What are the dangers and adverse effects of Gonadotropin-Releasing Hormone (GnRH) agonists, also known as puberty blockers?

From the Guidelines

The use of Gonadotropin-Releasing Hormone (GnRH) agonists, also known as puberty blockers, can have several potential dangers and adverse effects, including reduced height velocity and potentially reduced peak bone mass accrual, which must be carefully weighed against the psychological benefits for those with gender dysphoria or other conditions requiring pubertal suppression. When considering the use of GnRH agonists, it is essential to be aware of the potential risks, including decreased bone mineral density, which may not fully recover after treatment ends, potentially leading to increased fracture risk later in life 1. Some of the adverse effects of GnRH agonists include:

• Reduced height velocity
• Potentially reduced peak bone mass accrual
• Emotional changes, including increased depression or anxiety
• Physical effects, such as weight gain, decreased muscle development, and delayed growth plate closure
• Fertility impacts, which may affect future reproductive capacity, though this is generally considered reversible
• Cardiovascular effects, including changes in lipid profiles and potential impacts on heart health. It is crucial to regularly monitor patients on GnRH agonists, including bone density scans, psychological evaluations, and hormone level testing, to minimize the risks and ensure the best possible outcomes 1. The most recent and highest quality study, published in 2024, highlights the importance of careful consideration and monitoring when using GnRH agonists, as they have been shown to reduce suicidality and improve psychological function in trans adolescents 1. In contrast to older studies, such as the 2019 study on bone health in childhood cancer, which reported significant bone loss in both the trabecular and cortical bones after standard GnRH agonist treatment regimens of 6 months 1, the most recent evidence suggests that GnRH agonists can be a valuable treatment option for those with gender dysphoria or other conditions requiring pubertal suppression, when used carefully and with regular monitoring.

From the FDA Drug Label

Patients with known allergies to benzyl alcohol, an ingredient of the drug's vehicle, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site. Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. Based on findings in animal studies, leuprolide acetate may cause fetal harm when administered to a pregnant woman Androgen deprivation therapy may prolong the QT/QTc interval

The dangers and adverse effects of GnRH agonists include:

• Hyperglycemia and an increased risk of developing diabetes
• Increased risk of developing myocardial infarction, sudden cardiac death, and stroke
• Fetal harm when administered to a pregnant woman
• Prolongation of the QT/QTc interval
• Hypersensitivity reactions, usually local, in the form of erythema and induration at the injection site 2

From the Research

Dangers and Adverse Effects of GnRH Agonists

The use of Gonadotropin-Releasing Hormone (GnRH) agonists, also known as puberty blockers, has been associated with several dangers and adverse effects, including:

• Known serious side effects with uncertainty about their long-term use 3
• No improvement in mental health 3
• Potential impact on bone mineral accrual, with reduced bone mineral density (BMD) and bone mineral apparent density (BMAD) z-scores 4
• Changes in body composition, including decreased lean body mass percentage and increased fat percentage 5
• Potential effects on brain function and mental health, including increased hyperlocomotion, changes in social preference, and increased neuroendocrine stress responses in male mice, and increased hyponeophagia and despair-like behavior in female mice 6
• Potential limitations on future fertility and surgical options, including genital gender affirmation surgery (GAS) and chest reconstruction 7

Physical Health Effects

The physical health effects of GnRH agonists include:

• Suppression of gonadotropins and sex steroid levels 5
• Decrease in testicular volume in male-to-female subjects 5
• Regression of breast development in female-to-male subjects 5
• Decrease in height SD score and lean body mass percentage, and increase in fat percentage 5
• Potential impact on bone health, including reduced BMD and BMAD z-scores 4

Mental Health Effects

The mental health effects of GnRH agonists include:

• No improvement in mental health 3
• Potential effects on brain function and mental health, including increased hyperlocomotion, changes in social preference, and increased neuroendocrine stress responses in male mice, and increased hyponeophagia and despair-like behavior in female mice 6
• Potential impact on stress regulation and neural activity 6

Long-Term Consequences

The long-term consequences of GnRH agonist treatment are not well understood, but may include:

• Irreversible consequences, such as infertility and limitations on future surgical options 3, 7
• Potential impact on bone health and fertility 4, 7
• Uncertainty about the long-term effects on mental health and brain function 3, 6