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Gonadotropins and prolactin pituitary reserve in premature thelarche
Volume 91 Number 5
B r i e f cfinical and laboratory observations
at gestational ages from 26 to 42 weeks, Pediatrics 37:403, 1966. Boyd JD: Graphic portrayal of infants' growth with consideration of head size, Am J Dis Child 76:53, 1948.
Gonadotropins and prolactin pituitary reserve in premature thelarche A. Caufriez, M.D.,* R. Woiter, M.D., M. Govaerts, M.D., M. L'Hermite, M.D., and C. Robyn, M.D., Brussels, Belgium
PREMATURE THELARCHE in young girls refers to isolated breast development not accompanied by any other signs of sexual maturation. 1An increased sensitivity of breast tissue to the low levels of estrogens secreted during early childhood has been postulated as the cause of this premature breast development. 1 Normal or slightly increased plasma estradiol and basal gonadotropin (LH and FSH) levels have been reported. ~-7 However, conflicting results concerning gonadotropin responsiveness to synthetic gonadotropin-releasing hormone (LHRH) have been observed. :'-" The purpose of this study was to evaluate the luteinizing hormone and follicle-stimulating hormone response to LH-RH and the prolactin release after thyrotropinreleasing hormone in girls with premature thelarche as compared to normal prepubertal girls of comparable age. PATIENTS
AND METHODS
Fifteen girls (9/12 to 7 years old) with premature thelarche were investigated. The duration of breast development was two weeks to four months at the time of the From the Departments of Pediatrics and o f Obstetrics and Gynecology (Human Reproduction Research Unit), Free University o f Brussels. Supported in part by grants to Prof P.O. Hubinont from the Ford Foundation (USA) and the F.R.S.M. (Belgium). *Reprint address: Laboratoire de Gynbcologie et de Recherches sur la Reproduction Humaine, Hbpital SaintPierre, rue Haute 322, B-IO00 Bruxelles, Belgium.
751
10. Warkany J: Congenital malformations, Chicago, 1971, Yearbook Medical Publishers, Inc., pp 237-239. 11. Riopel DA, and Mullins CE: Thyrotoxicosis and paroxysmal tachycardia, Pediatrics 50:140, 1972.
first physical examination and testing, In all the subjects the breast development disappeared within three to six months after the first physical examination. The bone age was in each case compatible with the chronologic age. Except for uni- or bilateral breast enlargement, no other sign of sexual maturation was present. Vaginal smears did not show any estrogenic stimulation. The control group included 15 girls (1 to 7 years old) hospitalized for evaluation of growth retardation and in whom no endocrine anomalies were evident. Each subject received an intravenous bolus injection of LH-RH (Hoechst, FRG; 25 /~g/m2). Blood samples were withdrawn frequently for 150 minutes through an indwelling venous needle: LH and FSH were measured in all samples by previously described radioimmunoassays 9. 19; results are expressed as m l U / m l of the second International Reference Preparation of human menopausal gonadotropins. In all subjects, routine T4 and TSH determinations by competitive protein-binding assay and radioimmunoassay, respectively, were obtained on blood collected at 8 A~a; 24-hour urine specimens were collected for measurement of 17hydroxycorticosteroids and 17-ketosteroids by the Zimmerman reaction. Abbreviations used LH: luteinizing hormone FSH: follicle-stimulating hormone LH-RH: luteinizing hormone-releasing hormone PRL: prolactin TRH: thyrotropin-releasing hormone T4: thyroxine TSH: thyroid-stimulating hormone Five normal girls and seven with premature thelarche received an intravenous injection of 200 mg TRH (Roche, Belgium) simultaneously to that of LH-RH: serum PRL levels were determined in these samples using a homologous ovine radioimmunoassay. 11PRL levels are expressed in m U / m l of the laboratory standard (a pool of postpartum sera): 1.0 m U / m l of this standard was found to be equivalent to 2.3 mU of the serum research standard 71/ 167 (distributed by the MRC, Holly Hill, London). RESULTS All children had normal values ofT4, TSH, 17-hydroxycorticosteroids, and 17-ketosteroids.
752
Brief clinical and laboratory observations
The Journal of Pediatrics November 1977
CONTROLS
L,_]
E
e_s -r ...I
40
E 2C
-r CO LL
1c I
730
0
I
I
30 60 TIME (rain)
120
I
-~o
G
30 TIME
,2d
6'0 (mini
Fig. L Plasma LH and FSH levels (mean _+ SEM) before and after intravenous injection of LH-RH (25/~g/m 2) in 15 girls with premature thelarche and in 15 normal girls.
TRH
PREMATURE
TRH
40C
THELARCHE
300
~
200
13_ 100
O_;o
~
~o
Jo
Jo ,~6 -~o ~
TIME (rain)
~o
~o
~o ,~
TIME (rain)
Fig. 2. Plasma prolactin levels (mean +_ SEM) before and after intravenous injection of TRH (200 big)in seven girls with premature thelarche and in five normal girls.
Mean basal LH (1.1 m I U / m l ) and FSH (8.2 m l U / m l ) levels were not significantly different in girls with premature thelarche than in control girls. As shown in Fig. 1, the patterns of the LH and FSH responses to LH-RH were indistinguishable for the two groups: no statistically significant difference could be evidenced at any time. The calculation of the area of the response curve of the two groups showed no statistical difference. In seven girls with premature thelarche, the mean basal PRL level (102 m U / m l ) was not significantly different
from that (95 m U / m l ) of the five control girls: Similarly, the mean PRL response to TRH was somewhat lower, but not significantly different, in the girls with premature thelarche than in those of the control group (Fig. 2). DISCUSSION Hyperestrogenism as a cause of breast development in premature thelarche has only rarely been confirmed. 2, 4, 5 In premature thelarche, basal LH and FSH concentrations have been reported as normaP, 7 or slightly
Volume 91 Number 5
elevated. ~ In all of our patients with premature thelarche, basal LH and FSH levels were normal for age as were their responses to LH-RH; these observations are in agreement with those of Reiter and associates. ~ Job and associates, however, reported pubertal LH responses in some patients with premature thelarche and suggested that this may represent an early phase of precocious puberty. Ours and previous reports indicate that these subjects do have a normal regulation of their hypothalamo-pituitary-gonadal axis. No data concerning PRL secretion in girls with premature thelarche were previously reported. The present study shows a normal PRL secretion in basal conditions and in response to TRH in girls with premature thelarche. Prolactin does not seem to play a major role in the genesis of isolated breast development in prepubertal girls. The etiologic factors involved in premature thelarche have still to be determined. The authors gratefully acknowledge the technical help of Mr. A. Van Meenen and Mrs. A~ Michaux-DuchSne and J. DelogneDesnoeck; the NIAMDD (National Institutes of Health, Bethesda, Md.) for gift of the reagents used for FSH radioimmunoassays; Dr. G.D. Niswender (Fort Collins, Colo.) for gift of the ovine reagents used for human PRL radioimmunoassays; the secretarial work of Mrs. A. M. Pauwels and helpful advice of Dr. P. Malvaux in preparing the manuscript. REFERENCES 1. Wilkins L, Blizzard RM, and Migeon CJ: The diagIlosisand treatment of endocrine disorders in childhood and adolescence, ed 3, Springfield, I11., 1965, Charles C Thomas, Publisher, pp 206-207. 2. Jenner MR, Kelch RP, Kaplan SL, and Grumbach MM: Hormonal changes in puberty: IV. Plasma estradiol, LH, and FSH in prepubertal children, pubertal females, and in
A female patient with "'Aase syndrome" M. van Weel-Sipman, M.D., J. J. P. van de Kamp, M.D., and J. de Koning, M.D., Leiden, The Netherlands D I s o RD ER S of the hematopoietic system combined with upper limb malformations occur in two well-defined syndromes: aplastic anemia of the Fanconi type I and the From the Department of Pediatrics, University Hospital, and Institute for Anthropogenetics, University of Leiden. *Reprint address: Department of Pediatrics, University Hospital Leiden, The Netherlands.
Brief clinical and laboratory observations
3.
4.
5.
6.
7.
8.
9.
10.
11.
753
precocious puberty, premature thelarche, hypogonadism, and in a child with a feminizing ovarian tumor, J Clin Endocrinol Metab 34:521, 1972. Job JC, Guilhaume B, Chaussain JL, and Garnier PE: Le drveloppement prrmatur6 isol6 des seins chez les fillettes, Arch Fr Prdiatr 32:39, 1975. Escobar ME, Rivarola MA, and Bergada C: Plasma concentration of estradiol-17fl in premature thelarche and in different types of sexual precocity, Acta Endocrinol 81:351, 1976. Radfar N, Richards C, Brych M, and Kenny FM: Percentage of dialyzable estradiol 17fl from birth to adulthood and in sexual precocity and premature thelarche, Pediatr Res 8:373, 1974. Kenny FM, Midgley AR, Jaffe RB, Garces LY, Vasquez A, and Taylot FH: Radioimmunoassayable serum LH and FSH in girls with sexual precocity, premature thelarche and adrenarche, J Clin Endocrinol Metab 29:1272, 1969. Guyda HJ, Johanson AJ, Migeon CJ, and Blizzard RM: Determination of serum luteinizing hormone (SLH) by radioimmunoassay in disorders of adolescent sexual development, Pediatr Res 3:538, 1969. Reiter EO, Kaplan SL, Conte FA, and Grumbach MM: Responsivity of pituitary gonadotropins to luteinizing hormone-releasing factor in idiopathic-precocious puberty, precocious thelarche, precocious adrenarche and in patients treated with medroxyprogesterone acetate, Pediatr Res 9:111, 1975. Robyn C, L'Hermite M, Petrusz P, and Diczfalusy E: Potency estimates of human gonadotrophins by a bioassay and three immunoassay methods, Acta Endocrinol 67:417, 1971. L'Hermite M, and Midgley AR: Radioimmunoassay of human follicle-stimulating hormone with antisera to the ovine hormone, J Clin Endocrinol Metab 33:68, 1971. L'Hermite M, Delvoye P, Nokin J, Vekemans M, and Robyn C: Human prolactin secretion, as studied by radioimmunoassay: some aspects of its regulation, in Boyns A R, and Griffiths K, editors: Prolactin and carcinogenesis, Cardiff, 1972, Alpha Omega Alpha, pp 81-97.
thrombocytopenia-absent radius syndrome? In 1969 Aase and Smith 3 described a syndrome of congenital hypoplastic anemia with bilateral triphalangeal thumbs occurring in two brothers. Other patients were described by Murphy and LubinJ by Jones and Thompson, 5 and by Terheggen. 6 Since all of these patients were males, Xlinked inheritance has been suggested. 6 However, Harvey 7 Abbreviations used TAR: thrombocytopenia-absent radius CFUC: colony forming units in culture described a girl with congenital hypoplastic anemia and bilateral triphalangeal thumbs, and Diamond and associates ~ mentioned a girl with an extra phalanx in one thumb in their survey of congenital hypoplastic anemia. In this report we describe another female patient, which makes X-linked inheritance unlikely.
B r i e f cfinical and laboratory observations
at gestational ages from 26 to 42 weeks, Pediatrics 37:403, 1966. Boyd JD: Graphic portrayal of infants' growth with consideration of head size, Am J Dis Child 76:53, 1948.
Gonadotropins and prolactin pituitary reserve in premature thelarche A. Caufriez, M.D.,* R. Woiter, M.D., M. Govaerts, M.D., M. L'Hermite, M.D., and C. Robyn, M.D., Brussels, Belgium
PREMATURE THELARCHE in young girls refers to isolated breast development not accompanied by any other signs of sexual maturation. 1An increased sensitivity of breast tissue to the low levels of estrogens secreted during early childhood has been postulated as the cause of this premature breast development. 1 Normal or slightly increased plasma estradiol and basal gonadotropin (LH and FSH) levels have been reported. ~-7 However, conflicting results concerning gonadotropin responsiveness to synthetic gonadotropin-releasing hormone (LHRH) have been observed. :'-" The purpose of this study was to evaluate the luteinizing hormone and follicle-stimulating hormone response to LH-RH and the prolactin release after thyrotropinreleasing hormone in girls with premature thelarche as compared to normal prepubertal girls of comparable age. PATIENTS
AND METHODS
Fifteen girls (9/12 to 7 years old) with premature thelarche were investigated. The duration of breast development was two weeks to four months at the time of the From the Departments of Pediatrics and o f Obstetrics and Gynecology (Human Reproduction Research Unit), Free University o f Brussels. Supported in part by grants to Prof P.O. Hubinont from the Ford Foundation (USA) and the F.R.S.M. (Belgium). *Reprint address: Laboratoire de Gynbcologie et de Recherches sur la Reproduction Humaine, Hbpital SaintPierre, rue Haute 322, B-IO00 Bruxelles, Belgium.
751
10. Warkany J: Congenital malformations, Chicago, 1971, Yearbook Medical Publishers, Inc., pp 237-239. 11. Riopel DA, and Mullins CE: Thyrotoxicosis and paroxysmal tachycardia, Pediatrics 50:140, 1972.
first physical examination and testing, In all the subjects the breast development disappeared within three to six months after the first physical examination. The bone age was in each case compatible with the chronologic age. Except for uni- or bilateral breast enlargement, no other sign of sexual maturation was present. Vaginal smears did not show any estrogenic stimulation. The control group included 15 girls (1 to 7 years old) hospitalized for evaluation of growth retardation and in whom no endocrine anomalies were evident. Each subject received an intravenous bolus injection of LH-RH (Hoechst, FRG; 25 /~g/m2). Blood samples were withdrawn frequently for 150 minutes through an indwelling venous needle: LH and FSH were measured in all samples by previously described radioimmunoassays 9. 19; results are expressed as m l U / m l of the second International Reference Preparation of human menopausal gonadotropins. In all subjects, routine T4 and TSH determinations by competitive protein-binding assay and radioimmunoassay, respectively, were obtained on blood collected at 8 A~a; 24-hour urine specimens were collected for measurement of 17hydroxycorticosteroids and 17-ketosteroids by the Zimmerman reaction. Abbreviations used LH: luteinizing hormone FSH: follicle-stimulating hormone LH-RH: luteinizing hormone-releasing hormone PRL: prolactin TRH: thyrotropin-releasing hormone T4: thyroxine TSH: thyroid-stimulating hormone Five normal girls and seven with premature thelarche received an intravenous injection of 200 mg TRH (Roche, Belgium) simultaneously to that of LH-RH: serum PRL levels were determined in these samples using a homologous ovine radioimmunoassay. 11PRL levels are expressed in m U / m l of the laboratory standard (a pool of postpartum sera): 1.0 m U / m l of this standard was found to be equivalent to 2.3 mU of the serum research standard 71/ 167 (distributed by the MRC, Holly Hill, London). RESULTS All children had normal values ofT4, TSH, 17-hydroxycorticosteroids, and 17-ketosteroids.
752
Brief clinical and laboratory observations
The Journal of Pediatrics November 1977
CONTROLS
L,_]
E
e_s -r ...I
40
E 2C
-r CO LL
1c I
730
0
I
I
30 60 TIME (rain)
120
I
-~o
G
30 TIME
,2d
6'0 (mini
Fig. L Plasma LH and FSH levels (mean _+ SEM) before and after intravenous injection of LH-RH (25/~g/m 2) in 15 girls with premature thelarche and in 15 normal girls.
TRH
PREMATURE
TRH
40C
THELARCHE
300
~
200
13_ 100
O_;o
~
~o
Jo
Jo ,~6 -~o ~
TIME (rain)
~o
~o
~o ,~
TIME (rain)
Fig. 2. Plasma prolactin levels (mean +_ SEM) before and after intravenous injection of TRH (200 big)in seven girls with premature thelarche and in five normal girls.
Mean basal LH (1.1 m I U / m l ) and FSH (8.2 m l U / m l ) levels were not significantly different in girls with premature thelarche than in control girls. As shown in Fig. 1, the patterns of the LH and FSH responses to LH-RH were indistinguishable for the two groups: no statistically significant difference could be evidenced at any time. The calculation of the area of the response curve of the two groups showed no statistical difference. In seven girls with premature thelarche, the mean basal PRL level (102 m U / m l ) was not significantly different
from that (95 m U / m l ) of the five control girls: Similarly, the mean PRL response to TRH was somewhat lower, but not significantly different, in the girls with premature thelarche than in those of the control group (Fig. 2). DISCUSSION Hyperestrogenism as a cause of breast development in premature thelarche has only rarely been confirmed. 2, 4, 5 In premature thelarche, basal LH and FSH concentrations have been reported as normaP, 7 or slightly
Volume 91 Number 5
elevated. ~ In all of our patients with premature thelarche, basal LH and FSH levels were normal for age as were their responses to LH-RH; these observations are in agreement with those of Reiter and associates. ~ Job and associates, however, reported pubertal LH responses in some patients with premature thelarche and suggested that this may represent an early phase of precocious puberty. Ours and previous reports indicate that these subjects do have a normal regulation of their hypothalamo-pituitary-gonadal axis. No data concerning PRL secretion in girls with premature thelarche were previously reported. The present study shows a normal PRL secretion in basal conditions and in response to TRH in girls with premature thelarche. Prolactin does not seem to play a major role in the genesis of isolated breast development in prepubertal girls. The etiologic factors involved in premature thelarche have still to be determined. The authors gratefully acknowledge the technical help of Mr. A. Van Meenen and Mrs. A~ Michaux-DuchSne and J. DelogneDesnoeck; the NIAMDD (National Institutes of Health, Bethesda, Md.) for gift of the reagents used for FSH radioimmunoassays; Dr. G.D. Niswender (Fort Collins, Colo.) for gift of the ovine reagents used for human PRL radioimmunoassays; the secretarial work of Mrs. A. M. Pauwels and helpful advice of Dr. P. Malvaux in preparing the manuscript. REFERENCES 1. Wilkins L, Blizzard RM, and Migeon CJ: The diagIlosisand treatment of endocrine disorders in childhood and adolescence, ed 3, Springfield, I11., 1965, Charles C Thomas, Publisher, pp 206-207. 2. Jenner MR, Kelch RP, Kaplan SL, and Grumbach MM: Hormonal changes in puberty: IV. Plasma estradiol, LH, and FSH in prepubertal children, pubertal females, and in
A female patient with "'Aase syndrome" M. van Weel-Sipman, M.D., J. J. P. van de Kamp, M.D., and J. de Koning, M.D., Leiden, The Netherlands D I s o RD ER S of the hematopoietic system combined with upper limb malformations occur in two well-defined syndromes: aplastic anemia of the Fanconi type I and the From the Department of Pediatrics, University Hospital, and Institute for Anthropogenetics, University of Leiden. *Reprint address: Department of Pediatrics, University Hospital Leiden, The Netherlands.
Brief clinical and laboratory observations
3.
4.
5.
6.
7.
8.
9.
10.
11.
753
precocious puberty, premature thelarche, hypogonadism, and in a child with a feminizing ovarian tumor, J Clin Endocrinol Metab 34:521, 1972. Job JC, Guilhaume B, Chaussain JL, and Garnier PE: Le drveloppement prrmatur6 isol6 des seins chez les fillettes, Arch Fr Prdiatr 32:39, 1975. Escobar ME, Rivarola MA, and Bergada C: Plasma concentration of estradiol-17fl in premature thelarche and in different types of sexual precocity, Acta Endocrinol 81:351, 1976. Radfar N, Richards C, Brych M, and Kenny FM: Percentage of dialyzable estradiol 17fl from birth to adulthood and in sexual precocity and premature thelarche, Pediatr Res 8:373, 1974. Kenny FM, Midgley AR, Jaffe RB, Garces LY, Vasquez A, and Taylot FH: Radioimmunoassayable serum LH and FSH in girls with sexual precocity, premature thelarche and adrenarche, J Clin Endocrinol Metab 29:1272, 1969. Guyda HJ, Johanson AJ, Migeon CJ, and Blizzard RM: Determination of serum luteinizing hormone (SLH) by radioimmunoassay in disorders of adolescent sexual development, Pediatr Res 3:538, 1969. Reiter EO, Kaplan SL, Conte FA, and Grumbach MM: Responsivity of pituitary gonadotropins to luteinizing hormone-releasing factor in idiopathic-precocious puberty, precocious thelarche, precocious adrenarche and in patients treated with medroxyprogesterone acetate, Pediatr Res 9:111, 1975. Robyn C, L'Hermite M, Petrusz P, and Diczfalusy E: Potency estimates of human gonadotrophins by a bioassay and three immunoassay methods, Acta Endocrinol 67:417, 1971. L'Hermite M, and Midgley AR: Radioimmunoassay of human follicle-stimulating hormone with antisera to the ovine hormone, J Clin Endocrinol Metab 33:68, 1971. L'Hermite M, Delvoye P, Nokin J, Vekemans M, and Robyn C: Human prolactin secretion, as studied by radioimmunoassay: some aspects of its regulation, in Boyns A R, and Griffiths K, editors: Prolactin and carcinogenesis, Cardiff, 1972, Alpha Omega Alpha, pp 81-97.
thrombocytopenia-absent radius syndrome? In 1969 Aase and Smith 3 described a syndrome of congenital hypoplastic anemia with bilateral triphalangeal thumbs occurring in two brothers. Other patients were described by Murphy and LubinJ by Jones and Thompson, 5 and by Terheggen. 6 Since all of these patients were males, Xlinked inheritance has been suggested. 6 However, Harvey 7 Abbreviations used TAR: thrombocytopenia-absent radius CFUC: colony forming units in culture described a girl with congenital hypoplastic anemia and bilateral triphalangeal thumbs, and Diamond and associates ~ mentioned a girl with an extra phalanx in one thumb in their survey of congenital hypoplastic anemia. In this report we describe another female patient, which makes X-linked inheritance unlikely.