AndroGel Pharmacogenomics: How Genetic Variability Shapes Testosterone Gel Response

The short answer

The androgen receptor, the enzyme that makes DHT, the enzyme that clears testosterone and the enzyme that makes estradiol all have common gene variants, so differences in response between men are plausible [1][5][3][6]. The studies behind those variants were not done in men using AndroGel. The generic 1.62% gel label says to confirm low testosterone with morning serum testosterone on at least two separate days, start 40.5 mg once daily, and adjust by serum testosterone [4]. Its dosing instructions give no genotype-based dose [4].

What the androgen receptor CAG repeat shows

The AR gene contains a CAG repeat, and repeat length modifies androgen receptor transcriptional activity [2]. In a one-arm study of 66 hypogonadal men given intramuscular testosterone undecanoate, shorter AR CAG repeats combined with higher testosterone levels predicted hematocrit above 50%; longer repeats combined with lower testosterone levels were associated with high blood pressure and adverse lipid profiles [1]. That study used injections, not gel. A review says the CAG-related differences in androgen action may be small and that it remains to be shown whether the test is useful for individual patients [2].

SRD5A2, DHT and prostate data

SRD5A2 encodes 5-alpha reductase type 2, which converts testosterone to DHT. The V89L variant reduces 5-alpha reductase activity in vivo and is particularly common among Asians [5]. A49T is a different variant. In 265 men with prostate cancer, A49T was associated with extracapsular disease (OR 3.16, 95% CI 1.03 to 9.68) and higher pathological stage (OR 3.11, 95% CI 1.01 to 9.65), while V89L showed no association with the tumor characteristics studied [7]. That is a prostate cancer study, not a testosterone replacement study.

UGT2B17 and testosterone excretion

UGT2B17 is a glucuronidation enzyme involved in androgen metabolism, and a common deletion removes the gene. In 122 Swedish and 74 Korean healthy men, the deletion/deletion genotype was present in 9.3% of Swedish men and 66.7% of Korean men; all deletion/deletion men had no or negligible urinary testosterone [3]. Swedish men also had higher serum testosterone than Korean men [3]. This is evidence about urinary excretion and population differences, not about how an individual man clears a 40.5 mg gel dose.

CYP19A1 and estradiol

CYP19A1 encodes aromatase. The available CYP19A1 data are from 1,975 postmenopausal women, not men on testosterone. Two variants, rs10046 and the (TCT) repeat, were associated with estradiol level and the estradiol-to-testosterone ratio; rs10046 explained 1.6% of the variance in that ratio [6]. That is a small share of the variance, and it does not establish an effect on gynecomastia or estradiol in men using gel. Gynecomastia reflects excess estrogen action relative to androgen action in breast tissue [8].

What monitoring uses

The label's dosing instructions use serum testosterone [4]. It also says to monitor serum testosterone, PSA, hemoglobin, hematocrit, liver function tests and lipids periodically, and that checking hematocrit before treatment, again 3 to 6 months after starting and then annually would be appropriate [4]. It says testosterone gel 1.62% can increase blood pressure and is not recommended in men with uncontrolled hypertension [4].