Identification of Etiopathological and Clinical Factors in Persistent Genital Arousal Disorder
Condition: Restless Genital Syndrome; Sexual Arousal Disorder; Orgasmic Disorder; Psychosexual Disorder
MeSH terms: Sexual Dysfunctions, Psychological
Study type: Observational

Summary: 
      Investigation of (possible etiological) factors associated with PGAD symptomatology as well
      as description of comorbid disorders subjects with PGAD.

      Persistent genital arousal disorder (PGAD) is a presumably rare, although debilitating
      condition, which was first defined at the beginning of this century and has not yet found
      consideration by any of the international classification systems of diseases. PGAD is
      commonly characterized by persistent and unwanted sensations of genital arousal which are not
      related to subjective feelings of sexual desire or arousal. Affected patients which are
      predominantly women can suffer tremendously. The lack of basic research on the etiology of
      PGAD leads to insufficient therapeutical approaches.
    

Detailed description: 
      The entire approach is of multimodal and explorative nature as only very limited information
      on this disease is available so far (hypotheses generating). Moreover, the aim of the study
      is to characterize PGAD patients in terms of their biography (e.g. trauma), comorbidities and
      life quality.

      Clinical assessment:

        -  Psychological/psychiatric examination

        -  Neurological examination

        -  Gynecological/urological examination

        -  Laboratory assessment

        -  Structural and Functional Magnetic Resonance Imaging

      General Hypotheses:

        1. There is a morphological correlate of PGAD that affects or represents a neuronal
           structure leading to altered perception of genital sensation (e.g. Tarlov cysts,
           varices, …).

        2. There is a functional correlate of PGAD in the central nervous system (CNS) indicating a
           hyperfunction (excitation or disinhibition) or hypofunction (inhibition) of specific
           brain areas including hypothalamus, sensory cortex of the genitals and secondary brain
           areas, brain stem centers (e.g. raphe nuclei) and others.

        3. Patients with PGAD show an elevated rate of previous pharmacological treatment with
           drugs that may alter the central processing of sexual/genital perception or reveal a
           specific pattern of comorbid diseases (e.g. affective or somatoform disorders) that may
           predispose other disorders such as PGAD, pain disorders etc.

      Expected results and exploitation:

      The proposed project will help to identify clinical and neurobiological correlates of
      persistent genital arousal (PGAD) and will provide

        1. a deeper clinical, (neuro)psychological and (neuro)biological understanding of PGAD

        2. help to identify related etiopathological mechanisms of PGAD

        3. inform clinicians and (sex) therapists on diagnostic issues and promising treatment
           targets in PGAD derived from comprehensive clinical and experimental measures

        4. stimulate further neurobiological and clinical research in the field of PGAD, leading to
           further national and international cooperation and applications

        5. a considerable number of publications in leading scientific journals and raise awareness
           of a rare disease not only among all clinicians dealing with sexual problems but also
           general practitioners and others.

      Objective(s):

      Investigation of (possible etiological) factors associated with PGAD symptomatology as well
      as description of comorbid disorders subjects with PGAD.

      Statistical Analysis:

      Clinical (psychological, neurological and gynecological/urological) data is analyzed using a
      descriptive approach of frequencies and mean values of diverse clinical findings as well as a
      group comparison (patients versus healthy controls) using respective statistical analyses
      such as ttests, chi-square test and others after having tested for normal distribution where
      necessary. MRT data is analyzed using state-of-the-art special software (SPM) including group
      comparisons.

      Sample Size Justification:

      This is a cross-sectional study of a rare disease. At MHH usually 10 new patients occur per
      year. The investigator tries to include as many patients as possible and will probably
      achieve higher numbers by advertising the study and using data banks of already existing
      cases. Due to the presumably rare number of people affected with PGAD and the very few
      existing publications which are mostly case reports and the even fewer PGAD related MRI data
      a statistically neat sample size computing is not simple. The investigator cannot refer to
      prior carried out PGAD related MRI studies and to publications mentioning PGAD sample sizes.
      However, for MRI studies methodological work investigating the reliability of statistical
      effect in fMRI studies exist. An article by Thirion in 2007 shows that a sample size between
      20 and 30 subjects per group is sufficient to detect statistical effects. This is also in
      accordance with common practice in fMRI aiming at at least 20 subject per group at which
      results become quite stable (Murphy & Garavan 2004) Thus, the investigator aims at a sample
      size of 25 subjects per group. To account for potential dropouts (~10%, mainly due to
      excessive head movement in the MRI scanner) it is planned to include approximately 30
      subjects per group.

      Discussion of Perceived / Expected Risks and Benefits:

      When considering all exclusion criteria for MRI there are no risks known for using a magnetic
      resonance imaging system. Clinical and (neuro)psychological testing might be perceived
      stressful by some participants and therefore may lead to a temporary increase in blood
      pressure and/or heart rate that will normally end after testing. Clinical examination
      (neurological and gynecological/urological) might lead to discomfort in some participants.
      Besides the neurological examination which can result in uncomfortable feelings (e.g. minor
      pain) during the ENoG-testing and Pudendus-SEP and that will normally end immediately after
      testing the clinical examination is pain-free. Blood Sampling might be painful and lead to
      hematoma. The amount of blood is low (approx. 30ml). Any serious damage to the organism
      during clinical examination and blood sampling is very unlikely.
    

Intervention name(s): Psychological/psychiatric examination; Neurological examination; Gynecological/urological examination; Laboratory assessment; Structural and Functional Magnetic Resonance Imaging
Intervention type(s): Diagnostic Test; Diagnostic Test; Diagnostic Test; Diagnostic Test; Diagnostic Test
Intervention description(s): Thorough diagnostic and (neuro)psychological assessment using standardized clinical interviews (e.g. MINI, SOMS) as well as questionnaires assessing sexual function (e.g. SIS/SES), depression and anxiety (HADS), childhood trauma (CTQ) and life quality (WHOQOL-BREF). In a semi-structured interview sociodemographic data, drug history and sexual characteristics are captured.; Standardized clinical neurological examination as well as neurophysiological measurements (Pudenus-SEP, ENoG, clinical EEG).; Standard clinical investigation including ultrasound of the genital organs will be conducted to look for any somatic pathology (e.g. varices, tumors).; Blood sample will be analyzed to evaluate (epi-)genetic markers of increased central excitability or decreased inhibition including specific parameters of the serotonin-, dopamine- and endocannabinoid system.; Structural MRI of the pelvis is conducted to rule out any anatomical pathologies underlying PGAD (e.g. varices).
Structural MRI of the lumbosacral spinal cord to look for any pathologies on the spinal level, especially spinal level S2-4 (e.g. Tarlov cysts).
High-resolution structural MRI (T1) including brain stem will be applied to all participants in order to explore alterations in gray matter volume or density.
Structural differences in white matter will be assessed using a high-resolution DTI sequence. In addition to standard voxel-wise comparison of DTI derived parameters for white matter microstructural integrity, a tractography-based analysis will test for alterations in structural connectivity.
Resting-state functional MRI including brain stem scans will evaluate abnormal brain circuitry at rest (resting-state functional connectivity, RSFC).
Functional MRI to assess brain response towards sexual cue reactivity.
Observational model: Other
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        -  female and male patients or subjects between 18-65 years of age fulfilling the
             diagnostic criteria of persistent genital arousal disorder (PGAD) according to Leiblum
             & Nathan (2001).

          -  additionally, age and education matched healthy controls.
      
Keywords: Persistant Genital Arousal Disorder; PGAD