Precocious pubertal development: a challenge for pediatric endocrinologists

Abstract

Precocious puberty is one of the most common conditions encountered in the pediatric endocrinology clinic and can be defined as the appearance of secondary sexual characteristics in girls under 8 years and boys under 9 years of age. The timing of pubertal onset has received increasing attention because of a reported gradual decline in age at menarche in most populations. Proposed mechanisms for these changes include: an improvement in socioeconomic conditions with consequent increased nutritional status and a rise in a number of environmental pollutants. The challenges for pediatric endocrinologists are increasing: what are the mechanisms of precocious puberty in modern society? Should our diagnostic criteria be changed? When to treat? What are the consequences of treatment? Little is known of the short and long term consequences of GnRH-analog treatment, especially in terms of psychological consequences for children and their families.

Keywords:

• endocrine-disrupting chemicals
• ghrelin
• kisspeptin
• leptin
• nutrition
• psychological outcome
• puberty
• secular trend

Puberty is the transitional period between childhood and adulthood, characterized by the progression of secondary sexual characteristics from onset to full sexual maturation [1]. Even if it has been widely investigated, many challenges still remain to be elucidated, such as the timing of pubertal onset, factors influencing its development and long-term psychological outcomes related to treatments.

Timing of puberty: what it is known & what is changing

About 50 years ago, Tanner et al. designed the normal age range of pubertal onset as between 8 and 13 years in girls and between 9 years 6 months and 13 years 8 months in boys [2,3]. Consequently, precocious pubertal development has been defined as the appearance of secondary sexual characteristics in girls under 8 years and boys under 9 years of age. Pubertal timing has changed dramatically over the last two centuries, and therefore the definition of normal and abnormal onset may be expected to change. Historical European data show a clear secular trend in the decline in age of menarche from 17 years in the early nineteenth century to 13 years by the mid-twentieth century [4]. Cross-sectional data from the 1990s in the USA indicated that pubertal milestones had been reached earlier than previously thought by black girls, largely coinciding with the increasing prevalence of obesity. These observations led to the classification of puberty as precocious only when it occurs before the ages of 6 years in black girls and 7 years in all other girls in this population [5]. Recent European studies have also shown secular changes in the age of pubertal onset, but not with the associated parallel changes in age at menarche. In addition, several authors highlighted that from the 1960s, the trend in age at menarche has substantially leveled off in both Europe and USA, although minor decrements of 2.5–4 months have been reported during the past 25 years [4,6]. These quite discordant data have opened a lively international debate as to whether there should be a revision of the age range of pubertal precocity. There is a spectrum of possible underlying diagnoses in children presenting with signs of puberty at a younger age, and it remains of crucial importance to distinguish patients with pathological precocious puberty from those with early normal maturation. The international scientific community considered it inappropriate to re-define the age limit at which medical evaluation or intervention occurred based on the current available evidence as the potential for missed cases of pathological precocious puberty was felt to be too high. A proportion of children, presenting between 6 and 8 years, with central precocious puberty have been shown to have pathological brain MRI findings and would be among those missed if the age limits were changed [7].

Nutritional status & pubertal development

The timing of pubertal onset is influenced by both genetic and environmental factors. Genetic factors are thought to play the most important role in determining the timing of pubertal onset, especially in specific ethnic groups; however, the secular trend over the past 150 years has been without any documented change in gene frequencies [8]. Thus, it is plausible that environmental factors, such as the recent improved nutritional status in pediatric populations, play an important role in the earlier pubertal development. The prevalence of girls who are either obese or overweight at diagnosis of central precocious puberty or early puberty is higher compared to the general population [9]. Conversely, patients with anorexia nervosa tend to reach menarche later than the general population, with age of menarche in anorexia nervosa being influenced by both chronological age at onset of anorexia nervosa and the lowest BMI reached [10]. Connections between energy balance and reproduction have been widely investigated, focusing on the role of ghrelin, leptin and kisspeptin. Ghrelin is a peptide with multiple physiologic functions including stimulation of GH release and food intake. In mice, overfeeding during early development contributes to precocious pubertal activation by negative feedback to the expression of ghrelin in the hypothalamus. Ghrelin is a putative link between nutritional balance and hypothalamus–pituitary-gonadal axis activation, due to its capacity to inhibit gonadotropin-releasing hormone (GnRH) and luteinizng hormone secretions during pre-pubertal period [11] and the known dependency of the activation of the reproductive axis on the body energy status. Leptin, secreted by adipocytes, is an essential signal in the control of body weight homeostasis operating as a major signal of energy sufficiency. The molecular mechanisms of the neural pathway are still not completely understood; however, it seems that leptin mediates its effect on pubertal development by acting on the ventral premammillary nucleus. Leptin stimulates ventral premammillary nucleus neurons that in turn act on GnRH neurons and neurons in the anteroventral periventricular nucleus. The anteroventral periventricular nucleus neurons are thought to produce kisspeptin, a fundamental player in the control of the neuroendocrine reproductive axis. These connections facilitate the increase in frequency of GnRH pulses and luteinizng hormone secretion at the onset of puberty [12,13]. Kisspeptin is expressed in abundance in the arcuate nucleus (Arc) and stimulates the secretion of gonadotropins from the pituitary by stimulating the release of GnRH from the forebrain. Both estradiol and testosterone regulate the expression of kisspeptin on Arc participating in the negative feedback regulation of gonadotropin secretion, and they also influence kisspeptin neurons in the anteroventral periventricular nucleus contributing to the pre-ovulatory gonadotropin surge in the female [14]. The regulatory network responsible for the metabolic control of puberty is yet to be clarified, but it is convincing that nutrition plays an important role in modulating pubertal timing. The nutritional link was also confirmed by studies evaluating pollution and, in particular, environmental endocrine-disrupting chemicals. Endocrine-disrupting chemicals are compounds that could interfere at several control points in the hormone signaling pathways, changing the physiological hormonal and homeostatic system, influencing pubertal timing in experimental and wild animals. Several endocrine-disrupting chemicals such as phytoestrogens, pesticides, industrial chemicals and phthalates seem to condition puberty through their estrogenic or anti-androgenic effects or through their direct effects on GnRH. These effects may influence pubertal precocity, particularly if exposure occurs during critical time windows in either perinatal or pre-pubertal periods. Exposure of pre-pubertal mice to phytoestrogens, at levels reported in humans, has led to increased mammary gland development, and these effects were most marked when the exposure occurred close to the peri-pubertal period [15]. Even if genetics represents the greatest determinant of pubertal timing, puberty seems to be a multifactorial process, influenced by intrinsic and extrinsic factors working together.

Treatment & outcomes

A substantial difference between precocious and early puberty does exist: while the first always has to be considered as pathological, the second is associated to premature onset of pubertal maturation, without significant consequence in terms of final height and/or age at menarche [16]. Girls with early puberty are referred, in the main, between 6 and 8 years, with the emphasis of management on the initial clinical evaluation to exclude organic causes rather than possible treatment. The clinical decision to initiate treatment is dependent on the age of pubertal onset, the time of pubertal progress and the expected final height and consequent psychological factors. Treatment has to be monitored by height velocity, pubertal stage and bone age estimation and should be stopped when the child reaches an age at which puberty is acceptable. After cessation of treatment, follow-up is necessary to ensure the normal progression of puberty. A consensus statement on the use of GnRH-analog therapy (GnRH-a) underlines that when the treatment aim is to increase final height, its use is efficacious only in those with onset less than 6 years [17].

Even if the psychological consequences are considered fundamental in the treatment of these children, it is remarkable that only a few studies have evaluated psychological outcomes in adolescents or adults who have had central precocious puberty. The few studies examining psychological outcomes in girls treated with GnRH-a showed no consistent abnormalities at baseline and variable treatment effects among subjects and were published many years ago. More long-term studies are clearly needed. The extent to which psychosocial issues are considered a problem varies between families. Mood changes are often observed and can be disruptive. Many families may consider the medium-to long-term psychosocial effects of precocious or early puberty more important than the reduction in final height, and these issues thus require careful discussion. On a day-to-day basis, early menstruation and erections may cause embarrassment and practical difficulties. Early sexual development in girls may lead to unwanted sexual advances, which may be particularly challenging to manage in those with coexisting learning difficulties [18,19].

In conclusion, the management of precocious puberty remains a challenge for pediatric endocrinologists, due to both the unclear molecular mechanisms of development and the influencing environmental factors and the deficit of recent outcome data to help inform decisions for both the clinician and families.

Acknowledgements

The authors want to thank Dr. Avril Mason from Royal Hospital for Sick Children (Glasgow) for kindly reviewing this manuscript.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.