Complete Androgen Insensitivity Syndrome: Long-Term
Medical, Surgical, and Psychosexual Outcome*
AMY B. WISNIEWSKI, CLAUDE J. MIGEON, HEINO F. L. MEYER-BAHLBURG,
JOHN P. GEARHART, GARY D. BERKOVITZ, TERRY R. BROWN, AND
Department of Pediatrics, Division of Pediatric Endocrinology (A.B.W., C.J.M.); Department of Urology
and Chief, Pediatric Urology, James Buchanan Brady Urological Institute (J.P.G.); and Department of
Medical Psychology and Pediatrics (J.M.), The Johns Hopkins University School of Medicine, and
Department of Biochemistry, The Johns Hopkins University School of Public Health and Hygiene
(T.R.B.), Baltimore, Maryland 21287; Department of Psychiatry, Division of Child Psychiatry and
Program of Developmental Psychoendocrinology, Columbia University College of Physicians and
Surgeons and New York State Psychiatric Institute (H.F.L.M.-B.), New York, New York 10032; and
Department of Pediatrics, Division of Pediatric Endocrinology, University of Miami School of Medicine
(G.D.B.), Miami, Florida 33101
information regarding medical, surgical, and psychosexual outcome
in affected adults. We have assessed by questionnaire and medical
examination the physical and psychosexual status of 14 women with
documented complete androgen insensitivity syndrome (CAIS). We
have also determined participant knowledge of CAIS as well as opin-
ion of medical and surgical treatment. As a whole, secondary sexual
development of these women was satisfactory, as judged by both
participants and physicians. In general, most women were satisfied
with their psychosexual development and sexual function. Factors
and marked obesity in another. All of the women who participated
were satisfied with having been raised as females, and none desired
a gender reassignment. Although not perfect, the medical, surgical,
and psychosexual outcomes for women with CAIS were satisfactory;
however, specific ways for improving long-term treatment of this
population were identified. (J Clin Endocrinol Metab 85: 2664–2669,
velopment have been studied in a variety of intersex pop-
ulations (1–6). These investigations have led to the wide
acceptance of a multivariate conceptualization of gender de-
velopment that emphasizes the importance of both nature
and nurture (7–9).
Recent reports of psychosexual outcome in two penis ab-
latio patients (10, 11) have led to reconsideration of sex as-
signment practices for intersexuals. One of the issues raised
by these reports is the possibility that fetal androgen expo-
sure influences the brains of such patients, resulting in male-
chosexual development in penis ablatio patients are
conflicting, and to date it remains unclear how treatment of
intersex patients should be revised (12).
If androgens alone are important for male psychosexual
HE RELATIVE contributions of variables such as pre-
natal hormones and social rearing to psychosexual de-
development, then a group of intersex patients with com-
plete androgen insensitivity syndrome (CAIS) would not be
expected to exhibit a male bias, as they have a complete
end-organ resistance to androgenic effects. However, other
variables related to CAIS, such as the presence of a Y-chro-
mosome, testes and shallow vagina, have been suggested to
pose obstacles to healthy psychosexual development in this
group (13). Additionally, CAIS women provide an ideal op-
portunity to investigate potential influences of estrogens on
gender development in 46,XY individuals who are unre-
sponsive to androgens, yet respond to estrogens (14).
Subjects and Methods
The research reported here was approved by the Joint Committee of
Clinical Investigations of The Johns Hopkins University School of Med-
icine, The Johns Hopkins Hospital (Baltimore, MD). Written, informed
consent was obtained from all subjects before participation. Participants
were asked to complete a written questionnaire before their physical
to confirm their original questionnaire responses and also to elaborate
on responses that were unclear or for which the participant desired
Diagnostic criteria for CAIS subjects
CAIS diagnosis was based on the following: 1) presence of testes
along with normal female external genitalia in a 46,XY individual, 2)
identification of an androgen receptor (AR) gene mutation, 3) sponta-
with no virilization despite normal or high male levels of testosterone,
Received December 27, 1999. Revision received May 3, 2000. Rerevi-
sion received May 18, 2000. Accepted May 18, 2000.
Address all correspondence and requests for reprints to: Dr. Amy B.
Wisniewski, Department of Pediatrics, Division of Pediatric Endocri-
nology, The Johns Hopkins University School of Medicine, 600 North
Wolfe Street, Park 211, Baltimore, Maryland 21287.
* This work was supported by a grant from The Genentech Founda-
tion for Growth and Development (98–33C to C.J.M.), NIH National
Center for Research Resources, General Clinical Research Center Grant
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2000 by The Endocrine Society
Vol. 85, No. 8
Printed in U.S.A.
and 4) markedly decreased or absent postpubertal axillary and pubic
hair growth. The identification of an AR gene mutation is necessary for
accurate diagnosis of AIS, as other syndromes of 46,XY intersex phe-
notypically resemble and can be reported erroneously as AIS (15). This
is mostly true for partial forms of AIS.
The total population of adult women with CAIS recorded in The
Johns Hopkins Pediatric Endocrinology Clinic at the time of study con-
sisted of 20 individuals, among whom 4 were not located, 1 did not
respond to a study invitation, and 1 chose not to participate. The 14
women with CAIS who participated ranged in age from late 20s to
mid-60s (mean age, 45 yr). All had been previously examined at the
Johns Hopkins Pediatric Endocrinology Clinic. Nonparticipants did not
differ from participants in terms of age or medical/surgical treatment
received. To maintain participant anonymity age is presented in cate-
gories of 5 yr at the time of participation. Five of the 14 participants had
been included in previous psychological studies when they were ado-
lescents or young adults (16–18).
The specific AR gene mutations identified in subjects varied, as ex-
pected in light of the large number of AR gene lesions known to be
associated with CAIS (19).
The only variance in the physical characteristics related to CAIS was
with respect to adult sexual hair. Two women (14%) had absolutely no
pubic or axillary hair, whereas the remaining 12 participants (86%) had
no axillary or facial hair, but had minimal amounts of fine, silky pubic
hair (early Tanner stage 2; Table 1).
Physical measurements at birth. Appearance of external genitalia and
considered in light of previous reports of reduced birth weight associ-
ated with AIS (20).
Physical measurements in adulthood. These were obtained during an ex-
amination that took place in the Pediatric Clinical Research Unit at The
Johns Hopkins Hospital as well as from medical records. Adult height
was calculated as a percentile extrapolated from a growth chart for
women (Serono, Norwell, MA). Weight at time of participation was
determined in relation to medium build statistical norms published by
Metropolitan Life Insurance Co. for women (www.indexmedico.com).
Weight was documented according to the number of kilograms below
or above the mean value for healthy women in relation to height. This
mode of data presentation was elected to maintain the anonymity re-
quested by participants.
The cosmetic appearance of external genitalia and breast develop-
ment were evaluated independently and then agreed upon by an ex-
perienced pediatric endocrinologist (C.J.M.) and a reconstructive sur-
geon (J.P.G.). Vaginal depth was measured with graduated vaginal
dilators and reported in centimeters. Clitoral length was measured with
a tape measure and reported in centimeters. Breast size was also mea-
sured with a tape measure and reported in centimeters, both horizon-
tally and vertically for each breast, as conventionally performed by
obtained from medical records. The number of surgical procedures as
well as type of vaginoplasty procedure performed were obtained from
medical records and were verified during physical examination.
Participants were asked first with an open-ended question and then
as a review of the major body systems if they experienced medical
conditions other than CAIS, to determine whether women with this
syndrome were at an increased risk for additional problems. Finally,
participants were asked during the physical exam to indicate their level
of compliance with estrogen therapy after gonadectomy.
Sexual function. Participants were asked about the overall adequacy of
their genitalia for sexual functioning, the estimated strength of their
libido, and their ability to experience orgasms in a written questionnaire
and again during the physical examination. Subjects also reported their
degree of overall satisfaction with sexual functioning.
Body image. Participants were asked about their level of satisfaction with
their physical appearance in a written questionnaire and again during
the physical examination. When dissatisfied with their physical appear-
to this dissatisfaction.
Self-perceived femininity and masculinity. Participants were asked in a
written questionnaire, how masculine and feminine they considered
themselves during their childhood, adolescence, and adulthood. This
section of the questionnaire was based on the Sexual Behavior Assess-
ment Schedule–adult version (Meyer-Bahlburg, H. F. L., and A. A.
Sexual orientation. Participants were asked in a written questionnaire if
they were sexually attracted to, fantasized about, or participated in
sexual activity with men (female heterosexual orientation), women (fe-
male homosexual orientation), or both (female bisexual orientation)
adapted from the Sexual Behavior Assessment Schedule–adult version
(Meyer-Bahlburg, H. F. L., and A. A. Ehrhardt, unpublished).
Marriage and motherhood. Frequencies of marriage and motherhood by
adoption were asked for all participants in a written questionnaire.
Satisfaction with sex of rearing. Participants reported in a written ques-
tionnaire and during the physical examination on their degree of sat-
isfaction with being a woman. Furthermore, participants were asked if
at any point in their lives they had questioned their female gender or
considered changing sex.
TABLE 1. Information regarding race, age, androgen receptor gene mutation, ages at surgeries, and appearance of genitalia for CAIS
subjects at time of participation
ID no.Race Age (yr)
Age (yr) at
Age (yr) at
COMPLETE ANDROGEN INSENSITIVITY SYNDROME OUTCOMES2665
Participants’ opinions concerning timing of surgical treatment/third sex. Par-
ticipants were asked their opinion regarding appropriate timing of go-
nadectomy and vaginoplasty in a written questionnaire and during the
physical examination. Although the question of optimal timing for sur-
gical treatment of intersex patients has focused on the reconstruction of
ambiguous external genitalia, surgical modification of gonadal and pos-
terior vaginal status in CAIS women also leads to permanent conse-
quences and therefore should be considered in this patient group.
Participants were asked their opinion regarding the categorization of
intersex children as a “third gender” in opposition to the more tradi-
tional categories of male or female. Although this third gender classi-
fication usually applies to individuals with ambiguous external geni-
talia, it can be extended to CAIS women who possess a Y-chromosome
and testes. Participants were also asked if they agreed with the concept
of recognizing a third intersex category within our society as an alter-
native to treating intersex patients as either males or females. This
question was included due to suggestions that intersex patients should
not be raised according to strictly male or female categories (21, 22).
Long-term psychological treatment
Participants reported in a written questionnaire and during physical
examination whether they had ever received counseling concerning
Knowledge of medical history
edge of AIS in a written questionnaire. Participants were also evaluated
by a pediatric endocrinologist (C.J.M.) and psychologist (A.B.W.) to
determine their level of understanding of AIS at the time of study
participation. Specifically documented was participants’ knowledge of
apy as presented in our Patients’ Guide to Syndromes of Abnormal Sex
Due to the unique nature of CAIS, it is impossible to identify an
appropriate control group. Additionally, the low frequency of this syn-
drome in the general population led to data presentation in the form of
descriptive statistics and raw data.
Physical measurements at birth
Mean birth weight for participants was 3.5 kg (range,
2.26–4.1 kg), which did not differ from that of the general
population (3.4 kg; range, 2.5–4.6 kg) (24). External genitalia
was completely female with no abnormalities at birth for all
Physical measurements in adulthood
Adult height of eight subjects (57%) fell at or exceeded the
90th percentile of the range of control adult females. Adult
height of the remaining women (43%) fell between the 50th
and 75th percentiles. Seven participants (50%) were within
?10 kg of their ideal weight range. The remaining seven
participants exceeded their ideal weight by 15 kg or more,
three of whom exceeded their ideal by 80 kg or more.
Most gonadectomies and vaginoplasties were performed
on participants during their adolescence or adulthood (Table
1). Eight participants did not require vaginoplasty for peno-
vaginal intercourse (one was homosexual), and one woman
required vaginoplasty twice. Vaginoplasty consisted of a
McIndoe partial thickness skin graft in all cases. Both exam-
ining physicians rated the appearance of the external geni-
talia as good for all women. Average clitoral length was 0.83
cm (range, 0.1–1.5 cm); no participant exhibited clitoral en-
largement, and none required clitoroplasty. The eight
vaginal length of 9 cm (range, 4.5–13 cm). The six women
with a history of vaginoplasty had an average vaginal length
of 8.6 cm (range, 4.5–14 cm). These measures are consistent
7–11 cm (25–27). All women had breast development, with
wide variability in breast size (range, 16 ? 14 to 41 ? 31 cm).
Regarding the occurrence of other medical conditions
both reported most frequently (Table 2).
The degree of compliance with estrogen replacement ther-
obtained from written questionnaire responses, medical
participants reported that they were compliant, whereas the
remaining five women reported they had not taken estrogen
replacement for most of their adult lives after gonadectomy.
Sexual function. Eleven of the women with CAIS studied
(78%) reported satisfaction with their genitalia in terms of
sexual functioning, whereas 3 others (22%) reported dissat-
isfaction. Ten women (71%) reported satisfaction with their
sexual function overall, and four women (29%) were
Despite their complete end-organ resistance to androgens,
the majority of CAIS women (71%) reported a self-estimated
libido of average strength or stronger, and 10 of the 13 who
responded (77%) reported an ability to experience orgasms.
Body image. When provided with three response options
regarding degree of satisfaction with physical appearance,
eight women (57%) reported they were mainly satisfied, five
reported mainly dissatisfaction with her physical appear-
ance. Of the six women who reported being either somewhat
dissatisfied or mainly dissatisfied with their physical ap-
pearance, five reported inadequate body hair, five reported
looking younger than actual age, and three reported obesity
as factors that contributed to this dissatisfaction.
TABLE 2. Medical and psychiatric conditions reported by CAIS
Medical and psychiatric conditions
Osteoporosis, breast fibroid cysts, scoliosis
Obesity, hypothyroid, high cholesterol
Obesity, diabetes II, asthma
High blood pressure
Depression, drug addiction, poor general health
Obesity, high cholesterol, asthma, high blood pressure
Osteoporosis, stroke, gall stones
2666 WISNIEWSKI ET AL.
JCE & M • 2000
Vol 85 • No 8
Self-perceived femininity and masculinity. Women with CAIS
overwhelmingly reported a high degree of femininity along
with a low degree of masculinity throughout development.
Mean femininity rating (not feminine ? 1 to highly femi-
nine ? 5) for subjects during childhood was 4.4 (range, 2–5),
during adolescence was 4.2 (range, 3–5) and during adult-
hood was 4.6 (range, 4–5). Mean masculinity rating (not
masculine ? 1 to highly masculine ? 5) for subjects during
childhood was 1.4 (range, 1–4), during adolescence was 1.4
(range, 1–3), and during adulthood was 1.1 (range, 1–2).
Sexual orientation. A large majority of CAIS women reported
female heterosexual orientation in terms of sexual attraction,
fantasies, and experience during both adolescence (100%)
and adulthood (93%). The one participant who reported ho-
mosexual attraction, fantasies, and experiences indicated
that a lesbian orientation applied only to her adulthood.
Clearly, in this case the development of female homosexu-
ality was not associated with androgen exposure.
Marriage and motherhood. Seven women (50%) were married
was 27 yr (range, 16–38 yr). Five of these and one unmarried
woman (43%) were mothers through adoption. Of the seven
participants who were not married, one was engaged, one
remaining four women expressed a desire for marriage to a
man but had not yet met a satisfactory partner.
Satisfaction with sex of rearing. CAIS women unanimously
reported satisfaction with being a woman (100%). Two par-
ticipants (18%) questioned their physical status as women,
but none reported a desire to change sex to that of a man.
Participants’ opinions of timing of surgical treatment/third sex.
The majority of women who responded indicated the most
appropriate timing for their surgical procedures was during
adolescence or adulthood (8 of 10 respondents, or 80%). Two
women reported the most appropriate timing for surgery
was during infancy.
The vast majority of participants (81% of the 11 who re-
sponded) did not approve of rearing intersex children ac-
cording to a third gender.
Long-term psychological treatment
The majority of CAIS women studied received some form
of counseling (83%) at various ages and for various lengths
of time (1–15 yr) concerning aspects of their syndrome.
Knowledge of medical history
Eight CAIS women (57%) exhibited no understanding of
CAIS (i.e. were unaware of their karyotype, gonadal char-
acteristics, or the importance of estrogen replacement) at the
time of participation, and only 64% indicated that they were
satisfied with their level of knowledge regarding their con-
dition. It could not be determined if participants ever re-
ceived information about their syndrome or if they were
previously informed but did not recall the information. Nev-
ertheless, this finding emphasizes the importance of follow-
ing CAIS patients into adulthood and subsequently offering
them adult education about their syndrome.
To determine the natural history of CAIS and long-term
outcome of treatment intervention, it is necessary to follow
affected individuals over time. Previous knowledge of CAIS
has been based on studies of relatively young patients. Such
young CAIS women overwhelmingly report contentment
with being female, a desire for marriage and motherhood,
sexual attraction and practice exclusively oriented toward
men, as well as the ability to experience orgasms (16–18, 28).
However, it is likely that older women have the benefit of
to younger women and girls. The present study extends our
knowledge of CAIS to an older cohort of women.
Furthermore, quality of sexual function and appearance of
genitalia and secondary sexual characteristics were consid-
ered in conjunction with our psychosexual evaluation. Pre-
in terms of sexual function and appearance. It is likely that
factors such as an individual’s cosmetic appearance and
quality of sexual function influence gender and sexuality,
research concerning intersex populations.
in terms of birth weight or genital appearance. Consistent
with previous reports, CAIS women tend to be tall (29, 30)
and experience normal feminization of secondary sexual
characteristics, with the exception of lacking female-typical
amounts of axillary and pubic hair in adulthood (31). Inter-
estingly, 12 participants had a minimal amount of fine, soft
pubic hair but no axillary hair. This is consistent with pre-
vious observations in this group of vellus down on the body
that is not androgen dependent (32). Aside from lacking
normal. Six women (43%) had undergone vaginoplasty, but
none required or had clitoroplasty.
Most CAIS women were satisfied with their sexual func-
tioning. However, three (21%) were dissatisfied. Of these,
one did not receive any genital reconstructive surgery de-
to participate in peno-vaginal intercourse. Although this
woman has never attempted peno-vaginal intercourse, she
has discovered great satisfaction from homosexual sexual
activity. The remaining two had undergone vaginoplasties
that resulted in sufficient vaginal length for peno-vaginal
intercourse. Their dissatisfaction may be related to other
variables. One woman was a victim of sexual abuse early in
life and is presently in poor health resulting from substance
abuse; the other reported severe dissatisfaction with her
Libido and ability to experience orgasms were not a prob-
lem for the CAIS women in this study. This illustrates that
although androgens may contribute to libido and orgasmic
COMPLETE ANDROGEN INSENSITIVITY SYNDROME OUTCOMES 2667
be experienced by women who exhibit complete end-organ
insensitivity to androgens. Furthermore, there were no dif-
ferences in self-reported libido based on compliance with
estrogen therapy. Vaginal lubrication is another character-
istic of sexual functioning thought to be related to estrogen
levels. No participant reported difficulty with vaginal lubri-
cation on the written questionnaire or during the physical
Despite some of the unhappiness with physical attributes,
the majority of women with CAIS were mainly satisfied with
their physical appearance.
CAIS women overwhelmingly perceive themselves as
highly feminine and not masculine throughout develop-
ment. Additionally, CAIS women largely report their sexual
attraction, fantasies, and experiences were best described as
female heterosexual. Concerning the one woman who re-
ported heterosexual attraction and fantasies in adolescence
followed by homosexual thoughts and actions in adulthood,
perhaps a short vagina coupled with fear of vaginoplasty
contributed to this change. Several women were married
and/or mothers. All participants reported being mainly sat-
isfied when asked their degree of satisfaction in being a
woman. Of the two women who stated that they questioned
their physical status as women, one responded that this was
due to her inability to menstruate and become pregnant, and
the other reported that this was in response to media articles
she encountered regarding intersexuality.
Several issues of long-term health status are of concern in
our CAIS participants. First, long-term compliance with es-
older CAIS women as a group are obese. However, obesity
among women with CAIS mirrors rates observed in the pop-
ulation of American women at large and does not appear to
be directly related to this condition (36, 37). Lastly, women
with CAIS appear at to be at risk for bone-related disease. It
is unclear at this time, however, if this is a result of androgen
insensitivity per se, a consequence of inadequate estrogen
replacement, or both (38).
Most women (80% who responded) sought psychological
written questionnaire. The majority of participants did not
believe a third gender category was appropriate for intersex
patients. These points stress the importance of providing
well rounded care to these patients that includes counseling
services as well as medical and surgical care.
The great majority of these CAIS women (78%) reported
that the most appropriate timing of gonadectomy and vag-
inoplasty procedures was during adolescence or adulthood.
in adulthood, and the majority indicated a desire to better
understand their condition. However, all women stressed
the importance of confidentiality regarding their condition.
These results support the concerns of CAIS patient advocacy
groups regarding the disclosure of medical information to
patients and the postponement of vaginoplasty to late ado-
lescence or adulthood for CAIS patients (8, 39).
Complete insensitivity to androgen action is clearly an
extreme in the spectrum of congenital malformations of sex
organs. Additional studies of long-range outcome of subjects
with partial AIS and other conditions associated with am-
biguous genital development are in progress.
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