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The belief that Homo sapiens is absolutely dimorphic with the respect to sex chromosome composition, gonadal structure, hormone levels, and the structure of the internal genital duct systems and external genitalia, derives from the platonic ideal that for each sex there is a single, universally correct developmental pathway and outcome. We surveyed the medical literature from 1955 to the present for studies of the frequency of deviation from the ideal male or female. We conclude that this frequency may be as high as 2% of live births. The frequency of individuals receiving "corrective" genital surgery, however, probably runs between 1 and 2 per 1,000 live births (0.1-0.2%). Am. J. Hum. Biol. 12:151-166, 2000. Copyright 2000 Wiley-Liss, Inc.
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How Sexually Dimorphic Are We? Review and Synthesis
MELANIE BLACKLESS, ANTHONY CHARUVASTRA,
AMANDA DERRYCK, ANNE FAUSTO-STERLING,*
KARL LAUZANNE, AND ELLEN LEE
Department of Molecular and Cell Biology and Biochemistry, Brown
University, Providence, Rhode Island
ABSTRACT The belief that Homo sapiens is absolutely dimorphic with
the respect to sex chromosome composition, gonadal structure, hormone lev-
els, and the structure of the internal genital duct systems and external geni-
talia, derives from the platonic ideal that for each sex there is a single,
universally correct developmental pathway and outcome. We surveyed the
medical literature from 1955 to the present for studies of the frequency of
deviation from the ideal male or female. We conclude that this frequency may
be as high as 2% of live births. The frequency of individuals receiving “cor-
rective” genital surgery, however, probably runs between 1 and 2 per 1,000
live births (0.1–0.2%). Am. J. Hum. Biol. 12:151–166, 2000.
© 2000 Wiley-Liss, Inc.
Among primates, humans exhibit a mod-
est sexual dimorphism with regard to char-
acters such as body size or voice timbre
(Fedigan, 1982). With respect to sex chro-
mosome composition, gonadal structure,
hormone levels, and the structure of the in-
ternal genital duct systems and external
genitalia, however, we generally consider
Homo sapiens to be absolutely dimorphic.
Biologists and medical scientists recognize,
of course, that absolute dimorphism is a
Platonic ideal not actually achieved in the
natural world. Nonetheless, the normative
nature of medical science uses as an as-
sumption, the proposition that for each sex
there is a single, correct developmental
pathway. Medical scientists, therefore, de-
fine as abnormal any deviation from bimo-
dally distributed genitalia or chromosomal
composition (Conte and Grumbach, 1989).
If, however, one relinquishes an a priori be-
lief in complete genital dimorphism, one can
examine sexual development with an eye to-
ward variability rather than bimodality.
Conte and Grumbach (1989) list more
than 25 diagnoses affecting sexual differ-
entiation. While the incidence of some in-
dividual medical syndromes is fairly well
established, the overall frequency of inter-
sexuality is a matter of dispute. Fausto-
Sterling (1993a,b) cited a figure attributed to
John Money that the frequency of intersexu-
ality might be as high as 4% of live births, but
Money (1993) responded that he never made
such a claim. In fact, no well-documented
overview of the frequency of intersex exists at
present, and it is this lacuna that we address
in the present article. The question is of in-
terest to students of human development,
medical practitioners, and human biologists,
among others. Recently, the practice of surgi-
cally altering the genitals of intersexual in-
fants to conform to assumptions about ab-
solute dimorphism has been questioned
(Fausto-Sterling, 1995/1996; Post, 1995/
1996; Sandberg, 1995/1996; Walcutt, 1995/
1996; Diamond, 1996; Zucker, 1996; Dia-
mond and Sigmundse n, 1997 ; Kessl er,
1998). Thus, both because of a theoretical
interest in human sexual dimorphism and
medical questions about the treatment of in-
tersexuals, it is important to provide a fre-
quency baseline for the varied events which
lead to intersexuality.
METHODS
We surveyed the medical literature from
1955 to the present for studies of the fre-
Contract grant sponsor: Office of University President Vartan
Gregorian.
*Corresponde nce to: Anne Faust o-Sterling, Department of
Molecular and Cell Biology and Biochemistry, Brown Univer-
sity, Providence, RI 02912.
E-mail: Anne_Fausto-Sterling@brown.edu
Received 5 November 1997; Revision received 10 December
1998; Accepted 14 December 1998
AMERICAN JOURNAL OF HUMAN BIOLOGY 12:151–166 (2000)
© 2000 Wiley-Liss, Inc.
PROD #M97083R2
quency of deviation from the ideal male or
female. For a few rare syndromes, we con-
sidered the literature which predates 1955.
Our sources included population surveys,
genetic studies, case surveys from indi-
vidual medical practitioners, and environ-
mental population studies. In addition to
Medline as a starting point, government
documents, bibliographies in textbooks, pre-
viously located review articles, and specific
articles provided additional sources. We did
not exclude any articles which contained
frequency estimates derived from an unse-
lected population. Rather, where appropri-
ate we indicate the limitations of particular
publications.
We define the typical male as someone
with an XY chromosomal composition, and
testes located within the scrotal sac. The
testes produce sperm which, via the vas def-
erens, may be transported to the urethra
and ejaculated outside the body. Penis
length at birth ranges from 2.5 to 4.5 cm
(Flatau et al., 1975); an idealized penis has
a completely enclosed urethra which opens
at the tip of the glans. During fetal develop-
ment, the testes produce the Mullerian in-
hibiting factor, testosterone, and dihy-
drotestosterone, while juvenile testicular
activity ensures a masculinizing puberty.
The typical female has two X chromosomes,
functional ovaries which ensure a feminiz-
ing puberty, oviducts connecting to a uterus,
cervix and vaginal canal, inner and outer
vaginal lips, and a clitoris, which at birth
ranges in size from 0.20 to 0.85 cm (Ober-
field et al., 1989). In this article, we ask how
often development meets these exacting cri-
teria for males and females.
The literature which reports the frequen-
cies of syndromes that produce intersexual-
ity varies in quality and quantity. In some
cases there are multiple surveys with large
numbers replicated over many years and in
many different geographical locations. In
others no data exist with which to estimate
frequency, while in still others the lack of
better data dictated reliance on one or a
small number of reports of uncertain qual-
ity. In each case the available data are pre-
sented. The strength or weakness of an es-
timate is also indicated.
“SEX” CHROMOSOME COMPOSITION
Individuals with XXY, XO, XYY, XXYY,
XX males, and 47,XXX females comprise the
most frequently encountered deviations
from an XX (female) or XY (male) chromo-
somal make-up. An XO condition produces
individuals with female external genitalia
and streak gonads which are incapable of
fetal or pubertal gonadal hormone synthesis
and a variety of somatic alterations, while
47,XXX girls develop secondary sex charac-
teristics at puberty and are sometimes fer-
tile (Buckton, 1983). XXY individuals diag-
nosed with Klinefelter syndrome have ex-
ter n a l m ale g e n i tal i a , s mal l t e s tes ,
impaired spermatogenesis, and frequent gy-
necomastia. XXYY individuals are consid-
ered karyotypic variants of Klinefelter syn-
drome (Conte and Grumbach, 1989; Zinn et
al., 1993). XYY males are taller, on average,
than XY males, and commonly exhibit un-
derdeveloped testes (Vogel and Motulsky,
1979). Recent work, however, suggests that
many 47,XXY and 47,XYY males are undi-
agnosed because they present no symptoms
which pr ompt a ch romos omal an alysi s
(Abramsky and Chapple, 1997). The cat-
egory of XX males, which involves the trans-
location or deletion of a submicroscopic sec-
tion of the sex determining region of the Y
chromosome, is morphologically and geneti-
cally heterogeneous (Lo´pez et al., 1995).
Table 1 summarizes the results of 17
studies of the frequencies of XXYY, XX
(male), 47,XXX, and XYY individuals at
birth. The total frequency ranges from 0.002
to 2.15/1,000 live births, with a mean of
0.639/1,000 and a standard deviation of
0.665. The mean/1,000 live births and stan-
dard deviations for each of the non-XX, non-
XY chrom osome composit ions listed in
Table 1 are 0.155 (0.185) for XXYY, 0.05
(0.019) for XX males, 0.47 (0.364) for 47,
XXX, and 0.639 (0.665) for XYY.
In 24 different estimates of the frequency
of Klinefelter syndrome (XXY), the inci-
dence ranges from 0 (out of 3,890 births) to
2.13/1,000 births. The mean incidence for all
24 studies is 0.922/1,000 live births with a
standard error of 0.102 (Table 2). The 18
different estimates for the population fre-
quency of XO chromosome constitution are
shown in Table 3. The incidence ranges
from 0.0 for five small studies (sample size
of less than 3,993) to 1.67/1,000 live births.
The mean is 0.369/1,000 live births, with a
standard error of 0.111. Recent data show-
ing that not all Turner patients present
with XO identifiable by traditional karyol-
ogy suggest that the incidence calculated
152 M. BLACKLESS ET AL.
from previously published studies may be
an underestimate (Zinn et al., 1993).
Androgen insensitivity in XY individuals
Disruption of fetal hormonal metabolism
in XY fetuses results most commonly from
defects in androgen receptors. Clinical fea-
tures range from a fully female external
phenotype, with a blind-ending vagina and
little axillary hair development, to a mascu-
line phenotype with azoospermia and el-
evated levels of luteinizing hormone (Griffin
and Wilson, 1989). Estimates of the fre-
quency of complete androgen insensitivity
(AIS) range from 0.049 to 0.016/1,000 male
(Bangsbøll et al., 1992; Griffin and Wilson,
1989). In addition, 1–2% of girls with ingui-
nal hernias may have androgen insensitiv-
ity (Griffin and Wilson, 1989). Jagiello and
Atwell (1962) estimate the frequency of in-
guinal hernias in girls at 8/1,000 female
births. Hence, the frequency of complete
AIS may be 0.12/1,000 female births. Aver-
aging the estimates for male births and
combining them with the estimate for fe-
male births yields a figure of 0.076/1,000
live births. There are no solid estimates of
the frequency of partial AIS, but Griffin and
Wilson (1989) suggest that it is one-tenth as
common as complete AIS. Using these esti-
mates the rate would be 0.0076/1,000 live
births.
Griffin and Wilson (1989) cite three other
forms of AIS: 5!-reductase deficiency, Reif-
enstein syndrome and Infertile Male syn-
drome. The first two produce externally vis-
ible intersexuality, while those with Infer-
tile Male syndrome are phenotypically
male. 5-!-Reductase deficiency is quite com-
mon in a number of populations, ranging
from Central America to Vietnam (Mendoca
et al., 1996). Indeed, more than 50 families
with over 100 affected individuals have
been reported. However, no population or
gene frequencies are available (Conte and
Grumbach, 1989; Mendoca et al., 1996; Al-
TABLE 1. Incidence of XXYY, XX(male), 47,XXX and XYY births in 17 published surveys*
Location Year
Total #
surveyed XXYY XX male 47,XXX XYY
Incidence/1,000
live births Method Reference
Edinburgh 1964 20,725 1 11 0.575 Bs
a
Maclean et al.,
1964
Geneva 1968 8,184 1 0.122 Bs Mikamo, 1968
London 1969 2,081 4 1.922 K Sergovich et al.,
1969
New Haven 1970 4,366 3 3 1.374 K Lubs, 1970
Toronto 1974 73,229 1 2 2 0.068 Bs/K Bell, 1974
Moscow 1974 2,500 1 0.400 K Bochkov et al.,
1974
Winnipeg 1975 13,939 5 7
b
0.861 K Hamerton
et al., 1975
Ontario 1976 930 2 2.150 K Lin et al., 1976
Denver 1976 40,371 12 0.297 Bs/K Goad et al.,
1976
USA 1977 13,751 1 0.073 K Walzer et al.,
1977
Tokyo 1978 12,319 3 0.244 K Higurasi et al.,
1979
Edinburgh 1979 23,196 1 11 0.517 Bs/K Ratcliffe et al.,
1979
Edinburgh 1980 3,993 3 4 0.002 K Buckton et al.,
1980
USA 1982 19,675 25 0.001 K Schreinemacher
et al., 1982
Telemark 1982 1,830 1 0.546 K Hansteen et al.,
1982
Belgium 1988 77,000 32
c
0.416 K Kleczkowska
et al., 1988
Denmark 1991 34,910 5
d
2 18 20
b
1.289 K Nielsen, 1991
Average total/1,000 0.155 0.05 0.470 0.865 0.639
live births (SD) (0.185) (0.019) (0.364) (0.740) (0.665)
*K, karyotype. B
5
, buccal smear.
a
Excludes perinatal deaths.
b
Includes mosaic and nonmosaic.
c
Includes 25 people with more than two X chromosomes.
d
Includes four xx/xy mosaics.
FREQUENCY OF INTERSEXUALITY 153
Attia, 1996). Similarly, no such estimates
exist for Reifenstein or Infertile Male syn-
drome. Aiman and Griffin (1982) report evi-
dence of androgen resistance in more than
40% of men with no other obvious cause for
severe oligo- or azoospermia.
Congenital adrenal hyperplasia
The most common cause of intersexuality
in XX females is congenital adrenal hyper-
plasia (CAH), a label which covers a hetero-
geneous set of genetically inherited alter-
ations in steroid biosynthesis. The work on
CAH has been thoroughly reviewed (Laue
and Rennert, 1995; New et al., 1989; New-
field and New, 1997; Pang and Clark, 1990,
1993). Table 4 presents a summary. Al-
though not all forms of CAH result in am-
biguity at birth, the table includes esti-
mates for any manifestations which alter
sexually dimorphic presentation at any time
during the life cycle. The classic form of 21-
TABLE 2. Incidence of XXY births in 24 published surveys*
Location Year
Total #
surveyed
Total
XXY
a
Incidence/1,000
live births Method Reference
Winnipeg 1959 3,715 5 0.135 Bs Moore, 1959
Bombay, India 1962 3,890 0 0 ? Subray and Prabhaker, 1962
Seattle
b
1964 1,954 2 1.02 ? Paulsen et al., 1964
Edinburgh 1964 20,725 20 0.97 ? Maclean et al., 1964
Geneva 1968 8,184 6 0.73 ? Mikamo, 1968
London, England 1969 2,081 1 0.481 K Sergovich et al., 1969
USA 1970 3,543 5 1.411 K Gerald, 1970
New Haven 1970 4,366 4 0.916 K Lubs, 1970
Germany 1973 1,000 2 2.00 ? Golob, 1973
Dehli 1973 3,100 3 0.97 ? Verma et al., 1973
Toronto 1974 73,229 43 0.59 ? Bell, 1974
Moscow 1974 2,500 2 0.800 K Bochkov et al., 1974
Winnipeg 1975 13,939 6 0.430 K Hamerton et al., 1975
Ontario 1976 930 1 1.075 K Lin et al., 1976
Denver 1976 40,371 23 0.57 ? Goad et al., 1976
USA 1977 13,751 10 0.727 K Walzer, 1977
Edinburgh 1979 23,196 21 0.91 ? Ratcliffe et al., 1979
Tokyo 1979 12,319 2 0.162 K Higurasi et al., 1979
Edinburgh 1980 3,993 6 1.503 K Buckton et al., 1980
Telemark 1982 1,830 1 0.546 K Hansteen et al., 1982
Northeast (USA) 1982 19,675 20 1.017 K Schreinemacher et al., 1982
Germany 1984 13,168 28 2.126 K Murken, 1984
Denmark 1991 34,910 27 0.773 K Nielsen, 1991
*?, Not specified; K, karyotype; Bs, buccal smear.
a
Mosaic and nonmosaic.
b
Study reported only male births; we doubled the denominator to estimate total births.
TABLE 3. Incidence of XO births in 18 published surveys*
Location Year
Total #
surveyed Total
a
Incidence/1,000
live births Method Reference
Edinburgh 1964 20,725 4 0.400 Bs Maclean et al., 1964
Geneva 1968 8,184 2 0.509 Bs Mikamo, 1968
London 1969 2,081 0 0 K Sergovich et al., 1969
? 1970 3,543 0 0 K Gerald, 1970
New Haven 1970 4,366 1 0.458 K Lubs, 1970
Dehli 1973 3,100 1 0.644 Bs Verma et al., 1973
Toronto 1974 73,229 5 0.141 Bs Bell, 1974
Moscow 1974 2,500 2 1.671 K Bochkov et al., 1974
Winnipeg 1975 13,939 2 0.296 K Hamerton et al., 1975
Denver 1976 40,371 27 1.370 Bs Goad et al., 1976
Ontario 1976 930 0 0 K Lin et al., 1976
Edinburgh 1979 23,196 1 0.105 Bs Ratcliffe et al., 1979
Tokyo 1979 12,319 1 0.168 K Higurasi et al., 1979
Edinburgh 1980 3,993 0 0 K Buckton et al., 1980
Telemark 1982 1,830 0 0 K Hansteen et al., 1982
New York State 1983 76,474 9 0.118 K Hook, 1983
Denmark 1991 34,910 8 0.229 K Nielsen, 1991
a
Mosaic and nonmosaic.
*Bs, buccal smear; K, karyotype.
154 M. BLACKLESS ET AL.
hydroxylase deficiency is the most common,
and the frequency estimates are the most
reliable. Pang and Clark (1990, 1993; Pang
et al., 1988) have published detailed com-
parisons of estimates obtained from case re-
ports in large population databases, as well
as from more recentl y ava ila ble m ass
screening programs. The direct screening
programs have resulted in higher estimates
for the condition than have the more tradi-
tion al po pul ati on surveys. In both in-
stances, however, one striking fact emerges:
TABLE 4. Incidence of 21-OHase (classic) in 36 published surveys
Part A: Case surveys
Location and
subpopulation Sample size Date
Frequency/1,000
live births Reference
Switzerland 1,516,299 1980 0.0646 Werder et al., 1980
France 41,073,409 1985 0.031 Bois et al., 1985
France 13,921,803 1985 0.0356 Bois et al., 1985
Switzerland 1988 0.198 Pang et al., 1988
Canada 1988 0.038 Pang et al., 1988
Austria 1988 0.111 Pang et al., 1988
US (Wisconsin) 1988 0.067 Pang et al., 1988
Switzerland 1988 0.0542 Pang et al., 1988
Hungary 27,497,606 1989 0.0023 Thompson et al., 1989
Canada 346,000 1989 0.0689 Thompson et al., 1989
Hungary 2,119,727 1988 0.033 So´lyom, 1989
Japan 585,000 1990 0.0228 Pang and Clark, 1990
Kuwait 540,000 1990 0.001 Lubani et al., 1990
Sweden 1,727,928 1990 0.0827 Thile´ n and Larsson, 1990
Israel (Jewish population) 1986–1991 0.0333 Sack et al., 1997
Israel (Arab population) 1986–1991 0.1250 Sack et al., 1997
US 1993 0.025 Pang and Clark, 1993
Average (SD) 0.0584 (0.0495)
Range 0.001–0.198
Part B: Mass screening
Alaska-Caucasian 13,733 1982 0.0728 Pang et al., 1982
Hungary 968,303 1989 0.0537 So´lyom, 1989
France (La Reunion) 31,472 1990 0.315 Pang and Clark, 1990
US (Illinois) 357,825 1990 0.0838 Pang and Clark, 1990
Portugal 100,000 1990 0.070 Pang and Clark, 1990
Scotland 119,960 1990 0.0583 Pang and Clark, 1990
Washington 255,527 1990 0.0547 Pang and Clark, 1990
Japan 2,523,948 1990 0.0223 Pang and Clark, 1990
Switzerland 65,823 1993 0.0911 Pang and Clark, 1993
Germany 12,500 1993 0.08 Pang and Clark, 1993
Italy 133,198 1993 0.09 Pang and Clark, 1993
Sweden 660,000 1993 0.0848 Pang and Clark, 1993
France (regional) 270,060 1993 0.0778 Pang and Clark, 1993
Canada 50,000 1993 0.06 Pang and Clark, 1993
Brazil 82,870 1993 0.1327 Pang and Clark, 1993
Spain 206,875 1993 0.058 Pang and Clark, 1993
Alaska-Yupik 3,740 1993 3.47 Pang and Clark, 1993
Native 12,131 1993 1.236 Pang and Clark, 1993
Alaskan
New Zealand 536,915 1995 0.0428 Cutfield, 1995
Texas (white) 872,648 1989–1995 0.064 Therrell et al., 1998
Texas (Hispanic) 764,101 1989–1995 0.069 Therrell et al., 1998
Texas (African American) 253,854 1989–1995 0.0236 Therrell et al., 1998
Texas (other) 46,410 1989–1995 0.1293 Therrell et al., 1998
Average for
screening (SD)
0.280 (0.738)
Without Yupik or
Native Alaskan
0.083 (0.06)
Without Yupik,
Native Alaskan,
or La Reunion
0.0709 (0.0288)
FREQUENCY OF INTERSEXUALITY 155
the gene frequency for 21-hydroxylase defi-
ciency varies significantly among popula-
tions. Worldwide and national estimates
must be considered in this light.
Table 4 presents data obtained from origi-
nal sources and from reviews by Pang and
Clark (1990, 1993). The average frequency
for 21-hydroxylase deficiency using case
surveys is 0.0584 ± 0.0495 and a range of
0.001–0.198/1,000 live births. The corre-
sponding statistics from mass screening
(and minus the very high incidence among
Yupik Eskimos) are 0.083 ± 0.060, and a
range of 0.0428–0.315 per 1,000 live births.
The worldwide frequencies do not include
the Yupik data (3.47/1,000 live births) and
the incidence in La Reunion, France (0.315/
1,000 live births). It does not seem obvious,
however, that it was appropriate to elimi-
nate the La Reunion data; even though the
number is high, it is in the same order of
magnitude as other data used in the calcu-
lation (e.g., Brazil). Therefore, we averaged
the numbers arrived at with and without
the La Reunion data, arriving at a world-
wide frequency of classic CAH due to 21-
hydroxylase deficiency of 0.0770/1,000 live
births.
Tables 5 and 6 contain data concerning
the rarer enzyme deficiencies leading to
CAH. The average incidence for 3-"hydrox-
ysteroid dehydrogenase is 0.00068/1,000
live births, while that for 11-"-hydroxylase
(minus the very high frequency found in
Moroccan Jews) is 0.00362/1,000 live births
(0.00267) with a range of 0.0005–0.0071/
1,000. The one available frequency estimate
for 17-alpha hydroxylase places the number
at 7 ×10
5
/1,000 live births.
Finally, the unusual case of nonclassic or
late onset 21-hydroxylase deficiency needs
consideration. Nonclassic CAH is defined as
a deficiency that arises anytime after the
first 5 years of life. In childhood, such cases
may come to medical attention because of
premature signs of puberty, hirsutism, and
clitoral growth. In adults, the signs can in-
clude hirsutism, menstrual disorders, and
clitoral enlargement (Eldar-Geva et al.,
1990; Pollack et al., 1981). Speiser et al.
(1985) used estimates of gene frequencies
for late onset 21-hydroxylase deficiencies to
calculate the incidence of affected individu-
als in several different localities and ethnic
groups. While the incidence of late-onset 21-
hydroxylase varies widely among different
ethnic groups, its overall frequency is ex-
tremely high. The calculated frequencies
are 37/1,000 among Ashkenazi, 19/1,000
among Hispanics, 16/1,000 among Yugo-
slavs, 3/1,000 among Italians, and 0.01/
1,000 among a mixed Caucasian population.
Although the estimates are widely accepted
and cited (Arnaut, 1992; Eldar-Geva et al.,
1990; White et al., 1987; Newfield and New,
1997). We could not locate articles confirm-
ing the reported frequencies of Speiser et al.
(1985). Thus, while we use this estimate in
the final calculation of nondimorphism, fu-
ture reports may contain modifications of
the estimates.
Vaginal and penile agenesis
XY babies born with testes, but complete
absence of a penis, are extremely rare, prob-
ably occurring only once in a million births
(Bansal and Singh, 1990; Kumar et al.,
1986; Rupprecht et al., 1989). In contrast,
complete or partial vaginal agenesis is fairly
common. Harkins et al. (1981) report that 6
of 26 patients with vaginal agenesis had
AIS, while the remainder had M eye r-
Roki tansky- Ku¨ ster -Hauser (MRK H) syn-
drome, which is characterized by aplasia of
TABLE 5. Incidence of 11-B-hydroxylase (classic) in six published surveys
Location and
subpopulation Sample size Method
Frequency/1,000
live births Reference
Switzerland 1,516,299 Case 0.0032 Werder et al., 1980
France 13,921,803 Case 0.0071 Bois et al., 1985
Hungary 2,119,727 Case 0.0018 So´lyom, 1989
Kuwait 540,000 Case 0.0055 Lubani et al., 1990
Sweden 1,727,928 Case 0.0005 Thile´ n and Larsson, 1990
Moroccan Jews Gene frequency
estimates
0.1667 Ro¨ sler et al., 1992
Mean (SD) 0.031 (0.067)
Range 0.0005–0.1667
Mean (SD) and range 0.00362 (0.00267)
without Moroccan Jews 0.0005–0.0071
156 M. BLACKLESS ET AL.
the vagina, typical female secondary sexual
characteristics, attenuated fallopian tubes,
and typical ovaries and female karyotype
(Chervenak et al., 1982). To avoid “double
counting” of AIS patients, we report com-
plete estimates of vaginal agenesis inci-
dence, but in the final calculations, assume
that only 77% of these comprise an other-
wise unmeasured deviation from the usual
pathway of female development.
Unfortunately, the literature on the inci-
dence of vaginal agenesis appears more
promising than it actually is. Most articles
quote an incidence of 1/4,000 to 1/5,000
births. When one traces the citations, how-
ever, they all lead to two publications. Eng-
stad (1917, p. 330), reporting on cases en-
countered in a private practice, writes:
“From my own experience I should judge
that we might expect to find one case in
about five thousand.” Bryan et al. (1949)
note the Engstad report and cite a paper by
Owens, who reported six cases in 125,000
hospital admissions (0.048/1,000). From
their own clinical experience, Bryan et al.
(1949) estimate a frequency of 1/4,000 fe-
male patients (0.25/1,000). Currie (1974) re-
ported that between July 1969 and 1973
there were 5,189 deliveries and 2,988 gyne-
cological admissions at a USAF Medical
Center. Of the total of 8,177, there were two
records of complete or partial vaginal agen-
esis. In the most recent independent esti-
mate, Willemsen and Dony (1988) esti-
mated that 1/30,000 living Du tch-born
women have Mayer-Rokitansky syndrome.
Recognizing the limited basis of the present
knowledge of the frequency of vaginal agen-
esis, we use the figure of 1/4,500. Assuming
that 77% of these are due to unique causes,
the final incidence is 0.1694/1,000 live
births. Since congenital absence of the va-
gina can be asymptomatic, this may be an
underestimate.
Hormone-producing tumors and exogenous
sex hormones
Hormone-producing tumors are relatively
rare, and no population-level estimates of
incidence exist. They can, however, cause
virilization of adult women, including voice
changes, clitoral growth, and hirsutism. In
addition, they have been known to cause
fetal masculinization during pregnancy
(Hensleigh and Woodruff, 1978; Ireland and
Woodruff, 1976; Verhoeven et al., 1973). It
is also difficult to ascertain the frequency of
genital alterations caused by treatment
with progestins during pregnancy. A recent
meta-analysis of studies done on births fol-
lowing first trimester exposure to low doses
of sex hormones, especially from oral con-
traceptives, suggests little or no danger to
genital development (Raman-Wilms et al.,
1995). However, earlier studies focused on
much higher doses of progestin, used in ef-
forts to avoid miscarriage. Not only were the
doses greater in these cases, but treatment
occurred well into the second trimester of
pregnancy, a time when one might espe-
cially expect an effect on the development of
external genitalia (Steinberger and Odell,
1989). Not all progestin-treated pregnancies
result in fetal masculinization. However,
the rate for high-dose, second-trimester
treatments is probably quite high (Burstein
and Wasserman, 1974; Ishizuka et al., 1962;
Jacobson, 1962). Unfortunately, no good es-
timates exist of the number of individuals
currently living with iatrogenically induced
genital alterations. There is also no pres-
ently reliable way to know whether the
practice of treating threatened miscarriages
with progestins continues with any fre-
quency today, although the data presented
in Table 7 (section on True Hermaphrodites)
suggest that the practice has significantly
declined.
True hermaphrodites and idiopathic mixed
genitalia
There are no published population-wide
estimates of the frequency of true hermaph-
rodites (individuals born with both testicu-
lar and ovarian tissue). However, a number
of surgeons and endocrinologists, who spe-
cialize in the treatment of nonconforming
TABLE 6. Incidence of rare forms of classic CAH published surveys
Location and
subpopulation Type Sample size Method
Frequency/1,000
live births Reference
Switzerland 3-Beta Ohase (classic) 1,516,299 Case 0.0019 Werder et al., 1980
France 3-Beta Ohase (classic) 13,921,803 Case 0.0007 Bois et al., 1985
France 17-alpha-hydroxylase 13,921,803 Case 0.00007 Bois et al., 1985
Kuwait 3-Beta Ohase (classic) 540,000 Case 0.0055 Lubani et al., 1990
Average for 3-Beta 0.00068/1000
FREQUENCY OF INTERSEXUALITY 157
TABLE 7. Comparative numbers of true hermaphrodites and other forms of intersexuality
Year Hypospadias CAH
Gonadal
dysgenesis
(mixed and
pure)
AIS:
complete
and
partial
True
herma-
phrodites
Exo-
genous
Vaginal
agenesis
or
atresia
Penile
agenesis
Cloacal
malforma-
tions
Idio-
pathic
XY:
micro-
penis
Virilizing
adenoma Reference
1960 87 71 47 3 22 Wilkins, 1960
1965 100 116 66 4 18 20 Wilkins, 1965
1967 39 5 7 1 16 Jones and
Wilkins, 1967
1974 28 6 1 Kumar et al.,
1974
1986 19 29 7 1 1 3 11 8 Currarino, 1986
1987 0 24 8 5 6 1 14 Lobe et al., 1987
1987 4 1 2 1 1 Oesterling et al.,
1987
1989 21 10 2 Lorge et al.,
1989
1990 4 6 6 5 2 1 Pinter and
Koxatolanyi,
1990
1991 14 1 7 3 Abdullah et al.,
1991
1991 6 32 10 10 3 4 4 5 Coran and Z.,
1991
1992 6 46 8 4 9 1 2 6 7 Newman et al.,
1992
1992 12 5 7 38 9 Danso and
Nkrumah,
1992
1993 38 23 12 Ramani
et al., 1993
1994 39(total) 4 1 Greenfield
et al., 1994
Total 442 84
% of CAH (all entries) 19% 11%
% of CAH minus rows 7 (possible duplicate) and 13 (African data) 13%
physical sex types, report on the distribu-
tion of patients. Data extracted from 14
such reports are summarized in Table 7. Al-
though different reports come from different
specialties, rendering the referral bias for
any one report great, by analyzing a large
number of such reports and making use of
the fact that the frequency of CAH is well
established, an estimate of the order of mag-
nitude of the occurrence of true hermaphro-
ditism can be obtained.
Particularly striking in Table 7 are the
data of Danso and Nkrumah (1992), who re-
ported 38 true hermaphrodites in a data-
base of 71 patients with ambiguous genita-
lia. Although the reported numbers seem in-
ordinately high, the data are consistent
with other reports suggesting high frequen-
cies of true hermaphroditism in southern
Africa (Krob et al., 1994; Ramsay et al.,
1988). In addition, some forms of true her-
maphroditism are familial (Kuhnle et al.,
1993; Skordis et al., 1987; Slaney et al.,
1998), which opens the possibility that, as
with other inherited forms of sexual ambi-
guity, there may be pockets, perhaps even
large geographical regions, with relatively
high frequencies of true hermaphroditism.
The data in Table 7 were used to estimate
the relative frequency of true hermaphrodit-
ism. First we compared the number of true
hermaphrodites summed from all 14 reports
with the number of cases of CAH (19%).
Then we considered the percentage after
eliminating the report from southern Africa,
as well as the older of two reports which
may contain duplicate data. The latter ratio
is 11% and, splitting the difference, the es-
timate of true hermaphroditism equals 15%
of the frequency of classic 21-OHase CAH.
Using a figure of 0.0779/1,000 live births for
classic CAH, the average frequency of true
hermaphroditism is on the order of 0.0117/
1,000 live births, or one in 100,000.
The data in Table 7 also allow the calcu-
lation of the frequency of idiopathic sexual
ambiguity. Using the same reasoning as for
true hermaphrodites, the birth of a sexually
ambiguous child from unknown causes is
about 0.009/1,000 live births.
Overview
This article began by asking how fre-
quently members of the human population
deviate from a Platonic ideal of sexual di-
morphism. A summary of the frequencies of
known causes of sexual ambiguity based on
Tables 1–7 appears in Table 8. The grand
total is 1.728% of live births. Because there
are no general population-level frequency
estimates for iatrogenic variations in geni-
tal anatomy, penile agenesis, and disorders
of 5-!-reductase biosynthesis and some of
the rarer forms of CAH, the data in Table 8
provide a minimal estimate. However, ex-
cept for certain restricted populations the
frequencies of such events are quite rare
and would probably not greatly influence
the overall estimate. The two most frequent
deviations from complete sexual dimor-
phism arise from nondimorphic sex chromo-
some conditions and from alterations in ste-
roid hormone metabolism. Although this
generalization holds for a generic Euro-
American, Caucasian population, it is inap-
propriate in certain geographical settings.
Thus, there is strong evidence that CAH is
very frequent among native Alaskans and
that true hermaphroditism is surprisingly
common in southern Africa. Because of the
Eurocentric nature of most medical data,
there may well be other large population
groups worldwide which exhibit substantial
frequencies of intersexuality.
TABLE 8. Frequencies of various causes of nondimorphic sexual development
Cause Estimated frequency/100 live births
Non-XX or non-XY (except Turner or Klinefelter) 0.0639
Turner 0.0369
Klinefelter 0.0922
Subtotal for chromosomal difference 0.193
Androgen Insensitivity syndrome 0.00760
Partial Androgen Insensitivity syndrome 0.000760
Classic CAH (omitting very high frequency population) 0.00770
Late-onset CAH 1.5
Subtotal of known hormonal causes 1.516
Vaginal agenesis 0.0169
True hermaphrodites 0.0012
Idiopathic 0.0009
Total 1.728
FREQUENCY OF INTERSEXUALITY 159
Estimates that combine categories
The approach used to estimate intersexu-
ality, at all levels, from the chromosomal
and hormonal to the anatomical, is plagued
by the uncertainties inherent in the medical
literature. Therefore, we derived a second
type of estimate from statistics on the fre-
quencies of cryptorchidism (undescended
testes) and hypospadias (the incomplete clo-
sure around the urethra of the embryonic
genital folds). These estimates serve as an
order of magnitude check of the preceding
calculations. Hypospadias and cryptorchid-
ism both result from a variety of underlying
causes of intersexuality (Aaronson et al.,
1997; Aarskog, 1971; Gearhart et al., 1990;
Gill et al., 1989; Gill and Kogan, 1997; Raj-
fer and Walsh, 1976). A U.S. Army survey in
the 1940s (Rajfer and Walsh, 1976) found
that 0.7% of the adult male population had
cryptorchidism. Scorer and Farrington
(1971) noted that the incidence of cryptor-
chidism is higher at birth and declines
throughout the first year of life to 0.8% of
male births (or roughly 0.4% of all births).
Table 9 contains an overview of the data
for hypospadias. The mean incidence of hy-
pospadias, averaged from over 20 studies
over four decades, is 1.87/1,000 live births,
with a standard deviation of 1.105 and a
range of 0.352–1.043. The data on hypospa-
dias may be further subdivided into the in-
cidence of severe and medium types (ure-
thral opening in the perineal region or along
the shaft of the penis) and minimal types
(urethral opening between the corona and
the tip of the glans penis) (Sweet et al.,
1974). Indeed Fichtner et al. (1995) have re-
cently shown widespread variation in the
meatal opening along the length of the glans
penis. The authors suggested that such
variation, sometimes classified as minimal
or mild hypospadias, is normal and surgery
in such cases unwarranted. It is difficult to
obtain absolute estimates of the rates of
minimal, medium, and severe hypospadias,
because not all publications record the data
in the same manner, and some contain nu-
merical discrepancies. Nevertheless, the ra-
tio of minimal to medium and severe hypo-
spadias is about 3:1. If, as Fichtner et al.
(1995) suggest, only medium and severe hy-
pospadias represent deviations from a di-
morphic ideal, then the incidence calculated
from cases of hypospadias would be 0.5797/
1,000, or 0.05%.
Several studies suggest that the rate of
hypospadias has increased significantly in
TABLE 9. Incidence of hypospadias
Location Date Total sample
Incidence/1,000
live births Reference
Rochester, MN 1954 8,716 3.901 Harris and Steinberg, 1954
Brooklyn 1958 30,398 0.921 Shapiro et al., 1958
International 1966 416,695 0.586 Stevenson et al., 1966
Liverpool, UK 1968 91,176 1.228 Smithells, 1968
US, multiregion 1968 35,680 2.41 Chung and Myrianthopoulos, 1968
South Wales, UK 1972 92,982 1.097 Roberts et al., 1972
Sweden (general) 1973 550,000 0.949 Kallen, 1973
Sweden (Uppsala) 1973 96,733 1.158 Pettersson, 1973
Jerusalem 1973 59,261 3.004 Harlap, 1973
Athens 1973 74,390 1.949 Trichopoulos et al., 1973
Atlanta, GA 1974 137,179 2.012 CDC statistics cited in
(Avellan, 1975)
Jerusalem 1975 11,036 3.625 Harlap, 1973
Sweden 1975 480,607 1.386 Avellan, 1975
Latin American 1981 432,839 0.764 Neto and Paz, 1981
Emilia-Romagna, Italy 1986 42,156 3.985 Calzolari et al., 1986
Denmark 1986 801,241 0.975 Kallen et al., 1986
Hungary 1986 1,992,773 1.827 Kallen et al., 1986
Italy 1986 303,674 1.798 Kallen et al., 1986
Mexico 1986 162,105 0.352 Kallen et al., 1986
South America 1986 902,984 0.693 Kallen et al., 1986
Spain 1986 334,970 1.797 Kallen et al., 1986
Sweden 1986 896,954 2.085 Kallen et al., 1986
Alsace, France 1990 118,265 1.488 Stoll et al., 1990
Atlanta, GA 1993 ? 3.0 Paulozzi et al., 1997
USA 1993 ? 3.8 Paulozzi et al., 1997
Mean 1.87 SD 1.105 Range: 0.352–3.985
160 M. BLACKLESS ET AL.
the past two decades (Paulozzi et al., 1997;
Toppari et al., 1996; Kristensen et al., 1997).
Furthermore, severe hypospadias seems to
have increased at a more rapid rate than
the mild form, and there are both regional
(within the U.S.) and national differences in
overall rates of hypospadias, as well as in
the rate of increase. While the cause of such
increases is currently unknown, such trends
mean that current estimates of the rate of
intersexual births may require revision
with time.
DISCUSSION
Adding the estimates of all known causes
of nondimorphic sexual development sug-
gests that approximately 1.7% of all live
births do not conform to a Platonic ideal of
absolute sex chromosome, gonadal, genital,
and hormonal dimorphism. The incidence of
hypospadias (0.05%) and cryptorchidism
(0.4%), conditions of mixed origin affecting
the apparently male population, are lower
than the present estimate. However, the
calculation includes categories which result
in neither hypospadias nor cryptorchidism.
The single largest contribution to the higher
figure comes from late-onset CAH. If this
cause of nondimorphism is deleted, the fre-
quency estimates obtained from population
surveys would come to 0.228%, the same or-
der of magnitude found after combining the
incidences of severe and medium hypospa-
dias and cryptorchism (0.05 + 0.4 !0.45%).
Alternatively, if mild hypospadias and late-
onset CAH in the final calculations are in-
cluded the combined figure is 2.27% for hy-
pospadias and cryptorchidism, compared
with 1.728% obtained from summing the in-
cidence of all known causes for which avail-
able data exist. These data, obtained using
independent methods, are in general agree-
ment. Which number one chooses to use de-
pends on the specific population under
study, and the assumptions as to what
should count as true dimorphism. It would
appear, however, that earlier estimates that
intersexual births might run as high as 4%
are unwarranted, except in populations in
which a particular genetic condition occurs
wi th hig h freq uenc y (Fau sto- Ster ling ,
1993a,b; Money, 1993).
Recently, a nascent social movement to
recognize intersexuality as a legitimate
state of nature has criticized medical ap-
proaches to the management of intersexual-
ity (Nevada and Chase, 1995; Kessler, 1998)
and these criticisms have begun to appear
in more traditional medical settings (Dia-
mond and Sigmundsen, 1997; Phornphut-
kul et al., 1999). Members of the Intersex
Society of North America oppose the use of
genital surgery to “normalize” children who
are too young to decide for themselves
whether to modify their genital structures.
We define the intersexual as an individual
who deviates from the Platonic ideal of
physical dimorphism at the chromosomal,
genital, gonadal, or hormonal levels. Not all
intersexuals would be candidates for genital
surgery. Lilford and Dear (1987) suggest
that 0.05% (1 in 2,000) newborns have some
ambiguity of the external genitalia, al-
though they cite no medical or scientific lit-
erature to back up their claim. As one might
expect, even given the data in Table 8, esti-
mating the number of children subject to
controversial genital surgery is an uncer-
tain business. Turner and Klinefelter syn-
dromes do not usually call for surgical in-
tervention. However, many, although prob-
ably not all, of the other chromosomal
alterations do, since they often result in in-
termediate genital development (Mittwoch,
1992). All of the hormonal disruptions po-
tentially cause conditions which have been
treated surgically. The highest frequency of
intersexuality comes from late-onset CAH.
When late-onset CAH occurs in childhood or
adolescence and causes significant clitoral
growth, it is quite possible that surgical in-
tervention will ensue (Moreno and Goodwin,
1998). However, there is no way to estimate
what proportion of late-onset CAH patients
fall into this subcategory. Combining chro-
mosomal deviations other than Turner or
Klinefelter, all hormonal alterations, vagi-
nal agenesis, true hermaphrodites, and id-
iopathic genital intersex, produces an esti-
mate that 1.62% of the population may be
subject to genital surgery as a treatment for
intersexuality. Without late-onset CAH in
this calculation, the estimate falls to 0.08%,
or between one and two in a thousand. The
true frequency of such surgeries probably
lies somewhere in between.
Our culture acknowledges the wide vari-
ety of body shapes and sizes characteristic
of males and females. Most sexual dimor-
phisms involve quantitative traits, such as
height, build, and voice timbre, for which
considerable overlap exists between males
and females. Many cultures use dress code,
hair style, and cultural conventions, e.g.,
FREQUENCY OF INTERSEXUALITY 161
Fig. 1. (A) Absolute dimorphism; (B) incomplete dimorphism.
162 M. BLACKLESS ET AL.
the view that in couples the male should be
taller than the female, to accentuate aware-
ness of such difference (see Unger and
Crawford, 1992). But most consider that at
the level of chromosomes, hormones, and
genitals, dimorphism is absolute and, by im-
plication, such traits are discrete rather
than quantitative. Clearly, as a generaliza-
tion, such a viewpoint makes some sense.
However, developmental biology suggests
that a belief in absolute sexual dimorphism
is wrong. Instead, two overlapping bell-
shaped curves can be used to conceptualize
sexual variation across the population (Fig.
1). Within each major bell, genital morphol-
ogy varies quantitatively, as shown, for ex-
ample, by Fichtner et al. (1995). In the re-
gion of overlap, qualitative variation in
chromosomal and genital morphology and
in hormonal activity exists. If the view of
the human population schematically illus-
trated in Figure 1B is accepted, the require-
ment for medical intervention in cases of in-
tersexuality needs to be carefully reexam-
ined. It seems likely that changing cultural
norms concerning sex roles and gender-
related behaviors may encourage a willing-
ness to engage in such a reexamination.
ACKNOWLEDGMENTS
We acknowledge a support grant from the
office of University President Vartan Grego-
rian to Anthony Ch aruvastra, an d the
strong system of undergraduate/faculty col-
laboration supported by the Brown Univer-
sity curricular structure.
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We survey the treatment of sex and gender in the Computer Graphics research literature from an algorithmic fairness perspective. The established practices on the use of gender and sex in our community are scientifically incorrect and constitute a form of algorithmic bias with potential harmful effects. We propose ways of addressing these as technical limitations.
... 452). This view is corroborated by findings on the biological development of sexual markers (Fausto-Sterling 2000 showing how typically feminine and masculine genitalia are just two extremes of a variegated spectrum of possible configurations (see also Blackless et al. 2000) with respect to chromosomal, gonadal, hormonal, and genital sex. ...
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Chapter
Prenatal diagnosis offers the possibility of ascertaining distinct genetic defects through the analysis of fetal cells obtained by amniocentesis. The amniotic fluid is withdrawn in the 16th or 17th gestational week through a transabdominal tap. The fetal cells in the sample are cultivated over 2 weeks and chromosomal preparations (or metabolic tests) are performed using standard methods.
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A national register of congenital malformations covering about 80,000 annual births is described. The registration is intended to serve as an early warning system, should a new teratogen become widely spread in the environment. Such an instrument is very much needed, since existing methods for evaluation of teratogenic effects of exogenous factors–-especially drugs and other chemical substances–give no reliable protection to the human embryo. The essential of the registration procedure is that malformations observed during the newborn period are reported monthly to a malformation register by a verbal diagnosis or description–not by code numbers. The frequency of different malformations is thus kept under continuous control. The method was tested with available Swedish data from the thalidomide period. The results suggest that, had the register been at work at that time, it should have identified an epidemic some 5 months after the appearance of the first thalidomide embryopathies. A special effort has been made to analyze infants with multiple malformations. In only a minority of such cases can the child have been affected by two or more unrelated teratogens.
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We reviewed 283 cases of human true hermaphroditism published from 1980 to 1992. Of the 96 cases described in Africa 96.9% showed a 46,XX karyotype. In Europe 40.5% of 74 cases and 21.0% of the patients in North America had chromosomal mosaicism. The 46,XY karyotype is extremely rare (7%) and equally distributed through Asia, Europe and North America. Of 283 cases 87 were of black or black mixed origin with a 46,XX chromosomal constellation. The most common gonad in patients with true hermaphroditism, an ovotestis, was found in 44.4% of 568 gonads. Gonads with testicular tissue were more frequent on the right side of the body, while pure ovarian tissue was more common on the left. Histologically the testicular tissue was described to be immature and only twice was spermatogenesis reported while the ovarian portion often appeared normal. This coincides with 21 pregnancies reported in ten true hermaphrodites while only one true hermaphrodite apparently has fathered a child. Of the patients 4.6% were reported to have gonadal tumours. Position and type of the genital ducts, frequency of clinical findings such as genital abnormalities and gynaecomastia, correlations between assigned sex and karyotype as well as the age at diagnosis are reported.