Milton Diamond Ph.D., Teresa Binstock, and James V. Kohl
From Fertilization to Adult Sexual Behavior
Originally published in: Hormones and Behaviour, 30, 333-353 (1996)
This paper is dedicated to Robert (Bob) W. Goy, upon his retirement. Bob himself dedicated much of his life to understanding sexual behavior.
Research has established the broad mammalian developmental plan that genes on the sex chromosomes influence gonad development which determines gonadal hormone production (or its absence) leading to modification of the genitalia and simultaneously biasing the nervous system to organize adult sexual behavior. This might be considered the “gonad to hormones to behavior” model. It is clear, however, that although this model generally works well it is incomplete. The model does not account for behavioral influences attributed to the environment or to genetic but nongonadal or hormonal factors. In this essay we probe those areas of sexual development that are neither differentiated by hormones nor activated by them. The concept of the environment used for our discussion is very broad; it incorporates considerations of both the molar and the molecular levels. The general sense of the word “environment” as something exterior to the person is retained, even if that something influences intraperson processes. In addition, we focus directly on molecular events themselves. Here the “environment” involved can be that within a DNA segment. We also expand the notion of “biologically based sex differences.” Although many, and perhaps most, important sex differences arise from gonadal and hormonal development, also important are sex differences which are neither gonadal nor hormonal. All these factors affect the internal workings of the individual and intervene in structuring how the social environment might or might not modify sexual behavior. This discourse calls attention to features that are central to the so-called nature-nurture discussion.
As the millennium approaches and a respected leader in our discipline retires at about the same time, it is fitting to reflect on some seminal issues in the field of behavior. One major issue is to comprehend, particularly in regard to behavior, factors which are important influences on sexual expression and the development of sex differences. A series of major breakthroughs occurred some four decades ago that had many, at least among the more biologically minded behaviorists, believing that such an understanding would soon be with us. Unfortunately, the feeling was premature. It is the purpose of this discourse to discuss aspects of sexual development and to offer insight as to why understanding such processes is much more complicated than initially assumed.
Historically one of the first breakthroughs was the determination by Jost and colleagues (Jost, 1953, 1961) that the fetal gonad, responding to its genetic endowment, elaborates substances that can influence the development of the internal and external genitalia. A second milestone can be considered the findings, in 1956 by Tjio and Levan, that the typical human chromosomal complement contained 46 chromosomes: 44 autosomes and the sex chromosomes, XX for females and XY for males. This clarification of basic genetics gave hope that further related discoveries would soon follow. A third milestone was provided by the findings of Phoenix, Goy, Gerall, and Young (1959) that endogenous prenatal hormones are crucial in the organization of adult sexual behaviors. Such hormonal actions were seen powerful enough to structure (organize) behavior patterns that would be manifest (activated) at puberty or after.
These now-classic papers, along with many others, established the broad developmental plan that, at least for mammals, the following pathway occurs: genes on the sex chromosomes influence gonad development which determines gonadal hormone production (or its absence) leading to modification of the internal and external genitalia and simultaneously biasing the nervous system to organize adult sexual behavior (see e.g., Goy and McEwen, 1980). Even body morphology was supposed to follow along with this paradigm of sexual differentiation. This might hereafter be considered the classical “gonad to hormones to behavior” (Gd–H–B) model.
It soon became clear, however, that although this model worked well in broad strokes it was incomplete; many exceptions were obvious. For instance, the model did not account, in as ready a way, for other possible influences; i.e., those attributed to the environment or to genetic but non-Gd–H–B factors. For example, even among monozygotic twins reared together, while indeed most do parallel each other for as basic a trait as sexual orientation, a significant number are not concordant for androphilia or gynecophilia or even body configuration (Bailey and Pillard, 1995; Whitam, Diamond, and Martin, 1993). Clearly, additional factors intercede in the path from fertilization to adult phenotype.
Some further questions seemed to also arise to challenge a simple Gd–H–B paradigm. For instance, if prenatal androgens modify morphology directly and sexual behavior indirectly via the nervous system, why do we see some very masculine appearing men who are androphilic and some feminine appearing females who are gynecophilic? Either (i) homosexual effeminate males and masculine females or (ii) heterosexual masculine men and effeminate women would seem to better fit the model. Similarly the model does not account for individual women with the complete androgen insensitivity syndrome (CAIS) who are gynecophilic.
Typically, experiments to probe the workings of the Gn–H–B model introduce hormones or other drugs to prenatal or paranatal animals and then test them later in development. We will not go into that large body of data here. One set of studies, however, deserves mention since, like the human findings mentioned above, it directly challenges Gn–H–B expectations. Goy, Bercovitch, and McBrair (1988) exposed female fetuses to testosterone propionate either early or late in gestation. Their results indicate that the genitals of the early androgen treated females were virilized and those of the late treated females were not. Behaviorally, the late treated females, unlike the early treated ones, showed male-like elevated rough play and mounting with peers and the absence of a preference for male partners. The early treated females did not show such behaviors. These results indicate the androgen given to the late treated females altered their sexual preference as well as play and mounting behaviors without altering their genitalia. The early treated females, in contrast, had their genitals altered but not their sexual preferences. The structure of the genitals did not coincide with the sexual behavior displayed. Other experiments revealing discrepancies in the simple Gn–H–B model can be cited. These results have implications relative to different human conditions such as transsexualism, the congenital adrenogenital hyperplasia (CAH) syndrome, intersexualism, and perhaps homosexuality as well.
Interestingly, while mammals do seem to at least generally follow the Gn–H–B model, other vertebrate genera such as fish and amphibia follow a different one. In many of these species the paradigm which evolved is more like: genes prepare the individual to react to the environment which will bias the nervous system which will then lead to gonadal development and hormone release and this will influence adult behavior. A further significant difference between these two models is that, for mammals, once adulthood is reached, the processes are relatively fixed. Among many non-mammalian species, on the other hand, this is not so. The individuals can remain quite sensitive to the environment. Two examples are illustrative. Among certain turtles, females will develop at extreme hot and cold temperatures and males at moderate temperatures (Bull, 1983; Gutzke and Paukstis, 1984; Yntema, 1976). The reef fish Thalasoma duperrey is usually born as a female with appropriate coloration, behavior, and production of eggs. If there is no larger male in her visual vicinity, and there is a smaller conspecific female nearby, she will become a sperm producing male with male coloration and behaviors (Ross, Losey, and Diamond, 1983). We predict that humans will basically follow the mammalian model but maintain aspects of evolutionary development which show sensitivity to environmental influences.
Goy and McEwen (1980), for mammals, have classified sex differentiated aspects of behavior into three categories: (1) those that are differentiated by hormones and are activated by hormones; (2) those that might be differentiated independent of hormones but require activation by hormones; (3) those that are influenced by hormones during differentiation but do not require activation by hormones. To these three we add a fourth: (4) those that are neither differentiated by hormones nor activated by them. The focus of this paper is on processes associated with this last item.
An additional thought is appropriate here. The concept of the environment used for our discussion is very broad; it incorporates considerations of both the molar and molecular levels akin to those first envisioned in the classical psychological work of Tolman (1932). We note that environmental influences, e.g., family, society, education, can at the sight of an attractive and arousing sexual partner, induce change in gene expression, can change how neurotransmitters release, and can change long-term potentiation (Artola and Singer, 1993; Hawkins, Kandel, and Siegelbaum, 1993; Tolle, Schadrack, and Zieglgänsberger, 1995). To most people participating in the nature-nurture debate, the general sense of the word “environment” is something exterior to the person, even if that something influences intraperson processes. We retain that “molar” (whole organism) meaning.
In addition we focus directly on molecular events themselves. These include such things as the reshaping of DNA by proteins derived from homeobox genes—e.g., SRY, SOX9, etc. (Burgoyne, Thornhill, Boudrean, Darling, Bishop, and Evans, 1995; Schafer, Dominguez-Steglich, Guioli, Kwok, Weller, Stevanovic, Weissenbach, Mansour, Young, Goodfellow, Brook, and Foster, 1995). Here the “environment” involved is that of the DNA-segment in question. Unlike Tolman we reject the notion that any of these events are either purposive or cognitive.
For our immediate discussion, we also expand the notion of “biologically based sex differences.” Although many, and perhaps most, important sex differences arise from gonadal and hormonal development, also important are genetic sex differences which are neither gonadal nor hormonal. The totality of these factors affects the internal workings of the individual and intervenes in structuring how the external environment (weather, parents, peers, culture, advertisements, and so forth) considered by social scientists and others might or might not modify sexual behavior. We take for granted that any environmental factor has to somehow interact with a biological substrate to have an influence on an individual’s behavior (Diamond, 1965, 1979). On the other hand, we ignore in this discussion topics like positive or negative prejudice or other social (environmental) forces dealing with biological features of race, appearance, and the like.
From the preceding comments, it is apparent that this discourse calls attention to features that are central to the so-called nature-nurture or heredity-environment discussion. In such discussions, nature and heredity are often thought of simply: “nature” is often equated only with gonadal-ridge and gonad development and subsequent forces and “nurture” is equated only with upbringing and social factors. We are, herewith, greatly enlarging the scope of consideration.
Last, this paper is not intended as an extensively documented review of all such factors. Instead, we present and discuss a host of vectors that can modify an overly simple Gd–H–B construct and suggest a more complicated but realistic prototype. In doing so we divide the body of our paper into three broad concept areas: The Inner World; Inner and Outer Worlds Meet; and The Outer World. We then follow with an overall discussion and some conclusions.
THE INNER WORLD
In addition to the classical consideration given to the roles of the X and Y chromosomes, gonads, and hormones typically discussed in sexual development, three additional topics shall be considered in the internal environment: genomic sexual dimorphisms, neurosteroids, and immunological factors. Encoded genomically in ways independent of gonads and hormones, each of the three factors is present and has potential for modulating the more traditionally considered gonadal and hormonal events.
There is a tendency to discuss only a limited number of genes as participants in sexual differentiation; the most prominent being the presence or absence of SRY. This does not do justice to the complexity of sexual development and biological sex differences. For instance, there are molecular differences between specific homologous genes on the X and Y chromosomes (Fisher, Beer-Romero, Brown, Ridley, McNeil, Lawrence, Willard, Bieber, and Page, 1990; North, Sargent, O’Brien, Taylor, Wolfe, Affara, and Ferguson-Smith, 1991; Schneider-Gadicke, Beer-Romero, Brown, Mardon, Luoh, and Page, 1989; Weller, Critcher, Goodfellow, German, and Ellis, 1995; Zinn, Alagappan, Brown, Wool, and Page, 1994). Some genes exist on the Y and have no counterpart on the X, and certain nongene structural elements on the X and Y are sex-linked (Smith, Young, Talbot, and Schmeckpeper, 1987; Wolfe, Darling, Erickson, Craig, Buckle, Rigby, Willard, and Goodfellow, 1985). These numerous sets of genes and structural features of the X and Y chromosomes are sex differences which exist independently of the Gd–H–B pathway.
Sexually dimorphic genes (some prefer the term sex-linked genes), and their dimorphic proteins. It is generally understood that most genes code for the synthesis of specific proteins. Another example of biological sex differences which are neither gonadal nor hormonal, however, is provided by the homologous but dimorphic zinc finger proteins ZFX and ZFY encoded on the X and Y chromosomes (North et al.,1991). An early study of human expression of ZFX and ZFY reported different transcript sizes from the two genes and this difference was even apparent in somatic tissues (Page, Disteche, Simpson, De La Chapelle, Andersson, Alitalo, Brown, Green, and Akots, 1990). ZFX and ZFY are described as “DNA-binding proteins” and via their binding of sexually dimorphic proteins, chromatin structure and transcription could be modulated in sexually dimorphic ways as a result of females having only ZFX binding events, whereas males would have a mixture of both ZFX and ZFY binding events (Fiddler, Abdel-Rahman, Rappolee, and Pergament, 1995; Lau and Chan, 1989; Zwingman, Erickson, Boyer, and Ao, 1995).
Similarly, ribosomal proteins S4X and S4Y (rpS4X, rpS4Y) are produced by sexually dimorphic genes whose protein products are sexually dimorphic. This suggests the possibility of subtle nuances in the ribosomal translation of at least some mRNA, in certain cell types (Fisher et al.,1990; Zinn et al., 1994).
The Genome, positioning, timings. There are major structural differences between the X and Y chromosomes; e.g., centromeric aiphoid repeats sequences and distribution of heterochromatin (Graves, 1995; Wolfe et al., 1985). These structural differences correlate with sexually dimorphic chromosomal positioning within the nucleus and with male/female differences in replication timing of the active X, the inactive X, and the Y chromosomes, e.g., Boggs and Chinault (1994), Clemson and Lawrence (1996); Hansen, Canfield, and Gartler (1995). Increasingly the structure and timings within the nucleus are realized as contributing to gene expression regulation (Manders, Stap, Strackee, van Driel, and Aten, 1996; Stein, Stein, Lian, van Wijnen, and Montecino, 1996).
Molecular distance. As measured in centimorgans, human and other species’ male and female chromosomes, including the autosomes, tend to have different lengths in various segments. To some extent, this suggests a correlation with physical distance but instead the differing lengths are based upon rates of recombination; although sections of most female chromosomes are longer than their homologous counterparts in male chromosomes, in some segments of various chromosomes opposite length-difference occurs, with males having larger centimorgan values than females in those regions (Lawrence, Collins, Keats, Hulten, and Morton, 1993; Murray, Buetow, Weber, Ludwigsen, Scherpbier-Heddema, Manion, Quillen, Sheffield, Sunden, and Duyk, 1994; Straub, Speer, Luo, Rojas, Overhauser, Ott, and Gilliam, 1993). While ramifications of these centimorgan sexual dimorphisms are not yet clearly established, in recent years cis- and trans-acting factors contributing to these recombination length differences have been reported for a specific part of the murine major histocompatibility complex (MHC) (Shiroishi, Sagai, Hanzawa, Gotoh, and Moriwaki, 1991).
Molecular epigenetics. It is now understood that certain genes undergo a process called “genomic or parental imprinting.” Early in embryonic development attached methyl groups become removed from most genes. Several days later, methyl groups are reattached in appropriate sites. Fascinatingly, some such genes reestablish methylation patterns based upon whether the chromosomal segment carrying the gene came from maternal or paternal chromosomes. These sexually dimorphic patterns are labeled genomic or parental imprinting, and these imprintings are inheritable but non-genetic modifications of specific genes (Razin and Shemer, 1995; Reik, 1989; Surani, 1991; Zuccotti and Monk, 1995).
There are at least 16 known genomic-imprintings in the human genome and each particular imprint depends upon whether the chromosome is of maternal or paternal origin (Hurst, McVean, and Moore, 1996). Furthermore, these inherited imprintings are physiologically important and are capable of sex-specific effects as evidenced in the Prader-Willi and Angelman syndromes (congenital disorders with physical and mental characteristics) derived from imprinting anomalies in a specific region of chromosome 15 (Driscoll, Waters, Williams, Zori, Glenn, Avidano, and Nicholls, 1992).
Genomic-imprinting is also manifest in specific parts of the X-inactivation region’s related XIST gene. Here male- and female-specific methyl-group patterns participate in X-inactivation in females and also in the preferential inactivation of the paternal X in human placentae of female concepti (Harrison, 1989; Monk, 1995). This process indicates that tissues of the early conceptus can sense and react differentially to epigenetic sexual dimorphisms on the female conceptus’ own two X chromosomes. Furthermore, variations of X-inactivation patterns often account for traits discordance in monozygotic twin females. In other words, they are often found to have nonidentical patterns of X-inactivation, yielding differing expression of noticeable X-linked traits (Machin, 1996).
Pollard (1996) has hypothesized that sexual orientation may be encoded within imprinted genes. In a manner that also challenges the Gn–H–B paradigm she posits that genomic imprinting, as a preconception event, enables a gene to be “able to switch through different states of potential activity from the incomplete to the fully penetrant state resulting in a continuum of orientations ranging from asexual, through graded bisexual to homosexual” (p. 269). And she envisions these modifications to be potentially prompted by social environmental events.
Yet another kind of epigenetic imprinting occurs in species as diverse as yeast, Drosophila, mice, and humans and is based upon small DNA-binding proteins called “chromo domain” proteins, e.g., polycomb. These proteins affect chromatin structure, often in telomeric regions, and thereby affect transcription and silencing of various genes (Saunders, Chue, Goebl, Craig, Clark, Powers, Eissenberg, Elgin, Rothfield, and Earnshaw, 1993; Singh, Miller, Pearce, Kothary, Burton, Paro, James, and Gaunt, 1991; Trofatter, Long, Murrell, Stotler, Gusella, and Buckler, 1995). Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans (Adler and Hajduk, 1994; de Bono, Zarkower, and Hodgkin, 1995; Ge, Zuo, and Manley, 1991; Green, 1991; Parkhurst and Meneely, 1994; Wilkins, 1995; Wolfner, 1988). That similar proteins perform functions in humans suggests the possibility that some human sex differences may arise from alternative splicings of otherwise identical genes.
A potential ramification of epigenetic imprinting and alternative splicing may be occurring in Xq28, a chromosomal region implicated in homosexual orientation (Brook, 1993; Hu, Pattatucci, Patterson, Li, Fulker, Cherny, Kruglyak, and Hamer, 1995; Turner, 1995). Xq28 contains one of the X chromosome’s two pseudoautosomal regions (PARs), adjoins the telomere, and has various means of gene expression control (D’Esposito, Ciccodicola, Gianfrancesco, Esposito, Flagiello, Mazzarella, Schiessinger, and D’Urso (1996). Xq28, therefore, is a chromosomal region that has many of the heterochromatic and telomeric characteristics that participate in sexual determination and behavior in other species.
Researchers have long known that gonadal and adrenal steroids affect the development and function of the central nervous system (CNS) (Gandelman, 1992; McEwen, 1983) and are best labeled as “neuroactive steroids.” Relatively new, however, is the realization that various portions of the CNS itself can produce steroids and can do so independently of the gonads and adrenals (Baulieu and Robel, 1990; Roselli, 1995). These “neurosteroids” (steroids produced by neurons) have been reported in the fetal brain, suggesting localized organizational effects (Kabbadj, el-Etr, Baulieu, and Robel, 1993). Activational effects in sexual behavior have also been shown for neurosteroids (Genazzani, Palumbo, de Micheroux, Artini, Criscuolo, Ficarra, Guo, Benelli, Bertolini, Petraglia, and Purdy, 1995), even at intermediate levels of a steroid conversion sequence (Kavaliers and Kinsella, 1995).
Though neurosteroids research is relatively new, certain findings already are important. For instance it is now known that (i) the enzymes that produce neurosteroids are transcribed from the same genes that produce gonadal and adrenal steroids (Compagnone, Bulfone, Rubenstein, and Mellon, 1995b; Mellon and Deschepper, 1993); (ii) transcription regulation for neurosteroidal enzymes is different from gonadal and adrenal regulatory processes (Zhang, Rodriguez, and Mellon, 1995); (iii) within discrete brain nuclei, some subareas differ with regard to utilization of neuro- and nonneurosteroids (Compagnone et al., 1995a; Roselli, 1995); and (iv) even early stages in the neurosteroid route from cholesterol to various end-product steroids affect sexual perceptions and behavior (Kavaliers and Kinsella, 1995).
Ramifications of such neurosteroid findings are diverse. For instance, they suggest nuances of reinterpretation may be in order regarding past data from gonadectomy and adrenalectomy experiments. Endogenous neurosteroid production may have contributed to results described in many experiments wherein gonadectomized animals who were subsequently administered powerful cross-hormone regimens nonetheless retained bisexual-like responses both to males and to females (e.g., Brand, Houtsmuller, and Slob, 1993; Vega-Matuszczyk, Fernandez-Guasti, and Larsson, 1988) or they may have effected the persistence of typical sexual activity seen after castration in some species (Young, 1961).
Perhaps significantly, neuron-specific transcription regulation of neurosteroidogenic enzymes and subsequent neurosteroids production suggest clues to mechanisms that allow some persons to develop in accord with typical gonadal male-pattern or female-pattern hormones and have appropriate male-typical or female-typical physiques nonetheless have parameters of their sexual behavior profile quite opposite to their physical phenotype. For instance, it might be possible for local neurosteroid action in CNS loci specific for sexual orientation to operate independently of other hormonal production and separately from gross body morphology in general. This could, for instance, account for different manifestations of transsexualism and homosexuality.
The immune system has long been known to perceive certain sexual differences, e.g., the presence or absence of H-Y antigen (Simpson, 1991). Mice have been shown to enact kin selection on the basis of major histocompatibility complex characteristics within the perceiving mice and from other mice as chemosensitive identified. Humans have been shown to possess similar immune- related chemosensitive skills (Gilbert, Yamazaki, Beauchamp, and Thomas, 1996; Wedekind, Seebeck, Bettens, and Paepke, 1995).
Gilbert’s group found that humans could detect differences in individual chromosomes from otherwise syngeneic mice, including on the basis (i) of differing X or Y chromosomes or (ii) of differences introduced as nonidentical MHC haplotype (Gilbert et al., 1996). Wedekind et al. (1985) found that human females who were not taking oral contraceptives would select male-scented T-shirts in direct relationship to the males’ MHC-haplotypic difference from each perceiving female’s own MHC-haplotype. This indicates a dual awareness by the perceiver, i.e., of her own haplotype and of haplotypes sensed as different from her own. These findings establish that immunological components have the capacity, at a subconscious level, to contribute to adult human sexual interactions.
That humans possess such an ability to discriminate is at least consistent with the findings of Blanchard and colleagues (Blanchard and Bogaert, 1996; Blanchard and Zucker, 1994) who reported that sons born later in birth order to mothers who had already given birth to other sons, have a statistically higher likelihood of displaying an androphilic orientation. Not only are the Blanchard et al. findings consistent with an intrauterine immunological contribution to sexual orientation, but a mechanism for altered maternal interactions with subsequent male concepti is provided by the finding that cells derived from male fetuses have been found living in human maternal blood as early as the first trimester and as long as 27 years subsequent to the birth of a male child (Bianchi, Zickwolf, Weil, Sylvester, and DeMaria, 1996; Liou, Pao, Hor, and Kao, 1993). Such cells provide a basis for which maternal responses to Y-chromosome material would differ in regard to each subsequent conceptus.
As MHC components provide a new and exciting focus of sexological research they also prompt many questions. For instance, in what cells and by what processes does MHC recognition occur? Similarly, what are the cells and processes by which chromosome recognition occurs? Are such perceptions interpreted primarily in the brain? Or do those perceptions and recognitions occur primarily as intranasal molecular events which are then transmitted to the brain? Are MHC-related perceptions and recognitions mediated by olfactory or vomeronasal (VNO) tissues or is there additional participation by immunological tissues—tissues (i) long known to exist within the nasal cavity, and (ii) highly specialized for MHC-based interacting with molecules arriving from exogenous sources (Korsrud and Brandtzaeg, 1983)? This topic will reappear below. In any case, these several immunological findings and the presence of MHC-encoded, sexually dimorphic immunological tissues in both the nasal cavity and epidermis have prompted at least one researcher to formulate an immunological hypothesis of sexual and gender orientation (Binstock, 1996).
Other modifications to normal prenatal development can occur directly and indirectly from hormone, nutritional, or drug effects. These are not dealt with in our present purview.
INNER AND OUTER WORLDS MEET
All higher organisms are endowed with specialized sensory systems with which they interact with the world. The question arises: Are mammals, as are fish, amphibia, and other vertebrate species, sensitive to these sensory stimuli not only for everyday responses but for the organization of behavior? Intuitively, social-environmental sensory stimuli seem admirably suited for the activation of behaviors. Indeed the basic “stimulus-response” paradigm typically envisions a signal from the social environment as the stimulus provoking a response.
Evidence in mammals for such external stimuli organizing behavior involves several standard concepts. Classically the Gd–H–B model described for the “Inner World” does not speak of repetition or consider it although it might. This can be the counterpart to the duration of the stimulus, say of gonad on hormone production for the release of Müllerian inhibiting substance or testosterone. The notion or concern with this is dealt with under a rubric of “critical” or “sensitive” periods or intervals wherein a brief time span is shown to exist during which the influence of the “inducer” is maximum. We envision something of that order exists also for young mammals paranatally.
The common understanding of conditioning stimuli holds that repetitions of the crucial signal are needed contiguous with an event or response so the two can be paired (Black and Prokasy, 1972). Conceptually, once established, this can be said to be an organized response. Hypothetically we can also envision organization of a response that is activated by conditioning stimuli initially paired to elicit organization. For instance, Jakacki, Kelch, Sauder, Lloyd, Hopwood, and Marshall (1982) have shown that prepubertal children secrete luteinizing hormone (LH) and presumably gonadotropin-releasing hormone (GnRH) in a pulsatile manner, well before physical evidence of sexual maturation is apparent. Since the neuroendocrine mechanisms for the control both of gonadal and, in part, of adrenal steroidogenesis are active, if the Gd–H–B model is influenced by social-environmental sensory stimuli before puberty occurs, such stimuli also would be capable of influencing long-term behavior.
It is fair to also at least mention in this discussion the classical concept of “imprinting” as made famous by Konrad Lorenz and his following geese and ducks (Lorenz, 1935). This refers to the phenomenon, very different from our earlier discussion of “genomic-imprinting,” that soon after birth an animal can become attached to another animal or object by just being in its presence at a critical time. It will thereafter continue to associate itself with the paired stimulus. In Lorenz’s case it was he, near the goose eggs when they hatched, who was thenceforth seen to be taken as the goslings’ “mother.” The mother goose herself had previously been far removed from the nest. The goslings would then follow Lorenz everywhere (Lorenz, 1935). Such a dramatic one-time visual stimulus-response pairing, which can lead to a permanent behavior pattern, has never been documented in mammals (despite anecdotal reports of “love at first sight”).
Griffith and Williams (1996) have, however, partially detailed the “imprinting-like” importance of olfaction and vision in the adult-to-infant maternal bond established between a cow and her calf. They find “… the inhibitory influence of suckling on LH secretion can be sustained only in the presence of olfactory and/or visual signals unique to the cow’s own calf” (p. 767). The cow’s development of selectivity for her calf can be established in fewer than five minutes. Similarly, the development of a ewe’s selectivity for her lamb can be established in about two hours. This selectivity in sheep seems to be more dependent upon olfactory than visual stimuli. Griffith and Williams note: “In all species studied, olfaction is a critical factor in the cascade of physiological and behavioral events leading to the development of maternal selectivity” (p. 767). Maternal selectivity may be comparable to a human mother’s bond with her child.
Social-environmental cues during sexual experience may work on a broad range of levels that allow sensory mechanisms to influence information processing. Once processed, sensory information can be exploited by using socially determined behavioral codes. For instance, the lordotic posture of a female is a sensory cue that can facilitate as well as elicit copulatory behavior from the male. Sensory rewards that are experienced during copulation will then reinforce the coding of his behavioral response. However, neither the relative functional importance of visual, auditory, tactile, or chemosensory (e.g., gustatory and olfactory) cues, nor the effects of previous sexual experience on mammalian behavior, are completely known for any species. Furthermore, the influence of culture on human behavioral responses to sensory stimuli is a confounding factor in attempts to establish a causal relationship between either a particular sensory signal or a collection of sensory signals and any behavioral response that may be elicited.
We consider two broad categories of stimuli in this present discussion: the chemical senses of olfaction and gustation, and the visual, tactile, and auditory senses.
Chemical Senses: Olfaction and Gustation
Personal experiences and numerous experiments leave little doubt that chemosensory preferences, taste or smell, can vary widely and that these perceptions are mediated by genetic heritage (Bartoshuk and Beauchamp, 1994). For instance some people are tasters and others not, some are smellers and others not. Without the essential genetic coding for chemosensory perception there can be no development or learning of either olfactory or taste preferences.
While the chemical senses include taste, there is no evidence that taste can, in any way, organize or structure sexual behaviors. In one experiment to assess the effect of reducing oral-genital sensations on the copulatory behavior of hamsters, by removing the anterior half of the male hamster’s tongue, it was found the time spent in anogenital behaviors was reduced while self-grooming of the penis increased but no other feature of the male or female copulatory behavior was affected (Diamond and Henderson, 1980). It is also interesting to note that paranatal hormones administered to rats influenced adult oral-genital behaviors independently of other sexual behaviors (Diamond, Llacuna, and Wong, 1973).
Clearly the development, either of olfactory or of taste preferences, depends on genetics, gestational, and life-long associations with olfactory stimuli. In any case it is generally accepted that the two modalities of the chemical senses: taste and olfaction, are physiologically integrated. Also, the olfactory contribution to reproductive behaviors, especially that of the accessory olfactory system, has been demonstrated in hamsters, mice, and rats. Removal of the vomeronasal organ impairs mating behavior (for review see Meredith and Fernandez-Fewell, 1994). In the unlikely event that taste influences sexual expression, we will assume, for the present discussion, that it does so via an association with olfaction.
Attention to olfaction, rather than taste, is more likely to reveal organizing influences on sexual behavior since the perception of taste is generally believed to be hard-wired and evolutionarily consistent in response; e.g., sweet is pleasant and bitter unpleasant (Desor, Miller, and Turner, 1973, 1977), while the sense of smell seems immensely modifiable and conditionable by experience. This contrast has been emphasized by finding there are no innately pleasant or unpleasant odors (Engen, 1982) and odor conditioning can occur in utero and certainly within the first few days of birth (Van Toller and Kendal-Reed, 1995). Indeed, rat pups tested immediately after birth or after cesarean section, were found to prefer the odor of their mother’s amniotic fluid over another mother’s (Hepper, 1987). Studies on different animal species revealed that young animals will prefer flavors experienced in utero and in mother’s milk (Mennella, 1995). Whether similar mechanisms work in the human is not known (Mennella, 1996). The ability of individuals to learn prenatally about such tastes/odors is conjectured to be of particular importance in the development of kin recognition, ensuring that individuals learn about genetically related conspecifics (Hepper, 1987). What other such preferences are organized prenatally or neonatally have yet to be uncovered.
In the search for potential organizing effects of chemosensory stimuli it is beneficial to keep in mind our new understanding about odor perception. Previously it had been thought that odor was perceived in a manner similar to color; a small number of receptors would yield different perceptions depending upon the proportion of receptors stimulated by a given odorant. It is now believed, however, that odor perception is more akin to the immune system workings where multitudes of receptors are each uniquely responsive to chemical structures (Bartoshuk and Beauchamp, 1994; Buck and Axel, 1991). Moreover, these receptor proteins are chemically and structurally similar to those that bind neurotransmitters and hormones (Buck and Axel, 1991). Thus, the immunological forces spoken of under the heading of “The Inner World,” such as those associated with MHC, can interact with the stimuli to which we now attend. With appropriate feed-back mechanisms, one might expect social-environmental sensory stimuli to also modify sensory receptors.
Such reciprocity has been demonstrated. For example, Wysocki and Beauchamp (1984) have shown that the human ability to detect the boar pheromone: androstenone is, in part, genetically determined. However, sexually dimorphic changes in the ability to perceive androstenone occur with age and experience. Most children can detect androstenone, but 40-50% of adults cannot. Furthermore, the detection threshold decreases from 9- to 14-year-olds to age 20 in females but increases with age in males. Nonetheless, androstenone sensitivity can be induced in some people with exposure. A hypothesis that may explain these changes in sensitivity and these sex differences is that a genetic factor in olfactory receptor development elicits specific anosmia to androstenone due to hormonal effects on genes or their protein products (for review see Dorries, Schmidt, Beauchamp, and Wysocki, 1989). This hypothesis is consistent with evidence. Wang, Wysocki, and Gold (1993) showed that repeat exposure to androstenone and to isovaleric acid can induce olfactory receptor sensitivity in mice via stimulus-induced plasticity in olfactory receptor cells. Thus, it appears that olfactory sensitivity to at least some odors can vary from no sensitivity to markedly heightened sensitivity during the life cycle and that some sex differences in the organization of olfactory sensitivity can occur.
In this regard it seems important to emphasize that chemosensory communication is ubiquitous throughout life among species from single celled yeasts to primates, including humans (see for review Kohl and Francoeur, 1995). Chemical stimuli, odors, including pheromones, are essential components of reproductive sexual behavior in most, if not all, species. Pheromonal communication has been seen to elicit physiological and behavioral changes that benefit both male and female individuals and, in humans, these olfactory sensations seem to exert their influence whether or not an individual is conscious of odor detection.
Evolutionary conservation, both of pheromonal communication and its importance to behavior, is indicated by the involvement of a key mammalian reproductive hormone. For instance, a yeast pheromone, the alpha-mating factor, is very similar in structure to mammalian gonadotropic releasing hormone (GnRH). When injected into rats, this chemical binds to pituitary GnRH receptors and brings about the release of LH. Loumaye, Thorner, and Catt (1982) note: “GnRH and the yeast alpha-mating factor appear to represent a highly conserved effector system which includes the peptide ligand, the cell-surface receptor, and the physiological regulation of reproductive function” (p. 1325).
Extending this finding to mammalian development we note that from its embryonic origins, the hypothalamic GnRH pulse influences the maturation of the mammalian reproductive system, the neuroendocrine system, and the central nervous system. Though far removed from yeast in ontogeny and phylogeny, the mammalian model, including human studies, supports a role for chemosensory communication that appears to extend to a causal relationship among human pheromones, olfaction, the hypothalamic GnRH pulse, other hormones, including steroid hormones, and human behavior (Kohl, 1996). The following findings are offered as evidence.
GnRH cell development. In human embryos GnRH cell development matches a vertebrate-wide pattern, from fish onward. These neurosecretory neurons originate in the epithelium of the medial olfactory pit and migrate into the brain along a migration route formed by the central processes of the terminal (nervus terminalis) and vomeronasal nerves (Schwanzel-Fukuda, Crossin, Pfaff, Bouloux, Hardelin, and Petit, 1996).
Intracerebral GnRH response. Mammalian pheromones from opposite sex conspecifics typically influence a pulsatile intracerebral GnRH response (Meredith and Fernandez-Fewell, 1994) and subsequent increases in serum LH and/or testosterone in the males of several mammalian species (Meredith and Howard, 1992). Similarly, male pheromones may influence the LH secretion of females (Vandenbergh, 1994). Supporting these findings, olfactory stimuli appear to activate the immediate early gene c-fos (Guthrie, Anderson, Leon, and Gall, 1993). In signal transduction systems, c-fos appears to couple short-term intracellular signals elicited by a variety of extracellular signals to long-term responses by altering gene expression. This cascade has been linked to behavioral change (e.g., Sagar, Sharp, and Curran, 1988). For instance, Pfaus, Jakob, Kleopoulos, Gibbs, and Pfaff (1994) suggest a link between c-fos activation and enhanced lordosis in female rats; an increase in c-fos activation appears to be consistent with the effect either of vagino-cervical or of olfactory stimulation on endogenous GnRH release.
GnRH-olfaction link. GnRH neurons are long known to be important in the neuroendocrinology of reproduction (for review see Conn and Crowley, 1991). Less known is the GnRH link to olfaction, as demonstrated both in animal and human studies. In humans, individuals with Kallmann’s syndrome show a combination of hypogonadotropic hypogonadism with anosmia. There exists a complete absence of GnRH immunoreactivity in the brain yet a dense accumulation of GnRH-immunoreactive neurons in the nose (Schwanzel-Fukuda, Bick, and Pfaff, 1989) due to failure of the olfactory-GnRH neurons to reach and innervate the brain.
Kallmann’s syndrome has been noted to be accompanied by deficiencies in sexual relationships. For instance, Bobrow, Money, and Lewis (1971) reported: “None of the [Kallmann’s syndrome] patients, including the three who got married, reported an experience that sounded to have had the dramatic impact of genuine falling in love. In all four cases, the sexual relationship might be compared emotionally to an arranged marriage” (p. 336).
A single gene defect, the X-linked KALIG-1, has been linked to adverse effects on the human GnRH axon trajectory associated with Kallmann’s syndrome. This genetic defect also links the embryonic development of the GnRH neuronal system to disordered olfaction and gonadal incompetence (Caviness, 1992). GnRH deficiency without anosmia may reflect a difference in the ability of GnRH neurons to migrate which may result from the interaction of other genes with KALIG-1 (Crowley and Jameson, 1992).
The vomeronasal organ (VNO). Despite years of controversy, there now seems to be evidence enough to confirm the presence of a paired VNO, not only in nonhuman species (Vandenbergh, 1994) but in humans as well. Moran and colleagues have presented clinical, ultrastructural, electrophysiological, and neuroanatomical evidence which suggests the presence of paired VNO in most, if not all, humans (Moran, Monti-Block, Stensaas, and Berliner, 1995).
The VNO has been established as a sensory organ adapted for pheromone detection. Recent evidence suggests that human pheromones act via the VNO to alter the GnRH-induced pulsatile release of LH and of FSH and can as well alter other autonomic functions such as respiratory and cardiac frequency, electrodermal measurements, and electroencephalographic activity (Berliner, Monti-Bloch, Jennings-White, and Diaz-Sanchez, 1996). Berliner (1994) has also found that the VNO receptors of men and women are functionally different. Those of men, for example, are particularly sensitive to estratetraenol and the VNO receptors of women are particularly sensitive to androstadienone (see also Jennings-White, 1995).
Taken together, the evidence from the studies cited above suggests that social-environmental chemosensory stimuli from opposite sex mammalian conspecifics induce GnRH cascades leading to steroidogenesis. As it is generally agreed that steroids can influence behavior, there is thus established a pathway by which social-environmental chemosensory stimuli can influence reproductive physiology and sexual behaviors, if not directly at least indirectly. And such influences have been amply demonstrated. The classical work of McClintock showed that pheromonal cues can induce some women into menstrual synchrony and suppress menses in others (McClintock, 1971). Such human ovarian synchrony and its disruption may be controlled by a common air supply (Weller and Weller, 1993). Evidence also exists that the ovulatory pheromones of women can induce testosterone increases in men (e.g., Jütte, 1996). Persky, Lief, Strauss, Miller, and O’Brien (1978) have demonstrated the entrainment of hormone cycles in couples purportedly by pheromonal stimuli.
In what we believe are a significant group of findings, Perkins and Fitzgerald (1992) found that a pheromonally induced LH response in heterosexual rams exposed to sheep in estrous does not occur in homosexual rams. And the entrainment of hormonal cycles found by Persky et al. (1978) among heterosexual couples has been reported to also occur among homosexual male couples (Henderson, 1976) and female couples (Sanders and Reinisch, 1990). Of interest in this regard is speculation by Elias and Valenta (1992) “[that] anatomic differences in the hypothalamic nuclei concerned with sexual orientation may induce distinct patterns of GnRH secretion (frequency and pulsatility) resulting in intrinsic differences in pituitary gonadotropin responsiveness to hormonal stimuli such as pharmacological amounts of estrogen. This would then account for the LH response to acute estrogen administration in females and the female-type LH response to estrogen in male homosexuals” (p. 87). The involvement of pheromonally induced changes in gonadotropin secretion in the mammal suggests that in addition to the female-like LH response to estrogen in male homosexuals, there may be variability in response to the pheromones of male and female conspecifics. Might this variability be encoded in the perceptive cells of the nasal mucosa?
Data are available to suggest that postnatal environmental chemosensory behavioral imprinting may even influence human mate choice as occurs in mice. Among the Hutterian Brethren (the “Hutterites”), who live as somewhat social isolates, mating was nonrandom with respect to HLA haplotypes (Ober, Weitkamp, Elias, and Kostyu, 1993). Similarly, Wedekind et al. (1995) found that some genetically determined odor components can be important in human interactions. As mentioned earlier, women who were not taking oral contraceptives rated the body odors of genetically dissimilar men as more pleasant than those of men who are genetically similar. These findings are consistent with the expression of the major histocompatibility complex as an external odor cue in mice, rats, and humans. It is generally agreed that murine MHC is equivalent to the human HLA.
The question arises: How and when were such olfactory and pheromonal events organized? Were they developed independent of the Gn–H–B system? Segovia and Guillamón (1993) have found the mammalian olfactory system to be sexually differentiated prenatally. These investigators link this olfactory sexual-dimorphism to sex differences in reproductive process. But, regardless of how these sexually dimorphic systems themselves developed, once established they might be able to organize subsequent behavior patterns. In such cases, occurring postnatally, these might be considered conditioned reflexes.
Kohl (1996) has proposed that the early prenatal development of the olfactory and VNO systems and of the GnRH neuronal system allow paranatal and postnatal exposure to pheromones the power to exert organizational and activational effects on behavior, whenever in life this exposure occurs. In so doing, these chemosensory stimuli link the social environment to basic genetically determined substrates of human behavior.
Empirical evidence of a link among human pheromones, olfaction, gene activation in GnRH neurosecretory neurons, neuroendocrinology, and behavior comes primarily from the study of other mammals. Nevertheless, the interaction between sensory input and neuroendocrinology appears to be a general rule in endocrine relationships that underlie behavior (LeMagnen, 1982).
Visual, Tactile, and Auditory Senses
In everyday events and activities humans are markedly dependent upon visual, tactile, and auditory stimuli. It thus follows that such stimuli, in both humans as well as other species, could be involved in organizing subsequent sexual activities. They are certainly credited with the power to activate sexual behaviors.
Singh (1993) has found that there appears to be a woman’s waist-to-hip ratio (WHR) that affects a man’s decision to initiate contact. Following that, other factors such as facial attractiveness and compatibility then come into play. He suggests that men, subconsciously and from evolutionary molding, infer attributes of health and degree of fecundity to a woman on the basis of this WHR. Such a “releaser” allows morphological traits to reliably signal health and reproductive potential (Singh, 1995). Similarly, other studies suggest that people who exhibit greater facial symmetry have an easier time finding willing sexual partners, and who—surprisingly enough—also experience a greater number of orgasms (Thornhill, Gangestad, and Corner, 1995).
While Singh believes that dependence upon a certain WHR is hardwired, others disagree. Many think such preferences are culturally induced and conditioned. In either case, if the links occur early enough and at a nonvolitional level we might consider these relationships to be organized. This of course begs the question of what, in the first instance, makes females visually attractive to the majority of males and vice-versa, what makes males visually attractive to the majority of females? We hypothesize that the basic sexual attraction preference is established by the Gn–H–B model but it may be modified by social and cultural input and, as well, by the genomic forces mentioned above.
The social environment in which rat pups are raised is significant in how they develop sexually; particularly important is the role of the mother. When male rats are raised with litter mates but without their mothers, they are unable to mate when adults (Gruendel and Arnold, 1969). At least some rat pups will mate well if left alone with their mothers (Gruendel and Arnold, 1969; Hard and Larsson, 1968). One of the major factors seems to be the anogenital licking done by the mother to her neonates. This stimulates urination and defecation and is done more often to males than females (Moore and Morelli, 1979). This maternal difference in licking is in response to sex-specific chemosignals linked with the perinatally different levels of testosterone in newborn males and females (Moore, 1992). Lack of such anogenital licking has been shown to alter adult male copulatory performance; deprived males demonstrated longer interintromission times, ejaculatory latencies, and post-ejaculatory intervals (Moore, 1984). This tactile stimulus is believed crucial in many subsequent aspects of reproductive development and the divergence of males and females (Moore, 1995).
Some evidence exists that auditory stimuli can influence sexual development. MacLean (1985) examined the relevance of distinctive sounds to primate behavior (e.g., hunger cries, pain cries, and cooing between mother and infant) and their links both to phylogenetic order and to neuroanatomy of the primate brain. He noted that audiovocal communication becomes of the utmost importance in mammals for maintaining maternal-offspring contact. Such contact has been shown to be important in the behavioral development of many species. For example, Dizzino, Whitney, and Nyby (1978) reported that adult male mice require some experience with adult conspecifics before female urine acquires its ultrasound-eliciting properties. Thus, the infant experience primes the individual for later learning; “… the salience of female urine is learned during adulthood and the acquisition of this ‘pheromonally mediated’ behavior may be an instance of classical conditioning” (p. 111).
There is no direct neuroendocrine evidence that social environmental auditory stimuli can organize or structure human behavior. Nonetheless, it is generally agreed that what an animal hears may affect certain animal behaviors. The sound of a predator may elicit fear and thus concealment or freezing behavior. The sound of a soothing voice may not truly have the power “to soothe a savage beast” but it can certainly arouse one sexually. It is not clear how these behaviors develop.
THE OUTER WORLD
Intellectually, and with more than a bit of basic knowledge, one can envision genetic, steroid, and neuroendocrine forces, sensory and motor mechanisms, and other molecular vectors to be involved in the organization and influencing of subsequent behaviors. Many such topics were emphasized in the preceding sections. Intuitively, however, it seems easier to attribute behaviors to learned or major environmental and social factors. References to many such environmental and social factors can be found in classical as well as contemporary literature. Freud’s works (1953, originally published 1905; 1971, originally published 1920) are often quoted to infer that major aspects of adult sexual behavior are due to childhood upbringing; for instance the absence of a strong father figure or the presence of a dominating mother. More currently, popular scripting theory has purported that we behave sexually by following models we see in our surround (Gagnon and Simon, 1973), and much of the so-called “feminist” or deconstructionist literature holds that women and men are different mainly because of social and cultural forces that “construct” artificial differences (Foucault, 1980, originally published 1964).
To be sure, there are instances enough where obvious features of our environment do influence many sex-typed behaviors. Our dress is culturally prescribed as to male and female and these social guides are generally followed. Sex-related fads come and go with changes in many activities, occupations, and sports considered masculine or feminine. It is conceded that these patterns of behavior are highly malleable by society and external forces. In contrast, however, there is scant evidence that aspects of sexual identity, orientation, or sexual mechanisms are similarly influenced. Most attempts to substantiate such claims have been unsuccessful.
There is polemic (e.g., Kitzinger and Wilkinson, 1995) but no accepted proof, for instance, that one indulges in preferential homosexual activities because of meeting the right person and changing of sexual orientation, at least for lesbians, and only polemic holds that one is “no more driven by biology or subconscious urges [toward heterosexual or homosexual expression] than they are when, for instance, they change jobs” (p. 96) (Kitzinger and Wilkinson, 1995). And, despite earlier claims, there is no evidence we see ourselves as males or females because we are brought up in stereotypical blue or pink rooms (see, e.g., Diamond, 1997a; Diamond and Sigmundson, 1997). Indeed, it is these nonpattern aspects of behavior, such as one’s sexual orientation and sexual identity, that appear the most fixed (Diamond, 1995, 1996, 1997a). It is just these traits that are typically considered organized prenatally and activated with puberty. And for many, feelings of being male or female develop despite being reared in the other sex (Diamond, 1996, 1997b; Diamond and Sigmundson, 1997).
Certain events are, however, believed so traumatic that they might be considered significant enough to modify an adult’s sexual behavior. These can be called stresses and, in humans, at least, be of the order of a traumatic rape, the death of a significant “other,” a war situation, and so forth. The exact nature of these stresses has not been standardized. In humans the situations might be anticipated to be events that occurred prenatally or even postnatally such as post-traumatic stress disorder (PTSD) but most likely prepubertal. Childhood events that cannot be recalled, such as those alleged to have occurred in “forgotten or repressed memory syndrome” (FMS) have lately been claimed to be severe enough life stresses that they can structure adult sexual behaviors.
The work of Ingeborg Ward (1972) is classic in its definitive demonstration that environmental stresses can influence the development of fetal mammals. Pregnant rats, after repeated strict confinement and simultaneous exposure to bright light, subsequently gave birth to males that, after puberty, not only failed to mate but would lordose when mounted by normal males. Ward and Weisz (1984) found this stress was correlated with elevated corticosteroid levels in both mothers and fetuses. Breedlove (1994), in analyzing the work of Ward and her colleagues (Ward, 1992), concluded: “maternal stress releases endogenous opioids that inhibit gonadotropin secretion, which results in decreased androgen production by the fetal testes and reduced activities of aromatase in the brain” (p.398).
This effect due to “stress” of concurrent demasculinizing of males and simultaneous feminizing has subsequently been demonstrated in mice (Harvey and Chevins, 1984, 1985). It has also been induced by different rearing conditions such as overcrowding (Dahlöf, Hard, and Larsson, 1977) and with malnutrition (Rhees and Fleming, 1981).
The effects of stress, while potentially dramatic, are not invariable. Ward (1992) describes this situation among males derived from the same litter of highly inbred animals. “… if both male and female behaviors are assessed within the same [pregnancy stressed = PS] group of animals, four distinct subgroups become evident … A few males are completely asexual, a few show only the ejaculatory pattern, and the rest either exhibit only lordosis behavior or are bisexual; that is, they mount an estrous female but show lordosis when mounted by a vigorous male” (p.167). Just what causes the variability and dissociations in behavioral potentials among animals that all experienced the same prenatal treatment and are from the same litter is puzzling. Most probably, forces mentioned in earlier parts of this article are involved.
What might be called “feminization” along noncopulatory dimensions has also been shown related to prenatal stress. For instance, prenatally stressed male mice (vom Saal, 1983) and rats (Miley, 1983) are less prone to kill pups and more likely to show positive parental behaviors.
Several matters make particularly difficult our unveiling of the mechanisms behind stress as an organizing influence on sexual behavior. One major experimental factor is that, once adulthood is attained, there is as yet no nondestructive way a prenatally stressed male can be distinguished reliably from a nonstressed male. In a “destructive” way, however, among male rats such groups can be distinguished on the basis of central nervous system morphology. A comparison of the SDN-POA (sexually dimorphic nucleus of the preoptic area) of PS males and non-PS males revealed a marked reduction in nuclear size among the PS males; the SDN-POA of females was not affected (Anderson, Fleming, Rhees, and Kinghorn, 1986; Anderson, Rhees, and Fleming, 1985; Kerchner and Ward, 1992). Cortical thickness changes due to stress are also noticeable (Diamond, 1984) and an effect can also be seen among spinal cord neurons related to penile reflexes active during erection and ejaculation (the spinal nucleus of the bulbocavernosus muscle; SNB) and the dorsolateral nucleus (DLN) of stressed compared with nonstressed males (Grisham, Kerchner, and Ward, 1991).
Animal studies have also demonstrated quite reliably that environmental factors can differentially influence male and female brain morphology. Male and female rats, raised in so-called rich or complex (large cages with a changing set of objects or toys with which interaction was possible) or impoverished or isolated environments (typically empty and relatively small cages), show different patterns of neuron growth (Juraska, 1990). The type of environment in which the animals spent their early life shaped the length and branching of nerve cells and did so differently for the males and the females. Further, there is some evidence that the richer and more stimulating the environment, the greater the sex differences appear. This influence can be modulated by endocrine effects. When male rats were castrated at birth, the pattern of dendritic growth found in their brains was similar to that found in normal female rats (Juraska, Kopick, Washburne, and Perry, 1988). But there is no clear evidence that hormone mediation is needed for the sex differences normally seen in rat brains (Juraska, 1990).
Maternal and Peer Interaction
Experiments with monkeys have shown that the social conditions during development can severely alter their adult sexual behavior. The classical research of Harlow (1962, 1965, 1971) and his students has shown that male and female rhesus monkeys, reared in social isolation, demonstrate significantly distorted mating attempts. The males appear to want to mount but do so without any apparent orientation or proper technique. Not only do they not show the crucial foot-clasp which is an indispensable component of rhesus copulation, but they do not even always orient to the rear. Socially isolated males often appear to indiscriminately be climbing over the female. Similarly, females reared in isolation do not present or lordose properly. They might approach a normal male but sit down beside him rather than position themselves for mounting. Indeed, almost all social interactions are distorted in these animals although development to birth was normal. From this rearing, Harlow (1965) concluded, “we had developed, not a breeding colony, but a brooding colony” (p. 253). This phenomenon, however, has been shown to be species specific. Pig tail macaques, for instance, do not seem to be so sensitive to early social isolation (Sackett, Hoim, and Ruppenthal, 1976). An excellent review of socially induced psychopathology in primates is available (Soumi, 1982).
Work at the Wisconsin Regional Primate Center by Goy and colleagues elaborated on this early work, e.g., Goy and Wallen, 1979; Wallen, Bielert, and Slimp, 1977; Wallen, Goldfoot, and Goy, 1981. One experiment has been particularly noted. Goldfoot and colleagues (Goldfoot, Wallen, Neff, McBrair, and Goy, 1984) reared monkeys in cohorts of five or six in which the infant groups were all male, all female, or of mixed sex. Sexual and play behaviors were recorded for six 50-day periods from 3 months of age to 3½ years.
The behaviors of both males and females in the same-sex groupings were characterized by a partial inversion of the manifestation of protosexual activities. Isosexually housed males showed less foot-clasp mounting and more presenting than did heterosexually grouped males. Conversely, isosexually reared females showed more mounting and less presenting than heterosexually grouped females. The effect of rearing animals in same-sex groups was greater on heterotypical than on homotypical protosexual behavior. Among those males raised in all male groups, (female-typical) presenting responses deviated from the heterosexual male standard to a greater extent than did the male mounting. Among isosexually housed females, (male-typical) mounting behavior deviated from the heterosexual standard more than their presenting behavior. To put it succinctly, the expected sex-typical behaviors were effected less than the heterotypic sex’s behavior by the rearing condition. Nevertheless, significant changes occurred in both sexes.
Notably, particularly for the present discussion, the mode of grouping did not affect the incidence of rough and tumble play demonstrated by either sex. This remains predominantly a male behavior. Isosexually reared males did, however, show a statistically higher frequency of rough play than did heterosexually grouped males during the final observation session and isosexually housed females showed less rough play than did heterosexually grouped females. Presumably then, these behaviors are also affected by age and maturation. This behavior might show more dramatic effects if the tests were prolonged until the animals reached puberty.
The frequency with which these mounting and presentations were seen was significantly altered by weaning. The incidence of mounting sharply increased in both males and females following weaning (Goldfoot et al., 1984).
Goldfoot et al. (1984) summarize their findings with the following three main points: (1) Various social manipulations can influence sexual patterns known to be influenced by prenatal hormones; (2) different behaviors (e.g., mounting and rough and tumble play) believed to be subject to the same prenatal forces do not necessarily respond similarly to environmental conditions; (3) an individual is subject to, and sensitive to, the stimulus and behavioral qualities of its social companions.
A caveat is appropriate here. The actual mounting pattern displayed by the isofemales was a peculiar nonmasculine mounting pattern with the female “lying on the back of the partner.” Further, these social effects, upon subsequent testing seemed reversible in both the males and females depending upon the new social situation presented to the monkeys. Thus, the effects reported seemed on final analysis to be more modulatory than organizational (R. W. Goy, personal communication).
Stress in Humans
In Germany, Dörner and colleagues (Dörner, Geier, Ahrens, Krell, Munx, Sieler, Kittner, and Muller, 1980) studied a group of homosexual males born from 1934 to 1953. They found that a disproportionately large number of these males were conceived during the time of World War II. Reports from a comparable cohort of heterosexual, bisexual and homosexual men indicated that their mothers supposedly were exposed to stressful situations with an incidence of 0, 15, and 35%, respectively (Dörner, Schenk, Schmiedel, and Ahrens, 1983). This was an obviously strong correlation of homosexuality with maternal stress. This work did not go without challenge. Schmidt and Clement (1988) found, on the other hand, no evidence of increased homosexual behavior for a West German cohort conceived during WWII (abstract at 1988 IASR; reported in Bailey, Willerman and Parks, 1991) and Wille, Borchers, and Schultz, (1987), among a group of German mothers, failed to find any relationship between different types of stress during pregnancy and the orientation of their sons.
In the United States, Ellis and colleagues (Ellis, Ames, Peckham, and Burke, 1988) surveyed students and their mothers. As did Dörner, Ellis et al. found that mothers of homosexual males were significantly more likely than mothers of heterosexual males to report a significantly stressful pregnancy, particularly during the second trimester. Bailey and colleagues (Bailey et al. 1991), however, investigating a wider sample of heterosexuals and homosexuals did not find mothers from either group reporting any more stress than the other. Adding confusion to this matter is that Bailey et al. did find that mothers of effeminate boys were more likely to be stress-prone than mothers of gender-conforming boys but Ellis et al. did not. One other study seems appropriate here. Gunter (1963) compared groups of mothers that gave birth to premature infants with those that give birth to normal infants. She found that not only were the former mothers more likely to have suffered “stress” during the pregnancy but that these women, following extensive psychological testing, were described as “being inadequate as females; as rejecting heterosexual relationships; and as associating sex with guilt. The mothers of normal infants were described as having a desire for a close heterosexual relationship; asassociating sex with violence, aggression, and trauma; and as repressing hostility” (p. 340).
Clearly we have shown there are innumerable processes by which sexual differentiation and development can be modified by biological or biosocial processes other than via the traditional Gn–H–B path. These modifications, in minor and major ways, can alter the Gn–H–B path itself to affect minor or great changes in sexual behavior. And clearly while processes are offered which can modify the Gn–H–B path, it does not mean they do so to any significant degree or do so similarly in different individuals.
The complexity introduced, however, allows a broader perspective on how certain behaviors might be derived. For example, as predicted by Hamer and colleagues we believe it unlikely there will be found a so-called single sexual or gender-orientation gene or a “gay gene” as in their work or the work of Turner (Hamer and Copeland, 1994; Hamer, Hu, Magnuson, Hu, and Pattatucci, 1993; Turner, 1994, 1995). There are too many examples making clear that even when a gene and its role are known, other genes are necessary parts of a trait-related causal pathway that have the potential to inhibit or to manifest the trait, regardless of the status of the trait’s primary gene. The search is thus best for sexual-orientation related “genes.” The case of the search for a single gene responsible for insulin dependent diabetes (IDDM) provides a good example. It is a fairly “simple” syndrome that has numerous variations. The search for the insulin gene has now identified at least 12 genes whose individual dysregulation or mutation can induce IDDM (Morahan, Huang, Tait, Colman, and Harrison, 1996).
Also to be kept in mind is that gene effects are not necessarily 100%. For example, among individuals called “full mutation fragile X males,” many do not manifest various of the syndrome’s primary traits—e.g., extremely large ears (Butler, Pratesi, Watson, Breg, and Singh, 1993). And more directly applicable to our discussion of sexuality, human sex reversals can occur independently of the individual’s SRY status. It is now recognized that other genes on other chromosomes can induce sex reversal regardless of the individual’s SRY status (Bennett, Docherty, Robb, Ramani, Hawkins, and Grant, 1993; Kwok, Tyler-Smith, Mendonca, Hughes, Berkovitz, Goodfellow, and Hawkins, 1996; Schafer et al., 1995). Similarly, therefore, if specific genes or genomic regions are found to be primary determinants of sexual orientations, upstream and downstream genes are likely also to play crucial roles. And these multigene interrelationships will have profound impact upon phenotypes and judgments derived therefrom. Parenthetically it is interesting to note even the yeast Saccharomyces cerevisiae has a gene-based equivalent of sexual orientation (i.e., a-factor and alpha-factor physiologies). These differences arise from different epigenetic modifications of an otherwise identical MAT locus (Runge and Zakian, 1996; Wu and Haber, 1995).
The nuances of modification can easily, at least conceivably, allow for XY individuals who are quite masculine in body morphology to be androphilic, ambiphilic, or gynecophilic. And such vectors can account for XX feminine looking individuals who think they have been born into the wrong body. Certainly they might alter stereotypical behavior patterns attributed to males or females. While all features of an animal’s or individual’s sexual behavior profile (Diamond, 1995, 1996, 1997b) are taken to develop in concert it might be that closer inspection would reveal greater variation than presently perceived.
Superimpose on all this the idea that neurosteroidal effects can occur in subareas of the brain independent of other areas and independent of the Gn–H–B pathways and that there are direct neural mechanisms that can bypass the hypothalamic-pituitary axis to influence gonadal activity (Gerendai, Csaba, Voko, and Csernus, 1995) and we have doors enough through which many factors can pass to influence sexual differentiation, development, and expression.
With this array of potential variation in outcome that can be induced by biological and environmental factors of known and unknown origin, one might even cynically say it is a wonder so many individuals, of any species, exhibit relatively similar patterns of sexual behavior. Departures from the norm should be anticipated.
Recognize also that not all potential behavioral variations, even after having been induced, come to fruition. There are biological and social restraints on diversity. Conspecifics have to interact and too great a deviance might elicit anything from avoidance and lack of group support when needed to outright identification of the variant individual as a nonrecognizable kin or a significant threat. This can lead to the individual’s isolation or even death and thus render mute any unique sexual traits. Animals from social insects, to mammals of different species, to humans are known to kill conspecifics for reasons that are not always apparent. Humans still kill or isolate other humans for being too sexually different.
It is also possible that the environmental forces we consider under the broad heading of “society,” either animal or human, have as a primary function that of mediating variation to minimize the effects of biological diversity. To “keep the individual on track” so to speak. This might maximize the likelihood of reproduction and allow for yet further diversity. Biological diversity, in this vein, is seen as offering an evolutionary advantage but one that has to be “tamed.” The greater environment also has to evoke, stimulate, allow, and even promote those behaviors which might otherwise lie dormant yet be beneficial. For different mammalian species the interval between fertilization and the time adult sexual behaviors are manifest is sufficiently long to allow for a great many nature-nurture interactions. In essence, sexual differentiation and development must be seen resulting from multiple causes at many levels.
In the 1950s, when the milestones of which we spoke initially were being passed, the fields of genetics and neuroendocrinology were in their infancy; the fields of immunology and olfaction/pheromone research were still in gestation. Our new insights and visions allow us to see further because we stand on the shoulders of others. And there is still much to learn. Many things we take for granted today will, no doubt, be revised or reversed tomorrow. What is known for sure, however, is that biological processes called “nature” are not simplistic. Neither is the entity called “the environment.” The two separate worlds overlap and intertwine so only a single interactive one exists. Yes, it may be simpler to look at each singly, but one does so at intellectual peril.
Clearly this paper is just an opening to consider several ideas on how biological and environmental factors might interact in shaping human sexual behavior. We hope this will both expand the search and focus it to provide greater insight. Surely the most intense scrutiny and critical analysis presently is to focus on understanding how biological factors contribute. It remains for the environmental side of the picture to be equally explored and analyzed. We see the primary contribution of this discourse, not to give answers but rather to broaden the scope of investigation. It would be helpful if some other investigators would similarly shed more light on a microanalysis of social-environmental factors impacting on sexual development.
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