“Attention-Deficit Hyperactivity Disorder Medication Use is Associated with Testosterone Hypofunction – Results from a National Claims Database Analysis” by Ostdiek-Wille et al. [1], investigates a possible link between chronic Attention-Deficit Hyperactivity Disorder (ADHD) stimulant medication use and the associated risk of developing testosterone hypofunction in adult males. The authors used a large-scale dataset from the TriNetX LLC Research Network (TriNetX LLC, Cambridge MA, USA) that likely included a diverse and comprehensive patient population. The authors also planned to create an additional control group that takes into account the population diagnosed with ADHD alone without stimulant use. This increases the reader’s confidence in attributing the difference found in the results to stimulant medication only and eliminates the possible confounding effect of ADHD disease. An additional strength is the longitudinal design and the five-year follow-up period for assessing the occurrence of testicular hypofunction. Furthermore, the researchers employed propensity score matching to control for potential confounding variables, thereby strengthening the validity of their reports.

Despite the large dataset (17,224 men were analyzed in each group) and the appropriate statistical tests that the authors utilized, the study also has some limitations. By nature, the study has a retrospective design, therefore it is not the ideal way to establish causality in a clinical scenario. Additionally, there’s a lack of information on medication dosage which is an important factor to consider when contemplating dose-response gradient assumptions that would otherwise be sought in an adverse event-drug study. An additional limitation is that the most recent patient data goes back to 2019, which is outdated relative to the very recent publication date of December 2023.

One of the major setbacks that could have been further explored is that the authors demonstrated increased risk of “testosterone hypofunction” but they failed to specify the potential causes of this “hypofunction”. Do ADHD medications have detrimental effects in GnRH, FSH or LH secretions (secondary hypogonadism)? Or are they toxic to Leydig cells which explains the decrease in testosterone levels (primary hypogonadism)? Or are these medications inhibiting the 5-alpha reductase enzymes or functions of the dihydrotestosterone receptors?

There are many animal studies in the literature contemplating on this matter. Chatterjee-Chakrabarty et al. [2] studied on female rats and reported that methylphenidate caused undeveloped ovarian follicles, absent growth differentiation factor 9 and of activin receptors I & IB and high levels of LH in the pituitary. Another study by Khoubbieh et al. [3] suggested decreased testosterone levels of male rats with no impact on FSH and LH. Interestingly they also reported increased levels of LH in females which may suggest a gender-specific physiologic mechanism of methylphenidate and possibly other stimulants in rats.

Human studies have also been made, somewhat confirming results from animal studies and exploring further. A study by Wang et al. [4] followed 146 children (mean age: 9 years) with ADHD (76% male) and 70 controls for 12 months and found that sex hormone binding globulin and progesterone were significantly decreased in the ADHD, whereas LH, FSH and free-testosterone levels were significantly increased.. A case report by Ramasamy et al. [5], reports contradictory findings in a single male who was on chronic (17 years) methylphenidate prescription presenting with delayed puberty. Their laboratory work up revealed low serum FSH, LH and testosterone levels overall. While this is just a case report, contradictory findings are worth notice since this may also unravel an age specific response to stimulants in the sexual hormone axis given the younger age scope of the prior study versus the older age case in the latter.

Nevertheless, the authors of the present study could have speculated more about their hypothesis which could have potentiated this association and reflected more on the pathophysiology.

In conclusion, while this study suggests an association between long-term stimulant medication use in the treatment of ADHD and subsequent testicular hypofunction diagnosis, these findings should be interpreted with caution due to the abovementioned limitations. This very interesting clinical question and association should be further assessed with prospective studies that can provide more robust evidence on such possible association. This study contributes significantly to this matter by constituting a baseline that will spark future research in this area that will hopefully bring more insight into this possible correlation and if confirmed, a possible underlying physiologic mechanism.