Clinical Biologic Pathophysiologies of Women's Sexual Dysfunction

J Sex Med 2005; 2: 4–25

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Blackwell Science, LtdOxford, UKJSMJournal of Sexual Medicine1743-6095Journal of Sexual Medicine 2005 200521425Original Article

Biologic Pathophysiologies of Female Sexual DysfunctionNappi et al.

ORIGINAL RESEARCH—PATHOPHYSIOLOGY

Clinical Biologic Pathophysiologies of Women’s Sexual Dysfunction

Rossella Nappi, MD, PhD,* Andrea Salonia, MD,

†

Abdulmaged M. Traish, PhD,

‡

Rik H.W. van Lunsen, MD, PhD,

§

Yoram Vardi, MD,

¶

Ates Kodiglu, MD,** and Irwin Goldstein, MD

‡

*University of Pavia, Pavia, Italy;

†

Department of Urology, Università Vita-Salute San Raffaele, Milan, Italy;

‡

Boston University School of Medicine, Boston, MA, USA;

§

University of Amsterdam, Amsterdam, The Netherlands;

¶

Rambam Medical Center, Haifa, Israel; **Department of Urology, Istanbul University, Istanbul, Turkey

Summary of Committee. For the complete report please refer to

Sexual Medicine: Sexual Dysfunctions in Men andWomen

, edited by T.F. Lue, R. Basson, R. Rosen, F. Giuliano, S. Khoury, F. Montorsi, Health Publications, Paris 2004.

A B S T R A C T

Introduction.

Data concerning the biologic pathophysiology of desire, arousal, and orgasm inwomen are limited.

Aim.

To gain knowledge of biologic pathophysiology of female sexual function.

Methods.

To provide state-of-the-art knowledge concerning female sexual dysfunction, representingthe opinions of seven experts from five countries developed in a consensus process over a 2-year period.

Main Outcome Measure.

An International Consultation in alliance with key urological and sexualmedicine societies convened over 200 multidisciplinary specialists from 60 countries into 17 con-sultation committees. The aims, goals and intentions of each committee were defined. Expertopinion was based on grading of evidence-based medical literature, extensive internal committeedialogue, open presentation, and debate.

Results.

Three critical physiologic requirements, including intact sex steroids, autonomic/somaticnerves, and arterial inflow/perfusion pressure to women’s genital organs play fundamental roles inmaintaining women’s sexual function. Despite this, there are nominal data supporting a directpathophysiologic involvement of abnormal sex steroid values, and/or damage/injury to neurologicand/or blood flow integrity in women with problems in sexual desire, arousal, and/or orgasm. Thissummary details the available literature concerning hormonal, neurologic, and vascular organicpathophysiologies of women’s sexual dysfunctions.

Conclusions.

Additional research on clinical pathophysiologies in women’s sexual dysfunction isneeded. This chapter encompasses data presented at the 2nd International Consultation on SexualMedicine in Paris, France, June 28–July 1, 2003.

Key Words.

Pathophysiology of Desire; Pathophysiology of Arousal

Clinical Pathophysiologies of Women’s Sexual Dysfunction

exual dysfunction in women is defined as dis-orders of sexual desire, arousal, orgasm, and/

or sexual pain, which result in significant personaldistress and may have a negative effect on awoman’s health and on the quality of life. The aimof this manuscript is to review the most frequent

S

clinical pathophysiologic mechanisms of women’sdesire, arousal, and orgasmic dysfunctions. Thereare a limited number of evidence-based studiesconcerning pathophysiology.

Hormonal Pathophysiology

Sex steroids play a crucial role in maintaining theanatomical and functional integrity of all the

Biologic Pathophysiologies of Female Sexual Dysfunction

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structures involved in women’s sexual function[1,2]. Reproductive-related events and hormonalmanipulations are associated with consistentchanges in desire, arousal, and orgasm in women[3]. Despite this, direct involvement of sex steroidsin female sexual dysfunction (FSD) remainscontroversial.

Clinical symptoms of androgen insufficiencyinclude diminished well-being, lethargy, loss ofsex drive and interest, unexplainable fatigue,and blunted motivation. Other signs of androgeninsufficiency include reduced pubic hair, bonemass and muscle mass, poor quality of life, morefrequent vasomotor symptoms, insomnia, depres-sion, and headache [4]. Androgen insufficiencyoccurs in a number of circumstances, includingnormal aging, ovarian insufficiency, and adrenalinsufficiency [5].

Despite the growing interest in treatment ofsexual dysfunction with androgens in clinical prac-tice, no normal range of testosterone has beenagreed upon, due in part to the difficulties with thesensitivity of assays for total and free testosteronein women and the fluctuations during the men-strual cycle and menopausal status [4]. At present,it is considered reasonable to use values at orbelow the lowest quartile of the normal range forwomen in their reproductive years to support thediagnosis of androgen insufficiency syndrome.The biologically active androgen is testosterone,which circulates bound tightly to sex-hormone-binding globulin (SHBG) and loosely to albuminand transcortin. The fraction of testosterone thatremains unbound to SHBG is deemed bioavail-able. Thus, plasma levels of total testosterone andfree testosterone as well as SHBG need to bedetermined clinically. Despite the lack of sensitiv-ity of the assays and limited controlled clinicalstudies, an increasing body of evidence is emerg-ing suggesting that women with signs and symp-toms of androgen insufficiency respond well toandrogen therapy without significant side-effects.

A recent systematic review including all ran-domized and placebo-controlled trials of treat-ment for FSD in postmenopausal womenconcluded that many treatments that are used inpractice are not supported by adequate evidence[5]. Dyspareunia due to vaginal dryness appears tobe most responsive to estrogen therapy via resto-ration of vaginal cells, pH, and blood flow [6].Progestins can oppose these changes and lead to arecurrence of dryness and dyspareunia dependingon their biochemical properties [7,8]. However,even though estrogen therapy and estrogen/

progestin therapy may be effective treatments forvaginal atrophy, increasing vaginal lubrication,they have not been shown to consistently increasesexual desire or activity and many women withFSD remain unresponsive [9]. There is a signifi-cant subgroup of women whose sexual difficultiesrespond initially to estrogen therapy but who sub-sequently revert to their initial problems, espe-cially when that problem was loss of libido [10].Studies conducted in the 1970s reported that vag-inal dryness was significantly decreased with estro-gen therapy but women did not find any changesin masturbation, orgasm, frequency of intercourse,or coital satisfaction [11]. Other reports in surgi-cally and naturally menopausal women treatedwith oral conjugated estrogens failed to demon-strate positive effects on libido [12,13], while asignificant benefit of estrogen therapy on libido,sexual activity, satisfaction, sexual function andcapacity for orgasm was found in Swedish post-menopausal women [14]. A randomized, double-blind, placebo-controlled, crossover trial ofestrogen and progestin, alone and in combination,found beneficial effect of estrogen and estrogen/progestin therapy on sexual desire, enjoyment,orgasmic frequency, and vaginal lubrication, withno difference in coital frequency on a short-termbasis [15]. A recent study with transdermal estro-gen therapy in postmenopausal women showed animprovement in satisfaction with frequency of sex-ual activity, sexual fantasies, vaginal lubrication,and lack of pain during intercourse, without anyeffect on sexual arousal and frequency of orgasm[16].

Collectively, these data underline the evidencethat estrogen and estrogen/progestin therapiesare not univocally efficacious in treating FSD andthe addition of androgen has proved helpful.However, it is necessary to investigate the differ-ences, mainly on plasma sex steroid and SHBGlevels, among various schemes of conventionalhormone therapies in terms of type of molecule,route of administration, mechanism of action, andmetabolism.

The most interesting findings on positive sexualeffects of sex steroids at menopause come fromstudies with oral and transdermal combination ofestrogens and exogenous testosterone. In the past,testosterone propionate administered twiceweekly at a dose of 25 mg, starting on the 12th dayof the menstrual cycle, and at a maintenance doseof 10 mg monthly thereafter, was effective inrelieving menopausal symptoms in those womenwho did not have complete benefit with estrogen

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therapy [17]. While relieving hot flushes, estro-gen/androgen therapy improved well-being andlibido and produced a “smoother transition” [18].In a series of surgically menopausal women treatedwith estrogen/androgen therapy, sexual arousal,desire, and fantasies increased in comparison withestrogen therapy alone, and a positive effect onfrequency of coitus and orgasm was particularlyevident during the first two postinjection weeks[19]. In a pilot series of nonresponders to oralestrogen therapy, androgen therapy by implantswas added with a significant improvement inlibido, enjoyment of sex, ability to reach orgasm,and initiation of sex [20]. Similarly, women onestrogen therapy complaining of loss of desire andreduced enjoyment of sex who were treated withestrogen/androgen therapy implants showed sig-nificant improvement with a marked change inorgasmic capability and initiation of sex whenandrogen therapy was added [21]. When post-menopausal women unhappy with their estrogentherapy regimen were randomized to receiveeither esterified estrogens or esterified estrogenswith methyltestosterone for 8 weeks, a significantimprovement of sexual sensation and desire wasevident with a clear increase in vaginal blood flowmeasured by laser Doppler velocimetry [22]. Sex-ual function improved with estrogen/androgentherapy, even though circulating estradiol levelswere lower than those measured during previousestrogen therapy, leading to the conclusion thatandrogens play a pivotal role in sexual functionwhile estrogens do not have a significant impacton sexual drive and enjoyment [9]. The additionof testosterone undecanoate improved specificaspects of sexual function such as enjoyment ofsex, satisfaction with frequency of sexual activity,and interest in sex more than estrogen alone inovariectomized women [23]. A reproducible resultwas obtained treating women with surgical meno-pause on estrogen therapy with two doses of trans-dermal testosterone (150

m

g/day and 300

m

g/day)vs. placebo. A significant improvement in sexualfunction with a further increase in scores for fre-quency of sexual activity and orgasm when womenwere taking the higher dose was reported [24]. Inthis study, however, there was an extremely strongresponse in sexual function in women on placeboand 24% of study participants withdrew from thetrial because of androgen-related adverse effects[24]. Therefore, the use of androgens in the clin-ical management of menopause needs a certaindegree of caution, in particular because the long-term effects of such medications on women’s gen-

eral health are still unknown. The type and routeof androgen therapy seem crucial given the evi-dence that oral methyltestosterone, and not trans-dermal testosterone, decreases SHBG productionand affects bioavailable plasma sex steroid levelsdifferently when combined with different types ofestrogen therapy [22,24]. There is, however, nodoubt that estrogen/androgen therapy is effica-cious in treating FSD at menopause and should beuse in clinical practice to improve sexual symp-toms at menopause.

While peer review literature reports some con-tributions of thyroid disease to men’s sexual dys-function [25–30], there were no papers foundevaluating sexual function and dysfunction inwomen complaining of either hypothyroidism orhyperthyroidism. Preliminary data have recentlybeen reported regarding sexual function and dys-function in 48 women with thyroid disease [25].All patients underwent a detailed evaluation andthe results of their Female Sexual Function Index(FSFI) scores were compared with those of acontrol group of healthy age-matched women.Women complaining of thyroid problems hadlower scores for both the lubrication and theorgasm domain of the FSFI as compared with thecontrol group, and dysthyroidal women reportedsignificantly higher genital pain during both coitaland noncoital sexual activity than controls. Whencomorbidities were evaluated, a high rate ofdepression was found in the women with thyroiddisease; the Beck Depression Inventory (BDI)score correlated significantly with the desire,arousal, and satisfaction domains of the FSFI. Ahigher rate of depression also correlated with ahigher rate of sexual distress, as determined by theSpearman correlation analysis between the BDIand the Female Sexual Distress Scale (FSDS).When the FSDS was correlated with the differentFSFI domains, a significant correlation was foundbetween women’s sexual distress and overall sexualsatisfaction.

Hyperprolactinemia is the most common endo-crine disorder of the hypothalamic-pituitary axis[31], occurring more commonly in women. It isassociated with pronounced reductions of bothsexual motivation and function. Elevated levels ofprolactin (PRL) inhibit GnRH pulsatility [32,33].Although some experimental evidence suggeststhat hyperprolactinemia suppresses physiologicreproductive functions while maintaining sexualdrive, other studies clearly indicate that chronicPRL elevation negatively impacts sexual libido[34,35]. Hulter and Lundberg assessed sexual


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function and sexual appreciation in a comprehen-sive interview of 48 women with well-definedhypothalamo-pituitary disorders [36]. A total of79.2% of the women had developed a lack of or aconsiderable decrease in sexual desire, while prob-lems with lubrication and orgasm were reportedin 64.6% and 68.7% of the women, respectively.In this series, normal menstrual pattern, youngage, and intrasellar tumor growth correlated bet-ter with normal sexual desire and sexual functionthan did normal prolactin levels and normal test-osterone levels. In a previous study [37], the sameauthors investigated sexuality in 109 women withmorphologically verified hypothalamo-pituitarydisorders, finding that 62.4% had noticed adecrease in sexual desire. This problem was shownfor 84.1% of the women in this group with hyper-prolactinemia, but only in 32.6% of the womenwith normal serum prolactin.

A correlation between hyperprolactinemia andsexual disturbances among uremic women onhemodialysis has been reported [38,39]. Mastrogi-acomo et al. reported that among 99 women onmaintenance hemodialysis, the rate of sexual inter-course and the ability to reach orgasm were sig-nificantly lower than in age-matched controls [38].Eighty percent declared a reduction in their sexualdesire, and the frequency of intercourse decreasedafter dialysis. Aging, an unmodifiable risk factor,decreased the sexual activity in both the sick andhealthy populations, but in uremic patients sexualactivity ended at an earlier age. Patients withhyperprolactinemia reported lower frequency ofintercourse as well as lower percentage of orgasmthan women with normal prolactin levels.

Recently a correlation has been made betweenhyperprolactinemia and antidepressive, antipsy-chotic, and neuroleptic drugs. Several drugs areknown to affect sexual function negatively, includ-ing psychoactive drugs, hypotensive drugs, andantihistamines [32,40]. Antipsychotic and neuro-leptic drugs reduce sexual drive, in part related todrug-induced hyperprolactinemia. Neurolepticstypically elevate plasma prolactin, associated withboth loss of libido and anorgasmia [32,40–48].Antidepressant agents such as selective serotoninreuptake inhibitors (SSRIs) may induce hyperpro-lactinemia [49–52], although no research has beenfound which accurately reports prevalence andcharacteristics of this phenomenon. In women thissecondary hyperprolactinemia induces symptomsfrom decreased sexual drive to orgasmic distur-bances such as anorgasmia and delayed orgasm[49–53].

Further studies are needed to clarify the rele-vance of sex steroids to women’s sexual functionand the impact of hormonal treatments on theclinical expression of sexual symptoms. Well-defined end-points and outcomes and a generalconsensus on the diagnostic framework for assess-ment and treatment of FSD are important goalsfor the future of sexual health and well-being.Even from a hormonal perspective, FSD mustinvolve a multidisciplinary approach to avoiddangerous body–mind separations.

Neurologic Pathophysiology

Female sexual dysfunction due to neurologiccauses is currently underexplored. Many neuro-logical disorders such as multiple sclerosis (MS),peripheral neuropathy, and lumbar radiculopathycan cause abnormal innervation to the female gen-ital organs. It is assumed that any neural lesion,central or peripheral, which causes sexual dysfunc-tion, should have sensory deficit as its mainstay.Therefore, the need to quantitatively measure thesensory function of the vagina and clitoris isbecoming obvious.

Measurement of Sensory Function of the Genitalia

Quantitative sensory testing is used in assessmentof sensory function for diagnosis of neural disor-ders. It is most commonly used for assessment ofneuropathies and other peripheral disorders [54].These tests are based on administration of quan-tified stimuli, usually of pressure, vibration, ortemperature, in a controlled way. Most commonly,the subject defines the sensory threshold by indi-cating the onset of perceived sensation either ver-bally or by button-press.

Nerves consist of fibers of variable diameterwith the thicker fibers having a faster conductionvelocity. Three types of fibers are generally recog-nized in the sensory subclass of nerve fibers: A-beta fibers, the largest fibers, mediate touch, mildpressure, sensation of joint position, and vibration.A-delta fibers, smaller than A-beta fibers, mediatesensation of cold and early components of painsensation. C fibers, the slowest and smallest, medi-ate sensation of warmth, the main component ofpain sensation, and subserve most autonomicperipheral functions. The thermal senses, warmand cold, are served by small nerve fibers, and areprobably less relevant for sexual function. Never-theless, a complete assessment of sensory functionshould include modalities of all types. At theperipheral level, the same class of fibers that sub-serve autonomic function subserve thermal senses.

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Disorders that affect these fibers, such as diabeticneuropathy, affect both sensory and autonomicfibers [54]. Measurement of small fiber sensoryfunction can therefore give indirect insightregarding the function of the as yet unexploredautonomic system in these organs.

A system and methodology for quantitativeassessment of genital sensory functions with age-corrected normograms for thresholds of vibratoryand thermal sensations for the clitoris and vaginais available [55]. Age dependency of the genitalvibratory threshold is impressively similar to itsage dependency for the skin of limbs [56], support-ing the validity of this test in the genital area.Clitoral measurement was found to have a smallerage effect, perhaps due to the richer innervationof the clitoris, rendering the age effect less signif-icant. Quantitative sensory testing is often criti-cized or even dismissed because of its subjectivenature [57]; however, some authors have shownthat results are repeatable and, therefore, can beused as a valid descriptor of the sensory state[58,59].

Specific Disorders Affecting Sexual Dysfunction

Central and peripheral neurologic disorders maycause sexual dysfunction and could induce bothautonomic motor and sensory disorders. It isexpected that patients with MS, spinal cord inju-ries (SCIs), herniated disc disorders, lumbosacralplexus disorders, and peripheral neuropathies willhave impaired sensory function, which will beexpressed as sensory threshold increases.

Neuropathy.

It has been shown that sensory testingof the genitalia in 36 neurogenic females with sex-ual dysfunction (15 with diabetes, 14 with MS and7 with lumbar discopathy) can be a useful tool indiagnosing FSD of neurogenic origin (moststrongly the assessment of clitoral vibratory stim-uli) [60]. Although perineal trauma occurs in bothgenders, data supporting the association betweensexual dysfunction and blunt perineal trauma inwomen are lacking. A study that looked at thepatient characteristics of women with sexual dys-function that had undergone blunt perinealtrauma implicated a neurogenic form of sexualdysfunction, with primary complaints of orgasmicdisorders and abnormalities on genital sensorytesting [61]. In another publication the sameauthors reported three cases of post-traumatic cli-toral neuropathy and neuralgia resulting fromtrauma to the genitalia. The consequent numb-ness, pain, and dysautonomia have led to sexualdysfunction in all three women [62].

Spinal Cord Injury.

There is little available literatureabout sexual dysfunction in women with SCI [63–73]. Women’s desire for sexuality and sexual activ-ities seems to decrease after injury [71]. Charlifueet al. [74] reported that sex was less importantafter injury in their series of 231 SCI women;other authors found a significantly higher level ofhypoactive sexual desire after injury as comparedwith their sexual drive prior to injury itself [75]. Adecrease in frequency of self-masturbation in thesewomen has been reported [76] with preferredsexual activities after SCI reported to be kissing,hugging, and touching [74].

The influence of SCI on sexual responsedepends on the degree and location of injury inthe spinal cord. Among women with SCI, 7% to23% are unable to achieve orgasm [77]. Most ofthe data available about women’s sexual dysfunc-tion after SCI comes from laboratory-basedresearch [63–65,70–72]. Pathophysiology oforgasmic phase in women with SCIs has beenstudied in laboratory settings [63,64]. In a study of25 women with SCI at and above the level of T6and 10 able-bodied control subjects, the ability toachieve orgasm was documented [63]. Subjectsunderwent a 75-minute protocol in the laboratory,designed to obtain information on the physiolog-ical events accompanying orgasm. Data were ana-lyzed both within and across neurological groups:complete SCI, incomplete SCI, and able-bodiedcontrols. Fifty-two percent of subjects with SCIachieved orgasm. The capacity to achieve orgasmwas shown to be unrelated to level or complete-ness of injury in women at levels of injury T6 andabove.

Sipski et al. reported the results of a studyenrolling 12 women with a lower motor neuron(LMN) injury affecting the S2–S5 spinal reflex arcand 50 SCI women with upper motor neuron(UMN) injuries [64]. Ability to achieve orgasmwas assessed historically and in the laboratory.Historically, only 55% of SCI women were able toreach the orgasm post-SCI, whereas 44% wereorgasmic in the laboratory [63,64]. These authorsdemonstrated that in each condition, SCI subjectswere significantly less likely to achieve orgasmthan controls, and orgasm was less likely if awoman had a complete LMN injury affecting thesacral segments than any other level and degree ofinjury [63]. Latency to orgasm was greater inwomen with SCIs compared to normal subjects.Sipski showed a significant difference in averagelatency to orgasm when able-bodied subjects werecompared to SCI subjects [64]. On the other hand,


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the so-called systemic modifications that usuallyaccompany the orgasmic phase, such as bloodpressure, heart rate, and respiratory rate fluctua-tions, were generally similar between women withand without SCI.

In women with complete UMN injuries affect-ing the sacral segments, the ability for reflex with-out psychogenic lubrication of the vagina shouldbe maintained [68,72,74]. The presence of psy-chogenic arousal in the absence of arousal inducedby genital stimulation was documented in womenwith complete SCIs at and above the level of T6[72]. In contrast, in women with incompleteUMN injuries affecting the sacral segments dataseem to demonstrate an ability to maintain boththe capacity for reflex and psychogenic lubrica-tion. Sipski et al. also reported that those womenwith higher ability to perceive a combination oflight touch and pinprick sensation in the T11–L2dermatomes have a greater likelihood of achievingpsychogenic lubrication [64]. With all levels anddegrees of SCIs, the ability to achieve psychogenicarousal depends on the degree of sensory preser-vation in the T11–L2 dermatomes but not on thedegree of sensory preservation at T6–T9 or S2–S5 levels [64]. Moreover, psychogenic control offemale genital vasocongestion is dependent onsympathetic stimulation [74,75]. Therefore, pres-ervation of sensory function in T11–L2 is a pre-condition for the ability of SCI women to havepsychogenic arousal.

Orgasm has also been studied in SCI womenshowing that approximately 50% have the abilityto achieve orgasm [76]. In women with T6 injuryand above the capacity to achieve orgasm is unre-lated to the level of the injury [63]. A significantdifference was noted in the ability of women withcomplete LMN injuries, affecting S2–S5, toachieve orgasm as compared to other types of inju-ries [72]. The authors concluded that an intactsacral reflex arc is needed to achieve orgasm andthat orgasm may be a reflex response of the auto-nomic nervous system [63,78,79]. Furthermore,Sipski et al. [63] also proposed that the orgasmicsensory experience may be partially derived fromafferent autonomic innervation, which remainsafter complete SCI. Whipple et al., however, sug-gested that the vagus nerve can provide innerva-tion to the cervix and is the source of cerebraltransmission of orgasmic sensation in women [65].

Multiple Sclerosis.

Current prevalence rates forMS are 1/1000 Americans and 2/1000 NorthernEuropeans [79]. A disorder affecting both the

brain and the spinal cord, MS can cause difficultiesin achieving orgasm. Sexual dysfunction is com-mon among MS patients and has a reported prev-alence of 46–80% [78,80–84]. Sexual activityceases or is significantly unsatisfactory in 39% ofMS women [78]. Symptoms reported includedfatigue in 68%, reduced sensation in 48%,reduced vaginal lubrication and difficulty witharousal in 35%, difficulty reaching orgasm oranorgasmia in 72%, and dyspareunia and othersexual pain disorders Villeroy [78,80–83,85].

In a case–control study, Zorzon et al. [86]reported data concerning sexuality in a series of 70consecutive women suffering from MS as com-pared to a control group of age-matched womenwith chronic disease (rheumatoid arthritis, sys-temic lupus erythematosus, psoriatic arthritis, andankylosing spondylitis) and another of healthysubjects. The number of MS patients whoreported a reduction in sexual desire was higherthan in both patients suffering from a chronic dis-ease and normal subjects. The same authors founda significant difference in sexual desire betweenpatients and healthy controls. In this series MSwomen had decreased vaginal lubrication com-pared to healthy controls while the differencefrom chronic disease controls was not statisticallysignificant. Changes in vaginal sensation, whilevery common, were more common in MS casesthan in both chronic disease controls and healthysubjects. Overall, more than one-third of womenexperienced a decrease in vaginal lubrication andlibido.

Similar diminished frequency of sexual activity,decreased vaginal lubrication, genital sensation,orgasmic capacity, and sexual desire have beenreported by other researchers in women with MS[83,87–90]. Problems with sexual function werereported significantly more often by women withphysical disability due to the disease [expressed bylower Expanded Disability Status Scale (EDSS)scores] [89]. In 47 women with advanced MS,38.3% reported diminished orgasmic capacity and12.8% anorgasmia. The changes in sexual func-tion correlated with neurological symptoms fromthe sacral segments, such as weakness of the pelvicfloor and bladder and bowel dysfunction [91].Zivadinov et al. also reported data concerning acorrelation analysis in the same cohort of womenwith MS [92]. Spearman correlation analysesbetween symptoms of sexual dysfunction andcharacteristics of both patients and clinical type ofMS were performed. Sexual dysfunction signifi-cantly correlated with relapsing-remitting MS but

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not with either the primary progressive or thesecondary progressive type. A close correlationwas also found between sexual dysfunction and ageat onset of symptoms and the current age of thewoman but not with the duration of the neurolog-ical disease itself. Similarly, a significant correla-tion was found between sexual and physicaldisorders, sphincteric and bladder dysfunction,fatigue score and both cognitive deterioration, asassessed by the Mini Mental State Examination[93], and the neurological impairment, as assessedby the EDSS [94]. Other studies have shown acorrelation between sexual and bladder dysfunc-tion in MS patients [95,96]. Nortvedt et al. alsoreported a significant reduction in the quality oflife in MS patients with both sexual disorders andbladder dysfunction [96].

A similar correlation was demonstratedbetween sexual dysfunction and low educationallevel and a high value for either depression, asassessed by the Hamilton Depression Rating Scale(HDRS) [97], or anxiety [98], as assessed by theHamilton Anxiety Rating Scale (HARS) [97].After a 2-year follow-up, the percentage ofpatients with at least one sexual disorder remainedstable at more than 70% [99]. Although menreported at least one sexual dysfunction more fre-quently than women, when both men and womenwere considered altogether, in a univariate analy-sis, changes in sexual function throughout timecorrelated with modifications in bladder functionand EDSS score. After removing the effect of psy-chological aspects, only changes in bladder func-tion maintained a significant correlation withfluctuations in sexual function. When comparingwomen suffering from chronic diseases andhealthy subjects, Zorzon et al. reported that anor-gasmia and hypoorgasmia were the more com-monly reported sexual dysfunction in MS patients,followed by decreased vaginal lubrication andreduced libido [86]. Fewer women with MS wereable to achieve orgasm than their peers (chronicdisease controls and healthy controls) [86]. Morethan one-third of women reported greater diffi-culty or inability to achieve orgasm than beforethe disease, with a statistically significant differ-ence as compared with chronic disease controls.Anorgasmia or hyporgasmia was reported morefrequently with a statistically significant differencein comparison with healthy controls.

Interestingly, Hennessey et al. reported theresults of a survey on urinary, fecal, and sexualdysfunction in 68 men and 106 MS women [100]and found that although sexual problems occurred

in 52% of MS women enrolled, 61% were satisfiedwith their sexual activity.

Yang et al. performed pudendal somatosensoryevoked potential testing on 14 women with MS.The most common complaint among thesepatients was difficulty with orgasm. An abnormalor absent pudendal somatosensory evoked poten-tial was highly associated with lack of or difficultyachieving orgasm [101].

It is probable that primary sexual disorders insome neurogenic MS patient result from thedemyelination process that interrupts the continu-ity of the neural pathways, altering the neuralfunction that is essential for normal sexual per-formance. Clearly, the neuropathy caused byautoimmune-induced damage to the myelinsheath is the main reason for the classic neuralsymptoms of the disease. Moreover, electrodiag-nostic data imply that pudendal somatosensoryinnervation is necessary for normal female orgas-mic function [101]. Clinical use of sensory testingin MS patients was reported in a group of 24females, showing that sensory testing of the geni-talia in MS patients, most strongly the assessmentof clitoral vibratory stimuli, can be a useful tool indiagnosing FSD of neurogenic origin [102].

Diabetes Mellitus.

Few studies have investigatedthe significance of diabetes in causing women’ssexual dysfunction [103–113]. Neuropathy, vascu-lar impairment, and psychological problems havebeen correlated with decreased libido, spontaneityof arousal, vaginal lubrication, orgasmic function,and dyspareunia in women complaining of diabe-tes mellitus. The most common sexual dysfunctionin women with diabetes is decreased sexual arousalwith slow and/or inadequate lubrication. Womenwith diabetes may also experience a decrease insexual desire and increase in dyspareunia, whereasproblems with orgasm are not more frequent.

Jensen et al. reported that diabetic spouses ofdiabetic men had more problems with arousalthan healthy spouses [114]. Although the mecha-nism is unclear, the rate of sexual dysfunctionamong women with type II diabetes was signifi-cant, while type I did not demonstrate any sig-nificant change [109,112]. In 1998 Enzlin et al.wrote a review of the literature on this topic[115]. Enzlin showed that diabetes slightlyincreased the risk of women’s sexual disorders.Schiel et al. [116] studied 127 type I diabetics,36% of whom were women, and 117 type II dia-betics, 54% of whom were women. He showedthat overall prevalence of sexual dysfunction in


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women was 18% among type I diabetic patientsand 42% among type II diabetic subjects.

Enzlin et al. reported on prevalence and char-acteristics of sexual dysfunction in 120 womenwith type I diabetes mellitus as compared with 180age-matched healthy controls [117]. With aresponse rate of 80.8%, Enzlin showed that signif-icantly more women with diabetes (27%) thanage-matched controls (15%) reported sexual dys-function. Diabetic women presented a higherprevalence of arousal dysfunction than healthywomen; however, there was no significant differ-ence in decrease of desire. There was no signifi-cant difference in orgasmic disorders or sexualpain disorders between the women with and with-out diabetic complications. A significant differencewas found for decreased lubrication, althoughoften two and three sexual problems werereported.

Patients complaining of sexual disorders werenot significantly different in age, body mass index(BMI), length of disease, or HbA

1c

values as com-pared with those without sexual complaints. Asignificant association was found between thenumber of complications and the number of sexualcomplaints, although this analysis did not showany statistically significant correlation betweensexual complaints and peripheral neuropathy,autonomic neuropathy, nephropathy and retinop-athy, menopausal status, use of hormone therapyor use of oral contraceptive pill. Based on BDIscore, twice as many diabetic women weredepressed than controls.

Erol et al. published data on the prevalence ofsexual dysfunction in 72 women with type II dia-betes mellitus without other systemic comorbidi-ties and 60 age-matched healthy subjects [118].Mean FSFI scores of patients were 29.3 comparedto 37.7 for controls, with the main complaints ofthe diabetic women being reduced libido (77%),diminished clitoral sensation (62.5%), vaginaldryness (37.5%), vaginal discomfort (41.6%), andorgasmic dysfunctions (49%). The authors con-cluded that the higher rate of sexual disordersamong diabetic patients was responsible for low-ering their quality of life.

In order to evaluate the prevalence and predic-tors of sexual dysfunction in women with bothtype I and type II diabetes mellitus, 72 diabeticwomen, 42 type I and 30 type II, were comparedwith healthy age-matched controls [119]. Womencomplaining of diabetes mellitus had worse FSFIscores for the desire, lubrication, and orgasmdomains as compared with the control group, and

significantly higher sexual pain at the genitalialevel (both coital and noncoital sexual activity)than controls. The BDI score, 48% in diabeticwomen, was significantly correlated with thearousal, orgasm, and satisfaction domains of theFSFI. The Spearman correlation analysis was alsostatistically significant between BDI and FSDSscore. A significant correlation was also foundbetween aging and reduced desire and betweenaging and lubrication.

Sexual dysfunction is highly prevalent in dia-betic women and these patients are clearly athigher risk of developing sexual desire, arousal,and orgasm disorders than age-matched controls.More investigation is needed to better under-stand the contributions of the psychological anddiabetes-related somatic factors to sexual dysfunc-tion in women with diabetes mellitus.

Pelvic Surgery

Pelvic Surgery for Rectal Cancer.

When a conven-tional low anterior and abdominoperineal re-section (APR) with extended lymphadenectomy isperformed for advanced lower rectal cancer, sexualand bladder function are often sacrificed [120–122], reported to be between 10% and 60% [122].Extended circumferential margins are required fora complete resection, or multimodality treatmentis utilized, including preoperative external beamradiation therapy, radical surgery, and intraopera-tive radiotherapy, to improve the cure rate of boththe presentations of rectal cancer [122–127]. Sex-ual and bladder dysfunctions are usually caused bya non-nerve-sparing surgical approach during theprocedure, with the surgical damage of one ormore of the autonomic nerves consisting of thepaired sympathetic hypogastric nerve, sacralsplanchnic nerves, and the pelvic autonomic nerveplexus. Several kinds of nerve-sparing surgery fororgan-confined or advanced rectal cancer havebeen developed aiming at both preserving sexualand genitourinary function and extending the sur-gical margins [120,127–139]. Enker et al. reportedthat in patients undergoing abdominoperineal re-section for primary cancer of the rectum, per-formed in accordance with the principles of totalmesorectal excision (TME) and autonomic nervepreservation (ANP), sexual function was preservedin approximately 57% of patients undergoingAPR vs. 85% of patients undergoing sphincterpreservation [140].

Data on this topic in women are very rare andconflicting. A few papers reported the results ofboth prospective and retrospective studies aiming

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at evaluating urinary, bowel, and sexual functionin both men and women, but without any stan-dardized method from the woman’s point of view.In addition, most of the outcome studies enrollingboth men and women paid attention only to themale hemisphere.

Recently, Pocard et al. studied prospectively thepre- and postoperative urinary and sexual functionin seven women who underwent a sphincter-preserving operation for rectal carcinoma bymeans of a curative TME with ANP, without pre-operative irradiation, with complete surgical iden-tification and subsequent preservation of bothhypogastric and sacral splanchnic nerves [141].Four out of the seven women were sexually activebefore undergoing the surgical procedure. Sexualactivity and ability to achieve orgasm wasunchanged in these women and no incidence ofdyspareunia was reported. Chorost et al. reportedsimilar results in a retrospective review on themedical records of 52 consecutive patients whounderwent potentially curative procedures for rec-tal cancer [142]. Presurgical discussion about thepotential risk of sexual dysfunction was not docu-mented in the preoperative consent in 37 of 52patients; however, only 1 out of the 16 womenreported post-therapy sexual dysfunction.

Multimodality treatment can increase thechances of damaging the urogenital nerves andorgans which could result in voiding and sexualdisorders [120,126,135]. There is a paucity of lit-erature devoted to the impact of surgery alone ormultimodality treatment on women’s sexual func-tion. Mannaerts et al. reported the sexual outcomeresults of a population of both men and womensuffering from locally advanced primary andlocally recurrent rectal cancer [127]. Using ques-tionnaires, sexual function was evaluated duringthe 6 months prior to aggressive multimodalitytherapy as well as during follow-up (median14 months, range 4–60 months) to assess clinicaloutcome. Interest in sexual activity and ability toachieve orgasm decreased in women after thetreatments. Among the study population, themean quality of orgasm was reduced in boththe primary rectal cancer group and the locallyrecurrent rectal cancer group. Age greater than60 years significantly reduced the ability to havepostoperative orgasm as well as the ability to havesexual intercourse [127]. The same authors,reporting the long-term functional outcome aftera multimodality treatment for locally advancedprimary and locally recurrent rectal cancer, foundthat 56% of respondants complained of sexual

inactivity [143]. In a retrospective small survey of43 patients with low rectal cancer who underwentlow anterior resection with or without neoadju-vant or adjuvant radiotherapy, Chatwin found thatsexual dysfunction was reported 2 of the 11 sexu-ally active women [144]. Despite their reportedfecal, urinary and sexual dysfunction, mostpatients were satisfied with their quality of life.

Recently Quah et al. reported the results of aretrospective analysis of preoperative and postop-erative bladder and sexual function in patients whounderwent laparoscopically assisted and conven-tional open mesorectal resection for cancer [145].No significant difference in sexual function wasfound in women.

Radical Cystectomy for Urologic Malignancies.

Nopaper was identified dedicated to the evaluation ofsexual function in women after surgery for bladdercancer [146–152]. Genitourinary cancers are com-monly associated with treatment-related sexualdysfunction varying from mild to severe. Sexualdysfunction may occur as a result of cancer and itstreatment. Sexual function is sensitive to theeffects of both physical and emotional trauma,particularly when the cancer affects the genitalorgans.

Marshall et al. described anterior exenterationin women performed accurately with a disciplinedanatomic approach [148]. Women undergoingcystectomy with the simultaneous removal ofuterus, ovaries, and parts of the vaginal wall facehad issues regarding their femininity as well asconcerns regarding future sexual function. Exci-sion of the uterus, a portion of the vagina and theurethra, seems to reduce the potential for pelvicrecurrence but a vaginal reconstruction and con-tinent urinary diversion provide a better quality oflife with maintenance of sexual function and uri-nary continence.

Bjerre et al. conducted a study aimed at evalu-ating the sexual profile in women after urinarydiversion by either radical cystectomy with conti-nent Kock reservoir or ileal conduit diversion[149]. No significant differences were foundamong the 37 patients who completed the ques-tionnaire. Among those whose sexual activitydecreased, almost one-third gave physical prob-lems or decreased desire as the reason and 30%felt less sexually attractive, with cystectomizedpatients reporting a higher percentage than theothers. A higher frequency of dyspareunia amongpatients with a continent reservoir was an unex-pected finding.


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Nordstrom et al. described the sexual functionoutcome of 66 men and women who underwentan ileal conduit urinary diversion because of blad-der cancer or incontinence/bladder dysfunction[150]. Five of the six women treated by cystec-tomy, who had been sexually active preoperatively,reported either a decrease or cessation of coitalactivity postoperatively, due mainly to a decreasein sexual desire, dyspareunia, and vaginal dryness.One woman reported the inability to experienceorgasm after surgery. Compared with women withbladder cancer, those with incontinence/bladderdysfunction were more likely to have an activesexual life after urostomic surgery. A postoperativeincrease in activity was shown by seven women inthis group, four of whom had been sexually inac-tive before surgery, because the surgery eliminatedthe need for incontinence pads or indwelling cath-eters. Hautmann et al. presented data about anerve-sparing cystectomy with orthotopic bladderreplacement in women [151], but neglected tomake observations regarding sexual function.

Horenblas et al. have reported preliminaryresults of a modified cystectomy, called sexuality-preserving cystectomy and neobladder, the intentof the surgical technique being to achieve maximaltissue conservation, potentially preserving normalsexual function and satisfactory urinary tractreconstruction [152]. The surgery consists of pel-vic lymph node dissection followed by cystectomywith preservation of all internal genitalia. An ilealneobladder was then anastomosed to the urethra.This type of surgical approach was suggested forwomen suffering from bladder cancer stages T1–T3 with absent tumor growth in the bladder neckand absent invasive tumor in the bladder trigone.Three women aged 38–71 years were enrolled inthis protocol and all reported normal vaginallubrication during sexual activity.

Hysterectomy and Sexual Function.

Reports of dete-rioration of sexual function after hysterectomy isestimated to be between 13% and 37%, whichmay be through one or more mechanisms [153–158]. Quality of sexual life after hysterectomymay be influenced by several situations resultingin conflicting suggestions [159–165]. Many of thestudies exploring sexuality after hysterectomyhave methodological flaws, including vague mea-sures of sexual satisfaction and potential for recallbias [166]. In a comprehensive review article,Carlson reported that in women undergoing hys-terectomy for nonmalignant conditions there is amarked improvement in symptoms and quality of

life during the early years after surgery [159].Hysterectomy did not seem to cause long-termpsychiatric morbidity and psychological statusgenerally improved after surgery itself. Rhodeset al. [158] recently published the results of a 2-year prospective study which examined measuresof sexual function prior to hysterectomy and at 6,12, 18, and 24-month follow-up after surgery.A total amount of 1101 women completed thestudy. These authors showed that both sexualdesire and frequency of sexual relations signifi-cantly increased after hysterectomy and through-out the follow-up period. Frequency and strengthof orgasm also increased significantly after sur-gery. Lack of orgasm preoperatively was most sig-nificantly associated with absence of orgasm aftersurgery, possibly influenced by aging. Womenalso reported vaginal dryness improved afterhysterectomy.

In contrast, several papers reported a decreasein quality and frequency of sexual activity afterhysterectomy. Rako [160,161] emphasized theimportance of the ovaries as a critical source test-osterone as well as estrogen; thus removal of theuterus, even after ovary-sparing procedures, canjeopardize their function. Loss of a physiologiclevel of testosterone in women after hysterectomycan decrease quality of life in terms of libido, sex-ual pleasure, and sense of well-being. An analysisby Cutler and Genovese-Stone correlated theimpact of hormonal deficit on sexuality and overallquality of life in hysterectomized women [162]. Inthe U.S. more than half a million women per yearundergo hysterectomy as treatment for chronicbenign gynecologic conditions [167], a rate fivetimes higher than that of the European countries.Estrogen, progesterone, and androgen levels alltend to be altered by hysterectomy. Furthermore,all these sex hormones affect physiologic systemsincluding the cardiovascular system, bone metab-olism, cognitive function, sexual response, andsexual attractiveness [162].

These conditions are made worse when hyster-ectomy is accompanied by bilateral oophorectomy.Since the ovaries provide approximately half of thecirculating testosterone in premenopausal sub-jects, after surgery many women report impairedsexual function despite estrogen replacement.Shifren et al. [24,168] reported that in womenwith impaired sexual function after surgicallyinduced menopause high-dose transdermal test-osterone may be useful, increasing the Brief Indexof Sexual Functioning for Women (BISFW) [169]scores for frequency of sexual activity and

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pleasure-orgasm. In the same group of surgicallymenopausal women, the percentages of those whohad sexual fantasies, masturbated or engaged insexual intercourse at least once a week, increasedtwo to three times from baseline. This issue isactually strongly debated [24,170,171].

The estrogen deficiency that results frompremenopausal hysterectomy with bilateraloophorectomy is associated with vaginal dryness[158,172], although several reports also demon-strate vaginal dryness after premenopausal simplehysterectomy due to potential ovarian damage andfailure subsequent to the surgery itself [173–175].The vaginal orgasm, consequent to the stimula-tion of nerve endings in the uterovaginal plexus,should be hindered by hysterectomy with cervixremoval, but theoretically clitoral orgasm shouldnot be damaged [176]. However, surgical damageto the pelvic autonomic nerves during radical hys-terectomy is thought to be responsible for consid-erable morbidity, including sexual dysfunction.

Surgical preservation of the pelvic autonomicnerves in both laparoscopic and traditional radicalhysterectomy deserves consideration in an attemptto improve both cure and quality of life in cervicalcancer patients as well as chronic benign condi-tions [165,177–198]. Well-designed prospectivestudies are needed to evaluate the impact of thiscommon surgery on overall sexual function inboth pre- and postmenopausal women.

Cerebrovascular Accidents—Orgasmic Dysfunction

The most common sexual problems in womenthat have been identified after stroke includedecline in libido, coital frequency, vaginal lubrica-tion, and orgasm. A number of studies haveexamined the impact of stroke on FSD but thereare few prospective studies. In a prospective 6-month follow-up study, Korpelainen et al.assessed the impact of stroke on libido, sexualarousal, coital frequency, and satisfaction withsexual life in 38 men and 12 women, 32–65 yearsold [199]. Only married patients with an activesexual life before the stroke and without otherperipheral or central nervous system conditionsknown to affect the autonomic nervous system,severe aphasia or psychiatric illnesses or diseasesaffecting daily activity were included in the study.The women, all of whom were able to attainorgasm prior to their strokes, reported decreasedvaginal lubrication and ability to reach orgasm,with 30% and 20% anorgasmic at 2 and6 months, respectively.

Depression and Antidepressants

The incidence of depression in women varies dur-ing the life span. The peak incidence during child-bearing years appears to be associated with cyclichormonal changes. Women also present withreproductive-specific mood disorders: premen-strual dysphoric disorder (PMDD), depression inpregnancy, postpartum mood disorder (PDD), andperimenopausal depressive disorder [200–203].The fluctuation of ovarian steroids during specificphases of the reproductive cycle may bear somerelationship to the particular vulnerability ofwomen for mood disorders. The ovarian hor-mones could exert their effects on mood directlyor indirectly by their effects on neurotransmitter,neuroendocrine, or circadian systems. Hormonalchanges associated with the reproductive cyclemay provoke affective changes in predisposedindividuals. Moreover, there are a variety of dis-turbances in biological rhythms observed in mooddisorders. An example is depression associatedwith the luteal phase of the menstrual cycle [204–206].

Major depression is frequently related towomen’s sexual dysfunction (over 70% of patients)[206–208]. Changes in sexual interest/satisfactionand loss of libido are frequently and consistentlyrelated to major depression [209–211]. Neverthe-less, a good-quality sex life is regarded by 70% ofthe general population and by as many as 75% ofdepressed patients as a fundamental part of qualityof life [212,213].

Antidepressant medications can exacerbate pre-existing sexual dysfunction or induce new sexualdisorders [53,203,209–228]. Sexual dysfunctionhas been reported to be associated with all classesof antidepressants (MAOIs, TCAs, SSRIs, SNRIsand new-generation antidepressants) in patientswith depression and various anxiety disorders[222]. The clinical assessment of depressed womenrequires a comprehensive evaluation of sexualfunction prior to the affective disorder, distur-bances associated with the onset of depression, andchanges or dysfunctions associated with antide-pressant treatment. Other factors to be includedin evaluating sexual dysfunction include inquiryabout concurrent medical conditions, somatictreatments, lifestyle risk factors, and response toantidepressants [218].

Absent or delayed orgasms are the sexual side-effects most commonly associated with SSRIs[221], with desire and arousal disorders also fre-quently reported [218,219]. The negative effects ofSSRIs on sexual function appear strongly dose-


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related and can vary among group according toserotonin and dopamine reuptake mechanisms,induction of prolactin release, anticholinergiceffects, inhibition of nitric oxide synthase, andpharmacokinetics [218]. While men taking SSRIsreport higher rates of sexual side-effects, womenseem to experience more severe sexual dysfunction[223]. Sexual dysfunctions during long-termadministration of antidepressants may result intreatment discontinuation [217,218,224]. Thisplaces patients at increased risk for recurrence,relapse, chronic illness, and mortality (e.g., sui-cide). Recently, Zajecka et al. reported that in aseries of 681 outpatients with chronic forms ofDSM-IV [229] major depressive disorders, sexualdysfunction was reported by 48% of women beforeany antidepressant treatment [214]. After a 12-week treatment course with nefazodone or Cog-nitive Behavioral Analysis System (CBASP) or acombination of both nefazodone and CBASP, a sta-tistically significant linear improvement in sexualfunction was noted in all three treatment groups.Improvement in depressive symptoms was associ-ated with improved sexual interest and satisfaction.

Similar results have been reported by Bobeset al. [225]. Using the Changes in Sexual Func-tioning Questionnaire (CSFQ) [226], sexualdesire/interest showed a substantial baseline effect(30% of patients indicated a maximum score) fordepressed women treated with nefazodone at base-line and treated with paroxetine at final visit. Ascompared to the baseline, nefazodone treatmentwas able to promote significant improvement indepressed women in terms of sexual desire/fre-quency, pleasure, sexual arousal, and orgasm [225].Michelson et al. underlined similar results, evenaccounting for the decreased sexual function (mostpronounced with orgasm) that occurred duringcontinued treatment for increased depressivesymptoms [227]. Sexual function was assessed indepressed patients participating in a multicentertrial of acute and chronic fluoxetine therapy.Patients were evaluated at study entry (baseline),after 13 weeks of fluoxetine 20 mg daily, and dur-ing 25 weeks of chronic therapy with fluoxetine20 mg daily, fluoxetine 90 mg weekly, or placebo.In a 13-week open-label trial among 501 patientswho met DSM-IV criteria for depression, 51.6%of women reported improvement, 35.0% reportedno change, and 13.4% of women and 17.4%reported worsening of overall sexual function.During double-blind chronic therapy there wereno statistically significant differences in change insexual function between treatments [227].

Nappi et al. demonstrated that depression maybe bimodally related to women’s sexual dysfunc-tion [228]. In a cross-sectional study, frequencyof self-reported sexual symptoms in 355 womenattending menopause clinics was investigated andrelated to other vasomotor, psychological, physi-cal, and genital complaints. As expected, painduring sexual intercourse and low libido/lack ofarousal were significantly more frequent with ageand years since menopause. Reduction of sexualpleasure/satisfaction (45.9%) was common withage, but was more frequent the longer the timesince the menopause. However, examining theintensity of sexual symptoms in relation to thepresence of other complaints, Nappi and cowork-ers found that physical, psychological, and genitalwell-being significantly affects the components ofsexual response after the menopause and depres-sive symptoms were more common in women withsexual complaints [228].

Thus, depression is an important cofactor inmany diseases that are potentially associated withsexual dysfunction in women. Some authorsunderlined the role of depression in worsening thequality of life and sexual function in MS patients[230,231]. Janardhan and Bakshi demonstratedthat depression and fatigue were independentlyassociated with impaired quality of life in MS,after accounting for physical disability, suggestingthat their recognition and treatment can poten-tially improve quality of life [230].

Zorzon et al. examined 62 men and women withMS using magnetic resonance imaging (MRI) ofthe brain [231]. When comparing patients with andwithout sexual dysfunction, the only significantdifference was in the pontine brain parenchymalfraction (BPF). When a linear multiple regressionanalysis was performed, sexual disorders were asso-ciated with depression and, after adjusting fordepression and anxiety, with bladder dysfunctionand pontine BPF. This relationship between sexualdysfunction and pontine atrophy confirmed thecorrelation of sexual dysfunction with bladder dys-function and highlighted the role of depression indetermining sexual dysfunction even in this par-ticular subgroup of women. To confirm the signif-icant role of depression as a cofactor of sexualdysfunction, Salonia et al. recently reported dataabout sexual dysfunction in 30 women sufferingfrom coronary artery occlusive disease (CAD)[232]. Sexual dysfunction was reported by 9 of 30women, 7 of whom had this complaint prior tosymptoms of ischemic heart disease. Accordingto the results of the FSFI [233], 77.8% of these

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women reported hypoactive sexual desire disorder(HSDD), 77.8% sexual arousal dysfunction, 100%orgasmic disorder, and 67% a combination ofhypoactive sexual desire, arousal, orgasmic andsexual pain disorders. Fifty-seven percent of theenrolled women showed depressive symptoms, asdetermined by the BDI [234], which significantlycorrelated with the FSDS [235] and with each oneof the FSFI domains.

Vascular Pathophysiology

Investigators interested in the pathophysiology ofFSD have proposed that in some women, femalesexual arousal problems are associated with vascu-lar and clitoral erectile insufficiency [236]. Theseauthors suggest that future management strategiesfor women with sexual arousal problems should beaimed at assessing vasculogenic sexual dysfunc-tion, especially if these women are postmeno-pausal. It is highly unlikely that organic factors inFSD are absent. Nevertheless, the finding of avascular irregularity does not necessarily meanthat it is the organic factor causing the sexual dif-ficulties. Psychophysiological assessment there-fore should be more routinely implemented as adiagnostic tool to answer the question whether ornot an adequate genital sexual response is possiblein the presence of possible organic abnormalities.

An important question is how well the availablevaginal vasocongestion measures differentiatebetween women with and without sexual prob-lems. Only a small number of studies exist to datethat assessed differences in vaginal responsebetween women with and without sexual prob-lems, all using vaginal photoplethysmography.Some of these studied sexual responses to eroticstimulus materials in low arousal or nonorgasmicwomen [237–239], other studies combined womenwith different sexual dysfunctions into one group[240,241], one studied low desire and anorgasmicwomen [242], one study examined sexual res-ponses of women with dyspareunia to oral sex andintercourse scenes [243], and one study comparedsexual responses of women with and withoutFSAD [244]. It is difficult to compare these studiesand interpret the different findings, because thenature of the sexual problems varied between andeven within studies, different erotic stimuli wereused, and studies differed with respect to the wayvaginal responses were measured [using eithervaginal pulse amplitude (VPA) or vaginal bloodvolume (VBV) or both] and analyzed.

The Meston and Gorzalka [242] study was thefirst to compare different diagnostic categories,

thus making the important step toward differenti-ating patterns according to the presenting sexualproblem. Wouda et al. [243] were the first to studyvaginal responses of women with sexual problemsto sexual stimuli differing in content. Eighteenwomen with dyspareunia participated. In thisstudy an erotic scene depicting fellatio and cunni-lingus followed a neutral baseline period. Thenthe women were subjected to a return-to-baselineperiod followed by a cunnilingus scene and anintercourse scene. There were no differences inVPA between the women with dyspareunia and acontrol group of women without sexual problemsin the first four phases of the experiment. Butduring the intercourse scene, responses of the con-trol group further increased while in the dyspare-unia group responses declined. There were nodifferences in subjectively reported sexual arousalto the last scene. These results suggest a numberof things. First, differences in vaginal vasoconges-tion response may be highly situation or stimulusspecific. Only during the intercourse scene VPAwas significantly lower in the clinical group. Sec-ond, genital measures and subjective feelings didnot correspond.

A large number of studies have addressed thisissue of correlation between psychophysiologicalmeasurements and subjective feelings of arousal.In a few studies positive correlation between VPAor VBV and subjective feelings of sexual arousalwere reported, but the majority failed to find arelationship between genital and subjective sexualarousal [245,246]. This finding, confirmed in anMRI study [247], seems to be unique for women.In men without sexual problems, correlationbetween penile circumference change and subjec-tive report are usually fairly high [235].

Laan et al. consistently found VPA to occurautomatically in response to an explicit eroticstimulus such as erotic film [246]. That is, vaginalvasocongestion increases within seconds after theonset of the stimulus, without most women beingaware of this happening, even when the stimulusis negatively evaluated or induces little or nofeelings of sexual arousal. Women simply do notattend to genital changes when assessing theirsubjective feeling state. Their subjective experi-ence of sexual arousal is determined less by feed-back from their genitals (which becomes moreimportant as genital arousal increases) than bythe intensity and appraisal of the sexual stimulus.Therefore, genital measures should always beused concurrently with subjective measures ofsexual arousal.


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These findings suggest an important role forthe sexual stimulus in psychophysiological studies.In order to meaningfully compare clinical groupswithin and between labs, some level of standard-ization with respect to the type of erotic stimulusseems essential [248]. Finally, measuring vaginalvasocongestion in the absence of a sexual stimulusmay lead to false conclusions. For instance, arecent study demonstrated an estrogen-relateddifference in VPA between premenopausal anduntreated postmenopausal women during initialbaseline, before any erotic stimulation had takenplace [248]. During subsequent erotic stimulation,however, this difference in VPA between groupsdisappeared, suggesting that inadequate eroticstimulation may be more important in sexualarousal disorders than a vasculogenic dysfunctionrelated to menopause.

The findings of this study were replicated in arecent study where genital responses of fourgroups of women were compared: medicallyhealthy pre- and postmenopausal women with andwithout FSAD [244]. In selecting the groups withFSAD the criteria of DSM-IV were strictlyadhered to, meaning that the main complaint hadto be a diminished or absent lubrication-swellingresponse, that there was marked distress as a resultof the sexual dysfunction and no comorbidity ofmedication, medical condition, and/or psychopa-thology. The only significant difference that wasfound was a difference in VPA between pre- andpostmenopausal women in a nonsexually stimu-lated baseline condition. During visual sexualstimulation no differences in VPA between thefour groups could be observed. The sexual prob-lems of the pre- and postmenopausal women withFSAD are therefore not related to their potentialto become genitally aroused. During the visualsexual stimulation the women with FSAD, how-ever, reported weaker sexual arousal and genitalsensations, less positive affect, and more negativefeelings. These studies demonstrate that whenmeasuring VPA without adequate sexual stimula-tion, one could wrongfully determine organic fac-tors contribute to arousal problems, while in factwith adequate stimulation there is an adequatelubrication-swelling response. Contextual andrelational variables resulting in a lack of adequatesexual stimulation are therefore most likely theunderlying cause for their sexual arousal problems.In a recent MRI study no differences were foundbetween pre- and postmenopausal women inchanges during sexual arousal of the vaginal wall,vaginal mucosa, clitoris, femoral vein signal inten-

sity, relative regional blood volume, and clitoralvolume [247].

In assessing sexual arousal in women there is aneed for simultaneous measurements of both thecognitive and physical aspects of arousal. Subjec-tive arousal estimates are necessary to answer thequestion whether or not the women is able toexperience feelings of sexual arousal under differ-ent stimulus conditions. In assessment of the phys-ical aspects of arousal, the main question to beanswered is whether or not with adequate stimu-lation by means of audiovisual, cognitive (fantasy),and/or vibrotactile stimuli a sufficient lubrication-swelling response is possible. If such a response ispossible, even when other investigations indicatethe existence of a variable that might compromisephysical responses, an organic contribution to thearousal problem of the individual women is clini-cally irrelevant [249].

Conclusions

Sexual problems in women are highly prevalent,frequently distressing, and poorly understood atpresent. Current understanding of the psychologicand biologic mechanisms responsible for sexualfunction must be expanded in order to improveclinical management of sexual dysfunction inwomen.

Corresponding Author:

Irwin Goldstein, MD,Boston University School of Medicine, Boston, MA,USA. Tel: (617)638-8576; Fax: (617)638-8960; E-mail:[email protected]

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Clinical Biologic Pathophysiologies of Women's Sexual Dysfunction

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