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Central precocious puberty in girls: Internal genitalia before, during, and after treatment with long-acting gonadotropin-releasing hormone analogues
C
Central precocious puberty in girls: Internal genitalia before, during, and after treatment with long-acting gonadotropin-releasing hormone analogues
Anne-Mette Bæk Jensen, MD, Vibeke Brocks, MD, Kirsten Holm, MD, Eva M. Laursen, MD, and Jørn Müller, MD
Pelvic ultrasonography was systematically performed on 33 girls with idiopathic central precocious puberty to investigate the impact of treatment with gonadotropin-releasing hormone analogues on female internal genitalia. All girls were treated with a long-acting gonadotropin-releasing hormone analogue (Decapeptyl Depot; Ferring Co., Copenhagen, Denmark) 75 µg/kg every 4 weeks. Before, during, and after treatment, pelvic ultrasonography was performed and ovarian and uterine volumes were calculated. The size of follicles > 5 mm were accurately measured. The results were related to a normative study of healthy Danish schoolgirls. Our data demonstrated that ovaries and uterus are enlarged in a significant number of girls (50%) with the diagnosis of central precocious puberty at the time of diagnosis. Median ovarian volume at time of diagnosis was 1.1 standard deviation scores (range –0.6 to 3.2 SD), median uterine volume was 1.8 standard deviation scores (range 0.0 to 3.5 SD). Within 3 months of treatment, both ovarian and uterine volumes decreased significantly (p < 0.01) to normal values appropriate for age. Median ovarian volume after 3 months of treatment was 0.0 SD (range –2.4 to 1.5 SD); median uterine volume was 0.7 SD (range –0.6 to 4.1 SD). Ovarian and uterine volume remained within normal range (<2 standard deviation scores) after discontinuation of treatment. Follicles and macrocysts regressed during treatment. None of the girls’ ovaries had a polycystic appearance during or after treatment with the gonadotropin-releasing hormone analogue. Our results confirmed pelvic ultrasonography as a reliable tool for investigation of internal genitalia in girls with precocious puberty and as a valid method for evaluation of the efficacy of treatment with gonadotropin-releasing hormone analogues. We suggest that repeated investigations be performed when evaluating treatment because the morphologic changes, including follicular maturation or regression, reflect ovarian stimulation or suppression. We found no evidence that girls with precocious puberty treated with long-acting gonadotropin-releasing hormone analogues have enlarged polycystic ovaries develop. (J Pediatr 1998;132:105-8)
From the Department of Growth and Reproduction and the Department of Obstetrics and Gynecology, Rigshospitalet, State University Hospital, Denmark. Submitted for publication Sept. 9, 1996; accepted April 4, 1997. Reprint requests: Anne-Mette Bæk Jensen, Bavnestien 4, 2850 Nærum, Denmark. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/21/82508
Central precocious puberty in girls is defined as pubertal development caused by activation of the hypothalamic-pituitarygonadal axis before 8 years old. In this condition gonadotropin stimulation produces ovarian enlargement,1-3 and estrogen secretion results in uterine enlargement.2,4 Pelvic ultrasound has proven to be an ac-
curate and noninvasive technique for the investigation of internal genitalia in female patients.5 Earlier studies have shown that ultrasound examination, which can distinguish between centrally mediated precocious puberty, gonadotropin-independent precocious puberty, and premature thelarche, is useful in diagnosing disorders of sexual development.1,6-9 Other studies have investigated ultrasonographic changes in internal genitalia during treatment with long-acting GnRH analogues. Ovarian CPP GnRH LH
Central precocious puberty Gonadotrophin releasing hormone Luteinizing hormone
volume was enlarged in girls with CPP at the time of diagnosis and decreases during treatment,9-12 suggesting pelvic ultrasonography as a reliable tool in the evaluation of patients during treatment. Former studies have included small numbers of patients,1,6,13-16 and only one study has included data on follow-up ultrasonographic investigations after discontinuation of therapy.12 Bridges et al.12 found that girls with CPP treated with GnRH analogues and growth hormone had large ovaries develop and an increase in the prevalence of ovaries with polycystic appearance. However, data on girls with CPP treated with GnRH analogues alone after discontinuation of treatment have not been available. In this study we systematically performed pelvic ultrasonography in 33 girls with idiopathic CPP at diagnosis, during treatment with a long-acting GnRH analogue, and after discontinuation of therapy to investigate the impact of treatment on internal genitalia.
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Table I. Size of both ovaries in SDS before, during, and after treatment for central precocious puberty, median (range) and presence of follicles, macrocysts, and polycystic ovaries before, during, and after treatment for central precocious puberty
N Ovary SDS No. of patients with SDS >2 Follicles >5 mm Macrocysts*
Before
3
12
24
After
24 1.1 (–0.6-3.2) 5 19 5
29 1.1 (–0.6-3.2) 0 5 1
29 –0.4 (–1.8-1.0) 0 2 0
17 –0.6 (–2.3-1.1) 0 5 1
17 0.6 (–1.4-2.1) 1 11 3
SDS, Standard deviation scores. *Follicles > 9 mm.
METHODS Patients Thirty-three girls with the diagnosis of idiopathic CPP were included in the study. The diagnosis was based on development of secondary sexual characteristics before 9 years of age, increased height velocity, advanced bone age, pubertal response to GnRH test, and serum estradiol greater than prepubertal levels. Median age at the beginning of treatment was 8.5 years (6.5 to 10.5). Three girls had had menarche at the time of diagnosis.
Treatment All girls received a long-acting GnRH analogue (Decapeptyl Depot), 75 µg/kg, (maximum doses 3.75 mg) administrated as intramuscular injections every fourth week. Long-acting GnRH analogue is a decapeptide that stimulates synthesis and secretion of gonadotropins from the pituitary gland. During the first 1 to 2 weeks of treatment, more gonadotropins are released, after which a suppression of follicle-stimulating hormone and LH secretion is seen because of reduced sensitivity in the pituitary gland receptors. The efficacy of the treatment was ensured by repeated GnRH stimulation tests 3 and 12 months after diagnosis and at 12-month intervals during the course of therapy. The rationale for the decision to start treatment with GnRH and to determine the duration of therapy included (1) the psychologic problems of early development of secondary sexual characteristics and menstruation, and (2) the possibility of improving final height by a reduction in height velocity and advancement in bone age. Therapy was 06
continued until the age for onset of natural puberty. After discontinuation of therapy, another GnRH stimulation test was performed. The median treatment time was 2.4 years (range 1.5 to 4.7 years). GnRH stimulation tests were performed using a standard dose of 100 µg luteinizing hormone–releasing hormone administrated intravenously. Blood samples were obtained immediately before the injection and at 15, 30, 45, 60, and 90 minutes after injection. Peak values of LH >10.4 mlU/ml were considered as pubertal response, whereas peak values < 5.0 mlU/ml during treatment with a GnRH analogue were considered as sufficient suppression.17 LH was assayed before July 1993 with an enzyme-linked immunoassay and after July 1993 with a time-resolved fluoroimmunoassay (Delfia, Wallac Denmark Als).
Ultrasound Pelvic ultrasound was performed at diagnosis, 3, and 12 months after diagnosis and at 12-month intervals during the course of therapy. Three to 20 months after discontinuation of therapy, follow-up pelvic ultrasonography was performed. All ultrasound examinations were performed by the same investigator (V.B.) using an ALOKA SSD 680 (ALOKA Co., Japan) with a 3.5 MHz curved linear transducer. The ultrasound examinations were performed with the full bladder technique obtained by voluntary urine retention and oral administration of fluids. The detection limit of the ultrasound equipment was 1 mm. Uterine and ovarian volumes were calculated by measuring length, width, and depth and by assuming the forms to be el-
lipsoid using the formula based on a prolate ellipsoid: (d1 · d2 · d3)/2 where d1, d2, and d3 are the three maximal longitudinal, anteroposterior, and transverse diameters. Average ovarian volume was used for analysis. Ovarian follicles of 1 to 5 mm were defined as small follicles. The sizes of follicles > 5 mm were accurately measured. The size of the greatest follicle in either ovary was used for analysis. The presence of polycystic ovaries was noted. Polycystic ovaries were defined as ovaries having at least 10 follicles (2 to 8 mm diameter) at the periphery of the ovarian cortex, increased ovarian volume, and increased interstitial echogenicity.
Controls The results were related to a normative study of healthy Danish schoolgirls.18 These ultrasound scans were performed by the same investigator as in our study using the same equipment and methods. Age-specific standard deviation was calculated.
Statistics Changes in ovarian size, uterine size, and follicle size were analyzed by the Friedman and the Wilcoxon tests. All analyses were carried out by using a statistical package (SPSS/PC, SPSS Inc.). A probability value of less than 0.05 was considered statistically significant.
Ethics Written informed consent was obtained from the parents of all participants. The study was in accordance with the Helsinki II declaration and approved by the local ethical committee of Copenhagen, Denmark (approval no. v.200.1984/90).
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Table II. Size of uterus in SDS before, during, and after treatment for central precocious puberty, median (range)
N Ovary SDS No. of patients with SDS >2
Before
3
12
24
After
22 1.8 (0-3.5) 9
26 0.8 (–0.6-4.1) 4
26 0 (–1.7-2.3) 1
15 –0.5 (–2.0-1.8) 0
15 1.3 (0.4-2.8) 1
SDS, Standard deviation scores.
RESULTS Results from the first 24 months of treatment and from follow-up examinations 3 to 20 months after discontinuation were used for analyses.
Ovaries At time of diagnosis, the median volume was 1.1 SD (range –0.6 to 3.2 SD) corresponding to 4.6 ml (range 1.4 to 11.1 ml). Five (21%) of the girls had ovarian volumes greater than 2.0 SD (Table I). After 3 months of treatment with a GnRH analogue, a significant reduction was observed, with a median ovarian volume of 0.0 SD (range –2.4 to 1.5 SD). None of the girls had an ovarian volume > 2.0 SD. Ovarian volumes remained within normal limits for chronologic age during treatment. At the examination 3 to 20 months after discontinuation of treatment, median ovarian volume was 0.6 SD (range –1.4 to 2.1 SD). One girl (7%) had ovarian volume > 2.0 SD scores. None of the girls had ovaries with a polycystic appearance (Table I).
Uterus At time of diagnosis, the median volume was 1.8 SD (range 0.0 to 3.5 SD) corresponding to 7.5 ml (range 1.0 to 21.8 ml). Nine girls (41%) had uterine volumes > 2.0 SD scores (Table II). After 3 months of treatment, a significant reduction in uterine volume was seen, with a median uterine volume of 0.7 SD (range –0.6 to 4.1 SD). After 12 months of treatment, further reduction was seen, with the median volume at 0.0 SD (range –1.7 to 2.3 SD). After 3 months of treatment, four girls (15%) had uterine volumes > 2.0 SD; after 12 months of treatment one girl (3.8%) had a volume > 2.0 SD. At follow-up examination 3 to 20
months after discontinuation of treatment, one girl (7%) had a uterine volume > 2.0 SD. The median uterine volume was 1.3 SD (range 0.4 to 2.8 SD).
Follicles At time of diagnosis follicles > 5 mm were detected in 19 girls (83%). After 3 months of treatment, follicles > 5 mm were seen in five girls (17%), after 12 months in two girls (7%), and after 24 months in five girls (28%) (Table I). Macrocysts (>9 mm) were detected in five girls at diagnosis and in one girl after 3 months of treatment. During the rest of the period, no macrocysts were detected except in one girl, who after 24 months of therapy had one cyst of 10 mm (Table I). Ovarian and uterine volumes were in the prepubertal state. At diagnosis, the median follicle size was 8 mm (range 0 to 23 mm). The median follicle size decreased significantly after 3 months of treatment to a median size of 0 mm (range 0 to 12 mm). During the rest of the period, no further significant change was seen. Follow-up ultrasonography revealed follicles > 5 mm in 11 of the girls (65%) and macrocysts in 3 girls (18%) (Table I). Peak LH values after GnRH stimulation tests were significantly reduced during the first 3 months of treatment (p < 0.001) and satisfactorily suppressed in all patients. After discontinuation of treatment, all girls had pubertal LH response to GnRH stimulation test (>10.4 mlU/ml).
DISCUSSION In accordance with previous studies, we demonstrated enlarged ovaries at the time of diagnosis of central precocious puberty.12,19 We also demonstrated as did earlier investigations9,10,20 that ovarian volume decreased significantly during
treatment and returned to values appropriate for age. In contrast, a recent study could not document significant reduction during treatment, although in this investigation, findings were compared with agematched control subjects as well.12 It was suggested that ovarian activity might have persisted in some of the treated girls, resulting in enlarged ovaries. Our results confirmed the results of another recent study11 that ovarian volume decreased more rapidly than uterine volume. In contrast to this study we found a significant reduction in ovarian volume as early as the first 3 months of treatment, and all the girls in our study had ovarian volumes < 2.0 SD scores after 3 months of treatment. Little information is available on followup ultrasonography in girls with CPP treated with long-acting GnRH analogues. One recent study performed follow-up ultrasound examinations but only on girls receiving GnRH analogues in combination with growth hormone.12 This study found that the girls receiving therapy had very large ovaries when treatment was ended and had an increased prevalence of ovaries with polycystic appearance. They concluded that this might be a result of precocious puberty or of some aspect of its treatment. A previous study found that treatment with growth hormone appeared to influence ovarian growth.21 Our results may confirm this because we found only one girl with ovarian volume > 2.0 SD examined 3 to 20 months after discontinuation of therapy and none of the girls had ovaries with polycystic appearance.22,23 We conclude that ovarian volume remained within normal range for age after treatment with long-acting GnRH analogues and that neither CPP nor treatment with GnRH analogues induced the development of ovaries with polycystic appearance. 107
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Uterine volume decreased significantly as well during treatment. Uterine volume after therapy remained < 2.0 SD, reflecting hormonal status appropriate for age after discontinuation of therapy. A recent study found that uterine length rather than uterine volume provided an indicator of the hormonal status, but their results regarding uterine volume were not stated.11 In our study uterine configuration or presence of endometrial echo or the fundal/cervical ratio were not detected. It has been suggested that these parameters are the ultrasound findings best discriminating CPP from other forms of sexual precocity19 and that change in uterine shape from prepubertal tubular shape to pubertal heart shape is one of the first signs of the effect of estrogen on the uterus.24 One study found that endometrial echogenicity was a useful sonographic parameter only when absent and the fundal/cervical ratio only when it reflected infantile morphology.11 We suggest that these variables should be considered in ultrasonographic studies of girls with disorders of puberty. A significant reduction in the numbers of follicles > 5 mm was detected within 3 months of treatment. Although follicles 2 to 9 mm can be found in normal prepubertal ovaries,25,26 our findings seem to confirm that follicular maturation is a good indicator of ovarian response to hormonal stimulation1 and that absence of follicles > 5 mm or regression of follicles is an indicator of suppression. At follow-up ultrasonography 3 to 20 months after discontinuation of therapy, follicles > 5 mm were detected in 65% of the girls, an increased number but within normal limits.25,26 Macrocysts > 9 mm7 were detected in 18% and thus also slightly increased in number compared with findings after 24 months of therapy in which macrocysts were detected in 5%. Our results show the value of ultrasonography as an accurate and reliable tool for the investigation of female internal genitalia. A significant reduction in ovarian and uterine volume corresponding to the findings after GnRH stimulation tests was seen. Follow-up examinations revealed ovarian and uterine volumes within normal limits for chronologic age, and no evidence was found that
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treatment caused the development of polycystic ovaries. We conclude that pelvic ultrasonography is a reliable tool for investigating girls with precocious puberty and that it is also useful for evaluating treatment. Our study indicates that pelvic ultrasonography may be an alternative noninvasive investigation to dynamic hormone testing.
REFERENCES 1. Stanhope R, Adams J, Jakobs HS, Brook CGD. Ovarian ultrasound assessment in normal children, idiopathic precocious puberty, and during low dose pulsatile gonadotrophin releasing hormone treatment of hypogonadotrophic hypogonadism. Arch Dis Child 1985,60:116-9. 2. Stanhope R, Brook CGD. Disorders of puberty. In: Brook CGD, editor. Clinical pediatric endocrinology. Oxford: Blackwell Scientific Publishing; 1989. p.189-212. 3. Hall DA, Crowley WF, Wierman ME, Simeone JF, McCarthy KA. Sonography monitoring of LHRH analogue therapy in idiopathic precocious puberty in young girls. J Clin Ultrasound 1986;14:331-8. 4. Salardi S, Orsini LF, Cacciari E, Bovicelli L, Tassoni P, Reggiani A. Pelvic ultrasonography in premenarcheal girls: relation to puberty and sex hormone concentrations. Arch Dis Child 1985;60:120-5. 5. Siegel MJ. Pediatric gynecological sonography. Radiology 1991;179:593-600. 6. Stanhope R, Abdulwahid NA, Adams J, Brook CGD. Studies of gonadotrophin pulsatility and pelvic ultrasound examinations distinguish between isolated premature thelarche and central precocious puberty. Eur J Pediatr 1986;145:190-4. 7. Salardi S, Orsini LF, Cacciari E, et al. Pelvic ultrasonography in girls with precocious puberty, congenital adrenal hyperplasia, obesity, or hirsutism. J Pediatr 1988; 112:880-7. 8. Haber HP, Mayer EI. Ultrasound evaluation of uterine and ovarian size from birth to puberty. Pediatr Radiol 1994;24:11-3. 9. Manasco PK, Pescovitz OH, Hill SC, et al. Six-year results of luteinizing hormone releasing hormone (LHRH) agonist treatment in children with LHRH-dependent precocious puberty. J Pediatr 1989;115: 105-8. 10. Roger M, Chaussain J-L, Berlier P, et al. Long term treatment of male and female precocious puberty by periodic administration of a long-acting preparation of d-Trpluteinizing hormone–releasing hormone microcapsules. J Clin Endocrinol Metab 1986;62:670-7.
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11. Ambrosino MM, Hernanz-Schulman M, Genieser NB, Sklar CA, Fefferman NR, David R. Monitoring of girls undergoing medical therapy for isosexual precocious puberty. J Ultrasound Med 1994;13:501-8. 12. Bridges NA, Cooke A, Healy MJR, Hindmarsh PC, Brook CGD. Ovaries in sexual precocity. Clin Endocrinol (Oxf) 1995;42:135-40. 13. Stanhope R, Brook CGD. The larche variant: A new syndrome of precocious puberty? Acta Endocrinol (Copenhagen)1990; 123:481-6. 14. Lippe BM, Sample WF. Pelvic ultrasonography in pediatric and adolescent endocrine disorders. J Pediatr 1978;92:897-902. 15. Stanhope R, Adams J, Brook CGD. Disturbances of puberty. Clin Obstet Gynecol 1985;12:557-77. 16. Iversson S-A, Nilsson KO, Persson P-H. Ultrasonography of the pelvic organs in prepubertal and postpubertal girls. Arch Dis Child 1983;58:352-4. 17. Cavallo A, Zhou XH. LHRH test in the assessment of puberty in normal children. Horm Res 1994;41:10-5. 18. Holm K, Laursen EM, Brocks V, Müller J. Pubertal maturation of the internal genitalia. Ultrasound Obstet Gynecol 1995;5:1-7. 19. Griffin IJ, Cole TJ, Duncan KA, Hollman AS, Donaldson MDC. Pelvic ultrasound findings in different forms of sexual precocity. Acta Pediatr 1995;84:544-9. 20. Styne DM, Harris DA, Egli CA, et al. Treatment of true precocious puberty with a potent luteinizing hormone–releasing factor agonist: effect on growth, sexual maturation, pelvic sonography, and the hypothalamic-pituitary-gonadal axis. J Clin Endocrinol Metab 1985;61:142-51. 21. Bridges NA, Cooke A, Healy MJR, Hindmarsh CP, Brook CGD. Standards for ovarian volume in childhood and puberty. Fertil Steril 1993;60:456-60. 22. Tozzini RI, Colombero L. Diagnosis of polycystic ovarian syndrome. 15th World Congress on Fertility and Sterility, London; 1995;71-83. 23. Stanhope R, Adams J, Pringle JP, Jacobs HS, Brook CGD. The evolution of polycystic ovaries in a girl with hypogonadotropic hypogonadism before puberty and during puberty induced with pulsatile gonadotropin-releasing hormone. Fertil Steril 1987;47:872-5. 24. Brook CGD. Precocious puberty. Clin Endocrinol (Oxf) 1995;42:647-50. 25. King LR, Siegel MJ, Solomon AL. Usefulness of ovarian volume and cysts in female isosexual precocious puberty. J Ultrasound Med 1993;12:577-81. 26. Cohen HL, Eisenberg P, Mandel F, Haller JO. Ovarian cysts are common in premenarchal girls: a sonographic study of 101 children 2-12 years old. Am J Roentgenol 1992;159:89-91.
Central precocious puberty in girls: Internal genitalia before, during, and after treatment with long-acting gonadotropin-releasing hormone analogues
Anne-Mette Bæk Jensen, MD, Vibeke Brocks, MD, Kirsten Holm, MD, Eva M. Laursen, MD, and Jørn Müller, MD
Pelvic ultrasonography was systematically performed on 33 girls with idiopathic central precocious puberty to investigate the impact of treatment with gonadotropin-releasing hormone analogues on female internal genitalia. All girls were treated with a long-acting gonadotropin-releasing hormone analogue (Decapeptyl Depot; Ferring Co., Copenhagen, Denmark) 75 µg/kg every 4 weeks. Before, during, and after treatment, pelvic ultrasonography was performed and ovarian and uterine volumes were calculated. The size of follicles > 5 mm were accurately measured. The results were related to a normative study of healthy Danish schoolgirls. Our data demonstrated that ovaries and uterus are enlarged in a significant number of girls (50%) with the diagnosis of central precocious puberty at the time of diagnosis. Median ovarian volume at time of diagnosis was 1.1 standard deviation scores (range –0.6 to 3.2 SD), median uterine volume was 1.8 standard deviation scores (range 0.0 to 3.5 SD). Within 3 months of treatment, both ovarian and uterine volumes decreased significantly (p < 0.01) to normal values appropriate for age. Median ovarian volume after 3 months of treatment was 0.0 SD (range –2.4 to 1.5 SD); median uterine volume was 0.7 SD (range –0.6 to 4.1 SD). Ovarian and uterine volume remained within normal range (<2 standard deviation scores) after discontinuation of treatment. Follicles and macrocysts regressed during treatment. None of the girls’ ovaries had a polycystic appearance during or after treatment with the gonadotropin-releasing hormone analogue. Our results confirmed pelvic ultrasonography as a reliable tool for investigation of internal genitalia in girls with precocious puberty and as a valid method for evaluation of the efficacy of treatment with gonadotropin-releasing hormone analogues. We suggest that repeated investigations be performed when evaluating treatment because the morphologic changes, including follicular maturation or regression, reflect ovarian stimulation or suppression. We found no evidence that girls with precocious puberty treated with long-acting gonadotropin-releasing hormone analogues have enlarged polycystic ovaries develop. (J Pediatr 1998;132:105-8)
From the Department of Growth and Reproduction and the Department of Obstetrics and Gynecology, Rigshospitalet, State University Hospital, Denmark. Submitted for publication Sept. 9, 1996; accepted April 4, 1997. Reprint requests: Anne-Mette Bæk Jensen, Bavnestien 4, 2850 Nærum, Denmark. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/21/82508
Central precocious puberty in girls is defined as pubertal development caused by activation of the hypothalamic-pituitarygonadal axis before 8 years old. In this condition gonadotropin stimulation produces ovarian enlargement,1-3 and estrogen secretion results in uterine enlargement.2,4 Pelvic ultrasound has proven to be an ac-
curate and noninvasive technique for the investigation of internal genitalia in female patients.5 Earlier studies have shown that ultrasound examination, which can distinguish between centrally mediated precocious puberty, gonadotropin-independent precocious puberty, and premature thelarche, is useful in diagnosing disorders of sexual development.1,6-9 Other studies have investigated ultrasonographic changes in internal genitalia during treatment with long-acting GnRH analogues. Ovarian CPP GnRH LH
Central precocious puberty Gonadotrophin releasing hormone Luteinizing hormone
volume was enlarged in girls with CPP at the time of diagnosis and decreases during treatment,9-12 suggesting pelvic ultrasonography as a reliable tool in the evaluation of patients during treatment. Former studies have included small numbers of patients,1,6,13-16 and only one study has included data on follow-up ultrasonographic investigations after discontinuation of therapy.12 Bridges et al.12 found that girls with CPP treated with GnRH analogues and growth hormone had large ovaries develop and an increase in the prevalence of ovaries with polycystic appearance. However, data on girls with CPP treated with GnRH analogues alone after discontinuation of treatment have not been available. In this study we systematically performed pelvic ultrasonography in 33 girls with idiopathic CPP at diagnosis, during treatment with a long-acting GnRH analogue, and after discontinuation of therapy to investigate the impact of treatment on internal genitalia.
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Table I. Size of both ovaries in SDS before, during, and after treatment for central precocious puberty, median (range) and presence of follicles, macrocysts, and polycystic ovaries before, during, and after treatment for central precocious puberty
N Ovary SDS No. of patients with SDS >2 Follicles >5 mm Macrocysts*
Before
3
12
24
After
24 1.1 (–0.6-3.2) 5 19 5
29 1.1 (–0.6-3.2) 0 5 1
29 –0.4 (–1.8-1.0) 0 2 0
17 –0.6 (–2.3-1.1) 0 5 1
17 0.6 (–1.4-2.1) 1 11 3
SDS, Standard deviation scores. *Follicles > 9 mm.
METHODS Patients Thirty-three girls with the diagnosis of idiopathic CPP were included in the study. The diagnosis was based on development of secondary sexual characteristics before 9 years of age, increased height velocity, advanced bone age, pubertal response to GnRH test, and serum estradiol greater than prepubertal levels. Median age at the beginning of treatment was 8.5 years (6.5 to 10.5). Three girls had had menarche at the time of diagnosis.
Treatment All girls received a long-acting GnRH analogue (Decapeptyl Depot), 75 µg/kg, (maximum doses 3.75 mg) administrated as intramuscular injections every fourth week. Long-acting GnRH analogue is a decapeptide that stimulates synthesis and secretion of gonadotropins from the pituitary gland. During the first 1 to 2 weeks of treatment, more gonadotropins are released, after which a suppression of follicle-stimulating hormone and LH secretion is seen because of reduced sensitivity in the pituitary gland receptors. The efficacy of the treatment was ensured by repeated GnRH stimulation tests 3 and 12 months after diagnosis and at 12-month intervals during the course of therapy. The rationale for the decision to start treatment with GnRH and to determine the duration of therapy included (1) the psychologic problems of early development of secondary sexual characteristics and menstruation, and (2) the possibility of improving final height by a reduction in height velocity and advancement in bone age. Therapy was 06
continued until the age for onset of natural puberty. After discontinuation of therapy, another GnRH stimulation test was performed. The median treatment time was 2.4 years (range 1.5 to 4.7 years). GnRH stimulation tests were performed using a standard dose of 100 µg luteinizing hormone–releasing hormone administrated intravenously. Blood samples were obtained immediately before the injection and at 15, 30, 45, 60, and 90 minutes after injection. Peak values of LH >10.4 mlU/ml were considered as pubertal response, whereas peak values < 5.0 mlU/ml during treatment with a GnRH analogue were considered as sufficient suppression.17 LH was assayed before July 1993 with an enzyme-linked immunoassay and after July 1993 with a time-resolved fluoroimmunoassay (Delfia, Wallac Denmark Als).
Ultrasound Pelvic ultrasound was performed at diagnosis, 3, and 12 months after diagnosis and at 12-month intervals during the course of therapy. Three to 20 months after discontinuation of therapy, follow-up pelvic ultrasonography was performed. All ultrasound examinations were performed by the same investigator (V.B.) using an ALOKA SSD 680 (ALOKA Co., Japan) with a 3.5 MHz curved linear transducer. The ultrasound examinations were performed with the full bladder technique obtained by voluntary urine retention and oral administration of fluids. The detection limit of the ultrasound equipment was 1 mm. Uterine and ovarian volumes were calculated by measuring length, width, and depth and by assuming the forms to be el-
lipsoid using the formula based on a prolate ellipsoid: (d1 · d2 · d3)/2 where d1, d2, and d3 are the three maximal longitudinal, anteroposterior, and transverse diameters. Average ovarian volume was used for analysis. Ovarian follicles of 1 to 5 mm were defined as small follicles. The sizes of follicles > 5 mm were accurately measured. The size of the greatest follicle in either ovary was used for analysis. The presence of polycystic ovaries was noted. Polycystic ovaries were defined as ovaries having at least 10 follicles (2 to 8 mm diameter) at the periphery of the ovarian cortex, increased ovarian volume, and increased interstitial echogenicity.
Controls The results were related to a normative study of healthy Danish schoolgirls.18 These ultrasound scans were performed by the same investigator as in our study using the same equipment and methods. Age-specific standard deviation was calculated.
Statistics Changes in ovarian size, uterine size, and follicle size were analyzed by the Friedman and the Wilcoxon tests. All analyses were carried out by using a statistical package (SPSS/PC, SPSS Inc.). A probability value of less than 0.05 was considered statistically significant.
Ethics Written informed consent was obtained from the parents of all participants. The study was in accordance with the Helsinki II declaration and approved by the local ethical committee of Copenhagen, Denmark (approval no. v.200.1984/90).
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Table II. Size of uterus in SDS before, during, and after treatment for central precocious puberty, median (range)
N Ovary SDS No. of patients with SDS >2
Before
3
12
24
After
22 1.8 (0-3.5) 9
26 0.8 (–0.6-4.1) 4
26 0 (–1.7-2.3) 1
15 –0.5 (–2.0-1.8) 0
15 1.3 (0.4-2.8) 1
SDS, Standard deviation scores.
RESULTS Results from the first 24 months of treatment and from follow-up examinations 3 to 20 months after discontinuation were used for analyses.
Ovaries At time of diagnosis, the median volume was 1.1 SD (range –0.6 to 3.2 SD) corresponding to 4.6 ml (range 1.4 to 11.1 ml). Five (21%) of the girls had ovarian volumes greater than 2.0 SD (Table I). After 3 months of treatment with a GnRH analogue, a significant reduction was observed, with a median ovarian volume of 0.0 SD (range –2.4 to 1.5 SD). None of the girls had an ovarian volume > 2.0 SD. Ovarian volumes remained within normal limits for chronologic age during treatment. At the examination 3 to 20 months after discontinuation of treatment, median ovarian volume was 0.6 SD (range –1.4 to 2.1 SD). One girl (7%) had ovarian volume > 2.0 SD scores. None of the girls had ovaries with a polycystic appearance (Table I).
Uterus At time of diagnosis, the median volume was 1.8 SD (range 0.0 to 3.5 SD) corresponding to 7.5 ml (range 1.0 to 21.8 ml). Nine girls (41%) had uterine volumes > 2.0 SD scores (Table II). After 3 months of treatment, a significant reduction in uterine volume was seen, with a median uterine volume of 0.7 SD (range –0.6 to 4.1 SD). After 12 months of treatment, further reduction was seen, with the median volume at 0.0 SD (range –1.7 to 2.3 SD). After 3 months of treatment, four girls (15%) had uterine volumes > 2.0 SD; after 12 months of treatment one girl (3.8%) had a volume > 2.0 SD. At follow-up examination 3 to 20
months after discontinuation of treatment, one girl (7%) had a uterine volume > 2.0 SD. The median uterine volume was 1.3 SD (range 0.4 to 2.8 SD).
Follicles At time of diagnosis follicles > 5 mm were detected in 19 girls (83%). After 3 months of treatment, follicles > 5 mm were seen in five girls (17%), after 12 months in two girls (7%), and after 24 months in five girls (28%) (Table I). Macrocysts (>9 mm) were detected in five girls at diagnosis and in one girl after 3 months of treatment. During the rest of the period, no macrocysts were detected except in one girl, who after 24 months of therapy had one cyst of 10 mm (Table I). Ovarian and uterine volumes were in the prepubertal state. At diagnosis, the median follicle size was 8 mm (range 0 to 23 mm). The median follicle size decreased significantly after 3 months of treatment to a median size of 0 mm (range 0 to 12 mm). During the rest of the period, no further significant change was seen. Follow-up ultrasonography revealed follicles > 5 mm in 11 of the girls (65%) and macrocysts in 3 girls (18%) (Table I). Peak LH values after GnRH stimulation tests were significantly reduced during the first 3 months of treatment (p < 0.001) and satisfactorily suppressed in all patients. After discontinuation of treatment, all girls had pubertal LH response to GnRH stimulation test (>10.4 mlU/ml).
DISCUSSION In accordance with previous studies, we demonstrated enlarged ovaries at the time of diagnosis of central precocious puberty.12,19 We also demonstrated as did earlier investigations9,10,20 that ovarian volume decreased significantly during
treatment and returned to values appropriate for age. In contrast, a recent study could not document significant reduction during treatment, although in this investigation, findings were compared with agematched control subjects as well.12 It was suggested that ovarian activity might have persisted in some of the treated girls, resulting in enlarged ovaries. Our results confirmed the results of another recent study11 that ovarian volume decreased more rapidly than uterine volume. In contrast to this study we found a significant reduction in ovarian volume as early as the first 3 months of treatment, and all the girls in our study had ovarian volumes < 2.0 SD scores after 3 months of treatment. Little information is available on followup ultrasonography in girls with CPP treated with long-acting GnRH analogues. One recent study performed follow-up ultrasound examinations but only on girls receiving GnRH analogues in combination with growth hormone.12 This study found that the girls receiving therapy had very large ovaries when treatment was ended and had an increased prevalence of ovaries with polycystic appearance. They concluded that this might be a result of precocious puberty or of some aspect of its treatment. A previous study found that treatment with growth hormone appeared to influence ovarian growth.21 Our results may confirm this because we found only one girl with ovarian volume > 2.0 SD examined 3 to 20 months after discontinuation of therapy and none of the girls had ovaries with polycystic appearance.22,23 We conclude that ovarian volume remained within normal range for age after treatment with long-acting GnRH analogues and that neither CPP nor treatment with GnRH analogues induced the development of ovaries with polycystic appearance. 107
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Uterine volume decreased significantly as well during treatment. Uterine volume after therapy remained < 2.0 SD, reflecting hormonal status appropriate for age after discontinuation of therapy. A recent study found that uterine length rather than uterine volume provided an indicator of the hormonal status, but their results regarding uterine volume were not stated.11 In our study uterine configuration or presence of endometrial echo or the fundal/cervical ratio were not detected. It has been suggested that these parameters are the ultrasound findings best discriminating CPP from other forms of sexual precocity19 and that change in uterine shape from prepubertal tubular shape to pubertal heart shape is one of the first signs of the effect of estrogen on the uterus.24 One study found that endometrial echogenicity was a useful sonographic parameter only when absent and the fundal/cervical ratio only when it reflected infantile morphology.11 We suggest that these variables should be considered in ultrasonographic studies of girls with disorders of puberty. A significant reduction in the numbers of follicles > 5 mm was detected within 3 months of treatment. Although follicles 2 to 9 mm can be found in normal prepubertal ovaries,25,26 our findings seem to confirm that follicular maturation is a good indicator of ovarian response to hormonal stimulation1 and that absence of follicles > 5 mm or regression of follicles is an indicator of suppression. At follow-up ultrasonography 3 to 20 months after discontinuation of therapy, follicles > 5 mm were detected in 65% of the girls, an increased number but within normal limits.25,26 Macrocysts > 9 mm7 were detected in 18% and thus also slightly increased in number compared with findings after 24 months of therapy in which macrocysts were detected in 5%. Our results show the value of ultrasonography as an accurate and reliable tool for the investigation of female internal genitalia. A significant reduction in ovarian and uterine volume corresponding to the findings after GnRH stimulation tests was seen. Follow-up examinations revealed ovarian and uterine volumes within normal limits for chronologic age, and no evidence was found that
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treatment caused the development of polycystic ovaries. We conclude that pelvic ultrasonography is a reliable tool for investigating girls with precocious puberty and that it is also useful for evaluating treatment. Our study indicates that pelvic ultrasonography may be an alternative noninvasive investigation to dynamic hormone testing.
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11. Ambrosino MM, Hernanz-Schulman M, Genieser NB, Sklar CA, Fefferman NR, David R. Monitoring of girls undergoing medical therapy for isosexual precocious puberty. J Ultrasound Med 1994;13:501-8. 12. Bridges NA, Cooke A, Healy MJR, Hindmarsh PC, Brook CGD. Ovaries in sexual precocity. Clin Endocrinol (Oxf) 1995;42:135-40. 13. Stanhope R, Brook CGD. The larche variant: A new syndrome of precocious puberty? Acta Endocrinol (Copenhagen)1990; 123:481-6. 14. Lippe BM, Sample WF. Pelvic ultrasonography in pediatric and adolescent endocrine disorders. J Pediatr 1978;92:897-902. 15. Stanhope R, Adams J, Brook CGD. Disturbances of puberty. Clin Obstet Gynecol 1985;12:557-77. 16. Iversson S-A, Nilsson KO, Persson P-H. Ultrasonography of the pelvic organs in prepubertal and postpubertal girls. Arch Dis Child 1983;58:352-4. 17. Cavallo A, Zhou XH. LHRH test in the assessment of puberty in normal children. Horm Res 1994;41:10-5. 18. Holm K, Laursen EM, Brocks V, Müller J. Pubertal maturation of the internal genitalia. Ultrasound Obstet Gynecol 1995;5:1-7. 19. Griffin IJ, Cole TJ, Duncan KA, Hollman AS, Donaldson MDC. Pelvic ultrasound findings in different forms of sexual precocity. Acta Pediatr 1995;84:544-9. 20. Styne DM, Harris DA, Egli CA, et al. Treatment of true precocious puberty with a potent luteinizing hormone–releasing factor agonist: effect on growth, sexual maturation, pelvic sonography, and the hypothalamic-pituitary-gonadal axis. J Clin Endocrinol Metab 1985;61:142-51. 21. Bridges NA, Cooke A, Healy MJR, Hindmarsh CP, Brook CGD. Standards for ovarian volume in childhood and puberty. Fertil Steril 1993;60:456-60. 22. Tozzini RI, Colombero L. Diagnosis of polycystic ovarian syndrome. 15th World Congress on Fertility and Sterility, London; 1995;71-83. 23. Stanhope R, Adams J, Pringle JP, Jacobs HS, Brook CGD. The evolution of polycystic ovaries in a girl with hypogonadotropic hypogonadism before puberty and during puberty induced with pulsatile gonadotropin-releasing hormone. Fertil Steril 1987;47:872-5. 24. Brook CGD. Precocious puberty. Clin Endocrinol (Oxf) 1995;42:647-50. 25. King LR, Siegel MJ, Solomon AL. Usefulness of ovarian volume and cysts in female isosexual precocious puberty. J Ultrasound Med 1993;12:577-81. 26. Cohen HL, Eisenberg P, Mandel F, Haller JO. Ovarian cysts are common in premenarchal girls: a sonographic study of 101 children 2-12 years old. Am J Roentgenol 1992;159:89-91.