Irwin Goldstein, Elise JB De, Julie A Johnson
Introduction
Many organs and tissues are involved in the physiologic regulation of sexual arousal and orgasm in women. Physiologic sexual activity requires the integration of activity from key brain regions, the central and peripheral nervous systems, and sex steroid hormones. A healthy and intact circulatory system to and from genital tissues is necessary to support the hemodynamic changes associated with sexual arousal. Finally, sexual arousal is dependent upon functionally intact genital tissues, including the various tissue types (smooth muscle, connective tissue, endothelial cells, epithelial cells, neurologic tissue) within the clitoris, corpora spongiosa, vestibular glands, urethral meatus, periurethral glans, vagina, cervix, G-spot, and pelvic floor muscles.1
The exact physiologic mechanisms and pathways involved in the complex regulation of peripheral genital arousal and orgasm are not yet known. What is known is that during sexual excitement, genital tissue vascular and nonvascular smooth muscle undergoes loss of baseline contraction, and this relaxation leads to genital tissue engorgement. Following sexual excitement and/or orgasm, the physiologic genital changes eventually return to the baseline condition with restoration of the vasoconstrictive state.1
This chapter will address two unusual women’s sexual health conditions, persistent sexual arousal syndrome2,3 and clitoral priapism.4-9 Both conditions are extremely rare and both are usually associated with significant personal distress. These conditions are defined by physiologic peripheral genital arousal that persists for hours or days despite the absence of sexual desire or sexual stimulation. Specifically in patients with “persistent sexual arousal syndrome”, orgasm may temporarily resolve the persistent arousal for a short time, but without sexual thoughts or stimulation, or after what may appear to be a seemingly nonsexual stimulus (vibrations of a moving car), the arousal state returns. The purpose of this chapter is to describe what is currently known concerning these rarely reported conditions. There are limited evidence-based data on the epidemiology, pathophysiology, diagnosis, and treatment of both of these syndromes.
Relation to priapism conditions
Women’s sexual dysfunctions are common, complicated, and multidimensional. In the case of medical and biologic sexual dysfunctions, pathophysiologic factors may include abnormalities in the central and peripheral nervous system, hormonal milieu, and/or vascular system. Other pathophysiologic factors include the use of medications, such as antidepressants, that have an adverse effect on sexual function.10 Persistent sexual arousal syndrome and clitoral priapism are not among the more common sexual complaints, such as lack of interest, inability to achieve orgasm, lack of sexual pleasure, difficulty with lubrication, and sexual pain.11 A key question, then, is how persistent sexual arousal syndrome and clitoral priapism are distinct from these more often interrelated problems.
The extent to which persistent sexual arousal syndrome and clitoral priapism are similar to male priapism is unclear. In men, priapism is defined as a pathologic condition of peripheral genital arousal that persists beyond or is unrelated to sexual stimulation. There are three recognized forms of priapism: ischemic, low-flow priapism; arterial, high-flow priapism; and a stuttering or recurrent form of priapism.12 Clitoral priapism best fits the general conceptual definition of ischemic, low-flow priapism, whereas persistent sexual arousal syndrome more closely resembles arterial, high-flow and/or stuttering or recurrent priapism.
Clitoral priapism
The clitoris consists of two paired corpora cavernosa that form a midline shaft with attachment to the pubic bone by the suspensory ligament and two paired crura that attach to the ischio- pubic ramus. The most distal aspect, the pars descendens, extrudes only a short distance from the suspensory ligament. Each corporal body is surrounded by a fibrous sheath, the tunica albuginea, that encases cavernosal tissue consisting of sinusoids and surrounding smooth muscle. The glans clitoris appears to emanate from the paired corpora spongiosa (Fig. 16.9.1).
There has been little research on the basic physiology of clitoral engorgement/erection. At present, most researchers believe that nitric oxide is released from the autonomic nerves and from the corpora cavernosal endothelial cells after pelvic nerve stimulation. In one animal study, the mean baseline clitoral intracavernosal pressure was 6 mmHg and the mean internal pudendal arterial blood flow was 5 ml/min. Cavernous nerve stimulation resulted in an increase in the mean clitoral intracavernosal pressure to 10 mmHg and an increase in mean internal pudendal arterial blood flow to 13 ml/min. Pudendal nerve stimulation increased the mean clitoral intracavernosal pressure to 24 mmHg without associated increase in arterial blood flow. It is presumed that the pressure increase in the cli- toral corpora cavernosa provides deep anatomic support for extrusion of the sensory nerve-rich glans clitoris13 (Fig. 16.9.2).
During clitoral engorgement and erection, the ability to induce complete corporal venous outflow resistance or corporal veno-occlusive function is limited. The clitoral intracavernosal pressure at any time during sexual arousal is the result of the equilibrium between the cavernosal artery perfusion pressure and the resistance to blood outflow through the compressed subtunical venules. In the clitoris, during cavernous nerve stimulation, mean clitoral intracavernosal pressure increases approximately twofold from flaccid state measurements. In addition, mean clitoral intracavernosal pressure values decay quickly to baseline pressure values seconds after termination of cavernous stimulation. This would imply that, in the absence of overt clitoral cavernosal arterial disorder, there is limited veno-occlusive function in the clitoral corpora cavernosa. This is quite consistent with overall clitoral function; that is, tumescence/engorgement, pars descendens extrusion, support, and enhanced glans clitoris exposure.13
If the draining subtunical venules within the clitoral corpora cavernosa became obstructed, the result would be consistent with ischemic, low-flow priapism. Although this form of priapism is the most common form of priapism in men, this may not be the case in women. Ischemic, low-flow priapism in either gender is related to inability to drain blood from within the corporal bodies. This may occur in an extravascular sense, secondary to drug-induced, persistent, corporal smooth muscle relaxation. Priapism of the clitoris can occur after the use of oral psychotropic agents such as trazodone,5,9 citalopram,8 nefazodone,7 and olanzapine.6
Figure 16.9.1. Clitoral anatomy. The clitoris consists of two paired corpora cavernosa that form a midline shaft with attachment to the pubic bone by the suspensory ligament and two paired crura that attach to the ischiopubic ramus. The glans clitoris appears to emanate from the paired corpora spongiosa.
Figure 16.9.2. Clitoral physiology. Cavernous nerve stimulation resulted in an increase in the mean clitoral intracavernosal pressure and an increase in mean internal pudendal arterial blood flow. It is presumed that the pressure increase in the clitoral corpora cavernosa provides deep anatomic support for extrusion of the sensory nerve-rich glans clitoris.
Unusual clitoral erectile activity has been observed after the use of several oral pharmacologic agents. Bromocryptine has been noted to induce recurrent clitoral tumescent episodes of only several minutes in duration and occurring only in the upright position.14 Fluoxetine, a bicyclic propylamine antidepressant with potent inhibition of serotonin reuptake, has been observed to induce recurrent, short-duration, painless cli- toral engorgement in association with yawning and multiple, spontaneously occurring orgasms.15,16
Ischemic, low-flow priapism may also occur by an intravascular mechanism such as mechanical obstruction within draining subtunical venules. Clinical conditions associated with intravascular mechanisms include metastatic invasive carcinomas.17
Ischemic, low-flow priapism of the clitoris presents as acute clitoral pain and is a genuine medical emergency, since it is a closed compartment syndrome with potentially irreversible genital tissue damage.
Persistent sexual arousal syndrome
Persistent sexual arousal syndrome is not an acute state of clitoral priapism with acute pain in the clitoris. Persistent sexual arousal syndrome is, on the other hand, chronic and recurrent, and is not likely to be curable given our limited understanding of its pathophysiology. In most women, the persistent arousal state is not sought and interferes greatly with their quality of life. In our experience, women affected with the condition are frequently suicidal, socially ostracized, isolated, frustrated, miserable, embarrassed, and extremely humiliated. Persistent sexual arousal syndrome therefore is more consistent with the two other recognized forms of priapism. One is high-flow, arterial priapism, which is considered to be the inability to regulate physiologic arterial inflow to the corporal cavernosal bodies. Clinical conditions associated with persistent arterial inflow that bypasses sympathetic arteriolar regulation include arterial- lacunar fistulas from blunt or penetrating perineal trauma and pelvic arterial-venous malformations. In high-flow priapism, the state of abnormally increased arousal is persistent, not associated with pain, not wanted, felt to be intrusive, and not associated with sexual desire.12
The other form of priapism is stuttering or recurrent priapism. This condition is characterized by repeated episodes of unwanted genital arousal that may or may not proceed to classic ischemic, low-flow priapism. Stuttering priapism in men is reported in sickle cell disease and in those with so-called recurrent idiopathic prolonged erection. Preliminary data suggest that hypoxia might downregulate phosphodiesterase type 5A promoters, implying an involvement of phosphodiesterase type 5 in recurrent or stuttering priapism.18 Such patients cannot efficiently metabolize the second messenger cyclic guanosine monophosphate, resulting in a tendency to unrelenting genital smooth muscle relaxation. Ischemic, low-flow priapism associated with genital tissue damage from hypoxia, hypercapnia, and severe acidosis most commonly results in permanent erectile dysfunction. In unusual cases, however, ischemic, low-flow priapism has been reported to result in stuttering or recurrent priapism. One hypothesis to explain this unusual sequela of tissue ischemia is that the damage interfered with the biochemistry of contraction, resulting in a tendency to recurrent genital arousal. Unfortunately, there is little research on the topic.12
In both arterial, high-flow and stuttering or recurrent forms of priapism, the abnormal arousal condition is chronic and persistent, unsolicited, and not associated with sexual interest, and it adversely affects patients’ lives. There appear to be many parallels between these two forms of priapism and persistent sexual arousal syndrome in women.
Classification
The definition and classification of women’s sexual dysfunctions, especially disorders of arousal and orgasm, have been recently reconsidered. Persistent sexual arousal syndrome, but not clitoral priapism, has also been addressed in recent attempts at nomenclature and classification.19 The authors propose the following conditions for future consideration.
Clitoral priapism is a pathologic condition of clitoral engorgement/erection that is usually painful and persists beyond or is unrelated to sexual stimulation. Clitoral priapism is an important medical condition that requires evaluation and may require emergency management. Potential consequences are irreversible corporal fibrosis and permanent sexual dysfunction.
Persistent sexual arousal syndrome is a persistent, recurrent, or continuous unwanted state of sexual excitement, causing personal distress. It may be expressed as excessive subjective excitement or excessive genital (lubrication, swelling, engorgement) or other somatic responses. If the woman with persistent sexual arousal syndrome experiences repeated orgasm, another pathologic condition may exist, persistent orgasmic disorder. Persistent orgasmic disorder would be considered the persistent, recurrent, or continuous attainment of or need to attain orgasm after minimal or absent sexual stimulation and arousal, causing personal distress.
Epidemiology
Clitoral priapism has been reported rarely.4-9,14-17 Persistent sexual arousal syndrome has been reported in a few publications. At our outpatient sexual medicine clinic, we are managing approximately 20 women with persistent sexual arousal syndrome and are in communication with over 20 others. An Internet survey of women afflicted with persistent sexual arousal has been established.20 Women around the world have registered with this group and appear to have symptoms consistent with persistent sexual arousal syndrome. It is possible that the condition is more common than previously thought.
Case examples
The following are case examples of patients from our out-patient sexual medicine clinic who have been diagnosed with clitoral priapism and persistent sexual arousal syndrome. As in other portions of this textbook relating to difficult case management, all efforts have been made to protect the privacy of patients and to maintain the management strategies utilized in the case for teaching purposes.
Clitoral priapism
A 34-year-old woman reported a past history of alcohol and drug abuse and a positive family history for depression. She was diagnosed with adjustment disorder with anxious mood and major depression. The patient was prescribed fluoxetine 40 mg daily with a resultant effective clinical response for a period of 10 months. Due to drug-associated insomnia, trazodone hydrochloride was initiated at 25 mg a night for the first two nights, and then increased to 50 mg nightly, while fluoxetine was concomitantly decreased to 20 mg daily. Five days after initiating trazodone, the patient experienced a new onset irritation and itch-like discomfort in the region of the clitoris. Four days later, upon awakening from sleep, the patient observed a marked change in the quality of the introital discomfort, describing it as an intense pain, unlike anything she had previously encountered. The patient denied any history of trauma to the introitus. She denied any history of blood dyscrasia or previous malignancies. Physical examination by a gynecologist the same day confirmed introital changes consistent with clitoral priapism, including an erect, reddened, distended, tender, firm, and painful clitoris. The treatment strategy, which involved discontinuation of all psychotropic medications (fluoxetine and trazodone) and administration of phenylpropanolamine twice daily, successfully resolved the priapism, and no long-term sexual sequelae were reported.9
Persistent sexual arousal syndrome
Case 1
A 68-year-old woman with numerous medical problems presented with complaints of unrelenting orgasms. She had never had a problem reaching orgasm with masturbation and oral sex. Shortly after she had brain surgery for an arteriovenous malformation, she began to experience throbbing and fluttering sensations in the area of her clitoris and vagina, followed by multiple orgasms. The ability to have 100-200 orgasms per day without masturbation persisted. Sitting became unbearable, sometimes causing pressure to orgasm, and traveling by car became torture. Her only relief was standing, with orgasmic activity increasing throughout the course of the day. The sensations were in the clitoris, the right wall of the outer labia, and the G-spot. Physical examination revealed a distended glans clitoris in the absence of sexual stimulation (Fig. 16.9.3). Merely touching the vaginal opening would cause her to reach orgasm. Her husband remains sympathetic to her plight and relieves her pressure whenever asked. Her physician tried to help by prescribing paroxetine, which had no effect. While having an active sex life at 68 would be rewarding, this patient is miserable living with this condition.
Figure 16.9.3. Physical examination revealed a distended glans clitoris in the absence of sexual stimulation.
Case 2
A 43-year-old woman, who had experienced neck problems for a year, began having anxiety and panic attacks and was prescribed sertraline. Her neck pain worsened. Treatment included acupressure, physical therapy, soma, and hydrocodone. Within 2 months, she noticed an increase in libido and a need to reach orgasm once or twice a day rather than once a week as usual. She and her husband rarely had sexual activity due to her chronic neck pain and intense headaches. After surgery, she regained mobility in her neck and relief from the chronic pain and debilitating headaches, but the feelings of pulsation in her clitoris and need to reach orgasm became constant. Her release from orgasm lasted only 2-5 min at a time. Her gynecologist found her hormone values within normal limits and joked that she was every man’s dream. Her psychiatrist tried several medications including divalproex, citalopram, imipramine, and fluoxetine. While none of these decreased her libido, they did decrease her ability to reach orgasm, her only source of relief. Consequently, she discontinued these medications.
She calls her life sheer hell, resulting in depression, reclusiveness, weight gain, and inability to participate in normal activities. The vibration from the activities she used to enjoy causes so much stimulation as to be unacceptable. She continues to search for answers, and believes that there may be some relation between her problems and persistent sexual arousal syndrome.
Case 3
Another patient experienced similar symptoms, but with the additional complication of having survived sexual abuse. The patient was unable to sleep through the discomfort. She felt her level of arousal was increasing, and that orgasm was progressively less effective in relieving these feelings, sometimes taking hours over several days to reach orgasm with little relief afterward. The patient was diagnosed with a prolapsed urethra resulting in a hyperactive urethral-clitoral neurologic reflex (Fig. 16.9.4). After using topical estradiol cream twice daily, eliminating treatment with methylphenidate, and having the prolapse surgically repaired, she now goes for days and even weeks symptom-free, but is afraid to have sexual relations with her husband for fear of the persistent sexual arousal returning. Indeed, even after treatment, the patient’s feelings of sexual arousal continued to persist into the day after intercourse. However, this condition has improved over time, with sexual arousal eventually subsiding about 1 h after intercourse.
Case 4
“I was constantly feeling overwhelming sensations of sexual arousal, which were purely physical and not accompanied by romantic or sexual fantasies.” This patient needed to have repeated orgasms, but experienced little relief from them. She felt insatiable, and the constant sensation was “dreadful” in her words. Disabled from Lyme disease, the patient considered suicide rather than spending day after day masturbating continually. Treatment with oral contraceptives lessened the persistent sexual arousal, but gave her a cluster migraine. Treatment with nafarelin acetate nasal spray diminished the persistent sexual arousal syndrome somewhat but also lessened her ability to achieve orgasm. After years of using trazodone for insomnia, the patient eliminated the medication from her regimen, and her persistent sexual arousal syndrome symptoms decreased by 80%.
Case 5
Persistent sexual arousal syndrome severely impairs everyday life and relationships, often leading to feelings of depression and thoughts of suicide. One patient explained, “it continues to rule my life and I schedule my work and personal life around my physical pain and discomfort. It is still difficult to concentrate, focus, or achieve what I would like to both at work and at home. It has led to a renewed problem of depression and angry outbursts that are affecting my personal relationships. I have begun to contemplate suicide because I cannot imagine living like this for the rest of my life.” At the age of 12, this patient had perineal trauma, causing bleeding for 2 weeks. During her teen years, she experienced sensations of extreme pressure in her groin area. The heavy pressure and engorgement in the clitoris started in her late teens around the time she became sexually active, although it was not as intense as in later years. This was always managed by reaching orgasm every 2-3 days. However, after hysterectomy, it became more difficult for her to reach orgasm. The patient also began experiencing occasional acute pain in the groin that lasted for up to 10 min. This was not associated with any activity, but would force her to lie down.
Pressure on her bowels and bladder during sexual stimulation interrupted activity for toileting, causing further distress and lessening enjoyment of sexual activity. Reaching orgasm continued to be difficult, and normal function and normal relationships became increasingly disrupted. Although her clitoris was painfully engorged, she had no interest in sex. While the symptoms were lessened somewhat by eliminating hormone therapy and using ice packs, gradually her symptoms worsened and she contemplated suicide more often. She was ultimately diagnosed as having a pelvic, arteriovenous malformation (Fig. 16.9.5). After multiple embolizations, her condition has improved greatly.
Case 6
A 47 year old health-care professional, married for 24 years, with a lifelong history of depression, has been treated with a multitude of antidepressant medications. Despite the use of antidepressants, she had a healthy sex life and was multiorgasmic all her life. After being put on lamotrigone (lamictal) 2 years ago for treatment of depression, she developed symptoms of persistent sexual arousal. The symptoms of constant, unrelenting clitoral and genital engorgement remained 24 h a day, 7 days a week, with virtually no relief. In addition, despite the continual feeling of engorgement, she could not easily achieve orgasm for 2 years. “I never knew such a horrible, hideous thing could happen to someone.”
Figure 16.9.5. Aortography revealed a left internal iliac arteriovenous malformation. Selective internal pudendal arteriography revealed clitoral arteries communicating with the left arteriovenous malformation.
She was an avid antique coin dealer, and this hobby went downhill. She lived in an old farmhouse, and projects that used to get completed with passion just sat untouched. She felt the need to spend a large amount of time alone in her bedroom just trying to get some kind of relief, but that was not often possible.
She is a professional, and she had to go to work with very little sleep literally for days on end.
She was referred to both a multidisciplinary sexual medicine clinic and to a psychoneurologist. She was started on valproic acid (depakote) 125 mg/day for 1 week, and this was then increased each week by 125 mg until 1000 mg/day was administered. Although she had initial nausea, she tolerated the medication well. She felt some relief shortly after starting the medication, and every dose increase improved the persistent sexual arousal symptoms. While the valproic acid kept the persistent engorgement to a tolerable level, the medication did not fully resolve the symptoms.
She was also found to have very low androgen levels with low free testosterone, low total testosterone, low dehydro- epiandrosterone sulfate, low androstenedione, and modestly elevated sex hormone-binding globulin. She also had modest clitoral and labial atrophy, partial clitoral phimosis, and mild dyspareunia. She was also started on oral dehydroepiandros- terone, testosterone gel, vestibular estradiol, and intravaginal estradiol. She was temporarily happy. Life was better. She was orgasmic more easily. She stated that persistent sexual arousal without orgasm was infinitely worse than persistent sexual arousal with orgasmic release.
After 6 months of the valproic acid, she felt immobilized on the medication and gained over 45 pounds. Due to persistent depression, feelings of despair and suicide, and the persistent sexual arousal, she was offered electroconvulsive therapy as an extreme treatment for an extreme problem. Ultimately, after 3 years of persistent sexual arousal, she agreed.
Three months after undergoing 19 electroconvulsive therapy sessions, the persistent sexual arousal symptoms were completely gone. She stated she never thought she would be normal again. She felt reborn, so no more than six treatments were necessary at the time. She has no residual persistent sexual arousal symptoms and takes no antidepressant medication at present. She continues on the four sexual medications. She is sexually active, and says her sexual function, including desire, arousal, and orgasm, is back to normal, a statement she never thought she would get to make again.
Pathophysiology
The pathophysiology of clitoral priapism appears to be relatively straightforward. There are cases of drug-induced, persistent, smooth muscle relaxation and cases of infiltrative malignancy.4-9,14-17 The remainder of this chapter will focus on the biologic pathophysiologies of persistent sexual arousal syndrome, using the arbitrary classifications of neurologic, vascular, pharmacologic, idiopathic, and hormonal etiologies.
Neurologic - central and/or peripheral genital
Little is known of the central nervous system pathways controlling sexual function in women. The central anatomic structures or networks involved in the mediation of women’s genital arousal probably include the prefrontal cortex, hippocampus, amygdala, hypothalamus, midbrain, pons, and medulla. Supraspinal sites that project directly to the spinal cord center for women’s genital arousal probably include the paraventricular nucleus, locus cereulus, nucleus paragigantocellularis, para- pyramidal reticular formation, raphe magnus, raphe pallidus, A5-adrenergic cell group, and Barrington’s nucleus. The supraspinal anatomic organization of centers and pathways involved in women’s genital arousal can be theorized to function in terms of parallel processing.20
A generator system is theorized to exist within the spinal cord. This system can be activated by the pudendal, pelvic, and possibly the hypogastric nerve afferents. The spinal generator system is under inhibitory and excitatory descending modulatory control. Ascending pathways via the spinothalamic and spinoreticular pathways to the brainstem, hypothalamus, and forebrain modulate activity or level setting of the supraspinal sites. The ascending and descending pathways ultimately modulate the spinal generator system at the level of the spinal interneurons found in the intermediolateral column and dorsal interneurons.21
In the end, neurologic control of genital arousal consists of numerous spinal level reflexes, most activated by pudendal afferents. Theoretically, central or peripheral nervous system disorder may lead to persistent neurologic stimulation or facilitation of the motor autonomic nerves regulating smooth muscle control of the clitoris, labia, and/or vagina. The result would be persistent smooth muscle relaxation of the arterioles and corporal bodies of the clitoris and corpora spongiosa, leading to clitoral and labial engorgement. In addition, there would be increased blood flow in the vaginal lamina propria and relaxation of the vaginal muscularis, leading to vaginal engorgement. The end result would be consistent with persistent sexual arousal syndrome.
In our outpatient sexual medicine clinic, we have observed four women we considered to have persistent sexual arousal syndrome secondary to central neurologic pathophysiology. One woman developed persistent sexual arousal syndrome after neurosurgical intervention for arteriovenous malformation. Two noted persistent arousal after developing symptoms of cerebrovascular accident, in one case after discontinuing estrogens and in the other case after discontinuing a cholesterol-lowering agent. The fourth developed persistent arousal after neurosurgical intervention for severe neck pain. In one woman, persistent sexual arousal syndrome was observed that may have been secondary to neurologic peripheral pathophysiology. This woman developed persistent arousal after surgery for urethral prolapse. It was hypothesized that the inflammation around the urethra activated local urethroclitoral and/or urethrolabial nerves, activating the spinal reflex leading to persistent arousal. Re-establishing estrogen treatment, performing steroid- lidocaine nerve blocks around the urethral meatus, and surgically correcting the urethral prolapse led to a marked improvement in her condition.
Vascular
The main arterial supply to the peripheral genitals is from the iliohypogastric-pudendal arterial bed. The internal pudendal artery is the last anterior branch off the internal iliac artery. Distally, the internal pudendal artery traverses Alcock’s canal, and lies on the inner side in apposition to the ischiopubic ramus. The internal pudendal artery terminates as it supplies the inferior rectal and perineal artery, which supplies the labia. The common clitoral artery continues to the clitoris. This artery bifurcates into a dorsal clitoral artery and a cavernosal clitoral artery.20
The arterial supply to the vagina is derived from an extensive network of branching vessels surrounding it on all sides. The anterior branch of the internal iliac artery continually bifurcates as it descends through the pelvis with a series of the newly generated vessels, each supplying the vagina to some degree. After giving off an obturator artery branch, the umbilical, and the midrectal arteries diverge to supply a superior and inferior vesicle artery, respectively. Between the umbilical and the midrectal branches, there is a generation of a uterine artery, which further bifurcates to give the vaginal artery. The internal pudendal and accessory pudendal artery also sends a branch. Finally, the common clitoral artery sends a branch to the vaginal muscularis.20
Arterial blood flow through the iliohypogastric-pudendal- cavernosal bed or through the ilio-obturator-uterine-vaginal bed is regulated by the arteriolar resistance tone, as determined by the sympathetic nervous system. A pelvic arteriovenous malformation may bypass arteriolar regulation and lead to unregulated arterial inflow to the clitoris, labia, and/or vagina, resulting in persistent engorgement of the corporal bodies of the clitoris and corpora spongiosa. In addition, there would be increased blood flow in the vaginal lamina propria leading to vaginal engorgement. The end result would be consistent with persistent sexual arousal syndrome.
In our outpatient sexual medicine clinic, a woman, presenting with lifelong persistent sexual arousal syndrome, was found on clitoral ultrasound to have high baseline arterial blood flow. She subsequently underwent a selective internal pudendal arteriogram and was discovered to have a pelvic arteriovenous malformation with multiple branches feeding the clitoral corporal bodies (Fig. 16.9.5). After a series of embolizations, the patient’s condition improved.
Pharmacologic
Physiologic and pharmacologic investigations of the arousal phase of the female sexual response involve, in part, an understanding of the various local regulatory mechanisms that modulate smooth muscle tone in the clitoral and corpora spongiosal erectile tissue and the vaginal muscularis. Immunohistochemical studies in human vaginal tissues have shown the presence of nerve fibers containing neuropeptide Y, vasoactive intestinal polypeptide, nitric oxide synthase, calcitonin gene- related peptide, and substance P.1,20 The effects of sex steroid hormones on genital smooth muscle contractility are presently being studied. The state of tone of the genital smooth muscles in the clitoris, labia, and vagina determines the state of genital arousal. When the smooth muscles are relaxed, engorgement results. Pharmacologically induced inhibition of contraction or enhanced relaxation of the clitoral, labial, and/or vaginal smooth muscle results in persistent engorgement of the corporal bodies of the clitoris and corpora spongiosa, and increased blood flow in the vaginal lamina propria. This causes symptoms consistent with persistent sexual arousal syndrome.
Trazodone administration in men is associated with the development of prolonged penile erections, especially nocturnal erections.21 The mechanism is unknown but thought to be related in part to alpha-blocking activity and serontonergic blocking activity.21 The effect on erectile tissue is inability to induce smooth muscle contraction, with persistence of smooth muscle relaxation. While we and others have reported that trazodone induces clitoral priapism,5,9 we have also documented that chronic trazodone use is associated with persistent sexual arousal.22 In our outpatient sexual medicine clinic, two women presenting with persistent sexual arousal syndrome were found on history-taking to be long-term users of trazodone. In both cases, discontinuation of trazodone led to improvement of the condition.
We have one patient who believes her symptoms of persistent sexual arousal began after administration of lamotrigone. Her symptoms remained despite discontinuing the medication.
Idiopathic
Patients who do not have a distinct history of a central or peripheral nervous system pathophysiology, evidence of a vascular arteriovenous malformation, or use a medication such as an antipsychotic or trazodone have an idiopathic form of persistent sexual arousal syndrome. It would appear that most patients should be classified into this category because, for the most part, clearly recognized causes for the syndrome are limited.
Clues to the pathophysiology of the idiopathic form of persistent sexual arousal come from listening to what our patients claim to be responsible for initiating an attack. Precipitating factors have been categorized into arbitrary subheadings. Enhanced sensory input states, for example, are reported, such as pressure against the genitals, riding a bicycle or horse, or vibrations transmitted to the genital area, especially from riding in a car. Sexual stimulation states such as sexual intercourse, sexual foreplay, and/or masturbation can activate the persistent arousal response. Changed hormone states, such as pregnancy, premenstrual syndrome, high dietary intake of soy, menopause, and initiating or discontinuing hormone therapy, may also precipitate symptoms. These precipitating factors have in common the potential inclination to initiate genital smooth relaxation and/or inhibit genital smooth muscle contraction.
Other hints and signs of the pathophysiology of the idiopathic form of persistent sexual arousal come from paying attention to what terminates an attack. In virtually all patients with persistent sexual arousal syndrome, orgasmic relief by masturbation may for varying periods of time conclude an event of persistent arousal. Other patients assert that pain and the distraction from pain, as well as distraction via physical exercise and the application of cold to the genitals, can temporarily stop an event of persistent arousal. Orgasm, pain, and cold temperature all activate the sympathetic nervous system. These factors that induce loss of persistent arousal have in common the potential inclination to initiate genital smooth contraction and/or negate genital smooth muscle relaxation.
What is the unifying characteristic of idiopathic persistent sexual arousal syndrome? We hypothesize that these patients are vulnerable to persistent sexual arousal syndrome on the basis of unusual genital tissue biochemistry. Theoretically, patients with idiopathic persistent sexual arousal syndrome lack the ability to induce genital smooth muscle contraction once genital smooth muscle relaxation has been initiated. More specifically, as discussed earlier, persistent sexual arousal syndrome has much in common with stuttering or recurrent priapism. If the smooth muscles cannot be contracted once relaxed, the state of arousal will persist.23
What are the recognized biochemical regulatory controls over genital smooth muscle contraction once genital tissue is relaxed? Vascular and nonvascular smooth muscle contraction is under the control of several mechanisms. The one best studied is the contribution by alpha-adrenergic receptor activation from norepinephrine released by the sympathetic nervous system. Adrenergic activation involves alpha receptors, dissociation of G-protein receptor subunits, activation of phospholipase C, synthesis of inositol triphosphate and diacylglycerol, and activation of protein kinase C. The end result is an increase in intracellular calcium that promotes phosphorylation of myosin light chain and a contractile response of actin and myosin.23
Another contributory mechanism to induce vascular and nonvascular smooth muscle is endothelin-1 secreted by genital tissue endothelial cells. Endothelin-1 binds to endothelin-A receptors, leading to increased levels of intracellular calcium. The importance of endothelin in inducing genital tissue contractility remains to be determined.23
An additional fundamental means of inducing vascular and nonvascular smooth muscle contraction is by the RhoA and Rho-kinase system. The contractile effects of RhoA/Rho-kinase appear to be the result of Rho-kinase-mediated inhibition of myosin light-chain phosphatase through phosphorylation of the myosin-binding subunit. The end result is maintenance of phos- phorylated myosin light chain, promoting the binding of actin and myosin and smooth muscle contractile force generation.23
Another contributory mechanism promoting termination of genital smooth muscle relaxation after sexual stimulation is activation of the enzyme phosphodiesterase 5. The action of phosphodiesterase type 5 is to hydrolyze the second messenger cyclic guanosine monophosphate. Since high intracellular cyclic guanosine monophosphate concentrations decrease intracellular calcium by increasing the flux of calcium out of the cell and by increasing calcium binding to the sarcoplasmic reticulum, decreasing cyclic guanosine monophosphate by phosphodiesterase type 5 hydrolysis would promote and encourage increased intracellular calcium and genital smooth muscle contraction.23
In theory, alterations, modifications, or changes to any or all of the four mechanisms promoting increase in intracellular calcium and genital smooth muscle contraction may place an individual at risk of persistent sexual arousal syndrome. In such cases, once genital smooth muscle is relaxed, these theorized biochemical alterations would make it difficult to induce smooth muscle contraction and thereby inhibit further arousal.
Another theory is that in some patients with persistent sexual arousal, there are the equivalent of “mini-seizures”, with unregulated, excitatory central neurons firing constantly and activating peripheral genital arousal. Antiseizure medications may have some inhibitory effect on these individuals with uninhibited activated neurons. At least in one case, the dramatic effects of the electroconvulsive therapy suggest that once the “mini-seizure-like” activity was discontinued, the persistent sexual arousal symptoms were terminated.
The role of psychologic factors in the pathophysiology of the syndrome remains unclear. Precipitating psychologic factors reported to initiate persistent arousal include nervousness, concern, fretfulness, worry, strain, and tension. It is not understood how psychologic factors associated with stress and anxiety precipitate genital smooth muscle relaxation, and it is possible there is simply no obvious relation of psychologic factors to induction of persistent genital arousal. Once genital smooth muscle relaxation has been initiated and the persistent arousal response occurs, patients often become angry, mortified, and preoccupied. No matter how upset they become, afflicted patients continue to experience this condition and generally are unable to terminate the symptoms. This observation is consistent with an underlying biochemical contribution. The role of psychology in persistent sexual arousal syndrome perhaps is less in pathophysiology and more in treatment. Psychotherapy is an imperative and central additional treatment for women with persistent sexual arousal syndrome to assist in the management of the devastating psychologic sequelae, especially the helplessness associated with the condition.
Hormonal
The pathophysiology of persistent sexual arousal syndrome should be discussed in terms of a possible hormonal pathophysiology, such as a hyperandrogenic or a hyperestrogenic state. Theoretically, this can result in a persistent sexual arousal state, although this has not been observed in our sexual medicine clinic to date. The measurement of sex steroid hormone blood tests in all patients who were evaluated at our outpatient clinic has not revealed abnormally high levels of sex steroids. Most patients either had a normal or a hypoandrogen and/or hypoestrogen state. Luteinizing hormone-releasing hormone agonists, such as leuprolide acetate, were provided to several women with persistent sexual arousal syndrome, but no benefit was observed. While no patient has yet been encountered with persistent sexual arousal syndrome with an abnormal hormonal pathophysiology, blood test values are constantly being checked in light of this possibility.
Management paradigm
The management strategy for clitoral priapism is based on an underlying pharmacologic etiology. Under such pathophysiology, all potential offending medications (psychotropic, alphablocking agents) need to be discontinued. In addition, alpha-agonists need to be administered orally. If such treatment fails, clitoral intracavernosal administration of alpha-agonists (phenylephrine, 100 pg) should be considered.4-9
It is somewhat premature to discuss treatment of persistent sexual arousal syndrome, since the pathophysiologies are not fully elucidated. The following represent various biologic treatments, under the proposed classification system, that we have employed with varying success in the patients we have managed with persistent sexual arousal syndrome.
Neurologic - central
1. The medical treatment of irritating central nervous system lesion is as follows: neurosurgical excision of irritating space-occupying lesion; physical therapy, especially if there is a cervical disk lesion; acupressure; pain medications; and muscle relaxants.
2. Use medications that stabilize nerve transmission, theoretically decreasing excitation of the genital arousal reflex: divalproex, citalopram, gabapentin, clonazepam, imipramine, fluoxetine, paroxetine, olanzapine, and lorazepam.
3. Use local topical anesthetic agents, ice.
4. Normalize sex steroid hormonal milieu to improved orgasmic function, as orgasmic release consistently offers patients temporary relief.
Neurologic - peripheral genital
1. Medical treatment of irritating lesion, especially genital estrogen, may diminish the local inflammation of the sensory nerves.
2. Use local topical anesthetic agents, ice.
3. Use steroid nerve blocks (repeated).
4. Normalize sex steroid hormonal milieu to improved orgasmic function, as orgasmic release consistently offers patients temporary relief.
5. Surgical excision of the irritating lesion is another treatment.
Pharmacologic
Discontinue offending medication.
Arterial
1. Embolization of arteriovenous malformation.
2. Surgical excision of arteriovenous malformation.
Idiopathic
1. Use medications that stabilize nerve transmission, theoretically decreasing excitation of the genital arousal reflex: divalproex, citalopram, gabapentin, clonazepam, imipramine, fluoxetine, paroxetine, olanzapine, and lorazepam.
2. Local topical anesthetic agents, ice.
3. Normalize sex steroid hormonal milieu to improved orgasmic function, as orgasmic release consistently offers patients temporary relief.
For all patients who cannot be relieved of their symptoms, psychotherapy should be considered to manage the chronic adverse effects of the syndrome. In our experience, the reaction to persistent sexual arousal syndrome is unique for each individual. The initial distress, including confusion, shame, and isolation, is frequently compounded by a lack of access to health care. The overwhelming majority of women we evaluated at our clinic complain of depression. Work, family, and relationship roles are severely altered by the condition. Loss of employment due to poor concentration or time spent managing symptoms is common. Children are often aware that something has changed. In one case, a mother had to lock herself in her bedroom for entire afternoons to manage her persistent arousal.
The woman’s relationship with her partner frequently is adversely affected. Partners experience helplessness and confusion, uncertainty in providing relief, inadequacy, frustration, and isolation. A decline in the quality of life often occurs for not only the woman, but also her family, as she becomes less available emotionally.
For some of the patients, persistent sexual arousal syndrome was long-standing and manageable, but became unmanageable when new-onset orgasmic difficulty occurred, often due to aging or a medical change such as androgen insufficiency. Couples who had been managing the symptoms through frequent sexual activity suddenly were met with unsatisfactory sexual encounters, and extreme discomfort and frustration on the part of the woman. Both members of the couple have communicated a sense of relief at finding professional help and hope about treatment options. The awareness of other individuals regarding the diagnosis has decreased the sense of isolation that the overwhelming majority of individuals describe.
Consultation with a sex therapist should be standard practice. This can occur either in the physician’s office setting or by referral to a nearby practice with an understanding of the diagnosis. It should be made clear that the consultation is a standard adjunct of treatment while a diagnosis is being sought or treatment undertaken, and not because the physician considers the diagnosis to be psychogenic.
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