Table 5 Pros and cons of GnRH agonist in gender dysphoria

PROS

 • Alleviation of distress associated with puberty-induced physical changes, facilitating a calmer exploration of gender identity.

 • Prolongation of the assessment period and enhancement of diagnostic precision, allowing therapists to engage in ongoing psychological dialogue with adolescents, exploring all potential outcomes without the disruptive influence of pubertal changes. Moreover, this approach grants adolescents with gender dysphoria (GD) the opportunity to contemplate their gender identity and come to a decision regarding future gender-affirming interventions.

 • Prevention of irreversible physical changes that cause significant distress, obviating the need for potential future invasive medical and surgical procedures to align physical appearance with gender identity.

 • Reversibility of treatment: GnRH agonist (GnRHa) therapy does not constitute gender reassignment as it does not alter the body but maintains it in a neutral state. If GD resolves or the individual opts against gender transition, GnRH agonist therapy can be discontinued, allowing resumption of pubertal development aligned with biological sex.

 • Mitigation of adolescents seeking self-administration of hormones via alternative and hazardous methods (e.g., online medication purchases), thereby circumventing specialist supervision.

 • Attainment, upon reaching adulthood, of physical characteristics more congruent with the affirmed gender identity.

CONS

 • The utilization of triptorelin may impact the cognitive maturation of adolescents. Experimental models suggest that sex steroids play a role in promoting cognitive maturity and are vital for normal brain development [8,9,10]. However, puberty suppression (PS) with GnRH agonists does not appear to have a detrimental effect on higher-order cognitive processes [11]. Moreover, the association between pre-treatment IQ and post-treatment educational achievement in transgender adolescents undergoing gender-affirming hormone therapy (GAHT), including GnRHa, seems comparable to that of the general population [12].

 • The safety profile of puberty inhibitors is well-established in the context of early puberty. However, robust evidence regarding their safety in individuals with GD, including potential effects on fertility, remains lacking. Even if puberty is temporarily halted and subsequently allowed to progress, significant impacts on subsequent sexual function may arise, as the timing of hormone exposure during the peripubertal period is critical in determining adult sexual function [13].

 • Psychological outcomes following GnRHa treatment may vary [103]. Moreover, there is limited knowledge about the use of GnRHa to halt normally timed puberty in youth with GD, as there are no long-term, longitudinal studies addressing this indication.

 • A potential reduction in bone mineral density among subjects treated with GnRHa cannot be dismissed [72]. Various studies have suggested that interrupting puberty may disrupt the anticipated trajectory of bone mass accumulation during adolescence. The extended clinical implications of failing to achieve typical bone mass accrual remain uncertain [14, 15].

 • Possible short-term side effects of GnRHa treatment may include increased fat mass and body mass index, as well as reduced lean mass [16, 87] potentially impacting cardiometabolic health [105, 106].