Uterine artery pulsatility index as a functional biomarker of central precocious puberty: a scoping review

Abstract.

Central precocious puberty (CPP) results from the premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. Although the GnRH stimulation test remains the gold standard for diagnosis, the uterine artery pulsatility index (PI) has been proposed as a functional indicator of pubertal activation. The aim of this review, which included 11 studies and 1,151 patients, was to summarize the current evidence regarding the diagnostic role of uterine artery PI in CPP evaluation. A consistent inverse relationship was observed between the PI and pubertal progression. The reported PI sensitivity for detecting pubertal onset ranges from 77% to 100%, while the specificity varies between 48% and 100%, depending on the cutoff values and study populations. Diagnostic accuracy improved when the PI was combined with uterine morphometric parameters. In girls with CPP undergoing GnRH agonist therapy, the PI increased significantly during treatment, suggesting its potential role as a marker of therapeutic response. Thus, uterine artery PI represents a physiologically plausible and clinically informative adjunctive tool that suggests HPG axis activation. Although not suitable as a stand-alone diagnostic test, its integration into a multimodal diagnostic framework may enhance the non invasive evaluation and monitoring of CPP.

Highlights

● Innovative diagnostic tools are required to optimize the diagnosis of CPP.

● PI could be a strong predictor of CPP and efficacy of GnRH therapy.

● PI should be integrated with other ultrasound parameters.

Introduction

Central precocious puberty (CPP) is defined as the appearance of secondary sexual characteristics in girls before 8 yr of age, caused by premature reactivation of gonadotropin-releasing hormone (GnRH) pulsatile secretion and early activation of the hypothalamic-pituitary-gonadal (HPG) axis (1,2,3). This process results in progressive pubertal development, increased growth velocity, advancement of bone age, and potential reduction in the final adult height if not appropriately managed (4,5,6). The increasing incidence of CPP observed in recent years further emphasizes the need for a rigorous, standardized, and multidisciplinary diagnostic framework to ensure accurate identification and differentiation from nonprogressive or peripheral forms of early pubertal development (1, 2). The diagnostic approach to CPP relies on the integration of clinical, biochemical, and imaging findings; a thorough clinical evaluation includes detailed personal and family history, careful assessment of pubertal onset and progression, and longitudinal monitoring of growth velocity. Physical examination focuses on the evaluation of secondary sexual characteristics, classified according to the Marshall and Tanner staging system (6,7,8). Skeletal maturation is usually evaluated using radiography of the left hand and wrist. In most cases of CPP, bone age is significantly advanced, commonly by at least 2 yr or more than 2.5 standard deviations above the chronological age (6,7,8). Biochemical evaluation is essential to confirm central activation of the HPG axis. The initial assessment includes measurement of basal serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex steroids. However, particularly in the early stages of puberty, basal LH concentrations may remain within the prepubertal range, limiting the diagnostic sensitivity (6,7,8). Therefore, the gold standard diagnostic test is evaluation of the gonadotropin response following stimulation with exogenous GnRH or a GnRH agonist. A peak LH concentration exceeding approximately 5 IU/L, as measured using ultrasensitive immunoassays, is generally considered indicative of pubertal activation of the gonadotropic axis. This response is often accompanied by a predominance of LH over FSH, which is reflected in an increased LH/FSH ratio (1, 9, 10). Several studies have demonstrated significantly increased uterine and ovarian volumes in girls with CPP compared with prepubertal controls and girls with isolated premature thelarche, reflecting sustained estrogen exposure and activation of the HPG axis. Typical findings include not only increased uterine length and volume, but also transition to a pear-shaped uterine configuration, visualization of the endometrial stripe, enlarged ovarian volume with multiple follicles, and reduced uterine arterial resistance on Doppler assessment study (11,12,13,14). For these reasons, pelvic ultrasound is commonly incorporated into diagnostic algorithms for suspected CPP. In this setting, Doppler ultrasonography provides additional functional information by evaluating utero-ovarian blood flow and vascular impedance and calculating the pulsatility index (PI), defined as the difference between the peak systolic and end-diastolic velocities divided by the mean flow velocity (11,12,13,14). Lower PI values indicate reduced vascular resistance, a finding consistent with pubertal activation. The reduction in uterine arterial resistance in CPP is thought to be mediated by hormonal influences (15,16,17,18,19,20). The main mechanism proposed for changes in Doppler flow is the presence of estrogen receptors in the arterial wall. Estradiol has been shown to decrease vascular resistance by exerting a direct action on the smooth muscle cells of the middle layer of the uterine artery (18,19,20). Moreover, elevated LH levels may promote stromal vascularization through multiple mechanisms, including neo angiogenesis, catecholaminergic stimulation, and leukocyte and cytokine activation (15,16,17). The intrinsic relationship between enhanced uterine vascularization and premature activation of the HPG axis is further supported by an inverse correlation between uterine artery resistance indices and both the LH peak and LH/FSH ratio following GnRH stimulation testing (15,16,17,18). The aim of this scoping review was to analyze the current evidence in the medical literature regarding the role of uterine artery PI as an ultrasonographic parameter in the evaluation and diagnosis of CPP.

Materials and Methods

Data sources

We conducted a comprehensive literature review without temporal restrictions to evaluate the existing evidence concerning the diagnostic role of the uterine artery PI in CPP. A structured search was performed in PubMed using five separate query combinations with the following keywords: “precocious puberty AND uterine artery”, “precocious puberty AND Doppler”, “uterine artery pulsatility index AND puberty”, “central precocious puberty AND ultrasound”, and “uterine artery resistance AND early puberty”. This scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure the transparency and completeness of reporting. Studies were considered eligible if they met the following criteria: 1) girls evaluated for pubertal assessment, with a suspicion or confirmed diagnosis of CPP, or presenting with early pubertal manifestations; and 2) assessment of uterine artery PI as part of pelvic ultrasonography. The following exclusion criteria were applied: 1) articles published in languages other than English; 2) nonhuman studies; 3) studies in which uterine artery Doppler measurements were not performed according to standardized ultrasonographic protocols; and 4) studies lacking clearly defined diagnostic criteria for CPP. Titles and abstracts identified through the search strategy were independently screened by two reviewers (IC and CC), who rigorously applied the predefined inclusion and exclusion criteria to determine eligibility for full-text evaluation. All studies fulfilling the selection criteria were subsequently examined in full by the authors, and any discrepancies in study selection or interpretation were resolved through consensus discussions (IC, DR, and CC).

Study selection

A total of 150 records were initially identified through the database search. During the preliminary screening phase, 50 non-English publications were excluded, along with 20 records for which the full text was not accessible, and 40 duplicate entries. Subsequently, 20 articles were eliminated after title and abstract screening because they did not fulfil the predefined inclusion criteria. Of the 20 studies that underwent full-text assessment, 9 were excluded following in-depth evaluation and discussion concerning methodological quality and data reliability. Ultimately, 11 studies that met all the eligibility criteria were included in the present review. A comprehensive outline of the study selection process is provided in Fig. 1, and a detailed synthesis of the findings is presented in Table 1.

Fig. 1.

PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only.

Table 1. Studies related to uterine artery pulsatility index in puberty.

Data extraction

Data extraction was performed using a standardized template under the direct supervision of the principal investigator (CC). For each eligible study, the following variables were collected: study design, sample size and characteristics, mean age of the participants, and reported diagnostic outcomes related to uterine artery PI. As this study was based exclusively on previously published data, formal ethical approval was not required.

Results

Among the 11 studies included in this review (15, 18, 19, 21,22,23,24,25,26,27,28), 6 (18, 19, 22, 24,25,26) primarily investigated uterine artery PI in relation to general pubertal development, while 5 (15, 21, 23, 27, 28) specifically focused on CPP. The publication years spanned from 1996 to 2025, with the majority of articles being published in the past 15 yr highlighting the growing scientific interest in this topic. Collectively, these studies analyzed data from 1,151 girls, approximately 18% of whom had CPP. Most studies involved relatively small sample sizes, although two (24, 25) included larger cohorts. Six studies (18, 19, 22, 24,25,26) consistently reported a progressive decline in uterine artery PI with advancing puberty, which correlated with the Tanner stage and uterine or ovarian volume. Additionally, four studies (15, 18, 19, 21) found significant negative correlations between PI, hormonal markers (LH and FSH), and physical signs of pubertal development. Only one study (22) found no significant differences in PI between prepubertal and pubertal groups, although a correlation between uterine/ovarian volumes and pubertal stage was confirmed. When used alone, PI generally demonstrates higher sensitivity (77%–100%) but lower specificity (48%–85%) (25, 26), highlighting the importance of combining PI with additional ultrasound or hormonal parameters. Regarding CPP, four studies (15, 21, 24, 27) showed that PI, either alone or combined with uterine length, had good diagnostic performance, with sensitivity ranging from 50% to 100%, specificity from 48% to 100%, and overall accuracy between 72% and 98.5%. One study (27) reported more moderate sensitivity (50%) and specificity (77.8%), suggesting that PI cutoffs may vary across populations. Finally, two studies (18, 28) evaluated PI during GnRH therapy and observed a significant increase in PI during treatment (baseline 4.0 ± 1.6 → 6.5 ± 1.8; p < 0.001). ROC analyses demonstrated excellent accuracy for monitoring therapy (AUC 0.97), with sensitivity between 84% and 100% and specificity of 100%, reflecting effective suppression of pubertal hormonal activity.

Discussion

Ultrasound investigation is a valuable tool, mostly in childhood, as neither irradiation nor sedation is required and is easily repeated at the patient’s bedside (29,30,31,32). Pelvic ultrasonography is a safe, non-invasive, and accurate method for evaluating the internal genital organs in children (21, 24). During childhood, the uterine and ovarian size and morphology remain relatively stable, with significant growth occurring at the onset of puberty (14, 33, 34). Between 2 and 9 yr of age, the ovarian volume is generally < 2 mL, with follicles < 9 mm. The uterus measured < 4 cm in length, with a transverse diameter < 1.5 cm, and a uterine body-to-cervix width ratio < 1.2. From 9 yr onward, progressive enlargement of both the uterus and ovaries was observed. The uterine body became wider than the cervix, assuming a typical pear-shaped adult configuration (body-to-cervix ratio > 1.2). The uterine length increases to 5–8 cm, and the endometrium becomes visible, showing cyclical changes. Ovaries enlarge themselves (mean volume ~4 mL), adopt a more ovoid shape, and descend deeper into the pelvis in response to pubertal hormonal stimulation (35,36,37,38). Therefore, pelvic ultrasonography may be considered a supportive tool for the diagnosis of girls with suspected CPP. However, its diagnostic sensitivity is limited, partly because of the transabdominal approach and the substantial overlap between normal prepubertal measurements and pathological findings (24, 35, 36). For instance, Battaglia et al. reported (21) that increased uterine volume (> 4 mL) and the presence of a midline endometrial echo were associated with good specificity (90% and 80%, respectively) but showed relatively low sensitivity (78% and 56%, respectively). Furthermore, concordance with the GnRH stimulation test was moderate, reaching 76% and 69%, respectively (15). In this context, several studies have suggested that the assessment of uterine artery PI using Doppler ultrasonography may represent an objective parameter for evaluating pubertal development stages (18,19,20). The PI, calculated as “peak systolic velocity - end-diastolic velocity” divided by mean flow velocity, reflects vascular resistance and arterial compliance within the uterine circulation. With the onset of puberty, increasing circulating estrogen levels lead to reduced vascular resistance and, consequently, lower PI values. This effect is mediated by estrogen-induced neoangiogenic growth factors that enhance uterine perfusion. The resulting increase in blood flow may contribute to the enlargement of internal genital organs observed during pubertal maturation (18, 21, 24). PI is widely used in obstetric settings as a marker of uteroplacental vascular resistance and placentation, reflecting impedance to blood flow in the maternal compartment of the fetoplacental unit, and its clinical application relies on gestational age–specific reference ranges rather than fixed cutoff values (39,40,41). Physiologically, PI progressively decreases throughout pregnancy, particularly before 16 wk of gestation, due to trophoblastic invasion and remodeling of the spiral arteries, with reported mean values ranging approximately from 1.84 ± 0.55 in the first trimester to 0.78 ± 0.23 in the third (39,40,41). Abnormal PI is typically defined as values above the 95th percentile of the gestational age and is associated with major obstetric complications related to placental dysfunction, such as preeclampsia, hypertensive disorders, and fetal growth restriction (39,40,41).

This scoping review synthesized nearly three decades of evidence indicating that uterine artery PI represents a potential physiological and clinically informative marker of HPG axis activation in girls with suspected CPP. Cross-sectional and clinical studies have consistently reported an inverse association between PI and pubertal progression. Doppler waveforms shift from high-resistance, systolic-dominant patterns in prepubertal girls to low-resistance, continuous systolic-diastolic flow during mid- to late puberty, irrespective of chronological age (18,19,20). This hemodynamic transition is biologically plausible, and reflects estrogen-induced vasodilation and vascular remodeling driven by sustained gonadotropin stimulation. Accordingly, PI progressively declines throughout puberty, with the diastolic flow pattern evolving from interrupted to continuous, similar to that observed in ovulatory cycles. The PI is negatively correlated with age, uterine size, ovarian volume, and both basal and stimulated LH levels, supporting its role as a complement to assessing pubertal progression and defining adequate estrogenic activity (19, 21). Importantly, most investigations included in this review confirm a progressive decline in PI across Tanner stages, paralleling increases in uterine and ovarian volumes, thereby reinforcing the concept that vascular impedance mirrors structural and endocrine maturation (22, 24,25,26). From a diagnostic perspective, PI alone generally demonstrates high sensitivity but more variable specificity, with reported sensitivity ranging from 77% to 100% and specificity ranging from 48% to 100%, depending on the selected cutoff and study population. The combination of PI with morphometric parameters, particularly uterine length, significantly enhances diagnostic performance. Although uterine morphological parameters demonstrate a good diagnostic performance, PI provides complementary functional information regarding uterine vascularization. For instance, Battaglia et al. reported that uterine artery Doppler analysis showed the highest diagnostic performance for identifying CPP, with a sensitivity of 94%, specificity of 96%, and 98.5% concordance with the GnRH stimulation test, outperforming uterine volume and endometrial echo (21). Conversely, Paesano et al. found that uterine measurements, particularly longitudinal uterine diameter and volume, had strong diagnostic value (accuracies of 86% and 89%, respectively), while PI also showed good performance (AUC 0.91; accuracy 87%). Notably, combining PI with the longitudinal uterine diameter increased the diagnostic accuracy to 91%, approaching that of the LH peak (92%). In contrast, ovarian parameters generally show lower diagnostic performance, with accuracies ranging from 70% to 75% (24). Cheuiche et al. reported that uterine volume had the highest diagnostic performance (AUC, 0.897; accuracy, 80%), followed closely by uterine artery PI (AUC, 0.838; accuracy, 79%) and longitudinal uterine diameter (AUC, 0.837; accuracy, 79%). Ovarian volume and endometrial thickness showed slightly lower accuracy (76%–78%). Combining PI with uterine volume increased the specificity to 95% and the positive predictive value to 97% (AUC 0.866), while adding ovarian volume slightly increased the AUC to 0.886 without improving the overall accuracy (25). These findings indicate that uterine morphometric parameters and the PI are the most reliable ultrasound markers for identifying pubertal onset, particularly when used in combination.

The heterogeneity in the proposed cutoff values of the PI, as well as in the reported sensitivity and specificity, is likely related to differences in study populations, variability in the diagnostic criteria used to define pubertal onset, and methodological factors, including the ultrasound technique and Doppler angle standardization, which may limit the clinical applicability of the PI as a diagnostic tool. The main technical characteristics of the included studies are summarized in Table 2. Doppler ultrasonography of the uterine arteries was uniformly performed using a transabdominal approach across the included studies. When specified, the transducer frequency varied between 2 and 8 MHz, with 3.5 and 5 MHz probes being the most frequently used. In most studies, Doppler measurements were obtained from both uterine arteries, whereas a few assessed only one side or did not clearly report the sampling locations. A full bladder is generally required during the examination to facilitate better visualization of the pelvic structures. However, one study performed measurements under both full-bladder and empty-bladder conditions (24). Several studies have also reported adjusting the insonation angle to optimize the Doppler signal; however, this has not been consistently documented across all study protocols. Only one study (15) indicated that multiple cardiac cycles were analyzed when calculating Doppler indices, whereas this information has been frequently omitted in other reports. Likewise, blinding of the operator to clinical or diagnostic information was mentioned in only a few studies, suggesting differences in methodological rigor (15, 21, 24). Thus, there was substantial variability in the technical parameters and level of methodological reporting, particularly with respect to transducer frequency, evaluation of cardiac cycles, and operator blinding. In fact, methodological factors, including the ultrasound approach and the precise site of uterine artery sampling, significantly influence Doppler waveform acquisition, and therefore, PI values. In particular, transvaginal scanning allows improved visualization of more distal uterine artery segments than the transabdominal approach, which may result in differences in the measured impedance (39, 42,43,44). Moreover, there is a physiological resistance gradient along the uterine artery, whereby more proximal segments exhibit higher impedance than distal branches (42,43,44). Consequently, differences in the exact arterial segments sampled represent a major source of variability in reported PI values across studies.

Table 2. Doppler assessment methodology.

Few studies have investigated the role of PI in girls with CPP. Available evidence suggests that PI represents a promising and innovative tool for the evaluation and diagnosis of suspected pubertal disorders (15, 21, 24, 27, 28). Moreover, PI may serve as a marker of therapeutic response, as shown by the significant increase in PI values during GnRH agonist therapy, reflecting the restoration of higher vascular resistance in parallel with effective hormonal suppression (28).

Overall, the available evidence suggests that the uterine artery PI should be considered as part of a multidimensional diagnostic approach, together with clinical evaluation, bone age assessment, pelvic ultrasound morphometry, and hormonal investigations, rather than as an isolated diagnostic parameter. In this setting, uterine artery PI may be particularly useful in girls presenting with early pubertal manifestations, and distinguishing CPP from benign conditions such as premature thelarche remains a key clinical challenge. Evidence from several studies indicates that Doppler evaluation of the uterine arteries may act as a non-invasive complementary tool to improve early diagnostic stratification, potentially serving as a preliminary screening or triage method prior to GnRH stimulation testing, particularly in clinically ambiguous or borderline presentations. In addition to its potential role in the initial diagnostic evaluation, the uterine artery PI may also provide valuable information during long-term follow-up, as variations in uterine vascular resistance seem to parallel the activation level of the HPG axis. When assessed using a standardized ultrasound protocol and interpreted alongside pelvic morphological findings, the uterine artery PI may represent a reliable and physiological potential indicator of central pubertal activation. Thus, this parameter has relevant applications not only in the early differentiation of CPP from benign pubertal variants but also in tracking pubertal progression and evaluating the response to treatment over time.

Limitations

This study had several limitations. Most available studies were cross-sectional or retrospective, limiting causal inference and evaluation of temporal changes in the uterine artery PI. Moreover, longitudinal data were scarce and based on short follow-up periods. Considerable heterogeneity existed regarding sample size, age distribution, pubertal staging, diagnostic criteria for CPP, and ultrasound methodology, which reduces the comparability and generalizability of the proposed PI cutoff values. Additionally, standardized age-adjusted reference ranges for PI are currently lacking. Although the PI shows high sensitivity, particularly when combined with uterine morphometric parameters, its specificity remains variable, and no universally reproducible cutoff has been established. Finally, potential confounders, such as body mass index, ethnicity, and environmental factors, were inconsistently addressed, and the small CPP sample sizes in some studies may have introduced a selection bias.

Conclusions

Uterine artery PI appears to be a promising adjunctive marker for the assessment of CPP, reflecting estrogen-dependent changes in uterine vascular resistance associated with the activation of the HPG axis. Available evidence suggests that PI is consistently reduced in girls with pubertal development and may contribute to the non-invasive identification of central pubertal activation, particularly when integrated with pelvic morphometric and hormonal parameters. However, significant heterogeneity in study design, measurement protocols, and reported thresholds limit its independent diagnostic applicability. Further prospective, standardized studies are needed to define robust reference ranges and clarify their clinical roles within a multimodal diagnostic framework.

Conflict of interests

The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study.