There’s more than man and woman

(From "Horizons" no. 107, December 2015)​Calliope is the main character of Jeffrey Eugenides’ Pulitzer-Prizewinning
novel Middlesex (2002), and the drama of her life revolves around an inherited genetic defect. She is a seemingly normal girl, but during puberty she notices that she is becoming increasingly different. A specialist is given the task of solving her ‘problem’ by surgical means, but Calliope is given a glimpse of her medical records shortly before the operation is to take place. Here, she reads that her karyotype is 46/XY and she realises the truth: “I’m a boy”.

“It’s a wonderful book” says Anna Lauber-Biason, Professor of Endocrinology at
the University of Fribourg. “Besides its literary quality, it offers a good, comprehensible introduction to the topic of intersexuality”. She refers to Eugenides’ novel in her lectures – though the word ‘intersexuality' is no longer considered correct today when referring to those of ambiguous gender. The medical world tends instead to speak of disorders, or differences, in sexual development – ‘DSD’ for short.

So what exactly happens, in biological terms, when something goes awry with
sexual development? Lauber-Biason explains that human sexual development
takes place in three main phases. The first involves the chromosomes, the second the
gonads and the third the reproductive organs. The process begins at the moment of
procreation, when 23 chromosomes each from the egg and the sperm come together
to form a full set of 46, including the two sex chromosomes: 46/XX for a woman and
46/XY for a man.

Three sex chromosomes

“But this process is prone to error. Maldistribution or failed pairings can occur”,
explains Lauber-Biason. The known anomalies that affect the sex chromosomes include Klinefelter syndrome, where there is an extra X chromosome (karyotype 47/XXY). It’s thought to affect 1 in every 650 male new-borns. Those affected are infertile, have small testicles and sometimes female body proportions; they also produce too few male sex hormones. The chromosome set 45/X is also relatively common – in other words, when a person has a single X chromosome. In many cases it is responsible for spontaneous abortions. 98 percent of foetuses with this karyotype die in the womb, and if a foetus is indeed born, then this karyotype can cause Turner syndrome. The girls who are affected are small in stature, have no functioning ovaries and don’t develop breasts unless they are given hormones.

When there is a normal chromosomal distribution of XX or XY, the sex is genetically
fixed. At the beginning, however, the embryo is a hermaphrodite – the sex glands, or gonads, that form between the third and seventh weeks of pregnancy are initially identical in both male and female embryos. They only start to differ after the seventh week of pregnancy. Female embryos form ovaries, while males form testes. This development is steered by a whole series of different genes in each sex (see the
graphic). But this process can also be affected by mutations. “We know the main gene
that is involved in the development of the gonads, but when anomalies occur, we can
only determine the genetic reason in about 50 percent of cases”, says Lauber-Biason.

A fragile hormone cascade

A hormone cascade is responsible for subsequent developments. In the male foetus,
the SRY gene is indispensable. This gene lies on the Y chromosome and encodes
the TDF protein (the ‘testis-determining factor’). It is this gene that is primarily responsible for the development of the male. Together with other genes, SRY controls
the development of the testes, which already excrete large quantities of testosterone
while in the mother’s womb. It is under the influence of this male sex hormone
that the internal reproductive organs of the male develop (the prostate, the sperm ducts and the epididymis), as do the external genitalia (in other words the penis and
the testicles).

This cascade is also liable to disruption. A mutation in the gene for the androgen receptor can mean that the male hormones are absorbed only inadequately (or not at
all). “This androgen resistance means that the male genitalia do not develop properly
in the womb; instead, to all outward appearances, a girl is then born with female genitals”, says Lauber-Biason. Those affected often don’t notice that something isn’t right until they reach puberty and find that menstruation does not occur.

When gene control fails

During the course of pregnancy, various genes in the female foetus switch on and control the development of the internal and external reproductive organs. These include WNT4, whose significance for female sexual development was determined by the research of Lauber-Biason and her group. They were able to demonstrate that WNT4 is elemental to the development of functioning ovaries. A defect in WNT4 means that the ovaries of the girls affected produce a surplus of male hormones and are barely able to form egg cells.

For Lauber-Biason, WNT4 also helps refute the ‘female-by-default’ theory proposed in the 1950s – according to which the human organism is essentially female as long as it has no Y chromosomes. “There have to be two X chromosomes for a complete female organism to be formed”, she says, “and it needs the genetic control exercised by WNT4 in order for the ovaries to function properly”.

Lauber-Biason’s group recently made another contribution to the genetic jigsaw puzzle of sexual development in humans, by explaining the significance of the CBX2 gene. A mutation in foetuses with a male genotype leads to complete feminisation; furthermore, this gene seems to be involved in developing both the testes and the ovaries. Lauber-Biason discovered this mutation in a patient who seemed to have testes in her abdomen. “But when these ‘testes’ were supposed to be removed surgically, they proved to be ovary-like gonads – so they were left where they were”, relates Lauber-Biason. However, CBX2 anomalies are extremely rare, just as is the case with WNT4 mutations.

Doctors more frequently find the so-called adrenogenital syndrome in genetic females. This is a metabolic disorder that is inherited. “In this syndrome, female foetuses are exposed to large quantities of androgens that are formed in the adrenal cortex, meaning that they are born with masculinised genitals”, explains Lauber-Biason. These girls have a normal uterus and normal ovaries, but a clitoris that in some cases resembles a penis. They also lack a vagina, and the large vulva looks like a scrotum. Boys can also have this disorder, though they display different symptoms.

And what is Calliope’s problem in “Middlesex”? She too suffers from an inherited metabolic disorder, as a late consequence of an incestuous relationship of her grandparents. In her case, her androgen receptors were inadequately stimulated in the womb. Typically, the feminine characteristics of those affected disappear during puberty and they take on an increasingly male appearance. When this happens to Calliope, she runs away from home and lives thereafter as a man, and this is exactly what many do in real life. Cal, as he henceforth calls himself, is already over forty when he falls in love with a woman photographer and reveals himself to her. And she accepts him as he is.

Irène Dietschi is a freelance journalist in Olten.

How gender develops

This complex process is prone to error: gene mutations or a maldistribution of chromosomes can impair sexual development. By Valentin Amrhein