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ORIGINAL ARTICLE
Year : 2022  |  Volume : 25  |  Issue : 4  |  Page : 466-472

Evaluatıon of Pituıtary/Cranial imagıng results of central puberty precocıous cases


1 Department of Pediatrics, Clinics of Pediatric Endocrinology, Faculty of Medicine, Hitit University, Çorum, Turkey
2 Department of Pediatrics, Faculty of Medicine, Faculty of Medicine, Hitit University, Çorum, Turkey
3 Department of Radiology, Faculty of Medicine, Hitit University, Çorum, Turkey

Date of Submission05-Oct-2021
Date of Acceptance30-Nov-2021
Date of Web Publication19-Apr-2022

Correspondence Address:
Dr. H N P Kendirci
Pediatric Endocrinologist, Hitit University, Faculty of Medicine, Department of Pediatrics, Clinics of Pediatric Endocrinology, İnönü Street, No: 176 (19000) Çorum
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_1866_21

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   Abstract 


Background: The activation of the gonadotropin-releasing hormone (GnRH) pulse generator before the age of 8 years in girls and 9 years in boys results in central precocious puberty (CPP). Previous studies have shown that the height of the pituitary gland in the CPP cases is higher than in the normal children. Aim: In this study, ıt was aimed to evaluate the pituitary gland volüme by MRI in CPP children, and explore the intracranial lesions among children with CPP. Patients and Methods: The study was performed with 50 children (41 girls, 9 boys) who had been diagnosed with CPP. Pituitary MRI was performed in every child after the diagnosis of CPP. Pituitary gland volüme in CPP children was compared with age/sex-matched control subjects. In addition, if available, cranial MRI of patients were evaluated for the presence of additional intracranial abnormalities or space-occupying lesions. Results: The mean chronological age at diagnosis was 7.1 ± 1.0 (2.4–7.9) years in girls and 7.4 ± 1.7 (3.7–8.8) years in boys. CNS imaging showed pathological findings in 17% (7/41) of the girl cases and 55.5% (5/9) of the boy cases. Pituitary volumes of girls aged 6.0–7.9 years and boys aged 8.0–8.9 years were found to be increased compared to the control group. Conclusion: In this study, we found that CNS imaging showed pathological findings in 17% of the girl cases, and 55.5% of the boy cases. Pituitary volumes of girls aged 6.0–7.9 years and boys aged 8.0–8.9 years were found to be increased compared to the control group.

Keywords: Central nervous system, central puberty precocious, magnetic resonance imaging


How to cite this article:
P Kendirci H N, Kaba I, Fidan N. Evaluatıon of Pituıtary/Cranial imagıng results of central puberty precocıous cases. Niger J Clin Pract 2022;25:466-72

How to cite this URL:
P Kendirci H N, Kaba I, Fidan N. Evaluatıon of Pituıtary/Cranial imagıng results of central puberty precocıous cases. Niger J Clin Pract [serial online] 2022 [cited 2022 May 22];25:466-72. Available from: https://www.njcponline.com/text.asp?2022/25/4/466/343465




   Introduction Top


Precocious puberty is a clinical condition characterized by the early development of secondary sex characters compared to the population average.[1] The activation of the gonadotropin-releasing hormone (GnRH) pulse generator before the age of 8 years in girls and 9 years in boys results in central precocious puberty (CPP).[2] CPP can be treated with gonadotropin agonists (GnRHa) in order to prevent short final adult height and psychological effects on the child.[3] CPP may develop due to a previously identified or a new identifiable underlying central nervous system (CNS) disturbance (organic CPP) or by a nonidentifiable abnormality (idiopathic CPP).[4] The majority of cases of CPP in girls are defined as idiopathic as no organic lesion is found, whereas intracranial lesions are common in boys with CPP. Determination of gonadotrophin levels following luteinizing hormone releasing hormone (LHRH) stimulation does not help in identifying those patients with intracranial lesions.[5] Therefore, magnetic resonance imaging (MRI) is the currently preferred technique to image the brain/pituitary gland, and it is also performed in many tertiary care centers to rule out brain abnormalities for children diagnosed with CPP.[6],[7] The prevalence of CNS abnormalities in boys is reported to be as high as 40–75%, therefore, it is recommended that all boys with CPP have brain MRI.[3] The prevalence of unsuspected intracranial lesions is 8–13% in girls and decreases with age. Among girls with CPP (onset age of 6–8 years), unsuspected pathology and tumors were only involved in 2–7% and 1% of them, respectively.[8] At a conference in 2007, the North American and European Pediatric Endocrinology Societies concluded that all boys with CPP and all girls with CPP younger than 6 years should undergo brain MRI.[6] However, it is not clear if 6–8-year-old girls with CPP should undergo the same, and cranial MRI continues to be performed routinely in many centers for all the girls presenting with breast development before the age of 8 due to the risk of finding an occult intracranial lesion.[3],[8] Additionally, previous studies have shown that the height of the pituitary gland in the CPP group is higher than in the normal group. Since the pituitary gland enlarges at puberty, it tends to be slightly larger in height for girls (10 mm) than for boys (8 mm), and the pituitary volüme (PV) has also been found to be increased with age and associated with hormonal levels. However, the relationship between PV and hormones, and the role of PV in the diagnosis of CPP are still unclear.[7] Therefore, in this study, we aimed to evaluate the pituitary gland volüme by MRI in CPP children and compare it with age/sex-matched control subjects, and explore the prevalence and types of intracranial lesions among children with CPP.


   Patients and Methods Top


Patients

The study was performed with children who had been diagnosed with CPP at the Pediatric Endocrinology Clinic of the XXX Training and Research Hospital and who were receiving treatment with a GnRH analog.

There were 73 children who were diagnosed with CPP and were on treatment with GnRHa between December 2015 and December 2020 included in the study. Of these patients, 23 were excluded due to missing anthropometric measurements, physical examinations or laboratory measurements, pituitary/cranial MRI before treatment. Thus, 50 patients (41 girls, 9 boys) were included in this study. Cases with peripheral PP were excluded from this study.

Ethical considerations

The study was approved by the ethical board of XXX University Medical Faculty (11.03.2020/196) and conducted in accordance with the Helsinki Declaration.

Detection indicators

The data of the patients recorded in the hospital's information administration system were retrospectively analyzed. Chronological and bone age, chronological age/bone age ratio, body weight, height, body mass index (BMI) and the respective standard deviation scores (SDS), pubertal stage, serum basal LH, FSH, and estradiol (in girls), testosterone (in boys) levels, findings of pituitary/cranial MRI at diagnosis were recorded. Detailed medical histories of all cases were recorded at the time of application.

The patients' body weights were measured with a digital body weighing scale, and height measurements were performed in the standing position with a stadiometer by a personnel trained in height measurement and auxology. Percentile charts developed by Neyzi et al.[9] for Turkish children were used to interpret the growth data, which were represented as standard deviation scores. The BMI was calculated by dividing weight in kilograms by height in meters squared. BMI-SDS were calculated according to the LMS method by using the same percentile charts developed by Neyzi et al.[9] Pubertal staging of the participants were assessed by using the Tanner and Marshall criteria.[10],[11] A Prader orchidometer was used to measure the volume of the testicles. The bone age was estimated by the same pediatric endocrinologists (HNPK) using the Greulich and Pyle  Atlas More Details.[12]

The boys who had advanced bone age and testicular enlargement (≥4 ml) before 9 years of age with a peak luteinizing hormone (LH) level ≥5 IU/l during GnRH stimulation test and a testosterone level ≥0.3 ng/ml were considered as CPP cases.[13],[14]

The following criteria were used for the diagnosis of CPP in all girls referred for premature sexual maturation in our pediatric endocrinology clinic[13],[15],[16]:

–– Girls with breast development at Tanner stage 2 or 3 before the age of 8 years

–– Accelerated somatic development according to age and gender

–– Bone age was accelarated by 2 years compared to the chronological age

–– Increased gonadothropin levels in a range accepting as pubertal (basal LH level ≥0.3 mIU/mL or peak response LH ≥5 mIU/mL in standard IV GnRH test)

–– Pelvic ultrasounds also demonstrated positive pubertal findings (incrased ovarian volume and number and volume of follicles, and increased size of uterus)

Children with basal LH levels above 0.3 IU/L, who also met the above criteria were assumed to have CPP if no GnRH stimulation test was performed. The GnRH stimulation test was performed after the intravenous administration of 0.1 mg of Gonadorelin acetate (gonadorelin acetate, Ferring ®). LH and FSH levels were then measured at 15, 30, 45, 60, and 90 minutes after injection.[13],[15],[16]

For patients diagnosed with CPP, treatment was started with GnRH analog (3.75 mg as intramuscular or subcutaneous injection every 28 days).

Hormone analyses

Basal FSH, LH, E2, and testosterone levels were analyzed in blood samples collected between 8: 00 and 8: 30 a.m. The immunochemiluminometric assay (ICMA) method using commercial kits (ADVIA Centaur analyzer system, Bayer Diagnostics, USA) was used to measure FSH and LH levels. Serum testosterone levels were measured using the ICMA method on an IMMULITE 2000 System (Siemens, UK) using a commercial kit.

Radiologic evaluation (MRI analysis)

Pituitary MRI was performed in every patient after the diagnosis of CPP. All magnetic resonance (MR) examinations were performed with 1.5-T MR scanners (Magnetom Area, Siemens, Erlanger, Germany) by using a head coil. Measurements of pituitary gland were performed using electronic cursor on a work station by the experienced radiologist (NF) blinded to the hormonal results analyzed. Height was measured at the site of insertion of stalk as the maximum vertical distance between the upper and the lower border of the pituitary gland. Length was measured as the maximum anteroposterior extent of the pituitary gland in sagittal plane. Width was measured as the maximum transverse diameter of the pituitary in coronal T1WI showing pituitary stalk. Pituitary volume was calculated using Di Chiro's formula, that is, volume = 1/2 × height × length × width.[17],[18] Pituitary gland volüme by MRI in CPP children was compared with age/sex-matched control subjects. As the control group, the data of the study in which Sari et al.[19] evaluated the pituitary volumes of 0–18 years old Turkish children was used. In addition, if available, cranial MRI of patients with CPP were evaluated and recorded for the presence of additional intracranial abnormalities or space-occupying lesions.

Statistical analysis

Statistical analyses were performed with SPSS software 22.0 (SPSS, IBM, Chicago, IL, USA). The Kolmogorov–Smirnov test was performed to assess the normality of the distribution of data. Data with normal distribution variables were expressed as mean ± standard deviation (SD), and a paired sample t-test was used to compare values between the groups. Data without normal distribution were expressed as median (interquartile range), and a Wilcoxon test was used to compare values between the groups. Descriptive statistics for the continuous variables were expressed as mean ± standard deviation. The importance of difference between the groups in terms of the mean values was analyzed using the Student's t test when there were two independent groups. P values less than 0.05 were considered statistically significant.


   Results Top


Fifty children (41 girls and 9 boys), who were followed up for CPP at a single center between 2015 and 2020, were included in the study. The mean chronological age at diagnosis was 7.1 ± 1.0 (2.4–7.9) years in girls and 7.4 ± 1.7 (3.7–8.8) years in boys. The mean bone age at diagnosis was 8.6 ± 1.7 (2.5–11.0) years in girls and 8.6 ± 1.6 (6.0–11.5) years in boys. Breast budding was the most frequent complaint (68.3%) in girls, whereas pubic hair growth was the most frequent complaint (55.6%) in boys. When categorized according to their pubertal stage, 63.4% of the girls were at Tanner stage 2, 36.6% were at stage 3 at diagnosis, and median pubertal stage was Tanner stage 2 (2-3). Puberty was Tanner stage 2 in all boys, and median testicular volume was 4 ml (4–8). The auxological data and the laboratory results at the time of diagnosis are presented in [Table 1].
Table 1: Auxological data and laboratory parameters of CPP patients at the time of diagnosis

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Pituitary MRI was performed in every patient after the diagnosis of CPP. Pituitary MRI findings are presented in [Figure 1]a (girls) and [Figure 1]b (boys). In addition to pituitary MRI, cranial MRI was performed in 31.7% (n = 13) girls and 66.6% (n = 6) boys [Table 2].
Figure 1: (a) Pituitary MRI findings of girls with CPP (b) Pituitary MRI findings of boys with CPP

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Table 2: Cranial MRI findings of patients with CPP

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CNS imaging showed pathological findings in 17% (7/41) of the girl cases, and 55.5% (5/9) of the boy cases. While there was no difference between girl patients with normal and abnormal MRI in terms of age at diagnosis, height-SDS, and BMI-SDS (all P > 0.05), it was found that bone age and bone age/chronological age ratio was higher in the group with abnormal MRI (p = 0.024, P = 0.036, respectively). No difference was found between the two groups in terms of estradiol levels (p = 0.461); however, basal LH and FSH levels were higher in girls with abnormal MRI (p = 0.001, P = 0.007, respectively). In boys with CPP, there was no statistical difference between male cases with normal MRI and abnormal MRI in terms of auxological and laboratory parameters (all P > 0.05). No difference was found in terms of puberty stage in the groups with and without pathological findings in both sexes (p = 0.862 in girls, P = 0.363 in boys). Comparison of auxological and laboratory parameters of children with CPP according to brain MRI findings are shown in [Table 3].
Table 3: Comparison of auxological and laboratory parameters of children with CPP according to brain MRI findings

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None of the pathologies detected in the pituitary MRI (pituitary microadenoma, contrast-enhancing hetereogeneities) of the cases with CPP were previously known. These cases did not have neurological findings, any other clinical, or pituitary hormonal abnormality other than CPP. Repeat MRIs were performed in all of them. The lesion disappeared in one, reduced in size in one and remained the same size in two of the patients' duration of follow-up. While the pathologies detected in 14.4% (n = 2) of girls who underwent cranial MRI were previously known (operated meningomyelocele, operated medulloblastoma), none of the pathologies detected in the cranial MRI of the boys were previously known. All MRI lesions were consulted with neurology and neurosurgery sections and continued to be followed after completion of GnRH analog (GnRHa) treatment until resolution or final decision on their CNS lesions.

Pituitary gland volüme by MRI was calculated in CPP children and compared with age/sex-matched control subjects. As the control group, the data of the study in which Sari et al.[19] evaluated the pituitary volumes of 0–18 years old Turkish children was used. Pituitary volumes of girls aged 6.0–7.9 years and boys aged 8.0–8.9 years were found to be increased compared to the control group [Table 4] and [Table 5].
Table 4: Pituitary gland volüme in girls with CPP and the control group

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Table 5: Pituitary gland volüme in boys with CPP and the control group

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   Discussion Top


In this study, we found that CNS imaging showed pathological findings in 17% (7/41) of the girl cases with CPP and 55.5% (5/9) of the boy cases with CPP. In the CPP group, pituitary volumes of girls aged 6.0–7.9 years and boys aged 8.0–8.9 years were found to be increased compared to the control group.

CPP is idiopathic in 90% of girls, prevalence of unsuspected intracranial lesions is 8–13% in girls and decreases with age. Among girls with CPP (onset age of 6–8 years), unsuspected pathology and tumors were only involved in 2–7% and 1% of them, respectively.[20] A previous study of 3,528 girls reported a low prevalence (8.2%) of incidental lesions in girls with CPP.[6] Unlike this, similar to the findings of our study, Cisternino et al.[21] reported brain abnormalities in 18.4% of 304 CPP girls. Chalumeau et al.[22] reported 443 girls with CPP in France, 8% had an occult intracranial lesion, although the prevalence decreases with age. However, 17% of 35 patients who had occult pathological CNS lesions were older than 6 years at puberty onset, including astrocytoma, hamartoma, and arachnoid cyst. Therefore, the authors developed an algorithm to identify the risk of organic CPP, age below 6 years or estradiol above 45th percentile indicating high risk for organic brain lesion in European population. In our study, there was no difference between girl patients with normal and abnormal MRI in terms of age at diagnosis and estradiol levels; however, basal LH and FSH levels were higher in girls with abnormal MRI.

There are few studies in the literature that have evaluated the etiological factors in boys with CPP. According to these studies, the prevalence of an underlying organic cause in male CPP cases has been reported 73-94%.[23],[24] However, more recent studies have reported a wide range for the prevalence of male organic CPP cases (25–83%).[25] Similar to these studies, we found that CNS imaging showed pathological findings in 55.5% of the boy cases with CPP. However, in the study by Alikasifoglu et al.[2] that included 100 male cases conducted in Turkey, an underlying organic cause or developmental anomalies of CNS were observed in overall 26% of the cases. Similarly, Rizzo et al.[26] found that an underlying organic cause was present in 25% of the cases. The differences may be due to the number of patients in these studies. Various studies in the literature demonstrated that pubertal findings started earlier in the organic group compared to the idiopathic group.[2],[27] In the present study, we found that most organic cases had been diagnosed before the age of 7 years, whereas most of the idiopathic cases had been diagnosed after the age of 8 years; but we found no statistical difference. Based on the results of our study and other studies, it can be suggested that most of the male CPP cases diagnosed after 7 years of age are idiopathic, as there is still a possibility of an underlying organic pathology; CNS imaging should not be abandoned in this age group.

To date, the GnRH stimulation test is still the gold standard for precocious puberty diagnosis. However, it has many disadvantages including low sensitivity, high cost and invasive operation, risk of local reaction, and unavailability of GnRH in some centers. Therefore, the exploration of non-invasive diagnostic methods for CPP is urgent in the clinic. Previous studies have shown that the height of the pituitary gland in the CPP group is higher than in the normal group. The pituitary volüme (PV) has also been found to be increased with age and associated with hormonal levels. However, the relationship between PV and hormones, and the role of PV in the diagnosis of PP are still unclear.[7] In this study, we found that PVs of girls with CPP aged 6.0–7.9 years and boys aged 8.0–8.9 years were found to be increased compared to the control group. Wu et al. found that pituitary length, height, and PV of the ICPP group were significantly higher than those of the PT group, and they suggest that the PV might be a predictive marker for CPP, with a sensitivity of 54.10% and a specificity of 72.20% at the cutoff value of 196.01 mm3. Due to the disadvantages of the GnRH stimulation test, MRI has become an alternative method to evaluate the pituitary gland and also to be performed in many tertiary care centers.[7] However, pituitary MRI should be combined with clinical and laboratory tests to improve the diagnostic value of PV for CPP.

This study had several limitations, the first of which was its retrospective natüre, which might cause the loss of some clinical data. Second, only one experienced radiologist performed all imaging studies and the study enrollees were treated at a single medical center. Third, the prevalence of intracranial lesions among patients who did not undergo brain MRI remains unclear. In addition, the sample size is relatively small considering the incidence of precocious puberty.


   Conclusions Top


Given that central nervous system (CNS) abnormalities are much more likely (40–75%) to accompany CPP diagnoses in boys, CNS imaging is usually conducted for all boys with CPP.[2] However, CNS imaging may not necessary for all girls with CPP due to a lower risk of having other CNS abnormalities.[8] It should always be kept in mind that there is a significant number of patients with a CNS lesion who are diagnosed with CPP during follow-up.[28] The height of the pituitary gland in the CPP group is higher than in the normal group. Pituitary MRI should be combined with clinical and laboratory tests to improve the diagnostic value of PV for CPP, providing a non-invasive diagnostic method for PP.[7] It should not be forgotten that MRI is a technique to employ and may impose risks on the patients due to the use of sedatives (in children) and intravenous contrast agents. To avoid potential risks, all healthcare professionals should carefully consider the need for MRI.[29]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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