Rapidly progressive puberty is a distinct clinical problem from classic precocious puberty. Affected girls begin puberty at a roughly normal age, but then accelerate through the Tanner stages at an alarming pace, with bone age racing ahead of chronological age. Because estrogen drives the fusion of the growth plates, this acceleration locks in a compromised predicted adult height. Gonadotropin-releasing hormone agonists, or GnRHa, are the standard tool for halting central precocious puberty, and Chinese consensus guidelines now allow their use in rapidly progressive puberty when the height prognosis is severely threatened. Yet clinicians have noticed that some girls on GnRHa monotherapy continue to show bone age advancement, hinting that their estrogen supply does not come from the ovaries alone.

That observation points to aromatase, the CYP19A1 enzyme that converts adrenal-derived androgen precursors into estrogens in peripheral tissues. Block this enzyme with a drug like letrozole, the reasoning goes, and you shut down the second estrogen source, slowing growth plate fusion further. Third-generation aromatase inhibitors such as letrozole and anastrozole are already used for short stature, mainly in boys, where they can raise predicted adult height. In girls, however, their use has been rare—largely confined to McCune-Albright syndrome—because of a central concern: if aromatase is blocked while androgens keep flowing, androgens might accumulate and trigger virilizing effects such as hirsutism and acne.

The new study, led by researchers at the Second Hospital of Hebei Medical University in Shijiazhuang, was designed to test that concern with unprecedented hormonal resolution. The team enrolled 28 girls with advanced bone age between July 2025 and April 2026. Thirteen girls, designated Group A, started combination therapy—GnRHa injections every four weeks plus daily oral letrozole at 1.25 milligrams—from the outset. The other fifteen, Group B, were already on GnRHa monotherapy and were offered letrozole as an add-on. Group assignment reflected the timing of letrozole introduction in routine clinical care rather than systematic allocation, and the authors acknowledge this was not a randomized design.

The methodological centerpiece was liquid chromatography–tandem mass spectrometry, or LC-MS/MS, a technique that detects and quantifies steroid hormones with far greater sensitivity and specificity than traditional immunoassays. Blood samples drawn at baseline, one month, and six months were profiled across three androgen-producing routes: the classical pathway, running from DHEA through androstenedione to testosterone and dihydrotestosterone; the 11-oxygenated pathway, producing adrenal androgens such as 11-ketotestosterone; and the little-known backdoor pathway, which bypasses testosterone to generate potent dihydrotestosterone metabolites like 5α-dihydroprogesterone and 3α-androstanediol. Progestogens, estrogens, and reproductive hormones including anti-Müllerian hormone, inhibin B, and sex hormone-binding globulin rounded out the panel.

The results tell a nuanced story about which hormones respond to which part of the dual blockade. In Group A, where both drugs acted from the start, classical androgens—testosterone, androstenedione, and their metabolites—fell sharply by one month and stayed low through six months, alongside marked drops in key progestogens and both estrone and estradiol. The free androgen index, a marker of bioavailable androgen, declined progressively. Crucially, the 11-oxygenated androgens, which are largely adrenal in origin, remained essentially stable, with only a modest and transient dip in 11-ketotestosterone at one month. That pattern, the authors argue, indicates that GnRHa effectively suppresses gonadal androgen output while adrenal steroidogenesis is left untouched.

Group B offered a natural comparison: in girls whose hypothalamic-pituitary-gonadal axis was already suppressed, adding letrozole produced far fewer hormonal ripples. Estradiol and estrone fell significantly, as did AMH and inhibin B—markers of ovarian follicular activity—but most androgens and progestogens held steady. A modest rise in two upstream precursors, pregnenolone and 17-hydroxydihydroprogesterone, appeared without any corresponding increase in downstream androgens, possibly reflecting mild accumulation of substrates blocked from aromatizing. Across both groups, no girl developed clinical or biochemical hyperandrogenism: none showed hirsutism by the modified Ferriman-Gallwey score, and none developed moderate-to-severe acne.

The safety signal extended beyond androgens. No letrozole-related adverse events—liver dysfunction, rash, or gastrointestinal symptoms—were recorded during the six-month window. Bone age, assessed by hand-wrist radiographs, advanced by a mean of 0.30 years in Group A and 0.23 years in Group B over six months, both slower than the expected 0.5-year chronological progression. That slowing is exactly what dual estrogen suppression should produce at the growth plate, though the authors caution that whether it ultimately translates into taller adults can only be answered with longer follow-up. The AMH and inhibin B declines mirror findings from standard GnRHa therapy and are considered reversible after treatment stops.

The findings build on, and extend, earlier work. The Greek GAIL study showed in 2016 that anastrozole combined with leuprorelin improved predicted adult height in early-maturing girls without testosterone abnormalities or bone density problems, but it did not perform comprehensive steroid profiling. Data from postmenopausal women on letrozole, whose estrogen physiology resembles that of GnRHa-suppressed girls, show estradiol reductions of 75 to 95 percent with minimal effects on adrenal steroids—and androgen-related side effects have been reported only with the steroidal inhibitor exemestane, not with letrozole or anastrozole. In boys, letrozole monotherapy is known to cause testosterone surges through gonadotropin rebound, but the new data confirm that GnRHa counteracts that mechanism when the two are combined in girls.

The study’s authors and outside observers alike stress the limits of the evidence. With 13 and 15 participants per group, a single center, no control arm, non-randomized group assignment, and only six months of observation, the results are preliminary rather than practice-changing. Gonadotropin levels were not measured in parallel, leaving some ambiguity about hypothalamic-pituitary dynamics, and inter-laboratory variability in LC-MS/MS assays complicates comparisons across studies. Because both drugs suppress estrogen signaling, the authors call for long-term monitoring of bone mineral density and growth. Still, within those boundaries, the study delivers what the field has lacked: a steroid-wide map showing that combined GnRHa and letrozole suppresses gonadal estrogens and androgens, spares the adrenal axis, and—at least over six months—does not push girls into androgen excess. Larger, longer trials will now be needed to determine whether this dual blockade can reliably bank centimeters of adult height without trading away long-term endocrine health.

Subject of Research: Endocrine effects of combined GnRHa and letrozole therapy on serum steroid profiles in girls with advanced bone age

Article Title: Effects of combined GnRHa and letrozole on serum steroid profiles in girls with advanced bone age

Article References: Zhang, X., Zhang, Y., Xing, Y., Yang, W., Qin, Y., Gao, X., Kong, X., Cai, S., Xue, G., Fan, X., Chen, M., Liu, Y., Chen, B., Yan, X., & Zhang, H. (2026). Effects of combined GnRHa and letrozole on serum steroid profiles in girls with advanced bone age. Frontiers in Endocrinology, 17, Article 1984633. https://doi.org/10.3389/fendo.2026.1984633

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1984633

Keywords: puberty, advanced bone age, GnRHa, letrozole, aromatase inhibitor, steroid hormones, LC-MS/MS, hyperandrogenism, rapidly progressive puberty, pediatric endocrinology, predicted adult height, bone age

The study, published in Pediatric Radiology, comes from Wuhan Children’s Hospital and its affiliated medical college, where a prospective cross-sectional trial enrolled 144 consecutive outpatients between September 2023 and September 2024. The cohort was deliberately balanced, with 72 boys and 72 girls, and covered an extraordinarily wide developmental window: boys ranged in chronological age from 0.2 to 17.8 years, and girls from 0.4 to 17.8 years. Every child underwent both a conventional left-wrist radiograph and a multi-joint ultrasound examination of the wrist, elbow, shoulder, and knee, allowing the researchers to compare their new ultrasound parameter directly against the established radiographic benchmark.

The technical heart of the method lies in a quantity the researchers call the ossification ratio, or OR. On an ultrasound image, each ossification center appears as a discrete, variably sized echogenic focus wrapped in a circumferential halo of hypoechoic cartilage. The sonographer measures the maximum epiphyseal diameter, denoted D, and the diameter of the ossification center within it, denoted d, along the longitudinal axis of the bone. The ratio of these two values, d divided by D, expresses how far that particular growth center has progressed toward full ossification. Because cartilage and bone reflect sound waves differently, ultrasound can visualize these structures even before they are visible on X-ray, and it does so without any radiation exposure at all.

In the study, seven ossification centers and epiphyses were evaluated: the proximal first metacarpal, the distal radius, the distal ulna, the capitellum of the humerus, the proximal radius, the proximal humerus, and the medial epicondyle of the femur. All scans were acquired with a GE LOGIQ e system equipped with a 7.0 to 12.5 MHz high-frequency linear-array transducer, following standardized probe positioning protocols adapted from previous work. A single musculoskeletal sonographer with eight years of pediatric experience performed every scan while remaining blinded to each participant’s chronological age and radiographic bone age, a design feature intended to eliminate expectation bias from the measurements.

The headline result is a correlation so strong it borders on the theoretical limit. When the researchers summed the ossification ratios of just three bones, the distal radius, the distal ulna, and the proximal radius, the resulting composite parameter correlated with radiographic bone age, as assessed by the Greulich-Pyle atlas, at a Pearson coefficient of 0.98 in boys and 0.97 in girls. For context, a coefficient of 1.0 would indicate perfect correlation. Strikingly, adding the ossification ratios of other bones did not improve the correlation, and summing the ratios of all seven assessed bones actually reduced it slightly, to 0.97 in boys and 0.96 in girls. The three-bone combination appears to hit a sweet spot of information density without diluting the signal.

Reproducibility, the other pillar of any clinical measurement, proved equally impressive. The researchers evaluated both intra-observer and inter-observer reliability using intraclass correlation coefficients, with two blinded orthopedic surgeons of differing experience levels repeating measurements on images two months apart. For the summed three-bone parameter, intra-observer reliability reached an ICC of 0.99, with a 95 percent confidence interval of 0.98 to 0.99, and inter-observer reliability was also 0.99. Both values were significantly higher than those of any single sonographic parameter. The first metacarpal, by contrast, showed the weakest correlation with bone age of any individual bone, at 0.80 in boys and 0.77 in girls, and the lowest inter-observer reliability at an ICC of 0.84, underscoring why the composite approach outperforms single-bone measurements.

The choice of the proximal radius as a component of the index was not arbitrary. Among all seven bones examined, the proximal radius showed the strongest individual correlation with radiographic bone age, at 0.95 in boys and 0.94 in girls. This aligns with earlier forensic and orthopedic research showing that proximal radial epiphyseal fusion scores correlate most strongly with chronological age among elbow landmarks. Ossification of the proximal radius begins between three and six years of age, with the ossification center fusing at a mean age of 14.8 years in boys and 12.5 years in girls, making it a powerful developmental marker across a broad age range. The humeral capitellum and proximal humerus, by contrast, showed only moderate correlations of roughly 0.81 to 0.87 and were excluded from the final index.

The practical numbers behind the new parameter are easy to grasp. In adolescents with a bone age of 14 to 16 years, boys in the study exhibited ossification ratios of 82.3 percent for the distal radius, 61.7 percent for the distal ulna, and 79.1 percent for the proximal radius, summing to 232 percent. Girls in the same bone-age group showed corresponding values of 90.1, 81.6, and 76.1 percent, for a total of 247.5 percent. By ages 16 to 18, individual ratios approached 80 to 90 percent and the composite sum reached 250 to 260 percent, reflecting near-complete ossification as skeletal maturity arrives. These reference values, organized by bone-age group and sex, give clinicians a lookup framework for translating an ultrasound measurement into an estimated skeletal age.

Why does eliminating radiation matter so much? Although the effective dose from a single wrist radiograph is very low, children with growth disorders, short stature, or idiopathic scoliosis frequently require bone age assessments multiple times per year over many years, and the cumulative exposure adds up. Magnetic resonance imaging can assess skeletal maturity without ionizing radiation, but its high cost, long scan times, and limited accessibility make it impractical for routine repeated use. Ultrasound, by contrast, is inexpensive, widely available, well tolerated by children, and fast. The new three-bone index offers a further logistical advantage over a previously proposed composite that combined the radius, ulna, and femur: it requires only a single upper-limb scan, eliminating femoral imaging and repeated repositioning, which shortens preparation time, reduces discomfort, and improves cooperation in young or restless patients.

The authors are candid about the limitations that must be addressed before the method becomes standard practice. The study was conducted at a single center and enrolled a nearly homogeneous population of Han children from central China, raising questions about generalizability to other ethnic and regional groups, particularly given evidence that the historical Greulich-Pyle atlas itself fits contemporary Asian children imperfectly. Adolescents with already closed epiphyses were excluded, and in children aged zero to two years the ossification centers are often absent or extremely tiny, which markedly reduces ultrasound measurement accuracy in that youngest group. Ultrasound is also inherently operator-dependent, and although standardized scan planes and numeric ratios mitigate variability, multi-center and multi-operator validation studies remain necessary. Even so, the combination of a 0.98 correlation, 0.99 reliability, zero radiation, and a single-limb scanning protocol makes this summed ossification ratio one of the most compelling candidates yet for bringing bone age assessment out of the X-ray room and into the pediatric clinic.

Subject of Research: A radiation-free ultrasound parameter for pediatric bone age assessment based on summed ossification ratios

Article Title: Summation of ossification ratios of the distal radius, distal ulna, and proximal radius: a novel parameter for pediatric bone age assessment

Article References: Zeng, F., Shen, X., Xiao, X., & Wu, X. (2026). Summation of ossification ratios of the distal radius, distal ulna, and proximal radius: a novel parameter for pediatric bone age assessment. Pediatric Radiology. https://doi.org/10.1007/s00247-026-06772-2

Image Credits: AI Generated

DOI: 10.1007/s00247-026-06772-2

Keywords: bone age, ultrasound, ossification ratio, pediatrics, Greulich-Pyle atlas, radiation-free imaging, distal radius, proximal radius, skeletal maturity, pediatric radiology, growth disorders, diagnostic imaging