Ambiguous Genitalia With Perineoscrotal Hypospadias in 46,XY Individuals: Long-Term Medical, Surgical, and Psychosexual Outcome

Claude J. Migeon, MD*; Amy B. Wisniewski, PhD*; John P. Gearhart, MD‡; Heino F.L. Meyer-Bahlburg, Dr. rer. nat.§; John A. Rock, MDʈ; Terry R. Brown, PhD*¶; Samuel J. Casella, MD#; Alexander Maret, MD*; Ka Ming Ngai*; John Money, PhD**; and Gary D. Berkovitz, MD‡‡

ABSTRACT. Objectives. To identify and study adults We discuss factors that should be considered by parents (21 years or older) who have a 46,XY karyotype and and physicians when deciding on a sex of rearing for presented as infants or children with genital ambiguity, such infants. Pediatrics 2002;110(3). URL: http://www. including a small phallus and perineoscrotal hypospa- pediatrics.org/cgi/content/full/110/3/e31; intersex, sex as- dias, reared male or female. signment, gender, androgen insensitivity, gonadal dysgen- Methods. Participants were classified according to the esis, psychosexual, genital reconstruction, hormone cause underlying their intersex condition based on re- replacement. view of medical and surgical records. Long-term medical and surgical outcome was assessed with a written ques- tionnaire and physical examination. Long-term psycho- ABBREVIATIONS. PAIS, partial androgen insensitivity syn- sexual development was assessed with a written ques- drome; PGD, partial gonadal dysgenesis. tionnaire and semistructured interview. Results. Thirty-nine (72%) of 54 eligible patients par- uring fetal sex differentiation, genetic males ticipated. The cause underlying genital ambiguity of par- ticipants included partial androgen insensitivity syn- who are unable to masculinize their sex ducts men and 9 women), partial gonadal Dand external genitalia can be classified into 2 5 ;14 ؍ drome (n men and 4 women), and other major etiologic groups: 1) the inability of the fetus to 7 ;11 ؍ dysgenesis (n intersex conditions. Men had significantly more genital produce sufficient amounts of testosterone and dihy- surgeries (mean: 5.8) than women (mean: 2.1), and phy- drotestosterone or 2) the inability of the fetus to sician-rated cosmetic appearance of the genitalia was sig- respond to androgens that are present in normal nificantly worse for men than for women. The majority amounts.1 We previously described a population of of participants were satisfied with their body image, and 46,XY subjects who presented to the Pediatric Endo- men and women did not differ on this measure. Most crinology Clinic of Johns Hopkins Hospital with men (90%) and women (83%) had sexual experience with 2 a partner. Men and women did not differ in their satis- varying degrees of undermasculinized genitalia. In faction with their sexual function. The majority of par- this population, the most difficult group to treat in ticipants were exclusively heterosexual, and men consid- terms of gender assignment is that of individuals ered themselves to be masculine and women considered who were born with ambiguous genitalia that in- themselves to be feminine. Finally, 23% of participants (5 cludes a small phallus and perineoscrotal hypospa- men and 4 women) were dissatisfied with their sex of dias.3 For this group of patients, there is a lack of rearing determined by their parents and physicians. agreement about optimal sex assignment (in terms of Conclusions. Either male or female sex of rearing can the child developing a gender identity that is con- lead to successful long-term outcome for the majority of gruent with his or her rearing) and types of genital cases of severe genital ambiguity in 46,XY individuals. surgery associated with the best cosmetic and func- tional outcome. The dominant view has been that female sex as- From the *Department of Pediatrics, Division of Pediatric Endocrinology, and ‡Department of Urology and James Buchanan Brady Urological Insti- signment by physicians and parents is optimal in tute, Johns Hopkins University School of Medicine, Baltimore, Maryland; severely undermasculinized cases because feminiza- §Department of Psychiatry, Division of Child Psychiatry and Program of tion with surgical4 and endocrine5 treatment was Developmental Psychoendocrinology, Columbia University College of Phy- considered more successful than masculinization. sicians and Surgeons and New York State Psychiatric Institute, New York, New York; ʈDepartment of Gynecology and Obstetrics, Emory University The appropriateness of this type of sex assignment in School of Medicine, Atlanta, Georgia; ¶Department of Biochemistry and 46,XY individuals with a small phallus and perineo- Molecular Biology, Johns Hopkins Bloomberg School of Public Health, scrotal hypospadias has been questioned in response Baltimore, Maryland; #Department of Pediatrics, Dartmouth School of Med- to accounts of individuals who were raised female icine, Hanover, New Hampshire; **Department of Medical Psychology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Mary- and report dissatisfaction in adolescence or later with land; and ‡‡Department of Pediatrics and, University of Miami School of their female rearing. Some investigations do not pro- Medicine, Miami, Florida. vide precise physical descriptions of subjects to de- Received for publication Feb 6, 2002; accepted Apr 30, 2002. termine either cause underlying genital ambiguity or Reprints requests to (C.J.M.) 600 N Wolfe St/Park 211, Baltimore, MD 21287. E-mail: [email protected] extent of androgen exposure during fetal develop- 6 ␣ PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad- ment. Other reports relate to subjects with 5 -reduc- emy of Pediatrics. tase deficiency7,8 and 17␤-hydroxysteroid dehydro- http://www.pediatrics.org/cgi/content/full/110/3/Downloaded from www.aappublications.org/newse31 PEDIATRICS by guest on Vol.October 110 1, No.2021 3 September 2002 1of10 genase deficiency.9 In both of these conditions, the group of patients with complete androgen insensi- external genitalia are severely undermasculinized at tivity syndrome, good sexual function in terms of birth but present partial virilization at puberty if the patients’ satisfaction with their genitalia (78%), sat- gonads remain in situ. In mid-adolescence or later, isfactory libido (71%) and orgasm (77%) were re- some of these subjects have developed a male gender ported by study participants.23 Creighton et al18 re- identity despite their female rearing. Single case re- ported the results of several vaginoplasty procedures ports of similar outcomes associated with fetal phe- in girls and young women who were affected by a nytoin exposure10 and mixed gonadal dysgenesis11,12 variety of urogenital abnormalities resulting in am- also exist. biguous genitalia. In these patients, the vaginal in- Larger long-term outcome studies of gender devel- troitus was absent or small in 82%, vaginal length opment in male pseudohermaphrodites report ac- was inadequate in 27%, and additional vaginal pro- ceptance of sex assignment established by parents cedures were required in 75%. and physicians by the majority of participants, re- Investigations of masculinizing surgeries, like fem- gardless of female or male rearing.13,14 The common inizing surgeries, in 46,XY intersex individuals with predictor of gender transposition, defined in these perineoscrotal hypospadias are limited. The only studies as gender identity change and/or homosex- study to have evaluated exclusively the surgical out- uality, in subjects who were reared male or female come of the most severe cases of hypospadias re- was stigmatization related to having an intersex con- ported on 19 men, approximately half of whom ex- dition. perienced difficulties with micturition, urologic In addition to the question of acceptance of female function, and ejaculation.24 Roughly one third of pa- sex assignment by 46,XY intersex patients, one needs tients were affected by marked impairment in qual- to ask whether surgical feminization is easier and ity of life resulting from their ambiguous genitalia, preferable to surgical masculinization. Feminizing ranging from mild depression to severe psychiatric surgeries can include procedures to reduce the size impairment. Another follow-up assessment of hypo- of an enlarged clitoris by amputation (historical only spadias repair in adults included 8 men with perin- in the United States) or reduction/recession, to cre- eoscrotal hypospadias.25 In all cases, multiple hypo- ate a vagina (McIndoe and/or bowel segment pro- spadias repairs were attempted with a postoperative cedure), and to remove the gonads. complication rate of 64%. Repeated surgical proce- Results of clitoral surgery are mixed. For example, dures and complications are of particular concern preservation of nerve conduction in the neurovascu- because of scarring and loss of tissue associated with lar bundle of the phallus was reported after excision each surgery,26 as well as the presumed negative of the corporeal bodies in infants with ambiguous impact on sexual function. genitalia,15 although long-term sexual function re- In light of discrepant reports of long-term gender mains to be investigated in these patients. A second development and surgical outcome of 46,XY intersex article reported excellent cosmetic and functional individuals who were born with a small phallus and outcome after clitoral recession16; however, an un- perineoscrotal hypospadias, the current study was wanted outcome of clitoral necrosis can occur.17 designed to assess these variables in such patients When cosmetic outcomes of several types of clitoral treated at the Johns Hopkins Pediatric Endocrine surgeries were considered together (recession, reduc- Clinic. The specific goals of our investigation were to tion, and amputation), the postsurgical appearance document long-term satisfaction with the gender as- of the genitalia were considered to be poor by signment given by parents and physicians and with Creighton et al.18 The young age of some of the medical/surgical outcome in a group of patients participants in these studies makes it difficult to who presented with the same degree of severe gen- interpret the functional significance of the findings. ital ambiguity at birth. In addition, some of the above-mentioned studies used measures of cosmetic outcome that were deter- METHODS mined by the investigators, not by the patients them- The present research was approved by the Joint Committee on selves. Clinical Investigation of the Johns Hopkins University School of Follow-up studies of vaginoplasty are also limited Medicine (Baltimore, MD). Written, informed consent was ob- in number. A large study was conducted in women tained from all participants before participation. Participants were with mu¨ llerian agenesis or Mayer-Rokitansky- asked to complete a written questionnaire and to visit the Johns Ku¨ ster-Hauser syndrome (also referred to as Roki- Hopkins Clinical Research Center for the purpose of completing a 19 physical examination, at which time a discussion regarding their tansky syndrome) by Rock et al. In this group of health status was offered. Participants were asked to confirm their patients, the McIndoe vaginoplasty procedure was questionnaire responses and to elaborate on unclear or incomplete rated to be successful in terms of postsurgical vaginal responses. depth for sexual activity by all women. Women who had congenital adrenal hyperplasia as a result of Participants 21-hydroxylase deficiency and underwent a McIn- A total of 183 adults with a 46,XY karyotype and intersex doe procedure reported a lower success rate (62%) in condition had been cared for at the Pediatric Endocrine Clinic of terms of comfortable penovaginal intercourse.20 Out- the Johns Hopkins Hospital from 1950 to the present. Among come studies of the McIndoe procedure in women these, 54 presented with ambiguous genitalia, including perineo- scrotal hypospadias, and thus were eligible for study recruitment.2 with complete androgen insensitivity syndrome re- Thirty-nine individuals (72%) provided informed consent and ported satisfactory intercourse postoperatively in completed the study. Participants ranged in age from early 20s to 72% of patients21 and orgasm in 78%.22 In a similar early 50s (mean age: 34 years). For maintaining participant ano-

2of10 OUTCOME OF AMBIGUOUSDownloaded from GENITALIA www.aappublications.org/news WITH PERINEAL by guest HYPOSPADIAS on October 1, 2021 nymity, age is presented in categories of 5 years at the time of appearance of the external genitalia (stretched penile length [cm], participation (Tables 1 and 2). size of testes [cm], and quality of corporal bodies) were evaluated Fourteen participants, 5 currently living as men (1–5) and 9 independently and then agreed on by 2 physicians (C.J.M. and currently living as women (22–30), were classified as having par- J.P.G.). When all 3 genital measures were within the normal range, tial androgen insensitivity syndrome (PAIS) on the basis of andro- cosmetic appearance of the genitalia was rated as good. When 1 of gen receptor studies in cultured genital skin fibroblasts. These the 3 measures was abnormal, a rating of fair was given; and when participants had either a low number of receptor binding sites for 2 or more measures were abnormal, the cosmetic appearance of dihydrotestosterone or a low binding affinity. However, a muta- the genitalia was rated to be poor. tion in exons 2 through 8 of the androgen receptor gene was When breast enlargement was present, breast size was mea- detected in only 6 of these participants. In addition, for partici- sured (cm) both horizontally and vertically (pediatric endocrine pants in whom no androgen receptor mutations were identified, ␤ technique) for each breast. Measurement did not differentiate no mutations of the 17 -hydroxysteroid dehydrogenase gene, as between glandular and adipose tissue. Type and timing of surger- reported by Boehmer et al,27 were observed. ies used to masculinize the external genitalia were obtained from Eleven participants, 7 currently living as men (6–12) and 4 surgical records and then verified during the physical examina- currently living as women (31–34), were classified as having par- tion. The existence and size of the prostate gland were recorded. tial gonadal dysgenesis (PGD) on the basis of the presence of Pubic hair growth was rated according to male-typical Tanner well-defined mu¨ llerian duct remnants. Indeed, all participants in 29 the PGD group presented with a uterus initially. stage ratings. Fourteen participants, 9 currently living as men (13–21) and 5 For participants who were living as women, evaluation of the currently living as women (35–39), were considered to have a cosmetic appearance of the external genitalia included vaginal poorly defined cause underlying their genital ambiguity. Four depth measured with graduated vaginal dilators (cm) and place- participants (13, 19, 20, and 38) were believed to be affected by a ment of the vaginal introitus on the perineum. Clitoral length was timing defect of their hypothalamic, pituitary, and/or gonadal also measured (cm). As in the case of the men, cosmetic appear- function. Five participants (15–17, 21, and 39) presented with ance of the genitalia was rated as good when all 3 measures were multiple congenital malformations, including genital ambiguity. normal, fair when any 1 measure was abnormal, and poor when 2 One participant was a 46,XY true hermaphrodite (14). Finally, the or more measures were abnormal. Breast size was measured as cause of abnormal sex differentiation could not be determined in reported for men. Type and timing of surgeries to feminize the the remaining 4 participants (18, 35–37). external genitalia were obtained from surgical records and then verified during the physical examination. Pubic hair growth was Physical Measurements rated according to female-typical Tanner stage ratings.29 Both male and female participants were asked about their Physical Measurements at Birth endocrine treatment from childhood to the time of participation in Appearance of the external genitalia was determined from adulthood. Responses were compared with information obtained medical records and was agreed on by 2 of the authors (C.J.M. and from medical charts and questionnaire responses. A.B.W.). The grading scheme described by Quigley et al28 was used to classify the degree of undermasculinization of 46,XY in- dividuals with ambiguous external genitalia using a 7-point scale Psychosexual Assessment (1 ϭ male phenotype to 7 ϭ female phenotype). Genitosexual Function Physical Measurements in Adulthood Participants were asked about the adequacy of their genitalia Physical measurements in adulthood were obtained during an for sexual functioning (scale: 1 ϭ adequate, 3 ϭ somewhat inad- examination that took place in the Clinical Research Unit at the equate, to 5 ϭ totally inadequate), self-estimated strength of libido Johns Hopkins Hospital and also from medical records. (scale: 0 ϭ none, 3 ϭ average, to 7 ϭ very high), and experience of For participants who were living as men, rating of cosmetic orgasm (yes/no).

TABLE 1. Number of Genital Surgeries, Physician-Rated Appearance of the Genitalia, Self-Reported Body Image, Final Stretched Penile Length, and Self-Reported Satisfaction With Sexual Function in Adult 46,XY Patients Who Were Born With a Small Phallus and Perineoscrotal Hypospadias and Were Living as Men at the Time of Study Participation Patient Age of Final Age at Total No. Physician-Rated Self-Reported Final Stretched Self-Reported Male Gender Study of Male Appearance of Body Image Penile Length Sexual Function Assignment Participation Genital Adult Genitalia (Satisfied (cm)/Ϯ Z Score (Satisfied 1...5 (Years) Surgeries (Good 1...5Poor) 1... 5 Dissatisfied) Dissatisfied) 1 First week 35–39 Ն10 2 3 12/Ϫ0.8 3 2 First week 20–24 0 NA 3 NA 3 3 First week 25–29 3 3 3 7/Ϫ3.9 3 4 First week 45–49 5 4 3 6/Ϫ4.5 3 5 First week 40–44 6 3 3 5/Ϫ5.1 3 6 First week 30–34 3 5 3 6/Ϫ4.5 5 7 First week 40–44 4 4 3 7/Ϫ3.9 3 8 First week 30–34 4 2 1 10/Ϫ2.0 1 9 First week 40–44 NA 4 1 8/Ϫ3.3 1 10 First week 20–24 2 2 3 11/Ϫ1.4 3 11 Fourth month 35–39 5 4 1 14/ϩ0.4 1 12 First week 35–39 Ն10 3 1 9/Ϫ2.7 1 13 Fourth month 40–44 8 3 1 6/Ϫ4.5 3 14 First week 30–34 Ն10 2 1 10/Ϫ2.0 1 15 First week 40–44 3 4 1 11.5/Ϫ1.1 3 16 First week 30–34 NA 3 5 11/Ϫ1.4 5 17 First week 25–29 3 4 3 5/Ϫ5.1 5 18 Second week 25–29 2 NA 3 NA 3 19 Third week 30–34 7 4 1 14/ϩ0.4 3 20 23 y 40–44 NA NA 1 6/Ϫ4.5 3 21 First week 30–34 4 NA 3 NA 1 NA indicates not applicable.

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/110/3/ by guest on October 1, 2021 e31 3of10 TABLE 2. Number of Genital Surgeries, Physician-Rated Appearance of the Genitalia, Self-Reported Body Image, Final Clitoral Length and Vaginal Depth, and Self-Reported Satisfaction With Sexual Function in Adult 46,XY Patients Who Were Born With a Small Phallus and Perineoscrotal Hypospadias and Were Living as Women at the Time of Study Participation Patient Age of Final Age at Total No. of Physician-Rated Self-Reported Final Clitoral Self-Reported Female Study Female Appearance of Body Image Length (cm) Sexual Function Gender Participation Genital Adult Genitalia (Satisfied 1...5 and Vaginal (Satisfied 1...5 Assignment (Years) Surgeries (Good 1...5Poor) Dissatisfied) Depth (cm) Dissatisfied) 22 28 mo 35–39 2 2 1 0/11 3 23 First month 25–29 3 1 5 1/11 3 24 17 mo 30–34 2 2 1 0/8 5 25 Third month 20–24 2 1 3 1.5/15 3 26 First week 20–24 2 1 1 1.5/15 3 27 First week 40–44 2 2 1 0/9.5 3 28 First week 35–39 3 2 3 0.5/12 5 29 First month 25–29 2 NA 1 1/10 1 30 22 y 45–49 2 1 1 0/10 5 31 Fourth month 20–24 2 1 1 1/10 3 32 First week 20–24 2 2 3 0.5/9 1 33 14 mo 20–24 2 1 1 2.5/13 1 34 First week 30–34 2 2 3 0/8 1 35 First week 25–29 3 2 1 0/12 3 36 First month 50–54 1 1 3 0/6 3 37 First week 25–29 2 1 1 0/12 1 38 Fourth month 30–34 2 1 1 0.75/12 1 39 First week 20–24 2 2 1 0/14 2 NA indicates not applicable.

Body Image 3.4). One set of siblings with PAIS exhibited different Participants were asked about satisfaction with their appear- degrees of undermasculinization of their genitalia at ance (scale: 1 ϭ mainly satisfied, 3 ϭ somewhat dissatisfied, to 5 ϭ birth, consistent with previous reports of phenotypic mainly dissatisfied) and to indicate which physical characteristics 31–33 contributed to dissatisfaction, if any. diversity among patients with PAIS. Age at final male sex assignment occurred in the first few weeks Femininity and Masculinity Participants were asked to rate their degree of masculinity of life (parent/physician assigned) in all but the 1 (scale: 1 ϭ not at all masculine, 3 ϭ somewhat masculine, to 5 ϭ participant who elected to be reassigned to the male highly masculine) and femininity (scale: 1 ϭ not at all feminine , 3 sex in early adulthood (Table 1). ϭ somewhat feminine, to 5 ϭ highly feminine) at the time of study participation. Physical Appearance in Adulthood Sexual Orientation Physician-rated cosmetic appearance of the adult Participants were asked to rate on a 7-point scale whether they external genitalia ranged from 2 to 5 (mean: 3.3; were sexually attracted to, fantasized about, or participated in ϭ ϭ ϭ sexual activity with women and/or men (0 ϭ women only; 1 ϭ scale: 1 good, 3 fair, to 5 poor). Final stretched mostly women, rarely men; 2 ϭ both, but women more than men; penile length ranged from 5 to 14 cm (mean: 8.8; 3 ϭ women and men about equal; 4 ϭ both, but men more than Table 1). Ten of the 18 men who consented to a women; 5 ϭ mostly men, rarely women; 6 ϭ men only).30 physical examination (56%) attained a final penile Long-Term Romantic Relationships and Parenthood length at or below 2.5 standard deviations of the Frequency of long-term romantic relationships (marriage and mean established by Schonfeld and Beebe.34 It domestic partnership) and parenthood was asked of all partici- pants. should be noted that variation exists in what is con- sidered to be a normal distribution of penile Satisfaction With Physician/Parent-Assigned Sex 35,36 Participants were asked about their satisfaction with their phy- length. For the sake of comparing the present set sician/parent-assigned sex of rearing and whether at any point in of data with those in other reports, we used Schon- development they had considered changing their assigned sex of feld and Beebe’s34 norms as a comparison. rearing. Size of the testes varied for participants: some Long-Term Counseling were considered within normal limits, whereas oth- Participants were asked whether they had received psycholog- ers were small and replaced with prostheses earlier ical or psychiatric counseling for issues related to their medical in life. Size of the prostate gland was small or not condition. palpable for the 18 men who consented to this por- Statistical Analysis tion of the physical examination. Genital reconstruc- Ͼ Descriptive statistics were used for the physical and psycho- tive surgeries ranged in number from 0 to 10 sexual measures. Comparisons between responses from partici- (mean: 5.8) from early infancy through adulthood pants who were living as men and women were analyzed with (Table 1). Surgical procedures included release of 2-tailed t tests. Mean differences were considered statistically sig- Ͻ chordee, multiple-stage hypospadias repair with nificant at P .05. postoperative complications, removal of mu¨ llerian RESULTS remnants, orchiopexy, and implantation of pros- thetic testes. Participants Currently Living as Men Development of secondary sexual characteristics Physical Appearance at Birth varied among participants. Five men (24%) devel- Classification of the appearance of the external oped gynecomastia, 3 of whom underwent a mastec- genitalia ranged from Quigley grade 2 to 4 (mean: tomy. Two of these men developed additional gy-

4of10 OUTCOME OF AMBIGUOUSDownloaded from GENITALIA www.aappublications.org/news WITH PERINEAL by guest HYPOSPADIAS on October 1, 2021 necomastia after their first breast removal. Pubic hair substance abuse (n ϭ 5 [24%]), and teasing (n ϭ 6 development ranged from male Tanner stage 3 to 5 [29%]). (mean: 4.1). Ten men did not require testosterone replacement because they had sufficient endogenous Participants Currently Living as Women production in adulthood. Among the remaining 11 Physical Appearance at Birth who required testosterone replacement therapy to treat their hypogonadism, 5 (45%) were compliant Classification of the appearance of the external with their replacement and 6 (55%) were noncompli- genitalia ranged from Quigley grade 3 to 4 (mean: ant as reported during the physical examination. The 3.6). There was no significant difference in the Quig- remaining 8 men did not treat their hypogonadism at ley rating of the genitalia at birth between partici- pants who were reared male or female (t(36) ϭ 0.92, the time of participation despite their opportunity Ͼ for obtaining prescriptions for testosterone replace- P .05). Similar to participants who are living as ment. men, 1 pair of siblings who were reared female ex- hibited different degrees of ambiguity of their geni- Body Image talia at birth. All participants exhibited perineal hy- pospadias, a small phallus with chordee, urogenital Scores for body image ranged from 1 to 5 (scale: sinus, and bifid scrotum at initial presentation. 1 ϭ mainly satisfied, 3 ϭ somewhat dissatisfied, to ϭ Final female gender assignment was established at 5 mainly dissatisfied; mean score: 2.2; Table 1). various ages for the group. For 11 participants, par- Dissatisfaction with body image was attributed to the ents and physicians established a female sex assign- following characteristics: unusual appearing genitalia ϭ ϭ ment in the first month of life. For 6 participants, (n 15 [71%]), a small penis (n 16 [76%]), gyneco- physicians and parents established a female sex as- mastia (n ϭ 5 [24%]), abnormal patterns of body hair ϭ ϭ signment between 3 and 8 months. Two participants (n 3 [14%]), and short stature (n 5 [24%]). Self-rated had their gender reassigned by their parents and body image scores were significantly better for men physicians twice (F3M3F) during early childhood. than the physician-rated scores (mean score: 3.3) re- One participant initiated a male-to-female sex reas- garding the appearance of their genitalia (t(36) ϭ 3.1, Ͻ signment in early adulthood (Table 2). Genital recon- P .005). structive surgeries ranged in number from 1 to 3 (mean: 2.1) from early infancy through adulthood Genitosexual Function and included feminization of the external genitalia Satisfaction with sexual function ranged from 1 to and vaginoplasty (Table 2). Overall, participants who 5 (mean: 2.7) using the following scale: 1 ϭ mainly are currently living as women required fewer genital satisfied, 3 ϭ somewhat dissatisfied, to 5 ϭ mainly surgical procedures than those who are currently dissatisfied. Three men (14%) were mainly dissatis- living as men (t(17) ϭ 3.11, P Ͻ .05). fied with their sexual function (Table 1). Self-re- ported libido was above average for 7 men (33.3%), Physical Appearance in Adulthood average for 7 men (33.3%), and lower than average Physician-rated cosmetic appearance of the adult for 7 men (33.3%). All of the men who answered (n ϭ external genitalia ranged from 1 to 2 (mean: 1.5; 17) reported the ability to have erections. Four men scale: 1 ϭ good, 3 ϭ fair, to 5 ϭ poor; Table 2). were unwilling to answer this question. Contributing Women were considered to have a better cosmetic to dissatisfaction with genitosexual function were outcome of their genital reconstruction, as rated by surgical complications including penile fistulas and physicians, than men (t(25) ϭ 7.14, P Ͻ .05). Clitoral strictures, chronic urinary tract infections, urethral length ranged from 0 to 2.5 cm (mean: 0.6). Nine dilations, testicular pain, and discomfort resulting (50%) women had complete clitoral amputation, 5 from hair growth in the skin graft of the urethra. (28%) had clitoral reduction, and 4 (22%) had clitoral Despite these difficulties, 19 men (90%) reported recession. Vaginal depth ranged from 6 to 15 cm having had previous sexual experience with others (mean: 9.4). Seventeen women (94%) had a vaginal and 17 (81%) reported an experience with a sex part- depth within the normal range (Ͼ7cm)37,38 after ner in the past year. vaginoplasty. Vaginoplasty consisted of the McIndoe procedure for 11 women (61%), a colonic sigmoid Long-Term Romantic Relationships and Parenthood procedure for 6 women (33%), and 1 woman (6%) Eleven men (52%) were married or in long-term did not receive any type of vaginal construction. Two relationships, and 2 (10%) were parents via adoption women who underwent a McIndoe vaginoplasty or sperm donation. One man whose genital ambigu- subsequently elected to have a colonic sigmoid pro- ity was attributed to a timing defect had a low sperm cedure. count and is currently attempting in vitro fertiliza- Development of secondary sexual characteristics tion with his wife. was variable in this group. Two women had breast implants in early adulthood. However, each has Psychological Treatment since had the implants removed (an implant rupture Thirteen men (62%) received counseling for issues was cited by 1 woman as reason for removal, and the related to their diagnosis. Reasons listed included other woman considered her implants to be too concerns about romance and dating (n ϭ 7 [33.3%]), large). Breast size for the group was variable (range: sexual function (n ϭ 7 [33.3%]), problems with family 12 ϫ 9to20ϫ 24 cm). Pubic hair development members (n ϭ 5 [24%]), depression (n ϭ 8 [38%]), ranged from female Tanner stage 1 to 5 (mean: 2.6).

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/110/3/ by guest on October 1, 2021 e31 5of10 None of the women exhibited facial hair. All women Comparison of Men’s and Women’s Responses required hormone replacement therapy after gonad- Satisfaction With Parent/Physician-Assigned Gender ectomy, and 14 (78%) were compliant with this treat- Sixteen participants (76%) were mainly satisfied ment. with their male sex of rearing established by physi- cians and parents. Five participants (24%) reported Body Image dissatisfaction with their male sex of rearing, 1 of Scores for body image ranged from 1 to 5 (scale: whom preferred to think of himself as intersex and 1 1 ϭ mainly satisfied, 3 ϭ somewhat dissatisfied, to reassigned her gender to that of a woman in early 5 ϭ mainly dissatisfied; mean: 1.8). When dissatis- adulthood. Fourteen participants (78%) were mainly faction occurred, it was attributed to inadequate sex- satisfied with their physician/parent-established fe- ual hair (n ϭ 5 [28%]), unusual-appearing genitalia male sex of rearing. Four participants (22%) reported (n ϭ 4 [22%]), small breasts (n ϭ 3 [16.5%]), tall or dissatisfaction with their female sex of rearing. short stature (n ϭ 3 [16.5%]), and poor muscle devel- Among the dissatisfied women, 1 reported that her opment (n ϭ 2 [11%]). Self-rated scores by the female homosexual orientation was an obstacle and women did not differ from their physician-rated as a result she would have preferred a male sex of scores regarding the appearance of their genitalia rearing, and 1 subject reassigned his sex to that of an (t(23) ϭ 0.8, P Ͼ .05). Participants who are living as intersexed man in early adulthood. Satisfaction with either men or women did not differ overall in their physician/parent-established sex of rearing did not degree of satisfaction with their body image (t(36) ϭ differ between men and women (t(37) ϭ 0.57, P Ͼ 1.19, P Ͼ .05), and the majority of participants were .05; Fig 1). more satisfied than dissatisfied with their physical appearance. Self-Rated Masculinity and Femininity Mean self-rated masculinity score at the time of Genitosexual Function participation for men was 3.9 (range: 3–5). However, Satisfaction with sexual function ranged from 1 to 2 men (10%) did not respond to this question. Mean 5 (mean: 2.5; scale: 1 ϭ mainly satisfied, 3 ϭ some- self-rated femininity score was 1.5 (range: 1–3). How- what dissatisfied, to 5 ϭ mainly dissatisfied). ever, 5 men (24%) did not respond to this question. Women who had undergone clitoral amputation Mean self-rated masculinity score at the time of were more dissatisfied with their sexual function participation for women was 1.9 (range: 1–3), and (mean: 2.9) than women who had other types of mean self-rated femininity score was 3.3 (range: 1–5). clitoral surgery (mean: 2.3). However, this difference Men were significantly more masculine than women was not statistically significant (t(16) ϭ 0.82, P Ͼ .05). (t(35) ϭ 7.8, P Ͻ .05), and women were significantly Men and women did not differ according to their more feminine than men (t(30) ϭ 5.64, P Ͻ .05; Fig 2). degree of satisfaction with their sexual function (t(34) ϭ 0.47, P Ͼ .05). Sexual Orientation Self-reported libido was above average for 2 Most men rated themselves at the extreme male women (11%), average for 6 women (33%), and lower heterosexual end of the scale adapted from Kinsey et than average for the remaining 10 women (56%). al,30 and the majority of women rated themselves at Twelve women (67%) reported the ability to experi- the extreme female end of the scale (t(28) ϭ 6.77, P Ͻ ence orgasm, 3 (16.5%) were unsure, and 3 (16.5%) .05). More women than men indicated an intermedi- reported never having experienced orgasm. Contrib- ate response (Fig 3). uting to dissatisfaction with genitosexual function was an introitus placed too posterior, a small vagina, pain during intercourse, low libido, and lack of self- lubrication. Despite these problems, 15 women (83%) reported ever having had a sexual experience with a partner, and 10 women (56%) reported a sexual ex- perience with a partner in the past year.

Long-Term Romantic Relationships and Parenthood Similar to the men, 7 women (39%) were married or had established long-term romantic relationships. One woman was an adoptive parent.

Psychological Treatment The majority of women who participated (n ϭ 12 [67%]) received counseling for issues concerning their diagnosis. Reasons listed for receiving counsel- Fig 1. Self-reported degree of satisfaction with parent/physician- ing included concerns about romance and dating established sex of rearing in participants who were living as men or women at the time of study participation (scale: 1 ϭ mainly (n ϭ 5 [28%]), sexual function (n ϭ 9 [50%]), prob- ϭ ϭ ϭ satisfied, 3 somewhat dissatisfied, to 5 mainly dissatisfied). lems with family members (n 3 [16.5%]), depres- Satisfaction with sex of rearing did not significantly differ between sion (n ϭ 5 [28%]), and teasing (n ϭ 2 [11%]). men and women (t(37) ϭ 0.57, P Ͼ .05).

6of10 OUTCOME OF AMBIGUOUSDownloaded from GENITALIA www.aappublications.org/news WITH PERINEAL by guest HYPOSPADIAS on October 1, 2021 Fig 2. Self-reported degree of masculinity and femininity in participants who were living as men or women at the time of study participa- tion (scales: 1 ϭ not at all masculine, 3 ϭ some- what masculine, to 5 ϭ highly masculine; 1 ϭ not at all feminine, 3 ϭ somewhat feminine, to 5 ϭ highly feminine). Men rated themselves as significantly more masculine than women (t(35) ϭ 7.8, P Ͻ .05), and women rated them- selves as significantly more feminine than men (t(30) ϭ 5.64, P Ͻ .05).

particularly dissatisfied with their sex assignment established by parents and physicians and their med- ical or surgical treatment; in addition, some pre- ferred not to discuss their intersex condition. Finally, establishing a cause underlying the genital ambigu- ity of participants in the present study also proved difficult, particularly in cases of PAIS.

Physical Appearance and Choice of Gender at Birth That the degree of sexual ambiguity at birth was the same for participants who were reared male (Quigley scale 3.4) or female (Quigley scale 3.6) was an artifact of our sampling method to include only those patients who presented with a small phallus Fig 3. Self-reported sexual orientation in participants who were and perineoscrotal hypospadias. It is interesting that living as men or women at the time of study participation using the scale adapted from Kinsey et al30 to indicate sexual attraction half of these were raised male and the other half and experience with: 0 ϭ women only; 1 ϭ mostly women, rarely were raised female. It was not clear from the chart men; 2 ϭ both, but women more than men; 3 ϭ women and men review which factors contributed to the decision by about equal; 4 ϭ both, but men more than women; 5 ϭ mostly parents and physicians to choose a particular gender ϭ men, rarely women; 6 men only. The majority of men and for infants with severe genital ambiguity. Future women reported an exclusively heterosexual orientation. More women than men reported an intermediate response. studies should investigate this decision-making pro- cess.

DISCUSSION Physical Outcome Limitations of the Present Study More than half of participants who are currently Our purpose for studying long-range outcome of living as men had a stretched penile length below 2.5 patients affected by intersex conditions was to deter- standard deviations of the mean compared with only mine the success of female versus male sex of rearing 6% of participants who are currently living as in these individuals. The corollary is that results women and presented with a short vagina in adult- from this type of study will allow for better thera- hood. Women received fewer genital surgeries peutic decisions concerning sex of rearing for future (mean: 2.1 vs 5.8) and had a better cosmetic appear- patients. ance of their genitalia, as rated by physicians (mean: Regrettably, long-term outcome studies are inher- 1.5 vs 3.3), than men. Despite these seeming advan- ently limited by the amount of time needed for in- tages to feminizing surgery, women and men did not tersex patients to become adults, thus allowing for differ in their degree of satisfaction with their sexual the “real-life” test of living as a sexually mature man functioning (mean: 2.5 vs 2.7) or body image (mean: or woman. Some of our patients died before the start 1.8 vs 2.2) at the time of study participation (Table 3). of the present investigation, some had mental retar- Both groups cited the appearance of their genitalia as dation, some could not be located for study, and being the greatest contributing factor to their dissat- others were located but refused to participate. It is isfaction with their body image. Finally, the number possible that those who refused to participate were of clitoral amputations in the group of women re-

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/110/3/ by guest on October 1, 2021 e31 7of10 TABLE 3. Summary of Outcome Data for 46,XY Individuals Sex of Rearing Who Were Born With Ambiguous Genitalia Including Perineo- scrotal Hypospadias Our previous study of 46,XY individuals who were born with female genitalia indicated that fe- Gender at P Value Participation male sex of rearing was successful in terms of gender identity.23 For 46,XY patients with congenital micro- 21 Men 18 Women penis and no hypospadias, male sex of rearing was Diagnosis found to be optimal despite the success of some PAIS 5 9 patients who were raised female.42 PGD 7 4 Concerning patients with markedly ambiguous Other 9 5 Mean no. of genital surgeries 5.8 2.1 Ͻ.05 genitalia of the degree studied in the current inves- Physician-rated surgical outcome 3.3 1.5 Ͻ.05 tigation, establishing an optimal sex of rearing re- Participant-rated body image 2.2 1.8 NS quires the consideration of several variables. Partic- Participant-rated genital function 2.7 2.5 NS % Satisfied with sex of rearing 76 78 NS ipants in the present study were reared according to the sex decided on by their parents and physicians. NS indicates not significant. The majority of men (76%) and women (78%) were Female sex of rearing resulted in fewer genital surgical procedures overall and better cosmetic appearance of the external genitalia as satisfied with their assigned sex (Table 3). However, rated by physicians, compared with patients who were reared some dissatisfied participants were identified, re- male. Despite these seeming advantages to female sex of rearing, gardless of male or female rearing, indicating that men and women did not differ according to their degree of satis- general predictions cannot guarantee future gender faction with their physical appearance, genital function, and sex of rearing. development for any single case. In our sample, 2 participants (1 reared male and the other reared fe- male) chose to reassign their sex in early adulthood. To understand better why some patients who are flects a surgical approach that is no longer recom- affected by intersex conditions reject their parent/ mended for this population of patients.39 physician-assigned gender, future studies could in- vestigate the impact of parents, siblings, partners, Sexual Orientation and spouses on long-term psychosexual develop- Exclusive heterosexual orientation was observed ment in this group. In addition, the impact of vari- in the majority of men and women, indicating that a ables such as infertility, sexual dysfunction, and poor 46,XY chromosome complement with weak prenatal body image on gender development could be stud- androgen exposure is not sufficient to determine sex- ied in populations that are not affected by intersex ual orientation in this group of patients. These results conditions. Although it is gratifying to observe sat- are consistent with the hypothesis stating that gen- isfaction with gender assignment in the majority of der assignment and sex of rearing contribute, at least patients studied, the rate of dissatisfaction reported in part, to the development of sexual orientation. here is problematic and illustrates the importance of Women reported intermediate ratings of sexual additional studies. orientation more often than men. One could specu- An important consideration for deciding on female late that women in general, whether affected by an or male gender assignment in 46,XY infants with intersex condition or not, report greater variability markedly ambiguous genitalia is the underlying on scales of sexual orientation compared with men.40 cause of the intersex condition. The present study However, this speculation is not always supported illustrates the difficulty in establishing such diag- by data.41 Exposure to an abnormal endocrine milieu noses. Despite this difficulty, some intersex condi- in early development and/or the effects of genital tions are life-threatening, thus requiring prompt surgery may predispose these women to a wider identification and treatment. range of expression of their sexual orientation than The birth of an intersex infant is often viewed as a their male counterparts. Alternatively, participants major crisis by parents and other family members. In who have genital malformations and were reared male these instances, pediatric endocrinologists can offer may feel obliged to report exclusive heterosexuality. valuable support by helping the parents to under- These hypotheses deserve additional investigation. stand sex differentiation and medical/surgical op- The majority of participants (62% men and 67% tions that are available for their child. Specifically, women) sought counseling for problems that they physicians should inform parents about 1) long-term attributed to their diagnostic condition. Concerns about cosmetic and functional outcomes associated with dating and sexual function, as well as feelings of de- genital reconstruction, 2) the need for long-term sex pression, were evident in both groups. Clearly, patients hormone replacement, and 3) possibilities for repro- who were born with ambiguous genitalia face psycho- duction. logical obstacles regardless of their sex of rearing. In- Physician-rated appearance of the external genita- formation pertaining to membership of intersex patient lia is better in women than in men, and women advocacy and support groups was not elicited from required fewer genital surgeries than did men (Table study participants. Future studies should assess cohort 3). Despite these seeming advantages for women, effects in terms of medical, surgical, and psychosexual neither satisfaction with body image nor sexual func- outcome of individuals who belong to such groups tion differed significantly between women and men. compared with those who do not. In the most ambiguous cases, such as those in-

8of10 OUTCOME OF AMBIGUOUSDownloaded from GENITALIA www.aappublications.org/news WITH PERINEAL by guest HYPOSPADIAS on October 1, 2021 cluded in the current study, it is important to con- 6. Schober JM. Sexual behaviors, sexual orientation and gender identity in sider complications and outcomes of genital surgery. adult intersexuals: a pilot study. J Urol. 2001;165:2350–2353 7. Imperato-McGinley J, Peterson RE, Gautier T, Sturla E. Androgens and Men required more surgeries than women, but nei- the evolution of male-gender identity among male pseudohermaphro- ther obtained an end result that was entirely satis- dites with 5␣-reductase deficiency. N Engl J Med. 1979;300:1233–12137 factory: approximately half of all participants re- 8. Mendonca BB, Inacio M, Costa EMF, et al. Steroid 5␣-reductase 2 ported dissatisfaction with their body image, and deficiency: diagnosis, psychological evaluation, and management. Med- icine. 1996;75:64–76 two thirds were dissatisfied to some degree with 9. Mendonca BB, Inacio M, Arnhold IJP, et al. Male pseudohermaphrodit- their sexual function. ism due to 17␤-hydroxysteroid dehydrogenase 3 deficiency: diagnosis, All 46,XY intersex patients who were reared fe- psychological evaluation, and management. Medicine. 2000;79:299–307 male will require life-long hormone replacement 10. Phornphutkul C, Fausto-Sterling A, Gruppuso PA. Gender self- therapy. Excluding cases of 5␣-reductase deficiency, reassignment in an XY adolescent female born with ambiguous genita- lia. Pediatrics. 2000;106:135–137 17-ketosteroid reductase deficiency, timing defect, 11. Birnbacher R, Marberger M, Weissenbacher G, Schober E, Frisch H. and PAIS, patients who were reared male will also Gender identity reversal in an adolescent with mixed gonadal dysgen- require hormone replacement. esis. J Pediatr Endocrinol Metab. 1999;12:687–690 Finally, the consideration of fertility should enter 12. Reiner WG. Case study: sex reassignment in a teenage girl. J Am Acad the equation when deciding on an optimal sex of Child Adolesc Psychiatry. 1996;35:799–803 13. Money J, Devore H, Norman, BF. Gender identity and gender rearing for infants with a small phallus and perine- transposition: longitudinal outcome study of 32 male hermaphrodites oscrotal hypospadias. For example, patients who assigned as girls. J Sex Marital Ther. 1986;12:165–181 have PGD and were born with a uterus may find it 14. Money J, Norman BF. Gender identity and gender transposition: longi- advantageous to be raised female, whereas those tudinal outcome study of 24 male hermaphrodites assigned as boys. J ␣ Sex Marital Ther. 1987;13:75–92 with the potential for spermatogenesis (5 -reductase 15. Gearhart JP, Burnett A, Owen JH. Measurement of pudendal evoked deficiency and timing defect) may find it advanta- potentials during feminizing genitoplasty: technique and applications. geous to be raised male. J Urol. 1995;153:486–487 16. Newman K, Randolph J, Parson S. Functional results in young women having clitoral reconstruction as infants. J Pediatr Surg. 1992;27:180–183 CONCLUSION 17. Alizai NK, Thomas DF, Lilford RJ, Batchelor AG, Johnson N. Feminiz- For infants with markedly ambiguous genitalia, ing genitoplasty for congenital adrenal hyperplasia: what happens at puberty? J Urol. 1999;161:1588–1591 including a small phallus and perineoscrotal hypos- 18. Creighton SM, Minto CL, Steele SJ. Objective cosmetic and anatomical padias, sex of rearing should be decided by parents outcomes at adolescence of feminising surgery for ambiguous genitalia who have been thoroughly informed about their done in childhood. Lancet. 2001;358:124–125 child’s medical and surgical options and have also 19. Rock JA, Reeves LA, Retto H, Baramki TA, Zacur HA, Jones HW Jr. been informed of available outcome data. Advances Success following vaginal creation for Mu¨ llerian agenesis. Fertil Steril. 1983;39:809–813 in medical and surgical procedures used to treat 20. Azziz R, Mulaikal RM, Migeon CJ, Jones HW Jr, Rock JA. Congenital intersex conditions, along with better education and adrenal hyperplasia: long-term results following vaginal reconstruction. support provided to patients and their families, may Fertil Steril. 1986;46:1011–1014 further improve the quality of life experienced by 21. Azziz R, Jones HW Jr, Rock JA. Androgen-insensitivity syndrome: individuals who are affected by syndromes of abnor- long-term results of surgical vaginal creation. J Gynecol Surg. 1990;6: 23–26 mal sex differentiation. 22. Lewis VG, Money J. Gender-identity/role: G-I/R Part A: XY (androgen insensitivity) syndrome and XX (Rokitansky) syndrome of vaginal atre- Handbook of Psycho- ACKNOWLEDGMENTS sia compared. In: Dennerstien L, Burrow GD s, eds. somatic Obstetrics and Gynaecology. New York, NY: Elsevier Biomedical This work was supported by a grant from the Genentech Foun- Press; 1983:51–60 dation for Growth and Development (98-33C); National Institutes 23. Wisniewski AB, Migeon CJ, Meyer-Bahlburg HFL, et al. Complete of Health National Research Service Award F32HD08544; Na- androgen insensitivity syndrome: long-term medical, surgical and psy- tional Institutes of Health, National Center for Research Re- chosexual outcome. J Clin Endocrinol Metab. 2000;85:2664–2669 sources, General Clinical Research Center grant RR-00052; and an 24. Miller MAW, Grant DB. Severe hypospadias with genital ambiguity: Endocrine Society 2001 Summer Research Fellowship. Many of the adult outcome after staged hypospadias repair. Br J Urol. 1997;80: studies obtained on the patients in this article were made possible 485–488 by National Institutes of Health grant 5-ROI-DK-00180 (1953– 25. Hensle TW, Tennenbaum SY, Reiley EA, Pollard J. Hypospadias repair 1997). in adults: adventures and misadventures. J Urol. 2001;165:77–79 26. Baskin L. Hypospadias: a critical analysis of cosmetic outcomes using photography. Br J Urol. 2001;87:534–539 REFERENCES 27. Boehmer ALM, Brinkmann AO, Sandkuijl LA, et al. 17␤-Hydroxys- 1. Wilson JD. Androgen, androgen receptors, and male gender role be- teroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, havior. Horm Behav. 2001;40:358–366 population genetics, and worldwide distribution of ancient and de novo 2. Migeon CJ, Wisniewski AB, Brown TR, et al. 46,XY intersex individuals: mutations. J Clin Endocrinol Metab. 1999;84:4713–4721 phenotypic and etiologic classification, knowledge of condition, and 28. Quigley CA, De Bellis A, Marschke KB, El-Awady MK, Wilson EM, satisfaction with knowledge in adulthood. Pediatrics. 2002;110(3). Avail- French FS. Androgen receptor defects: historical, clinical and molecular able at: www.pediatrics.org/cgi/content/full/110/3/e32 perspectives. Endocrinol Rev. 1995;16:271–321 3. Money J. Hormones, hormonal anomalies and psychologic healthcare. 29. Tanner JM. Growth at Adolescence. Oxford, UK: Blackwell, 1969 In: Kappy M, Blizzard RM, Migeon CJ, eds. Wilkins: The Diagnosis and 30. Kinsey AC, Pomeroy WB, Martin CE. Sexual Behavior in the Human Male. Treatment of Endocrine Disorders in Childhood and Adolescence. 4th ed. Philadelphia, PA: WB Saunders; 1948 Springfield IL: Charles C Thomas; 1994:573–715 31. Evans BAJ, Hughes IA, Bevan CL, Patterson MN, Gregory JW. Pheno- 4. Gearhart JP. Surgical management of genital ambiguity. In: Carpenter typic diversity in siblings with partial androgen insensitivity syndrome. SE, Rock JA, eds. Pediatric and Adolescent Gynecology. New York, NY: Arch Dis Child. 1997;76:529–531 Raven Press; 1992:95–102 32. Maes M, Lee PA, Jeffs RD, Sultan C, Migeon CJ. Phenotypic variation in 5. Migeon CJ, Berkovitz GD. Congenital defects of the external genitalia in a family with partial androgen insensitivity syndrome (PAIS). Am J Dis the newborn and prepubertal child. In: Carpenter SE, Rock JA, eds. Child. 1980;134:470–473 Pediatric and Adolescent Gynecology. New York, NY: Raven Press; 1992: 33. Wilson JD, Harrod MJ, Goldstein JL, Hemsell DL, MacDonald PC. 77–94 Familial incomplete male pseudohermaphroditism, type 1. Evidence for

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/110/3/ by guest on October 1, 2021 e31 9of10 androgen resistance and variable clinical manifestations in a family ambiguous genitalia: a surgeon’s perspective. Curr Probl Pediatr. 2001; with Reifenstein syndrome. N Engl J Med. 1974;16:1097–1103 31:163–202 34. Schonfeld WA, Beebe GW. Normal growth and variation in male gen- 40. Laumann EO, Gagnon JH, Michael RT, Michaels S. The Social Organiza- italia from birth to maturity. J Urol. 1942;64:759–777 tion of Sexuality: Sexual Practices in the United States. Chicago, IL: Uni- 35. Flatau E, Josefsberg Z, Reisner SH, Bialik O, Laron Z. Penile size in the versity of Chicago Press; 1994 newborn infant. Pediatrics. 1975;87:663–664 41. Johnson AM, Wadsworth J, Wellings K, Field J, Bradshaw S. Sexual 36. Money J, Lehne GK, Pierre-Jerome F. Micropenis: adult follow-up and Attitudes and Lifestyles. London, UK: Blackwell Scientific Publications; comparison of size against new norms. J Sex Marital Ther. 1984;10:105–116 1994 37. Dickinson RL. The Vagina. Baltimore, MD: Williams & Wilkins; 1949 42. Wisniewski AB, Migeon CJ, Gearhart JP, et al. Congenital micropenis: 38. Masters WH, Johnson VE. The Vagina. Boston, MA: Little Brown; 1966 long-term medical, surgical and psychosexual follow-up of individuals 39. Aaronson IA. The investigation and management of the infant with raised male or female. Horm Res. 2001;56:3–11

10 of 10 OUTCOME OF AMBIGUOUSDownloaded from GENITALIAwww.aappublications.org/news WITH PERINEAL by guest HYPOSPADIAS on October 1, 2021 Ambiguous Genitalia With Perineoscrotal Hypospadias in 46,XY Individuals: Long-Term Medical, Surgical, and Psychosexual Outcome Claude J. Migeon, Amy B. Wisniewski, John P. Gearhart, Heino F.L. Meyer-Bahlburg, John A. Rock, Terry R. Brown, Samuel J. Casella, Alexander Maret, Ka Ming Ngai, John Money and Gary D. Berkovitz Pediatrics 2002;110;e31 DOI: 10.1542/peds.110.3.e31

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Downloaded from www.aappublications.org/news by guest on October 1, 2021 Ambiguous Genitalia With Perineoscrotal Hypospadias in 46,XY Individuals: Long-Term Medical, Surgical, and Psychosexual Outcome Claude J. Migeon, Amy B. Wisniewski, John P. Gearhart, Heino F.L. Meyer-Bahlburg, John A. Rock, Terry R. Brown, Samuel J. Casella, Alexander Maret, Ka Ming Ngai, John Money and Gary D. Berkovitz Pediatrics 2002;110;e31 DOI: 10.1542/peds.110.3.e31

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