Endocrinology Vol. 142, No. 8 3281-3287
Copyright © 2001 by The Endocrine Society
Minireview: Sex Differentiation
Ieuan A. Hughes
Department of Paediatrics, University of Cambridge, Addenbrooke’s
Hospital, Cambridge CB2 2QQ, United Kingdom
Address all correspondence and requests for reprints to: Ieuan A. Hughes, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Department of Pediatrics, Hills Road, Box 116, Cambridge CB2 2QQ, United Kingdom. E-mail: iah1000{at}cam.ac.uk
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Abstract
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Mammalian sex differentiation is a hormone-dependent process in the
male following the determination of a testis from the indifferent gonad
through a cascade of genetic events. Female sex differentiation is not
dependent on ovarian hormones, yet there is evidence that members of
the Wnt family of developmental signaling molecules play a role in
Müllerian duct development and in suppressing Leydig cell
differentiation in the ovary. The testis induces male sex
differentiation (including testis descent) through a time-dependent
production of optimal concentrations of anti-Müllerian hormone,
insulin-like factor(s) and androgens. Observations in several human
syndromes of disordered fetal sex development corroborate findings in
murine embryo studies, although there are exceptions in some gene
knockout models. The ubiquitously expressed AR interacts in a
ligand-dependent manner with coregulators to control the expression of
androgen-responsive genes. Preliminary studies suggest the
possibility of hormone resistance syndromes associated with coregulator
dysfunction. Polymorphic variants in genes controlling androgen
synthesis and action may modulate androgenic effects on sex
differentiation.
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Introduction
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SEX DIFFERENTIATION is defined as the
phenotypic development of structures consequent upon the action of
hormones produced following gonadal determination. In reality in
mammals, sex differentiation is gonad-dependent only in males because
in XX females, phenotypic development is female whether an ovary
develops or not. Hence, male development can only occur when the fetal
testis secretes two key hormones at a critical period in early
gestation, an embryological phenomenon clarified 50 yr ago by the
studies of Jost (1, 2). Sex determination is defined as
the commitment of the indifferent gonad to a testis or an ovary, a
development that is genetically programmed in a critically timed and
gene dosage-dependent manner. Much about what is known of this process
has been obtained from studies in early mouse embryos and observations
from gene knockout experiments. Similar information in humans has
mainly been obtained through studies of patients with sex reversal
syndromes, particularly in 46,XY complete and partial females (3, 4). The focus of this review is on the mechanisms that control
androgen production and action in mediating differentiation of the
internal and external genitalia in the male. Nevertheless, it is
necessary to briefly review the embryology of fetal sex development and
the genetics of sex determination.
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Embryology
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The temporal events in fetal sex development are shown
schematically in Fig. 1
. Primordial
germ cells migrate from the yolk sac to the urogenital ridge, which
develops as a thickening on the ventral surface of the primitive
mesonephros. This tortuous cell migration is impaired in mice with the
Steel mutation, rendering them sterile but appropriately sex
differentiated (5, 6). Thus, germ cells play no part in
sex determination. The first sign of testis determination is
aggregation of pre-Sertoli cells (probably derived from the adjacent
mesonephros) around the germ cells to form primary sex cords at about
6–7 wk of gestation. By the end of wk 9, the mesenchyme that separates
the seminiferous cords gives rise to the interstitial cells, which
differentiate as steroid-secreting Leydig cells. Figure 1 denotes the
increase in testosterone levels that approach concentrations in the
fetal serum to within the lower end of the adult male range (7, 8). Concomitantly, there is Leydig cell proliferation, increased
expression of steroidogenic enzymes (particularly
3ß-hydroxysteroid dehydrogenase and P450
17
-hydroxylase/C17–20-lyase) and expression of the AR in the
peritubular myoid cells (9).
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Figure 1. Embryologic events in male sex differentiation
depicted in temporal fashion. The line depicts the increase in
fetal serum testosterone concentrations. The word activity refers
indirectly to the action of AMH in causing Müllerian duct
regression and androgens to induce male sex differentiation.
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Primordia for both the male and female internal genital ducts are
present initially and are derived, respectively, from mesonephric ducts
and a coelomic epithelial cleft between the genital ridge and the
mesonephros. Müllerian duct regression starts at 8 wk of
gestation in the male through the action of anti-Müllerian
hormone (AMH) secreted by Sertoli cells, which binds to the type II AMH
receptor expressed in the surrounding mesenchyme of the Müllerian
ducts (10, 11). Stabilization of Wolffian ducts to
differentiate as the vas deferens, epididymis, and seminal vesicle is
dependent on testosterone primarily but is also responsive to weaker
androgens such as androstenedione (12). Wolffian ducts
regress in the female in the absence of androgens. Differentiation of
the male external genitalia is androgen regulated; this appears to be
dihydrotestosterone (DHT)-specific based on the expression profile of
5-reductase type II enzyme, and observations in human sex reversal
syndromes characterized by a deficiency of this enzyme (13, 14). Estrogens do not appear necessary for normal sex
differentiation of either sex as shown by murine estrogen receptor
knockout models and normal genital development in males with a mutant
ER gene or aromatase deficiency (15, 16, 17).
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Genetic Control of Sex Determination
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Numerous genes are involved in controlling determination of gonad
type. The process is fundamental to programming sex differentiation and
has been reviewed in detail recently (18, 19, 20, 21, 22). Because
this minireview is focused on sex differentiation, only a few key
features of sex determination are highlighted in this section.
SRY is the principal initiator of the cascade of gene
interactions that determine the development of a testis from the
indifferent gonad. SOX9 plays a crucial role in this pathway
where it is up-regulated by SRY and SF1 to
initiate differentiation of pre-Sertoli cells to Sertoli cells. That
SOX9 lies downstream of SRY in a cascade of
testis development is illustrated by a mouse transgene insertion that
deletes a regulatory element repressing SOX9 in XX fetal
gonads and leads to XX sex reversal (23). Thus, in XY male
development, this repressor function upstream of SOX9 is
normally repressed or inhibited by SRY, thereby allowing
SOX9 to induce testis formation. In normal female
development, SOX9 is repressed and no testis forms.
Only a minority (15–20%) of XY patients with gonadal dysgenesis and
sex reversal have a mutation in SRY to account for the
phenotype (24). Furthermore, the SRY gene is
not detected in 20% of XX males. Other genes required for testis
determination in humans remain to be identified, despite several
characterized in mouse gonadal development. Even though the human
syndrome of campomelic dysplasia and XY sex reversal is caused by
mutations in SOX9 (25), no mutations of this
gene have been found in XY gonadal dysgenesis alone (26).
Similarly, SOX3 from which SRY is believed to
have evolved (27), was normal in mutation analysis of a
group of patients with unexplained XX sex reversal and XY gonadal
dysgenesis (28). A novel gene, tescalcin, was
recently identified as specifically expressed in early fetal mouse
testis cords using the technique of representational difference
analysis (29). When the human homolog is cloned, it is
possible that this gene may be implicated in some forms of XY gonadal
dysgenesis. Some progress has been made in characterizing a locus on
terminal 9p, which leads to XY sex reversal when deleted
(30). Two candidate genes at 9p24.3 have been identified,
which are evolutionarily conserved and homologous with
doublesex (dsx) and mab3 genes
involved in sex development in Drosophila and Caenorhabditis,
respectively (31). They encode proteins with a DNA-binding
motif (DM domain). The human genes are termed DMRT1 and
DMRT2, doublesex and mab-3
related transcription factors. Extensive studies
in a large number of XY sex-reversed patients have yet to identify
mutations in these genes (32, 33).
The dogma of mammalian sex development attributes no specific active
gene regulatory events to ovarian determination and internal genital
development. However, it now appears that female development in the
mouse at least, is regulated by members of the Wnt family of
developmental signaling molecules (34, 35).
Wnt-4 is expressed in the developing mesonephros and hence
involved in gonad development (36). It is down-regulated
in the testis (perhaps by Sry) but remains in the ovary; it
is also expressed in the Müllerian ducts but is absent from
Wolffian ducts. Disruption of Wnt-4 in females results in
masculinized ovaries, which produce androgens from Leydig-like cells,
stabilization of Wolffian ducts and absence of Müllerian ducts
(37). Consequently, wnt-4 is normally required
for initial Müllerian duct development in both sexes and
subsequent suppression of Leydig cell differentiation in the developing
ovary. Another signaling molecule, wnt-7a, is needed to
complete the further development of Müllerian ducts into the
internal female genital tract (38, 39). Although human
homologues for wnt-4 and wnt-7a are identified,
their precise role in human female sex development remains to be
established. There are many other factors implicated in sex
determination not covered in this brief section but Fig. 2 summarizes their hierarchy in the
formation of a testis or an ovary. It is emphasized that much of the
information is gleaned from expression studies in mouse genital ridges
and from the result of gene knockout models. Thus WT1,
SF1, Liml, and Emx2 depicted in Fig. 2
are genes involved in formation of the genital ridge as well as other
primordia such as the adrenals and kidneys. The precise role for some
of these factors for human sex determination is not established.
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Figure 2. Factors controlling gonad determination. DAX-1 may
have an indirect role in ovarian development by acting as an
anti-testis factor.
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Hormonal Control of Sex Differentiation
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The post gonad determination phase of sex differentiation is
almost exclusively hormone-dependent and is an active sexually
unimorphic process for the male. AMH and testosterone are the two key
hormones produced by the testis in optimal concentrations during a
critical time frame in early gestation to ensure male development. Also
a key component in the process is the developmental expression of
cognate receptors for these hormones in target tissues. In later
gestation, the testis migrates transabdominally from its origin
adjacent to the developing kidney before final inguino-scrotal descent.
This can be regarded as part of the completion of sex differentiation
in the male and recent studies describe the role of
insulin-like 3 gene (Insl3) and its product in
this process.
AMH
AMH is a glycoprotein produced in fetal Sertoli cells and belongs
to the TGF-ß superfamily, which includes inhibin and activin
(40). The primary role for AMH in sex development is to
cause a gradient of cranial to caudal regression of Müllerian
ducts during a short period from 8–10 wk of gestation in the human.
This is achieved by the protein binding to a similarly expressed
gradient of AMH type II receptor in mesenchymal cells which, presumably
by a paracrine mechanism, induce apoptosis of the epithelial cells of
the Müllerian ducts. AMH signaling via the membrane-bound
serine/threonine kinase type II receptor requires recruitment and
phosphorylation also of a type I receptor. This mode of action for the
TGF-ß family involves signal transduction via the Smad pathway
(41). The AMH type I receptor has yet to be firmly
identified, but a candidate is the bone morphogenic protein type IB
receptor, which forms a complex with the AMH type II in a
ligand-dependent manner (42).
The role of AMH in male sex differentiation is illustrated by the
persistence of Müllerian duct derivatives in males with
inactivating mutations of either the AMH or AMH type
II receptor gene, but who otherwise develop normally (43, 44). Maldescent of the testes in the human syndrome is probably
the result of anatomical connection of the gonads to the persistent
Müllerian ducts rather than indicating a specific role for
AMH in testis descent. Furthermore, targeted disruption of
AMH and AMH type II receptor genes in mice does
not prevent testis descent (45, 46).
Control of testis descent
Migration of the testis from the lower pole of the kidney on the
abdominal wall or ovarian position into the extra-abdominal scrotal sac
is a two-stage process of transabdominal migration and inguino-scrotal
descent (47). Cryptorchidism affects up to 3% of male
newborns and the prevalence may be increasing (48).
Abdominal wall connections to the testis are through the cranial
suspensory ligament (CSL) and caudally, via the gubernaculum. This
latter mesenchymal tissue in the male contracts, thickens and develops
a bulbar outgrowth which, with regression of the CSL, results in the
testis located in the lower abdomen by the internal inguinal ring. CSL
regression appears to be an androgen-dependent process
(49). The gubernaculum remains a thin cord in the female
and preservation of the CSL anchors a stationary position for the
ovary.
Insulin-like factor 3 (Insl3) or relaxin-like factor is a member
of the insulin-like hormone superfamily and is expressed early in fetal
mouse Leydig cells. Insl3-/- male mice are
bilaterally cryptorchid; the gubernacular bulbs fail to develop and
resemble normal female gubernacular structures (50, 51).
The majority of Insl3+/- male mice also have some degree of
testis maldescent (unilateral or bilateral) at birth but which
rectifies itself by adult life. Leydig cell function and male
urogenital development is otherwise normal. A role for INSL3 in
transabdominal testis migration in humans is less persuasive as recent
studies in boys with bilateral cryptorchidism suggest INSL3
gene mutations are rare (52, 53, 54). However, unique
mutations which were reported in two boys with crytorchidism were
heterozygous, suggesting that INSL3 haploin sufficiency may
cause some sporadic cryptorchidism apparent only at birth
(53). If there is a specific receptor for INSL3, that
may be a cause of dysfunctional signaling. Inguino-scrotal descent is
androgen dependent as illustrated by observations in patients with
hypogonadotropic hypogonadism and the siting of testes in the androgen
insensitivity syndromes (56, 57). Exposure to estrogens
has been implicated as a causal factor in boys with cryptorchidism
(48, 57). Leydig cell expression of insl3 in
mice is inhibited during prenatal exposure to diethyl stilbestrol
(58, 59).
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Androgen Control of Sex Differentiation
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Role of gonadotropins
Next to testis determination, the production and action of
androgens is the essential requirement for male sex differentiation.
Gonadotropic control of fetal testicular steroidogenesis, mediated
initially by human CG and later by LH, operates through the well
characterized seven transmembrane G protein-coupled LH/CG receptor
(60). Regulation of testosterone biosynthesis in early
fetal rabbit gonads appears to be gonadotropin independent
(61), and recent studies of targeted disruption of the
LH/hCG receptor gene in mice showed normally differentiated,
but hypoplastic genitalia (62, 63). Inactivating mutations
of the LH receptor in humans result in varying phenotypes in males,
including complete sex reversal, ambiguous genitalia, or only isolated
micropenis (64).
Testosterone biosynthesis and metabolism
The enzymatic steps and their genetic control in the testicular
biosynthesis of testosterone from cholesterol and further metabolism to
the potent androgen, DHT, are well documented (65, 66, 67, 68, 69).
All steps are necessary for androgen production but key points include
the rate limiting step controlled by the steroidogenic acute regulatory
protein (StAR) in conjunction with the P450 side chain cleavage enzyme
(P450scc) and the enzyme P450c17 which, by virtue of having two enzyme
activities (17-hydroxylase and 17,20lyase), as a qualitative
regulator of steroidogenesis. The enzymes 17ß-hydroxysteroid
dehydrogenase and 5-reductase function to amplify the androgenic
signal through the synthesis of the more potent androgens,
testosterone, and DHT.
Much can be learned about the role of androgens in male sex
differentiation by studying patients with male undermasculinization
secondary to deficiencies of androgen biosynthetic enzymes (70, 71). What is intriguing is the extent of Wolffian duct
stabilization and development prenatally in disorders such as
17ß-hydroxysteroid dehydrogenase and 5-reductase enzyme
deficiencies, in contrast to the almost complete lack of male
development of the external genitalia at birth. In both enzyme
deficiencies, the external genitalia virilize at puberty if the testes
are left in situ; this androgenic effect has been attributed
to substrate conversion by other nonmutant isoenzymes. This does not
necessarily explain the difference in fetal internal and external male
phenotypes, but in the case of 17ß-hydroxysteroid dehydrogenase
deficiency, it is possible that a weaker-acting androgen such as
androstenedione is sufficient to stabilize Wolffian ducts.
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Mechanism of Androgen Action
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The cellular and molecular actions of androgen in developmental
regulation are key to understanding male sex differentiation. Central
to this process is the AR, a nuclear transcription factor that controls
androgen-dependent gene expression.
A single AR is ubiquitously expressed and binds all androgens
intracellularly in target cells (Fig. 3).
Unliganded AR is an inactive oligomer complexed to heat shock proteins
(e.g. Hsp90, Hsp70) and located in the cytoplasm. The
oligomeric complex dissociates on ligand binding, undergoes a
conformational change while transporting into the nucleus to bind as a
homodimer to DNA hormone response elements (72). In common
with other nuclear receptors, the AR comprises three functional domains
involved in transcriptional regulation, DNA and ligand binding. The
least conserved, large N-terminal domain contains an activation
function (AF-1) region which is autonomously involved in gene
transactivation. The AR has a unique N-terminal polymorphic glutamine
region as a result of a variable number of CAG repeats. Variations
in CAG repeat length affect AR transcriptional efficiency
(73). The central DNA-binding domain is the most conserved
region; the C-terminus contains a second activation function region
(AF-2) and mediates heat shock protein interactions, dimerization,
nuclear localization signaling as well as ligand binding.
The AF regions interact with an intermediary group of proteins termed
co-regulators to form protein: protein interactions in a
ligand-dependent manner to either increase (co-activator) or decrease
(co-repressor) gene transcription (74, 75). Figure 4 illustrates the interaction of
ligand-bound AR homodimers in a multiprotein complex with SRC-1 and
CBP, representative members of the nuclear receptor coregulator family
(76). AF-2 is ligand-dependent and is located within one
of the -helices (helix 12) which binds to receptor-interacting
motifs (LXXLL; L is leucine, X is any amino acid) of co-regulators
(77). The AR is unique in displaying constitutive activity
in vitro based on deletion experiments of the ligand-binding
domain (78). This suggests a critical role for AF-1 in
gene transactivation; interaction with SRC-1 is not apparently via
LXXLL motifs but with a conserved, glutamine-rich region in the
C-terminal region (79). Also depicted in Fig. 4 as part of
the multiprotein complex is SRA (steroid receptor RNA activator) which
is AF-1 selective and functions uniquely as an endogenous RNA
transcript (80). A co-regulator having relatively specific
interaction with the AR ligand-binding domain is ARA70
(81).
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Figure 4. Schematic of ligand-bound AR interacting with
co-regulator proteins. p160/SRC-1 (steroid receptor coactivator 1), CBP
(CREB-binding protein), pCAF (CBP-associated factor), SRA (steroid
receptor RNA activator).
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The X-linked disorder of androgen resistance characterized by the
androgen insensitivity syndromes has provided useful information on
androgen action and on what may be the phenotypic outcome with a defect
in this complex, multistep process.
Syndromes of androgen insensitivity
The androgen insensitivity syndrome (AIS) is defined by the
complete AIS (CAIS) or partial AIS (PAIS) absence of signs of androgen
responsiveness in XY males with normal testis determination and
androgen biosynthesis (82, 83). It is the clinical
paradigm of hormone resistance that relates to numerous examples of
both nuclear receptor and cell membrane receptor-related cell signaling
systems (84). A form of PAIS is also recognized where
infertility is the sole manifestation in normally sex differentiated
males (85).
Numerous AR gene mutations are reported in AIS and they are
detailed on an international database (86 ;
http//www.mcgill.ca/androgendb/). A preponderance of mutations
affect the AR ligand binding domain. Functional analysis provides
indirect evidence about critical regions in support of the recently
reported crystal structure of the AR ligand binding domain
(87). Homology modeling based on the known crystal
structure of the related progesterone receptor can also be used. For
example, arginine 779 is critical to ligand binding and subsequent
transactivation whereas a histidine 874 alanine substitution has only a
minimal effect on androgen binding (88).
Coregulator dysfunction
Compelling evidence for the role of coregulators in hormone action
comes from studies in SRC-1 mutant mice (89).
Sex hormone-dependent organs showed reduced growth response in
vivo to sex steroids compared with intact SRC-1 mice.
Only a few studies of coregulators in human hormone resistance
syndromes are reported to date. Two sisters with clinical and
biochemical evidence of resistance to glucocorticoids,
mineralocorticoids, and androgens but not thyroid hormones were
postulated to have a coactivator defect, but no molecular studies were
performed (90). A patient with CAIS in whom the
AR gene was normal was recently reported to lack a 90-kDa
band protein, which interacted with the AF-1 region of the AR in
control genital skin fibroblasts, thus raising the possibility of a
novel explanation for some forms of androgen resistance (91, 92).
In another recent study, the ARA70 cDNA was screened in a
group of XY patients with varying degrees of undermasculinization in
whom defects in the AR had been excluded; no mutations were identified
(93). The large family of nuclear co-regulators influence
transcriptional regulation in a combinatorial and ligand-dependent
manner. Whether the action of any one member when disturbed is so
specific as to cause a hormone resistance state has yet to be
determined in humans.
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Modulating Factors in Androgen Action
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Variations in the number of AR CAG repeats within the normal range
(11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31) are associated with male reproductive disorders
such as decreased spermatogenesis in otherwise normal males (94, 95). Longer repeats within the normal range are also associated
with varying degrees of undermasculinization of unknown cause
(96). In a subsequent study of a larger number of males
with abnormal genital development, there was evidence that a longer
repeat may contribute to the cause of genital maldevelopment,
particularly when less severe (97). On the basis of these
findings, a model for how the AR polymorphism may modulate androgen
action in sex differentiation is proposed (Fig. 5). Several of the numerous genes
involved in androgen biosynthesis and action are polymorphic; the
coordinated functional consequences of such variants may be relevant
for optimal androgen synthesis and action during the critical
developmental phase of sex differentiation.
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Figure 5. A model incorporating the effect of an AR
polymorphism on the etiology of genital abnormalities. The influence of
a longer glutamine repeat is greater when multifactorial causes lead to
moderate genital abnormalities. Reproduced with permission from
The Journal of Clinical Endocrinology & Metabolism.
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Acknowledgments
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The author thanks Han Lim, Nigel Mongan, and Howard Martin for
their helpful discussions. The support of the Birth Defects Foundation,
European Community, Sir Halley Stewart Trust, and the Cambridge
Children’s Kidney Care Fund for some of the studies described in this
review is gratefully acknowledged.
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Footnotes
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Abbreviations: AF-2, Activation function region; AIS, androgen
insensitivity syndrome; AMH, anti-Müllerian hormone; CAIS,
complete AIS; CSL, cranial suspensory ligament; DM, DNA-binding motif;
DHT, dihydrotestosterone; Insl3, insulin-like factor 3; PAIS, partial
AIS; P450scc, P450 side chain cleavage enzyme; StAR, steroidogenic
acute regulatory protein.
Received March 26, 2001.
Accepted for publication June 12, 2001.
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References
|
|---|
-
Jost A 1947 Recherches sur le
différentiation sexuelle de l’embryon de lapin III. Rôle
des gonades foetales dans la differentiation sexuelle somatique. Arch
Anat Microsc Morphol Exp 36:271–315
-
Jost A 1953 Problems of fetal endocrinology: the
gonadal and hypophyseal hormones. Recent Prog Horm Res 8:379–418
-
Sarafoglou K, Ostrer H 2000 Familial sex reversal:
a review. J Clin Endocrinol Metab 85:483–493[Free Full Text]
-
Quigley CA 2001 Genetic basis of sex determination
and sex differentiation. In: DeGroot LJ, Jameson JL, eds.
Endocrinology, ed. 4. Philadelphia: WB Saunders; 1926–1946
-
Bendel-Stenzel M, Anderson R, Heasman J, Wylie C 1998 The origin and migration of primordial germ cells in the mouse.
Semin Cell Dev Biol 9:393–400[CrossRef][Medline]
-
Wylie C 2000 Germ cells. Curr Opin Genet Dev 10:410–413[CrossRef][Medline]
-
Voutilainen R 1992 Differentiation of the fetal
gonad. Horm Res 38:66–71
-
Huhtaniemi I 1994 Fetal testis—a very special
endocrine organ. Eur J Endocrinol 130:25–31[Abstract/Free Full Text]
-
Murray TJ, Fowler PA, Abramovich DR, Haites N, Lea
RG 2000 Human fetal testis: second trimester proliferative and
steroidogenic capacities. J Clin Endocrinol Metab 85:4812–4817[Abstract/Free Full Text]
-
Baarendo WM, van Helmond MJL, Post M, et al. 1994 A
novel member of the transmembrane serine/threonine kinase receptor
family is specifically expressed in the gonads and in mesenchymal cells
adjacent to the Müllerian duct. Development 120:189–197[Abstract]
-
Allard S, Adin P, Gonedard L, et al. 2000 Molecular
mechanisms of hormone-mediated Mullerian duct regression: involvement
of ß-catenin. Development 127:3349–3360[Abstract]
-
Boehmer ALM, Brinkmann AO, Sandkuijl LA, et al. 1999 17ß-Hydroxysteroid dehydrogenase-3 deficiency: diagnosis,
phenotypic variability, population genetics, and worldwide distribution
of ancient and de novo mutations. J Clin Endocrinol Metab 84:4713–4721[Abstract/Free Full Text]
-
Thigpen AE, Silver RI, Guileyardo JM, et al. 1993 Tissue distribution and ontogeny of steroid 5-reductase isozyme
expression. J Clin Invest 92:903–910
-
Wilson JD, Griffin JD, Russell DW 1993 Steroid
5-reductase deficiency. Endocr Rev 14:577–593[CrossRef][Medline]
-
Crouse JF, Korach KS 1999 Estrogen receptor null
mice: what have we learned and where will they lead us? Endocr Rev 20:358–417[Abstract/Free Full Text]
-
Smith EP, Boyd J, Graeme RF, Takahashi H, Cohen RM,
Specker B, Williams TC, Lubahn DB, Korach KS 1994 Estrogen
resistance caused by a mutation in the estrogen-receptor gene in a man.
N Engl J Med 331:1056–1060[Abstract/Free Full Text]
-
Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin
K 1995 Aromatase deficiency in male and female siblings caused by
a novel mutation and the physiological role of estrogens. J Clin
Endocrinol Metab 80:3689–3698[Abstract]
-
Raymond CS, Shamu CE, Shen MM, Seifert KJ, Hirsch B,
Hodgkin J, Zarkower D 1998 Evidence for evolutionary conservation
of sex-determining genes. Nature 391:691–695[CrossRef][Medline]
-
Koopman P 1999 Sry and SOX9:
Mammalian testis-determination genes. Cell Mol Life Sci 55:839–856[Medline]
-
Swain A, Lovell-Badge R 1999 Mammalian sex
determination: a molecular drama. Genes Dev 13:755–767[Free Full Text]
-
Capel B 2000 The battle of the sexes. Mech Dev 84:127–131
-
Nef S, Parada LF 2000 Hormones in male sexual
development. Genes Dev 14:3075–3086[Free Full Text]
-
Bishop CE, Whitworth DJ, Qin Y, Agoulnik AI, Agoulnik
IU, Harrison WR, Behringer RR, Overbeek PA 2000 A transgenic
insertion upstream of SOX9 is associated with dominant XX sex reversal
in the mouse. Nat Genet 26:490–494[CrossRef][Medline]
-
Lim HN, Freestone SH, Romero D, Kwok C, Hughes IA,
Hawkins JR 1998 Candidate genes in complete and partial XY sex
reversal: mutation analysis of SRY, SRY-related genes and FTZ-F1. Mol
Cell Endocrinol 140:51–58[CrossRef][Medline]
-
Foster JW, Dominquez-Steglich MA, Guioli S, et al. 1994 Campomelic dysplasia and autosomal sex reversal caused by
mutations in an SRY-related gene. Nature 372:525–530[CrossRef][Medline]
-
Kwok C, Goodfellow PN, Hawkins JR 1996 Evidence to
exclude SOX9 as a candidate gene for XY sex reversal without skeletal
malformation. J Med Genet 33:800–801[Abstract/Free Full Text]
-
Katoh K, Miyata T 1999 A heuristic approach of
maximum likelihood method for inferring phylogenetic tree and an
application to the mammalian SOX-3 origin of the testis-determining
gene SRY. FEBS Lett 463:129–132[CrossRef][Medline]
-
Lim HN, Berkovitz GD, Hughes IA, Hawkins JR 2000 Mutation analysis of subjects with 46,XX sex reversal and 46,XY gonadal
dysgenesis does not support the involvement of SOX3 in testis
determination. Hum Genet 107:650–652[CrossRef][Medline]
-
Perera EM, Martin H, Seeherunvong T, et al. 2001 Tescalcin, a novel gene encoding a putative EF-hand
Ca2+-binding protein, Col9a3, and renin are
expressed in the mouse testis during the early stages of gonadal
differentiation. Endocrinology 142:455–463[Abstract/Free Full Text]
-
Bennett CP, Docherty Z, Robb SA, Ramani P, Hawkins JR,
Grant D 1993 Deletion 9p and sex reversal. J Med Genet 30:518–520[Abstract/Free Full Text]
-
Raymond CS, Murphy MW, O’Sullivan MG, Bardwell VJ,
Zarkower D 2000 Dmrt1, a gene related to worm and fly sexual
regulators, is required for mammalian testis differentiation. Genes Dev 14:2587–2595[Abstract/Free Full Text]
-
Raymond CS, Parker ED, Kettlewell JR, et al. 1999 A
region of human chromosome 9p required for testis development contains
two genes related to known sexual regulators. Hum Mol Genet 8:989–996[Abstract/Free Full Text]
-
Ottolenghi C, Veitia R, Barbieri M, Fellous M,
McElreavey, K 2000 The human doublesex-related gene, DMRT2, is
homologous to a gene involved in somatogenesis and encodes a potential
bicistronic transcript. Genomics 64:179–86[CrossRef][Medline]
-
Cadigan KM, Nusse R 1997 Wnt signalling: a common
theme in animal development. Genes Dev 11:3286–3305[Free Full Text]
-
Uusitalo M, Heikkila M, Vainio S 1999 Molecular
genetic studies of Wnt signalling in the mouse. Exp Cell Res 253:336–348[CrossRef][Medline]
-
Stark K, Vainio S, Vassileva G, McMahon AP 1994 Epithelial transformation of metanephric mesenchyme in the developing
kidney regulated by Wnt-4. Nature 372:679–683[CrossRef][Medline]
-
Vainio S, Heikkila M, Kispert A, Chin N, McMahon AP 1999 Female development in mammals is regulated by Wnt-4 signalling.
Nature 397:405–409[CrossRef][Medline]
-
Parr BA, McMahon AP 1998 Sexually dimorphic
development of the mammalian reproductive tract requires Wnt-7a. Nature 379:707–710
-
Miller C, Sassoon DA 1998 Wnt-7a maintains
appropriate uterine patterning during the development of the mouse
female reproductive tract. Development 125:3201–3211[Abstract]
-
Lane AH, Donahue PK 1998 New insights into
Müllerian inhibiting substance and its mechanism of action. J
Endocrinol 158:1–6[Abstract]
-
Massagué J 1998 TGF-ß signal transduction.
Annu Rev Biochem 67:753–791[CrossRef][Medline]
-
Gonedard L, Chen YG, Thevenet L, et al. 2000 Engagement of bone morphogenetic protein type IB receptor and Smad1
signalling by anti-Müllerian hormone and its type II receptor.
J Biol Chem 275:27973–27978[Abstract/Free Full Text]
-
Josso N, Picard JY, Imbeaud S, di Clemente N, Rey R 1997 Clinical aspects and molecular genetics of the persistent
Müllerian duct syndrome. Clin Endocriol 47:137–144[CrossRef][Medline]
-
Belville C, Josso N, Picard JY 1999 Persistence of
Müllerian ducts in males. Am J Hum Genet 89:218–224
-
Behringer RR, Finegold MJ, Cate RL 1994 Müllerian inhibiting substance function during mammalian sexual
development. Cell 79:415–425[CrossRef][Medline]
-
Mishina Y, Rey R, Finegold MH, et al. 1996 Genetic
analysis of the Mullerian-inhibiting substance signal transduction
pathway in mammalian sexual differentiation. Genes Dev 10:2577–2587[Abstract/Free Full Text]
-
Hutson JM, Beasley SW 1992 Descent of the testis.
London: Edward Arnold; 1–187
-
Toppari J, Skakkebaek NE 1998 Sexual
differentiation and environmental endocrine disruptors. Bailliere’s
Clin Endocrinol Metab 12:143–156[CrossRef][Medline]
-
Emmen JM, McLuskey A, Grootegoed JA, Brinkmann AO 1998 Androgen action during male sex differentiation includes
suppression of cranial suspensory ligament development. Hum Reprod 13:1272–1280[Abstract/Free Full Text]
-
Zimmerman S, Steding G, Emmen JM, et al. 1999 Targeted disruption of the Insl3 gene causes bilateral cryptorchidism.
Mol Endocrinol 13:681–691[Abstract/Free Full Text]
-
Nef S, Parada LF 1999 Cryptorchidism in mice mutant
for Insl 13. Nat Genet 22:295–299[CrossRef][Medline]
-
Koskimies P, Virtanen H, Lindstrom M, et al. 2000 A
common polymorphism in the human relaxin-like factor (RLF) gene: no
relationship with cryptorchidism. Pediatr Res 47:538–541[Medline]
-
Tomboc M, Lee PA, Mitwally MF, Schneck FX, Bellinger M,
Witchel SF 2000 Insulin-like 3/relaxin-like factor gene mutations
are associated with cryptorchidism. J Clin Endocrinol Metab 85:4013–4018[Abstract/Free Full Text]
-
Lim HN, Rajpert-De Meyts E, Skakkebaek, NE, Hawkins JR,
Hughes IA 2001 Genetic analysis of the INSL3 gene in patients with
maldescent of the testis. Eur J Endocrinol 144:1–9[Abstract]
-
Barthold JS, Kumasi-Rivers K, Upadhyay J,
Shekarriz B, Imperato-McGinley J 2000 Testicular position in the
androgen insensitivity syndrome: implication of the role of androgens
in testicular descent. J Urol 164:497–501[CrossRef][Medline]
-
Lim HN, Hughes IA, Hawkins JR Clinical and
molecular evidence for the role of androgens and WT1 in testis descent.
Mol Cell Endocrinol, in press
-
Bernstein L, Pike MC, Depue RH, Ross RK, Moore JW,
Henderson BE 1988 Maternal hormone levels in early gestation of
cryptorchid males: a case control study. Br J Cancer 58:379–381[Medline]
-
Emmen JM, McLuskey A, Adham IM, et al. 2000 Involvement of insulin-like factor 3 (Insl3) in
diethylstilbestrol-induced cryptorchidism. Endocrinology 141:846–849[Abstract/Free Full Text]
-
Nef S, Shipman T, Parada LF 2000 A molecular basis
for estrogen-induced cryptorchidism. Dev Biol 24:354–361
-
Misrahi M, Bean I, Meduri G, et al. 1998 Gonadotropin receptors and the control of gonadal steroidogenesis:
physiology and pathology. Bailliere’s Clin Endocrinol Metab 12:35–66[CrossRef][Medline]
-
George FW, Catt CJ, Neaves WB, Wilson JD 1978 Studies on the regulation of testosterone synthesis in the fetal rabbit
testis. Endocrinology 102:665–673[Medline]
-
Zhang F-P, Poutanen M, Wilbertz J, Huhtaniemi I 2001 Normal prenatal but arrested postnatal sexual development of
luteinizing hormone receptor knockout (LuRKO) mice. Mol Endocrinol 15:172–183[Abstract/Free Full Text]
-
Lei ZM, Mishra S, Zou W, et al. 2001 Targeted
disruption of luteinizing hormone/human chorionic gonadotropin receptor
gene. Mol Endocrinol 15:184–200[Abstract/Free Full Text]
-
Themmen APN, Huhtaniemi IT 2000 Mutations of
gonadotropins and gonadotropin receptors: elucidating the physiology
and pathophysiology of pituitary-gonadal function. Endocr Rev 21:551–583[Abstract/Free Full Text]
-
Mason JL 1993 The 3ß-hydroxysteroid dehydrogenase
gene family of enzymes. Trends Endocrinol Metab 4:199–202
-
Russell DW, Wilson JD 1994 Steroid 5-reductase:
two genes/two enzymes. Annu Rev Biochem 63:25–61[Medline]
-
Stocco DM, Clark BJ 1996 Role of the acute
regulatory protein StAR in steroidogenesis. Biochem Pharmacol 51:197–205[CrossRef][Medline]
-
Andersson S, Russell DW, Wilson JD 1996 17ß-hydroxysteroid dehydrogenase 3 deficiency. Trends Endocrinol
Metab 7:121–126
-
Miller WL 1998 Early steps in androgen
biosynthesis: from cholesterol to DHEA. Bailliere’s Clin Endocrinol
Metab 12:67–81[CrossRef][Medline]
-
Zhu Y-S, Katz MD, Imperato-McGinley J 1998 Natural
potent androgens: lessons from human genetic models. Bailliere’s Clin
Endocrinol Metab 12:83–112[CrossRef][Medline]
-
Forest MG 2001 Diagnosis and treatment of disorders
of sexual development. In: DeGroot LJ, Jameson JL, eds. Endocrinology.
Ed. 4. Philadelphia: WB Saunders; 1974–2010
-
White R, Parker MG 1998 Molecular mechanisms of
steroid hormone action. Endocrine-Related Cancer 5:1–14[Abstract]
-
Chamberlain NL, Driver Ed, Miesfeld RL 1994 The
length and location of CAG trinucleotide repeats in the androgen
receptor N-terminal domain effect transactivation function. Nucleic
Acids Res 22:3181–3186[Abstract/Free Full Text]
-
McKenna NJ, Lanz RB, O’Malley BW 1999 Nuclear
receptor coregulators: cellular and molecular biology. Endocr Rev 20:321–344[Abstract/Free Full Text]
-
Robyr D, Wolffe AP, Wahli W 2000 Nuclear hormone
receptor coregulators in action: diversity for shared tasks. Mol
Endocrinol 14:329–347[Free Full Text]
-
Onate SA, Tsai SY, Tsai MJ, O’Malley BW 1995 Sequence and characterization of a coactivator for the steroid hormone
receptor superfamily. Science 270:1354–1357[Abstract/Free Full Text]
-
Darimont BD, Wagner RL, Apriletti MR, et al. 1998 Structure and specificity of nuclear receptor-coactivator interactions.
Genes Dev 12:3343–3356[Abstract/Free Full Text]
-
Jenster G, van der Korput HAGM, van Vroonhoven C, van
der Kwast TH, Trapman J, Brinkmann AO 1991 Domains of the human
androgen receptor involved in steroid binding, transcriptional
activation, and subcellular localization. Mol Endocrinol 5:1396–1404[CrossRef][Medline]
-
Bevan CL, Hoare S, Claessens F, Heery DM, Parker MG 1999 The AF1 and AF2 domains of the androgen receptor interact with
distinct regions of SRC1. Mol Cell Biol 19:8383–8392[Abstract/Free Full Text]
-
Lanz RB, McKenna NJ, Onate SA, et al. 1999 A
steroid receptor coactivator, SRA, functions as an RNA and is present
in an SRC-1 complex. Cell 97:17–27[CrossRef][Medline]
-
Yeh S, Chang C 1996 Cloning and characterisation of
a specific co-activator, ARA 70, for the androgen receptor in human
prostate cells. Proc Natl Acad Sci USA 93:5517–5521[Abstract/Free Full Text]
-
Quigley CA, De Bellis A, Marschke KB, El-Awady MK,
Wilson EM, French FS 1995 Androgen receptor defects: historical,
clinical and molecular perspectives. Endocr Rev 16:271–321[CrossRef][Medline]
-
Ahmed SF, Cheng A, Dovey L, et al. 2000 Phenotypic
features, androgen receptor binding and mutational analysis in 278
clinical cases reported as androgen insensitivity syndrome. J Clin
Endocrinol Metab 85:658–665[Abstract/Free Full Text]
-
Jameson JL 1999 Hormone resistance syndromes.
Contemporary endocrinology. No 14. Totawa, NJ: Humana Press;
1–281
-
Giwercmann YL, Nikoshkov A, Bystrom B, Pousette A, Arver
S, Wedell A Two cases of male infertility associated with
missense mutations in the androgen receptor gene. Clin Endocrinol, in
press
-
Gottlieb B, Lehvaslaiho H, Beitel LK, Lumbroso R, Pinsky
L, Trifiro M 1998 The androgen receptor gene mutations database.
Nucleic Acids Res 26:234–238[Abstract/Free Full Text]
-
Matias PM, Donner P, Coelho R, et al. 2000 Structural evidence for ligand specificity in the binding domain of the
human androgen receptor. J Biol Chem 275:26164–26171[Abstract/Free Full Text]
-
Poujol N, Wurtz J-M, Tahiri B 2000 Specific
recognition of androgens by their nuclear receptors. J Biol Chem 275:24022–24031[Abstract/Free Full Text]
-
Xu J, Qiu Y, DeMayo FJ, Tsai SY, Tsai M-J, O’Malley
BW 1998 Partial hormone resistance in mice with disruption of the
steroid receptor coactivator-1 (SRC-1) gene. Science 279:1922–1925[Abstract/Free Full Text]
-
New MI, Nimkarn S, Brandon DD, et al. 1999 Resistance to several steroids in two sisters. J Clin Endocrinol
Metab 84:4454–4464[Abstract/Free Full Text]
-
Adachi M, Takayanagi R, Tomura A, et al. 2000 Androgen-insensitivity syndrome as a possible coactivator disease.
N Engl J Med 343:856–862[Free Full Text]
-
Hughes IA 2000 A novel explanation for resistance
to androgens. N Engl J Med 343:881–882
-
Lim HN, Hawkins JR, Hughes IA 2001 Genetic evidence
to exclude the androgen receptor co-factor, ARA 70 (NCOA4) as a
candidate gene for the causation of undermasculinised genitalia. Clin
Genet 59:284–286[CrossRef][Medline]
-
Tut TG, Ghadessey FJ, Trifiro MA, Pinsky L, Young
EL 1997 Long polyglutamine tracts in the androgen receptor are
associated with reduced trans-activation, impaired sperm production and
male infertility. J Clin Endocrinol Metab 82:3777–3782[Abstract/Free Full Text]
-
Dowsing AT, Yong EL, Clark M, et al. 1999 Linkage
between male infertility and trinucleotide repeat expansion in the
androgen receptor gene. Lancet 354:640–643[CrossRef][Medline]
-
Lim HN, Chen H, McBride S, Dunning AM, Nixon RM, Hughes
IA, Hawkins JR 2000 Longer polyglutamine tracts in the androgen
receptor are associated with moderate to severe undermasculinized
genitalia in XY males. Hum Mol Genet 9:829–834[Abstract/Free Full Text]
-
Lim HN, Nixon RM, Chen H, Hughes IA, Hawkins JR
Evidence that longer androgen receptor polyglutamine repeats are a
causal factor for genital abnormalities. J Clin Endocrinol Metab,
in press
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Top
Abstract
Introduction
