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TITLEINSTITUTIONREPORT NOPUB DATENOTE

DOCUMENT RESUME

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How Children Grow.National Institutes of Health (DREW), Bethesda, Md.nnDHEW-NIH-72-166Jun 7260p.

AVAILABLE FROM Superintendent of Documents, U.S. Government PrintingOffice, Washington, D.C. 20402 (Stock Number1740-0329, $.65)

EDRS PRICE MF-$0.65 HC-$3.29DESCRIPTORS Environmental Influences; *Exceptional Child

Education; *Genetics; *Growth Patterns; *HandicappedChildren; Nutrition; *Physical Development

ABSTRACTThe discussion of genetic and environmental factorsin the growth of children from infancy to adolescence focuses on

intrauterine life, the effects of nutrition, hormones, illness, andemotion in the childhood years, and obesity and puberty inadolescents. Described are processes, such as amniocentesis, formonitoring the physiology chemistry of the uterine environment. Theneonate suffering from intrauterine growth retardation isdistinguished from the premature infant, and risks of each arespecified. Noted are variant growth patterns in males and femalessuch as the much lower production of muscle cells in the female. Itis said that radioimmunoassay has revolutionized the chemicalanalysis of hormones such as human growth hormone, insulin, andthyrotrophin whose functions are explained. Also analyzed are theeffects on growth and development of emotional deprivation and ofillnesses such as malnutrition, sickle cell anemia, and heartdisease. Treated are the physiological processes underlying growthspurts of puberty, which are said to make puberty the most difficulttime in life to lose weight. gm

Clinical Research Atkin4ces in Human Growth and Deelopment

How Children Grow

Average Physical MeasurementsBlack lines indicate 59 percentile.

65

60

5.1

45

10

35

30

25

20

15

Boys (2 yrs or older)

tO

A HEIGHT

A WEIGHT

Girls (2 yrs. or older)1:1(1 65

1.41 60

120 55

3 - 6 7 8 9 10 11 12

AGE IN YEARS

110 50

100 45

90 0

80 35

70 30

GO 25

50 20

10 15

30 10

A HEIGHT

A WEIGHT

6 8 9 10 II 12

AGE IN EAltS

130

120

110

100

90

80

70

GO

I0

30

Clinical Research Advances in Human Growth and Development

How Children Grow

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U.S. DEPARTMENT OF HEALTH.EDUCATION S WELFAREOFFICE OF EDUCATION

THIS DOCUMENT HAS BEEN REPRO-OUCEO EXACTLY AS RECEIVED FROMTHE PERSON OR ORGANIZATION ORIG-INATING IT. POINTS OF VIEW OR OPIN-IONS STATED DO NOT NECESSARILYREPRESENT OFFICIAL OFFICE OF EDUCATION POSITION OR POLICY

DREW Publication No. (NIH) 72-166

4

Contents Introduction 8

Intrauterine Life 11

Low Birth Weight Babies 15

The Childhood Years 19

Effects of Nutrition 22

Effects of Hormones 27

Effects of Illness 34

Effects of Emotion 42

Adolescence 47

Obesity 49

Early and Late Puberty 53

General Clinical Research Centers BranchDivision of Research Resources

National Institutes of HealthBethesda, Maryland 20014

June 1972

6

Consultants

Thomas Aceto, Jr., M.D.Associate Professor of PediatricsDepartment of EndocrinologyBuffalo Children's HospitalBuffalo, New York

Gilbert P. August, M.D.Associate Endocrinologist, Children's

Hospital of the District of Columbia1Vashington, D.C.

Frederick C. Battaglia, M.D.Director, Division of Perinatal MedicineProfessor of PediatricsProfessor of Obstetrics and GynecologyUniversity of Colorado Medical CenterDenver, Colorado

Robert M. Blizzard, M.D.Professor of PediatricsDepartment of PediatricsJohns 1.Iopkins HospitalBaltimore, Maryland

George F. Cahill, Jr., M.D.Professor of MedicineHarvard Medical SchoolDirectorElliott P. Joslin Research LaboratoryBoston, Massachusetts

Alvro Camacho, M.D.Associate Professor of PediatricsCollege of MedicineUniversity of TennesseeMemphis, Tennessee

Ralph Cash, M.D.Clinical Assistant Professor of PediatricsChildren's HospitalWayne State University School of

MedicineChairman of PediatricsSinai Hospital of DetroitDetroit, Michigan

Donald B. Cheek, M.D.Professor of PediatricsChildren's Medical and Surgical CenterDepartment of PediatricsJohns Hopkins HospitalBaltimore, Maryland

John D. Crawford, M.D.Associate Professor of PediatricsHarvard Medical SchoolChief of PediatricsShriners Burn InstituteBoston, Massachusetts

John F. Crigler, M.D.Program Director, Clinical Research

CenterChief, Endocrine DivisionThe Children's Hospital Medical CenterBoston, Massachusetts

L. Allen Drash, M.D.Program DirectorClinical Study CenterAssistant Professor of PediatricsChildren's Hospital of PittsburghPittsburgh, Pennsylvania

Samuel J. Fomon, M.D.ProfessorDepartment of PediatricsUniversity HospitalsUniversity of IowaIowa City, Iowa

Arthur B. French, M.D.Program DirectorClinical Research UnitUniversity of Michigan HospitalAnn Arbor, Michigan

George G. Graham, M.D.Professor of International Health

(Human Nutrition)Associate Professor of PediatricsThe Johns Hopkins Medical InstitutionsBaltimore, Maryland

Robert B. Greenblatt, M.D.Professor and ChairmanDepartment of EndocrinologyMedical College of GeorgiaAmnia, Georgia

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il'AV 001Astioc sA.

Jerome A. Grunt, M.D., Ph.D.Attending Physician, Children's Mercy

HospitalProfessor of PediatricsSchool of MedicineUniversity of Missouri, Kansas CityKansas City, Missouri

Harold E. Harrison, M.D.Professor of PediatricsJohns Hopkins University School of

MedicinePediatrician-in-ChiefBaltimore City HospitalsBaltimore, Maryland

Felix 1'. Heald, M.D.Professor of PediatricsHead, Division of Adolescent Medicine of

the Department of PediatricsUniversity of Maryland HospitalBaltimore, Maryland

Andre K Hellegers, M.D.Professor of GynecologyProfessor of BiophysicsGeorgetown University Medical CenterWashington, D.C.

Jules Hirsch, M.D.Professor, Department of Human

Belavtor and MetabolismSenior Physician to the Rockefeller

University HospitalNew York, New York

David M. Kipnis, M.D.Program Director, Clinical Research

CenterProfessor of MedicineDepartm:,t. r.f MedicineWash;.:. iotversty School of

Saint Louis, Missouri

Nansen Liu, M.D.Assistant Professor of PediatricsDirector, Endocrine DepartmentWayne State University School of

MedicineChildren's Hospital of MichiganDetroit, Michigan

6

Victor A. McKusick, M.D.Professor of MedicineThe Johns Hopkins University School of

MedicineBaltimore, Maryland

Claude J. Migeon, M.D.Professor of PediatricsDepartment of PediatricsThe Johns Hopkins School of Medicine

and the Harriet Lane Service ofthe Children's Medical and SurgicalCenter

The Johns Hopkins Hospital andUniversity

Baltimore, Maryland

William 1). Odell, M.D., Ph.D.Chief, Department of EndocrinologyHarbor General HospitalProfessor of Medicine and PhysiologyUniversity of California, Los Angeles

School of MedicineTorrance, California

David L. Rintoin, M.D., Ph.D.Associate Professor of Pediatrics and

MedicineUniversity of California, Los AngelesChief, Division of Medical GeneticsAssociate Director of Clinical Study

CenterHarbor General HospitalTorrance, California

Robert Schwartz, M.D.Professor of PediatricsCase Western Reserve University School

of MedicineDirector, Department of PediatricsCleveland Metropolitan General HospitalCleveland, Ohio

Nevin S. Scrimshaw, Ph.D., M.D.Professor of Hinan Nutrition and Head,

Department of Nutrition and FoodScience

Massachusetts Institute of TechnologyCambridge, Massachusetts

J. Rodman Seely, M.D., Ph.D.Program DirectorClinical Research CenterAssociate Professor of PediatricsUniversity of Oklahoma Medical CenterOklahoma City, Oklahoma

Carl C. Seltzer, Ph.D.Senior Research AssociateBiological AnthropologyDepartment of NutritionHarvard School of Public HealthBoston, Massachusetts

Thomas Shepard, M.D.Professor of PediatricsHead, Central Laboratory for Human

EmbryologyDepartment of PediatricsSchool of MedicineUniversity of WashingtonSeattle, Washington

Henry K. Silver, M.D.Professor of PediatricsDepartment of PediatricsUniversity of Colorado Medical CenterDenver, Colorado

Clement B. Sledge, M.D.Surgeon-in-ChiefDepartment of OrthopedicsRobert Brigham HospitalProfessor of OrthopedicsHarvard Medical SchoolBoston, Massachusetts

David W. Smith, M.D.Professor in PediatricsUniversity of Washington School of

MedicineSeattle, Washington

Clive C. So !onions, Pl.D.Associate Professor of PediatricsUniversity of Colorado Medical CenterDenver, Colorado

Juan F. Solos, M.D.Director, Clinical Research CenterChildren's HospitalProfessor of PediatricsCollege of MedicineOhio State UniversityColumbus, Ohio

Lester F. Soyka, M.D.Associate Professor of Pharmacology and

PediatricsUniversity of Illinois Medical CenterChicago, Illinois

Matthew Steiner, M.D.Associate Professor of PediatricsNorthwestern University School of

MedicineCouncil Member, American Medical

Association Department of PediatricsAttending Physir;:mChildren's Memorial HospitalChicago, Illinois

Philip Sunshine, M.D.Associate Professor of PediatricsDirector of NurseriesStanford University School of MedicinePalo Alto, California

Charles F. Whitten, M.D.Professor of PediatricsWayne State University School of

MedicineDirector, General Clinical Research

Center for ChildrenChildren's Hospital of Michigan and

Wayne State University School ofMedicine

Detroit, Michigan

7

httroduction

The mature human body is the end result of aremarkable growth process that requires almosttwo decades for completion. During this 20-yearperiod, the individual who initially was the prod-uct of two germ cells, becomes an adult made upof 100,000 billion cells. Yet, contrary to popularbelief, size increase is perhaps the least significantof the many components of human growth.

The human being at. any age is very complex:he represents a marvel of specialized tissues andcomplementary functionsall coordinated toallow continuing integrity of his body as a whole.Fundamental to the growth process is the factthat all body systems must continue to work inconcert at every stage of growth. Changes mustbe timed with exquisite precision, not only to cul-minate in a unified adult, but also to insure theintegration of body activities which is essentialat each intermediate point in growth. For thishighly complicated process to evolve normally,physiologic systems must come into being innicely ordered sequence, and they must be syn-chronized with others already in existence or yetto come. This is why the study of growth at itsmost basic levels may be viewed as an approachto better understanding of the nature of life itself.

Research in any branch of medicine is usuallyfirst conducted at the basic science level usinglaboratory animals. For growth research, rats aremost commonly used since even after maturationthey can be induced to grow almost at will.Growth research advances arc next tested in pri-

10

mates (apes and monkeys) because their physio-logic systems most closely parallel those of man.Finally, growth is studied in human volunteers,whose normal or disordered growth proces.ses ulti-mately are not duplicated in any other livingcreature.

For the past decade, much of the clinical re-search in the United States on the Complexprocess of growth in humans has been conductedin General Clinical Research Centers supportedin medical institutions amass the Nation by theDivision of Research Resources of the NationalInstitutes of Health. The General Clinical Re-search Centers program currently funds 80 re-search centers in 70 of the Nation's research in-stitutions and medical schools. Within the pro-gram as a whole, there are 742 adult and 163pediatric research beds plus a manpower forceof over 2,000 physicians and other specializedmedical personnel.

Each clinical research center is a "hospital inminiature," a medical ward specifically designedfor research in human health. Generally locatedin a university hospital, the "average" center con-sists of 11 research beds, a director's laboratory,two research laboratories, a metabolic kitchen, aprocedure room, and a treatment room.

A patient is admitted to a research center onlyas part of a precisely defined research protocol,and his hospital stay is constantly supervised by aphysician-investigator. The details and aims ofthe study, as well as the risks, if any, have alwaysbeen carefully explained to the patient. The studyhas also been reviewed and approved in advanceby an appointed group of independent, hospitalphysicians.

In its 10-year history, the General Clinical Re-search Centers program of the National Institutesof Health has contributed more. than $68 millionin Federal funds to clinical research on humangrowth. Center investigators have used over 518,-000 bed-days to study growth processes. Thisrepresents research on an average of 142 in-patients each day for the past 10 years.

Within a recent 1-year period, over 1,500 sepa-rate studies on human growth were conductedin General Clinical Research Centers. More thanone-third of these projects concentrated on theinfluence of hormones on growth. (Hormones arcthe major chemical determinants of whengrowth begins, how it proceeds, and when, itstops.) Other projects sought to define the ef-fects on growth of such diverse influences as pre-natal life, heredity, nutrition, illness, and even sexand emotion.

Medical scientists study periods of intensegrowth with unusual interest. In addition to pro-viding ideal conditions for the basic study ofgrowth and its derangements, these periods alsorepresent a natural laboratory where solutionsmay be sought to many of the serious, nongrowth-related disorders that plague people throughoutlife.

For example, cells multiply at their greatestrate between the time of conception and the be-ginning of puberty. This periodthe fetal andchildhood yearsis perfectly suited for researchinto the control of human cell multiplication.Trough such research, physicians may in timelearn why, in many people, abnormal cell divisionproduces cells that, unfortunately, arc not car-bon copies of the originals, and why cellulargrowth in some people becomes completely un-controlled or cancerous.

422420 0 /2 - 2

As the difference in growth between boys andgirls becomes more fully documented, General

Research Center investigators may alsodefine those influencesboth genetic and en-vironmentalresponsible for the greater longev-ity enjoyed by women in all developed nations ofthe world.

Also, growth studies will undoubtedly result insignificant discoveries about the disabilities of oldage, particularly those due to unstable cellularchanges and to the diminishing ability of the bodyto repair itself. In tine, physicians may even beable to circumvent many of these infirmities.

As we have seen, clinical studies On humangrowth have application, directly or indirectly, tomany of the medical problems experienced bypeople of both sexes and of all ages. Today, medi-cal research at the basic science and laboratorylevels is being quickly translated into improvedmedical care for all people with the help of in-vestigators studying these and other health mys-teries in the General Clinical Research Centersof the Division of Research Resources, NationalInstitutes of Health.

11 9

t

The Initiation of Growth

Intrauterine Life

The most rapid and crucial period of growth inthe human being occurs in the 9 months beforebirth. Because this growth takes place within thecloistered setting of the uterus, it has not beenin ticc past readily available for study. However.this historic lack of knowledge is being rapidlyovercome as clinical investigators join with basicscientists in the development of new researchtechniques to study fetal growth during preg-nancy. The availability of these new techniqueshas improved obstetrical care strikingly withinthe past 5 years. Many of the disorders that causebreakdowns in the normal chain of events ofpregnancy can now be either detected early andtreated, or circumvented.

Scientists have known for years that, exceptfor the sperm and ova ( the reproductive cellsproduced by the nude and female), the billions ofcells in a single human body all share identicalgenesblueprints inherited from the parents thatdetermine how the body is to he constructed.These genes, themselves composed of specificsequences of chemical substances, arc normallylinked end-to-end in precise order to form longthin strands. Within the nucleus of each body cell,the strands exist in segregated, complementarypairs, the two strands intimately associated in aspirally entwined configuration. This double-stranded coil constitutes one "molecule" of de-oxyribonucleic acid (DNA), which, in associa-tion with the other DNA molecules in the nucleus,controls chemically every activity of the cell inwhich it exists.

13

When an ovum or a sperm is formed, the twostrands of each molecule of DNA uncoil and sepa-ate, and only one of each pair is donated to thegerm cell. At conception, with the union otovumand sperm to form one cell, single complementarystrands from each of the two parents unite to forma new paired DNA spiral, which will then heduplicated precisely in each body cell of' the newhuman. In this way, both parents contributeequally to the chemistry of life passed clown fromone generation to the next.

The first 2 weeks of pregnancy is the period inwhich the newly conceived life fastens itself tothe uterine wall. This union starts the enlarge-ment of the uterus and begins the development ofthe placentathe organ by which the unbornbaby is attached In the wall of the uterus and onwhich he will depend throughout the pregnancyfor nutrition, respiration, and excretion.

At various times during the ensuing pregnancy,the genes trigger or suppress the production ofenzymesorganic catalysts that determine howfast or how slowly specific chemical reactionsoccur within the body. These reactions, in turn,determine whether and when a developing cellwill become part of specialized tissue such asheart, lung, bone, mscle, or fat.

11

The uterus provides thc requisite environmentfor different organ systems to develop harmoni-ously. Much evidence is accumulating that theutcrinc environment may wield as great an in-fluence as does genetic endowment in determininghow large thc fetus may grow before birth.

Between thc 2d and 10th weeks of pregnancy,the cells for arms and legs, eyes and cars, andvital organs arc differentiated. This is now provento be a most vulnerable period of lift. Manysevere birth dcfccts have been traced by re-searchers to maldevelopment during this phaseof prenatal growth.

Today, scientists have new, reliable bioengi-neering tools for monitoring thc physiology andchemistry of the utcrinc environment, and theycan identify' very early some of the geneticmakeup of the fetus. For example, the process ofamniocentesis, developed at a General ClinicalResearch Center, allows a doctor to safely with-draw, through the mother's abdomen, some ofthe fluid in which the fetus is bathed. From anal-ysis of the fluid, physicians can detect within thcearly months of pregnancy whether certain birthdefects arc developing in the fetus. The test wasdeveloped as a research technique, but it is nowwidely used clinically as a diagnostic procedure.

Development of the skeleton begini in the 2dmonth of intrauterine lift. Almost all bone in thebody is first laid down in the fetus in the form ofcartilagea flcxiblc material which persists inadulthood in such areas as thc cars and nose.Ossification, the process by which cartilage is re-placed by true bone, however, only begins in fetallife. It continues throughout childhood and is notconcluded until the end of puberty.

12 14

The initial sign of impending ossification in aspecific area of cartilage is thc swelling up andarrangement of the mils into ordered columns.These cartilage cells then disintegrate, and as theybreak down, a protein matrixthe basic mate-rial of the subsequent bonegrows into the spacethey vacate. This matrix in turn absorbs min-erals, such as calcium and phosphorus, from theblood stream and thereby :utak the compositionof true bone. These areas in which the conversionof cartilage begins arc km:Min as primary centersof ossification. They, unlike cartilage, show up onX-ray.

As the process continucs, different areas of os-sification within a potential !me grow toward oneanother until a stage is reached in which a thindisc of cartilage is all that remains between twoareas of bone. This disc continucs actively to growon one surface while its conversion to bone pro-ceeds concomitantly on the other, milking insteady growth in length of the bone. The mostcommon examples of such linear growth are inthe long bones of thc arms and !cgs, in which,simplistically, a growing disc of cartilage at eitherend continues to proliferate throughout child-hood. These plates of actively growing cartilagebetween two areas of bone' arc known as epi-physes. At the end of puberty, in the processknown as epiphyseal closure, the cartilaginousplates are completely converted to bone, and nogrowth of the bone subsequently can occur.

As bones increase in length, so must they alsoincrease in width. This requires the deposition ofnew bone on the external surface of the shaft and,sinuiltaticonsly, an absorption of old bone fromthe center. The result is mature hones havingroughly the configuration of a hollow pipe, thecenter cavity of which becomes filled with bonemarrow, from which cells of the blood are even-tually produced.

Radioisotope studies have revealed that oncebone is formed, it does not remain inactive.Throughout life, it is constantly being destroyedand re-formed as minerals such as calcium andphosphorous are exchanged between bone cellsand body fluids. This bidirectional flow enablesbone to serve as a reservoir of minerals needed,on demand, by other body systems. In the grow-ing fetus and child, of course, bone mineraliza-tion exceeds demineralization, permitting theskeleton to grow in size and strength.

15

The latter months of pregnancy are devotedprimarily to further development of existent bodyorgans and systems. By the 6th month, fatty tissuestarts to build up; at every stage of pre- and post-natal growth, its main function will be to storeenergy and help regulate body temperature. Dur-ing the last 2 months, the fetus grows so rapidlythat it gains about one-half pound a week.

At one General Clinical Research Center, am-niotic fluids, blood pigments, waste products, andfetal cells are analyzed during the last months ofpregnancy to determine more accurately thechanges that normally occur during this time ofrapid fetal growth. This and other newly devel-oped ways to examine fetal growth reveal againthe remarkably favorable intrauterine environ-ment usually provided by the pregnant woman.In addition to the physical protection it affords thegrowing fetus, this environment is admirably de-signed to promote bctwccn mother and child thesteady, dynamic exchange of substances requiredfor optimal fetal growth.

Indeed, so long as the flow of blood to theuterus is normal, and the concentration of nutri-ents traveling through the placenta is adequate,the fetus will probably grow to be at least 51/2pounds at birththe dividing line between thenormal and the low birth weight newborn.

13

14

Premature and Growth-Retarded Infants

Low Birth Weight Babies

16

Many General Clinical Research Centers are con-ducting intensive studies of infants who fail togrow to normal size before birth. By focusing onthe unique problems of these low birth weightbabies, scientists may be able to halve the infantdeath rate in this country and, perhaps, eliminatethe major cause of brain damage in children. Asthe mysteries of prenatal growth are examinedmore intimately, increasingly sophisticated tech-niques of obstetrical care will likely be developed.And these new techniques may in time enablemore and more mothers to provide their unbornchildrea with the uterine environment most con-ducive to healthy growth.

The size of a new baby is closely linked withthe size of the placenta. This consistent correlationhas bccn part of midwife lore for ccnturics. Largeinfants always have large placentas. Twins, trip-lets, and other multiple births have even largerplacentas. Scientists, therefore, suspect that theupper limit in size that a fetus can attain is directlydependent on the amount of placental tissuc ade-quately conveying nutrients and oxygen to him.

Small babies usually have small placentas.Sometimes a small baby has a large placenta, butin such a case, a portion of the placental tissuemay have been defective and functioningimproperly.

Several scientists have found that, during anormal pregnancy, the adrenal glands of the fetuswork in concert with the placenta to manufacturehormones that dilate the arteries which supplyblood to the uterus. This allows the increasedblood supply required by the growing fetus. Thismetabolic interplay between the placenta and thefetal adrenal glands is mediated by the hormoneestriol. The measurement of this hormone in the

urine of the mother is one of the newest methodsan obstetrician can use to determine if placentaldevelopment is proceeding normally. A relation- .

ship also exists among a low excretion of estriolduring pregnancy, a constricted blood supply tothe uterus, and subsequent low birth weight ofthe baby. Having established this relationship, re-searchers are seeking ways to enable the physicianto increase blood flow to the uterus in an attemptto avert the delivery of a low birth weight baby.

Although human growth hormone ( HGH) hasbeen identified in fetal blood as early as 15 weeksafter conception, to this day no evidence existsthat HGH regulates the size of the. fetus. Consid-erable progress has bccn made in isolating humanplacental lactogcn, an HGH-like material presentin the placenta; yet, studies indicate this hormoneprobably does not reach the fetus in amountssufficient w control his growth.

Infant survival rate is inversely correlated withbirth weight; the lower the weight of the new-born, the greater the danger he faces. Until re-cently, all infants weighing less than 5/_ lbs. atbirth were automatically classified as "pre-mature," and their postnatal conditions wereevaluated and treated according to the sameguidelines of care. However, physicians are rec-ognizing increasingly that intrauterine growthretardation, not prematurity, may account forone-third to one-half of all low weight newborns.The distinction is of paramount importance inthat postnatal care appropriate for the true pre-mature, born before completing :36 weeks of in-tauterine life, may be inappropriate, or evencontraindicated, for the low birth weight infantwho has gone full term.

15

Early pregnancy is thc most propitious time todetermine if growth-retarded development istaking place. The sooner the suspicion can beconfirmed, the more effective are thc steps thatcan be taken to ward off, or diminish, the prob-lems of the affected infant. However, traditionalways of estimating whcthcr a fetus is growingnormally, based on a comparison of probableduration of pregnancy with clinically estimatedweight of the fetus, arc often little morc than edu-cated guesses. A new method to allow physiciansto accurately gage fctal size uses an ultrasonicsound device, developed in a General Clinical Re-search Ccntcr, which yiclds a three - dimensional"map" of the unborn child. In addition, amnio-centesis allows a very precise measure of the dura-tion of the pregnancy. A combination of thesetests enables a physician to determine preciselywhcthcr a fetus is of a size appropriate to his age.

If prenatal tests were not conducted, or wereinconclusive, clinical methods are available todistinguish at the time of birth thc intrauterinegrowth - retarded newborn from the true pre-mature. Charts relating the age at which variousneuromuscular relic= develop have been pre-pared by one clinical research center and arc nowprcscnt in most delivery rooms and nurseries inthis country. The true age of a given small new-born is determined as the age of his typical ncuro-logical behavior.

The growth- retarded newborn is expected toexhibit thc same patterns of behavior as any otherfull -term infant; the premature infant, on theother hand, should display patterns consistcntwith neurological functions which arc not com-pletely developed and may yet evolve.

16 18

The mature behavior of the growth-retardedinfant, as opposed to that of the premature, canbe quite striking. Many premature infants, forexample, havc poor sucking and swallowing re-flexes; fortunately, scientific advances at oneGeneral Clinical Research Ccntcr permit such aninfant to be fed through tubes inserted throughthe abdominal wall into the stomach, a procc-durc that has proved sufficient for adequate nutri-tion. This support is often not needed by growth-rctardcd infants. Instead, many of these infantsweighing less than 3 pounds can be observedvigorously enjoying nipple feeding in theirincubators.

One major complication to be anticipated forthe newborn suffering intrauterine growth re-tardation is a pathologically low blood sugarlevel, known as hypoglycemia. In thc normalsized, full-term infant, large stores of glycogen,a storage form of sugar, arc present in thc liver.This reserve enables the infant to maintain nor-mal blood sugar levels for relatively long periodsafter birth. The newborn with intrauterinegrowth retardation, however, has markedlydepleted his glycogen stores during pregnancyand stands grcat risk of developing, soon afterbirth, such low blood sugar levels that severebrain damage may result. Prompt injection ofglucose, therefore, is becoming a common procc-durc in newborns identified as growth - retarded.

The greatest danger faced by the prematurebaby is a respiratory condition known as hyalinemembrane disease. Marked by progressive col-lapse of the thin air sacs which make up the lung,the ailment causes the lungs to lose their powerto expand. As the lungs become increasinglyresistant to thc entry of air, they render the pre-mature baby vulnerable to heart and brain dam-

age from lack of oxygen. This discasc kills anestimated 25,000 premature infants each year.

For many years, premature infants were be-lieved to be free of the symptoms of this discascuntil at least 12 hours after birth. Today, it isknown that subtle signs of impending troubleshow up in the delivery room. A unique gruntingcry, for example, has been identified as beingemitted by virtually all these infants soon afterbirth.

A low-cost enzyme medication, capable of pre-venting or dissolving the membranes that coatthe lungs in hyaline membrane discasc, hasproved effective in tests with monkeys. At a Gen-eral Clinical Research Center, this preventivemedicine is undergoing trials in human infants.Hopefully, it may help cut the cost of treatmentfor each case from $2,000 to $40.

Ounce for ounce, the survival rate of growth-retarded babies is significantly higher than thatof premature babies. However, growth-retardednewborns do sustain a higher incidence of birthdefects than do the "preemies." Intrauterinegrowth retardation implies that some factorlimited normal growth during a full -tent preg-nancy; this factor could also be responsible for anassociated congenital Malformation.

A number of cases of intrauterine growth re-tardation have, in fact, been traced to genetic de-fects. Sometimes, the defect is caused by a randomaberration in the chromosomal makeup of thecells passed to a particular fetus and may affectno other prenatal germ cells.

To date, however, no genetic or chromosomaldamage has been implicated as a cause of pre-mature birth. Instead, premature delivery seemsto be linked either to obstetrical complications orto such environmental factors as maternal ciga-

452.2110 0- 72 - 3

19

rate smoking, exposure to high altitudes, toxemiaand chronic vascular disease in the mother, orfetal infection from German measles, syphilis, ormalaria. (These same factors have also been cor-related with sonic cases of intrauterine growthretardation.)

One cause of low birth weight in both the pre-mature and the growth-retarded baby appears tobe poor nutritional status of the mother. This,however, seems to be more a function of themother's long-term diet before pregnancy thanof her diet during pregnancy. Improving the qual-ity of an expectant mother's food intake can helpher unborn baby, but it cannot totally undo thechronic nutritional deficiencies of a lifetime.

On the other hand, the mother who was ade-quately nourished during her own growing-upyears has an excellent chance of delivering a nor-mal size baby even if she has taken an inadequatediet during pregnancy. The "old wives' talc"holds true that the unborn child has a competitiveadvantage in taking the nutrients it needs fromthe motherif the mother has an adequate re-serve of supplies from which the fetus ran draw.

No one knows if the low birth weight baby ulti-mately can reach his inherited potential height.There is no meaningful association between nor-mal size at birth and size finally attained at adult-hood. Scientists do know, 'however, that thesmaller newborn of a set of identical twins hasusually been on the "short end" of placental sup-ply and, therefore, has probably suffered somedegree of placental insufficiency. This smallertwin rarely reaches the same size as his sibling.Many scientists suspect, therefore, that during cer-tain critical periods of growthboth during andafter pregnancydamage to the full potentialof growth may be irreversible.

17

A Decade of Growth

The Childhood Years

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18

During the past few years scientists have starteddetailing the interplay between genetics, nutri-tion, emotions, illness, and time . . . exploringthe way these factors act, sometimes singly, butmore often in concert, to affect not only an indi-vidual's growth, but also his health, for betteror for worse. New research techniques are pro-viding insight into how healthy growth proceeds,what enhances it, and why boys and girls, frombirth, display markedly different patterns.

Scientists arc discovering that children through-out the world tend to show remarkably similarcapacities for growth. Nursing infants in devel-oping nations follow much the same pattern ofgrowth as that considered normal for infants inthe United States. The likelihood is that whileeach child proceeds to adulthood at his own pace,normal growth before puberty is dependent moreon the life a child leads than upon the genes withwhich he is endowed.

The average, full-term male infant weighs 8pounds and measures 20 inches. Some weight lossfollows birth. Growth thcn becomes so rapid thathe will probably weight 14 pounds and measure25 inches by the age of 4 months.

After the 4th month; growth starts to slowdown. Height now becomes more important thanweight in evaluating the health of the growingchild. When he celebrates his first birthday, theaverage boy should have grown to a height of30 inches.

By the time he is 2, a child's growth begins toreflect some genetic influence. The averagehealthy boy then measures about 35 irAes and

will have reached approximately half his adultheight. On his third birthday, he is close to 38inches: His growth rate then starts to level off,and for the next 9 years, he will grow at the rela-tively constant rate of only 21/4 inches a year.

In marked contrast to the dramatic and rapidchanges that occur during the pre- and earlypostnatal periods, growth during the later child-hood years is slowly progressive, and derange-ments may be subtle. Probably one of thesimplest gages of a child's health status is whetherhe is adding inches and pounds according to ac-cepted timetables of normal growth. The firstindication that something is amiss with a child'shealth may be the fall of his growth curve belowthe third percentile for normal children. Thisyoungster is probably suffering a period of de-pressed growth that should be investigated and itscause corrected.

Increase in height is due to progressive growthof bone. As noted earlier, development of theskeleton is quite incomplete at birth, and it con-tinues to undergo many changes throughoutchildhood. Most primary centers of ossification,for example, develop after birth; some do notmake their appearance until adolescence. Epiph-yses normally arc not completely closed until theend of adolescence.

Many investigators discuss human growth interms of two ages: chronological age, timed fromthe date of birth, and biological age, a measureof the degree of physical maturity of the individ-ual, determined by equating his degree of maturitywith the average age at which that degree of ma-turity normally becomes manifest. X-rays of thebones arc most often used to determine the bio-logical age of children. The greater the number ofcenters of ossification present on X-ray, and the

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greater the degree of epiphyscal closure, thegreater is the biological age of the childregard-less of his actual chronological age. Biological age,as measured by reference to X-ray of bones, isoften referred to as bone age.

Bone X-rays have helped establish, for example,that skeletal maturation in a girl on the clay ofbirth is one month ahead of that of her twinbrother. The female, thcrcforc, comes into lifea biologically older, more highly developed orga-nism. It will take the male close to 20 years tocatch up.

Measures of height, weight, and bone age haveserved as the traditional bases of growth studies.Scientists now, however, are seeking increasinglyspecialized techniques by which human growthmay be analyzed'. Enlargement of the human or-ganism is basically the result of a myriad of chemi-cal reactions, some of which can be measured ina short period of time by new biochemical tech-niques. Researchers at General Clinical ResearchCenters and other facilities, therefore, are nowinvestigating individual components of growth atthe tissue, cellular, and even molecular

At some General Clinical Research Centers,everything the research subjects cat, drink, oreliminate is carefully measured for weight, chemi-cal composition, and caloric value. In fact, thechild who enters the bathroom without telling thenurse is interrupted by an alarm system ; this pre-vents the loss of waste materials which must becarefully analyzed as part of precise Metabolicstudies.

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For almost three-quarters of a coati)). scien-tists believed that growth after birth was cluesolely to an increase in the size of body cells. NowGeneral Clinical Research Center investigators,in a new application of older knowledge, haveshown that specialized cells also increase in num-ber for many years after birth. For example,scientists have known for two decades that DNAis present in precisely equal quantities in thenuclei of all bock cells and that the amount ineach cell is constant throughout life. Therefore,from the total amount of DNA contained in aweighed muscle biopsy specimen, the numberof cells constituting the specimen can be deter-mined. Since the total weight of the specimen isknown, the weight and size of each constituentcell is easily calculated. Serial repeats of suchbiopsies over a number of years, coupled withrepeated measurement of total body muscle mass,allow investigators to calculate whether changesin muscle cell number Gr size have occurred.

An early conclusion drawn from such cellularanalyses is that while bone maturation is an indexof biological age, the number of muscle cells inthe body correlates more closely with chronologi-cal ageand is related to the sex of the child.Boys and girls are probably born with the samenumber and size of muscle cells. By 3 weeks ofage, however, the male child already has more,and larger, muscle cells than the female.

When she is 10, the girl will have undergonea fivefold increase in the number of her musclecells; from this age, little further increase occursin either her muscle cell size or number. In con-trast, a boy's muscle cells continue to multiplyuntil, at 18 years of age, he has 14 times as manymuscle cells as he did at birth. (A tall 18-year-old boy may have 20 times more muscle. cells.)

While muscle cell replication ceases at this age,some evidence exists that the muscle cells of theboy will continue to enlarge in size for another5 years.

Once muscle cells stop growing, gross enlarge-ment of muscle is due to an increase in the diam-eter of the fibrils contained inside the musclecells. This is often brought about by consciousexercise, such as that designed to enlarge thebiceps, or by the unconscious but physiologicaleffort of a muscle to sustain a greater body func-tion. This latter phenomenon can occur in theheart of an athlete; the fibrils of his heart maygrow in size to help handle an increased work-load.

Scientists have also discovered that, right fromthe beginning, a girl will have a greater percent-age of fatty tissue, increasing in greater propor-tional amounts as she grows, than the boy ofequal age and size. Because she has these fattytissue reserves, a girl's external requirements formaintaining her weight arc less than her brother's,and her caloric needs throughout life will be,pound for pound, less than his.

In almost every respect, the physical develop-ment of the female is more stable than that of themale. Not only is she biologically more mature,as measured by bone X-rays, but when sister andbrother arc exposed to the same growth-retardingcondition, the girl tends to show less damage. Thegrowth-retarded boy, on the other hand, reactsmore favorably to an improvement in the con-dition causing his growth lag, possibly becausehe has more catch-up growth to accomplish.

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Each successive generation in most of the in-dustrialized world has been growing taller thanthe generation preceding it. On an average,young adults of today measure 1 inch more thanparents and 2 inches more than their grandpar-ents. Males, moreover, arc increasing in adultheight more rapidly than females. Many re-searchers believe these height gains can be attrib-uted to bcttcr medical care and nutrition . . .and that the more rapid rate of increase in themale indicates how quickly his growth can re-spond to bcttcr times.

Will people keep growing taller and taller?No one knows. But scientists do suspect that theincrease is leveling off and that, once they com-plete growth, today's healthy and well-nourishedboys and girls will have reached the maximumheight allowed by the human genetic potential.

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Effects of Nutrition

A concern of scientists for over a century hasbeen the identification of foods essential togrowth. Today, they are working to define thosefoods that best prevent or cure childhood growthdisorders stemming from malnutrition. Nutrition-ists arc also looking into the possibility that thegrowth differences between boys and girls mayrequire that the two sexes be put on differentdiets right Irvin birth. And in the future lies yetanother horizon: definition of the foods that re-sult in optimaland not necessarily maximalbody development throughout life.

As the relationship between nutrition andgrowth becomes understood in a more sophisti-cated way, the failure of a child to adhere to uni-versal patterns of growth is not so readily ascribed,as in the past, to genetic predisposition. Instead,such deviations arc being interpreted as possiblesigns of undernutrition or overnutrition that canbe prevented and possibly cured.

Scientists know that at least 45 nutrients arcbasic to the maintenance of healthy growth. Lackof these nutrients over a period of time may de-press appetite, encourage disease, and thus retardchildhood growth. Conversely, the child whosegrowth rate is too slow from nonnutritionalcauses may also have a small appetite and de-creased resistance to disease. Despite this cycle ofcontributing factors, precise methods of cellcounting and analyzing body composition haveled researchers to conclude that only two elements

22

of dietprotein and caloric contentarc of pre-eminent importance to nonnal growth.

Milk produced by an adequately nourishedmotheror that provided in a specially prescribedmilk formulacontains, in appropriate quan-tities, all protein and calories required for an in-fant to grow normally. Even the milk of thepoorly nourished musing mother, often deficientin volume and vitamin supply, can provide an in-fant with the basic nutrients required in his veryearly growth period.

As the child decreases his milk intake and turnsto solid foods, a daily diet containing a sufficientand varied quantity of foods from the four basicgroups, I ) meat, poultry, fish, and eggs; 2) vege-tables and fruit; 3) milk and milk products; and4) enriched breads and cereal, provides properproteins and sufficient calories to allow continu-ing growth. Such a balanced diet will .also helpbuild up the large store of nutrients essential forthe accelerated growth demands that will be pre-cipitated later by puberty and, in the female bychildbearing. For the pregnant teenager, a whole-some nutritional background is of special im-portance; the expectant mother who is young andstill growing must meet her own dietary growth!Reds at the same time she is providing essentialnutrients to her growing fetus.

Calories have been implicated in cell multipli-cation. Protein, on the other hand, may be relatedprimarily to the ability of cells to enlarge. Sciin-tists arc beginning to suspect that failure of cellsto receive sufficient proteins and calories duringcertain periods of body growth may lead to slow-ing clown and, ultimately, to cessation of theability of the cells to enlarge, divide, and developspecialized functions.

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The child deprived of too many calories maynever attain a normal complement of cells. Lackof sufficient protein may 1ahibit the size of hiscells. Indeed, in some areas of the world whereprotein deficiency is widespread, many childrenhave remarkably small cells for their ages.

On the other hand, the increase in the size ofchildren, generation after generation, in the moredeVeloped nations of the world, may well be dueto improved nutrition. Japanese children bornafter World War II arc consuming a diet richerin protein by 20 percent. When they reach school,these children can no longer fit into the schooldesks used by their parents.

Proteins are large molecules in which variousamino acids, the basic building blocks of life, arelinked together in long, prmise sequences. Anadult needs to cat proteins that contain only eightamino acids, called the essential amino acids. Achild needs a diet with a ninth amino acid,histidinc.

Utilizing the amino acids in the proteins theycat, both normal adults and children go on tomanufacture additional amino acids. The result-ing 23 amino acids -made up from boll ingestedand manufactured. precursorsare then re-grouped chemically in the body, through a processknown as protein synthesis, into the various pro-teins needed for specialized functions in the body.DNA in the cell nucleus dictates which of themany possible specific chains of amino acids willbe manufactured by a given cell.

A new study has disclosed that a prematurebaby may lack the ability to manufacture cystinc,an amino acid not required in the diet of full-term babies. One treatment method now being

considered is to give human milk to the bottle-fedpremature baby; unlike cow's milk, human milkhas a high cystinc content. Another possibility isto add cystinc to infant formulas. These feedingmethods may prove to be the desired dietary regi-men for the non-nursing premature baby untilhe develops the natural ability to convert someof the amino acids he eats into cystinc.

The deficiency of manufactured cystinc inmany premature infants may explain why theyare more prone later to develop short height andmental deficiency than are full-term infants. In-deed, in one inherited illness, a child is never ableto develop the capacity to derive cystinc fromother amino acids. This ailment, homocystinuria,usually multi in a similar pattern of disorderedgrowth accompanied by mental retardation.

The most common nutritional deficiency in theworld caused by a chronic lack of protein in thediet is kwashiorkor. Originally identified inGhana in 1960, kwashiorkor is now known to berampant in most developing nations. Childrenwith this disease suffer severe growth retardation,vulnerability to illness, swelling of the abdomenwith water, and marked apathy. Kwashiorkorpatients lase so much responsiveness to eventsaround them that the treated youngster whoeventually smiles is considered to be on the roadto recovery.

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V ovo e k I-01..k 1,-Ai 'I e

Growth is work, and calories are- the units ofenergy that fuel it. Carbohydrates and fat caloriesarc the most readily available to supply the body'senergy mak, but protein as well can be burnedfor energy. If excess calories are eaten, a few ofthe unused ones are converted to glycogen, andthe remainder are stored as fat.

If insufficient calories are eaten, the body willfirst use up its caloric stores to meet its energyneeds. Then it will begin to devour itself by con -suming structural protein. During the years ofchildhood growth, extreme deprivation of caloriesresults in mamsmus, a condition marked by ex-treme wasting, emaciation, and starvation of bodytissues.

In developing nations, an estimated 300 mil-lion children suffer from marasnms, kwashiorkor,or a combination of both. Both diseases areusually precipitated by the weaning process andthe withdrawal from titr infant of his near ade-quate nutrition. After the mother ceases to nurseher infant, the baby's life is marked by recurrentdiarrheal infections from u Aygienically preparedfoods. He is also affected by the inability of hispoverty-stricken mother to find fruits, vegetables,grain, and edible underground shoots that mightmake up an adequate diet. This interaction be-tween infectious disease and malnutrition is theprimary reason why deaths in the 1-to-4-year-oldgroup arc 50 to 60 times greater in developingregions of the world than in the United States.

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Fortunately, new biochemical methods fordetermining the nature and extent of protein andcalorie deficiencies are leading to new kinds ofnutrition therapies. Some cases of kwashiorkor,for example, may now be prevented by the use ofnewly developed protein foods made from cotton-seed flour or other vegetable sources; they areusually less expensive and more readily availablethan animal protein.

The greater his degree of malnutrition, thehigher the caloric intake a child needs in order togrow at a satisfactory pace. This appears to holdtrue regardless of whether the malnutrition wasdue primarily to deficiency of calories or ofprotein.

The traditional therapy of children who havealready undergone the rigors of severe proteinand caloric malnutrition has been a high-proteindiet. Studies show, however, that after the firstfew days on such diets, malnourished childrenreact as do other growing children who receiveinsufficient calories. Their bodies use the proteinfor energy rather than for growth, and growthremains retarded.

Recently, a number of mamsmic and kwashior-kor children have shown significant benefit froma new kind of diet which is only minimally ade-quate in protein but vay high in calories. Chil-dren treated on the new diet usually achieve theproper weight for their height in 8 weeks and arethen strong enough to leave the hospital. As thediet is maintained at home, the treated child con-tinues to grow taller until his height is equal tothat of his "normal" siblings. However, they areprobably shorter than they should be as a resultof their own share of inadequate diets.

Youngsters treated with the minimal protein,high-calorie diet have also been shown to havebetter long-term resistance to disease and to haveless recurrence of severe malnutrition at home.They were contrasted to malnourished childrenwhose long-term hospital therapy stressed highprotein intake.

Until recently, severe malnutrition among chil-dren was thought to exist only outside the bordersof the United States. No truly reliable count existsof the number of people in this nation who sufferprimary malnutrition, due to inadequate diet.However, the first comprehensive survey of thenutritional status of the lowest economic quarterof the U.S. population is currently being con-ducted by the nutrition program of the Depart-ment of Health, Education, and Welfare.Surprisingly, the program is documenting thatprotein and caloric deficiency does exist in thiscountry, sometimes in marked degree. This is par-ticularly true among children in poverty areason Indian reservations, in Appalachia, in theSoutheast, and in large city ghettos. Studies showthat the average height of poorly nourished Amer-ican children in the 1-to-6 age group is from5 to 15 percent lower than that of their wellnourished contemporaries.

An alarming finding is that many children inthe United States even suffer kwashiorkor ormarasmus. Because low-income Americanmothers seldom breast feed, their children areoften denied the initial period of near normalgrowth enjoyed by children nursed by mothersin even the poorest of countries. Marasmus orkwashiorkor, superimposed upon this early de-ficiency, may prove to be even more detrimentalto affected children in the United States thanto those in nations where the diseases arc endemic.

452-280 0 - 72 - 4

Few American youngsters starve to death. Yet,there is justifiable concern over the long-termhazards of their nutritional deficiencies. A fewyears ago, man studies suggested that even afterthe causal nutritional deficiencies were corrected,children with below-normal head size, height,and intelligence, incurred between the ages of2 and 7, might never sufficiently catch up.Some scientists estimated that the brain cell countin nutritionally deprived children Wright be 20percent below normal when adulthood wasreached. (A number of other studies indicated ir-reparable damage in the brains of young farmanimals deprived of protein.)

New head size studies of older children whosedietary deficits were corrected, however, showthat some of the original head measures werein error. Latest figures reveal that head size (andpresumably brain size) frequently does increasein proportion to the catchup height being attainedby treated children. A number of growth experts,therefore, today believe that the neurological im-pairments seen in sonic undernourished childrenare caused not by faulty diet but rather by thedebilitating emotional conditions under whichmany of these children are raised.

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Current scientific opinion is that nutritionaldeprivation incurred before 4 months of life canoften be speedily and permanently remedied bya proper diet. After the child is 4 months of age,

. the more severe the malnutrition and the earlierit occurs, the more marked, and perhaps perma-nent, appear to be the adverse effects producedon any system in the body (including the nervoussystem). Indeed, in one study of the effects ofdiet on the intelligence of American youngsters,the only subjects who showed normal IQ's atage 3% were those whose malnutrition was ar-rested before they were 4 months old.

However, much more work remains to be doneto determine precisely how mental deficiencies,as well as impaired height and weight, arc in-curred in malnourished children, and whetherand when the defects become permanent.

In contrast to studies hinting at possible ir-reparable damage inflicted by under-feeding ofchildren, new cell-counting techniques paradox-ically also indicate that about 8 percent of young-sters in affluent nations arc being overfed.

Obesity in many children has origin in infancy.Since infants tend to regulate their food intakeby volume rather than by nutritional content,they often consume inordinate quantities of for-mulas highly concentrated in calories and protein.One theory is that this unconscious gluttony maystimulate into existence excessive numbers of fatstorage cells and, thereby, trigger in many infantsa genetic predisposition to overweight that canplague them throughout adult life.

Once a fat cell is stimulated into existence byexcess caloric intake in infancy, it is possible thatneither time nor diet can make that cell disappear.

26

Sonic scientists believe that a fat cell can shrinkonly in size, leaving that cell lurking in wait forthe extra fat that can fill it again. Other research-ers believe that just as fat cells can "come," soit is possible that weight loss can make them "go:'

Scientists at a General Clinical Research Centerhave already identified one group of overweightboys who weigh at least half again the optimumfor their age. In them, gross overweight is cor-related with infant overnutrition, advanced boneage, larger skeletal size, minimal physical activity,and three times the normal number of fat cells.

General Clinical Research Center studies havealso shown that obese adults of both sexes haveexcess fat cells. However, they have also shownthat whereas young obese boys have too manyfat cells, young girls do not. As there is a possiblecorrelation between coronary artery disease andlong-term burdens imposed on hearts pumpingblood through excess fatty tissue, such basic stud-ies as these, in children, may eventually provideresearchers the essential clues to discover whyheart ailments are more common in men thanin women.

Today, the important relationship between nu-trition and growth has begun to assume its right-ful place in the diagnosis of growth problems.Scientists conducting indepth investigations ofrates that are either too slow or fast now considerunder- or over-nutrition as one of the major prob-able causes of deviation from the normal.

Q

Effects of Hormones

Interaction of the hormones produced by thevarious endocrine glands in the body constitutesan important chemical control system for majorbody activities. Derangement in secretion or activ-ity of a single hormone can produce serious dis-ruption of this interlocking system and adverselyaffect growth in many ways. New measurementtechniques are today allowing investigators tostudy the actions and interactions of hormoneswith greater precision than ever before and, fromsuch research, to develop more effective methodsof treatment for patients with severe hormonaldisorders.

The biochemical analysis of hormones wasrevolutionized in the 1960's by the developmentof radioimmunoassaya laboratory test that canmeasure in body fluids one thousandth the amountof a hormone previously detectable. This complextechnique makes use of the precise specificity ofantibodies developed to the hormones beingmeasured and of the ability to attach radioactivelabels to these antibodies such that they may befollowed accurately through a series of chemicalreactions. The potential of this technique in thestudy of basic hormone chemistry cannot be over-estimated. A measure of its considered importancewithin the scientific community is the fact thatradioimmunoassays have been or are in theprocess of being developed for practically everyknown hormone in man.

Although synchronized activity of all hormones

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in the body is necessary for appropriate patternsof growth, human growth hormone (HGH) andinsulin are the two presently considered as funda-mental to normal growth processes.

Growth hormone is secreted by the pituitarygland--a pea-sized organ attached by a stalk ofnervous tissue to the base of the brain. HGH hasbeen identified in fetal blood as early as 15 weeksafter conception. So far as is known, it continuesto be produced by the pituitary throughout life.Radioimmunoassay has demonstrated that, in thenormal individual, HGH is released in bursts ofintermittent activity. Scientists at one GeneralClinical Research Center have shown, for the firsttime, that peak HGH release occurs between 60and 90 minutes after the onset of nocturnalsleep.

The growth-promoting activity of HGH wasthe first characterized, and from this activity, thehormone was named. However, evidence isaccumulating that HGH in fact serves as an over-all regulator of many metabolic processes in thebody and that its influence on growth is only theresult of these separate activities. For example,radioimmunoassay studies have confirmed thatthe release of HGH into the blood stream ispromptly and massively stimulated by a fall ofblood sugar levels. This and other studies indi-cate, therefore, that growth hormone may be fun-damental to the use of caloric energy in the bodyand, thereby, may exert control over the way cellsmultiply in number. (Since HGH may be impli-cated in the multiplication of cells, research onits biochemical activity may in time open anapproach toward the study, and possible cure, ofcancer.)

Insulin traditionally has been assigned therestricted role of promoting the transfer of sugarfrom the blood stream into the cells, where its

27

kto\p/

.q

energy can be utilized to drive body activities.Diabetes, in which insulin is deficient, is charac-terized by the unavailability to cells of the energyof sugar, despite its presence in the blood streamin pathologically elevated amounts. However,insulin too is beginning to be assigned a largerrole in the human growth process.

Before insulin injections were available astreatment, many juvenile diabetics who survivedto adulthood were of remarkably short stature andwere known as "diabetic dwarfs." Therefore, inaddition to its effect on sugar metabolism, insulinmay have L, profound effect on protein synthesis,the process involving manufacture and buildupof protein molecules within the body. This effect,in turn, could have great significance in the regu-lation of the size of cells in the growing humanand, ultimately, of the overall size of the adultbody.

In addition to increasing our fundamentalknowledge of the growth process, study of insulin'seffect on growth may also provide an understand-ing of why the pancreatic cells of some growth-retarded children fail to secrete insulin effectively,and why severely malnourished children oftenhave remarkably small cells for their age.

Gross defects in human growth hormone secre-tion have long been recognized clinically by thedisordered growth patterns they produce. Con-genital undersecretkin of HGH gives rise to hypo-pituitary dwarfism. The most important develop-mental characteristic of the hypopituitary dwarfis that while he usually is normal size at birth, andmay grow normally for the first 2 or 3 years oflife, he rarely grows more than I IA inches a yearafter the age of three. His growth, however, is

28 33

proportionate, and there are no deforming orunusual features. Intelligence is unaffected, andappetite is normal for size.

Because of the interaction between HGH,insulin, and blood sugar levels, the hypopituitarydwarf can be exquisitely vulnerable to insulin.Since its effect is not opposed by the contraryaction of HGH, a very minimal injection ofinsulin in these patients can produce a profoundfall in blood sugar.

Radioimmunoassay tests have indicated thatdeficient production of growth hormone in hy-popituitary dwarfs may actually begin in thefirst few months of life. In some instances, theinsufficiency stems from a tumor in, or an injuryto, the pituitary gland. In most cases, however,the reason for the low HGH production by thepituitary is completely unknown. Also unknownis why hypopituitary dwarfism is twice ascommon among boys as among girls and why it isfrequently accompanied by delayed sexualmaturation.

In the late 1950's, scientists discovered thatinjections of growth hormone extracted frommonkey pituitary glands increased the rate ofgrowth. of hypopituitary dwarfs. The amount ofthe hormone obtainable from monkey pituitarieswas, however, so minute that a method was de-veloped to secure the larger amounts availablein the pituitary glands of human cadavers.

The best test of the effectiveness of HGHinjections is the fact that growth during therapyincreases to two to three times the rate beforetreatment. Typically, the child grows 2 to 3inches in the first few months of therapy. Withinthe first year, a total growth of 3 to 5 inches gen-erally takes place.

Since 1958, human growth hormone has beenused in the treatment of an estimated 2,000 hypo-pituitary dwarfs, most of them as part of researchprotocols in General Clinical Research Centers.Thus far, the most common adverse reactionreported has been "the pain of the shot."

The degree and duration of responsiveness toHGH administration, however, are variable.Blood tests reveal that three-fourths of all treatedpatients develop antibodies to administeredHGH. This antibody formation markedly re-duces the growth stimulation of the injected hor-mone. In some instances of extreme antibodyreaction, patients develop a treatment insensitiv-ity which causes them to stop growing entirely.Unfortunately, in one out of every 10 to 20patients, resistance to the injected hormone re-sults in a complete halt to growth long before thedesired increase has been attained.

Each week of treatment for the average hypo-pituitary child requires the hormone extractedfrom two human pituitary glands. At present,only one-tenth of the human growth hormoneneeded for both research and treatment is avail-able in this country. Since only 10-15 percentof all dwarfism is caused by a lack of HGH, thesmall hypopituitary group is the only logical onefor hormone replacement therapy. The radio-immunoassay test has replaced the crude meas-ures previously used to determine HGH bloodlevel. In addition to enabling positive identifica-tion of the disorder so that precious supplies ofHGH might be conserved, the sensitivity of thistest also allows clinicians to make the diagnosisof hypopituitary dwarfism, and initiate treatment,long before retarded growth has progressed tothe point that the condition is clearly apparentbut irreversible.

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HGH supplies remain in such scarcity thatpriority for treatment is highest in the older childwhose epiphyses are near closure; once epiphysesarc closed, growth cannot be resumed by anyknown means. Also, in order that the limited sup-ply of HGH may be allocated to the maximumnumber of patients, therapy must usually be dis-continued once a child is brought up to theheight of 5 feet.

In 1963, as part of an effort to secure largerquantities of HGH for research and treatment,the College of American Pathologists and theNational Institute of Arthritis and MetabolicDiseases of the National Institutes of Healthestablished the National Pituitary Agency. Pitui-tary glands can be willed to this organization. Inaddition, the Agency is part of a cooperative proj-ect, in which many General Clinical ResearchCenters are included, that is attempting to definethe most economical and effective dosage scheduleof HGH. Finally, a search has been launched foranother growth hormone preparation whicheither can resist antibody formation or which,for whatever reason, does not have a waning effecton growth.

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One of the studies showing promise at a Gen-eral Clinical Research Center is the use of humanplacental lactogen as an HGH substitute. Thishormone, manufactured normally by the placentaduring pregnancy, may have a growth hormoneeffect on the growing fetus and, therefore, maybe a useful preparation to administer to childrenof short stature. At present, however, the processof refining human placental lactogen remains tooexpensive and time consuming to allow its use asa practical alternative to HGH for therapy.

Another line of research derives from the factthat growth hormonc removed from human ca-davers is an extremely large protein molecule.That portion wherein the growth-stimulating ac-tivity is locatedthe active sitelikely constitutesonly a small portion of the entire molecule. If thisactive site can be identified and its structure ana-lyzed, its relatively small size should make possiblethe manufacture in the laboratory of a syntheticgrowth stimulator in quantities sufficient to treatall deficient children.

In fact, an initial effort to isolate this site chemi-cally has recently proved successful. The synthe-sized protein contains 188 amino acids. Althoughit is only a small portion of the complete HGHmolecule, its synthesis is one of the most com-plex achievements to date in protein chemistry.The protein at present is only 10 percent as ac-tive as human growth hormonc; therefore, theprocess of analysis and synthesis must be furtherrefined before a compound sufficiently potent forpatient therapy can be made. However, when thatday comes, pediatricians may be dispensing agrowth hormone to hypopituitary dwarfs asreadily as they now provide insulin to youngdiabetics.

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Deficiency in HGH during the period of child-hood growth is but one of the defects which maybe associated with the hormone. Giantism andacromegalv, both extremely rare disorders, resultfrom excess secretion by the pituitary of 2 to10 times the normal amounts of growth hormone.

If excess secretion of HGH occurs during child-hood or puberty, when the epiphyses are open andbone growth can still occur, its overabundancecauses the long bones to undergo enormous sizeincreases, and giantism results. Acromegaly, onthe other hand, occurs when excessive HGH se-cretion begins only after the epiphyses arc closed.In this disorder, since no further growth in thelength of long bones can occur, the overgrowthproduced is disproportionate; a patient's heightmay remain the same, but there can be grotesqueincrease in size of fingers, toes, forehead, jaw, andinternal organs.

Usually, both patients with ac romegaly andpatients with giantism have markedly elevatedsecretions of insulin. As insulin ten to decreaseblood sugar levels and human growth hormonetends to elevate them, this hypersccretion of in-sulin is probably a physiologic compensation bythe body to maintain blood sugar at normal levelsin face of the tendency of the excess HGH to ele-vate them. Frequently, over time, the ability ofthe pancreas to secrete insulin is exhausted, andthe patient develops clinical diabetes.

As in so many ;treats of endocrinological re-search and treatment, the radioimmunoassaymethod to measure hormone levels has dramati-cally improved the outlook for potential giantsand acromegalics. The effective treatment foreither condition is the removal of the pituitarysurgically or its destruction by radiation; how-ever, all excess growth which has occurred priorto the time of pituitary ablation is permanent andcannot be reversed. Since radioimmunoassayallows physicians to detect pathologic hypersecre-tion of growth hormone very early, both diseasesmay now be diagnosed and treatment institutedlong before body growth has become obviously,and irreversibly, distorted.

In addition to growth hormone, the pituitarygland secretes other hormones which are indirectlyrelated to growth. These trophic, or sustaining,hormones control the secretion of other hormonesmore directly involved in human growth. Thetrophic hormones are thyrotrophin (which stimu-lates the thyroid gland to secrete thyroxine), theadrenocorticotrophic hormone, ACTH (whichstimulates secretion of steroid hormones by thecortex of the adrenal glands), and the gonado-trophins (which control production of sex hor-mones from the ovaries and testes).

There is a feedback mechanism by which eachof the hormones stimulated in turn regulates therelease of its own trophic hormone. The stimu-lated hormones first act on the hypothalamus,the area at the base of the brain to which thepituitary stalk is attached. The hypothalamus in

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turn releases chemical substances which flowthrough specialized veins to the pituitary glandand which inhibit or stimulate the release by itof trophic hormones.

Thyroxine, produced by the thyroid gland (amass of endocrine tissue located in front of thewindpipe), was one of the first hormones to beidentified as important in growth regulation.Thyroxine alone is not capable of producing nor-mal growth; however, its presence is essentialfor normal growth to occur. Some hypopituitarydwarfs lack sufficient quantities of both thyroxineand human growth hormone. They will grow onlyif thyroxine is administered concomitant withHGH.

As opposed to growth hormone deficiency,which produces proportionate short stature andno loss of intellect, thyroxine lack during thegrowth years can result in stunted growth inwhich bone development is disproportionate andmental capacity almost invariably defective.

The disorder can start during the prenatalperiod. If fetal thyroid tissue develops inade-quately during pregnancy, the affected newbornmay be severely retarded both intellectually andphysically. Although such congenitally deficientchildren, known as cretins, have a good chanceof attaining normal stature if thyroid therapy isinstituted at the time of birth, only a small num-ber are ever able to attain normal mentalcapacity.

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Today, a pregnant woman who is expectedto give birth to a cretinous child is given massivedoses of one of the thyroid hormones. Becauseof concentration effect, some of the hormonepasses through the placenta and permits the fetusto develop normally. After birth, for normalgrowth to occur, the child must continue to re-ceive the hormone throughout life.

A deficiency of thyroxine, which begins at anytime after birth, is known as hypothyroidism. Forunknown reasons, a growing child with hypo-thyroidism has excessively large cells and, there-fore, a reduced number of cells for his body size.He grows at one-half the normal rate, and ifthe condition remains untreated, he can developall the symptoms of cretinism. In an affectedchild, thyroxine treatment restores cell size to nor-mal and increases growth to three times the pre-treatment rate until his size again approximatesthat normal for this age.

Cortisone, a steroid hormone put out by thecortex of the adrenal glands, is essential to a num-ber of physiologic functions. It requires pituitaryadrenocorticotrophic hormone (ACTH) for itssecretion. Since hypopituitary dwarfs also tend tohave low levels of ACTH, both cortisone andHGH must sometimes be administered to them.

32 34

Unfortunately, the dominant effects on growthof cortisone oppose those of HGH. For example,children who secrete normal amounts of HGHbut for various reasons require cortisone therapyfrequently experience slowdowns in growth. Con-sequently, investigators at a number of GeneralClinical Research Centers in recent years havetraced the lack of therapeutic response to HGHseen in some hypopituitary dwarfs to the com-petitive activity of concurrently administered cor-tisone. When thd cortisone regimen is eliminatedor, if essential, its dosage schedule optimally ad-justed, these patients immediately spurt in growth.

The male hormones (androgens), of whichtestosterone is the one best characterized, arc ex-creted by the testes. The female hormones,estrogen and progesterone, arc secreted by theovaries. However, in both sexes both female hor-mones and androgens are also excreted in rela-tively small, appropriately different amounts bythe cortex of the adrenal glands.

The output of adrenal androgens in boys andgirls is radically increased during puberty, whenthe adrenal glands become unusually responsiveto ACTH. Recent scientific information indicatesthat the increased androgens initiate the growthspurt preceding adulthood, help prepare the bodyfor its adult reproductive function, and stimulate,in concert with other hormones, the closure ofthe epiphyses. Therefore, although androgensstimulate the adolescent growth spurt throughtheir action on epiphyses, they also promote theprocess by which bone growth is terminated. Thefinal stature attained by a young adult is in partthe resultant of these two conflicting activities.

Two remaining hormones are of particular sig-nificance in the growth of human beingscal-citonin and parathormonc. Calcitonin, a recentlydiscovered hormone, is a regulator of calciumand is excreted by the thyroid gland. Currentopinion holds that calcitonin production is stimu-lated by an increase in calcium levels in theblood. The hormone, in turn, promotes the uptakeby bone of calcium and thereby leads to reduc-tion of blood calcium levels to normal.

Parathormone is excreted by the parathyroids,tiny glands imbedded in the thyroid gland. Para-thormonc excretion is stimulated by a fall ofblood calcium levels. Through a number of mech-anisms, one of which is the promotion of cal-cium flow from bone into the blood stream, itacts to increase blood calcium levels to normal.

The two hormones, although derived fromdifferent glands, together function as an ex-quisitely sensitive control mechanism to maintainblood calcium levels within closely defined normallimits. Their principal importance to humangrowth seems to be their influence on the miner-alization of bone. Derangement in secretion ofeither can have profound effects upon the devel-opment of bone and, thereby, on the entire growthprocess.

Of curious interest is the fact that of all themany hormones which are important in the regu-lation of human growth, calcitonin and para-thormone arc the only two, so far as is known,which are not under the direct control of thepituitary gland.

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.1

Effects of Illness

Steady continuous growth during childhood re-quires careful synchrony of body activities andefficient utilization of energy available. Any ill-ness which disrupts this synchrony or which di-verts excessive energy to itself will likely disruptor retard normal growth processes. Study of therelationship between illness and growth is of par-ticular importance in that many growth disturb-ances evolve so slowly they are unapparent clini-cally, or even on X-ray, until the stage at whichirreversible damage has occurred. Conversely, anobservable growth deformitymay be the first, andsometimes the only, sign of a number of underly-ing causes which, if not detected and overcome,may have adverse effects far more serious thanthe growth disruptions they produce.

The entire physiology of the child is builtaround the growth process. Unless a health prob-lem intervenes to block his inherent tendency togrow, a youngster rarely stops working to achieveappropriate increases in height and weight; how-ever, investigators remain mystified as to howmany diseases produce their detrimental effect.

Some disorders slow proportionately the entiregrowth process. Congenital deficiency of humangrowth hormone produces a form of dwarfismin which a normally proportioned small adultresults. Other disorders affect only one componentof growth, making it disharmonious. For exam-ple, desultory inflammation of epiphyses can pre-

34

maturely fuse the growing ends of bones andshorten permanently one or more affected limbs.

Many illnesses produce adverse effects ongrowth by compromising the ability of the bodyto function at peak health. A common example issecondary malnutrition, in which an intestinalobstruction or cellular anomaly interferes withthe proper absorption and use of food.

Fifteen years ago, there were few remedies forsecondary malnutrition. Medical research hassince progressed to the point that restoration ofadequate nutrition in affected children is now therule rather than the exception.

One specific form of secondary malnutritionfor which therapy is available is found in thoseinfants who lack a digestive enzyme needed toconvert the sugar in cow's milk to a kind that canbe absorbed. This condition exists in 70 percentof American Negroes. In adults, of course, theenzyme deficiency is annoying but not life- orgrowth-threatening. However, since cow's milkis virtually the entire diet of most newborns inthe United States, infants lacking the enzymefrequently suffer severe diarrhea, intense discom-fort, and pronounced growth retardation. In moresevere cases, the infant may die. Scientific investi-gators have developed soybean and other non-milk formulas which contain sugars that can bedigested and absorbed by affected newborns.These formUlas can totally alleviate the ill effectsof the enzyme deficiency.

36

Another secondary form of malnutrition whichcan retard growth is sprue. At one General Clin-ical Research Center, studies have shown thatin sprue patients, glutena protein found in manycereal floursstimulates abnormal structural andfunctional changes in the cells lining the intestinalwall. These abnormal changes inhibit the youngchild's ability to absorb nutrients into the bloodstream. Most ill children who are placed on agluten-free diet recover their health and withina year begin to grow normally. Many subse-quently lose entirely their abnormal sensitivity tothe wheat protein and are able to return for theremainder of their lives to normal diets.

In general, therapeutic diets have been, or arcin the process of being, developed for a widevariety of food-related disorders that can pro-duce growth retardation. As in the case of sprue,some diets have been developed in which a singledamaging nutrient is omitted. In other diets, aprecursor of an unabsorbable substance, such asa vitamin, is fed in such large quantities that someof it is by concentration gradient forced throughthe intestinal wall into the blood stream andsubsequently converted into the needed dietaryproduct.

Infants with chronic diarrhea, congenital phys-ical obstruction of the esophagus, ineffective swal-lowing reflexes due to prematurity, or a host ofother difficulties that prevent the proper intakeand intestinal absorption of food can now fre-quently be nourished through use of a new tech-nique developed at a General Clinical ResearchCenter. The new techniqueintravenous hyper-alimentationallows the stomach and the intes-

37

tines to be bypassed completely; amino acids, fats,sugar, vitamins, and minerals are all injectedthrough the veins directly into the blood stream,from where they may be taken up directly bythe cells.

Vitamins arc chemical compounds, normalconstituents of a balanced diet, which are neces-sary for a number of metabolic processes in thebody. Childhood deficiency of any of the manyknown vitamins can lead to serious distortionsin growth. Too, particularly in highly developednations, scientists have in recent years been char-acterizing disorders resulting from excess intakeof a number of vitamins.

Vitamin A deficiency, for example, has longbeen known to thicken the long bones of a grow-ing child and lead to growth retardation. A morerecent finding in the United States, however, isthat excess intake of vitamin A may also producegrowth failure. Bone modeling is speeded lip, andthin bones are developed which are prone to frac-ture and sometimes fatal internal hemorrhage.Many clinical investigators now believe that theuse of vitamin A supplements in foods representsan unnecessary hazard to the growing child, par-ticularly since most children in this country derivesufficient amounts of vitamin A from their diet.

Vitamin D is required for the uptake of calciumfrom the intestine and is thereby essential forthe adequate mineralization of growing bone. Itsabsence in the diet can give rise to ricketsadisease characterized by soft bones, bowed legs,and cartilage that fails to mineralize adequately.In the late 1930's, irradiated milk was put on themarket, making vitamin D readily available inthe diets of most infants and children, and ricketsbegin to become in this country a disease of thepast.

35

Recent research findings have intiicated, how-ever, that a small number of children have a low-ered response to vitamin D and may appeardeficient despite an adequate amount of thevitamin in the diet. The insensitivity, which doesnot become of importance until after birth, iscaused by a number of different biochemical ab-normalities, may show several distinct patterns ofinheritance, and can present an unpredictablevariety of symptoms. Some of the victims are shortbut not dwarfed. Others may develop signs andsymptoms of classical rickets within months oreven years after birth.

The most common form of the disorder is acondition known as primary hvpophosphatemicvitamin D resistant rickets. The condition isfrequently sex-linked; a mother carrying theabnormal gene may he without the disease herselfand yet pass the gene and the resulting clinicaldisorder to a son. The inability to respond ade-quately to normal amounts of vitamin D may alsobe due to a second disorder in which the kidneysfail for some reason to reabsorb sufficient quanti-ties of phosphorous. The unabsorbed mineralescapes in the urine and is unavailable for incor-poration into growing bones.

36 38

until recently, therapy for both of these dis-orders consisted of administering massive amountsof vitamin D in order to build very high bloodlevels. This therapy was thought to work due tothe "pressure" of the high concentration of thevitamin overwhelming a block in a defective bio-chemical pathway. Such therapy, however, had tobe exceptionally judicious because very high levelsof vitamin D can produce serious injury to thekidneys.

Partial circumvention of this possible side effectresulted from a therapeutic innovation of oneGeneral Clinical Research Center. There, inves-tigators initiated use of a secondary form of vita-min D which works more quickly, is used up morerapidly, and therefore incorporates less threat ofinjuring the kidneys than does an overload of theprimary natural form.

An even more promising therapy has recentlybeen reported by researchers at another GeneralClinical Research Center. Scientists there theo-rized that a patient's inability to utilize normalamounts of vitamin D might be due to deficiencyof an enzyme which in normal people acts to con-vert the natural vitamin into an active form. Toevaluate this premise, they administered increas-ingly large, thrice-daily doses of the activatedvitamin D to five patients insenstitive to thenatural form. During 10 months of treatment atthe research center, dramatic clinical, chemical,and X-ray improvements have been observed, andthere is to date no evidence of side effects orkidney damage.

Recent evidence has indicated that parents whocarry genes for a vitamin D insensitivity, and whodo not display the MI form of the disease them-selves, have, nevertheless, certain blood abnormal-ities which reflect the genetic defect. A low con-centration of phosphorous in the blood is one ofthe abnormalities. If vitamin D insensitivity hasshown up in his family tree, and if one parent haslow blood phosphorous, an infant should be testedearly to determine if he has inherited, and willeventually exhibit, vitamin D insensitivity .

Early diagnosis is of great significance becausetherapy before 6 months of age usually avertscompletely 'the bone deformities and the growthretardation that might otherwise result. Treat-ment begun at a later age can heal the lesions andpossibly speed up growth, but no one knows ifdelayed therapy can in time fully restore a childto his optimal pattern of growth.

A third inherited lack of vitamin D responsive-ness, which also may cause growth retardationand rickets, is renal tubular acidosis. This condi-tion is caused by excessive excretion in the urineof bicarbonate, which is alkaline. The result isan excess retention of acid within the body. Thisbody .state, known as acidosis, in turn causesexcess elimination of phosphorous in the urine.Consequently, insufficient phosphorous circulatesin the body fluids, and bone mineralization isdefective.

Fortunately, total control of renal tubular aci-dosis is now achieved through the simple tech-nique of feeding sodium and potassium citrate inpalatable fruit-flavored bases. The citrate is me-tabolized into bicarbonate, replacing that lost inthe urine. A normal acid-alkaline ratio is main-tained, and proper mineralization of the bonescan then occur.

39

In recent years, concern has been expressedthat many children are ingesting too mnch,rather than too little, vitamin I), and that thisexcess may cause growth retardation. Recentstudies have shown that many children do indeedreceive moderate overdoses of %.itamin D andthat, consequently, they mar absorb more calciuminto the blood stream than they aced. This excesscalcium has not, however, been related to anygrowth impairment in normal children.

Occasionally, a child dees turn up at a Gen-eral Clinical Research Center suffering fromsevere hypercalcemiaa blood level of calciumsufficiently high to produce deflection in thecourse of growth. A prevailing theory holds thatsuch children have inherited a grossly exaggeratedresponse to even normal doses of vitmoio I).When placed on low calcium diets, these childrenshow remarkable growth improvement.

As scientists isolate more and more disorderswhich affect human growth, an increasing num-ber, such as vitamin I) insensitivity, are provingto be errors of metabolism genetically decreed atthe moment of conception.

37

The structure of proteins synthesized withinthe body is determined by the DNA within thenucleus of cells. Derangement in the placementor internal makeup of a single gene within theDNA can so distort protein synthesis that a pro-tein of markedly abnormal structure is produced.If this protein is integral to an important bio-chemical pathway, the pathway may be blocked.Chemical suhstanccs normally degraded or other-wise acted upon by the pathway may build up topathologically high levels, and essential productsof the reaction may be produced in seriously de-ficient amounts. The effect on the growth proc-ess of this inherited block depends upon theimportance of the pathway, the availability ofalternate competent pathways, the age at whichthe blocked pathWay becomes significant, and,finally, upon the external factors operatingconcomitantly.

Sickle cell anemia is an inherited cause ofgrowth retardation which is found only amongblack people. This trait may have evolved as avaluable adaptation to life in Africa, wheremalaria is endemic. The abnormal hemoglobinresponsible for the unique sickle shape of the redblood cells provides resistance to malaria para-sites. Chronic anemia, however, results becauseof a decreased capacity of these sickle-shapedblood cells to carry oxygen.

Children with this inherited disorder may growwithin normal limits; however, one study hasshown that, as a group, they weigh less, areshorter, and have a thinner body build than eithertheir normal siblings or normal no nblack children.Repeated blood transfusions, given in the past toaffected children as a research treatment, tem-porarily relieved them of anemia and placedthem in higher growth curves. Therapy had to

he discontinued, however, because the ill effectsproduced by repeated transfusions were foundto pose a greater threat to health. than did slowgrowth. The researchers felt that in view ofthe limited ability of these children to oxygenateadditional tissue, being small might well be anadvantage.

A much more rare, but treatable, inherited ail-ment is acrodennatitis cnteropathica. This dis-ease, which may he fatal if left untreated, is char-acterized by dwarfism and persistent fungus in-fections of the skin. It results from an inabilityof the affected child to manufacture or metabolizethe unsaturated fatty acids needed to maintaingrowth and skin integrity. Breast feeding preventsexpression of the disease for a time. Cow's milk,which has a higher proportion of nonhuman un-saturated fatty acids, exacerbates it.

A number of infants severely ill with acroder-matitis enteropathica arc today responding dra-matically to simple injections of cottonseed oil.Once these injections bring the disease under con-trol, a drug which has been used for over half acentury to treat yeast infections unexplainedlycan take over to control all further symptoms. Infact, only now is it apparent that some adults who,as children, had been routinely prescribed thedrug for yeast infections might well have "grownup" to be dwarfs had not their basic disease beenaccidently treated at the same time.

The need for the drug persists throughout life.Investigation has just been launched to study thedrug's relation to fatty acid metabolism and todetermine how it works.

Acrodcrm a t i tis enteropathica and its empiricaltreatment is a prime example of how science canoften control a genetically determined metabolicerror even before the underlying biochemical de-fect is fully understood.

In recent years, great strides have been madein identifying and distinguishing an array of en-zymatic malfunctions, all of which result in dis-proportionate dwarfism. Individuals affected withthese enzymatic disorders, who were once giventhe catch-all diagnosis of achondroplasia, tend topossess a normal length trunk; however, theirlimbs are too short and their heads are too largefor either their chronological or biological age.The lack of synchronous growth is clue to the factthat the forMation of cartilage, and its replace-ment with bone, is irregular throughout theskeleton.

Classical achondroplasia has now been identi-fied by a General Clinical Research Center as aspecific. illness in which cartilage formation ac-tually proceeds in an orderly fashion; subsequentbone formation, however, is too slow to keep pactwith both the normal development of connectivetissues covering the bones and the closing downof the epiphyses.

The same General Clinical Research Center hasshown another type of disproportionate dwarfismto result from markedly disordered cartilage for-mation. During the prenatal period, this disordercan. result in an abnormally narrow chest which,by restricting breathing, can cause death soonafter the newborn becomes dependent on his ownlung capacity.

As in vitamin D insensitivity, when a growthdisorder is inherited, the defective gene may havealso expressed itself by an observable abnormality

in the parent. More often, however, the geneticaberration in one strand of parental DNA is over-come by the normal functioning of the pairedgene in the parallel strand of DNA; in this case,the resulting illness is minimally or not at alldetectable in the parent. The aberrant gene isthen said to be recessive. Its adverse influence isovercome by the normal, or dominant. gene withwhich it is paired.

If both parents contain a recessive abnormalgene controlling the same function, one out ofevery four children produced by the two willlikely receive a pair of recessives, one from thegerm cell of each parent. The affected child willhave no dominant normal gene, and the abnormalfunction will be expressed fully in him.

The recessive method of inheritance is commonto a wide variety of genetic disorders. (Other in-herited metabolic errors have more complex meth-ods of transmission.) Sometimes, however, themetabolic error may represent a fresh mutationin an isolated gene. This mutation may resultfrom an external influence such as German

41 39

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measles, parental age, radiation, or drugs actingadversely on either the germ or the fetal cells.In such cases, there is no statistical pattern ofinheritance, and parents of an afflicted child needhave little fear of recurrence in future offspring.

One illustration of a fresh mutation resultingin a slow rate of growth after birth is mongolismor Down's syndrome. Only one-half of 1 percentof parents stand a chance of bearing such a child;this rate applies whether or not the family hasalready had a mongol child. The disorder cannotbe cured, but since fetal cells arc constantly castoff into the amniotic fluid in which the growingchild is suspended, amniocentesis by the 14th weekof intrauterine life can now reveal if the fetus iscarrying the defect.

Turner's syndrome and Hurler's syndrome aretwo other classic: examples of inherited, potentiallygrowth-retarding diseases which can be diagnosedin intrauterine life by amniocentesis.

Minor symptoms which are themselves of littleimmediate consequence to the patient may serveas diagnositic clues to serious illnesses which mayin the future severely retard growth. For example,only recently has it been discovered that a com-bination of slightly elevated temperature, greaterthan normal intake of oxygen, numerous nose-bleeds, and excessive perspiration can hint at thepresence of osteogencsis iniperfecta. This disorderin time results in bones which are brittle, thin, andfragile; an afflicted infant can suffer broken bonesjust from having his diaper changed. The bonesin the car arc also frequently affected. Some casesarc inherited from parents with defective genes;others are the result of fresh genetic mutations.

4240

The affected child usually grows normally atfirst. But, over the years, growth become:4stuntcd,and repeated fractures keep him not only fromnormal play but even from attending school.

Until 1968, no medical help was available.Now, during a second year of experimental treat-ment, osteogenesis imperfccta patients who havebeen prescribed capsules of magnesium oxide aredemonstrating a 50-percent reduction in fracturerate and arc putting on needed weight. Since thebones of many treated patients have already un-dergone irreversible deformity, the ultimate effectof this medication on height gain is still too meagerto assess. However, investigators feel that theearlier the diagnosis is made and therapy initiated,the greater is the chance that the affeoed childmay achieve near-normal patterns of growth.

Growth of children born with heart disease,whether congenital or inherited, often lags as

much as 2 years behind that of their peers. By thetime the child with a severe congenital heart con-dition reaches his fifth birthday, he may be bur-dened with a 1% -year growth lag. Extensivestudies of these youngsters are being conductedby investigators at a number of General ClinicalResearch Centers.

One finding is that the severity of the growthlag tends to parallel the severity of the heart de-fect. In only a limited number of specific: heartdisorders, however, does growth retardation seemto stem directly from a reduced ability of theheart to circulate blood to the growing bodytissues.

Clinical research center researchers have alsofound that many children with heart disease havean almost normal number of body cells for theirsize but not for their age. Some of the cells areabnormally large, while others arc abnormally

small. These cellular anomalies may result froman inefficient transport into the cells of aminoacids needed for protein synthesis, or they mayresult from excessive whole body intake of oxygen.They could also result from unknown effects ofheart ailments which stimulate or inhibit calorieor protein metabolism.

In almost all cases in which an underlyingillness has retarded growth, the stunted child canshow almost magical powers of compensatorygrowth once the illness has been adequatelytreated. Not all heart victims improve theirgrowthrate after corrective surgery, but in most accelera-tion does take place within 2 years followingthe correction. The most dramatic growth isexperienced by a child in whom a major, con-genitally narrowed artery between the heart andlungs is widened surgically. This youngster cangain as much as 4 years of biological age withina 6-month growth spurt, which brings him nearthe same point he would have reached had henever suffered the defect.

In other examples, the growth of one 12-year-old boy successfully treated for hypothyroidismaccelelitted to the rate experienced by a 1 /2-year-old child. Once a 4-year-old girl had a tumorremoved from her adrenal glands, she began togrow at the rate of a child of 6 months.

In almost all cases, a slowdown follows on theheels of the initial catchup spurt of growth; thechildren do not "overshoot" the mark. Investi-gators suspect that some unidentified mechanismattempts to return children to normal patterns ofgrowth even after significant deviations have oc-curred. This regulative force abiders by manyof the rules of normal growth.

43

Usually, the growth of a boy is much moreadversely affected than is that of a girl sufferingthe same medical disorder. Once relieved of thefactor that caused the growth lag, however, theboy tends to compensate more quickly than doesthe girl. For both sexes, the earlier the underlyingillness is successfully treated, the more rapid isthe rate of catchup growth. By the same token,correction of an illness in later childhood tendsto result in a slower rate of catchup growth andis less likely to allow either boy or girl to grow tofull potential height.

Weight deficits after illness are usually the mosteasily overcome. Short stature, the most commondisorder of growth, corrects itself less rapidly.Bone maturation, and therefore biological age,is the slowest of the growth parameters to accel-erate. For some children, it is almost as if a suc-cessfully treated illness signals the body to delayits maturation, and the resultant closure of epiph-yses, until the bones have had time to grow totheir full length.

41

Effects of Emotion

The hierarchy of neural and endocrine systemsinfluencing growth appears akin to "the housethat Jack built." The pituitary gland is underthe control of the hypothalamus., an area at thebase of the brain where unconscious activitiesappear to be initiated. It, in turn, is controlledby higher centers in the nervous system, whichthemselves are responsive to the cerebral cortex,the portion of the brain presumed responsiblefor complex and conscious thought. How thecerebral cortex ultimately controls the hypothala-mus has always intrigued physicians. To thislay, the mechanisms arc poorly understood, butthey are under increasingly intense investigationbecause they-constitute a physiological means bywhich basic body processes can be influenced byemotion.

Healthy infants living in institutions frequentlyfail to develop normally. Their failure to thrivehas traditionally been attributed to the effects of"emotional deprivation." As a result, social workagencies seek foster home care as an alternativeto institutionalization whenever feasible. Thetheory is that in a private home the child canbenefit from the emotional warmth, physical han-dling, social contact, and sensory stimulationprovided by intimate contact with an adequatemother figure. In general, the younger the child,the greater his need for a mother-substitute.

42

But the home atmosphere some children livein is very deprived. As an example, few physi-cians can recall a single instance in which anemotionally deprived, inadequately growing childwas spontaneously brought for treatment byworried parents. Instead, almost all cases ofgrowth lag are referred by third parties, suchas schools, relatives, or other physicians.

Impetus for research on the effect of emotionaldeprivation on growth and development came inthe middle 1960's. Investigators at two GeneralClinical Research Centers independently reportedthat a number of children suspected of hypopi-tuitary dwarfism began growing rapidly after theywere admitted to the research center and longbefore institution of HGH therapy.

Many of these children displayed such classicalsigns of hypopituitary dwarfism as low HGHlevels, retarded growth, delayed hone and sexualmaturation, and ACTH insufficiency. However,social work investigation revealed a number ofunusual factons, .The children were exceedinglyshy and immature. They came from environmentstorn by emotional strife, and they were usuallyrejected by one or both parents. A few patientseven showed overt or X-ray evidence of havingbeen physically beaten.

44

In one of the research center studies, childrenwhOse growth retardation was suspected to becaused by emotional deprivation were followedover a 5 -year period. For 22 cases in whom noother cause of growth failure could be docu-mental, the median agc at admission, was 6years, but the median bone age was only 3Y2years. The growth rate of nine of the patientsthose who could be evaluated before hospitaliza-tionwas only 1.4 inches a year.

Most of the children in this study were paleand pathologically short. Many also showed sig-nificant retardation in social, motor, and intellec-tual development. They did not play well withsiblings or other children. The infants in thegroup were lethargic, and some had a wide-eyedsearching look, known as "radar-like" gaze.

Separation from parents was the principaltherapy received by these children. In general,standard pediatric nursing care and normal dietswere provided in the hospital. No special caloriesor protein rations were offered, and medicationwas generally limited to vitamins and iron.

Despite the paucity of treatment, the majorityof the children showed dramatic response. Theirrate of growth increased to as much as 6.3 inchesa year. In addition, most showed marked physi-cal, emotional, and social improvement by thetime they were dismissal from the hospital.

Followup studies revealed that those childrensubsequently referred to foster care or convales-cent homes continued to display significant catch-up growth. On the other hand, the children whoreturned to their own homes frequently tailedto return for followup appointments. Except inthose instances in which the home situation hadimproved, those who did return tended to displaya slowdown in growth toward earlier depressedlevels.

On the basis of this study, the investigatorsconcluded that these children had normal pitui-tary glands capable of secreting the HG re-quired for adequate growth. Their growth re-tardation appeared clearly clue to the influence ofemotional deprivation which inhibited, through.sonic unknown mechanism inestimably involvingnervous pathways between the cerebral cortex andthe hypothalamus, sufficient release of the hor-mone.

Even tiny infants respond adversely to emo-tional deprivation. Typically, the low birth weightinfant spends the early weeks of life in the hygieni-cally controlled but monotonous environment ofan isolate. He receives maximum physical care.but minimal sensory stimulation. Actual handlingof the child is usually confined to times of feed-ing and diaper changes. One group of GeneralClinical Research Center investigators hypothe-sized that the subsequent lag in intellectual andphysical growth frequently observed in childrenof premature or intrauterine retarded birth mightbe largely due to this emotional isolation imposedupon them in the early weeks of life.

45 43

To study this hypothesis; the investigatorsselected one group of infants within the nurseryfor special stimulation. In addition to usual nurs-ing cart, for 10 days these infants had their backs,necks, and arms rubbed for 5 minutes every hour.Seven to 8 months after discharge from the nurs-ery, the stimulated infants wcrc found to have re-gained their initial birth weight more speedilyand to have developed a more advanced level ofactivity than had a control group of nonstimu-lated infants of the same age. These findingstended again to support the theory that emotionaldeprivation can indeed directly affcct rate of de-Velopment throughout childhood.

Among physicians, however, the existence of ahot -nonally mediated influence of emotion on hu-man growth processes is not universally accepted.One group of investigators, for example, has rc-portcd that growth retardation in emotionally dc-privcd children is morc likely caused by inadc-quatc nutrition. This undoubtedly accounted forthe growth failure in 11 of 13 emotionally de-prived infants who showed significant weight gainin a General Clinical Research Center study inwhich they wcrc intentionally denied emotionalstimulation greater than that which they had rc-ccivcd in their homes. It also seems documentedby another study in which thin, emotionally dc-privcd infants gained weight adequately in theirown homes when fed always in the presence of anobserver.

4644

Investigators studying these children believethat only part, or none, of the growth lag seen inemotionally deprived children stems from thehypothalamus. However, all thc children reportedin these two studies were under 3 years of age andprobably wcrc not comparable to the older chil-dren described in the preceding discussions. In thclatter groups, hypothalamic inhibition of growthhormone release, not nutritional inadequacy,remains the more likcly cause of growth failure.

It is true that parents frequently report feedingproblems in their emotionally dcprivcd, slowgrowing children. However, paradoxically, theymost often report that their children developedvoracious appetites in the first weeks of life thatcould be satisfied only with great difficulty. As thcchildren grew older and continued to demandexcessive quantities of food, the parents frc-qucntly made an attempt to limit their foodintake. Sometimes, children wcrc locked in theirrooms or out of their homes to keep thcm awayfrom food and drink. The children were said toraid garbage cans and animal dishes and to drinkfrom toilets and mud puddles. They slept poorlyand prowled at night, ostensibly looking for some-thing to cat. Stealing and hiding food were com-mon phenomena.

Some researchers have suggested that the con-tradiction between the "hormone" theory and"nutrition" theory of growth retardation in emo-tionally deprived children is only apparent. Theymaintain that there is a hypothalamic influenceon growth but that this influence is mediated notthrough inhibition of HGH secretion but ratherthrough a blockage of intestinal absorption andefficient assimilation of nutrients. Certainly, otherdisorders of digestion arc known to have psycho-somatic origin, and this theory would explain the

seeming paradox of poor growth in these childrendespite excessive food intake.

A study of the effects of anxiety on digestion hasbeen conducted at a General Clinical ResearchCenter. College students were found to requiresignificantly increased protein intake to maintainthe stepped-up metabolic activity produced bythe stress of preparing for and taking final exam-inations. This result has been interpreted as lend-ing support to yet another theorythat stress oremotional deprivation may interfere with theaction of insulin and, therefore, with the appropri-ate utilization within the body of sugar andprotein.

Thus, the evidence is clear that emotionaldeprivation can in fact seriously retard growthprocesses in children. To date, a variety ofmechanisms have been proposed to explain howthis adverse influence is exerted, and others willlikely be advanced in the future. Detailed under-standing of how emotions affect growth, however,must in all probability await an even more refinedunderstanding of the process of growth itself.

4745

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The psychology of adolescence has been studiedfor many years. Only since 1960, however, havemedical scientists appreciated that the physiologyof adolescence is sufficiently unique to warrantit as a specialized field of study.

Puberty begins when the pituitary gland startsto secrete the gonadotrophins and the gonads,under their influence, begin to release sex hor-mones. No one knows what triggers the pituitaryto begin this secretion or how the time of onset issynchronized with other body processes.

Each individual child, however, appears genet-ically programed for maturation. Indeed, pubertyhas now been shown to be the first time in thelife of the normal child when heredity over-shadows environment in determining how he willgrow. Even among abnormally short children, the"least short" are usually the offspring of the tall-est parents. Thus, although environmental fac-tors are causing children of the United Statestoday to enter puberty 3 years earlier than theydid a century ago, heredity remains the primaryreason tall parents beget tall adults, and short par-ents short adults.

Until the age of 10, boys and girls grow atalmost identical rates. Children sharing the samechronological age vary only slightly in size. How-ever, regardless of chronological age, the moreadvanced the biological age of any child, thecloser he is to sexual maturation and the lessgrowth potential he retains. Thus, just as thefemale comes into life with a more advancedbiological age (as measured by bone age), soshe enters puberty earlier and emerges from itan adult shorter than her male counterpart.

Puberty usually begins only after at least 85percent of eventual height has been achieved. Itsonset is marked typically by the beginning ofbreast development in the female and by genitalchanges in the male. And, although the initialmanifestations may be subtle, the growth, thesexual development, and the emotional changeswhich subsequently characterize puberty can besufficiently dramatic to make it as difficult a timeas any the human must endure.

In both sexes, adrenal androgen appears to beinstrumental in initiating the pubescent growthspurt. During the growth spurt, feet and handsfirst increase in size. The calves and forearms, thehips and chest, and the shoulders then follow,in that order. Because the last to increase is thesize of the trunk and chest, the young teenagermust almost invariably pass through a transitionalstage where his hands and feet arc large and un-gainly relative to the rest of his body. However,the rate of growth of the trunk in time exceedsthat of the lower limbs, and the overall increasein height which occurs during adolescence even-tually is derived more from increase in length ofthe trunk than from growth of the legs.

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Although there may be a variation of 3 yearsbetween the beginning of the growth spurt inone normal child and another, the typical girl inthe United States now begins puberty at the ageof 101/4. For the next 21/2 years, she grows atan average annual rate of 3 inches per year. Withthe onset of the menstrual cycle, about age 13,the adolescent girl then experiences a rapid de-cline in growth rate but will continue to grow,at a reduced pace, for another 3 years. By theage of 16, her epiphyses are usually closed, andfurther increase in height is impossible.

The average adolescent boy, on the other hand,is only beginning his growth spurt at age 13. Itwill usually be more marked, more intense, andof longer duration than that of the girl. Forexample, during the next 21/2 years, when hisheight is increasing most rapidly, the adolescentboy usually grows at least 4 inches a year. Thisis close to the dramatic rate of growth experi-enced by 2 -year -olds. By the time he is 15, he willbe eating seven times more protein and 50 per-cent more calories than he consumed at 'age 9.Between the ages of 12 and 16, he will almostdouble in weight.

Although the teenage boy will experience ulti-mately a decrease in growth rate (and appetite),his decrease is not so precipitous as that of thegirl. The epiphyses of his long bones usually donot close, and his increase in height is not over,until he reaches his late teens.

Perhaps as dramatic as the increase in bodysize which occurs during puberty is the concomi-tant development of male and female sexualcharacteristics. The pubescent girl developsrounded contours by accumulating fat on the

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breasts, hips, and thighs. The boy, on the otherhand, becomes during puberty more lean thanhe will ever be again. The pelvis of the girl en-larges more than do her shoulders; in this way, sheis prepared for childbearing. The shoulders andchest of the boy increase more in size than doeshis pelvis, and his total muscle mass makes tre-mendous competitive gains.

Bone age is a measure of degree of closure ofthe epiphyses. Since an adolescent may continueto amass new cells for some time after his epiph-yses have closed and his height has stabilized,bone age cannot be used to determine whenpuberty is complete and adulthood achieved.After full adulthood is reached, however, net in-crease in total number of body cells does not usu-ally occur; reproduction of cells does continuethroughout adult life, but its rate is usually syn-chronized with cell destruction so that new cellsjust replace those which arc lost. Adulthood, andthe end of puberty, therefore, may be definedscientifically as the time a steady state of cellpopulation is finally attained.

Obesity

Many of the medical disorders which disturb themiddle-aged and the aged have subtle origin dur-ing adolescence. Obesity which develops in child-hood tends to continue to plague the individualthroughout life. Unfortunately, neither the obesechild nor his parents usually become sufficientlyconcerned about his weight until he is rell intopubertywhen weight reduction is next to im-possible. Since excess weight can generate greatanxiety and depression in a teenager, and eventu-ally lead to ill health in adulthood, many clinicalinvestigators in this country are investigating thebiochemical reactions and the control mecha-nisms involved in the storage and breakdown offats in children. From such studies, hopefully, bet-ter methods can be developed to correct obesity inchildhood and prevent its becoming a lifelongproblem.

Fat infants and plump children may appeardelightful to their parents; however, the chancesarc four out of five that the overweight child willbecome an overweight teenager who, in turn, willcarry his problem throughout adulthood. An esti-mated one-tenth to one-fourth of the adolescentsin this country are overweight.

Adolescent girls negatively relate increasingweight with obesity, while boys tend to view in-creasing weight positively as a manifestation ofgrowing strength. One recent study of close to 600high school students showed this disparate, yetmutual, dissatisfaction with weight. Four-fifths

of the girls wanted to weigh less: almost all theboys wanted to weigh more. Only the obviouslyobese among the boys wanted to lose weight.

The young girl emerging into womanhood isfrequently torn between social pressures that placea premium on being slender and a maturingmetabolism that inexorably deposits fat on hergrowing body. From a medical standpoint, thesefat deposits may fall within the range of healthyfemale growth. So great are the pressures, how-ever, that previously thin girls may imagine them-selves doomed to obesity unless thcy diet rigor-ously. These girls constitute a large portion of theAmerican youngsters who, despite access to properfood, exist in a borderline state of nutrition be-cause of ill-advised attempts at weight reduction.Ironically, the diets of overweight girls, whosecaloric intake may even he excessive, are also fre-quently inadequate nutritionally.

To growth researchers, the high correlation be-tween teenage obesity and the incidence of suchdisorders of the later years as hypertension, heartailments, diabetes, and respiratory ills makes ex-cess body fat more a medical than an aestheticconcern. For example, in 85 percent of all adultdiabetics, obesity preceded the onset of the dis-ease. One theory is that excess body fat in someway produces resistance to the activity of insulin,which in turn causes blood sugar levels to in-crease. A compensatory increase in secretion of

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.insulin by the pancreas occurs and, continues untilthe capacity of the pancreas to produce the hor-mone is exhausted. Then, insulin production falls,and clinical diabetes results. Studies of obese in-dividuals who have lost weight indicate, on theother hand, that once normal weight is regained,elevated insulin levels will often return to normal.

Other studies have indicated that atheroscle-rosis (the most common form of hardening of thearteries) may begin in the pubescent male. Au-topsy studies of boys in the late teen years dem-onstrate consistently that the fatty arterial plaqueswhich are the constituent beginnings of athero-sclerosis can begin during adolescence. As athero-sclerosis is the fundamental cause of corollaryartery disease, research into its causation and pre-vention during the adolescent years, and its rela-tion to teenage obesity, may in time have signifi-cant influence in reducing the high mortality ofAmerican men from heart disease.

Unfortunately, physicians have discovered thatfor the medically obese boy or girl, puberty maybe the most difficult time in life to shed excesspounds. The entire physiology of the adolescentis geared to promote growth, and any attempt toreverse any of its growth parameters may be metwith insuperable resistance.

Only temporary decreases in weight have beenexperiewtd by obese adolescents in outpatientweight reduction programs. After I to 2 years,these teenagers have all reverted to their initialobese status. Greater success has frequently beenachieved by teenagers enrolled as inpatients ineither hospital or summer camp-based programs.Yet, even for these young people, long-term main-tenance of relatively reduced weight has yet to beconclusively demonstrated.

For obese teenagers, therefore, an ounce of pre-vention is literally worth a pound of cure. Theevidence is overwhelming that obesity is bestaverted, evaluated, or treated as early in life aspossible.

The most common, and the simplest, procedurefor determining whether an individual is tooheavy is to compare his weight with the weightconsidered normal for one of his height, bodyframe, age, and sex. However, since total bodymass is compoft::: not only of fat but also of bone,muscle, and water, a person may he overweight"by the chart" without being obese. For example,a number of football players were rejected formilitary duty during World War 11 because ofexcess weight. Subsequent analysis revealed thatthey had little excess fat but were heavier thanthe normal weight the tables allowed clue to theirgreat muscle and bone development.

In recent years, more refined research tech-niques have been developed to assess with preci-sion the amount of fat in overweight people. Theyhave arisen from the increased interest of physi-cians in detecting and modifying actual fatnessthe one component of overweight that can, andshould, be reduced.

One technique relies on the principle ofArchimedes. The patient is totally submergedunder water, and the volume of water he dis-placeswhich is equal to his body volumeismeasured. Total body weight divided by meas-ured body volume equals total body density. Since

the densities of fat, bone, muscle, and water areall different, this calculation of hotly density en-ables investigators to determine the proportionof fat in the patient's total weight.

Procedures such as this, however, are too de-tailed for other titan research use. Because halfof all pubescent fat is located immediately be-neath the skin, researchers have found that thethickness of a fold of skin on the hack of theupper arm correlates reasonably well with theamount of body fat present. For example, a 15-year -old girl whose skin fold measures more thanau inch is considered obese. Similarly, a 12-year-old boy with a skin fold thickness of at leastthree-quarters of an inch is also judged obese.

Careful measures of obcsity, conducted in alarge population of people, coupled with studiesof families, documentation of differences in fataccumulation between the sexes, comparisonsamong racial and ethnic groups, and investiga-tions of identical twins reared together and apart,are yielding impressive evidence that genetic fac-tors may be very important in predisposing certainpeople to obesity. Too, heredity may also under-lie why some underweight individuals do not gainweight despite an obviously excessive caloricintake.

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Still unknown, however, is how a genetic pre-disposition to obesity can be reinforced or over-come by such environmental variables asnutrition, occupation, geography, climate, andemotion. One hypothesis, as noted earlier, is thatovcrnutrition in infincy may stimulate into beinga pathologic excess of fat cells which then persistthroughout life and' tend always to become ladenwith fat. Another h)pothesis, being investigatedat a General Clinical Research Center, is thatovernutrition may trigger excess production ofinsulin and HGH in genetically susc.eptibie new -horns, which would also encourage excess fatstorage. If any such hypothesis can be docu-mented unequivocally, then a significant propor-tion of adolescent obesity may in time be ascribedmore to hormonal or genetic influences than tosimple overeating.

Some studies of obese teenage girls have infact shown their daily caloric intake to he lowerthan that of lean controls. A possibility, whichhas not yet been proven, is that these obese girlshave hormonal imbalances which in some fashionresult in depressed estrogen activity. This, in turn,could allow adrenal androgen, present in normalbut limited amount, to exert unopposed its mas-culinizing effects, with resultant weight gain.

However, neither hormonal dysfunction norexcess caloric intake seems to be the single deter-minant of obesity. For example, right from birth,obese children arc decidedly less active than thenonobese. Movies taken during physical educa-tion .-lasses at a swimming pool showed thatthe latter teenagers spent 72 percent of their timestanding around, whereas their normal weightpeers spent 75 percent of their time vigorouslyengaged in water sports.

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The causal relationship between obesity andinactivity is not known. Inactivity may contrib-ute to obesity through reducing the number offood calories which are utilized for energy; alter-nately, the obese child may be inactive as a resultof the heavier weight he must move about. Yet,one fact is certainevery caloric that is spentthrough increased physical activity is one lesscaloric that can be stored as fat.

In a recent test, 100 obese adolescent girls wereenrolled in a public school physical educationprogram which by design kept them in virtuallyconstant motion for 45 minutes each school day.Also included in the program were nutritioneducation, psychological support, and encourage-ment to continue vigorous physical exercise dur-ing days off from school.

After 5 months, the girls were compared witha control group of about 70 nonprogram girls.The study group had decreased skin fold thick-ness an average of 50.5 percent, compared with adecrease of 31.9 percent in the control. group.Average body weight decreased 27.7 percent, asagainst 11.6 percent in nonprogram girls.

As a result of this study, a number of schoolsare instituting physical education classes specifi-cally designed to help the obese child, who in thepast has emerged physiologically untouched (butoften scathed psychologically) from traditionalphysical ed programs that have served only toenhance the skills of the athletically endowed.

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Early and Late Puberty

In adolescent boys, the growth spurt occurs at alater age than in adolescent girls. Asa result, even.a tall boy wants to be taller, and a short boy isfearful he will be short forever. On the otherhand, since the girl shoots up much earlier thanthe boy, she is concerned she will be too tall asan adult and have the same difficulty finding ahusband as she does finding a suitably tall dancepartner. Since the accepted normal height' dif-ferential between men and women does not usu-ally result until the years of puberty are ended.increased understanding of the differences be-tween male and female growth rates duringadolescence permits physicians today to allaymany unwarranted teenage concerns aboutheight. Conversely, researchers are also develop-ing innovative techniques to enable teenagerswith medically confirmed growth problems togrow to a height consistent with their peers.

Heredity, not environment, paces the changesof puberty. Since each individual advances fromchildhood to adulthood at his own geneticallydetermined rate, a teenager cannot validly com-pare himself with others of the same age. Hereditycan either delay biological age and, therefore,growth in the short teenager, or it can usher atall teenager into puberty at an early age.

Recently developed clinical procedures, includ-ing the radioimmunoa.ssay tests, usually revealthat all body systems, in both tall and short teen-agers, arc working harmoniously. X-rays of wrist

epiphyses provide a measure of how far allepiphyses are from closure and, therefore, howmuch linear growth may yet be achieved.

These procedures reinforce more traditionalobservations that tall adolescents usually completegrowth early, whereas short adolescents continueto grow for long periods. The tail girl will usu-ally grow only a little taller; the height of theshort boy can in time exceed that of his tallestfriends. Such information can he of great help inreassuring and allaying the fears of the short boywho is afraid he is not growing enough or the tallgirl who thinks she will be a giant.

A girl will usually have achieved most of heradult height by the time regular menstrual pe-riods begin. The female hormones, estrogen andprogcAerone, are responsible for inducing themenarche. Under their influence, growth quicklyslows down for the adolescent girl and usuallyterminates in 2 to 3 years. This influence is thebasis for administering these hormones to inducegrowth retardation in premenstrual girls whoseapprehension of excessive adult height has beenscientifically confirmed.

Twenty years ago, administration of estrogenwas found inadequate to slow down the girl whowas growing too tall. In addition, considerable"breakthrough" vaginal Needing occurred whenit alone was given as therapy. In more recentyears, however, a research treatment usingestrogen in much larger closes and in combinationwith progesterone has proven very effective, andfew adverse effects have been noted.

One General Clinical Research Center confinesthis research treatment to healthy girls who haveinherited the propensity to be over 5 feet 10 inchesand in whom the wrist epiphyses are still wideopen.

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Each day, thc patient takes estrogen by mouth.The hormonc induces proliferation of the uterinelining, causing it to become progressively soft andthickjust as if the girl were normally ovulatingand the uterus were preparing for implantation ofa fertilized ovum. To preclude this buildup reach-ing a point where excessive bleeding might occur,the uterine lining is caused to slough off by injec-tion of a progesterone -like compound the first 5or 6 days of each month. This duplicates as nearlyas possible the cyclic bleeding brought on by thelarge quantities of progcstcronc produced physio-logically in normally menstruating girls.

In one group of 11 girls, treatment required8 to 24 months. A decrease in the rate of lineargrowth was observed in all. Some girls achievedcomplete growth arrest; others dropped from agrowth rate of 4 inches to four-tenths of an inchper year. For patients whose biological age wasunder 13 whcn treatment was begun, therapy prc-vcntcd 2 to 4 inches of prcdictcd growth. Girlswhose biological age was over 13 had prcdictcdgrowth rcduccd by 1% to 2% inches.

Treatment was discontinucd whcn wrist Xraysindicatcd that growth either had halted or hadbeen rcduccd to a rate acceptable to the patient.After therapy, menstrual periods resumed a nor-mal pattern. No patient experienced impairedpituitary-ovarian function or blood clots in legveinsboth of which are known, infrequent, butpotentially serious complications of this cyclichormonc therapy.

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In another similar study, each potentially tallgirl received estrogen via a capsule surgicallyimplanted beneath the skin of the abdomen. Eachcapsule gradually released its hormonc into thcblood stream and had to be replaced every 6months. A mcnstrual-like period was induced byhaving thc patient take a progesterone pill for 5days each month.

In this study, responsiveness to treatmentvaricd. In about 90 percent of the girls, lineargrowth halted after 1 to 3 additional inches ofgrowth had occurred. In the remaining 10per-cent, less dramatic but still significant growthrctardation resulted.

A number of girls from both studies have goneon to get married, cnjoy healthy pregnancies, andproduce normal babies.

Unlike thc girls, adolescent boys are primarilyconcerned that they may not grow tall enough.Since most boys who arc short in the early teenageyears will eventually, if slowly, reach normal adultheight, growth experts are less likely to intervenein their growth than in the case of girls who aregrowing too tall. However, if the boy is severely

disturbed by his temporary short stature, somephysicians will prescribe male hormones (andro-gens) to hasten his sexual maturation and,thereby, his growth spurt.

The time at which androgens are utilized topromote growth is important, however, becauseat the same time that they promote growth, theyalso begin to stimulate epiphyscal closure. Thereis a race against time. If sexual maturation pro-ceeds too rapidly, cpiphyscal closure may occurprematurely, and the patient may be deprived ofthe ultimate height he would have reached hadhis intrinsic chronology of growth been realizedwithout intervention.

In an attempt to avert this danger, someresearchers in recent years have begun adminis-tering androgens in low doses and on a discon-tinuous schedule. Usually the patient receives thehormone daily for 1 month and is then taken offall therapy the succeeding month. Bone matura-tion is evaluated frequently, and the medication isdiscontinued permanently as soon as the patient'sbiological age is observed to catch up with hischronological age.

In one study of 67 boys who underwent thisintermittent therapy, growth proceeded at therate of about 3 inches a year so long as all epiph-yses remained open. In most cases, ultimateheight attained was no more than that predicted;however, most of the boys achieved this heightearlier, and a few even grew taller than expected.

The periodic interruption of the medicationwas felt to lessen the tendency to too-rapid epiph-yseal closure. However, the studies are toorecent to allow conclusion either that this therapyaverts all danger of premature closure or, alter-nately, that it promotes growth to a height greaterthan the patient's genetic potential. In fact, onetheory as to the efficacy of the treatment is thatthe small amounts of androgen administered haveno direct effect on sexual maturation but thatthey promote growth only indirectly throughstimulation of appetite.

Precocious puberty is the extreme opposite ofdelayed sexual maturation. In this condition, agirl may develop secondary sexual characteristicsbefore the age of 8, or a boy before he is 10. Thisclearly can produce severe psychological problemsfor the affected child.

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'

Of equal importance is the fact that precociouspuberty stimulates the adolescent growth spurt tobegin prematurely. In normal children, childhoodgrowth is usually complete before the adolescentgrowth spurt is superimposed; in children withprecocious puberty, the growth spurt begins longbefore the childhood phase of growth is complete.Since sexual maturation tends to promote closureof the epiphyses, this results in epiphyses closed be-fore true potential height is realized and growthof the children into adults noticeably shorter thantheir contemporaries.

Precocious puberty is rare. Sometimes, it is thefirst symptom of a cyst or a tumor in the adrenalglands, the sex glands, or the brain. In certain in-stances, it occurs in families whose members havean inherited tendency to excrete at an early ageexcessive amounts of adrenal androgen. Manycases have no known ,origin and may be viewedonly as normal puberty occurring at an abnor-mally early age.

In these latter cases, the continuing develop-ment of secondary sexual characteristics can usu-ally be slowed down by the administration of a

progesterone-like hormone. Within the past year,researchers have begun to report that this treat-ment may also slow the accelerated rate of cpiphyscal closure. Although these findings remainpreliminary, they do indicate that appropriate

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hormone therapy may eventually allow growth tocontinue sufficiently long in children with preco-cious puberty to allow them to attain normaladult height.

Through such studies, scientists are learninghow to circumvent the whims of nature that toooften impose heavy burdens on young people- -particularly during those final years of growthwhen a young person's perception of himself canbe permanently enhanced or flawed. Also, fromthe information derived, physicians are able to re-assure the majority of young people concernedabout their growth that, in time, all variationswill be spontaneously resolved.

Information OfficeDivision of Research Resources

National Institutes of HealthBethesda, Maryland 20014

U. S. GOVERNMENT PRINTING OPPICF: f 1972 0 - 452 250

Average Physical MeasurementsBlack fines indicate 511 percentile.

Infant Boys Infant Girls

LENGTH

WEIGHT

8 12 16 20 24 28

AG,: IN M( )NTits

38

36

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28

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18

16

11

12

10

8

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8 12 16 20 24 28

AGE IN NII1NTI15

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFAREPublic Health Service National Institutes of Health

DHEW Publication No. (NIH) 72-166

For sale by the Superintendent of Documents, U.S. Government Printing OfficeWashington, D.C. 20402 - Price 65 cents

Stock Number 1740-0329

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