Biological sex isn’t settled at a single moment. It unfolds as a chain of steps in the womb, starting with the chromosomes a baby inherits. What those chromosomes do depends on a handful of genes and hormones acting in the right order. When one link in that chain works differently, a person’s chromosomes, internal organs and outward body can point in different directions.
The Y Chromosome’s Switch Gene
For the first weeks of development, every embryo has identical early gonads, glands that can become either testes or ovaries. A gene on the Y chromosome called SRY is the trigger that starts male development.1EBSCO. SRY gene When SRY is damaged by a new mutation, an XY embryo develops along the female path.2PubMed. Genetic evidence equating SRY and the testis-determining factor
SRY works by switching on a second gene. Its main job is to raise the activity of a related gene, SOX9, high enough.3PubMed. Sry: the master switch in mammalian sex determination SOX9 then turns supporting cells into the cells that organize the testis.4PubMed. Sry: the master switch in mammalian sex determination It also sets up loops that keep boosting itself, locking the male path in.5PubMed Central. The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation Other genes on the X, Y and other chromosomes are still needed for normal development and fertility.6EBSCO. SRY gene
SRY acts only briefly in early fetal development. It must reach a high enough level in that window for the testis path to start. If it switches on too weakly or too late, the gonads can drift toward the ovary path even in an XY embryo.
Older textbooks said ovaries form automatically when there is no Y. Newer work shows they need their own genes switched on. Genes called WNT4, RSPO1 and FOXL2 actively drive ovary development.7EBSCO. SRY gene WNT4 suppresses male development and keeps egg cells healthy, and RSPO1 appears to control how much WNT4 is made.8PubMed. WNT4, RSPO1, and FOXL2 in sex development The male and female paths actively hold each other back, so ovary-building is a process of its own, not merely the absence of SRY.9PubMed. WNT4, RSPO1, and FOXL2 in sex development
What XX and XY Really Tell You
Most people have 46 chromosomes, including either two X chromosomes or one X and one Y. The egg usually gives an X, while the sperm gives either an X or a Y, so the father’s sperm usually decides chromosomal sex at fertilization.
Only one of the 23 chromosome pairs differs between XX and XY people. The X is a large chromosome carrying many genes that have nothing to do with sex organs, such as genes affecting blood clotting and vision. The Y is much smaller and carries far fewer genes, and SRY is only one of them.
In XX cells, one X is largely shut down so both sexes get similar doses of X genes. Each cell picks one X to silence early in development, and different cells may silence different copies, which makes a woman’s body a patchwork. But at least 23% of X genes partly escape this shutdown.10PubMed Central. Landscape of X chromosome inactivation across human tissues Some genes therefore run slightly higher in women’s cells, creating sex differences in gene activity.11PubMed Central. Landscape of X chromosome inactivation across human tissues It may help explain why some diseases differ in risk between the sexes.12eLife. A whole-organism landscape of X-inactivation in humans
How Hormones Build the Rest of the Body
The order of events in a male fetus runs like this: SRY acts first, then testes form, and the testes release hormones that shape the rest of the body. Every embryo has early tubes that can become the uterus and fallopian tubes. These supporting cells in the testis release a hormone called AMH.13PubMed. Anti-Müllerian hormone, beta-catenin and Müllerian duct regression AMH makes those tubes shrink away, from top to bottom, so in a typical male fetus no uterus forms.14PubMed. Anti-Müllerian hormone, beta-catenin and Müllerian duct regression15PubMed Central. Osterix functions downstream of anti-Müllerian hormone signaling to regulate Müllerian duct regression
The ducts can only be removed during a limited window in fetal development, so AMH must arrive early enough. A lack of AMH, or of the cells that respond to it, can leave a uterus and fallopian tubes in an XY person.
Testosterone guides the inner male reproductive organs.16Androgens: Clinical Research and Therapeutics. From Conception to Adulthood: The Impact of Androgens on Abnormalities of Male Genital Development and Size Outer genitals depend mainly on testosterone being converted into DHT, a stronger form.17Androgens: Clinical Research and Therapeutics. From Conception to Adulthood: The Impact of Androgens on Abnormalities of Male Genital Development and Size A body that can’t make DHT may look female or ambiguous at birth, as a later section shows.
Separate hormones control separate structures, so if one signal fails, the others can still work normally. This is why some people have testes but female-looking genitals.
Hormones from outside can also push the process off course. In a human testis-cell line, estrogen lowered SOX9’s activity and the male genes it controls.18PubMed Central. Estrogen suppresses SOX9 and activates markers of female development in a human testis-derived cell line
When Hormones Don’t Work as Expected
In androgen insensitivity, the body makes testosterone but can’t respond to it. People with complete androgen insensitivity have XY chromosomes and a female outward appearance.19Archives of Medical Science. The challenges of androgen insensitivity syndrome Their cells can’t respond to male hormones, often because of a change in the androgen receptor gene.20AACE Clinical Case Reports. A Novel Androgen Receptor Gene Mutation in a 46,XY Patient: Complete Androgen Insensitivity Syndrome Their testes still make AMH, so there’s no uterus.21Archives of Medical Science. The challenges of androgen insensitivity syndrome The vagina is shorter and ends blindly, and the testes usually stay hidden in the abdomen or groin.22Archives of Medical Science. The challenges of androgen insensitivity syndrome
The condition is often found in the teens, when periods never start.23AACE Clinical Case Reports. A Novel Androgen Receptor Gene Mutation in a 46,XY Patient: Complete Androgen Insensitivity Syndrome Tests then reveal XY chromosomes and internal testes. Breasts usually develop, but body hair is sparse. Doctors often advise removing the testes because of cancer risk.24PubMed Central. Pure 46, XY gonadal dysgenesis and 46, XY complete androgen insensitivity syndrome: A case report
Insensitivity is not all-or-nothing. Some people have partial insensitivity, where cells respond to male hormones to a limited degree. Partial cases can produce outward bodies anywhere between typically female and typically male, including ambiguous genitals at birth. Babies with partial forms are often noticed at birth rather than in the teens.
5-alpha reductase deficiency shows how much DHT matters. Some XY babies can’t convert testosterone into DHT and are born with ambiguous genitals.25The Application of Clinical Genetics. Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide At puberty, rising testosterone can bring muscle growth, a deeper voice and genital growth.26MedlinePlus Genetics. 5-alpha reductase deficiency It is inherited when both parents pass on a changed gene.27The Application of Clinical Genetics. Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide
Too much adrenal hormone can masculinize an XX body. In congenital adrenal hyperplasia, the adrenal glands make too little cortisol and too many male-type hormones.28PubMed Central. 46,XX males with congenital adrenal hyperplasia: a clinical and biochemical description XX babies can be born with genitals that look more male to varying degrees.29PubMed Central. 46,XX males with congenital adrenal hyperplasia: a clinical and biochemical description
When Chromosomes and Body Don’t Match
SRY problems directly flip the outcome. In Swyer syndrome, people are XY but have female reproductive structures, because their gonads fail to develop properly.30MedlinePlus. Swyer syndrome Other people are XX yet develop as male because SRY moved onto an X chromosome.31PubMed Central. Clinical, molecular and cytogenetic analysis of 46, XX testicular disorder of sex development with SRY-positive They lack other Y genes needed to make sperm,32PubMed Central. Clinical, molecular and cytogenetic analysis of 46, XX testicular disorder of sex development with SRY-positive so they’re usually infertile. These men typically look and feel male, and the chromosome count is often discovered during fertility testing.
Extra or missing sex chromosomes produce their own conditions. A chromosome test result, called a karyotype, is written like 46,XY. Turner syndrome (45,X) has one X and varies from obvious to so mild it goes undiagnosed.33PubMed Central. Individuals with numerical and structural variations of sex chromosomes: interdisciplinary management with focus on fertility potential Many men with Klinefelter syndrome (47,XXY) are only diagnosed as adults during fertility testing.34PubMed Central. Individuals with numerical and structural variations of sex chromosomes: interdisciplinary management with focus on fertility potential A blood test for the karyotype confirms these conditions.
Is Sex Fixed After Birth
Researchers removed the FOXL2 gene from the ovaries of adult mice, not from embryos. In those mice, testis genes, including SOX9, switched on quickly.35PubMed. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation Ovary cells turned into testis-like cells and made male-level testosterone.36PubMed. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation FOXL2 had been holding back the male path all along.37PubMed. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation
This is a lab result in mice, and it hasn’t been shown in humans. It doesn’t mean adult humans can change sex this way.
Sex Differences in the Brain
The brain is exposed to testosterone before birth, and the male fetus makes much more of it than the female fetus. Brain cells carry receptors that respond to sex hormones, so the hormones can affect how the brain wires itself. Testosterone before birth is thought to shape the developing brain in a male direction.38PubMed. Sexual differentiation of the human brain in relation to gender identity and sexual orientation Some scientists believe gender identity and sexual orientation are partly set in the womb.39PubMed. Sexual differentiation of the human brain in relation to gender identity and sexual orientation Genes on the sex chromosomes may also affect brain development directly.40bioRxiv. Sex differences in early human fetal brain development
These are leading theories, not settled facts. Hormone effects on the brain are hard to study in human fetuses, and upbringing and experience also shape the adult brain.
How Other Animals Do It Differently
The SRY-carrying Y chromosome arose about 180 million years ago in the ancestor of most mammals.41PubMed. Origins and functional evolution of Y chromosomes across mammals Egg-laying platypuses use a different gene, AMH, as the likely switch.42PubMed. Origins and functional evolution of Y chromosomes across mammals Birds do it differently: females are ZW and males ZZ, the reverse pattern.43PubMed Central. Avian W and mammalian Y chromosomes convergently retained dosage-sensitive regulators The egg decides the chick’s sex, because the female’s egg carries either a Z or a W, which makes the mother the one who determines chromosomal sex. Bird and mammal sex chromosomes evolved separately.44PubMed. Relationships between vertebrate ZW and XY sex chromosome systems Some fish set sex by environment, such as temperature, through chemical tags on genes.45PubMed Central. Epigenetics of sex determination in mammals