Context. A reliable form of androgen substitution therapy regarding kinetics, tolerance and restoration of androgenicity is paramount in hypogonadal men. Intramuscular injection of the long-acting ester testosterone undecanoate (TU) offers a new modality.

Objective. To assess safety of TU regarding metabolic and pharmacogenetic confounders.

Design. Longitudinal one-arm open observation trial. A minimum of 5 individual assessments was a prerequisite. Putative modulators of safety parameters entering regression models were: nadir and/or delta total testosterone concentrations, body mass index (BMI), androgen receptor (AR) gene CAG repeat length and age.

Setting. Andrological outpatient clinic.

Patients. 66 hypogonadal men, mean age 38 ± 9.9 years.

Main outcome measures. 515 data time points each related to prostate, erythropoeisis, lipoproteins and circulation during 118 treatment-years with 1000 mg TU at 10 to 14-week intervals.

Results. Testosterone substitution resulted in significant decrements of serum levels of LDL- cholesterol, resting diastolic and systolic blood pressure and heart rate. Erythropoeisis was stimulated and concentrations of HDL-cholesterol increased. Parameters remained stable after 4 injections. No adverse effects regarding the prostate were observed. Significantly increased hematocrit > 50% was predicted by enhanced androgen action (shorter AR CAG repeats/higher testosterone levels). However, also insufficient androgen action (longer AR CAG repeats/lower testosterone levels) caused pathological safety parameters (high blood pressure, adverse lipid profiles). In addition, a BMI 30 kg x m^-2 represents a clinically relevant factor for the occurrence of all pathological safety parameters. Risk calculations for obese patients and non-linear pharmacogenetic models to tailor androgen substitution are presented.

Conclusions. Testosterone substitution with intramuscular TU is generally well tolerated. Modifications of androgen action are due to both AR CAG repeats and testosterone levels. Adverse observations are mostly seen in obese patients.