Female Sexual Arousal Disorder: New Insights

Female sexual arousal disorder: new insights

I Goldstein1*

1Department of Urology, Boston University School of Medicine, MA, USA

Epidemiologic investigations of women with female sexual dysfunction (FSD) from well-designed, random-sample, community-based populations are limited. Based on available information, FSD is common and estimated to occur in 22 ± 43% of women. There are limited data on age-related and para-aging risk factors, which are critical to understand when planning treatment and prevention efforts. Based on correlates of FSD, associated risk factors include age, education, history of sexual abuse or sexually transmitted disease, overall state general happiness and physical health. This brief overview attempts to review what is known about the female sexual anatomy, describes factors that may affect female sexual responsiveness, and identi®es several areas where additional research is needed to promote understanding of this complex physiological and psychosocial phenomenon. International Journal of Impotence Research (2000) 12, Suppl 4, S152±S157.

Keywords: female sexual function and dysfunction; female sexual arousal disorder

Introduction sensory input primarily genital. Orgasm consists of multiple sensory afferent information from trigger points such as clitoris, labia, vagina, periurethral The female sexual response has been characterized glans, etc, which pass centrally to supraspinal as consisting of desire, arousal and orgasm structures probably involving the thalamic septum. phases.1±3 Desire involves the existence of sexual Following suf®cient sensory stimulation, central fantasies, thoughts, and=or receptivity to sexual neurotransmitter discharge during orgasm results activity. Desire is the mental state created by in repeated 1 sec motor contractions of the pelvic external and internal stimuli that induces a need ¯oor (3 ± 8=orgasm) followed in 2 ± 4 sec by repeated or want to partake in sexual activity. Desire may be uterine and vaginal smooth muscle contraction. said to consist of: (1) biologic roots, which are in Pleasurable sensory information is also carried to part based on hormones such as androgen and the cortical pleasure sites. Orgasm involves a central estrogen; (2) motivational roots, which are in part thalamic sensory depolarizing wave resulting in based on intimacy, pleasure and relationship issues; synchronous motor activity following suf®cient and (3) cognitive issues such as risk and wish. sexual stimulation and arousal.3 Arousal involves the ability to attain, or maintain A speci®c and thorough description of the sexual adequate sexual excitement and may be experienced problems a woman experiences is achieved through as subjective excitement or genital lubrication and nosology. Female sexual dysfunction consists of or swelling or other somatic responses. Arousal is disorders of desire, arousal, orgasm and sexual pain. the state with speci®c feelings and physiologic Speci®cally for this review, the focus will be upon changes usually associated with sexual activity the condition of female sexual arousal disorder. involving the genitals. Arousal may be said to Sexual arousal disorder is de®ned as the persistent consist of: (1) central mechanisms including activa- or recurring inability to attain, or maintain adequate tion of thoughts, dreams and fantasies; (2) non- sexual excitement causing personal distress. It may genital peripheral mechanisms such as salivation, be experienced as a lack of subjective excitement sweating, cutaneous vasodilation and nipple erec- or a lack of genital (lubrication=swelling) or other tion; and (3) genital mechanisms such as clitoral, somatic responses.2 Disorders of female sexual labial and vaginal engorgement. Orgasm involves arousal include, but are not limited to, lack of or the altered state of consciousness associated with diminished vaginal lubrication, decreased clitoral and labial sensation, decreased clitoral and labial engorgement or lack of vaginal smooth muscle *Correspondence: I Goldstein, Doctor's Of®ce Building, 720 relaxation. These conditions may occur secondary Harrison Avenue, Suite P606, Boston, MA 02118-2334, USA. to psychological factors. However, there is often a E-mail: [email protected] medical or physiologic basis such as diminished Female arousal disorders I Goldstein S153 vaginal=clitoral blood ¯ow, altered hormonal milieu, including aging, hypertension, cigarette smoking, prior pelvic trauma, pelvic surgery such as hyster- hypercholesterolemia, are also associated with ectomy, vaginal injury from childbirth, or use of female sexual dysfunction. medications such as selective serotonin re-uptake inhibitors. Female sexual dysfunction is a multi-causal and Anatomy and physiology multi-dimensional medical problem that adversely effects physical health and emotional well being. The focus of this paper is to update new insights There are multiple anatomical structures which into the epidemiology, physiology, pathophysio- comprise the internal and external female genital logy, diagnosis and treatment of the speci®c dis- tract such as the clitoris, labia minora and vestibular order of female sexual arousal. (corpus spongiosum) erectile tissue, peri-urethral glans, urethra, G-spot, Halban's fascia, anterior fornix erogenous zone, pubococcygeus muscle and Epidemiology cervix. There are also multiple non-genital peripheral anatomic structures involved in female sexual responses such as salivary and sweat glands, Epidemiologic investigations of women with female cutaneous blood vessels and nipples.8±12 sexual dysfunction from well-designed, random- In response to neurogenic stimulation, clitoral sample, community-based populations are limited. and vaginal smooth muscle tone relax allowing for Based on available information, female sexual increased blood ¯ow, vaginal and clitoral engorge- dysfunction is common and estimated to occur in ment and increases vasocongestion. Thus, the state 22 ± 43% of women.4±7 There are limited data on of smooth muscle tone determines the changes in age-related and para-aging risk factors, both critical the hemodynamic and genital arousal.13 to plan treatments and prevention efforts. Based on Sexual stimulation results in physiologic arousal correlates of female sexual dysfunction, associated or sensory afferent activation of these structures risk factors include age, education, history of sexual ultimately leading to an orgasmic response. In abuse or sexually transmitted disease, overall state particular, the clitoris consists of two corpora of general happiness and physical health. Epide- cavernosa lined by the tunica albuginea. The miologic information from the large, well-designed internal erectile tissue includes endothelial-lined National Health and Social Life Survey revealed that lacunar spaces, trabecular smooth muscle and in 1622 US women between the ages of 18 and 59 y, trabecular connective tissue (collagen and elastin). trouble lubricating and sex not pleasurable was Efferent autonomic innervation occurs via the noted in 18.8% and 21.2%, respectively, of the cavernosal nerve. In the basal state, corporal smooth subjects. Overall, 43% of female subjects had muscle is under contractile tone. Following sexual complaints of sexual dysfunction. Women over the stimulation, neurogenic- and endothelial-mediated age of 60 were not included in this study, and no release of nitric oxide (NO) plays an important role adjustment or association was made for menopausal in clitoral cavernosal artery and helicine arteriolar status or medical risk factors.4,5 smooth muscle relaxation leading to clitoral engor- Rosen et al, in a non-population based study of gement. With sexual stimulation, increased blood 329 women aged 18 ± 73 y from a wellness out- ¯ow to the clitoral cavernosal arteries results in patient gynecology center, reported that lack of increased clitoral intracavernosal pressure and sexual pleasure and lack of lubrication was noted tumescence and protrusion of the glans. Studies in 16.3% and 13.65%, respectively, of the subjects. show that the clitoris achieves tumescence, but not Based on the 1997 US Department of Commerce rigidity or effective corporal veno-occlusion during Bureau of the Census, 26 million women are post- sexual arousal. Duplex ultrasounds of the clitoris menopausal. According to Rosen, 66% of post- reveal that during sexual simulation the clitoris menopausal women have intercourse, 45% and increases in length and diameter and blood ¯ow 20% have two and 10 intercourse occasions per almost doubles. In the clitoris, NO has been month, respectively. Thus, 17 million post-meno- identi®ed in human tissue and is hypothesized to pausal women are engaging in 600 million inter- be the primary mediator of clitoral and labial course occasions per year in the USA. Also engorgement. Organ bath analysis of rabbit clitoral according to Rosen, 57% experience lack of lubrica- cavernosal smooth muscle strips demonstrates tion; 13% in 37.5% and 44% in greater than 75% enhanced relaxation in response to sodium nitro- of intercourse occasions, respectively. Thus, 9.7 prusside and L-arginine (both NO donors) which million women experience lack of lubrication in supports the above hypothesis. Recently, phospho- 229 million intercourse occasions per year.7 diesterase Type V (PDE V), the enzyme responsible Ongoing epidemiologic studies in women suggest for degradation of cGMP, has been isolated in that the same disease processes and risk factors that human clitoral smooth muscle cell culture and is are associated with male erectile dysfunction inhibited by sildena®l citrate.14 ± 18

International Journal of Impotence Research Female arousal disorders I Goldstein S154 The labia minora or corpora spongiosa are paired amine mesylate into the vaginal spongy muscularis structures, each 3 cm in length, that lie along the layer increased vaginal wall pressure and vaginal sides of the vaginal ori®ce. They are composed of blood ¯ow, whereas injection of saline did not vascular smooth muscle and are separated from the change vaginal wall pressure or blood ¯ow. Histo- clitoris, urethra and vestibule of the vagina. The logic and arteriographic examination showed that main arterial supply is via bulbar, inferior perineal the ilio-hypogastric-pudendal arterial bed in these and posterior labial branches of the internal puden- control animals were normal. Using a novel, non- dal artery. The somatic sensory innervation of the invasive laser oximeter technique, changes in the labia minora travels via the perineal and posterior hemodynamics of the vagina are assessed by labial branches of the pudendal nerve. Autonomic monitoring changes in the fraction of blood oxy- innervation consists of sympathetic and parasympa- hemoglobin and deoxyhemoglobin. A rise in the thetic ®bers that travel with the vessels to reach the fraction of oxyhemoglobin and decrease in the vestibular bulb. In the labia minora, blood ¯ow fraction of deoxyhemoglobin is observed in response increases, particularly to the vestibular bulbs and to pelvic nerve stimulation. causes a two- to three-fold increase in diameter and Immunohistochemical studies in human vaginal eversion of the labia with exposure of its inner tissues have shown presence of nerve ®bers contain- surface.13 ing neuropeptide Y (NPY), vasoactive intestinal The vagina consists of a tube of autonomically- peptide (VIP), nitric oxide synthetase (NOS), calci- innervated smooth muscle (longitudinal outer, inner tonin gene-related peptide (CGRP) and substance P. circular layer) lined by strati®ed squamous epithe- Preliminary studies suggest that VIP and NO are lium and a sub-dermal layer rich in capillaries. involved in modulating vaginal relaxation and Three sets of skeletal muscles surround the vagina secretory processes. Human and rabbit vaginal including the ischiocavernosum, bulbocavernous, smooth muscle cells treated with the nitric oxide transverse perinei and levator ani and pubococcy- donor, sodium nitroprusside, in the presence of geus muscles. In the basal state, the vaginal smooth sildena®l, have enhanced intracellular cGMP syn- muscle is under contractile tone and the epithelium thesis and accumulation. PGE1 and forskolin also reabsorbs sodium from the submucosal capillary produced a marked increase in intracellular cGMP. plasma transudate. Following sexual stimulation, In organ bath studies, sildena®l causes dose-depen- neurotransmitters modulate vaginal and vaginal dent relaxation of female rabbit vaginal smooth arteriolar smooth muscle relaxation. Dramatic in- muscle strips further suggesting a role for NO as a creases in capillary in¯ow in the submucosa over- mediator of vaginal wall smooth muscle relaxation. whelms Na-reabsorption leading to 3 ± 5 ml vaginal However, the exact identity of the relaxatory non- transudate enhancing lubrication essential for plea- adrenergic=non-cholinergic (NANC) neurotransmit- surable coitus. Engorgement of the vaginal wall ter remains unclear. VIP is a NANC neurotransmitter raises intra-capillary pressure and increases transu- that, like NO, may play a role in enhancing vaginal dation of plasma through the vaginal epithelium. blood ¯ow, lubrication and secretions. The vagina is This vaginal lubricative plasma ¯ows through the heavily innervated with VIP-immunoreactive nerve epithelium onto the surface of the vagina, initially ®bers in close relation to the epithelium and blood forming sweat-like droplets that coalesce to form a vessels. In organ bath studies, VIP also causes dose lubricative ®lm that covers the vaginal wall. Addi- dependant relaxation of rabbit vaginal smooth tional moistening during intercourse comes from muscle tissue, suggesting a similar role for endo- secretions of the paired greater vestibular or Bartho- genous VIP as a NANC neurotransmitter in vaginal lin's glands, although some believe that these glands tissues.19 ± 26 have a more primal function of emitting an odifer- Preliminary organ chamber experiments using ous ¯uid to attract the male. The vaginal canal is rabbit vaginal tissue suggest that adrenergic mech- also lubricated by secretions from cervical=uterine anisms modulate smooth muscle tone. Exogenous glands. In addition to lubricating, the vagina length- norepinephrine (an alpha-1 and alpha-2 agonist) ens and dilates during sexual arousal as a result causes dose-dependent contraction of vaginal of relaxation of the vaginal wall smooth muscle. smooth muscle and alpha-1 (prazosin and tamsulo- In human and animal models, sexual stimulation sin) and alpha-2 (delaquamine) selective antagonists results in increased vaginal blood ¯ow and inhibit the contraction. These observations suggest decreases vaginal luminal pressure.19 ± 26 that adrenergic nerves mediate the contractile Park et al reported that pelvic nerve stimulation response. Furthermore, there appears to be a in female New Zealand White rabbits, caused a difference in the quality of the contractile responses 236% increase in vaginal blood ¯ow, a 198% in upper and lower vaginal segments, which is increase in vaginal wall pressure and a 114% consistent with their different innervation and increase in vaginal length.13 Vaginal luminal pres- embryologic origin.8±26 sure, as measured by balloon catheter in the vaginal There are large gaps in our understanding of canal, decreased with pelvic nerve stimulation. central nervous system control of female sexual Injection of papaverine hydrochloride and phentol- function. The sexual arousal responses of the

International Journal of Impotence Research Female arousal disorders I Goldstein S155 multiple genital and non-genital peripheral ana- ment ef®cacy. If ongoing therapy is desired or tomic structures are largely the product of spinal required, it should also be provided. cord re¯ex mechanisms. The afferent re¯ex arm is To assess subjective sexual function, in particular primarily via the pudendal nerve; the efferent re¯ex sexual arousal, several instruments are available. The arm consists of coordinate somatic and autonomic Brief Index of Sexual Function Inventory (BISF-W), activity. One spinal sexual re¯ex is the bulbocaver- for example, is a validated 21 item self-reported nosus re¯ex involving sacral cord segments S2, inventory of sexual interest, activity, satisfac- 3 and 4 in which pudendal nerve stimulation tion and preference and discriminates between results in pelvic ¯oor muscle contraction. Another depressed, sexually dysfunctional, and healthy pati- spinal sexual re¯ex involves vaginal and clitoral ents. Subjective sexual response data re¯ect the cavernosal autonomic nerve stimulation resulting personal experience of the patient, an important in clitoral, labial and vaginal engorgement. The variable to evaluate because the ultimate goal is to spinal segments are under descending excitatory enhance the personal sexual experience of the and inhibitory control from multiple supraspinal woman. Intervention is not considered successful sites. Limited data suggest that descending supra- unless the woman is able to subjectively experience spinal modulation of female genital re¯exes sexual arousal, pleasure and satisfaction. Thus, it is emanates from: (1) brainstem structures such as the important to determine if physiological changes or nucleus paragigantocellularis (inhibitory via sero- improvement in blood ¯ow translate into an improved tonin), locus ceruleus (norepinephrine, nocturnal sexual experience. For instance, a documented in- engorgement during REM sleep) and midbrain crease in blood ¯ow is irrelevant unless the patient periaqueductal gray; (2) hypothalamic structures actually experienced increased arousal, sensation, such as the medial pre-optic area, ventromedial and satisfaction re¯ected by the physiological change. nucleus and paraventricular nucleus; and (3) a Specialized vascular tests for sexual arousal, such forebrain structure such as the amygdala. Multiple as genital blood ¯ow testing of vaginal vasoconges- factors interact at the supraspinal levels to in¯uence tion, has literature-based measures of validity and the excitability of spinal sexual re¯exes such as: (1) speci®city and may be utilized in selected cases. gonadal hormones; (2) genital sensory information The most commonly used procedure is vaginal via the mylenated spinothalamic pathway and the photoplethysmography which utilizes a tampon- unmyelinated spinoreticular pathway; and (3) input sized light source=detector to record vaginal blood from higher cortical centers of cognition.8±26 volume (DC ampli®er) and vaginal pulse amplitude (AC ampli®er) during sexual stimulation. Alterna- tive diagnostic procedures of genital blood ¯ow Diagnosis include duplex Doppler ultrasonography (clitoral, labial, urethral, and vaginal peak systolic velocities and end diastolic velocities), laser Doppler and laser There is no consensus as to the routine diagnostic oximetry. Other procedures such as vaginal lubrica- algorithm of the female with sexual dysfunction. tion as re¯ected by pH and vaginal pressure ± Basic features of diagnosis include history (sexual, volume changes are being evaluated. Normative psychosocial and medical), physical examination data are limited, as most testing for sexual arousal (external genitalia, internal genitalia), psychologic follows sexual stimulation. It is important to note interview (psychologic issues, partner relationship) that objective vascular tests have repeatedly ob- and laboratory testing (estrogen, testosterone, glu- served a lack of subjective awareness of the vaginal cose, CBC, creatinine, LFT's, cholesterol, U=A, Pap vasocongestive arousal.24,27 ± 29 smear, vaginal cultures as considered appropriate). Specialized neurologic tests for sexual arousal Patient (and partner) education (anatomy, physio- may include somatosensory evoked potential and logy, epidemiology, risk factors, etc) as well as electromyography. Temperature and vibration test- reversing modi®able causes such as medical condi- ing of the clitoris and vagina have been utilized for tions, medication-related sexual dysfunction and assessment of genital sensory integrity and norma- lifestyle changes should be performed prior to the tive data are available. Such testing can be achieved initiation of treatment. as an out-patient and sexual arousal disorders All patients should be evaluated for emotional associated with such conditions as multiple sclero- and=or relational issues that may be contributing sis and vaginal birth injury can be investigated with to the sexual arousal problem. This includes the this technique. context in which the patient experiences her sexuality, her self-esteem and body image, and her ability to communicate her sexual needs with Treatment her partner. This is an integral component of the female sexual function evaluation. Emotional and= Concerning treatment of sexual arousal, there are or relational issues should be addressed prior to limited safety and ef®cacy outcome investigations of treatment, and certainly prior to determining treat- the various treatment modalities.

International Journal of Impotence Research Female arousal disorders I Goldstein S156 The ideal approach to female sexual dysfunction sensitivity, decreased vaginal dryness, and in- is a collaborative effort between therapists and creased libido, have been reported with the use of physicians and should include evaluation of the a 2% testosterone cream. Side effects are similar to partner or spouse in the treatment process. There is the oral preparation.36 ± 38 a multifaceted nature of female sexual dysfunction. Other treatment options with scant ef®cacy and The context in which a woman experiences her safety evaluations for sexual arousal include vaginal sexuality is equally if not more important that the lubricants, vaginal dilators, pelvic ¯oor rehabilita- physiologic outcome she experiences, and these tion such as biofeedback electromyography and issues need to be determined before beginning Kegel exercises. medical therapy or attempting to determine treat- Oral vasodilators, such as sildena®l, L-arginine, ment ef®cacy. Despite the presence of organic yohimbine, apomorphine and phentolamine, are disease, there are often psychosocial, emotional being tested in Phase II clinical safety and ef®cacy and=or relational factors that contribute to female trials. Concerning phentolamine, a pilot study in sexual dysfunction. For this reason, a comprehen- menopausal women with sexual dysfunction dem- sive approach, addressing both psychological as onstrated enhanced vaginal blood ¯ow and subjec- well as physiologic factors is instrumental to the tive arousal. Concerning sildena®l, a pilot study in evaluation of female patients with sexual com- women with spinal cord injury has demonstrated plaints. Psychologic therapy has demonstrated clinical ef®cacy over placebo. Topical prostaglandin ef®cacy in disorders of sexual desire, primary E1 and vasoactive intestinal polypeptide are cur- orgasm and vaginismus sexual pain, but not in rently under investigation for use in women with sexual arousal disorder.30 ± 35 sexual arousal disorder.24 Estrogen and=or androgen replacement hormonal therapy may be useful in sexual desire, arousal, orgasmic and dyspareunia sexual pain disorders. Conclusion Estrogen therapy is indicated in menopausal women (either spontaneous or surgical). Aside from reliev- ing hot ¯ushes, preventing osteoporosis, and low- Basic science and clinical research in FSD is needed ering the risk of heart disease, estrogen replacement to overcome the gender gap, achieve a more therapy results in improved clitoral sensitivity, balanced therapeutic perspective between psycho- increases libido, and decreased pain and burning logic and physiologic factors and offer female during intercourse. Local or topical estrogen appli- patients enhanced opportunity for relief of a cation relieves symptoms of vaginal dryness, persistent or recurrent sexual condition which burning, and urinary frequency and urgency. causes personal distress. In menopausal or oophorectomized women, complaints of vaginal irritation, pain, or dryness are relieved with topical estrogen cream. A vaginal References estradiol ring (Estring) is currently available, which delivers low-dose estrogen locally, and which may bene®t breast cancer patients and other women who 1 Leiblum SR. 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Appendix Dr Nehra: Are there any age matched controlled studies looking at patients who have undergone hysterectomies, non-hysterectomies in terms of Open discussion following Dr Goldstein's arousal disorders? presentation Dr Goldstein: This is a group of women who had Dr Moreland: Would you comment about all of those complaints with their uterus, either endometriosis blood vessels in the vagina and what happens to the or other various conditions, benign tumors. After neurophysiology in hysterectomies? hysterectomy, they were much happier, less pain, less bleeding and their sexual function was better. Dr Moreland: At BU we're doing autopsy studies So you could leave reading that article with the and we have a number of gynecologists working conclusion that if you had sexual dysfunction, you with us to identify the nerves in the area and see should have your uterus removed. Yet, there is a if we can spare them. Preliminary data of others different outcome if you took women who had suggests that, if you spare the cervix, there's a crux normal sexual function prior to the hysterectomy of nerves that will result in a higher prevalence of and then looked at their sexual functioning after the normal sexual function after you remove the uterus. hysterectomy.

International Journal of Impotence Research