causes such as hamartoma of the tuber cinereum, hypo- thalamic glioma, or pineal tumors. However, prior stud- ies have demonstrated the presence of specific ...
Pediatr Radiol (2000) 30: 444±446 Ó Springer-Verlag 2000
Prospective assessment of pituitary size and shape on MR imaging after suppressive hormonal therapy in central precocious puberty
Jeffrey T. Van Beek Melhem J. A. Sharafuddin Simon C. S. Kao Atchawee Luisiri Luigi R. Garibaldi
Received: 12 November 1999 Accepted: 2 February 2000
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J. T. Van Beek ´ M. J. A. Sharafuddin ( ) ´ S. C. S. Kao Department of Radiology-JPP 3889, University of Iowa Hospitals & Clinics, 200 Hawkins Drive, Iowa City, IA 52246, USA A. Luisiri Cardinal Glennon Children's Hospital, St. Louis, Missouri, USA L. R. Garibaldi Children's Hospital of New Jersey, Newark Beth Israel Medical Center, Newark, New Jersey, USA L. R. Garibaldi St. Barnabas Medical Center, Livingston, New Jersey, USA
Abstract Objective. The diagnostic significance of an enlarged pituitary gland regarding both shape and size parameters on MR imaging has previously been demonstrated in children with central precocious puberty. This study was designed to assess changes in these parameters following successful suppressive therapy of central precocious puberty with the gonadotropin-releasing hormone (GnRH) analogue. Materials and methods. Twelve girls (mean age 7.3 years) with central precocious puberty were prospectively enrolled in our study protocol. Sagittal and coronal MR images of the pituitary region were obtained in all patients before treatment and after at least 6 months of GnRH ana-
logue therapy (mean 18.0 months). Parameters measured included pituitary gland height, length, width, sagittal cross-sectional area, and volume. Results. All patients had excellent clinical response to treatment with arrest of secondary sexual development, normalization of serum estradiol levels, and complete obliteration of the LH response to diagnostic GnRH stimulation. No significant change occurred in any pituitary size or shape parameter following GnRH analogue therapy. Conclusion. Favorable clinical response to GnRH analogue therapy in central precocious puberty is not accompanied by significant a change in pituitary gland size and shape.
Introduction
Materials and methods
MR imaging of the brain is often performed in central precocious puberty (CPP) prior to treatment to exclude causes such as hamartoma of the tuber cinereum, hypothalamic glioma, or pineal tumors. However, prior studies have demonstrated the presence of specific changes in the shape and size of pituitary gland in patients with idiopathic CPP compared to age-matched normal subjects, such as enlargement in the size and increased Elster's grade (more spherical shape) of the pituitary gland [1, 2]. To our knowledge there have been no prior studies regarding change of pituitary shape and size following successful hormonal therapy. The goal of the present study was to compare these pituitary parameters before and after suppressive hormonal therapy.
Twelve girls (mean age 7.3 years, range 3.3±9.6) with idiopathic CPP were prospectively enrolled over a 2-year period prior to their treatment with the gonadotropin-releasing hormone (GnRH) analogue leuprolide (Lupron Depot; TAP Pharmaceuticals, Deerfield, Ill.). The GnRH was given intramuscularly at a dose of 261 23 mg/kg once every 4 weeks. The study was approved by the institutional review board (IRB), and all parents signed informed consent forms prior to enrollment. MR imaging of the sella turcica was performed prior to treatment and repeated after at least 6 months of hormonal therapy (mean 18.0 months, range 6.1±41.4). MR imaging was performed with a 1.0 T field magnet unit (Siemens Impact). Unenhanced magnified mid-sagittal and mid-sellar coronal T1-weighted spin-echo images [400±600/15±30/2±3 (TR/TE/excitations)] were obtained with 3.0-mm slice thickness and 10 % gaps. Care was taken to ensure that both the bulk of the anterior pituitary and the pituitary stalk were seen to define the mid-sagittal plane. The maximal
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Fig. 1 Unenhanced magnified mid-sagittal and mid coronal T1-weighted spin-echo images of the pituitary gland a preand b post-treatment
a
b mid-sagittal length (L), height (H), and width (W) were measured. The mid-sagittal cross-sectional area was obtained using NIH Image software from the mid-sagittal gland tracing. The area of the outline was measured in pixels, and its actual area (in cm2) was calculated using a squared centimeter reference obtained from the corresponding reference scale on the hard-copy image. The nearest ellipsoid volume was measured using the formula V = 1/2 L W H. Pituitary shape was assessed visually using the Elster's grade [3], based on the contour of the gland's superior surface in the mid-sagittal projection (grade 1 = marked concavity, grade 2 = mild concavity, grade 3 = flat, grade 4 = mild convexity, grade 5 = marked convexity). All measurements were subjected to statistical analysis using paired t-tests and Spearman-rank order correlation. The significance value is P < 0.05.
response of LH and FSH to GnRH stimulation was suppressed to prepubertal levels. The elevated serum concentration of insulinlike growth factor I (somatomedinC) was not significantly changed after therapy (Table 1). Comparison of morphologic and volumetric MR imaging parameters of the gland (Fig. 1) showed no statistical significant difference in any of the evaluated parameters following treatment (Table 2).
Table 1 Comparison of the biochemical endocrine profile before and after hormonal therapy. Each value represents the mean ± SD. Significance level is P < 0.05 (NS = not significant)
Results Pre-treatment pituitary sizes and shapes by MRI were consistent with CPP, in comparison to age-matched normal patients in previous studies [1, 2]. All patients demonstrated excellent clinical response to therapy with arrest of secondary sexual development. Serum estradiol normalized to prepubertal levels in all patients. Peak
Somatomedin-C (IGF-I) (ng/ml)
Before treatment
After treatment
P value
NS
365.6 ± 79.3
381.9 ± 133
Peak-LH (after GnRH) (IU/l)
26.4 ± 21.2
0.8 ± 0.5
0.004
Estradiol (pg/ml)
21.6 ± 20.6
4.6 ± 0.7
0.025
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Table 2 Comparison of the MR imaging parameter before and after hormonal therapy. Each value represents the mean ± SD. Significance level is P < 0.05 (NS = not significant) Before treatment
After treatment
P value
Height (mm)
5.19 ± 1.15
5.13 ± 1.26
NS
Length (mm) Width (mm)
8.91 ± 1.67 11.10 ± 1.89
8.84 ± 1.61 10.92 ± 1.68
NS NS
Sagittal area (mm2) Volume (mm3) Elster's grade
47.75 ± 17.20
43.91 ± 13.11
NS
260.65 ± 94.78 3.83
249.24 ± 86.03 3.75
NS NS
Discussion Central precocious puberty occurs when gonadotropin and sex steroid levels are elevated, reflecting premature activation of the hypothalamic-pituitary axis. Treatment of CPP is directed toward the hypothalamic-pituitary axis. Successful use of a GnRH agonist to inhibit secondary sex development and gonadotropin secretion associated with central precocious puberty was first reported in 1981 [4] and is currently the treatment of choice. GnRH agonists initially stimulate pituitary gonadotropin secretion, but eventually downregulate the GnRH receptors on the pituitary gonadotrophs. Suppression of gonadotropin secretion occurs within 1 month of the initial treatment. The LH response to GnRH is usually evaluated at intervals to determine the state of suppression of the hypothalamic-pituitary axis by measuring the peak LH response to diagnostic GnRH stimulation [5]. It has been previously demonstrated that CPP is accompanied by significant changes in the shape and size of the pituitary gland compared to age-matched normal subjects. Pituitary convexity (Elster's grade) and height are increased significantly in idiopathic CPP. Sagittal cross-sectional area and volume are both increased in CPP patients [1, 2]. Our study showed that the increased height, sagittal area, and volume of the pituitary gland did not return
to normal prepubertal values despite clinically successful treatment. Biochemically, there was normalization of estradiol serum levels and peak response of FSH and LH to GnRH stimulation. However, the serum concentration of insulinlike growth factor I (somatomedin-C), which was known to be increased for age in CPP [6], was not significantly changed. Gonadotrophs, the cells which secrete FSH and LH, represent only 10 % of the anterior pituitary cells. The cells are distributed diffusely throughout the anterior lobe [7]. One possible explanation for the lack of effect on the pituitary gland shape and size from successful hormonal therapy is since the action of GnRH-agonists is solely upon gonadotrophs, and gonadotrophs comprise only a small percentage of cells in the pituitary gland, the clinical results are not accompanied by significant volumetric changes. Another possible explanation is that pituitary hypertrophy is due to stimulation of growth-hormone-producing cells (somatotrophs) in the pituitary gland. This stimulation may persist despite therapy with GnRH analogues. This possibility is suggested by our previous findings that the pituitary enlargement at the time of puberty correlates best with serum levels of somatomedinC [2] and is corroborated by the persistently elevated somatomedin-C levels following treatment observed in the present study. In conclusion, our study suggests that clinically successful GnRH analogue therapy has no significant macroscopic effect on the pituitary gland, as evaluated by MR imaging. Despite the limited number of patients studied, the prospective nature of the observations and the consistency of the results in each paired observation indicate that a favorable clinical response to hormonal therapy in central precocious puberty is not associated with return of the pituitary gland to prepubertal size and shape. Acknowledgements The authors would like to acknowledge Kevin Berbaum, Ph.D., for his valuable assistance in statistical analysis.
References 1. Kao SC, Cook JS, Hansen JR, et al (1992) MR imaging of the pituitary gland in central precocious puberty. Pediatr Radiol 22: 481±484 2. Sharafuddin MJ, Luisiri A, Garibaldi LR, et al (1994) MR imaging diagnosis of central precocious puberty: importance of changes in the shape and size of the pituitary gland. AJR 162: 1167±1173
3. Elster AD, Chen MY, Williams DW, et al (1990) Pituitary gland: MR imaging of physiologic hypertrophy in adolescence. Radiology 174: 681±685 4. Comite F, Cutler GB Jr, Rivier J, et al (1981) Short-term treatment of idiopathic precocious puberty with a longacting analogue of luteinizing hormonereleasing hormone. N Engl J Med 305: 1546±1550
5. Wheeler MD, Styne DM (1991) The treatment of precocious puberty. Endocrinol Metab Clin North Am 20: 183±190 6. Pescovitz OH, Rosenfeld RG, Hintz RL, et al (1985) Somatomedin-C in accelerated growth of children with precocious puberty. J Pediatr 107: 20±25 7. Sternberg SS (1997) Histology for pathologists, 2nd edn. Lippincott-Raven, Philadelphia New York, pp 1059±1073
