Research suggests contraceptive pill changes women's brains

By Zaria Gorvett for BBC

There are nine different kinds of hormones in the contraceptive pill - some of which have subtle 'masculinising' effects. Why? And should we be concerned?

It all started with a Mexican yam.

It was 1942 and Russell Marker, a chemistry professor from Pennsylvania, was looking for a cheap source of progesterone.

Dr Marker stumbled upon a drawing in an obscure botany book. It was of a yam that had fat, knobbly roots that reportedly weighed up to 100 kg. He travelled to its native Mexico and smuggled one out of the country.

With an affordable source of progesterone found, researchers turned to its uses as a contraceptive. The birth control pill hit the market less than a decade later. Dr Marker, on the other hand, mysteriously disappeared from public life and became obsessed with collecting silver.

The economic and social side effects of the pill were as profound as they are well-documented. Sex could be enjoyed without fear of pregnancy. Suddenly women could devote their 20s and 30s to furthering their education and careers, rather than housework and nappies.

But right from the beginning, the pill has had a secret.

In recent years, scientists have started to realise that the brains of women on the pill look fundamentally different. Compared to women who are not taking hormones, some regions of their brains seem to be more typically 'male'.

There are behavioural changes, too. Women on certain types of pill are not as good at coming up with words - something our gender are usually highly skilled at. On the other hand, they are better at mentally rotating objects, as is often the case in men. Finally, women on a different type of pill are better at recognising faces - something women are usually good at.

Confused? So are scientists. What's going on?

We are often told that the pill contains oestrogen and progesterone. But no pill contains either hormone.

That is because, when taken orally, oestrogen and progesterone break down too quickly to be practical. Instead, the pill contains synthetic versions, which are built from more stable hormones that have been altered to mimic the hormones.

Every brand of combined pill on the market contains the same type of synthetic oestrogen, ethinyl estradiol, and one of eight synthetic progesterones, called progestins.

But though the hormones are effective at preventing pregnancy, they are not perfect matches for our natural hormones. The end result is that these synthetic versions also have effects that you would never get from raw progesterone.

The internet is awash with anecdotal reports of acne, sweating and unwanted hair growth after going on the pill. One women described sprouting hairs all over her cheeks, while another came down with "pizza face" after starting a new brand. These 'masculine' effects have been well-studied by scientists, and they are real: certain kinds of pill really do make them worse, especially in susceptible women.

But the reason is surprising. According to a study from 2012, 83 percent of US women who are on the pill are taking a version that contains progestins made from male hormones. This includes the popular brands Ortho Tri-Cyclen, Loestrin FE 1/20 and Tri-Sprintec®, among many others.

The male hormone that these pills use is a close relative of testosterone called nandrolone. A potent androgen (a hormone that influences the development of the male reproductive system), it can lead to the development of typically male characteristics.

"It's actually used for doping in men sometimes," says Belinda Pletzer, a cognitive neuroscientist at the University of Salzburg in Austria.

It helps build muscle, so it's popular with powerlifters and boxers.

We've known about these side effects for decades: the first progestin ever made, norethindrone, was androgenic.

Back in the 1940s, 50s and 60s, pregnant women sometimes took norethindrone in large doses to help prevent miscarriage. But the hormone also caused some unsettling changes to their bodies.

The women were sweatier, hairier and spottier. Some noticed that their voices had deepened. Nearly one in five baby girls born to mothers taking it had masculinised genitals. Some of these unlucky children required surgery.

Today androgenic progestins are much less androgenic. The doses in contraceptive pills are much smaller, and the hormones are usually combined with synthetic oestrogen, which cancels out many of the masculine effects on our bodies.

But there are some side effects.

"These progestins, which were decreased in dose over the years, are still related to the chemical structure of testosterone. All the derivatives came out to levonorgestrel, which is the most used or known of the progestins," says Regine Sitruk-Ware, a reproductive endocrinologist at the Population Council, New York. "It is still androgenic by itself, by the fact that it can bind to the androgen receptors."

Over the years, there have been several generations of progestins. Though the earlier ones are nearly all androgenic, more recently scientists have developed versions made from synthetic progesterone, instead. These have the opposite effects - they are often prescribed to treat acne or excessive hair growth because they are 'feminising' (though they, too, can have undesireable side effects resulting from a hormonal imbalance). Some examples include Yasmin® and Ocella™.

Generally speaking, the older, cheaper brands of pill tend to contain androgenic hormones, while newer, more expensive ones tend to contain anti-androgens. This may be one reason that just 17 percent of women on the combined pill in the US take the anti-androgenic versions.

There are androgen receptors all over the body, particularly in the sweat glands and hair follicles, which explains why androgenic progestins can make some women sweatier, hairier and spottier. But these powerful, gender-bending steroids also affect the brain.

In men, the androgens released at puberty are known to remodel the brain. This is also true in women, where relatively small quantities of testosterone can cause certain areas to shrink and others to grow.

Given what we know about the power of these hormones, it is perhaps surprising that until recently, no one had checked if progestins made from male hormones might have an impact.

"There has been a lot of research on their physical side effects," says Dr Pletzer. "There has also been research on the emotional side effects, because that's something that women keep complaining about. But very few studies have looked at the brain and cognition."

One of the first such studies was conducted only eight years ago - after the pill had already been in use for 50 years.

Dr Pletzer recruited a mixture of men and women on and off hormonal contraception, then scanned their brains.

What she found was striking. The scans revealed that several brain areas were larger in the women on the pill, compared to those of women who weren't. These areas just so happened to be larger in men than women, too.

The study involved a relatively small sample and didn't separate androgenic and anti-androgenic contraception, so Dr Pletzer cautions against reading too much into the results. But other research has hinted that both types of hormones actually may be changing our behaviour.

It turns out that women taking pills with androgenic progestins have lower verbal fluency. They were also better at rotating objects. This makes sense, since men are thought to be slightly less articulate than women in certain situations and have better spatial awareness.

Other studies have found that women on oral contraception remember emotional stories more like men - recalling the gist more than the details. They're also not as good at recognising emotions in others, such as anger, sadness, or disgust - just like men. It looks suspiciously like certain types of pill are "masculinising" women's brains.

Perhaps the most striking evidence, however, comes from a paper published in 2015. This time, Dr Pletzer compared the brains of women on the two types of pill with women who were not. Several brain areas were larger in the women whose pills contained the newer, anti-androgenic progestins.

Crucially, these changes seemed to be affecting their behaviour.

Two brain areas were particularly engorged: the fusiform face area, a region about the size of a pea that processes facial information and the parahippocampal place area, which is important for recognising places. These women were also better at recognising faces.

Facial recognition is something women are usually highly skilled at - even as babies - so this fits with the picture of oral contraceptives subtly influencing our brains. In this case, the anti-androgenic pills may be having a "feminising" effect.

Just as before, several brain areas were also larger in women on androgenic pills, including many which are typically so in men. The longer the women had been on the pill, the larger these areas were.

To complicate matters further, all combined pills contain synthetic oestrogen, which is feminising. This means that the same women may be experiencing both 'feminising' and 'masculinising' effects on their brains at the same time.

No one could have predicted that an ugly yam would give rise to a feminist revolution. The pill has repeatedly been called the greatest invention of the 20th Century and is said to be responsible for a third of the increase in women's wages since the 1960s.

But contraceptive pills may have a darker side. As Dr Pletzer wrote in 2014, when athletes take steroids we call it 'doping' - it's considered abuse and strongly condemned by society. But we are happy for millions of women to take these hormones every day, sometimes from puberty to menopause.

Scientists do not yet know if any of the pill's effects on the brain have much of an impact on our behaviour. But perhaps it is time we put it to the test.

- BBC