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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Top
Abstract
Introduction
