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Sexual differentiation in humans is the process of development ofsex differences in humans. It is defined as the development ofphenotypic structures consequent to the action of hormones produced following gonadal determination.[1]Sexual differentiation includes development of different genitalia and the internal genital tracts and body hair plays a role in sex identification.[2]
The development of sexual differences begins with theXY sex-determination system that is present in humans, and complex mechanisms are responsible for the development of the phenotypic differences betweenmale andfemalehumans from an undifferentiatedzygote.[3] Females typically have twoX chromosomes, and males typically have aY chromosome and an X chromosome. At an early stage inembryonic development, both sexes possess equivalent internal structures. These are themesonephric ducts andparamesonephric ducts. The presence of theSRY gene on the Y chromosome causes the development of the testes in males, and the subsequent release of hormones which cause theparamesonephric ducts to regress. In females, the mesonephric ducts regress.
Disorders of sexual development (DSD), encompassing conditions characterized by the appearance of undeveloped genitals that may be ambiguous, or look like those typical for the opposite sex, sometimes known asintersex, can be a result of genetic and hormonal factors.[4]
Mostmammals, including humans, have anXY sex-determination system: theY chromosome carries factors responsible for triggering male development. In the absence of a Y chromosome, the fetus will undergo female development. This is because of the presence of the sex-determining region of the Y chromosome, also known as theSRY gene.[5] Thus, male mammals typically have an X and a Y chromosome (XY), while female mammals typically have twoX chromosomes (XX).
Chromosomal sex is determined at the time offertilization; achromosome from thesperm cell, either X or Y, fuses with the X chromosome in the egg cell.Gonadal sex refers to the gonads, that is the testicles or ovaries, depending on which genes are expressed.Phenotypic sex refers to the structures of the external and internal genitalia.[6]
Six weeks elapse after fertilization before the first signs of sex differentiation can be observed in human embryos.[5] The embryo and subsequent early fetus appear to be sexually indifferent, looking neither like a male or a female. Over the next several weeks, hormones are produced that cause undifferentiated tissue to transform into either male or female reproductive organs. This process is called sexual differentiation. The precursor of the internal female sex organs is called theMüllerian system.
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![Figure One: The mesonephric System Pathway [7]](/mt/?noimg=&dark=on&url=https%3a%2f%2fwikipedia.org%2fwiki%2fFile%3aSRY_Gene_Pathway.jpg)
Differentiation between the sexes of the sex organs occurs throughout embryological, fetal and later life. In both males and females, the sex organs consist of two structures: the internal genitalia and the external genitalia. In males, the gonads are thetesticles and in females, they are theovaries. These are the organs that producegametes (egg and sperm), the reproductive cells that will eventually meet to form the fertilized egg (zygote).
As the zygote divides, it first becomes theembryo (which means 'growing within'), typically between zero and eight weeks, then from the eighth week until birth, it is considered the fetus (which means 'unborn offspring'). The internal genitalia are all the accessory glands and ducts that connect the gonads to the outside environment. The external genitalia consist of all the external reproductive structures. The sex of an early embryo cannot be determined because the reproductive structures do not differentiate until the seventh week. Prior to this, the child is considered bipotential because it cannot be identified as male or female.
The internal genitalia consist of two accessory ducts:mesonephric ducts (Woffian duct) andparamesonephric ducts (Müllerian ducts). The mesonephric system is the precursor to the male genitalia and the paramesonephric to the female reproductive system.[8] As development proceeds, one of the pairs of ducts develops while the other regresses. This depends on the presence or absence of the sex determining region of the Y chromosome, also known as the SRYgene.[5] In the presence of a functional SRY gene, the bipotential gonads develop into testes.Gonads are histologically distinguishable by 6–8 weeks of gestation.
Subsequent development of one set and degeneration of the other depends on the presence or absence of two testicular hormones:testosterone andanti-Müllerian hormone (AMH). Disruption of typical development may result in the development of both, or neither, duct system, which may produce morphologicallyintersex individuals.
Males: The SRY gene when transcribed and processed produces SRY protein that binds to DNA and directs the development of the gonad into testes. Male development can only occur when the fetal testis secretes key hormones at a critical period in early gestation. The testes begin to secrete three hormones that influence the male internal and external genitalia: they secrete anti-Müllerian hormone (AMH),testosterone, anddihydrotestosterone (DHT). Anti-Müllerian hormone causes the paramesonephric ducts to regress. Testosterone converts the mesonephric ducts into male accessory structures, including theepididymides,vasa deferentia, andseminal vesicles. Testosterone will also control the descending of the testes from the abdomen.[1] Many other genes found on otherautosomes, includingWT1,SOX9 andSF1 also play a role in gonadal development.[9]
Females: Without testosterone and AMH, the mesonephric ducts degenerate and disappear. The paramesonephric ducts develop into theuterus,fallopian tubes, and uppervagina (the lower vagina develops from the urogenital sinus).[9] There still remains a broad lack of information about the genetic controls of female development (as of 1992), and much remains unknown about the female embryonic process.[10] The mesonephric ducts are not completely useless in the female case: they secreteWNT9B, which is necessary for the elongation of the paramesonephric ducts. Elongation also happens through the active migration of the paramesonephric epithelium, which happens through aphosphoinositide 3-kinase pathway.[11]
By 7 weeks, a fetus has agenital tubercle,urogenital sinus,urogenital folds andlabioscrotal swellings. In females, without excess androgens, these become thevulva (clitoris,vestibule,labia minora andlabia majora respectively). Males become externally distinct between 8 and 12 weeks, as androgens enlarge the genital tubercle and cause the urogenital groove and sinus to fuse in the midline, producing an unambiguouspenis with a phallic urethra, and the labioscrotal swellings become a thinned, rugatescrotum where the testicles are situated. Dihydrotestosterone will differentiate the remaining male characteristics of the external genitalia.[1]
A sufficient amount of any androgen can cause externalmasculinization. The most potent isdihydrotestosterone (DHT), generated from testosterone in skin and genital tissue by the action of 5α-reductase. A male fetus may be incompletely masculinized if this enzyme isdeficient. In somediseases and circumstances, other androgens may be present in high enough concentrations to cause partial or (rarely) complete masculinization of the external genitalia of a genetically female fetus. The testes begin to secrete three hormones that influence the male internal and external genitalia. They secrete anti-Müllerian hormone, testosterone, and Dihydrotestosterone. Anti-Müllerian hormone (AMH) causes the paramesonephric ducts to regress. Testosterone, which is secreted and converts the mesonephric ducts into male accessory structures, such as epididymis, vas deferens and seminal vesicle. Testosterone will also control the descending of the testes from the abdomen into the scrotum. Dihydrotestosterone, also known as (DHT) will differentiate the remaining male characteristics of the external genitalia.[12]
Further sex differentiation of the external genitalia occurs atpuberty, when androgen levels again become disparate. Male levels of testosterone directly induce growth of the penis, and indirectly (via DHT) theprostate.
Alfred Jost observed that while testosterone was required for mesonephric duct development, the regression of theparamesonephric duct was due to another substance. This was later determined to be paramesonephric inhibiting substance (MIS), a 140 kD dimeric glycoprotein that is produced bySertoli cells. MIS blocks the development ofparamesonephric ducts, promoting their regression.[13] Today it’s better known as the anti-Müllerian hormone (AMH).
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Visible differentiation occurs atpuberty, whenestradiol and other hormones causebreasts to develop in typical females.
Human adults and children show many psychological and behavioral sex differences. Some (e.g. dress) are learned and cultural. Others are demonstrable across cultures and have both biological and learned determinants. For example, some studies claim girls are, on average, more verbally fluent than boys, but boys are, on average, better at spatial calculation.[14] It seems likely that this is due to males generally having a greater area allocated to the space-specialized parietal cortex, while females generally have relatively more brain area allocated to the verbal-associative-specialized temporal cortex.[15]
Disorders of sex determination (DSD) are classified into a multitude of categories.[16] These categories consists of different types of female disorders along with categories specifically for male DSDs. There are also sex chromosomal DSDs such as, the later mentioned, Klinefelter and Turner syndrome[16]
The following are some of the conditions associated with atypical determination and differentiation process:[17]
| Fetal age (weeks) | Crown-rump length (mm) | Sex differentiating events |
|---|---|---|
| 1 | blastocyst | X-inactivation, if more than one X chromosome present[20] |
| 4 | 2–3 | Development ofWolffian ducts |
| 5 | 7 | Migration of primordialgerm cells in the undifferentiatedgonad |
| 6 | 10–15 | Development ofMüllerian ducts |
| 7 | 13–20 | Male: Differentiation ofseminiferous tubules |
| 8 | 30 | Male: Regression of Müllerian ducts |
| 8 | 32–35 | Male: Appearance ofLeydig cells. First synthesis oftestosterone |
| 9 | 43 | Male: Total regression of Müllerian ducts. Female: Loss of sensitivity of Müllerian ducts in the female fetus |
| 9 | 43 | Female: First meioticprophase inoogonia |
| 10 | 43–45 | Male: Beginning ofmasculinization of externalgenitalia |
| 10 | 50 | Female: Beginning of regression of Wolffian ducts |
| 12 | 70 | Male: Fetaltestis is in the internalinguinal ring |
| 12–14 | 70–90 | Male: Penileurethra is completed |
| 14 | 90 | Male: Appearance of firstspermatogonia |
| 16 | 100 | Female: Appearance of firstovarian follicles |
| 17 | 120 | Male: Numerous Leydig cells. Peak of testosterone secretion |
| 20 | 150 | Male: Regression of Leydig cells. Diminished testosterone secretion |
| 24 | 200 | Female: First multilayered ovarian follicles. Canalisation of the vagina |
| 28 | 230 | Female: Cessation of oogonia multiplication |
| 28 | 230 | Male: Descent of testis |
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| Genetic basis |
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