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.

A survival of the fittest strategy for the selection of genotypes by which drug responders and non-responders can be predicted in small groups.

Phenotype Prediction Scores (PPS) might be powerful tools to predict traits or the efficacy of treatments based on combinations of Single-Nucleotide Polymorphism (SNPs) in large samples. We developed a novel method to produce PPS models for small samples sizes. The set of SNPs is first filtered on those known to be relevant in biological pathways involved in a clinical condition, and then further filtered repeatedly in a survival strategy to select stabile positive/negative risk alleles. This method is applied on Female Sexual Interest/Arousal Disorder (FSIAD), for which two subtypes has been proposed: 1) a relatively insensitive excitatory system in the brain for sexual cues, and 2) a dysfunctional activation of brain mechanisms for sexual inhibition. A double-blind, randomized, placebo-controlled cross-over experiment was conducted on 129 women with FSIAD. The women received three different on-demand drug-combination treatments during 3 two-week periods: testosterone (0.5 mg) + sildenafil (50 mg), testosterone (0.5 mg) + buspirone (10 mg), or matching placebos. The resulted PPS were independently validated on patient-level and group-level. The AUC scores for T+S of the derivation set was 0.867 (95% CI = 0.796-0.939; p<0.001) and was 0.890 (95% CI = 0.778-1.000; p<0.001) on the validation set. For T+B the AUC of the derivation set was 0.957 (95% CI = 0.921-0.992; p<0.001) and 0.869 (95% CI = 0.746-0.992; p<0.001) for the validation set. Both formulas could reliably predict for each drug who benefit from the on-demand drugs and could therefore be useful in clinical practice.

Androgen Receptor Polymorphism and Female Sexual Function and Desire.

INTRODUCTION: The effect of testosterone depends on the exposure of and the sensitivity of the androgen receptor (AR). It has been shown that a cytosine-adenine-guanine (CAG) trinucleotide repeat polymorphism in the AR gene has an impact on AR functional capacity in men. However, large studies are lacking on the impact of this polymorphism on female sexual function. AIM: To determine whether the CAG repeat length was associated with different aspects of women's sexual function and dysfunction, including desire, arousal, lubrication, orgasm, satisfaction, sexual pain, and sexually related personal distress. METHODS: This cross-sectional study included 529 healthy women, aged 19-65 years. Participants completed a questionnaire to provide demographic and sexual data. The CAG repeat length was analyzed in a blood sample. The correlations between CAG repeat lengths and different aspects of sexual function were calculated. Independent Student t-tests were performed to evaluate differences in the mean number of CAG repeats in the short and long allele and of the biallelic mean length determined by simple calculation and X-inactivation analysis, respectively, between women with sexual problems and women without sexual problems. P values <.05 were considered statistically significant. MAIN OUTCOME MEASURE: We used the Female Sexual Function Index, with 6 subdomains, to distinguish between women without and women with impaired sexual function; low sexual desire; impaired arousal, lubrication, or orgasm; diminished satisfaction; or pain during sex. The Female Sexual Distress Scale was used to measure sexually related personal distress. RESULTS: Overall, we found that increasing numbers of CAG repeats were correlated to increased sexual function. We found that women with problems achieving orgasm had a significantly lower number of CAG repeats than women that reported no problems reaching orgasm. We found no associations between CAG repeat lengths and other aspects of female sexual dysfunction, including hypoactive sexual desire disorder. CLINICAL IMPLICATIONS: The results could indicate an impact of the AR on women's sexual function, including the ability to reach orgasm. STRENGTH & LIMITATIONS: This is a large study using validated sexual questionnaires. A limitation is the cross-sectional design. Owing to the study design, this study is explorative and hypothesis generating. CONCLUSION: In this large cross-sectional study, we demonstrated that CAG repeat length is positively correlated to sexual function and that women with a reduced ability to reach orgasm had smaller numbers of CAG repeats in the AR gene than women with no orgasmic problems. These findings indicated that androgens and ARs might play a role in women's sexual function. Wåhlin-Jacobsen S, Flanagan JN, Pedersen AT, Kristensen E, Arver S, Giraldi A. Androgen Receptor Polymorphism and Female Sexual Function and Desire. J Sex Med 2018;15:1537-1546.

Differential DNA Methylation in Monozygotic Twins Discordant for Female Sexual Functioning.

BACKGROUND: Research has repeatedly suggested genetic and environmental factors in the etiology underlying female sexual dysfunction (FSD). Because sexual functioning is a highly variable trait, epigenetics could provide a promising approach to tackle the origins of FSD and consequently offer a step-change in our understanding of these problems. AIM: To identify differentially methylated CpG positions for sexual functioning in a sample of monozygotic twin pairs discordant for sexual functioning. METHODS: The sample consisted of 33 trait-discordant monozygotic twin pairs (mean age = 54.1 years, SD = 9.05) from the Twins UK Registry. Phenotypic data on sexual desire, arousal, lubrication, orgasm, satisfaction, and pain were collected using the Female Sexual Function Index-Lifelong (FSFI-LL). The Illumina Infinium HumanMethylation 450 DNA BeadChip was used for epigenome-wide analyses of DNA methylation in whole-blood samples. OUTCOMES: Comparison of DNA methylation patterns associated with the FSFI-LL total score and its six subdomains. RESULTS: Two differentially methylated CpG positions (cg09580409 and cg14734994) reaching experiment-wide statistical significance were found for overall sexual functioning, mapping to MGC45800 and the threonine synthase-like 2 gene (THNSL2), respectively. Furthermore, potential biologically relevant candidates for sexual desire (CUB and zona pellucida-like domains 1, CUZD1) and satisfaction (solute carrier family 6 member 19, SLC6A19) were identified. CLINICAL TRANSLATION: THNSL2 and SLC6A19, which have been linked to weight and adiposity, might represent novel candidates for sexual problems in women. STRENGTHS AND LIMITATIONS: This is the first study to investigate epigenetic mechanisms underlying FSD. The study used a relative small sample of monozygotic female twins. The cutoff to determine discordance in sexual problems was chosen based on a 10% FSFI score difference. Therefore, the results have to be interpreted with caution and need replication in larger clinical samples. CONCLUSION: Understanding how genes and environment interact to influence our sexuality might inform clinical practice and lead to new treatments for women experiencing FSD. Burri A, Leupin M, Spector T, Marinova Z. Differential DNA Methylation in Monozygotic Twins Discordant for Female Sexual Functioning. J Sex Med 2017;14:1357-1364.

Association of OPRK1 gene polymorphisms with opioid dependence in addicted men undergoing methadone treatment in an Iranian population.

Previous studies have shown significant associations between OPRK1 and susceptibility to opioid dependence and the relationships between libido dysfunction and insomnia among opium addicts who underwent methadone maintenance treatment. The authors investigated the single locus and haplotype association of rs997917, rs6985606, and rs6473797 with susceptibility to opioid addiction. Samples were selected among 202 healthy individuals and 202 opium addicts undergoing methadone maintenance treatment. Genomic DNA was extracted from the whole blood samples of all subjects through a salting out procedure. All three variants were genotyped in the studied subjects using Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR). The whole analysis process was performed using SNPAlyze and SPSS ver.20 software packages. According to the single locus analyses, rs997917 and rs6985606 represented significant associations with opium addiction under recessive (p = 0.0128) and co-dominant (p = 0.0001) inheritance models, respectively. The haplotypes C-T-C (Permutation p = 0.014) and C-T-T (Permutation p = 0.0002) were significantly associated with opioid dependence. Among methadone maintenance treatment individuals, rs997917 was significantly associated with insomnia in both allelic and genotypic levels (p = 0.0001 and p = 0.038, respectively). Furthermore, rs6985606 had the only significant association with the co-incidence of insomnia and libido dysfunction in the methadone maintenance treatment group (p = 0.038). The OPRK1 gene variants showed significant association with susceptibility to opioid dependence among Iranians.

Female Sexual Dysfunction in Presymptomatic Mutation Carriers and Patients with Huntington's Disease.

BACKGROUND: Although in Huntington's disease (HD) movement, cognition, and personality are most significantly affected, autonomic dysfunction should not be neglected. In women with HD sexual dysfunction has not been adequately studied yet. OBJECTIVE: To report sexual dysfunction in a systematically studied cohort of female HD patients and compare it with controls of a similar age. METHODS: In female HD patients and presymptomatic HD mutation carriers, we compared the Female Sexual Function Index (FSFI) questionnaire, neurologic assessment using the Unified Huntington's Disease Rating Scale (UHDRS) and the Total Functional Capacity (TFC). RESULTS: Of 44 female HD patients and 9 presymptomatic HD mutation carriers, 30 HD patients and 8 HD mutation carriers responded our invitation to complete FFSI questionnaire. Finally, 23 HD women with a partner were compared to 47 controls with a partner. HD patients had more problems with sexual arousal, lubrication, orgasm and sexual satisfaction. By contrast, we found no difference in sexual desire and pain. Sexual dysfunction progressed in parallel with the decline in the TFC; severe sexual dysfunction occurred with TFC <7/13. CONCLUSIONS: Our study demonstrated a significant impact of HD on female sexual function that progressed with patients' functional decline and impaired patients' quality of life. Sexual dysfunction may be caused by progression of the disease itself, side effects of medication, and comorbidities like depression or dementia.

Methylation of HPA axis related genes in men with hypersexual disorder.

Hypersexual Disorder (HD) defined as non-paraphilic sexual desire disorder with components of compulsivity, impulsivity and behavioral addiction, and proposed as a diagnosis in the DSM 5, shares some overlapping features with substance use disorder including common neurotransmitter systems and dysregulated hypothalamic-pituitary-adrenal (HPA) axis function. In this study, comprising 67 HD male patients and 39 male healthy volunteers, we aimed to identify HPA-axis coupled CpG-sites, in which modifications of the epigenetic profile are associated with hypersexuality. The genome-wide methylation pattern was measured in whole blood using the Illumina Infinium Methylation EPIC BeadChip, measuring the methylation state of over 850K CpG sites. Prior to analysis, the global DNA methylation pattern was pre-processed according to standard protocols and adjusted for white blood cell type heterogeneity. We included CpG sites located within 2000bp of the transcriptional start site of the following HPA-axis coupled genes: Corticotropin releasing hormone (CRH), corticotropin releasing hormone binding protein (CRHBP), corticotropin releasing hormone receptor 1 (CRHR1), corticotropin releasing hormone receptor 2 (CRHR2), FKBP5 and the glucocorticoid receptor (NR3C1). We performed multiple linear regression models of methylation M-values to a categorical variable of hypersexuality, adjusting for depression, dexamethasone non-suppression status, Childhood Trauma Questionnaire total score and plasma levels of TNF-alpha and IL-6. Of 76 tested individual CpG sites, four were nominally significant (p<0.05), associated with the genes CRH, CRHR2 and NR3C1. Cg23409074-located 48bp upstream of the transcription start site of the CRH gene - was significantly hypomethylated in hypersexual patients after corrections for multiple testing using the FDR-method. Methylation levels of cg23409074 were positively correlated with gene expression of the CRH gene in an independent cohort of 11 healthy male subjects. The methylation levels at the identified CRH site, cg23409074, were significantly correlated between blood and four different brain regions. CRH is an important integrator of neuroendocrine stress responses in the brain, with a key role in the addiction processes. Our results show epigenetic changes in the CRH gene related to hypersexual disorder in men.

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.

Efficacy of testosterone combined with a PDE5 inhibitor and testosterone combined with a serotonin (1A) receptor agonist in women with SSRI-induced sexual dysfunction. A preliminary study.

Selective serotonin reuptake inhibitors (SSRIs) are known to cause sexual dysfunction, such as decreased sexual motivation, desire, arousal, and orgasm difficulties. These SSRI-induced sexual complaints have a high prevalence rate, while there is no approved pharmacological treatment for SSRI-induced sexual dysfunction. It is hypothesized that a polymorphisms in the androgen receptor gene, encoded by the nucleotides cysteine, adenine, and guanine (CAG), influence the effect of testosterone on sexual functioning. In an explorative, randomized, double-blind, placebo-controlled, crossover study we investigated the possible effects of sublingual testosterone combined with a serotonin (5-HT)1A receptor agonist, and of sublingual testosterone combined with a phosphodiesterase type 5 inhibitor (PDE5-i) on sexual functioning in women with SSRI-induced sexual dysfunction. Furthermore, we did an exploratory analysis to assess if the CAG polymorphism influences this effect. 21 pre- and postmenopausal women with SSRI-induced sexual dysfunction participated and underwent the following interventions: a combination of testosterone (0.5 mg) sublingually and the PDE5-i sildenafil (50 mg) and a combination of testosterone (0.5 mg) sublingually and the 5-HT1A receptor agonist buspirone (10 mg). The results show that women who use a low dose of SSRI and have relatively long CAG repeats report a marked improvement in sexual function in response to both treatments compared to placebo. This explorative study and preliminary results indicate that in women with SSRI-induced sexual dysfunction, a combination of testosterone sublingually and a PDE5-i or testosterone sublingually and a 5-HT1A receptor agonist might be promising treatments for certain subgroups of women with this condition.

DSDs: genetics, underlying pathologies and psychosexual differentiation.

Mammalian sex determination is the unique process whereby a single organ, the bipotential gonad, undergoes a developmental switch that promotes its differentiation into either a testis or an ovary. Disruptions of this complex genetic process during human development can manifest as disorders of sex development (DSDs). Sex development can be divided into two distinct processes: sex determination, in which the bipotential gonads form either testes or ovaries, and sex differentiation, in which the fully formed testes or ovaries secrete local and hormonal factors to drive differentiation of internal and external genitals, as well as extragonadal tissues such as the brain. DSDs can arise from a number of genetic lesions, which manifest as a spectrum of gonadal (gonadal dysgenesis to ovotestis) and genital (mild hypospadias or clitoromegaly to ambiguous genitalia) phenotypes. The physical attributes and medical implications associated with DSDs confront families of affected newborns with decisions, such as gender of rearing or genital surgery, and additional concerns, such as uncertainty over the child's psychosexual development and personal wishes later in life. In this Review, we discuss the underlying genetics of human sex determination and focus on emerging data, genetic classification of DSDs and other considerations that surround gender development and identity in individuals with DSDs.

Androgen receptor gene CAG repeat polymorphism independently influences recovery of male sexual function after testosterone replacement therapy in postsurgical hypogonadotropic hypogonadism.

INTRODUCTION: Few and contradictory studies have evaluated the possible influence of androgen receptor (AR) gene CAG repeat polymorphism on male sexual function. AIM: In this study we evaluated the role of AR gene CAG repeat polymorphism in the recovery of sexual function after testosterone replacement therapy (TRT) in men affected by postsurgical hypogonadotropic hypogonadism, a condition which is often associated with hypopituitarism and in which the sexual benefits of TRT must be distinguished from those of pituitary-function replacement therapies. METHODS: Fifteen men affected by postsurgical hypogonadotropic hypogonadism were retrospectively assessed before and after TRT. MAIN OUTCOME MEASURES: Main outcome measures included sexual parameters as assessed by the International Index of Erectile Function questionnaire, levels of pituitary dependent hormones (total testosterone, free T3, free T4, cortisol, insulin-like growth factor-1 [IGF-1], prolactin), and results of genetic analysis (AR gene CAG repeat number). RESULTS: Plasma concentrations of free T3, free T4, cortisol, and prolactin did not vary significantly between the two phases, while testosterone and IGF-1 increased significantly after TRT. A significant improvement in all sexual parameters studied was found. The number of CAG triplets was negatively and significantly correlated with changes in all the sexual parameters, while opposite correlations were found between changes in sexual parameters and changes in testosterone levels; no correlation of change in IGF1 with change in sexual parameters was reported. On multiple linear regression analysis, after correction for changes in testosterone, nearly all the associations between the number of CAG triplets and changes in sexual parameters were confirmed. CONCLUSIONS: Shorter length AR gene CAG repeat number is associated with the recovery of sexual function after TRT in postsurgical male hypogonadotropic hypogonadism, independently of the effects of concomitant pituitary-replacement therapies.

Female sexual dysfunction in patients with major depressive disorder (MDD) treated with selective serotonin reuptake inhibitor (SSRI) and its association with serotonin 2A-1438 G/A single nucleotide polymorphisms.

INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are known for their sexual side effects. Different SSRIs may affect different areas of sexual function at different rates. AIMS: The study aimed to determine the prevalence of female sexual dysfunction (FSD), its clinical correlates, and association with 5HT2A (rs6311) single nucleotide polymorphisms (SNPs) in patients with major depressive disorder (MDD) who were on SSRI therapy. METHODS: This was a cross-sectional study on 95 female outpatients with MDD treated with SSRI. The patients were in remission as determined by Montgomery-Asberg Depression Rating Scale. Genomic DNA was isolated from buccal swabs and samples were processed using a real time polymerase chain reaction. MAIN OUTCOME MEASURES: The presence or absence of FSD as measured by the Malay Version of Female Sexual Function Index and 5HT2A-1438 G/A (rs6311) SNP. RESULTS: The overall prevalence of FSD was 32.6%. After controlling for age, number of children, education level, total monthly income, SSRI types, and SSRI dosing, being employed significantly enhanced FSD by 4.5 times (odds ratio [OR] = 4.51; 95% confidence interval [CI] 1.00, 20.30; P = 0.05). Those having marital problems were 6.7 times more likely to have FSD (OR = 6.67; 95% CI 1.57, 28.34). 5HT2A-1438 G/A (rs6311) SNP was not significantly associated with FSD. CONCLUSION: There was no significant association between FSD and the 5HT2A (rs6311) SNP in patients with MDD on SSRI therapy. Employment status and marital state were significantly associated with FSD among these patients.

Association between 5HT2A polymorphism and selective serotonin re-uptake inhibitor (SSRI)-induced sexual desire disorder (SDD) among Malaysian women.

INTRODUCTION: SSRIs are known for their sexual side-effects with a variable rate of sexual dysfunction (SD). 5HT2A (rs6311) single nucleotide polymorphism (SNP) was found to have significant association with SD. The purpose of this study was to determine the prevalence of female SDD, its clinical correlates and association with 5HT2A (rs6311) SNP in patients with major depressive disorder (MDD) treated with SSRIs. METHODS: This was a cross-sectional study. We evaluated 95 female outpatients with MDD treated with SSRIs who were in remission. Outcome measures were stratified by the presence or absence of SDD. A buccal swab was obtained from each patient and sent for genotyping in the Pharmacogenomics and Medical Biotechnology Laboratory of Universiti Malaya. RESULTS: The overall prevalence of female SD was 32.6%. The prevalence of female SDD was 62.1%. Those with arousal problem, lubrication problem, sexual satisfaction problem, orgasm problem and problematic marriage were more likely to have sexual desire disorder. The majority of participants who had sexual desire disorder had genotype TT (42.4%) but there was no significant association observed. After controlling for age, number of children, education level, SSRI type, lubrication problem, orgasm problem, satisfaction problem and marital problem, only arousal problem significantly enhanced the presence of sexual desire disorder by 8.5 times (odds ratio = 8.46, 95% confidence interval = 1.24-57.58; P = 0.018). DISCUSSION: This study showed that there was no significant association between SDD and the 5HT2A (rs6311) SNP. Arousal problem significantly enhanced the presence of sexual desire disorder.

Pharmacogenomics and sexuality: a vision.

Female sexual dysfunction (FSD) is multidimensional with a complex interplay of biopsychosocial factors modulating the clinical expression of sexual symptoms and associated distress. During the entire reproductive lifespan, intra- and interpersonal experiences shape human neuroendocrine and neurovascular sexual pathways. These are dependent on genetic and epigenetic mechanisms, including acquired medical conditions. Understanding the genetic basis of FSD can help to determine clinical phenotypes of women and therefore postulate the most effective intervention according to biological, psychological or environmental determinants. However, there is a paucity of studies demonstrating a genetic contribution to FSD and a diverse modulation of innate and acquired factors on discrete domains of sexual response and distress. This is evident from menarche to menopause. Pharmacogenomics is still in its infancy in the field of sexual medicine and most data regarding genetic polymorphisms of drug targets associated with susceptibility to sexual dysfunction have been obtained in males. Pharmacogenomics may be the future of medical practice in women with FSD and may guide an individualized approach by predicting both therapeutic effects at varying dosages of hormonal and non-hormonal agents, and disadvantageous side-effects and drug interactions.

A discordant monozygotic twin approach to testing environmental influences on sexual dysfunction in women.

The present study explored the causal role played by putative environmental factors on variation in female sexual dysfunction (FSD) by investigating FSD discordant monozygotic (MZ) twins, which permits a control over genetic confounders. In a population-based sample of female twins aged 25-69 years (M = 55 years), MZ twins discordant for recent and lifelong FSD were selected. Sample sizes varied depending on the specific sexual problem (N = 33-90 pairs). The Female Sexual Function Index (FSFI) score was used to discriminate cases from controls. Once genetic factors were controlled for, relationship satisfaction emerged as the strongest independent predictor for recent and lifelong FSD, being associated with FSFI dimensions measuring desire, arousal, and lubrication problems. The association with orgasm problems was especially strong (OR 7.1, 95% CI: 1.9-25.3) as was the association with sexual dissatisfaction (OR 5.1, 95% CI: 2.1-12.1). Furthermore, obsessive-compulsive symptomatology was weakly associated with desire problems (OR 1.5, 95% CI: 1.4-1.8) and anxiety-sensitivity with orgasm problems (OR 1.1, 95% CI: 0.9-1.3). Negligible effects were found for personality factors and small effects for self-reported abusive experiences. These data indicate, for the first time, that in women at identical genetic risk, relationship factors play a key role in the development of sexual problems. These findings require replication in prospective designs which can provide additional powerful tests of the direction of causality between interpersonal factors and later sexual dysfunction.

Etiology of female sexual dysfunction.

Evaluation of: Burri A, Corina G, Myriam L, Timothy S, Qazi R. A multivariate twin study of female sexual dysfunction. J. Sex. Med. 9, 2671-2681 (2012). This study highlights the complicated nature of female sexual dysfunction (FSD), demonstrating both genetic and environmental factors involved in its etiology. The authors gathered the Female Sexual Function Index scores in a twin population, and examined which dimensions of FSD may be genetically determined or environmentally shared. The results indicate that approximately one-third of the covariance between FSD dimensions was genetic, with one identified loci influencing all phases of the sexual response cycle, whereas the other loci influenced only arousal and orgasm function. They also show that specific types of sexual problems may be related more to nonshared environmental factors. Overall, the results suggest FSD is multifactorial.

MDR1 in paroxetine-induced sexual dysfunction.

Paroxetine-induced sexual dysfunction represents a frequent treatment complication of otherwise efficient antidepressants. The genetic polymorphism of pharmacokinetic genes may contribute to the occurrence of such dysfunctions. This study presents the effect of MDR1 gene polymorphisms on sexual function in 18 women with bulimia nervosa, 18 women with anxiety disorders, and 19 healthy control subjects. It also deals with the relation between MDR1 gene polymorphisms and paroxetine-induced sexual dysfunction. The results demonstrated that MDR1 G2677T/A gene polymorphism allele carriers treated with paroxetine presented with difficulties with orgasm (p = .008) and lubrication (p < .001).

No difference in 5-HTTLPR and Stin2 polymorphisms frequency between premature ejaculation patients and controls.

INTRODUCTION: Premature ejaculation (PE) is defined as the inability of men to control ejaculation and it is the most prevalent male sexual dysfunction. The neurobiogenesis of ejaculation is very complex and involves the serotoninergic (5-hydroxytryptamine [5-HT]) system. A genetic etiology of PE in humans was stated accounting for around 30%. Recently, genetic polymorphisms located on SLC6A4 gene codifying for 5-HT transporter (5-HTT or serotonin transporter [SERT]), the major regulator of serotonergic neurotransmission, have been linked with the pathogenesis of PE and associated with the clinical response to therapy with contrasting results. AIM: In order to establish a possible pathogenetic link between PE and SLC6A4 polymorphisms, we analyzed the 5-HTT-linked polymorphic region (5-HTTLPR), rs25531, and STin2 polymorphisms in 121 patients affected by lifelong and acquired PE. METHODS: Polymerase chain reaction (PCR)-based technology followed by restriction fragment length polymorphism (RFLP) analysis. MAIN OUTCOME MEASURES: Intravaginal ejaculatory latency time was measured by stopwatch in order to diagnose PE, and the results of the SLC6A4 polymorphisms analysis in PE patients was compared with the control group. RESULTS: Genotype frequencies for 5-HTTLPR, rs25531, and STin2 for both patients and controls showed no significant deviation from Hardy-Weinberg equilibrium. No statistically significant differences were found in the frequency of SLC6A4 gene polymorphisms in PE patients vs. controls, or in lifelong PE patients vs. controls, or acquired PE patients vs. controls, or lifelong PE vs. acquired PE patients. The obtained data were contrasting with three out of four previously published reports. CONCLUSIONS: The present results indicate that no difference exists in SLC6A4 polymorphisms frequency between PE patients and controls. A comparison with the previously published reports on this field is reported.

Pharmacogenetics of glutamate system genes and SSRI-associated sexual dysfunction.

We examined whether polymorphisms in the GRIK2, GRIA3 and GRIA1 genes were associated with selective serotonin reuptake inhibitor (SSRI)-associated sexual dysfunction in 114 participants treated for depression. One polymorphism in GRIA1 (rs1994862) was associated with arousal dysfunction, providing further evidence for the role of GRIA1 in mechanisms underlying SSRI-associated sexual side effects.

The etiological relationship between anxiety sensitivity, sexual distress, and female sexual dysfunction is partly genetically moderated.

INTRODUCTION: Presence of sexual distress is diagnostic requirement for female sexual dysfunction (FSD). However, previous correlational research indicates that sexual distress in women may be related to general anxiety per se rather than being an outcome of FSD. AIM: In this exploratory study, we test, for the first time, whether the correlation between anxiety sensitivity, sexual distress, and FSD can be explained by shared genetic and nongenetic factors using multivariate twin modeling. METHODS: Questionnaire data were available on a representative final sample of 930 Caucasian British female twin individuals (119 monozygotic twin pairs, 67 dizygotic twin pairs, and 558 single twins; aged 18-85 years). Validated scales assessed anxiety sensitivity, sexual distress, and FSD and included the Female Sexual Function Index, the Female Sexual Distress Scale, and the Anxiety Sensitivity Index. MAIN OUTCOME MEASURES: Questionnaire responses were subject to trivariate heritability analyses to assess common genetic and environmental influences underlying specific trait variance and the covariance between the phenotypes. RESULTS: Heritability for FSD was 28%, 48% for anxiety sensitivity, and 44% for sexual distress. The phenotypic associations among anxiety sensitivity, sexual distress, and FSD were all significant. Trivariate analysis indicated that additive genetic factors accounted for approximately 75% of the covariance between anxiety sensitivity and FSD 35% of the covariance between anxiety sensitivity and sexual distress, and 11% between sexual distress and FSD. CONCLUSIONS: The association between anxiety sensitivity and FSD has a common genetic component. There is a weaker genetic link between anxiety sensitivity and sexual distress and between sexual distress and FSD. These data, while silent on direction of causality, suggest a role for pleiotropic genetic factors influencing anxiety sensitivity and FSD. They also highlight a need to refine the inclusion of distress in classifications of disorders of female sexual functioning.