Normal Testosterone but Higher Luteinizing Hormone Plasma Levels in Men With Hypersexual Disorder (2020)

In this study, we found that male patients with HD had no significant difference in plasma testosterone levels compared with healthy volunteers. On the contrary, they had significantly higher plasma levels of LH. The mean testosterone and LH levels of both groups were within the reference range. To our knowledge, this is the first report of HPG dysregulation in men with HD. LH has a central role in the regulation of sexuality mainly through the consecutive production of androgens. Previous studies on LH plasma levels and sexual arousal have given contradictory results, which may be partly explained by more specific studies on LH pulsivity and bioactivity. Stoleru et al¹⁹ reported that sexual arousal in young men has an effect on LH pulse signal resulting in postponing the second peak after the arousal and increasing its height.¹⁹ It might also be that there are differences in the bioactive/immunoactive ratio of LH. Carosa et al²⁰ reported that patients with erectile dysfunction had a significantly lower bioactive/immunoactive ratio of LH than healthy men had, and this was reversed after the resumption of sexual activity.

Most studies on hormones and deviant sexual behaviors have been in forensic settings investigating sexual offenders. Kingston et al²¹ reported that gonadotrophic hormones, FSH, and LH were positively correlated with hostility in the sex offenders and were better predictors for long-term recidivism than testosterone levels in a study following up sex offenders for up to 20 years. The authors argued that some sex offenders have a dysregulation of LH with a failure of downregulation independent of their testosterone levels. In addition, in a study comparing men with pedophilia and non-pedophilic paraphilia, as well as normal male controls, although there were no differences among groups in testosterone and LH levels after the infusion of 100 mcg of synthetic LH-releasing hormone, the pedophile group had more elevation of LH, compared with the other 2 groups.²² It is, however, difficult to draw parallel between these findings reported in forensic settings and our study focusing on men with HD without pedophilia or history of sex offending.

The relationship between sexuality and testosterone levels is complex. Indeed, testosterone is directly related to sexuality and sexual arousal with effects on multiple systems including cognitive processes, emotions, autonomic processes, and motivation.^9,10 These effects can also be indirect through the conversion to estradiol and binding to respective receptors. Testosterone and LH levels are also affected by sexual behaviour and stimuli. Visual erotic stimulation, the frequency of orgasms through coitus or masturbation, and even anticipation of sexual interaction can influence testosterone levels.^9,10 Furthermore, the kind of stimuli, the context, and previous experiences can modulate these effects on testosterone levels. Rupp and Wallen²³, in a study of men exposed to visual erotica, argue that testosterone levels are modulated by experience, reporting that testosterone levels were more related to sexual interest in men viewing pornography who were repeatedly exposed to sexual stimuli and in men with more previous viewing experience of pornography before the study. The authors propose that testosterone is needed to enhance motivation and cognitive process when habituation of the stimuli has occurred through repeated exposure.²³ Although the testosterone levels did not differ between men with HD and healthy controls, the correlations between testosterone plasma levels and measures of hypersexuality showed a trend for significance in the entire group and a significant positive correlation in men with HD with highest testosterone levels in patients reporting more sexually compulsive behavior, sexual preoccupations, and sexually intrusive thoughts.

However, studies on testosterone in sex offenders reported mixed results, and a recent meta-analysis concluded that there is no support for difference in testosterone levels in sex offenders compared with non–sex offenders and that there might be differences within sex offenders as child molesters had lower testosterone.²⁴ But even regarding testosterone supplementation for sexual function, a systematic review of randomized controlled trials by Huo et al²⁵ comes to the conclusion that, regarding libido, although there are more positive than negative studies, the results remain mixed. In addition, testosterone supplementation was not consistently effective in improving sexual function. Finally, most studies have been experimental, investigating the effects on testosterone and LH after the influence of an acute sexual stimulus, for example, sexual arousal film, masturbation, or coitus¹⁹ and did not investigate the effects on the HPG axis in a more long-lasting condition such as in patients with HD. Thus, the finding of no difference of testosterone levels in hypersexual men compared with healthy volunteers is not surprising.

There are only a few studies investigating hypersexual men and endocrine systems. Safarinejad²⁶ measuring treatment effects of the long-acting analog of gonadotropin-releasing hormone, triptorelin, in non-paraphilic hypersexual men reported normal levels of baseline testosterone and LH levels, but the study design did not include a healthy control group. In that study, LH and testosterone levels as well as the sexual output (number of sexual attempts) of the hypersexual men decreased with treatment showing the close relationship of hormone levels and sexuality.

Testosterone levels have also been related to anxiety and depressive symptoms in hypogonadal men.^9,10 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 Stressful events through effects of the HPA axis may cause an inhibition of LH suppression and consequently of reproduction.²⁷ The 2 systems have reciprocal interactions, and early stressors may alter neuroendocrine responses through epigenetic modifications.^{28, 29, 30}

The correlations of testosterone plasma levels with measures of hypersexuality (SCS and HD: CAS) were at a trend level in the whole group, and testosterone was significantly positively correlated with SCS in patients with HD. The SCS measures sexually compulsive behavior, sexual preoccupations, and sexually intrusive thoughts and was developed for assessing high-risk sexual behaviors.¹⁵ Sexual risk takers’ behaviors include frequent sex with different partners, increased number of sexual partners, unprotected sexual intercourse, unprotected anal intercourse, acquired sexually transmitted diseases, and use of drugs and alcohol before sex.^1,31 Testosterone is implicated in risk taking behaviors and together with cortisol, as per the dual hormone hypothesis, they modulate risk taking.³² This dual hormone hypothesis proposes that status-relevant behaviors such as aggression and dominance are positively related with testosterone only when the levels of cortisol are low but not when cortisol levels are high. In this line, we have recently reported that the CSF testosterone/cortisol ratio was significantly positively correlated with impulsivity and aggressiveness in a cohort of suicide attempters.³³ Furthermore, cortisol plasma levels was negatively correlated with SCS scores in men with HD.¹³ Thus, both the negative correlation of cortisol levels with SCS and the positive correlation of testosterone levels with SCS are in line with the dual hormone hypothesis. Sexual desire is also multifaceted, and contextual factors such as stress, gender, and desire target might moderate associations with hormones such as testosterone.^34,35 The proposed mechanisms might include the HPA and HPG interaction, the reward neural network, or the inhibition of regulation impulse control of prefrontal cortex regions.³²

An alternative explanation would be that of the compensatory hypogonadism, which usually presents with normal or in the lower limits, testosterone plasma levels, and higher or in the higher limits of LH plasma levels as a compensatory mechanism. However, compensatory hypogonadism is related to advancing age and chronic comorbidities, unlike our sample, which is age matched to the control group and relatively free from other comorbidities.

Regarding the epigenomics, genome-wide methylation chips with more than 850 K CpG sites were used, but we focused on candidate genes related to HPA axis based on our previous findings¹⁸ as well as common HPG axis–related genes and novel reported systems related to sexual behavior such as oxytocin and kisspeptin.^{36, 37, 38}

In the multiple linear regression models for plasma testosterone levels, 12 CpG sites were nominally significant and 20 CpG sites for plasma LH levels. No individual CpG site was significant after corrections for multiple testing. This is the first epigenetic study of HPG axis–associated genes in HD, and we have previously reported epigenetic changes in HPAaxis–associated genes.¹⁸ Negative results should be interpreted with caution. Owing to the small sample size, it would be difficult to detect small effect sizes, especially after corrections for multiple testing.

The strengths of the study are a carefully selected, homogenous population of hypersexual men, the presence of an age-matched control group of healthy volunteers, excluding history of or present psychiatric disorders, family history of major psychiatric disorders, and severe traumatic experiences. Furthermore, the accounting for possible confounders in the analysis such as childhood adversity, depression, neuroinflammatory markers, and dexamethasone test results. Limitations such as the self-reporting of childhood adversity and the relatively small sample for the epigenetic analysis have to be mentioned. An additional strength is methylation patterns are highly tissue dependent, and the negative epigenetic findings could be related to the tissue source (whole blood). In addition, recent sexual activity might be a possible confounder by maintaining hormone levels³⁹ as we did not control for latest sexual activity. However, there was no association between hormone levels and sexual activity, in the past 2 weeks, measured with HD:CAS that would indicate such an effect. Furthermore, testosterone was measured by an immunoassay rather than the more accurate liquid chromatography–mass spectrometry methods.

Finally, the cross-sectional design of the study is a limitation for casual conclusions, and there is a need for replication in an independent cohort as this is the first study of HPG axis and epigenetics in HD.

In conclusion, we report for the first time increased LH plasma levels in hypersexual men compared with healthy volunteers. These preliminary findings contribute to growing literature on the involvement of neuroendocrine systems and dysregulation in HD.

Directions for further research in HD can be seen in different aspects. Most of the research has been conducted in men and in biased populations such as sex offenders. Thus, clinical phenotypes of hypersexual women, gender differences, and clinical populations are lacking. Comorbidities, especially with other psychiatric disorder including substance and behavior addictions needs to be clarified. One approach could be to study patients with HD/compulsive sexual behavior disorder without comorbidities. Finally, it would also be of great interest to apply the research domain criteria framework. Neuroimaging, molecular, genetic, as well as epigenetic studies in combination with traits such as aggression, impulsivity, and antisocial behavior would elucidate the pathophysiology of the disorder.