Feature

Early Arrival

Premature puberty among girls poses scientific puzzle

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11:03am, November 16, 2012
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Today it has become common for girls to enter puberty before discovering Are You There God? It’s Me, Margaret. Over the second half of the 20th century, the average age for girls to begin breast development has dropped by a year or more in the industrialized world. And the age of first menstruation, generally around 12, has advanced by a matter of months. Hispanic and black girls may be experiencing an age shift much more pronounced.

The idea of an entire generation maturing faster once had a strong cadre of doubters. In fact, after one of the first studies to warn of earlier puberty in American girls was published in 1997, skeptics complained in the journal Pediatrics that “many of us in the field of pediatric endocrinology believe that it is premature to conclude that the normal age of puberty is occurring earlier.” Today, more than 15 years later, a majority of doctors appear to have come around to the idea. Have a conversation with a pediatric endocrinologist, and it isn’t long before you hear the phrase “new normal.”

“If you basically say that the onset of puberty has a bell-shaped distribution, it seems to many of us the whole curve is shifting to the left,” says Paul Kaplowitz, chief of the division of endocrinology and diabetes at Children’s National Medical Center in Washington, D.C. More girls, he says, are starting puberty before age 8, putting them at “the lower end of the new normal range.”

Researchers are now turning their attention to what could be driving the trend. Many scientists suspect that younger puberty is a consequence of an epidemic of childhood obesity, citing studies that find development closely tied to the accumulation of body fat. But there are other possibilities, including the presence of environmental chemicals that can mimic the biological properties of estrogen, and psychological and social stressors that might alter the hormonal makeup of a young body.

These possibilities could also be occurring simultaneously in ways that are not understood. A study published in September in the Journal of the American Medical Association found that children with high levels of a common environmental pollutant were more likely to be obese. “Although I’m convinced that obesity is part of the story, I’m no longer convinced it’s the whole story,” Kaplowitz says.

Scientists hope more research will help explain why the puberty trend for boys isn’t as clear as it is for girls, though a recent study in Pediatrics does suggest that boys, too, may be maturing earlier. The concern is not parental squeamishness but the potential for future health consequences. Children reaching puberty too young, some data suggest, face a higher risk of cancer, bone fractures and other problems in adulthood. Doctors also fear a body that belies true age, especially in girls, could put children at risk for sexual abuse and other problems.

“The early maturing girl has greater vulnerabilities and is more likely to be involved in risky behaviors,” says Frank Biro, director of adolescent medicine at Cincinnati Children’s Hospital Medical Center. When a 9-year-old looks 12, “her peers and adults take the cues from what she looks like. But she’s still a 9-year-old.”

Earlier than thought

Observations of sexually abused girls are what helped launch the scientific study of early puberty. In the 1980s, Marcia Herman-Giddens was evaluating such girls as a physician’s associate at Duke University Medical Center. She began to notice that patients as young as 5 were coming to the doctor with breasts and pubic hair. To Herman-Giddens, this seemed awfully young, but the best references she could find for comparison was a British study conducted decades earlier.

To try to find out if the girls in her office were somehow on an accelerated time line, she began compiling information, first publishing small investigations and then looking at more than 17,000 girls seen at 225 pediatricians’ offices. She reported the larger study in 1997 in Pediatrics. At the time, Herman-Giddens says, the generally accepted average age for puberty onset was about 11. She and colleagues found that, on average, black girls were beginning to develop breasts and pubic hair before age 9, and white girls around age 10 and a half. Her earlier studies had already hinted at racial differences in the timing of puberty, she says. “The thing that shocked us was the girls were developing much earlier than everyone thought.”

The report ignited pointed debates. “There were a couple of groups of pediatric endocrinologists who said, ‘We can’t sign onto this,’ ” Biro says. One of the criticisms was that, by drawing data from doctors’ offices, the 1997 study might have overrepresented girls brought in by concerned parents.

Soon after, Biro and colleagues gathered data on a cross section of American girls for a research project into possible environmental contributors to the onset of puberty. The new findings, published in 2010 in Pediatrics, support the idea that girls are developing breasts earlier, with results that vary widely by race.

By age 7, Biro’s team found, breast development was occurring in about 10 percent of white girls, 23 percent of black girls and 15 percent of Hispanic girls. By age 8, the numbers rose to about 18 percent of white girls, 43 percent of black girls and 31 percent of Hispanic girls. All of these proportions were greater than those found in older studies, including Herman-Giddens’ research.

“Clearly what we consider normal today, 20 or 30 years ago would have been considered precocious puberty,” Biro says, using the medical term for extremely young puberty. Other studies have also been consistent with the idea that puberty is occurring earlier, including a 2009 study from Danish researchers that put breast development about a year earlier among girls studied in 2006 compared with girls studied in 1991, and put the age of first menstruation more than three months earlier.

The diet debate

Childhood obesity tops the list of suspects that might account for this change. The percentage of American children who are obese has tripled over the last 30 years, now at about one-fifth of children and adolescents. The timing of the obesity epidemic roughly corresponds with the apparent drop in age of puberty.

There’s a certain evolutionary logic to a tie between body fat and reproduction, says Kaplowitz. “If there’s a decrease in food supply and your body fat stores decrease, it would not be an optimal time for your body to support a pregnancy,” he says. But once a girl’s body contains enough fat for the energy demands of reproduction, hormonal signals start clearing the way for sexual maturation.

As early as the 1960s, researchers noted that sexual maturation in rats correlated more closely with body size than age. More recently, studies in people find a similar connection. In 2007, a study in Pediatrics reported that, among other findings, a girl’s weight as early as age 3 could predict her odds of going through puberty before her peers. Later research follows the same pattern. Last year in the journal Fertility and Sterility, scientists reported on a group of more than 3,000 girls born in Denmark in the 1980s. The team recorded the girls’ ages when menstruation began, and determined body mass index (a measurement of weight in relation to height). For every point increase in body mass index, based on weight and height reports from mom, the age of first menstruation dropped by about a month.

Scientists cannot conduct direct experiments testing overeating’s effects on puberty, and it is hard to sort out other contributors such as genetics, environment and activity levels. But researchers from the University of Wisconsin–Madison recently measured how eating more affects the timing of puberty in monkeys. In April, the scientists published a study of four female juvenile monkeys raised in the same extended family colony and randomly assigned to have snacks every morning and afternoon. The treats increased the monkeys’ calorie intake by about 30 percent compared with four monkeys on a regular diet. Everything else between the two groups of monkeys, including living conditions and activity levels, remained almost identical.

Less than a year later, all of the monkeys with extra food had begun menstruating, but none of their cage mates had, the scientists reported in Endocrinology. The monkeys eating more also experienced puberty earlier than previous generations of the colony. “We were surprised,” said physiologist Ei Terasawa, who led the research. “The only change was the diet.”

At issue is probably not weight gain alone but fat, researchers say. One of the main biological conduits between obesity and puberty — for girls, at least — occurs through the hormone leptin, released by fat tissue to notify the brain about the body’s energy stores. Research has found that leptin levels rise before puberty. Other clues point to leptin, too: Mice born with an inability to produce leptin, in addition to becoming obese, do not go through puberty. Neither do people who are born with genetic abnormalities that interfere with leptin production.

In boys, the onset of puberty is more gradual and thus harder to measure than it is in girls. But if obesity is a big contributor to the trend, boys might be less affected. The role of body fat and related hormonal cues are probably less important, or more complex, in male development.

Even among girls, the endocrinology is far more complicated than leptin alone — it is not the only puberty-related hormone affected by obesity. The female hormone estrogen, too, is key for breast development. Although fat tissue can also produce estrogen, when it comes to triggering puberty, “the role of estrogen is more controversial,” Biro says.

Pollution and puberty

Nonetheless, estrogen is central to another early puberty hypothesis. That is, whether the estrogen-like qualities of some chemicals, including environmental pollutants, are to blame. It’s known that many substances used in plastics, pesticides, detergents and other products can mimic the effect of estrogen in animals, sometimes dramatically. Exposure to these compounds can even cause male reptile and bird hatchlings to become feminized.

Studies have pretty consistently found that the timing shift in breast development appears to be greater than in menstruation, Finnish and Danish researchers wrote in 2010 in Molecular and Cellular Endocrinology. Since breast tissue is more sensitive to estrogen than is menstruation, “the reason for the development of glandular breast tissue at much younger ages over a short period of time must be of environmental origin,” wrote scientists from Turku and Copenhagen.

Among the list of suspected culprits are polychlorinated biphenyls (once used in electrical transformers and capacitors), polybrominated biphenyls (found in some flame retardant materials), phthalates (added to plastics, and even beauty products) and dioxins (a common industry by-product). Among more than a dozen human epidemiological studies reviewed by the researchers, the results were mixed. While some found that exposure to pollutants sped up puberty, others found a delay in puberty or no effect.

A study in November in Environmental Health Perspectives shows the difficulty of studying any one environmental exposure. Researchers from the U.S. Centers for Disease Control and Prevention in Atlanta examined urine samples from girls ages 12 to 16, looking for an association between a variety of environmental chemicals and the reported age at which menstruation began. The team found an effect for 2,5-dichlorophenol, the breakdown product of an ingredient commonly used in mothballs and toilet deodorizers. But other chemicals examined did not appear to have an effect.

A grab bag of results isn’t surprising, said chemist Mary Wolff, who heads the Center for Children’s Environmental Health and Disease Prevention Research at Mount Sinai School of Medicine in New York City. Some studies aren’t valid because they measure chemical exposure through blood samples, she says, when its presence can be detected only in urine. A study may measure only a few chemicals individually, when in fact an effect may require a certain combination. Or the effect may be real but drowned out in study results by the greater influence of body fat and genetics.

Wolff is hoping that a study under way now will help eliminate many of these uncertainties. The U.S. government-funded project is following more than 1,200 girls ages 6 to 8 recruited before puberty. As they grow older and sexually mature, the girls’ environmental exposures are being monitored. “There will be some papers in the next year,” she says. “I think they will be very informative.”

Another complicating factor may take years to work out. There could be a yet-unknown window of exposure that makes a difference; perhaps, for example, an exposure has an effect early in life, but not as the time of natural puberty approaches.

“What concerns me is that most studies are looking at exposures at the time of puberty,” Wolff said. “With all environmental exposures, you have to measure at a time that fits with the window of action. I’m beginning to suspect it is early in life.”

Stress test

A third area of investigation into early puberty is trying to determine the influence of a girl’s physical, social and emotional surroundings. A wide body of research supports the idea that an undercurrent of stress in early life affects timing of puberty, probably by activating hormonal responses to danger, says psychologist Julianna Deardorff of the University of California, Berkeley’s School of Public Health. Still, when Deardorff began researching stress and puberty more than a decade ago, she says, “I came at it very skeptically.”

Experiments since then have changed her mind. Among them: Last year, in Development and Psychopathology, she and her colleagues reported that children who showed a high sensitivity to their circumstances (as measured by biological reactions to stress) were more likely to undergo puberty earlier if they also had poor relationships with their parents. Also last year, in the Journal of Adolescent Health, Deardorff and her colleagues published a study linking the absence of a father to earlier puberty. The researchers, who followed girls for two years beginning before puberty, reported that the finding held even after they accounted for household income and weight.

Previous studies had suggested that the stress of being raised in a single-parent household might lead to early puberty, but many had failed to account for the influence of obesity, income, ethnicity and other possible factors.

While the influences of stress and living conditions are still under investigation, it is not far-fetched to think that the body would respond to its surroundings, Deardorff says. Recent studies are helping scientists understand much more about how experience can change which genes get turned on or off in any particular circumstance. When life begins without excess anxiety, she says, “the signal is, this is a safe world and I can delay reproduction.”

Questions about early puberty would be easier to answer if sexual development itself were better understood, says Patrick Chappell, who researches the molecular and cellular biology of sexual development at Oregon State University in Corvallis. Puberty occurs when a young body reaches some precise combination of genetic programming, metabolism and environmental stimuli, all of which correspond to a biological calendar set over the course of human evolution. The hormones involved in this transition have been well studied, but how exactly they are awakened is still unknown, he says.

“What influences the timing of puberty?” Chappell says. “In order to know that, you have to know why it happens in the first place, and we don’t.”


Placing puberty blame

Scientists now agree that the age of onset of puberty is shifting, at least among girls. But the culprit behind that shift is not yet known. Recent studies point to a number of possible contributors that could be acting on their own, together or with unexplored factors to explain the trend.

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