Gender Differentiation in Humans

By Rene Fester Kratz

Humans are no strangers to the effects of hormones during development. In fact, human males and females are identical organisms until the time sexual differentiation occurs.

In the very early stages of development, human fetuses have two sets of ducts: one for the female reproductive system, and one for the male reproductive system. When both sets of ducts are present, the stage of development is called the indifferent stage (because there’s no difference yet between male and female).

Humans remain in this stage until about seven weeks after fertilization (about the end of the second month of pregnancy), which is why an ultrasound done any earlier than this time can’t tell the sex of the developing embryo.

The first ultrasound of a normal pregnancy is usually performed at 16 weeks of gestation, allowing visualization of the sex of a developing fetus.

The two sets of ducts are the Wolffian ducts, which eventually become the male vas deferens, epididymis (on the testes), and seminal vesicles, and the Müllerian ducts, which eventually become the oviducts, uterus, and vagina.

Inside the cells, the chromosomes determine whether the embryo will develop into a male or a female. Of the 46 human chromosomes, the last pair — the two Chromosomes 23 — are either two X chromosomes or an X and a Y chromosome. Two X chromosomes indicate female; an X and a Y indicate male. If two X chromosomes are inside the cells of the developing reproductive system, the female ducts develop, and the male ducts disintegrate. The reverse happens if an X chromosome and a Y chromosome are in the cells.

How boys become boys

A gene called SRY (for sex-determining region Y chromosome) is the specific gene that determines maleness. SRY contains the blueprint for a protein called testes determining factor (TDF), which is a transcription factor that interacts with DNA to turn on the transcription of the genes necessary for testes development. (Transcription factors are proteins that turn genes on and off.)

After the testes are formed, they begin to secrete the hormone testosterone (in the form dihydrotestosterone, or DHT). Testosterone supports the development of the male reproductive system and directs development of external genitalia. The tubules necessary for ejaculation of semen are complete at about 14 weeks of gestation (which is the beginning of the second trimester of pregnancy).

At about that time, the penis, testes, and scrotum develop from the urogenital tubercle, urogenital swellings, and urogenital folds. The urogenital tubercle becomes the glans penis in the male, the urogenital folds become the shaft of the penis, and the urogenital swellings become the scrotum.

If SRY is absent, the primary gonad develops into ovaries, but two X chromosomes are required for the ovaries to be maintained.

How girls become girls

The absence of DHT in a fetus is what spurs the development of female external genitalia. Without DHT, the urogenital tubercle becomes the clitoris (which is equivalent to the glans penis), the urogenital swellings become the labia majora, and the urogenital folds become the labia minora.

A female’s external genitalia develop even if the internal genitalia fail to develop. External female structures are completed between 14 and 16 weeks of gestation.

Problems with sexual development

The complex process of sexual differentiation involving genes and hormones isn’t without error. Following are the problems that can occur in the hormonal stimulation of genitalia:

  • Androgen insensitivity: A male who can’t develop external male genitalia has androgen insensitivity. Embryos with an abnormal androgen receptor can’t bind the DHT necessary to produce male genitalia. Therefore, they may be male genetically (XY), but they have female external genitalia.
  • Hermaphrodites: People with some male and some female characteristics are hermaphrodites. This condition can result from hormonal imbalances. In embryos that oversecrete adrenal androgens (hormones that are involved in the normal synthesis of DHT and testosterone), a genetic female may have masculinized external genitalia complete with a penis but have normal ovaries and other female internal reproductive structures. Or, a genetic male may be undermasculinized.
  • Klinefelter’s syndrome: Males with Klinefelter’s syndrome have at least two X chromosomes and one Y chromosome (XXY). They usually have small testes that don’t produce enough testosterone. As a result, male secondary sex characteristics, such as facial hair, may not develop completely, and the male is usually infertile. Males with Klinefelter’s syndrome tend to be taller; they may also have feminizing characteristics such as enlarged breasts. Treatment with hormone therapy can greatly reduce these effects and allow males to develop more normally and have normal sex lives.
  • Turner syndrome: This genetic disorder, which leaves females infertile, can occur in two ways. First, a genetically female (XX) individual may be missing part or all of one of the X chromosomes, resulting in an XO individual (a person with only one sex chromosome, an X) that’s neither completely female nor male. Second, an embryo may have an X chromosome and a Y chromosome, which normally indicates male, but a deletion occurs in the region of the sex-determining gene on the Y chromosome. This deletion prevents development of testes, so no DHT is produced. Female internal and external genitalia develop, but the ovaries fail prematurely.

Women with Turner syndrome are often shorter than other women, may have extra folds of skin around the neck, and may fail to enter puberty. However, recent advances in hormone therapy have significantly reduced these effects.