Sexual differentiation

This article is about the development of sexual dimorphisms in humans. For sex differences for all animals, see Sexual dimorphism.

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, and psyche.

Sex differences range from nearly absolute to simply statistical. Sex-dichotomous differences are developments which are wholly characteristic of one sex only. Examples of sex-dichotomous differences include aspects of the sex-specific genital organs such as ovaries, a uterus or a phallic urethra. In contrast, sex-dimorphic differences are matters of degree (e.g., size of phallus). Some of these (e.g., stature, behaviors) are mainly statistical, with much overlap between male and female populations.

Nevertheless, even the sex-dichotomous differences are not absolute in the human population, and there are individuals who are exceptions (e.g., males with a uterus, or females with an XY karyotype), or who exhibit biological and/or behavioral characteristics of both sexes.

Sex differences may be induced by specific genes, by hormones, by anatomy, or by social learning. Some of the differences are entirely physical (e.g., presence of a uterus) and some differences are just as obviously purely a matter of social learning and custom (e.g., relative hair length). Many differences, though, such as gender identity, appear to be influenced by both biological and social factors ("nature" and "nurture").

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 various ways that genes, hormones, and upbringing affect different human behaviors and mental traits are difficult to test experimentally and charged with political conflict.

Chromosomal sex differences

Humans have forty-six chromosomes, including two 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).

Timeline

Human prenatal sexual differentiation

Fetal age (weeks)	Crown-rump length (mm)	Sex differentiating events
0	blastocyst	Inactivation of one X chromosome
4	2-3	Development of wolffian ducts
5	7	Migration of primordial germ cells in the undifferentiated gonad
6	10-15	Development of müllerian ducts
7	13-20	Differentiation of seminiferous tubules
8	30	Regression of müllerian ducts in male fetus
8	32-35	Appearance of Leydig cells. First synthesis of testosterone
9	43	Total regression of müllerian ducts. Loss of sensitivity of müllerian ducts in the female fetus
9	43	First meiotic prophase in oogonia
10	43-45	Beginning of masculinization of external genitalia
10	50	Beginning of regression of wolffian ducts in the female fetus
12	70	Fetal testis is in the internal inguinal ring
12-14	70-90	Male penile urethra is completed
14	90	Appearance of first spermatogonia
16	100	Appearance of first ovarian follicles
17	120	Numerous Leydig cells. Peak of testosterone secretion
20	150	Regression of Leydig cells. Diminished testosterone secretion
24	200	First multilayered ovarian follicles. Canalisation of the vagina
28	230	Cessation of oogonia multiplication
28	230	Descent of testis

• Reference: PC Sizonenko in Pediatric Endocrinology, edited by J. Bertrand, R. Rappaport, and PC Sizonenko, (Baltimore: Williams & Wilkins, 1993), pp. 88–99.

Gonadal differentiation

Early in fetal life, germ cells migrate from structures known as yolk sacs 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 theca cells and granulosa 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.

Genital differentiation

Main article: Development of the urinary and reproductive organs

A differentiation of the sex organ can be seen. However, this is only the external genital differentiation. There is also an internal genital differentiation.

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. Disruption of typical development may result in the development of both, or neither, duct system, which may produce morphologically intersexual individuals.

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

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.

Hair differentiation

The amount and distribution of body hair differs between the sexes. Males have more terminal hair, especially on the face, chest, abdomen and back, and females have more vellus hair, which is less visible. This may also be linked to neoteny in humans, as vellus hair is a juvenile characteristic.

Other body differentiation

The differentiation of other parts of the body than the sex organ creates the secondary sex characteristics.

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, in addition to breast differentiation, 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.

The difference in adult masculine and feminine faces is largely a result of a more prominent chin, heavier jaw and jaw muscle development and thicker orbital eyebrow bossing. Masculine features on average are slightly thicker and coarser. Androgen-induced recession of the male hairline accentuates these differences by middle adult life.

Sexual dimorphism of skeletal structure develops during childhood, and becomes more pronounced at adolescence. Sexual orientation has been demonstrated to correlate with skeletal characters that become dimorphic during early childhood (such as arm length to stature ratio) but not with characters that become dimorphic during puberty (such as shoulder width) (Martin & Nguyen, 2004).

Brain differentiation

In most animals, differences of exposure of a fetal or infant brain to sex hormones produce significant differences of brain structure and function which correlate with adult reproductive behavior. This seems to be the case in humans as well; sex hormone levels in male and female fetuses and infants differ, and both androgen receptors 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.^{[citation needed]}

Psychological and behavioral differentiation

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 are demonstrable across cultures and may have both biological and learned determinants. For example, girls are, on average, more verbally fluent than boys, but males, on average, are better at spatial calculation. Because we cannot explore hormonal influences on human 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.

Current theories of mechanisms of sexual differentiation of brain and behaviors in humans are based primarily on three sources of evidence: animal research involving manipulation of hormones in early life, observation of outcomes of small numbers of individuals with disorders of sexual development (intersex conditions or cases of early sex reassignment), and statistical distribution of traits in populations (e.g., rates of homosexuality in twins). Many of these cases suggest some genetic or hormonal effect on sex differentiation of behavior and mental traits;^[1] others do not^{[citation needed]}.

In addition to affecting development, changing hormone levels affect certain behaviors or traits that are gender dimorphic, such as superior verbal fluency among women.^[2]

In most mammalian species females are more oriented toward child rearing and males toward competition with other males.

Biology of gender

Main article: Biology of gender

Biology of gender is the scientific analysis of the physical basis for behavioural differences between men and women. It deals with gender identity, gender roles and sexual orientation.

Defeminization and masculinization

Main article: Defeminization and masculinization

Defeminization and masculinization are the differentiating processes that a fetus goes through to become male. From this perspective, the female is the default path for a developing human being in that gene actions that are eliminated and that are necessary for formation of male genitalia lead to the development of external female genitalia.

Biologically, this perspective is supported by the fact that there are neither female genes nor female hormones that correspond to the hormones active in males only. Estrogen, for instance, is present in both the male and female fetus.

See also

• Sex determination and differentiation (human)
• Virilization
• Sexual dimorphism
• Sex differences in humans
• List of homologues of the human reproductive system
• gender
• Sex-determination system
  • XY sex-determination system
  • X0 sex-determination system
  • ZW sex-determination system
  • Haplo-diploid sex-determination system
• Fetal genital development

References

1. ^ Pinker, Steven. The Blank Slate. New York: Penguin. 2002. pages 346-350
2. ^ Pinker, Steven. The Blank Slate. New York: Penguin. 2002. pages 347-348

Bibliography

• Baum MJ. Mammalian animal models of psychosexual differentiation: When is ‘translation’ to the human situation possible? (2007)Hormones and Behavior 50:579–88.
• Crouch RA. Betwixt and between: the past and future of intersexuality. J Clin Ethics 9:372-384.
• Hughes IA, Houk C, Ahmed SF, Lee PA, LWPES/ESPE Consensus Group. (2006) Consensus statement on management of intersex disorders. Arch Dis Childhood.
• Martin, J. T. and Nguyen, D. H. (2004). Anthropometric analysis of homosexuals and heterosexuals: implications for early hormone exposure. Hormones and Behavior 45. 31-39.
• Phoenix, C.H., Goy, R.W., Gerall, A.A. and Young, W.C. (1959). Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology 65, 369-382.
• Wallen, K. (2005) Hormonal influences on sexually differentiated behavior in nonhuman primates. Frontiers in Neuroendocrinology 26, 7-26.
• Wilson BE, Reiner WE. (1998) Management of intersex: a changing paradigm. J Clin Ethics 9:360-9.

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