Background
Puberty is a complex progression of hormonal alterations leading to the achievement of mature reproductive capacity. The onset of puberty is activated by pulsatile release of gonadotropin-releasing hormone (GnRH). With the development of the social economy and improvements in living conditions, the age at pubertal onset has advanced worldwide, and the incidence and morbidity of precocious puberty is increasing annually [
1‐
3]. Precocious puberty is more common in girls than in boys. In girls, the onset of secondary sexual characteristics before the age of 8 years is considered precocious puberty. It can be divided into two kinds, central precocious puberty (CPP) and peripheral precocious puberty [
4]. CPP may result in accelerated growth and an early age at menarche, and then it would lead to a decreased final adult height and some psychological and health problems in adulthood, taking diabetes, cardiovascular disease for example [
5,
6]. Therefore, in the long run, early and accurate diagnosis of CPP is especially significant. In addition to examinations of secondary sexual characteristics and bone age, the GnRH stimulation test has been indispensable in the diagnosis of CPP. However, this test, while requiring 3 collections (0, 30 and 60 min), is often done with 5 samples, including 90 and 120 min time points. Not only is the GnRH stimulation test invasive, time-consuming, and expensive, but patient cooperation is also sometimes difficult. To explore convenient and accurate diagnostic procedures for CPP, many researchers have assessed the value of urinary gonadotropins from urinary samples, including first-voided urine samples and random urine samples. Both types of samples have been used to evaluate the levels of urinary luteinizing hormone (ULH) and urinary follicle-stimulating hormone (UFSH). First-voided urine is collected from patients who were informed to empty their bladder before going to bed and to refrain from voiding until the next morning. Random urine samples are collected at any time during the period of the GnRH stimulation test. To date, many authors have found that urinary gonadotropin measurements are a potential alternative approach for the diagnosis of CPP. However, this remains a controversial issue because of the absence of unified standards and evidence-based support for this approach.
Nocturnal ULH and UFSH can represent gonadotropin excretion in children with normal and early puberty [
7]. Therefore, this meta-analysis was performed to assess the value of first-voided ULH and the ratio of ULH to UFSH in the diagnosis of female CPP and to compare the accuracy between urinary gonadotropins and serum GnRH-stimulated gonadotropins.
Methods
This meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol for this systematic review was registered on INPLASY (registration number: INPLASY 2021120076) and is available in full on inplasy.com (
https://doi.org/10.37766/inplasy2021.12.0076).
Literature search
We searched the databases of PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang for relevant literature published until 7 December 2020 in all languages. The search was performed using a combination of keywords and free words. The keywords were “puberty, precocious,” “urinary luteinizing hormone,” and “urofollitropin.” According to the PRISMA diagnostic test accuracy guidelines, the keywords regarding research methods were “sensitivity” and “accuracy.” Each keyword and its free words were combined with “or.” The different keywords were combined with “and.”
Study selection
The inclusion criteria were as follows.
(1)
The study was designed as a diagnostic test study, and the results had been published.
(2)
All patients in the study were female with Tanner stage ≥ 2 breast development, advanced bone age by ≥ 1 year, and accelerated growth.
(3)
Urine and serum samples were collected for gonadotropin measurement on the same day for each patient.
(4)
First-voided urine was used for all urinary samples. For reliable evaluation of urinary gonadotropins, all patients had been informed to empty their bladder before going to bed and to refrain from voiding until the next morning.
(5)
The gold standard was a serum LH level of ≥ 5 mIU/L or a serum LH:FSH ratio of > 0.6.
Studies that did not meet the inclusion criteria were excluded. Additional exclusion criteria were fundamental experimental studies, such as animal studies; reviews, conference reports, repeatedly published studies, summary articles, and case reports; and studies without sufficient data.
Literature quality assessment
Literature quality assessments were performed by two independent investigators. They independently extracted and incorporated the data. When disagreements arose, the investigators discussed the study until a consensus was reached. The assessment was performed based on the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) [
8].
Microsoft Excel 2010 (Microsoft Corp., Redmond, WA, USA) was used for data extraction. The following relevant information required for this meta-analysis was extracted: first author, publication year, nationality, sex, age, ethnicity, numbers of participants in CPP group and control group, gold standard test results, and sensitivity, specificity, true positive, false positive, true negative, false negative, and accuracy measures [
9].
Statistical analysis
In this article, Meta-DiSc version 1.4 (
http://www.hrc.es/investigacion/metadisc_en.htm) was used to evaluate threshold effects and heterogeneity. We performed Cochran’s Q test to assess heterogeneity and used the inconsistency index (I
2 test) to assess the magnitude of heterogeneity among studies. If the
P-value of Cochran’s Q test was > 0.1 and the I
2 value was < 50%, no heterogeneity was present, and a fixed-effects model was performed. If the
P-value was < 0.1 or I
2 was > 50%, great heterogeneity was present, and a random-effects model was performed. The pooled sensitivity, pooled specificity, pooled diagnostic odds ratio, pooled positive likelihood ratio (PLR), and pooled negative likelihood ratio (NLR) were all calculated by Meta-DiSc, and the
P-values and 95% confidence intervals (CIs) were calculated at the same time. The area under the summary receiver operating characteristic curve (AUC) was also calculated. Sensitivity evaluation and publication bias were performed with STATA version 15.0 (StataCorp, College Station, TX, USA) [
10]. If > 10 articles were included in this meta-analysis, we applied Deeks’ funnel plot to assess the extent of potential publication bias. Otherwise, we used the Begg rank correlation test and Egger test to analyze publication bias.
Discussion
Although the number of included studies was limited, we still found that some results were statistically significant. All urinary samples in the six included studies were the first-voided urine. Urinary sample collection and the GnRH stimulation test were performed on the same day. Additionally, there were few differences in the strength of the evidence among the included studies. Although the number of included articles was limited, no publication bias was found in meta-analysis of ULH and the ULH:UFSH ratio. From the six studies included in this meta-analysis, we found that compared with the GnRH stimulation test, the first-voided urinary gonadotropin test can also effectively diagnose CPP without repeated venipuncture, venous blood collection, and excessive time consumption. Furthermore, the sample collection and evaluation are more convenient, more acceptable, less expensive, and noninvasive. The test can be performed after the sample is brought to the hospital without requiring the presence of the patient. Thus, the data from this meta-analysis suggest that the first-voided urinary gonadotropin test can be used to accurately diagnose CPP.
Previous studies have indicated that first-voided urinary gonadotropins increase because of their physiological secretion during the nighttime in female patients with early puberty [
17], and the present meta-analysis supports this finding. However, there are no accepted diagnostic criteria of first-voided urinary gonadotropins in pediatric endocrinology. First, all the samples were first-voided urinary samples, but the sample collection period was inconsistent across studies. The subjects in Shim et al.’s study emptied their bladder before going to bed the previous night, and first-voided urine samples were collected as soon as they woke up. There was no control for time in their study. Kobly et al.’s study used the same methods to collecte urine samples, but this study corrected all the periods by 8 h. In Yang et al.’s, Chen et al.’s and Ma et al.’s studies, there was a clear beginning time for sample collection at 20:00 h the previous night. However, the time of finishing collecting samples was not at one time, but at the time when the subjects woke up in the morning. Zhang et al.’s study used the clear time limit for sample collection, from 19:00 h to the next day at 07:00 h. Second, to avoid errors between different patients, Kolby et al. [
12] used the corrected urinary gonadotropin levels along with osmolality, whereas Ma et al. [
15] and Chen et al. [
14] corrected the urinary gonadotropin levels along with urinary creatinine. Moreover, the test methods used across the studies in this meta-analysis were not identical. Serum gonadotropins were mainly examined by an electrochemiluminescence immunoassay, immunofluorometric assay, or chemiluminescence immunoassay. Urinary gonadotropins were measured by a dissociation-enhanced lanthanide fluorescence immunoassay, an immunofluorometric assay, a chemiluminescence immunoassay, or an immunochromatography assay. Every diagnostic approach has its own diagnostic sensitivity and specificity. Differences not only existed between the assessment of serum and urine gonadotropins but also among each of the included studies. Finally and most importantly, as mentioned above, gonadotropins in nocturnal urinary samples have been employed for CPP diagnosis for decades. In 1995, Demir et al. [
18] found that urinary LH and FSH were age-related and significantly increased during puberty. However, this has not been widely adopted in clinical practice and remains an unresolved problem. In summary, the widespread use of first-voided urinary gonadotropins in the diagnosis of true precocious puberty will require a standardized examination procedure, a consistent cut-off value, and accordant urine sample collection instructions.
Although there was no fixed threshold of urinary gonadotropins in the included studies, no threshold effects existed in this meta-analysis. The meta-analysis of ULH for the diagnosis of CPP showed that the AUC was 0.8812 (sensitivity = 0.79, specificity = 0.84). In the sensitivity analysis of the outcomes in which we excluded trials with a high risk of bias one by one, we found no obvious difference in the AUC, sensitivity, or specificity. However, after excluding the data from Chen et al. [
14], the diagnostic accuracy was slightly higher (AUC = 0.90, sensitivity = 0.81, specificity = 0.85), possibly because of the lower sensitivity and specificity. Regardless, ULH is a reliable indicator for the diagnosis of CPP. Similarly, the meta-analysis of the ULH:UFSH ratio for the diagnosis of CPP showed that the AUC was 0.8661 (sensitivity = 0.79, specificity = 0.84). There was no change in the sensitivity analysis of outcomes by excluding trials with a high risk of bias one by one. From this analysis, it seems apparent that the diagnostic accuracy of ULH is slightly higher than that of the ULH:UFSH ratio. No publication bias was found in this meta-analysis. In general, urinary gonadotropins can be used to effectively diagnose CPP.
First-voided urinary gonadotropin levels reflect the nighttime physiological secretion of gonadotropins in early puberty. Previous studies have shown that measurement of the nocturnal ULH and the ULH:UFSH ratio could be a proper substitute for the GnRH stimulation test [
19]. In terms of the quantitative results, we found that ULH had higher diagnostic value than the ULH:UFSH ratio. However, this study had a few limitations: no large-scale study was included in the analysis; fewer than 10 studies were included, with one from Europe, one from Korea and four from China. Therefore, our results could have been skewed by the lack of studies from other parts of the world. Additionally, all the included studies were single-center studies. Thus, to better apply first-voided urinary gonadotropins in pediatric clinics, larger-scale, multicenter, and prospective studies should be conducted in the future.
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