Early Human Sexual Development
Up to the ninth week of gestation, the external genitalia (external sexual organs) are identical in appearance in both male and female human embryos. There is a phallus that will become a penis in males and a clitoris in females and labioscrotal swelling that will become a scrotum in males and labial folds in females. Sexual differentiation into a male or female is governed by his or her sex chromosomes (the X and Y chromosomes) and hormones. An individual who has two X chromosomes normally develops into a female, and one who has one X and one Y chromosome normally develops into a male. It is the Y chromosome that determines the development of a male. The Y chromosome causes the primitive gonads (the gonads that have not developed into either an ovary or a testis) to develop into testes and to produce testosterone (the male sex hormone). It is testosterone that acts on the early external genitalia and causes the development of a penis and scrotum. If testosterone is not present, or the receptors for it are lacking, regardless of the chromosome constitution of the embryo, female external genitalia will develop.
Intersexuality: Causes and Effects
Intersex individuals have both male and female gonads. At birth, intersex individuals can have various combinations of external genitalia, ranging from completely female to completely male genitalia. Many intersex individuals have external genitalia that are ambiguous (genitalia somewhere between normal male and normal female) and may consist of what appears to be an enlarged clitoris or a small penis, hypospadias (a urinary tract opening at the base of or along the penis or scrotum instead of the tip), and a vaginal opening. The extent to which the genitalia are masculinized depends on how much testosterone was produced and received by the testicular portion of the gonads during development. The gonadal structures of an intersex individual can range from a testis on one side and an ovary on the other side, to testes and ovaries on each side, to an ovotestis (a single gonad with both testicular and ovarian tissue) on one or both sides.
Intersexuality has different causes. The chromosomal or genotypic sex of an intersex individual can be 46,XX, 46,XY, 45 XO (Turner syndrome), 47,XXX (triple X), or 47 XXY (Klinefelter syndrome). Chromosomal mutations can cause intersexuality. The absence or dysfunction of the SRY locus produces an individual with normal female genitalia but a 46,XY karyotype. Individuals with a 46,XX karyotype who have the SRY locus transposed to one of their X chromosomes will have a normal male appearance. Likewise, the genes WT1, SOX9, and SF1 are necessary for normal testicular development.
Some affected individuals have different types of mosaicism, such as 46,XX/47,XXY or 45,X/46,XY. Individuals with a 46,XX/46,XY karyotype are known as chimeras. Chimerism usually occurs through the merger of two different cell lines (genotypes), such as when two separate fertilized eggs fuse together to produce one embryo. This can result in a single embryo with some cells being 46,XX and some being 46,XY. Mosaicism means having at least two different cell lines present in the same individual, but the different cell lines are caused by losing or gaining a chromosome from some cells early in development. An example would be an embryo that starts out with all cells having a 47,XXY chromosome constitution and then loses a single Y chromosome from one of its cells, which then produces a line of 46,XX-containing cells. This individual would have a karyotype written as 46,XX/47,XXY. In a chimera or mosaic individual, the proportion of developing gonadal cells with Y chromosomes determines the appearance of the external genitalia. More cells with a Y chromosome mean that more testicular cells are formed and more testosterone is produced.
Hormones also play a part in determining the sex of an individual. Abnormalities of testosterone production or abnormalities in the testosterone receptor at the cellular level can cause 46, XY intersex (formerly called "male pseudohermaphroditism"). One example is a deficiency in 5-alpha-reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT). When there is a deficiency of this enzyme, there will be a deficiency of DHT, which is the hormone primarily responsible for masculinization of external genitalia. An individual who is genetically male but lacks DHT will have female-appearing external genitalia or ambiguous genitalia at birth. Often these individuals are reared as females, but at puberty they will masculinize because of greatly increased production of testosterone. These individuals may actually develop into nearly normal-appearing males. Abnormalities of the testosterone receptor, known as androgen insensitivity syndrome, can also result in a range of different conditions in affected males, from normal female appearance (a totally defective receptor) to ambiguous genitalia (partially defective receptor). These individuals will not masculinize at puberty because no matter how much testosterone or DHT they produce, their bodies cannot respond to the hormones. Similarly, deficiency in aromatase (an estrogen-producing enzyme), overproduction of androgen due to congenital adrenal hyperplasia, and in utero exposure to testosterone can cause 46, XX intersex (formerly "female pseudohermaphroditism").
The cause of intersexuality in the majority of affected individuals is unknown, although it has been postulated that those intersex individuals with normal male or female karyotypes may have hidden chromosome mosaicism in just the gonadal tissue.
Impact and Applications
Intersex individuals with ambiguous genitalia are normally recognized at birth. It is essential that these individuals have a thorough medical evaluation, since some causes of ambiguous genitalia, such as congenital adrenal hyperplasia, can be life-threatening if not recognized and treated promptly. Once intersexuality is diagnosed in a child, the decision must be made whether to raise the child as a boy or a girl. This decision is made by the child’s parents working with specialists in genetics, endocrinology, psychology, and urology. Typically, the karyotype and appearance of the external genitalia of the child are the major factors in deciding the sex of rearing. Previously, most intersex individuals with male karyotypes who had either an absent or an extremely small penis were reared as females. The marked abnormality or absence of the penis was thought to prevent these individuals from having fulfilling lives as males. This practice has been challenged by adults who are 46,XY but were raised as females. Some of these individuals believe that their conversion to a female gender was the wrong choice, and they prefer to think of themselves as male. Intersex individuals with a female karyotype and normal or near-normal female external genitalia are typically reared as females.
The debate over what criteria should be used to decide sex of rearing of a child is ongoing. An increasingly important part of this debate is the concept of gender identity, which describes what makes people male or female in their own minds rather than according to what sex their genitalia are. This is an especially important issue for those individuals with chimerism or mosaicism who have both a male and female karyotype. The decision to raise these individuals as boys or girls is made primarily on the basis of the degree to which their external genitalia are masculinized or feminized.
Those intersex individuals who have normal female or male genitalia at birth are at risk for developing abnormal masculinization in the phenotypic females or abnormal feminization in the phenotypic males at puberty if both testicular and ovarian tissue remains present. Thus, the gonad that is not specific for the assigned sex of the individual may be surgically removed. Gonadal tissue may be also removed because the cells of the gonad(s) that have a 46,XY karyotype are at an increased risk of becoming cancerous. Medical professionals increasingly recommend that surgeries, other than those necessary for urinary function, be delayed until the affected individual is old enough to have input in the decision-making process.
Key terms
ambiguous genitalia
:
external sexual organs that are not clearly male or female
genotype
:
an organism’s complete set of genes
gonad
:
an organ that produces reproductive cells and sex hormones; termed ovaries in females and testes in males
karyotype
:
a description of the chromosomes of an individual’s cells, including the number of chromosomes and a physical description of them (normal female is 46,XX and normal male is 46,XY)
phenotype
:
the physical and biochemical characteristics of an individual based on the interaction of genotype and environment
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