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Eff..rs of ott.-PoFllat i What woLrld hoppen ro our colnrry i, it is ovetsp.pulored? When our counrry is ovâŹ.-populdted, re @ âŹxpâŹri.nce rh⏠foll.wirg: Food is our bdsic h@d. WhâŹn thâŹ.Cs an ih.re.se ir populdtion it neans thar hore ,@d is iealed. It rheds ho .naJgh food, rrtrple irll srruggle wirh eddr othâŹr in ordeLro âŹ!'r- As o l!fllr, lhde rill be o f@d -- , ond ou, now]nert of on ihdiyiduol fron d c..tair - the move$eni o, on individudl our of o cerrain pla.e which help râŹduce ihe populotion of th6t fr ArcihâŹ. b.sic ned is w.ra. Wde. shorroge ocu.s when there is on ircreare of hu,nber of p@ple ro be $pptied. rn owr-popur.t d ore.s, woler is rdiorâŹd, Ir rEB rhoi supplies like ti,tWSS ond ,IWSI can'i $pply enoish worer. Do you hdve enough supply of sai.. in your oreo? Aside f.om food alld worer, shelier is olso ohe o, our inportant heeds. As the populoiion ihcre.!e!, building n.w hoLr!âŹs or rheltâŹr is limit.i. To find solulion to this prcblâŹn, some goverihent og.ncies dnd orhs non{ovâŹIhrehl offi.iofs (N6O) .onvefied sot@ ti.elields, du,np site. dnd nountcirlr inlo flbdivisions dnd relidentiols. Sut whot uould be ths effect o{ coMrtiig .i@fields to .6idâŹnri6l uits in our food supply? z , 2 Z Z :'", becouse there ore no enough space for prcpex garbage dkposol. ^s o râŹsulr, sore peoPle lend to ihrow'their gorbdge onywh.fâŹ. oorbdge baones brc{niry ond rursing ground of iEecrs and onidols ihot @se horm ro pe.ple. Dec.yiry garboge olso produces r,hpleaiant odor ard ehen burn if pmduces pois.nour qds @lled nelhohe As ihe populdtion incrâŹa3*, the 9d6.9e dso incraes. nris is T't ,,8 T H Wha you de living in on oa-populdi.d pla@, you moy oqaiae halrh prcblerns. Ir is be@@. the woi.r srpply is limit.d ihct will l..d you to poor hygi.ni. hobirs. In plo.4 like rhis, the surrouhdiigs naybe uniidy. o focrorthoi @uld oko cfFe.t your h4l'th. The common oilments rhot yd @uld oc$rire in ovesfDpllarâŹd ploces ore bEnchil is, o5l hnq. diqrrha and rube.culosis. 7,\ ,\\ \1" 6. Lnck of Herlrh sarvice llosi Pelple in 6n oM-populciâŹd 6ra 90 ro rubli. heilrh @trtas ond governhent hospirols be6u.e ii prcvides fr@ @Eulrorion oid los @sr rEdicdrions. A3 a ..suli, lhâŹs⏠gow.nnenr dgâŹrciB b.@ne itud.4$re in mcetiig ihe n eds b..ou!⏠df ihsrfficiâŹnr funds. Lock of medicol personnel ,o odmaiisiâŹI is also s problen in mosr hosptols evâŹn rhere or. od.audtc supply of hedicire!. 7_ Do you how wlry rhe crim⏠roi⏠hexs ih becdur⏠fiDre pe.ple o.e fnJrrctâŹd d@ ro sLfficiâŹ.i naE io supp.rr their forniliG. ouf country inclY{ses? If is uh.mploymâŹni dnd hdve no arinet .re u$dv grâŹ{rer ia dn dq-popltdled ra whq. tl, , a, v, tlr I E. Air ard WatâŹr Pollutioh How dir be.o'nes pollutâŹd? I11⏠dir b@'nâŹs p.llurn be.4ne of rhe hormfolgoees thot ser. produ.4 by the fdcioriâŹs and vehicles. Itete {octories ond whi.l6 @ fuel ro run nochiB ond .JBin6. In ,h⏠prc.ess, they give our Cdrboh Dioxide ond other ho.6ful gars.r such 6 Nittugei Oxide, Corbon l oioxide dnd Le.d iiio the oir. Do you know whot .ontdbute io ihe incrâŹasing number of whides qnd foctories? It is ihe inc.6e o, populdtion. As whdt I hove dis.!sse!, wirh a lihired sra.e 9@bd9e disposalie one of the problens thot .o!ld ise i, dh o!er-pop!,.tâŹd ploce. exn,jple ot thie orc rhos⏠pelpl⏠livi,rg oh the raverside teid 'ro ,hrou, lheir gEr&ge Hde you seen 'th. P6si9 river or the Tulyahan river? Did you {ind it Whdr do you think i! ihe effâŹ.t of ihis ih the.re4iures sho lives ih Ahothd f6do.s thal could.on rlbule to wdtd pollutioh dre oil s?ills, gorbqg⏠fro,n boa, or ships ahd som⏠ihdust.iol wosre. 9. Ite l@96f p4.enroge group. Individuols who orc this grclp. of olr popllarioh is compos.n of the working @pobla of s'rpporting ,heir fomilies nok !-up Though rhas group hol& the lojgeei percenroge of d. populaiion, rhis olso becomer one o{ oveFpopulored problâŹ]ns bâŹ4use there ore rc jobs awildble fo. oll of iha10. Erergy Shortdge ltere will be on energy shortdge iJ ihe populdtion incre63"l be.dise rhe d.,nand i. âŹle.iriciry is high. Why is thai wh.n th. PoPqldion inclE.g, rhe d4ord in el4tricity is high? Ir B be.ouse there $,ould be 8to.e hdsat dnd blildirys to lighr ond nore el?riric oPPliohces ro run. rt.6rcznho!3.Ef+ed Whor is rhe grernho@ effâŹ.r? In whoi say il c.uld offect c2 6re.hhG. effed is rhe wdrniltg of rhe drltlosphee. lvhen the 5un worft rhe.nrrh s1jrf.@, sone of rhe h@r goâŹJ bo.k ro rhe ornos?herc. Air an the dtnDsphere which is C@boi Dioxid. ,rops ihe heot 6hd it mok6 the a.th very worm. As ihe populdtion coniinuou!|,l gtol4 , the gt@rl$use etfe.t b@res no.e visible. Ir is becaosu ,hera ore mo.e focrories snd whicl.s iha, produce wdstâŹs ond fuma5 which cduses more C{.bo. Diodde ir the ormosphere. As a rcsutt, ,herc eiould be nore h4, ,rop in the ornosphere uhich osk6 th. @ih nuch wornerIf this will hoppen continuously, ,h⏠fish ih th⏠ocah *ill diâŹ, ricerields/f@mlands will dry too due to lh⏠wcm clitnole 12. Destruction of rhe Ozone Loyer A5 whot you hove l@med lrheh you de in v5-6, rhot the qzore ldver is 'the proiecrive loyâŹ. of the olnosPhdâŹ. ft protects us {rom the homful effects of ultrdviolei rays of the su. Do you khow ,hot our Ozore lolâŹt q4. dQ4tt\!ci.d? Il olreadY hod holes lhai dllow the ulrroviolet rdys to .4dt ihe @rrh. How do6 this hdpPei? Does th. in rc$e of poPuldioh h@⏠sonething 'to do tr,lh ir? Yes, rhe I6i grov/irts PoPuldiion .odribuied o lot be@use 6 th' populotion incre3es, rhe u5e of refrigerd'tors, dâŹrosol lProvs 6nd pl4srics 6bo ihcre&s6. The sid producls coiiojn chemicol called Chlorofluorocdrbons (CFCS) which is mix wafh ihe dir in ihe ormosPherâŹ. As o resulr. ihe hcrmfirl chernicol râŹoches the Prolectiw ldver dnd lhrowh. hole in {hid ult@iolzi cahders aid cai4.ct3 ,F.*Y.iis hi!586$qâŹ9.7,- Ho$ doas dcid rdin form? Is cid roii hdmful ro rEn? In the prcvious dis.ussions, yodt⏠t.onâŹd rhd more vel .1e3 dnd fdctoriâŹs or⏠necded fo het the iii:.e.siry number o{ P@Pla. Lefs now fihd af hd f@tot.iâŹs dnd vehicle! .ontribure in the forrEtion of ocid When foctories 6nd whi.ler give off woste gd..3 ,hot will ,nix on lhe noisture i. rhe oir, it will ihen Produ.e sulPhu.i. ocld dnd Nitri. o.id. 'Ihe clol,Jd folb will ,hâŹh obsorb rhese ccids ond ehei ihe clold f.lls os .oin, ih. ccid is ahady Pdrr of itU/ha d.id ftin falls oh lok"!, ,46 or ocan ih⏠fish sill die d.d if h fdlls oh fopnlonds,lhe pldni. together oith the soil B desrroyed. When you inhole dir with Niiric acid, your blood will los. irs @pobilily io fonspori OxygâŹh to your diffâŹ.ai bodY Po.i3. ScieniisB include other rorns oJ dcidic prâŹcipiigrion. Thes⏠drc nisi, Do you krcw ihot Nuclerr power slotionr Use .adiodctive ,ndie.ials in producirE fuels, yet, rhey do and those .odioactiw rndlqlotE gi\e otf radio'ting en.rgy thoi is harmrul 'to livirq thilEs. wlren rodiotion enlert ihe body ot living things it {ill srq rhere for o lorg ,eriod of ri'ne. Exonple fhe rodiqtion vG srilled to the c.m. Then rhe @rn will be aie by rhe chicken, the .odiotion o the c.rn 'rill also 'tronsfâŹr to the chi.kâŹn. Wha on individuol als ihe nat of the chickeh sith mdiarion, helshe rill .ko oblorb ihe rodi@.tirc mtaid that will destrcy hB/her .âŹlls ond ruket hnn/hd si.r. Over-populoiion .on leld to food shoridgâŹ, wdter shorroqe, housiB problâŹms, qdrbog⏠problâŹrs, lock of halrh sdi.e. tisa ol clit@ rote, oir ond woiâŹr pollution, uhanpl6ynat, eiergy 5horr69e, grenhoq3⏠efreci, desrruction o( th. ozo@ lat/e?, rci.l roi. olld e.lâŹd. wattaAssessment (4th Grade Social Studies and Science) Standards: L.4.1 Demonstrate command of the conventions of standard English grammar and usage when writing or speaking. a. Use relative pronouns (who, whose, whom, which, that) and relative adverbs (where, when, why). b. Form and use the progressive (e.g., I was walking; I am walking; I will be walking) verb tenses. c. Use modal auxiliaries (e.g., can, may, must) to convey various conditions. d. Order adjectives within sentences according to conventional patterns (e.g., a small red bag rather than a red small bag). e. Form and use prepositional phrases. f. Produce complete sentences, recognizing and correcting inappropriate fragments and run-ons. g. Correctly use frequently confused words (e.g., to, too, two; there, their). 4.LS.1: Changes in an organismâs environment are sometimes beneficial to its survival and sometimes harmful. SYI-1.D: Describe the structure and/ or function of subcellular components and organelles. â
SYI-1.E: Explain how subcellular components and organelles contribute to the function of the cell. â
SYI-1.F: Describe the structural features of a cell that allow organisms to capture, store, and use energy. â
ENE-1.B: Explain the effect of surface area-to-volume ratios on the exchange of materials between cells or organisms and the environment. â
ENE-1.C: Explain how specialized structures and strategies are used for the efficient exchange of molecules to the environment. â
ENE-2.A: Describe the roles of each of the components of the cell membrane in maintaining the internal environment of the cell. â
ENE-2.B: Describe the Fluid Mosaic Model of cell membranes. â
ENE-2.C: Explain how the structure of biological membranes influences selective permeability. â
ENE-2.D: Describe the role of the cell wall in maintaining cell structure and function. â
ENE-2.E: Describe the mechanisms that organisms use to maintain solute and water balance. â
ENE-2.F: Describe the mechanisms that organisms use to transport large molecules across the plasma membrane. â
ENE-2.G: Explain how the structure of a molecule affects its ability to pass through the plasma membrane. â
ENE-2.H: Explain how concentration gradients affect the â
movement of molecules across membranes. â
ENE-2.I: Explain how osmoregulatory mechanisms contribute to the health and survival of organisms. â
ENE-2.J: Describe the processes that allow ions and other molecules to move across membranes. â
ENE-2.K: Describe the membrane-bound structures of the eukaryotic cell. â
ENE-2.L: Explain how internal membranes and membrane- bound organelles contribute to compartmentalization of eukaryotic cell functions. â
EVO-1.A: Describe similarities and/or differences in compartmentalization between prokaryotic and eukaryotic cells. â
EVO-1.B: Describe the relationship between the functions of endosymbiotic organelles and their free-living ancestral counterparts 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 DesirĂ©e Nieuwenhuis | NatĂ lia 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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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 âonset of puberty and adiposity/obesityâ, âonset of pubertyâ, âchildren with obesityâ, âadipose tissueâ, âchildhood obesityâ, âadiposityâ, âobesityâ, âadipokine(s)â, âHPG axisâ, âadipokines ovary/ova- riesâ, or âadipokines testesâ, either alone or in combination. 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The usefulness of circulating levels of leptin, kisspeptin, and neurokinin B in obese girls with precocious puberty. 2018;34:627-630. 69. Lee J, Song J, Hootman JM, et al. Obesity and other modifiable fac- tors for physical inactivity measured by accelerometer in adults with knee osteoarthritis: data from the osteoarthritis initiative (OAI). Arthritis Care Res (Hoboken). 2012;53-61. 70. Bramswig J, Dubbers A. Disorders of pubertal development. Deutsches Arzteblatt international. 2009;106:295-303. quiz 04 71. Elias CF, Purohit D. Leptin signaling and circuits in puberty and fertil- ity. Cell Mol Life Sci. 2013;70(5):841-862. 72. Riumallo J, Durnin JV. Changes in body composition in adolescent boys. Eur J Clin Nutr. 1988;42(2):107-112. 73. Siervogel RM, Demerath EW, Schubert C, et al. Puberty and body composition. Horm Res. 2003;60(Suppl 1):36-45. 74. Zhang J. Gong M. Andrologia: Review of the role of leptin in the regu- lation of male reproductive function; 2018. 75. Kauffman AS, Gottsch ML, Roa J, et al. Sexual differentiation of Kiss1 gene expression in the brain of the rat. Endocrinology. 2007;148(4): 1774-1783. 76. Zeydabadi Nejad S, Ramezani Tehrani F, Zadeh-Vakili A. The role of kisspeptin in female reproduction. Int J Endocrinol Metab. 2017;15:1- 11, e44337. 77. Sorensen K, Aksglaede L, Petersen JH, Juul A. Recent changes in pubertal timing in healthy Danish boys: associations with body mass index. J Clin Endocrinol Metab. 2010;95(1):263-270. 78. Juul A, Magnusdottir S, Scheike T, Prytz S, Skakkebaek NE. Age at voice break in Danish boys: effects of pre-pubertal body mass index and secular trend. Int J Androl. 2007;30(6):537-542. 79. Lee JM, Wasserman R, Kaciroti N, et al. Timing of puberty in overweight versus obese boys. Pediatrics. 2016;137(2):137-146, e20150164. 80. He F, Guan P, Liu Q, Crabtree D, Peng L, Wang H. The relationship between obesity and body compositions with respect to the timing of puberty in Chongqing adolescents: a cross-sectional study. BMC Pub- lic Health. 2017;17:664-673. 81. Ishikawa T, Fujioka H, Ishimura T, Takenaka A, Fujisawa M. Expres- sion of leptin and leptin receptor in the testis of fertile and infertile patients. Andrologia. 2007;39(1):22-27. 82. Martins AD, Moreira AC, Sa R, et al. Leptin modulates human Sertoli cells acetate production and glycolytic profile: a novel mechanism of obesity-induced male infertility? Biochim Biophys Acta. 1852;2015: 1824-1832. 83. Morash BA, Willkinson D, Ur E, Wilkinson M. Resistin expression and regulation in mouse pituitary. FEBS Lett. 2002;526(1-3):26-30. 84. Cabrera SM, Bright GM, Frane JW, Blethen SL, Lee PA. Age of thelarche and menarche in contemporary US females: a cross- sectional analysis. Journal of pediatric endocrinology & metabolism: JPEM. 2014;27(1-2):47-51. 85. Herman-Giddens ME, Steffes J, Harris D, et al. Secondary sexual characteristics in boys: data from the Pediatric Research in Office Settings Network. Pediatrics. 2012;130(5):e1058-e1068. 86. WHO. Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser. 1995;854:1-452. 87. Akin I, Tolg R, Hochadel M, et al. No evidence of âobesity paradoxâ after treatment with drug-eluting stents in a routine clinical practice: results from the prospective multicenter German DES.DE (German Drug-Eluting Stent) Registry. JACC Cardiovasc Interv. 2012;5(2): 162-169. 88. Marcovecchio ML, Chiarelli F. Obesity and growth during childhood and puberty. World Rev Nutr Diet. 2013;106:135-141. How to cite this article: Nieuwenhuis D, Pujol-Gualdo N, Arnoldussen IAC, Kiliaan AJ. Adipokines: A gear shift in puberty. 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 goverChapter 22 Antihypertensive Drugs Hypertension Defined (JNC-8) Pharmacology Overview 7 main categories of drugs to treat HTN Adrenergic drugs (old friend) Angiotensin-converting enzyme (ACE) inhibitors Angiotensin II receptor blockers (ARBs) Calcium channel blockers (CCBs) Diuretics Vasodilators Direct renin inhibitors A. Adrenergic Drugs: 5 Subcategories and where they act A1. Adrenergic neuron blockers (central and peripheral)- we wonât talk about this A2. Alpha1 receptor blockers (peripheral) A3. Alpha2 receptor agonists (central) A4. Beta receptor blockers (peripheral) A5. Combined α and ÎČ receptor blockers (peripheral) A2. Peripherally Acting Adrenergic Drug Alpha1 Blockers (weâve met these) Doxazosin, prazosin, alfuzosin Block alpha1-receptors which causes BP to decrease Reduces peripheral vascular resistance and BP by dilating both arterial and venous blood vessels Main Use: benign prostatic hyperplasia (BPH) Alpha1 Blockers REMEMBER Tamsulosin (Flomax)* is an α1 blocker BUT *Tamsulosin is not used to control BP, just for BPH. A3. Centrally Acting Adrenergic Drugs Alpha 2 agonist Clonidine and methyldopa 1- Stimulate alpha2-adrenergic receptors. in the brain Decreases sympathetic outflow from the CNS which decreases NE production 2. Stimulate alpha2-adrenergic receptors in kidneys remember alpha 2 opposes alpha 1 Dilates peripheral blood vessels â lowers peripheral resistance â Results in decreased BP So âŠ.Clonidine (Catapres) Used primarily for its ability to decrease blood pressure in an urgent setting Also use in opioid withdrawal as previously discussed Oral (multiple times a day), and topical patch formulations Do not stop abruptly as it may lead to rebound hypertension In reality, Clonidine and methyldopa Not prescribed as first-line home antiHTN drugs High incidence of unwanted adverse effects: orthostatic hypotension, fatigue, and dizziness MIGHT be uses as adjunct drugs after other drugs have failed, in conjunction with other antiHTN such as diuretics A4. Adrenergic Drugs Selective Beta 1 Blockers Metoprolol, Atenolol Reduction of HR through ÎČ1 receptor blockade (remember adrenergic blocking of this receptor???) HR results in BP Cause reduced secretion of renin = BP A4. Adrenergic Drugs Selective Beta1 Blockers Nebivolol (Bystolic) Uses: hypertension and HF Action: blocks ÎČ1 receptors and produces vasodilatation, which results in a decrease in SVR High doses loses selectivity and blocks both ÎČ1 and ÎČ2 Less sexual dysfunction All BB- Do not stop abruptly; must be tapered over 1 to 2 weeks A4. Adrenergic Drugs NONSelective Beta Blockers Propranolol Acts equally on ÎČ1 and ÎČ2 Other uses include situational anxiety associated with public speaking, test taking As mentioned on previous slide, nebivolol at high doses becomes beta nonselective A5. Dual-Action Adrenergic Drugs α1 and ÎČ Receptor Blockers Dual antihypertensive effects of reduction in heart rate (beta1 receptor blockade) and vasodilation (alpha1 receptor blockade) Examples are carvedilol (common) and labetalol (not as common) A5. Dual-Action Adrenergic Drugs α1 and ÎČ Receptor Blockers Carvedilol (Coreg) Widely used drug that is well tolerated Uses: HTN, mild to moderate HF in conjunction with digoxin, diuretics, and ACE inhibitors Contraindications: severe bradycardia or unstable HF, bronchospastic conditions such as asthma, and various cardiac conduction problems Adrenergic Drugs Indications - HTN But also for Glaucoma (topical) BPH: doxazosin, prazosin, and terazosin (2 for 1) Management of severe HF when used with cardiac glycosides and diuretics Contraindications Acute HF- have to stabilize first MOAIs- yeah doesnât everything interact with MAOIs? Peptic ulcers Severe liver/kidney disease Asthma (with beta blockers) Adrenergic Drugs: Adverse Effects Orthostatic hypotension 1st-dose syncope Rebound hypertension with abrupt discontinuation Most common: Dry mouth, drowsiness, constipation, sedation Interactions- always check for specific drug interactions Can cause additive CNS depression with alcohol, benzodiazepines, opioids Question #1 When administering an alpha-adrenergic drug for hypertension, it is most important for the nurse to assess the patient for the development of what response? Hypotension Hyperkalemia Oliguria Respiratory distress Answer A Hypotension This is a key point in patient education These drugs have strong vasodilating properties and may cause severe hypotension, especially at the beginning of therapy. B. Angiotensin-Converting Enzyme Inhibitors aka ACE Inhibitors or ACEi Large group of safe and effective drugs Currently are 10 ACEi Often used as first-line drugs for HF and hypertension May be combined with a thiazide diuretic, loop diuretic, or Calcium Channel Blocker (CCB) You need to understand the basics ACE Inhibitors: Review RAAS ACE converts angiotensin I, formed through the action of renin, to angiotensin II Angiotensin 2 is a potent vasoconstrictor and also induces aldosterone secretion by the adrenal glands Aldosterone stimulates sodium resorption (H20 follows Na Both act to raise BP which causes kidneys to reduce renin production ACEi= Great drug to treat HTN BUT contraindicated in pregnancy (2nd,3rd trimester due to fetal renal damage) and breastfeeding first few weeks after birth B. ACE Inhibitors - PRIL Lisinopril (Prinivil) super common, often the 1st drug Enalapril (Vasotec) also common Captopril (Capoten) great if liver disease present Benazepril (Lotensin) Fosinopril (Monopril) Perindopril (Aceon) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik) Primary Effects of the ACE Inhibitors Prevent Na (and H2O) resorption by inhibiting aldosterone secretion (volume reduction) (GO BACK TO RAAS DIAGRAM) blood volume decreases work of the heart preload, or the left ventricular end-diastolic volume which is important in HF ACE SUMMARY OF ACTIVITY 1) Prevent vasoconstriction caused by angiotensin 2 (2) Prevent aldosterone secretion ïš less sodium and water resorption Cardioprotective Effects of ACEi They slow progression of left ventricular hypertrophy (ventricular remodeling) after MI so considered cardioprotective ACE inhibitors have been shown to decrease morbidity and mortality in patients with HF Renal Protective Effects of ACEi ACE inhibitors: reduce glomerular filtration pressure by volume reduction Cardiovascular drug of choice for patients with diabetes since it helps protect kidneys by reducing pressure. Sometimes used low dose for kidney protection with DM without HTN B. ACEi Enalapril (Vasotec) Only ACEi available in both oral and IV Enalapril IV does not require cardiac monitoring Oral enalapril: prodrug (metabolized in liver) Improves patientâs chances of survival after an MI Reduces the incidence of HF B. ACEi Captopril (Capoten) Uses: prevention of ventricular remodeling after MI; reduce the risk of HF after MI Shortest half-lifeïš Must be administered multiple times throughout the day so this limits its use Not a prodrug so good for patient with liver disease Question #2 A patient with diabetes has a new prescription for the ACE inhibitor lisinopril. She questions this order because her provider has never told her that she has hypertension. What is the best explanation for this order? The doctor knows best The patient is confused This medication has cardioprotective properties This medication has a protective effect on the kidneys for patients with diabetes Answer D ACE inhibitors have been shown to have a protective effect on the kidneys because they reduce glomerular filtration pressure. This property makes them the cardiovascular drug of choice for patients with diabetes. Question #3 A patient with a history of pancreatitis and cirrhosis is also being treated for hypertension. Which drug will most likely be ordered for this patient? Clonidine Prazosin Diltiazem Captopril Answer D Captopril Captopril is not a prodrug; therefore, it does not need to be metabolized by the liver to be effective. This is an advantage in patients with liver disease. ACE Inhibitors: Adverse Effects *Dry, nonproductive cough, which reverses when therapy is stopped. This is a class effect Dizziness- Note: First-dose hypotensive effect may occur Headache & Fatigue Possible hyperkalemia ** Angioedema: rare but potentially fatal Not safe in pregnancy-are contraindicated during the second and third trimesters of pregnancy because of increased risk of fetal renal damage C. Angiotensin II Receptor Blockers (ARB) Considered an alternative to ACEi Less likely to cause a dry cough and hyper K+ that is common with ACE inhibitors Angiotensin II Receptor Blockers: Mechanism of Action Go back to RAAS diagram! ARBs affect primarily 2 places 1. Vascular smooth muscle - blocks vasoconstriction 2. Adrenal gland -Selectively blocks the binding of Ang 2 to certain Ang 2 receptors inhibiting secretion of aldosterone Lowers volume retention and BP Angiotensin II Receptor Blockers -ARTAN Losartan (Cozaar)- very common Eprosartan (Teveten) Valsartan (Diovan) Irbesartan (Avapro) Candesartan (Atacand) Olmesartan (Benicar) Telmisartan (Micardis) Azilsartan (Edarbi) C. ARB Losartan (Cozaar) Beneficial in patients with HTN and HF Used with caution in patients with kidney or liver dysfunction and in patients with renal artery stenosis ***Not safe for breastfeeding women and should not be used in pregnancy (Cat C 1st trimester, Cat D 2nd-3rd trimester), potential fetal toxicity Appear to be equally effective for the treatment of hypertension and well tolerated ARBs less likely to cause cough and hyperK+ but can still happen Evidence that ARBs are associated with lower mortality after MI than ACE inhibitors Never take ACEi and ARBs at the same time* 5. Calcium Channel Blockers (CCB) Primary use: HTN, angina, some dysrhythmias Cause smooth muscle relaxation by blocking the binding of calcium to its receptors, preventing muscle contraction Results in: Relaxed blood vessels to the heart Decreased peripheral smooth muscle tone Decreased SVResistance Decreased BP E. Diuretics First-line antiHTN in JNC 8 guidelines Decreases fluid volume The results from diuresis: preload, Peripheral resistance Overall effect ï Decreased workload of the heart and decreased BP Thiazide diuretics are the most commonly used diuretics for HTN Ie hydrochlorothiazide (HCTZ), chlorthalidone We will discuss diuretics further in the chapter on diuretics F. Vasodilators Directly relax arterial or venous smooth muscle (or both) Results in: Decreased SVR Decreased afterload Peripheral vasodilation Indicated for treatment of HTN May be used in combination with other drugs F. Vasodilators Hydralazine (Apresoline) Orally: routine cases of essential hypertension Injectable: hypertensive emergencies BiDil: specifically indicated as an adjunct for treatment of HF in African-American patients F. Vasodilators Sodium Nitroprusside (Nitropress) *Sodium nitroprusside and IV diazoxide are reserved for the management of hypertensive emergencies. Contraindications: severe HF, known inadequate cerebral perfusion (especially during neurosurgical procedures) F. Vasodilators Adverse Effects Hydralazine: dizziness, headache, tachycardia, edema, dyspnea, N/V/D, vitamin B6 deficiency, rash Sodium nitroprusside: hypotension, bradycardia, decreased platelet aggregation, rash G. Direct Renin Inhibitors Aliskirin (Tekturna) Blocks the RAS pathway at the point of activation. Inhibiting renin production prevents the downstream production of Ang II (potent vasoconstrictor) Adverse effects: N/V, severe hypotension, hyponatremia, hyperkalemia⊠Contraindicated in patients with DM taking ACEi or ARB Miscellaneous Antihypertensives Eplerenone (Inspra) Newer class of drugs called selective aldosterone blockers (remember RAAS?) Reduces BP by blocking the actions of aldosterone at its corresponding receptors in the kidney, heart, blood vessels, and brain Indications: routine treatment of hypertension and for post-MI HF Contraindicated if serum potassium levels are high (above 5.6 mEq/L) A Special Form of HTN Treatment of Pulmonary Hypertension Sildenafil and Tadalafil Commonly used for erectile dysfunction Used for pulmonary hypertension but with different trade names Sildenafil: Revatio* (Viagra for ED) Tadalafil: Adcirca* (Cialis for ED)finding the GCF and LCM(free text)Math 4 Quarter 2 Finding the GCF and the LCMGenerate all of these 25 questions Part A: Each correct answer is worth 5. 1. The regular pentagon shown has a side length of 2 cm. The perimeter of the pentagon is (A) 2 cm (B) 4 cm (C) 6 cm (D) 8 cm (E) 10 cm 2 cm 2. The faces of a cube are labelled with 1, 2, 3, 4, 5, and 6 dots. Three of the faces are shown. What is the total number of dots on the other three faces? (A) 6 (B) 8 (C) 10 (D) 12 (E) 15 3. The equation that best represents \a number increased by _ve equals 15" is (A) n ô 5 = 15 (B) n _ 5 = 15 (C) n + 5 = 15 (D) n + 15 = 5 (E) n _ 5 = 15 4. The line graph shows the number of bobbleheads sold at a store each year. The sale of bobbleheads increased the most between (A) 2016 and 2017 (B) 2017 and 2018 (C) 2018 and 2019 (D) 2019 and 2020 (E) 2020 and 2021 Number of 2016 2017 2018 2019 2020 Year Sale of Bobbleheads 2021 Bobbleheads 20 40 60 80 5. Starting at 72, Aryana counts down by 11s: 72; 61; 50; : : : . What is the last number greater than 0 that Aryana will count? (A) 4 (B) 5 (C) 6 (D) 7 (E) 8 6. In the diagram, \ABC = 90_. The value of x is (A) 68 (B) 23 (C) 56 (D) 28 (E) 26 Day of the Week 44° x° A B C x° 7. Which of the following values is closest to zero? (A) ô1 (B) 5 4 (C) 12 (D) ô4 5 (E) 0:9 Grade 8 8. A jar contains 267 quarters. One quarter is worth $0.25. How many quarters must be added to the jar so that the total value of the quarters is $100.00? (A) 33 (B) 53 (C) 103 (D) 133 (E) 153 9. A package of 8 greeting cards comes with 10 envelopes. Kirra has 7 cards but no envelopes. What is the smallest number of packages that Kirra needs to buy to have more envelopes than cards? (A) 3 (B) 4 (C) 5 (D) 6 (E) 7 10. For the points in the diagram, which statement is true? (A) e > c (B) b < d (C) f > b (D) a < e (E) a > c y x (e, f ) (a, b) (c, d ) Part B: Each correct answer is worth 6. 11. The 26 letters of the English alphabet are listed in an in_nite, repeating loop: ABCDEFGHIJKLMNOPQRSTUVWXY ZABC : : : What is the 258th letter in this sequence? (A) V (B) W (C) X (D) Y (E) Z 12. A public holiday is always celebrated on the third Wednesday of a certain month. In that month, the holiday cannot occur on which of the following days? (A) 16th (B) 22nd (C) 18th (D) 19th (E) 21st 13. A circular spinner is divided into three sections. An arrow is attached to the centre of the spinner. The arrow is spun once. The probability that the arrow stops on the largest section is 50%. The probability it stops on the next largest section is 1 in 3. The probability it stops on the smallest section is (A) 1 4 (B) 2 5 (C) 1 6 (D) 2 7 (E) 3 10 14. A positive number is divisible by both 3 and 4. The tens digit is greater than the ones digit. How many positive two-digit numbers have this property? (A) 4 (B) 5 (C) 6 (D) 7 (E) 8 15. A rectangular pool measures 20 m by 8 m. There is a 1 m wide walkway around the outside of the pool, as shown by the shaded region. The area of the walkway is (A) 56 m2 (B) 60 m2 (C) 29 m2 (D) 52 m2 (E) 50 m2 20 m 8 m 1 m Grade 8 16. The results of asking 50 students if they participate in music or sports are shown in the Venn diagram. What percentage of the 50 students do not participate in music and do not participate in sports? (A) 0% (B) 80% (C) 20% (D) 70% (E) 40% Music Sports 15 5 20 17. There are 2 3 as many golf balls in Bin F as in Bin G. If there are a total of 150 golf balls, how many fewer golf balls are in Bin F than in Bin G? (A) 15 (B) 30 (C) 50 (D) 60 (E) 90 18. In the sequence shown, Figure 1 is formed using 7 squares. Each _gure after Figure 1 has 5 more squares than the previous _gure. What _gure has 2022 squares? (A) Figure 400 (B) Figure 402 (C) Figure 404 (D) Figure 406 (E) Figure 408 Figure 1 Figure 2 Figure 3 19. Mateo's 300 km trip from Edmonton to Calgary passed through Red Deer. Mateo started in Edmonton at 7 a.m. and drove until stopping for a 40 minute break in Red Deer. Mateo arrived in Calgary at 11 a.m. Not including the break, what was his average speed for the trip? (A) 83 km/h (B) 94 km/h (C) 90 km/h (D) 95 km/h (E) 64 km/h 20. Equilateral triangle ABC has sides of length 4. The midpoint of BC is D, and the midpoint of AD is E. The value of EC2 is (A) 7 (B) 6 (C) 6:25 (D) 8 (E) 10 Part C: Each correct answer is worth 8. 21. The positive factors of 6 are 1, 2, 3, and 6. There are two perfect squares less than 100 that have exactly _ve positive factors. What is the sum of these two perfect squares? (A) 177 (B) 80 (C) 145 (D) 52 (E) 97 22. In the list p; q; r; s; t; u; v, each letter represents a positive integer. The sum of the values of each group of three consecutive letters in the list is 35. If q + u = 15, then p + q + r + s + t + u + v is (A) 85 (B) 70 (C) 80 (D) 90 (E) 75 Grade 8 23. The net shown is folded to form a cube. An ant walks from face to face on the cube, visiting each face exactly once. For example, ABCFED and ABCEFD are two possible orders of faces the ant visits. If the ant starts at A, how many possible orders are there? (A) 24 (B) 48 (C) 32 (D) 30 (E) 40 A D B C E F 24. The number 385 is an example of a three-digit number for which one of the digits is the sum of the other two digits. How many numbers between 100 and 999 have this property? (A) 144 (B) 126 (C) 108 (D) 234 (E) 64 25. Student A, Student B, and Student C have been hired to help scientists develop a new avour of juice. There are 4200 samples to test. Each sample either contains blueberry or does not. Each student is asked to taste each sample and report whether or not they think it contains blueberry. Student A reports correctly on exactly 90% of the samples containing blueberry and reports correctly on exactly 88% of the samples that do not contain blueberry. The results for all three students are shown below. Student A Student B Student C Percentage correct on samples 90% 98% (2m)% containing blueberry Percentage correct on samples 88% 86% (4m)% not containing blueberry Student B reports 315 more samples as containing blueberry than Student A. For some positive integers m, the total number of samples that the three students report as containing blueberry is equal to a multiple of 5 between 8000 and 9000. The sum of all such values of m is (A) 45 (B) 36 (C) 24 (D) 27 (E) 29