What is sexual differentiation? |

Fundamentals

The chromosomal sex of a human is determined at the time of conception, when the ovum from the mother is fertilized by a single sperm from the father. All ova (eggs) produced by a female contain one chromosome, denoted X. Sperm from the male can carry either an X or a Y chromosome. The Y chromosome is smaller than the X and contains fewer genetic codes. Men normally produce equal numbers of X- and Y-bearing sperm. The type of chromosome carried by the one sperm that fertilizes the ovum will determine the sex of the embryo. A Y-bearing sperm joining with the ovum will result in an embryo with one X and one Y; this embryo will develop as a male. If the ovum is fertilized with an X-bearing sperm, the embryo will have two X’s and will develop as a female.

Although the genetic sex is determined at conception, male and female embryos initially look alike, both internally and externally. For the first seven weeks of development, each human embryo has the anatomical potential to develop in either a male or a female direction: This period is referred to as the sexually indifferent stage. Internally, the gonads, which lie in the kidney region, cannot yet be identified as ovaries or testes. The other internal reproductive organs are represented in every embryo by two pairs of ducts: the Müllerian ducts, which will later develop in the female but will be lost in the male; and the Wolffian ducts, which will later develop in the male but will regress in the female. Externally, male and female embryos possess the same rudimentary genital organs, which will later be remodeled to become either male or female genitalia.

The first organ to differentiate in the embryo is the gonad. Starting at about seven weeks of development in a male embryo, the cells within the gonad are reorganized to form a testis. This reorganization is brought about by the presence of the Y chromosome, which contains the codes for the production of a substance called testis-determining factor (TDF). The chemical nature of TDF has not yet been determined, but its existence is clear from experimental evidence. TDF acts on the gonad to cause it to become a testis. In the absence of a Y chromosome and TDF in a female embryo, the gonad develops into an ovary at about twelve weeks of development. If an individual has only one X chromosome (a condition known as Turner syndrome), the gonads will develop into ovaries, but these ovaries will not contain ova, and so the person will be infertile.

The development of the other reproductive organs is not directly determined by the X and Y chromosomes, but rather by hormones secreted by the gonads. In the male, the fetal testes begin to produce testosterone by the tenth week of development, and this testosterone acts on the Wolffian duct system to cause it to develop into the epididymis, vas deferens, and seminal vesicles. The Müllerian duct system in the male regresses under the influence of another hormone from the testes, called Müllerian-inhibiting hormone (MIH). In the female, MIH is not produced, and the Müllerian ducts develop into the oviducts, uterus, and upper part of the vagina. The Wolffian ducts in the female regress in the absence of testosterone. Normal female development does not, at this stage, require any hormone produced by the ovaries, but instead occurs spontaneously in the absence of testicular hormones. Thus, the presence or absence of the Y chromosome determines which type of gonad develops, and the presence or absence of gonadal hormones
determines which type of internal reproductive organs develop.

Similarly, the development of the external genitalia is hormonally directed. In the male, testosterone is converted by the action of the enzyme 5-alpha-reductase to 5-alpha-dihydrotestosterone (DHT). DHT acts on the undifferentiated external genital tissue, causing it to take on a male appearance: A pea-shaped structure (the genital tubercle) at the front of the crotch area grows to become the penis, a slitlike opening (the urethral groove) is enclosed within the penis to become the urethra when two folds behind the genital tubercle fuse together, and two swellings on the sides of the urethral groove become enlarged as the scrotum. In the female, it is the absence of DHT that causes development in the female direction: The genital tubercle remains as the relatively small clitoris; the folds do not fuse, allowing the urethral groove to remain as an open area where the vagina and urethral openings are located; and the swellings that become the scrotum in the male remain separated as the labia in the female.

Hormones also cause sexual differentiation of the brain, but this mechanism is not fully understood in humans. The most obvious result of brain differentiation is the difference in adult hormone production patterns. In the adult male, hormone production is relatively constant from day to day, and this results in constant production of sperm in the testes. In the female, hormone production changes in a monthly cycle that is associated with ovum maturation and ovulation. The difference in the pattern of hormone release in adult males and females appears to be attributable to hormonal programming of the fetal brain. Animal studies indicate that the development of the male pattern results from exposure of the fetal brain to testosterone or one of its derivatives. The female pattern of development is prevalent when testosterone is absent. In humans, testosterone also affects brain differentiation, but the effect appears to be less permanent than in animals.

It is not known for sure if there is any direct influence of the chromosomes or prenatal hormones on male and female behavior. Most researchers agree that human behavior is heavily influenced by social and cultural factors, so the importance of prenatal programming is difficult to assess. Indeed, it appears that gender identity, the internal view of oneself as male or female, is so heavily influenced by learning that a child with a disorder of sexual differentiation can be successfully reared in the gender that is opposite to that of the chromosomes. For example, a child born with female-appearing genitalia, but with XY chromosomes and internal testes, can be reared as a girl and may firmly adhere to this identity even if some masculinization occurs at the time of puberty.

Disorders and Diseases

Disorders of sexual differentiation—also referred to as differences of sexual differentiation by those who object to pathologizing genetic variations that are atypical but not harmful—result from errors in the signaling systems that normally direct male and female anatomical development. There are several different classes of these disorders, some of which result in a mixture of male and female reproductive organs. "Intersex" is an umbrella term that has come into use for individuals not clearly identifiable as male or female based on their internal or external sex characteristics.

True hermaphrodites are intersex individuals who possess both ovarian and testicular gonadal tissue. There may be one ovary and one testis, two gonads in which ovarian and testicular tissue are combined (ovotestes), or an ovotestis on one side and a normal ovary or testis on the other. True hermaphroditism can result from several distinct genetic anomalies. Some hermaphrodites have been shown to be chimeras, or individuals that develop from the fusion of two separate embryos at an early stage. These individuals possess two distinct cell populations, one with an XX pair of chromosomes and one with XY. It is thought that expression of both of these chromosome pairs leads to the mixture of ovarian and testicular tissue seen in true hermaphrodites. A similar condition is mosaicism, in which the mixture of XX and XY cells is caused by errors of chromosome replication in a single early embryo. Other true hermaphrodites are neither chimeras nor mosaics; they appear to have a normal pair of XX or XY chromosomes, but on closer examination, one of the chromosomes is found to have a defect. For example, a Y chromosome may be missing a tiny piece, or an X chromosome may contain a portion of a Y.

There is much variation in the anatomical features of true hermaphrodites. One basic guideline is that the effects of the presence of testicular tissue are local. Thus, a true hermaphrodite with a testis on the left side and an ovary on the right will have Wolffian duct-derived (male) organs on the left side but Müllerian duct-derived (female) organs on the right. The external appearance depends on the relative levels of estrogen and testosterone but might include a typical male penis along with enlarged breasts. There are documented cases of ovulation and even pregnancy in true hermaphrodites. Successful sperm production appears to be less frequent than ovulation, and sperm production and ovulation are not seen in the same individual.

Pseudohermaphrodites are individuals whose external reproductive organs do not match their gonadal sex. Male pseudohermaphrodites have testes but external organs that appear to be female; female pseudohermaphrodites have ovaries and varying degrees of external male development.

Female pseudohermaphroditism has only one basic cause: the exposure of an XX fetus to masculinizing hormones. These hormones might come from the fetus itself, as in certain disorders involving the adrenal gland, or synthetic hormones given to a pregnant woman may have a masculinizing effect on a female fetus. The extent of masculinization depends on the timing of the hormone exposure, with earlier exposure leading to more extensive malelike appearance of the external genitalia, including fusion of the urethral folds and enlargement of the clitoris. The internal organs are normal female.

Male pseudohermaphroditism arises from a wide variety of causes. There may be failure of testosterone production, or the reproductive organs may lack testosterone receptors, causing them to fail to respond to the hormone. Because of the hormonal abnormalities, the Wolffian duct organs may fail to develop, and the external genitalia will appear female to some extent. If MIH production is normal, internal female organs will not be present. The appearance at puberty is variable, depending on the exact hormonal deficiency. Some individuals undergo the typical male responses of increased muscle mass, deepening of the voice, and growth of beard and chest hair; others do not. Most male pseudohermaphrodites are infertile because of the hormonal problems.

Treatment of disorders of sexual development depends on the exact symptoms and their cause, but the prevailing overall philosophy is to attempt to produce an individual who will be able to function sexually as an adult, even if that means sacrificing fertility and rearing the child in the sex opposite to that of the child's chromosomes. Early diagnosis is a key, since most authorities agree that for the most part, gender identity (a person's subjective perception of their own gender) is established by the age of eighteen to twenty-four months. After that time, few physicians would recommend trying to alter the individual’s gender identity from that which has already been established. On the other hand, some intersex activists oppose any kind of medical intervention in cases of intersexuality until the individual is old enough to give informed consent.

For true hermaphrodites, the choice of sex for rearing usually depends on the predominant appearance of the external genitalia. If the genital tubercle has remained small, like a clitoris, the decision is usually for a female sex assignment; if the tubercle appears more penislike, the individual can be reared as a male. Usually, the gonadal tissue that does not correspond to the sex of rearing will be removed, to prevent the production of hormones that would interfere with the desired appearance. Appropriate hormone treatment and surgery can enhance the body form of the chosen sex. For example, testosterone treatment will cause beard growth, and estrogen treatment will cause breast development.

In the case of female pseudohermaphrodites, most can successfully be reared as girls. Surgical alteration of the external genitalia and hormone treatment to correct the original problem may be necessary. Assuming early diagnosis and treatment, most female pseudohermaphrodites will be fertile as adults.

Similarly, hormonal treatment of male pseudohermaphrodites who do not produce testosterone can allow these individuals to be reared as boys, even if they are not fertile later. There is no treatment, however, that will allow a male pseudohermaphrodite who is unresponsive to testosterone to develop a male appearance; these individuals are usually reared as girls, with female pubertal development induced by estrogen treatment.

Perspective and Prospects

Anatomical descriptions of people with disorders of sexual development are found in writings beginning in the pre-Christian era. The word “hermaphrodite”—which is no longer universally accepted, considered by some to be pejorative—itself derives from the Greek myth about Hermaphroditos, the son of Hermes and Aphrodite, whose body was permanently merged with that of a nymph in a loving embrace. The myth probably arose from a desire to explain the existence of intersex people.

Although the existence of intersexuality was known long ago (and called by different terms), there was no understanding of the mechanism of sexual differentiation until modern times. During the nineteenth century, embryological studies firmly established the concept that the early human embryo is sexually indifferent anatomically. In the twentieth century, genetic and hormonal studies revealed the controlling factors in male and female development.

It was in the 1920s that the X and Y chromosomes were first discovered and recognized to be important in sex determination. Since the 1960s, researchers have had the ability to pinpoint the exact chromosome sites associated with many disorders of sexual differentiation. Ongoing efforts deal with the identification of the TDF coded by the Y chromosome and the mechanism by which TDF causes testicular development.

The nature of the hormonal control of sexual differentiation was determined by experiments such as those performed on rabbit embryos by A. Jost in the 1940s and 1950s. Jost systematically removed or transplanted embryonic testes and ovaries, and treated the embryos with estrogen and testosterone, in order to demonstrate the importance of hormones from the testis on the development of the internal and external reproductive organs.

Jost’s conclusions for rabbits were confirmed in humans by studying individuals with disorders of sexual differentiation caused by genetic factors. Additional confirmation came from observations of the offspring of pregnant women treated with synthetic hormones as a possible preventive for miscarriage. Such treatment was later found to be ineffective in preventing miscarriage, and resulted in the birth of masculinized female babies. It is now recognized that synthetic hormones in oral birth control pills can also masculinize female fetuses.

Discovery of the causes of true hermaphroditism and pseudohermaphroditism have allowed physicians to make important distinctions between these conditions, with a clear physical cause and manifestation, and the psychological disorders of sexuality that were previously confused with them. For example, until the middle of the twentieth century, the term “hermaphrodite” was used to refer not only to people with a mixture of male and female reproductive organs, but also, in some cases, to those with a subjective gender identity that did not match their assigned sex. The latter individuals are now called transgender; transgender individuals may identify themselves by the gender opposite from the one indicated by their reproductive organs, or they may identify with both genders, or they may identify with neither gender; there are a host of evolving terms for each of these and other varieties of gender identity. A final point is that physical sexual differentiation is a separate subject from, and not necessarily correlated with, sexual orientation.

Bibliography

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