PRECOCIOUS PUBERTY

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PRECOCIOUS

PUBERTY

By CHARLES

W.

LLOYD, M.D., JULIA LOBOTSKY,

M.S.,

AND MURIEL MORLEY, B.A.

Syracuse, N.Y.

P

RECOCIOUS puberty represents the premature differentiation of secondary sexual

tissues

as

a result of stimulation by certain steroid substances-androgens or estrogens.

Two

different

and

distinct

types

of

precocity

exist,

although

the

external

manifestations

resulting from the steroid effects on the sexual tissues may be identical. One type of

precocity,

in which both germinal and endocrine elements of the gonad are stimulated, is the result of increased gonadotrophin secretion by the adenohypophysis and is therefore called “pituitary precocity.” The term “constitutional precocity,” first proposed by Novak,’

is employed as synonymous with “pituitary precocity of constitutional origin’ ‘ and is used

to designate patients in whom none of the known causes of precocity can be found and

who

are

shown

to have

increased

gonadotrophin

excretion.

In the

other

type

of precocity,

which

results from autonomous secretion of steroids by the adrenals or gonads, the

germinal elements are not stimulated. When the source of steroid is the adrenal cortex,

these patients are said to have “juvenile adrenogenitalism.” The term “gonadal precocious puberty” implies that the source

of the

increased

steroids

is the gonad

and

that

the gonad

has an autonomous secretory pattern. ‘ Hamblen2 has termed sexual precocity resulting

from increased gonadotrophin secretion, associated with germinal epithelial stimulation,

‘‘precocious sexual maturation’ ‘; he calls the early development of the secondary sexual

characteristics

due

to elevated

steroid

levels

of

whatever

cause

‘‘precocious

sexual

differ-entiation.” Normal and abnormal sexual development has been reviewed by Wilkins.3 A fairly large number of patients with hypophyseal precocity resulting from

hypo-thalamic

lesions

has

been

described.

Tumors

of

many

types

as well

as infectious

processes

may be involved. Ham4 summarizes only 17 such cases from the literature, but Hamblen2

has found at least 28 cases. Papez and Ecker5 have studied in detail the brain of a boy with hypophyseal precocity due to a hypothalamic tumor. Ham states that males are much

less commonly affected than are females.

Novakl in 1944 reported nine cases of “constitutional precocious puberty.” Ham4 has

recently

summarized

the

literature,

finding

13 females reported and adding 5 female cases of his own. He accepts the

boy

described by Young6 as being a possible case of

“constitutional precocity” but states that he has not been able to find any other reports

of males with constitutional precocity.

Ham

describes two boys with this syndrome. Wilkins3 believes that probably 80 to 90% of the cases of precocious sexual development

fail

into

this

category.

Because the present authors believe that these conditions are more frequently

encoun-tered

than

the

relatively

few

cases

reported

would

indicate

and

to illustrate

the

features

which permit a differentiation from juvenile adrenogenitalism or gonadal precocious

puberty, four juvenile cases of probable constitutional precocity and one juvenile case of

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hypophyseal

precocity

associated

with

a hypothalamic

lesion

of

undetermined

type

are

described

in this

paper.

An

adult

female

with

a history

of

constitutional

precocity

who

illustrates the outcome to be expected

in

patients

of

this

type

is also

briefly

presented.

METHODS

The technics for measuring mouse uterine weight increasing (m.u.u.) and mouse ovarian hyper-emia producing (m.h.u.) materials in the urine have been described.7 Urinary estrogen excretion was

measured by the method of Smith, Smith, and Schiiier’ and 17-ketosteroid excretion by a modification

of the method of Callow, Callow and Emmens.’ (See table 1.)

TABLE 1

URINARY HORMONE VALUES FOR NORMAL PREPUBERAL CHILDREN

Gonadotrophin

Uterine Wt. Ovarian Hyperemia 17-Ketosteroid Estrogen m.u.u./24 hr. m.h.u./24 hr. mg./24 hr. Rat units/24 hr.

<4 <4 .3-3.5 4

CASE REPORTS

Case 1, E. S., a

5#{188}

yr. old male (Figs. 1 and 2).

Chief Complaint: Statural and sexual precocity for 2 yr.

Present Illness: Two years before admission the patient was first noted to have genital development greater than normal for his age and to be considerably taller than his coevais. Development has since

been symmetric and rapid. Sexual activity has been marked, with frequent masturbation.

Physical Examination: Patient is a symmetrically developed, large boy whose height of 1 37.4 cm. is 20 cm. greater than the upper limit of the normal range for his age. Other measurements are com-mensurately increased. Musculature is excellent and the body appears to be that of a 10 yr. old boy. Pubic hair is fairly abundant, with a feminine escutcheon. No axillary hair is present. The genital

development is marked. Penis is large, measuring 10 cm. long by 10 cm. in circumference at the corona.

Testes measure 3.5 cm. in length and are of normal turgor.

Laboratory Examination: Routine hematologic studies and urinalysis are not remarkable; BMR + 6% ; roentgenogram of the skull shows no abnormalities with a normal sella turcica; RGs of epiphyses show a bone age of 10 yr. ;

I.V.

pyclograms show no renal defect; 17-ketosteroid excretion

3 mg. in 24 hr. ; gonadotrophin excretion in 3 different 24 hr. periods 0, 4, 16 m.u.u. and 4 m.h.u. in 24 hr. on 1 occasion; testicular biopsy (Fig. 2) shows early spermatogenesis. Psychometric evalua-tion shows a mental age of 6 yr., I.Q. of 1 1 1.

Diagnosis: Probable constitutional pituitary precocity.

Case 2, N.S., a

5#{188}

yr. old female (Fig. 3). (Patient of Dr. T. C. Wyatt.)

Chief Complaint: Excessive statural and breast development.

Present Illness: Development of the breasts of this child has been prominent for the past 3 yr.

Body growth has been symmetric and rapid, the patient being taller than her coevals. No vaginal

bleed-ing has occurred. One year ago, the patient was examined rectally by a gynecologist who could find no

pelvic abnormality.

Physical Examination: Patient is a symmetrically developed, fairly well nourished girl whose height of 123.3 cm. is 13 cm. taller than the upper limit of normal range for her age. There is no axillary hair, a slight pubic fuzz. Breasts are developed in the primary mamma stage. Ductular

tissue is palpable in each breast. On rectal examination (performed by Dr. E. C. Hughes) the

cervico-uterine ratio is juvenile, ovaries are palpable but not enlarged.

Laboratory Examination: Routine hematologic studies and urinalysis are not remarkable; RG of

the skull shows no abnormalities with a normal selia turcica; RGs of the epiphyses show a bone

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estrogen excretion less than 5 ru. in 24 hr. Vaginal smear shows considerable estrogen effect with polygonal nucleated basal cells in predominance, and an occasional cornifled cell.

Case 3, J. H., an 11 yr. old female (Fig. 4). (Patient of Dr. N. R. Chambers.) Chief Complaint: Precocious sexual development.

Present Illness: Menarche occurred at 7 yr., periods since being regular with an approximate 28 day cycle. Recently has had lower abdominal cramps and fullness premenstrually. Taller and more mature than coevals.

Physical Examination: Thin, mature appearing, symmetrically developed girl who is 164.5 cm.

bules contain spermatids and few early spermatozoa.

tall, this being 5.5 cm. taller than the upper limit of the normal range for her age. She is well feminized with normal adult body hair distribution, well developed breasts and gynecoid body

habitus. Genitalia are well developed and rectal palpation discloses a uterus two thirds adult size with a utero-cervical ratio of 1:1.

Laboratory Examination: Routine hematologic and urine studies are not remarkable. RG of the skull shows no abnormalities with a normal sella turcica. RGs of epiphyses show a bone age of 17 yr. 17-Ketosteroid excretion 5.3 mg. in 24 hr.; gonadotrophin excretion 8 m.u.u. in 24 hr.; vaginal smear shows marked estrogen effect with numerous cornifled cells.

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346

C.

W. LLOYD,

JULIA

LOBOTSKY

AND

MURIEL

MORLEY

Case 4, B. H., a

7#{189}

yr. old female (Fig. 5).

Chief Complaint: Precocious sexual development.

Present Illness: Menarche occurred 2 wk. before admission, bleeding lasting 1 wk. Breast develop-ment first was noticed 5 mo. ago and pubic hair first appeared 1 mo. ago. Rubeola, without encephalitis

or sequelae, occurred 6 mo. ago.

Physical Examination: Tall, vell nourished girl, who is 142 cm. tallwhich is 16 cm. greater

than the upper limit of normal for her age. There is a slight growth of black pubic hair. Breasts

FIG. 3. N. S.,

5#{188}

yr. old girl with constitutional pituitary precocity. Vaginal smear shows considerable estrogen effect. Menarche has not occurred.

FIG. 4.

J.

H., 11 yr. old girl with constitutional pituitary precocity. Menarche occurred at age of 7 yr.

are in the primary mamma stage with definite glandular tissue present. Rectal palpation reveals a

uterus one quarter adult size, with utero-cervical ratio of 1: 1.

Laboratory Examination: Hematologic and urine studies are not remarkable. RG of the skull shows no abnormalities with a normal sella turcica. RGs of the epiphyses show a bone age of 9#{189}

yr. 17-Ketosteroid excretion 2.36 mg. in 24 hr.; gonadotrophin excretion 4 m.u.u. and 64 m.h.u. in 24 hr. Vaginal smear shows a marked estrogen effect with numerous cornifled cells.

Course: For 1 yr. patient has continued in good health, having acyclic menses at 1 to 5 mo. in-tervals.

Case 5, E. K., a 24 yr. old female (Fig. 6). (Patient of Dr. Seymour Schwartzberg.)

Chief Complaint: Obesity and shortness of stature.

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bleeding. Following cessation of linear growth at 12 yr. of age, patient gained weight fairly rapidly

until at present she is quite obese.

Physical Examination: Patient is a short (1-16 cm.), stocky woman who has the superficial appearance of an achondroplastic dwarf with a fairly normal body length but markedly shortened extremities. Span is 7.5 cm. less than height, lower measurement is 16.5 cm. less than upper

measure-FIG. 5. B. H., 71/2 yr. old girl with probable constitutional precocity. Menarche occurred at age of 7#{188}yr.

FIG. 6. E. K., 24 yr. old woman with history of probable constitutional pituitary

precocity. Menarche occurred at 8 yr., linear growth ceased at 12th yr. FIG. 7. B. G., 10 yr. old girl with pituitary sexual precocity associated with lesion in

hypothalamus. Menarche occurred at 8 yr.

ment. Obesity is generalized. Patient is well feminized with feminine distribution of body hair and well developed breasts. Uterus and adnexal structures are normal.

Diagnosis: Dwarfism due to premature epiphyseal closure caused by constitutional pituitary pre-cocity.

Case 6, B. G., a 10 yr. old female (Fig. 7). (Patient of Dr. \X’. J. Peacher.) Chief Complaint: Precocious sexual development.

Present Illness: Menarche occurred at 8 yr. and periods have since been about 2 mo. apart. Breast development’ has been marked for several years but exact age of onset of breast growth is not known.

Patient has been mentally deficient since birth.

Physical Examination: Patient is a fairly well developed, large girl with a moderate kyphosis,

whose height of 145.5 cm. is about 5 cm. greater than the upper limit of the normal range for her age. The fades is dull and lethargic. Speech is slurred and nasal. Skin is oily with facial comedones. Axillary and pubic hair is abundant. Teeth are well formed second dentition. Thyroid is not re-markable. Breasts are large, the left breast being larger than the right. The areolae are large; the

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of intact hymen. Rectal examination: the uterus is anterior, has a cervico-uterine ratio of 1, and is two thirds normal adult size. No ovaries or adnexal masses are felt.

Laboratory Examination: Routine hematologic studies and urinalysis are not remarkable; RG of sella turcica is not abnormal. Encephalograms show abnormal filling in the region of the hypo-thalamus; RGs of the long bones and epiphyses show a bone age of greater than 12 yr. and normal long bone architecture; I.Q. 43; urinary gonadotrophin excretion, 16 m.u.u. and 240 m.h.u. in 24 hr.; vaginal smear shows full estrogen effect with cornification.

Diagnosis: Pituitary sexual precocity associated with a lesion in the region of the hypothalamus.

DisCussioN

Hormone excretion findings in patients with precocious puberty are

summarized

in

table 2. The first five patients described probably represent examples of hypophyseal

pre-cocity

of the constitutional

type.

This

diagnosis

was

made

for E. S., N.

S. and

J.

H.

because

TABLE 2

URiNARy HORMONE VALUES FOR CHILDREN WITH PRECOCIOUS PUBERTY

Gonadotrophin 1 7-Ketosteroid Estrogen

mg./24 hr. Rat units/24 hr. Uterine Wt.

m.u.u./24 hr.

Ovarian Hyperemia m.h.u./24 hr.

Pituitary Precocity 4 to 64 4 to 64 Slight increase Slight increase

Adrenogenitalism

Gonadal Precocity in

Males

<4 <4 Considerable

increase

Little or no

in-crease

Gonadal Precocity in

Females

? ? Slight increase Considerable

increase

of

the

advanced gonadal function with no demonstrable lesion and only moderately

in-creased 1 7-ketosteroid excretion, coupled with definitely elevated gonadotrophin excretion. The diagnosis was made from the history in the case of E. K. In this patient, the menarche

at 8 years with excessive tallness until 12 years of age, at which time linear growth ceased, and the present tendency towards dwarfism with apparently normal ovarian

func-tion

are

typical

of

the

picture

of constitutional

precocity.

The

history

of

rubeola

in B. H,

shortly before the appearance of first signs of sexual differentiation introduces the

possi-bility

that

the

hypothalamus

may

have

been

injured

by the

infection.

Although

this

pos-sibility cannot be definitely excluded, it is unlikely because of the complete absence of any symptoms of altered hypothalamic function. The lesion of the hypothalamus in B. G. probably is related to the cause of the precocity. Therefore, the diagnosis of “pituitary

precocity associated with a lesion in the region of the hypothalamus” was made in this case.

Differentiation between pituitary precocity and adrenogenitalism or gonadal precocity

is relatively simple. Since pituitary precocity represents simply the early appearance of normal phenomena, these patients have the appearance of normal children of several years’ greater age. Physical and laboratory examinations reveal findings normal for children

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PRECOCIOUS

PUBERTY

349

function can be evaluated

by the gonadotrophin

and

steroid

excretion

values,

which

are

in

the

usual

range

for

children

of an

age

equivalent

to the

patient’s

‘‘sexual age.’ ‘

In

these

patients, the steroid pattern is the result of stimulation to the gonad by gonadotrophin. Similarly, the germinal epithelium reflects gonadotrophin stimulation.

In

patients

with

increased

androgen

production,

such

as

occurs

in

adrenogenitalism,

arrhenoblastoma

and

Leydig

cell

tumor

or hyperplasia,

abnormalities

detected

by physical

and laboratory examinations are principally the results

of the high

androgen

level.

In both

males

and

females,

sexual

differentiation

is in

the

masculine

pattern.

Hirsutism,

acne,

marked muscular development with a masculine body habitus, clitoral or penile

hyper-trophy,

advancement

of

bone

age

and

increased

androgen

excretion

are

found.

In

the

presence

of

an

increased

estrogen

production,

such

as occurs

with

granulosa

cell

tumors

or occasionally

with

abnormal

adrenal

cortical

“

precocity

is of the

feminine pattern. Stigmata of increased estrogen production, such as feminization, maturation of the vaginal epithelium, uterine enlargement and bleeding, advancement of

bone age and increased urinary estrogen excretion will be found. In males, feminization occurs. Germinal precocity is not present.

Recently,

a procedure

has

been

devised

which

utilizes

the

production

of ovarian

hyper-emia in

the

mouse

as an

end-point

for

estimation

of

urinary

gonadotrophin.7

It

is felt

that this reaction is the result

of

luteinizing

hormone

or of luteotrophin.

It can

be used

in conjunction with the uterine weight assay, which is considered to be primarily an index

of

follicle-stimulating

hormone,”

to

give

a

rough

differentiation

of

urinary

gonado-trophins. The urine of sexually mature humans of both sexes contains materials which produce both of these reactions. These materials have not been found in the urine of

sexually immature children. The material which produces uterine weight increase and is

considered

to be

follicle-stimulating

hormone

has

been

found

in the

urine

of

all

of

the

five

patients in this group studied by this method and in

many

patients

with

pituitary

precocity reported

in the

literature.

Ovarian

hyperemia-producing

material

was

found

in

the

urines

of the

three

patients

studied.

The

demonstration

that

a material

which

probably

is luteinizing hormone is excreted by these children bears out in the human the work of

Greep, Van Dyke and Chow13 who have shown that luteinizing hormone alone in males

and in conjunction with follicle-stimulating hormone in females causes sex steroid secretion

by the gonad.

A patient with adrenogenitalism due to an adrenal neoplasm has recently been studied and found to excrete no gonadotrophin detectable by either of the preceding methods.

These values are those which would be expected from the findings in the adult that

androgen

causes

a decrease

in luteinizing

hormone

excretion

by adults

of

both

sexes.’4

Although determinations of ovarian hyperemia-producing material have not been made

on patients with increased estrogen levels as the result of autonomous secretion by neo-plastic tissue, it is theoretically possible that an increased amount of this substance might

be found, since administration of estrogen to castrate women results in an increase.’4

SUMMARY

Five cases of probable hypophyseal precocious puberty of constitutional origin and one

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REFERENCES

1. Novak, E., Constitutional type of female precocious puberty with report of nine cases, Am. J. Obst. & Gynec. 47:20, 1944.

2. Hambien, E. C., Enlocrinology of Woman, ed. 1, Springfield, Ill., Charles C Thomas, Publisher, 1945.

3. Wilkins, L., in Advances in Pediatrics, edited by S. Z. Levine, A. M. Butler, L. E. Holt, Jr., and

A. A. Weech, New York, Interscience Publishers, Inc., 1948, vol. 3, p. 159.

4. Ham, A. M., Constitutional type of precocious puberty, J. Clin. Endocrinol. 7:171, 1947. 5. Papez,

J.

W., and Ecker, A., Precocious puberty with hypothalamic tumor (infundibuloma);

Case report, J. Neuropath. & Exper. Neurol. 6:15, 1947. 6. Young, H. H., cited by Ham.4

7. Lloyd, C. W., and others, Estimation of urinary gonadotrophin of non-pregnant human by mouse uterine weight and ovarian hyperemia responses, J. Clin. Endocrinol. 9:636, 1949. 8. Smith, 0. W., Smith, G. V., and Schiller, S., Estrogens of urine from women: Hydrolysis,

separation and extraction, Endocrinology 25:509, 1939.

9. Callow, N. H., Callow, R. K., and Emmens, C. W., Colorimetric determination of substances containing grouping-CH2CO-in urine extracts as indication of androgen content, Biochem.

J, 32:1312, 1938.

10. Karnaky, K. J., Premature sexual precocity in young girl, J. Clin. Endocrinoi. 5:184, 1945. 11. Wilkins, L., Feminizing adrenal tumor causing gynecomastia in boy of five years contrasted with

virilizing tumor in five-year-old girl, J. Clin. Endocrinol. 8:111, 1948.

12. Klinefelter, H. F., Jr., Albright, F., and Griswold, G.

C.,

Experience with quantitative test for normal or decreased amounts of follicle stimulating hormone in urine in endocrinological diagnosis, J. Ciin. Endocrinol. 3:529, 1943.

13. Greep, R. 0., Van Dyke, H. B., and Chow, B. B., Gonadotrophins of swine pituitary. I. Various biological effects of purified thylakentrin (F.S.H.) and pure metakentrin (L.C.S.H.), Endo-crinology 30:635, 1942.

14. Lloyd, C. W., and others, Estimation of urinary gonadotrophin of non-pregnant human by mouse uterine weight and ovarian hyperemia responses, abstracted, J. Clin. Endocrinol. 9:654, 1949.

SPANISH ABSTRACT

Pubertad

Precox

Los autores describen 6 casos de pubertad precox. Cinco de los pacientes fueron considerados tener una precocidad constitucional, y un paciente tuvo una lesion en ci hipotalamus. La excrecion de los esteroides sexuales en estos pacientes estuvo en relacion con ci grado dci desarrollo sexual.. La excrecion de gonadatropina estuvo aumentada a los valores normalmente hallados en las personas adultas. La cantidad de gonadatropina fu#{233}medida por Ia propiedad dci extracto urinario de aumentar ci peso del utero de ratones y por ci grado de hiperemia ovarico.

Los haliazgos en estos casos de pubertad precox son distintos a los encontrados en casos de adrenogenitalismo o “precocidad gonadal” en los cuales Ia excrecion de los esteroides sexuales

esta marcadamente elevada, pero Ia excrccion de ia gonadatropina no esta aumentada.

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1950;6;343

Pediatrics

CHARLES W. LLOYD, JULIA LOBOTSKY and MURIEL MORLEY

PRECOCIOUS PUBERTY

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