HPA axis dysregulation is associated with differential methylation of CpG-sites in related genes.

DNA methylation shifts in Hypothalamic-pituitary-adrenal (HPA) axis related genes is reported in psychiatric disorders including hypersexual disorder. This study, comprising 20 dexamethasone suppression test (DST) non-suppressors and 73 controls, examined the association between the HPA axis dysregulation, shifts in DNA methylation of HPA axis related genes and importantly, gene expression. Individuals with cortisol level ≥ 138 nmol/l, after the low dose (0.5 mg) dexamethasone suppression test (DST) were classified as non-suppressors. Genome-wide methylation pattern, measured in whole blood using the EPIC BeadChip, investigated CpG sites located within 2000 bp of the transcriptional start site of key HPA axis genes, i.e.: CRH, CRHBP, CRHR-1, CRHR-2, FKBP5 and NR3C1. Regression models including DNA methylation M-values and the binary outcome (DST non-suppression status) were performed. Gene transcripts with an abundance of differentially methylated CpG sites were identified with binomial tests. Pearson correlations and robust linear regressions were performed between CpG methylation and gene expression in two independent cohorts. Six of 76 CpG sites were significantly hypermethylated in DST non-suppressors (nominal P < 0.05), associated with genes CRH, CRHR1, CRHR2, FKBP5 and NR3C1. NR3C1 transcript AJ877169 showed statistically significant abundance of probes differentially methylated by DST non-suppression status and correlated with DST cortisol levels. Further, methylation levels of cg07733851 and cg27122725 were positively correlated with gene expression levels of the NR3C1 gene. Methylation levels of cg08636224 (FKBP5) correlated with baseline cortisol and gene expression. Our findings revealed that DNA methylation shifts are involved in the altered mechanism of the HPA axis suggesting that new epigenetic targets should be considered behind psychiatric disorders.

MANAGEMENT OF ENDOCRINE DISEASE: Female sexual dysfunction for the endocrinologist.

Sexual function is an important component of either general health and quality of life in both genders. Many studies have focused on the different risk factors for sexual dysfunctions, proving an association with several medical conditions. Endocrine disorders have been often mentioned in the pathogenesis of female and male sexual dysfunctions; however, particularly in women, sexual function is rarely addressed during clinical, in general, and endocrinological, in particular, consultations. As a thorough diagnosis is required in order to provide an adequately tailored treatment, knowing how each endocrine dysfunction can impair sexual health is of the utmost importance, considering the high prevalence of conditions such as disorders of pituitary, thyroid, adrenal, gonads, as well as metabolic disorders. We performed a thorough review of existing literature on the different mechanisms involved in the pathogenesis of female sexual dysfunctions secondary to endocrine disorders in order to provide an up-to-date reference.

A Longitudinal Study of Sexual Function in Women With Newly Diagnosed Inflammatory Bowel Disease.

BACKGROUND: The literature provides conflicting data on sexual function in women with inflammatory bowel disease (IBD). We aim to describe sexual function at baseline and over time in a prospective inception cohort of adult women with IBD. METHODS: Women age 18 years or older enrolled in the Ocean State Crohn's & Colitis Area Registry (OSCCAR) with 2 years of prospective follow-up were included in the study. All subjects were enrolled within 1 year of IBD diagnosis. Female sexual function was assessed using the Female Sexual Function Index (FSFI). Linear mixed effects models were used to assess changes in FSFI by various demographic and clinical factors. RESULTS: One hundred sixteen of 130 eligible women (89%) were included in the study. Ninety-seven percent of women had sexual dysfunction, defined as an FSFI score of <26.55, with a baseline mean FSFI score (SD) of 16.4 (8.4) overall (15.5 [8.6] in Crohn's disease, 17.4 [8.1] in UC, P = 0.22). Despite improvement in overall disease activity, there was no significant change in the FSFI score or individual domain scores over the entire 2-year study period. Among all women with IBD, older age, nonsingle marital status, lower Short Form Health Survey (SF-36) Physical Component Summary score, and the use of biologics were independent risk factors for sexual dysfunction. CONCLUSIONS: Almost all women experienced sexual dysfunction that did not improve over time despite improvement in overall disease activity. Future studies are warranted to identify underlying mechanisms that explain the associations between demographic and clinical factors and sexual dysfunction among newly diagnosed women.

Can pharmacotherapy help persistent genital arousal disorder?

INTRODUCTION: Persistent genital arousal disorder (PGAD) is a presumably rare, although debilitating condition, which was first defined only at the beginning of this century and has not yet found consideration by any of the international classification systems of diseases. As affected patients can suffer tremendously, this report aims at providing an overview and an expert opinion on the few existing studies and case reports, guiding clinicians in the treatment and pharmacotherapy of PGAD. Areas covered: In this article case reports, case series and surveys on drugs that may both alleviate or worsen/induce PGAD are reported. Expert opinion: Data on pharmacological treatment options in PGAD are sparse and mainly rely on case reports making conclusions difficult. Most importantly, some drugs such as serotonin reuptake inhibitors (SSRIs) may even induce or worsen PGAD during treatment or withdrawal. We now need an initial spark in order to promote basic research on the etiology of PGAD as well as clinical trials on possible treatment options. In the meanwhile, clinicians should provide careful diagnostics and counseling for affected patients. In case pharmacotherapy is desired, drugs that are able to inhibit sexual excitation and/or modulate sensory perception such as pregabalin or duloxetin might be worth a trial.

Maladaptive Sexual Behavior Following Concurrent Methamphetamine and Sexual Experience in Male Rats is Associated with Altered Neural Activity in Frontal Cortex.

The use of psychostimulants is often associated with hypersexuality, and psychostimulant users have identified the effects of drug on sexual behavior as a reason for further use. It was previously demonstrated in male rats that methamphetamine (Meth), when administered concurrently with sexual behavior results in impairment of inhibition of sexual behavior in a conditioned sex aversion (CSA) paradigm where mating is paired with illness. This is indicative of maladaptive sex behavior following Meth and sex experience. The present study examined the neural pathways activated during inhibition of sexual behavior in male rats and the effects of concurrent Meth and sexual behavior on neural activity, using ERK phosphorylation (pERK). First, exposure to conditioned aversive stimuli in males trained to inhibit sexual behavior in the CSA paradigm increased pERK expression in medial prefrontal (mPFC), orbitofrontal cortex (OFC) and areas in striatum and amygdala. Second, effects of concurrent Meth and sex experience were tested in males that were exposed to four daily sessions of concurrent Meth (1 mg/kg) or saline and mating and subsequently exposed to CSA one week after last treatment. Meth and mating-treated males showed significant impairment of inhibition of mating, higher pERK expression under baseline conditions, and disrupted pERK induction by exposure to the conditioned aversive stimuli in mPFC and OFC. These alterations of pERK occurred in CaMKII-expressing neurons, suggesting changes in efferent projections of these areas. Altogether, these data show that concurrent Meth and mating experience causes maladapative sexual behavior that is associated with alterations in neural activation in mPFC and OFC.

Neurobiological Basis of Hypersexuality.

Until now, hypersexuality has not found entry into the common diagnostic classification systems. However it is a frequently discussed phenomenon consisting of excessive sexual appetite that is maladaptive for the individual. Initial studies investigated the neurobiological underpinnings of hypersexuality, but current literature is still insufficient to draw unequivocal conclusions. In the present review, we summarize and discuss findings from various perspectives: neuroimaging and lesion studies, studies on other neurological disorders that are sometimes accompanied by hypersexuality, neuropharmacological evidence, genetic as well as animal studies. Taken together, the evidence seems to imply that alterations in the frontal lobe, amygdala, hippocampus, hypothalamus, septum, and brain regions that process reward play a prominent role in the emergence of hypersexuality. Genetic studies and neuropharmacological treatment approaches point at an involvement of the dopaminergic system.

The use of magnetic resonance imaging for studying female sexual function: A review.

Many would agree that there are two quintessential sexual organs in the female: the clitoris and the brain. Using non-invasive techniques of magnetic resonance imaging (MRI), investigators have gained insight into the mental and physical factors involved in female sexual function. Since only the external clitoral glans is easily accessible for direct measurement, the complete anatomy of the clitoris (including the internal components-paired corpora, crura, and bulbs) has only recently been described, with MRI providing the most sensitive way of distinguishing among the various soft tissue planes. Average sizes of clitoral structures and average distances between the clitoral complex and other pelvic landmarks have been measured. These measurements have been correlated with female sexual function: a longer distance between the clitoral complex and the vaginal lumen correlates with poorer sexual function, consistent with prior imaging studies. However, whether clitoral size influences function is debatable, so further studies are needed. Physiological investigations have demonstrated that female arousal disorder is unlikely to be due to inadequate genital engorgement. Some consider the brain to be the ultimate sexual organ, and several recent studies have used functional MRI (fMRI) to reveal sexual excitability in the brain. The normal sexual response requires deactivation of the frontal lobe and activation of the instinctual limbic system of the midbrain. As MR technology continues to improve, the mysteries of female sexuality will be further unraveled.

Clitoral size and location in relation to sexual function using pelvic MRI.

INTRODUCTION: The female sexual response is dynamic; anatomic mechanisms may ease or enhance the intensity of orgasm. AIM: The aim of this study is to evaluate the clitoral size and location with regard to female sexual function. METHODS: This cross-sectional TriHealth Institutional Board Review approved study compared 10 sexually active women with anorgasmia to 20 orgasmic women matched by age and body mass index (BMI). Data included demographics, sexual history, serum hormone levels, Prolapse/Incontinence Sexual Questionnaire-12 (PISQ-12), Female Sexual Function Index (FSFI), Body Exposure during Sexual Activity Questionnaire (BESAQ), and Short Form Health Survey-12. All subjects underwent pelvic magnetic resonance imaging (MRI) without contrast; measurements of the clitoris were calculated. MAIN OUTCOME MEASURES: Our primary outcomes were clitoral size and location as measured by noncontrast MRI imaging in sagittal, coronal, and axial planes. RESULTS: Thirty premenopausal women completed the study. The mean age was 32 years (standard deviation [SD] 7), mean BMI 25 (SD 4). The majority was white (90%) and married (61%). Total PISQ-12 (P < 0.001) and total FSFI (P < 0.001) were higher for orgasmic subjects, indicating better sexual function. On MRI, the area of the clitoral glans in coronal view was significantly smaller for the anorgasmic group (P = 0.005). A larger distance from the clitoral glans (51 vs. 45 mm, P = 0.049) and body (29 vs. 21 mm, P = 0.008) to the vaginal lumen was found in the anorgasmic subjects. For the entire sample, larger distance between the clitoris and the vagina correlated with poorer scores on the PISQ-12 (r = -0.44, P = 0.02), FSFI (r = -0.43, P = 0.02), and BESAQ (r = -0.37, P = 0.04). CONCLUSION: Women with anorgasmia possessed a smaller clitoral glans and clitoral components farther from the vaginal lumen than women with normal orgasmic function.

Measuring the health-related quality of life and sexual functioning of patients with rectal cancer: does type of treatment matter?

The literature on the health-related quality of life (HRQOL) after rectal cancer is growing, however, a comparison between patients with nonadvanced disease (NAD), locally advanced rectal cancer (LARC), locally recurrent rectal cancer (LRRC) and a normative population has not been made. Data on the sexual functioning of patient groups is also scarce. We compared (i) the HRQOL of patients with NAD, LARC, or LRRC, with a special focus on sexual functioning and (ii) the HRQOL of the three treatment groups with a normative population. The EORTC QLQ-C30 and QLQ-CR38 were completed by 80 patients with NAD, 292 LARC patients and 67 LRRC patients. The normative population (n = 350) completed the EORTC QLQ-C30 and the Sexual Functioning and Sexual Enjoyment scales of the CR38. LRRC patients reported a lower Physical Function, Social Function, Future Perspective, Sexual Functioning and more Pain compared with LARC and NAD patients. Also, LRRC patients had a worse Body image than NAD patients and a lower Male Sexual Functioning than LARC patients. More than 75% of men and 50% of women were sexually active preoperative, compared with less than 50% and less than 35% postoperative. Male LRRC patients had more problems with erectile or ejaculatory functioning and felt less masculine than NAD or LARC patients. Women did not differ on Lubrication, Dyspareunia and Body Image. About 10% of patients used aids in order to improve erectile functioning (men) or lubrication (women). The treatment groups reported a lower HRQOL and sexual functioning compared with the normative population.

Reduced gray matter volume and increased white matter fractional anisotropy in women with hypoactive sexual desire disorder.

INTRODUCTION: Models of hypoactive sexual desire disorder (HSDD) imply altered central processing of sexual stimuli. Imaging studies have identified areas which show altered processing as compared with controls, but to date, structural neuroanatomical differences have not been described. AIM: The aim of this study is to investigate differences in brain structure between women with HSDD and women with no history of sexual dysfunction, and to determine sexual behavioral correlates of identified structural deviations. METHODS: Sexual functioning and gray matter (GM) and white matter (WM) were assessed in 29 women with HSDD and 16 healthy control subjects of comparable age and socioeconomic status with no history of sexual dysfunction. MAIN OUTCOME MEASURES: WM properties were measured using diffusion-weighted imaging and analyzed using fractional anisotropy (FA). GM volume was measured using three-dimensional T1-weighted recordings and analyzed using voxel-based morphometry. Sexual functioning was measured using the Sexual Function Questionnaire. RESULTS: Women with HSDD, as compared with controls, had reduced GM volume in the right insula, bilateral anterior temporal cortices, left occipitotemporal cortex, anterior cingulate gyrus, and right dorsolateral prefrontal cortex. Also, increased WM FA was observed within, amongst others, the bilateral amygdalae. Sexual interest and arousal correlated mostly with GM volume in these regions, whereas orgasm function correlated mostly with WM FA. CONCLUSION: HSDD coincides with anatomical differences in the central nervous system, in both GM and WM. The findings suggest that decreased salience attribution to sexual stimuli, decreased perception of bodily responses and sexual emotional stimulus perception, and concomitant altered attentional mechanisms associated with sexual response induction.

Neurological rehabilitation: sexuality and reproductive health.

Sexuality is the embodiment of sexual and reproductive activities involving complex interactions among biological, psychological, and social systems. An individual's perception of their sexuality, as well as society's perception, can have an inestimable impact on self-esteem, and hence willingness to openly address these issues Earle S (2001). Disability, facilitated sex and the role of the nurse. J Adv Nurs 3: 433-440. Such barriers to communication represent a real challenge to practicing clinicians. However, advances in treatment options obligate the clinician providing care to those with neurogenic sexual/reproductive dysfunction to learn to communicate effectively about these issues, provide effective therapies, and refer patients to appropriate specialists. This chapter will address counseling, an overview of male and female sexual and reproductive physiological responses in the case of an intact nervous system, and a description of the impact of disorders of the nervous system on sexual function and reproductive health. Treatment options are also reviewed.

Opposed hemispheric specializations for human hypersexuality and orgasm?

With a multiple case report analysis we demonstrate that hypersexuality more often results from right hemisphere (RH) (n=26) than left hemisphere (LH) (n=7) lesions, possibly because of LH release after the RH lesion, and that ictal orgasm more often occurs in patients with right-sided (n=23) than left-sided (n=8) seizure foci, with the symptom probably resulting from RH activation. The LH may be specialized for increasing sexual tension, whereas the RH may be specialized for release of this tension (orgasm), the former being catabolic and the latter anabolic. Several other interpretations of the findings are also discussed.

Citalopram (antidepressant) administration causes sexual dysfunction in male mice through RF-amide related peptide in the dorsomedial hypothalamus.

Citalopram is the most potent selective serotonin reuptake inhibitor (SSRI) which is used as an antidepressant but causes sexual dysfunction. Whether citalopram induced sexual dysfunction is a result of gonadotropin-releasing hormone (GnRH), kisspeptin or RF-amide related peptide (RFRP) alteration is unknown. In this study, we tested mice for sexual behavior after vehicle (0.9% NaCl) and citalopram treatment (5 mg/kg) daily for 1 day (acute) and 21 or 28 days (chronic). Effects of acute and chronic treatments on neuronal numbers and mRNA expression of GnRH, kisspeptin and RFRP were measured. In addition, RFRP fiber projections to preoptic (POA)-GnRH neurons were analyzed using double-label immunohistochemistry. The expression of 14 different serotonin receptor types mRNA was examined in immunostained laser dissected single RFRP neurons in the dorsomedial hypothalamus (DMH), however only 11 receptors types were identified. Acute citalopram treatment did not affect sexual behavior, whereas, the total duration of intromission was reduced with chronic treatment. There was no effect in the expression of kisspeptin (neuronal numbers and mRNA) in the anteroventral periventricular nucleus and the arcuate nucleus and expression of GnRH (neuronal numbers and mRNA) in the POA after citalopram treatment. However, RFRP neuronal numbers in the DMH and fiber projections to the POA were significantly increased after chronic citalopram treatment, which suggests citalopram induced inhibition of sexual behavior involves the modulation of RFRP through serotonin receptors in the DMH.

Who's afraid of the G-spot?

INTRODUCTION: No controversy can be more controversial than that regarding the existence of the G-spot, an anatomical and physiological entity for women and many scientists, yet a gynecological UFO for others. METHODS: The pros and cons data have been carefully reviewed by six scientists with different opinions on the G-spot. This controversy roughly follows the Journal of Sexual Medicine Debate held during the International Society for the Study of Women's Sexual Health Congress in Florence in the February of 2009. MAIN OUTCOME MEASURE: To give to The Journal of Sexual Medicine's reader enough data to form her/his own opinion on an important topic of female sexuality. RESULTS: Expert #1, who is JSM's Controversy section editor, reviewed histological data from the literature demonstrating the existence of discrete anatomical structures within the vaginal wall composing the G-spot. He also found that this region is not a constant, but can be highly variable from woman to woman. These data are supported by the findings discussed by Expert #2, dealing with the history of the G-spot and by the fascinating experimental evidences presented by Experts #4 and #5, showing the dynamic changes in the G-spot during digital and penile stimulation. Experts #3 and #6 argue critically against the G-spot discussing the contrasting findings so far produced on the topic. CONCLUSION: Although a huge amount of data (not always of good quality) have been accumulated in the last 60 years, we still need more research on one of the most challenging aspects of female sexuality.

Kluver-Bucy syndrome, hypersexuality, and the law.

A 51-year-old right-handed man developed hypersexuality after a second right temporal lobectomy to treat epilepsy. His hypersexuality started with increased marital intercourse and masturbation but he later downloaded child pornography. Hyperphagia and distractibility, other features of the Kluver-Bucy syndrome, also developed. Resection of the amygdala and/or temporal lobe neocortical areas that inhibit other limbic areas may contribute to the pathogenesis of hypersexuality. Neurological factors mitigate the criminal responsibility for hypersexual activity in patients with Kluver-Bucy syndrome. Most previously reported patients were never charged with a crime despite uninvited physical contact in some instances. Our patient was convicted and imprisoned.

Preliminary investigation of the impulsive and neuroanatomical characteristics of compulsive sexual behavior.

In recent years, there has been increased interest in a clinical syndrome characterized by excessive sexual thoughts, sexual urges, and/or sexual behaviors that has many aspects in common with impulse control disorders. This study provides a preliminary examination of the impulsive aspects of this syndrome, compulsive sexual behavior (CSB). Sixteen male subjects, eight CSB patients and eight non-patient controls, completed psychometric measures of impulsivity and compulsive sexual behavior, performed a behavioral task designed to assess impulse control (Go-No Go task), and underwent diffusion tensor imaging (DTI) procedures. The results indicated that CSB patients were significantly more impulsive; whether measured by psychometric testing or the Go-No Go procedure, than controls. The results also indicate that CSB patients showed significantly higher superior frontal region mean diffusivity (MD) than controls. A correlational analysis indicated significant associations between impulsivity measures and inferior frontal region fractional anisotropy (FA) and MD, but no associations with superior frontal region measures. Similar analyses indicated a significant negative association between superior frontal lobe MD and the Compulsive Sexual Behavior Inventory. Thus, while CSB patients were more impulsive than controls, the DTI results were not consistent with impulse control disorders.

Persistent genital arousal disorder and trazodone. Morphometric and vascular modifications of the clitoris. A case report.

INTRODUCTION: Persistent genital arousal disorder (PGAD) is an unwanted genital arousal which occurs in absence of sexual interest and desire. AIM: To report a case of PGAD presumably due to the use of trazodone in a young eumenorrheic woman. METHODS: A young (29 years old), eumenorrheic (menstrual cycle of >25 and <35 days) woman suffered of unwanted genital arousal and uncontrollable orgasms. In the past, the patient undertook trazodone treatment. The patient was submitted, in the periovulatory (day 12) phase of the menstrual cycle, to bi- and tri-dimensional ultrasonographic and color Doppler analyses of the clitoral structures prior and after an unwanted orgasm. MAIN OUTCOMES MEASURES: 2D ultrasonographic evaluation of the clitoral body volume and color Doppler evaluation of the dorsal clitoral arteries; 3D power Doppler reconstruction of the clitoral vascularization. RESULTS: The clitoral volume was 1.33 mL before the orgasm and resulted 1.36 mL and 1.33 mL, respectively after 1 minute and 15 minutes from the orgasm. The Pulsatility Index (PI) of the dorsal clitoral artery was 1.05 before the orgasm. It resulted lower after 1 minute (PI = 0.82) and 15 minutes (PI = 0.85) from the orgasm. CONCLUSIONS: A subtle and intermittent clitoral priapism may favor the feeling of arousal persistence and elicit unbidden and unwelcomed orgasms.

Women with hypoactive sexual desire disorder compared to normal females: a functional magnetic resonance imaging study.

Lack of sexual interest is the most common sexual complaint among women. However, factors affecting sexual desire in women have rarely been studied. While the role of the brain in integrating the sensory, attentional, motivational, and motor aspects of sexual response is commonly acknowledged as important, little is known about specific patterns of brain activation and sexual interest or response, particularly among women. We compared 20 females with no history of sexual dysfunction (NHSD) to 16 women with hypoactive sexual desire disorder (HSDD) in a functional magnetic resonance imaging (fMRI) study that included assessment of subjective sexual arousal, peripheral sexual response using a vaginal photoplethysmograph (VPP), as well as brain activation across three time points. Video stimuli included erotic, sports, and relaxing segments. Subjective arousal to erotic stimuli was significantly greater in NHSD participants compared with HSDD. In the erotic-sports contrast, NHSD women showed significantly greater activation in the bilateral entorhinal cortex than HSDD women. In the same contrast, HSDD females demonstrated higher activation than NHSD females in the medial frontal gyrus (Brodmann area (BA) 10), right inferior frontal gyrus (BA 47) and bilateral putamen. There were no between group differences in VPP-correlated brain activation and peripheral sexual response was not significantly associated with either subjective sexual response or brain activation patterns. Findings were consistent across the three experimental sessions. The results suggest differences between women with NHSD and HSDD in encoding arousing stimuli, retrieval of past erotic experiences, or both. The findings of greater activation in BA 10 and BA 47 among women with HSDD suggest that this group allocated significantly more attention to monitoring and/or evaluating their responses than NHSD participants, which may interfere with normal sexual response.