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Received: 26 November 2019 Revised: 10 January 2020 Accepted: 19 January 2020 DOI: 10.1111/obr.13005 PEDIATRICS/PHYSIOLOGY Adipokines: A gear shift in puberty Desirée Nieuwenhuis | Natàlia Pujol-Gualdo Amanda J. Kiliaan Department of Anatomy, Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Preclinical Imaging Center PRIME, Nijmegen, The Netherlands Correspondence Amanda J. Kiliaan, PhD, Associate Professor, Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Preclinical Imaging Center PRIME, Radboud university medical center, 6500 HB Nijmegen, Geert Grooteplein 21N 6525 EZ Nijmegen, The Netherlands. Email: amanda.kiliaan@radboudumc.nl Funding information Europees Fonds voor Regionale Ontwikkeling (EFRO), Grant/Award Number: BriteN 2016 1 | INTRODUCTION The prevalence of obesity in adolescents and children is increasing in | Ilse A.C. Arnoldussen | Summary In this review, we discuss the role of adipokines in the onset of puberty in children with obesity during adrenarche and gonadarche and provide a clear and detailed overview of the biological processes of two major players, leptin and adiponectin. Adipokines, especially leptin and adiponectin, seem to induce an early onset of puberty in girls and boys with obesity by affecting the hypothalamic-pituitary- gonadal (HPG) axis. Moreover, adipokines and their receptors are expressed in the gonads, suggesting a role in sexual maturation and reproduction. All in all, adipokines may be a clue in understanding mechanisms underlying the onset of puberty in child- hood obesity and puberty onset variability. KEYWORDS adipokines, obesity, puberty 1,2 the age of 5 years were overweight or were with obesity in 2016, and 3 Obesity is defined by an excessive accumulation of white adipose tissue (WAT), and it is often indicated by a body mass index (BMI) 4 above 30. Two main types of adipose tissue were described: WAT and brown adipose tissue (BAT), which differ in morphology and func- 5-7 Ilse A.C. Arnoldussen and Amanda J. Kiliaan contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation Obesity Reviews. 2020;21:e13005. wileyonlinelibrary.com/journal/obr 1 of 10 https://doi.org/10.1111/obr.13005 alarming rates. Specifically, worldwide, 41 million children below this number is expected to increase to 70 million in 2025. obesity is associated with various severe health complications, includ- ing increased risk of diabetes mellitus type 2, hypertension, heart dis- eases, and disturbances in sex hormone levels. 5,6 and mitochondria and plays a role in thermogenesis. Adipocytes in tion. BAT consists of adipocytes containing multiple lipid droplets WAT contain only a few mitochondria and a single lipid droplet. Adipose tissue has several functions including the storage of energy, thermogenesis, and the production and secretion of adipokines Generally, two physiological processes, adrenarche and gonadarche, 11,24 Childhood 5,7,8 a key role in puberty onset. Puberty is known as a period through which the body changes physically, being a physiological process resulting in the maturation of children, i.e. they develop sexual characteristics and obtain reproduc- 9,11 Adipokines are involved in a number of physiological processes including blood pressure, metabo- lism, glucose, and vascular homeostasis and may play amongst others 8-10 (hormones, cytokines, and peptides). tive functions. between obesity and puberty,2,12-23 the biological mechanisms under- lying obesity and puberty onset remain unclear. Hereafter, we review in detail the role of adipokines in the onset of puberty in childhood obesity. Although many studies have shown associations 2 | INITIATION OF PUBERTY PHYSIOLOGICAL PROCESSES IN THE interact to regulate the onset of puberty. During adrenarche, the adrenal cortex secretes steroid hormones (including 2 of 10 NIEUWENHUIS ET AL. androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and cortisol), insulin-like growth factor, and growth hormone, which contribute to the pubertal insights on new genetic loci (e.g. melanocortin-4 receptor, mitochon- drial carrier 2, and mitogen-activated protein kinase 13) and on sev- eral pathways that regulate the timing of puberty; however, it partly 34 9,24,25 Both adrenarche and gonadarche are involved in the development growth spurt, body odor, skin oiliness, and skeletal maturation. explains puberty timing variation. Thereby, defining the role of 25 adipokines is of importance in elucidating the variability in puberty as the expression of adipokines is sex-specific and is altered with body composition, adiposity, and during growth spurts. Moreover, adipokines and their receptors are expressed in gonads and several brain regions suggesting involvement in the onset of puberty and sex- ual maturation. Lastly, adipokines interfere in processes regulating timing and duration of puberty, for instance in the HPA and HPG axes which are both key players during adrenarche and gonadarche. Involvement of adipokines in the onset of puberty and specifically in individuals with obesity will be further reviewed in the next 2,24 3 | Puberty onset in girls is assessed using different markers, such as thelarche (breast development), menarche (the start of of pubic hair. pituitary-gonadal (HPG) axis is activated,2,26 and several hormones have been identified to participate in the activation of the HPG axis During gonadarche (Figure 1), the hypothalamic- 2,27 Kisspeptin, neurokinin B, and dynorphin are released by specialized including kisspeptin, neurokinin B, dynorphin, leptin, and ghrelin. 28 key regulator of the pulsatile secretion of gonadotropin releasing neurons, the KNDy neurons in the hypothalamus. Kisspeptin is a 29,30 B stimulates, and dynorphin inhibits the release of kisspeptin, which hormone (GnRH) from the hypothalamus. In addition, neurokinin implies that both coordinate a pulsatile release of kisspeptin. 31 Sub- sections. sequently, the activated HPG axis induces the pituitary gland to secrete luteinising hormone (LH) and follicle stimulating hormone (FSH). As a result, gametogenesis occurs, and the gonads will release sex hormones. Consequently, secondary sex characteristics develop including breast development in girls and an increased testicular vol- 2,26,32 is possibly due to differences in levels of body fat, hypothalamic-pitui- THE ONSET OF PUBERTY IN GIRLS ume in boys. The age at puberty onset varies greatly among individuals, which 19 35 menstruation), and pubic hair development. 33 genome-wide association studies have provided important new tary-adrenal (HPA) axis activity, and genetic background. Recent The average age of However, this age differs between cultures and ethnicities, and since 1980, age at menarche is girls at start of menarche is 12.4 years. 36 significantly decreasing. 36-39 F I G U R E 1 Hormonal regulation in the initiation of puberty in boys and girls. The secretion of kisspeptin, neurokinin B, and dynorphin from KNDy neurons initiate the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. This activates the pituitary gland to produce and secrete luteinising hormone (LH) and follicle stimulating hormone (FSH), which in turn stimulate the gonads to produce estrogen and testosterone in girls and boys, respectively 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 3 of 10 T A B L E 1 Summary of included studies Authors Year Country Study Design Primary Outcome Sex Sample Size (n) Age (y) Data Collection Lian et al21 2019 China Cross-sectional Puberty starts earlier in Chinese Han girls with obesity compared with Chinese Han girls with normal weight. Girls 2996 9-19 2012 and 2013 Biro et al12 Lazzeri et al20 2018 USA 2018 Italy Longitudinal Cross-sectional Body mass index had a greater effect on age at menarche than did race and ethnicity. Girls 946 6-16 2004-2014 Li et al23 2018 China Longitudinal For both, boys and girls, a higher BMI (ie, overweight and obese) is associated with earlier onset of puberty Girls Girls Boys Girls 542 Deng et al22 Flom et al15 2017 China Cross-sectional Increased BMI is associated with early timing spermarche and menarche. Boys Girls Girls 1278258 9-15 2005-2012 He et al24 Holmgren et al17 2017 China 2017 Sweden Cross-sectional Longitudinal Onset of puberty is not related to obesity in boys. Boys Boys Girls Girls 782 7-17 972 929 5839 Kelly et al19 2017 UK 2016 Brazil 2016 USA Longitudinal prospective cohort Higher BMI in girls is associated with the onset of menstruation at an earlier age. 11 10-18 11-17 Barcellos Gemelli et al25 Cross-sectional Longitudinal Excess weight is associated with early age of menarche. Girls 727 2014 2003-2009 Glass et al16 Lee et al26 In girls, but not in boys, greater adiposity is associated with the earlier onset of puberty. Boys Girls 135 Cabrera et al27 Leonibus et al14 2014 USA 2013 Italy Cross-sectional Longitudinal Thelarche occurred earlier than recently reported, while age of menarche remained unchanged. Girls 610 3-17.9 2007 2005-2012 Currie et al13 2012 Europe, USA, Canada Cross-sectional Overweight/obesity during childhood predicts the early onset of puberty in girls. Girls 20410 11, 13, 15 2005-2006 2017 USA Prospective birth cohort Overweight/obese status at the age of 7 ye was associated with increased risk of early menarche 788 From birth to menarche occurred Pregnancies 1959-1966 2016 USA Cross-sectional Boys with overweight enter puberty earlier compared with boys with normal weight or obesity, while puberty starts later in boys with obesity compared with boys with normal weight and overweight. Boys 3872 6-16 2005-2010 Overweight during childhood shows a relation with the early onset of puberty in girls. 6535 4259 695 11 15 5.8-12.2 2009/2010 2013/2014 2014-2017 Higher BMI during childhood is associated with early puberty. 2008 and 2009 2000-2002 Obesity during childhood is related to the earlier onset of puberty. Boys Girls 84 123 71 (Continues) 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 10 NIEUWENHUIS ET AL. 3.1 | Fat storage For the initiation of puberty, the timing of stimulation and/or inhibi- tion of different hormones is important, and additionally, a certain amount and distribution of body fat is needed in order to start menar- che, which emphasizes the importance of body fat. From an evolution- ary point of view, body fat increases in mammalian females during puberty onset, and it highlights the need to guarantee a healthy preg- 40 women with anorexia nervosa. particularly body fat localized predominantly on the gluteofemoral fat depots, is profoundly associated with start of menarche, more than nancy, offspring, and maternal survival. fat, sex-hormones, and neuroendocrine alterations can evolve in men- strual dysfunction, for instance, in women with severe obesity or in 41-43 44-46 to gluteofemoral fat depots suggesting that leptin may convey infor- amount of total body fat. mation on body fat distribution to the hypothalamus during puberty. An improper level of body Importantly, body fat distribution, Blood leptin levels are strongly related 45 3.2 | HPG axis The HPG axis is activated by the release of kisspeptin resulting in the release of GnRH from the hypothalamus, and LH and FSH from the pituitary gland. In girls, FSH is involved in the development of the folli- cles in the ovaries, and it promotes the secretion of estrogen. LH stim- ulates the production of androgen hormones and induces ovulation 48 9,47 the release of kisspeptin and neurokinin B, and kisspeptin thereby (Figure 1). The secretion of estrogen has an inhibitory effect on inhibits the GnRH release from the hypothalamus. pattern of GnRH is important for the regulation of the menstrual cycle. This roughly 28-day-cycle comprises several phases, including the follicular phase and luteal phase. During the follicular phase, increasing levels of FSH stimulate the maturation of follicles and the production of estrogen from the ovaries. This in turn inhibits the release of FSH from the pituitary gland. A high level of estrogen will induce the production of LH by the pituitary gland, resulting in ovula- tion. The matured follicle secretes progesterone thereby inhibiting the release of GnRH. When the corpus luteum is demolished, there is less 48 3.3 | Adipokines According to results from studies reported in Table 1, girls with obe- sity enter puberty earlier compared with girls with normal higher leptin concentrations inhibit the intake of food and increases inhibition of GnRH. As a consequence, the cycle will start again. whole process, starting from the activated HPG axis, results in the development of the secondary sex characteristics in girls including 9,47 thelarche and menarche. 13,14,16-23,49-51 weight. these girls might be found in the secretion of adipokines. For instance, leptin is positively associated with the amount of body fat. Generally, energy expenditure. 9,52-54 An explanation for the early onset of puberty in The expression This TABLE 1 (Continued) Authors Year Country Study Design Primary Outcome Sample Sex Size (n) Age (y) Data Collection Herman-Giddens et al28 2012 USA Cross-sectional Observed mean ages of beginning genital and pubic hair growth and early testicular volumes were earlier than in past studies, depending on the characteristic and race/ethnicity. Boys 4131 6-16 2005-2010 Sorensen et al29 Aksglaede et al30 2010 2009 Denmark Denmark Cross-sectional/longitudinal Longitudinal Puberty onset at earlier ages was associated with an increased BMI in boys. Boys 1528 5.8-19.9 1991-1993/2006-2008 1930-1969 Juul et al31 Ribeiro et al32 2007 2006 Denmark Portugal Retrospective cohort Cross-sectional Higher BMI is associated with early voice break. 11-15 10-15 1990-1999 Kaplowitz et al18 Abbreviation: BMI, body mass USA Cross-sectional The early onset of puberty in Caucasian girls is likely related to an increased BMI. 5-12 1992-1993 2001 index. The higher BMI in boys and girls at 7 y of age, the earlier they enter puberty. Boys 21 612 Girls 135 223 Boys 463 Boys 382 Girls 437 Girls 10 750 Early sexual maturation in boys and girls is associated with overweight. 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 5 of 10 Leptin may possibly play a role in adrenarche as its plasma level increases with higher levels of body fat and as it can modulate both girls. 33 ing adrenarche. In coherence, in children with obesity, the androgen These findings suggested that lower reproductive status was associated with higher total adiponectin concentrations and that a higher reproductive status was related to higher HMW adiponectin the HPA and HPG axes. These axes are functionally integrated dur- DHEAS was positively associated with leptin levels. Nevertheless, concentrations in girls. In addition, individuals with obesity often another study showed that enhanced adrenal androgen secretion in girls with premature adrenarche was not explained by leptin or BMI 55 ated with androgen levels in girls ; however, it was not related to levels. and IL-6. TNF-α alters, and IL-6 inhibits the expression of 56 8 In addition, the adipokine adiponectin was negatively associ- 57 differences of adiponectin seem to develop during the progression of 56 adiponectin (Figure 2). Thereby, a low level of total adiponectin and/or high levels of inflammatory cytokines in individuals with obe- sity can promote the onset of puberty. Many more adipokines are secreted by WAT including omentin, 52,65-67 9,36,62,68 adrenarche in girls with Prader-Willi syndrome. Interestingly, sex puberty. adrenarche; however, both are not required factors. Thus, leptin and adiponectin might be able to influence In gonadarche, leptin can stimulate the secretion of kisspeptin, and subsequently activation of the HPG axis, which eventually increases the expression of estrogen and androstenedione in the ova- 58 2,60 65-67 The expression of these ries (Figure 2). Ob gene in WAT, resulting in the synthesis and secretion of leptin. Thus, high levels of leptin promote onset of puberty in girls via secre- tion of kisspeptin, and estrogen stimulates leptin secretion addition- ally. Moreover, adiponectin can affect the HPG axis due to the expression of adiponectin receptors in the hypothalamus, pituitary In return, estrogen stimulates the expression of the 59 gland, and gonads. onset as it inhibits the secretion of kisspeptin and GnRH in the hypo- thalamus and the release of GH and LH in the pituitary gland, and 2,60-62 52,60 63 girls with central precocious puberty (CPP). Moreover, total adiponectin had negative correlations with progression of puberty in girls (defined by Tanner stages), whereas HMW adiponectin had FIGURE 2 Adipokinesaffectingthe initiation of puberty in girls. Leptin stimulates the release of kisspeptin in KNDy neurons, which activates the hypothalamus to produce gonadotropin releasing hormone (GnRH). In response to the release of GnRH, the pituitary gland secretes follicle stimulating hormone (FSH) and luteinising hormone (LH), which stimulates the ovaries to release estrogen resulting in the formation of secondary sex characteristics in girls. Estrogen stimulates the production of leptin. Adiponectin inhibits GnRH release resulting in reduced levels of GnRH and thereby a delayed onset of puberty. TNF- α and IL-6 inhibit the production of adiponectin and therefore stimulate the onset of puberty In detail, adiponectin is a regulator of puberty thereby inhibiting the onset of puberty (Figure 2). with obesity often have low levels of adiponectin. et al. showed that total adiponectin was significantly lower, whereas high molecular weight (HMW) adiponectin was significantly higher in ment. 55 63 develop a chronic low-grade inflammatory state, which can be indi- cated by a high level of circulating inflammatory cytokines like TNF-α 64 Individuals Sitticharoon positive associations with LH levels and the progression of puberty in 63 visfatin, resistin, and chemerin. and visfatin are expressed in the ovaries. adipokines in the ovaries suggests a role within the reproductive sys- tem; however, the exact biological processes have to be examined. Thus, specifically leptin, adiponectin, and inflammatory cytokines pro- duced by WAT could be permissive key players during an early onset of puberty in girls with obesity. As an exception, HMW adiponectin seems to have a stimulatory effect on peripheral repro- ductive function as HMW is not able to cross the blood brain 63 barrier. 4 | Markers that are used to assess puberty onset in boys are THE ONSET OF PUBERTY IN BOYS spermarche, voice break, testicular volume, and pubic hair develop- 35 spermarche develop in the early stages of puberty onset, voice In women, omentin, chemerin, While pubic hair development, larger testicular volume, and 69 testicular volume increases, which occurs at an average age of break usually appears in later stages of puberty. Generally, first 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 10 NIEUWENHUIS ET AL. 11.9 years, followed by the development of pubic hair at 12.2 years of average, and lastly, boys experience spermarche around an aver- 55 related with leptin levels. Thereby, leptin plausibly has a minor impact in adrenarche in boys. Since leptin receptors are found in the hypothalamus, pituitary gland, and testes, they might be involved in the onset of puberty by affecting the HPG axis during gonadarche. Leptin stimulates the release of kisspeptin and GnRH, and as a consequence, it accelerates the onset of puberty (Table 1, Figure 3). In contrast, adiponectin inhibits the secretion of GnRH, GH, LH, and FSH therewith delaying the onset of puberty. However, adiponectin levels are generally lower in men compared with women and even lower in men with obe- age age of 13.4 years. 70 4.1 | Fat storage Many aspects of the reproductive physiology are energetically demanding,71 and therefore, an adequate energy level is necessary. In boys, a dynamic change in body composition occurs around the age of 10 to 13 years, in which they gain approximately 40% of sity. culating inflammatory cytokines. levels can stimulate the HPG axis and therewith an early onset of puberty in boys. Nevertheless, leptin can inhibit the production of tes- 72 mostly consisting of lean mass, which causes exhaustion of most of fat. Subsequently, a growth spurt follows in which they gain tissue 72 in boys, an adequate amount of body fat is important in the onset of their body fat. These alterations in amount of body fat indicate that 4.2 | Puberty in boys is initiated by the release of kisspeptin. As mentioned before, this activates the HPG axis, resulting in the release of GnRH from the hypothalamus, and consequently the release of LH and FSH 9,74 puberty. tosterone from the testes, to estrogen (Figure 3). of the development of secondary sex characteristics in boys. Additionally, leptin can affect fertility in men as it can modulate the nutritional support of spermatogenesis, and moreover, dysfunction of spermatogenesis is associated with an increased leptin level and 73 58 2,60-62 HPG axis from the pituitary gland (Figure 1). and LH stimulates the secretion of testosterone from the testes, which inhibits the release of kisspeptin from the KNDy neurons and 9,48 in men, the release of kisspeptin is more consistent, causing a con- 29,48 subsequently GnRH from the hypothalamus. receptors expressed on KNDy neurons. In humans, KNDy neurons Contrarily to women, LH-induced testosterone levels lead to the stant release of LH. development of secondary sex characteristics in boys. differences between sexes in kisspeptin release are related to a sex- specific and sex steroid-dependent kisspeptin system as estrogen and progesterone modulate kisspeptin activity through the sex-steroid 48 in the infundibular nucleus are involved in negative and positive sex- 48 tal exposure to sex steroids and result in sex-specific differences in steroid feedbacks. kisspeptin release. These sexual dimorphisms are induced by perina- 75,76 4.3 | Adipokines The association between obesity and puberty onset in boys is rather controversial compared with findings in girls. Most studies reported an early onset of puberty in boys associated with increased ate adipose tissue from actual breast tissue. stages are more difficult to assess than female stages as boys lack a more determined marker such as menarche. Thirdly, puberty onset can be indicated by the activation of the HPG axis, and the presence of these secondary sex characteristics is the result of hormonal 2 14,17,22,23,50,51,77,78 BMI, 20,49 all while others reported no associations at Current markers used 79 16,80 or a delayed onset of puberty (Table 1). The presence of excessive adipose tissue can be involved in puberty onset in boys as the secretion of adipokines can modulate both adrenarche and gonadarche. Leptin can affect adrenarche by modulating both the HPG and HPA axes,33 and moreover, androgen levels were positively 55 nal androgen secretion in boys with premature adrenarche was not associated with plasma leptin levels. Nevertheless, enhanced adre- 9 In more detail, 61,62 adiponectin, and individuals with obesity often have high levels of cir- Moreover, inflammatory cytokines, TNF-α, and IL-6, inhibit expression of the leptin receptor in the testis. FSH induces spermatogenesis, too. function and role still have to be examined. 64 High leptin and low adiponectin and fat tissue can convert testosterone Both processes might result in the delay 29,61,79 81,82 In men, other adipokines like chemerin are found in the gonads 65 Thus, particularly high leptin and low adiponectin levels stimulate the HPG axis and thereby accelerate the onset of puberty in boys. Additionally, leptin can dysregulate the development of secondary sex characteristics and spermatogenesis by affecting testosterone levels and nutritional sup- port of spermatogenesis. 5 | LIMITATIONS AND FUTURE RESEARCH DIRECTIONS Even though multiple epidemiological studies have shown the link between puberty onset and obesity, there are some important limita- tions. Firstly, determining both the onset and stage of puberty is rather difficult. For instance, assessing the stage of breast develop- ment in girls with obesity is complicated as clinicians should differenti- 2 changes in response to the activated HPG axis. to determine the onset of puberty refer to secondary sex characteris- tics, such as testicular volume in boys and breast development in girls. A more accurate measurement of puberty onset would be to combine secondary sex characteristics with plasma or serum hormone level measurements such as LH, FSH, adipokines, e.g. leptin. Thereby, differences in puberty measurements could explain variations in the age of puberty onset between boys and girls within different Thereby, resistin is expressed in the testes of rats, but its exact 83 Secondly, male pubertal 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 7 of 10 FIGURE 3 Adipokines affecting the initiation of puberty in boys. Leptin activates kisspeptin secretion in KNDy neurons, this activates the production of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH stimulates the pituitary gland to secrete follicle stimulating hormone (FSH) and luteinising hormone (LH), activating the production of testosterone from the testes allowing the development of secondary sex characteristics. Leptin also inhibits the production of testosterone, which may cause a delayed onset of puberty. Adiponectin inhibits GnRH release. Low levels of adiponectin, as a result of TNF-α and IL-6 expression, lead to a reduced inhibition of GnRH. In response to GnRH release, the pituitary gland will secrete FSH and LH, and the testes will produce testosterone resulting in the development of secondary sex characteristics in boys countries, and In addition, the inclusion of a of puberty. ferent time points is complicated, as subjects examined several decades ago presented pronounced differences concerning lifestyle patterns such as nutrition and exercise habits. Lastly, obesity or over- weight is often determined by BMI, a classification based on weight and height measurements. Additionally, it is important that all studies studies or across continents, ethnicities proper age range (8-16 years) is important when assessing the onset (Figure 4). 12-15,17,20-23,49,77-79,84,85 30,47 Furthermore, comparison between studies from dif- 86 Specifically in children, BMI is often dependent on age and growth use the same anthropometric standards and sex-specific cut-offs. 13,14,16-23,49-51,77-80 fat and would represent a more accurate measurement in its regard. Based on this review, several suggestions can be made for further research. Firstly, the roles of adipokines like resistin, chemerin, visfatin, and omentin in puberty onset, fertility, and sexual maturation should be examined in detail. Secondly, future research examining the onset of puberty should combine indicators of puberty onset (e.g. breast development or testicular volume) with plasma or serum hor- mone measurements such as LH, FSH, sex-steroids, adipokines (e.g. spurts. ment in case of growth spurts. distribution of body fat should be taken into account in determining puberty and obesity in children. For instance, the body adiposity index (BAI), which was introduced in 2011 by Bergman et al.,87 uses hip cir- cumference and height in order to estimate the percentage of body 87 Thereby, BMI is a less accurate measure- F I G U R E 4 87,88 Therefore, both percentage and Average age of puberty onset in Europe, China, and the United States according to several studies from Table 1. Age of puberty onset ranges from 8.47 to 13.33 years in girls and from 8.63 leptin), and body fat distribution (e.g. BAI,87 waist-hip ratio's and/or dual-energy X-ray absorptiometry (DXA)2). Additionally, defining con- sistent and general measurements of puberty in both boys and girls, combined with a proper age range (8-16 years), would facilitate the comparisons between different studies and their results. 12-15, 17, 20-23, 25-29, 31 to 13.7 years in boys. included if average age of markers used to assess puberty was not reported. Pink: girls. Blue: boys Studies (Table 1) were not 39, 56 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 10 NIEUWENHUIS ET AL. 6 | CONCLUSION In conclusion, epidemiological data regarding obesity and puberty onset in girls show similar outcomes as adiposity results in the early onset of puberty in girls. 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BMC Womens Health. 2018;18(1):168-174. thereby an early onset of obesity. leptin can inhibit the production of testosterone in boys and subse- quently inhibit the development of secondary sex characteristics affecting spermatogenesis. for other adipokines, like resistin and omentin, are present in the testes and ovaries suggesting a role in puberty or reproduction; 58, 71 however, their plausible function is still unknown. that adipokines may be key regulators in an early onset of puberty in both girls and boys with obesity, specifically by affecting the HPG axis during gonadarche. Future research should focus on assessing puberty onset by measuring consistent puberty markers and determine the percentage of body fat and its distribution and adipokines and hormone serum levels particularly involved in the HPG axis. CONFLICTS OF INTEREST The authors declare no conflict of interest. FUNDING INFORMATION This research was funded by Europees Fonds voor Regionale Ontwikkeling (EFRO), project BriteN 2016. ORCID Ilse A.C. Arnoldussen Amanda J. Kiliaan https://orcid.org/0000-0002-7395-5284 https://orcid.org/0000-0002-2158-6210 13, 14, 16-26, 29-32 Furthermore, several receptors Nevertheless, We conclude Search strategy We searched PubMed for articles published before Novem- ber 15th, 2019 using relevant keywords, including ‘onset of puberty and adiposity/obesity’, ‘onset of puberty’, ‘children with obesity’, ‘adipose tissue’, ‘childhood obesity’, ‘adiposity’, ‘obesity’, ‘adipokine(s)’, ‘HPG axis’, ‘adipokines ovary/ova- ries’, or ‘adipokines testes’, either alone or in combination. 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Trends in menarcheal age between 1955 and 2009 in the Netherlands. PLoS ONE. 2013;8:e60056-e60056. 40. Kaplan HS, Lancaster JB. An evolutionary and ecological analysis of human fertility, mating patterns, and parental investment. Off- spring: Human fertility behavior in biodemographic perspective. 2003;1: 170-223. 41. Mitan LA. Menstrual dysfunction in anorexia nervosa. J Pediatr Adolesc Gynecol. 2004;17(2):81-85. 42. Xu H, Li P-H, Barrow TM, et al. Obesity as an effect modifier of the association between menstrual abnormalities and hypertension in young adult women: Results from Project ELEFANT. PLoS ONE. 2018; 13(11):e0207929-e0207929. 43. Tauqeer Z, Gomez G, Stanford FC. Obesity in women: insights for the clinician. J Womens Health (Larchmt). 2018;27(4):444-457. 44. de Ridder CM, Thijssen JH, Bruning PF, Van den Brande JL, Zonderland ML, Erich WB. Body fat mass, body fat distribution, and pubertal development: a longitudinal study of physical and hormonal sexual maturation of girls. J Clin Endocrinol Metab. 1992;75(2): 442-446. 45. Lassek W, Gaulin S. Brief communication: menarche is related to fat distribution. Am J Phys Anthropol. 2007;133(4):1147-1151. 46. Loomba-Albrecht LA, Styne DM. Effect of puberty on body composi- tion. Curr Opin Endocrinol Diabetes Obes. 2009;16:10-15. 47. Simonneaux V, Bahougne T. A multi-oscillatory circadian system times female reproduction. Front Endocrinol. 2015;6:1-15. 48. Marques P, Skorupskaite K, George JT, Anderson RA. Physiology of GNRH and gonadotropin secretion. In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext. Endotext.org: South Dartmouth (MA); 2000. 49. Barcellos Gemelli IF, Farias EDS, Souza OF. Age at menarche and its association with excess weight and body fat percentage in girls in the Southwestern Region of the Brazilian Amazon. 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Obesity Reviews. 2020;21:e13005. https://doi.org/ 10.1111/obr.13005 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are gover0:01 i pasticciotti presentano Federico II di 0:05 Sveia 0:07 Nel 0:09 1186 Costanza D'Alta Villa figlia del re 0:12 normno di Sicilia Ruggero II sposò ormai 0:16 trentenne Enrico VI di Svevia figlio 0:20 dell'imperatore Federico Barbarossa che 0:23 si servì di questo matrimonio per 0:26 stringere un'alleanza politica con la 0:28 monarchia siciliana 0:31 Purtroppo non fu un'unione felice sia 0:34 perché il marito aveva 10 anni in meno 0:37 della moglie sia perché lui non aveva un 0:40 bel carattere e pare che rinfacciasse 0:44 continuamente a costanza la sua età 0:47 avanzata temendo che ciò fosse causa di 0:50 sterilità 0:52 Alla morte di Federico Barbarossa nel 0:56 1190 Enrico VI ereditò dal padre il 1:00 titolo di imperatore del Sacro Romano 1:02 Impero ma era incapace di esercitare un 1:06 buon governo nei confronti dei sudditi 1:09 normanni che vivevano nel regno di 1:11 Sicilia portatogli in dote dalla moglie 1:14 Costanza 1:16 Così nel 1:18 1994 Enrico partì per una spedizione in 1:22 Sicilia senza la moglie al seguito e 1:25 fece in modo di essere incoronato re di 1:28 Sicilia il giorno di Natale nella 1:31 cattedrale di 1:33 Palermo Lo stesso giorno Costanza che 1:36 era in avanzato stato di gravidanza e 1:39 stava viaggiando in direzione di Palermo 1:42 per raggiungere il marito si rese conto 1:44 di essere prossima al 1:47 parto Se oggi nessuno più si meraviglia 1:50 della gravidanza di una quarantenne nel 1:52 Medioevo una gestazione a quell'età 1:55 sembrava una cosa praticamente 1:57 impossibile Pertanto si erano alimentate 2:01 voci malevoli sulla vera condizione di 2:04 costanza e neppure il marito pareva 2:07 realmente convinto della gravidanza 2:09 della moglie E dato che Costanza prima 2:12 di sposarsi era stata per un periodo in 2:16 monastero circolava addirittura la voce 2:19 che nel suo grembo ci fosse 2:21 l'anticristo che secondo una leggenda 2:24 medievale sarebbe nato dall'unione di 2:26 una vecchia monaca con un 2:29 frate Così Costanza decise di fermarsi 2:33 nella cittadina di Iesi e per fugare 2:36 ogni dubbio sulla sua gravidanza fece 2:39 allestire una tenda nella piazza 2:42 centrale della cittadina 2:44 marchigiana in modo da partorire al 2:47 cospetto di tutte le donne sposate del 2:50 paese Alcuni riferirono che il giorno 2:53 successivo al parto la regina lattò 2:56 pubblicamente il piccolo che poi fu 2:59 battezzato nella cattedrale di San 3:01 Ruffino di Assisi con il nome di 3:04 Federico 3:06 Ruggero Federico per indicare la 3:09 discendenza sveva quale nipote di 3:12 Federico 3:13 Barbarossa e Ruggero per sottolineare la 3:17 discendenza normanna dal primo re di 3:20 Sicilia Ruggero 3:23 d'Altavilla A soli 3 anni il piccolo 3:26 Federico rimase orfano e fu posto sotto 3:30 la tutela di Papa Innocenzo II da cui si 3:33 affrancò a 14 anni quando divenne prima 3:37 re di Sicilia e poi re di 3:41 Germania acquisendo il nome di Federico 3:44 II congiuntamente al titolo di 3:47 imperatore nel 1220 3:50 Ma Federico era più interessato 3:53 all'Italia che alla 3:54 Germania Così stabilì la sua corte in 3:57 Sicilia a 4:00 Palermo Federico II organizzò un regno 4:04 forte e 4:05 accentrato costruendo in tutta l'Italia 4:08 meridionale vari castelli dove collocò 4:11 le sue truppe che dovevano controllare 4:14 il territorio e sedare eventuali rivolte 4:18 Vanno menzionati in particolare il 4:21 castello di Melfi in Basilicata dove 4:25 furono promulgate le famose costituzioni 4:29 melfitane una raccolta di leggi scritte 4:32 rivolte a tutti gli abitanti del regno 4:35 con cui si limitavano i poteri dei 4:38 baroni locali e si vietava il ricorso 4:41 alla vendetta personale per affidarsi 4:44 invece alla giustizia stabilita dalle 4:47 leggi 4:48 C'era poi il castello di Trani che aveva 4:51 la funzione di sorvegliare l'ingresso 4:54 alla città e al porto E infine il 4:58 celeberrimo castel del Monte 5:01 caratterizzato da un'originale pianta 5:03 ottagonale attorniata da torri anch'esse 5:07 ottagonali che fungeva da dimora come 5:10 testimoniato dalla presenza di grandi 5:13 camini Uomo colto fine giurista 5:17 Amante dell'arte della letteratura 5:20 Federico II ospitò alla sua corte 5:22 studiosi e artisti provenienti da tutta 5:25 Europa Dialogò con intellettuali arabi e 5:29 fondò l'Università di Napoli che ancora 5:32 oggi porta il suo 5:35 nome Con l'editto di Salerno regolamentò 5:38 per la prima volta la professione del 5:41 farmacista separandola di fatto da 5:44 quella del medico scrisse anche un libro 5:48 un manuale sulla falconeria e sull'arte 5:52 venatoria chiamato de Arte venandi cum 5:57 avibus ossia l'arte di cacciare con gli 6:01 uccelli che fu uno dei primi manoscritti 6:04 con disegni a tema 6:08 naturalistico In una nota alla sua morte 6:11 il monaco Matteo Paris lo chiamerà 6:14 stupor Mundi cioè stupore del mondo Un 6:19 appellativo che racchiude l'essenza 6:21 della sua inestinguibile curiosità 6:25 intellettuale che lo portò ad 6:27 approfondire la filosofia l'astrologia 6:30 la matematica l'algebra la medicina e le 6:34 scienze naturali ha al punto da 6:37 impiantare a Palermo persino uno zoo 6:40 famoso ai suoi tempi per il gran numero 6:43 di animali esotici che conteneva anche 6:46 un 6:47 elefante I rapporti col papo però non 6:51 furono idiaci 6:53 Sia Papa Onorio II che Gregorio Io detto 6:57 anche il Papa Guerriero lo costrinsero a 7:00 intraprendere una nuova crociata in 7:02 Terra Santa minacciando di scomunicarlo 7:06 qualora non l'avesse 7:08 fatto Così dopo tanta insistenza da 7:11 parte del papato Federico si mise in 7:13 viaggio per la Terra Santa 7:16 Giunto in Oriente però non mosse guerra 7:19 ai musulmani ma preferì stringere 7:22 accordi con il sultano d'Egitto 7:25 ottenendo il controllo della città di 7:27 Gerusalemme e una tregua di 10 anni 7:32 Si trattava di conquiste importanti dal 7:34 punto di vista diplomatico ma al suo 7:37 ritorno Federico II fu accusato 7:40 duramente di essere sceso a patti con 7:42 gli 7:43 infedeli Nel suo programma di governo 7:47 Federico II era intenzionato a 7:49 riaffermare la sua autorità sui comuni 7:52 del Nord Italia fatto che preoccupava il 7:56 Papa il quale temeva il rafforzamento 7:59 del potere imperiale anche a nord dello 8:02 Stato Pontificio già confinante a sud 8:05 con il Regno di Sicilia 8:08 In pratica il Papa si sentiva 8:11 schiacciato sia a nord che a sud 8:14 dall'imperatore Così Papa Gregorio Io 8:18 appoggiò alcuni comuni che si riunirono 8:20 nella Lega Lombarda e che furono detti 8:24 guelfi A questi si contrapposero i 8:27 comuni ghibellini che decisero di 8:30 schierarsi a sostegno 8:33 dell'imperatore Iniziò così una 8:35 lunghissima contesa che avrebbe 8:38 dilaniato le città 8:41 italiane Tutto 8:43 chiaro ciao e al prossimo 8:49 video Se questo video ti è piaciuto ti 8:52 chiedo di fare mi piace cliccando 8:53 sull'icona qui sotto Per me è molto 8:55 importante quindi grazie in anticipo se 8:57 lo farai Per essere informato ogni volta 8:59 che pubblico un nuovo video ricorda di 9:01 cliccare anche sul grande pulsante rosso 9:02 Iscriviti e sulla campanella di fianco 9:05 [Musica]In this video we take a look at the 0:02 fetch to code 0:03 execute cycle including its effect on 0:06 the various registers we've previously 0:12 [Music] 0:14 discussed a computer is defined Definition 0:17 as an electronic device that takes an 0:20 input 0:22 processes data 0:25 and delivers output 0:29 in this simple example you can see we're 0:31 taking the input 5 0:35 we're multiplying it by 2 that's our 0:37 process 0:39 and we're outputting 10. 0:44 but this could be way more complex for 0:46 example of a game console 0:48 the input could be the buttons you press 0:50 on a controller 0:53 the processes would then be carried out 0:55 by the console itself 0:59 and the output would be some form of 1:01 update to a monitor 1:02 and sound out for a speaker possibly 1:04 vibration feedback through the 1:06 controller 1:10 to process data a computer follows a set 1:13 of instructions 1:14 known as a computer program 1:18 if we take the lid off a typical desktop 1:20 computer we can identify 1:22 two critical components the memory 1:26 that stores the program and the central 1:29 processing unit or processor 1:31 which is under this large fan and 1:33 carries out the instructions 1:37 a computer carries out its function by 1:40 fetching 1:41 instructions decoding them and then 1:43 executing them 1:44 in a continuous repetitive cycle 1:46 billions of times a second 1:48 let's look at each of these stages in a 1:50 little more detail Fetch 1:53 so let's start with the fetch stage the 1:55 very first thing that happens 1:57 is the program counter is checked as it 2:00 holds the address 2:01 of the next instruction to be executed 2:07 the address stored is then copied into 2:09 the memory address register 2:14 the address is then sent along the 2:16 address bus to main memory 2:18 where it waits to receive a signal from 2:21 the control 2:22 bus so it knows what to do 2:27 as we want to read the data that's 2:29 stored in memory address 2:30 0 0 0 0 the control unit sends 2:34 a read signal along the control bus to 2:36 main memory 2:41 now main memory knows the data needs to 2:44 be read 2:45 the content stored in memory address 000 2:49 can be sent along the data bus to the 2:51 memory data register 2:56 now as we're currently in the process of 2:58 fetching an instruction 3:00 the data received by the memory data 3:03 register gets copied 3:04 into the current instruction register 3:11 the instruction effectively has now been 3:14 fetched from memory 3:16 just before we proceed to the decode 3:18 phase we now 3:19 increment the program counter so that 3:22 the address it contains 3:24 points to the address of the next 3:26 instruction which will need to be 3:30 executed 3:32 the instruction now being held in the 3:33 current instruction register 3:35 is ready to be decoded 3:39 now as we mentioned in the previous 3:41 video the instruction is made up of two 3:43 parts 3:44 we have the op code that's what it is we 3:47 need to do 3:50 and we have the operand what are we 3:53 going to do it to 3:55 now the operand could contain the actual 3:57 data 3:58 or indeed it could contain an address of 4:01 where the data is to be found 4:06 by decoding this instruction we can see 4:08 the operation we need 4:10 is a load operation so we need to load 4:14 the contents of memory location0101 4:18 into the cpus accumulator 4:25 in the exam a simple model will be used 4:27 to describe the 4:29 structure of any given instruction 4:32 you're not going to be expected to 4:34 define how an opcode is made up 4:36 but simply to interpret opcodes in the 4:39 given context of an exam 4:40 question in the example here 4:44 you can see there's a total of 16 4:46 different opcodes available 4:48 and this is because we're using four 4:50 bits for our representation 4:56 so now we've fetched the instruction and 4:59 we've decoded it so we know what we need 5:00 to do 5:01 we're finally ready to execute it 5:05 so we now send address 0101 5:08 to the memory dress register 5:13 now we're in the memory address register 5:15 we can finally send the address 5:18 down the address bus to main memory 5:24 this time we want to read the data 5:26 that's stored in memory 5:28 and so the control unit again sends a 5:30 read signal along the control bus 5:36 so main memories now receive an address 5:38 and a read signal 5:40 so the content stored at memory location 5:43 0101 5:44 can now be sent along the data bus back 5:46 to the cpu 5:47 and into the memory data register 5:54 finally the contents of the memory data 5:56 register are copied to the accumulator 5:59 and this is one of a number of general 6:00 purpose registers found in the cpu 6:04 this first instruction is now complete Branching 6:11 so what does this program actually do 6:14 you should be able to work it through 6:16 carefully and figure it out 6:19 we're now pointing instructions zero 6:21 zero zero one in the program counter 6:23 and we're ready to fetch the second 6:25 instruction 6:27 at the end of this video we're gonna 6:29 provide you with the answer 6:34 so let's talk a second about programs 6:37 that branch 6:40 on the left here we have a very simple 6:42 piece of pseudo code 6:44 line zero says first execute this line 6:46 of code 6:47 line 1 now execute this line and then 6:50 line 2 says 6:52 if the age is greater than 18 then 6:56 we're going to execute lines 3 and 4 6:58 otherwise 6:59 we're going to execute lines six and 7:02 seven 7:03 so this program doesn't necessarily 7:05 follow strictly in sequence from line 7:07 zero through to seven there's a chance 7:10 here the program may branch and jump 7:14 around 7:16 so we're going to pretend that this 7:17 program has been loaded into memory 7:20 each line of code on the left here has 7:23 ended up 7:24 as a location in memory now this is not 7:27 strictly how this would happen in this 7:28 one-to-one way 7:29 but for the purpose of example it's 7:31 absolutely fine 7:35 so the program counter starts by 7:37 pointing to memory address zero 7:39 and we fetch the first instruction 7:41 decode it and execute it 7:44 it then updates and tells us the next 7:47 instruction 7:48 is zero zero zero one because remember 7:50 the program counter is being incremented 7:52 so we fetch it decode it and we execute 7:55 line one of our program 7:59 we then fetch line two which in binary 8:01 is one 8:02 zero 8:06 now at this point depending on what 8:10 happens during the execution 8:11 of line two the program may be required 8:15 to fetch line three from memory or 8:18 line five from memory 8:25 so let's look at how this actually works 8:27 because we've said the program counter 8:28 simply gets incremented 8:31 well in the current instruction register 8:33 we have an instruction with the op code 8:36 0 1 1 0. 8:41 now when we look this up in the decode 8:43 unit we discover that this 8:45 code means branch always 8:51 this replaces the value held in the 8:54 program counter 8:56 with the contents of the operand that's 8:58 the second part of the instruction 9:01 from the current instruction register so 9:03 this case 9:04 one zero zero one 9:09 now when the next fetch cycle begins the 9:12 program counter is obviously checked 9:14 and as its contents have been previously 9:16 updated to a new memory location 9:19 and not simply incremented the program 9:22 effectively is able to jump 9:24 around memory 9:28 so having watched this video you should 9:30 be able to answer the following key 9:32 question 9:33 how does a cpu work 9:39 okay so let's um answer the question we 9:41 posed 9:42 earlier what did that program actually 9:48 do 9:50 so this is the first fetch to code 9:53 execute cycle 9:55 and this is the one that we ran through 9:57 in detail earlier 9:58 it effectively loaded the contents of 10:01 the memory 10:02 stored at location location0101 10:05 into the accumulator in other words 10:08 the dna number 3 is moved 10:11 from memory into the cpu 10:18 we then proceed onto the second fetch 10:20 decode execute cycle 10:23 now this one adds the contents of memory 10:27 located at 0 1 1 0 10:30 to the current contents of the 10:32 accumulator 10:34 so in other words the dna number one 10:38 because that's what's stored at address 10:40 zero one one zero 10:43 is added to the number three that was in 10:45 the accumulator 10:46 the results are stored back over the 10:48 accumulator 10:49 so effectively we've done three plus one 10:53 equals four 10:58 the third fetch to code execute cycle 11:00 stores the contents which are in the 11:02 accumulator 11:03 into memory location zero one one one 11:07 and that's because the op code the first 11:09 part of this current instruction 11:10 zero zero one one is the command to 11:13 store when we look it up in the decoder 11:15 unit 11:16 so in other words the result of the 11:17 previous calculation three plus one 11:19 equals four 11:20 is now written back into main memory 11:28 the fourth fetch decode execute cycle 11:30 outputs the contents of the accumulator 11:33 remember they were copied into main 11:34 memory but they're still held in the 11:35 accumulator 11:37 so in this simple abstraction the number 11:40 four is now 11:41 output to the user so they can see the 11:43 result of the calculation 11:49 the fifth and final fetch code execute 11:51 cycle 11:52 brings a halt to the current program 11:58 so this very simple program which has 12:01 five 12:02 fetch decode execute cycles has 12:04 performed the calculation 12:06 three plus one is then stored the result 12:09 in main memory 12:10 and displayed the result four to the 12:12 user 12:13 and in a high-level language this may 12:15 look something very similar to the 12:17 following two lines of code 12:20 sum variable equals num1 plus num2 12:24 print sum to the user 12:27 so you can start to get an appreciation 12:29 here of how the high level code you 12:32 write actually ends up being fetched 12:34 decoded 12:35 and executed inside a processor 12:38 of course your processor is doing 12:40 billions and billions of these 12:42 operations a second 12:43 which when you think about it is really 12:45 very impressive 12:52 [Music] 13:03 you. make 10 questions for a standerd of a level6/27 quiz6/27 TOEFL ADV 6/27 TOEFL INT6.27-indefinite-pronouns-dai-tu-bat-dinhNSSIS Refresher (6/27/2022)