Difficulty: Foundational | Prerequisites: Basic cell biology, chromosome structure
This topic is the starting point for the entire reproductive physiology block. Before you can understand how the male (or female) reproductive system works in adulthood, you need to know how the body decides which system to build in the first place. Sex determination is the genetic event at fertilisation; sex differentiation is the developmental programme that translates that genetic instruction into gonads, internal ducts and external genitalia. Everything downstream, from puberty to spermatogenesis to hormonal regulation, rests on the concepts here.
Genetic sex is fixed at fertilisation by the sperm's sex chromosome (X or Y). The SRY gene on the Y chromosome triggers male gonadal development; its absence permits female development. Hormones produced by the developing testes then direct the formation of male internal and external genitalia over the course of foetal life.
Sexual dimorphism
The observable physical differences between males and females of a species.
In simple terms, this is why men and women look different from each other.
Gonads
The organs that produce gametes: testes in males (producing sperm) and ovaries in females (producing eggs). They also secrete sex hormones.
Think of them as both the factory for reproductive cells and a hormone-production centre.
Sex determination
The process by which an organism's genetic sex is established, occurring at the moment of fertilisation.
In simple terms, this is the "coin flip" that happens when sperm meets egg.
Sex differentiation
The developmental process during foetal life by which the undifferentiated embryo develops male or female anatomy, directed by the genome and subsequent hormonal signals.
Think of it as the construction phase: the blueprint (genes) has been chosen, and now the body builds accordingly.
Karyotype
The full set of chromosomes in an individual, used to identify genetic sex. Males are 46,XY; females are 46,XX.
In simple terms, it is your chromosome "fingerprint."
SRY gene (sex-determining region of the Y chromosome)
A gene on the Y chromosome that encodes the SRY protein (also called testis-determining factor). Its presence initiates male gonadal development.
Think of it as the master switch for male development.
Bipotential gonad
The undifferentiated gonad present in the early embryo (up to approximately six weeks), which has the potential to develop into either a testis or an ovary.
In simple terms, every embryo starts with the same blank-slate gonad.
Wolffian duct (mesonephric duct)
The embryonic duct system that, in the presence of testosterone, develops into the male internal genitalia: epididymis, vas deferens, seminal vesicles and ejaculatory duct.
Müllerian duct (paramesonephric duct)
The embryonic duct system that, in the absence of anti-Müllerian hormone, develops into female internal organs: fallopian tubes, uterus and upper vagina. In males, it is actively broken down by AMH.
Anti-Müllerian hormone (AMH)
A peptide hormone secreted by Sertoli cells of the developing testis that causes the Müllerian ducts to regress.
Think of it as the "demolition order" for the female duct system in a male embryo.
Dihydrotestosterone (DHT)
A potent androgen converted from testosterone by the enzyme 5-alpha reductase. It is responsible for the development of male external genitalia and, later, certain secondary sex characteristics.
5-alpha reductase
The enzyme that converts testosterone to DHT in peripheral tissues.
Humans have 23 pairs of chromosomes: 22 pairs of autosomes and 1 pair of sex chromosomes
Females carry two X chromosomes (XX); males carry one X and one Y (XY)
All eggs from the mother carry an X chromosome
Sperm from the father carry either an X or a Y chromosome
The sperm therefore determines the genetic sex of the offspring
Haploid cells (sperm and egg) each contain 23 chromosomes; the resulting zygote contains 46
Until approximately six weeks of gestation, the embryo's reproductive structures are undifferentiated and identical regardless of genetic sex
At this stage the embryo possesses:
A pair of bipotential gonads
Two pairs of internal genital ducts: the Wolffian duct (male precursor) and the Müllerian duct (female precursor)
A primitive bipotential structure for external genitalia
The gonad has two regions with different fates:
Medulla: develops into testis tissue if SRY is present
Cortex: develops into ovarian tissue if SRY is absent
Male development: cortex regresses, medulla differentiates
Female development: medulla regresses, cortex differentiates
The SRY gene on the Y chromosome is the initiating event. Its presence triggers the following cascade:
SRY protein directs the gonadal medulla to differentiate into a testis
The developing testis contains two critical cell types:
Sertoli cells, which secrete anti-Müllerian hormone (AMH), causing regression of the Müllerian ducts
Leydig cells, which secrete testosterone
Testosterone converts the Wolffian duct into the male internal genital structures (epididymis, vas deferens, seminal vesicles)
Testosterone also controls prostate development and the migration of the testes into the scrotum
In peripheral tissue, testosterone is converted to DHT by 5-alpha reductase
DHT drives the development of male external genitalia (penis, scrotum)
The SRY gene and its protein are absent
Without SRY, the gonadal cortex develops into ovarian tissue
Without testosterone, the Wolffian ducts degenerate
Without AMH, the Müllerian ducts persist and develop into the fallopian tubes, uterus and upper vagina
In the absence of androgens, external genitalia develop along female lines
At six weeks, external genitalia are bipotential in both sexes, consisting of:
Genital tubercle
Urethral groove and urethral fold
Labioscrotal swelling
In males (driven by DHT):
Genital tubercle becomes the penis (glans)
Urethral folds fuse to form the shaft of the penis
Labioscrotal swellings fuse to form the scrotum
In females (absence of androgens):
Genital tubercle becomes the clitoris
Urethral folds become the labia minora
Labioscrotal swellings become the labia majora
The testes descend from the abdominal cavity into the scrotum during the third trimester
No mathematical formulas for this section. Key diagrams to review:
Flowchart of SRY gene activation leading to testis differentiation, hormone secretion and duct development
Side-by-side comparison of bipotential external genitalia at six weeks versus male and female outcomes at birth
Disorders of sex development (DSDs), such as androgen insensitivity syndrome or 5-alpha reductase deficiency, arise when one step in the differentiation cascade goes awry. Understanding this pathway is how clinicians diagnose and counsel patients with ambiguous genitalia at birth.
Students often think the X chromosome is "female" and the Y is "male." In reality, the Y chromosome's contribution is primarily the SRY gene; most other sex-related genes sit on the X or autosomes.
A common mistake is believing that female development requires an active genetic signal. It does not; female is the default pathway in the absence of SRY and its downstream hormones.
Students sometimes confuse testosterone and DHT. Testosterone drives internal duct development; DHT (converted from testosterone) drives external genital development.
The Müllerian ducts do not simply "fail to develop" in males. They are actively destroyed by AMH from Sertoli cells.
⚠️ The SRY gene and its downstream cascade (Sertoli cells producing AMH, Leydig cells producing testosterone, 5-alpha reductase converting testosterone to DHT) is a classic exam question pathway.
⚠️ Know the distinction between sex determination (genetic, at fertilisation) and sex differentiation (developmental, during foetal life). These are not the same process.
⚠️ Be able to match each hormone to its specific role: AMH regresses Müllerian ducts, testosterone develops Wolffian ducts, DHT develops external genitalia.
⚠️ Understand that the bipotential gonad's medulla becomes testis and cortex becomes ovary, not the other way round.
True or false: The mother's egg determines the genetic sex of the offspring.
Fill in the blank: The _______ gene on the Y chromosome is the master switch for male development.
True or false: DHT is responsible for the development of the epididymis and vas deferens.
Fill in the blank: Anti-Müllerian hormone is secreted by _______ cells and causes regression of the _______ ducts.
True or false: Female sex differentiation requires active signalling from ovarian hormones during foetal life.
Answers: 1. False (the father's sperm determines sex). 2. SRY. 3. False (testosterone develops internal structures; DHT develops external genitalia). 4. Sertoli; Müllerian. 5. False (female development is the default pathway in the absence of SRY and testicular hormones).
Q: What are the two processes that together establish an individual's sex, and when does each occur?
A: Sex determination is the establishment of genetic sex at fertilisation (XX or XY). Sex differentiation is the developmental process during foetal life that translates that genetic instruction into male or female anatomy.
Q: An embryo is 46,XY but has a non-functional SRY gene. What phenotype would you predict at birth, and why?
A: The phenotype would be female. Without functional SRY protein, the gonadal medulla does not differentiate into testes, no testosterone or AMH is produced, the Wolffian ducts degenerate, the Müllerian ducts persist, and external genitalia develop along female lines.
Q: Explain the specific roles of testosterone versus DHT in male foetal development.
A: Testosterone, secreted by Leydig cells, drives the development of the Wolffian duct into the epididymis, vas deferens and seminal vesicles. It also controls prostate development and testicular descent. DHT, converted from testosterone by 5-alpha reductase, is responsible for the development of male external genitalia (penis and scrotum).
Q: A male foetus has normal Leydig cell function but absent Sertoli cell function. What anatomical outcome would you expect?
A: Testosterone would still be produced, so the Wolffian ducts would develop normally into male internal structures. However, without Sertoli cells there would be no AMH, meaning the Müllerian ducts would not regress. The individual would have both male internal structures (from Wolffian ducts) and female internal structures (from Müllerian ducts).
Q: Name the three structures present in the bipotential external genitalia at six weeks, and state what each becomes in the male.
A: The genital tubercle becomes the glans penis. The urethral folds fuse to form the shaft of the penis. The labioscrotal swellings fuse to form the scrotum.
This material connects directly to the next topic in the block, gametogenesis and sexual maturation, because the gonads formed during differentiation are the same organs that will later produce gametes and sex hormones at puberty. It also links to endocrinology, since the hypothalamic-pituitary-gonadal axis that regulates adult reproduction depends on the same hormones (testosterone, oestrogen) whose foetal roles are covered here.
sex determination, sex differentiation, sexual dimorphism, SRY gene, testis-determining factor, Y chromosome, bipotential gonad, gonadal medulla, gonadal cortex, Wolffian duct, mesonephric duct, Müllerian duct, paramesonephric duct, anti-Müllerian hormone, AMH, Sertoli cells, Leydig cells, testosterone, dihydrotestosterone, DHT, 5-alpha reductase, karyotype, 46 XY, 46 XX, genital tubercle, labioscrotal swelling, urethral fold, foetal development, male reproductive development, disorders of sex development