AndroGel and Nicotine Interaction Profile: What TRT Patients Who Smoke Need to Know

Is There a Direct Interaction Between AndroGel and Nicotine?

Nicotine and testosterone gel are not known to interact directly. For a testosterone gel 1.62% product, the prescribing information's drug interactions section names insulin, oral anticoagulants and corticosteroids; nicotine and tobacco are not named there [1]. That label is not the AndroGel brand label, and topical testosterone products can differ in dose, strength and application instructions [1].

Nicotine is a substrate of CYP2A6 [6]. The enzyme induction that makes cigarette smoking change levels of other drugs is attributed to polycyclic aromatic hydrocarbons in tobacco smoke acting on CYP1A2; nicotine itself is not the inducer [2][3]. The smoking interactions that prompt dose changes are with CYP1A2 substrates such as caffeine, clozapine, olanzapine and theophylline [2][3].

The combined effect of smoking, nicotine replacement or vaping with testosterone gel has not been tested.

Does It Matter Where the Nicotine Comes From?

Nicotine replacement delivers nicotine without tobacco smoke. A review of smoking cessation states that the hepatic enzyme effect is not related to the nicotine component of tobacco, so nicotine replacement will not alter it [3]. When a person quits smoking, CYP1A2 induction reverses, which can raise levels of drugs such as clozapine and theophylline [3].

A nicotine patch uses the skin, but the gel's drug interactions section does not address transdermal nicotine [1]. The gel label says to apply it to clean, dry, intact skin of the shoulders and upper arms, and not to the abdomen, genitals, chest, armpits or knees [1].

Blood Pressure: Where Smoking and Testosterone Gel Overlap

Nicotine causes peripheral vasoconstriction, tachycardia and higher blood pressure, and tolerance does not develop to its catecholamine-releasing effects [4]. Testosterone raises blood pressure too: FDA's review of ambulatory blood pressure studies confirmed an increase with all testosterone products, class-wide [5].

In TRAVERSE, a randomized, double-blind, placebo-controlled trial of 5,246 men with hypogonadism and existing or high cardiovascular risk, mean systolic pressure rose 1.0 mm Hg on daily 1.62% testosterone gel versus a 0.5 mm Hg fall on placebo at 36 months [1][8]. That gel's prescribing information says it can increase blood pressure and is not recommended in men with uncontrolled hypertension, and it advises monitoring blood pressure periodically, especially in men with hypertension [1].

Hematocrit and Clot Risk

Testosterone raises hematocrit. In a network meta-analysis of 29 placebo-controlled randomized trials with 3,393 men, gel raised mean hematocrit by 3.0% versus placebo [7]. For the 1.62% gel, the label says to check hematocrit before starting, re-evaluate it 3 to 6 months after starting and then annually, and to stop therapy until hematocrit decreases to an acceptable concentration if it becomes elevated; it notes that an increase in red blood cell mass may increase the risk of thromboembolic events [1]. That section does not single out smokers [1].

Venous thromboembolism, including deep vein thrombosis and pulmonary embolism, has been reported with testosterone products. In TRAVERSE, VTE occurred in 1.7% of men on gel versus 1.2% on placebo [1]. Smoking increases blood coagulability, while transdermal nicotine does not appear to [9].

Does Smoking Change Testosterone Levels?

Observational data run against the idea that smoking lowers testosterone. In NHANES III (1,275 men), current smokers had higher geometric mean total testosterone than never-smokers (5.42 versus 5.26 ng/mL) and higher free testosterone (0.110 versus 0.104 ng/mL) [10]. In the Tromsø study (1,563 men), total and free testosterone were positively associated with tobacco consumption, and SHBG was positively associated with smoking [11]. Both studies measured the body's own testosterone, not levels achieved from a gel.

What Should a Smoker Using Testosterone Gel Watch For?

Nicotine and testosterone products can each raise blood pressure, but their combined effect has not been tested [4][5]. The testosterone gel 1.62% label says to measure blood pressure periodically and to check hematocrit on the schedule above [1]. It also says to evaluate leg pain, swelling, warmth and redness, or sudden shortness of breath, for a possible clot, and to monitor serum testosterone, PSA, hemoglobin, hematocrit, liver function tests and lipids periodically [1].