br Fig Predicted risk of severe postoperative adverse events
Fig. 2. Predicted risk of severe postoperative adverse events graded 3 þ according to Clavien-Dindo in relation to the preoperative change in serum testosterone. The curve describes the expected change in risk for severe postoperative adverse event with 95% confidence interval related to the preoperative change in serum testosterone.
significantly elevated preoperative LH/T-ratio in AEþ. The con-founding effect of age, ASA and BMI on the investigated association between primary testicular failure and postoperative AE is ex-pected as these factors are known to affect sex hormone levels and the hypothalamic-pituitary-gonadal axis .
The literature on the impact of endocrine testicular function on perioperative morbidity, while observed in diverse clinical/pre-clinical settings, seem limited in rectal cancer patients. Low T in patients undergoing abdominal surgery was a risk factor for post-operative complications in both sexes, and postoperative AE resulted in delayed recovery of T levels after surgery . Andro-gens have also been related to increased morbidity after trauma, with possible exception for thermal injuries . In critical illness, the hypothalamicepituitaryegonadal axis is suppressed, with decreased T and increased estradiol levels [33,34]. Estradiol has been described as a “marker of injury severity and a predictor of death in the critically injured patient”, with elevated levels in non-survivors of both sexes in an intensive care unit setting . In men, about 80% of the circulating estradiol comes from testos-terone, converted by the intracellular enzyme aromatase .
Circulating GW3965 and estradiol levels have been shown to be positively correlated . Primary testicular failure deprives the male body from its main anabolic hormone, tipping the scale to-ward a more catabolic state. It may further restrict the substrate, testosterone, for aromatase in these patients and result in decreased estradiol. However, the mechanisms behind the protec-tive effect of circulating T regarding postoperative severe adverse events in men treated with abdominal surgery have not been investigated in detail. In rat models, androgens act inhibitory on intestine perfusion and endothelial function, which may be re-flected in reduced healing of intestinal anastomoses . Mucosal wound healing is decreased with higher testosterone in younger men while estrogen is beneficial for cutaneous wound healing [38,39]. The potential adverse effect of T on anastomosis healing is in contrast to the beneficial effects described above. The present study is to small and includes all types of severe adverse events which precludes further inference on specific T actions. r> The results of this are based on a study population with het-erogeneity regarding type of RT and surgery for rectal cancer. However, the included study participants were not restricted on age, comorbidity, tumor distance from anal verge, TNM status or preoperative levels of sex hormones. There was a high proportion of APE, due to referrals to the tertiary centers. Setting the bar of severe postoperative events at Clavien-Dindo grade 3þ, minimizes the risk of missed information as the severity of those events forces inclusion in the study participants’ medical records. Sex hormone levels were assessed according to standardized guidelines to decrease the risk of information bias. The longitudinal regression analysis did not show association with known risk factors for severe postoperative AE, such as age and high ASA-score, which could be interpreted as type two errors as the study was not powered to do so [2,4]. The sample size was still large enough to detect the asso-ciations between T and LH/T-ratio and severe postoperative AE. Internal validity of this study is deemed adequate. External validity is affected by the study participants in general having more advanced, and lower situated, rectal cancer than in the comparable population, yielding a relatively higher TD resulting in a more se-vere primary testicular failure.