DISCUSSION
Men receiving exogenous TTH may experience side effects, including elevations in E2 levels, which may impact libido and cause gynecomastia. AZ is a safe and effective option for men with elevated E2. Our study evaluated men with TD in which a small subset had elevated E2 requiring intervention (AZ). Overall, we demonstrated a statistically significant reduction in E2 levels to normal physiologic levels with maintenance of T levels, but were unable to identify predictors for men most likely to respond to therapy.
Only 2.6% of men had E2 which warranted treatment with AZ. AZ has been used in men with TD in an effort to reduce the conversion to E2 to T while maintaining fertility.6 We employed a cut-off for the use of AZ, but the literature does not support a clear cut-off or indication for the initiation of estradiol-lowering therapy.7 Similar to our series, in a national sample, 3.5% (1,200/34,016) of men were placed on an AI.7
Men in our series receiving AZ, and therefore with higher E2, had greater rates, although not statically significant, of OSA. Obesity is a common risk factor for OSA, and men with obesity have increased physiologic levels of aromatase therefore increasing the conversion of T to E2.8, However, while not statistically significant, BMI of the AZ+ group was greater than the AZ- group. Obese men on TTH for TD may warrant closer observation of E2 levels
AZ- in our series had statistically significant use of topical TTH, whereas AZ+ men had statistically significantly greater proportions of intramuscular TTH and lower topical TTH use. This reflects some data which suggested that statistically significant increases in E2 were observed in men on injectable therapy 3 months after initiating TTH.9
Almost all men had recovery of E2 within normal levels (<40 pg/mL) with simultaneous maintenance of a serum T. This highlights the importance of appropriate regulation given the important physiological processes regulated by E2.5 While AZ is commonly used as an adjunctive therapy to increase T levels in men whom spermatogenic preservation is important and therefore avoidance of exogenous testosterone is crucial, in our series AIs did not impact testosterone levels. However, other studies suggest coadministration of an AI with exogenous TTH increases serum T.10 All of these received T pellets, suggesting a differential response based on TTH type.
No statistically significant predictors were found in our series to predict E2 recovery in men on AZ. To the best of our knowledge, this has not been previously reported. Furthermore, limited data exists with respect to a clear cut-off or consideration of response to AZ, and therefore our composite cut-off was suggested based on a clinically meaningful response.
The clinical implications of AZ in men with elevated E2 while on TTH are evident. Given the importance of E2 in male physiology and the impact of TTH on E2, careful monitoring by practitioners providing exogenous therapy is critical.
Limitations to our study include the retrospective design, but all data were collected prospectively. The study does have limited external validity as data were obtained from a single institution and single provider. We also did not discern nor account for possible physiologic differences in men on AZ on clomiphene citrate versus those on exogenous TTH. We were not able to validate if AZ or clomiphene citrate did not interfere with E2 immunoassay testing. Furthermore all men did not have measurements completed by LCMS but were included in order to obtain a reasonable sample size. A sensitivity analysis only using LCMS measurements revealed similar results (Supplementary Table 3). Finally, while the number of men on AZ in our series is small which limited statistical analysis for predictors of estradiol recovery, the total number of men assessed with TD was significant and over a large period of time.
CONCLUSION
In patients with elevated E2 on TTH, using AZ 0.5mg TID, results in a statistically significant reduction in E2, with 76% completely normalized with simultaneous maintenance of T levels. No statistically significant predictors were found for recovery of E2 levels. Further research and larger studies are warranted.
