Puberty-Blocking Drug Reshapes Cortical Growth and Brain Metabolism in Animal Study

One of the most contested questions in modern medicine is what happens to the adolescent brain when puberty is chemically paused. Gonadotropin-releasing hormone agonists, or GnRHa, are widely prescribed to suppress the hormonal surge of puberty in adolescents with gender dysphoria, yet the neurobiological consequences of this intervention have remained largely unresolved. A new longitudinal study published in Translational Psychiatry now offers the most detailed multimodal picture to date of how pubertal endocrine suppression alters cortical development, using an animal model tracked with structural magnetic resonance imaging, diffusion imaging, and high-resolution nuclear magnetic resonance spectroscopy.

The research team, led by Alberto Marcos and Antonio Guillamon of the Universidad Nacional de Educación a Distancia in Madrid, together with colleagues at the Institute for Biomedical Research Sols-Morreale, the University of A Coruña, the University of Deusto, and the Biomedical Research Networking Centre on Rare Diseases, designed a translational experiment to isolate the effects of pubertal hormones on the developing brain. Animals received long-acting triptorelin, a GnRHa, beginning at the onset of puberty, and were then followed over time with repeated in vivo brain imaging. The design is significant because it is longitudinal: rather than comparing snapshots of different individuals, the researchers watched the same brains change, or fail to change, across the pubertal window.

Triptorelin works by flooding the pituitary’s GnRH receptors, which paradoxically desensitizes the hypothalamic-pituitary-gonadal axis and shuts down the release of luteinizing hormone and follicle-stimulating hormone. The result, confirmed in this study, is that testosterone was held at prepubertal levels throughout the treatment period. This pharmacological clamp allowed the investigators to ask a deceptively simple question: if the hormonal signal of puberty is removed, does the brain still follow its usual developmental script?

The structural imaging data delivered a clear answer: it does not, at least not entirely. Animals treated with triptorelin showed attenuated growth of bilateral neocortical volume, meaning the cortex, the brain’s wrinkled outer sheet responsible for sensory processing, executive control, and complex cognition, expanded less than expected during the pubertal period. Crucially, this effect was regionally specific rather than global. Total brain volume remained unchanged, indicating that the drug did not simply stunt overall brain growth or cause generalized tissue loss. Instead, the hormonal suppression selectively blunted the developmental expansion of the neocortex, the very structure that undergoes some of its most dramatic maturational change during adolescence.

This dissociation between total brain volume and cortical volume is scientifically important. Puberty is known to be a period of profound cortical reorganization, including ongoing myelination, synaptic pruning, and changes in the relative proportions of gray and white matter, all of which are sensitive to gonadal steroids. Estrogens and androgens bind to receptors distributed throughout the cortex and influence dendritic growth, spine density, and glial development. By removing the steroid signal at its source, triptorelin appears to have removed one of the drivers of cortical expansion, while leaving subcortical and overall brain growth comparatively spared. The finding provides causal, experimental support for the idea that pubertal hormones actively shape cortical trajectories rather than merely coinciding with them.

The second imaging modality, diffusion-weighted magnetic resonance imaging, probed the microstructure of brain tissue by measuring how water molecules move through it. In the triptorelin-treated animals, diffusivity indices were increased in ways consistent with altered microstructural maturation. In the developing brain, falling diffusivity is typically interpreted as a signature of tissue organization: as axons become myelinated, as cells pack more densely, and as membranes proliferate, water movement becomes more constrained. Elevated diffusivity during a period when it should normally be declining therefore suggests that the normal cellular and architectural maturation of the tissue was delayed, slowed, or rerouted. The authors interpret these changes as evidence of altered microstructural development, a conclusion that dovetails with the cortical volume findings and points to the same underlying biology viewed through a different lens.

Perhaps the most novel contribution of the study comes from its metabolic arm. Using ex vivo proton high-resolution magic angle spinning spectroscopy, a technique that can quantify the chemical contents of tissue samples with exquisite sensitivity, the researchers examined the neurochemical profile of the treated brains. Long-term triptorelin treatment produced coordinated metabolic changes, most notably reduced levels of creatine and glutamine. Multivariate analyses, which look for patterns across many metabolites simultaneously, further identified creatine, glutamine, glutamate, and myoinositol as the key contributors separating the treated animals from controls.

Each of these metabolites tells a story. Creatine reflects the brain’s energy buffering system, serving as a reservoir for phosphate bonds that stabilize ATP supply; reduced creatine can indicate shifts in energy metabolism or in the density of metabolically active tissue. Glutamine and glutamate sit at the heart of the glutamate-glutamine cycle, the metabolic partnership between neurons and astrocytes that recycles the brain’s principal excitatory neurotransmitter; alterations in this pair suggest changes in excitatory neurotransmission or glial metabolism. Myoinositol, an osmolyte and glial marker, is often read as an index of astrocytic state and membrane-related signaling. That all four moved together, in a coordinated pattern that reliably distinguished treated from untreated animals, indicates that pubertal hormone suppression does not merely change brain shape but reconfigures the underlying neurochemistry of the developing cortex.

The authors frame their findings as providing a translational framework for interpreting structural and functional neuroimaging results in adolescents undergoing GnRHa treatment. This is a careful and consequential claim. Human studies of adolescents on puberty blockers have produced findings that are sometimes difficult to interpret, in part because it has been unclear which brain changes reflect the underlying condition, which reflect normal development, and which might reflect the treatment itself. By establishing, in a controlled animal model, that suppressing pubertal hormones attenuates cortical growth, alters tissue microstructure, and shifts the metabolic profile of the brain, the study supplies a mechanistic reference point against which human imaging findings can be benchmarked.

The work also carries broader implications for developmental neuroscience. Puberty is increasingly recognized as a second major window of synaptic and structural plasticity, comparable in importance to early postnatal development, and hormones are believed to be among its principal architects. This study demonstrates experimentally that removing the gonadal signal during this window leaves a measurable, multimodal imprint on the brain: smaller cortical volumes, altered diffusion characteristics, and a distinct neurochemical signature. It does not, and cannot, speak directly to the reversibility of these effects, to their functional or behavioral consequences, or to outcomes in humans, and the authors are appropriately measured in their interpretation. What it does establish is that the question is no longer speculative. Pubertal endocrine suppression measurably reshapes cortical developmental trajectories, and the tools now exist to map exactly how. As GnRHa treatment continues to be prescribed to adolescents around the world, studies of this kind, combining longitudinal imaging with molecular-level metabolic profiling, will be essential for building an evidence base robust enough to guide both clinical practice and the families navigating it.

Subject of Research: Effects of pubertal hormone suppression with GnRHa on cortical structure and brain metabolism

Article Title: Cortical and metabolic brain development during pubertal hormone suppression

Article References: Marcos, A., González-Alday, R., Rodríguez del Cerro, M. C., Fernandez, R. M., Pásaro, E., Arias-Ramos, N., Zubiaurre-Elorza, L., López-Larrubia, P., & Guillamon, A. (2026). Cortical and metabolic brain development during pubertal hormone suppression. Translational Psychiatry. https://doi.org/10.1038/s41398-026-04505-5

Image Credits: AI Generated

DOI: 10.1038/s41398-026-04505-5

Keywords: puberty blockers, GnRHa, triptorelin, cortical development, magnetic resonance imaging, diffusion imaging, MR spectroscopy, brain metabolism, glutamate, creatine, gender dysphoria, adolescent neurodevelopment