AndroGel Pharmacokinetics: How Testosterone Gel Is Absorbed, Distributed, Metabolized, and Excreted

How much of an AndroGel dose gets into the blood?

The AndroGel 1% label describes a hydroalcoholic formulation that dries quickly on the skin, with the skin serving as a reservoir for sustained release of testosterone into the circulation; approximately 10% of the testosterone applied is absorbed [4]. It says AndroGel 1% provides continuous delivery for 24 hours after a single application to intact, clean, dry skin of the shoulders, upper arms and/or abdomen [4]. In a pharmacokinetic study of 227 hypogonadal men, 50 mg of testosterone in 5 g of gel delivered about 5 mg a day and 100 mg in 10 g delivered about 10 mg a day, and roughly 9 to 14% of the testosterone applied was bioavailable [1].

The label notes that topical testosterone products may have different doses, strengths or application instructions that may result in different systemic exposure, and that dosage and administration for AndroGel 1% differ from AndroGel 1.62% [4].

How quickly do serum levels rise and stabilize?

In a study with AndroGel 1% 100 mg, all patients showed an increase in serum testosterone within 30 minutes, and eight of nine had a serum testosterone concentration within the normal range by 4 hours after the first application [4]. Serum concentrations approximate steady state by the end of the first 24 hours and are at steady state by the second or third day of dosing [4]. In the 227-man study, serum testosterone rose rapidly into the normal adult male range on day 1, and an earlier study the investigators cite showed steady state 48 to 72 hours after the first application [1].

After that the profile stayed flat. The label says serum testosterone concentrations are generally maintained within the eugonadal range at 30, 90 and 180 days, with an average daily concentration on day 30 of 566 (plus or minus 262) ng/dL on 50 mg and 792 (plus or minus 294) ng/dL on 100 mg [4]. In the 227-man study, total and free testosterone pharmacokinetics were very similar on days 30, 90 and 180 [1]. The label reports no differences in average daily serum testosterone at steady state based on age, cause of hypogonadism or body mass index [4].

Dose changes do not scale cleanly. In the 227-man study, moving men from 50 mg to 75 mg a day did not significantly raise the 24-hour average serum testosterone, while moving from 100 mg down to 75 mg brought most men back into the normal range [1]. The 24-hour average was highest in the 100 mg group, 1.4-fold higher than in the 50 mg group and 1.9-fold higher than in men wearing a patch delivering 5 mg a day [1].

In a separate year-long trial, 790 men aged 65 or older with serum testosterone below 275 ng/dL were assigned to testosterone gel or placebo gel, and treatment raised serum testosterone to the mid-normal range for men aged 19 to 40 [5].

Where testosterone goes once it is in the blood

The AndroGel 1% label says circulating testosterone is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin: approximately 40% is bound to SHBG, 2% remains unbound (free), and the rest is bound to albumin and other proteins [4]. In the 227-man study, free testosterone levels paralleled total testosterone and the percentage of free testosterone did not change with transdermal treatment [1]. The label reports that SHBG decreased very slightly (1 to 11%) during treatment [4].

How testosterone is broken down

Two conversions matter. 5-alpha-reductase turns testosterone into dihydrotestosterone, a more potent androgen [2]. Aromatase converts androgens to estrogens, and 17-beta estradiol is measurable in the blood of men [3]. The AndroGel 1% label says testosterone is metabolized to various 17-keto steroids through two pathways and that its major active metabolites are estradiol and DHT [4]. DHT concentrations increased in parallel with testosterone, with a mean steady-state DHT/T ratio over 180 days of 0.23 to 0.29 on 50 mg a day and 0.27 to 0.33 on 100 mg a day [4]. Serum estradiol increased significantly within 30 days of starting treatment and stayed within the normal range for eugonadal men [4].

Gynecomastia shows up in the label's adverse reaction table: 1% of men at 50 mg, 0% at 75 mg and 3% at 100 mg in the 180-day controlled study [4]. Estrogens stimulate growth of breast tissue and androgens inhibit it, and most cases of gynecomastia result from deficient androgen action or excessive estrogen action [6].

How testosterone is eliminated

The label says there is considerable variation in the half-life of testosterone concentration reported in the literature, ranging from 10 to 100 minutes. It says about 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites, about 6% of a dose is excreted in the feces, mostly unconjugated, and inactivation of testosterone occurs primarily in the liver [4].

When AndroGel 1% treatment is discontinued after achieving steady state, the label says serum testosterone concentrations remain in the normal range for 24 to 48 hours but return to their pretreatment concentrations by the fifth day after the last application [4].

What changes how much is absorbed

Application site is specified rather than left to preference. The label directs application to clean, dry, healthy, intact skin of the upper arms and shoulders and/or abdomen, limited to the area a short-sleeve T-shirt would cover, and not to the genitals, chest, armpits, knees or back [4]. It gives a starting dose of 50 mg once daily in the morning, adjusted to 75 mg or 100 mg if serum testosterone is below the normal range [4]. The label advises avoiding swimming or showering for at least 5 hours after application and says the gel is flammable until dry [4].

Can testosterone transfer from your skin to someone else?

The AndroGel 1% label carries a boxed warning on secondary exposure. Virilization has been reported in children exposed to testosterone gel, with signs including enlargement of the penis or clitoris, pubic hair, increased erections and libido, aggressive behavior and advanced bone age, and children should avoid contact with unwashed or unclothed application sites [4]. In most reported cases the signs regressed once exposure stopped; in a few, enlarged genitalia did not fully return to age-appropriate size [4].

Transfer was measured in a study of 38 couples. Two to 12 hours after the men applied 100 mg of AndroGel 1%, the couples engaged in daily 15-minute sessions of vigorous skin-to-skin contact; all unprotected female partners had a serum testosterone concentration more than 2 times their baseline value at some time during the study, and when a shirt covered the application sites, transfer from the men to the female partners was completely prevented [4].