Often the first question parents are asked after the birth of their child is “congratulations, girl or boy?”. For parents of one in 2,000 to 4,000 births, however, there is not an easy answer. This is when the baby has “ambiguous” genitalia, where it is not clear which sex they belong to. In baby boys, this was long thought to be caused by problems linked to testosterone – as were more common disorders such as undescended testicles and malformed penises, which respectively occur in 9% and 1% of births.
But now it is clear that the reality is slightly different. According to new research in which I am a co-author, another hormone known as androsterone – which originates in the placenta and foetal adrenal gland – is also vital to the process that turns foetuses in boys. These insights have the potential to make a big difference to how we treat sexual disorders in male babies in future – and are also relevant to the whole debate about male and female identity.
Even small children are aware that men and women usually look different. It is common knowledge that boys become men because the testes of the man produce the “male” hormone testosterone and, in turn, testosterone makes men masculine. We know this thanks to the French endocrinologist Alfred Jost’s groundbreaking studies in the early 1950s.
There are several times in boys’ lives in which bursts of testosterone play a key role in their development as males. The most well known is of course puberty, in which the testes start making much more testosterone. This makes boys hairier, grows their genitals and makes their voices break.
The other times are the “mini-puberty” that takes place at around three months after birth, which leads certain changes in the testes and brain; and when a boy is still a foetus in the womb, around three months into his mother’s pregnancy. While all these bursts of testosterone are probably very important in making a normal male, it is the one in the womb that affects whether the child will be a boy at all. What is now clear is that testosterone and the testes have been hogging the podium when in fact we need to share the honours around.
Testosterone and super-testosterone
Testosterone is part a family of male sex hormones called androgens. To get a normal male, testosterone needs to be turned into another androgen called dihyrotestosterone or DHT, a “super-testosterone” that is five times more potent than its cousin. This conversion is done in the tissue of what will become the penis, along with the other parts of the body that develop male characteristics. The consequences of the process are clear: boys who cannot turn testosterone into DHT are born looking female and only become more obviously male at puberty.
These include the Guevedoces in the Dominican Republic, who, due to a genetic mutation, lack the enzymes to make the DHT conversion. Studying these extraordinary children in the early 1970s led the American researcher Julianne Imperato-McGinley to develop the drug finasteride to treat prostate cancer.
For years, this story was considered complete – masculinisation was due to testosterone and the conversion of testosterone to DHT. Then an Australian zoologist named Marilyn Renfree, in an elegant series of studies in the 2000s, published the first evidence that things may not be that simple. She was actually studying wallabies, since the young in the pouch were easily accessible for experimental purposes and they mimic much of the period of pregnancy in humans and other mammals with placentas. Renfree found that the genitals of the young male wallabies made DHT even without testosterone from their testes. The only reliable conclusion was that they were converting other androgens to DHT.
It became clear that there are two ways to make a “male signal” in a wallaby foetus, both of which are necessary to normal sexual development. The first is by testosterone from the testes. The second is through different androgens that can also be made by other organs in the human, including the foetus’s adrenal glands, liver and the placenta. These other processes came to be known as the “backdoor” pathway.
But was the same thing true in humans? It was later shown that it was, by studying male human newborns who were not properly masculinised; they had undescended testes and ambiguous genitals, despite having testes that made testosterone. It turned out they were unable to make the backdoor androgens because they had mutations in the genes of enzymes that were key to the process of the conversion into DHT.
As further evidence that both types of male signal are essential to normal development of human male foetuses, it was also discovered that foetuses whose placentas are not working properly are around twice as likely to be born with undescended testes or with malformed penises – especially if they are also born abnormally small (for their gestational age).
What we have shown
In our research, which also involved the University of Glasgow and French and Swedish collaborators, we have been able to explain why. We measured the levels of different male sex hormones in the blood of male and female foetuses, and were surprised to find that only two androgens were higher in males than females: testosterone and androsterone. The relevance to the placenta is that it is up to 6,000 times heavier than the foetus and it makes large amounts of a hormone called progesterone, which it can convert into androsterone – as can the foetal liver and adrenal glands. The human foetuses’ testes have no ability to make this conversion.
We then also showed that the testosterone and adrosterone were converted into DHT in male target tissues like the penis. And not only are both androgens required to masculinise the foetus, there can be abnormalities where levels are lower than normal: for example, a good index of the degree of masculinisation is the distance between the anus and genitals, and this is shorter than usual in newborns with malformed penises.
People affected by disorders of sexual development, including malformed penises, can have a very difficult time and face delicate surgery, hormone therapy and other treatments. Every new piece of information into how masculinisation happens raises the prospect of improving when and how these disorders are detected and treated in future. Early enough diagnosis of reduced placental function related to androgen production in early pregnancy might enable treatment before penis formation is complete, avoiding the need for corrective surgery later in life.
A final take-home message from our study is that while testosterone and androsterone are indeed higher on average in male than female foetuses, the difference is quite small. There is also considerable overlap between the lowest levels in boys and the highest levels in girls. Those in society who are adamant that the only choice for people is a binary choice of man or woman are not basing their views on biological reality. Treasured beliefs about the supremacy of testosterone and the testes in making a man are also obviously flawed.