Yes, I am well aware that it has been some time since my last entry. I will try to do better in the future. But, at least in the past several months I have been thinking of writing something about the swirling controversy about early puberty. It was only this past week, however, when I was consulted by a pediatric endocrinologist regarding a patient with early puberty, that I finally decided to put some thoughts to paper.
The case history
The patient was a 5 year old female with a two-month history of pubic hair. There was no history of rapid growth, acne, body odor, or any of the other signs or symptoms associated with early puberty. There was a family history of early pubic hair in the mother, whose first menstrual period was at age 13 years, about average. A maternal aunt also had early development of pubic hair. The patient was taking no medications and her general health had been excellent. Her physical examination showed height and weight at 99%, scant pubic hair, and no signs of male hormone effects on the genitalia. The patient had no under arm sweating or hair and no pubertal breast changes. At first, the physician thought the patient most likely had premature pubarche/premature adrenarche (the term adrenarche comes from the word “androgen” which is a generic term for male-like hormones such as testosterone), benign conditions which are often familial and generally of no clinical significance. But, as a routine part of the evaluation, the physician ordered a bone age, an x-ray of the hand to assess bone maturation. To the physician’s surprise, the bone age was almost 9 years, very advanced and not what one would expect to see in premature pubarche/adrenarche. Further studies showed that the patient actually had a condition called congenital adrenal hyperplasia (CAH) with partial deficiency of an important enzyme for adrenal cortex synthesis of cortisol and aldosterone, the 21-hydroxylase enzyme. Genetic testing showed that the patient was homozygous for a mutation in the gene responsible for controlling synthesis of the enzyme. I hope I have not confused those of you who do not have a science background. But, I do not want to get into a long discussion of congenital adrenal hyperplasia at the moment, but rather, I want to talk about the more general subject of early sexual development in both boys and girls. Don’t worry, I promise to come back soon to an in depth discussion about CVAH, a very interesting group of disorders.
Is puberty starting earlier in boys and girls?
Until 1997, the dogma among pediatric endocrinologists was that normal puberty involved two basic developments which were more or less independent of one another: adrenarche, which is activation of adrenal cortex androgen synthesis (testosterone, androstenedione, and dehydroandrostenedione and its derivatives); and gonadarche, stimulation of the gonads by the pituitary gonadotropins, LH and FSH (leading to formation of testosterone and other androgens in males, and estrogen as well as some androgens in females). Studies carried out quite some time ago in England by James Tanner (of Tanner staging) and colleagues established a time-line for both male and female puberty. In summary, gonadarche in females with breast budding started, on average, at age 10 yr 8 mo, followed shortly thereafter by adrenarche with pubic and axillary hair, with menarche, the first menstrual period, at age 12 yr 8 mo. As part of this orderly progression, females showed rapid acceleration in linear growth and weight gain concomitant with onset of gonadarche; by the time of menarche, females had on average, only about 6 cm (about 2.5 inches) of further growth in height.
In males, gonadarche started, on average, at age 11.5 yrs, with adrenarche about 18 months later. In contrast to the developmental pattern in females, male linear growth and weight acceleration was delayed until about age 13 yrs with still considerable linear growth potential until well past age 16 yrs.
I think every pediatric endocrinologist knew this time-line for pubertal development but also knew that for quite a number of children, the timing was far different. We had all seen many children, particularly females, with much earlier development of pubic hair than was considered normal. Particularly in black females, and in overweight males and females, it was not unusual to see evidence of adrenarche by age 6-7 yrs with gonadarche, particularly in the females, by age 8-9 yrs. So, few if any pediatric endocrinologists were surprised to see the results of a study that showed many females had evidence of sexual hair and breast development by age 8-9 yrs. The study was carried out by Maria Herman-Giddens et al., and was entitled: “Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatrics Research in Office Settings network” and was published in Pediatrics (1997;99:505). The study design was to survey a large number of pediatric practices to determine the ages at which female children first showed pubic hair and breast development. The data showed onset of breast development at about age 10 yrs in white females and at age 8.9 yrs in black females. One journalist, Elizabeth Weil described the findings as creating a “social and endocrinological firestorm.” Many pediatric endocrinologists just yawned at the report although some criticized the study design and questioned the validity of the data collection. Regardless, in the lay press and in the “foodie” and environmentalist communities, the study was pointed to as good evidence for the evil effects of various environmental chemicals on human development.
Phytoestrogens, isoflavones, xenoestrogens, endocrine disrupters, and such
For quite a long time now, scientists have known about many natural and synthetic compounds that have estrogen-like or anti-estrogen-like effects. Probably best studied have been the phytoestrogens which are plant-derived dietary estrogens first discovered in the 1920s which are diverse, nonsteroidal plant compounds that have very similar structures to estradiol, the predominant human estrogen. The word “phyto” comes from the Greek word meaning plant; the word “estrogen” comes from the word “estrus” meaning sexual desire. It is thought that the phytoestrogens are a plant defense against herbivores; they can affect male fertility in sheep. The idea is that with fewer sheep, there will be less grazing with the net result of more plants in the meadow. Who knows if this hypothesis is correct? Many foods that people consume have high levels of phytoestrogens. Examples include nuts, oil seeds (flax), soy products, cereals, breads, legumes, meats, and many processed foods. These compounds are also referred to as isoflavones and lignans. Man-made chemicals can also have estrogen-like effects. These are called xeno-estrogens and are widely distributed in food additives, cosmetics, plastics, insecticides, and other commonly used products. The phytoestogens and xeno-estrogens have been shown to bind to estrogen receptors and can affect proteins in the blood that carry estrogen (sex-binding globulins, or SBG)s. The $64 question is whether any of these estrogen-like agents have clinically meaningful effects on humans. In the context of our discussion, the question is whether these compounds are responsible for the possible changes in the timing and of puberty in males and females.
In my view, the data in the scientific literature are very unconvincing, despite many studies in experimental animals that show effects of these compounds on behavior, hormone levels, and sexual development. For example, male and female children should be exposed equally to these compounds. If that is true and if the compounds are responsible for early gonadarche, why don’t we find early breast development in males as well as females? That was certainly true a few years back when farmers were adding estrogens to chicken feed. Many of you may not remember the epidemic of early breast development in both boys and girls caused by that short-lived (thank goodness) attempt to fatten up chickens more quickly. I am sure all senior (i.e, old) pediatric endocrinologists remember that debacle. Anyway, I am not aware of any data showing a increase of pre-pubertal breast development in males (since about 90% of males do have some transient breast development during puberty-called gynecomastia- one can’t use rates of pubertal gynecomastia to assess possible effects of phytoestogens and xeno-estrogens). In addition, if these compounds were responsible for “pushing” children into true puberty earlier, one would expect a significantly earlier age of menarche in females, something that has not been observed. Finally, if these compounds were pushing children into puberty earlier, we would expect to see shorter adults since, on average, the earlier the onset of puberty, the shorter the individual ends up as an adult; if anything, we are seeing somewhat taller adult males and females. Of course, if the effects of these compounds are real but very subtle, we might not expect to see significant changes in the timing of menarche in females and in adult heights in males and females.
The effects of obesity
I didn’t discuss, except briefly, what may be the most important thing about the early puberty story. It is now well known that overweight children tend to have earlier onset of puberty than normal weight children. There are many possible reasons for this, including endogenous estrogens produced in fat. Of course, everyone knows there has been a very large increase in the percentage of male and female children who are overweight. Anyway, most of the recent studies on pubertal timing have not paid much of any attention to this factor, making the results of the studies nearly impossible to interpret. For example, a very recent study headed up by Maria Herman-Giddens, the same lead author as in the 1997 Pediatrics report, was recently summarized in the NYT (April 20, 2012). The NYT article was entitled, “Boys now enter puberty younger, study suggests but it’s unclear why,” written by Pam Belluck. The actual study which was entitled, “Secondary sexual characteristics in boys: data from the Pediataric Research in Office Settings Network,” was publishd in Pediatrics (volume 130, November 1,2012, pages e1058-e1068). As in the earlier study it was (as the title implies) a pediatric-office-based design. The study analyzed pubertal status in 4131 males ages 6-16 years of age. The investigators, who were general pediatricians, were trained to estimate testis size, which is a useful measure of male gonadarche status. The investigators found gonadarche in black males at about age 9 yrs and in white and hispanic males at a bit over age 10 yrs. The relationship of the timing of the gonadarche to body weight was not explored in any depth but the data showed that males with BMIs <15% had later development than males with BMIs >85% (in children, BMIs are expressed as a percentile not as a unitless number, and in children, overweight/obesity is defined as a BMI>85%). It was problematic that the investigators had to combine the various ethnic/racial groups to have sufficient numbers of subjects in the various weight categories. The other problem with the study, and one which the investigators acknowledged, was that their testis assessments were “graded” differently than in earlier studies to which they tried to compare results. For example, in the recent Pediatrics study, testis size was estimated by comparing each testis to 4 testis models with the following volumes: 1 mm, 2 mm, 3 mm, and 4 mm or greater. Earlier studies by Tanner and colleagues used the following models: less than 3 mm, 3 mm, and 4 mm or greater. So, the data cannot be compared directly. I do think that overall, the study was very well designed and well executed, but in my opinion, the study conclusions must be viewed with great caution.
The bottom line
So, I don’t really know if these various compounds that are truly everywhere have clinically relevant deleterious effects (on the other hand, I do not know of any data showing these compounds are good for us). I do know that we as pediatric endocrinologists should not just assume that early sexual development in either males or females should be considered the new norm. As the clinical vignette I presented above shows, the “party line” that onset of pubertal changes in females before age 8 yrs or before age 9 yrs in males should be considered abnormal until proven otherwise, continues to be a good way to think about precocious puberty. The pediatric endocrinologist did well to work-up the patient. Ignoring the presenting signs and symptoms would have likely turned out to be disastrous (at the very least, the patient’s adult height potential would have been severely compromised).
One thing is clear: we still have a lot to learn about puberty in children.
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