PREMATURE
THELARCHE
Precocious
Development
of
the
Breast
Henry K. Silver, M.D., and
Daryoosh
Sami,
M.D.
Department of Pediatrics, University of Colorado Medical Center, 4200 East 9th Avenue,
Denver 20, Colorado
(Submitted October 28, 1963; accepted for publication March 6, 1964.)
Aided by Grant No. GM08255-03 of the Public Health Service.
Present address: D.S., 114 Meshat Street, Simetni Avenue, Tehran, Iran.
ADDRESS: (H.K.S.) University of Colorado Medical Center, 4200 East 9th Avenue, Denver 20,
Colorado.
107
PEDIATRICS, July 1964
P
REMATURE THELARCHE (precociousde-velopment of the breast) is not
uncom-mon and may develop at any age during
childhood. Most published reports indicate
that this condition is not associated with
other evidence of sexual 2 3
and it has been assumed to represent
un-usual sensitivity of the end-organ (the
breasts) to the amount of circulating
estro-gen normally present in the pre-adolescent
2 This study reports our findings in
16 girls with premature thelanche in whom
evidence of estrogenic stimulation of
des-quamated cells in the urinary sediment was
present in 15.
MATERIALS AND METHODS
Sixteen consecutive girls with precocious
development of the breast were studied
(Table I). Whenever possible, information
was obtained regarding the type of feeding,
possible ingestion or contact with hormone
preparations by the child or by the mother during pregnancy, and the age of the
mother’s menarche. In certain cases,
roent-genographic examination of the skull,
de-termination of epiphyseal development and
assay of the urinary excretion of
17-keto-steroids and gonadotropins was performed.
Unfortunately, quantitative assay of blood
and urinary estrogens could not be carried
out.
The urinary sediment of each patient
was examined for hormonal stimulation by
a modification of the method previously
5 Urinary sediment was
ob-tamed by passing the urine through a plain
white Millipore filter (SMUP 04700) in a
Millipore Pyrex No. 4 filter holder
(XX1004700). The filter was then washed
with tap water, absolute isopropyl alcohol,
and 70% and 50% ethyl alcohol before being
stained with Schorr’s Single Differential Stain.
The sediment was interpreted as being
positive for estrogen effect when large
cornified cells with thin, transparent,
acido-philic, wrinkled cytoplasm, and pyknotic
deep-staining nuclei or precornified cells
with basophilic cytoplasm and vesicular
nuclei showing fine granulations of
chroma-tin were present.
RESULTS
The following findings were noted in the
series of 16 girls with premature thelarche:
The onset of breast enlargement was
within the first two years of life in 14
(87.5%); in 11 (68%) it developed prior to the
first birthday. The breasts were noted to
be enlarged during the first few weeks of
life in 6 (38%) of the entire group and in
these patients this may have represented a
continuation of the breast hypertrophy
al-most uniformly present in the neonatal
period in normal, full-term infants.
Both breasts were involved in all but
one child.
As far as could be determined, none of
the children had been exposed to any
preparation containing hormones. Except
for the mother of one child (Case 13) who
received a progestational preparation
PREMATURE THELARCHE
TABLE I
Case
‘ ,ez Race
Physical Findings
I F V
Laboratory Data Follow-up
Ace Breast Hype,-(yr) trophy Breast Fedf + + + Age Breast Ilyper-trophy Noted (i,r) 41’l Dirt), is Birth Birth is is Birth is 315 Before Birth 11 Birth IJcighI 30% 90% 30% 30% 97% 50% 73% 50% 50% 10% 50% 50% 3 4 5 6 7* B 9 10 II 13 14 15 16 F F F F F F F F F F F F F F F N ‘V ‘V ‘V N N JFeight 73% 50% 10% 50% 10% 73% 50% 50% 3% 50%
“Bone Skull
Gonado-Age” X-ray iropius
Normal Neg. Neg. 6MUU
Neg.
Neg.
Normal Neg.
Neg.
Normal Neg. Neg.
6MUU
Neg.
year Neg. Neg.
advanced 6MtU Normal Neg. Xeg. 17-KS mg./24 hr. 1.6 0.57 0.1 Urinary Cytology Esiro-Age yen (yr) Effect 5 + 15 + ‘is + ‘is + 15 + 115 ‘2 + uS + 1i + 415 + 715 + 9 + 4i5 + uS +11 1 + 1s + it’ 4 111, is 5 7is 9 5 uS Present Present Present Absent Present Present Present Absent Present Present Present Present Present Present Present Present
aOnly patient with unilateral breast hypertrophy.
tBreast fed for more than one month. Approximate percentile for age. (i4)
lFirat examination ‘doubtfully positive’; second specimen positive.
4First examination negative; second specimen positive.
known to have received any endocrine
product. Only three infants were breast
fed for more than the first few days of life.
There was no history of premature
the-larche among the relatives of the patients.
The mother of one patient (Case 1) first
menstruated at the age of 9 years; in all
other instances the age of the menarche
was reported to have been “normal.”
Thirteen of the girls were Caucasian;
3 were Negro. This ratio is similar to that
seen in the general population from which
these eases were drawn.
Height, weight, and patterns of growth
were normal in all the children. No other
clinical evidence of sexual maturation was
noted in any of the girls.
The excretion of urinary 17-ketosteroids
and gonadotropins, as well as
roentgeno-grams of the skull and epiphyseal
develop-ment (“bone age”) were all consistent with
the chronological age of the children in
those cases where these tests were
per-formed.
Cytologic study of desquamated cells
ob-tamed from the urinary sediment indicated
that estrogenic stimulation was present in
15 of 16 girls with precocious breast
109
largement. Only 7 of 86 “control” girls of
similar ages and with no known endocrine
disturbance exhibited an estrogenic effect in
desquamated cells (p = < 0.001).
Enlargement of the breast persisted for
periods up to 7 years. In 14 of the 16 girls
(87.5%), it was noted for more than 12
months and in 4 (25%) some swelling was
still present 3 or more years after it was
first noted. In only two cases had the
hyper-trophy completely disappeared at the time
of the last examination. In one, it had
per-sisted for 6 months; in the other, it had been
present for over 48 months.
COMMENT
Premature thelarche is characterized by
the asymptomatic development of
enlarge-ment of the breasts occurring
predom-inantly during the first two years of life.
Hypertrophy is usually bilateral but
some-times unilateral. The enlargement is not
cx-cessive and no significant changes of the
nipples or areolae develop. Tile cilildren are
of normal height and weight and have
nor-mal patterns of growth. No other signs of
sexual maturation are evident on physical
examination; the external genitalia remain
infantile, pubic and axillary hair does not
develop, and the size of the ovaries and
uterus is found to be consistent with the
child’s chronologic age. The enlargement of
the breasts may be transient but in most
cases it persists for many months or years.
Puberty follows at the usual age with the
pattern of sexual development and function
being completely normal. Epiphyseal
de-velopment, roentgenograms of the skull,
and the urinary excretion of 17-ketosteroids
and gonadotropins are consistent with the
chronologic age of the children. No therapy is indicated for premature thelarche, but the
children should be examined at intervals to
be certain that other evidences of sexual
maturity are not developing. The enlarged
breast(s) should not be removed or biopsied.
The 16 patients herein presented
cx-hibited the typical clinical findings of
pre-mature thelarche. In 87.5% the onset was
within the first 2 years of life. Both breasts
were involved in all hut one girl. None of
the children had received or been known to
have been exposed to any hormone. In all
cases the family history was negative for
premature breast hypertrophy or any other
type of sexual precocity. In 87.5 the
hyper-trophy persisted for more than 12 months
and in 25% it was noted for periods over 3
years; no other clinical evidence of sexual
maturation appeared during this time.
Enlargement of the breasts may occur in
various conditions in childhood. The most
common of these are: (1) hyperplasia of the
newborn infant, (2) premature thelarche, (3)
as a manifestation of true precocious
pu-herty of the constitutional (idiopathic) type,
(
4) secondary to tile administration ofestro-gens, and (5) with tumors of the ovary.
Malignant tumors of the breast are
cx-tremely rare; Tausig#{176}has reported that
can-cer of the breast has not been observed in
the first decade of life. Other uncommon
conditions which may he associated with
precocious breast enlargement include
or-ganic lesions of the central nervous system, estrogen-producing tumors of tile adrenal,
and a group of unclassified causes including
presacral teratomas, primary liver tumors,
and the syndrome of shortness of stature,
congenital asymmetry, and variations in the
pattern of sexual 78
There is a difference of opinion in the
literature regarding the pathogenesis of this
condition and the type of evidence of
hor-monal stimulation one might find in these
patients. Wilkins1 and Talbot et al.2
con-sidered premature thelarche to result from
unusual sensitivity of the breasts as a
re-sponse to the minute quantities of estrogen
circulating in young children, and they
pointed out that estrogenization was not
demonstrable in the vaginal smear. In a
limited number of cases of idiopathic breast
hypertrophy Talbot reported that the
un-nary excretion of estrogen was normal for
the age. Dresch et al.3 also concluded that
an increased excretion of estrogen was not
the cause of the condition since other clini-cal manifestations of estrogenic stimulation
smears were examined in 17 cases and all were negative for estrogen effect. They sug-gested that there might be some association
between the hyperplasia of the breasts and
the maillutnition or gastrointestinal
disturb-ance present in some of their patients.
Fer-ncr et al.bo similarly failed to find
estrogeni-zation in the vaginal smear in any of the 10
patients whom they studied. In contrast,
Bongiovanni and Eberlein1’ have reported
that some cases of precocious breast
de-velopment may show a moderate estrogenic
effect on the vaginal smear during the pe..
nod of breast enlargement, but that this
regressed as the hypertrophy subsided.
17-ketosteroids, gonadotropins, and the
Aschheim-Zondek test were assayed in a
few patients in the various series that have
been reported and in all instances they were found to be within normal limits. Urinary
estrogens were assayed by Seckel’2 in two
patients; in one, estrogen excretion was
“normal” while in the other, a child 53
years old, estniol excretion was elevated to
the level normally found in 8- to 11-year-old girls. Hagberg and Lyttkens9 reported that
there was no increase of estrogen in blood
or urine, but they gave no specific data
re-garding these measurements.
Of particular interest in our cases was the finding in 15 of the 16 cases of a positive
estrogenic effect in desquamated cells
ob-tamed from the sediment of random voided
tinines. Using the same method of assay in a
“control” group of girls of similar ages and
with no known endocrine abnormality or
other condition which might have been
in-strumental in affecting the urinary cytology, only 7 of 86 demonstrated a hormonal effect.
It has been shown that the results
ob-tamed from the examination of the urinary
sediment are comparable to those derived
from studies of cells obtained from the
vaginal mucosa.5 Del Castillo13 reported
that when smears of the vagina and urinary
sediment were taken at the same time from
the same patient there was a striking
paral-lelism of the cellular composition of both
sites with each one undergoing the same
morphologic and staining characteristics in
relation to the absence or presence of estro-gens.
The presence of estrogenic stimulation in
cells obtained from the urinary sediment of
15 of the 16 girls in this series is evidence
that hormonal effect in children with
pre-mature thelanche is not limited to the
breasts, but involves the estrogen-sensitive cells of the terminal urethra and/or vagina
as well. Although the exact mechanism
pro-ducing premature thelarche is as yet
un-known, evidence of hormonal stimulation in
at least two tissues suggests that the breast
hypertrophy may be the result of
temporar-ily increased amounts of circulating estrogen
rather than unusual responsiveness of the
breasts.
SUMMARY
The findings in 16 cases of premature
thelarche (precocious development of the
breast) are described.
Of particular interest in this series of
cases was the finding of estrogenic
stimula-tion of desquamated cells in the urinary
sediment in 15 of the 16 cases. Only 7 of 86
“control” patients demonstrated a similar
hormonal effect of the urinary cytology.
The findings in most patients with
pre-mature thelarche of hormonal stimulation in
at least two estrogen-responsive tissues of
the body suggests that in the prepubertal
period the breast enlargement may occur
secondarily to a temporary increased
excre-tion of estrogen by some mechanism as yet
unknown.
REFERENCES
1. Wilkins, L. : The Diagnosis and Treatment of Endocrine Disorders in Childhood and Ado-lescence, 2nd Ed. Springfield, Ill. : Charles C Thomas, 1957.
2. Talbot, N. B., Sobel, E. H., McArthur, J. W.,
and Crawford, J. D. : Functional
Endocrin-ology from Birth through Adolescence, Cambridge, Mass. : Harvard University Press, 1952.
3. Dresch, C., Arnal, M., and Prader, A. : Etude de 22 cas de developpement premature isole
des seins ou “premature thelarche.” Helv. Paediat. Acta, 15:585, 1960.
5. Del Castillo, E. B., Argonz, J., and Gall
Mainini, C.: Cytological cycle of the urinary sediment and its parallelism with the vaginal cycle. J. Clin. Endocrinol., 8:76, 1948. 6. Tausig, F. J., and Allen, W. M. : The Female
Reproductive System, Brennemann-McQuar-ne, Practice of Pediatrics, Vol. III, chap. 3,
pp. 27 f., Hagerstown, Maryland: W. F. Prior Co., Inc., 1950.
7. Silver, H. K. : Congenital asymmetry, short stat-ure and elevated urinary gonadotropin. J. Dis. Child., 97:768, 1959.
8. Stool, S., and Cohen, P. : Silver’s syndrome.
Syndrome of congenital asymmetry, short
stature, and altered pattern of sexual
de-velopment. Amer. J. Dis. Child., 105:199,
1963.
9. Hagberg, B., and Lyttkens, C. : Praematur
thelarche-en godartad form av
brostkortel-forstoring hos smaflickor. Svensk Lakartidn., 57:2.333, 1960.
10. Ferrier, P., Shepard II, T. H., and Smith, E. K.: Growth disturbances and values for hormone extraction in various forms of precocious
sexual development. PEDIATRICS, 28:258,
1961.
11. Bongiovanni, A., and Eberlein, W. R. Pre-adolescent gynecomastia. Penn. Med. J., 60:
66, 1957.
12. Seckel, H. P. G. : Conditions simulating sexual
precocity. Ann. Paediat. (Basel), 176:361, 1951.
13. Del Castillo, E. B., Argonz, J., and Galli Mainini, C.: Smears from the female urethra and their relationship to smears of the
un-nary sediment. J. Clin. Endocrinol., 9: 1362, 1949.
14. Stuart, H. D., and Stevenson, S. S. in W. E.
Nelson, Textbook of Pediatrics, 7th Ed. Philadelphia: W. B. Saunders, 1959, p. 12.
Acknowledgment
We wish to thank Doctors J. Amen, N. Bogard, H. S. Cerzonski, P. Fernier, C. Fraser, V. C. Kelley, H. D. Kievit, B. D. \IcKneeiey, P. Rhodes, W/. E. Stevens, M. E. Westerlund, and W. L. Ziegler for
