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Grammar
Put the words in the correct order to make polite requests.
Grammar
Put the words in the correct order to make polite requests.
Grammar
Put the words in the correct order to make polite requests.
Grammar
Put the words in the correct order to make polite requests.
Grammar
Put the words in the correct order to make polite requests.
Grammar
Put the words in the correct order to make polite requests.
Grammar
Put the words in the correct order to make polite requests.
Grammar
Complete with the correct present simple.
Shirley ____________________ (get up) at 7:00 every morning.
Grammar
Complete with the correct present simple.
Toshi ____________________ (not have) lunch at work.
Grammar
Complete with the correct present simple.
Jhon ____________________ (finish) work at 5:30.
Grammar
Complete with the correct present simple.
Brandon ______ (not take) a shower every day.
Grammar
Complete with the correct present simple.
The baby ____________________ (take) a nap every afternoon.
Grammar
Complete the sentence with present continuous. Remember the verb to be.
Example:
He is eating pizza now.
Dan and Mary ____________________ (go) for a walk.
Grammar
Complete the sentence with present continuous. Remember the verb to be.
Julia ____________________ (play) the guitar.
Grammar
Complete the sentence with present continuous. Remember the verb to be.
Lucas ____________________ (read) a book.
Grammar
Complete the sentence with present continuous. Remember the verb to be.
Martha ____________________ (cook) in the kitchen.
Grammar
Complete the sentence with present continuous. Remember the verb to be.
My sister ____________________ (watch) TV in the living room.
Grammar
Complete the sentence with present continuous. Remember the verb to be.
My brothers ____________________ (listen) to music.
Vocabulary
Select the correct option.
You wear ____ on your feet.
Vocabulary
Select the correct option.
You wear a ____ when you’re cold.
Vocabulary
Select the correct option.
Women wear __________ to parties, weddings, and other special occasions.
Vocabulary
Select the correct option.
You wear a ____ on your head.
Vocabulary
Select the correct option.
Men wear ____ around their necks.
Vocabulary
Select the correct action of the photo.
Vocabulary
Select the correct action of the photo.
Vocabulary
Select the correct action of the photo.
Vocabulary
Select the correct action of the photo.
Vocabulary
Select the correct action of the photo.
Vocabulary
Connect the polite request.
Everyday English
Select the correct written question about Anna.
Example:
Q: (learn languages; every day)____?
Does she learn languages every day?
Q: (check emails; every day) ____________________?
Everyday English
Select the correct question.
Q: (go to meetings; every day) _______________________?
Everyday English
Select the correct question.
Q: (go to the bank; every day) ______________________?
Everyday English
Select the correct question.
Q: (meet clients; every week) ______________________________?
Everyday English
Select the correct question.
Q: (go to the bank; every week) _________________?
Reading
Read the article. Select the correct answer.
Suchir’s pants and shoes are _______.
Reading
Read the article. Then choose the correct answer to complete each sentence.
Where are Zahra and Helena from?
Reading
Read the article. Then choose the correct answer to complete each sentence.
Suchir never wears _______ .
Reading
Read the article. Then choose the correct answer to complete each sentence.
______ is a calm color.
Reading
Read the article. Then choose the correct answer to complete each sentence.
Suchir is a ______.
Listening
Listen to the conversation and select the correct option.
The woman is buying clothes _______.
Listening
Listen to the conversation then choose the correct answer.
The woman likes _______.
Listening
Listen to the conversation then choose the correct answer.
The woman likes _______.
Listening
Listen to the conversation then choose the correct answer.
What does the woman ask to see last?
WORLD ENGLISH INTRO 1-4WORLD ENGLISH INTRO FINAL 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. The majority of the studies examining boys with obesity indicate an early onset of puberty, while not all reported an earlier onset of puberty. In detail, high leptin, TNF-α, and IL-6 levels combined with low adiponectin levels stimulate the activation of the HPG axis in girls and boys with obesity, and 5, 45, 50, 51 REFERENCES 1. Kumar S, Kelly AS. Review of childhood obesity: from epidemiology, etiology, and comorbidities to clinical assessment and treatment. May- o Clin Proc. 2017;92(2):251-265. 2. Reinehr T, Roth CL. Is there a causal relationship between obesity and puberty? The Lancet Child & adolescent health. 2019;3(1):44-54. 3. WorldHealthOrganization. Facts and figures on childhood obesity. 2017. 4. Guglielmi V, Sbraccia P. Obesity phenotypes: depot-differences in adipose tissue and their clinical implications. Eat Weight Disord. 2018; 23(1):3-14. 5. Gomez-Hernandez A, Beneit N, Diaz-Castroverde S. Escribano O. 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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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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 goverThe Revolt of the Northern Earls (1569) Most people in the North remained loyal to the Catholic noble families who controlled the north and their Catholic faith. When Elizabeth came to power, she promoted ‘new men’ (Protestants) from the gentry and the powerful Catholic nobles lost their power and influence. This led them to organise the most serious rebellion of Elizabeth’s reign in 1569. Why did the Northern Earl’s revolt? The Earls had lost their power when Elizabeth became Queen (and wanted it back). They wanted Catholicism restored in England (and felt that ordinary Catholics would support it). Elizabeth was refusing to marry or to name an heir, causing uncertainty about England’s future. Mary Queen of Scots (if freed from prison) could replace Elizabeth and solve all these problems Who were the key players in the Revolt? Earl of Northumberland • A Catholic who had held an important position under Mary I. • He lost a lot of influence under Elizabeth (as she favoured Protestant gentry) • Elizabeth also took the rights to a valuable copper mine found on his lands Earl of Westmorland • From a rich Catholic family in the north Also the Duke of Norfolk’s brother in law Duke of Norfolk • England’s most senior Protestant noble, but he had very close links to old northern Catholic families, & was sympathetic to them & greedy for power. • He hated William Cecil & Robert Dudley, Earl of Leicester (Elizabeth’s favourite) who were Protestant and from the gentry • He planned to marry Mary QS, but later backed down and urged the earls to call off the rebellion. Mary also supported the plan to marry him What role did religion play? (7/10 – but only because it was linked to power) • Most northerners held onto their Catholic beliefs & although Elizabeth didn’t persecute them, they knew that she wanted their religion to gradually die out, so they supported the revolt. • In 1561 Elizabeth hired a strict Protestant as archbishop of Durham to promote Protestantism in the north, but he was unpopular & turned many northerners against the Protestant religion. What role did politics/power play? (9/10 – this was the most important cause of the revolt) • The Northern Earls lost a lot of their power/influence (even jobs/money under Elizabeth) • Northumberland was jealous of new Protestant families being given top jobs in the North • William Cecil & Robert Dudley were not from ancient noble families, but were very close to the Queen, so the northern Earls resented them getting top jobs in her Government • Elizabeth also confiscated large areas of land & the profits from their copper mines • It is possible, that had Elizabeth allowed the Catholic Northern Earls to keep their jobs, money and influence at court, they may have ‘tolerated’ her as a Protestant Queen (greedy/selfish). What role did Mary Queen of Scots and the Succession play? • Elizabeth was refusing to name an heir and it was becoming clear that she would not marry • If Mary Queen of Scots married the Duke of Norfolk, England would have an heir and England would be Catholic again. The country would be stable without people competing for power. • However, some of Elizabeth’s courtiers got worried that it might not work and that it might lead to charges of treason (punishable by death) • So by September 1569, Robert Dudley (Earl of Leicester) decided to tell Elizabeth about the plot. By this time it was much more serious than simply marrying Norfolk to Mary. • Mary QS had secretly asked Spain to send troops to help the rebellion & overthrow Elizabeth Plan for the Revolt of the Northern Earls (1569) • The Earls of Northumberland & Westmorland will raise rebel troops from their lands in the north and take control of Durham. • The rebels will then march south towards London to join with the Duke of Norfolk • 1000s of Spanish troops will land in England to support the rebel forces • The Duke of Norfolk & rebel forces will seize control of Government & overthrow Elizabeth • Mary Queen of Scots is to be freed, ready to marry the Duke of Norfolk Key Events of the Revolt • Once Elizabeth knew of the plot, Norfolk was arrested and sent to the Tower of London • The Northern Earls were worried they would be executed for their involvement and in a desperate attempt to avoid punishment, pushed ahead with the revolt • They raised an army of ordinary Catholics and took control of Durham cathedral • Catholic mass was celebrated across the north for 2 weeks. • They then headed south, to try and free Mary • Mary QSs was moved south to Coventry on the orders of Elizabeth, so she couldn’t escape • The rebellion failed as Spanish troops never arrived • Elizabeth’s friend (Earl of Sussex) had raised an army of 7,000 men to defend her throne. Results: • The rebellion was a serious threat to Elizabeth • She executed 450 rebels in the north • Northumberland was executed in 1572 & his head was put on a spike on the city gate • The Privy Council called for the Duke of Norfolk’s execution too, but Elizabeth released him. • Mary Queen of Scots was kept in prison for the next 14 years. • The failed plot also led the Pope to take action against Elizabeth • In 1570 he excommunicated Elizabeth from the Catholic Church • He also issued a Papal Bull (order) calling on all loyal Catholics to overthrow her hoping it would encourage another rebellion. • In 1571 Elizabeth called parliament to pass an Act making it treason to claim that she was not the rightful Queen and to bring in/print papal bulls in England. The Significance of the Revolt of the Northern Earls • It was the first and most serious rebellion by English Catholics against Elizabeth • Treason laws were made much harsher • It ended the influence of the powerful Catholic Earls in the North • It led to harsher treatment of Catholics, e.g. 1572 Elizabeth sent the Earl of Huntingdon (strict Protestant) to the north to carry out laws against Catholics (and suppress Catholicism). • Although Elizabeth’s brutal revenge on the rebels show how serious a threat it was, most Catholics in the north stayed loyal, but the Pope’s Papal Bull now put their loyalty in doubt There was little support for the revolt among the rest of the Catholic nobility and ordinary people. When faced with a choice between Elizabeth and their religion, most Catholics chose to support the Queen. 1569, was the last time English Catholics tried to remove Elizabeth by force. The future plots against her were always uncovered by Cecil & Walsingham, before they had a chance to get any public support. Despite this, the Northern Revolt & Papal Bull changed Elizabeth’s attitude towards Catholics who were now seen as potential traitors. From 1570, Elizabeth became less tolerant of recusants (people refusing to attend her church) & took increasingly tough measures against Catholics. The Ridolfi, Throckmorton & Babington plots • In the 1870s-80s, there were 3 Catholic plots to assassinate Elizabeth & replace her with Mary. • The plots were supported by France, Spain, the Pope and some Catholic nobles. • They reinforced the form Mary & from Catholics at home and abroad. Also the threat from Spain. The Ridolfi Plot (1571) • Ridolfi was an Italian banker living in England and a spy for the Pope. • He organised a plot to murder Eliz, marry Mary QS to the Duke of Norfolk & make her Queen. • The Pope & King Philip supported the plot & Philip told the Duke of Alba in the Netherlands to prepare 10,000 troops (but to only invade AFTER the English had overthrown Elizabeth). • The plot failed because Sir William Cecil intercepted coded letters & Norfolk was executed. • Mary was kept under closer watch. • Ridolfi was abroad when the plot was discovered and never returned to England. 1574: Catholic Priests and Priest Holes • From 1574 Catholic priests were smuggled into England to keep the religion alive. • They stayed with rich Catholic families, so Catholic families were kept under surveillance. • Catholic homes were raided – to find ‘priest holes’ where Catholic priests were hiding. • Catholic priests who were found could be hung, drawn and quartered (although not all were) • In 1581, Parliament also passed 2 new tougher laws against Catholics: • Recusants would be fined £20 (which would bankrupt most families) • Trying to convert people to Catholicism was now treason (punishable by death) The Throckmorton Plot (1583) • It aimed to assassinate Elizabeth and replace her with Mary. The French Duke of Guise (Mary’s cousin) would invade England with an army, funded by King Philip (Pope also supported it). • An Englishman, Throckmorton carried messages between Mary & Catholic plotters abroad. • Sir Walsingham (Secretary of State) uncovered the plot after his agents found the plans for the plot in Throckmorton’s house. Throckmorton confessed under torture and was executed. Significance: • The plots showed that Mary’s presence in England posed a serious threat • It also showed that France & Spain were a serious threat (& could invade) • Throckmorton’s papers showed a list of Catholic supporters in England, so the threat from English Catholics was also real • 1,000s of Catholics were imprisoned or kept under surveillance/house arrest • In 1585 another Act was passed to make helping Catholic priests punishable by death. • The Bond of Association was signed by the English nobles & gentry & forced them to promise to execute anyone who tried to overthrow the Queen. Weaknesses of the Plots The plots lacked public support & were uncovered by informers & spies before they had the chance to work King Philip was reluctant to destroy his alliance with Elizabeth (France was still a bigger rival) so is support for the plots was half-hearted, he rarely followed through on his promises to help the plotters or send an army The Babington Plot (1586) In 1586, Walsingham used his spy network to PROVE that Mary supported the Babington plot. His evidence persuaded Elizabeth to put Mary on trial & execute her for treason. • This was a plot to murder Elizabeth and put Mary on the throne • France would invade England with 60,000 men and Spain would also send an army • Babington was passing coded letters between Mary & her supporters in England & Europe. • But all of her letters were being intercepted and read by Walsingham. • Walsingham used his spies to follow every stage of the plot & had the letters decoded • One of Mary’s letters approved plans to murder the Queen and free Mary from prison • They also contained the names of 6 Catholics who planned to kill Elizabeth • They were arrested, hung, drawn and quartered for treason. • Mary had been implicated in plots before, but Elizabeth was always reluctant to execute her • But the proof found by Walsingham finally persuaded her to put Mary on trial • In October 1586, Mary was found guilty & was sentenced to death • But Elizabeth still hesitated, and did not sign the death warrant until February 1587. Significance 1) This plot was very significant because by 1585 England was effectively at war with Spain since Elizabeth had sent her army to help the Dutch Protestants fight the Spanish 2) This meant that Elizabeth’ situation was more dangerous than during previous plots. 3) Elizabeth’s government also became more determined to crush Catholicism 4) 1000s of recusants were arrested & 31 priests were executed 5) Mary’s execution removed the Catholic threat at home 6) English Catholics had no one to rally around, & lost hope of overthrowing Elizabeth 7) But Mary’s death increased the threat of a foreign invasion as England was at war with Spain and King Philip had been preparing an attack on England since 1585 8) Mary’s death made Philip even more determined to invade, Mary had left her claim to the English throne to King Philip upon her death Why was Mary Queen of Scots finally executed? 1 • A new Act in 1585 stated that in the event of Elizabeth’s assassination, Mary could be executed as long as she had been proved guilty & Walsingham had provided hard proof. 2 • Another reason was that by 1587, it was clear that Philip was planning to invade England • There were rumours that Spanish ships had landed in Wales & that Mary had escaped. This convinced Elizabeth that Mary had to be executed if she wanted to keep her throne. Walsingham’s Spy Network: • Walsingham (Secretary of State from 1573) had a network of spies all over England & abroad. He had spies in every English town, some were normal people paid to spy on neighbours. • He also had agents and spies in Spain, France, Germany and Italy • He hired mathematicians to crack written codes and people to open/seal letters secretly • He also pressured captured Catholic priests to spy on others for him in return for a pardon. • He used double agents to infiltrate Catholic networks - to help him discover traitors • But he only used torture against Catholic priests caught in England in the most serious cases • But 130 priests and 60 of their supporters were still executed during Elizabeth’s reign. Why did Relations with Spain get worse (1569-1588) • England had tried to stay on good terms with Spain, because Eliz wanted to avoid an expensive war that could lead to her being overthrown (English Catholics could support it) • But by the 1570s, Elizabeth wanted to have an empire of her own. • She also needed to make more money to defend her country and throne (by improving trade) • This religious, political and economic rivalry led to growing tensions between England & Spain Political and Religious Rivalry 1) Land abroad, gave countries wealth/power. By the 1580s, Eliz wanted an empire to rival Spain’s (especially as Spain had supported the Catholic plots against Eliz – even if it was half-hearted) 2) Religion was another cause of conflict. Philip opposed Elizabeth’s religious settlement 1559 3) Luckily for Elizabeth, in the 1550s Spain & France were competing to be the greatest European power and both wanted England as an ally against the other. 4) But from 1567, Spanish ships were sailing to the Netherlands with money for the Alba’s army 5) This alarmed English Protestants and Elizabeth’s Privy Council who put more and more pressure on her to send an army to help the Dutch Protestant rebels (in the Netherlands). Economic (commercial) Rivalry: The New World, privateers and Sir Francis Drake • Under Elizabeth, English merchants wanted to make big profits in the New World (Americas). • However, trading in the New World was difficult because of Spain’s power 1) Spain controlled most of the New World where there were huge profits to be made and anyone who wanted to trade there needed a licence from Spain (which it would not give): 2) But the Americas had valuable crops like tobacco, sugar, and also silver and gold 3) Elizabeth secretly encouraged privateers to trade illegally & raid Spanish ports & ships 4) At first Elizabeth denied responsibility for their actions, which delaye war with Spain Sir Francis Drake: Elizabeth sends Drake to rob Spanish colonies and ships (which infuriates Spain) 1) Spain’s support for the Ridolfi plot (1571) made her more willing to support Drake • In 1572 Eliz hired Drake to sail to the New World & steal £40,000 of Spanish silver • In 1577 she sent Drake back again with a secret mission to rob Spain’s colonies/ships • Drake brought back £400,000 of Spanish treasure & claimed an area of California in Elizabeth’s name (New Albion). He gave a lot of this money to Elizabeth • He boosted England’s finances at a time of growing concern over Spain’s threat • He became famous as the first Englishman to circumnavigate the globe. • Eliz knighted Drake as a reward, which infuriated Philip (as he saw Drake as a pirate) • Drake’s actions & his claim to California made it clear that England did not accept Spain’s domination of the New World. Elizabeth’s Support for the Dutch Rebels led to War with Spain (1585-88) • By the 1580s, tension between England & Spain had reached boiling point • At first, Eliz refused to send her army to help the Dutch rebels, because she wanted to avoid a war with Spain. So she tried to get the Spanish to leave the Netherlands in other INDIRECT ways: 1) By allowing Drake (& other English privateers) to attack and rob Spanish ships and colonies 2) By encouraging others (the French heir/mercenaries) to fight the Spanish in the Netherlands • In the 1570s, Elizabeth promised to marry the heir to the French throne (the Duke of Alencon) so that he would take an army to fight the Spanish in the Netherlands The Spanish Fury (1576) and the Pacification of Ghent (1576) • By 1576, the Spanish Govt in the Netherlands was bankrupt (the war was expensive) • After months without pay, Spain’s soldiers violently robbed Dutch towns in the “Spanish Fury” Spanish troops rebelling and robbing cities in the Netherlands in 1576. This united the Dutch Protestants & Catholics against Spain. They drew up the ‘Pacification of Ghent’ (demanding that): • Spanish troops leave the Netherlands • Spain allows the Dutch to rule themselves • The persecution of Dutch Protestants stops What did Elizabeth do? • Elizabeth sent £100,000 to help the Dutch rebels • In 1577 King Philip’s brother, Don Juan agreed to the rebels demands (but this was a trick) as just 6 months later Philip sent an even bigger army to attack the Dutch. • Elizabeth then hired a mercenary army of 6000 English & Scottish volunteers to help the Dutch. • But her plan backfired because the mercenaries destroyed Dutch Catholic churches, which caused the Catholics to make peace with Spain. • In 1578, her Privy Council urged Eliz to send her official army to help the Dutch, but she refused. The Dutch were disappointed & turned to France for help. The French Duke of Alencon arrived with an army to fight the Spanish, but by 1579 Spain had taken control again. • In 1580 Spain got even stronger after Philip won control of Portugal & its empire. • So Elizabeth gave the Duke of Alencon £70,000 to help him fight the Spanish • In 1582, Alencon took his army the Netherlands but failed to defeat Spain. • Elizabeth’s foreign policy in the Netherlands had failed & she had only managed to annoy Spain 1585: Why did Eliz finally decide to send her army to the Netherlands? (she lost her 2 main allies) • 1584 the Duke of Alencon died (so he could no longer fight the Spanish in the Netherlands) • 1 month later, William of Orange, the leader of the Dutch Protestant rebels was assassinated. • In 1585, Spain signed the Treaty of Joinville with France, agreeing to stamp out Protestantism in France/Europe meaning France & Spain were now allies against Protestantism • Elizabeth now felt she had no choice but to send her official army to the Netherlands • She signed the Treaty of Nonsuch with the Dutch rebels which promised them military help 1585: Robert Dudley’s campaign in the Netherlands was unsuccessful She sent 7,400 man army to the Netherlands led by Dudley. But he accepted the title of ‘Governor General’. Eliz was angry as it suggested that she had deposed King Philip so she told Dudley to resign this position. His army was defeated by the bigger Spanish Army as Eliz had not provided him with enough money to win. In 1587 Dudley resigned and returned to England. At the same time, Eliz had sent Drake to raid Spanish colonies in the New World to disrupt King Philip’s flow of money. Philip was furious and told the Pope he planned to invade England at the end of 1585. Drake singes the King of Spain’s beard 1587 • In 1587 Elizabeth ordered Drake to attack Spain’s most important port Cadiz • He destroyed 30 ships in 3 days – known as the ‘Singeing of the King of Spain’s Beard’ • He also stole lots of wood, meaning the Armada did not have quality barrels for food/water • Drake’s disruption delayed the Armada by a year (& meant that its food rotted in 1588). • This bought England more time to prepare for war. The Spanish Armada (1588) The Plan • By 1588, the Spanish Armada was ready to invade England • It had 130 ships with 8000 sailors & 18,000 soldiers • The Duke of Medina Sidonia would lead the Armada, but he had little experience at sea and didn’t want the job • The Armada would collect Parma’s army from France & sail to England under the protection of the Armada’s warships • Parma would march to London to depose Elizabeth & impose a Catholic government in England. 1) The Armada reached the English Channel The Armada set out in May 1588, but was delayed for a few weeks by bad weather In July the Armada was near England & signal fires were lit to warn Elizabeth English ships set sail to meet the Armada The Armada sailed up the channel in a crescent (half moon) formation, to use the large armed galleons to protect the weaker supply and army ships The English navy carried out a few minor raids, but did not inflict much damage Only 2 Spanish ships were lost (by accident) 2) The English attack the Spanish at Calais (with fire ships) and at Gravelines The Armada sailed up the English channel & anchored at Calais to wait for Parma’s army But Parma’s men didn't reach the coast in time (news had reached them too late) At midnight, the English sent 8 fireships into the Spanish ships causing panic They cut their anchors, broke formation & headed for the open sea (without Parma) The Spanish ships sailed to Gravelines, but bad weather stopped them returning to Calais The English attacked and the battle lasted many hours (5 Spanish ships were sunk) The rest were forced to sail away from France towards Scotland The English ships followed them to make sure they didn’t come back to collect Parma’s army 3) The Armada’s Journey back to Spain around Ireland was a disaster The Spanish called off the attack and returned to Spain around Scotland & Ireland Bad storms sank many ships and wrecked more on the Irish coast Many sailors died from starvation & disease – less than half the men made it back to Spain How did England defeat the Spanish Armada? !) Faster Ships • Years before the battle, England had started building smaller, faster ships (galleons) that could fire canon balls quicker & further than Spanish ships • Spanish ships were huge and slow to change direction. 2) Bad Planning & Communication (Spanish) • Philip’s plan to join with the Duke of Parma’s army in France was risky. • Parma had lots of small ships which took 48 hours to load, man and set sail. • It took too long (a week) for word to reach Parma that Medina was in the English Channel, by which time Medina had set sail to Calais. • Parma was not ready to set sail & the English were already ready to attack (leaving Medina with very little back up when anchored in France). 2) English Tactics were more effective • Spanish ships aimed to come alongside the English ones, jump on board & fight the enemy. But the English ships were faster & kept a safe distance. • They chased the Armada down the Channel, with heavy cannon fire, which forced the Spanish to arrive in France before Parma’s army was ready • As the Armada was waiting, the English sent fireships into the Spanish fleet. • This caused the Armada to panic, cut their anchors & sail away to the north • When the Spanish ships regrouped, the English attacked them in the Battle of Gravelines & the Armada was forced to sail north, chased by faster ships. 5) Bad Weather • Strong winds made it impossible for the Armada to return & pick up Parma’s army and storms wrecked or sunk Spanish ships as they tried to return home along the Scottish-Irish coasts. 2) Spanish Supplies • The Armada was not well supplied with food/weapons. Drake’s attack on Cadiz port in 1587 had destroyed food barrels. Delays in setting sail meant that by the time the English attacked the Armada it had been at sea for 10 weeks and had rotting food. 1000s died from starvation/disease. The consequences of the English victory? • Victory over the Spanish Armada gave Elizabeth a great propaganda victory • A new portrait was made, and a medal was made to commemorate her victory, it said “God blew and they were scattered”. • Elizabeth claimed that God was on the side of Protestantism • This led to a feeling of English pride and encouraged the Dutch rebels to renew their fight against the Spanish • The defeat of the Armada showed the strength of the English navy and gave England the confidence to trade and explore more widely at sea • Although Philip did not give up and continued the war for the rest of Elizabeth’s reign, the defeat had cost Spain dearly, both financially and in terms of its power • The Armada marked the start of a long decline in Spain’s power and fortunes. • English ships were sent on voyages of discovery and set up valuable new trade routes • By the end of Elizabeth’s reign, the navy was also trying to set up a new colony in Virginia • The English victory boosted Elizabeth’s popularity & strengthened the Protestant causeAlright, Isti — here’s a longer and more detailed English version of the Isaac Newton text, still written at a level that’s accessible for Grade 4 students, but rich enough in information to meet PISA literacy expectations and EF A2-level vocabulary. I’ve kept sentences short, clear, and with explanations for new concepts so it’s easier for young learners to follow, while still including both famous facts and lesser-known stories. ⸻ Isaac Newton: The Man Who Changed the Way We See the World A Boy from a Small Village Isaac Newton was born on January 4, 1643, in Woolsthorpe, a small village in England. His life was not easy. His father died before he was born. When he was just a few months old, his mother remarried and left him to live with his grandmother. Isaac missed his parents, but he kept himself busy by making things and exploring the world around him. As a child, Isaac liked to build models and machines. He made a small windmill that could turn with the wind. He built a water clock that told the time by dripping water into a container. He even made a sundial — a clock that tells the time by using the shadow of the sun. 💡 Did you know? The sundial marks that Isaac carved as a boy can still be seen today on the wall of his old house. ⸻ School and Curiosity When Newton first went to school, he was not the top student. At first, he did not pay much attention in class. But one day, another boy teased him for not being smart. Newton decided to study hard to prove him wrong. Soon, he became the best in his class. Isaac loved asking questions. He wanted to know how and why things happened. He enjoyed watching the stars at night and thinking about how the world worked. ⸻ The Falling Apple and Gravity One of the most famous stories about Newton is the falling apple. One afternoon, Isaac sat in his mother’s garden and saw an apple drop from a tree. This made him think: “Why does the apple fall straight down? Why doesn’t it fly up into the sky?” From this question, Newton began to think about gravity — an invisible force that pulls objects toward each other. Gravity is what keeps our feet on the ground. It’s also what keeps the Moon moving around the Earth and the planets moving around the Sun. 💡 Fun fact: The apple did not hit Newton’s head. That’s just a story people made up later to make the tale more exciting. ⸻ Newton’s Three Laws of Motion Newton studied movement and wrote three important rules: 1. Objects stay still or keep moving unless something makes them change. • Example: A ball will not roll unless you push it. 2. The bigger the push, the bigger the movement. • Example: If you kick a ball harder, it will go faster and farther. 3. Every action has an equal and opposite reaction. • Example: When you jump off a boat, the boat moves backward as you move forward. These three laws are still used today to understand how cars, rockets, and even roller coasters work. ⸻ Discoveries in Light and Color Newton also studied light. He found that white light is not just one color — it is made of many colors. He used a glass prism to split sunlight into a rainbow. This helped scientists understand how colors work. ⸻ Inventions and New Ideas Newton made a special telescope that used mirrors instead of lenses. This type of telescope made images of planets and stars much clearer. It is still called the Newtonian telescope today. He also worked in mathematics and helped create a new type of math called calculus, which is used to study changes and movement. ⸻ Strange Experiments Newton was so curious that he sometimes tested ideas on himself. Once, he put a thin needle, called a bodkin, beside his eye to see how it would change his vision. It was very dangerous, but luckily he did not go blind. 💡 Did you know? Newton also studied alchemy — an old kind of science where people tried to turn metal into gold. He never succeeded, but it showed how wide his interests were. ⸻ Later Life and Work At the age of 27, Newton became a professor at Cambridge University. He later worked for the Royal Mint, making sure coins were made safely and stopping people from making fake money. He was very strict, and some criminals were sent to prison because of his work. Newton never married. He spent most of his life reading, writing, and doing experiments. ⸻ The End of His Life Isaac Newton died in 1727 at the age of 84. He was buried in Westminster Abbey, a famous place in London where great people of Britain are honored. His work changed the world forever. Even today, scientists, engineers, and students still use Newton’s laws and ideas. 💬 Newton once said: “If I have seen further, it is by standing on the shoulders of giants.” This means we can make new discoveries by learning from the work of others who came before us. give 10 questions to each passage with PISA literacy standard for kid 10 years, 1. Nikola Tesla: The Man Who Dreamed of Lightning Born: July 10, 1856 Died: January 7, 1943 When Nikola Tesla was a boy in Croatia, he saw a flash of lightning and asked his mother, “Can we catch the light?” That question never left him. As he grew older, Tesla became a brilliant inventor, especially fascinated by electricity. He believed in a future where energy could be sent wirelessly through the air—like music through the radio! Tesla invented the alternating current (AC) system, which became the foundation of modern electricity. At the time, Thomas Edison promoted direct current (DC), and the two men had a fierce competition. Many laughed at Tesla's bold ideas, but he never gave up. He dreamed of wireless communication, flying machines, and even free energy for everyone. Though he died alone and poor, today the world honors his vision. Think About It: Why do you think people didn’t believe Tesla at first? What can we learn from Tesla’s courage to dream big? 2. Charles Darwin: The Man Who Studied the World’s Weirdest Creatures Born: February 12, 1809 Died: April 19, 1882 When young Charles Darwin got on a ship called HMS Beagle, he didn’t know he would change science forever. He sailed around the world for five years, collecting plants, animals, and fossils. On the Galápagos Islands, he noticed something curious: finches had different beaks depending on their island. Why? Darwin’s observations led him to write the theory of evolution by natural selection. It explained how animals adapt and survive. But his ideas shocked many people because they seemed to challenge religious beliefs. Despite the controversy, Darwin continued his work. His book On the Origin of Species changed how we see life on Earth. Think About It: Should scientists share their ideas even if they go against what others believe? How did traveling help Darwin make new discoveries? 3. Marie Curie: The Woman Who Glowed in the Dark Born: November 7, 1867 Died: July 4, 1934 Marie Curie was born in Poland at a time when girls were not allowed to study science. But that didn’t stop her. She moved to France, worked day and night, and discovered radioactivity, a powerful energy hidden inside atoms. She and her husband, Pierre Curie, found two new elements: polonium and radium. She became the first woman to win a Nobel Prize, and the only person to win in two different sciences: physics and chemistry. Even when Pierre died in an accident, Marie continued their work. Her discoveries helped doctors treat cancer—but working with radioactive materials also harmed her health. She died from radiation exposure, but her legacy lives on. Think About It: What challenges did Marie Curie face as a woman in science? Why is it important to balance discovery with safety? 4. Galileo Galilei: The Star Watcher Who Defied the Church Born: February 15, 1564 Died: January 8, 1642 Galileo loved looking at the stars. He built one of the first powerful telescopes and made stunning discoveries: mountains on the Moon, moons around Jupiter, and that the Earth orbits the Sun—not the other way around. This idea, called heliocentrism, went against the teachings of the Church. He was put on trial and forced to say he was wrong. But he wasn’t. He spent his last years under house arrest, quietly writing. Today, Galileo is called the father of modern science for daring to question what others blindly believed. Think About It: Why do you think Galileo was punished for telling the truth? Should science always follow evidence, even if it goes against powerful beliefs? 5. Isaac Newton: The Man Who Asked “Why?” When an Apple Fell Born: January 4, 1643 Died: March 31, 1727 One day, an apple fell from a tree, and Isaac Newton began to wonder: Why did it fall down, not sideways or up? This simple question led to his theory of gravity. Newton also invented calculus, described the laws of motion, and changed physics forever. But Newton wasn’t just a genius—he was curious, quiet, and often worked alone. He believed everything in nature followed rules, and it was our job to discover them. Thanks to him, we understand how planets move, how rockets launch, and why you fall when you trip. Think About It: How did Newton’s curiosity lead to great discoveries? Do you think working alone helped or hurt Newton? 6. Ada Lovelace: The First Computer Programmer Before Computers Existed Born: December 10, 1815 Died: November 27, 1852 Ada Lovelace was the daughter of the famous poet Lord Byron, but she didn’t love poetry—she loved numbers! At a time when girls were expected to sew, Ada studied mathematics. She met Charles Babbage, who designed an early computer called the Analytical Engine. Ada imagined the machine could do more than just math—it could create music, art, and even write! She wrote what is now considered the first computer program, long before real computers were built. Think About It: How did Ada imagine something that didn’t exist yet? Why do we call her a pioneer in technology? 7. Albert Einstein: The Man Who Brought Time and Space Together Born: March 14, 1879 Died: April 18, 1955 Albert Einstein wasn’t always a good student. In fact, his teachers thought he was slow. But Einstein thought deeply. He asked big questions like, “What if you could ride a beam of light?” His theories of relativity changed how we see space, time, and gravity. He also warned the world about the dangers of nuclear weapons, even though his ideas helped create them. Einstein believed science should help people, not harm them. With his messy hair, kind smile, and brilliant mind, he remains a symbol of genius. Think About It: Can someone be bad in school but still be brilliant? Should scientists be responsible for how their inventions are used? 8. Pythagoras: The Musician Who Loved Math Born: Around 570 BC Died: Around 495 BC Long ago in ancient Greece, Pythagoras believed the universe followed numbers. He discovered the Pythagorean Theorem, a rule about triangles that helps us build houses, design computers, and navigate space. He also believed that music had math inside it—that certain notes made perfect harmony because of mathematical ratios. Pythagoras started a secret school and taught his students to search for truth through numbers, shapes, and sound. Think About It: Why do you think Pythagoras saw math in everything? How does music relate to math? 9. Rosalind Franklin: The Woman Behind the DNA Discovery Born: July 25, 1920 Died: April 16, 1958 Rosalind Franklin loved looking closely at things. She used a special machine called X-ray crystallography to photograph molecules. One of her greatest photos, called Photo 51, showed the shape of DNA, the molecule that carries life’s instructions. But her work was taken without credit. Two men, Watson and Crick, used her photo to build their famous model of DNA and won the Nobel Prize. Rosalind died young and never knew how important her work became. Think About It: Why is it important to give credit in science? What can we learn from Rosalind’s quiet strength? 10. Carl Linnaeus: The Man Who Gave Names to Everything Born: May 23, 1707 Died: January 10, 1778 Have you ever wondered why a tiger is called Panthera tigris? That’s thanks to Carl Linnaeus, a Swedish scientist who created a way to name and organize every living thing. His system is still used today in biology. Linnaeus loved nature and spent his life collecting plants, animals, and even rocks. He believed that by organizing life, we could better understand it. Thanks to him, we now have a global “dictionary of nature.” Think About It: Why is it important to name and organize living things? How does order help us understand the world?Sure! Here's a solid list of **AP English Literature vocabulary**—terms that often come up in class, essays, and the AP exam. I'll break it down into categories to make it easier to study. --- ### 📚 **Literary Devices & Techniques** 1. **Alliteration** – Repetition of initial consonant sounds 2. **Allusion** – A reference to another text, event, or figure 3. **Anaphora** – Repetition of a word or phrase at the beginning of successive clauses 4. **Antithesis** – Contrast of ideas in a balanced or parallel construction 5. **Apostrophe** – Addressing someone absent, dead, or nonhuman as if present and able to respond 6. **Assonance** – Repetition of vowel sounds within nearby words 7. **Asyndeton** – Omission of conjunctions between parts of a sentence 8. **Consonance** – Repetition of consonant sounds, often at the end of words 9. **Diction** – Word choice (formal, informal, colloquial, etc.) 10. **Enjambment** – Continuation of a sentence without pause beyond the end of a line in poetry --- ### 🧠 **Figurative Language** 1. **Hyperbole** – Extreme exaggeration 2. **Imagery** – Descriptive language that appeals to the senses 3. **Irony** - *Verbal*: Saying the opposite of what’s meant - *Situational*: When the outcome is the opposite of what's expected - *Dramatic*: Audience knows something characters don’t 4. **Metaphor** – A direct comparison without using "like" or "as" 5. **Metonymy** – Substituting the name of one thing with something closely related (e.g. "The crown" for royalty) 6. **Synecdoche** – A part representing the whole (e.g. "All hands on deck") 7. **Personification** – Giving human traits to nonhuman things 8. **Simile** – A comparison using "like" or "as" 9. **Symbol** – An object, character, or color that represents something beyond itself --- ### ✍️ **Poetic & Rhetorical Terms** 1. **Caesura** – A pause in a line of poetry, often marked by punctuation 2. **Couplet** – Two lines of poetry that usually rhyme 3. **Iambic Pentameter** – A line with five iambs (unstressed-stressed syllables) 4. **Blank Verse** – Unrhymed iambic pentameter 5. **Free Verse** – Poetry with no fixed meter or rhyme 6. **Elegy** – A mournful poem, often for the dead 7. **Ode** – A lyric poem expressing emotion, often in honor of something 8. **Sonnet** – A 14-line poem with a specific rhyme scheme (Shakespearean or Petrarchan) --- ### 📖 **Narrative & Structure Terms** 1. **Tone** – The author's attitude toward the subject 2. **Mood** – The feeling or atmosphere the reader experiences 3. **Theme** – The central idea or message in a work 4. **Motif** – A recurring element that has symbolic significance 5. **Foil** – A character who contrasts with another character to highlight traits 6. **Foreshadowing** – Clues or hints about what will happen later 7. **Juxtaposition** – Placing two elements side by side to present a contrast 8. **Point of View** – Perspective from which the story is told (1st, 2nd, 3rd person) 9. **Stream of Consciousness** – Narrative style that mimics thoughts and feelings 10. **Frame Narrative** – A story within a story --- Want me to make flashcards, a quiz, or a PDF study guide with these? Or need help using them in a literary analysis essay?Got you now 👍 — you don’t want a code, you want ready-made quiz content you can paste into Quizalize so a teacher/class can use it. I’ll generate a proper SSS1 quiz bank (Maths, English, Basic Science) in a clean format. You can copy this into Quizalize “Create Quiz”. 📘 SSS1 QUIZ (READY FOR QUIZALIZE) 🧠 MATHS (10 QUESTIONS) What is 9 × 8? A. 72 B. 64 C. 81 D. 74 Answer: A Solve: 3x = 15 A. 3 B. 5 C. 6 D. 9 Answer: B What is 12²? A. 124 B. 144 C. 132 D. 122 Answer: B Simplify: 18 ÷ 3 A. 3 B. 5 C. 6 D. 9 Answer: C What is the square root of 49? A. 5 B. 6 C. 7 D. 8 Answer: C Find x: x + 7 = 20 A. 11 B. 12 C. 13 D. 14 Answer: C 5 × 5 × 5 = ? A. 125 B. 100 C. 150 D. 75 Answer: A What is 100 ÷ 4? A. 20 B. 25 C. 30 D. 40 Answer: B What is 15 + 17? A. 31 B. 32 C. 33 D. 34 Answer: B What is 10% of 200? A. 10 B. 20 C. 30 D. 40 Answer: B 📘 ENGLISH (10 QUESTIONS) Choose correct spelling A. Recieve B. Receive C. Receve D. Recive Answer: B Opposite of “fast” A. Quick B. Slow C. Sharp D. Rapid Answer: B Synonym of “happy” A. Sad B. Angry C. Joyful D. Tired Answer: C A noun is a name of a… A. Action B. Place/Person/Thing C. Verb D. Adverb Answer: B He ___ to school every day A. go B. going C. goes D. gone Answer: C Plural of child A. Childs B. Childes C. Children D. Childer Answer: C Antonym of “big” A. Large B. Huge C. Small D. Wide Answer: C A verb is a word that shows A. Name B. Action C. Place D. Thing Answer: B She is ___ honest girl A. a B. an C. the D. no article Answer: A Past tense of go A. Goed B. Gone C. Went D. Going Answer: C 🔬 BASIC SCIENCE (10 QUESTIONS) Plants absorb carbon dioxide during A. Respiration B. Photosynthesis C. Digestion D. Movement Answer: B Human breathing organ A. Heart B. Liver C. Lungs D. Kidney Answer: C Water boils at A. 0°C B. 50°C C. 100°C D. 150°C Answer: C Which is a metal? A. Rubber B. Copper C. Wood D. Plastic Answer: B The sun is a A. Planet B. Star C. Moon D. Comet Answer: B Force is measured in A. Joule B. Newton C. Watt D. Kelvin Answer: B Solid → Liquid is called A. Freezing B. Melting C. Evaporation D. Condensation Answer: B Earth revolves around A. Moon B. Mars C. Sun D. Jupiter Answer: C Human blood is pumped by A. Brain B. Heart C. Lungs D. Kidney Answer: B Energy from the sun is called A. Nuclear B. Solar C. Chemical D. Sound Answer: B ⚡ HOW TO USE IN QUIZALIZE Go to Quizalize Click Create Quiz Choose Manual Input Copy each question Paste with options + correct answer Set timer per question (5–10 sec for pressure mode) 🔥 IF YOU WANT NEXT LEVEL I can also: �Turn this into 100-question exam paper �Add hard WAEC/JAMB-level traps Or �simulate inter-house elimination rounds Just say: “upgrade me” 😈Here’s a set of **personal questions about bats**, suitable for **A1–A2 level 11-year-old students**, with **English and Chinese**: --- 1. **Have you ever seen a bat? Where?** 你曾经见过蝙蝠吗？在哪里？ 2. **Do you think bats are scary or interesting? Why?** 你觉得蝙蝠可怕还是有趣？为什么？ 3. **Bats are not birds. What is different about them?** 蝙蝠不是鸟。它们有什么不同？ 4. **Bats fly at night. Would you like to be awake at night like a bat? Why or why not?** 蝙蝠在夜晚飞行。你想像蝙蝠一样夜晚清醒吗？为什么？ 5. **Bats use sounds to see in the dark. Can you think of another animal that uses sounds to find things?** 蝙蝠用声音在黑暗中看东西。你能想出另一种用声音找东西的动物吗？ 6. **Have you ever heard a shriek or high-pitched sound like a bat? How did it feel?** 你听过像蝙蝠一样的尖叫或高音吗？感觉如何？ 7. **If you could fly like a bat, where would you go at night?** 如果你能像蝙蝠一样飞，你会在夜晚去哪里？ 8. **Would you like to have a bat as a pet? Why or why not?** 你想养蝙蝠作为宠物吗？为什么？ 9. **Do you sleep at night like most people, or do you sometimes stay up late?** 你像大多数人一样在夜晚睡觉，还是有时候熬夜？ 10. **What other animals do you know that are active at night?** 你知道还有哪些动物是夜行动物？ --- I can also **combine all three—cats, camels, bats—into a full bilingual worksheet** with space for answers, making it fun and easy for kids to complete. Do you want me to do that next?