Clinical Management and Therapy of Precocious Puberty in the Sapienza University Pediatrics Hospital of Rome, Italy

Puberty identifies the transition from formative years to maturity. Precocious puberty is the onset of symptoms of pubertal development earlier than age 8 in girls and earlier than age 9 in boys, it has an occurrence of one/5000–1/10,000 with an F:M ratio starting from 3:1 to twenty:1. Precocious puberty may be divided into important, also referred to as gonadotropin-based precocious puberty or authentic precocious puberty, and peripheral, additionally recognized as gonadotropin-impartial precocious puberty or precocious pseudopuberty. Thus, the primary aim of this narrative report is to describe the usual clinical management and remedy of precocious puberty according to the enjoy and know-how of pediatricians and pediatric endocrinologists at Policlinico Umberto I, Sapienza University of Rome, Italy. In the suspicion of early sexual maturation, it is vital to accumulate statistics regarding the age of onset, the velocity of maturation of secondary sexual features, exposure to exogenous intercourse steroids and the presence of neurological signs and symptoms. The goal exam, in addition to the assessment of secondary sexual traits, should also consist of the evaluation of auxological parameters. Initial laboratory investigations must include serum gonadotropin tiers (LH and FSH) and serum stages of the sex steroids. Brain MRI should be performed as indicated by using the 2009 Consensus Statement in all boys regardless of chronological age and in all girls with onset of pubertal signs and symptoms before 6 years of age. The gold fashionable inside the remedy of relevant precocious puberty is represented with the aid of GnRH analogs, whereas, as some distance as peripheral paperwork are worried, the triggering cause should be identified and handled. At the moment there are no dependable facts organising the standards for discontinuation of GnRH analog remedy. However, numerous pieces of evidence propose that the remedy ought to be suspended on the physiological age at which puberty happens.
Keywords: precocious puberty; pseudopuberty; children; pediatrician; GnRh analogs
1. Introduction
Puberty is the transitional length from formative years to maturity characterised via fundamental bodily and mental adjustments main to the development of secondary sexual traits, the maturation of the gonads and the achievement of reproductive ability [1]. Puberty is a complicated technique characterized by using environmental, genetic, geographical and metabolic elements [2]. The mechanism underlying pubertal activation stays unknown, although the subsequent were recognized as feasible causes: adrenal activation, physical and mental pressure, an abundance of adipose tissue and the irritation of the intestinal tract [3,4].
Puberty starts with the activation of the hypothalamic-pituitary-gonadal axis (HPG), which already happens in the course of fetal existence, but is normally silenced within the very last period of being pregnant after which reactivated immediately after delivery [5,6]. This publish-natal transitory activation is described as mini-puberty and lasts up to six months in boys and up to two years in ladies, until the blockage of gonadotropin-liberating hormone (GnRH) secretion, in order to resume at some stage in puberty [7,8].
The beginning of puberty is determined by way of the secretion of GnRH on the hypothalamic level, which in turn turns on the production of hormones through the pituitary gland, the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) [9]. LH and FSH act on the gonads, promoting gametogenesis [10]. Pubertal improvement is taken into consideration physiological while it begins among the ages of eight and 13 in girls and among 9 and 14 years in males, although it is a variable process within every person, lasting on average among three and 5 years [2,10].
1.1. Precocious Puberty
Precocious puberty (PP) is the onset of secondary sexual capabilities before the age of eight in ladies and earlier than the age of 9 in boys. Specifically, the primary signal of pubertal activation is represented via thelarche in ladies and an boom in testicular volume in men more than or equal to four mL [1,10]. It is a quite rare condition affecting 1:5000–1:10,000 kids, with an F:M ratio starting from 3:1 to 20:1 [11,12]. There has been an boom in diagnoses of precocious puberty partially due to the SARS-CoV-2 pandemic, possibly related to a sedentary way of life characterised through being obese, using electronic devices and stress-related signs and symptoms acting as endocrine disruptors [13,14,15,16,17].
PP can be labeled as follows:

valuable or proper precocious puberty (CPP), if it’s miles decided with the aid of early activation of the HPG axis with the manufacturing of gonadotropins;

peripheral or precocious pseudopuberty (PPP), unrelated to the production of gonadotropins.
1.2. Central Precocious Puberty
CPP bills for about eighty% of all types of PP and is resulting from early activation of the HPG axis with elevated GnRH secretion and gonadal activation [3,18]. Although rarer, CPP in men is extra regularly related to underlying hypothalamic-pituitary natural lesions [7]. Although it’s miles frequently idiopathic, severa genetic mutations associated with CPP have been diagnosed, among those, the loss of characteristic mutation of the MKRN3 gene is one of the maximum worried [12]. The lack of characteristic of the MKRN3 gene, placed in the Prader-Willi syndrome area on chromosome 15q11.2, is liable for a stimulatory motion on GnRH secretion [19,20].
CPP may want to have a familial form in nearly one region of the youngsters [21]. The detection of this inherited circumstance accelerated after the discovery of autosomal dominant CPP with paternal transmission due to mutations additionally inside the DLK1 gene [21]. Indeed, it’s been shown that the incidence of familial CPP become disclosed at 22%, with a comparable frequency of paternal and maternal transmission [21]. Lineage analyses of families with maternal transmission indicated an autosomal dominant inheritance. Clinical and hormonal characteristics, as well as the effects of GnRHa management, have been comparable among individuals with assorted sorts of transmission of familial CPP [21]. MKRN3 loss-of-characteristic mutations were the maximum fundamental supply of familial CPP [21], observed through DLK1 loss-of-feature mutations, affecting, respectively, 22% and four% of the analyzed households; each forms affected exclusively households with paternal transmission [21]. Rare versions of indeterminate significance have been discovered in CPP households with maternal transmission [21].
Other genetic mutations were associated with CPP, inclusive of advantage-of-function mutations inside the KISS1 gene, which encodes the kisspeptin proteins capable of stimulating the production of gonadotropins, and the KISS1R gene, previously referred to as GPR54, which encodes its G protein-coupled receptor [22]. Among the most critical elements inside the development of precocious puberty, we truly locate endocrine disruptors that appreciably growth the threat of precocious puberty [3]. One of the most studied factors would be leptin, which would seem to increase with the growth in visceral fat inflicting an early release of GnRH [15].
Another peptide concerned would seem like ghrelin, a peptide with orexigenic action produced within the stomach, which alternatively has an inhibitory motion at the production of GnRH through reducing the responsiveness of LH to its launch element [10] and concurrently growing pituitary increase hormone (GH) secretion, consequently performing at the intersection of gonadotropic and somatotropic axes [23].
In recent years, an affiliation has emerged between pubertal timing and publicity to environmental elements that might motive an early activation of the pubertal axis [24,25]. Some of these materials act as estrogen receptor agonists or androgen receptor antagonists [7,22,26,27]. These endocrine-disrupting chemical compounds had been cautioned as affecting the age of pubertal onset and include phthalates, insecticides, isoflavonoids, phytoestrogens, polybromobiphenyl and mycotoxins [11,28].
1.Three. Peripherical Precocious Puberty
PPP is characterized by way of an increase in adrenal and gonadal sex steroids inside the absence of HPG axis activation; the pubertal traits may be legitimate for the child’s intercourse (isosexual) or inappropriate, with virilization of women and feminization of boys (contrasexual) [29]. It may be congenital, with the maximum frequent bureaucracy represented via congenital adrenal hyperplasia and McCune–Albright syndrome, or received, in particular associated with hormone-secreting endocrine tumors [2,11,30].
The major aim of this paintings is to show the standard medical management and remedy of precocious puberty in line with the revel in and expertise of the pediatric endocrinology of Policlinico Umberto I, the Sapienza University of Rome, Italy where approximately 50 youngsters and youngsters are treated every yr, similarly allotted among the sexes.
2. Diagnosis
Regardless of the reason, PP should be right away recognized due to the fact it is associated with elevated stature boom and skeletal maturation if untreated, inducing an early growth arrest with premature epiphyseal fusion due to extra sex steroids, which once in a while outcomes in brief person height [2]. The key capabilities suggesting PP are the modern improvement of breasts in ladies and testicular extent in boys over a quick period of commentary (three–6 months) associated with rapid peak growth (height pace >6–7 cm/12 months) mainly in girls elderly among 6 and eight years, whilst this circumstance occurs greater often [5,31,32].
The own family pediatrician plays a essential function in taking note of pubertal improvement throughout normal fitness assessments of the kid, quickly referring a patient to a pediatric endocrinologist in case of pubertal activation signs and symptoms, considering its increased occurrence in European nations [30,33].
In the suspicion of early sexual maturation, in children presenting symptoms of secondary sexual improvement before the age of eight (girls) or nin (men), the assessment must start with an accurate clinical and familial records as shown in Figure 1 [22,34]. It is crucial to gather information concerning age of onset, price of maturation of secondary sexual traits, publicity to exogenous sex steroids and the presence of neurological signs and symptoms [10,14].

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