Infectious Diseases Fall 2003 - AAP.org...Page 4 Section on Endocrinology - Spring 2014 results in full reproductive potential: spermatogenesis in males and ovu - latory menstrual

The Executive Committee hassolicited the opinions of theSection membership with thegoal of creating a Strategic Plan toguide our efforts. Survey questionswere sent and 55 responses werereceived which represented 27% ofour members. The ExecutiveCommittee is now proceeding toimplement these actions, but it isimportant that we continue to haveinput from the membership of theSection.

The AAP has powerful advocacyavenues. The Department of FederalAffairs employs lobbyists and ana-lysts to represent the needs of chil-dren to our legislative bodies. Some

of our membersrequested thatattention be paidto the problem of unavailability ofsome of the medications we use dueto pharmaceutical company supplyissues. Many of us are concernedabout adequate compensation toour programs for the multidiscipli-nary staff our patients require. Thefuture of our workforce and incen-tives for pediatricians to enter ourfield was also mentioned.

Solutions to these issues do notcome quickly. However, the AAPDepartment of Federal Affairs is fullyaware of the subspecialty issuesregarding payment and training offuture pediatric endocrinologists.

The Academy successfully advo-cated for increased Medicaid pay-ment for pediatricians in theAffordable Care Act, includingensuring that the payment increaseapplies to pediatric subspecialists.Additionally, the Academy stronglyadvocates for funding programs toimprove the subspecialty workforceincluding the Children’s HospitalGraduate Medical EducationProgram (CHGME) and the PediatricSubspecialty Loan RepaymentProgram. The AAP also continues towork with the administration andthe states to advocate for the needsof children in the implementation ofthe Affordable Care Act (ACA) andprovide resources to pediatriciansand parents regarding the ACA.Drug shortages are another area thataffect many pediatric subspecialistsand the Academy continues to workon the implementation of threepediatric drug and device laws andend shortages of important drugs forchildren. Lastly, the AAP is an advo-cate for basic and translational pedi-atric research funding as well as theimportance of including children inclinical research. The AAP closelytracks the National Children’s Studyand translational research activitiesat the National Institutes of Health.For more information about activi-ties going on in the AAP Departmentof Federal Affairs, we encourage section members to read theFebruary 2014 Washington Reporton Academic and SubspecialtyAdvocacy. The report will be sentalong with this newsletter, but is also

Volume 23 • Spring 2014

The Section on

ENDOCRINOLOGYNewsletter

Section on Endocrinology Newsletter Copyright © 2014 American Academy of Pediatrics

Continued on Page 2

IN THIS ISSUEChairperson’s Column ..................................................................................... 1-22014 AAP Council & Section Elections are Underway! ....................................... 2Gonadotropins, sex steroids and gonadotropin-releasing analogs: A practical approach to the assessment of a child with early onset of secondary sex characteristics ...................................................................... 3-9Editor’s Comments: ............................................................................................ 9Not a Member? Joining is Easy! .......................................................................... 9“Pediatric fellowship information for dummies”! ....................................... 10-11New Members................................................................................................... 11Book Review: Auxology Studying Human Growth and Development ............... 12TODAY Study Publications Summarized from June 2013 Diabetes Care Journal Feature .................................................................... 13-14Federal Legislative Update ................................................................................ 14EQIPP: Growth Surveillance .............................................................................. 15Executive Committee ....................................................................................... 16Endocrinology Meeting Schedule ...................................................................... 16

Chairperson’s ColumnWhere Are We Heading?

Irene N. Sills, FAAP

available to members in electronic form atwww.aap.org/subspecialty.

The Section Executive Committee is also taking a role inadvocating for issues of importance to pediatric endocri-nologists. Dr. Jane Lynch has written a resolution to beconsidered at the Annual Leadership Forum (ALF) thatstates that the AAP supports policies that ensure thatinsurance plans cover adequate numbers of glucosestrips for children with diabetes. The resolution was dis-cussed and voted on during the ALF March 13 – 16, 2014.If there are other issues that you feel should be consid-ered and addressed by the Section Executive Committee,please let us know.

The survey included questions about which PediatricEndocrinology topics should receive attention for educa-tion to the primary care pediatrician. The diagnosis andearly management of precocious puberty was onefavored, therefore, Drs. Paul Kaplowitz and Clifford Blochhave begun work on such a Clinical Report for the AAPmembership. Growth and short stature was also a favoredtopic and we need a volunteer to investigate the existingstatements and ascertain if a need exists for a new reportor an update of an earlier report. There were many others mentioned and the Committee would welcomeothers of you who agree to be involved.

AAP has become a leader in providing resources for Maintenance of Certification (MOC). PREPENDOCRINOLOGY Self-Assessment has become a suc-cessful way to obtain MOC part 2 credit. The Educationin Quality Improvement for Pediatric Practice (EQIPP)courses allow physicians to collect and analyze practicedata over time to document improved quality of care andmeets MOC part 4 requirements. STEP Up Diabetes Care– Screening, Testing, Education and Prevention is cur-rently available and a course on Growth Surveillance andGrowth Failure will be available in the near future. Visithttp://eqipp.aap.org/ for information on availablecourses and to receive notification when upcomingcourses will be available. One suggestion from the surveywas to develop an EQIPP module on congenital hypothy-roidism.

Lastly, the Executive Committee feels and the survey sup-ports that it is time to improve our Section website.Wonderful suggestions include a comprehensive list ofPediatric Endocrinology meetings, links to relevant AAPclinical statements and reports, information about mem-bers and memberships, FDA updates, links to otherendocrinology/diabetes organizations, and updates onMOC certification. However, the Executive Committee issearching for a group of interested individuals and this

may be a valuable way for you to contribute to our organ-ization.

As the Section Chairperson, I am always interested toknow what you think. Please e-mail me [email protected] with any comments, critiques,requests, or news.

Page 2 Section on Endocrinology - Spring 2014

Chairperson’s Column Continued from Page 1

2014 AAP Council

& Section Elections are Underway!

WHAT:Elect the future leaders of your AAP Councils & Sections and vote on any applicable bylaw referendums

WHY:To exercise your right to vote as a member and toinfluence the direction of the Council or Section inthe future

WHEN:March 1 -31, 2014. The elected Council leaderswill take office on July 1, 2014. The elected Sectionleaders will take office on November 1, 2014.

WHERE:http://www2.aap.org/elections to view the

on-line ballot and biographical information onthe candidates (if available). Use your AAP ID and password to log in. If you’ve signed up forhealthychildren.org you will need to use youremail address.

Note:If you are a member of more than one Council orSection, you will see ballots only for the council(s)and section(s) conducting elections this year.

Any questions about this service may be directedto Yolanda Mackey Amjad, Manager, Council andSection Programs, Department of SubspecialtyPediatrics, 847/434-4079 or [email protected].

Thank you in advance for your participation!

Section on Endocrinology - Spring 2014 Page 3

Glossary of Terms

Sexual precocity: early onset of sec-ondary sexual characteristics of anytype without reference to an estab-lished cause.

Central precocious puberty (CPP):early onset of secondary sexual characteristics derived from GnRHand gonadotropin dependentgonadal activity. Central precocious puberty may also be referred to asgonadotropin dependent preco-cious puberty.

Physiology of Sexual Maturation

Puberty is a developmental phase inthe continuum of the maturation ofthe reproductive axis across the lifes-pan. The hypothalamic-pituitary-gonadal axis (HPGA), which is drivenby hypothalamic gonadotropin-releasing hormone (GnRH), is activein utero and early infancy. In the firstfew months after birth, the activity ofthe GnRH pulse generator decreasesuntil it enters a relative quiescentstate by 4 months of age, oftenreferred to as the inhibitory phase.This juvenile pause lasts throughoutchildhood until 8 to 9 years of age. It has been postulated that the rela-tively quiescent state of the repro-ductive system during theprepubertal years is the result of acombination of two mechanisms:first and most importantly, an intrin-sic central nervous system (CNS)inhibition responsible for maintain-ing GnRH and gonadotropin secre-tion at low levels and minimalpulsatility; second and to a lesserdegree, an increased sensitivity ofthe HPGA to sex steroid negativefeedback1,2.

The underlying mechanism that dic-tates when the inhibitory phase, alsodescribed as a “neurobiologicalbrake”, ends is unknown3. The linkbetween a critical amount of somaticgrowth and the central initiation ofpuberty has been in the literature fordecades and is thought to dependon a hypothalamic somatometer,analogous to a clock34. In the eyes ofthe clinician, this link is best illus-trated when the level of physicalmaturation is aligned with indices ofphysical progression such as skeletalbone age, nutritional state andgrowth velocity. For example, a boneage of 13 years in a 10 year old malewould make one anticipate midpu-bertal characteristics that may notnecessarily reflect the chronologicalage of the patient. Another exampleis the overweight girl with tallerstature who is more likely to reachand progress through pubertal mat-uration at a faster pace than her nor-mal-weight counterparts.

At the onset of the pubertal phase,the reactivation of the reproductiveaxis is believed to result from thegradual decrease of the CNSinhibitory tone and decreased sensi-tivity to sex steroid feedback. As aresult, there is increased pulsatilesecretion of GnRH, heightened pitu-itary responsiveness to GnRH, risingsecretion of gonadotropins predom-inantly at night5, especially luteiniz-ing hormone (LH), and enhancedgonadal production of sex steroidsmainly represented by circulatingestradiol and testosterone concen-trations. These gonadal hormoneswill induce the morphologicalchanges of puberty.

Gonadarche and Adrenarche

When pubertal maturation isassessed, there is an overlap of twodistinct maturation processes. Onerelates to adrenarche reflected by thedevelopment of body odor, pubicand axillary hair. The other relates togonadarche with breast develop-ment in girls and testicular enlarge-ment in boys, the initial clinical signsof true puberty.

Adrenarche is expected to occur after8 years in both boys and girls but theonset is subject to wide individualvariations. Progressive increase inthe secretion of weak androgens bythe adrenal glands, in particulardehydroepiandrosterone (DHEA)and its sulfate (DHEAS), occurs untiladult values are reached at about 15years of age or in the mid- to latepubertal years 6. Precociousadrenarche will occur before the ageof 8 years, usually between 5 and 7years and is a common reason forreferral to a pediatric endocrinologyclinic6. It is thought to be a normalvariant of development as long asthe growth velocity is in the prepu-bertal range, the bone age is at mostonly mildly advanced (

Section on Endocrinology - Spring 2014

results in full reproductive potential:spermatogenesis in males and ovu-latory menstrual cycle in female.

From a clinical standpoint, it isimportant to assess the develop-mental stages of adrenarche andgonadarche separately and as accu-rately as possible. This strategyassists in distinguishing various clin-ical entities including the focus ofthis article, central precociouspuberty.

Timing of sexual maturation

Based on the Third National Healthand Nutrition Examination Survey(NHANES III), in boys, the medianage for the onset of genital develop-ment was approximately 9.2 yearsfor non-Hispanic black boys,approximately 10.0 years for non-Hispanic white boys, and 10.3 yearsfor Mexican American boys. Thethreshold for pubertal developmentin boys is 9 years10 and the first stageof puberty in boys is characterizedby testicular enlargement or Tannerstage 2 genitalia, assessed as testic-ular volume > 3 ml in volume or 2.5cm in length [Marshall WA, TannerJM. Variations in the pattern ofpubertal changes in boys. Arch DisChild 1970; 45: 13-23. Prader, A.Testicular size: Assessment and clin-ical importance. Triangle 1966;7:240-243.]

In girls, the threshold for breastdevelopment is 8 years regardless ofethnicity12,13. It has been found thatthe median age for the onset ofbreast development was approxi-mately 9.5 years for non-Hispanicblack girls, approximately 9.8 yearsfor Mexican American girls, andapproximately 10.4 years for non-Hispanic white girls. As studied byTanner et al.11,14 the onset of pubertyin girls is typically characterized bythe development of thelarche orTanner stage 2, which is best evalu-ated by both inspection and palpa-tion.

For all practical purposes, sexualmaturation, distinct from simpleadrenarche, should be consideredprecocious if secondary sex charac-teristics appear before 8 years of agein girls and before 9 years of age inboys. One has to bear in mind how-ever that early puberty can be elusiveif there are competing physical char-acteristics such as obesity.

In boys, the accumulation of supra-pubic fat can obscure the examina-tion of the genitalia and makepuberty staging difficult.Furthermore, extreme obesity in themale can paradoxically be associ-ated with delayed onset of puberty,which will not be discussed here.

One of the major challenges in ascer-taining pubertal maturation in girlsis recognizing that adipose tissuecan masquerade as early breastdevelopment, particularly in thecontext of rising rates of childhoodobesity15. In contrast, menarche, areadily identifiable event, is a robustindicator of pubertal progressionthat is not as dependent on clinicalskills. Thus, despite considerablemedia coverage suggesting earlieronset of puberty in girls mostlybased on clinical assessment thatdid not adjust for adiposity, statisti-cal data points to remarkable stabil-ity of the average age of menarche inaffluent nations where previous sec-ular trends have plateaued 16.

Based on NHANES III, the averageage at menarche in the US is 12.54years; this data represents a decreaseof �~2½ months over the previous 25years17. During the same timeperiod, the percentage of 10 to 15-year-old girls in the United Stateswho were above the 85th percentilefor BMI increased from 16% to27%17, thereby increasing the likeli-hood of obese preadolescent girlswith central adiposity to be misla-beled as early pubertal. Most recentresults from NHANES indicate that

the prevalence of childhood obesityin the United States remainsunchanged although increases inobesity prevalence may be occurringamong males 18.

Higher relative weight has beenstrongly associated with earlierachievement of menarche after con-trolling for age and race. This findingsupports the long-understood asso-ciation between sexual maturationand adiposity and the role of rela-tive weight as a possible explanatoryfactor for the secular trend towardearlier onset of puberty, which hassince stabilized in the US popula-tion.

Precocious puberty: Why evaluate?

When a patient presents with a ques-tion of early pubertal maturation therole of the clinician is to establishwhether this sexual precocity isgonadotropin dependent or inde-pendent, bearing in mind that a sig-nificant proportion of patients willpresent with adrenarche which canbe established after careful clinicalexamination. One example is the 7year old girl brought in by hermother because she is “developingtoo fast”. If the physical examinationreveals only pubic hair and axillaryhair without breast development,the sexual precocity is likely relatedto adrenarche rather than earlypuberty.

Central precocious puberty is a clas-sification that can be used whenthere is a clear link between second-ary sexual characteristics and GnRHactivated gonadotropins19. Centralprecocious puberty is much morecommon in girls than in boys. In girlsthe most common final diagnosis isCPP that is idiopathic or without arecognizable cause. This centrallymediated precocious puberty usu-ally follows a sequentially normal,although accelerated pattern of mat-

Gonadotropins, sex steroids and gonadotropin-releasing . . . Continued from Page 3

Continued on Page 5


uration. Approximately 85 % of casesof precocious puberty in girls and 35% in boys can be attributed to idio-pathic, premature maturation of theHPGA.20 Despite the high incidenceof centrally mediated, “idiopathic”precocious puberty, the clinicianmust diligently search for pathologiccauses, especially in boys. The ini-tial motivation for the evaluationrests on the possibility that an iden-tifiable cause for CPP could be treat-able with the potential of reversal ofsymptoms. Aside from the primaryconcern of a treatable cause, sec-ondary outcomes considered relateto potential compromise of finaladult height.

Causes of precocious puberty

GnRH-dependent puberty

Central precocious puberty is con-sidered to be organic when it is asso-ciated with a lesion of the CNS andas idiopathic when the magnetic res-onance imaging (MRI) shows noidentifiable lesion of the centralnervous system. The incidence ofidiopathic forms and the pattern ofdevelopment of CPP vary accordingto gender. All boys with CPP and girlswith organic CPP have rapidly pro-gressive forms, while girls with idio-pathic CPP may have a slowlyprogressive variant in which pre-dicted height is not altered even after2 years of spontaneous evolution21.

Any type of intracranial disturbancecan cause organic precociouspuberty including hamartomas,CNS tumors such as astrocytoma,ependymoma, pinealomas, andoptic and hypothalamic gliomas.CNS irradiation may also cause pre-cocious puberty and is commonlyassociated with growth hormone(GH) deficiency. Other CNS lesionsinclude hydrocephalus, cysts,trauma, CNS inflammatory disease,and congenital mid-line defects,such as optic nerve hypoplasia.

GnRH-independent puberty

The causes of GnRH-independentpuberty include gonadal, adrenal orectopic sources of hormone produc-tion or may result from exposure toan exogenous source of sex steroid.Gonadal causes include McCune-Albright syndrome, familial maleprecocious puberty, and ovarian ortesticular neoplasms. Adrenal causesinclude congenital adrenal hyper-plasia (CAH) and tumors. Ectopiccauses include human-chorionic-gonadotropin secreting tumors. Arelatively new source of exogenoussteroids in children results fromcross-contamination from adultsusing testosterone gels or creams.

Diagnosis

The challenge of diagnosing centralprecocious puberty with a single LHmeasurementGonadotropins are mostly secretedat night, therefore a random daytimesample has a limited use althoughseveral studies have attempted tosupport its utility as an initial labora-tory screening test for precociouspuberty.23 24

Multiple generations of gona -dotropin assays have improved sen-sitivity at the lower limits ofdetection. However, in girls there issignificant overlap between prepu-bertal controls and early pubertalpatients which further limits the use-fulness of random gonadotropinscreening. In boys, a cut-off value of0.1 UI/L has been suggested butthere are limited studies that clearlysupport this threshold value. 25,26 2623

GnRH stimulation test: A historicalgold standardGnRH is a decapeptide with a veryshort half-life which has not beensuccessfully sampled from theperipheral circulation. As a result,pediatric endocrinologists haverelied for years on the use of GnRH

for the assessment of gonadotrophs’response by comparing the 1 hour-post-challenge LH and FSH levels tobaseline27. Pituitary responsivenessin prepubertal children is character-ized by a preferential release of FSHin response of GnRH. Girls havemore pronounced FSH release thantheir male counterparts at all stagesof puberty26. The interpretation ofpubertal status relies on a semi-quantitative assessment of “prefer-ential LH release” or an LH to FSHratio greater than 115. The validationof absolute cut-off values inresponse to stimulation have beenhampered by the rapid developmentof new assays with greater sensitivity,thereby generating a moving targetfor normative data15.

GnRH testing refers to stimulatedgonadotropin values at 20-40 min-utes. Long-acting gonadotropinreleasing hormone analogs havebeen used as a substitute for GnRHbecause of reduced manufacturingof the synthetic hormone replicat-ing the original physiologicdecapeptide. GnRH analog stimu-lated values are collected at 60 min-utes post-injection. Although therehas been no systematic validation ofthe interchangeability of the testsrecent summary reports haveincluded data from both methods ofassessment of the HPGA.

There is no consensus on a hor-monal threshold that defines earlyCPP as a distinct group from prepu-bertal children. The development ofnew assays have allowed GnRH ana-log-stimulated LH concentrationcut-off to drop from >10 to 6 to morerecently 3.3 to 5 mIU/mL28. Thegreatest challenge however residesin the great variability in assays usedfrom institution to institution,thereby severely limiting the appli-cability of these cut-off values for theaverage clinician. What hasremained consistent however, from


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both research and clinical data isthat centrally-mediated puberty ischaracterized by a predominant LHrelease in response to GnRH stimu-lation. It is our opinion that stimula-tion tests should combine theabsolute values of both LH and FSHand that LH/FSH ratio of 1 or greateris consistent with CPP.

Sex steroids and Precocious puberty

In tandem mass spectrometry assayscommercially available, measurableestradiol >15 pg/mL relatively con-firms advanced puberty30. Similarly,testosterone assays with detectionlimits of >10 ng/dL may discriminateprepubertal from early pubertal lev-els3130. Random estradiol levels mayor may not be measurable at thepresentation of CPP for several rea-sons. Most commercial laboratoriesprocess large volumes of adult sam-ples and are calibrated for higherconcentrations of estradiol. Hencemany routine assays are not sensi-tive enough to capture low concen-trations of circulating estradiol asseen in early puberty. In addition tothe limitation associated with lowhormonal levels, circulating estra-diol also fluctuates through the daywith higher concentrations detectedin the morning for early pubertalgirls29. Bearing in mind the limita-tions associated with these methods,we recommend using laboratoriesthat provide normal ranges for bothsex steroids classified by Tannerstage. We also recommend deliber-ate timing of the sample in earlymorning to provide a better yield, asit is more likely to reflect overnightgonadotropin activity.

Establishing the diagnosis of cen-tral precocious puberty

The clinician should evaluate forpotential triggering circumstancesand identify treatable causes. In thisprocess an MRI of the brain with aspecial focus of the hypothalamicpituitary is recommended although

the universal application of thisstrategy has been challenged in thepast 32-34. The discussion with thefamily should emphasize that thepubertal process is not a disease;rather the early timing may haverepercussions on overall health,especially if there is a CNS pathologyat the outset. Once immediatethreats to wellbeing have been setaside, a discussion about the impactof CPP on final height can take place,taking into account family historyand with the support of a bone ageand calculated predicted heightfrom standardized tables35.

Cases in which the height predictionis consistent with the genetic back-ground of the child and/or fall withinnormal range, do not necessarilyrequire treatment on the basis ofheight alone. Girls with CPP betweenthe ages of 7 to 8 have not beenshown to benefit from suppressivetherapy with improved height pre-dictions 36,37. [This statement is con-troversial, based upon the editor’sexperience.] Further considerationscan be given to the psychosocialimpact of precocious puberty par-ticularly in girls but the outcomesappear to be linked to cognitive abil-ities, cultural norms and familialattitude towards sexual develop-ment16.

There is mounting evidence thatsubclinical estradiol concentrationsin prepubertal girls have a beneficialeffect on long-term bone density.This observation may have rele-vance to the discussion related to theduration of GnRH analog suppres-sive therapy38. A comprehensive dis-cussion weighing all of theseparameters can assist the family inmaking an informed decision forthose cases in which treatment maynot necessarily improve their heightprediction.

It is now suggested that daytimespontaneous LH concentrations

may provide a useful laboratoryscreening test in patients that arebeing evaluated for CPP. Elevatedbasal values may be considered forfurther evaluation by the gold stan-dard GnRH stimulation test. Thereis no single level of LH, FSH, or estra-diol with 100% sensitivity and speci-ficity for CPP. As with all clinical tests,both clinical presentation and labo-ratory findings should be taken intoconsideration for the accurate diag-nosis of CPP.

Treatment considerations

Once CPP has been conclusivelyestablished, long-acting GnRHanalogs provide the most efficacioussuppressive therapy. The goals ofcurrent therapy with these GnRHanalogs include suppression ofpubertal progression, delay of onsetof menses and improved final heightpotential. A discussion about thebone age and the percentage of adultcompleted height associated withthat bone age can assist the clinicianand the patient’s family in articulat-ing goals for treatment. One has tobear in mind that more advancedbone age is less likely to benefit withimproved final height outcome.

Treatment with long-acting GnRHanalogs implies an initial gona -dotropin stimulation phase; there-fore an advancement of the bone ageat the beginning of therapy is antic-ipated in most cases. Great careshould be undertaken to avoidrepeating this initial stimulationphase and the risk of impairingheight outcomes. Thus strict adher-ence to the prescribed schedule ofsuppressive therapy and commit-ment from the family are requisitesfor a successful outcome. GnRHanalog treatment in patients with abone age reflecting more than 95%final height, might further acceleratethe skeletal maturation with mini-mal hopes of capitalizing on the few



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References

1) Kulin HE, Grumbach MM, Kaplan SL. Changing sensitivity of the pubertal gonadal hypothalamic feedback mechanism in man.Science. 1969;166(3908):1012-1013.

2) Kelch RP, Kaplan SL, Ghumbach MM. Suppression of urinary and plasma follicle-stimulating hormone by exogenous estro-gens in prepubertal and pubertal children. J Clin Invest. 1973;52(5):1122-1128.

3) Plant TM. Hypothalamic control of the pituitary-gonadal axis in higher primates: Key advances over the last two decades. JNeuroendocrinol. 2008;20(6):719-726.

4) Rosen DS, Kletter GB, Kelch RP. Puberty what to do when the clock doesn’t ring. Journal of Pediatric Endocrinology andMetabolism. 1998;5 (3) de Gruyter(Jul 1,):29-41.

5) Cemeroglu AP, Foster CM, Warner R, Kletter GB, Marshall JC, Kelch RP. Comparison of the neuroendocrine control of puber-tal maturation in girls and boys with spontaneous puberty and in hypogonadal girls. J Clin Endocrinol Metab. 1996;81(12):4352-4357.

6) Sizonenko PC, Paunier L. Hormonal changes in puberty III: Correlation of plasma dehydroepiandrosterone, testosterone, FSH,and LH with stages of puberty and bone age in normal boys and girls and in patients with addison’s disease or hypogonadismor with premature or late adrenarche. J Clin Endocrinol Metab. 1975;41(5):894-904.

7) von Oettingen J, Sola Pou J, Levitsky LL, Misra M. Clinical presentation of children with premature adrenarche. Clin Pediatr(Phila). 2012;51(12):1140-1149.

8) Miller WL. The molecular basis of premature adrenarche: An hypothesis. Acta Paediatr Suppl. 1999;88(433):60-66.

9) Rege J, Rainey WE. The steroid metabolome of adrenarche. J Endocrinol. 2012;214(2):133-143.

10) Sun SS, Schubert CM, Chumlea WC, et al. National estimates of the timing of sexual maturation and racial differences amongUS children. Pediatrics. 2002;110(5):911-919.

11) Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969;44(235):291-303.

12) Rosenfield RL, Lipton RB, Drum ML. Thelarche, pubarche, and menarche attainment in children with normal and elevatedbody mass index. Pediatrics. 2009;123(1):84-88.

13) Rosenfield RL, Bachrach LK, Chernausek SD, et al. Current age of onset of puberty. Pediatrics. 2000;106(3):622-623.

14) Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child. 1970;45(239):13-23.

15) Kasa-Vubu J. Obesity and puberty: The impact of childhood obesity on central precocious puberty. Pediatric Endocrinology

centimeters of somatic growth left.In that case, if improved final heightis the principal motivation for thefamily to seek treatment, proceed-ing with GnRH analog suppressivetherapy is debatable.

The duration of treatment should bediscussed with patients and theirfamilies with the understanding thatpuberty may not resume for severalmonths after discontinuation ofsuppressive therapy and a longerduration may achieve better finalheight outcomes. In general, discon-tinuing treatment at the time whenage-matched peers are initiatingspontaneous puberty is appropriate.Despite the theoretical risk, there isno evidence thus far that pubertysuppressive therapy is associatedwith decreased bone density but

conclusive long-term data is lackinggiven the lifespan implicationsrelated to bone health.

Biochemical suppression is ade-quate when LH levels are suppressedbut variability between assaysshould be interpreted with cau-tion39,40. If testosterone and estra-diol are measured, levels should bein a prepubertal range for the assayused.41

Clinicians need to be aware that anoptimal index for LH suppression(random or stimulated) has not yetbeen defined. If the clinical evalua-tion reveals progression of breast ortesticular development, increasedgrowth velocity or rapid bone ageadvancement, these clinical signsare suggestive of insufficient dosing,

lack of compliance with the fre-quency of dosing or treatment fail-ure. Anyone of these possibilitiesimplies the need for further assess-ment41, including discontinuationof therapy.

Conclusion

Central precocious puberty resultsfrom the activation of the HPGAbefore age thresholds that are thesame across major ethnic groups42,43. The evaluation should focus ondefining the source of sex steroidsand, if indicated, assessing whetherthe maturation is centrally-medi-ated. Aside from the possibility ofCNS pathology, secondary concernsrelate to the potential compromiseof final adult height and in somecases, the potential of a negative psy-chosocial impact.



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Reviews. 2007;4(SUPPL. 3):291-299.

16) Parent AS, Teilmann G, Juul A, Skakkebaek NE, Toppari J, Bourguignon JP. The timing of normal puberty and the age limits ofsexual precocity: Variations around the world, secular trends, and changes after migration. Endocr Rev. 2003;24(5):668-693.

17) Anderson SE, Dallal GE, Must A. Relative weight and race influence average age at menarche: Results from two nationally rep-resentative surveys of US girls studied 25 years apart. Pediatrics. 2003;111(4 Pt 1):844-850.

18) Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity and trends in body mass index among US children and ado-lescents, 1999-2010. JAMA. 2012;307(5):483-490.

19) Klein KO. Precocious puberty: Who has it? who should be treated? J Clin Endocrinol Metab. 1999;84(2):411-414.

20) Kelch RP. Management of precocious puberty. N Engl J Med. 1985;312(16):1057-1058.

21) Trivin C, Couto-Silva AC, Sainte-Rose C, et al. Presentation and evolution of organic central precocious puberty according tothe type of CNS lesion. Clin Endocrinol (Oxf). 2006;65(2):239-245.

22) Listernick R, Charrow J, Gutmann DH. Intracranial gliomas in neurofibromatosis type 1. Am J Med Genet. 1999;89(1):38-44.

23) Houk CP, Kunselman AR, Lee PA. Adequacy of a single unstimulated luteinizing hormone level to diagnose central precociouspuberty in girls. Pediatrics. 2009;123(6):e1059-63.

24) Neely EK, Wilson DM, Lee PA, Stene M, Hintz RL. Spontaneous serum gonadotropin concentrations in the evaluation of pre-cocious puberty. J Pediatr. 1995;127(1):47-52.

25) Neely EK, Hintz RL, Wilson DM, et al. Normal ranges for immunochemiluminometric gonadotropin assays. J Pediatr.1995;127(1):40-46.

26) Resende EA, Lara BH, Reis JD, Ferreira BP, Pereira GA, Borges MF. Assessment of basal and gonadotropin-releasing hormone-stimulated gonadotropins by immunochemiluminometric and immunofluorometric assays in normal children. J ClinEndocrinol Metab. 2007;92(4):1424-1429.

27) Eckert KL, Wilson DM, Bachrach LK, et al. A single-sample, subcutaneous gonadotropin-releasing hormone test for centralprecocious puberty. Pediatrics. 1996;97(4):517-519.

28) Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children.Pediatrics. 2009;123(4):e752-62.

29) Boyar R, Finkelstein J, Roffwarg H, Kapen S, Weitzman E, Hellman L. Synchronization of augmented luteinizing hormone secre-tion with sleep during puberty. N Engl J Med. 1972;287(12):582-586.

30) Endocrine Sciences Reference Laboratory. Endocrinology syllabus. http://www.esoterix.com/files/Endocrinology_Syllabus_3.22.11.pdf. Updated 2011.

31) Wang C, Catlin DH, Demers LM, Starcevic B, Swerdloff RS. Measurement of total serum testosterone in adult men: Comparisonof current laboratory methods versus liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab.2004;89(2):534-543.

32) Bridges NA, Christopher JA, Hindmarsh PC, Brook CG. Sexual precocity: Sex incidence and aetiology. Arch Dis Child.1994;70(2):116-118.

33) Chemaitilly W, Trivin C, Adan L, Gall V, Sainte-Rose C, Brauner R. Central precocious puberty: Clinical and laboratory features.Clin Endocrinol (Oxf). 2001;54(3):289-294.

34) Grunt JA, Midyett LK, Simon SD, Lowe L. When should cranial magnetic resonance imaging be used in girls with early sexualdevelopment? J Pediatr Endocrinol Metab. 2004;17(5):775-780.

35) Greulich W PI. Radiographic atlas of skeletal development of the hand and wrist. Second ed. Standford: Stanford University Press;1959.

36) Cassio A, Cacciari E, Balsamo A, Bal M, Tassinari D. Randomised trial of LHRH analogue treatment on final height in girls withonset of puberty aged 7.5-8.5 years. Arch Dis Child. 1999;81(4):329-332.

37) Mul D, Oostdijk W, Otten BJ, et al. Final height after gonadotrophin releasing hormone agonist treatment for central preco-cious puberty: The dutch experience. J Pediatr Endocrinol Metab. 2000;13 Suppl 1:765-772.

38) Neely EK, Bachrach LK, Hintz RL, et al. Bone mineral density during treatment of central precocious puberty. J Pediatr.1995;127(5):819-822.

39) Cohen D, Janfaza M, Klein KO. Importance of leuprolide acetate variable dosing for precocious puberty: A range of accept-able suppression. J Pediatr Endocrinol Metab. 2009;22(7):629-634.

40) Kunz GJ, Sherman TI, Klein KO. Luteinizing hormone (LH) and estradiol suppression and growth in girls with central preco-cious puberty: Is more suppression better? are pre-injection LH levels useful in monitoring treatment? J Pediatr EndocrinolMetab. 2007;20(11):1189-1198.


Continued on Page 9

41) Eugster EA, Clarke W, Kletter GB, et al. Efficacy and safety of histrelin subdermal implant in children with central precociouspuberty: A multicenter trial. J Clin Endocrinol Metab. 2007;92(5):1697-1704.

42) Chumlea WC, Schubert CM, Roche AF, et al. Age at menarche and racial comparisons in US girls. Pediatrics. 2003;111(1):110-113.

43) Rosenfield RL, Bachrach LK, Chernausek SD, et al. Current age of onset of puberty. Pediatrics. 2000;106(3):622-623.



Editor’s Comments:Clifford A. Bloch, MD, FAAP

With the expectation that we as clinicians ought to strive to practice evidence-based medicine, it is vital thatwe understand normal, human physiology. Once we fully understand this, we might appreciate the varia-tions of normal, and finally draw the margins that define a disease state. When we arrive at that point, wetypically design studies to determine the consequences of the untreated disease state v outcomes of intervention thatalters the course of the disease state.

In this article, Drs Granados and Kasa-Vubu have presented a brief, clinical overview of the physiology of puberty andits variants. It highlights some of the gaps in our knowledge in understanding the physiology of normal puberty andits variants, thereby blurring the margins between when we ought to consider puberty to be pathologically early v withinthe physiologic range of normal. It touches on some of the caveats involved in choosing and interpreting the hormonaltests that we use to assess puberty, including use of newer and more sensitive assays. Given the many variables andpaucity of normative hormone data, it is no wonder that we lack consensus on the diagnosis of central precociouspuberty, resulting in a dilemma of whom to treat and whom not to treat. If we lack consensus, can we ever really prac-tice evidence-based medicine, or do we still place some stock on the fabled “art of medicine?” The authors suggestthat we discuss the diagnosis and goals of intervention with the family, listening to their perceptions and needs beforemaking any treatment decisions. This amounts to complete transparency in discussing what we know, admitting to the uncertainties in what we don’t know, and allowing the patient and family to participate in any intervention strategy.

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For those of you who wonder ifYou need to draft another PIF

It’s not “CLER” that “NAS” will spiff“EPA” assessments in a jiff

As “milestones” now take the stageThe “CCC” is all the rage

If you understand this pageYou’ve done well and been engaged

The new vocab is quite confusingAs are rules that we are using

Few find the changes to be amusingAnd competencies now are fusing

New fellows in ERAS successfully matchedWith PhDs and med/peds also snatchedMatch day snafus were luckily patched

As 2014 plans were being hatched

Leaders of Pedi Endo tossed inIdeas to be shared by Bruce Boston

Fellows from Portland, Miami & AustinWill enjoy schedules with less exhaustion

Pedi endocrinologists continue to ageYet Teen DKA will still rampage

Let’s hope the MCA improves our wageWith workforce data hard to gage

Here is a “cheat sheet” for the changes in graduate medical education (GME) that are affecting our training programs. There are lots of ideas and acronyms floating around the programs this past year and many of thenext accreditation plans will be outlined in more detail within the upcoming year.As of 2013, there were a total of 272 pediatric endocrine fellows (94 PL4/ 85 PL5/ 93 PL6) in accredited US programswith the majority of programs using ERAS applications and the NRMP match (as of spring 2012). Applicants apply inthe fall of their PL2 year with interviews beginning in December and ending in late April for an early May match day.

Once in fellowship, the fellows meet 3-4x/year to present their research to a pediatric scholarship oversight commit-tee (PSOC). New requirements for additional review by a clinical competency committee (CCC) went into place inJune 2013. “SITE” exams are given each spring. A yearly ACGME survey combined with board pass rates, scholarly activity information and other basic descriptors in the “ADS” annual program director summary are now used to monitor the fellowship quality and alert the ACGME to local issues.

Board exams are proctored at test centers every 2 years with new standardized absolute scores (1-300) and pass rateof 83% for first-time takers.


“Pediatric fellowship information for dummies!”Jane L. Lynch, MD, FAAP

Continued on Page 11

In the past, curriculum goals and objectives were integral parts of a dreaded program information form (PIF) whichwas reviewed with required details of the local fellowship program at an equally dreaded “ACGME site visit” in cyclesof 2-5 years depending on how the visit went in order to maintain accreditation. As of 2013, established pediatric fellowship programs will be evaluated instead at “CLER” visits in conjunction with their core pediatric residency program with a focus on curriculum “milestones” which are being developed to assess fellows on a set of essentialskills and knowledge based expectations. The competencies describe categories of professional aspects of trainingwhich will now be used to guide the list of specific skill sets and professional activities “entrustable professional activities” or EPA’s considered to be either common to core training or unique to subspecialty pediatric endocrinetraining. By standardizing basic expectations for programs and decreasing the burdens of documentation, it is thegoal that there will be space for some innovative teaching.


“Pediatric fellowship information for dummies!” Continued from Page 10

Sungeeta Agrawal, MD

Nidhi Bansal, MBBS, MPH, FAAP

Katie Barger, MD

Deepti Chaturvedi, MD

Abby Fleisch, MD, FAAP

Shannon French, MD, FAAP

Anthony Gannon, MD, FAAP

Kimberly Henrichs, MD

Katherine Hwu, MD, FAAP

Jake Kushner, MD, FAAP

George Jeha, MD, FAAP

Hillary Lockemer, MD, FAAP

Anamaria Manea, MD

Nivedita Patni, MD

Tracey Patel, MD, FAAP

Stacy Rustico, MD, FAAP

Rajan Senguttuvan, MD

Monica Serrano-Gonzalez, MD

Stephanie Sisley, MD, FAAP

Lydia Snyder, MD, FAAP

Rona Sonabend, MD, FAAP

Stephen Stone, MD

Sunitha Sura, MD

Shadi Tabba, MBBS, FAAP

Teresa Tseng, MD

New Memberssince July 2014

The Section on Endocrinology welcomes the following new members:

AUXOLOGYStudying human growth and developmentMichael Hermanussen (Ed.)Publisher: Schweizerbart, 2013.Hardcover, 324 pages. ISNB 978-3-510-65278-5

This book is a comprehensive reference book on the auxology of growth, edited by DrHermanussen, with an extensive list of interna-tional contributors. It contains text, figures, tables, andillustrative cartoons in color, and an extensive list of references.

The book is divided into sections and subsections, numbered as 9.1, 9.2, 9.2, etc. The first section is a briefintroduction into growth, followed by the next section,“Basics.” This section is discussion on patterns of growthand a variety of factors that may influence growth. The 3rd

section is a very brief discussion on body shape, compo-sition and proportions, followed by a lengthier sectionthat deals with the effects of genetics, gender, puberty andthe more controversial topic, “Community Effects onGrowth.” This discusses the “community effects” on thesize of Swiss conscripts, which this reviewer found con-fusing. It cites a number of observational studies, spec-ulates about socio-political environment which mayinfluence height, but provides no convincing evidence inthe form of prospective, comparative studies, to supportthe hypothesis that community affects height independ-ently of factors such as nutrition, exercise, weight, etc. Inthe subsection of puberty, the subject of “tempo” is madeunusually complicated. By my understanding, temposimply refers to the rate of change. Thus, it is fair to com-pare and contrast the timing and tempo of puberty withthe tempo of height or the tempo of height SDS, or withthe tempo of skeletal age. Insulin is discussed as a majordeterminant of intrauterine growth. However, it is not dis-cussed as a contributor to post-natal growth, via its effectson metabolism and via cross-reactivity with the IGF-1receptor. It is discussed briefly in the context of T1DM, vis a vis insulin deficiency at diagnosis and insulinreplacement, but is not discussed in hyperinsulinemicstates.

The sections that follow include an excellent discussionon height predictions, followed by a less helpful discus-sion of “Prevention and Health,” and “Auxology of thePast.” The book lives up to its title about halfway through,as the discussion turns to the actual “Auxological

Methods” and “Statistical Approaches.” These 2 sectionsare excellent, discussing the standardization of meas-urements, the inaccuracies and pitfalls in the variousmethods of measurement, bone age determination,height prediction models, growth charts, statistical meth-ods for data smoothing and harmonization of growthcurves derived from populations of different nationali-ties. There is a detailed section on knemometry, whichappears to be a particular interest of the editor, and a sec-tion that discusses the automation of bone age determi-nation and prediction of height [the BoneXpert method].The latter subject may be of interest to American readers,as the method has yet to be approved by the Food andDrug Administration. This reviewer accessed the refer-enced website for final height prediction using a formula:www.willi-will-wachsen.com, but was disappointed atits lack of functionality. At the back of the book is a seriesof reference tables of measurements, largely derived fromEuropean population data. The listing of the referencesat the back of the book is clumsy, some being out of order.Although there is a glossary of abbreviations and termi-nology at the back of the book, some of the abbreviationsare not defined in the text the first time they are used,while others are not defined or listed anywhere. Thismakes reading difficult.

I found the first half of this textbook to be a collection ofcut and paste material with a number of unsubstantiatedand sometimes perplexing statements presented in theform of text, figures and cartoons. The strength of thisbook is in the discussion of the scientific methods inmeasurements of growth, prediction of height, and inthe compilation of growth charts in a complex and chang-ing growth environment that includes puberty, the tempoof puberty and variations in the tempo of growth with ageand illness. It highlights the statistical methods andpotential flaws in interpretation of growth data againstthis background.


Book Review:Auxology Studying Human Growth and Development

Clifford A. Bloch, MD, FAAP

The TODAY Study primary outcome results were reported in a June 2012 NEJM article which found that half ofthe youth in the study were unable to maintain glycemic control when treated with metformin alone and neededto be put on insulin. The study’s initial findings also showed that treating youth with both metformin and rosigli-tazone reduced/delayed the need to transition them to insulin. Further analysis of the complications and character-istics of the patients were published in a series of articles in the June issue of Diabetes Care. The TODAY studyrecruited youth who had met ADA criteria for Type 2 Diabetes within 2 years of diagnosis and required a trial run inperiod to assess for compliance and eligibility before randomly assigning patients to one of three treatment arms:metformin alone; metformin plus rosiglitazone; and metformin plus an intensive lifestyle intervention that includeddiet, exercise and counseling on how to lose weight.

Despite optimal therapy which provided education, medications including metformin, insulin, ACE inhibitors andstatin therapy and laboratory monitoring oversight to ensure compliance with therapy, the study found that youthwith type 2 diabetes were developing early and rapidly progressing signs of heart and kidney disease, poor glycemiccontrol and diabetes-related eye disease., even in the group receiving more intensive two-drug therapy, shown in pre-viously released results to be the most effective treatment for maintenance of glycemic control.

Although rosiglitazone is not currently recommended for use as treatment in youth, the addition of rosiglitazone tometformin as a treatment not only reduced the need to transition participants to insulin therapy, it appears to havedone so because it helped to preserve beta cell function. In the first six months of treatment, those in the rosiglita-zone plus metformin arm saw a 20 percent improvement in insulin sensitivity, while the other two treatment armssaw either a deterioration (metformin alone) or no change (metformin plus lifestyle), lessening the burden on betacells to produce insulin. The rate of deterioration of beta cell function in youth was almost four times higher than hasbeen reported in adults, researchers found, noting a 20-35 percent decline in beta cell function per year on average,compared to 7-11 percent for adults (as reported in previous research). Initial preserved beta cell function and lowerHbgA1c were factors that reduced the risk of failing treatment and requiring insulin therapy during the study.

Both hypertension and kidney disease also progressed rapidly in the study participants, regardless of treatment arm.The incidence of hypertension rose from 11.6 percent of participants to 33.8 percent after 3.9 years. Males were at 81percent higher risk for developing high blood pressure than females, which is consistent with adult findings in termsof gender differences in hypertension. As boys grew older, their risk for developing hypertension increased: for everyadditional year of age at baseline, there was a 14 percent greater risk of hypertension. Weight also played a role inincreasing risk: for every one unit of increased BMI, there was a 6 percent increased risk for high blood pressure. Therewere no differences in hypertension risk based on differences in race, ethnicity or randomized treatment group.

In contrast, gender did not appear to impact the increased incidence of early kidney disease. The rates of microalbu-minuria overall rose from 6.3 percent of participants at the beginning of the study to 16.6 percent of participants. Poorglycemic control was the major factor which influenced kidney disease progression risks in participants. For every 1percent rise in A1C (e.g., from 7 percent to 8 percent), there was a 17 percent increased risk of developing microal-buminuria. 57 participants developed macroalbuminuria and one-third of those advanced to proteinuria within the3.9 average duration of study participation. Of the 205 participants who required ACE inhibitors for hypertension orkidney disease, 79 needed maximal ACE dosing and needed a second medication added during these 3.9 years of thestudy.

Regardless of which treatment arm they were in, participants also experienced a worsening of cardiovascular riskswith LDL, triglycerides and other inflammatory markers all rising during the first 12 months and then stabilizing overthe next 24 months. Overall, only 55.9 percent of participants remained at their LDL goal of less than 100 mg/dl overthe 36 months. The participants in the study arm with lifestyle interventions did no better for their LDL goals but didhave less triglyceride elevations.. Whereas LDL levels rose with increasing A1C levels regardless of treatment group,


TODAY Study Publications Summarized from June 2013Diabetes Care Journal Feature

Jane L. Lynch, MD, FAAP

Continued on Page 14


higher A1C levels were not associated with higher triglyceride levels in the lifestyle intervention group.

The group treated with metformin and rosiglitazone, conversely, experienced the largest accumulation of body fatbut maintained the best glycemic control. The improved weight loss and body compositions associated with thelifestyle arms were significant during the initial six months but these effects were disappointingly minimal by 24 monthswhen compared to metformin.

An accompanying editorial by the Diabetes Care Editor in Chief William Cefalu, MD lamented. “We are not preparedas a medical community or as a global society at this time to effectively address the growing problem of type 2 diabetes in youth.

Excerpted from the American Diabetes Association May 23, 2013 press release.

TODAY Study Publications Summarized from June 2013 . . . Continued from Page 13

Federal Legislative Update

The February 2014 Washington Report on Academic and Subspecialist Advocacy in now available! (member log-in required) www.aap.org/subspecialtyHighlights of the newsletter:

• Medicaid Payment Increase

• Academic and Subspecialty Workforce – including Pediatric Subspecialty Loan Repayment, Children’s HospitalGME Funding and Reauthorization

• Health Care Reform Implementation

• Pediatric Drugs and Devices – Drug Shortages, FDA Action on Reduce Drug Shortages, GAO Report on DrugShortages, Reporting a Drug Shortage, BPCA and PREA Implementation

• Pediatric Research

• Drug shortages

◦ June 15 – 17, 2014 Legislative Conference in Washington, DC. Visit www.aap.org/legcon for more informationabout the conference, including a brochure, scholarships, and how to register.


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Endocrinology Meeting Schedule

Pediatric Endocrine Society Annual Meetinghttp://www.pedsendo.org/May 3-6, 2014Vancouver, Canada

Pediatric Academic Societies Annual Meetinghttp://www.pas-meeting.orgMay 3-6, 2014Vancouver, Canada

American Diabetes Associationhttp://professional.diabetes.org/HomeContinuingEducationAndMeetings.aspx?hsid=574th Scientific SessionsJune 13 -17, 2014San Francisco, CA

ICE/ENDO 2014https://www.endocrine.org/endo-2014June 21-24, 2014McCormick Place WestChicago, IL

40th Anniversary Conference of the InternationalSociety of Pediatric and Adolescent Diabeteshttp://www.ispad.org/2014/homeDiversity in DiabetesSeptember 3-6, 2014Toronto, Canada

AAP National Conference and Exhibitionhttp://www.aapexperience.org/October 11-14, 2014San Diego, CA

84th Annual Meeting of the American Thyroid Associationhttp://www.thyroid.orgOctober 29-November 2, 2014Hotel Del CoronadoCoronado, CA

AAP Section

on Endocrinology

ExecutiveCommittee

2014 - 2015

ChairpersonIrene N. Sills, MD, FAAP

Executive CommitteeClifford A. Bloch, MD, FAAP

Samuel J. Casella, MD, MSc, FAAPJose L. Gonzalez, MD, JD, MSEd, FAAP

Jane L. Lynch, MD, FAAPKupper A. Wintergerst, MD, FAAP

Immediate Past ChairpersonPaul B. Kaplowitz, MD, PhD, FAAP

Newsletter EditorsClifford A. Bloch, MD, FAAP

Jane L. Lynch, MD, FAAP

StaffLaura N. Laskosz, MPH

Journal Production SpecialistMark A. Krajecki

Statements and opinions

expressed in this publica-

tion are those ofthe authors

and not necessarily those of

the American Academy of

Pediatrics or the Section on

Endocrinology.

Documents

Infectious Diseases Fall 2003 - AAP.org...Page 4 Section on Endocrinology - Spring 2014 results in full reproductive potential: spermatogenesis in males and ovu - latory menstrual