Diagnostic utility of the average peak LH levels measured during GnRH stimulation test.

OBJECTIVES: Gonadotropin-releasing hormone (GnRH) test is the gold standard test to evaluate the hypothalamus-pituitary-gonadal (HPG) axis for the diagnosis of central precocious puberty (CPP). However, the diagnosis of cases with clinical features of CPP whilst have borderline peak luteinizing hormone (LH) remain challenges. We aimed to evaluate diagnostic performance of the average of LH levels measured during GnRH stimulation test. METHODS: Cases with diagnosis of CPP and premature thelarche (PT) who had a GnRH stimulation test results were retrospectively reviewed. Anthropometric measurements (weight, height, and body mass index), age and sex-specific standard deviation scores, growth velocity, puberty stages, bone ages, serum FSH, LH, and estradiol levels were measured by electrochemiluminescence immunological method (ECLIA), and the GnRH stimulation test results, which performed by obtaining venous blood samples at basal, 20th, and 40th minutes for FSH and LH measurement, were recorded. RESULTS: A total of 76 girls (38 CPP, 38 PT) were included. We detected an average peak LH cut-off value of 4.25 IU/L with 94.7 % sensitivity and 97.4 % specificity, a 97.3 % positive predictive value, and a 94.9 % negative predictive value in GnRH test to differentiate cases with CPP from PT. CONCLUSIONS: This is the first study evaluating the diagnostic utility of the average of LH levels measured during GnRH stimulation test. We showed that the average of two LH measurements has a high diagnostic performance. Therefore, it can be used as a valid and reliable diagnostic tool for assessment of HPG axis activation, particularly for cases with a borderline peak LH level.

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OBJECTIVES: To investigate the value of single-phase gonadotropin releasing hormone (GnRH) stimulation test in the diagnosis of central precocious puberty (CPP) in girls with different levels of body mass index (BMI). METHODS: A retrospective analysis was performed for the data of 760 girls with breast development before 7.5 years of age who attended the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2023. According to the results of GnRH stimulation test and clinical manifestations, they were divided into a CPP group (297 girls) and a non-CPP group (463 girls). According to the values of BMI, the girls were divided into a normal weight group (540 girls), an overweight group (116 girls), and an obese group (104 girls). The receiver operating characteristic (ROC) curve was used to investigate the value of single-phase GnRH stimulation test in the diagnosis of CPP in girls with different levels of BMI. RESULTS: Luteinizing hormone (LH)/follicle-stimulating hormone at 30 minutes after GnRH stimulation had an area under the curve (AUC) of 0.985 in the diagnosis of CPP, which was higher than the AUC at 0, 60, and 90 minutes (P<0.05). LH at 30 minutes had a similar diagnostic value to LH at 60 minutes (P>0.05). LH at 30 minutes was negatively correlated with BMI and BMI-Z value (P<0.05).The AUC for diagnosing CPP in normal weight, overweight, and obese girls at 30 minutes LH was 0.952, 0.965, and 0.954, respectively (P<0.05). CONCLUSIONS: The 30-minute GnRH stimulation test has a good value in the diagnosis of CPP in girls with different levels of BMI and is expected to replace the traditional GnRH stimulation test, but the influence of BMI on LH level should be taken seriously.

Case report: Development of central precocious puberty in a girl with late-diagnosed simple virilizing congenital adrenal hyperplasia complicated with Williams syndrome.

Congenital adrenal hyperplasia (CAH) and Williams Syndrome (WS; MIM # 194050) are distinct genetic conditions characterized by unique clinical features. 21-Hydroxylase deficiency (21-OHD; MIM #201910), the most common form of CAH, arises from mutations in the CYP21A2 gene, resulting in virilization of the external genitalia in affected females, early puberty in males, and short stature. Williams syndrome, caused by a microdeletion of 7q11.23, presents with distinctive facial features, intellectual disability, unique personality traits, early puberty, and short stature. This case report describe the clinical features of a 4-year-old girl referred due to progressive virilization and developmental delay. Genetic analysis confirmed concurrent CAH and WS, identifying a novel mutation in the CYP21A2 gene (c.1442T>C). Following corticosteroid therapy initiation, the patient developed central precocious puberty. This case report delves into the pubertal change patterns in a patient affected by overlapping genetic conditions, providing valuable insights in to the intricate clinical manifestation and management of these rare complex disorders.

Irisin combined index to diagnose central precocious puberty in girls: a cross-sectional study.

BACKGROUND: To investigate serum irisin levels in girls at different developmental status and explore the significance of irisin for the diagnosis of central precocious puberty (CPP) in girls. METHODS: In this cross-sectional study 111 girls were enrolled, including 43 cases of CPP, 44 cases of peripheral precocious puberty (PPP) and 24 cases of girls with normal sexual development as controls. The data on age, weight and height, measured blood levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, and irisin were collected. Pelvic Doppler ultrasound was performed to evaluate uterine length, transverse diameter, anteroposterior diameter. The girls were divided into non-CPP group and CPP group according to gonadotropin-releasing hormone (GnRH) stimulation test. RESULTS: Serum irisin levels were significantly higher in CPP group than in PPP group and normal control group. Serum irisin level was positively correlated with basal LH level, basal FSH level, peak LH level, peak LH /FSH ratio, uterine volume, bone age, and bone age index. The area under the curve, cut-off value, sensitivity and specificity of serum irisin were 0.958, 219.255 pg/ml, 100% and 80.6%. The combined diagnosis of CPP in girls by serum irisin and serum basal LH combined with uterine volume had an AUC, sensitivity, and specificity of 0.994, 97.6%, and 100%, superior to that of the single index. CONCLUSIONS: Serum irisin level in girls with CPP is significantly increased. An irisin combined index could help the diagnosis of CPP in girls.

α-Klotho levels in girls with central precocious puberty: potential as a diagnostic and monitoring marker.

Background: Recent studies suggest a link between the Klotho protein, sex hormones, and insulin-like growth factor-1 (IGF-1), indicating that α-Klotho levels may rise during puberty, including in central precocious puberty (CPP) cases. This study aimed to explore α-Klotho levels in girls with CPP to assess its potential as a diagnostic and monitoring tool for this condition. Methods: In total, 139 girls, comprising 82 patients diagnosed with CPP and 57 healthy prepubertal controls, were enrolled in this study. From March 2020 to May 2023, we assessed both α-Klotho levels and clinical parameters. α-Klotho concentrations were measured using an α-Klotho ELISA kit. For the girls with CPP, we additionally analyzed samples taken 6 months after GnRH agonist treatment. Results: α-Klotho levels were higher in the CPP group compared with the control (CPP group: 2529 ± 999 ng/mL; control group: 1802 ± 675 pg/mL) (P < 0.001), and its level modest decreased after 6 months of GnRH agonist treatment (2147± 789 pg/mL) (P < 0.001). The association between α-Klotho and IGF-1 SDS, follicular stimulating hormone and baseline luteinizing hormone was assessed by partial correlation after adjusting for age, BMI SDS (r= 0.416, p= <0.001; r= 0.261, p= 0.005; r= 0.278, p= 0.002), respectively. Receiver operating characteristic curve analysis identified an α-Klotho cut-off differentiating CPP from controls, with a cut-off of 1914 pg/mL distinguishing girls with CPP from controls with a sensitivity of 69.5% and specificity of 70.2%; the area under the curve was 0.723. Conclusion: The findings of our study are the first step towards deciphering the role of α-Klotho in puberty induction. With additional data and further research, α-Klotho could potentially be utilized as a significant diagnostic and monitoring tool for CPP.

Premature Pubarche: A Pragmatic Approach.

Premature pubarche (PP) is a common and usually benign variant of normal puberty most often seen in 5-year-old to 9-year-old children. Some providers routinely order laboratory testing and a bone age to try to rule out other diagnoses including nonclassic congenital adrenal hyperplasia and gonadal or adrenal tumors. I review the natural history of PP and studies which suggest that without clinical features such as rapid growth and progression or genital enlargement, it is unlikely that a treatable condition will be found. Therefore it is recommended that patients with PP not undergo testing unless there are red flags at the time of the initial visit.

Diagnosis, Treatment, and Outcomes of Males with Central Precocious Puberty.

Central precocious puberty (CPP) among males is less frequent than among females but more likely to have an underlying pathologic cause. Diagnosis of CPP is often straightforward among males because increased testicular volume, the first sign of puberty, can be verified although careful central nervous system (CNS) assessment is generally necessary. Treatment with gonadotropin-releasing hormone agonist (GnRHa) is indicated, given in conjunction with any therapy needed for CNS lesions. Monitoring of treatment usually can consist of evaluating growth and physical puberty and with testosterone levels as the only lab data. Short-term and long-term outcome data indicate efficacy and safety, although data are limited. Such data need to be reported.

Isolated Vaginal Bleeding Before the Onset of Puberty.

Isolated vaginal bleeding before the onset of puberty is a rare presentation of isosexual precocity. In most cases, isolated vaginal bleeding without an abnormal genital examination is self-limited with resolution usually within 1 to 3 episodes. Watchful waiting is appropriate in most patients who do not have persistent bleeding, other signs of puberty, or signs/symptoms of an underlying etiology. Workup for patients with concerning features may include puberty hormone levels and/or transabdominal and transperineal ultrasound.

Diagnostic Value of Stimulated Urine Luteinizing Hormone After Triptorelin Stimulation Test in Girls with Central Precocious Puberty.

OBJECTIVE: To investigate the diagnostic value of urine luteinizing hormone (ULH) after the triptorelin stimulation test detected by immunochemiluminometric assay (ICMA) in girls with central precocious puberty (CPP). METHODS: The girls with precocious puberty were included. The triptorelin stimulation test at 8:30 a.m. was performed. Two consecutive 12-hour urine samples were collected after the test, defined as the first 12-hour and second 12-hour urine, respectively. ICMA measured ULH. Urine creatinine (Cr) concentration was measured. CPP and peripheral precocious puberty (PPP) were diagnosed by the same pediatric endocrinologist based on clinical symptoms, signs, and progression of clinical development. RESULTS: A total of 97 cases (CPP n=69; PPP n=28) were included, with 12 cases not meeting the receiver operating characteristic analysis criteria. The first and second 12-hour ULH/Cr in the CPP group were higher than those in the PPP group. When the first 12-hour ULH/Cr was≥287.252 IU/mol, the sensitivity and specificity for diagnosing CPP were 87.3% and 90.9%, respectively. When the second 12-hour ULH/Cr was≥152.769 IU/mol, the sensitivity and specificity for diagnosing CPP were 92.1% and 90.9%, respectively. The area under the curve of the first and second 12-hour ULH/Cr were 0.933 and 0.954, respectively. CONCLUSION: The ULH detection method after the triptorelin stimulation test has clinical significance for diagnosing CPP in girls. When blood sampling compliance in girls with precocious puberty is poor, the first 12-hour ULH/Cr≥288 IU/mol (or second 12-hour≥153 IU/mol) after the triptorelin stimulation test can serve as a laboratory indicator for diagnosis of CPP.

Diagnosis of Central Precocious Puberty.

A thorough history and physical examination including Tanner staging and growth assessments can guide differential diagnosis and aid in the evaluation of precocious puberty. Basal luteinizing hormone levels measured using a highly sensitive assay can be helpful in diagnosing central precocious puberty (CPP). Brain MRI is indicated with males diagnosed with CPP and females under the age of 6 with CPP. As more information becomes available regarding the genetic etiologies of CPP, genetic testing may preclude the need for imaging studies and other hormonal testing, especially in familial cases.

Females with Breast Development before Three Years of Age.

Breast development in a girl 3 years of age or younger is a commonly encountered scenario. Nearly all of these cases will either regress or fail to progress during follow-up, confirming a diagnosis of premature thelarche (PT). Studies show that these girls will have onset of true puberty and menses at a normal age. The authors present evidence that laboratory testing, particularly basal and gonadotropin hormone-releasing hormone -stimulated gonadotropin levels, will show overlap between girls with PT and the rare patients with the onset of central precocious puberty before age 3, mainly of whom have hypothalamic hamartomas.

Presentation and Care for Children with Peripheral Precocious Puberty.

Peripheral precocious puberty (PPP) refers to the early onset of sexual maturation that is independent of central nervous system control. The extensive differential diagnosis includes congenital and acquired causes. Presenting features depend on which class of sex steroids is involved, and diagnosis rests on hormonal and, if indicated, imaging and/or genetic studies. Effective treatment exists for nearly all causes of PPP. Ongoing research will advance our therapeutic armamentarium and understanding of the pathophysiologic basis of these conditions.

Elevated serum irisin levels in boys with central precocious puberty independent of BMI.

INTRODUCTION: Central precocious puberty (CPP) is a prevalent endocrine disorder. Research has indicated that pubertal development is linked to nutritional metabolism. Irisin, a novel myokine/adipokine, has been identified as a potential predictor of CPP in girls. This study aims to examine the relationship between serum irisin levels and CPP in boys. MATERIAL AND METHODS: An enzyme-linked immunosorbent assay (ELISA) was used to measure serum irisin levels in 32 boys diagnosed with CPP and 33 prepubertal age-matched boys as normal controls (NC). To assess the impact of body mass index (BMI) on irisin levels, both the CPP and NC groups were divided into overweight/obese and normal-weight subgroups. Spearman correlation analysis was employed to assess the connection between irisin and clinical and biochemical parameters. Additionally, a receiver operating characteristic curve was utilised to determine the optimal threshold value for irisin. RESULTS: In the normal-weight subgroups, boys with CPP exhibited elevated irisin levels compared to controls, but not in the overweight/obese subgroups. The optimal cut-off value for irisin levels to predict CPP in the normal-weight groups was 93.09 ng/mL, yielding a sensitivity of 47.6% and a specificity of 100%. Furthermore, a positive correlation was noted between irisin levels and bone age (BA), bone age advancement (BA-CA), and BMI. CONCLUSIONS: Serum irisin levels correlate with BMI and pubertal development. Given its limited sensitivity, irisin level can only be utilised as a supplementary rather than a standalone diagnostic indicator for CPP.

Does Basal Morning Luteinizing Hormone (bLH) Predict Central Precocious Puberty (CPP) in Girls?

Background and Objectives: bLH is considered an excellent biochemical predictor of CPP. However, its utilization in clinical practice shows some uncertainties. This study aims to evaluate the diagnostic power of bLH and propose a diagnostic algorithm for CPP. Materials and Methods: We conducted a monocentric cohort retrospective study evaluating all females referred for suspicion of CPP between 1 January 2017 and 31 December 2020 who underwent a GnRH test. Auxological, hormonal, and instrumental data were collected, including pelvic ultrasonography and bone age (BA) assessment. Simple linear regression, t-test, and ROC tests were utilized to study the diagnostic value of basal hormone levels. Two hundred thirteen girls were included in the study. They were subdivided into two groups according to the results of the GnRH test: Group 1, with LH peak > 5 IU/L (pubertal) and 79 patients (37%), and Group 2, with an LH peak ≤ 5 IU/L (prepubertal) and 134 patients (63%). Results: The ROC curve showed that bLH level > 1.5 Ul/L best predicts a pubertal response to the GnRH test (AUC 0.8821, accuracy 82%), with low sensitivity (34%). The multivariate analysis found that bLH > 0.5 IU/L, basal FSH (bFSH) > 3.5 IU/L, bLH/bFSH ratio > 0.16, BA advancement > 1.7 years, uterine volume > 3.6 mL, longitudinal uterine diameter > 41 mm, and the presence of endometrial rhyme were significantly associated with a pubertal response at the GnRH test. An algorithm based on these features was created, and its application would reduce the number of GnRH tests by 34%. Overall, 96.2% of Group 1 patients reached the LH peak at the 30th minute of the GnRH test, supporting the hypothesis that the GnRH test duration could be reduced to 30 min. Conclusions: Morning bLH > 1.5 IU/L could be carefully used as a diagnostic predictor of CPP. The GnRH test, even reduced to 30 min, could be reserved for girls who show low intermediate morning bLH and specific clinical signs of pubertal development.

Congenital adrenal hyperplasia complicated by gonadotropin-dependent precocious puberty.

Precocious puberty, characterised by the early appearance of secondary sexual characteristics, poses challenges in diagnosis and management. Here, we describe a case of precocious puberty diagnosed in a boy in middle childhood, who presented with progressive phallus enlargement, pubic hair development and increased aggressive behaviour. Hormonal evaluation confirmed the diagnosis of congenital adrenal hyperplasia (CAH), complicated by gonadotropin-dependent precocious puberty. The case highlights the importance of assessment of testicular volume in a patient presenting with precocious puberty. Symmetrical testicular enlargement in a patient with CAH suggests premature activation of the hypothalamic-pituitary-gonadal axis. The patient received glucocorticoid therapy to suppress androgen production related to CAH and gonadotropin-releasing hormone analogue therapy to control premature activation of the hypothalamic-pituitary-gonadal axis. Follow-up visits showed regression of secondary sexual characteristics and improved growth velocity.

Screening for central precocious puberty by single basal Luteinizing Hormone levels.

PURPOSE: To identify cut-off for basal LH levels and for pelvic ultrasound uterine and ovarian parameters indicating an Hypotalamic-Pituitary-Gonadal (HPG) axis activation as diagnostic of Central Precocious Puberty (CPP). METHODS: 248 girls referred for suspected precocious/early puberty who had undergone a GnRH stimulation test were enrolled and divided into three groups: Premature Idiopathic Thelarche (PIT), CPP, and Early Puberty (EA). For every patient basal serum Luteinising Hormone (LH) and Follicle Stimulating Hormone (FSH), basal LH/FSH ratio and pelvic ultrasonographic parameters were also collected. Through the use of Receiver Operating Curves (ROCs) the sensitivity (Se) and specificity (Sp) of basal LH, FSH, LH/FSH ratio and ultrasonographic parameters were evaluated at each level and Area Under the Curve (AUC) was measured. RESULTS: Basal LH model ≥0.14 mIU/mL reached the highest predictability (90.6% and 78.2%, Se and Sp, respectively). Basal LH/FSH ratio ≥0.1 showed a sensitivity of 85.90% and a specificity of 78.14%, while basal FSH cut-off (≥2.36 mIU/mL) had the lowest predictability, with a less favourable sensitivity (71%) and specificity (70.5%). Cut-off point for uterine length as 35 mm, (83.5% and 42.9% of Se and Sp, respectively) was calculated. For ovarian volumes, ROC curves showed very low sensitivity and specificity. CONCLUSION: A single basal LH measurement under the cut-off limit may be adequate to exclude an HPG axis activation as CPP.

Urinary gonadotropin assay on 24-h collections as a tool to detect early central puberty onset in girls: determination of predictive thresholds.

STUDY QUESTION: Is the 24-h urinary gonadotropin assay an effective diagnostic tool in central precocious puberty (CPP) in girls? SUMMARY ANSWER: This study is the first to provide 24-h urinary gonadotropin assay data, using an electrochemiluminescent immunoassay (CMIA), and to report its usefulness as a tool for the diagnosis of CPP. WHAT IS KNOWN ALREADY: Data about the GnRH test in the diagnosis of CPP are variable and there is no consensus regarding its interpretation. The measurement of FSH and LH in urines was previously reported to be an alternative biological tool. STUDY DESIGN, SIZE, DURATION: This is a retrospective two-cohort study, involving a setting and a validation cohort. A total of 516 girls, included between October 2012 and July 2015, and 632 urinary collections were analyzed in the setting cohort. In the validation cohort, 39 girls were included between January 2021 and May 2023, and 49 urinary collections were analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included girls who consulted for an investigation of disturbed growth rate or a clinical suspicion of puberty onset in different medical centres across France (setting cohort). Girls with a suspicion of precocious puberty onset were addressed at the expert centre of paediatric endocrinology of the Groupement Hospitalier Lyon Est (validation cohort). Pelvic ultrasonography was performed and enabled their classification according to clinical and morphologic changes criteria (prepubertal or pubertal groups). The parents collected 24-h urine samples (u24) according to standardized instructions. FSH and LH (urinary or plasmatic) were measured using a current and automated CMIA. MAIN RESULTS AND THE ROLE OF CHANCE: The area under the ROC curves for CPP prediction was 0.709 for u24FSH (P < 0.001), 0.767 for u24LH (P < 0.001), and 0.753 for the u24LH/u24FSH ratio (P < 0.001). We retained all possible combinations of the four thresholds in the validation cohort (u24FSH = 1.1 or 2.0 IU/24 h; u24LH = 0.035 or 0.08 IU/24 h). The combination of u24FSH > 1.1 IU/24 h and u24LH > 0.08 IU/24 h had a positive PV of 85.7% and a negative PV of 94.3%, a sensitivity of 85.7% and a specificity of 94.3%, for classifying prepubertal and pubertal girls in this cohort. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study, in which a margin of error remains due to the inherent uncertainty regarding the clinical assessment of pubertal onset. It must be considered that the thresholds can only apply to the used reagents; measurements without extractions using other reagents are likely to show important heterogeneity. WIDER IMPLICATIONS OF THE FINDINGS: The assay performed herein is a simple, non-invasive, and analytically robust technique meeting the criteria for an alternative to the GnRH test which could be used to supplement its lack of sensitivity. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used. All authors declared no conflict of interest. TRIAL REGISTRATION NUMBER: In-house #23-5214 registered study.

Central precocious puberty in boys: secular trend and clinical features.

OBJECTIVE: Recent studies suggest that boys enter puberty at a younger age, and the incidence of male central precocious puberty (CPP) is increasing. In this study, we explore the incidence of male CPP and identify key clinical and auxological indicators for organic CPP (OCPP). DESIGN: A retrospective registry-based study. METHODS: The medical records of 43 boys treated with CPP at the Helsinki University Hospital between 1985 and 2014 were reviewed. Clinical, auxological, and endocrine data of the CPP patients were included in the analyses. RESULTS: Based on brain MRI, 26% of patients had OCPP. Between 2010 and 2014, the CPP incidence in boys was 0.34 per 10 000 (95% CI 0.20-0.60). Between 1990 and 2014, the male CPP incidence increased (incidence rate ratio [IRR] 1.10, P = .001). This increase was driven by rising idiopathic CPP (ICPP) incidence (IRR 1.11, 95% CI 1.05-1.19, P < .001), while OCPP incidence remained stable (P = .41). Compared with the patients with ICPP, the patients with OCPP were younger (P = .006), were shorter (P = .003), and had higher basal serum testosterone levels (P = .038). Combining 2 to 4 of these readily available clinical cues resulted in good to excellent (all, area under the curve 0.84-0.97, P < .001) overall performance, differentiating organic etiology from idiopathic. CONCLUSIONS: The estimated incidence of CPP in boys was 0.34 per 10 000, with 26% of cases associated with intracranial pathology. The increase in CPP incidence was driven by rising ICPP rates. Patients with OCPP were characterized by shorter stature, younger age, and higher basal testosterone levels, providing valuable cues for differentiation in addition to brain MRI. Utilizing multiple cues could guide diagnostic decision-making.

Multi-omic analysis of precocious puberty girls: pathway changes and metabolite validation.

Objective: Precocious puberty (PP) is a prevalent endocrine disorder affecting the physical and mental wellbeing of children. Identifying the triggering factors of PP has become a central issue. This study seeks to investigate the metabolomic and transcriptomic alterations in PP. Material and methods: First, 37 school-aged girls diagnosed with PP and 25 age-matched prepubertal control girls were recruited, and the fecal samples were collected for non-targeted metabolomic analysis to screen for differentially expressed metabolites (DEMs). Subsequently, an animal model of PP was constructed by danazol administration to neonatal female rats, and both fecal non-targeted metabolomics and serum next-generation transcriptomic sequencing were performed to screen DEMs and differentially expressed genes (DEGs) in PP. Moreover, the DEM co-existing in clinical and animal models was administrated to PP rats to explore the role of the target metabolite in PP. Results: A total of 24 DEMs in PP clinical samples and 180 DEMs and 425 DEGs in PP animal samples were identified. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these DEMs and DEGs were enriched in disease-associated pathways, including fatty acid synthesis, glycerolipid metabolism, pyrimidine metabolism, steroid hormone biosynthesis, progesterone-mediated oocyte maturation, and gonadotropin-releasing hormone (GnRH) signaling pathway, forming a tight DEM-DEG pathway regulatory network. Further DEM validation demonstrated that thymine supplementation delayed the opening of the vagina and development of PP in model rats. Conclusion: This study reveals that the metabolomic and transcriptomic changes, along with enriched pathways, are implicated in PP based on clinical and animal analyses. The findings may provide new strategies and research avenues for PP treatment.