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International Journal of Impotence Research (2005) 17, S44–S51 & 2005 Nature Publishing Group All rights reserved 0955-9930/05 $30.00 www.nature.com/ijir of female sexual function and dysfunction

JR Berman1*

1Director Female and Female , Rodeo Drive Women’s Center, Beverly Hills, California, USA

Female is age-related, progressive, and highly prevalent, affecting 30–50% of American women. While there are emotional and relational elements to female sexual function and response, female sexual dysfunction can occur secondary to medical problems and have an organic basis. This paper addresses and physiology of normal female sexual function as well as the pathophysiology of female sexual dysfunction. Although the female sexual response is inherently difficult to evaluate in the clinical setting, a variety of instruments have been developed for assessing subjective measures of sexual and function. Objective measurements used in conjunction with the subjective assessment help diagnose potential physiologic/organic abnormal- ities. Therapeutic options for the treatment of female sexual dysfunction, including hormonal, and pharmacological, are also addressed. International Journal of Impotence Research (2005) 17, S44–S51. doi:10.1038/sj.ijir.3901428

Keywords: female sexual dysfunction; anatomy; physiology; pathophysiology; evaluation; treatment

Incidence of female sexual dysfunction updated the definitions and classifications based upon current research and clinical practice. The definitions were broadened to include both psycho- Female sexual dysfunction is a multicausal and genic and organically based dysfunctions.4 multidimensional medical problem that has both biological and psychosocial components. It is age-related, progressive, and highly prevalent The female sexual response cycle affecting 30–50% of American women.1,2 Based on the National Health and Social Life Survey of 1749 women, 43% have complaints of sexual dysfunction.1 Masters and Johnson5 first characterized the female Recent studies evaluating the impact of age and sexual response in 1966 as consisting of four status on the female sexual response demon- successive phases: excitement, plateau, orgasmic, strated that older women and menopausal women and resolution phases. During , both not receiving replacement therapy had the and the minora become engorged decreased genital flow compared to controls.3 with blood and vaginal and clitoral length and Ongoing epidemiological studies in women sug- diameter both increase. ob- gest that the same disease processes and risk factors served that the increase in diameter by that are associated with male two to three times during sexual excitement and including aging, , cigarette , consequently become everted, exposing their inner hypercholesterolemia, as well as pelvic are surface. In 1979, Kaplan proposed the aspect of also associated with female sexual dysfunction.4 ‘’, and the three-phase model, consisting of Until recently, little basic science research or clinical desire, arousal, and , with desire being the has focused on female sexuality. One major barrier to factor inciting the overall response cycle.6 This the development of research in this field has been three-phase model is the basis for the DSM IV the absence of well-defined diagnostic classification definitions of female sexual dysfunction, as well as system. The 1998 AFUD consensus Conference the recent re-classification system made by the American Foundation of (AFUD) Consensus Panel in October of 1998.4 Others have *Correspondence: JR Berman, MD, Female Urology and recently suggested that sexual function should be Female Sexual Medicine, Rodeo Drive Women’s Health considered as a circuit, with four main domains: Center, 421 North Rodeo Drive, PH 1, Beverly Hills, , arousal, orgasm, and satisfaction. Each aspect CA 90210, USA. may overlap and/or negatively or positively feed- E-mail: [email protected] back on the next.7 Female sexual function and dysfunction JR Berman S45 AFUD classification and definition of decreased clitoral and labial sensation, decreased female sexual disorders clitoral and labial engorgement or lack of vaginal relaxation. These conditions may occur secondary to psychological factors; however, The Sexual Function Health Council of the Amer- often there is a medical/physiologic basis such as ican Foundation convened the AFUD Consensus diminished vaginal/clitoral blood flow, prior pelvic Panel, an interdisciplinary consensus conference trauma, pelvic , or medications. panel, consisting of 19 experts in female sexual dysfunction selected from five countries. The panel included specialists for endocrinology, family Orgasmic Disorder medicine, gynecology, nursing, , phy- siology, psychiatry, , rehabilitation medicine, and urology. The objective of the panel The persistent of recurrent difficulty, delay in, or was to evaluate and revise existing definitions and absence of attaining orgasm following sufficient classifications of female sexual dysfunction. Speci- and arousal that causes personal fically, medical risk factors and etiologies for female distress. This may be a primary (never achieved sexual dysfunction were incorporated with the orgasm) or secondary condition, as a result of pre-exciting psychologically based definitions surgery, trauma, or hormone deficiencies. Primary 1998 AFUD Consensus Panel Classifications and anorgasmia can be secondary to emotional trauma or Definitions of Female Sexual Dysfunction. ; however, medical/physical factors as well as medications (ie Seratonin re-uptake inhibi- tors) can contribute to or exacerbate the problem. Hypoactive Disorder

Sexual Disorders The persistent or recurring deficiency (or absence) of sexual fantasies/thoughts, and/or receptivity to sexual activity that causes personal distress. : recurrent or persistent genital pain Hypoactive Sexual Desire Disorder may result from associated with . Dyspareunia can psychological/emotional factors or be secondary to develop secondary to medical problems such as physiologic problems such as hormone deficiencies vestibulitis, vaginal atrophy, or vaginal infection. and medical or surgical interventions. Any disrup- It can be either physiologically or psychologically tion of the female hormonal milieu caused by based, or a combination of the two. natural , surgically or medically induced : recurrent or persistent involuntary menopause, or endocrine disorders, can result in spasms of the musculature of the outer third of the inhibited sexual desire. that interferes with vaginal penetration, and which causes personal distress. Vaginismus usually develops as a conditioned response to painful Sexual Aversion Disorder penetration, or secondary to psychological/emo- tional factors. Other sexual pain disorders: recurrent of persis- The persistent or recurring deficiency (or absence) tent genital pain induced by noncoital sexual of sexual fantasies/thoughts, and/or receptivity to stimulation. This includes anatomic and inflamma- sexual activity, that causes personal distress. tory conditions including infections (ie HSV), Sexual Aversion Disorder is generally a psycholo- vestibulitis, prior genital mutilation or trauma and gically or emotionally based problem that can result . for a variety of reasons such as physical or sexual These classifications are subtyped as lifelong abuse, or childhood trauma. versus acquired, generalized versus situational, and organic versus psychogenic or mixed. The etiology of any of these disorders may be multi- factorial and often times the disorders overlap.

The persistent or recurring inability to attain, or Physiologic changes in the vagina during sexual maintain, adequate sexual excitement causing per- arousal sonal distress. It may be experienced as lack of subjective excitement or lack of genital (lubrication/ swelling) or other somatic responses. During sexual arousal, genital oc- Disorders of arousal include, but are not limited curs as a result of increased blood flow. The vaginal to, lack of or diminished , canal is lubricated by secretions from uterine glands

International Journal of Impotence Research Female sexual function and dysfunction JR Berman S46 and from a transudate that originates from the Nonadrenergic/noncholingeric mediated responses subepithelial vascular bed, passively transported through the intraepithelial spaces, sometimes re- ferred to as intercellular channels. Engorgement of Immunohistochemical studies in vaginal the vaginal wall raises pressure inside the capil- tissues have shown the presence of fibers laries and creates an increase in transudation of containing NPY, VIP, NOS, CGRP and substance 11,12 plasma through the vaginal .8 This P. Preliminary studies suggest that vasoactive vaginal lubricative plasma flows through the epithe- intestinal polypeptide (VIP) and nitric oxide (NO) lium onto the surface of the vagina, initially forming are involved in modulating vaginal relaxation and sweat-like droplets that coalesce to form a lubrica- secretory processes. In the clitoris, NO has been tive film that covers the vaginal wall. Additional identified in human tissue and is hypothesized to be moistening during intercourse comes from secre- the primary mediator of clitoral and labial engorge- 10 tions of the paired greater vestibular or Bartholin’s ment. bath analysis of clitoral glands, although some believe that these glands cavernosal smooth muscle strips demonstrates en- have a more primal function of emitting an odifer- hanced relaxation in response to sodium nitroprus- ous fluid to attract the male. In addition to side and L-arginine (both NO donors), which lubricating, the vagina lengthens and dilates during supports the above hypothesis (Berman et al, un- sexual arousal as a result of relaxation of the vaginal published data). Recently, phosphodiesterase Type wall smooth muscle. In human and animal models, V (PDE V), the enzyme responsible for degradation sexual stimulation results in increased vaginal of cGMP has been isolated in human clitoral, blood flow and decreased vaginal luminal pres- vestibular bulb and vaginal smooth muscle culture, 9 sure.9,10 and is inhibited by citrate. Human and rabbit vaginal smooth muscle cells treated with the NO donor, sodium nitroprusside, in the presence of sildenafil, have enhanced intracellular cGMP synth- Physiologic changes in the clitoris and vestibular esis and accumulation. PGE1 and forskolin also bulbs during sexual arousal produced a marked increase in intracellular cGMP.13 In organ bath studies, sildenafil causes dose- dependent relaxation of female rabbit clitoral and With sexual stimulation, increased blood flow to the vaginal smooth muscle strips (unpublished observa- clitoral cavernosal and labial resulting in tion) further suggesting a role for NO as a mediator increased clitoral intracavernous pressure, tumes- of clitoral cavernosal and vaginal wall smooth cence, and protrusion of the clitoris, and muscle relaxation. However, the exact identity of eversion and engorgement of the labia minora. the relaxatory NANC remains Studies show that, unlike the , the clitoris unclear. VIP is a nonadrenergic/noncholinergic and vestibular bulbs lack a subalbugineal layer neurotransmitter that like NO, may play a role in between the and the tunica albuginea enhancing vaginal blood flow, lubrication, and layer. In the male, this layer possesses a rich venous secretions. The vagina is heavily innervated with plexus that, during sexual excitement, expands VIP-immunoreactive nerve fibers in close relation to against the tunica albiginea, reducing venous out- the epithelium and blood vessels.14 In organ bath flow and making the penis rigid. The absence of this studies, VIP also causes dose-dependent relaxation venous plexus in the clitoris and vestibular bulbs of rabbit clitoral cavernosal and vaginal smooth suggests that this organ achieves , but muscle tissue, suggesting a similar role for endo- not rigidity during sexual arousal. genous VIP as a NANC neurotransmitter in clitoral and vaginal tissues (Berman et al, unpublished data). Physiologic and biochemical mediators of the female sexual arousal response Impact of on female sexual function Within the central , the medial preoptic, anterior hypothalamic region, and related Estrogen libmic–hippocampal structures are responsible for sexual arousal. Upon activation, these centers transmit electrical signals through the parasympa- Estrogen plays a significant role in regulating female thetic and sympathetic nervous system. The neuro- sexual function. levels affect cells through- genic mechanisms modulating vaginal and clitoral out the peripheral and central nervous system and smooth muscle tone, and vaginal and clitoral influence nerve . A decline in serum vascular smooth muscle relaxation are currently estrogen levels results in thinning of vaginal under investigation. mucosal epithelium and atrophy of vaginal wall

International Journal of Impotence Research Female sexual function and dysfunction JR Berman S47 smooth muscle. Decreased estrogen levels also bed.21 Although other underlying conditions either result in a less acidic environment in the vaginal psychological or physiological/organic may also canal. This can ultimately lead to vaginal infections, manifest as decreased vaginal and clitoral engorge- urinary tract infections, and incontinence as well ment, arterial insufficiency is one etiology that complaints of sexual dysfunction.15 should be considered. Diminished pelvic blood flow also have vaso-protective and vasodila- secondary to aortoiliac or atherosclerotic disease tory effects which result in increased vaginal and leads to vaginal wall and clitoral smooth muscle clitoral and urethral arterial flow resulting in fibrosis. This can ultimately result in symptoms of maintenance of the female sexual response by vaginal dryness and dyspareunia. Histomorpho- preventing atherosclerotic compromise to pelvic metric evaluation of clitoral erectile tissue from arteries and arterioles.16 atherosclerotic animals demonstrates clitoral caver- With menopause, and the decline in circulating nosal wall thickening, loss of corporal smooth estrogen levels, a majority of women experience muscle and increase in deposition.9 In some degree of change in sexual function. Common human clitoral tissue, there is a similar loss of sexual complaints include loss of desire, decreased corporal smooth muscle with replacement by fi- frequency of sexual activity, painful intercourse, brous in association with athero- diminished sexual responsiveness, difficulty achie- sclerosis of clitoral cavernosal arteries.9 While the ving orgasm, and decreased genital sensation. precise mechanism is unknown, it is possible that Masters and Johnson17 first published their findings the athersclerotic changes that occur in clitoral of the physiologic changes occurring in menopausal vascular and trabecular smooth muscle interfere women that related to sexual function in 1966. We with normal relaxation and dilation responses to have since learned that symptoms related to altera- sexual simulation. tions in genital sensation and blood flow are, in part, Aside from atherosclerotic disease, alterations in secondary to declining estrogen levels, and that circulating estrogen levels associated with meno- there is a direct correlation between the presence of pause contribute to the age-associated changes in sexual complaints and levels of estradiol below clitoral and vaginal smooth muscle. In addition, any 50 pg/cm3.15 traumatic injury to the iliohypogastric/pudendal arterial bed from pelvic fractures, blunt trauma, surgical disruption, or chronic perineal pressure from bicycle riding, for instance, can result in diminished vaginal and clitoral blood flow and complaints of sexual dysfunction. Low testosterone levels are also associated with a decline in sexual arousal, genital sensation, libido, and orgasm. This can be accompanied by loss of pubic , vaginal mucosal thinning, and overall Neurogenic diminished sense of well being.13,18 Therapeutic success with testosterone for inhibited desire in The same neurogenic etiologies that cause erectile naturally menopausal women has been reported 19 dysfunction in men can also cause sexual dysfunc- using a testosterone pellet. Testosterone also tion in women. These include: (1) injury reportedly improves sexual desire in women, who 20 or disease of the central or peripheral nervous are postmenopausal secondary to . system, including, and (2) complete upper There is evidence that testosterone supplementation motor neuron injuries affecting sacral spinal seg- decreases HDL levels and increases triglyceride ments. Women with incomplete injuries retain that levels, making women with history of hypercholes- capacity for psychogenic arousal and vaginal lubri- terolemia and cardiac disease at significant risk. cation.22 With regard to orgasm, women with spinal Women with history of should not be cord injury have significantly more difficulty prescribed testosterone due to the fact that it can be achieving orgasm than normal controls. The effects converted to estrogen. of specific spinal cord injuries on female sexual response as well as the role for vasoactive pharma- Etiologies of female sexual dysfunction cotherapy in this population are being investigated. One recent report suggested a potential role for sildenafil in women with spinal cord injury. Vasculogenic

Hormonal/endocrine The recently named clitoral and vaginal vascular insufficiency syndromes are directly related to diminished genital blood flow secondary to athero- Dysfunction of the hypothalamic/pituitary axis, sclerosis of the iliohypogastric/pudendal arterial surgical or medical , menopause and

International Journal of Impotence Research Female sexual function and dysfunction JR Berman S48 premature ovarian failure, and chronic control relationship with her partner can all affect her use are the most common causes of hormonally ability to respond sexually. In addition, based female sexual dysfunction. The most common and other psychological and disorders are complaints associated with decreased estrogen and/ associated with female sexual dysfunction. Further- or testosterone levels are decreased desire and more, the medications commonly used to treat libido, vaginal dryness, and lack of sexual arousal. depressions can significantly affect the female Estrogen improves the integrity of vaginal mucosal sexual response. The most frequently used medica- tissue and has beneficial effects on vaginal sensa- tions for uncomplicated depression are the seroto- tion, vasocongestion, and secretions, which all leads nin re-uptake inhibitors (SSRIs). Women receiving to enhanced arousal. Estrogen deprivation causes a these medications often complaint of decreased significant decrease in clitoral intracavenosal blood desire, decreased arousal, decreased genital sensa- flow and vaginal and urethral blood flow.3,16 tion, and difficulty achieving orgasm. Several Histologically, diffuse clitoral fibrosis, thinned studies have recently been published documenting vaginal epithelial layers, and decreased vaginal improvement in SSRI-induced sexual dysfunction submucosal vasculature. Thus, a decline in circulat- in women with sildenafil.23 ing estrogen levels can produce significant adverse effects on structure and function of the vaginal and clitoris, ultimately affecting sexual function. Andro- Clinical evaluation of the female sexual gen deficiency in women is characterized by response impaired sexual function, lessened well-being, loss of , and negative effects on bone mass. Testosterone, together with its metabolite dihydro- Historically, evaluation of female patients with testosterone, is the most potent endogenous andro- complaints of sexual dysfunction has been limited gen in both men and women. It is also the major to psychological assessment. Physiologic evaluation precursor of estrogens. During the reproductive of the female sexual response in the clinical setting years, testosterone levels fall substantially, and by has been complicated by the difficulty of objectively the mid-40s, circulating testosterone levels are quantifying the changes that occur with arousal. approximately half of those of women in their 20s. Also, in contrast to the male erectile response, many There is, however, no dramatic decrease at the time genital changes that comprise the female sexual of spontaneous menopause. A major fall does occur response are not only difficult to measure, but also following bilateral ovariectomy.18 may go unnoticed by the patient.

Musculogenic Medical/physiologic evaluation

The muscles, in particular the levator Evaluation of the patient with sexual dysfunction ani and perineal membrane, participate in female should contain a thorough sexual function and responsiveness. The perineal including a , psychological and membrane, consisting of the bulbocavernosus and psychosocial assessment, laboratory or hormonal ischicavernosus muscles, when voluntarily con- studies as indicated and physiologic monitoring of tracted contributes to and intensifies sexual arousal measures of arousal. In this way, both subjective and and orgasm. In addition, they are responsible for the objective measures can be obtained and evaluated. involuntary rhythmic contractions during orgasm. The suggested hormonal profile includes FSH, LH, The muscles also modulate motor total and free testosterone levels, SHBG responses during orgasm as well as vaginal recep- and estradiol levels. Testosterone is bound to both tivity. When hypertonic, vaginismus can develop albumin and serum hormone binding globulin leading to or causing dyspareunia and other sexual (SHBG) in the blood. SHBG levels increase with pain disorders. When hypotonic, vaginal hypo- age and decrease with administration of exogenous anesthesia, coital anorgasmia as well as urinary estrogens.15,16 If an abnormal estrogen and/or tes- incontinence during sexual intercourse or orgasm tosterone level is documented, appropriate replace- can develop. ment therapy can be initiated with subsequent resolution or improvement of the patient’s symp- Psychogenic toms. Women with low estrogen and/or testosterone levels typically experience symptoms of decreased libido, decreased sensation, vaginal dryness, dys- In women, despite the presence or absence of pareunia, and decreased arousal. organic disease, emotional and relational issues Medical conditions including those that disrupt significantly affect sexual arousal. Issues such as the hypothalamic–pituitary axis or hormone defi- self-esteem, body image, and the quality of the ciencies secondary to menopause, chemotherapy, or

International Journal of Impotence Research Table 1

Treatment Company Ingredient Already used for Bottom line/side effects

Alista Vivus Inc. Topical Alprostadil/PGE 1 Male ED Transient burning in men; in trials in women now Androsorb () Novavax Testosterone Hormone-booster for Early stages of clinical trial; may heighten hypogonadal men libido in postmenopausal women -CTD Urometrics Clitoral therapy device New product Increase sensation and blood flow to clitoris via gentle suction Estratest (pill) Solvay Pharmaceuticals Estrogen–testosterone Hormone replacement therapy Heightens libido in some women; side effects combination (HRT) include acne and hair growth Femprox (cream) NexMed, Inc. Erectile dysfunction Improves blood flow to genitals; enhances arousal Intrinsa (patch) Proctor & Gamble Testosterone New product In 6-month study women reported increased Watson Laboratories sexual activity and pleasure Livial (pill) Organon Synthetic steroid HRT Approved in Europe for menopause symptoms; improved mood and libido NM1-870 (pill) NitroMed African tree bark fortified New product Increases vaginal blood flow in with nitric oxide postmenopausal women; may enhance arousal Premarin or Estrace cream Estrogen Vaginal dryness and discomfort; not for use in Berman dysfunction JR and function sexual Female women with history of blood clots or breast or Steryl-Norleucine VIP (cream) SenetekPLC Synthetic version of brain New product Same as above chemical Testosterone creams Off-label prescriptions from Testosterone Not FDA approved compounding Pharmacies Side effects include weight gain, hair growth, oily skin or enlarged clitoris Tostrelle (gel) Cellegy Testosterone Hormone-booster for Early study—testosterone levels in women on hypogonadal men HRT jumped to levels of teenage Uprima Tap Pharmaceuticals Apomorphine Targets the brain and stimulates the release of . Side effects: nausea, vomiting, not yet FDA approved Vagifem Pharmacia Upjohn Estrogen New product Improves dryness and Vasotem () Zonagen Blood vessel dilator New product Increases blood flow to genitals Viagra Pfizer Blood vessel dilator Male erectile dysfunction Same as Vasotem

nentoa ora fIptneResearch Impotence of Journal International Sample treatments available and under investigation for Female Sexual Function complaints. S49 Female sexual function and dysfunction JR Berman S50 following bilateral salpingo- should irrelevant, unless the patient actually experiences be determined and medications that adversely effect increased arousal, sensation, and satisfaction re- sexual function should also be addressed and flected by those physiological processes. changed if not contraindicated (Table 1). Table 1 lists the latest for women that show Evaluating the female sexual response in the promise in treating sexual dysfunction problems. clinical setting, both validates the patient’s problem Some treatments are available now while others are and potentially diagnoses organic disease such as still in the testing phases. vascular insufficiency, hormonal abnormalities, or The ideal approach to female sexual dysfunction neurologic disorders. The studies being undertaken is a collaborative effort between therapists and at our institution seek to define ranges of normal for physicians and should include a complete medical the following parameters: and psychosocial evaluation, as well as inclusion of the partner or spouse in the evaluation and treat- (1) Genital blood flow: clitoral, labial, urethral, and ment process. Although there are significant ana- vaginal peak systolic velocities and end diastolic tomic and embryologic parallels between men and velocities using Duplex Doppler . women, the multifaceted nature of female sexual (2) Vaginal lubrication measurements. dysfunction is clearly distinct from that of the male. (3) Vaginal compliance/elasticity: pressure–volume Thus, we cannot approach female patients or their changes. sexual function problems in the identical fashion as (4) Genital sensation: vibration thresh- male patients. The context in which a olds as well as temperature perception thresh- experiences her sexuality is equally if not more olds. important than the physiologic outcome she experi- These measurements can be recorded at baseline ences, and these issues should be determined before and following sexual stimulation. Eventually, defi- beginning medical therapy or determining treatment nition of the parameters prior to initiating medical efficacies. therapy may become the standard of care.

Psychosocial/psychosexual assessment References

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International Journal of Impotence Research