We Have More to Learn About Weight Gain, Pubertal Timing and Treatment for Precocious Puberty

There was a secular trend in declining age at menarche in industrialised countries from the middle of the 19th century to the mid 20th century [1]. The earliest registered data showed that the age at menarche was 16–17 years for girls, but it is now 12–13 years in many countries [2]. The trend towards younger ages at pubertal onset in girls continued, but slowed down, according to a meta-analysis of data from 1977 to 2013 [3]. Boys experienced the same pattern from 1947 to 1996, with their voices breaking earlier and pubertal growth spurts at younger ages [4]. The main reasons for earlier puberty are thought to be improved socioeconomic conditions, better nutrition and overall health. In addition, the global rise in overweight and childhood obesity over recent decades has been linked to earlier pubertal onset, particularly in girls [3]. Precocious puberty is defined as breast development before 8 years of age in girls and a testicular volume of 4 mL or more in boys before 9 years. It is more common in girls, and in the majority, puberty starts with activation of the hypothalamic–pituitary-gonadal (HPG) axis. Treatment with a gonadotropin-releasing hormone (GnRH) analogue is possible, but can cause weight gain in many children.

Two studies have been published in Acta Paediatrica on the relationship between weight gain and pubertal timing and treatment for precocious puberty.

The first is by Nummela et al. [5], who looked at whether weight gain in infancy and childhood was associated with pubertal development in boys and girls. The authors used data from a Finnish longitudinal study that originally aimed to assess atherosclerosis risk factors in early infancy. It started in 1990 to 1992 and comprised 1062 children. Families in the intervention group received individualised counselling about dietary matters twice a year. The main aim of this was to encourage children to consume more unsaturated fat and increase their intake of fruits, vegetables and whole grain products. The families in the control group received standard counselling from baby clinics and schools. About half (47.8%) of the original study population was followed at least once a year until 20 years of age, and their height, weight and pubertal stages were monitored from 9 years of age. Pubertal timing was similar for both groups, and the data for 278 girls and 230 boys were combined. Most of the children had normal weight and were not born small for gestational age. Weight gain of one standard deviation in infancy or childhood was associated with earlier puberty in both sexes. The girls experienced breast development 5.2 months earlier and menarche 3.6 months earlier per standard deviation weight gain. Puberty also lasted 1–2 months longer in these girls. The boys had genital development 2 months earlier for each standard deviation weight gain, but the duration of puberty was not altered. Both early weight gain between birth and age 2 years and 2 and 8 years of age were associated with the earlier onset of puberty in these predominantly normal-weight children. The novel finding was that weight gain, even among children of normal weight, may influence pubertal timing. This was mainly noticed in girls, but it also occurred in boys, although it was less evident. The results also suggested that there may be certain periods during childhood when weight gain might be more important for pubertal timing than others.

The second study published in Acta Paediatrica, by Ong et al. [6], is a systematic review with a meta-analysis of 46 published studies. This examined increases in body mass index percentiles in girls with central precocious puberty who received gonadotropin-releasing hormone analogues. Data were analysed from 3606 girls treated with GnRH analogues in 17 countries and focused on weight gain during and after treatment. The authors reported that body mass index (BMI) standard deviation scores increased during the first 2 years of treatment. They found that girls with a normal BMI at baseline were more likely to experience a significant rise in BMI than girls with obesity and overweight. The novel finding was that girls who were followed after the treatment stopped, in some studies until final height, no longer had significant BMI increases. So, the effect on BMI seemed to be transient. The authors also pointed out that it is common knowledge that BMI usually increases when treatment with GnRH analogues is started and patients should be given advice on healthy eating and physical activity.

We still do not know why girls often start puberty earlier and boys often have delayed puberty, despite our increased knowledge about what influences the pulsatile production of GnRH in the hypothalamus. When kisspeptin, a neuropeptide produced in the hypothalamus, was discovered it appeared that the mystery had been solved. Kisspeptin stimulates the release of GnRH but other regulators that influence this have also been discovered. There is probably a complex network involved in GnRH activation, including leptin and insulin. These might provide the key to how weight gain and obesity can influence pubertal timing and result in earlier puberty. Catch-up growth and accelerated weight gain among children born small for gestational age have also been shown to influence pubertal onset [7]. However, the other study, by Nummela et al., also pointed out that an increase in the BMI standard deviation score can also trigger earlier pubertal onset in normal-weight children, not just those born small for gestational age.

Pubertal timing is 60%–80% genetically determined [2], as it follows a familial pattern. The rest is thought to be influenced by a number of environmental factors. These include improved nutritional status, migration to countries with better socioeconomic conditions and health status, and chronic or frequent infectious diseases [8]. It is also thought to be affected by pollution and exposure to environmental endocrine-disrupting chemicals [8], but it is hard to prove causation because of the vast number of substances that interact and occur simultaneously. All these factors are candidates for affecting the endocrine milieu and causing earlier activation of the HPG axis, which is active already during fetal life and mini puberty in infancy. The trend for earlier puberty seems to be continuing.

The earlier mentioned meta-analysis, which covered the period from 1977 to 2013, reported that the age when breast development started in girls decreased by around 3 months per decade. The earliest onset was observed in the USA and the latest in Africa [3]. Genetic predisposition and ethnicity may be of some importance for pubertal timing, but it is difficult to know how factors like socioeconomic differences, overweight and obesity play a role. One study noted that the onset of breast development was earlier among black girls than among Mexican Americans or non-Hispanic white girls [9]. However, the age of menarche showed no difference after adjusting for socioeconomic factors and BMI, so there seemed to be a longer duration of puberty. Rapidly maturing children also tended to have a higher body BMI. The study was criticised because of the limitation that breast development was assessed through visual inspection and not palpation. This raised the risk of misclassification, especially in overweight children, where subcutaneous fat can be mistaken for glandular breast tissue. In contrast, a Danish study classified pubertal stages by palpating the girls' breast tissue [8]. They found the same trend for earlier onset of breast development, as the previously mentioned meta-analysis [3]. However, the Danish study did not find any significant decline in the age at menarche between 1991–1993 and 2006–2008. This implied a longer duration of puberty, similar to the findings by the Nummela et al. [5] paper covered by this editorial. The Danish study adjusted for BMI and concluded that BMI could not explain the changes, suggesting that other factors, such as environmental endocrine disrupters, may have been involved. Danish boys showed the same trends for earlier pubertal onset during the same time periods, but the authors suggested that this was mainly due to increased BMI [10].

Precocious puberty could be caused by central nervous system tumours and genetic conditions, such as McCune–Albright syndrome, but in most cases it is idiopathic, particularly in girls. It is more common in girls; boys more often have an underlying organic cause. Precocious puberty can cause psychological stress, and there is a risk of shorter final height. Treatment is possible, as a GnRH analogue can effectively suppress the release of gonadotropins from the pituitary and efficiently halt puberty. The disadvantage is that this treatment can cause weight gain in many children, and clinicians may be hesitant about starting treatment if children are already overweight or have obesity.

These two new papers in Acta Paediatrica add valuable information to the ongoing debate about childhood overweight and obesity and the relation to pubertal timing and treatment for precocious puberty.

Nummela et al. [5] present the novel finding that weight gain, even in normal-weight children, may influence pubertal timing in both girls and boys, and add that periods during childhood may be more important than others.

The systematic review and meta-analysis by Ong et al. [6] provides reassuring data on the transient impact of GnRH analogue treatment for BMI in girls with precocious puberty, by reporting no significant BMI increase at follow-up and final height. This information is valuable when discussing treatment options with affected girls and their families.

The author declares no conflicts of interest.