Puberty: Neurologic and Physiologic Development -Volume II

Duarte Miguel Henriques-Neto ^1,2* Miguel Peralta ^3,4 Adilson Marques ³

• ¹ University of Maia, Maia, Portugal
• ² Research Centre in Sports Sciences, Health Sciences and Human Development (CIDESD), University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
• ³ Interdisciplinary Center for Human Performance, Faculty of Human Motricity, University of Lisbon, Dafundo, Portugal
• ⁴ Institute of Environmental Health, Faculty of Medicine, University of Lisbon, Lisbon, Lisbon, Portugal

Puberty is the transition from childhood to adulthood, during which secondary sexual characteristics develop and the reproductive system matures. This process is complex and influenced by genetic, hormonal and environmental factors (Manotas et al., 2022).Research suggests that genetics play a significant role, accounting for 50 to 70% of the timing of puberty onset and completion (Zhu et al., 2018).Genetic regulation of puberty involves a balance between inhibitory and excitatory mechanisms. The inhibitory mechanism is controlled by genes such as GAD67, PDYN, and GnIH, while the excitatory mechanism is influenced by GnRH, GLS, KISS1, and TTF1 (Toro et al., 2018). One key player in this process is the melanocortin 4 receptor (MC4R), which belongs to the G protein-coupled receptor family. This receptor regulates energy balance and is linked to both obesity and puberty onset (Yanik & Durhan, 2023). Disruptions in MC4R function can lead to excessive hunger (hyperphagia), alterations in puberty timing, and interactions with the kisspeptin-GnRH system an essential pathway for activating the hypothalamic-pituitary-gonadal (HPG) axis, which drives the development of secondary sexual characteristics (Albuquerque et al., 2014;Butler & Trevaskis, 2005).Early activation of the HPG axis leads to the production of gonadotropins, such as luteinising hormone (LH) and follicle-stimulating hormone (FSH), which can result in early puberty, particularly central precocious puberty (CPP) (Kota AS, 2023). Clinical signs of CPP include thelarche (breast development) or menarche (first menstruation) before age 8 in girls, and the appearance of pubic hair or testicular enlargement before age 9 in boys. These early puberty signs require careful evaluation due to their potential impact on long-term health (Kota AS, 2023). Given these concerns, there is a growing need to improve CPP diagnosis through clinical assessments, laboratory tests, and imaging techniques. Understanding the mechanisms behind early puberty can help minimise health risks through preventive strategies (Shokri et al., 2021;Zevin & Eugster, 2023). In this editorial we go through each of the articles published in the special issue "Puberty: Neurologic and Physiologic Development -Volume II"showcasing the main findings.Dimerisation of MC4R may control puberty onset and body size polymorphism 2.1 Rational: MC4R in the hypothalamus is linked to the regulation of appetite and energy expenditure. Functional alterations in the MC4R can lead to changes in the timing of pubertal maturation, associated to hyperphagia and leptin resistance.In a Xiphophorus fish model MC4R was concluded to be a class A G protein-coupled receptor with physiological and regulatory value, not only important for the Xiphophorus fish but also possibly relevant for understanding metabolic regulation in other fish species and even metabolism and obesity in humans (Liu et al., 2023).The HPG axis is activated by the kisspeptin-GnRH system, which stimulates the production of LH and FSH and the consequent development of secondary sexual characteristics. LH and FSH regulate the synthesis and secretion of oestrogens, progesterone, and the menstrual cycle. A high concentration of LH and FSH at baseline (i.e. LH>0.2IU/L or LH/FSH ratio >0.6) indicate the onset of puberty. In addition, monitoring SHBG can be a biomarker of CPP, as it is a homodimeric peptide that regulates the metabolism of hormones such as oestradiol and testosterone.A cohort of 121 girls found that a baseline concentration of LH ≥0.58 IU/L and SHBG ≤58.79 nmol/L can serve as relevant biomarkers for determining rapidly progressive CPP (Zhang et al., 2024).4.1 Rational: CPP can significantly impact young people's health. The pineal gland is in the epithalamus and is responsible for the synthesis and regulation of melatonin.Pineal cysts are benign intracranial lesions that may or may not cause clinical symptoms.In a single-centre study from China it was concluded that pineal cysts correlate with CPP, especially when the cysts are larger than 5 mm (Yang et al., 2025).5.1 Rational: Dysfunction in the division of the rostral notochord and the prechordal plate during blastogenesis is generally associated with abnormalities in the central nervous system, including pituitary duplication. Nevertheless, pituitary duplication is rare.The combination of isolated pituitary duplication and CPP is rare in clinical contexts. Its prognosis is limited, and meticulous and continuous follow-up is suggested to check for temporal changes. Even so, this clinical case with a literature review shows that treatment with inhibitors seems to have therapeutic efficacy (Yang et al., 2025). (Joo et al., 2024).Magnetic resonance imaging (MRI) for assessing cranial pathologies in rapidly progressive early puberty cases 7.1 Rational: CPP can lead to organic pathologies in the central nervous system, especially if progressing rapidly. One way of assessing these changes at the cranial level is through MRI.This research highlights the need for MRI imaging for children between 6-8 years of age continues to be debated, the results suggest that imaging decisions should be individualised (Kılınç Uğurlu et al., 2024).Adolescence is characterised by important physiological and psychological changes that impact present and future health. This editorial highlights the importance of developing in-depth knowledge of pubertal processes and the need for methodologies and tools for diagnosing CPP. The role of the MC4R in regulating the onset of puberty and body weight was highlighted by its differentiated dimerisation. The baseline values of LH and SHBG proved useful for the early diagnosis of rapidly progressing CPP, allowing for more timely interventions. MRI has also revealed that some intracranial abnormalities are associated with CPP, although in very specific cases, such as the presence of pineal cysts.