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Archives of Sexual Behavior, Vol. 26, No. 4, 1997

A Monoamine Hypothesis for the Pathophysiology of Paraphilic Disorders Martin P. Kafka, M.D.1,2

A monoamine pathophysiological hypothesis for paraphilias in males is based on the following data: (i) the monoamines norepinephrine, dopamine, and serotonin are involved in the appetitive dimension of male sexual behavior in laboratory animals; (ii) data gathered from studying the side effect profiles of antidepressant, psychostimulant, and neuroleptic drugs in humans suggest that alteration of central monoamine neurotransmission can have substantial effects on human sexual functioning, including sexual appetite; (iii) monoamine neurotransmitters appear to modulate dimensions of human and animal psychopathology including impulsivity, anxiety, depression, compulsivity, and pro/antisocial behavior, dimensions disturbed in many paraphiliacs; (iv) pharmacological agents that ameliorate psychiatric disorders characterized by the aforementioned characteristics, especially central serotonin enhancing drugs, can ameliorate paraphilic sexual arousal and behavior. KEY WORDS: paraphilias; monoamines; sexual behavior; serotonin; comorbidity: pharmacotherapy.

PARAPHILIC SEXUALITY: A DIATHESIS MODEL FOR SEXUAL

IMPULSIVITY

Paraphilias are socially deviant, repetitive, highly arousing sexual fantasies, urges, and activities that have a duration of at least 6 months. In addition, paraphilias must be accompanied by clinically significant distress or impairment in social, occupational, or other areas of interpersonal functioning (American Psychiatric Association [APA], 1994, pp. 522-532). 1Harvard

Medical School, Boston, Massachusetts. whom correspondence should be addressed at McLean Hospital, 115 Mill Street, Belmont, Massachusetts 02178.

2To

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0004-0002/97/0800-0343$12.50/0 c 1997 Plenum Publishing Corporation

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Although more than eight distinct primary paraphilic subtypes are consistently identified by DSM-III, DSM-III-R, and DSM-IV nosology, there is substantial overlap among paraphilic categories as well as between paraphilic sexuality and socially nondeviant forms of sexual impulsivity, e.g., compulsive masturbation, protracted promiscuity, and pornography dependence (Carnes, 1983, 1989; Kafka, 1994a 1994b; Kafka and Prentky, 1992a). Large-sample reports of male paraphilic sex offenders have demonstrated that it is more common for male paraphiliacs to have multiple paraphilias, sometimes simultaneously and sometimes serially (Abel et al, 1988; Abel and Osborn, 1992; Bradford et al, 1992). Pedophiles, for example, commonly acknowledge repetitive acts of exhibitionism, voyeurism, and rape (Abel and Osborn, 1992; Bradford et al, 1992) and only a relatively low proportion of incarcerated pedophiles report that acts against children represent either their primary or exclusive source of deviant sexual arousal (Freund et al, 1991; Gebhard et al, 1965; Langevin, 1983; Mohr et al, 1964). Thus, contemporary data suggest that men with paraphilias have a diathesis for multiple sexual impulsivity disorders (Abel et al, 1988; Abel and Osborn, 1992; Bradford et al, 1992; Kafka, 1995, 1997) characterized by heightened sexual arousal, socially deviant sexual preference, volitional impairment, and periods of temporal stability. In addition, Kafka (1991a, 1991b, 1995, 1997) reported that men with paraphilias frequently report persistently increased sexual appetite as measured by their weekly total sexual outlet, an attribute characterized by other theoreticians as "sexual addiction" (Carnes, 1983, 1989, 1990, 1991), "sexual compulsivity" (Coleman, 1986, 1987; Quadland, 1985), "sexual impulsivity" (APA, 1994; Barth and Kinder, 1987), or "male hypersexuality" (Brotherton, 1974; Davies, 1974; Kafka, 1997; Oxford, 1978). Persistently elevated total sexual outlet is correlated with the presence of multiple paraphilias (Kafka, 1997, 1995; Malamuth et al, 1995), sexual promiscuity (Malamuth et al, 1991), and measures of expressed aggression, sadism, and pornography use (Malamuth et al, 1995). PARAPHILIAS AND PSYCHIATRIC COMORBIDITY

A pathophysiological framework that can encompass the diversity, persistence, and socially deviant proclivities of paraphilic sexuality should help to explain those nonsexual comorbid characteristics that appear to be associated with paraphilic disorders. Many of the extant studies examining comorbid psychiatric disorders in paraphilic sex offenders report symptom clusters derived from personality inventories (e.g., MMPI) and do not identify syndromes as defined by Axis I of DSM-III, DSM-III-R, and DSM-IV

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(e.g., Anderson et al, 1979; Grossman and Cavanaugh, 1990; Kalichman, 1990; Langevin et al, 1990a, 1990b; McCreary, 1975). Although paraphilic sex offenders are a heterogeneous group, the cooccurrence of substance abuse, especially alcohol abuse (Langevin and Langs, 1990; Mio et al, 1986; Rada, 1975), conduct and attention deficit disorder (Hunter and Goodwin, 1992; Kavoussi et al, 1988) and antisocial impulsivity (Prentky and Knight, 1986, 1991; Rosenberg et al., 1988), mixed anxiety-depression (Becker et al, 1991; Fagan et al, 1991; Grossman and Cavanaugh, 1990; Kavoussi et al, 1988; Wise et al, 1991) and social anxiety with concomitant social skill deficits (Baxter et al, 1984; Cohen et al, 1969; Pagan and Wexler, 1986; Knight and Prentky, 1990; Levin and Stava, 1987; Marshall, 1989) have been documented repetitively in adolescent and adult sex offender populations. Pearson (1990) and Kafka and Coleman (1991) first suggested that paraphilias are disorders whose pathophysiology might include a disturbance of central serotonin neurotransmission. In this manuscript, a monoaminergic hypothesis for the pathophysiology of paraphilias is proposed based on the following data: (i) the monoamines norepinephrine, dopamine, and serotonin are involved in both the appetitive and performance related dimensions of male sexual behavior in laboratory mammals; (ii) data gathered from studying the side-effect profiles of antidepressant, psychostimulant, and neuroleptic drugs in humans also suggest that alteration of central monoamine neurotransmission can have substantial effects on human sexual functioning, including sexual appetite; (iii) monoamine neurotransmitters appear to modulate dimensions of human psychopathology and animal behavior including impulsivity, anxiety, depression, compulsivity, and pro/antisocial behavior, dimensions that are disturbed in many paraphiliacs; and (iv) certain pharmacological agents that ameliorate psychiatric disorders characterized by the aforementioned characteristics may ameliorate paraphilic sexual arousal and behavior as well.

MONOAMINES AND SEXUAL BEHAVIOR: ANIMAL DATA The central monoamines are synthesized and released by a relatively small number of neurons whose cell bodies lie in the brain stem but whose projections are extensive throughout the brain. Prior to a discussion of the functional role of monoamines in sexual as well as other behavioral dimensions, it must be emphasized that monoaminergic neuronal pathways interact both with each other as well as with other neurotransmitter and neuromodulatory systems (Hsiao et al, 1987; Linnoila et al, 1988; Meltzer and Lowy, 1987; Siever, 1987; Sulser, 1987; van Praag et al, 1991; Wald-

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meier and Delini-Stula, 1979). While it is beyond the scope of this paper to rigorously review the current concepts of the functional role of the monoamines, neuronal pathways transmitting monoaminergic signals have been conceptualized as neuromodulators mediating attention, learning, physiological functions, affective states, goal-motivated and motor behavior as well as appetitive states such as sleep, sex, thirst, and appetite (Heninger, 1995; Le Moal, 1995; Robbins and Everitt, 1995). Although many studies of psychiatric pathologies report alterations of monoamines in the context of either enhanced or diminished neurotransmission, these are relatively simplistic approaches to the complexities of integrated brain functions. Alternative theoretical models might include constructs such as neurotransmitter dysregulation, alterations in the relative influence of one neurotransmitter in homeostatic balance with others or, as yet undetermined downstream effects of monoamines on nonmonoamine neuromodulators. Thus, a hypothesized role of monoamines for sexual impulsivity disorders does not necessarily imply that monoaminergie dysfunction or dysregulation is synonymous with a simplistic etiological explanation for these complex behavioral disorders. Monoamines can mediate similar as well as distinct sexual behavioral response sets in males and females both within and across species (Gorzalka at al., 1990; Meyerson, 1984; Pfaus and Everitt, 1995). In addition, monoaminergie neuronal pathways can exhibit sexually dimorphic patterns in several brain areas (Siddiqui and Gilmore, 1988; Watts and Stanley, 1984). Inasmuch as paraphilic disorders are almost exclusively disorders affecting human males (APA, 1994), this review emphasizes mammalian studies of masculine sexual behavior. Although it is beyond the scope of this review to speculate as to why paraphilias are almost exclusively human male disorders, it is known that androgenic hormones, especially testosterone and its metabolically active metabolites dihydrotestosterone and estradiol, mediate sexually dimorphic behavior including sexual appetitive and copulatory response repertoire differences between males and females (Everitt and Bancroft, 1991; Feder, 1978; Meyerson, 1984). The efficacy of antiandrogens, cyproterone acetate and medroxyprogesterone acetate to mitigate paraphilic arousal and reduce sexual appetite in males (Bradford, 1995a, 1995b) also lends credibility to the assumption that androgens contribute to the sex differences in the prevalence of paraphilic sexuality. Although there are no animal models for "sexual impulsivity disorders," it has been suggested that the dimension of rodent sexuality most likely warranting comparison with the humans is the dimension of sexual appetite rather than the copulatory response repertoire (Everitt and Bancroft, 1991). Inasmuch as I suggest that paraphilias can be conceptualized

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as disorders that include increased sexual appetite, a comparison with male animal models of sexual appetite is germane. Taken together, the animal data suggest that decreased central (i.e., brain) serotonin (5-hydroxytryptamine [5-HT]) may disinhibit or increase appetitive sexual behavior and, conversely, enhancing central serotonin activity may inhibit or reduce sexual appetitive behavior in some male and female mammalian species (Everitt and Bancroft, 1991; Mas, 1995; Tucker and File, 1983). Increased noradrenergic postsynaptic activity enhances sexual behavior while certain noradrenergic antagonists can have an inhibitory effect on sexual arousal (Clark et al, 1985). Last, decreased central dopaminergic neurotransmission decreases motivated behavior, including male sexual appetite behavior (Everitt, 1983; Pfaus and Everitt, 1995; Segraves, 1989). Conversely, pharmacological enhancement of dopaminergic neurotransmission can augment male sexual behavior, including sexual appetite (Everitt and Bancroft, 1991; Gessa and Tagliamonte, 1975; Mas, 1995; Pfaus and Everitt, 1995; Segraves, 1988). Laboratory studies of rats have demonstrated that the effect of monoamines on sexual behavior can be as profound as the effect of the depletion of "sex" hormones. For example, the depletion of central serotonin in rats, through the administration of parachlorophenylalanine (PCPA), a selective 5-HT biosynthesis inhibitor, appears to increase measures of sexual excitement and mounting behavior and provided a model of "compulsive" sexual behavior in rats (Sheard, 1969; Tagliamonte et al, 1969) and cats (Ferguson et al, 1970). In addition, two serotonin blocking agents, cyproheptadine and methysergide, both facilitate sexual activity in male rats (Menendez-Abraham et al, 1988). Sexual behavior in castrated male rats can be restored with a very low dose of testosterone in combination with a pharmacological agent that reduces the availability of central serotonin while a low dose of testosterone alone failed to restore sexual activity (Haensel et al, 1993; Sodersten et al, 1976). In contrast, treatment of female rhesus monkeys with clomipramine, a potent enhancer of serotonin neurotransmission, markedly decreased sexual receptivity in the presence of male monkeys. These changes in sexual behavior were correlated with increased cerebrospinal fluid levels of the metabolites of serotonin (Everitt, 1980). Yohimbine and idozoxan, a2-receptor antagonists that enhance noradrenergic neurotransmission, increase mounting and intromission and decrease ejaculation latency in sexually naive male rats (Clark et al, 1984, 1985) while receptor agonists have an opposing effect (Clark et al, 1985). Central dopamine D2-receptor blockade, utilizing traditional neuroleptic drugs, can abolish all male rat sexual behavior, including sexual appetite, mounting, intromission, and ejaculation (Baum and Starr, 1980;

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Malmnas, 1973). Conversely, dopaminergic agonists such as apomorphine and L-DOPA enhance male rat copulatory behavior in gonadally intact (Paglietti et al., 1978) as well as castrated male rats maintained on low dose testosterone (Malmnas, 1973) and d-amphetamine released into the nucleus accumbents (ventral striatum) increased male rat instrumental responding to an estrus female (Everitt, 1990). The sex hormones estradiol, testosterone, and progesterone, can induce alterations in the binding of monoamine neurotransmitters in the limbic system, suggesting that one of the cellular mechanisms of hormone action may be at the level of monoamine receptors (Everitt, 1983). In male rats, for example, testosterone may affect changes in central serotonin concentrations that accompany sexual maturity (Kendall and Tonge, 1976) and induce alterations in the binding of norepinephrine, dopamine, and serotonin in the hypothalamus (Everitt et al, 1983). Testosterone effects on male rat sexual response are also mediated by its primary active metabolites, estradiol and 5-a-dihydrotestosterone. In some reports, these metabolites augment mesolimbic dopaminergic and inhibit hypothalamic serotonergic neurotransmission (Alderson and Baum, 1981; Baum and Starr, 1980; Bitran and Hull, 1987; Sodersten et al, 1976), effects that synergistically enhance male sexual appetite and copulatory response. It is most likely that hormones and monoamine neurotransmitters interact in a dynamic fashion that determine the form and intensity of drive behaviors, including sexual behavior (Sicuteri, 1974). The exact nature of the interrelationship of these hormone-monoamine systems in humans may hold clues to further elucidating the biological basis for sexual behaviors, including human sexual impulsivity disorders.

MONOAMINES AND SEXUAL BEHAVIOR: HUMAN DATA The neuromodulation of sexual desire in men and women is poorly understood in comparison to laboratory mammals. The elucidation of the biological mechanisms that determine human sexuality are hampered by limitations in the selectivity of biological probes, undesirable side effects of selective biological agents, as well as the absence of a noninvasive methodology to identify, localize, and selectively affect the brain areas most responsible for the substrates of sexual appetite and copulatory responses (Everitt and Bancroft, 1991). For example, there is less direct evidence that diminished central serotonin may increase sexual desire and performance in the human species (Everitt and Bancroft, 1991; Segraves, 1989). The use of PCPA in human males as a probe for sexual behavior mediated by central serotonin has produced negative results in comparison with experi-

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ments with laboratory mammals (Benkert et al, 1976; Cremata and Koe, 1966). In addition, I could not find studies that specifically measure monoaminergic metabolites or utilize biological probes to provoke monaminergic neurotransmission in male paraphiliacs. Such studies are clearly needed to support or revoke the hypothesis proposed in this manuscript. Despite these limitations, data supporting this hypothesis are presented below. The serotonin-reuptake inhibitors, clomipramine and fluoxetine, increase postsynaptic serotonergic effects and have been reported to produce a high frequency of human sexual dysfunction side effects including the cluster of loss of sexual desire and impaired copulatory response in males (ejaculatory delay, erectile dysfunction, and anorgasmia) (Jacobsen, 1992). These reports support the observation that enhanced central serotonin neurotransmission reduces or inhibits sexual desire and associated sexual performance behaviors. Yohimbine, a a2-receptor antagonist has been shown to enhance erectile function in heterogeneous samples of males with erectile disorders (Morales et al., 1987; Sonda et al, 1990). It is not clear, however, that yohimbine has a direct effect on sexual appetite. In humans, D2-receptor blockade utilizing traditional neuroleptic drugs diminishes sexual appetite and has been used to reduce paraphilic arousal (Tennent et al., 1974; Zbytovsky, 1993). Conversely, increased sexual desire, as measured by self-report of fantasies, erections, and activities, has been reported in men treated with dopamine agonists such as L-DOPA (Bowers et al, 1971; O'Brien et al, 1971) and amphetamine (Angrist and Gershon, 1976; Bell and Trethowan, 1961).

MONOAMINES AND COMORBID SYNDROMES ACCOMPANYING PARAPHILIAS IN HUMANS The neurobiological substrates for impulsivity, compulsivity, anxiety, and depression are better elucidated in humans in comparison with sexual behavior. Inasmuch as some paraphilias can include acts of sexual aggression and are, by current nosological definition, socially deviant disorders of impulse control, it is noteworthy that human studies have consistently pointed to an association between reduced central serotonin neurotransmission and the release of suppressed behaviors (Soubrie, 1986) including impulsive behaviors and aggression (Brown and Linnoila, 1990; Coccaro, 1989; Insei et al, 1990; Kavoussi and Coccaro, 1993; Linnoila et al, 1983; Stein et al, 1993). Central serotonergic disturbance may accompany some depressive disorders (Meltzer, 1990; Risch and Nemeroff, 1992), anxiety

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disorders (Kahn et al, 1987; van Praag et al, 1987), and consummatory behaviors (Amit et al, 1991), including alcoholism (Amit et al, 1991). The functional role of dopamine and norepinephrine for psychopathological disorders associated with paraphilic sexuality is less clear. Research literature exploring a relationship between impulsivity and these latter catecholamines is scant in comparison with the burgeoning data regarding serotonin. Dopamine appears to be associated with the mobilization, facilitation, and sustenance of goal- or incentive-related behavior (Blackburn et al, 1992; Crow, 1973; van Praag et al., 1990) and impairment in dopamine neurotransmission may mediate impulsivity and inattentiveness characteristic of attention-deficit disorder (Levy, 1991). Van Praag has hypothesized that central noradrenergic neurotransmission modulates the experience of pleasure and sensation. For example, alterations in plasma and CSF metabolites of norepinephrine have been reported in high sensation-seeking individuals (Ballanger et al., 1983; Roy et al, 1989) and may contribute to the etiology and symptomatology of depressive conditions (Siever and Davis, 1985).

PSYCHOPHARMACOLOGY, MONOAMNES, AND PARAPHILIC DISORDERS If monoamine neuorotransmitters contribute to the pathophysiology of sexual impulse disorders and these same neuromodulatory agents are implicated in the Axis I disorders and personality characteristics that are comorbid with sex offender paraphiliacs, then pharmacological agents that affect monoaminergic neurotransmission should affect paraphilic arousal as well. The three classes of drugs most commonly used to affect the neuroregulation of monoamines are the neuroleptics, psychostimulants, and antidepressants. A limited role for neuroleptics in the treatment of paraphilias has been discussed above. There are no published reports regarding the use of psychostimulants for the control of deviant sexuality, despite the diagnosis of learning disabilities and attention deficit hyperactivity disorder in some male paraphiliacs. It is possible that these agents have been underutilized because of the difficulty in assessing residual symptoms of attention deficit hyperactivity disorder in adults (Shaffer, 1994) as well as some case reports suggesting that psychostimulant abuse may disinhibit sexual behavior (Boffum et al, 1988). There have been case reports suggesting the efficacy of tricyclic antidepressants (Goldner, 1961; Kafka, 1991a; Snaith, 1981) and two case series with lithium carbonate (Bartova and Nahanek, 1979; Bartova et al., 1978) reporting a mitigation of

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paraphilic behaviors. A small but double-blind placebo-controlled crossover study comparing clomipramine, a predominantly serotonin reuptake inhibitor with desipramine, a predominantly norepinephrine reuptake inhibitor (Kruesi et al, 1992), reported that both were effective pharmacological agents to reduce paraphilic behavior. There are multiple case reports utilizing fluoxetine (e.g., Bianchi, 1990; Emmanuel et al, 1991; Jorgensen, 1991; Kafka, 1991a, 1991b; Lorefice, 1991; Perilstein et al, 1991), and open trials in inked groups of paraphiliacs utilizing fluoxetine in 16 males (Kafka and Prentky, 1992b), measuring outcome at 12 weeks, and either sertraline or fluoxetine in 24 males, measuring outcome at last visit, up to 1 year after the initiation of pharmacotherapy (Kafka, 1994b). In the aforementioned open-trial reports, there were reductions in total time consumed by deviant fantasies as well as reductions in paraphilic-related masturbation and overt sexual behaviors, regardless of primary paraphilic diagnosis. In general, socially conventional sexual behavior was not adversely affected by pharmacotherapy. Although many of the males were diagnosed with depressive conditions, a positive treatment response was independent of baseline depression rating. Bradford (1995a) reported a 12-week open trial of sertraline for 18 predominantly personality disordered heterosexual pedophiles. Statistically significant last-visit effects were reported including diminished pedophilic fantasies, decreased masturbation to pedophilic fantasies, and decreased penile tumescence to sexually arousing descriptions of pedophilia in comparison to baseline measures. In all the aforementioned reports utilizing serotonin reuptake inhibitors, statistically significant effects on target sexual behaviors are usually apparent after 4 weeks on active drug. Inasmuch as published manuscripts emphasize "positive" findings, it is worth mentioning that there are no published reports that contradict the aforementioned ameliorative effects of serotonergic agents on paraphilias. In conclusion, the review of the literature presented here affords suggestive evidence that paraphilias are disorders characterized by pathological dimensions including altered sexual preference, relative temporal stability, volitional impairment, and, possibly, increased sexual drive-related behaviors. Multiple paraphilic disorders appear to occur more commonly in affected persons implying that there is a paraphilic diathesis that predisposes to a variety of socially anomalous sexual outlets. In addition, paraphilic disorders can be accompanied by low self-esteem, social anxiety, social skills impairment, low grade anxious and depressive symptoms, and additional expressions of socially deviant impaired impulse control. These symptoms and syndromes may be, in part, mediated by perturbations in central monoamine neurotransmitters and can be ameliorated by pharmacological agents that affect serotonin, norepinephrine, and dopamine. Although

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much more research utilizing antidepressants and perhaps other pharmacologic monoaminergic neuromodulators (e.g., psychostimulants) remains to be investigated and reported, the most recent data are suggestive that serotonergic agents may represent a contemporary advance in the treatment of deviant sexuality.

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Archives of Sexual Behavior, Vol. 26, No. 4, 1997

Psychoendocrinological Assessment of the Menstrual Cycle: The Relationship Between Hormones, Sexuality, and Mood Stephanie H. M. Van Goozen, Ph.D.,1.6 Victor M. Wiegant, Ph.D.,2.3 Erik Endert, Ph.D.,4 Frans A. Helmond, Ph.D.,3 and Nanne E. Van de Poll, Ph.D.5

The role of sex hormones in sexuality and mood across the menstrual cycle was investigated. Twenty-one normal healthy women were followed for one menstrual cycle. Blood samples were taken frequently, and analyzed for estradiol, progesterone, testosterone, androstenedione, dehydroepiandrosterone sulfate, cortisol, and sex hormone-binding globulin. A diary concerning sexual interest and behavior, and different moods, was completed daily. Although the sample was not large, a clear effect of menstrual cycle phase on levels of testosterone and the free testosterone index was demonstrated. In a preliminary screening interview, 11 of the 21 women had reported that they suffered from premenstrual complaints (PC), the other 10 had reported no complaints in the premenstrual phase (NPC). Significant differences between the two groups were established in estradiol and the estradiol-progesterone ratio, with the NPC group having higher levels of both endocrine parameters across different menstrual samples. Psychologically, a cycle effect on tension and sexual interest was demonstrated. The NPC group reported a peak in sexual interest in the The study was supported by grants from the "De Drie Lichten" Foundation the "Dr. Saal Van Zwanenberg" Foundation and Organon International BV. 1Department of Child and Adolescent Psychiatry, University Hospital Utrecht B01-201, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. 2Departmentof Medical Pharmacology, Rudolf Magnus Institute of Neurosciences, Utrecht University, The Netherlands. 3Department of Human and Animal Physiology, Agricultural University, Wageningen, The Netherlands. 4Laboratory for Endocrinology and Radiochemistry, Academic Medical Center, Amsterdam, The Netherlands. 5Department of Psychology, University of Amsterdam, The Netherlands. 6To whom correspondence should be sent.

359 0004-0002/97/0800-0359$12.50/0 © 1997 Plenum Publishing Corporation

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premenstrual phase, whereas the PC group reported a peak in the ovulatory phase. There was a difference between the two groups in feelings of fatigue but not in other moods across the menstrual cycle. The study provides further evidence of the importance of androgen levels in women's sexuality and shows again that the relationship between menstrual cycle phase and sexuality is much clearer than between phase and mood. KEY WORDS: sexuality; mood; androgens; premenstrual complaints; sex hormones.

INTRODUCTION Background During the last decades the menstrual cycle has captured the interest of scientists as a naturalistic model for investigating the influence of gonadal steroids on brain and behavior (Hamilton et al., 1988). Activating effects of sex hormones on various mental and behavioral functions in women have been demonstrated by studying the covariation of levels of sex steroids and self-reports of these psychological factors at different phases of the menstrual cycle. Much attention has focused on sexuality. Earlier studies on a variety of female mammals indicated that the ovulatory period, when estrogen levels are high, is the prime phase of the cycle in which the female is responsive to males and sexual behavior is shown (Beach, 1976). In line with these findings, a midcycle peak in sexual activity has been reported in human females (Adams et al., 1978; Matteo and Rissman, 1984). However, there have also been frequent failures to find an ovulatory peak in sexual behavior (Sanders and Bancroft, 1982); some studies found evidence of a premenstrual peak (Schreiner-Engel et al., 1981; Bancroft, 1984), whereas others found evidence of both an ovulatory and pre- or postmenstrual peak (Bancroft et al., 1983). The inconsistency of results concerning changes in sexuality throughout the cycle could not lead to a consistent idea about which hormones are primarily involved in these behavioral functions. Studies showing a midcycle ovulatory peak in sexuality have led researchers to infer that estrogens are the most important hormones for sexual activity in women. However, despite the large differences in estradiol and progesterone levels resulting from normal variations in steroid levels during the menstrual cycle, Abplanalp et al. (1979) found that measures of sexuality were stable throughout the cycle; they also did not find a relationship between estradiol levels and enjoyment of heterosexual activity or number of heterosexual activities. Persky, Charney, et al. (1978) failed to demonstrate a direct relationship between plasma estradiol levels and sexual arousal, intercourse frequency, and

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sexual gratification. The occurrence of a premenstrual peak in sexuality has been ascribed to an inhibiting effect of progesterone (Bancroft, 1984). Schreiner-Engel et al., (1981), on the other hand, found a positive correlation between subjectively experienced sexual arousal and progesterone levels during the luteal phase. Animal studies have indicated that androgens contribute significantly to the expression of sexual behavior in female mammals (Van de Poll and Van Goozen, 1992). A distinction has been drawn between receptivity, which is the passive acceptance of a male animal by the female, which is primarily estrogen-dependent, and proceptivity, which is the active searching for a male and the initiation of copulation by the female (Beach, 1976). Studies have provided evidence of a relation between androgens and proceptivity in female rats (De Jonge and Van de Poll, 1984; De Jonge et al., 1986). In women, both the adrenal cortex and the ovary contain the biosynthetic pathways necessary for androgen synthesis and secretion, with the ovary producing 5-25% of plasma-testosterone, 45-60% of androstenedione, and approximately 20% of dehydroepiandrosterone (DHEA), whereas the adrenal cortex produces 5-25% of circulating testosterone, 3040% of androstenedione, 80% of DHEA, and more than 95% of dehydroepiandrosterone sulfate (DHEAS). The remainder of circulating androgens in the female results from peripheral conversion which presumably accounts for a production rate of 50-70% of testosterone and 10% of androstenedione (Greenspan, 1991; Sherwin, 1988). On the basis of animal research and a growing number of studies on women, the current balance of opinion is leaning toward the view that androgens play a more important role than estradiol. Higher levels of testosterone have been associated with more intense sexual interest and arousal (Alexander and Sherwin, 1993; Bancroft et al., 1980; Dabbs and Mohammed, 1992; Schreiner-Engel et al., 1981). In two studies (Persky, Lief et al., 1978; Morris et al., 1987) a relation was demonstrated between midcycle peak values of testosterone in women and intercourse frequency of couples. Moreover, research on the effects of androgen replacement therapies in postmenopausal women (Sherwin et al., 1985; Sherwin and Gelfand, 1987) and studies on the effects of testosterone administration to female-to-male transsexuals and of androgen-deprivation in male-to-female transsexuals (Van Goozen et al., 1995) demonstrated that androgenic hormones are an important factor in libido of both men and women. It is unclear which androgens are responsible for the behavioral effects of androgens. For example, not only is androstenedione—as a prehormone—peripherally converted to estrogen and other androgens, but it is unclear whether androstenedione has much psychological action in its

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own right. Ribeiro et al. (1974) tested the hypothesis that serum levels of androstenedione, as a precursor of estradiol, had a similar secretion pattern. In six normal menstrual cycles no clear pattern of changing levels of androstenedione was found equivalent to the one observed for estradiol and progesterone. Although the daily fluctuations of androstenedione were great, the mean levels of androstenedione generally increased from menstruation to midcycle, but did not parallel the patterns of estradiol, and declined again from midcycle to menstruation. There were no clearcut differences between the levels of androstenedione in the follicular and luteal phases. In a sample of six women, Judd and Yen (1973) found that the mean androstenedione level during the middle third of the menstrual cycle was significantly higher than during the earlier or later portions. The same applied to the mean testosterone level, but the rise in testosterone was smaller than that of androstenedione. And finally, it is unclear whether there are cycle-related fluctuations in baseline levels of the androgenic hormones with a strong adrenocortical component (DHEA and DHEAS) and of cortisol (Abplanalp et al., 1977; Beck et al., 1990; Saxena et al., 1974), and if so, whether these are related to changes in psychological attributes. Research on the relation between hormonal changes during the menstrual cycle and changes in the experience of emotions has focused mainly on whether the period preceding the onset of menstruation is accompanied by an increase in negative mood. The results of different studies are conflicting: sometimes an increase in negative mood during the premenstrual phase has been reported (Backstrom et al., 1983; Sanders et al, 1983), and sometimes not (Abplanalp et al., 1979). Parlee (1982) even found significantly lower negative mood scores in the premenstrual than in the periovulatory phase. Studies on the effects of hormonal fluctuations during the menstrual cycle on sexuality and emotional well-being suffer from a number of methodological problems: (i) different aspects of sexuality have been studied, ranging from frequency of intercourse and masturbation to intensity of feeling passionate and affectionate; (ii) different groups of women have been involved: normal women, normal women who suffer from emotional and physical complaints in the premenstrual phase (i.e., premenstrual symptoms), and women who attend a gynecological clinic because of their severe premenstrual complaints; and (iii) different methodologies have been used to infer menstrual phases (e.g., body temperature measurements, subjective reports, hormone measurements). The fact that studies vary along these lines is probably to a large extent responsible for the mixed and inconsistent findings in this domain.

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Purposes of the Study For the duration of one menstrual cycle a sample of normal and regularly menstruating women was followed. Blood samples were gathered frequently to assess a number of different ovarian and adrenocortical hormones, including some for which there is hardly any information concerning their secretion pattern during the menstrual cycle [cortisol, DHEAS, sex hormone binding globulin (SHBG), and the free testosterone index (FTI), i.e., the proportion of unbound, biologically active, testosterone]. Daily reports of sexual motivation and behavior, and emotional wellbeing were made. All endocrinological and psychological variables were analyzed to establish whether or not there was a cyclic variation throughout the cycle. As yet, it is unclear whether women suffering from premenstrual complaints have an aberrant menstrual pattern of changing ovarian hormones: It is unclear whether sex hormones are involved, and if so, which ones they are and whether a deviant pattern is restricted to the premenstrual phase or also extends to other phases of the menstrual cycle. For example, it has been claimed that premenstrual syndrome (PMS) is related to the withdrawal of estradiol or of progesterone, or to a disturbance in the estrogen-progesterone ratio (Clare, 1985; Janowsy and Rausch, 1985). However, Backstrom et al. (1983) did not find evidence of a hormonal difference between women with and without PMS complaints on progesterone, estradiol, testosterone, and androstenedione. As a subsidiary goal of the present study we investigated whether there were endocrinological and/or psychological differences between women who reported suffering from premenstrual complaints and women who reported being free of premenstrual problems. To that end, the group was composed of women who differed in the perception of the severity of their premenstrual complaints.

METHOD Subjects An advertisement was placed in local newspapers, asking for subjects willing to participate in research on the relation between hormonal changes during the menstrual cycle and moods and sexuality. Four hundred fortyfour women responded by telephone. During this telephone call questions were asked about the length and regularity of the menstrual cycle, use of contraception, marital status, and occupation, and the procedure of the study was explained. On the basis of the information gathered 93 women

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were selected for an extensive structured interview held at our laboratory. The other 348 women were not invited because they had no regular menstrual cycles, they were using contraceptives, or they were not willing to take part in a 1-month study involving, among other things, coming to the laboratory every other day to give blood samples. The focus of the selection interview was broad, ranging from questions about sociodemographic status, personal history and development, education, employment status, and sexuality, to current and past menstrual cycle functioning. The goal of the selection procedure was to compose a group of women satisfying the following criteria: report of a regular menstrual cycle of 26-30 days, no use of oral contraceptives, leading a sexually active life, and making a psychologically stable impression. Fifty-eight women fulfilled these criteria and took part in a study on the effects of the premenstrual phase on emotionality during aversive events (Van Goozen et al., 1996). Of this group, 21 women were willing to take part despite the rather arduous procedure of this particular study in which blood samples were gathered frequently. Of these, 11 women had reported diverse premenstrual problems returning every cycle. The most frequently mentioned complaints were irritability, mood swings, headaches, depression, nausea, and complaints related to water retention. None of the women was under treatment by a physician for these complaints.7 Furthermore, it was established that they had these complaints only in the premenstrual phase. This was the premenstrual complaints or PC group. No attempt was made to verify whether these women actually experienced the symptoms they complained of because this was not the focus of the study. The other 10 women reported not suffering from any complaints across all phases of the cycle (NPC group). Of the NPC group 7 women used condoms, 1 a coil, and 2 were lesbian; of the PC group 7 women used condoms and 4 a coil. The age of the women was between 24 and 40 years (mean age of the PC group = 29.9; mean age of the NPC = 27.9). All subjects were involved in a stable, single-partner sexual relationship, but not all of them were married or lived together. Fifteen subjects had at some time in the past taken oral contraceptives, but all had ceased taking the pill at least 6 months prior to the time of the study. Medical histories based on interview information indicated that all subjects were in good health and were not taking any medication that might interfere with endocrine function or emotional state; none of the women were overweight. All had reported a history of normal and regular 7We

emphasize that the group of women who reported suffering from premenstrual complaints (PC) cannot be compared to women suffering from PMS or late luteal phase dysphoric disorder. For that, the complaints should meet certain criteria. Our distinction between NPC and PC women is solely based on the subjective perception of women about their premenstrual experience.

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menstrual cycles (28 ± 2 days) and the sociodemographic data of the two groups were similar.

Procedure

Each subject was studied for one complete menstrual cycle. For each subject, depending on the length of the menstrual cycle, 12-14 blood samples were collected: two 10-ml blood samples were taken by venipuncture. Since it is known that cortisol displays a marked diurnal variation, blood samples were drawn between 7.30 and 8.30 AM, three times per week at 2-day intervals. Subjects were not allowed to smoke, drink coffee, or have a high cholesterol breakfast before blood was collected. Throughout the study subjects were asked to refrain from drinking alcohol and from going to bed late. Subjects were asked to choose a period during which they expected no special life events (negatively or positively stressful occasions, such as parties, birthdays, vacations, exams) to occur. The total sample was divided into three groups of 7 women; all subjects within one group started on the same day, irrespective of the day of her menstrual cycle. Moods, sexuality, physical symptoms, and experience of stressors were reported every evening: subjects filled out a shortened (32 item) version of the Profile of Mood States (POMS; McNair et al., 1971), consisting of five subscales: depression, anger, fatigue, tension, and vigor. Each subscale contains a number of different emotions and moods (for example: lonely, sad, depressed) and the subject had to indicate on a 5-point intensity rating scale how strongly she experienced that particular feeling that day. A mean mood score was calculated for each subscale on each day. Also, a self-constructed questionnaire containing items about interest in own appearance, interest in sex with and without a partner, and need for physical contact (each item rated on a 7-point intensity scale) was administered daily. Descriptive data were collected concerning sexual behavior: On a daily basis subjects indicated whether they had had sexual activity with a partner, who had taken the initiative (self, partner, jointly; percentage score), whether they had masturbated (either when being alone or in the company of a partner), and whether they had had an orgasm (and if so, how many). Further questionnaires about physical symptoms and daily stressors are not described here since the data will be presented elsewhere. Complete confidentiality of all data was assured. Subjects received Hfl. 500 (approx. $250) after participation in the study.

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Hormonal Assays Cortisol, estradiol, and progesterone were assayed in plasma without prior extraction using coated-tube radioimmunoassay (RIA) test kits (EuroDiagnostica B.V., Apeldoorn, The Netherlands). All RIAs were performed in duplicate. Characteristics of the RIA test kits, as provided by the manufacturer, were as follows: Cortisol RIA. Sensitivity, 6 nmol/L; intra-assay coefficient of variation (CV), 2.5-7.9%, interassay CV, 2.6-8.9%; crossreactiviry of cortisol, 100%; prednisolone, 33%; corticosterone, 9%; cortisone, 2.2%; dexamethasone, 0.4%; 11-deoxycorticosteroids (DOC), 3.8%; 17-OH-progesterone, 1.0%; testosterone, 0.14%. Estradiol RIA. Sensitivity, 0.2 nmol/L; intra-assay CV, 6.7-9.7%, interassay CV, 9.0, 9.4%; crossreactivity of estradiol, 100%; estradiol, 0.57%; cortisol, 0.003%; testosterone, 0.001%; 17-p-estradiol, 0.43%. Progesterone RIA. Sensitivity, 0.3 nmol/L; intra-assay CV, 5.6-7.5%, interassay CV, 4.2-5.3%; crossreactivity of progesterone, 100%; corticosterone, 2.46%; estriol, 0.24%; cortisol, 0.13%; 11-DOC,