Sexual differentiation

Sexual differentiation is the process of development of the differences between males and females from an undifferentiated zygote (fertilized egg). As male and female individuals develop from zygotes into fetuses, into infants, children, adolescents, and eventually into adults sex and gender differences at many levels develop: genes, chromosomes, gonads, hormones, anatomy, psyche, and social behaviors.

Sex differences range from chromosomes to anatomy to behavior. For most persons, sex-dichotomous differences are absolute (e.g., a uterus or penile urethra), while sex-dimorphic differences are matters of degree (e.g., size of phallus). Some (e.g., stature, behaviors) are mainly statistical, with much overlap between male and female populations. Differences may be induced by specific genes, by hormones, by anatomy, or by learning. However, in a significant minority of individuals the usual sequence of differentiation described below does not follow the usual track, and discordances between various levels of differentiation develop. In a few people, even some of the typically dichotomous differences may be "in-between."

The early stages of human differentiation appear to be quite similar to the same biological processes in other mammals and the interaction of genes, hormones and body structures is fairly well understood. In the first weeks of life, a fetus has no anatomic or hormonal sex, and only a karyotype distinguishes male from female. Specific genes induce gonadal differences, which produce hormonal differences, which cause anatomic differences, leading to psychological and behavioral differences, some of which are innate and some induced by the social environment.

The relationship of biological factors to more advanced and more specifically human aspects of differentiation, and especially the ways and degrees by which social and environmental influences contribute to differentiation, is less well understood.

Although an oversimplification in many respects, there is still some heuristic validity in describing human physical development as inherently female unless there are specific instructions to the contrary at the genetic, gonadal, and hormonal levels.

Chromosomal sex differences

Humans have 46 chromosomes, including 2 sex chromosomes, XX in females and XY in males. It is obvious that the Y chromosome must carry at least one essential gene which determines testicular formation (originally termed TDF). A gene in the sex-determining region of the short arm of the Y, now referred to as SRY, has been found to direct production of a protein which binds to DNA, inducing differentiation of cells derived from the genital ridges into testes. In transgenic XX mice (and some human XX males), SRY alone is sufficient to induce male differentiation.

Investigation of other cases of human sex reversal (XX males, XY females) has led to discovery of other genes crucial to testicular differentiation on autosomes (e.g., WT-1, SOX9, SF-1), and the short arm of X (DSS).

Gonadal differentiation

Early in fetal life, germ cells migrate to the genital ridge. By week 6, undifferentiated gonads consist of germ cells, supporting cells, and steroidogenic cells.

In a male, SRY and other genes induce differentiation of supporting cells into Sertoli cells and (indirectly) steroidogenic cells into Leydig cells to form testes, which become microscopically identifiable and begin to produce hormones by week 8. Germ cells become spermatogonia.

Without SRY, ovaries form during months 2-6. Failure of ovarian development in 45,X girls (Turner syndrome) implies that two functional copies of several Xp and Xq genes are needed. Germ cells become ovarian follicles. Supporting and steroidogenic cells become granulosa cells and theca cells , respectively.

Hormonal differentiation

In a male fetus, testes produce steroid and protein hormones essential for internal and external anatomic differentiation. Leydig cells begin to make testosterone by the end of month 2 of gestation. From then on, male fetuses have higher levels of androgens in their systemic blood than females. The difference is even greater in pelvic and genital tissues. Antimullerian hormone (AMH) is a protein hormone produced by Sertoli cells from the 8th week on. AMH suppresses development of müllerian ducts in males, preventing development of a uterus.

Fetal ovaries produce estradiol, which supports follicular maturation but plays little part in other aspects of prenatal sexual differentiation, as maternal estrogen floods fetuses of both sexes.

Internal genital differentiation

Gonads are histologically distinguishable by 6-8 weeks of gestation. A fetus of that age has both mesonephric (wolffian) and paramesonephric (mullerian) ducts. Subsequent development of one set and degeneration of the other depends on the presence or absence of two testicular hormones: testosterone and AMH.

Local testosterone causes each wolffian duct to develop into epididymis, vas deferens, and seminal vesicles. Without male testosterone levels, wolffian ducts degenerate and disappear. Müllerian ducts develop into a uterus, fallopian tubes, and upper vagina unless AMH induces degeneration. The presence of a uterus is stronger evidence of absence of testes than the state of the external genitalia.

External genital differentiation

For illustrations, see the External links section.

By 7 weeks, a fetus has a genital tubercle, urogenital groove and sinus, and labioscrotal folds. In females, without excess androgens, these become the clitoris, urethra and vagina, and labia.

Males become externally distinct between 8 and 12 weeks, as androgens enlarge the phallus and cause the urogenital groove and sinus to fuse in the midline, producing an unambiguous penis with a phallic urethra, and a thinned, rugated scrotum.

A sufficient amount of any androgen can cause external masculinization. The most potent is dihydrotestosterone (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 is deficient. In some diseases 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.

Further sex differentiation of the external genitalia occurs at puberty, when androgen levels again become disparate. Male levels of testosterone directly induce growth of the penis, and indirectly (via DHT) the prostate.

Breast differentiation

Visible differentiation occurs at puberty, when estradiol and other hormones cause breasts to develop in girls. However, fetal or neonatal androgens may modulate later breast development by reducing the capacity of breast tissue to respond to later estrogen.

Other body differentiation

General habitus and shape of body and face, as well as sex hormone levels, are similar in prepubertal boys and girls. As puberty progresses and sex hormone levels rise, obvious differences appear.

In males, testosterone directly increases size and mass of muscles, vocal cords, and bones, enhancing strength, deepening the voice, and changing the shape of the face and skeleton. Converted into DHT in the skin, it accelerates growth of androgen-responsive facial and body hair. Taller stature is largely a result of later puberty and slower epiphyseal fusion .

In females, breasts are the most obvious manifestation of higher levels of estrogen, but estrogen also widens the pelvis and increases the amount of body fat in hips, thighs, buttocks, and breasts. Estrogen also induces growth of the uterus, proliferation of the endometrium, and menses.

Brain differentiation

In most animals, differences of exposure of a fetal or infant brain to sex hormones produce significant and irreversible differences of brain structure and function which correlate with adult reproductive behavior. In humans, sex hormone levels in male and female fetuses and infants differ, and both androgen and estrogen receptors have been identified in brains. Several sex-specific genes not dependent on sex steroids are expressed differently in male and female human brains. Structural sex differences begin to be recognizable by 2 years of age, and in adult men and women include size and shape of corpus callosum and certain hypothalamic nuclei, and the gonadotropin feedback response to estradiol.

Psychological and behavioral differentiation

Sex steroid differentiation of adult reproductive and other behavior has been demonstrated experimentally in many animals. In some mammals, adult sex-dimorphic reproductive behavior (e.g., mounting or receptive lordosis) can be shifted to that of the other sex by supplementation or deprivation of androgens in fetal life or early infancy, even if adult levels are normal.

Psychological and behavioral differentiation in humans

Human adults and children show many psychological and behavioral sex differences, both dichotomous and dimorphic. Some (e.g., dress) are learned and obviously cultural. Others (e.g., early verbal fluency, spatial reasoning) are demonstrable across cultures and may have both biological and learned determinants. Because we cannot explore hormonal influences on human reproductive behavior experimentally, and because potential political implications are so unwelcome to many factions of society, the relative contributions of biological factors and learning to human psychological and behavioral sex differences (especially gender identity, role, and orientation) remain unsettled and controversial.

Gender identity, role, and orientation

Gender identity is the subjective sense of being male or female-- it cannot be externally measured, only asserted by a person or sometimes inferred from the gender role, which consists of all behaviors which are sex-dimorphic in that person's culture. For an anatomically normal person, a sense that one's true gender identity differs from the sex of anatomy and rearing is termed gender identity disorder, also known as transsexualism or transgender.

In the 20th century it was widely assumed and taught by academics that gender identity and gender role are purely learned, with minimal biological determination. However, many individual cases are suggestive of hormonal and other physical influence.

Sexual orientation, the sex to which one is erotically most attracted is the most politically contentious aspect of psychosexual differentiation. Although the idea of a biological "cause" of homosexuality was mostly rejected in academic quarters in the 1970s and early 80s, recent reports of structural brain differences and mendelian inheritance patterns make a persuasive case for reconsidering a role for biologic factors in male homosexuality.

Although we are simply "M" or "F" in many of our relations with the institutions of our society, the degree to which various aspects of gender identity, gender role and sexual orientation are sex-dimorphic, rather than dichotomous, varies widely among cultures. Some argue that social gender roles should be even less dimorphic, or that more than two sexes/genders should be recognised.

These issues complicate management of infants with anatomic ambiguity or intersex conditions.

See also

• List of homologues of the human reproductive system
• gender

External links

• Human Sexual Differentiation by P. C. Sizonenko
• The Ciba Collection of Medical Illustrations: Vol.2, Reproductive System by Frank H. Netter, M.D. comparing female and male reproductive systems development and anatomy
• Development of the Female Sexual & Reproductive Organs – illustrations comparing female and male genitalia during the early development