Biological factors in human sexuality.

In most species sexual behavior principally serves the purposes of reproduction. In humans, and in some other primates, other purposes for sexual behavior in addition to reproduction have evolved. In the human such purposes have been shaped and influenced by cultural factors, so that human sexuality has been expressed in many different ways, varying across cultures and over history. In spite of these powerful cultural influences, biological factors involved in sexual arousal and response remain fundamental to human sexual experience and need to be taken into account in our attempts to understand and explain the complexities and problems as well as the positive aspects of the human sexual condition. The relevant literature is vast and this paper makes no attempt to provide a comprehensive review; rather, it should be considered an overview of a number of key concepts relevant to understanding the role of biology and its interaction with culture in shaping human sexuality.

SEXUAL DIFFERENTIATION

Biological differentiation into male and female makes sexual reproduction possible. Males have two sex chromosomes, an X and a Y; females have two X chromosomes. Sexual differentiation is determined by the presence or absence of the Y chromosome. If there is no Y chromosome, development is along female lines. A specific part of the Y chromosome, the SRY (sex-determining gene region of the Y chromosome) is responsible for male differentiation (Haqq & Donahoe, 1998). This results in the differentiation of the primitive gonad into a testis rather than an ovary during early fetal development. The resulting testis produces not only testosterone but also Mullerian Inhibiting Factor (MIF) which actively suppresses any further development of those parts of the embryo which would otherwise develop into internal female reproductive organs. The testosterone stimulates development of male genitalia and reproductive organs: It also has organizing effects on the central nervous system which are not well understood but which increase the likelihood of male patterns of behavior after birth (Collaer & Hines, 1995). The SRY, or possibly other parts of the Y chromosome, may have other gender differentiating effects on the central nervous system which are not dependent on testosterone, but these have not as yet been identified.

The bisexual potential of the embryo allows for selection of development along either male or female lines (Beach, 1976). In some instances, as with the gonad becoming either a testis or an ovary, or the female reproductive tract being actively suppressed during male development, there is clear differentiation. In other cases, such as the nipples of the male or the clitoris of the female, there is no biological need to suppress their development, even though they play no direct role in sexual reproduction. This undifferentiated overlap between male and female may apply to other structures or functions, such as orgasm in the female. Whereas orgasm is essential for the male's contribution to reproduction, orgasm in the female has no obvious reproductive purpose. It has been argued that female orgasm has positive benefits which would justify its existence on evolutionary grounds, but it seems more likely that its benefits to women are a "biological bonus" resulting from the absence of active suppression of its development (Lloyd, 1993; Symons, 1979). The role that female orgasm plays in the interaction between biology and culture is probably complex, and its relevance to the cultural shaping of women's sexuality is poorly understood. There is good historical evidence, however, of the extent to which cultural constraints have made it difficult for women to realize their full biological sexual potential (Bancroft, in press-a).

Normally we develop a core gender identity (the belief that "I am a boy" or "I am a girl") which is consistent with our genetic XY or XX status. However, sexual differentiation can go wrong in a variety of ways, resulting in intersex conditions. The fact that some intersex individuals can be brought up successfully in the gender which best matches their degree of gender differentiation rather than their sex chromosome constitution indicates that there is a degree of plasticity in this process (Zucker, 1999).

There are other forms of plasticity to consider. The central nervous system is not fixed by early development, as was once thought, but continues to develop after birth influenced by environmental factors (Hofer, 1996). How long this neural plasticity continues during childhood is not yet known, but it emphasizes the importance of always considering the interaction between biological (and genetic) processes and the environment (or culture).

SEXUAL RESPONSE

Sexual response in the adult is characterized by a subjective sense of sexual excitement or arousal and physiological changes in the body, involving the genitalia but also the cardiovascular system, and a tendency, particularly in the male, to pursue sexual stimulation until orgasm occurs. This process is a complex interaction between cognitive (information processing), central brain mechanisms, including sexual arousal and other emotional states, and peripheral physiological processes such as penile erection in the male and clitoral, vulvar, and pelvic vaso-congestion in the female. It can usefully be regarded as a "psychosomatic circle" (Bancroft, 1989) in which awareness of changes in the genitalia feeds back to influence the central processes in either an augmenting, excitatory, or inhibitory fashion. The activation of this psychosomatic system can start at various points in the cycle, such as the occurrence of a sexually exciting thought, a sexually stimulating image, or tactile stimulation of those parts of the body which are erotically sensitive. The information processing component identifies what is "sexual," a process which is heavily influenced by learning and cultural factors. The central brain mechanisms activate the neural signals that descend mainly down the spinal cord, along pathways that include reflex centers at certain levels of the cord (Steers, 2000), to evoke the peripheral sexual responses. The sensory input from these peripheral responses and further tactile stimulation, as well as continuing information processing of the experience, result in increasing levels of central arousal and excitement to the point when an orgasm is triggered. Conversely, if the ongoing process is interpreted in negative terms suggesting threat, danger, fear of failure, or some other negative consequence, then the process may lead to inhibition of further sexual response.

There is much that we do not understand about this psychosomatic circle. In the case of the cognitive component, a distinction has been made between automatic cognitive processes (of which the subject is more or less unaware) and controlled cognitive processes, involving ongoing awareness of the subject. In addition, the impact of emotional states on these cognitive processes has been recognized as important (Janssen & Everaerd, 1993). As yet, however, we understand little about the nature and origins of these automatic processes. The interface between such information processing (i.e., how we interpret what is happening to us in the sexual context) and the physiological systems involved in sexual response is also little understood. Research on brain mechanisms involved in sexual response has largely depended on animal studies, and much has been learned in this area over the past few years, particularly in relation to male sexual response (e.g., Steers, 2000). Although such studies are important and helpful, they cannot investigate the role of cognitive processing of the kind that characterizes the human. Also, as we learn more about the physiological processes, so their complexity increases to the extent that our earlier, simple explanatory models become overwhelmed. At an earlier stage we could envisage most of the key neurophysiological processes involved in sexual response, both in the brain and in the periphery, as being controlled by a small number of monoamines, like norepinephrine, dopamine, serotonin, and acetylcholine. We then learned that neuropeptides, a different class of chemical messenger, were involved, often working in combination with our more traditional monoamines. Whereas we once knew of a handful of such neuropeptides, they now number more than a hundred. Excitatory and inhibitory amino acids such as glutamate and GABA (gamma-aminobutyric acid) then became recognized as probably the most ubiquitous neurotransmitters in the central nervous system. (See Powis & Bunn, 1995, for recent overview.) modern techniques of molecular biology are finding more and more different receptors for these chemical messengers, each with potentially different functions. According to Heaton (2000) "our current capacity to identify and manipulate these targets of control is in the process of explosive growth from an estimated few hundred identifiable systems to well over 100,000" (p. 562). Although, whether this is an exaggeration or not, such growth of inevitably fragmented knowledge may have benefits in our search for treatments for sexual problems, it is arguable that in the face of this overwhelming complexity we should revert to simpler but new conceptual systems to guide our research and shape our explanatory models.

An example of such a conceptual system is the development of a dual control model to explain control of sexual response which assumes that there are both excitatory and inhibitory conceptual systems in the brain and spinal cord, and that sexual response depends on the balance between them. Furthermore, the model postulates that individuals vary in their propensity for both excitation and inhibition (Bancroft, 1999). Such propensities are now being measured by simple questionnaire techniques showing that people do indeed vary considerably in both respects. Those with either high or low propensities for either excitation or inhibition are proving to be more vulnerable to problems such as sexual dysfunction (in the case of low excitation and/or high inhibition) (Bancroft & Janssen, 2000), or compulsive sexual behavior (in the case of high excitation and low inhibition). Current research at the Kinsey Institute is focusing on the relationship between mood and sexuality. A significant minority of men experience an increase in sexual interest when they are anxious or stressed, and a somewhat smaller proportion when they are depressed. These paradoxical relationships between mood and sexuality can be predicted from excitation and inhibition proneness, and help explain some forms of high risk sexual behavior where sex becomes a form of mood regulator, or stress reliever (unpublished evidence).

A number of new methodological as well as conceptual developments offer promise for testing such theoretical models in the human rather than the laboratory animal. Of particular interest is the use of brain imaging, employing either PET scanning or functional MRI to explore areas of activity in the human brain during sexual arousal. Such research is at an early stage. Stoleru and his colleagues (Redoute et al., in press; Stoleru et al., 1999), using PET scanning, have made an interesting start, showing that sexual arousal in men in response to visual stimuli is correlated with activation (rCBF) in limbic and paralimbic cortex and some subcortical structures, together with deactivation in several parts of the temporal cortex. This is consistent with the dual control model, and its basic assumption that there is an inhibitory tone in the CNS which needs to be reduced (deactivated) to allow sexual arousal to develop (Bancroft & Janssen, 2000). However, we should not expect such evidence to provide simple answers. Already, on the basis of limited evidence, it is apparent that sexual arousal, as we conceptualize it, involves a variety of processes, some of which are specific to sexual response and some which are involved in other types of emotional or motivational states.

New techniques of molecular genetics, which can identify individual variations in levels or potency of genetic factors linked to key neurotransmitters such as dopamine (Miller, Pasta, MacMurray, Chui, & Comings, 1999) or serotonin (Lesch et al., 1996), offer the potential for explaining individual differences in human sexuality, particularly if combined with more sexual response oriented approaches such as the dual control model.

THE ROLE OF SEX HORMONES

During childhood, the capacity for sexual response and the experience of sexual pleasure as well as the potential for orgasm exists, at least in a proportion of children. Whether this apparently variable potential among children reflects different learning experiences during childhood, different opportunities for realizing the potential, or different genetic influences is not known. The importance of gonadal hormones, in particular testosterone, in organizing early brain development and function has been discussed earlier. During childhood, gonadal steroid hormones are little in evidence, but from the ages of 9 or I0 years they start to increase as the child approaches puberty. From then on we have to consider the activating role of these hormones on sexuality, and the impact they have on sexuality during three stages of the life course: around puberty and during early adolescence, during adulthood until middle age, and during the later years.

In the male, the role of testosterone and related androgenic hormones is relatively well understood and straightforward for the adult phase of the life course, and less clear during the early and late phases. The onset of puberty has a major organizing effect on the emergence of sexual responsiveness and interest. Shortly before or shortly after puberty the large majority of boys start to masturbate (Bancroft, Herbenick, & Reynolds, in press; Kinsey, Pomeroy, & Martin, 1948), and for most of their teen years they remain at their maximum capacity for sexual arousability and response. This is, to a considerable extent, a result of the activating effect of the major increases in testosterone and other androgens that accompany and follow puberty. However, puberty is a complex process: There are both hormonal and physical changes as well as psychological and social reactions to such changes, and it is likely that during these early years of increasing testosterone the body is adapting to higher levels and at the same time developing and activating inhibitory mechanisms to allow control of these newly activated excitatory responses. This may explain why studies of the relationship between testosterone and the unfolding sexuality of the adolescent boy have produced complex and somewhat contradictory results (Halpern, Udry, Campbell, & Suchindran, 1993; Udry, Billy, Morris, Groff, & Raj, 1985). More research is required to throw light on this developmental stage. The evidence is relatively consistent, however, in showing that boys with an earlier onset of puberty also tend to show higher levels of sexual interest and activity when they are older (Halpern et al., 1993; Kinsey et al., 1948).

An adult male's continued interest in sex depends on his having a normal level of circulating testosterone. If an otherwise normal male has his testosterone lowered by testicular suppressive drugs, he experiences a decline in sexual interest, which returns when the process is reversed (Bagatell, Heiman, Rivier, & Bremner, 1994). In cases of testicular impairment (primary or secondary hypogonadism), when testosterone levels fall below the normal range almost all males experience a decline in sexual interest and capacity for ejaculation. This is reversed by testosterone replacement therapy. This is a robust, predictable finding across a substantial number of placebo-controlled studies. A similar pattern is observed with spontaneous erections during sleep, or nocturnal penile tumescence, which decline and return with testosterone withdrawal and replacement (Bancroft, 1988). These erections are interesting manifestations of the sexual arousability of the brain uncomplicated by cognitive processes, and this evidence clearly points to the role of testosterone in central sexual arousal mechanisms. It is important to emphasize, however, that normal levels of testosterone are necessary but not sufficient for normal levels of sexual desire. There are other factors which can inhibit or alter sexual desire in the presence of normal testosterone levels.

The role of testosterone then becomes less clear as men get older. There is a normal, but variable, tendency for testosterone levels to decline in men beyond the fifth decade, and this is often accompanied by an age-related decline in sexual interest. This is sometimes referred to inappropriately as the "male menopause." However, there is no clear evidence that this pattern can be reversed by testosterone replacement. It is possible that there is a decline in responsiveness to testosterone in addition to a fall in the hormone level (Schiavi, 1999).

There is also a common (though variable) age-related decline in erectile responsiveness, such that as men get older erections develop less consistently and are less strong and less well-sustained. The mechanisms for this are not well understood but may be related to changes in neurotransmitter responsiveness in the erectile tissues (Lerner, Melman, & Christ, 1993).

In the female, we find the relevance of hormones, particularly testosterone, to sexuality less clear at each of the three phases of the life course. First, there is not the same organizing effect of puberty on sexual interest and response as is found in boys. Interest in masturbation does not peak around puberty as it does in boys (Bancroft et al., in press-d; Kinsey, Pomeroy, Martin, & Gebhard, 1953) and age of onset of masturbation is much more widely distributed among females than males, suggesting a more variable constitutional propensity for sexual responsiveness and interest in females, with a proportion of females being affected strongly by hormones such as testosterone whereas others are affected weakly or not at all. Gifts are unlikely to engage in sexual intercourse before they reach puberty (Rowe, Rodgers, & Meseck-Bushey, 1989). As with boys, studies relating testosterone levels to emerging sexuality have produced conflicting results (Halpern, Udry, & Suchindran, 1997; Udry, Talbert, & Morris, 1986).

It is paradoxical that we have substantially more evidence of sex hormone-behavior relationships in adult women than in men, and many more opportunities to study them, with the normal menstrual cycle, the widespread use of steroidal contraceptives, the impact of pregnancy and lactation, and menopause, and yet, compared with the male, the picture remains unclear and the evidence often contradictory (Bancroft, in press-b).

With the menstrual cycle the most predictable pattern is for women to feel least interested sexually when they are menstruating. There are a number of possible explanations for this which do not involve hormonal effects. A proportion of women experience a predictable peak in sexual interest around ovulation, which would suggest hormonal determinants. But these women are a minority, and peaks premenstrually and postmenstrually are reported by some, while other women say that they are not aware of any consistent pattern (Hedricks, 1994).

The impact of steroidal contraceptives on the sexuality of women has been poorly studied. But there is evidence that in a proportion of women oral contraceptives (OC) reduce sexual interest (Graham, Ramos, Bancroft, Maglaya, & Farley, 1995), and such adverse effects are strong predictors of early discontinuation of oral contraceptive use (Sanders, Graham, Bass, & Bancroft, 2001). Whether such effects result from the invariable reduction of free testosterone that results from OC use, or from other effects of the OC, (e.g. progestagenic), has not yet been established. Clearly, in many women these negative effects do not happen and the freedom from fear of pregnancy may be associated with an enhancement of sexual pleasure and interest.

Lactation, or breast feeding, in many parts of the world acts as a birth spacer, partly because women who are relatively undernourished are likely to be infertile while breast feeding. In the developed world nutrition is not usually a problem, and women can get pregnant while breast feeding. However a proportion of women experience a decline in sexual interest following childbirth which may take a year or more before it returns to prepregnancy levels. This pattern is more likely in women who breast feed (Hyde, DeLamater, Plant, & Byrd, 1996). There are a variety of nonhormonal mechanisms which might account for this picture (e.g., the greater disruption of mother's sleep with breast feeding), but there is some evidence that breast feeding women who experience loss of sexual interest have lower levels of testosterone than those who do not (Alder, Cook, Davidson, West, & Bancroft, 1986).

In general, correlations between testosterone levels and various aspects of sexuality in women of reproductive age have been found in some studies but not in others (Bancroft, in press-b).

Although menopause is widely considered to have a negative impact on women's sexuality, the evidence is inconsistent, with recent studies tending to show that the decline in sexual interest that many women experience during their middle years is related to age rather than menopause per se (Cawood & Bancroft, 1996). There is little disagreement, however, that estrogens are necessary for normal vaginal lubrication, and the increase in vaginal dryness that is associated with menopause in many women probably results from reduced estradiol and is readily corrected by hormone replacement therapy. Untreated vaginal dryness can have negative effects on a woman's sexual relationship. Testosterone levels decline in the few years before menopause, but there is no consistent decline around menopause or after (Bancroft, in press-b)

Interestingly, the most convincing evidence of the effects of testosterone on women's sexuality comes from studies of women given testosterone after surgical removal of ovaries (Sherwin & Gelfand, 1987). In such cases testosterone will be much lower than in women with normal menopause, whose postmenopausal ovaries continue to produce significant amounts of testosterone. However, such hormone replacement studies have relied on supra-physiological levels of testosterone making it more difficult to use such evidence to explain the normal physiological role of testosterone in women's sexuality.

There are a number of possible explanations for this confused picture in women, including methodological shortcomings in many of the studies. The most plausible explanation, however, is that, compared to men, women vary in the impact that reproductive hormones have on their sexual interest and responsiveness. There may be a minimal level of testosterone which is necessary for most women and which requires the presence of ovaries to be maintained. But some women are probably particularly sensitive to the behavioral effects of testosterone, and are therefore more vulnerable to declining testosterone levels. Such women are likely to benefit from testosterone treatment. Other women are relatively unaffected by changing levels of testosterone, providing that the minimum levels are maintained. Women may vary in their sexual responsiveness to other hormonal mechanisms as well. Why should women be more variable than men in this respect? An explanation which is again plausible but not as yet proven is that men who are behaviorally unresponsive to their reproductive hormones are unlikely to reproduce, and hence such men will be selected out in the evolutionary process. Women, on the other hand, will continue to repro, duce whether or not they are sexually responsive to their reproductive hormones. As a consequence we may expect to find a more variable genetic pattern of sexual responsiveness in women. While such an explanation is plausible, it is not so easy to account for a genetically determined tendency being expressed in women but not in men. A theoretical explanation for this apparent conundrum, based on a desensitization of the central nervous system (CNS) to testosterone effects in the male during early development, has been proposed elsewhere (Bancroft, in press-c). There is much that we have to learn about the role of hormones in sexuality, particular in women.

THE SIDE EFFECTS OF DRUGS

Given the complexity of the brain, and its mechanisms of control, it is not surprising that any one mechanism is involved in a variety of different response patterns. Thus, mechanisms relevant to control of sexual response may also be relevant to control of other motivated behaviors such as eating or aggressive behavior. For this reason it is difficult to develop drugs which selectively influence specific aspects of brain function. As a consequence, drugs developed for one purpose have other unwanted or unintended side effects. Sexual side effects of drugs aimed at the CNS are not uncommon. Although biochemical mechanisms in the CNS are enormously complex, as previously discussed, we can consider drug effects which are likely to be predominantly central and those predominantly peripheral. We can also consider drugs which have serotonergic, noradrenergic, and dopaminergic effects. The best examples are modern antidepressants which involve inhibition of serotonin re-uptake (SSRI's such as fluoxetine; Rosen, Lane, & Menza, 1999). Such drugs commonly inhibit orgasm in women or delay ejaculation in men, and are even used to treat problems of rapid ejaculation. These effects reflect the predominantly inhibitory role of serotonin in the central control of sexual response, and the most clearly defined sexual inhibitory system in the CNS involves the nucleus paragigantocellularis in the brain stem and its descending projections to the spinal cord. This system clearly involves serotonin (McKenna, 1998), although serotonergic inhibition may well be involved in other mechanisms also. Dopaminergic drugs are relevant to central processes leading to response. Dopamine antagonists commonly result in loss of sexual interest or responsiveness, and dopamine agonists, such as apomorphine, have been used to enhance sexual response. Noradrenergic drugs have more complex actions, with the potential for alpha-2 effects enhancing central sexual arousal, and alpha-1 effects inhibiting peripheral response (Bancroft, 2000). Sexual side effects of hypotensive agents and diuretics are likely to involve peripheral mechanisms of various kinds. Drugs may interfere with sexuality via their effects on hormonal mechanisms; thus, some anticonvulsants reduce free testosterone by stimulating sex hormone binding globulin. Cimetidine, used in the treatment of peptic ulcers, disrupts the hypothalamo-pituitary-gonadal axis, and spironolactone, an aldosterone antagonist used for hypertension, also has an anti-androgenic effect (see Rosen, 1991, for review). Sildenafil (Goldstein et al., 1998), recently developed for the treatment of erectile failure, has its effects in the penile tissues by blocking the breakdown of the second messenger, cyclic GMP, in nitrergic mediation of vasodilatation. As yet there is no evidence that it has any relevant effects centrally.

THE INTERACTION BETWEEN THE INDIVIDUAL'S BIOLOGY, THE ENVIRONMENT AND CULTURE--CONCLUDING COMMENTS

As indicated earlier, the biological individual is interacting with his or her environment more or less from conception, and such interaction influences the continuing development of the nervous system well into childhood. We can consider the interaction between the individual and the environment at several different levels. There are biological influences from the environment--thus, sexual contact with a male partner on a regular basis, presumably as a result of pheromonal signals, increases the likelihood of a regular ovulatory cycle (Cutler, Garcia, & Krieger, 1980; Stern & McClintock, 1998); chronic stress can alter the neuropeptidergic system resulting in suppression of sexual interest or fertility (Herbert, 1996). There is the impact of learning, by which sexual response patterns are shaped. Such learning can basically result from immediate positively or negatively reinforcing consequences of behavior, where little cognitive processing may be involved. And there is the impact of culture. Here we can assume that learning plays a crucial mediating role; the culture provides guidelines or scripts for appropriate sexual responses, and the individual learns them accordingly. However, we also have to consider the possibility that one cultural group, particularly if it is relatively specific and genetically homogeneous, may carry with it a different set of genetic determinants than another cultural group.

Although we have a certain amount of evidence of the effects of environment on the biological individual, we have very little that addresses the interaction between culture and biology. Lock (1998) has studied women's experience of menopause in different cultures, finding that both the social construction of menopause and its significance to a woman's status in society, and its physical manifestations (e.g., vasomotor symptoms) vary across cultures. Two studies that involved the author are more directly relevant to sexuality. Graham et al. (1995) studied the effects of oral contraceptives (OC) on two groups of women, one from Scotland, the other from the Philippines. Negative effects of the OC on sexuality was observed in the Scottish but not in the Filipino women. It is not yet clear whether this difference was due to methodological inadequacies (we may not have been using the most appropriate methods of assessment for the Filipino women), differences in the scope for OC effects (the Filipino women reported more negative sexual lives at baseline), or a cultural impact which resulted in the Filipino women reacting differently to the OC hormonally mediated effects. In another study (Anderson et al., 1999), the effects of testosterone replacement for hypogonadal men were compared in a group of men from Scotland and another group from Hong Kong. The results of androgen withdrawal and replacement which had been demonstrated in a series of studies in Europe and North America, were as expected in the Scottish men, but much less marked in the Hong Kong subjects. Once again, we do not have an adequate explanation for this difference, but it is conceivable that the cultural environment of Hong Kong would influence male sexuality in such a way that the direct effects of testosterone would be experienced differently. There is a great need for more systematic study of the interaction of biology and culture in many aspects of human sexuality. Until progress is made in this respect, we will remain with a very partial understanding of the human sexual condition.

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John Bancroft
Indiana University

Address correspondence to John Bancroft, M.D., Director, The Kinsey Institute for Research in Sex, Gender and Reproduction, Morrison Hall 313, Indiana University, Bloomington, IN 47405; e-mail: [e-mail].