Testosterone Enanthate and Nicotine Interaction Profile

Is there a direct drug interaction between testosterone enanthate and nicotine?

The generic testosterone enanthate label's drug interaction section names four groups. Oral anticoagulants: C-17 substituted testosterone derivatives such as methandrostenolone have been reported to decrease the anticoagulant requirement, and the label says people taking oral anticoagulants require close monitoring when androgens are started or stopped [4]. Antidiabetic drugs and insulin: androgens may lower blood glucose and insulin requirements. ACTH and corticosteroids: an enhanced tendency toward edema. Oxyphenbutazone: elevated serum levels may result [4]. Smoking and nicotine do not appear in that list.

The liver-enzyme effect seen in smokers does not belong to nicotine. Polycyclic aromatic hydrocarbons in tobacco smoke are potent inducers of CYP1A1 and CYP1A2 [1][2], and a review of drugs affected by quitting concludes that the enzyme effect is not related to the nicotine component of tobacco, so nicotine replacement will not alter it [3]. One rat study found that a single nicotine dose induced CYP1A1 in lung tissue, 4.4-fold at 6 hours and 14.7-fold at 12 hours, back to near baseline by 24 hours, but did not significantly change liver CYP1A2 protein or mRNA [7]. Human relevance of that animal finding is unknown.

What the caffeine studies show about smoke and drug clearance

The size of a smoke-driven CYP1A2 effect is measured best with caffeine. In 13 smokers and 13 non-smokers, caffeine half-life was 3.5 hours in smokers versus 6.0 hours in non-smokers, and clearance was 155 versus 94 mL/kg/h [8]. When 12 heavy smokers who used 20 or more cigarettes a day stopped abruptly, caffeine clearance fell 36.1%, from 2.47 to 1.53 mL/min/kg, with an apparent half-life of the enzyme decline of 38.6 hours [9]. These are caffeine measurements; they do not give a testosterone clearance figure.

Blood pressure and blood vessels

The generic enanthate label carries an explicit warning: testosterone can increase blood pressure, which can increase cardiovascular risk over time. The label directs periodic blood pressure monitoring, especially in men with hypertension, and states that testosterone products are not recommended in patients with uncontrolled hypertension [4].

Nicotine acts on the same system from another direction: peripheral vasoconstriction, tachycardia and higher blood pressure, with no tolerance developing to its catecholamine-releasing effects [1].

Hematocrit and red cell mass

The enanthate label reports that androgens have been reported to stimulate red blood cell production by enhancing erythropoietic stimulating factor, and lists polycythemia among hematologic adverse reactions [4]. A network meta-analysis of 29 placebo-controlled randomized trials involving 3,393 men compared several testosterone formulations. In it, intramuscular testosterone enanthate or cypionate raised mean hematocrit by 4.0% (95% CI 2.9 to 5.1) compared with placebo, a significantly larger rise than the 1.4% seen with the patch [5].

Smoking raises red cell mass by a different route. A 1975 case series described five smokers whose red cell mass was high enough to create a diagnostic problem with polycythemia; their carboxyhemoglobin levels were sufficient to cause clinically significant hypoxemia, and in two of them the erythrocytosis improved when they stopped smoking [6].

The 2010 Endocrine Society guideline recommends against starting testosterone therapy in men with a hematocrit above 50% [10].

Venous thromboembolism

The enanthate label reports postmarketing cases of deep vein thrombosis and pulmonary embolism with testosterone products. It directs evaluation of leg pain, edema, warmth and erythema for DVT and of acute shortness of breath for PE, and says to discontinue testosterone enanthate and begin workup if a venous thromboembolic event is suspected [4].

Smoking carries its own association with VTE: a meta-analysis of 32 observational studies with 3,966,184 participants found a relative risk of 1.23 (95% CI 1.14 to 1.33) for current smokers versus never-smokers, rising 10.2% for every additional ten cigarettes per day [11].

Cardiovascular outcome trials of testosterone

In TRAVERSE, 5,246 men aged 45 to 80 with hypogonadism and existing or high cardiovascular risk received daily 1.62% testosterone gel or placebo gel. The primary cardiovascular endpoint occurred in 7.0% on testosterone versus 7.3% on placebo (hazard ratio 0.96), meeting noninferiority [12]. TRAVERSE tested testosterone gel, not testosterone enanthate injections. The generic enanthate label still contains the older paragraph saying that studies have been inconclusive for major adverse cardiovascular events and that some studies, but not all, have reported an increased risk [4].

An earlier trial in 209 men aged 65 and older with mobility limitations was stopped early after 23 men on testosterone gel versus 5 on placebo had cardiovascular-related adverse events; the authors cautioned that the small size and unique population prevented broader inferences [13].

How do testosterone esters and smoking compare on cholesterol?

Intramuscular testosterone esters were associated with a small decrease in HDL cholesterol. In a meta-analysis of 19 studies in 272 hypogonadal men given intramuscular testosterone esters, on average 179 mg every 16 days for 6 months, HDL cholesterol fell 4 mg/dL (95% CI minus 5 to minus 2) [14]. Smokers also had lower HDL cholesterol than nonsmokers: across 54 published studies, HDL was 5.7% lower, with a dose-response that reached 8.9% lower in heavy smokers [15]. That comparison cannot isolate nicotine's effect.

Does smoking change testosterone or estradiol levels?

Cross-sectional data point in an unexpected direction. In the Tromsø Study of 1,563 men, SHBG was positively associated with smoking (P=0.004), and both total and free testosterone were positively associated with tobacco consumption [16]. A cross-sectional study cannot establish cause, and it does not describe men injecting testosterone enanthate.

The estradiol question has only laboratory evidence. Aqueous extracts of cigarette smoke inhibited the conversion of androstenedione to estradiol in cultured human granulosa cells in a dose-dependent manner, the inhibition reversed completely when the extract was removed, and nicotine and anabasine also inhibited the enzyme in those cells [17]. Those are ovarian cells in culture, not fat or breast tissue in a man on testosterone replacement.

Nicotine replacement versus cigarettes: what actually changes

Switching from cigarettes to nicotine replacement removes the combustion products in smoke while nicotine exposure continues [2][3]. The review of drugs affected by quitting states that nicotine replacement will not alter the enzyme de-induction that follows quitting [3].

Nicotine itself still has cardiovascular actions: vasoconstriction, tachycardia and higher blood pressure [1]. A review of nicotine's cardiovascular toxicity concluded that nicotine may contribute to cardiovascular disease through sympathetic stimulation and catecholamine release, but that cigarette smoke contains many other cardiovascular toxins. It found that cigarette smoking increases blood coagulability while transdermal nicotine does not appear to, and that trials in stable coronary disease suggested nicotine did not raise cardiovascular risk, with replacement therapy at worst no more than smoking [18].