AndroGel Transfer to Women and Children: Alternatives Without This Side Effect

What the boxed warning says

The testosterone gel 1% prescribing information opens with a boxed warning headed Secondary Exposure to Testosterone. It states that virilization has been reported in children who were secondarily exposed to testosterone gel, and that children should avoid contact with unwashed or unclothed application sites in men using the gel [1].

The label's warnings section lists the reported signs as enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases these signs regressed with removal of the exposure. In a few cases, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronological age. The label adds that the risk of transfer was increased in some cases by not adhering to the precautions for appropriate use [1].

This is the Teva testosterone gel 1% label, not AndroGel's. The 1% label says its dosage and administration differ from testosterone gel 1.62%, and that topical testosterone products may have different strengths or application instructions that result in different systemic exposure [1].

Pregnancy and other adults in the household

Testosterone gel 1% is contraindicated in women who are pregnant, and the label states it can cause virilization of the female fetus. It says pregnant women need to be aware of the potential for transfer of testosterone from men treated with the gel [1]. For adult women, the label lists changes in body hair distribution, a significant increase in acne, or other signs of virilization as possible signs of secondary exposure [1].

How much testosterone stays on the skin

A small study of a 2.5% testosterone gel measured the residue directly. In 12 healthy male volunteers, about 60% of the applied testosterone could still be recovered from the skin 8 hours after application; when the skin had been washed with water, only about 14% was recovered [6].

The same report ran a contact experiment in 28 men whose own testosterone production had been suppressed with norethisterone enanthate. After intense skin contact with the forearm of a volunteer who had applied the gel, their serum testosterone did not rise, and the authors concluded that contamination of a second person, especially a female or prepubertal one, seemed very unlikely for that gel [6]. Separately, the testosterone gel 1% label reports virilization in children after secondary exposure [1].

Injections: no gel on the skin

Testosterone cypionate and enanthate injections go into muscle, and the Xyosted autoinjector delivers enanthate subcutaneously in the abdomen, so no gel sits on the skin surface.

A 2009 review of testosterone gel says injectable testosterone esters are associated with peaks and troughs with each dose, that gels are as efficacious as injectable forms in their effects on sexual function and mood, and that the risk of polycythemia is lower with gels than with injectables. The same review says interpersonal transfer is a concern with gels if appropriate precautions are not taken [7].

A long-interval injection also exists. In a 24-week, single-arm, open-label study of 130 hypogonadal men, testosterone undecanoate 750 mg given intramuscularly at weeks 0, 4 and 14 produced a mean average serum testosterone of 494.9 ng/dL across the 70-day interval after the third injection, with 94% of patients inside the 300 to 1,000 ng/dL range [3].

Nasal gel and pellets

Testosterone nasal gel is applied inside the nostrils. The 90-day randomized, open-label, dose-ranging trial enrolled 306 men and used 11 mg per dose (5.5 mg per nostril), twice or three times daily, for total daily doses of 22 mg or 33 mg. At day 90, 200 of 273 men in the intent-to-treat group (73%) had an average testosterone concentration in the normal range. The report describes avoidance of secondary transference as an advantage of the nasal route; the trial did not directly test transfer to household contacts [2].

Testosterone pellets are an implantable form rather than a topical one. In a retrospective single-center review of 178 men followed for 3 years, erythrocytosis (hematocrit above 50%) occurred in 35.1% of men on pellets [8].

What does not change when the transfer risk goes away

Hematocrit. A network meta-analysis of 29 placebo-controlled randomized trials covering 3,393 men found that every testosterone formulation raised mean hematocrit, by 4.0% with intramuscular enanthate or cypionate and by 3.0% with gel; the difference between those two was not significant [5]. In the 178-man review, erythrocytosis occurred in 66.7% of men on injectable testosterone versus 12.8% on gels, though the injection group was younger (mean 42.5 versus about 54 years) with a higher baseline hematocrit and the study was not randomized [8].

Blood pressure. FDA reported that the ambulatory blood pressure studies it required confirmed an increase in blood pressure with all testosterone products, class-wide [4].