropharmacology
(2014) - et al.
Reward devaluation and heroin escalation is associated with differential expression of CRF signaling genes
Brain Res. Bull.
(2016) - et al.
Time-dependent effects of dexamethasone plasma concentrations on glucocorticoid receptor challenge tests
Psychoneuroendocrinology
(2016) - et al.
Epigenomic profiling reveals DNA-methylation changes associated with major psychosis
Am. J. Hum. Genet.
(2008) - et al.
The biological basis of human sexual orientation: is there a role for epigenetics?
Adv. Genet.
(2014) - et al.
Postprandial alterations in whole-blood DNA methylation are mediated by changes in white blood cell composition
Am. J. Clin. Nutr.
(2016)
Corticotropin releasing factor in neuroplasticity
Front. Neuroendocrinol.
Report of findings in a DSM-5 field trial for hypersexual disorder
J. Sex. Med.
A comparison between the beck depression inventory (BDI) and the self-rating version of the montgomery asberg depression rating scale (MADRS)
J. Affect. Disord.
Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review
Biol. Psychiatry
Corticotropin releasing factor: a key role in the neurobiology of addiction
Front. Neuroendocrinol.
The role of corticotropin-releasing factor in depression and anxiety disorders
J. Endocrinol.
Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays
Bioinformatics
Controlling the False Discovery Rate: a practical and powerful approach to multiple testing
J. R. Stat. Soc. Ser. B
Childhood Trauma Questionnaire: A Retrospective Self-Report Manual
Hypersexuality addiction and withdrawal: phenomenology, neurogenetics and epigenetics
Cureus
Maternal deprivation in rats is associated with corticotrophin-releasing hormone (CRH) promoter hypomethylation and enhances CRH transcriptional responses to stress in adulthood
J. Neuroendocrinol.
From inflammation to sickness and depression: when the immune system subjugates the brain
Nat. Rev. Neurosci.
Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis
BMC Bioinf.
Robust Statistics: the Approach Based on Influence of Functions
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2020, Sexual MedicineCitation Excerpt :We did not find significant correlation between testosterone levels and depressive symptoms. HD includes in its definition that the behavior can be a result of dysphoric states and stress,1 and we have previously reported a dysregulation with hyperactivity of the HPA axis13 as well as related epigenetic changes in men with HD.18 There are complex interactions between HPA and HPG axis, both excitatory as well as inhibitory with differences depending on the developmental stage of the brain.27