NEWS AND VIEWS The Neurobiology of Sexual Function

Cindy M. Meston, PhD; Penny F. Frohlich, MA

his article provides a review of the past and current literature on the neurobiology of sexual function. The influence of endocrine, neurotransmitter, and central nervous sys- tem influences on male and sexual function are discussed for sexual desire, arousal, and orgasm or ejaculation stages of sexual responding. Endocrine factors reviewed in- Tclude the following: androgens, , progesterone, prolactin, oxytocin, cortisol, and phero- mones. Neurotransmitters and neuropeptides discussed include nitric oxide, serotonin, dopa- mine, epinephrine, norepinephrine, opioids, acetylcholine, histamine, and ␥-aminobutyric acid. Central nervous system influences on sexual function are discussed briefly with reference to - stem regions, the , and the forebrain. Arch Gen Psychiatry. 2000;57:1012-1030

Within the past decade, increasing re- tending animal findings to the complex ex- search attention has been paid to the neu- perience of human sexual function. robiology of sexual function. This has been Wherever possible in the present re- fostered, in part, by a growing awareness view, the effects of endocrine, neurotrans- of the deleterious effects of pharmacologi- mitter, and CNS influences are discussed cal agents on sexual behavior, by an in- separately as they pertain to the sexual re- creased recognition of the high incidence sponse phases of desire, arousal, and or- of sexual difficulties present in men and gasm (including ejaculation in males). This women and, most recently, by the enor- classification of sexual disorders draws mous success of using sildenifil citrate heavily on Masters and Johnson’s Human (Viagra) for the treatment of male erec- Sexual Response2 model and Kaplan’s3 tri- tile dysfunction. In this article, we provide phasic model of sexual response in which a concise review of the past and current desire, arousal, and orgasm are conceptu- literature on the endocrine, neurotrans- alized as distinct and sequential phases. In mitter, and central nervous system (CNS) actual clinical practice, however, sexual de- influences on male and female sexual func- sire, arousal, and orgasm difficulties more tion. We would like to acknowledge the often than not coexist—suggesting an in- enormity of the field at the outset, and em- tegration of phases, and desire does not phasize that this article is meant as a broad necessarily precede arousal—arousal re- overview of the field. Wherever appli- sponses may also ignite desire (for a re- cable, within each section, we refer the view of problems associated with this clas- readers to more in-depth, specialized re- sification system in women, see Leiblum4). views. While the focus of this article is on human research, in areas such as the brain STAGES OF HUMAN SEXUAL localization of sexual function where little RESPONSE human data exist, we also briefly summa- rize the findings from the animal litera- Sexual desire is commonly defined as the ture (for a more detailed review of the ani- broad interest in sexual objects or expe- mal literature in this field, see Pfaus1). One riences. Because there is no objective physi- must, of course, exercise caution when ex- ological criterion for desire, it is gener- ally inferred by self-reported frequency of sexual thoughts, fantasies, dreams, wishes, From the Department of Psychology, University of Texas, Austin. and interest in initiating and/or engaging

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1012

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 in sexual experiences. Definition of the pons) sends noradrenergic fi- ated muscles that surround the bul- this construct is complicated by fac- bers to the forebrain and , bar urethra.9 The extent to which tors such as attitudes, opportunity including those areas controlling central neurophysiological events are and/or partner availability, mood, erection (for a review of male sexual related to the intensity or experi- and health. physiology, see Creed et al6). ence of orgasm is unknown. While Intimately connected with Physiological sexual arousal in orgasm is generally the result of both sexual desire, sexual arousal is de- women begins with increased clito- genital and psychological stimula- fined in both subjective (eg, feeling ral length and diameter, and vaso- tion, evidence suggests central sexually excited) and physiological congestion of the vagina, vulva, stimulation alone may trigger or- terms (eg, genital vasocongestion). clitoris, uterus, and possibly the ure- gasm.7 Physiological sexual arousal in males thra. Comparable to the , the involves the regulation of penile he- corpora cavernosa of the clitoris con- RESEARCH METHODS modynamics that is dependent on sist of a fibroelastic network and signal input from central and pe- bundles of trabecular smooth Insight into the neurobiology of ripheral nervous systems, and on a muscle. Pelvic nerve stimulation re- sexual function comes from 3 prin- complex interplay between neuro- sults in clitoral smooth muscle re- cipal research methods: (1) animal transmitters, vasoactive agents, and laxation and arterial smooth muscle studies, (2) human studies involv- endocrine factors. Within the pe- dilation. With sexual arousal, there ing laboratory manipulations of nile sinusoidal tissue is a central ar- is an increase in clitoral cavernosal sexual responding, and (3) clinical tery and veins that exit and drain the artery inflow and an increase in reports of sexual dysfunction sec- erectile bodies. The smooth muscles clitoral intracavernous pressure that ondary to drug treatment or dis- that line the sinusoidal spaces and leads to tumescence and extrusion ease. In male mammals, behavioral the central artery are tonically con- of the clitoris. Engorgement of the indexes of sexual initiation, main- tracted during the flaccid state. Erec- genital vascular network increases tenance, efficacy, ejaculation la- tion begins with smooth muscle re- pressure inside the vaginal capillar- tency and intervals, and reinitiat- laxation mediated by nonadrenergic- ies and results in lubrication of the ing after ejaculation serve as noncholinergic autonomic nerves epithelial surface of the vaginal wall. models for sexual interest, arousal, that, together with the vascular en- The neurotransmitters that medi- orgasm, and refractory periods, re- dothelium, release nitric oxide (NO) ate clitoral and arterial smooth spectively, in human males. In fe- into the corpus cavernosum of the muscle dilation remain undeter- male mammals, the most fre- penis. The second messenger, cy- mined. Recent animal studies sug- quently studied sexual behavior is clic guanosine monophosphate gest that adrenergic nerves induce the lordosis response—a spinal re- (cGMP), mediates the effects of NO contraction and ␣-adrenergic recep- flex in response to a male’s attempt that causes smooth muscle relax- tors mediate contraction in both clit- to mate. It is unclear how lordosis ation. Smooth muscle relaxation re- oral cavernosal and vaginal tissue responding might reflect the hu- duces vascular resistance and the (for a review of female sexual physi- man female sexual response, and erectile bodies fill with blood. Once ology, see Levin7). Preliminary stud- whether it even provides an appro- the erectile bodies become en- ies suggest that NO may play an im- priate model for studying female gorged, the emissary veins are com- portant role in relaxing clitoral sexuality. Other measures of sexual pressed under the tough fibroelas- corpus cavernosum smooth muscle, behavior in female mammals such tic covering and blood is trapped in and vasoactive intestinal peptide may as ear wiggling and rejection behav- the penis.5 Normally, detumes- play an important role in the relax- iors all reflect sexual interest or mo- cence occurs with the release of - ation of vaginal tissue.8 tivation. There is no appropriate ani- echolamines during orgasm and In males and , orgasm mal model for female sexual arousal ejaculation. Activation of the sym- is characterized by a peak in sexual or orgasm. Also limiting the gener- pathetic adrenergic nerves causes the pleasure that is accompanied by alizability of animal studies is the fact release of noradrenaline, which acts rhythmic contractions of the geni- that cognitive aspects of sexuality on adrenoceptors in the trabecular tal and reproductive organs, cardio- (eg, fantasy) are more likely to play smooth muscle of the corpus caver- vascular and respiratory changes, an important role in human sexu- nosum and in penile vessels. In ad- and a release of sexual tension. In ality than in other species. dition to mediating detumescence, men, during the emission stage of or- Laboratory studies of sexual re- the sympathetic nervous system may gasm that is believed to be under sponding focus primarily on sexual play a role in maintaining a non- thoracolumbar control, seminal fluid arousal. In males, erectile re- erect state. Centrally, penile erec- is propelled into the bulbar urethra sponses are most commonly mea- tion is controlled by centers lo- via the release of norepinephrine that sured in response to visual stimuli cated in the thoracolumbar and acts on ␣-adrenergic receptors, the using a mechanical strain gauge that lumbosacral regions of the spinal smooth muscles of the vas defer- measures changes in penile tumes- cord. Erections are elicited in a va- ens, prostate, and seminal vessels. cence via an increase in penile cir- riety of physiological contexts via in- During the ejaculatory phase, which cumference. No information is pro- formation sent from the periphery is mediated by a sacral spinal re- vided regarding the firmness or and supraspinal nuclei to these cen- flex, semen is released through the rigidity of erection with this de- ters. The locus ceruleus (located in urethra via contractions of the stri- vice. The device consists of 2 arcs of

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1013

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 surgical spring material with a pair havior were limited by techniques that than normal males’ circulating lev- of mechanical strain gauges at the were either too crude or too invasive els of testosterone. Consequently, junction. Increases in penile circum- for use with humans. Consequently, variability in testosterone levels ference cause a flexing of the gauges most of our knowledge in this re- above this threshold level, or exog- and a corresponding change in re- gard comes from animal studies. enously induced testosterone sistance. The device is simple to use, Functional brain imaging tech- changes above this level, would not reliable, and relatively unobtrusive niques such as positron emission to- be expected to influence sexual in- (for a review of the techniques used mography have only begun to be ap- terest or behavior.9 In aging males, to measure male sexual arousal, see plied to the field of . androgen dehydroepiandrosterone Rosen and Beck10). Reports on the sexual conse- has been publicized to increase Assessment of physiological quences of pharmacological treat- sexual and overall well-being. Find- sexual arousal in women relies pri- ment or disease provide an indirect ings from a recent well-controlled, marily on indirect measurement of means for generating hypotheses double-blind study, however, found vaginal blood flow (direct assess- about the pathways involved in hu- only minimal beneficial effects on ment of vasocongestion is too inva- man sexuality. This method is lim- sexual function.23 sive a technique to be used with hu- ited by a general lack of controlled Testosterone has been shown to man subjects) and includes vaginal inquiry, and the various concerns as- restore nocturnal penile tumescence photoplethysmography, indirect sociated with self-report measures of responses in hypogonadal men with measures of heat dissipation, and sexuality (eg, response biases)(for re- impaired nocturnal penile tumes- pulsed wave Doppler ultrasonogra- view, see Meston et al14). cence.24 It is unclear whether testos- phy. The most frequently studied of terone also influences erectile re- these techniques is vaginal photo- ENDOCRINE FACTORS sponses to external stimuli. A recent plethysmography. The vaginal pho- study25 showed testosterone in- toplethysmograph is a clear acrylic, Androgens creased sexual arousal and enjoy- tampon-shaped device that con- ment among hypogonadal and nor- tains either an incandescent light In men, numerous studies have mal men, and had a positive effect on source, or an infrared light-emitting shown that withdrawal of exog- mood only among men with abnor- diode as a light source and a photo- enous testosterone in hypogonadal mally low testosterone levels. Other sensitive light detector. The light or castrated men causes a rapid and studies have found testosterone does source illuminates the capillary bed marked decrease in sexual interest not significantly influence erectile re- of the vaginal wall, and the photo and activity that is reinstated in a few sponses to erotic stimuli among hy- transistor detects the light that is re- weeks with testosterone replace- pogonadal men, nor do erectile re- flected back from the vaginal wall and ment therapy.15-17 One study18 that sponses differ significantly between the blood circulating within it (for a differentiated between hypergonado- hypogonadal and normal men.16,24,26 review of the techniques used to mea- tropic and hypogonadotropic hypo- Among males with normal testoster- sure female sexual arousal, see gonadal males found long-term tes- one levels, testosterone has not been Meston11). A recurrent issue with this tosterone treatment to be more shown to facilitate erection.27 measurement technique in women is beneficial for enhancing the subjec- In an early study of women who the low correlation between psycho- tive quality of sexual acts, sexual had undergone bilateral oophorec- physiological measures and verbal re- excitement, and frequency of sexual tomy and adrenalectomy,28 re- ports of sexual arousal (eg, Meston thoughts among males with hy- moval of the ovaries decreased and Gorzalka12,13). This contrasts pergonadotropic hypogonadism. sexual desire to a certain extent, but findings reported in men that usu- In adolescent boys, levels of free removal of the adrenal glands had an ally indicate a high positive corre- testosterone have been shown to even more deleterious effect on spondence between penile photo- predict the frequency of sexual sexual desire. The findings from this plethysmography and subjective thoughts19,20 and monthly mea- and similar studies conducted in pa- reports of sexual arousal. It is un- sures of salivary testosterone have tients with cancer29 and patients with clear whether this desynchrony be- been positively correlated with the polycystic ovaries30 are limited by the tween responses in women reflects an initiation and rate of sexual inter- unique characteristics of the pa- inability of women to detect subtle course.21 It is possible that in this lat- tients and by the anecdotal and un- changes in vaginal blood flow, or ter study increased intercourse fre- controlled nature of the reports.31 whether women estimate the de- quency may have caused the increase Studies of surgically menopausal gree to which they are subjectively in the testosterone level. In normal women generally indicate that de- aroused according to standards other adult males there exists wide indi- sire drops from presurgery levels32 than genital blood flow changes. That vidual variability in circulating tes- and may be restored with exog- is, for women, external stimulus in- tosterone levels that do not seem to enous administration of supraphysi- formation may play a more impor- be linked in any meaningful way ological levels of testosterone with tant role in assessing feelings of sexual with individual differences in lev- or without .33,34 Consis- arousal than do internal, physiologi- els of drive or sexual behavior.22 It tent with these findings, Sherwin35 cal cues. is believed that the level of testos- found that sexual desire, arousal, and Until recently, laboratory stud- terone required for sexual interest fantasies in oophorectomized ies of centrally mediated sexual be- and activity in adult males is lower women were higher among those

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1014

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 women who had high vs low ratios sexual arousal, and Schreiner-Engel levels of sexual desire, treat- of total testosterone-sex – et al46 found menstrual cycle– ments alone have generally not binding globulin. With natural related changes in physiological shown to be successful.34,58 menopause, androgen levels are sexual arousal unrelated to gonadal Estrogen deficiency, as occurs positively correlated with sexual in- hormone variations. Two recent psy- with menopause, causes a decrease in terest.32,36 Testosterone administra- chophysiological studies examined genital vasocongestion and lubrica- tion to female-to-male transsexuals the effects of exogenous dehydroepi- tion and atrophy of the vaginal epi- and androgen deprivation in male- androsterone administration on sub- thelium. Such changes not only im- to-female transsexuals37 also sup- jective and vaginal blood flow pair the physiological sexual arousal port the notion that androgenic hor- measures of sexual arousal in pre- response in women and may cause mones play an important role in the menopausal47 and postmeno- dyspareunia (pain during inter- sexual desire of males and females. pausal48 women. Neither study found course), but can adversely influence Studies on the relation between a significant difference in physiologi- the psychological experience of sexual testosterone level and sexual desire in cal sexual arousal with acute dehy- arousal. Together with changes in premenopausal, healthy women have droepiandrosterone vs placebo ad- mood that frequently accompany es- rendered somewhat inconsistent re- ministration. The study conducted in trogen loss, these changes could be sults. Persky et al38 noted a relation postmenopausal women48 did, how- expected to indirectly impair sexual between midcycle testosterone lev- ever, note a significant increase in sub- desire. In such cases estrogen replace- els and intercourse frequency. Ban- jective ratings of sexual arousal with ment therapy has been shown to ef- croft et al39 reported a relationship dehydroepiandrosterone administra- fectively restore vaginal lubrication between testosterone levels and mas- tion. and consequently enhance sexual de- turbation but not intercourse fre- sire and satisfaction.61 quency, and Udry et al40 reported a re- Estrogens lationship between testosterone levels Progesterone and sexual interest among adoles- Most research suggests that estro- cents but found that peer relation- gens have little direct influence on Little research has examined the ef- ships were a more important deter- sexual desire in either males or fe- fects of progesterone on male sexu- minant of sexual behavior. Halpern males. In men, relatively high levels ality. One early study62 noted a de- et al41 also reported a significant re- of exogenous estrogen have been crease in sexual “libido” in 4 men lationship between adolescent fe- somewhat effective in inhibiting receiving intramuscular progester- males’ testosterone levels and initia- sexual desire among sex offenders one treatment, and other early stud- tion of coitus. While sexual desire is and men who experience uncontrol- ies63 have used progesterone treat- influenced by androgen levels in lable sexual urges.49-51 In women, ment to reduce excessive sexual women, androgens alone are not suf- some early studies have claimed that desire in men. To our knowledge, no ficient for the experience of sexual de- estrogen (especially estradiol) is im- controlled studies have been con- sire. This is evident from studies that portant for normal sexual desire,52 but ducted on the relation between pro- have failed to find significant differ- most researchers agree that estro- gesterone treatment and sexual de- ences in testosterone levels between gens play only a minimal role in fe- sire in men. women with and without clinically di- male sexual desire. For example, Certain oral contraceptives that agnosed hypoactive sexual desire dis- Schreiner-Engel et al31 found no sig- increase progesterone levels through- order,31,42 and from studies that show nificant differences in estrogen lev- out the female cycle have been asso- androgen antagonists and oral con- els between women with and with- ciated with decreased sexual interest traceptives do not consistently sup- out clinically diagnosed hypoactive and desire64-66 (but see also McCul- press libido in women.43 Testoster- sexual desire; Dennerstein et al53 lough67) as have subfascially im- one treatment seems to be useful in found fluctuations in sexual desire planted progesterone pills that are facilitating sexual desire in a subset across the menstrual cycle to be used to treat various gynecological of women with hypoactive sexual de- unrelated to estrogen levels; Ab- disorders.68 However, an early study sire, but it requires safety monitor- planalp et al54 found no significant re- by Bakke69 found estrogen and pro- ing for potential lipoprotein changes, lationship between estradiol levels gesterone treatment enhanced sexual cardiovascular effects, and andro- and enjoyment of heterosexual ac- desire among hysterectomized, meno- genic skin changes (eg, acne, hirsut- tivity or number of heterosexual ac- pausal women to a greater extent than ism, or androgenic alopecia).43 tivities; and an abundance of stud- did estrogen alone. It is generally With regard to testosterone’s af- ies have reported no change in sexual agreed on, however, that progester- fect on sexual arousal, Schreiner- desire secondary to exogenous estro- one treatment does not have a sub- Engel et al44 found higher levels of genic compounds given to women stantial influence on the sexual de- vaginal blood flow responses to erotic with a variety of gynecological dis- sire of either premenopausal46,70,71 or stimuli among women with high vs orders55-58 (but see also Dennerstein postmenopausal32,33,56,72-76 women. lower levels of circulating testoster- and Burrows59and Dennerstein et one. Also using psychophysiological al60). Moreover, while administra- Prolactin techniques, Meuwissen and Over45 tion of both estrogen and androgen failed to find menstrual cycle– to natural or surgically menopausal Men and women with abnormally related changes in physiological women has been shown to restore high levels of prolactin frequently re-

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1015

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 port a decrease in sexual interest that induced sexual arousal, masturba- either centrally or peripherally has is restored with bromocriptine treat- tion, or coitus.100-104 A number of also been shown to facilitate sexual ment, a dopamine agonist that low- methodological differences between behavior, as measured by increases ers prolactin levels77-82 (but see also studies such as the sexual stimuli in lordosis responding.113 Perhaps Franks et al83 and Koppelman et al84). used and the time point at which the best-known roles of oxytocin are It is unclear whether the reversal of blood assays were taken could pos- related to maternal behaviors, sexual symptoms secondary to bro- sibly explain these discrepant find- namely, parturition, milk ejection mocriptine treatment is attribut- ings. Using a more precise continu- and lactation, and possibly mater- able to the lowering of serum pro- ous blood sampling and endocrine nal bonding.113 lactin levels, to the correction of assessment technique, the prolactin hypothalamic dopaminergic dys- level was shown to substantially Cortisol regulation, or to an interaction be- increase during masturbation- tween these 2 mechanisms.85 Other induced sexual arousal in men.105 Hypercortisolism, also known as evidence for an inhibitory influ- In women, Exton et al95 reported a Cushing syndrome, can produce a ence of prolactin on sexual desire in significant and 2-fold increase in constellation of symptoms includ- women comes from a limited num- prolactin levels in women following ing depression, insomnia, and ber of studies that have found lac- orgasm that remained elevated decreased libido in males and tating women (who have naturally when measured 60 minutes after females.114-117 This syndrome is increased levels of prolactin) re- sexual arousal. associated with increased cortico- port decreased sexual desire com- tropin levels, and symptom severity pared with prepregnancy levels.86 Oxytocin is most severe when corticotropin Such findings could of course be the and cortisol levels are high114 and result of numerous other psycho- Circulating levels of the neuropep- less severe when cortisol levels are logical factors associated with post- tide hormone oxytocin increase dur- high but corticotropin levels are partum changes. Indeed, a number ing sexual arousal and orgasm in low.115 Some evidence suggests that of studies have associated high lev- both men and women.106-109 Using a this pattern of abnormal regulation els of prolactin with mood distur- continuous blood sampling tech- of corticotropin and cortisol levels, bances including anxiety and de- nique and anal electromyography, and the resulting symptoms, may pression79,87 (but see also Waterman Carmichael et al107 reported a posi- be the result of hypersecretion of et al88). tive correlation between oxytocin corticotropin-releasing hormone. Prolactin’s effect on other as- levels and the intensity, but not du- Depression, like Cushing syn- pects of human sexual behavior re- ration, of orgasmic contractions in drome, is associated with both mains equivocal. Erectile dysfunc- males and females. For multiorgas- overactivity of cortisol and loss of tion has been described in men with mic women, the amount of oxyto- libido.116-118 abnormally high levels of prolac- cin level increase also correlated Blood cortisol levels, drawn tin,89-92 but has also been described positively with subjective reports of continuouslywhilesubjectsviewedan in men with unusually low levels of orgasm intensity. In a few case re- eroticfilm,didnotsignificantlychange prolactin,93 suggesting more than a ports a synthetic form of oxytocin in male and female subjects during ei- simple inhibitory role of prolactin on used to facilitate breastfeeding was ther arousal or orgasm.95,100,105,119,120 erectile ability. In women, abnor- linked to increased sexual desire and Cortisollevelswerehigherinmenwith mally high levels of prolactin have vaginal lubrication.110,111 A recent psychogenic erectile dysfunction who been associated with amenorrhea, in- study conducted by Turner et al112 demonstrated a poor response to in- fertility, and decreased sexual activ- found a positive relationship be- tracavernosal injection of a smooth ity (for review, see Muller et al94). tween plasma oxytocin levels and musclerelaxant.Thesemenalsoscored The affect of prolactin on sexual measures of positive affect. To the higher on measures of anxiety.121 arousal may occur peripherally, cen- extent that positive mood and sexual trally (given its ability to enter into interest may be related, oxytocin cerebrospinal fluid), or via dopa- may play an indirect role in sexual minergic regulation.95 Animal stud- desire. Pheromones are substances se- ies indicate that prolactin has an Most of what we know about creted from glands at the anus, uri- overall inhibitory influence on male the influence of oxytocin on sexual nary outlet, breasts, and mouth.122 and, although less well docu- behavior, however, is based on ani- In nonhuman mammals, a special- mented, female sexual behavior, al- mal studies. In male animals, oxy- ized olfactory structure, the vom- though short-term hyperprolac- tocin facilitates penile erections eronasal organ, acts as the ana- tinemia seems to facilitate some when injected into specific areas of tomic locus for pheromonal signals. aspects of sexual behavior in male the brain (ie, periventricular nucleus The vomeronasal organ has been rats (for review, see Drago96). of the hypothalamus), and short- identified in humans,123 but, to date, A number of studies in human ens the ejaculation latency and there have been no human studies males have found prolactin levels postejaculation interval when in- linking behavioral change and to either decrease immediately fol- jected either centrally or peripher- stimulation of vomeronasal organ re- lowing sexual arousal,97-99 or to ally (for review see Carter113). In fe- ceptors. Most of the research on remain unchanged after film- male animals, oxytocin injected pheromones and sexuality in hu-

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1016

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 mans has centered on female repro- dysfunction can result when this pro- to specifically increase serotonin ductive cycle influences. For ex- cess is not working normally or when activity and they are also associ- ample, menstrual synchrony has it is partially or completely dis- ated with sexual side effects such been demonstrated among women rupted. Sildenafil, a drug designed to as decreased libido and impaired living together,124 and menstrual treat erectile difficulties, prolongs the ejaculation (for review, see Rosen cycle regularity125-127 and increased action of cGMP by inhibiting the me- et al153). Indeed, depending on the estrogen levels during the luteal tabolism of cGMP by phosphodies- study, between 2% and 75% of phase126,128 have been noted among terase type 5.136 Numerous well- patients prescribed SSRIs report women with frequent sexual expo- controlled studies have reported that sexual side effects151,154-158 that are sure to men. In a recent double- sildenafil is well tolerated and effec- often alleviated by reducing the blind, placebo-controlled study, Cut- tive in alleviating erectile dysfunc- dosage.159 ler et al129 reported that men exposed tion resulting from organic, psycho- It is not known why SSRIs pro- to a synthesized human male phero- genic, and mixed causes.137-143 duce sexual side effects but some evi- mone reported higher levels of Sildenafil has not yet been ap- dence suggests that activation of the , sleeping with a proved for women by the Food and serotonin2 receptor impairs sexual romantic partner, and petting/ Drug Administration. Sildenafil is ef- functioning and stimulation of the affection/kissing, but no change in fective in inhibiting the metabolism serotonin1A receptor facilitates sexual masturbation frequency. The au- of cGMP in clitoral tissue.144 Prelimi- functioning. Cyproheptadine re- thors interpreted these findings as nary findings from a double-blind, duces activity at postsynaptic sero- evidence for male pheromones in- placebo-controlled, 2-way cross- tonin receptors such as the seroto- creasing the sexual attractiveness of over study showed a significant in- nin2 receptor and has been reported men to women. crease in vaginal pulse amplitude (ie, to reduce antidepressant-induced Table 1 summarizes the en- a measure of moment-to-moment sexual side effects.160 Cyprohepta- docrine factors and sexual function changes in vasocongestion) with a dine also affects the activity of the in males and females. single dose of sildenafil citrate (50 other monoamines making it diffi- mg) among 12 sexually functional cult to determine whether the re- NEUROTRANSMITTERS women. Subjective reports of sexual versal of sexual side effects results AND NEUROPEPTIDES arousal were not significantly al- from activity on the serotonin re- tered with sildenafil treatment in this ceptors or on the receptors of other Nitric Oxide study.145 Some studies have found monoamines. Nefazodone is a se- sildenafil treatment reverses antide- lective serotonin reuptake inhibi- Nitric oxide is an essential compo- pressant-induced sexual dysfunc- tor as well as a serotonin2 receptor nent in the production of penile, and tion in women.146-148 A recent 12- antagonist161 and reportedly causes possibly, clitoral vasocongestion and week study conducted internationally fewer sexual side effects compared tumescence. Sexual stimulation leads in 577 primarily premenopausal with traditional SSRIs.154,158,162,163 It to NO production that in turn stimu- women with female sexual arousal is believed that nefazodone pro- lates the release of guanylate cy- dysfunction found 30% to 50% of the duces both a reduction in number clase. Guanylate cyclase converts women taking sildenafil reported an and a down-regulation of seroto- guanosine triphosphate to cGMP increase in sexual function com- nin2 receptors as well as an up- and cGMP produces relaxation of the pared with 43% of the women who regulation of serotonin1A recep- smooth muscles of the penile arter- received placebo.149 In an open- tors.161 Some evidence suggests that ies and corpus cavernosum result- label, nonrandomized 12-week study the serotonin1A agonist, buspirone, ing in increased blood flow into the conducted among 33 sexually dys- may be useful in reversing SSRI- penis.130,131 Some evidence suggests functional, postmenopausal women, induced sexual dysfunction164 al- that this may also occur in the cli- receiving sildenafil showed a signifi- though findings as to its effective- toris. Immunohistochemical evalu- cant therapeutic response in only 6 ness have been mixed.165 ation of the human clitoris re- women.150 Studies conducted on male rats vealed that NO is produced in this The Figure summarizes pro- suggest that activation of some se- tissue132 and, with the exception that cess that leads to penile and clitoral rotonin receptor subtypes facili- the clitoris does not contain a sub- tumescence. tates sexual behavior while activa- albugineal layer (which contrib- tion of other receptor subtypes utes to the rigidity of the penis), the Serotonin inhibits sexual behavior. Specifi- anatomy of the clitoris is similar to cally, activation of the serotonin1A re- that of the penis.133 A variety of psychoactive medica- ceptor lowers the threshold for Normally, cGMP is metabo- tions that affect serotonin activity ejaculation and antagonism of the se- lized by cyclic nucleotide phospho- produce sexual side effects, but rotonin2 receptor inhibits sexual be- diesterase isozymes into guanosine many of these drugs are not spe- haviors (such as mounting), while 5Ј-monophosphate. As long as sexual cific to serotonin (eg, monoamine activation of the serotonin1B and stimulation continues, cGMP pro- oxidase inhibitors and atypical serotonin1C receptors inhibits sexual duction and metabolism remain bal- antipsychotics).151,152 Selective behaviors.166 anced and penile or clitoral tumes- serotonin reuptake inhibitors A previous review of the hu- cence is sustained.134,135 Erectile (SSRIs), as the name indicates, act man and animal literature suggests

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1017

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 Table 1. Endocrine Factors and Sexual Function in Males and Females*

Males Females

Change in Change Change in Change Hormone in Sexual Population Sampled/ Hormone in Sexual Population Sampled/ Hormone Level Functioning Study Details Level Functioning Study Details Testosterone Sexual desire ↑↑Transexuals male → female37 ↑↑Naturally menopausal32,36 ↑↑Hypogonadal or castrated15-17 ↑↑Surgically menopausal33,34 ↑↑Adolescent boys19,20 ↑↑Intercourse frequency in normal women38 ↑ 0 Normal range testosterone levels22 ↑↑Initiating intercourse in adolescent females41 ↓↓Hypogonadal or castrated15-17 ↑↑Masturbation frequency in normal women39 ↑ (Chronic) ↑ Hypergonadotropic or hypergonadal18 ↑ 0 Intercourse frequency in normal women39 ↑ (DHEA) 0 Aging males23 ↓↓Oophorectomy; adrenalectomy28,32,35 ↓↓Transexuals male → female37 0 ↑↓ Hypoactive sexual desire disorder vs normal no difference in testosterone levels31,42 Sexual arousal ↑↑Nocturnal penile ↑↑Vaginal blood flow in normal women44 tumescence—hypogonadal24 ↑ 0 Erotic stimuli—hypogonadal16,24,26 ↑↑Subjective arousal to films with DHEA—postmenopausal48 ↑↑Erotic stimuli—hypogonadal or ↑ 0 Subjective arousal to films with normal25 DHEA—premenopausal47 ↑ 0 Physiological arousal to films with DHEA—premenopausal and postmenopausal47,48 Estrogen Sexual desire ↑ 0 Normal males27 ↑↑Normal women52 ↑↓Sex offenders49-51 ↑ 0 Menopausal women34,58 ↑ 0 Miscellaneous gynecological disorders55-58 0 ↑↓ Hypoactive sexual desire disorder vs normal31 Sexual arousal ...... ↓↓Menopausal61 ↑↑HRT—menopausal61 Progesterone Sexual desire ↑↓Intramuscular injections in normal ↑↓Subfascially implanted progesterone pill subjects62 users68 ↑↓Hyperactive sexual desire63 ↑↓Contraceptive users64-66 ↑↑Hysterectomized, menopausal69 ↑ 0 Premenopausal46,70,71 ↑ 0 Postmenopausal32,33,56,72-76 Prolactin Sexual desire ↑↓Hyperprolactemia77-82 ↑↓Hyperprolactemia77-82 ↓↑Bromocriptine treatment for ↑↓Sexual activity in hyperprolactemia94 hyperprolactemia77-82 ↑↓Lactating women86 ↓↑Bromocriptine treatment for hyperprolactemia77-82 Sexual arousal ↑↓Hyperprolactemia89-92 ...... ↑↑During masturbation105 ...... ↓↓Hypoprolactemia93 ...... ↓↑Postarousal from masturbation or ...... coitus97-99 0 ↑ Postarousal from masturbation or ...... coitus100-104 Orgasm ...... ↑↑Following orgasm in normal women95 Oxytocin Sexual desire ...... ↑↑Breast feeding110,111 Sexual arousal ↑↑Normal men106-108 ↑↑Normal women106-108 ↑↑Breast feeding110,111 Orgasm ↑↑Normal men106-108 ↑↑Normal women106-108 ↑↑Intensity of orgasm107 ↑↑Intensity of orgasm107 Cortisol Sexual desire ↑↓Cushing syndrome114-117 ↑↓Cushing syndrome114-117 Sexual arousal 0 ↑ Normal men100,105,119,120 0 ↑ Normal women95,119 ↑↓Psychogenic erectile dysfunction, poor responders to ICI121 Orgasm 0 ↑ Normal men120 0 ↑ Normal women95 Pheromones Sexual attractiveness ↑↑Normal men129 ......

*↑indicates increase; ↓, decrease; 0, no change; DHEA, dehydroepiandrosterone; ellipsis, not applicable; HRT, hormone replacement therapy; and ICI, intracavernous injection.

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1018

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 that some sexual side effects of SSRIs may result from serotonin’s Sexual Stimulation actions in the periphery of the body 167 Nitric Oxide Synthesized in rather than the CNS. Approxi- Nerve and Vascular Tissue mately 95% of serotonin receptors of Penis or Clitoris are located in the periphery of the body and peripheral serotonin acts Nitric Oxide Activates GTP on the smooth muscles of the vas-

cular system to produce vasodila- GTP ➔ GMP tion and vasoconstriction, acts on the smooth muscles in the genitals, and cGMP Metabolized Into is active in peripheral nerve func- GMP by cGMP PDE5 tions including those of the sexual organs. cGMP Relaxes Smooth Muscles Sildenafil Citrate Recent studies indicate that of the Corpus Cavernosum Inhibits cGMP PDE5 and Arterioles in Penile or SSRIs may be a useful treatment for Clitoral Tissues premature ejaculation. Paroxetine, sertraline, and fluoxetine168-175 have Vasocongestion of Penile all been found effective in increas- or Clitoral Tissues ing the latency to orgasm from less than 1 minute to between 2 and Sexual stimulation leads to the production of nitric oxide which in turn stimulates a cascade of events 6 minutes. The increase in ejacu- that, providing normal functioning, leads to penile and clitoral tumescence. Erectile dysfunction, and possibly female sexual arousal dysfunction, can be treated with a medication such as sildenafil (Viagra) lation latency is dose dependent that facilitates and/or prolongs penile or clitoral tumescence by inhibiting the metabolism of cyclic although at higher doses the like- guanosine monophosphate (cGMP). GTP indicates guanosine triphosphate; PDE, phosphodiesterase; lihood of an ejaculation also in- and PDE5, phosphodiesterase type 5. creases.171 A study comparing men with ejaculation latencies of less than male rats become sexually recep- dol, which antagonizes the D2 1 minute to men with ejaculation la- tive.185 receptor.210 In male rats, the dopa- tencies of greater than 1 minute mine agonists apomorphine, LY found that paroxetine treatment in- Dopamine 163502, and RDS-127, decrease the creased the ejaculation latency 420% latency to ejaculation.190-192 The de- and 480%, respectively, suggesting Antiparkinsonian medications (eg, gree to which dopamine agonists af- that the paroxetine-induced delay in apomorphine hydrochloride, le- fect sexual behavior seems to be de- ejaculation is a function of baseline vodopa) act as dopamine agonists and pendent on both drug dose and the latency.175 have been reported to increase sexual amount of time between drug intro- Side effects such as decreased desire186,187 (such cases occur in Ͻ1% duction and behavioral observa- libido, delayed orgasm, and anor- of patients188; for a thorough review tion, although small doses of dopa- gasmia have been reported with of dopamine and sexual behavior, see mine agonists have been reported to monoamine oxidase inhibitor and Melis and Argiolas189). Animal stud- delay ejaculation.190,192 SSRI use in women.151,153,176 Women ies generally support this notion. Do- Few articles have reported the also experience lower rates of sexual pamine agonists, such as apomor- role of dopamine in female sexual- dysfunction when taking nefaz- phine, LY 163502, and RDS-127, ity. An increase in sexual behavior has odone as compared with more tra- increase mounting behavior190-192 and been noted in one isolated case re- ditional SSRIs such as parox- cause an increase in sexual behavior port of a woman receiving a combi- etine.154,158,163 Cyproheptadine, a in sexually satiated male rats.193 nation of levodopa and carbidopa serotonin2 antagonist, has been ef- Several reports indicate that the treatment that increased dopamine fective in alleviating antidepressant- parkinsonian medication, le- activity.187 Delayed or inhibited or- induced anorgasmia160 but can pro- vodopa, produces erection.194-196 The gasm in women has been associated duce a reversal in depressive D1 and D2 dopamine agonist, apo- with antipsychotic medications that symptoms.176 A prospective study morphine facilitates erection in men decrease dopamine activity such as examining 344 male and female out- with normal erectile capacity.197-203 As trifluoperazine hydrochloride, flu- patients found that SSRI-induced noted earlier, bromocriptine, which phenazine hydrochloride, and thio- sexual dysfunction was more se- decreases prolactin levels and is also ridazine hydrochloride.211-213 Find- vere in women than in men.155 Ani- a long-acting dopamine agonist, fa- ings from animal studies are mal studies have conflicting find- cilitates erectile functioning. Anti- conflicting with some studies indi- ings with some studies reporting that psychotic medications, which tend to cating that dopaminergic activity fa- serotonin antagonists and agonists decrease dopaminergic activity, have cilitates lordosis responses while inhibit lordosis in female rats177-182 been reported to both impair erec- other studies reported that it inhib- while others report that serotonin tion204-205 and produce prolonged its lordosis.214 The contradictory find- agonists facilitate lordosis.183,184 En- erections (priapism).206-209 A dopa- ings could be explained by the fact dogenous serotonin levels increase mine-induced erection was antago- that female rats differ in their re- during proestrus, the time when fe- nized by the antipsychotic, haloperi- sponse to dopamine depending on

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1019

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 their degree of receptivity prior to ma- film.100 Adrenergic activity plays a ing sexual activity. In men, blood nipulation of dopamine activity. That role in maintaining the penis in a plasma NE levels were positively cor- is, low doses of dopamine agonists fa- flaccid state and in producing detu- related with arousal and erection dur- cilitate receptivity in females with low mescence. ␣1-Adrenergic receptors ing masturbation and sexual activ- receptivity while high doses inhibit have been found in human penile tis- ity and increased up to 12-fold at 105,234,235 105 receptivity in females exhibiting high sue and blockade of ␣1-adrenergic re- orgasm. Kruger et al re- receptivity.214 ceptors produces an erection.6 ported that NE levels declined to Cocaine enhances dopamine Adrenergic systems are active in baseline levels within 2 minutes of activity by blocking the presynap- women as they become sexually reaching orgasm. In contrast, NE tic autoreceptor215 and cocaine is aroused. The epinephrine and nor- urine levels did not significantly dif- commonly believed to enhance epinephrine metabolite, vanillylman- fer in 8 males 4 hours before and 4 sexual pleasure. Low doses of co- delic acid, increases prior to inter- hours after viewing a sexually ex- caine may enhance sexual enjoy- course and continues to be elevated plicit film.100 Given that Carani et al100 ment by stimulating the limbic sys- over baseline up to 23 hours follow- did not measure NE levels until 4 tem and by delaying ejaculation.216 ing sexual activity.227 Ephedrine, an hours following sexual stimulation, Studies of cocaine addicts suggest ␣- and ␤-adrenergic agonist, has been it is feasible that NE levels did in- that chronic cocaine use may im- shown to significantly increase vagi- crease during sexual stimulation but pair sexual functioning. Thirty per- nal pulse amplitude responses to an were no longer detectable. cent of male cocaine abusers re- erotic videotape compared with pla- Studies reporting the effects of ported that cocaine impaired cebo.228 Consistent with this find- drugs that act on NE receptors fur- ejaculation and 80% of female abus- ing, clonidine, an antihypertensive ther indicate that NE is important in ers reported that it reduced sexual medication that blocks sympathetic sexual activity in men. As noted ear- enjoyment.217,218 High doses of co- nervous system (SNS) activation, sig- lier, antidepressants such as SSRIs caine may impair erectile capac- nificantly diminishes vaginal pulse produce a whole host of sexual side ity216 possibly as a result of the va- amplitude responses to erotic stimu- effects151 and newer classes of anti- soconstrictive effects of cocaine.219 lus compared with placebo under depressants that act on NE neuro- High doses of cocaine can produce conditions of SNS arousal.229 In- transmission have been found to pro- anorgasmia and high doses and long- tense acute exercise known to sig- duce fewer sexual side effects. For term use may also produce a reduc- nificantly increase SNS activity, sig- example, mirtazapine is a newly de- tion in sexual desire.216 With- nificantly increases vaginal pulse veloped antidepressant that in- drawal from cocaine use can produce amplitude and vaginal blood vol- creases both serotonergic and nor- a temporary reduction in sexual de- ume responses to erotic stimuli in adrenergic activity and early reports sire220 that may be restored after 3 sexually functional women and suggest that rates of sexual dysfunc- weeks of abstinence.221 women with hypoactive sexual de- tion with mirtazapine are lower than Controlled studies of rats and sire disorder.230-232 Anorgasmic placebo.236 Similarly, some evidence nonhuman primates suggest that co- women showed an inhibition in suggests that yohimbine, a drug that caine affects sexual functioning dif- physiological sexual arousal under increases NE activity, may be useful ferently after short- vs long-term use. conditions of SNS activation.232 Mes- in treating erectile dysfunction and Acute cocaine administration in rats ton and Gorzalka230-232 suggested that anorgasmia.237-239 facilitates erection222,223 but also in- there may be an optimal level of SNS Studies suggest that NE is also creases the number of mounts needed activation for facilitation of female active during the sexual response to ejaculate.224 After long-term (eg, 5 sexual arousal. Blood plasma levels cycles of women. Blood plasma lev- days) cocaine administration, co- of epinephrine have been shown to els of NE increased during mastur- caine no longer facilitated erection increase prior to viewing an erotic bation, peaked at orgasm, and slowly even after 1 week after termination film, slowly increase during mastur- declined following orgasm in nor- of the drug.223,224 Short-term co- bation, peak at orgasm, and re- mally functioning women.95,235 This caine administration in nonhuman turned to baseline levels within sev- finding is consistent with that of a primates produced a dose-depen- eral minutes of orgasm.95 Reports of similar study that found that the lev- dent delay in initiation of copula- decreased sexual arousal and or- els of NE and epinephrine metabo- tion and ejaculation225,226 and did not gasm in females taking antipsy- lite, vanillylmandelic acid, were el- produce an increase in sexual activ- chotic medications (thioridazine and evated 1 hour prior to intercourse ity.226 These effects were reversed by trifluoperazine),151 which act to sup- and continued to be elevated up to 226 233 the D2 antagonist, haloperidol. press ␣ -adrenoreceptors, also pro- 23 hours after intercourse. Given vide evidence for a facilitatory influ- that vanillylmandelic acid is a me- Epinephrine ence of adrenergic activity in female tabolite of both NE and epineph- sexual responding. rine, it is unclear whether the eleva- In sexually functional men, the tions found resulted from increases blood plasma epinephrine level Norepinephrine in NE, epinephrine, or both.227 Yo- shows a nonsignificant increase just himbine produced an increase in NE prior to masturbation105 and urine Several studies examining blood activity (as measured by levels of the levels of epinephrine remain un- plasma levels of norepinephrine (NE) NE metabolite 3-methoxy-4- changed after viewing an erotic indicate that NE levels increase dur- hydroxyphenylglycol) in women

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1020

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 with hypoactive sexual desire dis- creased spontaneous erections, morn- nerves253 and contains cholinergic re- order, but did not significantly al- ing erections, and coitus in men with ceptors254,255 suggesting endogenous ter sexual drive. Furthermore, com- erectile failure248-250 and naloxone in- cholinergic activity in the penile tis- pared with normally functioning duced a partial erection in 3 of 6 men sue. Furthermore, administration of women, women with hypoactive with normal erectile functioning.251 exogenous acetylcholine chloride to sexual desire disorder did not dif- Men taking naltrexone did not differ precontracted corpus cavernosum tis- fer in 3-methoxy-4-hydroxyphenyl- in luetinizing hormone, follicle- sue results in a relaxation of the glycol levels.240 stimulating hormone, prolactin, or smooth muscles.256 An in vitro study testosterone.248,250 Some evidence sug- of the corpus cavernosal tissue of men Opioids gests that naloxone administration with diabetes mellitus, a condition may reduce the subjective pleasure commonly associated with erectile Much of what is known about opi- experienced during arousal and or- dysfunction, suggests that acetylcho- oids’ role in the sexual response cycle gasm.251 line-induced relaxation may be im- comes from research on the effects of The role of endogenous opiates paired in this group.257 The cholin- narcotics241,242 and agonists and an- in normal sexual functioning is un- ergic agent bethanechol has been tagonists of naturally occurring opi- clear. Two studies that compared reported to be useful in reversing an- oids such as endorphins, enkepha- blood plasma levels of ␤-endorphins tidepressant-induced erectile and lins, and dynorphins243 (for a in men as they viewed an erotic film ejaculation difficulties.258,259 In male thorough review of opioids and sex, vs a neutral film failed to find a sta- rats, cholinergic agonists and antago- see Pfaus and Gorzalka244). Indeed, it tistically significant difference. In both nists reduced sexual activity while in- is well established that abuse of opi- studies, the ␤-endorphin levels were creased cholinergic activity led to oids leads to sexual difficulties.242 In lower during the erotic film than dur- more rapid ejaculation.260,261 Al- men, long-term opioid use leads to ing the neutral film.100,105 One of the though cholinergic fibers may be pre- loss of libido, erectile dysfunction, and studies examined ␤-endorphin lev- sent in the peripheral nervous sys- when erection is present, inability to els during orgasm as well but also tem, evidence suggests that penile achieve orgasm. Long-term opioid use noted no significant change.105 A pre- erection is controlled at the level of produces a decline in sexual func- vious review of the literature exam- the brain and spinal cord.262 tioning that typically follows a course ining male laboratory animals (eg, There is little mention in the lit- from mild problems (eg, loss of in- mice, rats, rabbits, dogs, monkeys, erature of cholinergic involvement terest in sex although performance is and chimpanzees) suggests that en- in vaginal vasocongestion. In 2 stud- not impaired when sexual activity oc- dogenous opiate levels may increase ies, atropine, an acetylcholine an- curs) to complete loss of sexual func- during sexual activity.244 tagonist, was administered to women tioning.244 One study examining the Women who become addicted and no change was found in vaso- effects of intraspinal administration to narcotics, such as heroin, experi- congestion or orgasm.263,264 of opioids found that within 1 month ence changes in sexual functioning in- of treatment initiation subjects expe- cluding decreased libido, increased li- Histamine rienced a reduction in libido and erec- bido, anorgasmia, and a loss of libido tile difficulties.245 Withdrawal from during heroin withdrawal.244 In one A previous review of the litera- opiate addiction is characterized by isolated study, short-term adminis- ture265 cited a handful of case stud- increased frequency of morning erec- tration of the opiate antagonist, nal- ies in men reporting loss of libido and tions, spontaneous ejaculation (in the oxone, increased sexual desire in 1 of erectile failure associated with the his- absence of sexual stimuli), and a slow 4 women but did not affect vaginal tamine2 (H2) antagonists, cimeti- return of sexual drive. Some men, lubrication in any of the subjects.251 dine hydrochloride and ranitidine hy- however, experience a complete loss Blood plasma levels of ␤-endor- drochloride. When histamine was of ability to achieve erection and or- phins have not been shown to change injected into the corpus caverno- gasm.244 Although the mechanism by during sexual arousal and orgasm in sum, it produced full or partial erec- which opiates affect sexual function- women95 and naloxone vs saline so- tions in 74% of men with psycho- ing is unclear, some evidence sug- lution has not been effective in alter- genic impotence. Work with in vitro gests that increased opioid activity ing sexual arousal among women preparations suggests that the H2 and 252 produces a decrease in the levels of with sexual arousal disorder. possibly H3 receptor may be in- circulating , such as lutein- volved.266 In one isolated case, a izing hormone and testosterone, and Acetylcholine woman experienced loss of libido as- that it is the reduction in hormones sociated with cimetidine use.265 The that leads to sexual dysfunc- Acetylcholine, together with vaso- sexual difficulties associated with H2 tion.245,246 active intestinal peptide, has been antagonists may result from a reduc- Opioid antagonists such as nal- implicated in penile erection (for tion in the uptake of testosterone.265 oxone and naltrexone hydrochlo- review, see Creed et al6). Erection oc- ride have been used to treat erectile curs when the smooth muscles of the ␥-Aminobutyric Acid dysfunction, but 2 case reports sug- corpus cavernosum relax permitting gest that they may also be used to treat increased blood flow into the penile A previous review of the animal lit- unwanted spontaneous erections.247 tissue. The human corpus caverno- erature suggests that ␥-aminobu- Naltrexone vs placebo significantly in- sum is innervated by cholinergic tyric acid (GABA) activity inhibits

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1021

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 male rat sexual behaviors includ- rats276 and following genital stimu- mation with motivational states), ing mounting, intromitting, erec- lation in male rats,277 and electrical and the activation of the left ante- tion, and ejaculation.166 As human stimulation of the paraventricular rior cingulate cortex (a paralimbic males also engage in analogous be- nucleus elicits penile erections.278 area known to control autonomic haviors, it is possible that GABA in- The paraventricular nucleus is la- and neuroendocrine function).292 To hibits these behaviors in human beled after pseudorabies virus injec- date, no similar studies have been males as well. To our knowledge, no tion into the penis, penile muscles, conducted in females. For a recent studies have been published indi- clitoris, and uterus.269-272 During and more in-depth review of the cating the direct effects of GABA on sexual arousal and orgasm, oxyto- CNS control of sexual behavior, see human sexual behavior, or female rat cin from the paraventricular nucleus McKenna.268 sexual behavior (Table 2). is secreted from the posterior pitu- itary into the blood stream in both CONCLUSIONS THE CNS .279,280 As noted earlier, oxyto- cin injected into the CNS activates We attempted to provide a concise Regions penile erections.113 overview of the endocrine, neuro- transmitter, and CNS influences on The nucleus paragigantocellularis Forebrain sexual desire, arousal, and orgasm that projects directly to pelvic effer- in males and females. Because of an ent and interneurons in the Using Fos staining in copulatory overall scarcity of human studies in lumbosacral spinal cord (the re- tests, the medial amygdala and the this field, and the widely varying gion whereby sexual afferents en- bed nucleus of the stria terminalis methodological quality of those ter the spinal cord)267 has been iden- have been identified as playing a role studies available, in many areas of tified as important in male, and in female sexual behavior.112,281,282 this review the evidence presented possibly female, orgasm.268 Neu- The medial amygdala is believed to appears conflicting and/or incom- rons in this area have been trans- play a role in the control of sexual plete, and we are able to generate neuronally labeled following virus motivation in the male.275,283 Elec- only tentative hypotheses. While be- injection into the penis269 and clito- trical stimulation of the hippocam- ing cognizant of these limitations, we ris,270 and lesions to this area sup- pus has been reported to elicit pe- summarize the findings as follows. press a tonic inhibition of the climax- nile erections,284,285 and stimulation A certain level of testosterone like response.267 Evidence suggests of the septal region has been asso- is necessary for sexual desire in that this region may also play a role ciated with reports of orgasm. In- males above which testosterone lev- in SSRI-induced anorgasmia in males terpretation of such findings are lim- els are unrelated to levels of sexual and females.268 The raphe nuclei pal- ited by the fact that patients were drive. Administration of testoster- lidus, the magnus and parapyrami- experiencing severe neurological and one above this level is ineffective in dal region, and the locus ceruleus all psychiatric conditions. treating hypoactive sexual desire in project to the lumbosacral spinal Electroencephalographic stud- men. Testosterone plays a role in cord and may play a role in sexual ies have shown a pattern of right nocturnal penile tumescence; function.268 The temporal activation in right- whether it influences erectile re- area of the midbrain acts as a relay handed men presented with visual sponses to external stimuli is un- center for sexually relevant stimuli. sexual stimuli.286,287 Right-to-left clear. Testosterone is related to Neurons in this region are labeled hemispheric activity asymmetry was sexual desire in women but the re- following viral injection into the pe- also note during nocturnal penile tu- lationship is not straightforward. nis, penile muscles, clitoris, and mescence.288 A study in right- Many women with hypoactive uterus.269-272 handed men, using single photon sexual desire have normal testoster- emission computed tomography one levels, some women with low Hypothalamus found an increase in right prefron- testosterone levels have normal tal cortex blood flow during or- sexual drive, and a higher testoster- Animal studies indicate that le- gasm.289 Hypersexuality has been as- one level is not usually associated sions to the medial preoptic area, an sociated with the bilateral removal with high libido. Exogenous testos- area that has widespread connec- of temporal lobes,290 and following terone treatment is effective for treat- tions to the limbic system and brain- frontal lobotomy.291 Recently, posi- ing a subset of women with low li- stem,273,274 significantly impairs male tron emission tomography was used bido—most of the research to this copulatory behavior275 by impair- to identify the brain areas activated regard has focused on surgically ing the animal’s ability to recognize in healthy males during visually menopausal women. Laboratory a sexual partner.268 In females, le- evoked sexual arousal.292 Results in- studies and studies of menstrual sions to this area increase lordosis dicated a 3-fold pattern of activa- cycle changes have not consis- behavior but also increase avoid- tion: the bilateral activation of the tently linked testosterone levels with ance of male partners, suggesting a inferior temporal cortex (a visual as- sexual arousal in women. Estro- role in mate selection rather than sociation area), the activation of the gens and progesterone do not seem sexual motivation.268 Neurons in the right insula and right inferior fron- to play a significant role in sexual paraventricular nucleus are acti- tal cortex (paralimbic areas relat- desire for either males or females. vated during in female ing highly processed sensory infor- Estrogen deficiency impairs genital

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1022

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 Table 2. Neurotransmitter (NT) Influences on Sexual Function in Males and Females

Males Females

Change Change Change Change in NT in Sexual Population Sampled/ in NT in Sexual Population Sampled/ Neurotransmitter Level Functioning Study Details Level Functioning Study Details Serotonin Sexual arousal ↑↓MAOI, SSRI, antipsychotic users151-158 ↑↓MAOI, SSRI users151,153 ↓↑Cyproheptadine hydrochloride with antidepressants160 Sexual arousal ↑↓Antipsychotic users151,152 Orgasm ↑↓MAOI, SSRI, antipsychotic users151,158 ↑↓MAOI, SSRI users151,153 ↓↑Cyproheptadine with ↑↑Cyproheptadine with antidepressants160 antidepressants160 ↑↓SSRIs as a treatment for premature ...... ejaculation168-175 Dopamine Sexual desire ↑↑Apomorphine ↑↑Levodopa/carbidopa—patients hydrochloride/levodopa—patients with Parkinson disease with Parkinson disease186-188 (case study)187 Sexual arousal ↑↑Apomorphine/levodopa—Parkinson ...... disease194-196 ↑↑Apomorphine treatment—erectile ...... failure202-203 ↓↑Antipsychotic medication users206-209 ...... ↓↓Antipsychotic medication users204-205 ...... ↑↓Chronic cocaine user216 ...... Orgasm ↑↓High doses and chronic cocaine ↑↓Antipsychotic medication user216 users211-213 Adrenaline Sexual desire ...... ↑↑Normal95 Sexual arousal ↑↓Sexually functional6 ↑↑Normal95,227,228 0 ↑ Viewing an erotic film100 ↑↓Heightened nervous system arousal—(normal and HSDD)230-232 ↑↓Heightened nervous system arousal—(anorgasmic women)232 ↑↓Heightened nervous system arousal232 ↓↓Clonidine user with heightened nervous system arousal229 ↓↓Antipsychotic treatment151 Orgasm ...... ↑↑Normal95 ↓↓Antipsychotic treatment151 Norepinephrine Sexual drive ...... ↑ 0 Hypoactive sexual desire disorder240 Sexual arousal ↑↑Normal105,234,235 ↑↑Normal95,235 ↑↑Yohimbine treatment for ED237-239 Orgasm ↑↑Normal105,234,235 ↑↑Normal95,235 ↑↑Yohimbine treatment for anorgasmia237-239 Acetylcholine Sexual arousal ↑↑Precontracted corpus cavernosum ↓ 0 Atropine administration to tissue256 normal women263 ↑ 0 Corpus cavernosum of men with diabetes mellitus257 ↑↑Bethanechol for antidepressant induced erectile dysfunction258,259 Orgasm ↑↑Bethanechol chloride for ↓ 0 Atropine administration to antidepressant-induced ED258,259 normal women263 Histamine Sexual desire ↓↓Cimetidine and ranitidine users265 ↓↓Cimetidine user (case study)265 Sexual arousal ↑↑Injection into corpus ...... cavernosum—psychogenic impotence266 ↓↓Cimetidine and ranitidine users265 ......

(Continued)

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1023

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 Table 2. Neurotransmitter (NT) Influences on Sexual Function in Males and Females (cont)

Males Females

Change Change Change Change in NT in Sexual Population Sampled/ in NT in Sexual Population Sampled/ Neurotransmitter Level Functioning Study Details Level Functioning Study Details Opioids Sexual desire ↑↓Long-term opiod users244 ↑↓Long-term opiod users244 ↑↓Intraspinal injections245 ↑↑Long-term opiod users244 ↓↑Withdrawal from opiate addiction244 ↓↓Withdrawal from opiate addiction244 ↓↑Naloxone hydrochloride users (1 in 4 women)251 Sexual arousal ↑↓Long-term opiod users244 ↓ 0 Naloxone users251 ↑↓Intraspinal injections245 ↓ 0 Naloxone treatment for arousal disorder252 ↓↑Withdrawal from opiate addiction244 0 ↑ Blood plasma level while viewing an erotic film95 ↓↓Withdrawal from opiate addiction244 ...... ↓↑Naltrexone treatment247 ...... ↓↑Naltrexone treatment for erectile ...... failure248-250 ↓↑Naloxone in men with normal ...... erectile functioning251 0 ↑ Blood plasma level while viewing an ...... erotic film100,105 Orgasm ↑↓Long-term opiod users244 ↑↓Long-term opiod users244 ↓↑Withdrawal from opiate addiction244 0 ↑ Blood plasma level while viewing an erotic film95 ↓↓Withdrawal from opiate addiction244 ...... 0 ↑ Blood plasma level while viewing an ...... erotic film105

*↑indicates increase; ↓, decrease; ellipsis, not applicable; MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor; 0, no change; HSDD, hypoactive sexual desire disorder; and ED, erectile dysfunction.

vasocongestion and lubrication in fe- arousal disorder is under way. Find- ␣1-receptors produces erection. In males and this may adversely influ- ings from animal studies suggest se- women, by contrast, adrenergic ac- ence sexual arousal and desire. Find- rotonin may facilitate, inhibit, or tivation facilitates vasocongestion ings from uncontrolled studies and have no effect on sexual behavior de- and suppression of adrenergic ac- animal studies tentatively suggest pending on which serotonin recep- tivity impairs sexual arousal and or- prolactin may have an inhibitory in- tor subtype is involved. Studies on gasm. Norepinephrine levels in- fluence on drive in males and fe- the effects of antidepressants on hu- crease during sexual arousal in men males. Controlled human studies man sexual function suggest activa- and women. Minimal research sug- suggest the levels of prolactin and tion of the serotonin2 receptor im- gests increasing the level of NE may oxytocin increase during sexual pairs all stages of the sexual response facilitate erectile responding in men; arousal in men and women. Abnor- in males and females. Case reports comparable studies have not been mally high levels of cortisol de- in males showing a facilitatory in- conducted in women. Long-term crease sexual drive in men and fluence of antiparkinsonian medi- opioid use impairs erection in men women possibly owing to in- cations (which enhance dopamine possibly via suppression of circulat- creased corticotropin-releasing hor- activity) and an inhibitory influ- ing hormones such as testosterone. mone. Minimal research on phero- ence of antipsychotic medications Case reports indicate opioid antago- mones and sexual response suggest (which suppress dopamine activ- nists may restore erectile function- a facilitatory influence on sexual at- ity) on desire and erection argue for ing in dysfunctional men. Limited tractiveness in men. a facilitatory influence of dopamine studies suggest opioids have an Nitric oxide (via the conver- on male sexual behavior. Research analogous effect in women. Acetyl- sion of guanosine triphosphate to in male rats indicating dopamine fa- choline facilitates penile erection via cGMP) is essential for penile and cilitates sexual drive, erection, and the relaxation of smooth muscles of possibly clitoral vasocongestion. ejaculation corroborates these hu- the corpus cavernosum. The role of Sildenafil prolongs the action of man findings. Limited research con- acetylcholine in female vasoconges- cGMP and is effective in treating ducted in females suggests a facili- tion is unknown. Case studies sug- erectile dysfunction of organic, psy- tatory role of dopamine on sexual gest histamine facilitates erection in chogenic, and mixed causes. Re- desire and orgasm. Adrenergic ac- men with erectile failure. One com- search on the effectiveness of silde- tivity (ephedrine) inhibits erectile re- parable case study has been re- nafil treatment for female sexual sponding in men and blockade of ported in women. The H2 and pos-

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1024

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 20. Udry JR, Billy JO, Morris NM, Groff TR, Raj MH. sibly H3 receptors have been Corresponding author: Cindy M. implicated. Animal studies indicate Meston, PhD, University of Texas at Serum androgenic hormones motivate sexual be- havior in adolescent boys. Fertil Steril. 1985;43: an inhibitory influence of GABA on Austin, Department of Psychology, 90-94. male sexual responding. Studies ex- Mezes Hall 330, Austin, TX 78712. 21. Halpern CR, Udry JR, Suchindran C. Monthly amining the effects of GABA on hu- measures of salivary testosterone predict sexual man sexual behavior have not been activity in adolescent males. Arch Sex Behav. REFERENCES conducted. 1998;27:445-465. 22. Schiavi RC, White D. Androgen and male sexual To date, only one study of neu- function: A review of human studies. J Sex Mari- roanatomical activation in human 1. Pfaus JG. Neurobiology of sexual behavior. Curr tal Ther. 1976;2:214-228. following laboratory- Opin Neurobiol. 1999;9:751-758. 23. Flynn MA, Weaver-Osterholtz D, Sharpe- 2. Masters WH, Johnson VE. Human Sexual Re- Timms KL, Allen S, Krause G. Dehydroepiandros- evoked sexual arousal has been con- sponse. Boston, Mass: Little Brown & Co Inc; ducted. This study found sexual terone replacement in aging humans. J Clin En- 1966. docrinol Metab. 1999;84:1527-1533. 3. Kaplan HS. Disorders of Sexual Desire. New York, arousal in males to be associated 24. O’Carroll R, Shapiro C, Bancroft J. Androgens, NY: Brunner/Mazel Inc; 1979. with bilateral activation of the infe- behavior and nocturnal erection in hypogo- 4. Leiblum SR. Definition and classification of fe- rior temporal cortex, the right insu- nadal men: the effects of varying the replace- male sexual disorders. Int J Impot Res. 1998; ment dose. Clin Endocrinol. 1985;23:527-538. lar and inferior frontal cortex, and 10(suppl 2):S104-S106. 25. Alexander GM, Swerdloff RS, Wang CW, Dav- the left anterior cingulate cortex. 5. Kloner RA, Jarow JP. Erectile dysfunction and idson T. Androgen-behavior correlations in hy- sildenafil citrate and cardiologists. Am J Car- This review focused on the in- pogonadal men and eugonadal men, I: mood and diol. 1999;83:576-582. dependent influences of endocrine, response to auditory sexual stimuli. Horm Be- 6. Creed KE, Carati CJ, Keogh EJ. The physiology hav. 1997;31:110-119. neurotransmitter, and CNS factors on of penile erection. Rev Reprod Biol. 1991;13: 26. Bancroft J, Wu FCW. Changes in erectile respon- sexual function. However, these sys- 73-95. siveness during androgen replacement therapy. tems also interact with one another 7. Levin RJ. The mechanisms of human female sexual Arch Sex Behav. 1983;12:59-66. arousal. Annu Rev Sex Res. 1992;3:1-48. to affect sexual functioning. For ex- 27. O’Carroll RE, Bancroft J. Testosterone therapy ample, when the level of testoster- 8. Kim N. Regulation of smooth muscle contrac- tility: organ bath studies. Paper presented at: Bos- for low sexual interest and erectile dysfunction one is increased in the medial pre- ton University School of Medicine and the De- in men: a controlled study. Br J Psychiatry. 1984; optic area, it increases NO release partment of Urology Conference: New 145:146-151. that, in turn, facilitates dopamine re- Perspectives in the Management of Female 28. Waxenberg SE, Drellich MG, Sutherland AM. The role of hormones in human behavior, I: changes lease. If testosterone or NO release is Sexual Dysfunction; October 23, 1998; Burling- ton, Mass. in female sexuality after adrenalectomy. J Clin disrupted, normal sexual behavior, 9. Schiavi RC, Segraves RT. The biology of sexual Endocrinol. 1959;19:193-202. resulting from dopamine release, is function. Psychiatr Clin North Am. 1995;18:7-23. 29. Drellich MG, Waxenberg SE. Erotic and affec- impaired in male rats.293 Similarly, in- 10. Rosen RC, Beck JG. Patterns of Sexual Arousal: tional components of female sexuality. In: Masser- creased prolactin activity results in Psychophysiological Processes and Clinical Ap- man J, ed. Science and Psychoanalysis. New York, plications. New York, NY: Guilford Press; 1988. NY: Grune & Stratton Inc; 1966:192-217. decreased dopamine activity in the 30. Gorzynski G, Katz JL. The polycystic ovary syn- 294 11. Meston CM. The psychophysiological assess- medial preoptic area and it has been ment of female sexual function. J Sex Educ Ther. drome: psychosexual correlates. Arch Sex Be- suggested that prolactin antago- 2000;25:6-16. hav. 1977;6:215-222. nism of dopamine may be respon- 12. Meston CM, Gorzalka BB. The effects of sym- 31. Schreiner-Engel P, Schiavi RC, White D, Ghiz- pathetic activation on physiological and subjec- zani A. Low sexual desire in women: the role of sible for the refractory period in reproductive hormones. Horm Behav. 1989;23: 295 tive sexual arousal in women. Behav Res Ther. males. Serotonin administration to 1995;33:651-664. 221-234. the lateral hypothalamic area pro- 13. Meston CM, Gorzalka BB. The differential ef- 32. Leiblum S, Bachmann G, Kemmann E, Colburn duces a suppression of normal do- fects of sympathetic activation on sexual arousal D, Schwartzman L. Vaginal atrophy in the post- pamine release in the nucleus accum- in sexually functional and dysfunctional women. menopausal woman: the importance of sexual activity and hormones. JAMA. 1983;249:2195- bens of the male rat.296 A previous J Abnorm Psychol. 1996;105:582-591. 14. Meston CM, Heiman JR, Trapnell PD, Paulhus 2198. review of the male rat literature sug- DL. Socially desirable responding and sexuality 33. Sherwin BB. Changes in sexual behavioral as a gests contradictory evidence that self-reports. J Sex Res. 1998;35:148-157. function of plasma sex steroid levels in post- gonodal hormones and serotonin in- 15. Davidson JM, Kwan M, Greenleaf WJ. Hor- menopausal women. Maturitas. 1985;7:225- teract to affect sexual function- monal replacement and sexuality. Clin Endocri- 233. 166 nol Metab. 1982;11:599-623. 34. Sherwin BB, Gelfand MM, Brender W. Andro- ing. Previous reviews of the fe- 16. Kwan M, Greenleaf WJ, Mann J, Crapo L, gen enhances sexual motivation in females: a pro- male rat literature suggest that all Davidson JM. The nature of androgen action on spective, crossover study of sex steroid admin- lordosis-facilitating agents (eg, ␣1- male sexuality: a combined laboratory/self- istration in the surgical menopause. Psychosom adrenergic agonists) require initial es- report study on hypogonadal men. Clin Endo- Med. 1985;47:339-351. trogen priming to effectively pro- crinol Metab. 1983;57:557-562. 35. Sherwin BB. The free testosterone index as a pre- 17. Skakkeoaek NE, Bancroft J, Davidson DW, dictor of sexual behavior in postmenopausal duce the lordosis response and Warner P. Androgen replacement with oral tes- women receiving hormone replacement therapy estrogen affects noradrenaline and se- tosterone undecanoate in hypogonodal men: a [abstract]. In: Program and abstracts of the Sev- rotonin turnover.297,298 To our knowl- double-blind controlled study. Clin Endocrinol. enth Conference of the Society for Menstrual edge, no studies have been pub- 1981;14:49-61. Cycle Research; 1987; Ann Arbor, Mich. Ab- 18. Gooren L. Hypogonadotropic hypogonadal men stract. lished in the human literature respond less well to androgen substitution treat- 36. McCoy N, Davidson JM. A longitudinal study of examining the interaction between ment than hypergonadotropic hypogonadal men. the effects of menopause on sexuality. Maturi- hormones, neurotransmitters, and Arch Sex Behav. 1988;17:265-270. tas. 1985;7:203-210. neuropeptides. 19. Halpern CT, Udry JR, Campbell B, Suchindran 37. Van Goozen SHM, Frijda NH, Wiegant VM, Endert C, Mason GA. Testosterone and religiosity as pre- E, Van de Poll NE. The premenstrual phase and dictors of sexual attitudes and activity among reactions to aversive events: a study of hor- Accepted for publication August 4, adolescent males: a biosocial model. J Biosoc monal influences on emotionality. Psychoneu- 2000. Sci. 1994;26:217-234. roendocrinology. 1996;21:479-497.

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1025

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 38. Persky H, Lief HI, Strauss D, Miller WR, O’Brien cal symptoms in postmenopausal women. Acta 77. Bancroft J. Hormones and human sexual behav- CP. Plasma testosterone level and sexual behav- Obstet Gynecol Scand. 1984;63:655-661. ior. J Sex Martial Ther. 1984;10:3-21. ior in couples. Arch Sex Behav. 1978;7:157-173. 57. Nathorst-Boos J, von Schoultz B, Carlstrom K. 78. Bancroft J, O’Carroll R, McNeilly A, Shaw R. The 39. Bancroft J, Sanders D, Davidson D, Warner P. Elective ovarian removal and estrogen replace- effects of bromocriptine on the sexual behavior Mood, sexuality, hormones, and the menstrual ment therapy: effects on sexual life, psychologi- of a hyperprolactinaemic man: a controlled case cycle; III: sexuality and the role of androgens. Psy- cal well-being and androgen status. J Psycho- study. Br J Psychiatry. 1984;21:131-137. chosom Med. 1983;45:509-516. som Obstet Gynaecol. 1993;14:283-293. 79. Buckman MT, Kellner R. Reduction of distress 40. Udry JR, Talbert LM, Morris NM. Biosocial foun- 58. Salmon UJ, Geist SH. Effect of androgens upon in hyperprolactinemia with bromocriptine. Am dations for adolescent female sexuality. Demog- libido in women. J Clin Endocrinol. 1943;3:235- J Psychiatry. 1984;6:351-358. raphy. 1986;23:217-230. 238. 80. Dornan WA, Malsbury CW. Neuropeptides and 41. Halpern CT, Udry JR, Suchindran C. Testoster- 59. Dennerstein L, Burrows GD. Hormone replace- male sexual behavior. Neurosci Biobehav Rev. one predicts initiation of coitus in adolescent fe- ment therapy and sexuality in women. Clin En- 1989;13:1-15. males. Psychosom Med. 1997;59:161-171. docrinol Metab. 1982;11:661-679. 81. Muller P, Musch K, AS. Prolactin: vari- 42. Stuart FM, Hammond DC, Pett MA. Inhibited 60. Dennerstein L, Burrows GD, Wood C, Hyman G. ables of personality and sexual behavior. In: sexual desire in women. Arch Sex Behav. 1987; The effect of estrogen and progestogen. Obstet Zichella L, Pancheri P, eds. Psychoneuroendo- 16:91-106. Gynecol. 1980;56:316-322. crinology in Reproduction. Amsterdam, the Neth- 43. Redmond G. Testosterone and female sexual dys- 61. Sherwin B. The psychoendocrinology of aging erlands: Elsevier/North Holland Biomedical Press; function. Paper presented at: Boston University and female sexuality. Annu Rev Sex Res. 1991; 1979:357-372. School of Medicine and the Department of Urol- 2:181-198. 82. Schwartz MF, Bauman JE, Masters WH. Hyper- ogy Conference: New Perspectives in the Man- 62. Heller CG, Laidlaw WM, Harvey HT, Nelson WO. prolactinemia and sexual disorders in men. Biol agement of Female Sexual Dysfunction; Octo- Effects of progestational compounds on the re- Psychiatry. 1982;17:861-876. ber 23, 1998; Burlington, Mass. productive processes of the human male. Ann 83. Franks S, Jacobs HS, Martin N, Nabarro JDN. Hy- 44. Schreiner-Engel P, Schiavi RC, Smith H, White N Y Acad Sci. 1958;71:649-665. perprolactinaemia and impotence. Clin Endocri- D. Sexology: sexual biology, behavior and 63. Money J. Use of an androgen-depleting hor- nol. 1978;8:277-287. therapy. In: Hoch Z and Lief HI, eds. Selected Pa- mone in the treatment of male sex offenders. 84. Koppelman MCS, Parry BL, Hamilton JA, Al- pers Of The Fifth World Congress Of Sexology. J Sex Res. 1970;6:165-172. agna SW, Loriaux DL. Effect of bromocriptine on Amsterdam, the Netherlands: Exerpta Medica; 64. Huffer V, Levin L, Aronson H. Oral contracep- mood, affect and libido in hyperprolactinemia. 1982:88-92. 1982:165. tives: depression and frigidity. J Nerv Ment Dis. Am J Psychiatry. 1987;144:1037-1041. 45. Meuwissen I, Over R. Sexual arousal across 1970;151:35-41. 85. Gooren L. Preliminary evidence that not prolac- phases of the human menstrual cycle. Arch Sex 65. Kane FJ, Lipton MA, Ewing JA. Hormonal influ- tin itself, but the underlying dopaminergic dys- Behav. 1992;21:101-119. ences in female sexual response. Arch Gen Psy- regulation causes male sexual dysfunction in the 46. Schreiner-Engel P, Schiavi RC, Smith J, White chiatry. 1979;20:202-209. cases of hyperprolactinemia. Paper presented at: D. Sexual arousability and the menstrual cycle. 66. Warner P, Bancroft J. Mood, sexuality, oral con- International Academy of Sex Research, Au- Psychosom Med. 1981;43:199-214. traceptives and the menstrual cycle. J Psycho- gust 16, 1986; Amsterdam, the Netherlands. 47. Meston CM, Heiman JR. Acute DHEA effects on som Res. 1988;32:417-427. 86. Kayner CE, Zager JA. Breast-feeding and sexual sexual arousal in premenopausal women. J Sex 67. McCullough RC. Rhythms of sexual desire and response. J Fam Pract. 1983;17:69-73. Marital Ther. In press. sexual activity in the human female [abstract]. Dis- 87. Fava GA, Fava M, Kellner R, Serafini E, Mastro- 48. Hackbert L, Heiman JR, Meston CM. The ef- sertation Abstracts Int. 1974;34:4669B-4670B. giacomo I. Depression, hostility and anxiety in fects of DHEA on sexual arousal in postmeno- 68. Greenblatt RB, Mortara F, Torpin R. Sexual li- hyperprolactinemic amenorrhea. Psychother Psy- pausal women. Paper presented at: Annual Meet- bido in the female. Am J Obstet Gynecol. 1942; chosom. 1981;36:122-128. ing of the International Academy of Sex Research; 44:658-663. 88. Waterman GS, Dahl RE, Birmaher B, Ambrosini June 24, 1998; Stony Brook, NY. 69. Bakke J. A double-blind study of a progestin- P, Rabinovich H, Williamson D, Novacenko H, 49. Bancroft J, Tennent G, Loucas K, Cass J. The con- estrogen combination in the management of the Nelson B, Puig-Antich J, Ryan ND. The 24-hour trol of deviant sexual behavior by drugs, I: be- menopause. Pacific Med Surg. 1965;73:200-205. pattern of prolactin secretion in depressed and havioral changes following oestrogens and anti- 70. Persky J, O’Brien CP, Kahn MA. Reproductive normal adolescents. Biol Psychiatry. 1994;35: androgens. Br J Psychiatry. 1974;125:310- hormone levels, sexual activity and moods dur- 440-445. 315. ing the menstrual cycle. Psychosom Med. 1976; 89. Besser GM, Thorner MO. Prolactin and gonadal 50. Cooper AJ. Progestogen in the treatment of male 38:62-63. function. Pathol Biol (Paris). 1975;23:779-794. sex offenders: a review. Can J Psychiatry. 1986; 71. Persky H, Charney N, Lief HL, O’Brien CP, Miller 90. Buvat J, Ashour M, Buvat-Heraut M, Fossati P. 31:73-79. WR, Strauss D. The relationship of plasma es- Prolactin and human sexual behavior. In: Rubin 51. Field LH, Williams M. The hormonal treatment tradiol level to sexual behavior in young women. C, Harter M,eds. Progress in Prolactin Physiol- of sexual offenders. Med Sci Law. 1970;10:27- Psychosom Med. 1978;40:523-535. ogy and Pathology. Amsterdam, the Nether- 34. 72. Utian WH. The true clinical features of post- lands: Elsevier/North Holland Biomedical Press; 52. Benedek T, Rubenstein BB. The correlations be- menopause and oophorectomy and their re- 1978:258-264. tween ovarian activity and psychodynamic pro- sponse to oestrogen therapy. S Afr Med J. 1972; 91. Horrobin DF. Prolactin and mental illness. Br J cesses, II: the menstrual phase. Psychosom Med. 46:732-737. Psychol. 1974;124:456-458. 1939;1:461-485. 73. Campbell S. Double-blind psychometric stud- 92. Legros J, Mormot C, Servalis J. A psychoendo- 53. Dennerstein L, Gotts G, Brown JB, Morse CA, Far- ies on the effects of natural estrogens on post- crine study of erectile psychogenic impotence: ley TM, Pinol A. The relationship between the menopausal women. In: Campbell S, ed. The a comparison between normal patients and pa- menstrual cycle and female sexual interest in Management of the Menopausal and Post- tients with abnormal glucose tolerance test. In: women with PMS complaints and volunteers. Menopausal Years. Baltimore, Md: University Carenza L, Pancheri P, Zichella L, eds. Clinical Psychoneuroendocrinology. 1994;19:293-304. Park Press; 1976:149-158. Psychoneuroendocrinology and Reproduction. 54. Abplanalp JM, Rose RM, Donnelly AF, Livingstone- 74. Coope J. Double-blind cross-over study of es- New York, NY: Academic Press Inc; 1992:301- Vaughan L. Psycho-endocrinology of the men- trogen replacement. In: Campbell S, ed. The Man- 319. strual cycle, II: the relationship between enjoy- agement of the Menopausal and Post- 93. Deutsch S, Sherman L. Hypoprolactinaemia in ment of activities, moods and reproductive Menopausal Years. Baltimore, Md: University men with secondary sexual impotence and men hormones. Psychosom Med. 1979;41:605-615. Park Press; 1976:159-168. with premature ejaculation [abstract]. In: Endo- 55. Burger HG, Hailes J, Menelaus M, Nelson J, 75. Campbell S, Whitehead M. Oestrogen therapy and crinology Society Meeting Abstracts. New York, Hudson B, Balazs N. The management of the menopausal syndrome. Clin Obstet Gyne- NY: Endocrinology Society; 1979:350. persistent menopausal symptoms with col. 1977;4:31-47. 94. Muller P, Musch K, Wolf AS. Prolactin variables oestradiol-testosterone implants: clinical, lipid 76. Studd JWW, Collins WP, Chakravarti S, New- in personality and sexual behavior. In: Zichella and hormonal results. Maturitas. 1984;6:351- ton JR, Oram D, Parsons A. Oestradiol and tes- L, Pancheri P, eds. Psychoneuroendocrinology 358. tosterone implants in the treatment of psycho- in Reproduction. Amsterdam, the Netherlands: 56. Furuhjelm M, Karlgren E, Carlstrom K. The ef- sexual problems in the postmenopausal woman. Elsevier/North-Holland Biomedical Press; 1979: fect of estrogen therapy on somatic and psychi- Br J Obstet Gynaecol. 1977;84:314-315. 359-372.

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1026

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 95. Exton MS, Bindert A, Kruger T, Scheller F, Hart- drome: relationship to cortisol and adrenocor- 135. Ballard SA, Gingell CJ, Tang K, Turner LA, Price mann U, Schedlowski M. Cardiovascular and en- ticotropic hormone levels. Arch Intern Med. 1981; ME, Naylor AM. Effects of sildenafil on the re- docrine alterations after masturbation-induced 141:215-219. laxation of human corpus cavernosum tissue in orgasm in women. Psychosom Med. 1999;61: 116. Gold PW, Kling MA, Khan I, Calabrese JR, Kalo- vitro and on the activities of cyclic nucleotide 280-289. geras K, Post RM, Avgerinos PC, Loriaux DL, phosphodiesterase isozymes. J Urol. 1998;159: 96. Drago F. Prolactin and sexual behavior: a re- Chrousos GP. Corticotropin-releasing hor- 2164-2171. view. Neurosci Biobehav Rev. 1984;8:433-439. mone: relevance to normal physiology and to the 136. Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, 97. Rowland DL, Heiman JR, Gladue BA, Hatch JP, pathophysiology and differential diagnosis of hy- Muirhead GJ, Naylor AM, Osterloh IH, Gengell Doering CH, Weiler SJ. Endocrine, psychologi- percortisolism and adrenal insufficiency. Adv Bio- JC. Sildenafil: an orally active type 5 cyclic GMP- cal, and genital response to sexual arousal in men. chem Psychopharmacol. 1987;43:183-200. specific phosphodiesterase inhibitor for the treat- Psychoneuroendocrinology. 1987;12:149-158. 117. Nieman LK, Chrousos GP, Kellner C, Spitz IM, Ni- ment of penile erectile dysfunction. Int J Impot 98. La Ferla J, Anderson D, Schalch D. Psychoen- sula BC, Cutler GB, Merriam GR, Bardin CW, Lori- Res. 1996;8:47-52. docrine response to sexual arousal in human aux DL. Successful treatment of Cushing’s syn- 137. Montorsi F, McDermott TE, Morgan R, Olsson males. Psychosom Med. 1978;40:166-172. drome with the glucocorticoid antagonist RU 486. A, Schultz A, Kirkeby HJ, Osterloh IH. Efficacy 99. Stoleru SG, Ennaji A, Counot A, Spira A. LH pul- J Clin Endocrinol Metab. 1985;61:536-540. and safety of fixed-dose oral Sildenafil in the treat- satile secretion and testosterone blood levels are 118. Kennedy SH, Dickens SE, Eisfeld BS, Bagby RM. ment of erectile dysfunction of various etiolo- influenced by sexual arousal in human males. Sexual dysfunction before antidepressant therapy gies. Urology. 1999;53:1011-1018. Psychoneuroendocrinology. 1993;18:205-218. in major depression. J Affect Disord. 1999;56: 138. Dinsmore WW, Hodges M, Hargreaves C, Os- 100. Carani C, Bancroft J, Del Rio G, Granata ARM, 201-208. terloh IH, Smith MD, Rosen RC. Sildenafil ci- Facchinetti F, Marrama P. The endocrine ef- 119. Exton NG, Truong TC, Exton MS, Wingenfeld SA, trate (Viagra) in erectile dysfunction: near nor- fects of visual erotic stimuli in normal men. Psy- Leygraf N, Saller B, Hartmann, U, Schedlowski malization in men with broad-spectrum erectile choneuroendocrinology. 1990;15:207-216. M. Neuroendocrine response to film-induced dysfunction compared with age-matched healthy 101. Purvis K, Landgren B, Cekan Z, Diczfalusy E. En- sexual arousal in men and women. Psychoneu- control subjects. Urology. 1999;53:800-805. docrine effects of masturbation in men. J Endo- roendocrinology. 2000;25:187-199. 139. Marks LS, Duda C, Dorey FJ, Macairan ML, San- crinol. 1976;70:439-444. 120. Ismail AAA, Davidson DW, Loraine JA, Fox CA. tos PB. Treatment of erectile dysfunction with 102. Brown WA, Heninger G. Cortisol, growth hor- Relationship between plasma cortisol and hu- sildenafil. Urology. 1999;53:19-24. mone, free fatty acids, and experimentally evoked man sexual activity. Nature. 1972;237:288- 140. Padma-Nathan H, Steers WD, Wicker PA. Effi- affective arousal. Am J Psychol. 1975;132:1172- 289. cacy and safety of oral sildenafil in the treat- 1176. 121. Granata A, Bancroft J, Del Rio G. Stress and the ment of erectile dysfunction: a double-blind, pla- 103. Lee R, Jaffe R, Midgley A. Lack of alteration of erectile response to intracavernosal prostaglan- cebo-controlled study of 329 patients. Int J Clin

serum gonadotropins in men and women fol- din E1 in men with erectile dysfunction. Psycho- Pract. 1998;52:375-379. lowing sexual intercourse. Am J Obstet Gyne- som Med. 1995;57:336-344. 141. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, col. 1974;120:985-987. 122. Cohn BA. In search of human skin pheromones Steers WD, Wicker PA. Oral sildenafil in the treat- 104. Lincoln G. Luteinizing hormone and testoster- [a review]. Arch Dermatol. 1994;130:1048- ment of erectile dysfunction. N Engl J Med. 1998; one in man. Nature. 1974;252:232-233. 1051. 338:1397-1404. 105. Kruger T, Exton MS, Pawlak C, von zur Muhlen 123. Garcia-Welasco J, Mondragon M. The inci- 142. Derry FA, Dinsmore WW, Fraser M, Gardner BP, A, Hartmann U, Schedlowski M. Neuroendo- dence of the vomeronasal organ in 1000 hu- Glass CA, Maytom MC, Smith MD. Efficacy and crine and cardiovascular response to sexual man subjects and its possible clinical signifi- safety of oral sildenafil (Viagra) in men with erec- arousal and orgasm in men. Psychoneuroendo- cance. J Steroid Biochem Mol Biol. 1991;39: tile dysfunction caused by spinal cord injury. Neu- crinology. 1998;23:401-411. 561-563. rology. 1998;51:1629-1633. 106. Carmichael MS, Humbert R, Dixen J, Palm- 124. McClintock, MK. Menstrual synchrony and sup- 143. Giuliano F, Hultling C, El Masry WS, Smith MD, isano G, Greenleaf W, Davidson JM. Plasma oxy- pression. Nature. 1971;229:244-245. Osterloh IH, Orr H, Maytom M. Randomized trial tocin increases in the human sexual response. 125. Cutler WB, Garcia CR, Krieger AM. Sexual be- of sildenafil for treatment of erectile dysfunction J Endocrinol Metab. 1987;64:27-31. havior frequency and menstrual cycle length in in spinal cord injury. Ann Neurol. 1999;46:15-21. 107. Carmichael MS, Warburton VL, Dixen J, David- mature premenopausal women. Psychoneuro- 144. Park K, Moreland RB, Goldstein I, Atala A, Traish son JM. Relationships among cardiovascular, mus- endocrinology. 1979;4:297-309. A. Sildenafil inhibits phosphodiesterase type 5 cular, and oxytocin responses during human sexual 126. Cutler WB, McCoy N, Davidson JM. Sexual be- in human clitoral corpus cavernosum smooth activity. Arch Sex Behav. 1994;23:59-77. havior, steroids and hot flashes are associated muscle. Biochem Biophys Res Comm. 1998; 108. Murphy MR, Seckl JR, Burton S, Checkley SA, during the perimenopause [letter]. Neuroendo- 249:612-617. Lightman SL. Chances in oxytocin and vaso- crinol Lett. 1983;5:185. 145. Laan E, van Lunsen RHW, Everaerd W, Heiman pressin secretion during sexual activity in men. 127. Cutler WB, Preti G, Huggins GR, Erickson B, Gar- JR, Hackbert L. The effects of sildenafil on wom- J Clin Endocrinol. 1987;65:738-741. cia CR. Sexual behavior frequency and biphasic en’s genital and subjective sexual response. Pa- 109. Blaicher W, Gruber D, Bieglmayer C, Blaicher AM, ovulatory-type menstrual cycles. Physiol Be- per presented at: 26th Annual Meeting of the In- Knogler W, Huber JC. The role of oxytocin in re- hav. 1985;34:805-810. ternational Academy of Sex Research; Paris, lation to female sexual arousal. Gynecol Obstet 128. McCoy N, Cutler W, Davidson JM. Relation- France; June 23, 2000. Invest. 1999;47:125-126. ships among sexual behavior, hot flashes, and 146. Ashton AK. Sildenafil treatment of paroxetine- 110. Anderson-Hunt M, Dennerstein L. Increased fe- hormone levels in perimenopausal women. Arch induced anorgasmia in woman [letter]. Am J Psy- male sexual response after oxytocine [edito- Sex Behav. 1985;14:385-394. chiatry. 1999;156:800. rial]. BMJ. 1994;309:929. 129. Cutler WB, Friedmann E, McCoy NL. Pheromo- 147. Ashton AK, Bennett RG. Sildenafil treatment of 111. Anderson-Hunt M, Dennerstein L. Oxytocin and nal influences on sociosexual behavior in men. serotonin reuptake inhibitor-induced sexual dys- female sexuality. Gynecol Obstet Invest. 1995; Arch Sex Behav. 1998;27:1-13. function [letter]. J Clin Psychiatry. 1999;60:194- 40:217-221. 130. Burnett AL. Role of nitric oxide in the physiol- 195. 112. Turner RA, Altemus M, Enos T, Cooper B, ogy of erection. Biol Reprod. 1995;52:485-489. 148. Nurnberg HG, Hensley PL, Lauriello J, Parker LM, McGuinnesss T. Preliminary research on plasma 131. Burnett AL. Nitric oxide in the penis: physiology Keith SJ. Sildenafil for women patients with an- oxytocin in normal cycling women: investigat- and pathology. J Urol. 1997;157:320-324. tidepressant-induced sexual dysfunction. Psy- ing emotion and interpersonal distress. Psychia- 132. Burnett AL, Calvin DC, Silver RI, Peppas DS, chiatr Serv. 1999;50:1076-1078. try. 1999;62:97-112. Docimo SG. Immunohistochemical description 149. Basson R, McKinnis R, Smith M, Hodgson G, 113. Carter CS. Oxytocin and sexual behavior. Neu- of nitric oxide synthase isoforms in human cli- Spain T, Koppiker N. Efficacy and safety of silde- rosci Biobehav Rev. 1992;16:131-144. toris. J Urol. 1997;158:75-78. nafil in estrogenized women with sexual dys- 114. Starkman MN, Schteingart DE, Schork MA. De- 133. Toesca A, Stolfi VM, Cocchia D. Immunohisto- function associated with female sexual arousal pressed mood and other psychiatric manifesta- chemical study of the corpora cavernosa of the hu- disorder. Abstract presented at: Annual Meet- tions of Cushing’s syndrome: relationship to hor- man clitoris. J Anat. 1996;188(Pt 3):513-520. ing of the American College of Obstetrics and Gy- mone levels. Psychosom Med. 1981;43:3-18. 134. Beavo JA. Cyclic nucleotide phosphodiester- necologists; San Fransisco, Calif; May 23, 2000. 115. Starkman MN, Schteingart DE. Neuropsychiat- ases: functional implications of multiple iso- 150. Kaplan SA, Reis RB, Kohn IJ, Ikeguchi EF, Laor ric manifestations of patients with Cushing’s syn- forms. Physiol Rev. 1995;75:725-748. E, Te AE, Martins AC. Safety and efficacy of sil-

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1027

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 denafil in postmenopausal women with sexual double-blind, randomized, dose-response study. dotic responding on proestrus. Neuroendocri- dysfunction. Urology. 1999;53:481-486. Br J Urol. 1997;79:592-595. nology. 1993;57:946-954. 151. Meston CM, Gorzalka BB. Psychoactive drugs and 169. Ludovico GM, Corvasce A, Pagliarulo G, Cirillo- 186. Courty E, Durif F, Zenut M, Courty P, Lavarenne human sexual behavior: the role of serotoner- Marucco E, Marano A, Pagliarulo A. Paroxetine J. Psychiatric and sexual disorders induced by gic activity. J Psychoactive Drugs. 1992;24:1- in the treatment of premature ejaculation. Br J apomorphine in parkinson’s disease. Clin Neu- 40. Urol. 1996;77:881-882. ropharmacol. 1997;20:140-147. 152. Aizenberg D, Zemishlany Z, Dorfman-Etrog P, 170. McMahon CG, Touma K. Treatment of prema- 187. Uitti RJ, Tanner CM, Rajput AH, Goetz CG, Kla- Weizman A. Sexual dysfunction in male schizo- ture ejaculation with paroxetine hydrochloride as wans HL, Thiessen B. Hypersexuality with anti- phrenic patients. Clin Psychiatry. 1995;56:4: needed: 2 single-blind placebo controlled cross- parkinsonian therapy. Clin Neuropharmacol. 137-141. over studies. J Urol. 1999;161:1826-1830. 1989;12:375-383. 153. Rosen R, Lane R, Menza M. Effects of SSRIs on 171. McMahon CG. Treatment of premature ejacula- 188. Goodwin FK. Psychiatric side effects of le- sexual function: a critical review. Clin Psycho- tion with sertraline hydrochloride: a single- vodopa in man. JAMA. 1971;218:1915-1920. pharmacol. 1999;19:67-85. blind placebo controlled crossover study. J Urol. 189. Melis MR, Argiolas A. Dopamine and sexual be- 154. Feiger A, Kiev A, Shrivastava RK, Wisselink PG, 1998;159:1935-1938. havior. Neurosc Biobehav Rev. 1995;19:19-38. Wilcox CS. Nefazodone versus sertraline in out- 172. Biri H, Isen K, Sinik, Z, Onaran M, Kupeli B, Boz- 190. Clark JT, Stefanick ML, Smith ER, Davidson JM. patients with major depression: focus on effi- kirli I. Sertraline in the treatment of premature Further studies on alterations in male rat copu- cacy, tolerability, and effects on sexual function ejaculation: a double-blind, placebo controlled latory behavior induced by the dopamine- and satisfaction. J Clin Psychiatry. 1996;57 study. Int Urol Nephrol. 1998;30:611-615. receptor agonists RDS-127. Pharmacol Bio- (suppl 2):53-62. 173. Kim SW, Paick JS. Short-term analysis of the ef- chem Behav. 1983;19:781-786.

155. Montejo-Gonzalez AL, Llorca G, Izquierdo JA, fects of as needed use of sertraline at 5 pm for 191. Foreman MM, Hall JL. Effects of D2-dopaminer- Ledesma A, Buosono M, Calcedo A, Carrasco JL, the treatment of premature ejaculation. Urol- gic receptor stimulation on male rat sexual be- Ciudad J, Daniel E, De La Gandara J, Derecho J, ogy. 1999;54:544-547. havior. J Neural Transm. 1987;68:153-170. Franco M, Gomez MJ, Macias JA, Martin T, Perez 174. Kara H, Aydin S, Yucel M, Agargun MY, Odabas 192. Hull EM, Bitran D, Pehek EA, Warner RK, Band V, Sanchez JM, Sanchez S, Vicens E. SSRI- O, Yilmaz Y. The efficacy of fluoxetine in the treat- LC, Holmes GM. Dopaminergic control of male Induced sexual dysfunction: fluoxetine, parox- ment of premature ejaculation: a double-blind pla- sex behavior in rats: effects of an intracerebrally- etine, sertraline, and fluvoxamine in a prospec- cebo controlled study. J Urol. 1996;156:1631- infused agonist. Brain Res. 1986;370:73-81. tive, multicenter, and descriptive clinical study 1632. 193. Mas M, Fumero B, Perez-Rodriquez I. Induc- of 344 patients. J Sex Marital Ther. 1997;23: 175. Waldinger MD, Hengeveld, MW, Zwinderman AH, tion of mating behavior by apomorphine in sexu- 176-193. Olivier B. Effect of SSRI antidepressants on ejacu- ally sated rats. Eur J Pharmacol. 1995;280:331- 156. Patterson WM. Fluoxetine-induced sexual dys- lation: a double-blind, randomized, placebo- 334. function [letter]. J Clin Psychiatry. 1993;54:71. controlled study with fluoxetine, fluvoxamine, par- 194. Bowers MB, Woert MV, Davis L. Sexual behav- 157. Pearlstein TB, Stone AB. Long-term fluoxetine oxetine, and sertraline. J Clin Psychopharmacol. ior during L-dopa treatment for parkinsonism. treatment of late luteal phase dysphoric disor- 1998;18:274-281. Am J Psychiatry. 1971;127:1691-1693. der. J Clin Psychiatry. 1994;55:332-335. 176. Goldbloom DS, Kennedy SH. Adverse interac- 195. Hyyppa M, Rinne OK, Sonnine V. The activating 158. Preskorn SH. Comparison of the tolerability of tion of fluoxetine and cyproheptadine in two pa- effect of L-dopa treatment on sexual functions bupropion, fluoxetine, imipramine, nefaz- tients with bulimia nervosa. J Clin Psychiatry. and its experimental background. Acta Neurol odone, paroxetine, sertraline, and venlafaxine. 1991;52:261-262. Scand Suppl. 1970;43(suppl 46):223-224. J Clin Psychiatry. 1995;56(suppl 6):12-21. 177. Uphouse L, Andrade M, Caldarola-Pastuszka M, 196. O’Brien CP, DiGiacomo JN, Fahn S, Schwarz GA.

159. Gitlin MJ. Psychotropic medications and their ef- Jackson A. 5-HT1A receptor antagonists and lor- Mental effects of high-dosage levodopa. Arch Gen fects on sexual function: diagnosis, biology, and dosis behavior. Neuropharmacology. 1996;35: Psychiatry. 1971;24:61-64. treatment approaches. J Clin Psychiatry. 1994; 489-495. 197. Danjou P, Alexandre L, Warot D, Lacomblez L, 55:406-413. 178. Uphouse L, Andrade M, Caldarola-Pastuszka M, Puech AJ. Assessment of erectogenic proper-

160. Woodrum ST, Brown CS. Management of SSRI- Maswood S. Hypothalamic infusion of the 5-HT2/1C ties of apomorphine and yohimbine in man. induced sexual dysfunction. Ann Pharmaco- agonist, DOI, prevents the inhibitory actions of Br J Clin Pharmacol. 1988;26:733-739. ther. 1998;32:1209-1215. the 5-HT1A agonist, 8-OH-DPAT, on lordosis be- 198. Danjou P, Lacomblez L, Warot D, Peuch AJ. As- 161. Eison AS, Eison MS, Torrente JR, Wright RN, havior. Pharmacol Biochem Behav. 1994;47: sessment of erectogenic drugs by numeric ple- Yocca FD. Nefazodone: preclinical pharmacol- 467-470. thysmography. J Pharmacol Methods. 1989;21: ogy of a new antidepressant. Psychopharmacol 179. Uphouse L, Caldarola-Pastuszka M. Female sexual 61-69. Bull. 1990;26:311-315. behavior following intracerebral infusion of the 199. Lal S, Ackman D, Thavundayil JX, Kiely ME, Eti- 162. Cyr M, Brown CS. Nefazodone: its place among 5-HT1A agonist, 8-OH-DPAT, into the medial pre- enne P. Effect of apomorphine, a dopamine re- antidepressants. Ann Pharmacother. 1996;30: optic area. Brain Res. 1993;601:203-208. ceptor agonist, on penile tumescence in normal 1006-1012. 180. Uphouse L, Caldarola-Pastuszka M, Maswood S, subjects. Prog Neuropsychopharmacol Biol Psy- 163. Robinson DS, Roberts DL, Smith JM, Stringfel- Andrade M, Moore N. Estrogen-progesterone and chiatry. 1984;8:695-699. low JC, Kaplita SB, Seminara JA, Marcus RN. The 8-OH-DPAT attenuate the lordosis-inhibiting ef- 200. O’Sullivan JD, Hughes AJ. Apomorphine- safety profile of nefazodone. J Clin Psychiatry. fects of the 5-HT1A agonist in the VMN. Brain Res. induced penile erections in Parkinson’s dis- 1996;57(suppl 2):31-38. 1994;637:173-180. ease. Mov Disord. 1998;13:536-539. 164. Landen M, Eriksson E, Agren H, Fahlen T. Effect 181. Uphouse L, Caldarola-Pastuszka M, Moore N. In- 201. Segraves RT, Bari M, Segraves K, Spirnak P. Ef-

of buspirone on sexual dysfunction in de- hibitory effects of the 5-HT1A agonists, 5-hy- fect of apomorphine on penile tumescence in men pressed patients treated with selective seroto- droxy- and 5-methoxy-(3-(DI-n-propylamino) with psychogenic impotence. J Urol. 1991;145: nin reuptake inhibitors. J Clin Psychopharma- chroman), on female lordosis behavior. 1174-1175. col. 1999;19:268-271. Neuropharmacology. 1993;32:641-651. 202. Lal S, Laryea E, Thavundayil JX, Nair NPV, Ne- 165. Michelson D, Bancroft J, Targum S, Kim Y, Tepner 182. Uphouse L, Colon L, Cox A, Caldarola- grete J, Ackman D, Blundell P, Gardiner RJ. Apo- R. Female sexual dysfunction associated with an- Pastuszka M, Wolf A. Effects of mianserin and morphine-induced penile tumescence in impo- tidepressant administration: a randomized, pla- ketanserin on lordosis behavior after systemic tent patients - preliminary findings. Prog cebo-controlled study of pharmacologic interven- treatment or infusion into the ventromedial Neuropsychopharmacol Biol Psychiatry. 1987; tion. Am J Psychiatry. 2000;157:239-243. nucleus of the hypothalamus. Brain Res. 1996; 11:235-242. 166. Bitran D, Hull EM. Pharmacological analysis of 718:46-52. 203. Lal S, Tesfaye Y, Thavundayil JX, Thompson TR, male rat sexual behavior. Neurosci Biobehav Rev. 183. Aiello-Zaldivar M, Luine V, Frankfurt M. 5,7- Kiely ME, Nair NPV, Grassino A, Dubrovsky B. 1987;11:365-389. DHT facilitated lordosis: effects of 5-HT ago- Apomorphine: clinical studies on erectile impo- 167. Frohlich PF, Meston CM. Evidence that seroto- nists. Neuroreport. 1992;3:542-544. tence and yawning. Prog Neuropsychopharma- nin affects female sexual functioning via periph- 184. Gorzalka BB, Mendelson SD, Watson NV. Sero- col Biol Psychiatry. 1989;13:329-339. eral mechanisms. Physiol Behav. In press. tonin receptor subtypes and sexual behavior. Ann 204. Aizenberg D, Zemishlany Z, Dorfman-Etrog P, 168. Waldinger MD, Hengeveld MW, Zwinderman AH. N Y Acad Sci. 1990;600:435-444. Weizman A. Sexual dysfunction in male schizo- Ejaculation-retarding properties of paroxetine in 185. Luine V. Serotonin, catecholamines and metabo- phrenic patients. J Clin Psychiatry. 1995;56:137- patients with primary premature ejaculation: a lites in discrete brain areas in relation to lor- 141.

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1028

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 205. Marder SR, Meibach RC. Risperidone in the treat- 227. Ende N, Gertner SB, Hwang SG, Kadi RS. Mea- 247. Sandyk R. Naltrexone suppresses abnormal ment of schizophrenia. Am J Psychiatry. 1994; surement of postcoital sympathetic activity in fe- sexual behavior in Tourette’s syndrome. Int J 151:825-835. males by means of vanillylmandelic acid. Horm Neurosci. 1988;43:107-110. 206. Chan J, Alldredge BK, Baskin LS. Perphenazine- Behav. 1989;23:150-156. 248. Brennemann W, Stitz B, van Ahlen H, Brensing induced priapism. DICP. 1990;24:246-249. 228. Meston CM, Heiman JR. Ephedrine-activated KA, Klingmuller D. Treatment of idiopathic erec- 207. Jackson SC, Walker JS. Self-administered in- sexual arousal in women. Arch Gen Psychiatry. tile dysfunction in men with the opiate antago- traurethral chlorpromazine: an unusual cause of 1998;55:652-656. nist naltrexone: a double-blind study. J Androl. priapism. Am J Emerg Med. 1991;9:171-175. 229. Meston CM, Gorzalka BB, Wright JM. Inhibition 1993;14:407-410. 208. Merkin TE. Priapism as a sequela of chlorproma- of subjective and physiological sexual arousal in 249. Fabbri A, Jannini EA, Gnessi L, Moretti C, Ulisse zine therapy. JACEP. 1977;6:367-368. women by clonidine. J Psychosom Med. 1997; S, Franzese A, Lazzari R, Fraioli F, Frajese G, 209. Mutlu N, Ozkurkcugil C, Culha M, Turkan S, 59:399-407. Isidori A. Endorphins in male impotence: evi- Gokalp A. Priapism induced by chlorproma- 230. Meston CM, Gorzalka BB. The effects of sym- dence for naltrexone stimulation of erectile ac- zine. Int J Clin Pract. 1999;53:152-153. pathetic activation on physiological and subjec- tivity in patient therapy. Psychoneuroendocri- 210. Gower AJ, Berendsen HG, Princen MM, Broek- tive sexual arousal in women. Behav Res Ther. nology. 1989;14:103-111. kamp CL. The yawning-penile erection syn- 1995;33:651-664. 250. van Ahlen H, Piechota HJ, Kias HJ, Bren- drome as a model for putative dopamine auto- 231. Meston CM, Gorzalka BB. The effects of imme- nemann W, Klingmuller D. Opiate antagonists in receptor activity. Eur J Pharmacol. 1984;103: diate, delayed, and residual sympathetic activa- erectile dysfunction: a possible new treatment 81-89. tion on sexual arousal in women. Behav Res Ther. option? Eur Urol. 1995;28:246-250.

211. Ghadirian AM, Chouinard G, Annable L. Sexual 1996;34:143-148. 251. Charney DS, Heninger GR. ␤2–Adrenergic and dysfunction and plasma prolactin levels in neu- 232. Meston CM, Gorzalka BB. The differential ef- opiate receptor blockade. Arch Gen Psychiatry. roleptic treated schizophrenic outpatients. J Nerv fects of sympathetic activation on sexual arousal 1986;43:1037-1041. Mental Dis. 1982;170:463-467. in sexually functional and dysfunctional women. 252. Brady JP, Bianco F. Endorphins: naloxone fail- 212. Shen WW, Sata LS. Inhibited female orgasm re- J Abnorm Psychol. 1996;105:582-591. ure to increase sexual arousal in sexually unre- sulting from psychotropic drugs: a clinical re- 233. Sleight AJ, Koek W, Bigg DCH. Binding of anti- sponsive women: a preliminary report. Biol Psy-

view. J Reprod Med. 1983;28:497-499. psychotic drugs at ␣1- and ␣1B-adrenoceptors: chiatry. 1980;15:627-631.

213. Shen WW, Sata LS. Inhibited female orgasm re- risperidone is selective for the ␣1B-adrenocep- 253. Blanco R, Saenz de Tejada I, Goldstein I, Krane sulting from psychotropic drugs: a five-year, up- tors. Eur J Pharmacol. 1993;238:407-410. RJ, Wotiz HH, Cohen RA. Cholinergic neuro- dated, clinical review. J Reprod Med. 1990;35: 234. Wiedeking C, Lake R, Ziegler M, Kowarski A, transmission in human corpus cavernosum, II: 11-14. Money J. Plasma noradrenaline and dopamine– acetylcholine synthesis. Am J Physiol. 1988; 214. Melis MR, Argiolas A. Dopamine and sexual be- beta-hydroxylase during sexual activity. Psycho- 254:H468-H472. havior. Neurosci Biobehav Rev. 1995;19:19- som Med. 1977;39:143-148. 254. Adaikan PG, Karim SMM, Kottegoda SR, Rat- 38. 235. Wiedeking C, Ziegler MG, Lake CR. Plasma nor- nam SS. Cholinoreceptors in the corpus caver- 215. Julien RM. A Primer of Drug Action: A Concise, adrenaline and dopamine–beta-hydroxylase dur- nosum of the human penis. J Auton Pharma- Nontechnical Guide to the Actions, Uses, and Side ing . J Psychiatr Res. 1979; col. 1983;3:107-111. Effects of Psychoactive Drugs. 7th ed. New York, 15:139-145. 255. Godec CJ, Bates H. Cholinergic receptors in cor- NY: WH Freeman & Co; 1995. 236. Stimmel GL, Dopheide JA, Stahl SM. Mirtazap- pus cavernosa. Urology. 1984;24:31-33. 216. Miller NS, Gold MS. The human sexual re- ine: an antidepressant with noradrenergic and 256. Saenz de Tejada I, Blanco R, Goldstein I, sponse and alcohol and drugs. J Subst Abuse specific serotonergic effects. Pharmaco- Azadzoi K, de las Morenas A, Krane RJ, Cohen Treat. 1988;5:171-177. therapy. 1997;17:10-21. RA. Cholinergic neurotransmission in human cor- 217. Smith DE, Wesson DR, Apter-Marsh M. Co- 237. Morales A, Condra M, Owen JA, Surridge DH, pus cavernosum, I: responses of isolated tis- caine and alcohol-induced sexual dysfunction in Fenemore J, Harris C. Is yohimbine effective in sue. Am J Physiol. 1988;254:H459-H467. patients with addictive disease. J Psychoactive the treatment of organic impotence? results of 257. Saenz de Tejada I, Goldstein I, Azadzoi K, Krane Drugs. 1984;16:359-361. a controlled trial. J Urol. 1987;137:1168-1172. RJ, Cohen RA. Impaired neurogenic and endo- 218. Gay GR, Newmeyer J, Ellison R, et al. Drug-sex 238. Price J, Grunhaus LJ. Treatment of clomipramine- thelium-mediated relaxation of penile smooth practices in Haight-Ashbury of the “sensuous - induced anorgasmia with yohimbine: a case re- muscle from diabetic men with impotence. N Engl pie.” In: Sandler M, Gessa DL, eds. Sexual Be- port. J Clin Psychiatry. 1990;51:32-33. J Med. 1989;320:1026-1030. havior: Pharmacology and Biochemistry. New 239. Reid K, Morales A, Harris C, Surridge DH, Con- 258. Segraves RT. Bethanechol reversal of imipra- York, NY: Raven Press; 1975. dra M, Owen J, Fenemore J. Double-blind trial mine-induced ejaculatory dysfunction [letter]. Am 219. Cohen S. Cocaine. JAMA. 1975;231:74-75. of yohimbine in treatment of psychogenic im- J Psychiatry. 1987;144:1243. 220. Cocores JA, Dackis CA, Gold MS. Sexual dys- potence. Lancet. 1987;2:421-423. 259. Yager J. Bethanechol chloride can reverse erec- function secondary to cocaine abuse in two pa- 240. Piletz JE, Segraves KB, Feng Y, Maguire E, Dunger tile and ejaculatory dysfunction induced by tri- tients. J Clin Psychiatry. 1986;47:384-385. B, Halaris A. Plasma MHPG response to yohim- cyclic antidepressants and mazindol: case re- 221. Cocores JA, Miller NS, Pottash AC, Gold MS. Sexual bine: treatment in women with hypoactive sexual port. J Clin Psychiatry. 1986;47:210-211. dysfunction in abusers of cocaine and alcohol. Am desire. J Sex Martial Ther. 1998;24:43-54. 260. Hull EM, Bitran D, Pehek EA, Holmes GM, Warner J Drug Alcohol Abuse. 1988;14:169-173. 241. Stimmel B. Historical perspective. In: Stimmel RK, Band LC, Clemens LG. Brain localization of 222. Chang AYW, Kuo TBJ, Chan JYH, Chan SHH. B, ed. Heroin Dependency. New York, NY: Strat- cholinergic influence on male sex behavior in rats: Concurrent elicitation of electroencephalo- ton International Medical Book Corp; 1975:1-8. agonists. Pharmacol Biochem Behav. 1988;31: graphic desynchronization and penile erection by 242. Wikler A. Drug dependence. In: Baker A, ed. Clini- 169-174. cocaine in the rat. Synapse. 1996;24:233-239. cal Neurology. New York, NY: Harper & Row; 1971. 261. Hull EM, Pehek EA, Bitran D, Holmes GM, Warner 223. Ferrari F, Guiliani D. Influence of eticlopride on 243. Bloom FE, Rossier J, Battenberg EL, Banyon A, RK, Band LC, Bazzett T, Clemens LG. Brain lo-

cocaine- and DA D2 agonist-induced behavioral French E, Henricksen SJ, Siggins GR, Segal D, calization of cholinergic influence on male sex effects in rats. Pharmacol Biochem Behav. 1996; Brown R, Ling N, Guillemin R. Beta-endorphin: behavior in rats: antagonists. Pharmacol Bio- 53:525-530. cellular localization, electrophysiological and be- chem Behav. 1988;31:175-178. 224. Ferrari F, Guiliani D. Involvement of dopamine havioral effects. In: Costa E, Trabucchi M, eds. 262. Giuliano FA, Rampin O, Benoit G, Jardin A. Neu-

D2 receptors in the effect of cocaine on sexual Advances in Biochemical Psychopharmacol- rological control of penile erection. Urol Clin North behaviour and stretching-yawning of male rats. ogy. New York, NY: Raven Press; 1978:89-109. Am. 1995;22:747-766. Neuropharmacology. 1997;36:769-777. 244. Pfaus JG, Gorzalka BB. Opioids and sexual be- 263. Wagner G, Levin RJ. Effect of atropine and meth- 225. Pomerantz SM, Hepner BC, Wertz JM. Impair- havior. Neurosci Biobehav Rev. 1987;11:1-34. ylatropine on human vaginal blood flow, sexual ment of male copulatory behavior in rhesus mon- 245. Paice JA, Penn RD, Ryan WG. Altered sexual arousal, and climax. Acta Pharmacol Toxicol. keys following acute administration of cocaine. function and decreased testosterone in patients 1980;46:321-325. Life Sci. 1994;54:917-925. receiving intraspinal opioids. J Pain Symptom 264. Riley AJ, Riley EJ. Cholinergic and adrenergic 226. Linnankoski I, Gronroos M, Carlson S, Per- Manage. 1994;9:126-131. control mechanisms in human sexual re- tovaara A. Effect of cocaine on sexual behav- 246. Mirin SM, Meyer RE, Mendelson JH, Ellingboe sponse. In: WheatleyD, ed. Psychopharmacol- iour in male stumptail macaques. Pharmacol Bio- J. Opiate use and sexual function. Am J Psy- ogy of Sexual Dysfunction. Oxford, England: Ox- chem Behav. 1995;52:11-216. chiatry. 1980;137:909-915. ford University Press; 1983:125-137.

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1029

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016 265. White JM, Rumbold GR. Behavioral effects of his- 277. Yanagimoto M, Honda K, Goto Y, Negoro H. Af- 288. Rosen RC, Goldstein L, Scoles V, Lazarus C. Psy- tamine and its antagonists: a review. Psycho- ferents originating from the dorsal penile nerve chophysiologic correlates of nocturnal penile tu- pharmacology. 1988;95:1-14. excite oxytocin cells in the hypothalamic para- mescence in normal males. Psychosom Med. 266. Cara AM, Lopes-Martins RAB, Antunes E, Na- ventricular nucleus of the rat. Brain Res. 1996; 1986;48:423-429. houm CRD, Nucci DE. The role of histamine in 733:292-296. 289. Tiihonen F, Kuikka J, Kupila J, Partanen K, Vainio human penile erection. Br J Urol. 1995;75:220- 278. Chen KK, Chan SHH, Chang LS, Chan JYH. Par- P, Airaksinen J, Eronen M, Hallikainen T, Paanila 224. ticipation of paraventricular nucleus of hypo- J, Kinnunen I, Huttunen J. Increase in cerebral 267. Marson L, McKenna KE. The identification of a thalamus in central regulation of penile erec- blood flow of right prefrontal cortex in man dur- brainstem site controlling spinal sexual reflexes in tion in the rat. J Urol.1997;158:238-244. ing orgasm. Neurosci Lett. 1994;170:241-243. male rats. Brain Res. 1990;515:303-308. 279. Carmichael MS, Humbert R, Dixen JH, Palm- 290. Terzian H, Dalle Ore G. Syndrome of Kluver and 268. McKenna K. The brain is the master organ in isano G, Greenleaf W, Davidson JM. Plasma Bucy reproduced in man by bilateral removal of sexual function: central nervous system con- oxytocin increases in the human sexual temporal lobes. Neurology. 1955;5:373-380. trol of male and female sexual function. Int J Im- response. J Clin Endocrinol Metab. 1987;64: 291. Freeman W. Sexual behavior and fertility after pot Res. 1999;11(suppl 1):S48-S55. 27-31. frontal lobotomy. Biol Psychiatry. 1973;6:97- 269. Marson L, Platt KB, McKenna KE. Central ner- 280. Carmichael MS, Warburton VL, Dixen JH, Dav- 104. vous system innervation of the penis as re- idson JM. Relationships among cardiovascu- 292. Stoleru S, Gregoire M, Gerard D, Decety J, La- vealed by the transneuronal transport of pseu- lar, muscular, and oxytocin responses during hu- farge E, Cinotti L, Lavenne F, le Bars D, Vernet- dorabies virus. Neuroscience. 1993;55:263- man sexual activity. Arch Sex Behav. 1994;23: Maury E, Rada H, Collet C, Mazoyer B, Forest MG, 280. 59-79. Magnin F, Spira A, Comar D. Neuroanatomical 270. Marson L, McKenna KE. CNS cell groups in- 281. Tetel MJ, Getzinger MJ, Blaustein JD. Fos ex- correlates of visually evoked sexual arousal in volved in the control of the ischiocavernosus and pression in the rat brain following vaginal- human males. Arch Sex Behav. 1999:28:1-21. bulbospongiosus muscles: a transneuronal trac- cervical stimulation by mating and manual prob- 293. Hull EM, Du J, Lorrain DS, Matuszewich W. Tes- ing study using pseudorabies virus. J Comp Neu- ing. J Neuroendocrinol. 1993;5:397-404. tosterone, preoptic dopamine, and copulation in rol. 1996;374:161-179. 282. Erskine MS. Mating-induced increases in Fos pro- 271. Marson L. Central nervous system neurons iden- tein in preoptic area and medial amygdala of cy- male rats. Brain Res Bull. 1997;44:327-333. tified after injection of pseudorabies virus into cling female rats. Brain Res Bull. 1993;32:447- 294. Lookingland KJ, Moore KE. Effects of estradiol the rat clitoris. Neurosci Lett. 1995;190:41-44. 451. and prolactin on incertohypothalamic dopamin- 272. Papka RE, Williams S, Miller KE, Copelin T, Puri 283. Everitt BJ, Cador M, Robbins TW. Interactions ergic neurons in the male rat. Brain Res. 1984; P. CNS location of uterine-related neurons re- between the amygdala and ventral striatum in 323:83-91. vealed by trans-synaptic tracing with pseudora- stimulus-reward associations: studies using a 295. Mas M, Fumero B, Gonzales-Mora JL. Voltam- bies virus and their relation to estrogen receptor- second-order schedule of sexual reinforce- metric and microdialysis monitoring of brain immunoreactive neurons. Neuroscience. 1998; ment. Neuroscience. 1989;30:63-75. monoamine neurotransmitter release during so- 84:935-952. 284. MacLean PD. Brain mechanisms of primal sexual ciosexual interactions. Behav Brain Res. 1995; 273. Simerly RB, Swanson LW. The organization of function. In: Sandler M, Gessa, GL, eds. Sexual 71:69-79. neural inputs to the medial preoptic nucleus of Behavior, Pharmacology and Biochemistry. New 296. Lorrain DS, Riolo JV, Matuszewich L, Hull EM. the rat. J Comp Neurol. 1986;246:312-342. York, NY: Raven Press; 1975:5-7. Lateral hypothalamic serotonin inhibits nucleus 274. Simerly RB, Swanson LW. Projections of the 285. Chen KK, Chan JY, Chang LS, Chen MT, Chan accumbens dopamine: implications for sexual sa- medical preoptic nucleus: Phaseolus vulgaris leu- SH. Elicitation of penile erection following acti- tiety. J Neurol. 1999;19:7648-7652. coagglutinin anterograde tract-tracing study in vation of the hippocampal formation in the rat. 297. Everitt BJ, Fuxe K, Hokfelt T, Jonsson G. Role the rat. J Comp Neurol. 1988;270:209-242. Neurosci Lett. 1992141:218-222. of monoamines in the control by hormones of 275. Meisell RL, Sachs BD. The physiology of male 286. Cohen AS, Rosen RC, Goldstein L. EEG hemi- sexual receptivity in the female rat. J Comp sexual behavior. In: Knobil E, Neill JD, eds. The spheric asymmetry during sexual arousal: psy- Physiol Psychol. 1975;89:556-572. Physiology of Reproduction. New York, NY: chophysiological patterns in responsive, unre- 298. Kow LM, Mobbs CV, Pfaff DW. Roles of Raven Press Ltd; 1994:3-105. sponsive, and dysfunctional men. J Abnorm second-messenber systems and neuronal 276. Flanagan-Cato LM, McEwen BS. Patterns of Fos Psychol. 1985;94:580-590. activity in the regulation of lordosis by neuro- and Jun expression in the female rat forebrain 287. Tucker DM, Dawson SL. Asymmetric EEG transmitter, neuropeptides, and estrogen: a after sexual behavior. Brain Res. 1995;673:53- changes as method actors generated emo- review. Neurosci Biobehav Rev. 1994;18(2): 60. tions. Biol Psychol. 1984;19:63-75. 251-268.

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, NOV 2000 WWW.ARCHGENPSYCHIATRY.COM 1030

©2000 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Texas at Austin User on 06/08/2016