The Pharmacotherapy of Persistent Genital Arousal Disorder

Persistent genital arousal disorder (PGAD), also named restless genital syndrome (ReGS) or persistent sexual arousal syndrome (PSAS), is a rare and debilitating disease. The most common term ‘PGAD’ will be used in the following work. The aetiology and pathogenesis of PGAD are unknown. Hence, we are far from having any concrete ideas about how to effectively help people with PGAD. Nevertheless, a number of open trials, case reports and expert experiences may help the practitioner not only to better identify PGAD but also to initiate pharmacological or non-pharmacological compassionate use. In this review article, I will put an emphasis on the possible risks and benefits of pharmacological treatments.

The supposed symptoms of PGAD were first reported in a paper by Jack G. Modell in 1989 [1], in which a case of a woman is described with repeated yawning, clitoral engorgement and orgasms associated with fluoxetine administration. At the beginning of this century, the term PGAD was then defined by Leiblum and Nathan in women, independent of any drug intake [2•], and characterised by five diagnostic criteria:

These criteria have also been covered by more recent sexual disorder nomenclature and a definition by the International Society for the Study of Women’s Sexual Health [3]. PGAD is most often observed in women, with few reports in men [4‐7], children [8] or adolescents [9]. Further information on the epidemiology, comorbidities, heritability and the course of the disorder is sparse. Representative studies on the prevalence are missing. Surveys of sexual clinics and extrapolations point towards a prevalence between 0.5 and 6.7% [10••]. For an overview on theories on the causes, pathophysiology and triggers of PGAD, the reader is referred to the review by Jackowich and co-workers [10••]. It is assumed that different pathological factors may lead to PGAD, with all of them involving any kind of affection of the central (brain and spinal cord) and/or peripheral nervous system (pudendal nerve) with states of pathologically increased sensory perception, neuronal hyperexcitability and/or disinhibition [4, 10••, 11].

From a clinical point of view, persons with suspected PGAD should undergo comprehensive clinical and laboratory investigations with a complete patient history, including sexual and reproductive issues and a careful drug history. Various factors have been associated with the occurrence of PGAD, including Tarlov cysts, pelvic congestion and varices, pelvic injuries or injuries of neural structures, nerve compression, tumours, pudendal neuralgia or other rare peripheral neuropathies (e.g. ilioinguinalis/iliohypogastricus syndrome and spermaticus neuralgia) and restless legs syndrome (see [10••] for review and [12]). Per differential diagnoses, the practitioner should screen for genitopelvic pain disorders, bladder disorders, vulvodynia and somatoform disorders. All of these differential diagnoses occur rarely in those patients that present during our consultation hours after having made a self-diagnosis according to information obtained from the Internet. The abovementioned factors may lead to additional investigations, including an orientating laboratory assessment; ultrasound examination of pelvic organs and magnetic resonance imaging (MRI) of the pelvis, brain, spinal cord and spinal roots as well as an electroencephalogram. It seems that only few cases depict a specific somatic pathology that might account for PGAD.

Different therapeutic strategies have been undertaken so far, with rather crude underlying concepts. As not uncommon in rare diseases, there is not a single randomised placebo-controlled clinical trial (RCT) for PGAD, and clinicians usually do an individual pharmacological or non-pharmacological treatment trial with some of them being published as case reports or case series. Most probably, there is an underreporting of treatment failures, which, however, might also provide important information for research and treatment.

With regard to non-pharmacological treatment options, dietary modification and counselling (n = 1, soy-based diet); pelvic floor physiotherapy (n = 1); transcutaneous electrical nerve stimulation (TENS, n = 4, one of them without response); transcranial magnetic stimulation (TMS, n = 2); pudendal or sacral neuromodulation (n = 2); electroconvulsive therapy (ECT, n = 3); surgical procedures, such as removal of periclitoral mass, clitoridectomy or neurolysis of the dorsal branch of the pudendal nerve (n = 8); coil embolisation of a dilated ovarian vein (n = 3) and wearing a V-brace (n = 1) have been reported as successful in the respective cases (for an overview, see [10••], as well as [12‐14]). From a psychotherapeutic perspective, success with couple therapy and hypnotherapy have been described in one case, respectively [10••]. A systematic overview of non-successful treatment efforts does not exist.

As there is currently no aetiopathological model of PGAD, there are only crude ideas on pharmacological strategies for PGAD. It has been suggested that it may be due to some kind of central nervous system (CNS) hyperactivity, disinhibition, functional hyperconnectivity between specific brain areas, small fibre neuropathy or psychiatric or neurological comorbidities [10••, 11, 15]. Drugs that have been used to treat PGAD can be categorised into the following groups (see also Table 1):

Additionally, dopamine agonists have been tried in two cases [25, 26], which sounds counterintuitive unless a shared pathophysiology (such as a dopaminergic deficit) with restless legs syndrome or Parkinson disease is assumed. At our institution, dopamine agonists have never been tried as a first-choice treatment, since there are plenty of cases reporting elevated rates of impulse control disorders during l-DOPA and dopamine agonist treatment, including hypersexuality, pathological gambling, compulsive shopping and binge eating [30••, 31••]. Thus, pharmacologically increasing the central dopaminergic tone requires sensitive management.

As outlined in Table 1, there are a small number of individual treatment trials that have used one of the drug classes described above. This includes treatments with antiandrogens (n = 1), antidepressants (n = 10), anticonvulsants (n = 6, one without improvement), a partial acetylcholine receptor agonist (n = 1), dopamine agonists (n = 2), dopamine antagonists (n = 2), botulinum toxin as a periclitoral injection treatment (n = 4), tramadol (n = 1), tetrahydrocannabinol (THC, n = 1) or cannabidiol (n = 2, without improvement).

Apart from this limited data on the pharmacotherapy of PGAD, a question of outmost importance is whether the administration or discontinuation of these or other drugs is associated with an induction or worsening of PGAD. A number of reports have clearly suggested such a link. As outlined in Table 2, these drugs again include antidepressants, anticonvulsants and antipsychotics. From a pharmacodynamic point of view, all of them relate in various degrees to the serotonergic system by blocking presynaptic serotonin reuptake transporters and/or antagonising or agonising different postsynaptic serotonin receptors. One recent and extensive investigation acknowledged six cases of PGAD after SSRI treatment (two males, four females) among 300 cases of enduring sexual dysfunction from 37 countries, following different drugs such as SSRIs, 5α-reductase inhibitors and isotretinoin and using data from an independent drug safety website (https://​rxisk.​org/​) [34••]. Although not mentioning PGAD, a European Medicine Agency (EMA) warning in 2019 has highlighted the risk of SSRI-induced persistent sexual dysfunction (https://​rxisk.​org/​ema-acknowledges-persistent-sexual-dysfunction-after-ssris-snris/​). Indeed, for quite some years, there has been a discussion about how SSRIs and 5α-reductase inhibitors may induce sexual dysfunction not only during intake but also as a tardive sexual or ‘legacy’ syndrome (for reviews, see [41••, 42]). In case the serotonin system plays a specific role in PGAD, one of the most important questions now is how serotonergic drugs might be able to sustainably alter this neurotransmitter system (e.g. by influencing pre- and postsynaptic function, receptor up- and downregulation, change of second messengers and change in neuronal structure and function) and how these alterations persist after cessation of treatment. Transporter and receptor imaging studies might yield first evidence in this context.

The pharmacotherapy of PGAD is a tricky thing. There is a paucity of controlled data, knowledge merely relies on case reports and there is evidence that a number of drugs with serotonergic properties can induce PGAD during intake or discontinuation of the drug. As it is often the case in rare or only recently described diseases, the aetiology is unknown and pathophysiological theories are rare and appear weak due to missing scientific data. Therefore, pharmacotherapy lacks a solid basis. However, therapeutic nihilism will not aid any patient, and there are some cases in which treatment with an anticonvulsant or SNRI has led to substantial improvement (see Table 1). Nevertheless, we should keep in mind that SSRIs and SNRIs are most clearly related to sexual dysfunction—not only during intake but sometimes even persisting after drug discontinuation, which is discussed as post-SSRI sexual dysfunction (PSSD) [43].

Apart from pharmacotherapy, we should treat our patients in a comprehensive way and keep in mind a number of other treatment options briefly mentioned above. As soon as diagnostic procedures have been finished and a somatic reason excluded, I usually offer a 3-column approach incorporating (1) pharmacotherapy, (2) physiotherapy of the pelvis and (3) psychotherapy/counselling. Patients often feel ashamed of their symptoms, and some of them have had negative experiences when presenting their symptoms to medical doctors that are unaware of PGAD. Therefore, I hope to increase the awareness of a rare disease with this paper. Clinicians should keep in mind (a) a proper diagnostic procedure; (b) that men, children and adolescents may also suffer from PGAD and (c) that some form of treatment deserves a trial after a careful risk-benefit analysis and shared decision-making with the patient.