The Teen geen

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How puberty begins

DID you stare into the mirror every morning, desperate for signs that your body was starting to develop like those of your classmates? Or perhaps you were the one who started sprouting breasts or facial hair years before your peers, and got teased just as much as the late developers.

Though it happens to practically everyone, the start of puberty is highly unpredictable: it can happen as naturally to a girl of 8 as to one aged 13. The range is just as wide in boys, though puberty tends to strike them a couple of years later. Though that whole range is considered "normal", the age at which the hormones start flowing can affect everything from how tall you will grow, how strong your bones will be, your risk of getting breast or prostate cancer many decades later to maybe even your mental health. And it's entirely out of our hands.

Or is it? What triggers puberty has been a long-standing mystery. Why does it come to some so young? Some so old? What gives it the ultimate push, and why does the average age seem to be falling? It's common knowledge that puberty is a process that starts in the brain, well before the outward signs begin to show. The hypothalamus in the brain suddenly begins secreting gonadotropin-releasing hormone, or GnRH, and this substance unleashes the chemical cascade of puberty (see Diagram). Before we know it, we are reproductive adults, capable of producing mature sperm and eggs and even having our own kids. The question was, what triggers the release of GnRH?

We now know the answer. In the past few years scientists have identified and characterised the key protein that kick-starts the process. Block it, and puberty is delayed. Inject it, and it brings on sexual maturity. It's still early days, but there's reason to believe that this protein, known as kisspeptin, could hold the key to controlling puberty. For girls or boys maturing too early, it could forestall adulthood; for teenagers who are behind the curve, it could speed things up; for people who have health reasons warranting a delay - and even those who do not - the timing of puberty could for the first time be a matter of preference rather than providence. Peter Pan mice

Kisspeptin was identified almost by accident. It all began with some mice that never grew up. The mice lacked a gene, gpr54, and although the researchers knew it coded for a receptor protein, they didn't know what that receptor did. At birth, the mice appeared normal, and as pups they behaved as expected. The first sign that something was wrong came when it was time to separate the males from the females. "The technical staff couldn't sex the mice," because no one could find the genitals, recalls Sophie Messager of Paradigm Therapeutics in Cambridge, UK, who managed the project. Little did they know that they had stumbled onto the gatekeeper of puberty. The gpr54 protein, it turns out, is the receptor for kisspeptin. Kisspeptin had been discovered some years before and explored for its anti-cancer properties, but it had never been linked to sexual development - the "kiss" is a reference to a brand of chocolate, not sexual awakening. Now another role was clear: without the receptor, the mice in were like Peter Pan: they were never going to grow up.

Though most of us have gone through puberty by our mid-teens, a few unlucky people never do. Without intervention, they are forever stuck in a childlike state. Men never develop a lower voice, facial hair or a strong jaw. Their genitals remain undeveloped, and they have no sexual urges. It's a similar story for women, who don't develop breasts or rounded hips, and never have a period. For both, hormone levels remain low and they can't have children.

The condition is called idiopathic hypogonadotropic hypogonadism (IHH) and it can have a variety of causes. Sometimes certain neurons don't migrate to their proper positions during fetal life, or hormones such as leptin that should be communicating about energy stores aren't able to do so.

A few cases, however, are a complete mystery. Messager and her colleagues wanted to know if some of those people whose condition couldn't be explained had similar mutations to the Peter Pan mice.

By sheer coincidence, Stephanie Seminara and her colleagues at Harvard University had been studying a large intermarried Saudi Arabian family in which six people had been diagnosed with IHH. What's more, Seminara's team had narrowed the gene search to a stretch of chromosome 19 - exactly where the gpr54 gene was located in mice.

One of the Paradigm team called Seminara and told her they had engineered a mouse with IHH, and that they knew the exact gene responsible. Seminara said that she too knew the identity of the gene (she was in fact preparing a paper on the specific mutation). There was a long electric pause. "We didn't say the name of the gene," says Seminara, who looks back on it as "one of the most wonderful days of my career". The two groups published their data together in one paper in The New England Journal of Medicine in 2003, the first time in the journal's 191-year history that it had ever published animal data.

What the teams jointly established is that a single protein, kisspeptin, conserved throughout evolution in both mouse and man, is responsible for unleashing puberty. "I would say it's a watershed event in the last 30 years," says Robert Steiner at the University of Washington in Seattle, whose lab is dedicated to understanding the neuroendocrine mechanisms of reproduction.

Identifying kisspeptin doesn't completely solve the mystery, of course. We still don't know what triggers its release. The answer is bound to be complicated. All sorts of factors appear to affect the timing of puberty, particularly in girls. Genes must play an important role, as girls tend to go through puberty at the same age as their mothers did. Sociological factors may also have a hand: girls whose fathers are absent, or who have a bad relationship with their fathers, seem to hit puberty earlier. Environment is also important. Living at high altitude can delay puberty, for instance, and being exposed to hormone-mimicking chemicals can hasten it.

The single most important non-genetic factor, at least for girls, appears to be their nutritional status. That makes sense, since sexual maturity for females means being able to carry and nourish a fetus. Nutritional status and the availability of energy stores can have a huge impact on reproductive function. Being extremely thin or malnourished or even exercising too much can suppress fertility, causing circulating hormones to go down and, in females, bring ovulation to a halt. We know that information about energy stores is relayed to the hypothalamus via metabolic hormones such as insulin and leptin, a hormone produced by fat cells. But it's never been entirely clear how the final tally is done.

Could that be the job of kisspeptin? Could kisspeptin be weighing all the various factors and deciding when we are reproductively viable? It's worth noting that about 40 per cent of neurons with kisspeptin receptors also carry leptin receptors. This means that leptin targets many of those neurons, suggesting a strong link between the state of a child's energy reserves and the onset of puberty. Food and sex

Intrigued by the fact that leptin-deficient mice are infertile, and that no one knows quite why, Steiner's team measured levels of kisspeptin production in a part of the hypothalamus known as the arcuate nucleus. They compared levels in normal mice with those in mice that had had their leptin gene knocked out and found that kisspeptin activity in the "knockouts" was significantly less. Could leptin-deficient infertility be caused by inadequate stimulation of kisspeptin neurons? Steiner reckons so.

Manuel Tena-Sempere at the University of Cordoba in Spain has also been exploring the interplay between leptin and kisspeptin. He restricted the food intake of female rats and, as expected, found that this delayed their sexual maturation. But when underfed rats were given kisspeptin, they went through sexual maturation on time. This is more evidence that kisspeptin neurons are downstream of leptin and may be mediating its effect.

This opens up the possibility of new treatments for people who have defective genes either for the kisspeptin receptor, gpr54 - like the Saudi family - or for kisspeptin itself. It also might help women who have stopped having normal menstrual cycles due to excessive exercise or inadequate fat stores. These women are at risk of early bone loss, says Seminara, and there can be other long-term health effects. There are already ways of helping them, but could kisspeptin provide a new way to get things back on track?

More intriguingly - and controversially - kisspeptin may also offer new treatments on the other end of the spectrum: in the girls who start menstruating at 6, for instance, or in aggressive 8-year-old boys who are already growing pubic hair. Roughly speaking, if girls show breast development before age 8 and boys show penile or testicular growth before age 9, it is considered "precocious puberty", a condition doctors often recommend treating with drugs. Some cases of precocious puberty are caused by tumours in the brain or ovaries, but many are unexplained.

Unexplained or not, precocious puberty is a slippery concept. Cases are defined simply by their relation to the mean age at which children enter puberty. Over the past 150 years, in the US in particular, that mean has been shifting downwards. A controversial 1999 paper even suggested that, in light of this, the cut-off for precocious puberty should be lowered - to under 7 in white girls and under 6 in African-American girls (Pediatrics, vol 104, p 936). This would mean that no one ought to blink at female puberty commencing in the first or second year of school.

This downward trend is evident in practically all western countries and has been going on for a long time. In the mid-18th century, European girls started menstruating around age 17 on average; by the mid-19th century that age had dropped steadily to 14. The average now is about 13. In the US, about half of African-American girls have started having periods by age 12 years and 2 months.

Why is puberty coming to ever younger children? The simple answer is that no one knows. One possibility is the increasing prevalence of obesity in children. There is evidence that overweight girls are more likely to start puberty early, and there is that link between kisspeptin and energy stores. But obesity cannot be the only factor. For instance, it does not appear to explain why early puberty is more common among African-American girls, who are not in general more likely to be obese than white girls.

Marcia Herman-Giddens of the University of North Carolina School of Public Health in Chapel Hill, whose landmark 1997 study on the declining age of puberty among American girls brought the issue to the fore, thinks obesity may play a part. But she also suspects that lack of exercise and endocrine-disrupting chemicals, such as fire retardants and plastic additives, are interfering with our reproductive systems and driving down the start of puberty to an unnaturally low age.

Another explanation, proposed by endocrinologist Peter Gluckman of the University of Auckland in New Zealand, is that the age of puberty has merely settled back to historically typical levels for human beings, after anomalous delays caused by poor health and nutrition during the agricultural and industrial revolutions.

Even if Gluckman is right, there is no reason for complacency. He says this is probably the first time that we have had such a tremendous mismatch between reproductive maturity and social maturity. Our palaeolithic ancestors probably started having children at 12 or 14, but by that age they were also fully mature members of society, he argues. The same is not true in the modern world, when it can take people until their 20s to be considered mature. Could kisspeptin someday provide a way to bring sexual and social maturity more closely in line with each other? Should we expect to see a little more tinkering around the edges of "normal"?

No matter what age we regard as normal for the onset of puberty, there could be advantages in delaying it. The strongest push would come if a clear health benefit were to emerge. Early puberty increases the risk of cancers of the breast, womb and prostate. It also increases the risk of endometriosis and polycystic ovarian syndrome. Early bloomers also tend to grow into shorter adults. What if we found that delaying puberty by a few years in early bloomers could cut their cancer risk in half - would we do it? Would we do it for an extra inch in height?

Other obvious benefits would be social. It could be argued that primary-school girls and boys simply aren't meant to be reproductively mature. Delaying puberty would give them time to mature mentally and psychologically, putting off the distractions of the opposite sex till they are better able to handle them. Boys tend to become more aggressive after puberty strikes; girls become more sullen, and often lose their self-confidence. Girls who develop early are also more likely to date and have sex at a younger age. They are more likely to drink, smoke and use drugs, more likely to suffer depression or be socially withdrawn and more likely to attempt suicide. Delaying the transition to adulthood could spare thousands of girls some of these problems - would we do it for that? Perhaps it could cut the teen pregnancy rate - would we do it for that?

In truth, parents or doctors who want to tinker can already do so. Kids who enter puberty precociously are offered treatment, usually involving drugs that act via the hormone GnRH to shut things down until the timing is more appropriate. There appear to be few side effects in children, apart from rare instances of pain or rash, but the drug is expensive and has to be injected. Also, although there's no evidence of harm, a parent would have to balance the benefits of delaying puberty against the possibility of as-yet unknown long-term dangers.

Many researchers believe that because kisspeptin and its receptor are upstream of GnRH, and are what triggers its release, they may make a more attractive target for drugs either to kick-start puberty or to shut it down. "It's at the top of the hierarchy, so there's more possibility of natural feedback control, and less possibility of getting the dose wrong," says Steve Bloom at Imperial College London. His group is exploring kisspeptin's potential as a drug for restarting periods in women with amenorrhoea. He and other researchers are hoping that it might be possible to develop the protein into an oral tablet form, to spare people the injections they have to take if they use GnRH.

Seminara and her colleague Tony Plant, at the University of Pittsburgh, recently confirmed that kisspeptin can be targeted to shut down monkeys' reproductive development, just like GnRH does. Too much too young?

If kisspeptin is ever developed into an effective drug, used to treat people with disorders of puberty and shown to be relatively safe, could it become a treatment option for parents wanting to delay their child's puberty to be better in line with social maturity? Will an 8-year-old girl some day have the option of waiting till she's 10 or 12? It's not hard to imagine the abstinence movement promoting voluntary postponement of puberty. Will kisspeptin ever be used widely to shift puberty up to what is considered a socially appropriate age?

Herman-Giddens thinks it probably will. "A lot of parents don't like it when their girls develop early," she says. "If they could delay it, they would." Bloom also concedes that a puberty-suppressing drug could end up being used for non-medical reasons. "But you're interfering with a fairly fundamental aspect of the human being without knowing the long-term effects," he cautions.

Perhaps the greatest worry is the potential effect on the brain. It is now accepted that adolescence is a dynamic time for brain development and that puberty hormones have a strong influence on the process. Without them, normal behaviours fail to develop. Cheryl Sisk at Michigan State University in East Lansing, for example, has found that male hamsters not exposed to sex hormones during puberty are much less likely as adults to mount females, spread their scent to communicate their status or indeed to have a dominant status worth boasting about. And these behavioural changes are long-lasting: hormone replacement in adulthood does not put things right. A handful of studies suggests the same may apply to humans. Seminara's colleague at Harvard, William Crowley, has shown that men who were not exposed to sex hormones at the normal age for puberty, but were treated afterwards, had worse spatial abilities than other men.

Sisk has also shown that the earlier an animal is exposed to puberty hormones, the greater the effects on behaviour and - by inference, she says - on the brain. She castrated male hamsters at 10 days old, then exposed each to exactly 18 days of testosterone but varied the timing of that exposure. Some got testosterone before puberty would normally have occurred, some during, and the others after. They found that sensitivity to the testosterone gradually diminished as the animal aged. "It's as though the window was open in early life," she says, "then it's gradually closing until puberty - when it shuts."

This could have huge implications for humans, she says. In precocious puberty, she suspects, the brain is probably highly sensitive to sex hormones. But what that means for intervention is not clear. "Is it a good thing? A bad thing?" she asks. "We don't know." But what we do know is that tinkering with timing will affect far more than simply when underarm hair starts to grow.

Perhaps it's no surprise that researchers are generally wary of interfering in such an important yet poorly understood process. "I'm very nervous about a medical approach to puberty," says Gluckman. He accepts that mistimed puberty is a problem that needs to be tackled. "But I'm very reluctant to solve it medically. I'd rather solve it socially. Maybe it would be better to help young people face biological maturity."