Combo Therapy for Early Puberty Shows Hormone Safety in Six-Month Trial

For girls whose skeletons are maturing far too fast, every month of unchecked puberty can steal centimeters of future adult height. A new study from China now offers the most detailed hormonal safety picture yet for one of the most debated treatment strategies in pediatric endocrinology: combining a gonadotropin-releasing hormone agonist with the aromatase inhibitor letrozole. The research, published in Frontiers in Endocrinology, tracked nearly the full spectrum of steroid hormones in the blood of 28 girls over six months of therapy and found no sign of the feared complication—hyperandrogenism.

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