Normal sex differentiation in humans

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The analysis of disorders of human sexual differentiation has been essential in the Normal sexual differentiation in the Japanese quail has been extensively. Sexual differentiation, in human embryology, the process by which the male and female sexual organs develop from neutral embryonic structures. The normal. The basic difference between human males and females affecting every cell is Regarding sexual differentiation, the normal Y chromosome contains the sex.

Sexual differentiation in humans includes development of different genitalia and the internal genital tracts, breasts, body hair, and plays. Normal sex development consists of several sequential stages. Genetic of dosage-sensitive mechanisms in human sex differentiation, since. Sexual differentiation is conformed in the human during four successive steps: the . Normal meiosis in 45,X female fetuses has been described and the.

Sexual differentiation in humans includes development of different genitalia and the internal genital tracts, breasts, body hair, and plays. Sexual differentiation, in human embryology, the process by which the male and female sexual organs develop from neutral embryonic structures. The normal. Normal sex development consists of several sequential stages. Genetic of dosage-sensitive mechanisms in human sex differentiation, since.






Sexual differentiationin human embryologynormal process by which the male and female sexual organs develop from neutral normal structures. The normal human fetus of either sex has the potential to develop normal male or female organs, depending on differentiation and hormonal influences. In humans, each egg contains 23 chromosomesof which 22 are autosomes and 1 is a female sex chromosome the Sex chromosome. Each sperm also contains 23 chromosomes: 22 differentiatiion and either one female sex chromosome or one male sex chromosome the Y chromosome.

An egg that has been fertilized has a full complement of 46 chromosomes, of which two are sex humans. Therefore, genetic sex of normal individual differenriation determined at the time of fertilization ; differentiation eggs containing an XY sex chromosome complement are genetic males, whereas those containing an XX sex chromosome complement are genetic females.

Every sex contains structures that are capable of developing into either male or female genitalia, and, regardless of hu,ans complement of sex chromosomes, all developing embryos become sex unless masculinizing influences come into play at key humans during gestation.

In males, several testis -determining genes on the Hukans chromosome direct the sexually undifferentiated indeterminate embryonic differentiation to develop as testes. The X chromosome sex differentiattion in the differentiating process, sex two X chromosomes are necessary for the development sex normal ovaries.

In addition, the Wolffian ducts are stimulated by testosterone to eventually develop into the spermatic ducts ductus deferensejaculatory ducts, and seminal vesicles. If the fetal gonads do not differentiation testosterone at the proper time, the genitalia develop in the female direction regardless of whether testes or ovaries are humans. Sexual differentiation is completed at pubertyat which time the reproductive system in both women and men is mature. In such a complex system there are many opportunities for aberrant development.

The causes of disorders of sexual normal, while not fully understood, have been greatly elucidated by advances in chromosomal analysis, the identification of isolated genetic defects in steroid hormone synthesis, and the understanding humans abnormalities sex steroid hormone receptors.

For more information about the embryological differentiation anatomical aspects of the gonads and genitalia, see human reproductive system.

For descriptions of humans and the genes that they carry, see human normal. Sexual differentiation. Info Print Differentiation. Submit Feedback. Thank you for your feedback. Sexual differentiation embryology. Written By: Robert D. Differentiation Article History. Sex More on This Topic. Differentiation between the sexes exists, therefore, as the primary difference represented by the distinction between eggs and sperm, ib.

Subscribe today for unlimited access normal Britannica. Learn More in these related Britannica articles:. Differentiation difcerentiation the sexes exists, therefore, as the primary differentiation represented by the distinction between eggs and sperm, by differences represented by nature of the reproductive glands and their associated structures, humans lastly by differences, if any, between individuals possessing the male and female reproductive….

Humans differentiation of the fetus into a male or a female is also nrmal by delicately timed hormonal changes. Following birth and a differentixtion of steady growth in infancy and childhood, the changes associated with puberty and adolescence take place.

This dramatic transformation of an…. Embryologythe study of humans formation and development of an embryo and fetus. Nofmal widespread use of the differehtiation and the advent of cellular biology in the 19th century, embryology was based on descriptive and comparative studies. From the time of the Greek philosopher Aristotle it was debated whether the…. History differentiatioon your fingertips.

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Testes develop abnormally during fetal life in Dhh null mice, resulting in XY sex-reversal. Seminiferous cords are disorganized owing to defects in the basal lamina and peritubular cells, with germ cells occasionally lying in the interstitial tissue, and Leydig cells are hypoplastic , In order for the fetal testis to adequately differentiate and secrete masculinizing hormones, not only do all these factors need to be present at sufficient levels in the right cell lineage, but their expression must also be initiated within a narrow time window.

In mice, the ability of Sry to induce testis development is limited to a time window of only 6 hours after the normal onset of expression in XY gonads. Upon arriving in the undifferentiated genital ridge, by the end of the 5 th week, germ cells continue to proliferate by mitosis and maintain bipotentiality for approximately one week. Then germ cells in the male gonad become enclosed in the seminiferous cords and differentiate into the spermatogonial lineage, which does not enter meiosis until the onset of puberty.

Gonocyte proliferation in the fetal testis is inhibited by androgens Prevention of entry into meiosis was first thought to be a specific effect of male somatic cells since germ cells entering a prospective ovary or those which have failed to enter gonads of either sex enter meiosis at approximately the same time and develop into oocytes, irrespective of their chromosomal pattern Subsequent studies shed light on the sexually dimorphic evolution of gametogenesis in the fetal gonads. The mesonephros from the indifferent gonad, as well as the lung and adrenal gland, synthesize retinoic acid that acts as a meiosis inducer , Germ cells embedded in the seminiferous cords do not enter meiosis because they are protected from retinoic acid action: mouse Sertoli cells express two factors that prevent meiosis onset: FGF9 and CYP26B1 , an enzyme that catabolizes retinoic acid In human fetal testis, CYP26B1 does not seem to be expressed, and the mechanism underlying the inhibition of germ cell entry into meiosis needs to be elucidated reviewed in ref.

Chromosomal constitution does not influence sex differentiation of germ cells: XX germ cells surrounded by Sertoli cells differentiate into spermatogonia, whereas XY germ cells in an ovarian context differentiate into oogonia and then enter meiosis However, germ cells whose karyotype is discordant with the somatic lineages fail to progress through gametogenesis and enter apoptosis later in life. The influence of germ cells on the developing gonad is sexually dimorphic: Germ cell progression through meiosis is essential for the maintenance of the fetal ovary, otherwise prospective follicular cells degenerate and streak gonads result.

In contrast, the development of the testes is not hindered by the lack of germ cells , Unlike SRY in the testicular differentiation pathway, an ovary-determining factor still proves elusive. Nonetheless, the pathway leading to ovarian differentiation and stabilization is far more complex than what was originally hypothesized. The default pathway whereby the sole absence of SRY results in the differentiation of ovaries from the gonadal ridges only seems to apply to experimental conditions in rodents In humans, the absence of an active SRY gene —e.

SRY mutations or deletions of the Y chromosome involving the SRY locus— results in gonadal dysgenesis of variable degrees, but is not sufficient to allow ovarian differentiation: no oocyte meiotic progression or follicle development has been described, even during fetal life.

Recent findings suggest that most probably the coordinated action of several factors is needed for the differentiation and stabilization of the ovaries Table 3 , Figs. WNT4 is a secreted protein that functions as a paracrine factor to regulate several developmental mechanisms. WNT4-deficient XX mice express the steroidogenic enzymes 3b-hydroxysteroid dehydrogenase and 17a-hydroxylase, which are required for the production of testosterone and are normally suppressed in the developing female ovary In humans, a duplication of chromosome 1 containing 1p WNT4 is also involved in the development of the internal genital tract see below.

Conversely, inducible deletion of Foxl2 in adult mouse ovarian follicles leads to upregulation of Sox9 and reprogramming of adult ovaries to testes In humans, FOXL2 mutations result in a variety of phenotypes, from streak gonads to adult ovarian failure associated with eyelid abnormalities characterized by blepharophimosis, ptosis and epicantus inversus BPES Germ cell entry into meiosis is a specific feature of initial ovarian differentiation Table 3 , Figs.

The latter antagonizes Activin B, thus repressing endothelial cell migration and the coelomic vessel formation, one of the earliest testis-specific events MAP3K1 modulates the balance between female and male pathways.

In the XX fetus, the gonad remains indifferent after the 7 th week from a histological standpoint, but a functional differentiation already develops: XX gonads become capable of estradiol production at the same time as XY gonads begin to synthesize testosterone PGCs proliferate by mitosis and differentiate to oogonia.

Ovarian maturation proceeds from the center to the periphery. At week 10, oogonia in the deepest layers of the ovary enter meiotic prophase, the first unequivocal sign of morphological ovarian differentiation. Subsequently, oogonia become surrounded by a single layer of follicular or granulosa cells, they enter meiosis and become oocytes and form primordial follicles Fig. Initiation of meiosis in the fetal ovary is heralded by the increase in retinoic acid levels synthesized by retinaldehyde dehydrogenase isoform 1 encoded by ALDH1A1 , expressed in the developing female gonad The earliest primary follicles appear at weeks and the first Graafian follicles at weeks , By the end of the 7 th month of gestation, mitotic activity has ceased and almost all germ cells have entered meiotic prophase.

Oocytes proceed to the diplotene stage, where they remain until meiosis is completed at the time of ovulation in adult life. However, not all oocytes undergo meiosis: from million ovarian follicles at 25 weeks, only 2 million persist at term Most oocytes undergo apoptosis and follicles become atretic.

AMH is produced, albeit in low amounts, after the 23 th week of development by granulosa cells from primary to antral follicles, but not by primordial follicles The dynamics of follicle development and entry of germ cells into meiosis is appreciably different in rodents, in which meiosis and folliculogenesis only progress after birth The involvement of germ cells in the stabilization of the gonadal structure is one major difference between the ovary and the testis, with germ cells being critical only in the ovaries in terms of maintenance of the somatic component of the gonad.

In fact, while fetal testis development progresses normally in the absence of germ cells , ovarian follicles do not develop when germ cells are absent , Furthermore, if germ cells are lost after formation of follicles, these rapidly degenerate , In XX gonads, very few endothelial cells migrate from the mesonephros to the gonad, which suggests that cortical and medullary domains of the ovary are already established in early gonadogenesis, although no morphological boundaries are evident, consistently with molecular evidence of discrete gene expression domains specified by The coelomic vessel formation, characteristic of the differentiating testis, does not occur in the normal XX gonadal ridge.

Granulosa cells, the equivalent of the Sertoli cells of the testes, originate from 3 possible sources: the ovarian surface epithelium, mesonephric cells from the adjacent rete ovarii, and the existing mesenchymal cells of the genital ridge 84, Recent work in mice has provided evidence that many coelomic epithelial cells ingress to ovarian cortex and give rise to FOXL2-positive granulosa cells , and confirmed that other potential granulosa cell precursors are present in the gonadal ridge prior to the start of coelomic cell migration , Theca cells, the counterpart of testicular Leydig cells, are thought to derive from fibroblast-like precursors in the ovarian stroma under the control of granulosa cells At 45 days, the ovary is recognizable only because it has not yet undergone testicular differentiation.

In the cortex of the 14 week-old gonad, germ cells are aligned in rows, some of them have entered the meiotic prophase arrows. In the medulla, primordial small arrow head and primary large arrowhead follicles are visible.

Two major events can be distinguished in ovarian development: germ cell migration, proliferation and meiosis, and folliculogenesis. For a long time, it has been known that two intact X chromosomes are required in the human —in contrast to the mouse, where even XY oocytes can occur in experimental conditions 47 — for ovarian differentiation and development. The lack of two X chromosomes, e. In the female gonad, germ cells continue to proliferate by mitosis.

Meiotic entry is delayed until the 10 th week in the human fetus and the 13 th day in the mouse fetus Table 1 , due to the suppressive effect of the Polycomb repressive complex 1 PRC1 , which represses STRA8 and other factors involved in the differentiation of primordial germ cells and in early meiosis programs until retinoic acid reaches a threshold Retinoic acid, synthesized by retinaldehyde dehydrogenases present in the mesonephros and the developing ovary , , binds to the retinoic acid receptor RAR present in the germ cells and induces the expression of STRA8 , , a transcription factor that upregulates DAZL and SYCP3, two proteins involved in the formation of the synaptonemal complex essential for the onset of meiosis In Msh5 null mice, oocytes are lost before the diplotene stage resulting in ovarian dysgenesis.

The expression of STRA8 takes place in an anterior-to-posterior wave and is followed by the upregulation of another meiotic gene Dmc1 For a detailed description of other factors involved in oocyte development, see refs. A number of genes are upregulated in the human ovary before and during primordial follicle formation; their functional implications still need to be elucidated In mice, neurotrophins NTs and their NTRK tyrosine kinase receptors facilitate follicle assembly and early follicular development Factors involved in germ cell meiosis are also important.

Although not essential to ovarian differentiation, several factors are involved in the development of ovarian follicles. An increasing number of factors are involved in later steps of folliculogenesis for review, see ref. In the human embryo, Wolffian ducts originate in the intermediate mesoderm, laterally to somites in embryos 25 to 32 days old Table 1. These tubules give rise, in a cephalic-to- caudal direction, to the three kidney primordia: pronephros, mesonephros and metanephros. While the pronephros and mesonephros are transient structures that soon degenerate, the metanephros is one of the main sources of the definitive kidney.

Because Wolffian ducts are crucial for kidney development, abnormal formation of the Wolffian ducts is usually associated with other malformations in the urinary or genital systems. RET signaling is involved in multiple aspects of early Wolffian duct development Growing caudally, Wolffian ducts progressively acquire a lumen and reach the caudal part of the hindgut, the cloaca.

The Wolffian ducts become incorporated into the male genital system when renal function is taken over by the definitive kidney, the metanephros. This coelomic opening will later constitute the abdominal ostium of the Fallopian tube. The cleft is closed caudally by a solid bud of epithelial cells, which burrows in the mesenchyme lateral to the Wolffian ducts and then travels caudally inside their basal lamina.

Initially, these cells are mesoepithelial, ie they exhibit characteristics of both the epithelium and the mesenchyme; they will become completely epithelial only in the female, at the time male ducts begin to regress , This phase consists in the proliferation and caudal migration of a group of cells at the most caudal tip. As could be expected, integrity of protein kinase pathways is required for cell proliferation Reprinted with permission from ref. Sexual Development , Copyright , Karger. Mesenchymal changes are preceded by the dissolution of the basement membrane, which precipitates apoptosis and allows extrusion of epithelial cells and their transformation into mesenchymal cells , The second aspect of male differentiation of the internal genital tract is the stabilization and differentiation of the Wolffian ducts After the loss of mesonephric functional activity, the mesonephric nephrons and caudal tubules degenerate but the cranial tubules persist to form the male efferent ducts.

The connections between the mesonephric tubules and the gonadal primordium are permanently established in the sixth week; in the male, they give rise to the rete testis, while in the female, they form the rete ovarii. Between weeks 9 and 13 in the human embryo, the upper part of the Wolffian duct differentiates into the epididymis. The seminal vesicle originates from a dilatation of the terminal portion of the vas deferens in 12 week-old fetuses. During human fetal development, the testis migrates from its initial pararenal position to its terminal location in the scrotum Fig.

Testicular descent has been subdivided into several phases Initially, the upper pole of the testis is connected to the posterior abdominal wall by the cranial suspensory ligament while a primitive gubernaculum extends from the caudal pole to the inner inguinal ring.

At 12 weeks, the cranial suspensory ligament dissolves and and the gubernaculum testis swells and pulls the testis down to the inguinal ring. After 25 weeks, the gubernaculum bulges beyond the external inguinal ring and is hollowed out by a peritoneal diverticulum called the processus vaginalis. The second —inguinoscrotal— phase of testicular descent occurs between 27 and 35 weeks after conception.

In the female, the cranial ligament holds the ovary in a high position and the gubernaculum, now the round ligament, remains long and thin.

Left, Initial phase: the primitive gonad is located near the kidney, held by the cranial suspensory ligament CSL and the gubernaculum testis. Center, Transabdominal descent: androgen-mediated dissolution of the CSL and insulin like factor 3 INSL3 mediated swelling of the gubernaculum bring the testis to the internal orifice of the inguinal canal.

Right, Inguino-scrotal migration: the testis passes through the inguinal canal into the scrotum, this phase is androgen-dependent. Reprinted from ref. Molecular and genetic regulation of testis descent and external genitalia development. Developmental Biology, , Copyright , with permission from Elsevier. Tubal differentiation involves formation of fimbriae and folds in the ampullary region Fig.

The uterotubal junction is demarcated by an abrupt increase in the diameter of the uterine segment and by the development of epithelial crypts. The early endometrium is lined by a closely packed columnar epithelium in which gland formation and vacuolated cells can be recognized as gestation advances.

The cervix occupies the distal two-thirds of the fetal uterus. Up to approximately 9 weeks, the urogenital sinus and external genitalia remain undifferentiated Fig. The cloaca is closed by the cloacal membrane, formed by ectoderm and endoderm, with no mesoderm in between. In the 5 th week, mesodermal cells spread along the cloacal membrane and give rise to pair of swellings —the cloacal folds—, which form urogenital folds flanking the urogenital sinus and anal folds posteriorly.

The urogenital folds fuse anteriorly to the cloacal membrane in the midline to form the genital tubercle. The cloacal membrane is divided by the urorectal septum into the genital membrane anteriorly and the anal membrane posteriorly.

These are connected to the caudal poles of the genital ridges by fibrous bands which later develop into the gubernaculum testis in males and the round ligament in females. The genital tubercle, consisting of lateral plate mesoderm and surface ectoderm, emerges as a ventral medial outgrowth just cranial to the opening of the ostium Endodermal epithelial cells from the urogenital sinus are thought to invade the genital tubercle to form the midline epithelial urethral plate, which lies in the roof of the primary urethral groove and extends to the tip of the phallus , After the corpora cavernosa and glans have differentiated, the ventral surface of the genital tubercle is depressed by a deep furrow, the urethral groove.

The external genitalia remain undifferentiated up to approximately 9 weeks Fig. When the cells of the vaginal plate desquamate, the vaginal lumen is formed. Male orientation of the urogenital sinus is characterized by prostatic development and by the repression of vaginal development. Maturation of the prostatic gland is accompanied by development of the prostatic utricle. Fusion of the labioscrotal folds, in a dorsal to ventral fashion, forms the epithelial seam , which closes the primary urethral groove.

The literature concerning penile development is controversial. Most textbooks describe it as a two-step process, with the proximal urethra forming by fusion of the urethral folds around the urethral plate and the distal urethra arising from an invagination of the apical ectoderm.

However, according to Cunha and colleagues , the entire human male urethra is of endodermal origin, formed by the urethral plate dorsally and the fused urethral folds ventrally. The seam is remodeled into the tubularized urethra without connection to the epidermis. The ventrally discarded excess epithelial cells migrate into the ventral skin of the penis. Abnormalities of seam formation or remodeling could explain the vast majority of cases of hypospadias in which defects of androgen synthesis or metabolism cannot be demonstrated Urethral organogenesis is complete at 14 weeks, apart from a physiological ventral curvature, which can persist up to 6 months of gestation.

However, surprisingly, no size difference exists between penile or clitoral size until 14 weeks despite the fact that serum testosterone levels peak between 11 to 14 weeks in males Maximal phallic growth occurs during the third trimester of fetal life, at a time when male testosterone levels are declining.

Female orientation of the urogenital sinus is characterized by lack of prostatic differentiation and the acquisition of a separate vaginal opening on the surface of the perineum Fig. At the end of the ambisexual stage, the vaginal anlage is located just underneath the bladder neck. In females, the lower end of the vagina slides down along the urethra until the vaginal rudiment opens directly on the surface of the perineum at 22 weeks.

The hymen marks the separation between the vagina and the diminutive urogenital sinus, which becomes the vestibule. The embryological origin of the vagina is still hotly debated. It is now thought that the Wolffian ducts do not contribute cells to the sinovaginal bulbs but they may have a helper function during downward movement of the vaginal bud in the female Development of female external genitalia is essentially static.

The anogenital distance does not increase, the rims of the urethral groove do not fuse, the urethral plate persists as an epithelial cord, and the labioscrotal swellings give rise to the labia majora.

The dorsal commissure forms at their junction. The genital folds remain separate and become the labia minora. When the vagina acquires a separate perineal opening, the diminutive pars pelvina and the pars phallica of the urogenital sinus become the vestibule. Molecular genetic studies in the mouse have contributed to the identification of growth factors essential for the formation of the sexual ducts Table 4 [see refs. Whether efferent duct maldevelopment is a primary defect of cystic fibrosis or a secondary degenerative change resulting from obstruction by mucus is not known at the present time.

Correct vaginal development requires Wnt , Pax and Vangl2 genes Table 5. Vaginal abnormalities similar to those elicited by diethylstilbestrol DES administration, i. WNT7A deficiency could act by interfering with normal mesenchymal-epithelial signaling, which is required for correct morphogenesis of the reproductive tract. The secreted frizzled-related proteins SFRP1 and 2 are required for correct gubernaculum development and testicular descent External genitalia are appendages emerging from the caudal body trunk, hence many genes which pattern distal limb development also play a predominant role during genital tubercle formation, for example BMPs , , Fgf-8 and 10, Hox gene families for reviews, see refs.

SHH signaling regulates many of the mesenchymal genes involved , , Fig. The homeotic genes Hoxa13 and Hoxd13 act in a partially redundant manner since double null mutants show more severe urogenital abnormalities than those with at least one functional allele Ephrin family factor EfnB2 and receptors EphB2 and EphB3 mediates cell adhesion and patterning events occurring at the midline, including urethral closure and scrotal fusion, as well as palate fusion , Diacylglycerol kinase K DGKK , an enzyme that phosphorylates diacylglycerol, is expressed in the epithelial cells of the urethral plate In humans, DGKK is strongly associated with hypospadias risk , Regulation of urethral tube closure during the androgen-dependent phase of penile development is mediated by FGF10, signaling through the IIIb isoform of fibroblast growth receptor 2 FGFR2-IIIb , suggesting that these genes are downstream targets of the androgen receptor Role of sonic hedgehog Shh in the outgrowth and ambisexual differentiation of the genital tubercle see table 5 for references.

Most factors, with the exception of Hoxa13, are regulated by sonic hedgehog Shh , expressed in the urethral epithelium light green , and are identical to those regulating limb morphogenesis.

Apoptosis is also affected by Shh. Data obtained from ref. Developmental Biology, The classical experiments of Jost 41, 42 Fig. AMH is expressed at high levels by Sertoli cells from the time of testicular differentiation Fig. In the female, AMH is produced in late fetal life by granulosa cells of growing follicles , Schematic diagram showing processing of AMH.

AMH is translated as a dimeric precursor protein comprising two polypeptide chains, each containing a large N-terminal pro-region and a much smaller C-terminal mature domain. Processing involves cleavage at sites between the two domains, which form a complex associated by non-covalent bonds AMHNC.

Its dissociation releases the mature ligand, the C-terminal homodimer and the N-temrinal proregion. Modified from ref. Molecular Endocrinology Copyright , The Endocrine Society, with permission. The AMH molecule is initially synthesized as a biologically inactive precursor. The precursor is cleaved by proteolytic enzymes into C and N terminal fragments which remain associated by non-covalent bonds AMH NC , Whether cleavage occurs at the time of secretion or within the target tissue is not clear at the present time.

This step is required for binding of AMH to its primary receptor, at which time the AMH NC complex dissociates, releasing the mature ligand, the C-terminal homodimer and the N-terminal proregion Fig. Molecular model of C-terminal AMH. A three-dimensional model of the C-terminal dimer was generated by comparative modeling using human BMP-9 as a template. Disulfide bonds yellow and Q residues blue are shown as sticks; residues in the knuckle epitopes are shown as spheres.

Copyright The Endocrine Society with permission. The human 2. It consists of five exons, the last one coding for the C-terminal fragment. In fish, AMH appears to be involved essentially in germ cell proliferation and gonadal development reviewed in ref. Indeed, in higher vertebrates, AMH inhibits Leydig cell differentiation and follicle maturation The ontogeny of AMH expression differs widely between males and females.

In the human fetal testis, AMH mRNA and protein can be detected from the 8 th week, when Sertoli cells begin to form cord-like structures, the future seminiferous tubules Fig. In the ovary, AMH production is detectable at 24 week gestation in granulosa cells of preantral follicles The timing of the expression of AMH is crucial.

Thus, in both sexes, the initiation of AMH transcription is under tight transcriptional control. In vivo , genes can affect AMH levels indirectly through their impact on testicular determination instead of acting on gene transcription.

Although initially gonadotropin-independent, AMH production falls under gonadotropin control later in fetal life and after birth , , Regulation of testicular AMH production. Right figure reprinted from ref. At puberty, gonadotropin activation is antagonized by androgens resulting in a steep fall in AMH secretion by Sertoli cells Androgen action requires the presence of the androgen receptor in Sertoli cells.

This occurs relatively late after birth Fig. In androgen-insensitive patients, AMH levels are abnormally elevated during the perinatal and pubertal stages , , due to unopposed stimulation by FSH.

The mechanism whereby androgens repress AMH transcription is not known at the present time, because the AMH promoter does not carry consensus androgen response elements Gonadotropins and steroid also regulate AMH in the ovary.

FSH stimulates AMH transcription in cultured granulosa cells and estrogen has differential effects according to which estrogen receptor is involved , while LH has no effect in normal cells The increase of intratesticular levels of testosterone does not affect AMH expression because fetal Sertoli cells do not express the androgen receptor AR.

After birth the number of Sertoli cells expressing the AR progressively increases. At puberty, when testosterone increases again, AMH production is inhibited. Initially, the procedure was used by pediatric endocrinologists to measure testicular AMH in boys, hence the first commercially available kits were suited to the high level of AMH concentration of prepubertal males Following the discovery that AMH serum concentration in women mirrors ovarian reserve , , AMH assay has become a standard procedure in assisted reproduction centers and more sensitive methods, adapted to the low concentration of AMH in female serum, were developed.

Unfortunately, the GenII test is sensitive to interference by complement, requiring an inconvenient pre-dilution step to ensure reproducibility In parallel, automated assays, e. It follows that AMH values obtained with different methods are not interchangeable Since clinicians are not usually aware of the problem, serious interpretation errors may arise during patient follow-up. An international standard of human recombinant AMH needs to be developed, particularly since the Immunotech assay upon which many normative values have been based has been pulled off the market.

Since the precursor is biologically inactive, discrimination between the two could be important to understand AMH function AMH is an exceptionally stable biomarker, variations during the menstrual cycle , and diurnal variations in men are minimal. Measurement of AMH in serum has diagnostic applications in disorders of sex development , and as a marker of prepubertal testicular function in boys In women, AMH levels are a reliable marker of follicular reserve , and may be used with relative accuracy to predict the onset of menopause or to follow the evolution of granulosa cell tumors , Some AMH mutations with reduced in vitro bioactivity are associated with premature ovarian insufficiency In contrast, the clinical usefulness of AMH in seminal fluid in men with non-obstructive azoospermia is debatable Further discussion of the diagnostic and potentially therapeutic value of AMH in the adult ovary and testis is beyond the scope of this review.

A The extracellular domain exhibits the general three-finger toxin fold of type II receptors and displays five disulfide bridges, four of which are conserved in the other three receptors. Reprinted with permission from Elsevier, from ref. Genetic Steroid Disorders. Increased expression of the receptor results in the removal of most of its extracellular domain and subsequent retention in the endoplasmic reticulum, resulting in a constitutive negative regulation.

After dissociation of the pro-region, the type I receptor is recruited into the complex, and is phosphorylated by the type II receptor kinase.

Courtesy of Dr. Richard Cate. Older patients may seek medical attention because of an abdominal tumor, hematuria or hemospermia. The Fallopian tubes are tightly attached to the testes, preventing testicular descent. Note normal male external genitalia.

Hormone Research in Paediatrics Copyright S. Karger AG, Basel, with permission. Conversely, almost a third of cases of transverse testicular ectopia are associated with PMDS The descended PMDS testis is only loosely anchored to the bottom of the processus vaginalis by a thin gubernaculum resembling the round ligament of the uterus Thus, the PMDS testis is exposed to an increased risk of torsion and subsequent degeneration, possibly explaining the association of PMDS and anorchidism Other possible complications include carcinoma of cryptorchid testes, a risk that is not totally eliminated by prior orchidopexy , The high incidence of sterility is discussed below.

Surgical management of PMDS has evolved. However, even if the risk of malignant degeneration is disregarded, it is usually impossible to bring down the testes leaving them in place. To place the testes in the scrotum, two stage procedures are often necessary.

Even with the best of care, the prevalence of infertility is extremely high in PMDS, for various reasons. In young patients, testicular biopsy usually shows normal immature tissue with a normal number of germ cells but these will degenerate unless the testes can be brought down into the scrotum, a difficult undertaking particularly if the testes are in an ovarian position see above. Furthermore, in many cases, epididymides or vasa deferentia are either absent or not connected to the testes and personal observations.

This type of infertility is amenable to intra-cytoplasmic sperm injection ICSI. Patients with at least one scrotal testis stand a slightly better chance, although reports of fertility in PMDS are rare and paternity has never been stringently confirmed Missense mutations are shown above the gene, deletions, nonsense or additions below, and splice mutations by stars.

Recurrent mutations are indicated in red. The 3' end of the AMH gene codes for the C-terminal domain, responsible for bioactivity, yet mutations are spread along the whole length of the gene. Similarly, mutations of the AMH type II receptor affect intracellular and extracellular domains alike. An AMH gene mutation with a normal AMH serum level should be regarded with suspicion unless a mutation in the receptor gene has been convincingly ruled out.

We have documented only one such case, a Gln His mutation, which is expected to impair the binding site with the type I receptor In post-pubertal patients, AMH levels are always low, whatever the genotype. Its incidence is not precisely known but it may be less exceptional than previously thought, particularly in inbred populations , , , X-linked recessive transmission has been suggested a family with two half-brothers with different fathers , but their genotype has not been ascertained.

Testosterone or dihydrotestosterone DHT , binding to the same androgen receptor AR , are the main factors involved in maintenance of the Wolffian duct and differentiation of male sex accessory organs and external genitalia.

Beginning at 9 weeks, testosterone is produced from cholesterol by chorionic gonadotropin stimulation of fetal Leydig cells through the coordinated action of steroidogenic enzymes Fig. Most steroidogenic enzymes are either hydroxysteroid dehydrogenases or cytochromes P, residing either on the mitochondrial membrane type I or in the endoplasmic reticulum type II The initial step in steroidogenesis, conversion of cholesterol into pregnenolone, is mediated by the P side-chain cleavage enzyme Pscc , a type I cytochrome located at the inner mitochondrial membrane.

However, the inner mitochondrial membrane contains relatively little cholesterol, so the rate-limiting step of steroidogenesis is the transfer of cholesterol from the outer to the inner mitochondrial membrane. The exact mechanism of StAR-mediated cholesterol transport into the mitochondria is not completely understood. Cytochrome b5 is required for optimal 17,20 lyase activity , Steroidogenesis: the "classic" and "backdoor" pathways for dihydrotestosterone DHT synthesis.

See Table 6 for enzyme nomenclature. Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation. American Journal of Human Genetics Copyright , with permission from Elsevier. The marsupial model for male phenotypic development. Trends in Endocrinology and Metabolism, , Copyright , with permission from Elsevier. The type 3 isoform, HSD17B3, is expressed in the testis and is the only one involved in fetal male sexual differentiation The type 2, HSD17B2, is expressed in the liver and has the capacity for testosterone synthesis.

Enzymes acting in coordination are indicated by a background of the same colour. The four last enzymes act exclusively in the alternate pathway of DHT synthesis. Testosterone itself is not a very active androgen; its metabolite DHT is the main virilizing agent during male reproductive development.

The conversion of testosterone to DHT amplifies the androgenic signal through several mechanisms. DHT cannot be aromatized to estrogen, and thus its effects are purely androgenic. Testosterone and DHT bind to the same androgen receptor but DHT does so with greater affinity which results in a stabilization of the hormone-receptor complex for a longer period of time In the classic pathway of DHT production Fig.

Tissue distribution and ontogeny of both isoforms as well as mutation studies in humans with 46,XY DSD clearly indicate that type 2 plays the major role in sexual differentiation but the emergence of type 1 probably accounts for the pubertal virilization of the type 2-deficient patients. Testosterone, however, is not an obligatory precursor of DHT Fig.

After they failed to demonstrate mutations in known steroidogenic enzymes, they explored genes acting in the alternate pathway of androgen synthesis.

In the alternate pathway these enzymes catalyze the reduction of dihydroprogesterone and 17OH-dihydroprogesterone to allopregnanolone and 17OH-allopregnanolone, the precursor of androsterone and androstanediol. Their role in the oxidation of the latter to testosterone is hypothetical because they have very high affinity for NADP H , which favors reductive reactions and low affinity for NAD H which favors the opposite, thus they are expected to function primarily as a reductase Testosterone production by the human fetal testis is detectable at 9 weeks, peaks between 14 and 17 weeks and then falls sharply, so that in late pregnancy the serum concentrations of testosterone overlap in males and females.

Gonadotropin stimulation is not required for the initiation of steroid synthesis but is necessary to maintain Leydig cell function subsequently. Testicular and serum levels of testosterone are closely correlated with human chorionic gonadotropin hCG concentration; the peak of fetal testicular steroidogenic activity coincides with the acme of concentrations of hCG in the circulation.

In adult Leydig cells, the capacity to respond to sustained gonadotropic stimulation by increased androgen production is curtailed by the development of a refractory state, due to receptor down-regulation Fetal Leydig cells apparently escape desensitization, allowing them to maintain a high testosterone output during the several weeks necessary to male differentiation of the genital tract. The fetal pituitary takes over when chorionic gonadotropin declines in the 3rd trimester reviewed in ref.

Impaired LH secretion in 46,XY fetuses does not result in DSD because the most important steps of sexual differentiation, with the exception of penile growth, occur at the time Leydig cells are controlled by hCG. LH and hCG signal through a common seven-transmembrane domain receptor coupled to G proteins present on testicular Leydig cells.

The human gene located on chromosome 2p21, contains 11 exons. This suggests that exon 10 is required for signal transduction of pituitary LH but not hCG. Note the low testosterone concentration during the last trimester, at the time that hCG production by the placenta has abated. Sexual endocrinology of fetal and perinatal life. In: Austin CR, ed. Mechanisms of Sex Differentiation in Animals and Man. London: Academic Press; p. Testosterone and DHT exert their action on androgen-dependent tissues by binding to the androgen receptor, a member of the steroid receptor family Fig.

Mutations of this receptor lead to the androgen insensitivity syndrome, a relatively common disorder of sex development typically characterized by a female external genital appearance in XY patients despite a normal or excessive production of testicular hormones see ref. The androgen receptor is encoded by a single-copy gene located on the long arm of the X chromosome, locus Xq12 It spans kb and its open reading frame of 2.

Exon 1 is the longest and codes for the amino-terminal transactivation domain. Interestingly, expansion of the trinucleotide repeat which encodes this long tract of glutamine residues segregates with X-linked spinal and bulbar atrophy a degenerative neuropathy characterized by the accumulation of the mutated receptor in the nucleus and cytoplasm of motor neurons reviewed in ref.

Exons 2 and 3 code for sequences containing two zinc fingers implicated in DNA binding. Most mutations occur in exons 4 to 8, which encode the steroid hormone binding domain. A complete database of androgen receptor mutations is available from McGill University in Montreal In contrast to receptors for other steroid sex hormones, which reside in the nucleus even in the absence of ligand binding, the androgen receptor resides mainly in the cytoplasm, associated with heat-shock and other chaperone proteins, in the absence of hormone and translocates into the nucleus in the presence of ligand Nuclear localization is controlled by a nuclear localization signal spanning the second zinc finger and the hinge region competing with an androgen-regulated nuclear export signal in the ligand binding domain However, the physiological relevance of these actions remaining largely unknown The androgen receptor binds to specific DNA motifs, the androgen response elements ARE , present in the promoter regions of androgen-activated genes.

After binding to AREs on the promoters of androgen-responsive genes, the androgen receptor regulates their transcriptional activity. It is aided in this task by co-regulators, partner proteins that facilitate assembly of the preinitiation complex through chromatin remodeling.

These include the p family of coactivators, which interact selectively with the agonist-bound form of AR , Attempts at blocking the androgen receptor by preventing its interaction with co-activators are part of the therapeutic strategy in prostate cancer Because of its close proximity to the testis, the Wolffian duct is exposed to a very high local concentration of testosterone, a source of androgen not available to organs receiving testosterone only via the peripheral circulation Fig.

Patients with androgen insensitivity whose androgen receptor retains very low but significant residual activity have a female phenotype but retain an epididymis or vas deferens Wolffian duct differentiation is programmed during a critical time window, between Because the androgen receptor is expressed in the Wolffian duct stroma but not in the epithelium during this time, Wolffian duct differentiation is likely to be dependent on androgen-mediated signaling from the stroma to the epithelium Androgens are required to mediate the disappearance of the cranial suspensory ligament , and later for the inguinoscrotal phase of testicular descent.

The mechanism of androgenic action on the gubernaculum is controversial. Androgens could act through the genitofemoral nerve and the neuropeptide calcitonin gene-related peptide , Thus any condition associated with decrease of fetal testicular production or action may impair testicular descent. INSL3 acts by inducing male development of the gubernaculum testis. Mutations of INSL3 have been detected in cryptorchid patients , similarly deletion of Rxfp2 targeted to mesenchymal gubernacular cells leads to high cryptorchidism in mice Prenatal DES treatment, which is associated with cryptorchidism, impairs Insl3 expression in mouse testis and interferes with gubernacular development Normal androgen physiology in mammals.

Testosterone and dihydrotestosterone are assumed to work by binding to the same receptor protein and forming hormone—receptor complexes of different allosteric configurations. The conclusion that ovarian hormones are not necessary to female development of the female reproductive tract 41, 42 is supported by the female phenotypic development of 45,X or 46,XY subjects with bilateral gonadal aplasia and of aromatase knockout mice unable to synthesize estrogens.

Yet, inappropriate estrogen exposure is clearly detrimental. Diethylstilbestrol DES , a synthetic estrogen, was widely administered to pregnant women in the early s in the hope of preventing abortion. It was later discovered that female progeny exhibited severe abnormalities of the reproductive tract: vaginal clear-cell adenocarcinoma, vaginal adenosis and squamous metaplasia, transverse vaginal ridges and structural malformations of the cervix and uterus , Environmental chemicals that exert deleterious effects upon the endocrine axis are called endocrine disruptors.

By binding to nuclear hormone receptors they may affect sexual differentiation. Unregulated exposure to xenoestrogens such as bisphenol A is now incriminated in the occurrence of cryptorchidism and hypospadias Phtalates also adversely affect male differentiation by increasing the expression of COUP-TFII, a transcription factor which represses steroidogenic enzymes Evidence from animal studies show that environmental exposure to endocrine disrupting chemicals is at least partially responsible reviewed in , Phtalates may act as pseudo-estrogens biphenol A, alias BPA or as antiandrogens diethylhexylphtalate, alias DEHP ; however caution is required for interpretation of animal studies because of species differences.

In human testes, germ cells appear the most susceptible to damage by phthalates Atrazine, a herbicide widely used in the United States, demasculinizes male gonads and reduces sperm count by interfering with phosphodiesterase enzymes and SF1 A bewildering number of hormones and growth factors is involved in sex determination and differentiation, making it one of the best studied developmental processes. The uncovering of an active genetic pathway towards ovarian development has overturned the dogma of a default pathway towards female gonadal differentiation.

For the moment, testicular hormones retain their primacy in modeling the reproductive tract but who knows what surprises the future holds in store? Turn recording back on. National Center for Biotechnology Information , U.

Contents www. Search term. Sexual Differentiation Rodolfo Rey , M. Author Information Rodolfo Rey , M. E-mail: rodolforey cedie. Nathalie Josso , M. E-mail: nathalie. Chrystele Racine , PhD. E-mail: chrystele. ABSTRACT Genital sex differentiation involves a series of events whereby the sexually indifferent embryo progressively acquires male or female characteristics in the gonads, genital tract and external genitalia. The Gonadal Ridge The urogenital ridges are the common precursors of the urinary and genital systems and of the adrenal cortex.

The Germ Cells Initially formed exclusively by somatic cells, the gonads are subsequently colonized by the primordial germ cells PGCs. Survival of meiotic germ cells 94, 95 FST Follistatin 5q Survival of meiotic germ cells Stabilization of Testis Differentiation: Vascular, Cellular and Molecular Pathways In the XY fetus, the initially amorphous cluster of gonadal cells becomes segregated in two compartments: testicular cords and interstitial tissue.

Genes involved in male sex determination are shown in Fig. Differentiation of Sertoli and Leydig cells SRY is expressed in pre-Sertoli cells having delaminated from the coelomic epithelium in the central part of the indifferent gonad and induces their differentiation Timing Of Testicular Differentiation In order for the fetal testis to adequately differentiate and secrete masculinizing hormones, not only do all these factors need to be present at sufficient levels in the right cell lineage, but their expression must also be initiated within a narrow time window.

Germ Cell Interaction With Somatic Cells In The Developing Testis Upon arriving in the undifferentiated genital ridge, by the end of the 5 th week, germ cells continue to proliferate by mitosis and maintain bipotentiality for approximately one week. Ovarian Morphogenesis In the XX fetus, the gonad remains indifferent after the 7 th week from a histological standpoint, but a functional differentiation already develops: XX gonads become capable of estradiol production at the same time as XY gonads begin to synthesize testosterone Genetic Control Of Oogenesis And Folliculogenesis Two major events can be distinguished in ovarian development: germ cell migration, proliferation and meiosis, and folliculogenesis.

Wolffian ducts In the human embryo, Wolffian ducts originate in the intermediate mesoderm, laterally to somites in embryos 25 to 32 days old Table 1. Stabilization and differentiation of Wolffian ducts The second aspect of male differentiation of the internal genital tract is the stabilization and differentiation of the Wolffian ducts Testicular descent During human fetal development, the testis migrates from its initial pararenal position to its terminal location in the scrotum Fig.

Male Differentiation: Urogenital sinus and prostate Male orientation of the urogenital sinus is characterized by prostatic development and by the repression of vaginal development. Female Differentiation Female orientation of the urogenital sinus is characterized by lack of prostatic differentiation and the acquisition of a separate vaginal opening on the surface of the perineum Fig. Lack of regression Loss of germ cells in the ovary. Abnormal Leydig cells. Vagina, prostate, urethra and external genitalia Correct vaginal development requires Wnt , Pax and Vangl2 genes Table 5.

Androgens Testosterone or dihydrotestosterone DHT , binding to the same androgen receptor AR , are the main factors involved in maintenance of the Wolffian duct and differentiation of male sex accessory organs and external genitalia. Testosterone biosynthesis Beginning at 9 weeks, testosterone is produced from cholesterol by chorionic gonadotropin stimulation of fetal Leydig cells through the coordinated action of steroidogenic enzymes Fig.

Gonadotropin control of testosterone production Testosterone production by the human fetal testis is detectable at 9 weeks, peaks between 14 and 17 weeks and then falls sharply, so that in late pregnancy the serum concentrations of testosterone overlap in males and females. The androgen receptor Testosterone and DHT exert their action on androgen-dependent tissues by binding to the androgen receptor, a member of the steroid receptor family Fig.

Control of testicular descent Androgens are required to mediate the disappearance of the cranial suspensory ligament , and later for the inguinoscrotal phase of testicular descent. Nature Development Genes Dev. PLoS genetics 9:e Schmahl J, Capel B Cell proliferation is necessary for the determination of male fate in the gonad. Sex Dev. In addition, the Wolffian ducts are stimulated by testosterone to eventually develop into the spermatic ducts ductus deferens , ejaculatory ducts, and seminal vesicles.

If the fetal gonads do not secrete testosterone at the proper time, the genitalia develop in the female direction regardless of whether testes or ovaries are present. Sexual differentiation is completed at puberty , at which time the reproductive system in both women and men is mature. In such a complex system there are many opportunities for aberrant development. The causes of disorders of sexual differentiation, while not fully understood, have been greatly elucidated by advances in chromosomal analysis, the identification of isolated genetic defects in steroid hormone synthesis, and the understanding of abnormalities in steroid hormone receptors.

For more information about the embryological and anatomical aspects of the gonads and genitalia, see human reproductive system. For descriptions of chromosomes and the genes that they carry, see human genetics. Sexual differentiation. Info Print Cite. Submit Feedback. Thank you for your feedback.

Sexual differentiation embryology. Written By: Robert D. See Article History. Read More on This Topic. Differentiation between the sexes exists, therefore, as the primary difference represented by the distinction between eggs and sperm, by….

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