The Prepuberal and Puberal Growth of the Adrenal (Adrenarche)

Beitr. Path. Bd. 150,357-377 (1973) Pathologisches Institut der Universitat des Saarlandes, Homburg/Saar

The Prepuberal and Puberal Growth of the Adrenal (Adrenarche) Das prapuberale und puberale Nebennierenwachstum (Adrenarche) GEORG DHOM With 13 Figures and 2 Tables· Received July 18, 1973 . Accepted September 4,1973

Summary The increase in adrenal weight and structural development of the cortex is studied in 630 pairs of adrenals from children between I and 19 years. In the group of cases of sudden death adrenal weight increases from 2 g in the 2nd year of life to 4 g in the loth year. Adult values are achieved at the end of puberty. There exists a significant correlation between adrenal weight, age and body surface. A sex difference does not exist. In cerebral lesions adrenal weight at any period is highly significantly above that of the group of sudden deaths. The adrenal weights of the group of all other cases, designated as consuming diseases, occupy an intermediate position. The breakdown of the medullary capsule and the development of the zona reticularis are the outstanding features of structural development of adrenal cortex. Focal development of a zona reticularis starts at the age of 5 years, at 8 years it usually is present as a continuous zone. The juvenile reticularis cells have larger nuclei than the cells of the zona fasciculata and show a compact cytoplasm without pigment granules. No signs of increased cell destruction are seen. In stress-situations mitotic figures are found predominantly here. The development of the zona reticularis is considered to be the morphologic equivalent of adrenarche and is brought into relation with production of androgens. In 22 cases we found a delayed adrenarche. In such cases a complete medullary capsule is still found after the 5th year of life, whereas development of the zona reticularis has not yet started after the loth year of life. Cerebral lesions and congenital cardiac defects are present in 17 of these 22 cases. In I I cases an accelerated adrenarche is seen, of these 8 show cerebral lesions. By the age of 3 years the medullary capsule has already disappeared completely and the zona reticularis is beginning to develop. In the majority of these cases gonadarche is disturbed too, congruity between gonadarche and adrenarche does not necessarily have to exist.

Many details regarding the morphology of the adrenal of the fetus, the newborn and the infant (SWINYARD, 1943; ROTTER, 1949; TAHKA, 1951;

35 8 . G. DHOM

KLOOS and STAEMMLER 1953; LANMAN, 1957; DHOM, 1965), its ultrastructure (JOHANNISSON, 1968; MXUSLE, 1972), and its changing function (BLOCH et aI., 1955; TELLER, 1967; LAURITZEN et aI., 1968; DICZFALUSY, 19 69; VILLEE, 1969; SCHINDLER, 1972) between fetal development, birth and extra-uterine life are known today. The development of the funktion of the adrenal cortex parallel with growth during childhood and also with puberal maturation is well documented by endocrinological studies (KADAR et aI., 1964; KNORR, 1965; PAULSEN, 1966; TELLER, 1967; BERGER et aI., 197 0). With the onset of puberal maturation the adrenal cortex of the child again starts to produce androgens, is it did during fetal life, particularly dehydroepiandrosteron (DHA) and its sulfate, a process known as adrenarche (ALBRIGHT, 1947). The morphology of prepuberal and puberal growth of the adrenal cortex, on the other hand, has been documented only rather insufficiently up to now. According to SYMINGTON (1969) we do not know the "true" adrenal weight during childhood. As far as we know, the 20 cases of children between the 3rd and loth year of life studied by MAX LANDAU (1915) and the 44 children studied by BENNER (1940) are the largest series of adrenals of children beyond the period of infancy that have been sub· jected to systematic microscopic study. The present study is based on a collection of endocrine organs of children obtained by the aid of numerous departments of pathology and forensic medicine. So far 630 pairs of adrenals could be evaluated.

Material and Methods The adrenals obtained at autopsies were sent to us together with a questionnaire, that had been completed by the department where the autopsy was done. The data asked for were age, sex, length, body weight, basic disease, cause of death and organ weights. The organs had been fixed in 10 Ofo formalin. In our laboratory, any remaining adjacent fat tissue was carefully dissected away, the organs were checked regarding integrity and then weighed separately on a Mettler scale, type K 7. In previous studies we have seen that formalin-fixation reduces the weight of the adrenals by about 15 %. All calculations are based on the weights of fixed organs. Each adrenal was divided into 5 blocks by sections vertical to the long axis. 4 of these blocks were embedded in paraffin, the 5th block was used for frozen sections. Stains: H & E, Goldner, PAS, Oil red. Statistical Evaluation of the Material The relationship between adrenal weight, age, sex, and body surface was studied by Bartlett-test, variance- and regression analysis. The regression is adapted to the 2nd degree polynome. Body surface was calculated according to Duboi's formula.

Adrenarche . 359

Results I.

Adrenal Weight

32I pairs of adrenals that proved to be completely preserved both grossly and microscopically were selected for statistical calculations of adrenal weight. The organs are from children between the end of the Ist and the end of I5th year of life. They are divided into 3 samples according to basic disease and cause of death: I. Sudden death (group S); n = 93. 2. Basic disease cerebral lesion (group C); n = 77. 3. The remainder, classified as consuming diseases (group CD); n = I51. We found a highly significant correlation between adrenal weight and age and also between adrenal weight and body surface, which as an indicator for the growth of the body. Therefore, one of the two parameters - body surface and age - is sufficient to describe the connection with adrenal weight. From now on only the relation between adrenal weight and age is shown. The following equidistant division into 4 age groups is obtained with the factor 1.968 (fig. I). The lowest adrenal weights at any period are found in the group of sudden deaths. This group consists primarly of accidents, complications of anaesthesia, and diseases terminating fatally within 24 hours. Only such cases where cortical structure was intact histologically were considered.

7

adrenal weight (g)

C

6

CD 5

S

3

I = 12-23 months II = 24-47 m =48-91 IV = 92-180

II

m

IV

age (months)

Fig. I. Correlation between adrenal weight and age. Curve of regression in sudden death (S), consuming diseases (CD) and cerebral lesions (C).

360 . G.

DHOM

SUDDEN DEATHS. 12

adrenal weight I g I n =105

10 8 o

•

e

0

o

1

Fig.

1.

2

3

4

5

6

7

8

9 10 11

0

12 13 14 15 16 17 18 19 years

Adrenal weights in sudden death: Line of regression up

to

the 13th year of life.

The mean weight of the formalin-fixed adrenals rises from 2. r g in the 2nd year of life to 4.9 g in children between 7 and r 5 years (fig. 3). The curve has the shape of a flat parabola. The speed of growth of the adrenals thus increases with increasing age. r 2 cases between r 5 and r 8 7/ 12 years were not included into these calculations as the material is too small yet. We find , however, in these cases, as can be expected, a further increase in weight up to the values between 8 and ro g as found in adults (fig. 2). The variance analysis of sample S shows that there is no sex difference regarding adrenal weight, and that the age groups chosen show significant differences. The group of cerebral deaths (C) is with a weight of 3 g in the youngest age group, already distinctly higher than group S and achieves a value of 6.8 g in the group of children between 7 and 15 years (fig. 4). The parable is steeper than that of group S. The difference between the values of group C and S is highly significant (P = o.oor). The cerebral lesions of this group show a wide range: cerebral lesions of early childhood, hydrocephalus, tumors and encephalitis present the major portion. The adrenal weights of the group presenting all the other cases, desi gnated as consuming diseases (CD), are found to be between those of groups Sand C. The F-test shows siglnificance regarding the differences between CD and S (P = 0.05) and between C and CD (P = o.or). We thus found that the "true" adrenal weight in childhood (SYMINGTON, r 969) can be elucidated when great care is taken to select only cases of sudden death. In such a sample, however, the weight is distinctly lower than in those with preexistent diseases. Between the 2nd and roth year of life, the combined weight of the formalin-fixed adrenals is just doubled from about

2

g to 4 g and it is doubled once more at the end of puberty,

when it attains adult value. A sex difference is not found.

Adrenarche . 361

a

b

c

Fig. 3. a) Dyspepsia. I 10/12 0, adrenals 2.73 g. b) Head injury. 6 0/12 ';', adrenals 4.2 g. c) Head injury. 12 Oh2 0, adrenals 7.2 g. Normal adrenal growth during childhood. Natural sIze.

362 . G. DHOM

a

b Fig. 4. a) I 7/12 'il, diffuse cerebral sclerosis. Adrenals 5-I g. Hyperplasia. Histology: Accelerated adrenarme. b) 8 II I 12 0 , head injury. Adrenal weight 5.67 g, normal weight. Natural size. 2. Microscopic Development of Adrenal Cortex During Childhood Involution of the cortex fetalis is completed by the end of the 1st year of life. The collaps of the stroma going along with this involution results in formation of a medullary capsule. This capsule first is seen as a long broad band of connective tissue that later becomes gradually narrow and sharply delineates medulla and permanent cortex (fig. 5). The capsule extends into the poles of the organ. The cortex of the infant thus consists of a clearly demarkated continuous and lipoid-rich glomerulosa and a spongiocytic fasciculata that extends down to the medullary capsule. A zona reticularis does not exist at this time. The sinusoids of the cortex penetrate the

medulIary capsule a nd empty into the vascular system of the medulla.

Macrophages containing lipid and siderin granules are seen only occas-

Adrenarche . 363

Fig. 5. Complete medullary capsule. cortex and medulla. H & E, X r60.

I2

month-old infant. Bands of collagen fiber between

sionally during the 2nd year of life within the medullary capsule, they present remnants of the process of involution. The important structural changes of the adrenal cortex in childhood up to puberty take place in the inner zones. They are characterized by a gradual dissolution of the medullary capsule and an equally slow subsequent development of the zona reticularis. The narrow band of collagen fibres disappears first in the central portions of the organ between medulla and cortex. It is preserved longer at the poles, where during the course of involution the opposing portions to the cortex come into contact. Together with the fading of the medullary capsule, medullary and cortical elements increasingly come into direct contact and are located on the same sinusoidal wall (fig. 6). The break-down of the medullary capsule itself leaves no "traces". Occasionally a rather loose capillarization of the fibrous plate is found (fig. 7). During the period of disintegration of the medullary capsule lumps and sheets of large acidophilic cortical cells appear as first formations of a zona reticularis. They are seen first in the area of the so-called central cortex, i. e., those portions of the cortex located around the central vein. Small cell buds are formed between peripheral cortex and medulla, these

Fig. 6. After breakdown of medullary capsule direct contact between spongiocytic fasciculata cells and medulla. No reticularis developed yet. 7 years, t;', H & E, X r60.

buds grow towards the medulla (fig. 8). The cytoplasm of these cells is compact-granular, the nuclei are round, without pyknosis or other signs of regression. The nuclear diameter is larger than that of the fasciculata cell nuclei. In stress situations with lipid depletion of the fasciculata, particularly with infectious diseases or burns, mitotic figures are found sometimes in large numbers in these groups of reticularis cells (fig. 9)' Pigment granules cannot be demonstrated at this early phase of development of the retlCUlans. Later during the course of development, these solitary complexes of cells form a narrow band of a zona reticularis that gets increasingly broader (fig. 10). At this stage the zona reticularis is recognized mainly by its compact acidophilic cell type and not by the arrangement of the capil•

1

•

Adrenarche . 365

lary system. As long as there is only focal development of a zona reticularis, spongiocytic elements of the fasciculata are in immediate contact with the cell clusters of the medulla. Studying the temporal sequence of changes at the medullary-cortical junction in cases of sudden death, which have to be considered as being representative for normal development, we find that break-down of the medullary capsule together with the first appearance of reticularis cells starts at the age of 3 years (fig. I I). The existence of a continuous medullary capsule during the following years becomes increasingly rarer, remnants of a medullary capsule are in some cases found up to the loth year of life. Focal development of a zona reticularis is found at the age of 5 years already in more than half of the cases, at 6 years of age a continuous zona reticularis can first be seen. All of the 8-years-old in our sample show formations of a zona reticularis, as a continuous zone in all cases, however, it is not found until 13 years of age. With a fully developed reticularis, as it is eventually seen in young adults, the relation between the thickness of reticularis to that of glomerulosa and fasciculata is about I : 1. The zona glomerulosa, which in adrenals of infants is always present as a continuous zone, becomes disconinuous

Fig. 7. Capillarization and brea kdown of medullary capsule. Spongiocytic cortex above, medulla below. 4 3/ 12 years, o. H & E, X 400.

366 . G. DHOM

Fig. 8. Solitary clusters of compact reticularis cells between fasciculata and medulla. 8 years, o. H & E, X 400.

during the course of prepuberal development, the marked variability of this zone is already known from studies of adult adrenals. The development of structures at the medullary-cortical junction allows a rough estimation of the age in "normal cases". Retardation and acceleration of both the dissolution of the medullary capsule and maturation of the reticularis are to be expected, though. This is most frequently seen in connection with cerebral lesions. In this sample we find already at 4 years a rather pronounced development of the zona reticularis, occasionally even as a continuous zone, as sign of accelerated structural maturation. On the other hand, there are cases of children 10 to 12 years old with partially preserved medullary capsule and correspondingly delayed development of

the reticularis.

149

26.8

47 3E

'i'

15 6h2 17 2/12

21. 22.

19· 20.

0

'i'

0

'i' 'i'

12 II / 12 13 3/12 15 1/12

18.

17·

0 0

10 7 / 12 10 II / 12

0 0 0 0 0 0

'i' <3

0 'i'

47 66

32

34·5

21 20 19

10 5 114 108 119 II8 122 126 II8 110 10 5 96

14 17·5 16.6 19. 8 17 22·3

'i'

16.

4· 5· 6.

'i'

155 188

14 6 147 152

168 140

10 4 10 5 10 5

12 15 15

0 0

Length (cm)

Weight (kg)

Sex

Delayed Adrenarche

5 0/12 5 1/12 5 2/12

I.

5 3 / 12 5 6h2 60/ 12 7· 6ri12 8. 64 h2 9· 65/ 12 10. 69 /12 II. 7 0h2 12. 7 0h2 13· 74 h2 14· 7 8/ 12 15· 9 8/ 12

3·

2.

I.

Age

Table

tuberculous meningitis cardiomegaly

interventricular aneurysm massive cerebellar hemorrhage leukemia mucoviscidosis vitium cordis

congenital heart disease medulloblastoma multiple congenital malformations, congenital heart disease alcohol intoxication seIzures endocardial fibroelastosis sudden death enterocolitis tumor of pons hydrocephalus vitium cordis tetralogy of Fallot myelomeningocele spastic cerebral palsy hydrocephalus internus

Basic Disease

10·4

3. 6

3·9

6 ·49 4·9

4·3

4·4 2·45 5. 2 5. 2 6.1

3·9 2·9 2.6 3. 12 4. 1

2.2

4·0 4. 62 2.1

Adrenal Weight (g)

'f) m.c.

=

medullary capsule

m.c. partially hypoplastic reticularis

m.c. partially preserved almost no reticularis no reticularis

m.c. preserved m.c. preserved m.c. preserved nearly complete m.c. m.c. preserved m.c. preserved nearly continuous m.c. m.c. preserved advanced continuous m.c. m.c. partially preserved advanced continuous m.c. m.c. still broad, few clusters of reticularis cells m.c. preserved m.c. partially preserved

m.c."· preserved m.c. preserved complete m.c.

Adrenal Histology

retarded retarded lower range of normal normal

pubertas precox normal

normal retarded normal normal retarded retarded retarded normal considerably delayed retarded retarded normal

retarded normal retarded

Gonadal Development

9-

'I

'"

'-H

"

>~ .,"::I

368 . G. DHOM

Thereafter all cases where a complete medullary capsule is found after the 5th year of life (fig. 12) or where after the loth year of life a reticularis has not yet developed are designated as cases of delayed adrenarche. Applying these criteria we found 22 cases of delayed adrenarche in 630 pairs of adrenals from children (table 1). There were 14 boys and 8 girls between 5 and 17 years of age. In 10 cases a cerebral lesion was the basic disease, in 7 cases congenital heart disease was present. The development of the gonades, particularly the growth of the tubulus of the testis and the development of spermatogonia (STADTLER 1973) are usually also inhibited. In one case, though, a retarded adrenarche was found associated with a genuine pubertas precox. The adrenal weight does not reflect the retarded adrenarche. We speak of accelerated adrenarche when the medullary capsule has already completely disappeared in a 3-year-old child (fig. 13) or when in a 6-year-old the zona reticularis is present as a continuous band. In our total material there are 11 cases meeting this criteria (table 2). 8 of these had severe cerebral lesions. The adrenal weight in some of the cases is distinctly above the average. Gonadal development in the majority of cases is also interfered with. There is, however, no congruity between gonadarche and adrenarche. The gonadarche more commonly is even retarded in cases of accelerated adrenarche.

Fig. 9. Mitoses in zona reticularis. 97/12 years, ii. H & E, X 640.

II.

9· 10.

7· 8.

6.

3· 4· 5·

2.

I.

Age

3 8ir2 4 10/12 5 0 / 12 54/ 12 6 1/12 6 10/12

I 7/12 [ IIir2 3 0 / 12 3 3/ 12

I 3/12

14.0 20.0 16.0

(\

(\

(\

Q Q

(\

15·7 15·3

8·3

Q

(\

9·5 9. 2

7. 0

Weight (kg)

Q Q

Q

Sex

Table 2. Accelerated Adrenarche

100 10 7 113 II3 122 108

75 84 108 90

72

Length (cm)

microcephalus hydrocephalus spongioblastoma laryngitis, intoxication cerebral lesion idiocy

5· [

cerebral sclerosis pneumonia burn hydrocephalus

4·3 5. 6 7. 6

4·[ 10·4 7. 2

5-5

2·4

Adrenal Weight (g)

meningomyelocele

Basic Disease

partial breakdown of m.c. partial breakdown of m.c. continuous reticularis disappearance of m.c., focal reticularis continuous reticularis continuous reticularis continuous reticularis continuous reticularis continuous reticularis continuous reticularis

partial breakdown of m.c.

Adrenal Histology

retarded retarded normal strong follicle growth strong retardation retarded

normal (strong follicle growth) normal normal accelera ted retarded

Gonadal Development

'"

c-.,

\.;.>

'"

'"g.

>...0.. ::> '"

370 . G. DHOM

Fig. 10. Narrow compact reticularis betw een fasciculata and medulla. 17 yea rs,

o. H

& E,

X 160.

Discussion Adrenarme is to be understood as a change in adrenal cortical function and structure to be seen together with the gonadarche (ALBRIGTH, 1947). The production of mineralo- and glucocorticoids is primarly independent upon sexual maturation and is correlated with body surface and excretion of creatinine, respectively (KNORR, 1965; KELLY et aI. , 1966; KENNY, 1970). The break-down of steroids in the liver, though, is influenced by puberal maturation as the increasing secretion of androgens elevates the 5 a-reductase-activity of the liver (GUPTA and ZIMPRICH, 1966; TELLER, 1967, 1970). The basic functional change taking place in connection with adrenarche is related to the production of androgenic compounds, mainly dehydroepi-

Adrenarche .

37 1

androsterone (DHA) and its sulfate (DHAS). BERGER et al. (1970) found an increase of DHAS-secretion in 24-hours-urine from 25 flg in 5-years-old boys to 65 flg at 10 years, 120 flg at 13 years and 580 flg at 16 years. In girls, these values are lower at all stages of maturation; the increase, however, starts a little earlier. According to TANNER and GUPTA (1968), individual adrenal androgen production shows a steep rise in both boys and girls at a bone age of 10 to I I years. As testes and ovaries produce only insignificant amounts of DHA (ROSENFIELD and EBERLEIN, 1969), the urinary secretion basically corresponds to production of DHA by the adrenal cortex. Consequently, the plasma values of DHA increase during puberal maturation (YAMAI and lBAYASHI, 1969). The androgens of the adrenal cortex bring about the growth of public hairs, the pubarche, in girls. This effect in boys is superimposed by the tes'tosterone production of the testicle, which is then beginning. The anabolic effect of adrenal androgen is low at physiologic of secretion. In cases of premature adrenarche only little acceleration in growth and maturation of bones is seen (PRADER, 1971). The physiologic role of DHAS is still a mystery today considering the high plasma levels during adolescence (DRUCKER et aI., 1972). Our studies show that the increase in weight of the adrenal is correlated with age but also with body surface, whereas a sex difference does not exist. At 10 years the adrenal weight is only around 4 g. This is the weight

reticularis

SUDDEN DEATHS

100 %

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

~

no reticula ris

f§I

focal reticularis

fill

continuous reticularis

age (years)

medullary capsule 100%

e:J

continuous medullary capsule

f§I

medullary capsule preserved partially

fill

no medull ary capsule

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 age (years)

Fig. II. Percentage distribution of breakdown of the medullary capsule and development of the reticularis in the group of sudden death. 25 Beitr. Path. Bd. 150

37 2 . G.DHoM

Fig. I2. Delayed adrenarche, narrow medullary capsule between fasciculata and medulla. No development of reticularis. 7 8lr2 years, 0, with spastic cerebral palsy. H & E, X I60.

of formalin-fixed adrenals. It is some 15 Ofo lower than that of the fresh organs. Adult values are not obtained until termination of the phase of puberal maturation. The outstanding structural feature of adrenarche is the slow development of the reticularis which at first appears only in the form of isolated foci. The juvenile reticularis cells are large elements without signs of regression. Nuclei and cytoplasm are larger than those of the fasciculata cells, a clear difference in comparison to findings in later adult age (BACHMANN, 1954). Under the electron microscope, the human reticularis cell can be clearly distinguished from the cells of the fasciculata. In addition to numerous polymorphous dense bodies the reticularis cell contains more smooth endoplasmic reticulum than the fasciculata cell. There are only few liposomes present. Mitochondria are elongated and

Adrenarche . 373

contain tubular internal structures (MXUSLE, 1973). Whether there exists also a functional identity of the zona reticularis has up to now not yet been proven (SYMINGTON, 1969; SIEBENMANN, 1971). According to JONES et al. (1968), the zona reticularis of the human adrenal cortex is mainly responsible for transforming DHA into the sulfate. The parallel development of androgen secretion of the adrenal cortex and that of the zona reticularis during prepuberty and puberty together with these biochemical findings seemed to us sufficient evidence for the assumption that the zona reticularis is the source of this androgen production. The regression of the zona reticularis with advancing age (STIEVE, 1946; SIEBENMANN, 1971) corresponding to an "adrenopause" as formulated by ALBRIGHT (1947) has in our opinion not yet been adequately documented in a sufficiently large sample of essentially healthy persons. Neither do we find - other than STIEVE - a sex dimorphism in regard to the zonation of the human adrenal cortex. The observation regarding retardation and acceleration of structural development of the adrenal cortex seem to us of interest in respect to a better understanding of the adrenarche. In our material we find that in particular cerebral and cardiac processes can lead to a retardation of deve-

Fig. 13. Accelerated adrenarche. Medullary capsule has disappeared, compact clusters of reticularis cells between fasciculata and medulla. 3 8/12 years, 0, microcephalus. H & E, X r60.

374 .

G.DHOM

lopment of the reticularis. Cerebral lesions, however, can also have the opposite effect, i. e., that of an adrenal cortical prematurity. Premature adrenarche and pubarche are well-known to the clinician (THAMDRUP, 1955; VISSER and DEGENHARDT, 1966; CONLY et aI., 1967; PRADER, 1971). Without any other signs of sexual development, especially without rising estrogen secretion in girls, pubic hair appears in early childhood together with an increased androgen production of adrenal cortex. In this clinical material too we find predominantly children with cerebral lesions; cerebral palsy, idiotism and epilepsy are rather common. Testicular development of our cases, measured by tubular diameter and number of spermatogonia (STADTLER, 1973), frequently shows both in delayed and accelerated adrenarche delayed maturation of the tubules. A few cases, though, show gonadal prematury. Similar features apparently are present in the ovaries whose weights are usually in the lower range of the corresponding age groups. We have, however, not yet been able to obtain significant data regarding this problem. We thus find in the majority of cases with disturbance of the adrenarche also a disturbed gonodarche, a temporal congruity does not necessary exist. Alterations of adrenal weights by cerebral lesions, as is demonstrated in our material, has already been described by E. J. KRAUS (1937). An intact hypothalamic-anterior pituitary system is the prerequisite for adrenal cortical hyperplasia. The limbic system regulates the release of CRF (SCHADE, 1970), chronic cerebral pressure possibly favors release of CRF or lowers the threshold of the cortisol receptors. As our observations show, cortical hyperplasias secondary to cerebral stimulation is not necessarly associated with an accelerated adrenarche. The circadian rhythm of adrenal cortical secretion is significantly disturbed in disease of hypothalamus, temporal lobe and pretectum (KRIEGER and KRIEGER, 1966). The mechanism triggering adrenarche is still unclear (PRADER, 1956; TANNER, 1970; VISSER, 1973). ACTH can hardly be responsible, because in that case cortisol secretion too should steeply rise during puberty; this, however, is not the case (PRADER, 1971). Exogenous administration of ACTH, though, is able to increase DHA secretion (VAITUKAITIS et aI., 1969; YAMAJ and IBAYASHI, 1969; NIESCHLAG et aI., 1973). The cortical hyperplasia found by us in children with cerebral lesions which his to be related to an increased release of ACTH is not necessarily associated with a premature development of the reticularis. The importance of LH for triggering of the adrenarche is a matter of dispute. Since estrogens in Turner-syndrome stimulate the growth of pubic hair, it has been discussed whether in this case the release of LH (BIERICH, 1971) or of another as yet unknown "adrenarche hormone" (TANNER, 1970; PRADER, 1971; VISSER,

Adrenarche . 375

1973) from the anterior pituitary lobe is being stimulated. It is rather peculiar that in premature adrenarche LH and FSH are not elevated, but more likely even lowered (KENNY et aI., 1969; PENNY et aI., 1970). HCG does not increase the DHAS-concentration in plasma (YAMAJ and IBAYASHI, 1969), but it does increase that of DHA (NIESCHLAG et aI., 1973). Our findings in delayed and accelerated adrenarche show that adrenal and gonadal maturation do not necessarily run a parallel course, the course of development can even be a contrary one. From clinical observations too it is known that a premature adrenarche can occur without gonadarche and a true pubertas precox without adrenarche (PRADER, 1971). It thus seems that the adrenarche is not subject to the same mechanism of regulation as gonadarche.

Zusammenfassung An 630 Nebennierenpaaren von Kindem zwischen dem I. und 19. Lebensjahr wird das Gewichtswachstum und die Strukturentwicklung der Nebennierenrinde dargestellt. In der Gruppe pliitzlicher Todesfalle steigt das Nebennierengewicht zwischen dem 2. und 10. Lebensjahr von etwa 2 auf 4 g an. Am Ende der Pubertat werden Erwachsenenwerte erreicht. Es besteht eine signifikante Korrelation zwischen Nebennierengewicht, Lebensalter und Kiirperoberflache. Eine Geschlechtsdifferenz besteht nicht. Bei cerebralen Leiden liegt das Nebennierengewicht in jeder Altersstufe hochsignifikant tiber der Gruppe pliitzlicher Todesfalle. Die Nebennierengewichte der Gruppe aller tibrigen, als konsumierend bezeichneten Erkrankungen, nehmen eine Mittelstellung ein. Der Abbau der Markkapsel und die Entwicklung der Zona reticularis sind die wesentlichen Merkmale der Strukturentfaltung der Nebennierenrinde des Kindesalters. 1m Alter von 5 Jahren beginnt eine herdfiirmige Reticularisentwicklung, im Alter von 8 Jahren ist in der Regel eine durchlaufende Zona reticularis abgrenzbar. Die jugendliche Reticulariszelle besitzt griiBere Keme als die Fasciculatazelle und ein kompaktes Cytoplasm a ohne Pigmentgranula. Zeichen vermehrten Zellunterganges werden nicht gesehen. 1m Stress treten bevorzugt hier Mitosen auf. Die Reticularisentwicklung wird als das morphologische .Aquivalent der Adrenarche angesehen und zur Produktion der Nebennierenandrogene in Beziehung gesetzt. 22 Faile zeigen eine verziigerte Adrenarche. Dabei wird eine komplette Markkapsel noch nach dem 5. Lebensjahr gesehen und nach dem 10. Lebensjahr fchlt noch die Reticularisentfaltung. Cerebra Ie Erkrankungen und congenitale Vitien liegen in 17 dieser 22 Faile vor. In II Fallen wird eine beschleunigte Adrenarche gesehen, davon haben 8 cerebra Ie Grundleiden. Bis zum Alter von 3 Jahren ist hier die Markkapsel bereits vollstandig abgebaut und die Zona reticularis in Entfaltung begriffen. In der Mehrzahl der faile ist auch die Gonadarche gestiirt, ohne daB eine Kongruenz zwischen Gonadarche und Adrenarche bestehen muK Acknowledgements I want to thank the numerous departments of pathology and forensic medicine, particularly the morgue attendants for contribution of the material for this study. For technical preparation, registration and statistical evaluation I am indebted to Mrs. GLA:TZEL, Mrs. KUBATSCH, and Mrs. REGITZ.

376 . G.DHOM I am in particular obliged to Prof. KOSSWIG, Bonn, college of agriculture, for his advice regarding statistics, and to Boehringer Inc., Ingelheim, who generously made available to us the computer.

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