Precocious puberty

The etiology of central precocious puberty is multiple and heterogeneous, with possible congenital or acquired causes, regardless of the cause, and the onset of central precocious puberty is due to the premature reactivation of the hypothalamic-pituitary-gonadal axis caused by a premature secretion of hypothalamic GnRH^(8,9).

The importance of environmental factors in the early onset of puberty was clearly defined with the help of the pandemic, when numerous studies reported increases in CPP globally. Thus, between April 2020 and April 2021, 2.5 times more cases of CPP were recorded in the pediatric endocrinology outpatient clinic of the University of Campania Luigi Vanvitelli than in the period 2017-2020, the main comorbidities identified being Body Mass Index (BMI) changes and sleep disorders^(10,11).

A report from China revealed a three-fold increase in the number of CPP cases in 2020 compared to 2019, noting that the BMI of diagnosed girls was significantly higher in 2020. In addition to weight gain, processed food, reduced physical exertion, vitamin D deficiency and the long time allocated to electronic devices are the factors favoring this significant increase in cases of CPP⁽¹²⁾.

A three-fold increase was also recorded in Turkey between 2020 and 2021, compared to the 2019-2020 period, and 69% of girls with rapidly progressive early puberty were overweight or obese⁽¹³⁾.

It is unanimously accepted that, in addition to improper nutrition, overweight or obesity, psychological stress also intervenes in the onset of central precocious puberty, along with sedentary lifestyle, lack of sufficient quantitative or non-qualitative sleep and vitamin D deficiency, and all these factors were very well highlighted during the COVID-19 pandemic^(14-17).

The negative effects of the installation of CPP are multiple and act multisystemically. The risk of breast and uterine cancer is higher among girls with central precocious puberty, according to studies, and the early onset of menarche and breasts can lead to serious disorders in the psychiatric sphere, ranging from depression of varying degrees, anxiety, low self-esteem and non-responsible sexual behaviors to low bone mineralization, type 2 diabetes and cardiovascular diseases, installed in adulthood, with the mention that we can find an advanced bone age without precocious puberty^(1,18-23).

Due to the fact that precocious puberty is a common indication for sending a child to a doctor specialized in endocrinology, especially on an outpatient basis, and also the short- and long-term complications that can occur in the absence of a diagnosis and prompt treatment, along with the need for a multidisciplinary team of specialists, we consider it useful for the professionals in the field to provide an update on the management of central precocious puberty.

Diagnosis and treatment of central precocious puberty

The diagnosis of PPC is made based on a thorough anamnesis, complete physical examination, along with investigations for bone age, the most important of which are the dosage of sex hormones and the radiological examination. In the anamnesis, it is important to focus on the onset of puberty in case of the parents, genetics also playing an important role; the moment when the first pubertal changes were triggered, exposure to sex steroids, and the presence or absence of symptoms in the central nervous system (CNS) sphere (headaches, visual disturbances, seizures)^(24,25).

During the physical examination, attention should be focused on anthropometric measurements and the evaluation of secondary sexual characteristics, according to the Marshall and Tanner classification (Figure 1)^(26,27). In addition to these major indicators, the redistribution of adipose tissue on the hips, the growth of labia majora and minora, vaginal discharge, facial acne or axial hair are also indicators of the onset of puberty, with the mention that axial or pubic hair as the only sign is not a sign of precocious puberty, there being isolated pubarche or even thelarche, without evolution to precocious puberty^(24,28).
 

In a first phase, the evaluation of sex steroids and serum basal gonadotropins is vital to establish the correct diagnosis, the gold standard being represented by the performance of the GnRH stimulation test, or using the synthetic analogue triptorelin. In radiological exploration, a bone age greater than 2.5 SD is significantly associated with CPP. It should be noted that, in the presence of a normal bone age, we should not exclude the diagnosis of central precocious puberty^(24,29).

To rule out CNS damage, which are common causes of CPP, some studies indicate MRI, a controversial investigation when we talk about girls aged 6 to 8 years old, because central precocious puberty caused by CNS damage sets in much earlier, under the age of 6 years old, and predominates in males^(30,31).

Genetic analysis is suggested in the presence of two or more family members with a definite diagnosis of PPC or other signs suggestive of the presence of genetic pathologies^(32,33).

In the management of central precocious puberty, preparations of GnRH depot form are used, GnRHa being the gold standard in the therapeutic management of CPP, with safety and efficacy proven over the years, being well tolerated^(6,8,34). The main target of GnRHa therapy is to slow down pubertal progression. We need this slowdown to achieve an appropriate increase in height. In addition to this aspect, we must not omit the reduction of the undesirable effects on physical and mental health caused by the aforementioned untreated CPP.  The most common side effects are allergic reactions, hot flashes or seizures. There are studies that support weight gain under GnRHa therapy which then remits after stopping the treatment, while others support weight gain only in underweight girls or some that do not associate GnRHa therapy with an increased BMI^(35-39).

The timing of when GnRHa treatment should be discontinued is also debated between the average age at which puberty sets in and the bone age of about 12 years⁽⁴⁰⁾.

The decision to initiate or stop GnRHa therapy requires careful, individualized analysis and family preferences.

The role of nutrition in the appearance of CPP

Nutrition plays an important role when puberty sets in. Therefore, specialized studies draw attention to the fact that nutrition is important to you from the preconception stage, just like in obesity. The next important stage is the period of pregnancy. Studies associate maternal excess weight with a high birth weight, and this correlates in the long term with a low age of onset of puberty^(41-43). Not only the maternal BMI value plays a role in the onset of central precocious puberty, but also the composition of the diet; thus, phytoestrogens are identified as risk factors for CPP, such as isoflavones and lignans. Two important groups of phytoestrogens are found in soybeans, seeds, cereals and some fruits, with the possibility of crossing the placental barrier. Taking foods high in steroid hormones or extortionists, phytoestrogens can also be a cause for the onset of periphe­ral precocious puberty or precocious pseudopuberty^(44-47).

Feeding exclusively with breast milk during the first six months is a benefit for an onset of puberty at an older age, and thus to avoid central precocious puberty. When we talk about formula feeding, their role in determining CPP is different and, contrary to the debate in the specialized medical world, the basis from which the formula is made matters; but, regardless of the content, they tend to have a higher protein intake than mother’s milk, which over time leads to weight gain and a BMI above normal values, being a risk factor for CPP⁽²⁰⁾.

Diversification initiated at the right age and in compliance with the nutritional recommendations in force is recommended. A balance between macro- and micronutrients is essential for a good development. Proteins are an essential category of macronutrients in the development of the child, contributing to the formation of tissues; however, a high intake of proteins accelerates the onset of puberty, which leads to an increase in the secretion of adrenal androgens^(48,49).

Lipids are essential in the CNS myelination process, with a role in the absorption of fat-soluble vitamins, being a category of macronutrients that provide an important source of energy. When consumed in excess, they can lead to the installation of CPP through their actions on estrogen metabolism. Also, polyunsaturated fatty acids (PUFA), with direct effects on steroidogenesis and the development of the mammary glands, lead to the installation of central precocious puberty^(49-51).

Carbohydrates are the main source of energy, essential macronutrients for the feeling of satiety, to prevent constipation, with indispensable functions in the normal functioning of cells^(50,52). 

A high weight in childhood has also been linked to an onset of CPP and early menarche^(53-55). Thus, nutrition is important throughout life and, when balanced, is a protective factor for multiple pathologies.

Discussion

The increasingly early installation of central precocious puberty is an alarming sign; globally, there has been an increase in the percentages of CPP in recent years. In South Korea, there was an increase from 89.4 to 415.3 per 100,000 girls under the age of 9 from 2008 to 2014⁽⁵⁶⁾.

A rising prevalence for females was also reported in a six-year study in Korea, where a prevalence of 57.6 per 100,000 was identified, with a female/male ratio of 55.9 to 1.7 and with an incidence rate of 15.9 per 100,000 (15.3 females and 0.6 males)^(4,57).

The Cebu Longitudinal Health and Nutrition Survey revealed a 6% decrease in the risk of developing CPP for each month of exclusive breastfeeding, the beneficial effect of breastfeeding in preventing central precocious puberty being shown by several studies. Thus, Lee et al. demonstrate that exclusive breastfeeding for six months is associated with lower rates of developing CPP versus exclusive breastfeeding for less than six months, based on an analysis conducted on a group of 219 children^(58,59). Also, in a study conducted in the UK, an association was found between exclusive breastfeeding and the older age of menarche⁽⁶⁰⁾.

The feeding of soy products to the child is a controversial issue. There are studies that support the negative impact of soy consumption and associate it with the onset of CPP. A higher level of urinary isoflavones in girls with precocious puberty compared to the control group has been identified in numerous specialized studies^(4,61). There are also studies that have not identified a correlation between soy intake and the onset of CPP, therefore we consider that future studies are needed on this topic^(62,63).

Early diversification, before the age of 6 months old, leads to overweight, which, as mentioned before, is a risk factor for central precocious puberty, and the incorrect diversification, without taking into account the recommendations of medical staff, will have the same effect of increasing energy intake⁽⁶⁴⁾.

According to specialists, the toddler’s diet should be balanced and adapted to the child’s age, without snacks rich in simple sugars and junk-foods, with the mention that many studies consider nutrition during this period a modifiable variable for CPP⁽⁶⁵⁾.

Berkey et al. demonstrated that a protein intake of more than 8 grams/day leaded to a 0.6 year delay in the onset of puberty, a claim also supported by research conducted by Gunther et al.^(66,67)

The Avon Longitudinal Study supports the claim of the two researchers, showing in their study an association between increased protein intake in the prepubertal period and the lower age of onset of puberty⁽⁶⁸⁾.

Excess protein intake was also associated with the onset of CPP in a study of adolescent girls in China, and an adequate fruit and vegetable intake was found to be a protective factor. Of note, the role of protein in the proper development of children and adolescents is vital, but the quantity and quality of protein, in turn, can be harmful – especially an increased consumption of red meat. Under these conditions, a consumption of red meat greater than or equal to two servings per day was associated with 64% increased chances to develop CPP⁽⁵⁶⁾. 

Zinc – a micronutrient with multiple roles, including supporting the immune system, maintaining fertility and regulating metabolism – when taken as a supplement, leads to the development of CPP⁽⁶⁹⁾.

Childhood obesity is a risk factor for central precocious puberty, through hyperandrogenemia and insulin resistance that develops⁽⁵⁷⁾. In a review of eighty-two studies or case reports to identify the causes of the onset of CPP, genetic, pediatric and ethnic obesity accounted for three of the six identified causes, along with psychosocial stress, early exposure to a sexualized society, and environmental toxins⁽⁷⁰⁾.

The lipid levels were significantly elevated in girls with CPP compared to the control group, and the increased triglycerides present in the 1023 girls, from a total of 14 studies, draw attention to the risk of cardiovascular diseases to which these future young adults will be exposed far too early. By an early prevention of obesity, preferably from the preconception stage, we will reduce the prevalence of obesity, along with the multitude of chronic noncommunicable diseases that are installed due to an excess of adipose tissue in the body⁽⁷¹⁾.

An ultrasonographic analysis of 1977 girls, where the length of the uterus was measured, raised the possibility of using the length of the uterus in the differential diagnosis between CPP and early thelarche, with the mention that a length of 3.2 cm or more may be a diagnostic marker of puberty^(72-74).

The unbalanced lifestyle brought by the COVID-19 pandemic has led to an increase in the number of cases of central precocious puberty reported worldwide, thus clearly highlighting the importance of external risk factors, such as stress, lack of physical exertion, excessive time spent on gadgets and poor nutrition in the development of CPP^(75-77).

We can affirm that a balanced lifestyle with adequate macronutrient and micronutrient nutrition, along with regular physical exercise, limitation of screen time and a good psychological mood will contribute to the physical and mental health necessary for a normal nutritional status and prevent the onset of CPP, a statement also supported by Fu et al. in a report of the analysis of central precocious puberty during the COVID-19 pandemic⁽¹²⁾.

Conclusions

Puberty is considered to be the bridge between childhood and adulthood, with numerous repercussions on the physical and mental health of the future adult.

Nutrition is a modifiable risk factor in the onset of precocious puberty. It also has an essential role for the proper development of the adolescent. For this reason, we draw attention to the need for nutritional education programs that should start at an early age.

We believe that it is the role and duty of us, the medical personnel who interact with the pediatric population, to prevent, early identify and appropriately treat cases of central precocious puberty.  

 

Autor corespondent: Heidrun Adumitrăchioaiei E-mail: ad.heidi91@gmail.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.