In the study of human sexual behavior, aside from special ethical and social problems, we are faced with the same questions posed from any other arbitrary category of human behavior, be it aggression or schizophrenia. Such questions include: what are the origins of the behavior, what factors control it, and how can it best be modified?
In answering these questions for sexual behavior, however, we perhaps actually have an advantage not available for these other areas of behavior. Although the study of reproduction and sexuality has only been tolerated (if not fully respected) for the last 40 or so years, and many gaps still exist in our knowledge, there are available a remarkable wealth of clinical observations and animal research data in regard to the origins, control, and modification of sexual behavior. Some of these data pertaining to human genitosexual anomalies and accompanying psychosexuality, consolidated and analyzed here, arc believed to exemplify this.
Support for the validity of studies in this area may be linked to successfully meeting the five general criteria for behavior-genetic studies enumerated by E. Anderson (1966), i.e., survival, intelligence, frequency, biochemistry, and treatment.
1. Survival: The genetic characters associated with sexual anomalies are usually not lethal and many carriers may reproduce and live to old age.
2. Intelligence: The IQ range of individuals with sexual anomalies falls within normal limits and is thus high enough to allow for personal interview and a wide range of behavior patterns for study.
3. Frequency: Genitosexual anomalies are not rare and estimates of their occurrence range from 1 in 200 to 500 (Overzier, 1963; Crew, 1965) to 2 to 3 per 100 (Overzier, 1967).
4. Biochemistry: The metabolic pathways and endocrinopathies involved are well known in many instances.
5. Treatment: Medical and psychological treatment is often available to counteract the effects of the anomaly and allow observation under the altered condition.
For many nonhuman species, including other anthropoids, the evidence seems clear and the data well accepted that the prenatal endocrine environment is crucial for determining adult patterns of both gonadal cyclicity and sexual behavior (see Chapters 5 and 20). In the case of the human, however, many clinicians and investigators concerned with the question, while conceding that the gonads and genitalia may be affected, usually still hold that sexual behavior and psychosexual outlook is primarily a product of upbringing and environmental influences. The present paper will further examine this question and attempt to show that sexual behavior in the human is more dependent upon pre- and post-natal genetic-endocrine influences than upon the postnatal environment. Some reasons for the opposite appearance are presented.
The following two individuals will serve to present the problem:
The first patient (Fig. 1) came to Louisville General Hospital at the age of 22 with a complaint of failure to menstruate. She was married and wanted children. Physical examination revealed a generally normal phenotypic female lacking, however, typical adult pubic or axillary hair and possessing what appeared to be bilateral inguinal hernias. This now-classical syndrome (Morris, 1953) suggested a diagnosis of testicular feminization. Follow-up laparotomy sustained this suspicion by revealing the herniating masses to be testes and demonstrating the absence of ovaries or uterus. Subsequent karyotypes of the patient showed typical male X and Y chromosomes. In manner and expression the patient revealed “herself” psychologically as a typical anovulatory female concerned with her marriage, the prospect of bearing children, and other “womanly” interests. No indications of an ambivalent psychosexual status were seen. The patient considered herself a well-adjusted female and all interviewers agreed.
The second patient (Figs. 2 and 3) was originally seen as a probationary problem and was referred incidentally to the Louisville Children’s Hospital for investigation of “his” pendulous breast development. Examination initially revealed a 12-year-old Negro boy with chief findings of enlarged breasts and hypospadias. Karyotyping seemed difficult to standardize, due to mosaicism in this case, but an eventual diagnosis of XX was confirmed by repeated cell smears and chromosome studies.
Shortly after admission to Children’s Hospital, the patient began to menstruate. Psychiatric evaluation revealed the patient as a boy sensitive to the ambiguities of his condition yet fully convinced of his male status and place despite the development of pendulous breasts and the onset of menses. His discipline problem stemmed from his “playing hookey” to avoid the jibes and comments of his classmates. He was quite outspoken in his desire to have his breasts removed, the bleeding stopped, and that he be left alone to continue life as a male,
In short, two patients with two distinct problems have been presented. In the first case a genetic male is seen to be phenotypically and psychosexually a female. To the present he has never expressed doubt as to his status. In the second instance we see a genetic female, who until puberty was a phenotypic and psychosexual male. This masculine psychosexual orientation persists to the present day despite breast development, the onset of menstruation, and several attempts at psychological counseling. The problem, thus, is how to reconcile the psychosexual role with the apparently incongruent genetic status.
The etiology of these conditions is best appreciated by an understanding of the general process of embryonic sexual differentiation. Sexual differentiation may be considered from three points of view: morphologic, endocrine, and behavioral. Once these general processes are reviewed the patients will be discussed in light of these data. The present review of morphological differentiation will be brief, since many excellent ones covering this area exist; among the latest are those of Grumbach and Barr (1958), Burns (1961), Jost (1961), Sohval (1963), Watzka (1963), Bruner-Lorand (1964), Van Wyk (1965), and N. Anderson (1966).
It is well established that up to the sixth or seventh week the human fetus contains neither testes nor ovaries but only indifferent gonads (Fig. 4). At this time two systems of primitive ducts also exist in the fetus (Fig. 4). These are the Müllerian duct system, which can give rise to oviducts, uterus, and upper vagina, and the Wolffian duct system, which normally gives rise to the epididymides, vas deferens, and seminal vesicles.
Normally the individual’s genotype will determine the direction of development for the primitive gonads. The gonads will normally develop into testes in individuals bearing a Y chromosome. Correspondingly, ovaries will normally develop in individuals with two X chromosomes. If only a single X chromosome is available, gonadal agenesis or dysgenesis will result. Once the gonad differentiates, it induces direction to the development of the two pairs of genital duct structures. An as-yet-unidentified fetal morphogenic testicular substance (F.M.T.S.) will not only induce masculine development of the Wolffian duct system but will simultaneously inhibit the development of the Müllerian duct system (Jost, 1947b, 1947c, 1955).1 On the other hand, the ovary does not elaborate a corresponding substance inducing development of the Müllerian duct system and regression of the Wolffian ducts; these phenomena have been shown to result from the absence of the F.M.T.S., since in animals of either sex, fetal castration or destruction of the gonads prior to sexual differentiation invariably leads to development along female lines (Jost, 1947a, 1947b, 1953; Raynaud, 1950; Raynaud and Frilley, 1947).
Similar, but not identical, processes are at work on the external genitalia. Prior to sexual differentiation, an indifferent genital tubercle exists and remains undifferentiated until about the end of the third month. Watzka (1963) considers this long interval prior to differentiation as an important factor accounting for the frequency and wide variety of sexual anomalies seen in man. For male or female differentiation of these external structures, however, F.M.T.S. does not seem too crucial. These sexually bipotential structures are differentiated as female genitalia unless stimulated by testicular, adrenal, maternal, or exogenous androgens (Fig. 5).
As will be discussed below, the presence of circulating androgen, by itself, is not sufficient for virilization of tissues. The capability for proper end-organ response of pertinent tissues is required for masculinization. I consider this crucial and wish to emphasize it here and later demonstrate the significance of this.
This sexual differentiation of the soma discussed so far is known and accepted from many studies. Differentiation of a different type is also directly related to our interest: sexual differentiation of the neural-endocrine axis and the nervous tissues associated with reproduction and sexual behavior. This subject has been adequately reviewed previously (Diamond, 1965a; Phoenix et al., Chapter 5; Whalen, Chapter 20) and need not be repeated here. These references present evidence indicating that the same hormonal processes involved in genital differentiation are also active in differentiation of the neural tissues which mediate behavioral activities. In the adult this neural sexual differentiation affects reproductive behavior as well as gonadal cyclicity.
It is to be emphasized that the development of the genital tracts and external genitalia has its counterpart in the development of the endocrine and behavior mediating neural tissues. Moreover, the developing neural tissues show greater sensitivity than the developing genitalia to the prenatal-neonatal endocrine environment. This is evidenced by experiments in which low levels of androgens were seen to induce sexual differentiation of the hypothalamus while somatic effects were not seen in rodents (Phoenix et al., 1959) and primates (Goy, 1966). Admittedly, the behavioral evidence so far presented has been from nonhuman species. Clinical evidence of a sort is also available for this point, however. John Money and Anke A. Ehrhardt at the Johns Hopkins University have followed 10 normal appearing female children of mothers given androgenic progestins during gestation. They report that nine of the ten were tomboys according to their mothers and themselves. The chief symptom was abundant energy for outdoor athletic pursuits (although within limits acceptable for a female in today’s upper middle class families) (Ehrhardt and Money, 1967). In summary, then, the presence of F.M.T.S. and androgens lead to masculine differentiation and bias, while the absence of these substances leads to feminine differentiation.
This may seem to imply a simple male versus female mechanism for setting the sexual thresholds within the nervous system. Actually no evidence exists for this extreme position. The absolute or relative amounts of F.M.T.S. and androgens present and biologically available, and the receptivity of the neural tissues at the various times of differentiation, will determine where, and to what extent, an individual’s sexual range and bias will be established. As our methods of testing sexual behavior become refined, we may be able to distinguish, for various patterns, extensive gradations of behavior on a continuum with ends which for convenience we now call male to female; the center point need not be neuter but may reflect equipotential or ambivalent male/female behavior capacities. We may indeed find the sexual behavior repertories of males and females to be parallel and discontinuous rather than continuous.
One additional point needs to be made. Although postnatal sexual behavior is seen to be subject to prenatal endocrine organization, it must be emphasized that the magnitude of the effect is determined by time of onset, duration, and degree of endocrine exposure. This is seen clinically (Witschi et al., 1957) as well as experimentally (Goy et al., 1964; Swanson and van der Werff ten Bosch, 1964). The exact timing needed to produce the various sexual endocrinopathies in the human is only generally known. When more data are available we might see that these conditions actually reflect very limited and specific intervals in development. For humans, Lenz and Knapp (1962) and Lenz (1965) have reported that the intake of thalidomide between day 27 and day 30 of gestation will affect only the arms, whereas intake between days 30 and 35 will affect mainly the legs. Similarly, sexual biasing of the nervous system may occur during specific and short intervals for specific manifestations.
In a broad way testosterone has demonstrated the capacity to participate in time-critical sexual differentiation. If administered during adulthood, the behavioral effects of androgens are usually temporary. If administered during pregnancy, however, the hormones may be without effect on the mother, although the female fetuses being carried arc permanently masculinized (Diamond and Young. 1963; Diamond, 1966). Considered in other terms, during fetal development hormones can act to organize the nervous system with a sexual bias for future sexual behavior. During adulthood, hormones act to instigate or “make manifest” this built-in bias (Phoenix et al., 1959; Harris, 1964; Diamond, 1965a; Young, 1961, 1965; Phoenix et al., Chapter 5). This built-in bias may be comparable to what Stoller refers to as a “biological force” (Stoller, 1964).
The first patient, with testicular feminization, was an XY male with the appearance and psychosexual orientation of a female. Of six “sisters” at home, three have a similar problem. He has three normal brothers. In reviewing a large number of such cases, Morris and Mahesh (1963) consider the possibility that two classes of this disease exist and conclude that “this syndrome is either an X-linked recessive trait or a male-limited autosomal dominant inheritance.” Boczkowski and Teter (1965) make a further distinction and consider this condition “a sex-controlled rather than a sex-limited trait.”
Regardless of the mode of inheritance it is now fairly well established that the testes in these males may elaborate normal amounts of androgen as well as considerable amounts of estrogen (Simmer et al., 1965). However, it is both the lack of action of the androgen as well as the positive action of the estrogens which is responsible for this condition (Morris and Mahesh, 1963; David et al., 1965; Simmer et al., 1965). Wilkins (1950) has shown that administered androgens have repeatedly failed to masculinize individuals of these types and postulates that a defect exists in the responsiveness of the pertinent end-organ tissues. This theory is still applicable and has been consistent with subsequent findings. A recent study by Neuman and Elger (1965) supports this thesis. By administration of an antiandrogenic substance to fetal and neonatal rats, these investigators demonstrated that the general body build, external genitalia, mammary glands and sexual behavior of the growing pup develops along female, not male, lines, so that the resulting adult rat may be considered an experimental counterpart of the human “testicular female.’
The lack of external somatic end-organ response to testicular androgens is in contrast to the response of the internal organs to F.M.T.S. Internally these patients show a male duct system and testes. Significantly, however, as discussed previously, the differentiation of the nervous tissues mediating the reproductive and sexual behavior patterns parallels the differentiation of the external genitalia and is androgen-dependent. In these patients with a demonstrated inability to respond to androgen, we may assume that the neural tissues which mediate sexual behavior were not primed toward maleness in utero, and as adults cannot be masculinized. Despite adequate circulating androgens, a “masculine” response of the nervous system is missing. These patients never have any doubt as to their female identity and role and never, on their own initiative, seek a change of sex.
The second patient during a subsequent panhysterectomy and chromosome study of the gonads was finally diagnosed as a true female. Despite extensive breast development and menstruation, this individual considered herself a male, refused repeated opportunities of change, and threatened suicide were she made to live as a girl. Either her gonads or adrenals may be assumed to have, at one time, secreted androgens, because the external genitalia have been masculinized (Figs. 3 and 5). Since experimental and clinical evidence indicate that the developing neural tissues usually have thresholds lower than the somatic tissues (Phoenix et al., 1959; Young et al., 1964; Ehrhardt and Money, 1967; Phoenix et al., Chapter 5), it may be concluded that not only did this modify her external genitalia but also affected (masculinized) her psychosexual bias as well.
It may be rightly argued that so far in this presentation I have ignored all the “environment” in favor of the “heredity” and all the “nurture” in favor of the “nature.” In both cases presented, the bodily configuration determined the sex of upbringing and the respective female and male roles may be construed as derived from events and learning during this crucial early period of ontogeny. Many investigators (Money, 1961; Hampson and Hampson, 1961) and a preponderance of psychotherapists even have considered this the most crucial determinant of psychosexuality. It has even been claimed that change of sex status from male to female or vice versa may be psychiatrically traumatic and even disastrous after this initial “imprinting” even if the original sex assignment was in error (Hampson and Hampson, 1961; Money et al, 1955).
Two additional patients will be introduced at this point to clarify this issue. B.B. first came to Louisville Children’s Hospital in 1952 at the age of 14 for an emergency appendectomy. Admitted as a female patient, it was noted during surgery that she had neither ovaries nor uterus. Closer investigations revealed the presence of a hypospadic penis, bifid scrotum, and cryptorchid testes. The family was informed of the nature of the findings and a change of sex role with appropriate surgery was recommended. The family and patient refused the offer. After surgery a note was made on the record and the patient was released.
Three years later this patient voluntarily presented himself for surgical repair and on his own volition requested a change of sex. He has since undergone over 25 surgical procedures in an attempt to rectify the anatomical problems but considers it worth the final outcome. In other words, despite the sex of rearing, an individual not only can, but may, switch voluntarily and without psychotic mishap to a sex role in which he feels best suited psychosexually. This is not an isolated case (Dewhurst and Gordon, 1963; Diamond, 1965a; Armstrong, 1966; Barton and Ware, 1966). These switches must, however, be preceded by appropriate biological “priming.”
It has been indicated previously (Diamond, 1965a) that the desire for change of sex assignment, as in this case, usually occurs at or shortly after puberty. This is consistent with the emphasis on endocrine mediation of psychosexual orientation, since it is during this life stage that the nervous system is first beset with an adult endocrine physiology and the adult expression of the psychosexual basis is being goaded into action. Also, in cases, like this, the absence of normal female development probably contributes to self-doubt within a malassigned role.
The second additional patient, T.L.E., was born at Louisville General Hospital in 1960 and diagnosed at that time as having a salt-losing adrenogenital syndrome. In this condition a malfunctioning adrenal gland elaborates excessive amounts of androgen, leading, among other things, to masculinization. The child was placed on a medical-treatment schedule to arrest this condition and the mother told to return her periodically for outpatient care. Despite this advice to the mother, the patient was not seen again until she was brought back to Children’s Hospital at the age of 5 years and 6 months. Phenotypically she displayed extensive virilization, i.e., stocky male somatotype, clitoral hypertrophy of 5 cm, and male hair distribution over her body, head, and pubis. She was replaced on an adequate drug-treatment schedule and a clitorectomy was performed one month later.
The initial interview with the child revealed an individual with interests and actions closer to those of a 6-year-old boy than of a girl and interview with the mother tended to confirm this impression. As the youngest sib with four older brothers and four older sisters, T. was considered by her mother to behave more like her brothers than her sisters. Her mother reported her as a “tomboy” in every respect. Observations in the hospital showed her to be quite aggressive, active, and to prefer boys’ toys and games. She has volunteered to her mother that she is a “boy.”2
In this case, as in the one before, the sex of rearing was female, yet the psychosexual-behavioral orientation seems inclined toward maleness.
These cases are not presented to imply that upbringing has nothing to do with psychosexual orientation, for both patients could function within the sex in which they were reared and, in fact, one (T.L.E.) still does. This, however, should be considered a credit to human role flexibility and adaptability rather than an indelible feature of upbringing (Diamond, 1965a). It seems that the effect of the sex of rearing is strong when reinforcing the fetal and developmental endocrine predisposition but meets strong opposition when going counter to it. In fact, as seen in the case of B.B., a biological bias may be enough to overcome the upbringing if the bias is of the crucial endocrine-organizing type which occurs during differentiation of the nervous system, and the upbringing is such that the feelings of self-doubt may be entertained. This might even be predicted from a mathematical analysis of various psychosexual conditions and intersex states as formulated by Cappon et al. (1959). It is too early to predict the adult feelings of T.L.E. but some alteration from normal female role orientation and acceptance may be anticipated, even though basically overcome by the combination of endocrine therapy as well as rearing.
Normally the problem of a conflicting constitution and upbringing does not confront us. A normal male is brought up as a male and a normal female is brought up as a female. The various experiences during childhood, puberty, and adulthood tend to reinforce the biological predisposition. When due to some biological quirk, usually of genetic origin, and a conflict exists among the biological variables of sex, we may expect some concern as to the role of upbringing.
The numerous variables of sex may or may not be coincident with each other. As so often stated by many investigators, an individual’s sex may be judged by the gonads, internal genitalia, external genitalia, hormone titers, chromosomal complement, or psychosexual orientation. For the normal individual, these are usually concordant. The genetic complement will induce proper gonadal development which, via the presence or absence of F.M.T.S., controls the differentiation of the internal genitalia and, via the presence or absence of androgens, controls differentiation of the external genitalia and the nervous system. With this involved process the human seems to be one of several species, along with the goat and pig, in which genitosexual anomalies are not uncommon.
Fortunately in pathologic as well as in normal cases, however, the presence or absence of androgens will usually determine differentiation of the external genitalia to male or female as well as affecting psychosexual differentiation of the nervous system. Therefore, regardless of incongruity, with the other variables of sex, rearing, usually based only on the appearance of the external genitalia, most often conforms to the sex of psychosexual bias. It is when these are in conflict that we may expect most instances of psychosexual problems.
Cappon et al. (1959) have concluded, after studying 17 intersexed patients, that to raise an individual contrary to his main physical nature would be to raise him “against the bulk of his psychosexual nature.” Roth and Ball (1964), in a comprehensive review of this area, have stated: “Even if it is accepted that most individuals with ambiguous sexuality accept the role conferred on them, whether biologically correct or otherwise, it can not be assumed until detailed comparisons along these lines have been conducted, that a more accurate assignment might not have yielded better psychological results.” Or to put it another way: the acquiescence to a malassigned sex role by an individual does not by itself constitute “correctness” of assignment; a more correct assignment may (and should) be made when the error of assignment becomes apparent or is felt by the individual.
Among the common genitosexual anomalies are two others which are seen frequently enough to be considered here, i.e., Turner’s and Klinefelter’s syndromes. The Turner’s individual usually has an XO chromosome complement, but mosaicism such as XO/XX and XO/XXX also occurs; an approximately equal ratio of chromatin-positive and chromatin-negative patients results (Hauser, 1963). This lack of an adequate second sex chromosome leads to gonadal agenesis and the subsequent absence of F.M.T.S. and androgen. As expected, this results in the development of female internal and external genitalia.
We may also thereby question whether in the chromatin-negative as well as the chromatin-positive individuals a female-biased nervous system does not also result. Witkin et al. (1966), based on verbal and performance IQ data collected by Shafer (1962), and Alexander et al. (1966), based on tests of visual-constructional ability, have indicated that patients with Turner’s syndrome consistently score lower in tests of cognitive functions than normals. The possibility exists that these functions and analytic abilities (nervous system functions) are under the influence of sex chromosomes. The mediating mechanism may be hormonal. Lansdell (1961, 1962) had previously demonstrated sex differences in the cognitive processes of the nervous system.
These facts are concordant with the routine findings that men and women consistently differ in analytic (cognitive) abilities, females usually scoring lower. Since patients with Turner’s syndrome are normally reared as females, no psychosexual problem should be anticipated despite possible incongruity with the sex-chromatin status, since their cognitive abilities are feminoid. Most investigators, as reviewed by Hauser (1963), find these patients to have sexual behavior reduced but heterosexual as a female. As long as no gonad is present, no F.M.T.S. or androgen secretion would be anticipated and we would predict the genitalia and rearing assignments to be female. No conflict should ensue, since neural organization would also have been female. As previously indicated by Dewhurst (1962) and Sohval (1964) for morphology, we can now also say for behavior that the clinical features demonstrated by these patients depend less upon the precise sex chromosome constitution and more upon the extent and nature of the fetal testicular failure.
The Klinefelter’s syndrome usually results from a 47/XXY karyotype and is typified by a phenotypic male with small testes, gynecomastia, and female hair-distribution pattern. While testicular development occurs in these individuals it is not completely normal. Testicular biopsy during adulthood usually reveals hyalinized seminiferous tubules composed mainly of sustentacular cells with oligospermia. Adenomatous clumping of the interstitial (androgen-producing) cells is also seen. While F.M.T.S. secretion may be judged to have been normal on the basis of male differentiation of the Wolffian duct structures and regression of the Müllerian duct structures, these patients typically show androgen titers below normal and gonadotropin titers higher than normal. During embryonic periods of differentiation, the androgen supply may also have been deficient, leading to a less than complete sexual differentiation or nervous system bias. Concomitantly the same genetic process involved in the chromosomal anomaly also may be directly involved in a neural alteration of the psychosexual substrate. There is some indication that this is so, since these phenotypic males, reared as normal males, nevertheless are often found weakly heterosexual with low libido (Pasqualini et al., 1957; Money, 1963; Nielsen and Fischer, 1965) and suffer related marital difficulties (Sipova and Raboch, 1961). If only upbringing were involved, this could not be predicted, since these individuals are reared as normal males. The patients express and manifest difficulty in performing as normal males. They may occasionally be homosexual or transvestite (Money, 1963; Money and Pollitt, 1963; Roth and Ball, 1964; Benjamin, 1966). Schultz (1963) considers them close to an undifferentiated sex, and Crowley (1965) describes their sex role as ambivalent. It has been found clinically in many hospitals that these individuals are often passive or ambivalent toward their own androgen treatments.
As with the testicular feminization syndrome, androgen treatment of patients with Klinefelter's syndrome is not always successful in affecting libido. It is known that variability exists in the sexual orientation of these patients, as there is variability in masculine somatotypes and in elaboration of, and response to, androgen. It is possible that these differences reflect the different ways in which this condition may be brought about, e.g., by the union of a normal Y sperm with an abnormal XX ovum or the union of a normal X ovum with an abnormal XY sperm. When looked at critically, these circumstances may be expected to result in different syndromes. Despite the usually male upbringing. the nervous system seems to display a reduced capability for responding to sexual stimuli—as if the proper embryonic critical period priming were absent and the proper adult response lacking, even when adequate levels of androgens are present.
Some additional comments are warranted in regard to the adrenogenital syndrome. This condition has many subtypes, but basically involves either a congenital adrenal cortical hyperplasia with increased androgen secretion or a genetically determined enzymatic loss resulting in the production of abnormal quantities of androgen. The genetic condition has been determined to be due to a recurring autosomal recessive mutant gene (Childs et al., 1956; Grumbach and Barr, 1958). At birth a genetic male child usually appears normal, but, as seen for T.L.E., the affected genetic female appears masculinized. Occasionally, owing to the equivocal appearance of the genitalia, the sex of rearing is equivocal. However, even when the upbringing is normal, it is with these individuals that psychosexual conflicts may be anticipated.
If the female is reared as a boy and the disease not brought under control, the child’s development will continue along male lines and she will present as a case of precocious puberty. If, at this time, a correct diagnosis is made (these patients usually seek treatment between 3 and 7 years of age). the disease can be arrested and the individual directed toward a female role. The difficulty involved in this switch may or may not be great and will depend upon the individual’s self-evaluation, which in turn is related to the extent of androgenic differentiation of the somatic and neural tissues as well as age and the severity of rearing. Some evidence that the nervous system and end organs have been affected may be gleaned from reports from these patients, when adults, that when erotically excited their clitorides are subject to erection and occasional priapism (Money, 1965). This is a manifestation of excitement not usually seen in normal females (Masters and Johnson, 1966) but only in androgenized ones. If the individual’s condition is not diagnosed she will develop phenotypically as a male with stunted growth, and a concomitant male sexual orientation.
When the individual is raised as a female, the virilization of her body type will usually prompt medical consultation and the problem will be treated from then on. Depending on when, how long, and how much androgen was present during her development, she will exhibit various degrees of psychosexual masculinization. As observed by Money (1965), this behavioral masculinization may be primarily manifest in a reduced threshold and increased frequency of sexual arousal and sexual initiative. However, as seen in the present patient, T.L.E., via such an alteration in thresholds, even object selection may have been affected, since her choice of toys, games, and identification are male despite female upbringing. More astute questioning of virilized adults may similarly reveal a male shift in goal orientation. Significantly, this reduced threshold to sexual stimuli may be seen in treated cases as well as untreated ones (Money, 1965)—again, an indication of a possible built-in sexual bias. In adults the androgenic bias seems to be manifest as an indiscriminate aphrodisiac, a feature it seems to possess for the normal male.3 It will be interesting to watch the development of sexual behavior patterns and desires in those girls whose mothers were treated with androgens to see if they, too, are affected, as are the adrenogenital patients. It may be predicted that they will be. However, the inherent flexibility in sexual behavior expression for humans, and the loose definition of proper female behavior, may allow for their sexual performance to fall within the broad range of females in general (Diamond, 1965a).
Considering clinical and experimental data, human psychosexuality and derived sexual behavior are seen to be dependent upon genetic and endocrine factors present prior to birth. Normally the genetic factors structure the endocrine environment and this in turn affects the psychosexual bias of the nervous system.
The organization of these behavioral characters is seen most often to parallel the organization of the external genitalia. The totality of this sexual differentiation, coupled with the individual’s somatotype, upbringing, and postnatal endocrine status, will determine to what extent his diasthetic bias develops and how the sexual world will be approached and reacted to. It is at this level that the sex of rearing is operating.
In genetic syndromes affecting the gonads or adrenals, it may be anticipated that some sort of psychosexual problem may need to be considered; the extent of concern should be related to the amount and type of hormonal imbalance thereby engendered and usually manifest by genital ambiguity.
When an individual is reared in the sex concordant with his prenatal endocrine heritage, psychosexually all will usually go well. When the prenatal influence is only moderate, the child still may adjust to his sex of rearing, owing to human behavioral flexibility, although he may have difficulty. But when the sex of rearing and the sex of the prenatal hormone environment are strongly conflicting. a situation unacceptable to the individual concerned may be anticipated. Thankfully, owing to the usual parallel differentiation of the external genitalia and the neural tissues which mediate sexual behavior, this last possibility is rare, since assignment of sex most often is based on the appearance of the genitalia.4
It should also be kept in mind that psychosexual problems may also arise, as in the Turner’s or Klinefelter’s syndrome, as the result of a genetic-endocrine defect despite apparently proper sex-role assignment. These are problems, however, only if we accept as “normal” that a human psychosexually must strongly be committed to a definite stereotyped male or female orientation and sexual behavior. It probably would be more correct biologically if we culturally accept a multiplicity of behavioral configurations concurrent with the many genetic and ontogenetic conditions which may lead to various levels of psychosexual bias within the nervous system.
As in the past, advances in our understanding of psychosexuality will depend upon multidisciplinary findings rather than data from any single source.
In the laboratory, efforts will be made toward uncovering the actual substances involved in the sex differentiating and activating processes, e.g., what is fetal morphogenic testicular substance (F.M.T.S.), just which biochemical entities are involved in the organization and activation of psychosexuality, and how do these substances vary during the individual’s life. A start has already been made in these directions (Diamond and Gennaro, 1967; Phoenix et al., Chapter 5). Further, since many processes differ in the developing and mature individual not only substances but mechanisms must be exposed. and studies will be directed to that end. For example, research will elucidate: the processes involved, during development, in the selective dominance of cortical (ovarian) versus medullary (testicular) areas of the indifferent gonad (see Burns, 1961); the persistence of one duct system and degeneration of the other (e.g., Price et al., 1967); the factors involved in protecting the pregnant adult female from genital and psychosexual alteration while leaving the fetal and nonpregnant adult female vulnerable (Diamond and Young. 1963; Diamond, 1967); and the means by which various maturational processes prod the latent. biased nervous system to manifest itself, e.g., via alteration in cognitive ability (Witkins et al., 1966). Of crucial importance will be developments in studies which demonstrate how endocrines affect genes within nervous tissues and thus provide a possible mechanism by which hormones would alter subsequent behavior. Here, too, a start has been made (see Karlson, 1963). We can equally envision compatible studies of drug, memory, and learning effects on human sexual behavior and psychosexuality.
From genetic studies per se, after extensive attempts, we should expect to see techniques developed which not only facilitate chromosome identification but allow mapping and analysis of genes as well. These techniques, once developed, would be used to compare behaviorally different individuals of a given phenotype and chromosome constitution as well as behaviorally similar individuals with similar constitutions. We must not, however, expect to find human sexual behavior the function of a single gene but rather a polygenic dependent variable. This simultaneously makes the original task of gene identity more difficult while facilitating theoretical interpretations. The difficulty arises from the need to locate many rather than a few gene loci. The facilitation accrues from the genetic concepts of multigenic penetrance, expressivity, and pleiotropism, which provide ample leeway for interpreting genetic-environmental interactions. These concepts parenthetically emphasize the contention that heredity and environment are interdependent in an individual’s development. With these anticipated genetic methods in concert with additional research using classical twin-study techniques (e.g., Kallmann, 1952a, 1952b; Rainer et al., 1960), in addition to well conceived and competently executed long-term longitudinal studies of sexual developments, further inroads into the analysis of the involved nature-nurture controversy will be made.
Clinically most all psychotherapists, regardless of their own professional orientation, admit that psychosexual bias and sex-role identity of genetic-endocrine origin is usually refractory to extensive permanent change. Although, owing to personal flexibility, some individuals will accept a role outside their diasthetic predisposition (Diamond, 1965a), evidence, mainly from the Johns Hopkins Hospital in this country and from Scandinavia, Great Britain, and Morocco abroad, indicates that individuals with such problems may be best treated by surgery and acquiescence to their personal wishes rather than by extensive depth therapy. Regrettably, this course of action is not yet generally considered most appropriate. The future, however, will no doubt see this feeling change so that elective sexual surgery and sex role changes will fall into a category akin to other plastic surgery procedures or mode of life changes, with individualized treatment and compassion prevailing rather than a blank caveat (see Benjamin, 1966).
While much more conclusive evidence is needed to consider them as such it is appealing to speculate that homosexuality and transsexualism might fit into this category of genetic-endocrine psychosexual problems. This is probable since these behavior patterns are among the most firmly entrenched of psychosexual deviations and environmental influences seem of no, or only minor, importance in their etiology (Kallmann, 1932a, 1952b; Benjamin, 1966). If indeed these do prove of genetic-endocrine origin rather than environmentally determined, a far-reaching reappraisal of our clinical and social approach to these conditions may be anticipated.
From all of this we may expect to see develop an acceptable concept of sex and “proper” sexual behavior, as broad or narrow, dependent upon an individual’s anatomic, physiologic, and psychologic constellation rather than on two arbitrarily arranged stereotypes of male or female. This realization, in itself, can have societal consequences far transcending biological or medical implications, since in this all-important sphere of sexuality in general and sexual behavior in particular, personal differences and desires will not be seen as abnormal or pathologic but as manifestations of a full continuum of human flexibility within a bimodal macrocosm.
Appreciation is extended to Drs. Warren N. Cox, Walton M. Edwards, Harold J. Kosasky, and Duncan R. MacMillen for cooperation in working with the patients presented and to Dr. Leonard E. Reisman for karyotype determinations.
Appreciation is also extended to Ciba Pharmaceutical Company for use of some of their illustrative material by Frank H. Netter, M.D.
This research was supported in part by U.S. Public Health Service Research Grants HD-02326 and HD-03394 from the National Institute of Child Health and Human Development.