Referrals for early puberty increasing, but number of actual cases remains low

Research during the past few years has suggested that American girls are entering puberty earlier — some as young as 6 years of age. The phenomenon has been linked to specific pathologies, obesity and even environmental toxins.

Fortunately, this problem has limited scope and there are ways to help children in early puberty. Researchers continue their efforts to identify the causes.

“There seems to be a very minimal trend to earlier puberty,” Henry Anhalt, MD, a pediatric endocrinologist from Hackensack, N.J., told Endocrine Today. “Nothing dramatic, nothing marked.”

The number of children who experience precocious puberty is small, with estimates suggesting that about 5% of American girls exhibit precocious puberty. Adding to the issue at large, precocious puberty is sometimes misdiagnosed.

Girls are much more likely to enter puberty early, according to Craig Alter, MD, professor of clinical pediatrics at The Children’s Hospital of Philadelphia.

“Of every 15 kids who come to me with concerns about early puberty, one is a boy and 14 are girls,” Alter said. “It is almost all a phenomenon of girls.”

Concern about the age of pubertal onset declining drastically in girls arose from a study published by Marcia Herman-Giddens, PA, DrPH, and colleagues in 1997. The researchers evaluated more than 17,000 girls aged 3 to 12 years in pediatric office practices. Their data showed that at age 3 years, 3% of black girls in the trial and 1% of white girls had breast or pubic hair development; the proportions grew to 27.2% and 6.7%, respectively, at age 7 years. By age 8 years, 48.3% of black girls and 14.7% of white girls had begun pubertal development.

However, there are a few problems with these data, according to Robert L. Rosenfield, MD, professor of pediatrics and medicine and a pediatric endocrinologist at the University of Chicago in Illinois. “A big problem with the Herman-Giddens study is that it was not conducted in a normal population; it was just kids in a doctor’s office. Precocious puberty may be a common problem in doctors’ offices, but it doesn’t mean it is that common in the general population,” he told Endocrine Today.

In 2009, Rosenfield and colleagues published a re-evaluation of data obtained from the Third National Health and Examination Survey (NHANES) in a representative sample of the general population. Their premise was that earlier puberty might be, in part, related to the current obesity epidemic. They reported that signs of puberty were present in fewer than 8% of girls with a normal weight, defined as the 10th to 84th percentile BMI. However, breast development occurred by age 8 years in 12% and 19% of normal-BMI, non-Hispanic black and Mexican-American girls. Excessive adiposity was indeed found to be associated with earlier appearance of pubertal milestones in girls, Rosenfield said.

A subsequent study, led by Frank Biro, MD, in which the onset of breast development was ascertained with more accuracy (by palpation, rather than only inspection), reported intermediate results in 2010. The trial included 1,239 girls who were recruited at 6 to 8 years of age for a longitudinal study. By 7 years of age, 10.4% of white, 23.4% of black non-Hispanic and 14.9% of Hispanic girls had achieved breast budding (Tanner stage 2 development). By 8 years, 18.3% of whites, 42.9% of black non-Hispanic and 30.9% of Hispanic girls had entered this stage (see Chart). The results suggest that the number of 7- and 8-year-old girls, particularly white girls, with breast development is higher than studies of girls who were born 10 to 30 years earlier. Higher BMI percentiles were associated with early puberty. The extent to which excess adiposity accounted for early puberty is unclear, however, as is the extent to which this population is representative of the general population, Rosenfield said.

Normal vs. precocious puberty

Mark A. Sperling

Puberty is the time when sexual and physical characteristics mature; it normally begins between the ages of 8 and 13 years in girls and 9 and 14 years in boys. The process begins in the hypothalamus, which secretes pulses of gonadotropin-releasing hormone (GnRH), according to Mark A. Sperling, MD, professor in the department of pediatrics at the University of Pittsburgh and Endocrine Today Editorial Board member. The GnRH stimulates the pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In girls, the FSH causes an egg to ripen. As the egg ripens, it produces estrogen, which leads to secondary changes such as breast development, Sperling said.

In contrast, precocious puberty is defined as the appearance of secondary sexual characteristics in girls younger than 8 years and boys younger than 9 years. In girls, it can be characterized by breast development, vaginal bleeding and appearance of either pubic or axillary hair; in boys, it is marked by enlargement of the penis and testicles, facial hair and voice deepening. Girls and boys both display pubic or underarm hair, a growth spurt, acne and adult body odor.

Accurate diagnosis of precocious puberty relies on accurate determination of the Tanner stage, knowledge of the rate of progression of signs of puberty, and the change in the pattern of growth. Simply visualizing what looks like breast development is insufficient, as often the breast is only composed of fatty tissue and not true ductile tissue and thus would not be indicative of true puberty, Alter said.

“Endocrinologists count on palpating a breast bud to stage the onset of puberty,” Rosenfield said. “Part of the problem in girls is that overweight girls are thought to be, by inspection, putting on breast tissue, when all they are doing is putting on fat in their chest and elsewhere.”

Diagnosis should also involve bone age X-rays, serum hormone measurements, and possibly a pelvic ultrasound, brain MRI or CT, experts said.

Pathology as a cause of puberty

True precocity and pseudo-precocious puberty have different causes.

“True precocious puberty in girls, in more than 90% of cases, has no serious cause,” Rosenfield said. “In the remainder, it does have a serious cause. These causes seldom involve pituitary disease; they involve hypothalamic activation of pituitary gonadotropin release.”

Fifty percent of the time, the cause is idiopathic in boys, he said.

“Half of boys with true precocity have an organic cranial problem,” he said. It can occur after treatment with cranial radiation for a tumor, he added.

Causes of pseudo-precocious puberty, for boys and girls, include:

• Congenital adrenal hyperplasia;
• Disorders of the testicles, ovaries or adrenal glands;
• Hypothalamic hamartoma;
• McCune-Albright syndrome; and
• Human chorionic gonadotropin (hCG)-releasing tumors.

In addition, Rosenfield said endocrinologists must consider that true precocious puberty may “arise from meningitis, complications from meningitis, late sequelae from meningitis and hydrocephalus.”

Ethnicity also plays a role in pubertal onset. Compared with white girls, black and Hispanic girls start puberty 1 year earlier, Rosenfield said.

The question lies in why certain ethnicities enter puberty earlier.

Henry Anhalt

“There are clearly differences in dietary habits, differences in social interactions, differences in the communities that may have some unidentified cause of early puberty that may put them at greater risk,” said Anhalt, who is a member of the Advocacy and Public Outreach Core Committee of The Endocrine Society.

“It is tempting to say it’s all about the juice intake or fried foods or fatty foods that may be consumed in greater quantities.” However, that discounts genetics and environment, he said. “In fact, it could be something that traces back to an earlier generation.”

Obesity leads to early changes

Obesity has been implicated as an important factor in the premature puberty of girls. It is both a trigger of puberty and can also cause pseudo-puberty because excessive chest fat deposition mimics breast development.

“Some of that is related to the fact that there is a signal coming from our fat tissue called leptin,” Sperling said. Leptin signals the body about the state of nutrition.

The body needs a critical level of leptin to start puberty, Rosenfield said.

“If you do not have leptin, you do not go into puberty,” he said. A child gains weight and puts on fat, and those fat cells produce leptin. Research has demonstrated that leptin levels are higher in obese children than non-obese kids. “It’s like a gate — [leptin] opens the gate and the other factors go to work.”

It is also clear that leptin stimulates GnRH secretion, which encourages LH and FSH production, he said.

“We have published pilot data that LH levels are higher in overweight pre-pubertal children than in normal-weight pre-pubertal children,” Rosenfield said. This research was a secondary analysis.

“Leptin plays a role in early onset of pubertal LH section in response to excessive adiposity,” Rosenfield said.

Endocrine disruptors

Mary Lee

Researchers are investigating another cause of precocious puberty: endocrine disruptors. These disruptors are natural or synthetic compounds that interact with the body’s endocrine system, according to Mary Lee, MD, professor of pediatrics and cell biology and director of pediatric endocrinology and diabetes at the University of Massachusetts Medical School in Worcester, Mass. They function by signaling through the body’s system or block hormone action.

To date, there is no direct link between endocrine disruptors and precocious puberty; however, the shift in the age of pubertal onset is obvious, as is the huge increase in the production of and subsequent exposure to chemicals, Lee said.

“They sort of occur coincidentally,” she said.

Animal models show that some of these compounds cause early pubertal onset and reproductive problems.

“The thought is that exposure, in girls, to some of the estrogenic endocrine disruptors may be stimulating the onset of puberty,” Lee said.

The evidence is not as clear in boys. Lee’s own research has shown that some compounds are associated with later pubertal onset in boys, whereas other work indicates that certain compounds may be associated with earlier onset.

Phytoestrogens and early puberty

Lee said the compounds most often linked to early puberty include phytoestrogens found in soy products, such as genistein, a plant-derived isoflavone, and coumestrol, a phytoestrogen that mimics the biological activity of estrogen. Lee is studying how dioxins and polychlorinated biphenyls influence pubertal onset.

There has been some news linking bisphenol A (BPA) exposure and precocious puberty. In mice, BPA has not been shown to influence early onset, although it accelerates how quickly mice mature, according to Lee.

“Once [the mice] show the first signs of puberty, they go from there to full puberty more quickly,” she said.

Researchers continue to study the significance of the role that endocrine disruptors play in early pubertal onset and what the long-term effects are, Lee said.

“It is not quite as clear whether earlier onset of puberty is associated with the sort of pubertal problems, in terms of menstrual irregularity or infertility; but in animals, exposure to some of these compounds is associated with decreased fecundity and, depending on which compound, maybe smaller litter size,” Lee said. “There are reproductive consequences of these exposures.”

Experts Endocrine Today interviewed agreed that more research on endocrine disruptors is needed.

“I’ve had people who’ve eaten organic foods their entire life who have come to me for precocious puberty,” Alter said. And although there is research indicating the presence of hormones in food, “the reality is that in this current day, I have not had any patient who was proven to have a hormone from a food.

“In fact, if estrogen was in food, I would expect to see boys with breast development, and I don’t see that, at a young age,” Alter said. “I may see adolescent boys with a little breast development, but that is normal development.”

A long-term, three-center study that is currently under way should clear up some of these questions. Investigators in Cincinnati, San Francisco and New York are examining whether endocrine disruptors influence the age of puberty.

Treatments available

The good news is both types of precocious puberty are treatable. The first step is to make the diagnosis, Sperling said. From there, treatment is straightforward and depends on the cause.

“If there is a tumor, you take it out,” Rosenfield said. In non-classic congenital adrenal hyperplasia, a common virilizing disorder among Ashkenazi Jews and several other ethnic groups, the body is unable to produce cortisol efficiently, he said. The adrenal gland compensates by making too much androgen. This is easily treatable with hydrocortisone or its analogs.

Functional disorders, such as McCune-Albright syndrome, are trickier to treat, Rosenfield said. This syndrome, which is more common in girls, requires hormone-like drugs that lower estrogen levels or estrogen effects. Tamoxifen-like drugs have been used with limited success.

There are hormonal treatments for true, central precocious puberty as well. Standard treatment involves an intramuscular injection of a GnRH agonist such as leuprolide depot, Alter said.

Another option is a histrelin implant, a small, rubbery tube “the size of a fuse in a fuse box” that a surgeon places in a child’s arm, Alter said. Depending on the child’s age, average treatment time is about 2 to 3 years.

Unique challenges

Treating a young, pubertal child presents unique challenges.

“I tell the family that the first job is figure out if there is a disease process causing the early pubertal development,” Alter said. After eliminating a pathological cause such as a tumor, Alter discusses treatment options with the family. “I never ‘tell’ a patient to go on treatment for precocious puberty; it is always a joint decision.”

Lee said that although more children are being evaluated for precocious puberty, not all require treatment. Children who are progressing slowly do not need treatment.

According to Alter, there are three primary reasons to offer treatment:

• How will precocious puberty affect final height? If a bone age X-ray predicts that the child’s final height will be 4 feet, 11 inches, for example, he will offer treatment.
• How is the child affected by looking older than her peers? “I get my gestalt of how the child is handling it by looking at them,” Alter said. “I get some kids who look and sound so mature and other kids are sucking their thumb.”
• How is estrogen affecting the body and behavior? While some girls are mature enough to handle the physical changes, Alter said, “the fact is, she’s thinking about boys and she’s only in the third grade.”

Precocious puberty may have long-term effects. If untreated, the child will mature rapidly and will have early epiphyseal closure.

“So, they’re tall youngsters, but short adults,” Sperling said.

Early breast development means longer exposure to estrogen, which may increase breast cancer risk, Anhalt said. In addition, other research has indicated that girls who have an earlier onset of menarche, have an earlier onset of menopause, Lee said.

The key element to approaching treatment, Anhalt said, is to be “sensitive to the fact that the child may not necessarily understand what is happening. It’s not that you just go ahead and treat it and don’t worry about the rest of it. We have to worry about the emotional component, which I think is as important, if not more important, than the medical issues.”

The psychological effects of early puberty are unclear, Rosenfield said.

“There are very little data [on this] on precocious puberty,” he said. But data in children who mature earlier than average — but who were not in precocious puberty — show that they “tend to hang out with older, more sophisticated kids who get into sexual activity earlier, become pregnant earlier, and so on.” – by Colleen Owens

For more information:

• Biro FM. Pediatrics. 2010;126:583-590.
• Carel JC. Pediatrics. 2009;123:e752-e762.
• Herman-Giddens ME. Pediatrics. 1997;99:e505-e512.
• Rosenfield RL. Pediatrics. 2009;123:84-88.

Disclosures: Drs. Anhalt, Lee, Rosenfield and Sperling report no relevant financial disclosures. Dr. Alter reports consulting for Endo Pharmaceuticals.

Is a trend toward early puberty also occurring in boys?

Maybe

Paul Kaplowitz

The issue of whether boys, like girls, are maturing early is interesting because it depends upon which study you look at. One study, by Herman-Giddens et al published in 2001, using data from the National Health and Nutrition Examination Survey (NHANES III 1988-1994), reported that the mean age of achieving Tanner stage 2 genital development was about 10 years, which would suggest that onset of puberty before age 9 years — the usual definition of precocious puberty in boys — would be much more frequent than endocrinologists typically see. Thus, there were concerns as to whether genital development was properly categorized by the examiners, and many dismissed the finding as due to bad methodology. With girls, onset of puberty is defined as when breasts appear; in boys, it is more difficult to pinpoint when the penis or testes start to grow. While I get many referrals for early puberty in boys, nearly all have had premature adrenarche (just early appearance of pubic hair) and few have had central precocious puberty, which is characterized by enlarging testes and elevated testosterone levels.

The relationship between early puberty and obesity is fairly strong for girls, but that is not to say that obesity is the only factor. A study conducted in Copenhagen found that the age of breast development declined by 1 year between 1991-1993 and 2006-2008, but it could not be attributed to an increase in mean BMI. Other studies from the US have suggested a link between obesity and early puberty in girls, but the studies in boys are not definitive. Some suggest that obesity delays puberty in boys, some find no effect, and a few suggest that obesity may accelerate puberty.

Leptin levels increase in girls early in puberty and continue to rise during puberty. In boys, leptin levels tend to fall as puberty progresses, likely related to the decreased percent body fat. There is evidence for girls that leptin may be permissive for onset of puberty, so that increased fat and earlier puberty may be linked; this evidence in boys does not exist. A related hypothesis is the evolutionary consideration that it is important for females to have an adequate amount of body fat to successfully sustain a pregnancy, but linking puberty and body fat in males would have no survival advantage.

My argument is that incidence of precocious puberty is not increasing in boys and that a plausible reason is that we do not see the same clear connection between early puberty and obesity in boys that we are seeing in girls.

Paul Kaplowitz, MD, is chief of endocrinology at Children’s National Medical Center in Washington, D.C.

Disclosure: Dr. Kaplowitz reports no relevant financial disclosures.

• Herman-Giddens ME. Arch Pediatr Adolesc Med. 2001;155:1022-1028.

Yes

Anders Juul

I do believe there has been a trend toward earlier pubertal development in boys. However, it is not nearly pronounced as the change seen in girls.

At an expert meeting in Chicago some years ago, we concluded that there was not evidence of an ongoing, downward secular trend in puberty timing among boys. However, things may have changed since then, as several European studies have now shown this trend in boys. Previous US studies were impaired by the fact that proper genital palpation, including estimation of testicular volume, was not performed.

The association between adiposity and pubertal onset may not be as straightforward in boys, as we believe it is in girls. Thus, increasing overweight may be associated with early puberty in boys — but only until a certain point. Overweight or obese boys may tend to mature at later ages, although controversy exists on this matter.

We have studied normal and pathological puberty in our department, and I have supervised several PhD students on the topic. In one of our studies (Sørensen et al), we evaluated secular trends in pubertal onset during 15 years and the relationship to BMI in healthy Danish boys. We found that the estimated mean age at onset of puberty declined significantly by 4 months during the recent 15 years, and the decline was associated with the coincident increase in BMI. Some years ago, we also reported a trend toward earlier voice break among Copenhagen choir boys (Juul et al). Also, a UK study (Monteilh et al), based on the Avon Longitudinal Study of Parents and Children (ALSPAC), reported earlier pubertal timing among boys. Using self-reported pubic hair Tanner staging collected annually, about 5% of boys reported Tanner pubic hair stage >1 at age 8 years. Monteilh and colleagues concluded that the data provide additional support to the influence of pre-adolescent body size on male pubertal development; the heaviest and tallest boys at 8 years reached each Tanner stage earlier.

Anders Juul, MD, DMSc, PhD, is clinical professor at the University of Copenhagen and head of the department of growth and reproduction at Copenhagen University Hospital, Denmark.

Disclosure: Dr. Juul reports no relevant financial disclosures.

• Juul A. Int J Androl. 2007;30:537-542.
• Monteilh C. Paediatr Perinat Epidemiol. 2011;25:75-87.
• Sørensen K. J Clin Endocrinol Metab. 2010;95:263-270.