Central precocious puberty during COVID-19 pandemic and sleep disturbance: an exploratory study

On January 2020, a new severe acute respiratory syndrome (SARS) due to a previously unknown coronavirus infection was firstly reported in China [1]. Since then, the diffusion of the so-called COVID-19 (coronavirus infectious disease-19) has reached pandemic proportion.

With the aim of containing the spread of COVID-19, several Governments have imposed restrictive policies promoting social isolation and “stay at home”. National lockdowns lead to sudden and radical changes in social interactions and in study and working conditions. Italian government declared national lockdown on March 10^th, 2020, since then people were forced to stay at home, and children dramatically changed their lifestyle for several months. In addition to national closures, Campania region imposed more severe restrictions and longer lockdown periods (March 2020 to May 2020 and November 2020 to April 2021). Given that, significant changes in lifestyle habits have been reported in children and adolescents. It has been registered an increase in sedentary behavior, junk food and sugar sweetened beverage intake, and sleep–wake rhythm dysregulation [2, 3]. Moreover, during the last months, scientific evidence has been produced about indirect consequences of lock-down and lifestyle habits modifications on children’s wellbeing. A significant and rapid raise of precocious puberty has been reported in Italy compared to past years [4, 5]. Puberty is known to be a complex phenomenon that is influenced by genetic, metabolic, psychological, and environmental factors. The mechanisms underlying puberty timing have not been completely clarified as several hormones and systems are involved [6]. Among them, melatonin has been proposed as one of neuromodulator of puberty onset [7‐9]. Melatonin is secreted by pineal gland, and it is mainly involved in sleep–wake cycle regulation. However, it also influences hypothalamic-pituitary–gonadal axis maturation [10].

Based on this evidence, our study aims were: 1- to evaluate the changes in precocious puberty rates during lockdown in our tertiary centre of paediatric endocrinology in South Italy (where confinement measures and school closure were more severe compared to other Italian regions); 2- to investigate the differences in sleep habits and disturbances in girls with central precocious puberty compared to healthy controls.

Our study confirms previous reports of increased CPP incidence rates during and after lockdown for COVID-19 in Italy [4, 5]. In our population, disease incidence more than doubled compared to the previous 3 years. Additionally, we found increased oestradiol, LH, and FSH levels in girls diagnosed after lockdown compared to previous years. This finding is in line to those reported by Stagi et al. that observed an acceleration of puberty progression in cases diagnosed after lockdown compared to the previous 5 years [4].

It is well known that puberty timing is influenced by both environmental and genetic factors. The dramatical changes in everyday routine that characterized lockdown period might have been a powerful trigger for puberty onset. However, the underlying mechanisms have not been elucidated and several hypotheses have been proposed, such as weight gain, psychological stress, and electronic devices overuse. In our sample we found no differences for electronic device use and adiposity measures between CPP and controls. Conversely, we observed higher prevalence of sleep disturbance and shift in later bedtime in CPP compared to control group. Main differences were observed for total disturbs score, sleep breathing disorders, sleep–wake transition disorders, and daily excessive somnolence.

The directionality of this association needs to be clarified. In fact, sexual steroids have been associated with changes in circadian rhythm in animal studies reporting later phase shift of daily rhythms in animals [20, 21]. However, these data have not been replicated in humans. Jessen et al. reported a correlation between 17OH-progesterone plasma level and bedtime in girls with premature pubarche. Nevertheless, no significant association were observed in girls with CPP [22]. Another study investigating the effect of oestrogens on sleep architecture in girls with CPP, failed to find any difference in sleep patterns in this group of patients before and after hormonal therapy, suggesting that oestrogens are not involved in sleep architecture regulation in this group of patients [23]. Therefore, more studies are needed to investigate whether sexual hormones might affect sleep homeostasis in humans, especially during puberty.

At the same time, it has been reported that changes in sleep hormones might influence puberty timing. In fact, melatonin plasma levels decrease has been associated with puberty onset in children [10, 24]. A study comparing melatonin plasma levels between precocious puberty (PP), normal puberty, and pre-pubertal girls, revealed that girls with PP had significantly lower melatonin levels compared to the other groups [25]. Whether melatonin directly inhibits the hypothalamus or reduces the pituitary response to GnRH should be further investigated. However, melatonin plasma levels physiologically decrease throughout growth; therefore, this reduction might allow the activation of the hypothalamus-pituitary-gland axis [24]. In our sample, girls with CPP showed higher rates of SBD and SWTD compared to controls. Sleep disturbances have been associated with lower levels of melatonin secretion and with melatonin secretion pattern disruption [26‐28]. Therefore, it might be hypothesized that CPP group experienced a more severe melatonin plasma decrease compared to controls that could have acted as puberty trigger. Additionally, the age of this group is close to physiologic puberty onset, therefore melatonin reduction might enable the activity of an almost mature hypothalamic-pituitary-gonad axis [29].

On the other hand, sleep homeostasis is essential for cognitive and emotional development [30]. In fact, sleep disturbances have been associated with poor quality of life, impairment of everyday functioning, increased rate of mood and behavioral disorders [31‐33] and impairment of academic performance [34‐36]. Therefore, it is very important to recognize and treat sleep disruption. Considering our findings, girls with CPP might constitute a group of patients at higher risk of presenting sleep disorders and clinicians should be aware of this association and investigate the presence of sleep disturbances in this subgroup of patients. Therefore, we plan to extend our investigation to new CPP diagnosis even outside lockdown period aiming to eventually confirm this observation. Additionally, our exploratory findings might constitute the basis for new longitudinal studies investigating the mechanisms underlying the relationship between puberty and sleep homeostasis in larger cohorts.

In conclusion our study supports the observation of increased incidence of CPP after lockdown. Home confinement has significantly altered daily routine in children and adolescents and indirect health consequence of confinement are arising. In our sample, sleep disturbs are a frequent comorbidity in girls with CPP, and clinicians should be aware of this association. Further pathophysiologic studies are needed to investigate whether sleep alteration might be a trigger for puberty onset.