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Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75235-8857
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Abstract |
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 Top Abstract I. IntroductionII. Sexual Behavior of...III. Control of Libido...IV. Gender Identity/Role...V. Gender Role Behavior...VI. DiscussionVII. ConclusionsReferences |
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-reductase 2 deficiency -reductase 2 deficiencies |
I. Introduction |
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TopAbstractI. IntroductionII. Sexual Behavior of...III. Control of Libido...IV. Gender Identity/Role...V. Gender Role Behavior...VI. DiscussionVII. ConclusionsReferences |
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In humans gonadal steroids are responsible for phenotypic sexual differentiation, sexual maturation, and development of libido and potentia. Human sexual behavior also involves gender identity, the perception of oneself as male or female, and gender role behavior (also termed social sex or social identity), the various processes by which gender identity is communicated to others. Gender identity cannot be assessed in animals, and gender role behavior in animals can be difficult to separate from sexual orientation. Whether gonadal steroids are involved in the development of human gender identity and role behavior is difficult to examine. These two aspects of behavior are normally in accord, but most studies on this subject focus on gender role behavior because the change of legal registration of sex from one gender to another is unambiguous, whereas gender identity can be a graded character and difficult to quantify. It is obviously not possible to devise definitive experiments to examine the role of hormones in human behavior but, on the basis of studies of subjects with a variety of forms of human intersex and/or endocrine abnormalities, it has been the predominant view that human behavior is more complex than that of other species and that human gender identity and gender role behavior are determined primarily, if not exclusively, by psychological and social forces (reviewed in Ref. 2 ). According to this anthropocentric view, the human species has been emancipated from biological controls so that the hormones that mediate this aspect of sexual behavior in animals do not play a significant role in controlling human behavior (3 ). As summarized by Herdt (4 ),"the sex of rearing outweighs the biological sex in the development of gender identity and social identity."
This belief that hormones do not play a significant role in controlling human gender role behavior persists despite a large body of evidence to the contrary, indicating that androgens play an important role in human male gender identity/behavior. This evidence stems largely from the work of Imperato-McGinley and her colleagues (5 6 ), who documented that genetic males with either of two autosomal recessive mutations that impair androgen synthesis or androgen metabolism during embryogenesis, and hence cause formation of female external genitalia and female sex of rearing in genetic males, may change gender role behavior to male at or after the time of expected puberty. The fact that single gene mutations can be associated with change in gender role behavior raises fundamental questions about the factors that regulate human sexual behavior.
The molecular biology of these two autosomal recessive disorders has
been explored in some detail. The cDNAs and genes that encode the two
critical enzymes involved, 17ß-hydroxysteroid dehydrogenase 3 and
steroid 5-reductase 2, have been cloned, and a great deal has been
learned about the underlying pathophysiology. This review is designed
to consider some of the implications of these studies for understanding
human behavior.
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II. Sexual Behavior of Animals |
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TopAbstractI. IntroductionII. Sexual Behavior of...III. Control of Libido...IV. Gender Identity/Role...V. Gender Role Behavior...VI. DiscussionVII. ConclusionsReferences |
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1. Sexually dimorphic behaviors of a variety of types are regulated by gonadal steroids, including the songs and mating behaviors of birds, copulatory patterns in mammals, and complex forms of ritual behavior such as musth in elephants and male dominance in mice. By way of illustration, male and female rodents differ in the types of sexual postures they assume during coitus; these behaviors can be changed to those of the other sex by appropriate hormonal manipulation.
2. Androgens and estrogens are formed in both males and females, and both hormones may play a role in the physiology of both sexes. However, androgens (and androgen metabolites including estrogens in some species) are the primary determinants of male sexual behavior (13 ).
3. Gonadal steroids act in the central nervous system by the same receptor mechanisms that operate in peripheral tissues. Intracellular receptors for these hormones are expressed within specific regions of the brain (14 15 ), and gonadal steroids may also exert central nervous system effects by other mechanisms such as by influencing ion channels in cell membranes (16 17 18 ).
4. The behavioral effects of steroid hormones are due to interactions between peripheral and central actions of the hormones (2 ). One of the best studied paradigms of sexual behavior in the mammal is the mounting reflex of the female rat. Mounting of a female rat in estrus by a male causes the female to extend the hind legs and elevate the rump, thus dorsiflexing the vertebral column. These actions require sensory input from the rump and involve a well defined neural reflex that includes motor and sensory components and steroid-mediated effects in the central nervous system. While there is no doubt that the central nervous system plays a vital role in the hormonal control of sexual behavior, different behaviors may be influenced to different degrees by central and peripheral actions of the hormones. Even under defined laboratory conditions, it may be difficult to quantify the relative contribution of each to a given action (2 ).
5. In the rodent the surge of testosterone secretion during the neonatal period appears to play a vital role in virilizing hypothalamic function, e.g., in imprinting a tonic pattern of gonadotropin release in contrast to the cyclical secretory pattern in females. (Again, this action may be mediated by estrogenic metabolites of testosterone in the central nervous system.) Whether the neonatal increase in testosterone levels in the human male infant is of physiological significance is not known, but blocking the neonatal surge delays the onset of puberty in male monkeys (19 ).
6. Phoenix and colleagues (20 ) delineated two types of behavioral effects of steroid hormones. Organizational effects are exerted by hormones at a specific time in development; they appear to have permanent effects on function or behavior, effects that persist after the steroid is no longer present. Such organizational effects may be accompanied by changes in anatomical development of the brain (21 ). Activating effects require the continued presence of the steroid for full manifestation of the effects (20 ), e.g., the mounting response of the female rat during estrus. Although the delineation of these two types of behavioral effects is of conceptual importance, there is considerable overlap between them. Organizational effects may be silent in the absence of the proper hormonal signals, and concurrent phenomena such as male copulatory behavior may persist for variable periods after castration. Furthermore, different animal species differ in the extent to which hormones exert permanent organizational effects. In particular, organizational effects appear to be less clear cut in primates than in rodents (22 ); for example, the administration of estrogens in appropriate amounts to male rhesus monkeys of any age elicits a positive release of LH, analogous to the ovulatory surge of LH release in females (7 ).
7. Even when hormones are involved in specific aspects of behavior, stereotyping can also play a critical role. For example, development of the characteristic male song pattern in bird species such as the zebra finch and canary require both the action of androgen in the central nervous system and exposure of the immature male to a mature male of the same species. Otherwise, the male will sing a garbled song instead of learning a song that will attract a female of the same species (23 ). This androgen action is mediated by estrogenic metabolites formed in the brain (24 ).
In summary, the role of gonadal steroids in sexual behavior in animals involves, at a minimum, sexual dimorphism of the genital tracts, direct effects on the central nervous system, sensory and motor aspects of neurosensory reflexes, and, probably, integration of the various neural subsystems that control the behavioral process.
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III. Control of Libido and Potentia in Humans |
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TopAbstractI. IntroductionII. Sexual Behavior of...III. Control of Libido...IV. Gender Identity/Role...V. Gender Role Behavior...VI. DiscussionVII. ConclusionsReferences |
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In contrast, removal of ovarian secretions by ovariectomy or via the natural menopause does not have a consistent effect on sexual activity in women (2 ). The common interpretation is that once sexual patterns are fixed in women, sexual drive is hormone independent. This interpretation may not be correct because removal of the ovaries does not impair formation of adrenal androgens. Adrenalectomy (34 ) or hypophysectomy (35 ) in previously castrated women is reported to decrease sexual desire. Consequently, it is possible that the sexual life of women is as hormone-dependent as that of men. Adrenal androgen (which would be ablated by hypophysectomy or adrenalectomy) could have a direct effect on sexual desire in women or could act as a prohormone for the synthesis in extraglandular tissues of other steroid hormones (36 ) that could maintain sexual drive in the absence of ovarian hormones. Whether hormones are involved in the genesis of normal sexual drive at female puberty is also unclear.
A similar uncertainty exists as to whether adrenal steroids can affect male sexual behavior. Occasional castrate males of all species sustain a capacity and drive for intercourse for long periods (2 26 ). In the castrated human male, considerable estrogen and small amounts of testosterone are formed in extraglandular tissues from adrenal androgens (37 ), and in some animal species estradiol enhances the effect of androgen on male sexual drive (38 ). Thus, the small amounts of testosterone and/or estrogen formed from adrenal androgens may be enough to sustain libido and potentia in some adult male castrates. In other words, libido and potentia would be preserved in those castrated men able to produce sufficient active hormones by this mechanism.
In summary, gonadal steroids play an important role in the sexual drive of males of all species and in controlling the sexual drive of female animals and possibly of women. Organizational effects do not appear to play as important a role in the control of gonadotropin secretion by gonadal steroids in the primate as in lower animals. In brief, although there may be slight differences, the control of libido and potentia appears to be similar in humans and animals.
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IV. Gender Identity/Role Behavior in the Human |
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TopAbstractI. IntroductionII. Sexual Behavior of...III. Control of Libido...IV. Gender Identity/Role...V. Gender Role Behavior...VI. DiscussionVII. ConclusionsReferences |
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A. Normal and abnormal sexual development
The embryos of both sexes develop in an identical fashion until
the seventh week of gestation. Thereafter, the anatomic and
physiological development in the two sexes diverge. As formulated by
Jost (39 ), normal sexual development in the mammal depends on three
sequential processes. The first involves the establishment of genetic
sex at the time of conception, the heterogametic sex (XY) being male
and the homogametic sex (XX) female. In the second phase information
encoded on the sex chromosomes causes the establishment of gonadal sex
in which the indifferent gonad develops into either an ovary or a
testis. The final stage involves the translation of gonadal sex into
phenotypic sex. In the presence of an ovary or in the absence of a
functional gonad, the development of phenotypic sex proceeds along
female lines. Masculinization of the urogenital tract and the external
genitalia, in contrast, requires the actions of three hormones,
antimullerian hormone, testosterone, and dihydrotestosterone, the
5-reduced metabolite of testosterone. The formation of antimullerian
hormone in the fetal testis is essential for suppression of the
mullerian ducts and hence for prevention of development of the uterus
and fallopian tubes in the male. Testosterone, which is synthesized
primarily in the testes and circulates in the plasma, converts the
wolffian ducts into the epididymis, vasa deferentia, and seminal
vesicles, and dihydrotestosterone, which is formed predominately in the
target cells themselves, induces the formation of the male urethra and
prostate and the male external genitalia (Fig. 1
).
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First, the phenotypic manifestations of the various abnormalities differ markedly. For example, men with 47,XXY Klinefelter syndrome or with the 46,XX male syndrome develop as men (albeit infertile) and have endocrine abnormalities only in later life. Likewise, women with 45,X gonadal dysgenesis or with 46,XX or 46,XY pure gonadal dysgenesis have a female phenotype, and most subjects with true hermaphroditism have unequivocal male or female phenotypes. Thus, many if not most individuals with abnormalities of sexual development end up with unambiguous male or female anatomical development; this is the consequence either of the fact that the formation of testicular hormones was sufficient to induce a male phenotype or that the failure of formation/action of testicular hormones was complete enough to result in formation of a female phenotype. Since sex assignment and the sex of rearing are determined by anatomical development, any direct hormonal effects on behavior in most individuals with abnormal sexual development would not be apparent because they would correspond to anatomical development and hence to gender assignment and sex of rearing.
Second, disorders that appear phenotypically similar can result from
different mechanisms. For example, men with 45,X/46,XY mixed gonadal
dysgenesis can have phenotypes similar to those of men with steroid
5-reductase 2 deficiency or with mutations of the androgen receptor.
Since these disorders have distinct pathophysiologies, it is essential
that diagnoses be unequivocally established before attempting to draw
interpretations as to the behavioral consequences of any given
abnormality.
Third, ambiguity of genital development occurs in relatively few disorders of human intersex and is due to one of three mechanisms: 1) The testes do not produce sufficient hormones to virilize the male embryo—either because of developmental abnormality of the testes or because of a defect in one of the enzymes required for testosterone biosynthesis; 2) Sufficient testosterone is synthesized by the testes, but due to impairment of androgen action (usually a defect in the androgen receptor) the hormone cannot virilize the embryo normally; or 3) Overproduction of androgen occurs in the female embryo, as in congenital adrenal hyperplasia due to deficiency of the steroid 21-hydroxylase enzyme. In these disorders gender assignment usually corresponds to the predominant or apparent anatomy. If hormones are involved directly or indirectly in development of gender identity, one would predict that gender identity/behavior would be more likely to be discordant or uncertain in subjects with ambiguous genitalia. Nevertheless, all abnormalities that cause ambiguous genitalia vary in severity among affected individuals and can cause variable phenotypes. For example, the external phenotypes of males with abnormalities of the androgen receptor and of females with steroid 21-hydroxylase deficiency can span the entire spectrum from male to ambiguous to female. One would not expect abnormalities of gender identity in those individuals with normal or near-normal genital development.
Fourth, even when the degree of ambiguity of the external genitalia is
similar, disorders can have different times of onset and different
long-term endocrine consequences. For example, disorders of androgen
synthesis and/or action influence embryonic development beginning at
about week 8 of gestation, whereas virilization in females with steroid
21-hydroxylase deficiency does not commence until somewhat later in
gestation. Furthermore, as the result of compensatory mechanisms, adult
males with 17ß-hydroxysteroid dehydrogenase 3 deficiency, mixed
gonadal dysgenesis, or 5-reductase 2 deficiency may have the
endocrine profiles of normal (or near normal) adult men despite having
profound defects in androgen action during embryogenesis. In contrast,
the endocrine defects in the Klinefelter syndrome and in the 46,XX male
become progressively more severe with age. Any behavioral consequences
of disorders of sexual development would depend on when in development
gonadal steroids exert an effect on the behavior in question.
In summary, abnormalities of sexual development differ in their effects on the sexual phenotypes, their effects on hormone levels at various times of life, the times during life when they become manifest, and the ultimate metabolic consequences. Any interpretation as to possible behavioral consequences of a specific disorder must take these various factors into account. Furthermore, since different abnormalities vary in the severity of their effects on the sexual phenotypes and on endocrine function, some disorders would not be predicted to influence behavior even if hormones are normally involved in controlling the behavior in question. For these reasons, it is necessary to be cautious in interpreting negative results.
B. Behavioral studies in subjects with abnormal sexual
development
While different forms of abnormal sexual development have been
lumped together in some reports, sufficient numbers of individuals with
specific diagnoses have been studied to allow a few generalizations:
1. Exposure of females to excess androgens as a result of congenital adrenal hyperplasia causes a variable degree of virilization of the external genitalia. Gender identity in such individuals is usually female even in virilized women and despite the fact that behavioral changes, such as tomboyish behavior and characteristic male energy expenditure, have been described in some studies (40 41 42 43 44 45 46 47 ). [Occasional women with congenital adrenal hyperplasia have male gender role behavior, but this usually occurs in severely virilized women in whom diagnosis and surgical correction of the external genitalia are delayed beyond infancy or in whom glucocorticoid therapy is inadequate (48 49 ).]
2. Children exposed to exogenous estrogens or progestogens during gestation have appropriate male or female phenotypes; in general, such agents have only minor effects on sexually dimorphic behavior and do not influence gender role behavior/identity (50 51 52 53 54 55 56 ).
3. True hermaphrodites have both testes and ovaries (or ovotestes) and may have male, female, or ambiguous phenotypes. In such individuals, gender role behavior usually corresponds to the sex of rearing, although many of them have anomalous secondary sexual characteristics (57 ).
4. Women with gonadal dysgenesis have female phenotypes and female gender identity/gender role behavior (58 ). Since such women are profoundly estrogen deficient, it has been inferred that ovarian estrogen plays at best a minor role in the evolution of female gender identity.
5. Men with the Klinefelter syndrome form sufficient androgen during embryogenesis to induce formation of a male phenotype but usually have diminished androgen production and enhanced estrogen production after puberty. Nevertheless, most men with Kleinfelter syndrome have male gender role behavior, suggesting that these hormones play no continuing role in gender identity/behavior at or after the time of expected puberty (59 ).
6. 46,XY women with profound androgen resistance due to mutations of the androgen receptor develop a female phenotype and unambiguous female behavior (see below) (60 61 62 ).
The common thread in these various studies involving many types of subjects and many different socioeconomic groups is that gender identity and gender role behavior usually develop in conformity with the sex assignment and the sex of rearing (62 63 ). In other words, gender identity and role behavior correspond with the predominant anatomical development and hence with the prenatal hormonal milieu. This conformity can withstand perturbations that include contradictory patterns in which girls virilize or boys feminize during adolescence, tomboyish energy expenditure in girls, and incomplete development of the secondary sexual characteristics at puberty. Despite the inherent weaknesses in design in all such studies and despite the fact that none of the disorders constitutes a perfect experiment, the consistency of the findings in such studies is impressive.
The problem is that the findings are open to diametrically opposite interpretations. The predominant view—most eloquently formulated by Money (63 ) and Lev-Ran (64 )—is that sex assignment at birth influences parental attitudes and the manner in which infants are treated from the time of birth, and that these social factors are paramount in determining human gender identity and gender role behavior, so powerful as to be irreversible after early infancy. According to this view, any effects of hormones in influencing gender identity in the human are secondary and probably minor. A diametrically opposite interpretation is possible. Testicular hormones could be important determinants of gender identity/behavior, but since they also control development of the external genitalia (and hence determine sex assignment and the sex of rearing) gender identity and anatomical sex would almost invariably be the same in these various patient groups. In such a view, it is difficult or virtually impossible in most studies of subjects with disorders of intersex to ascertain the extent to which psychological/social and endocrine determinants contribute to this development because the psychological/social forces almost always correspond with the anatomical and endocrine factors.
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V. Gender Role Behavior in Individuals with Male Pseudohermaphroditism |
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TopAbstractI. IntroductionII. Sexual Behavior of...III. Control of Libido...IV. Gender Identity/Role...V. Gender Role Behavior...VI. DiscussionVII. ConclusionsReferences |
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However, ambiguity of the genitalia cannot be the sole cause of changes in gender role behavior as illustrated by the case described by Stoller (70 ). This individual was thought to be a normal female at birth and was raised as a girl but exhibited tomboyish behavior from early childhood that became more and more masculine with time. She was an average student, but as adolescence ensued she became more and more withdrawn. Because of coarsening of the voice she was evaluated and found to be a genetic male with female external genitalia (including an apparently normal clitoris) but with testes in the labia majora. After psychiatric evaluation at age 14 she was told that she was a genetic male [the diagnosis was subsequently established to be 17ß-hydroxysteroid dehydrogenase 3 deficiency (5 )]. She promptly changed to male clothing and began to act, behave, and assume the role of a male. The parents decided to move to a new community; the boy’s grades improved, and he participated in men’s sports in high school, obtained a university degree in mathematics, and after urological surgery married. This individual has been studied by several different groups over the years and apparently is a successful and well adjusted man.
The fact that a single gene mutation could be associated with a
reversal of gender role behavior has far reaching implications for
understanding gender behavior, and in the ensuing years it has been
established that female-to-male reversal of gender role behavior
appears to be a common feature of two autosomal recessive forms of male
pseudohermaphroditism—5-reductase 2 deficiency (6 71 ) and
17ß-hydroxysteroid dehydrogenase 3 deficiency (5 72 73 ) (Fig. 1
). A
similar change in gender role behavior has been described in genetic
males with 3ß-hydroxysteroid dehydrogenase deficiency (74 ), an even
rarer autosomal recessive form of male pseudohermaphroditism, and in a
few individuals with mixed gonadal dysgenesis (65 ). This review focuses
on the two more common disorders, and we will compare the consequences
of mutations in these two enzymes with those of mutations of the
androgen receptor on gender role behavior.
A. 17ß-Hydroxysteroid dehydrogenase 3 deficiency
The 17ß-hydroxysteroid dehydrogenase reaction is the terminal
step in the synthesis of testosterone in the Leydig cell and of
estradiol in the granulosa cell, and the rate of the back reaction in
extraglandular tissues plays a major role in determining the steady
state levels of these steroids in tissues (Fig. 2). Isoenzymes that perform these
reactions are encoded by at least five genes (75 ) (Table 1), and mutations of the type 3 isoenzyme
(76 ) are responsible for a rare, autosomal recessive form of male
pseudohermaphroditism originally described by Saez and colleagues in
1971 (77 ). The typical features of this disorder are summarized in
Table 2. In brief, affected 46,XY infants
have female external genitalia, despite the presence of testes and male
wolffian structures; they are usually assigned a female gender at birth
and raised as females. They usually come to medical attention because
of virilization at puberty or because of failure to menstruate. On
endocrine evaluation they have low testosterone levels (for men),
normal ratios of plasma testosterone to dihydrotestosterone, and
variable estrogen levels. The diagnosis is made by finding
androstenedione levels that are usually 10 times normal [Stoller’s
patient had typical endocrine features for this disorder (5 ).]
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This disorder is rare and believed to be even less common than
5-reductase 2 deficiency. Andersson and colleagues (76 78 79 ) have
identified 16 different mutations in affected subjects that cause 12
different amino acid substitutions, 3 splice junction abnormalities,
and 1 small deletion that causes a frame shift. The latter types of
mutations are believed to preclude the formation of functional enzyme,
but the missense mutations impair enzyme function to variable degrees
(78 79 ).
In addition to the Stoller patient, several individuals identified and raised as females have undergone a changed gender role behavior from female to male at the time of expected puberty (72 73 76 80 ). In some case reports affected individuals were too young to assess gender identity, and a few affected subjects have been raised from the beginning as male. However, in a number of families, affected adult individuals have female sexual identity/role behavior (75 78 ). If one excludes case reports in infants and small children, gender role reversal appears to occur in about half of affected males. Because change in gender role behavior is so common in this disorder, careful psychiatric evaluation must be obtained before any corrective surgery is undertaken. Although it is not certain why this behavioral change occurs only in some patients, this difference is not due to variations in the severity of the mutation. Changes in gender role behavior have occurred in one individual who is believed to make no functional isoenzyme 3 as a result of a splice junction defect (72 76 ) and in the Arab family from Gaza who make a kinetically abnormal enzyme that nevertheless can function partially (73 76 ). While affected males from the Gaza family usually change gender role behavior from female to male, it is interesting that two Brazilian sisters with the identical mutation (R80Q homozygotes) have female gender role behavior (76 ). Furthermore, in at least one family with another mutation (A203V), one affected individual changed gender role behavior to male whereas the other is a married female (76 ).
B. Steroid 5-reductase 2 deficiency
The conversion of testosterone to dihydrotestosterone (Fig. 3) changes a weak hormone to a more
potent hormone and is essential for many androgen actions (reviewed in
Ref. 81 ). This reaction is irreversible and is mediated by two enzymes
that are encoded by separate genes (Table 3). Enzyme 2 is the principal enzyme in
the male urogenital tract and plays a critical role in the virilization
of the external genitalia and urogenital sinus during embryogenesis.
Enzyme 1, which after puberty is expressed in many tissues, may play a
role in androgen metabolism in sebaceous glands and in the central
nervous system.
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-Reductase deficiency causes an autosomal recessive form of male
pseudohermaphroditism in which the phenotype resembles that in
17ß-hydroxysteroid dehydrogenase 3 deficiency. Namely, virilization
of the external genitalia is impaired, and affected males are usually
assigned a female gender at birth and raised as females (the mutation
appears to be silent in women) (Table 4).
When the cDNAs for these genes were cloned, it was found as expected
that the mutations involve the gene for enzyme 2 (reviewed in Ref. 81 ),
and 45 different mutations have been described to date, including 35
different missense mutations, 3 premature stop codons, 3 small
deletions and 1 deletion of the entire coding sequence, 1 small
insertion, and a change from a stop codon to a missense code (82 83 ).
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Imperato-McGinley et al. (6 ) reported that 18 of 19 affected
individuals from one family with 5-reductase deficiency in the
Dominican Republic were initially raised as females but subsequently
changed gender role behavior to male at the time of expected puberty. A
similar phenomenon has been described in other parts of the world:
about two-thirds of individuals raised as females change to male gender
role after the time of expected puberty (82 ). In one study of 16
patients from 10 families studied by the same psychologist, 3
individuals retained a female gender role, 12 changed to male gender
role, and one was raised as a male (85 ), and in a study of 10 affected
individuals from 8 families studied in another unit, 6 changed gender
role behavior to male, 3 have female gender role behavior, and 1 was
raised as a male (86 87 ). Thus, reversal of gender role behavior may
be even more common in this disorder than in 17ß-hydroxysteroid
dehydrogenase 3 deficiency. As in 17ß-hydroxysteroid dehydrogenase
deficiency, however, change in gender role behavior is not a simple
function of the severity of the mutation, since the phenomenon occurs
with mutations that partially impair the kinetics of the 5-reductase
and in at least one family with a splice junction abnormality that is
thought to prevent formation of functional enzyme (82 ). Furthermore,
families have been reported in which some, but not all, affected
individuals undergo the change in social sex (85 88 ).
It is of interest that the earliest description of gender role reversal
and possibly of 5-reductase deficiency appears to be Herculine
Barbin, a French woman who lived during the 19th century and who is
believed to be the first person to have changed legal sex from one
gender to the other; her phenotype, including evidence from autopsy, is
compatible with the diagnosis (89 90 ).
It should be emphasized that no prospective studies have been done in either of these disorders so that it is not possible to be certain that gender identity before expected puberty was ever unambiguously female. Indeed, several such persons have stated in retrospect that they had been aware of uncertainties as to their correct gender from a very early age (91 ); consequently, one cannot be certain that this is a change in gender identity as contrasted to a resolution of a confused gender identity—only that gender role behavior changes from that of the sex of rearing to that of the genetic, gonadal, and endocrine sex of the individual. This change could either be the result of a change in gender identity or the resolution of an uncertain gender identity as virilization progresses at the time of expected puberty.
C. Features common to 17ß-hydroxysteroid dehydrogenase 3 and
steroid 5-reductase 2 deficiencies
5-Reductase 2 deficiency and 17ß-hydroxysteroid dehydrogenase
3 deficiency share several common features (Table 5): 1) In both, 46,XY males are given
gender assignments at birth; in this sense, gender role change, when it
occurs, is a correction of a incorrectly assigned gender. 2) In both
disorders the impairment of virilization during embryogenesis is
limited to the external genitalia; the internal urogenital tract
(testes, epididymis, vas deferens, seminal vesicle, and ejaculatory
ducts) is male in character, and the testes usually descend into the
inguinal canals or labia majora. 3) In both disorders considerable
virilization takes place at the time of expected puberty, particularly
the growth of a phallus capable of erection; indeed, penile erections
are the rule. 4) In both disorders an alternate pathway exists;
testosterone can be formed by an alternate pathway in
17ß-hydroxysteroid dehydrogenase 3 deficiency, and
dihydrotestosterone can be formed by enzyme 1 in 5-reductase 2
deficiency. Consequently, in the postpubertal steady state in both
conditions, testosterone and dihydrotestosterone levels can be in the
normal or near-normal male range, causing affected individuals to
undergo considerable virilization. 5) Change in gender role
behavior in the two disorders at expected puberty is common but not
universal; the reason for this inconsistency is not readily apparent
and cannot be explained in any straightforward way by variations in the
severity of the mutations themselves. Whether this inconsistency might
be explained by variability in the completeness of compensation by the
alternate pathways in the two disorders is unknown.
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) can cause a phenotype that is similar to those caused
by the two enzyme deficiencies (Table 6),
gender role behavior in these subjects almost invariably corresponds to
the gender assignment at birth (83 ): if the impairment of receptor
function is severe enough at birth to cause the syndrome of complete
testicular feminization and a female sex assignment, such individuals
not only maintain the female sex assignment as adults but rank high in
feminine traits as defined by psychological criteria (60 61 ). Rare
women with the syndrome of incomplete testicular feminization (whose
mutated androgen receptors have partial residual function and who
virilize to a variable degree at puberty) have been described in whom
gender identity was male despite being reared as female (92 93 ); the
significance of this phenomenon is not clear. Many men with partial
androgen resistance and even less severe impairment of receptor
function virilize sufficiently during embryogenesis to result in a male
sex assignment at birth and characteristically have unequivocal male
gender role behavior as adults (83 ).
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) (37 ), the role of androgens in
gender role behavior cannot involve the conversion of androgens to
estrogens, as appears to be the case in some animal species (17 23 24 ). This conclusion is supported by the fact that a man with a
mutation that impaired function of the estrogen receptor (94 ) and two
men with profound aromatase deficiency (95 96 ) have been reported to
have male gender identity.
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VI. Discussion |
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TopAbstractI. IntroductionII. Sexual Behavior of...III. Control of Libido...IV. Gender Identity/Role...V. Gender Role Behavior...VI. DiscussionVII. ConclusionsReferences |
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This is not to say that there are not formidable unresolved aspects of
this problem. For example, it is not known whether this action of
androgen takes place during embryogenesis, during infancy, or at the
time of expected puberty, the phases of male life associated with high
levels of plasma testosterone (Fig. 4).
As stated above, several such individuals have reported that they were
conscious of gender conflicts from early infancy (91 ), implying that
the effect is either prenatal or occurred during the neonatal period.
Virilization at the time of expected puberty may influence this process
but is probably not critical because in some individuals [such as
Stoller’s patient (70 )], there is no evidence of genital ambiguity
when the change in gender role behavior occurred. Likewise, in animal
studies effects of androgens on behavior can sometimes be identified in
the absence of virilization of the urogenital tract (10 ). It is also
unclear whether the effect of androgen on gender behavior is mediated
at the level of the central nervous system, the urogenital tract, or
both; nor is it intuitively clear how to investigate this issue in
humans. Finally, it is not known whether this androgen action is
mediated by testosterone or by dihydrotestosterone; insight into the
latter question may be possible with the availability of potent
inhibitors of both isoenzymes or double-knockout animals in which both
5-reductase isoenzymes are missing. These model systems may make it
possible to investigate the effects of testosterone and
dihydrotestosterone independently.
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VII. Conclusions |
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TopAbstractI. IntroductionII. Sexual Behavior of...III. Control of Libido...IV. Gender Identity/Role...V. Gender Role Behavior...VI. DiscussionVII. ConclusionsReferences |
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-reductase and 17ß-hydroxysteroid
dehydrogenase enzymes do not undergo a change in gender role behavior
means that other factors–social, psychological, or biological–are of
equal or greater importance in modulating human sexual behavior.
Indeed, the sex of rearing may be more important in this regard than
the endocrine milieu under ordinary circumstances, and it may not be a
coincidence that many (although not all) of the instances of reversal
of gender role behavior in these two disorders have occurred in
countries and/or ethnic groups in which men play a dominant role; in
this situation, endocrine factors may be more important determinants of
behavior than would be the case in more egalitarian societies. Endocrine and psychological factors must interact to influence these behaviors. Perhaps the most appropriate animal model for this aspect of human behavior is the song bird in which androgen action in the central nervous system and a pattern of behavior learned from a male of the same species are both necessary to learn a song that will attract a female of the same species (23 ). It may never be possible to assign quantitative importance to the roles of the two processes in human behavior, but it may be possible to determine how, where, and when in development androgen plays its role in this process.
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TopAbstractI. IntroductionII. Sexual Behavior of...III. Control of Libido...IV. Gender Identity/Role...V. Gender Role Behavior...VI. DiscussionVII. ConclusionsReferences |
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-reductase deficiency. N Engl
J Med 300:1233–1237[Abstract]
-reductase deficiency and
three patients with the complete form of testicular feminization.
J Clin Endocrinol Metab 49:861–865-reductase:
two genes/two enzymes. Annu Rev Biochem 63:25–61[Medline]
-reductase 2 deficiency. Endocr Rev 14:577–593-reductase 2 deficiency,
testicular feminization, and related disorders. In: Scriver CR, Beaudet
AL, Sly WS, Valle D, Vogelstein B, Childs B (eds) The Metabolic and
Molecular Basis of Inherited Disease, ed 8. McGraw-Hill, New York, in
press
-reductase isozyme expression. J Clin Invest 92:903–910
-reductase 2 deficiency: diagnosis, psychological evaluation, and
management. Medicine 75:64–76[CrossRef][Medline]
-reductase deficiency: variation in gender identity in seven
Mexican patients from five different pedigrees. J Endocrinol Invest 18:205–213[Medline]
-reductase type 2 gene in eight Mexican
patients from six different pedigrees with 5-reductase-2 deficiency.
Clin Endocrinol (Oxf) 46:155–160[CrossRef][Medline]
reductase-2 deficiency.
Psychoneuroendocrinology 21:651–657[CrossRef][Medline]
-reductase deficiency and disorders of the androgen receptor.
J Clin Invest 74:1496–1508
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