The term “intersex,” as defined in Stedman’s Medical Dictionary and in the Compact Oxford English Dictionary, is “one having characteristics of both sexes.” Unfortunately the characteristics are not defined in any manner. Therefore, the interpretation may be physical, mental, in personality, or in other ways. Despite this confusion, the term today is used primarily, but not exclusively, to denote physical ambiguity-having the genital/gonadal/reproductive structures characteristic of both sexes. It is this interpretation that is referred to in this commentary.
A purpose of this commentary, which relates to articles by Migeon et al1,2 in this month’s Pediatrics electronic pages, is to highlight the complexities and conundrums of intersex issues prevalent in our society that affect urologists, surgeons, endocrinologists, geneticists, and pediatricians. The conundrums deal with gender assignment of neonates with ambiguous genitalia of whatever cause but most particularly those with a 46,XY karyotype. The questions include: “When should surgical procedures be undertaken?” “What are the ethics and legal consequences of proceeding with the current standard of care when that standard of care has been loudly challenged by displeased adult individuals who are displeased because of decisions and surgery rendered to them as infants with ambiguous genitalia?”
A second purpose of this commentary is to provide insight into what we know from the past, what we currently know, what we need to know, and what I believe we should be doing in our practices between today and the time in the future when we are reasonably sure that what we are doing is correct. The 2 articles1,2 from Johns Hopkins University provide data that set the stage for helping the reader better understand the continuing conundrums of intersex issues. Even pediatricians who have never seen an intersex patient in their practice may do so tomorrow, and will consequently be involved in making important mental decisions in response to self-directed questions such as, “What do I tell the parents?” “To whom do I refer the patient?” “What do I believe when I see a TV show featuring entertainment instead of science concerning intersex issues?”
In the 2 articles by Migeon et al,1,2 the subjects studied are adults with a 46,XY or 46,XY/XO karyotype, almost all of whom were initially seen by 24 months of age with undermasculinized genitalia. The goal of the first one of the articles2 was to establish and study 75 patients divided into 3 groups based on the phenotype of the external genitalia: 1) 18 subjects with normal-appearing external female genitalia, 2) 18 with micropenis without hypospadias, and 3) 39 subjects with ambiguous genitalia including perineohypospadias. All 18 patients in group 1 had been raised as female. In group 2, 5 had been assigned as females and 13 as males. In group 3, 18 had been assigned as females and 21 as males. All were evaluated by at least 1 MD and usually by 2 physicians (endocrinologist and urologist), and all by a senior psychologist specializing in intersex psychohormonal research and therapy. The “Results” and “Discussion” sections cover 1) data gathered concerning the recruiting techniques, 2) the selection of 96 qualified participants of which 21 (22%) elected not to participate, 3) the subjects’ knowledge of their medical/surgical history and karyotype, 4) their satisfaction with their gender assignment and sexual function, and 5) their need for consultative psychological assistance.
The objective of the other study1 was to more completely evaluate the 39 adult subjects in the third group from the first study who are 46,XY individuals with genital ambiguity, 37 of which presented as infants or children before 2 years of age. The members in this group are the most difficult to treat in respect to gender assignment, as their genital appearance is undermasculinized as compared with nonaffected XY males or overmasculinized as compared with nonaffected XX females. The specific goals were to determine 1) the long-term satisfaction of these patients with their gender assignments (21 as male and 18 as female) which had been given by parents and physicians, and 2) the medical/surgical/psychological outcomes in this group of 39 subjects presenting with similar degrees of significant genital ambiguity at birth but raised in opposite sexes.
The ultimate goals of these studies were to determine retrospectively how physicians can better work with parents in helping them decide for their infant with an intersex problem the gender assignment and the timing of genital surgery if it is required, and in helping the parents’ comprehend the related long-term implications of each choice available to them.
The tentative conclusions reached and the discussions within the articles,1,2 based on the data presented, included first and foremost that either male or female sex of rearing can lead to successful long-term outcome for the majority of cases of severe genital ambiguity in 46,XY/or 46,XY/XO individuals. Second, in the 39 patients reported in the second study, the 21 raised as men had significantly more genital surgeries (means of 5.8 vs 2.1) than the 18 raised as females. Third, the physician’s evaluation of the cosmetic appearance of the genitalia of those raised as men was significantly more abnormal than that in those raised as women. Fourth, a significant number in each group (9 of 21 and 12 of 18) were satisfied with their body image. Of the remainder only 1 in each gender group was totally dissatisfied with his/her body image, and 11 of 21 raised as males and 5 of 18 as females were “somewhat” dissatisfied. In respect to sexual function, only 3 of 21 subjects raised as males and 3 of 18 as females were “totally” dissatisfied. In contrast, 6 in each group were “totally” satisfied, and 12 of 21 men and 8 of 18 women were “somewhat” dissatisfied. In the total group of 39, 37 rated their body image no worse than “somewhat” dissatisfied and 33 of 39 rated their sexual function similarly. Ninety percent of men and 83% of women had had a recent sexual experience with a partner. In summary, men and women did not differ in their satisfaction ratings of their body image, sexual function, their sex of rearing, gender identity, or deviation from heterosexuality, which was minimal (Figs 1–3 in reference 1).
The authors also concluded in a previous publication3 that children with micropenis without hypospadias should be reared as males instead of females in most instances. Other conclusions can be found in these articles, and readers are encouraged to digest the content of each article thoroughly to better comprehend the subsequent comments.
“Gender identity” refers to the sex in which we each have our self-image. A spectrum exists between the extremes of total male gender identity to total female. “Gender role” is the way we conduct ourselves in our daily activities—male, female, or between. A spectrum also exists from total male to total female. “Psychosexual preference” refers to heterosexuality, homosexuality, and bisexuality. The data of the Johns Hopkins group can be interpreted to indicate that establishing one’s gender identity is usually malleable, a result of the influences of both nature (hormone exposure and/or gene influence) and nurture (environment including culture and/or behavior modification). These findings are in accord with the current beliefs of many reputable investigators,4 although others might remain skeptical, believing that nature is significantly dominant over nurture in determining gender identity. In the Johns Hopkins studies the gender roles of the subjects were not significantly addressed. The psychosexual orientation of these subjects in a significant majority was heterosexual. On the basis of these and other studies, one can currently conclude that 46,XY infants with ambiguous genitalia can or could adapt to being assigned to either sex. If this conclusion is accepted, however, there must be considerations in respect to the maleness of the genitalia. For example, to assign a 46,XY patient with minimal virilization, the etiology of which was complete or nearly complete androgen insensitivity, to the male sex would usually be a catastrophe. Consequently, these data are valuable in supplying us with reasonable temporary guidelines for having discussions with the parents of 46,XY or 46,XY/XO neonates who must decide about the gender assignment of their offspring.
From the pediatrician’s perspective—whether general pediatrician, endocrinologist, surgeon, or other—the decision of sex assignment must be made by the parents, and not the doctor, after being fully informed of all the implications of the specific etiologic diagnosis, the anatomy present, the realistic potential for satisfactory altering of abnormal genital structures, the possibility of resultant loss through surgery of sexual pleasure and satisfaction, and other pertinent considerations.
The above comments pertain primarily, but not exclusively, to gender assignment. Of equal or greater controversy is the consideration of surgery, including whether nonlife-threatening surgery should be deferred until the child is mature enough to participate in the decision-making. A significant groundswell has been initiated by concerned intersex adult patients who are disappointed in the gender assignments designated by their doctors and/or parents when they were infants. The Intersex Society of North America (ISNA) (www.isna.org) was formed in 1993 by such patients and has been influential in drawing to the attention of the medical community that the traditional approach to diagnosing and treating intersex patients needed to be reexamined. The traditional approach has been used synonymously with the paternalistic approach. The latter refers to the John Money approach also, but conceptually the traditional/paternalistic approach is that the doctor and his associates made (make) the decision for the parents and the patient whether a particular patient was (is) to be raised as a boy or girl. In this context the parents were passive decision-makers but were expected to be activists on the stage of everyday life—activists in training and convincing the affected subject that he/she was truly a boy or girl with unfinished sexual development in utero. In the standard or traditional approach, the hypothesis was that nurture influence(s) outweighed nature influence(s) in establishing gender identity. The 2 criteria thought necessary in testing the hypothesis were that the sex of rearing needed to be established early (probably no later than 18 months) and the external genitalia had to be compatible with the sex of rearing. The potential for reproduction also was considered in the decision-making process. The possibility that imprinting of the brain occurred was not ignored by Money and his associates, but it was believed, as is still the case, that guinea pigs and other lower animals (see Meyer-Bahlberg4 for further discussion) were much more prone to testosterone imprinting of the brain than was Homo sapiens. Therefore, early surgery on the unfinished genitalia was essential to establish the influence of nurture on the intersex infant. Fifty years later, we have learned, in significant part from the members of ISNA and from other observations, that imprinting of the brain with testosterone and/or other androgens does occur to a greater extent than initially believed. This has become evident as a significant number (more than in the usual nonaffected population) of 46,XY intersex males raised as females, but whose etiology was not complete androgen insensitivity, elected to reassign themselves as males when they reached adolescence or adulthood. Not surprisingly, such individuals are disappointed, frustrated, and often angry. Thus, members of ISNA have campaigned for surgery of the ambiguous genitalia in only life-threatening situations until the patient can participate in the decision.
Much has been written condemning the traditional approach, and much has been written that no surgery be done on the genitals until the child can participate in the decision-making. Ethical and legal implications of performing early surgery in the 21st century are prominent in the news media and in medical journals. For example, Kipnis and Diamond,5 present case reports on which they base 3 recommendations: 1) that there be a general moratorium on such surgery when it is done without the consent of the patient, 2) that this moratorium not be lifted unless and until the medical profession completes comprehensive look-back studies and finds that the outcomes of past interventions have been positive, and 3) that efforts be made to undo the effects of past deceptions by physicians (“deceptions” refers to not telling the patient the complete history, physical findings, karyotype, anticipated outcome, etc). However, Meyer-Bahlberg,4 in a statesman-like, scientifically accurate rebuttal, counters the data on which these recommendations were made. Nonetheless, other reports6–8 continue to tout that surgery should not be done unless a life-threatening situation prompts such surgery. Many surgeons, psychologists, and pediatric endocrinologists believe the stance of such recommenders is extreme in that the delay will produce as many or more problems for the majority of patients as surgery in infancy creates.
Interestingly, pediatric urologists are polarized in respect to performing early surgery or delayed surgery. A plea for delayed surgery was made in 2001 by Creighton et al9 on the basis of a review of 44 adolescent patients of various etiologies including 11 with congenital adrenal hyperplasia, 11 with abnormalities with development of the cloaca and/or urogenital structure, and 12 with other causes. The average age that surgery was first performed was 8 months. All surgeries were done between 1979 and 1995. On the basis of the need for repeated surgery in most of the patients plus other poor outcome data, Creighton and colleagues concluded, “It is important that clinicians and parents understand that genital ambiguity cannot be corrected in infancy by a single procedure. For most individuals, additional treatment will be necessary in adolescence and the long-term impact of such treatment on adult sexual function is still unknown. Alizai et al,10 also from the United Kingdom, on the basis of postpubertal examination of 14 adult congenital adrenal hyperplasia patients, concluded that the results were disappointing when surgery was done early even by the hands of competent specialists. Alizai and colleagues recommended that early surgery not be done except for simple surgical procedures, and that with the presence of a high or intermediately high vagina, surgery should be delayed until after puberty.
In 2001 the British Association of Paediatric Surgeons Working Party on the Surgical Management of Children Born With Ambiguous Genitalia11 produced a statement on the current thinking about, and suggestions for, surgical practice on children with genital ambiguity. In respect to delaying surgery until the patient can consent, the UK urologists believed this policy would be too prescriptive; however, parents (all of whom must provide consent) must be made aware of the possibility that nonoperative management with psychological support for the child and family (such as recommended by the ISNA and others5–9) is an alternative to surgery. In this report the recommendation for the severely undervirilized genetic male is that the assignment of such individuals to the female gender by surgery should only be undertaken with considerable caution and after complete multidisciplinary investigation and full counseling of the parents. The second study1 by the Johns Hopkins investigators reports more favorable results than was expected by most working in this field. However, despite the equalness of outcome results of the infants assigned as male and those assigned as female in the Johns Hopkins report, my inclination, if I was the responsible physician is this situation, would be in the manner recommended by the UK group generally in favor of seeing the infant assigned in the male gender. However, I would certainly not encourage the assignment of the male sex if the infant had a very small phallus, little fusion of the labial folds, and was demonstrated to have partial androgen insensitivity. Each case must be considered individually.
In contrast to the recommendations presented above, many urologists recommend early surgery. Donahoe and Schnitzer12,13 recommend that in structuring female genitalia, including vaginal repositioning such as in congenital adrenal hyperplasia (CAH), surgery be performed early using meticulous dissection that avoids a narrow introitus, which historically has been a frequent complication. The infant’s pelvis is also shorter at this age, making the mobilization of the vagina less problematic than if the procedure was done later. The authors state, “This procedure has yielded excellent results over the past 3 or 4 years.” To paraphrase the remainder of their comments, the short-term outcome has been encouraging as compared with previous procedures that do not incorporate use of the square anterior flap. The long-term test of its efficacy (sexual intercourse) remains to be evaluated. These highly respected surgeons also describe a 3-stage procedure for those 46,XY infants who are to be raised as males. Rink and Yerkes15 also recommend early vaginal repair with a technique they recently devised to substitute for the vaginal pull-through procedure, which historically by older methods is associated with stenosis and the need for frequent dilatation of the vagina, a procedure tolerated poorly by preadolescent and early adolescent girls and associated with noncompliance more frequently than compliance.
Two points involved in the consideration of early surgery are important: 1) the experience, including the use of modern techniques, of the urologist or surgeon in performing surgery on infants, children, and adolescents, and 2) the decision preference of the parents with respect to having surgery undertaken quickly or at a later time when the patient can participate in the decision. Essential to the second point is the most complete education of the parents as feasible. The participation of a team—including the surgeon, endocrinologist, pediatrician, psychologist, and possibly others—becomes highly desirable. In most instances of an intersex problem, a medical emergency is not present but a mental and/or social emergency very likely is. The solving of mental emergencies usually requires time, education, consultation, and contemplation followed by decision-making.
In considering practice decisions pertaining to intersex patients, you may find the following particularly useful. Daaboul and Frader16 reviewed the controversies surrounding the management of patients with ambiguous genitalia to determine the strengths and weaknesses of recommendations for clinical practice. They state that modern scientific evidence about sexual determinations reflects earlier theories supporting the appropriateness and need for early decisions. Daaboul and Frader note that the traditionalist approach no longer conforms to modern legal or ethical standards of care. Also, the position of some intersex activists ignores the potential for psychosocial harm to intersex children when years pass before decision-making is finalized, and ignores the strong deference in our culture to parental discretion in decisions for and about their children. They argue for a middle way involving both shared decision-making with parents of children with intersex and the honoring of parental preferences for or against surgery. These guidelines and suggestions are thoughtfully and logically presented. As a pediatrician and pediatric endocrinologist, I agree with the proposals for consideration and recommend the article to interested readers. A copy kept in the office of each pediatrician could be helpful when the pediatrician is unexpectedly faced with talking with parents of an intersexed child.
An issue concerning intersex that has not been considered in-depth until recently is the cultural differences between western Caucasians and other ethnic groups such as Islamics, Buddhists, Hindus, and Taoists. As emphasized by Kuhnle and Krohl,17 cultural differences must be considered in dealing with intersexed individuals as these differences influence the patient’s own psychosexual development and also the medical decisions by doctors and parents regarding sex assignment and management of these patients. There is evidence that attitudes concerning gender and sexuality, including the acceptance of intersexuality, differ significantly among various cultures. These cultural differences must be taken into account in counseling and in decision-making. These authors not only reviewed the literature, which is scanty regarding this topic, but used their presence in Malaysia to study the cultural and ethnic differences in respect to intersex of the 3 ethnic groups (Indian, Malaysian, and Chinese) living in Malaysia. This report is highly recommended for reading, as the authors use longitudinal case histories of intersex children progressing to adulthood to emphasize the varied influences of different cultures on acceptance or nonacceptance of gender reassignment, gender identity, gender role, etc. The authors also provide thoughts and questions that can serve as the basis for productive research in the intersex arena that will lead to more logical counseling and decision-making for intersex patients of any culture.
Guidelines published before those suggested by Daaboul and Frader were published by the American Academy of Pediatrics.18 These guidelines include sections entitled “Understanding Sexual Differentiation,” “Which Newborns Need Investigation,” “The History and Examination, Laboratory and Imaging Studies,” “The Causes of Ambiguous Genitalia,” “Deciding the Sex of Rearing,” “Follow Up,” and “Conclusions.” Because these guidelines were published 2 years ago and written >3 years ago, the following comments seem appropriate. The sections preceding the one on “Deciding the Sex of Rearing” remain appropriate and reasonable in my opinion, although possibly somewhat oversimplified. The section dealing with sex of rearing is outdated in the minds of many. A subsection entitled “Fertility Potential” exists. The topic is briefly discussed. The statement is made that all female (XX presumably) infants virilized because of CAH should be raised as girls. This statement is considered by some as too dogmatic, as inadequate data are available concerning the markedly virilized patients with complete fusion of the urethrolabial and urethrolabial folds with a resultant penis-like phallus (Prader 5 sex staging). Possibly these patients should be considered for male gender assignment, which would avoid surgical procedures to the external genitalia, leave the phallus intact to enhance sexual satisfaction, and be in accord with the probability that significant imprinting of the brain with testosterone has occurred. Controversy exists whether fertility should be dominant in the decision-making, as the loss of sexual pleasure and the acquisition of an inadequate vagina may be too high a penalty to pay. The parents must make the decision regarding the gender assignment and type and timing of surgery. Therefore, this guideline is open to question. Research studies are planned and needed to determine the outcomes in such XX patients with CAH and Prader 5 genitalia. In many such patients, pathology went unrecognized until late childhood or adulthood.
Also in the section on “Deciding the Sex of Rearing” is a subsection entitled “Capacity for Normal Sexual Function.” The guidelines state that infants with ambiguity (such as those presented in Migeon et al1) should be raised as girls. Of course, this conflicts with recommendations by the British group.11 Many involved in the field say this is an overstatement because it does not take into account variables other than penile size. If partial androgen insensitivity is the etiologic diagnosis, most would agree that following the initial guidelines (assignment as female) is advisable. But in other instances, because of multiple variables—including parental decision-making and the fact that assignment of the male sex in 46,XY intersexed patients1 produces as much self-satisfaction as assignment of female—the guideline to raise all such patients as female is questionable.
The subsection dealing with “Timing of Surgery” contains statements that were acceptable when defining the traditional handling of an intersex problem, but are passé in the eyes of ethicists and legal advisors in 2002. Individuals in these fields urge that the parents must make the decision of sex assignment for their child and not the doctors or their colleagues on the team.
In my opinion, one should be cautious about using the currently published AAP guidelines without knowing that more recent guidelines exist and may be preferable.
Attention to the conundrums of intersex issues has intensified in the past few years. Practical applications will evolve from pediatricians, urologists, endocrinologists, geneticists, and psychologists working together in discussing appropriate guidelines for patient care and in pursuing research that will resolve the conundrums. Recently the Lawson Wilkins Pediatric Endocrine Society and the European Pediatric Endocrine Society sponsored a consensus meeting of endocrinologists, urologists, surgeons, psychologists, and others that focused on the treatment of CAH, including medical, surgical, psychological, prenatal, postnatal issues. (A consensus statement from that meeting will soon be published.19) This working group concluded that there currently is insufficient evidence to support rearing a 46,XX infant at Prader stage 5 as male. The conundrum still exists, as described a few lines above.
In March 2002 at the “Third National Symposium: Bioethical Considerations in Human Subject Research,” sponsored by the University of South Florida, the topic “Bioethical Issue in Sex Assignment” was thoroughly discussed. Subjects included consideration of surgical issues, psychological issues, attorneys’ perspective, advocacy group perspective, and pediatric endocrinology perspectives. A publication is forthcoming.
In addition, the National Institute of Child Health and Human Development recently sponsored a research planning workshop on intersex issues and the need for expanding investigation to resolve some of the controversies. It is self-evident that extensive clinical and basic science investigation is necessary.
Fifty years after Money’s hypothesis began to be tested, our knowledge about phenotypic sexual differentiation of the gonads, genitalia, and internal ducts is encyclopedic. However, the actions of genes, their product proteins, the hormones, and the hormone receptors are not completely known. There exists a series of conundrums regarding gender assignment, gender identity, gender role, and sexual preference that need solving before we can be comfortable in providing reasonable answers to the questions posed by parents of intersexed patients and those of the patients themselves. The many conundrums concerning the optimal surgical procedures and the timing of those procedures remain to be solved. The experience of working in the human intersex area, with all its variables, is gratifying, frustrating, challenging, and rewarding. Solutions to the conundrums will come sooner if collegial sharing of information, efforts, and ideas between members of multiple medical disciplines occurs. The research required to answer these questions must be prospective and retrospective, involve humans with various intersex phenotypes and cerebrotypes, use approaches in basic science and clinical research, capitalize on animal studies correlated with studies in humans, and adequately supported financially by our national research institutes. It is gratifying to know that leaders of the National Institutes of Health, particularly the National Institute of Child Health and Human Development and the National Institute of Mental Health, are rising to the challenges present. As paraphrased from Holmbeck:20 point 1: Good science leads to the best good deeds (in medicine); point 2: Good science provides answers to questions that minimizes alternate explanations; and point 3: Although some scientific studies may not seem to have direct clinical relevance, they make clinical contributions later in unforeseen ways.
The application of science to solving the conundrums of intersex issues fortunately is in good hands. The common good on behalf of the patients will bring the good hands together.
Without Juanita Bishop, the designing, composing, and writing of this commentary would not have been possible. Therefore, I express publicly my deepest appreciation for her many years of dedication and collaboration.
- Received June 17, 2002.
- Accepted June 18, 2002.
- Address correspondence to Robert M. Blizzard, MD, Department of Pediatrics, University of Virginia Health Sciences Center, 1224 W Main St, Suite 701, Charlottesville, VA 22903
The opinions expressed in this commentary are exclusively mine and should not be viewed as those of an authority. I am a student of the subject and not an authority.
- ↵Migeon CJ, Wisniewski AB, Gerheart JP, et al. Ambiguous genitalia with perineal scrotal hypospadias in 46,XY individuals: long-term medical, surgical, and psychosexual outcome. Pediatrics.2002;110(3) . Available at: http://www.pediatrics.org/cgi/content/full/110/3/e31
- ↵Migeon CJ, Wisniewski AB, Brown TR, et al. 46,XY Intersex individuals: phenotype and etiologic classification, knowledge of condition, and satisfaction with knowledge in adulthood. Pediatrics.2002;110(3) . Available at: http://www.pediatrics.org/cgi/content/full/110/3/e32
- ↵Wilson BE, Reiner WG. Management of intersex: a shifting paradigm. J Clin Ethics.1998;9 :366– 369
- ↵British Association of Paediatric Surgeons Working Party on the Surgical Management of Children Born With Ambiguous Genitalia. 2001. Statement of the British Association of Paediatric Surgeons Working Party on the surgical management of children born with ambiguous genitalia. Available at: http://www.baps.org.uk/documents/Intersex%20statement.htm
- ↵Donahoe PK, Schnitzer JJ. Ambiguous genitalia in the newborn. In: O’Neill JA, Rowe ML, Grosfeld JL, Fonkalsrud EW, Coran AD, eds. Pediatric Surgery. 5th ed. St Louis, MO: Mosby-Yearbook; 1998:chap 118
- ↵Rink RC, Yerkes EB. Surgical management of female genital anomalies, intersex (urogenital sinus) disorders and cloacal anomalies. In: Gearhart JP, Rink R, Mouriquand PDE, eds. Pediatric Urology. Philadelphia, PA: WB Saunders; 2001
- ↵Kuhnle U, Krohl W. The impact of culture on sex assignment and gender development in intersex patients. Perspect Biol Med.2002:85– 103
- ↵American Academy of Pediatrics, Committee on Genetics and Sections on Endocrinology and Urology. Evaluation of the newborn with developmental anomalies of the external genitalia. Pediatrics.2000;106 :138– 142
- ↵The Lawson Wilkins Pediatric Endocrine Society & European Society of Pediatric Endocrinology CAH Working Group: consensus statement on 21-OH deficiency. Pediatrics. In press
- ↵Holmbeck GN. Methodological plenary: new directions in pediatric psychology research: research design issues and lessons from developmental psychology. Presented at the Great Lakes Regional Meeting on Child Health Psychology; April 2002; Milwaukee, WI
- Copyright © 2002 by the American Academy of Pediatrics