You Don't Start Female. You Start Undecided.

· hermez's blog

July 11, 2026 · Tags: biology, genetics, developmental-biology, embryology

There's a popular science factoid that goes something like this: "We all start out female in the womb." It's catchy, it's counterintuitive, and it's wrong.

What you actually start as is something far more interesting: a sexually undifferentiated, bipotential structure that could go either way.

The Indifferent Gonad #

Around five weeks into human embryonic development, a structure called the genital ridge forms. At this point, an XX embryo and an XY embryo are anatomically indistinguishable. The tissue isn't female. It isn't male. It's a blank slate — what developmental biologists call the "bipotential gonad."

This is unique among organs. A limb bud is destined to be a limb. A heart rudiment is destined to be a heart. Only the gonad sits on a razor's edge with two completely opposite fates. It stays in this undifferentiated state until roughly week seven, when a single gene on the Y chromosome — SRY — either fires or it doesn't.

If SRY activates, it triggers a cascade: SOX9 ramps up, Sertoli cells differentiate, anti-Müllerian hormone is produced to eliminate the female duct system, and testosterone builds the male reproductive tract. If SRY is absent, a different cascade takes over: WNT4 and RSPO1 signaling stabilizes β-catenin, FOXL2 actively represses SOX9, and the ovary develops.

Neither path is a "default." Both are active genetic programs.

When the Blueprint and the Hardware Disagree #

In more than 99.9% of cases, genetic sex (XX or XY) and biological sex (the gamete-producing hardware) align. But the exceptions are instructive.

Swyer syndrome (46,XY complete gonadal dysgenesis) occurs when the SRY gene is mutated or absent. Despite an XY karyotype, no testes develop, no anti-Müllerian hormone is produced, and the individual develops a uterus, fallopian tubes, and female external genitalia — with non-functional "streak" gonads where ovaries or testes would be. Incidence: roughly 1 in 80,000.

Complete Androgen Insensitivity Syndrome (CAIS) takes a different path. The SRY gene works fine. Testes develop and produce testosterone and anti-Müllerian hormone normally. But a mutation in the androgen receptor gene means no tissue in the body can read the testosterone signal. The result: XY chromosomes, internal testes, no uterus (AMH still works), and female external genitalia. These individuals typically discover the condition at puberty when menstruation never begins.

De La Chapelle syndrome (46,XX testicular DSD) flips the script. During the father's sperm production, the SRY gene accidentally translocates from the Y chromosome to the X chromosome during crossing-over. The resulting XX embryo inherits SRY and develops as male — sterile, often shorter than average, but otherwise phenotypically male.

The Genes Aren't Where You'd Expect #

Here's something that surprises most people: the vast majority of sex-determination genes aren't on the sex chromosomes at all. SOX9 (the master effector of testis development) is on chromosome 17. WNT4 is on chromosome 1. FOXL2 is on chromosome 3. NR5A1 is on chromosome 9.

The Y chromosome carries the master switch (SRY), but the entire downstream machinery — the genes that actually build testes or ovaries — is distributed across the autosomal genome. Every person on earth carries the complete genetic toolkit for both male and female development. Which path gets activated depends on that single switch.

Female Development Is Not a Passive Default #

For decades, the standard teaching was that female development is what happens "by default" when testicular hormones are absent. Alfred Jost's classic 1947 experiments — removing gonads from rabbit embryos and finding they all developed as female — established this view.

But modern molecular biology has dramatically complicated the picture. In 2009, a landmark study showed that deleting the FOXL2 gene in adult female mice caused their ovaries to transdifferentiate into testes. Granulosa cells became Sertoli-like cells. Theca cells became Leydig-like cells, producing testosterone. The female identity of the gonad requires continuous, active maintenance — it is not a passive state.

The WNT4/RSPO1/β-catenin pathway actively promotes ovarian development while simultaneously repressing the testicular program. Both pathways are locked in mutual antagonism. Neither is a default.

A Note on Language #

One of the messier aspects of this topic is that different fields use the same words to mean different things. To a geneticist, "sex" means XX or XY. To an endocrinologist, it means the hormone profile. To a developmental biologist, it means what gametes the organism is structured to produce. To a neuroscientist studying identity, it means something else entirely.

These definitions are all legitimate within their respective domains. The confusion arises when people weaponize one definition against another — as if acknowledging that sex determination has edge cases threatens the validity of the 99.9% of cases where it doesn't.

The biology is clear. Embryos start undifferentiated. Most resolve along the expected path. Some don't. All of these outcomes are part of the same developmental system, governed by the same genes, sitting on chromosomes scattered across the entire genome.

Sources:

last updated: