Drug Treatments for Women's Sexual Disorders.

Drug treatment for women's sexual disorders is a relatively new field. We will review possible prosexual treatments and will attempt to explain responsible psychophysiological and behavioral mechanisms, to eventually arrive at relevant insight into the workings of the drugs. We begin with a description of what is known about women's sexual disorders and the psychophysiology of women's sexual response. We will briefly consider subjective experience and relevant physiological changes in the domains of behavior, cognition, and emotion, with specific attention to sexuality. This will function as a background for a sketch of drug effects on hypoactive sexual desire, arousal disorders, and inhibited orgasm.

The picture we will be sketching is a rather bleak one. There is not much consensus and standardization in any of the separate domains of female sexual dysfunction. Despite steady progress over the past decades, knowledge of female sexual function still seriously lags behind that of male sexual function. With the advent of the new vasoactive drugs, interest in female sexual dysfunction is now rapidly increasing. This upsurge in attention has once again uncovered the lack of consensus and knowledge in the field of female sexuality.

WOMEN'S SEXUAL PROBLEMS

Several studies investigated the prevalence of sexual dysfunctions in women (e.g., Garde & Lunde, 1980; Laumann, Paik, & Rosen, 1999; Rosen, Taylor, Leiblum, & Bachmann, 1993; Spector & Carey, 1990). The National Health and Social Life Survey of Laumann et al. is both the most recent and the largest study. One third of the women report lack of sexual interest, and almost one fourth of the women don't experience orgasm. A little bit less than 20% have lubrication difficulties, and more than 20% find sex not pleasurable. An addition of these numbers shows the widespread prevalence of sexual complaints. Also, these data suggest substantial comorbidity of sexual problems (Laumann et al., 1999). Data were collected by presenting subjects with seven dichotomous response items, measuring presence of symptoms during the past months. The items covered the DSM-IV classification of sexual dysfunctions (American Psychiatric Association [APA], 1994). However, the implication that these data allow an assessment of the prevalence of sexual dysfunction remains uncertain. From the simple yes/no answers it seems impossible to estimate whether the subjects meant to indicate sexual problems (dysfunctions) or problems with sex (difficulties). The classification of all these answers as dysfunctions may easily result in an overestimation of their prevalence. Frank, Anderson, and Rubinstein (1978) reported that in their sample 50 percent of the men and 77 percent of the women reported difficulty that was not dysfunctional in nature. It further appears that the number of difficulties reported was more strongly and consistently related to overall sexual dissatisfaction than the number of dysfunctions.

In the current DSM-IV classification system female sexual disorders are described as disturbances in desire, arousal, and orgasm; there is a separate sexual aversion disorder and there are two sexual pain disorders, dyspareunia and vaginismus (APA, 1994). Although it is widely accepted, this classification system lacks objective, empirically grounded criteria.

Derogatis and Conklin-Powers (1998) recently formulated a hypothesis on how the disorders are related to the widely accepted Human Sexual Response Model by Kaplan (1974) and Masters and Johnson (1966). They suggested that the majority of DSM-IV categories reflect disruptions in sexual arousal. An example may be vulvar vestibulitis. According to Meana, Binik, Khalife, and Cohen (1997a, 1997b), vulvar vestibulitis is the most frequent cause of dyspareunia in premenopausal women. Vulvar vestibulitis is characterized by severe pain on vestibular touch or attempted vaginal entry, exquisite tenderness to a cotton-swab palpation of the vestibular area, and local red spots that are not necessarily related to the intensity of the pain. Several authors have suggested that an arousal disorder may underlie this (e.g., de Jong, Ramakers, & van Lunsen, 1998). Having sex without sufficient sexual arousal may lead to pain. Repeated intercourse without arousal may result in vulvar infections and chronic irritation, and may even lead to secondary vaginismus, fear of sex, or the avoidance of sexual activity altogether.

To further complicate matters, we suggest it is very unlikely that hypoactive sexual desire and female orgasmic disorder are unrelated to arousal. Orgasm without arousal is impossible, and lack of arousal can lead to lack of desire. Why would someone have desire for something that does not excite her or him? In fact, Segraves and Segraves (1991) reported that in their sample of 906 people comorbidity of hypoactive sexual desire and sexual arousal disorders was high.

The concept of sexual desire is problematic for yet another reason. The Human Sexual Response Model is a sequential model; it places desire before arousal (Kaplan, 1995). But how are we to conceive of sexual desire if there is not already sexual activation of some kind? In our model of sexual response, desire is part of arousal, triggered by a stimulus that has sexual meaning, regulated, that is, facilitated or inhibited, by situational and sexual partner variables (Everaerd, Laan, Both, & van der Velde, 2000; Everaerd, Laan, & Spiering, 2000).

The validity of the Human Sexual Response Model aside, actual clinical practice confronts us with a large comorbidity of sexual dysfunctions in women. Our difficulties in differentially discriminating between disorders may have to do with the lack of adequate physical markers for most of the disorders, inadequate theory, and lack of normative data as to what is functional and what is dysfunctional. We have suggested that lack of sexual arousal may well be the underlying mechanism for many different sexual complaints. However, diagnosing female arousal disorder is not unproblematic in itself. The DSM-IV focuses entirely on physical indices of arousal, described as a lubrication-swelling response, while it is often the lack of subjective arousal, lack of desire, orgasm difficulties, or sexual pain which lead women to seek treatment. Many women are unaware of whether they have adequate lubrication. This problem in diagnosing female arousal disorder is related to the lack of specificity as to what exactly constitutes a normal sexual arousal phase. Women vary greatly in the ease and latency of sexual arousal, and in the kind of sexual stimulation that is adequate for sexual arousal to occur (Leiblum, 1998).

PSYCHOPHYSIOLOGICAL ASSESSMENT OF FEMALE SEXUAL FUNCTION

Physical Markers of Women's Sexual Response

To date there is no reliable physical marker for sexual desire, at least in the current conceptualization of desire as occurring prior to sexual arousal. Vaginal surface electromyography of the pelvic floor is used in the investigation of sexual pain disorders. Van der Velde and Everaerd (1999) found no difference in baseline pelvic floor muscle activity between women with vaginismus and controls. They also failed to find differences in voluntary control of the pelvic muscles between the two groups. In this study women were asked to quickly contract and release their pelvic floor muscles (flick contractions) and also to perform sustained contractions. A similar percentage of controls and women with vaginismus were able to do this, about 60%. Also, both groups of women reacted with enhanced pelvic floor muscle activity to threatening and sexually threatening film excerpts, compared to erotic and neutral scenes. What is striking in these studies is the large variability in muscle activity in both groups. There is evidence that pelvic floor and postural muscles (e.g., m. trapezius) synergistically act as a general withdrawal reaction, which is not specific for threatening sexual situations. This again suggests that the classification of vaginismus and dyspareunia as sexual dysfunctions is problematic (Reissing, Binik, & Khalife, 1999). In addition to their usefulness in studies of vaginismus, EMG measures of pelvic floor muscle activity may also be applied to monitor orgasmic contractions (Rosen & Beck, 1988).

More research efforts have been devoted to developing physiological measures of sexual arousal. Three of them are especially relevant. (a) The oxygenation temperature method, which measures vaginal blood flow, was developed by Levin and Wagner (1985). This method uses a device that consists of a heated oxygen electrode fitted into a suction cup that is attached to the vaginal wall. An electric current to a set temperature heats the electrode. The amount of electrical power needed to keep the disc at this temperature can be monitored, which reflects the pooling of blood in the vascular bed. (b) Labium minus temperature was first used by Henson, Rubin, and Henson (1979a, 1979b). A small surface thermistor is glued onto one leg of a small clip. It can be attached to one of the minor labia by adjusting the position of a small bead that encircles both legs of the clip. (c) Vaginal photoplethysmography also measures vaginal blood flow and was introduced by Sintchak and Geer (1975). The vaginal photoplethysmograph is a menstrual tampon-sized device. It contains an infrared light-emitting diode as a light source and a phototransistor as a light detector. The light source illuminates the capillary bed of the vaginal wall, and the phototransistor picks up the light that is backscattered from the vaginal wall and the blood circulating within it. When the signal is coupled to a direct current amplifier, slowly developing changes in vaginal blood volume (VBV) are observed, which are thought to reflect pooling in the vaginal tissue. With alternate current coupling, a measure of vaginal pulse amplitude (VPA) is obtained, reflecting phasic changes in vaginal engorgement with each heart beat, with larger amplitudes reflecting higher levels of blood flow (Sintchak & Geer, 1975). Vaginal photoplethysmography is the only sexual arousal measure that has been thoroughly studied for its validity. For a comprehensive discussion of these psychophysiological measures we refer to Laan and Everaerd (1998).

Differentiation Between Women's Sexual Problems

How good are available measures in differentiating between women with and without sexual problems? This is the crucial question in view of classifying female sexual dysfunction.

There are no studies available using the oxygenation-temperature method. The studies of Slob, Koster, Radder, and van der Werff ten Bosch (1990) and Wincze, Albert, and Bansal (1993) in women with diabetes suggest that VPA is more sensitive than labial temperature. But to date, only a few studies assessed differences between women with and without sexual problems using the vaginal photoplethysmograph, and the results are conflicting. Some studies found differences while others did not, the nature of the sexual problems varied between and even within studies, and different erotic stimuli were used. For example, Wouda et al. (1998) showed three erotic film clips to women with dyspareunia and control women. An erotic scene depicting fellatio and cunnilingus followed a neutral baseline. Then there was a return-to-baseline period followed by a cunnilingus scene and an intercourse scene. There were no VPA or subjective differences between the two groups in the first four phases of the experiment. But during the intercourse scene VPA responses of the control group further increased while in the dyspareunia group responses declined, yielding the only significant difference in the study. There were no differences in subjectively reported sexual arousal. These results suggest a number of things. First, differences in blood flow response may be highly situation or stimulus specific. Only during the intercourse scene was VPA significantly lower in the clinical group. Second, blood flow and subjective feelings did not significantly correlate.

A large number of studies have addressed this issue (for reviews see Dekker & Everaerd, 1989; Laan & Everaerd, 1995). In some studies positive correlations between VPA or VBV and subjective feelings of sexual arousal were reported, but the majority failed to find a relationship between physiological and subjective arousal. This problem seems unique for women. In men without sexual problems correlations between penile circumference change and subjective report are fairly high. In recent years we studied this phenomenon more closely in women. VPA was consistently found to occur fairly automatically in response to an explicit erotic stimulus such as erotic film. That is, VPA increased within seconds after the onset of the stimulus, without most women being aware of this

happening, even when the stimulus was negatively evaluated or induced little or no feelings of sexual arousal. Women do not simply attend to genital changes when assessing their subjective feeling state. Their subjective experience of sexual arousal is determined both by feedback from their genitals (which becomes more important as genital response increases) and by the intensity and appraisal of the sexual stimulus (Laan & Everaerd, 1995).

These findings suggest the following. Firstly, in a laboratory study blood flow measures should always be used concurrent with subjective measures of sexual arousal. The reason for this is a very practical one. Suppose that the new vasoactive drugs increase vaginal blood flow relative to neutral baseline and relative to placebo. The extent to which women are aware of these genital changes will determine the extent to which they find the drug helpful. Especially small changes in blood flow may not be perceived. Therefore, subjective measures are crucial in establishing drug efficacy. Secondly, the role of the sexual stimulus, usually erotic film, is very important (e.g., Wouda et al., 1998). Blood flow is directly dependent upon the intensity of the sexual stimulus, and subjective feelings depend on both the intensity and the appraisal of the sexual stimulus. And what is intense in terms of blood flow may differ from what is intense in terms of subjective arousal. Thirdly, measuring blood flow in the absence of a sexual stimulus may lead to false conclusions. A recent study may illustrate this point.

In this study of Laan and van Lunsen (1997) a comparison was made of differences in VPA between premenopausal and untreated postmenopausal women during the first neutral baseline, before any erotic stimulation had taken place, and during sexual fantasy and erotic film. The premenopausal women had significantly higher levels of VPA than the postmenopausal women during first baseline, indicating an estrogen-related difference in basal flood flow. As an aside, this finding adds to the discriminative ability of VPA, the measure being able to discriminate between atrophied and nonatrophied vaginal walls. When only baseline data are taken into account, one may be inclined to conclude that postmenopausal women suffer from a vasculogenic dysfunction (Goldstein & Berman, 1998). However, during subsequent erotic stimulation, this difference in VPA between both groups almost entirely disappeared. That is, during fantasy and erotic film the increase in VPA relative to preceding baseline did not significantly differ between groups, suggesting that inadequate erotic stimulation may be more important in sexual arousal disorders than a vasculogenic dysfunction related tO menopause. Also, in this study there were no between-group differences in subjective sexual arousal during sexual fantasy and erotic film.

Recently, Park et al. (1998) proposed that in some women, female sexual arousal problems are associated with vascular and clitoral erectile insufficiency. These authors suggest that future management strategies for women with sexual arousal problems should be aimed at assessing vasculogenic sexual dysfunction, especially if these women are postmenopausal. Of course, organic factors may contribute to the etiology of female sexual dysfunction, and physiological assessment should be more routinely implemented as a diagnostic tool. One nevertheless has to be careful not to oversimplify and take any vascular irregularity as the organic factor causing the sexual difficulties. This happens way too often. We are worried that studies of female sexual dysfunction will follow the same path as the majority of studies of erectile dysfunction, that we will devote our time to studying body parts whereas we ought to study function: How do these body parts behave in the situation they are designed for, namely a sexual situation. Findings from the Laan and van Lunsen (1997) study point to the importance of measuring genital function in a sexually stimulated state, and of designing physiological measures that generate valid data in a situation that allows women to become sexually stimulated.

Goldstein and Berman (1998) are currently using duplex ultrasonography to measure vaginal and clitoral blood flow. If duplex ultrasonography proves to be valid when normative data are collected, this technique may be very promising, for it combines the advantages of all the measures mentioned in this article. One disadvantage still remains, however. The probe needs to be held in place by the experimenter. One may wonder if that would not seriously inhibit subjects from becoming sexually aroused. The challenge here is to develop a transducer that can be comfortably attached to the measurement site without requiring continuous monitoring by another person.

PROSEXUAL DRUG TREATMENTS

One way to understand how the brain transforms sexual stimuli into efferent messages is to think of the nervous system as a set of modules, or nuclei, that each contributes in a specific way to determine a sexual outcome. In this view there are provisions in anatomically specified areas for the processing of sexual information. These areas recognize information as sexual and connect with other units, which respond to the incoming information. Imagine that we are able to follow this neural processing--this would result in tracing a pathway for sexual information. Of course, there are many other processes that help determine the expression of sexual response and which are not specifically sexual. Among these are emotional responses, muscular responses, and cognitions about a sexual response in an actual social situation.

There is another way to understand the processing of sexual information that is not anatomical but is neurochemical. This view does not conflict with the modular view. Neuronal systems can now be characterized both by their topography and by their neurochemical content, particularly amino acids, amines, peptides, and steroid receptors. Neurons can be classed into chemical categories according to genes they express that enable them to make or respond to a particular neurochemical (Herbert, 1996, p. 8). In this view, the role of a neuron is determined not only by its specific anatomic location and connections, but also by its use of transmitters.

The interaction of anatomical locations and neurochemical transmitters results in very complicated pathways, which cannot be easily specified. The combined view provides a rich heuristic for the study of sexual functioning. However, a preliminary condition for the success of such studies is the specification of psychological processes and behavioral endpoints. Most of the work on anatomy and the neurobiology of sexual response has been done with animals. Sexual response, or sexual behavior, has been very narrowly defined as reproductive behavior. Transposition of the results of this animal work to human sexuality should be accompanied by an awareness of the social and cultural constructions in human sexual experience and behavior.

EMBASE and Medline (and PubMed) were searched for the effects of drugs that enhance sexual function. The available data on prosexual drugs in women show that the search for these drugs has not been guided by a heuristic similar to the one we just have sketched. Most of the findings consist of unexpected and ill-reported, but very interesting, side effects. Crenshaw and Goldberg (1996) give a comprehensive overview of drugs that affect sexual functions. In addition, Chan and Brock (1997); Rosen, Lane, and Menza (1999); and Shen, Urosevich, and Clayton (1999) recently have reviewed adverse effects on sexual function and possible pharmacological solutions. It is neither possible nor useful to reiterate what these authors have found. Instead we will give an impression of what may be expected--prosexually in women--from our current knowledge.

Pheromones 

Pheromones are airborne chemicals that are released by an individual and may act as a chemical signal to influence the physiology or behavior of another individual of the same species (Stern & McClintock, 1998). Pheromones may have different functions. Releaser and priming pheromones stimulate physiological and behavioral changes, whereas information pheromones are indicators of territory or identity (Weller, 1999). Pheromones may exert their influence without being consciously detected as an odor. Weller indicates that, although it was considered to be atrophied in adults, humans have a vomeronasal organ (VNO) with receptors for pheromones. The VNO is located close to the nasal cavity.

Interest in pheromonal effects in women has been aroused by McClintock's (1971) famous demonstration of influences of armpit compounds of donor women on cycle length of recipients. Armpit compounds were applied daily above the recipient's upper lip, during a number of cycles. Subjects received a compound either collected during the follicular phase of donors or during the ovulatory phase of donors. Compounds collected during the follicular phase of donors shortened cycle length in the recipients, and compounds collected during the ovulatory phase made cycles longer. The two pheromones phase-advance or phase-delay the preovulatory surge of luteinizing hormone (LH). Through this modulation of ovulation timing in a social group of women cycles may synchronize, desynchronize, or stabilize (Stern & McClintock, 1998).

Androstenol and androstenol-like secretions from the male armpit seem to have an influence on the tendency to bonding and the sexual attractiveness of men for women (Miller, 1999). A pheromonal compound of an as yet unpublished origin apparently had such an effect in a recent study by Cuttler, Friedmann, and McCoy (1998).

Peptides

Three important peptides have been reviewed for prosexual effects by Crenshaw and Goldberg (1996): oxytocin, vasopressin, and luteinizing-hormone releasing hormone (LHRH). Animal studies have indicated possible prosexual effects of Adrenocorticotropin (ACTH), a-melanocite stimulating hormone (a-MSH), and oxytocin, and adverse effects of opioid peptides, corticotropin-releasing hormone (CRF), cholecystokinin, and neuropeptide Y. For the neuropeptide galanin and LHRH there are contrasting results (Argiolas, 1999). There is some information on prosexual influences of oxytocin in women. Oxytocin is responsible for milk expulsion during nursing in the postpartum, initiates labor and augments contractions during labor, and is responsible for postpartum contractions. It is implicated in contractions during orgasm. Oxytocin is frequently prescribed to support lactation and labor; however, there are few reports about sexual effects in women.

From animal studies it has been hypothesized that oxytocin may have behavioral effects on sexual arousal, orgasm, and social bonding (Carter, 1992; Carter, Williams, Witt, & Insel, 1992). Anderson-Hunt and Dennerstein (1994, 1995) published some notes about the sexual effects of a synthetic oxytocin (nasal) spray in a woman who took the drug for low milk expression during lactogenesis. Two hours after taking the spray she observed abundant vaginal lubrication, followed by intense desire and intensified contractions during orgasm and heightened pleasure. She also reported feelings of mild arousal with breast-feeding. Herbert (1994), in an editorial comment on this case history, speculates about the possible mechanism. It is uncertain how central effects (intense desire) could occur, because oxytocin does not readily cross the blood brain barrier. Oxytocin appeared to be sexually effective because the woman used a pill (levenogestrel). According to Herbert, levenogestrel has appreciable androgenic activity, which suggests synergy between oxytocin and androgens. It is well known that androgens have prosexual effects in women (Herbert, 1994).

Smooth muscle contractions of the reproductive tract and contractions of striated muscles of the pelvic floor are supposed to be the cause of sensations of orgasm. Carmichael et al. (1987) hypothesized that oxytocin is involved in orgasmic muscle contractions, because of its classical function in smooth muscle contractions during parturition and for milk ejection. In women and men oxytocin release was measured before, during, and after orgasm in blood samples taken from the forearm. An anal probe allowed monitoring of EMG and blood-pulse amplitude changes. Subjects indicated the beginning and end of their subjective orgasm. Data of the anal probe and the subjective report proved to be closely matched. Oxytocin levels increased throughout self-stimulation and peaked during orgasm, followed by a decrease. Mean plasma oxytocin level in women was significantly higher than in men. Recently, Blaicher et al. (1999) corroborated the oxytocin release for women. They provide oxytocin values for baseline, 1 minute after orgasm, and 5 minutes after orgasm. An increase in oxytocin from baseline to 1 minute after orgasm occurs in all subjects, although with considerable between-subject variation. These results confirm the conclusion of Carmichael et al. (1987) that oxytocin plays an important role in the physiology of sexual responses by facilitating contractions of the uterus and the vagina in women.

The bonding features of oxytocin have been explored in a study that investigated changes in plasma oxytocin as a consequence of emotions and interpersonal distress in women (Turner, Altemus, Enos, Cooper, & McGuinness, 1999). Oxytocin changes were provoked in subjects by "soft Swedish massage of neck and shoulders'" (p. 101) and by induction of negative and positive emotions. Interpersonal variables were measured with questionnaires. Oxytocin was assessed using blood samples drawn from an indwelling catheter during experimental manipulations. The results indicate that changes in peripheral oxytocin are related to interpersonal characteristics. Although considerable individual differences were found, positive emotion, massage, and being in a current relationship tended to be associated with oxytocin increase. Negative emotion seemed to inhibit oxytocin.

On the basis of animal data vasopressin is suspected to have the same social bonding effects as oxytocin. Thus far, there are no reports about specific effects in women. Vasopressin is implicated in memory and emotion, and it has been used as a treatment for memory problems in older people. The sexual action of vasopressin is dependent on testosterone. One may speculate that it has a role in sexual fantasies, and consequently in sexual desire (Crenshaw & Goldberg, 1996).

Sex Steroids

Prosexual effects of sex steroids are discussed in relation to the normal menstrual cycle and during the postmenopause. It has proven to be difficult to establish the role of sex steroids in women. Most women experience an increase in their sexual functioning during puberty. They also experience considerable changes in hormone levels and in hormonal patterns in their reproductive and postmenopausal years. However, it has been difficult to relate serum levels of sex steroids to sexual functioning (Gooren, in press).

Androgens have been considered the typical prosexual hormones. Halpern, Udry, and Suchindran (1997) found that postmenarcheal adolescent Black and White women showed a significant relationship between testosterone (T), changes in testosterone, and transition to first coitus. Among White adolescent women the effects of T were moderated by frequency of attendance at religious services. Men have considerably higher levels of androgens compared to women. According to Gooren (in press), from an endocrine viewpoint it is therefore of interest that women react to androgen levels for which men are insensitive. He speculates that relative changes in testosterone, independent of its magnitude, temporarily stimulate sexual arousal until adaptation to that change occurs. In addition, the continuously changing hormone levels during the cycle might explain women's sensitivity to low levels of androgen.

The relationship between cycle phase and sexual behavior is uncertain. Slob, Bax, Hop, Rowland, and van der Werff ten Bosch (1996) did find some effects on genital physiological arousal in a psychophysiological study. In both the follicular phase and the luteal phase, they induced arousal with films and tactile vibration in women who were between 18 and 45 years of age, had normal cycles, and were not using oral contraception. On subjective measures of sexual excitement no cycle effects were found. A modest effect appeared for reported sexual desire in the follicular phase when subjects were exposed to the erotic film for the first time.

Recent studies of perceptual preferences over the menstrual cycle shed some light on the relationship between cycle phase and (possibly sexual) emotions. There are indications that positive mood and a perceptual bias for sexual stimuli occur during the follicular phase and are estrogen dependent. During the luteal phase negative affect and nonsexual stimuli (e.g., babies) seem to prevail (Johnston & Wang, 1991; Krug, Pietrowski, Fehm, & Born, 1994; Wang & Johnston, 1993). The interpretation of the findings was in line with the authors' hypotheses that these perceptual phenomena are adaptively regulated by the reproductive status of the women.

Phase-dependent prosexual preferences seem to be related to androgen levels, which suggests that preferences, and as a consequence arousal and desire, may be sensitive to pharmacological influences. However, according to Crenshaw and Goldberg's (1996) review, no deficient androgen levels have been found in premenopausal women with sexual dysfunctions.

Hormonal deficiencies, as a consequence of menopausal transition, influence vaginal atrophy and decrease vaginal lubrication as a consequence of lowered estrogen levels. Sexual arousability and sexual desire may drop as a consequence of lowered androgen levels. Mood is dependent on estrogens as well as androgens. Sexual effects of hormonal replacement have been extensively studied by Sherwin (1985; 1987; 1988a, 1988b; 1991; 1998) and Sherwin, Gelfand, and Brender (1985). Current opinion is in favor of combined estrogen/androgen replacement (Sarrel, 1999; Sherwin, 1998; van Lunsen & Laan, 1997). Androgens are necessary to satisfactorily restore sexual function, which in most women will not occur with estrogen replacement alone.

Noradrenaline, Dopamine, and Serotonin

These monoaminergic drugs have multiple functions in information processing of the brain. It is generally accepted that noradrenaline has an arousing function, dopamine is an activating neurotransmitter, and serotonin is an inhibitor. However, it is also generally accepted that this division of functions is too simplistic. Functions of transmitters, and their paradoxical effects, seem to be better understood when characteristics of receptors and events at the receptor are considered (Baskys & Remington, 1996).

Noradrenaline. Noradrenergic activation has common effects on emotional arousal; it facilitates attentional focus on emotional events, and it may boost subjective emotional experience through feedback from peripheral arousal. Meston and her associates (Meston & Gorzalka, 1995, 1996; Meston, Gorzalka, & Wright, 1997; Meston & Heiman, 1998), in a number of psychophysiological studies, have provided evidence suggestive of prosexual effects on sympathetic nervous system activation. Noradrenergic activity was modulated through physical exercise prior to visual sexual stimulation; ephedrine released noradrenaline and clonidine inhibited noradrenaline release during exposure to erotic stimuli. As expected, genital vasocongestion increased through exercise and ephedrine. Clonidine inhibited vasocongestion. However, subjective sexual experience remained unaffected by both exercise and ephedrine, but it dropped with clonidine. Piletz et al. (1998) treated women with hypoactive sexual desire with yohimbine, an alpha-2 receptor antagonist, to release noradrenaline. No improvement of sexual desire was found, although in the article no data are presented on subjective sexual experience and sexual behavior.

More intense genital arousal has been found to influence subjective sexual experience (Laan, Everaerd, & Evers, 1995). However, such greater intensity is unattainable because negative side effects preclude treatments with larger drug doses. Meston and Heiman (1998) speculate that drugs that enhance adrenergic activation boost genital arousal in women without sexual dysfunction, but may provide a "jump start" to women with arousal or desire disorders.

Dopamine. Dopamine is implicated in mechanisms of brain reward (Robbins & Everitt, 1999). Prosexual effects have been reported among patients with Parkinson's disease who were treated with levodopa (Uitti et al., 1989). The patients were brought to the attention of the clinic staff because concerns arose in the family or with social agencies about the hypersexual behavior of the patients. Among them were two women, case 5 and case 6. The woman described as case 5 was Hutterite, and was considered unsuitable for marriage. She possibly never had a sexual relationship with a man. At age 54 she fell ill and at 55 she was diagnosed as having Parkinson's disease. Her hypersexuality apparently consisted of "She would frequently lie on her back and make rhythmic up and down movements similar to sexual intercourse, at times uncovering her genitalia during such episodes" (Uitti et al., 1989, p. 377). The observation for case 6 indicates feeling overly sexy.

Bowers, van Woert, and Davis (1971) found no increase in desire in women treated with levodopa. Crenshaw, Goldberg, and Stern (1987) treated men and women with inhibited sexual desire with bupropion (a dopamine uptake inhibiter). On investigator and patient judgements the women showed improvement in sexual desire. Improvement scores, as reported in Crenshaw and Goldberg (1996), show a clear advantage for bupropion over placebo. The investigators, as compared to the patients, were a little bit more optimistic about improvement.

Serotonin. Serotonin has well documented inhibitory effects on sexual function (Crenshaw & Goldberg, 1996; Rosen et al., 1999). Several authors have observed hypersexual effects, which appear to be rare. Rosen et al. (1999) mentioned three cases of clitoral priapism, which were transient and did not recur. Balon (1994) reported sexual obsessions associated with fluoxetine in a 46-year-old woman. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) was prescribed for her dysthimia. After two months she reported diarrhea as the only side effect and continuous improvement of her depression. At her six month follow-up she reported discontinuation of fluoxetine because of an obsessive preoccupation with sex. She had sexual dreams every night, thoughts about sex every day, and her preoccupation with sex intensified when men approached her. The sexual preoccupation disappeared after discontinuation of fluoxetine. Stevenson and Solyom (1990) reported on two women treated for bulimia with fenfluramine, a central serotonin releaser. Because of side effects of fluoxetine medication one woman was switched to fenfluramine. On a dose of 60 mg she began to complain of frequent sexual arousal during the day. On a dose of 120 mg she felt that her libidinal needs were embarrassing. She was asked to keep a daily record of the intensity of orgasm, the time taken to reach orgasm, and the degree of satisfaction with orgasm. During the next 10 days on 120-mg fenfluramine in the morning, she had intercourse 11 times, masturbated once, had 28 orgasms with intercourse, experienced intense pleasure with most intercourse, and had reduced time to orgasm. The mechanism of these hypersexual effects is unclear. The complicated multiple effects of serotonergic drugs also become clear when considering general side effects and adverse effects on sexual function (Rosen et al., 1999). The evidence for the role of specific 5-hydroxytriptamine (5-HT) receptor subtypes is still contradictory. Currently, [5-HT.sub.1A] and [5-[HT.sub.2C] receptors are supposed to have opposing effects. The [5-HT.sub.1A] receptor may facilitate sexual behavior while the [5-HT.sub.2C] receptor has an inhibitory effect (Barnes & Sharp, 1999; Baskys & Remington, 1996; Rosen et al., 1999). This is suggestive of a balance between enhanced serotonergic activity and diminished dopaminergic effects (Bartlik, Kaplan, & Kaplan, 1995; Crenshaw & Goldberg 1996; Rosen et al., 1999).

The management of SSRI-induced sexual dysfunction has been reviewed comprehensively by Rosen et al. (1999). Adding drugs to the existing SSRI prescriptions (augmentation therapy) has restored sexual function. Prosexual effects of augmentation therapy have been reported for antiserotonergics (e.g., cyproheptadine, nefazodone, mirtazapine, mianserin, granisetron), [[Alpha].sub.2] adrenergic receptor antagonists (e.g., yohimbine), dopamine agonists (e.g., amantadine, dextroamphetamine, pemoline, methylphenidate), bupropion, buspirone, and ginkgo biloba (Rosen et al., 1999; Shen et al., 1999). Segraves (1998) in his review of adverse effects of antidepressant drugs concludes that bupropion and nefazodone have an unusually low incidence of sexual side effects.

Vasodilators 

Spectacular effects of sildenafil (Viagra[R]), a smooth muscle relaxant, on erectile disorder in men, has encouraged the search for the applicability of this drug in women with sexual disorders. Thus far, no data from controlled trials are available. Fava, Rankin, Alpert, Nierenberg, and Worthington (1998) reported positive results in women whose sexual problems resulted from the use of antidepressants. Nurnberg, Lauriello, Hensley, Parker, and Keith (1999) have reported similar effects of counteracting anti-depressant use. Kaplan et al. (1999) treated 33 postmenopausal women with various sexual dysfunctions with sildenafil. No appreciable improvement was established. However, improved vaginal lubrication and increased clitoral sensitivity were observed. Shen et al. (1999) reported on a 38-year old woman treated with fluoxetine for a depressive disorder, who reported difficulty in becoming aroused and inability to orgasm or delayed orgasm. Augmentation therapy with cyproheptadine or bupropion did not improve sexual function. She was then switched to dextroamphetamine with some improvement. In one visit she reported to have taken 50 mg of sildenafil which was prescribed to her husband. With fluoxetine and sidenafil combined she experienced normal sexual function.

Recreational and Life-style Drugs

Moor-Mommers (1994) reported prosexual effects for alcohol (low dose), amphetamines and related compounds, amylnitrate (poppers), anabole steroids, cocaine, and marijuana. Effects of this class of drugs are mixed and often dose dependent (Chan & Brock, 1997).

After having reviewed the literature on drug treatments for women's sexual disorders it is fair to ask how valid these findings are. Few studies had adequate designs and many effects were observed by chance. In studies of side effects of drugs there has been little systematic attention for changes in sexual function (Chan & Brock, 1997; Rosen et al., 1999). Bancroft (1998) has pointed to a number of relevant issues in clinical trials which apply to the outcome of this review. Most pharmacological agents act on neurotransmitter systems that are not specific for sexual function. If a relevant sexual effect can be assumed this is certainly mediated by cognitive information processing. When a drug has a specific effect on an individual, the extent to which this effect is sufficient as a treatment should be established. And last but not least, Bancroft (1998) points to the capacity for change in relationships as a source of "considerable variance" (p. 4) to account for when evaluating well being in sexual relationships.

CONCLUSION

Substitution therapy in postmenopause is the only well-documented treatment to relieve sexual problems. There is evidence from experimental studies for an influence of adrenergic compounds on physiological sexual arousal, but not on subjective sexual experience. Knowledge about prosexual effects in women of most other drugs is based on studies of augmentation therapies or studies of doubtful design, and often report about case studies with reliance only on subjective reports.

We need more and better measures for all domains of sexual dysfunction. More standardization is needed in terms of erotic stimuli, designs, and analysis. We definitely need more basic studies focussing on differential diagnosis and treatment effect. Given the many unresolved issues in this area, and the complex relationship between physiological changes, sexual stimulation, and sexual experience, it seems very important that everybody who is involved in diagnosing and treating sexual dysfunctions is knowledgeable about sexuality.

In drug trials it seems important to avoid overuse of brief questionnaires assessing endorgan function. There certainly is a need for clear endpoints to measure direct effects, but there are so many factors that may predict response and nonresponse, such as the status and quality of the sexual partner and the relationship, age, health, sexual orientation, personality, and cultural factors, just to name a few. This is certainly not easy, but if we really want to understand why treatments do or do not work we cannot afford to neglect them.

We need more public education on how drugs may be beneficial and for whom, and we should be sensitive as to what new drugs mean for sex partners. Finally, and this may come as a surprise in this high-tech era of vasoactive drugs, we need more general public sex education. In the case of women, we need to teach them how their bodies work and how they can become aroused and lubricated. It is our belief that a fair part of the sexual problems of women (and men) can be explained by lack of knowledge.

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Manuscript accepted March 30, 2000

Walter Everaed and Ellen Laan University of Amsterdam Amsterdam, The Netherlands

We are indebted to the two anonymous reviewers who provided constructive and helpful criticisms, and to Mrs. H. C. Dyserinck, clinical librarian at the Amsterdam Medical Center of the University of Amsterdam, for her generous and kind assistance.

Address correspondence to Walter Everaerd, Department of Clinical Psychology, University of Amsterdam, Roetersstraat 15, 1018 WB Amsterdam, The Netherlands; e-mail: [e-mail].