0022-5347/04/1716-2497/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 171, 2497–2501, June 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000125269.91938.f7
PSYCHOSEXUAL OUTCOME IN WOMEN AFFECTED BY CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY AMY B. WISNIEWSKI,* CLAUDE J. MIGEON, MATTHEW A. MALOUF
AND
JOHN P. GEARHART
From the Division of Pediatric Endocrinology, Department of Pediatrics and Division of Pediatric Urology, Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins School of Medicine and Department of Psychological and Brain Sciences, The Johns Hopkins University, Baltimore, Maryland
ABSTRACT
Purpose: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency results in increased adrenal androgen secretion. When the deficiency is severe, the result is the salt losing (SL) form, and when the deficiency is partial, the result is the simple virilizing (SV) form of CAH. We documented long-term satisfaction with gender, cosmetic appearance and function of the genitalia, and surgical management practices in a group of women with CAH due to 21hydroxylase deficiency. Materials and Methods: Psychosexual and surgical outcome were assessed in 41 women with CAH using an interview, a written questionnaire and a physical examination. When appropriate, outcome measures were compared to those in unaffected control women. Results: Women in the SL group were more likely to question their female gender and report sexual concerns, and less likely to have sexual relations with a partner than those with the SV form or control women. Overall women with CAH were moderately satisfied with the cosmetic appearance of the genitalia but the SL group reported worse genital function than the SV group. Physician rated appearance of the genitalia was better than ratings provided by patients and women with the SL form were judged to have a worse cosmetic outcome of genital reconstruction than women with the SV form. The most common response concerning the optimal timing for genital reconstruction was during infancy and early childhood, although a number of women favored waiting until later for these procedures or did not respond to this question. Conclusions: Women with the SV form reported greater satisfaction and fewer concerns regarding their psychosexual and surgical outcome than women with the SL form. KEY WORDS: hermaphroditism; abnormalities; sexual dysfunctions, psychological; genitalia, female; adrenal hyperplasia, congenital
The appropriateness and efficacy of genital surgical treatment in girls and women affected by congenital adrenal hyperplasia (CAH) resulting from 21-hydroxylase (21-OH) deficiency is currently under review.1–3 A recent CAH consensus statement reported that the goals of surgical management of girls and women affected by CAH due to 21-OH deficiency included genital appearance compatible with female sex of rearing; unobstructed urinary emptying without incontinence or infections; and good adult sexual and reproductive function.4 Recent outcome studies of genital surgery in females with CAH have focused primarily on adolescent girls and young women. Problems identified by these studies include removal and atrophy of the clitoris, intravaginal stenosis,5, 6 poor cosmetic outcome of the external genitalia and a need for repeated surgical procedures.5, 7 The need for repeated surgical procedures following an initial vaginoplasty performed prior to puberty has also been identified in studies of older women affected by 21-OH deficiency.8, 9 Patient satisfaction with sexual function was diminished in women who received repeated vaginal surgical procedures prior to 16 years of age.10 Finally, a recent study of approximately 20 women with CAH investigated the longterm outcome of genital surgery on sexual function.11 In
addition to a need for repeat vaginal procedures noted in previous investigations, Minto et al reported that regrowth of the corpora resulted in repeated clitoral procedures for 4 women with CAH.11 The present study was designed to assess psychosexual development and outcome of genital reconstruction in women affected by CAH due to 21-OH deficiency using criteria outlined by the joint European Society for Paediatric Endocrinology and Lawson Wilkins Pediatric Endocrine Society regarding genital appearance, urinary continence and infections, and sexual function.4 Furthermore, participants’ opinions regarding optimal timing for surgical procedures were collected. MATERIALS AND METHODS
Written informed consent was obtained from all participants prior to enrollment. Participants were asked to complete a confidential questionnaire and physical examination. During the examination participants were asked to confirm their original questionnaire responses and elaborate when they desired to do so. Participants. English speaking women 21 years or older who presented in childhood to the pediatric endocrine clinic at our institution for treatment of CAH due to 21-OH deficiency were eligible for study participation. Females with salt losing (SL) tendencies and markedly masculinized external genitalia were considered to have a more severe form of 21-OH deficiency than those with the simple virilizing (SV) form who had moderate masculinization. The degree of pre-
Accepted for publication January 23, 2004. Study received joint committee of clinical investigation approval. Supported by National Institute of Child Health and Human Development Grants F32HD08544 and R01HD37940, and General Clinical Research Center Grant RR-00052. * Correspondence: 600 North Wolfe St., Park 211, Baltimore, Maryland 21287 (telephone: 410-614-5576; FAX: 410-955-9773; e-mail:
[email protected]). 2497
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PSYCHOSEXUAL OUTCOME AND CONGENITAL ADRENAL HYPERPLASIA TABLE 1. Demographic characteristics and long-term psychosexual outcome in study participants
No. subjects Mean age at participation (range) Mean yrs education (range) Mean birth Prader rating (range) No. questioned female gender (%) No. ever sexually active (%) Mean age first sexual experience with partner (range) * Statistically significant group differences.
Control
SV
SL
Statistic
20 45.3 (23–73) 15.5 (12–18) 0 (0–0) 1 (5) 20 (100) 18.8 (14–25)
19 51.42 (32–71) 14.16 (10–18) 2.47 (2–4)* 3 (16) 19 (100) 19.0 (12–36)
22 40.23 (21–57)* 14.48 (10–18) 3.6 (2–5)* 8 (37)* 18 (82)* 20.6 (15–29)
F(2, 55) ⫽ 4.15, p ⬍0.005 F(2, 55) ⫽ 1.86, p ⬎0.05 F(2, 55) ⫽ 1.63E2, p ⬍0.0005 Chi-square (2) ⫽ 6.48, p ⬍0.05 Chi-square (2) ⫽ 7.22, p ⬍0.05 F(2, 50) ⫽ 1.07, p ⬎0.05
natal masculinization of the external genitalia was determined from pediatric endocrinology records at our institution prior to surgical reconstruction. Masculinization of the genitalia was rated according to the 6-point Prader scale of 0 —normal female genitalia to 5—normal male genitalia, including a penile urethra. Women unaffected by CAH due to 21-OH deficiency who were matched for age and education served as controls. Controls consisted of sisters of CAH participants and women referred to our institution for the evaluation of polycystic ovary syndrome (PCOS). Unaffected sisters were studied because they share genetic and environmental backgrounds similar to those of participants with CAH. Women with PCOS were included because they experienced medical treatment and concerns from adolescence through adulthood, eg infertility and hirsutism, that were similar to those in women with classic CAH. Therefore, we reasoned that group differences, if observed, could be attributed to early androgen exposure or genital surgical procedures unique to CAH. Unaffected sisters were contacted only if women with CAH first provided consent for invitation and then provided contact addresses or a telephone numbers for the sisters. Women with PCOS were mailed a general invitation from their primary gynecologist and then they contacted our group if they wished to participate in the current study. None of the control women were affected by genital masculinization at birth and none underwent genital reconstructive surgery. Endocrine outcome measures. The biochemical precursors to cortisol most commonly used to assess compliance with replacement therapy in CAH, namely 17hydroxyprogesterone (17-OHP), testosterone and androstenedione, were measured in all participants at 8:00 a.m. Psychosexual outcome measures. Satisfaction with female sex of rearing was assessed with a 3-point scale 1—satisfied with female rearing to 3—thoughts of being better off as male. Additionally, women were asked (yes/no) if they were ever unsure about their female gender. As part of a sexual history, women were asked if they ever experienced sexual concerns (yes/no). Furthermore, women were asked if they ever participated in genitosexual activity with a partner (yes/ no), including but not limited to vaginal intercourse. For women who experienced sexual activity with a partner age at sexual debut was asked. Surgical outcome measures. Information about the type(s) and timing of genital reconstructive surgery as well as recommendations for using vaginal dilators was collected retrospectively from participants with CAH by reviewing surgical records and asking women about their experiences with open-ended questionnaire items. Participants were also asked in the questionnaire if they had experienced urinary tract infections and/or urinary incontinence throughout their lives. Some participants elaborated on their questionnaire responses during a face-to-face interview at physical examination. Questions pertaining to the opinions of participants with CAH of surgical treatment were rated on a 5-point Likert scale from 1—not at all satisfied to 5— extremely satisfied. They included the participant degree of satisfaction with the postoperative appearance of the genitalia as well as the degree of satisfaction with the postoperative function of
the genitalia. To assess the opinions of participants with CAH regarding appropriate genital surgery in girls and women affected by CAH women were asked to indicate the optimal timing for such surgeries using the scale, 1—not before adulthood to 5—as an infant. Measures of the external genitalia of women with CAH were collected by a pediatric endocrinologist (CJM) at the clinical research unit at our institution at the time of participation. Physician rated cosmetic appearance of the external genitalia was based on a 5-point Likert scale of 1—poor appearance to 5— good appearance. A point was subtracted for any of certain characteristics, including an unusualappearing clitoris, an unusual-appearing introitus, an unusual-appearing labia and/or genital scarring. Vaginal depth was measured with graduated vaginal dilators and
Mean 17-OHP, testosterone and androstenedione ⫾ SEM. Women with CAH had significantly elevated 17-OHP compared to unaffected women. Adrenal androgens did not differ between groups.
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reported in cm. Clitoral length was measured with a metric tape and reported in cm. Statistical analyses. Descriptive statistics were generated for participant characteristics, psychosexual outcome and surgical outcome. Control subjects (unaffected sisters of women with CAH and women with PCOS) did not differ on any outcome measures (all ps ⬎0.05). Thus, they were treated as a single comparison group. Group differences (control vs SV vs SL) were analyzed with the chi-square test for dichotomous variables. ANOVA and the t test (2-tailed unless otherwise stated) were used to analyze continuous variables. Differences were considered statistically significant at p ⬍0.05. RESULTS
Participant characteristics. A total of 134 women with CAH were recorded to have had at least 1 visit to the pediatric endocrine clinic at our institution. Of these women 73 were not eligible to participate because they were dead (19 or 14%), lost to followup (52 or 39%) or unable to provide informed consent (2 or 1.5%). A total of 61 women with CAH (SV in 22 and SL in 39) as well as 30 unaffected control women were located and mailed a study invitation. Of the women with CAH 41 (67%) participated in the current study, including 19 who had the SV and 22 who had the SL form. Of invited control women 20 participated. Participation rates did not differ between groups (chi-square (2) ⫽ 3.96, p ⬎0.05). Group differences were observed for age at study participation. Prader rating at birth was higher in women with CAH compared to controls and masculinization was greatest in the SL group (F(2,55) ⫽ 1.63E2, p ⬍0.0005, table 1). Years of formal education did not differ between the groups (F(2,55) ⫽ 1.86, p ⬎0.05). Endocrine outcome. A group difference was observed for 17-OHP concentrations (F(2,37) ⫽ 3.7, p ⬍0.05, see figure). Women affected by CAH regardless of SV or SL status had elevated 17-OHP compared to unaffected women. No group differences between testosterone or androstenedione were
observed (F(2,37) ⫽ 1.23, p ⬎0.05 and F(2,37) ⫽ 0.48, p ⬎0.05, respectively, see figure). Psychosexual outcome. There was no group difference (control mean 1.11, SV mean 1.00 and SL mean 1.19) for satisfaction with female sex of rearing (F(2,54) ⫽ 1.06, p ⬎0.05). Women in the SL group were more likely to question their female gender than control women, although none desired to change sex to male (table 1). When asked if they experienced sexual concerns, more women in the SL group (74%) responded that they did compared to those in the control (37%) and SV (38%) groups (chi-square (2) ⫽ 6.58, p ⬍0.05). Additionally, fewer women with the SL form had participated in sexual relations with a partner compared to controls and women with the SV form. Despite these dissimilarities no group differences were observed for age at first sexual experience with a partner (table 1). Surgical outcome. Table 2 lists the type and timing of genital surgeries experienced by women with CAH. Women with the SL form experienced clitoral surgery at a younger age than women with the SV form. Four women (21%) with the SV form and 4 (18%) with the SL form of CAH reported noteworthy urinary tract infections during their lives compared to none of the control women (chi-square (2) ⫽ 4.31, p ⬎0.05). None of the participants reported urinary incontinence. A total of 14 (74%) and 19 (86%) women in the SV and SL groups, respectively, answered questions about genitalia (chi-square (1) ⫽ 1.04, p ⬎0.05). Nonresponders did not differ from responders in terms of Prader rating or the number and type of genital surgeries that they underwent (t(31) ⫽ 0.21, p ⬎0.05). Women reported moderate satisfaction with the adult appearance of the genitalia and their responses did not differ according to SV or SL status (table 2). A group difference was observed for satisfaction with genital function (t(31) ⫽ 1.41, 1-tailed p ⬍0.05) with women in the SL group less satisfied those in the SV group (mean 2.79 vs 3.50). A group difference was also reported for the number of women with CAH who were advised to use vaginal dilators during
TABLE 2. Genital surgical history and long-term cosmetic outcome in study participants in women with CAH SV
SL
Statistic
Genital surgery No. subjects Clitoral surgery: Mean age (range) No. clitoral excision (%) No. clitoral reduction (%) No. clitoral recession (%) No. repeat surgeries (%) No. unknown (%)
19
22
5.6 (0.3–14) 13 (68) 3 (16) 0 0 0
2.5 (0.1–10)* 13 (59) 4 (18) 2 (9) 0 2 (9)
16
21
Overall (%) Vaginal surgery: Mean age (range) No. skin flap (%) No. repeat (%) No. unknown (%)
12.27 (0.5–29) 8 (42) 2 (11) 2 (11)
Overall (%)
10
Participant rated genital appearance:† No. subjects Mean (range) Physician rated genital appearance:‡ No. subjects Mean (range) Vaginal depth: No. subjects Mean cm (range) Clitoral length: No. subjects Mean cm (range) * Statistically significant group differences. † Scale 1—not satisfied to 5—satisfied. ‡ Scale 1—poor to 5— good.
14 3
(84)
(53) Cosmetic outcome
(95)
7.02 (0.5–20) 9 (41) 2 (9) 8 (36) 17
Chi-square (1) ⫽ 1.46, t(27) ⫽ 2.21, p ⬍0.05 Chi-square (1) ⫽ 0.38, Chi-square (1) ⫽ 0.04, Chi-square (1) ⫽ 1.81, Chi-square (1) ⫽ 0.00, Chi-square (1) ⫽ 1.81, Chi-square (1) ⫽ 2.75, t(21) ⫽ 1.52, p ⬎0.05 Chi-square (1) ⫽ 0.06, Chi-square (1) ⫽ 0.04, Chi-square (1) ⫽ 3.69,
(77)
(1–5)
19 2.9
(1–5)
t(31) ⫽ 0.14, p ⬎0.05
11 4.96 (4.5–5)
13 4.5
(3–5)
t(20) ⫽ 1.84, p ⬍0.05
11 13.7
(9–19)
13 11.3
(9–14)*
t(22) ⫽ 2.4, p ⬍0.05
11 1.0
(0–2)
13 1.25
(0–3)
t(22) ⫽ 0.5, p ⬎0.05
p ⬎0.05 p p p p p
⬎0.05 ⬎0.05 ⬎0.05 ⬎0.05 ⬎0.05
p ⬎0.05 p ⬎0.05 p ⬎0.05 p ⬎0.05
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PSYCHOSEXUAL OUTCOME AND CONGENITAL ADRENAL HYPERPLASIA
adolescence or adulthood to widen the vaginal introitus or increase vaginal depth (chi-square (1) ⫽ 8.62, p ⬍0.05). Of women in the SV group 21% were advised to use dilators compared to 68% of those in the SL group. Only 50% of women who were instructed to use vaginal dilators believed that they were helpful. In the current study 24 women with CAH (59%) (SV in 11 and SL in 13) consented to genital examination at the time of participation. Women who consented to a genital examination did not differ from those who did not consent in terms of Prader rating at birth or the number and type of genital surgeries that they underwent (t(37) ⫽ 0.20, p ⬎0.05). Physician rating of the cosmetic appearance of the external genitalia differed from self-ratings by the women (t(52) ⫽ 5.17, p ⬍0.0005). Mean cosmetic ratings of physicians were better than those generated by participants (4.73 vs 3.05). As determined by a physician, the cosmetic appearance of the genitalia was marginally worse in the SL than in the SV group (t(20) ⫽ 1.84, 1-tailed p ⬍0.05). Mean vaginal depth differed between the groups (t(22) ⫽ 2.4, p ⬍0.05), in that women in the SL group had a shorter vagina than those in the SV group (mean 11.3 vs 13.7 cm). Normal vaginal depth in women without an intersex condition is 7 to 11 cm.12, 13 Mean clitoral length did not differ according to SV or SL status (table 2). When questioned about their opinion regarding the appropriate timing of feminizing genital surgeries, the most common answer provided was during infancy (SV 31% and SL 41%). Few participants with CAH reported that surgeries should not occur prior to adulthood, although a significant number did not respond to the question (table 3). DISCUSSION
Participants with the SL form were an average of a decade younger than those with the SV form and controls. Prior to the 1950s cortisol treatment was unavailable and most individuals with the SL form died in early infancy, thus, explaining the age difference observed in the current study. In addition, the high number of clitoral amputations experienced by women with CAH reflects a dated style of surgical management that is no longer recognized as appropriate.14 A goal of feminizing surgery in girls and women with CAH is that the postoperative genital appearance is compatible with female rearing.4 Physician and participant ratings indicated a poorer cosmetic outcome in the SL than in the SV group. A second goal of genital surgery is to allow unobstructed urination without infections or incontinence.4 Women affected by CAH who underwent such surgeries in the current study did not report more urinary tract infections or problems with urinary incontinence than unaffected women who did not undergo clitoral or vaginal surgeries. Finally, as outlined by the European Society for Paediatric Endocrinology and Lawson Wilkins Pediatric Endocrine Society CAH Working Group, the third goal of genital surgery in females affected by CAH due to 21-OH deficiency is to allow good adult sexual function.4 Women with the SL form reported significantly greater sexual concerns, poorer genital function and fewer sexual relations with partners than their counterparts with the SV form or control women. The fact TABLE 3. Opinion of women with CAH on optimal feminizing genitoplasty timing Not before: Adulthood Adolescence Elementary age Toddler age During infancy No answer
No. SV (%)
No. SL (%)
1 (5) 2 (11) 2 (11) 2 (11) 6 (31) 6 (31)
1 (5) 3 (14) 2 (9) 3 (13) 9 (41) 4 (18)
that women in the SL group presented with significantly greater genital masculinization at birth may indicate that genital surgery in this group is more challenging. Perhaps this explains the poorer sexual outcome in these women observed in the current study. However, that there was no difference in the number of repeat clitoral or vaginal surgeries between the SV and SL groups argues against this explanation. Women in the SV and SL groups most frequently reported that infancy and early childhood were the best times for genital reconstructive surgery, although a number of participants did not respond to this question. Women in the SL group experienced clitoral surgery at a younger average age than those in the SV group and yet the former reported less satisfaction with genitalia and sexual function than the latter. These inconsistencies make it difficult to offer optimal guidelines for the timing of genitoplasty. The prenatal diagnosis and treatment of 21-OH deficiency minimizes genital masculinization in females. Thus, this management approach may alleviate the sexual difficulties experienced by girls and women with the most severe genital masculinization in the future.15 The current study has a number of weaknesses. For example, we did not question control women about the cosmetic appearance of the genitals. This information would allow a better interpretation of the satisfaction or lack thereof pertaining to surgical outcome in women affected by 21-OH deficiency. Additionally, in the current study we used general questions about sexuality and health. Future investigations should gather detailed information in areas such as sexual concerns and noteworthy urinary tract infections. Finally, of our original sample of women with CAH a significant number was not located or, if located, they chose not to answer some or all of the questions posed. Larger samples would greatly improve the ability to determine if the information gathered from participants at our institution generalizes to a larger population of women affected by CAH.
REFERENCES
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PSYCHOSEXUAL OUTCOME AND CONGENITAL ADRENAL HYPERPLASIA 9. Sotiropoulos, A., Morishima, A., Homsy, Y. and Lattimer, J. K.: Long-term assessment of genital reconstruction in female pseudohermaphrodites. J Urol, 115: 599, 1976 10. Azziz, R., Mulaikal, R. M., Migeon, C. J., Jones, H. W., Jr. and Rock, J. A.: Congenital adrenal hyperplasia: long-term results following vaginal reconstruction. Fertil Steril, 46: 1011, 1986 11. Minto, C. L., Liao, L. M., Woodhouse, C. R. J., Ransely, P. G. and Creighton, S. M.: The effect of clitoral surgery on sexual outcome in individuals who have intersex conditions with ambiguous genitalia: a cross-sectional study. Lancet, 361: 1252, 2003
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12. Dickinson, R. L.: The vagina. In: Human Sex Anatomy, 2nd ed. Baltimore: Williams & Wilkins Co., pp. 34 –35, 1949 13. Masters, W. H. and Johnson, V. E.: The vagina. In: Human Sexual Response. Boston: Little Brown and Co., pp. 73–75, 1966 14. Aaronson, I. A.: The investigation and management of the infant with ambiguous genitalia: a surgeon’s perspective. Curr Probl Pediatr, 31: 168, 2001 15. New, M. I., Carlson, A., Obeid, J., Marshall, I., Cabrera, M. S., Goseco, A. et al: Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab, 86: 5651, 2001
