The Initial Genetic Switch
Biological sex in humans is a complex developmental process initiated at fertilization, involving a cascade of genetic and hormonal signals that direct the formation of reproductive anatomy. The process begins from a sexually indifferent state in the developing embryo, where reproductive structures have the potential to develop along either a male or female pathway.
The primary determinant is the combination of sex chromosomes inherited at conception: XX or XY. For the first several weeks of gestation, the embryonic gonads—the structures that will eventually become either testes or ovaries—remain undifferentiated. The decisive factor that breaks this indifferent state is the SRY gene (Sex-determining Region Y), located on the Y chromosome.
The SRY gene acts as a genetic master switch, triggering the male developmental pathway. It encodes a transcription factor that initiates a signal cascade within the bipotential gonad around the sixth to seventh week, leading to the formation of testes. The SRY protein causes supporting cells to differentiate into Sertoli cells, which organize into testis cords.
In the absence of SRY, as in XX embryos, the genetic cascade for testis development is not activated. Instead, other genes, such as WNT4 and RSPO1, actively promote the differentiation of the undifferentiated gonad into an ovary. The presence or absence of SRY is the initial event that controls gonadal development, which then dictates subsequent anatomical differentiation.
Hormones Driving Differentiation
Once the gonads are determined as either testes or ovaries, they begin to produce hormones that act as the second major force in sex differentiation, driving the physical development of the internal and external reproductive structures. In the developing testes, two specific hormones are synthesized: Anti-Müllerian Hormone (AMH) and testosterone.
Sertoli cells secrete AMH, a peptide hormone that causes the regression and disappearance of the Müllerian ducts, which are the embryonic precursors to the female internal reproductive tract. Simultaneously, Leydig cells produce the androgen testosterone. Testosterone promotes the development of the Wolffian ducts, which are the precursor structures for the male internal reproductive tract.
In contrast, the developing ovaries do not produce significant amounts of AMH or testosterone during the early fetal period. This absence of testicular hormones allows the female pattern of differentiation to proceed. Without AMH, the Müllerian ducts persist and develop. The lack of androgens, rather than the presence of high estrogen levels, is the primary driver for the differentiation of internal reproductive structures along the female pathway during this fetal stage.
Formation of Internal and External Anatomy
The hormonal signals initiated by the developing gonads dictate the fate of the two sets of embryonic duct systems: the Wolffian (mesonephric) ducts and the Müllerian (paramesonephric) ducts. The action of testosterone and AMH determines which duct system persists and which regresses.
In the presence of testicular hormones, the Wolffian ducts are stimulated by testosterone to develop into the internal male reproductive organs, including the epididymis, the vas deferens, and the seminal vesicles. The simultaneous secretion of AMH causes the Müllerian ducts to break down and largely disappear.
Conversely, in the absence of AMH, the Müllerian ducts persist and fuse to form the upper portion of the vagina, the cervix, the uterus, and the Fallopian tubes. The lack of testosterone causes the Wolffian ducts to regress.
The external genitalia also develop from a common set of precursor tissues, including the genital tubercle, the urethral folds, and the genital swellings. Development is primarily driven by the potent androgen dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5-alpha reductase.
In the presence of DHT, the genital tubercle enlarges to form the glans penis, the urethral folds fuse to enclose the penile urethra, and the genital swellings form the scrotum. In the absence of this strong androgen signal, the genital tubercle develops into the clitoris, the urethral folds remain unfused to form the labia minora, and the genital swellings become the labia majora.
Understanding Variations in Biological Sex
The process of sex determination and differentiation relies on the precise timing and quantity of genetic signals, enzyme activity, and hormone production. Variations can occur at any step, resulting in what are collectively referred to as Differences of Sex Development (DSD). These variations represent a spectrum of biological conditions where chromosomal, gonadal, or anatomical development does not follow the typical pattern. The underlying causes can be broadly categorized into chromosomal variations, alterations in hormone action, and enzyme deficiencies.
One category involves chromosomal variations, such as Klinefelter syndrome (XXY) or Turner syndrome (XO), where an extra or missing sex chromosome affects overall development and gonadal function. Other variations stem from the inability of the body’s cells to respond to hormonal signals, such as in Androgen Insensitivity Syndrome (AIS).
In AIS, a person with XY chromosomes develops testes that produce testosterone and AMH. However, a non-functional androgen receptor prevents the body from responding to testosterone, leading to the development of female external genitalia and a regressed Wolffian duct system.
Variations can also arise from enzyme deficiencies that disrupt the production or conversion of steroid hormones. Congenital Adrenal Hyperplasia (CAH), for example, involves a lack of an enzyme needed to produce cortisol and aldosterone, which leads to an overproduction of androgens. In XX individuals, this excessive androgen exposure before birth can result in the masculinization of the external genitalia. These examples illustrate that biological sex development is a spectrum of outcomes arising from the intricate interplay of genetics, hormones, and anatomical development.