Childhood obesity: Implications In Pubertal Process

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	Elpis-Athina Vlachopapadopoulou
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Introduction 

Puberty is the process of physical maturation leading to sexual maturity and reproductive capacity. Somatic changes are accompanied by psychological and behavioural changes (1, 2). Multiple factors affect pubertal onset and progression, including genetics, epigenetic, environmental, metabolic, nutritional, and steroidal factors, and the pubertal process is a complex interaction between these factors (3). Neuroregulation of weight control and pubertal initiation are interrelated. This chapter elaborates on the effects that the adipose-gut-brain axis exerts on the hypothalamo-pituitary-gonadal (HPG) axis system, as well as on the impact of the prenatal and postnatal environment on the development of obesity and pubertal timing. Secular trends in pubertal development among girls and boys, as well as the role of obesity will be addressed as well. 

Figure 1. Factors affecting pubertal onset and progression. 

Regulation of sexual maturation  

The hypothalamus plays a critical role in regulating various physiological processes, including growth, metabolism, as well as puberty and reproduction (4). The neuroendocrine substrate of puberty is defined by an activation of the hypothalamic-pituitary-gonadal (HPG) axis (1). The pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH) into the hypophyseal portal system, stimulates the gonadotroph cells of anterior pituitary to release gonadotropins, luteinising hormone (LH), and follicle-stimulating hormone (FSH) (5, 6). Gonadotropins are involved in the maturation and function of the gonads (testes and ovaries), which are responsible for producing sex hormones, promoting the development of secondary sexual characteristics and the production of gametes (5, 6). 

Puberty is an energy-intensive process. The strong relation between BMI and puberty initiation during childhood supports the theory that a certain amount of fat mass is necessary for pubertal induction (3, 7). Prospective studies suggest that an increase in BMI during the childhood years leads to earlier pubertal development in girls (8). Moreover, genome-wide association studies (GWAS) have demonstrated an association between BMI-increasing alleles in several genetic loci and earlier puberty (9). The connecting link between nutrition, adiposity and neurohormonal changes leading to pubertal development is leptin.  

The interplay between metabolism and puberty underscores the connection between the latter and energy reserves (10). Hypothalamic circuits play a crucial role in tightly linking body energy status with the onset of puberty. Within these circuits, GnRH neurons serve as the final pathway for centrally controlling puberty onset, with numerous metabolic hormones and neuropeptides tightly regulating their function (3, 11). Before puberty begins, there’s a dynamic balance in reducing inhibition on the hypothalamic-pituitary-gonadal (HPG) axis. Hypothalamic kisspeptin is a likely candidate to serve as the gatekeeper of puberty onset (12). The interaction between kisspeptin and its receptor, along with the coordinated activity of Neurokinin-B, glutamate, and leptin, are key drivers of GnRH pulse generation. Conversely, endogenous opioid peptides like dynorphin A, gamma-aminobutyric acid (GABA), and Makorin Ring Finger Protein 3 (MKRN3) act as inhibitors of GnRH release (3, 11, 13, 14). The expression, synthesis, and release of kisspeptin are tightly regulated by metabolic signals at multiple levels (4). 

Figure 2. The neurosecretory control of the pubertal onset 

Adapted from http://aorigamiedu.weebly.com/timing-of-puberty.html 

Abbreviations: AMH Anti-müllerian Hormone, BMI Body Mass Index; GABA  gamma-aminobutyric acid; GnRH Gonadotropin hormone-releasing hormone; FSH Follicle-stimulating hormone; KISS R Kisspeptin Receptor; KNDy Kisspetin Neurokinin Dynorphin; LH Luteinizing hormone; MKRN3 Makorin Ring Finger Protein 3 

Effect of the adipose-gut-brain axis on puberty 

Obesity is associated with a range of metabolic and hormonal alterations that can influence the hypothalamic-pituitary-gonadal (HPG) and play a role in regulating the onset of puberty (2, 15). Key hormones like leptin regulate energy balance and signal nutritional status to the brain, thereby affecting pubertal process (16). 

Obesity is characterized by a state of hyperleptinemia secondary to the expansion of the adipocytes together with leptin resistance (17). Hyperleptinemia is associated with hyperinsulinemia, insulin resistance, increased levels of inflammatory markers, increased free fatty acids, decreased SHBG, hypogonadotrophic hypogonadism and subfertility. Mice overexpressing leptin demonstrate early vaginal opening followed by ovarian and uterine maturation, suggestive of accelerated maturation of the HPG axis (18). 

 Leptin, along with other factors like adiponectin, Delta-like homologue 1 (DLK1), and ghrelin, modulates GnRH and kisspeptin secretion, crucial for pubertal initiation. Insulin resistance and hyperinsulinemia in obesity also contribute to early puberty by increasing sex steroid levels and bioavailability. Additionally, fibroblast growth factor 21 (FGF21), brain ceramides and cellular metabolic sensors like mTOR, AMPK, and SIRT1 play roles in puberty regulation, with obesity altering their activity. The following paragraphs provide more details about the effect of the adipose-gut-brain axis on puberty. 

Leptin is a hormone predominantly secreted by adipose tissue. Leptin levels are directly related to the amount of body fat (11, 16, 19). It plays a pivotal role in regulating energy balance and metabolism (16). Leptin can pass the blood-brain barrier; acting on certain neurons in the hypothalamic nuclei, particularly the arcuate nucleus, leptin communicates nutritional status to the brain, thereby modulating food intake and energy expenditure. Leptin exerts anorexigenic effects and stimulates thermogenesis, and inflammation while  it lowers glucose levels and inhibits lipogenesis (16, 19, 20). 

In addition to its metabolic effects, leptin is a permissive factor for pubertal activation (2). GnRH secreting cells do not express leptin receptors; thus leptin affects pubertal process through the release of kisspeptin, that binds to the Kiss receptors, inducing an increase in GnRH secretion from the arcuate hypothalamic neurons, expediting the onset of puberty. A sexual dimorphism in leptin secretion during puberty has been described. In girls, the peak in leptin concentrations precedes the peak in LH and FSH concentrations, while in boys, leptin concentrations rise before puberty onset but decline during mid-puberty (21). This variance may contribute to the later onset of puberty in boys and the earlier onset in girls with obesity (22). The subsequent response of leptin to the sex steroids is sexually dimorphic: while leptin levels increase in response to estrogens, they decrease in response to testosterone (23). Leptin has been demonstrated to have a role in adrenal androgen synthesis through its specific, dose-dependent, stimulatory effect on enzymes involved in the process (15, 24). 

Obesity is associated with a chronic low-grade inflammatory state. Pro-inflammatory cytokines, including TNF-α and IL-6, inhibit the expression of adiponectin, a fat-derived hormone, resulting in low adiponectin levels in individuals with obesity. Adiponectin impedes secretion of kisspeptin and GnRH in the hypothalamus and LH in the pituitary gland, thus inhibiting pubertal onset (25). Therefore, a low level of total adiponectin in children with obesity may trigger the onset of puberty (15).  

Another, recently discovered  factor related to adipose tissue is Delta-like homologue 1 (DLK1), a maternally imprinted gene, located on the long arm of chromosome 14 (14q32.2). DLK1 is a non-canonical ligand of the delta–notch signalling pathway, which controls a range of developmental processes, including adipocyte differentiation; this factor is also expressed in kisspeptin cell lines and hypothalamic nuclei, and is considered a link between puberty and metabolism (3, 26). Loss-of-function mutations in DLK1 have been identified in families with non-syndromic CPP and an unfavourable metabolic phenotype (27). The exact mechanism by which DLK1 regulates pubertal timing is not yet elucidated; nevertheless, it is hypothesized that DLK1 may interfere with kisspeptin neuron formation/maturation, and/or kisspeptin secretion (28). 

Moreover, the orexigenic gut hormone ghrelin has been found to be a direct regulator of kisspeptin neurons. Ghrelin is expressed in the brain, in the hypothalamus, and in the anterior pituitary. Past studies have signalled that ghrelin has a direct inhibitory action on GnRH release (12). Also, ghrelin inhibits LH release from the anterior pituitary in vivo and in vitro (29). Plasma ghrelin levels are negatively correlated with BMI and body fat percentage, and they are reduced in patients with obesity (15). 

Neuropeptide Y (NPY), is a potent orexigenic peptide, synthesized in the arcuate nucleus, which exerts an inhibitory effect on GnRH secretion. Leptin decreases NPY secretion, thus disrupting the NPY inhibitory action on pulsatile GnRH release (15, 30). 

Furthermore, insulin is a pancreatic hormone that plays a role in the regulation of GnRH neurons and reproduction. Hyperinsulinemia has been found to lead to dysfunctional hormonal secretion at multiple levels of the reproductive axis, including the hypothalamus, the anterior pituitary, and the gonads (31-33). Insulin resistance and compensatory hyperinsulinemia, common in obesity, may trigger early pubertal onset and precocious adrenarche/pubarche. In peripubertal obesity, hyperinsulinemia stimulates ovarian and adrenal androgen production and in parallel decreases sex hormone-binding globulin levels (SHBG), leading to a higher bioavailability of sex steroids, both androgens and estrogens (15, 34, 35). Insulin has been also found to exert a direct stimulatory effect on the steroidogenic factor-1 and the steroidogenic genes, leading to an increase in the production of adrenal gland hormones (36, 37). Insulin may also indirectly affect pubertal onset by stimulating leptin secretion (38).  

Fibroblast growth factor 21 (FGF21), a peptide hormone involved in metabolic regulation, and its co-receptor, β-klotho, contribute to pubertal maturation in humans and rodents by promoting GnRH release (3, 39). In mouse models, FGF21 overexpression is associated with pubertal delay and infertility in females, as well as with small size but unaltered fat mass and leptin and adiponectin concentrations, which suggests that the role of FGF21 in pubertal maturation and is independent of adipokines (40). Low levels of FGF21 have been found in children with obesity (41); further research is needed to assess the link between FGF21 and pubertal maturation in this population.   

Puberty is a high-energy demanding process. Cellular metabolic sensors, including the mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and sirtuin (SIRT1), have been found to play crucial roles in the metabolic regulation of puberty (3, 11). In the hypothalamus, mTOR and AMPK signalling pathways function oppositely to regulate pubertal onset: mTOR promotes puberty by activating Kiss1 neurons in the arcuate nucleus, while AMPK represses it by inhibiting these neurons, both actions being dependent on the body’s energy status (4). Childhood obesity inhibits AMPK activity, which might relieve the suppression of the Kiss 1 gene, and contribute to the development of central precocious puberty. SIRT1 is expressed in hypothalamic Kiss1 neurons (42). Early-onset overnutrition has been shown to reduce hypothalamic SIRT1 content and enhance Kiss1 expression and therefore advance puberty (43). 

Figure 3. The role of cellular metabolic sensors in the regulation of puberty. 

Metabolic sensors affect GnRH secretion through the activation or suppression of Kiss1 neurons. 

Abbreviations: AMPK AMP-activated protein kinase ; mTOR mammalian target of rapamycin;  SIRT1 sirtuin 1. 

Brain ceramides have been suggested as possible mediators of energy balance regulation in adult rodents. Elevated hypothalamic ceramide levels block leptin’s appetite-suppressing effects, potentialize orexigenic actions of ghrelin, and regulate brown adipose tissue activity (44, 45). Preserved brain ceramide synthesis seems to be permissive for the stimulatory effects of kisspeptin on pubertal initiation (44). In a rat model, obesity was found to increase paraventricular ceramide synthesis and the maturation of ovarian sympathetic input. Pharmacological activation of ceramide synthesis replicated the obesity-induced acceleration of puberty, particularly in females, whereas blocking central de novo ceramide synthesis delayed puberty (44). 

Androgens 

Childhood obesity is associated with increased androgen production. The regulating factors have not been fully elucidated, nevertheless insulin, IGF-1, and leptin have been suggested as factors stimulating adipose androgen synthesis (35, 46). In children with insulin resistance and obesity, a higher 5α-reductase, 21-hydroxylase, 17-hydroxysteroid dehydrogenase, and a lower 11β-hydroxysteroid dehydrogenase type 1 activity has been documented, leading to an increase in adrenal androgens, glucocorticoids, and mineralocorticoids (36, 47). Moreover, another plausible mechanism for increased androgen production is that altered peripheral increased cortisol metabolism in children with obesity leads to a compensatory increase in ACTH production, with a subsequent ACTH-dependent increase in adrenal androgens (15, 35). Moreover, higher levels of morning LH concentrations, as well as a significant correlation between morning LH and testosterone levels have been described in early pubertal girls with obesity, signifying that LH is a permissive factor for androgen excess (35). Hyperandrogenaemia may reduce the normal inhibitory feedback of GnRH pulse frequency by progesterone, leading to GnRH and LH pulse secretion and further increasing ovarian androgen production (48).  

Aromatase is the enzyme that is responsible for the conversion of androgens into estrogens. Aromatase is expressed in various tissues, including the adipose tissue, within which its activity is fat mass dependent. Increased sex steroid levels can, in turn, stimulate pubertal onset and progression, acting peripherally or centrally on the HPG axis (2, 15, 34). 

Prenatal and postnatal environment, obesity, and puberty 

A growing amount of evidence  suggests many adult diseases originate during fetal and early childhood development, a concept known as the developmental origins of health and disease (DOHaD). The first 1,000 days refers to the period from conception to 24 months of age in child development. During this critical time, nutrition and environmental factors may have life-long effects on a child’s overall health (49). Regarding maternal factors, maternal pre-pregnancy BMI, gestational weight gain, and gestational diabetes are independent risk factors for excess adiposity in the offspring (50, 51). Prenatal maternal smoking and exposure to antibiotics as well as cesarean section have been associated with future offspring obesity (52-55). In terms of fetal factors, a U-shaped relation between birthweight and adult BMI has been documented, and low (˂ 2500gr) and high (˃4000gr) birthweight, small and large for gestational age, and intrauterine growth restriction are associated with increased adiposity in childhood and adolescence (50, 56, 57). Finally, early life factors associated with an increased risk for r obesity in childhood or adolescence, are rapid growth during the first months of life (58, 59), high-​protein intake (60, 61), sugar-sweetened beverages consumption during infancy (50, 62), and short sleep duration during the first years of life (63, 64). 

Recent evidence has also linked high-fat diet with earlier pubertal development, especially in females; some of the potential mechanisms leading to the activation of the HPG axis involve hypothalamic microglial cells activation, kisspeptin signalling pathway activation by phoenixin, and modification of gut microbiota and hormones (65, 66). 

Early life exposures to environmental chemicals or poor nutrition may alter developmental pathways, leading to later-life diseases, including obesity and reproductive system disorders (3, 67, 68). Endocrine-disrupting chemicals (EDCs) are defined by the Endocrine Society as chemicals that mimic, block, or interfere with hormones in the body’s endocrine system. EDCs have been associated with various health problems, including obesity pubertal disorders, cancer, etc (15, 67). EDCs include industrial products such as plastics (bisphenol A), plasticizers (phthalates), pesticides,  fungicides, solvents/lubricants (biphenyls, dioxins), flame retardant additives, pharmaceutical agents (i.e., antibiotics, synthetic estrogens), natural substances (metals, phytoestrogens) and food components (phytoestrogens, preservatives)  (69-71) 

A variety of substances have been classed as obesogens, including pesticides (e.g. dichlorodiphenyltrichloroethane – DDT), flame retardants in clothing and furniture, solvents (e.g. polychlorinated biphenyls – PCBs), food additives (e.g., parabens, monosodium glutamate), substances used in personal care products (e.g., phthalates, parabens), and in plastics and resins (e.g., bisphenols), air pollutants (e.g. polycyclic aromatic hydrocarbons – PAHs) and some pharmaceutical drugs (70, 72). The Western diet, a dietary pattern characterized by a high intake of processed foods, added sugars, trans and saturated fat, salt, red and processed meats, and a low intake of vegetables, fruits, fish, and grains is also obesogenic (70, 73). Exposure to obesogens is thought to mediate changes in metabolic set-points through various mechanisms (nuclear receptor activation, hormonal regulation, metabolic  signalling  pathways, cellular differentiation, epigenetic regulation, etc), leading to an increased risk of obesity (67). Psychological problems, exposure to adverse childhood experiences, and poor school performance have been also associated with adolescent obesity (74, 75). 

Furthermore, various studies have assessed the association between exposure to EDCs and the onset of puberty; in all, these studies show inconsistent results and a causal effect cannot be proved (3, 4, 76). The role of EDCs in pubertal timing and progression needs to be evaluated in large longitudinal studies including complete data on EDC exposure (dose, duration, timing, type of EDC/combination) and whether there is a direct action  or the effect on pubertal process is mediated through the impact on the adipose tissue development. (4).  

Figure 4 illustrates the hypotheses and plausible mechanisms linking obesity, the adipose-gut-brain axis, and the process of puberty. Further elucidating these mechanisms is crucial for comprehending the complex interplay between metabolism and reproduction (or HPG axis). 

Figure 4. Hypotheses and plausible mechanisms linking obesity, the adipose-gut-brain axis, and the process of puberty. 

Adapted from Reinehr et al. Lancet 2019 and Huang A et al. Curr Opin Endocr Metab Res. 2020 

Abbreviations: GnRH Gonadotropin hormone-releasing hormone; HPG Hypothalamic-pituitary-gonadal; SHBG Sex hormone binding globulin. 

Pubertal onset and advancement in girls and contribution of obesity 

Historical records from Europe and the USA show a decline in the menarcheal age over two centuries, from about 17 years in the early 1800s to around 13 years by the mid-1900s, due to advancements in nutrition, hygiene, and socioeconomic conditions (2, 77, 78). This decline halted in the mid-20th century, with subsequent decreases averaging around 2 months over 25 years (34, 79). A recent meta-analysis examining secular trends in thelarche revealed a decline of nearly 3 months per decade from 1977 to 2013, indicating a consistent trend toward earlier pubertal onset (80). Studies conducted in the USA (81, 82), but also in Europe (83), China, India, and Nigeria (84-86) have found an association between overweight/obesity and early puberty in girls. These findings collectively support the notion of earlier pubertal onset by several months in overweight girls compared to those of normal weight.  

Menarche is a significant event for the adolescent and the reproductive life of the woman in general. Several factors influence the age at menarche which can be divided in two groups: genetic and non-genetic. Genetic studies show that the heritability of the age at menarche ranges from 57 to 82 % (87, 88). Non-genetic factors are of significant interest, as they can be modified and thus influence the age of menarche. Age at menarche is negatively associated with BMI (89). Frich and Revell first hypothesized that a critical weight has to be reached for the initiation of menses and that body fat is positively correlated with menarche (90, 91). As discussed earlier, the discovery of leptin provided the physiological explanation linking body fat and initiation of menses, since leptin stimulates the pulsatile release of GnRH (92). Among adolescent girls, childhood obesity has been associated with the earlier onset of puberty and menarche, which can result in negative psychosocial consequences, as well as adverse effects on physical health in adulthood (93). Two weight related factors are associated with age at menarche: weight per se and proportion of body fat. Several studies support the evidence that excess weight gain in infancy, childhood, pre puberty and puberty is associated with earlier age at menarche. Other conflicting studies suggest that the distribution of body fat may also have a significant effect on the age at menarche. Guo and Ji (94) report that higher waist circumferences are strong predictors of earlier menarche and are associated with long-term sequelae. Lassek and Gaulin (95) suggest that gluteofemoral fat distribution has the greatest influence on menarche. Recently, Xue et al.(96) found a negative correlation between whole body fat mass, left leg fat percentage and mass, and left arm fat percentage and mass, and left arm fat mass and  age at menarche.  

Pubertal onset and advancement in boys and contribution of obesity 

The investigation of pubertal timing in boys has been less extensive compared to girls and the relationship between body weight and pubertal onset remains contradictory. Studies in North American populations suggested a secular trend towards earlier puberty onset in boys during the past century (2, 97-99). European studies did not show a marked secular trend towards earlier puberty onset in boys between 1964 and 1991-93 (100) but showed a decrease in the age of pubertal onset in boys from 1991–93 to 2006–08 (101). Similarly, earlier pubertal maturation (i.e. voice break and age at first ejaculation of semen) was observed in two more recent European studies, both in a Danish population (102, 103). Trends toward earlier sexual maturation have been also reported in China and India (85, 86). The relationship between BMI and pubertal onset in boys is less clear than in girls, with some studies suggesting earlier (82, 102-106), and others reporting delayed pubertal onset in boys with higher BMI (107-110). A recent study reported delayed onset of puberty in adolescents with obesity compared to those with overweight, suggesting a non-linear, J-shaped relationship between BMI and pubertal onset (15, 110). The interplay between pubertal timing and obesity/overweight in boys warrants further investigation to better elucidate this intricate relationship (2). 

Polycystic ovary syndrome 

Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women of reproductive age, defined by hyperandrogenism, irregular menses, and/or PCO morphology (111). Worldwide, the prevalence of PCOS in adolescents is approximately 10% (3.4–19.6%) and rises persistently (112, 113). The definition of PCOS in adolescence includes irregular menstrual cycles and hyperandrogenism, clinical and/or biological (111, 114). Symptoms of PCOS typically manifest in adolescence, however diagnostic criteria for PCOS in adolescence remain controversial, primarily because the diagnostic features used in adult women may be normal pubertal physiological events (111). Of note, clinical hyperandrogenism and biochemical hyperandrogenism occur in 16.1% and 6.6% of adolescents respectively (115). Moreover, following menarche, it often takes time for regular menstrual cycles to establish due to the gradual activation of the gonadal axis. Menarche indicates the beginning but not the full maturation of the hormonal feedback loop involving the hypothalamic-pituitary-ovary axis. Early adolescence menstrual irregularities and anovulatory cycles and menstrual irregularities are attributed to the lack of the physiological positive estrogen feedback necessary for the mid-cycle LH surge required for ovulation, as well as immaturity in the FSH and ovarian responses (113). Studies evaluating ovulation in adolescents have shown ovulation in only 20% of the menstrual cycles during the 1st year post-menarche, 25–35% in the 2nd year, 45% in the 4th year, and 70% of the cycles between 5–9 years post-menarche (113). Moreover, polycystic ovary morphology (PCOM) was observed ultrasonographically in 40%, 35%, and 33.3% of patients at 2, 3, and 4 years after menarche respectively;  PCOM was not linked to any abnormalities in ovulatory rates or menstrual cycle duration (116, 117). International guidelines recommend avoiding pelvic ultrasound until 8 years post-menarche (111).  

PCOS is associated with a higher risk for type 2 diabetes, dyslipidemia, cardiovascular disease, non-alcoholic fatty liver disease, infertility, pregnancy complications, and depression (111). Obesity seems to play a significant role in the development of PCOS. The contribution of obesity in the development of PCOS is supported by the relatively frequent development of the syndrome after a significant weight gain (118) and the resolution of the syndrome while maintaining normal weight (119). A large percentage of PCOS adolescents also present insulin resistance and hyperinsulinemia. Insulin resistance in PCOS is thought to be tissue-specific – the adipose tissue, liver, and muscles being insulin-resistant whereas the adrenal glands while the hypothalamo-pituitary-ovary axis is insulin-sensitive (120).  

The etiology of PCOS remains elusive; it is thought to be multifactorial encompassing genetics, epigenetics, the intrauterine environment, neuroendocrine function, inflammatory factors, metabolism, lifestyle, and gut microbiota dysbiosis (112). The neuroregulatory dysfunction underlying PCOS involves an increased GnRH pulse frequency and amplitude, favoring LH over FSH synthesis, leading to a high LH/FSH ratio (120, 121). LH stimulates androgen production in ovarian theca cells, causing hyperandrogenemia and arrested follicle development. Additionally, increased LH pulse frequency hinders estrogen and FSH synthesis, thereby inhibiting follicle growth and ovulation. LH also enhances ovarian secretion of IGF-1, which boosts LH binding and androgen synthesis in theca cells, contributing to polycystic ovary development. This central regulation of PCOS is modulated by central regulators including KNDy neurons, POMC neurons, and neurotransmitters (121). Peripheral factors are also involved in PCOS development, through their action on hypothalamic neurons. Androgens and AMH directly stimulate GnRH neurons, creating a vicious cycle that promotes ovarian dysfunction and reproductive disorders (122). Additionally, insulin and leptin resistance contribute to GnRH neuron abnormalities. Gut microbiota dysbiosis is also thought to contribute to PCOS development; these effects are mediated by gut microbiota-derived neurotransmitters and metabolites acting on the gut-brain axis (121, 123).  Recently, PCOS was described as a reversible endocrine-metabolic condition, arising as an adaptive response to ectopic fat in growing girls, which becomes maladaptive in older adolescents (124). The mutually reinforcing cycle between obesity and insulin and leptin resistance seems to play a crucial role in the pathogenesis of PCOS. Increasing evidence suggests that sympathetic nervous system activation also contributes to the development of both PCOS and obesity (121).  

Reproduction 

Obesity is associated with infertility in both women and men. The deleterious impact of female obesity on reproduction is linked to various ovarian and extra-ovarian factors. The adipose tissue through the production of various mediators, such as leptin, free fatty acids, and cytokines, and the associated state of insulin resistance and compensatory hyperinsulinemia may alter the hypothalamic-pituitary-ovary axis function, the ovarian reserve, oocyte maturation, and endometrial epithelium receptivity. Women with overweight or obesity tend to take longer to conceive, experience lower fertility rates, require assisted reproduction more frequently, and have higher miscarriage and stillbirth rates and pregnancy complications compared to women of normal weight (125, 126).  

The prevalence of  hypogonadism in adolescent and young adult males (18-35 years) with obesity varies from 30–60% based  on different criteria used for the diagnosis and severity of obesity (127). Men with obesity have decreased testosterone and gonadotropin levels and increased estrogen levels (128). As a result of increased peripheral conversion, they have increased estrogen concentrations which are related to erectile dysfunction through an increased negative feedback from the estrogen and a subsequent hypogonadotropic state (129, 130). Additionally, impaired spermatogenesis and poor quality and sperm motility have been reported in obese men (130) . Inhibin-B concentrations have been found to be lower in obese young adult men compared with normal-weight men but not in prepubertal boys (131). A current hypothesis is that the negative impact of obesity on Sertoli cells proliferation during (peri)puberty may contribute to male reproductive dysfunction in adulthood (132). Obesity can lead to subfertility primarily through disruption of the HPG axis, increased testicular temperature, reduced sperm quality, and erectile dysfunction caused by peripheral vascular disease (126). The connecting link is again leptin: reduced leptin signaling leads to reduced GnRH neuronal activity. Increased leptin resistance associated with obesity also results in altered concentrations of reproductive hormones and may explain the association between BMI, altered semen parameters and infertility (133). Whether the mechanisms identified in adult men are applicable to prepubertal and peripubertal boys needs further clarification 

Conclusion  

Puberty is the transition to sexual maturity and is influenced by genetic, environmental, metabolic, and hormonal factors. Obesity and its associated metabolic changes can affect the HPG axis, altering pubertal timing. Leptin and insulin, among other hormones, play key roles in this regulation. The onset of puberty is tightly linked to energy balance and body fat. Additionally, prenatal and early life factors can influence obesity and pubertal development. Obesity is associated with infertility and adverse reproductive outcomes. Understanding these intricate mechanisms is crucial for addressing puberty and reproduction in individuals with obesity. 

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