Vaginal Estradiol and Nicotine Interaction Profile

What do the estradiol labels say about smoking?

The vaginal product label used here is Estradiol Vaginal Cream 0.01%; vaginal tablets, rings and inserts are separate products with their own labeling. That cream label warns that systemic absorption may occur and that the warnings, precautions and adverse reactions tied to oral estrogen treatment should be taken into account [4].

The cream label lists tobacco use among the risk factors for arterial vascular disease [4]. The oral estradiol tablet label uses the same wording [5].

The CYP3A4 sections of the estradiol labels list St. John's wort, phenobarbital, carbamazepine and rifampin as inducers that may lower estrogen concentrations and reduce effect, and erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice as inhibitors that may raise them. Smoking and nicotine are not named there [5][6].

What does cigarette smoke do to estradiol?

One human study measured estradiol 2-hydroxylation in 14 premenopausal women who smoked at least 15 cigarettes a day and in 13 nonsmoking controls: 53.6% versus 35.1%, a rise of about 50% (P<0.001) [7]. That pathway produces 2-hydroxyestrogens, which have minimal peripheral estrogenic activity and are cleared quickly from the circulation [7].

The induction itself is credited to polycyclic aromatic hydrocarbons in tobacco smoke, which are potent inducers of CYP1A1 and CYP1A2 and possibly CYP2E1 [1][2].

A 1990 study looked at postmenopausal women. Baseline estrone, estradiol, estrone sulfate and estrone glucuronide were similar in smokers and nonsmokers, but unbound estradiol was significantly lower in the smokers (P<0.05) and sex-hormone-binding-globulin binding capacity was higher (P<0.001) [10]. After 1 or 2 mg of oral micronized estradiol, estrone and estradiol profiles were similar between groups and unbound estradiol was still significantly lower in smokers [10]. In that oral estradiol study, the smoking-related changes did not appear to require a higher dose to reach physiologic estrogen levels; the study did not test vaginal estradiol [10].

Does any of this apply to a vaginal product?

Absorption from a vaginal tablet was measured in 58 postmenopausal women with vaginal atrophy. Mean 24-hour average plasma estradiol was 9.39 pg/mL with the 10 mcg tablet and 19.84 pg/mL with the 25 mcg tablet on day 1, 6.56 and 18.29 pg/mL on day 14, and 4.64 and 9.41 pg/mL on day 83 [8]. With the 10 mcg dose, mean levels stayed inside the published postmenopausal reference range from the first day, which the study described as minimized estradiol absorption [8].

No study has measured estradiol levels, symptom response or endometrial change from a vaginal estradiol product in smokers compared with nonsmokers. How much the metabolic differences above would matter at these low circulating levels is therefore unmeasured.

Does nicotine itself change anything?

Nicotine replacement is a different exposure from smoke. A review of smoking cessation states that the enzyme effect is not related to the nicotine component of tobacco and that nicotine replacement will not alter it [3]. The combustion products, the polycyclic aromatic hydrocarbons, are what induce CYP1A1 and CYP1A2 [1][2].

Animal work adds a small caveat. A single 2.5 mg/kg subcutaneous dose of nicotine in rats raised lung CYP1A1 activity 4.4-fold at 6 hours and 14.7-fold at 12 hours, back near control by 24 hours, but did not significantly change liver CYP1A2 protein or its mRNA [11]. Human relevance is unknown.

On the cardiovascular side, nicotine may contribute to cardiovascular disease through sympathetic stimulation and catecholamine release [12]. A review of nicotine's cardiovascular toxicity notes that cigarette smoking increases blood coagulability, whereas transdermal nicotine does not appear to [12].

Does estrogen change nicotine levels?

In the other direction, estrogen induces CYP2A6, the enzyme that handles nicotine. Nicotine concentrations are lower in women than in men, an effect described as most pronounced in women taking oral contraceptives [9].

What does the cream label say about clots?

Estradiol Vaginal Cream 0.01% is contraindicated in women with active DVT or PE, or a history of either, and in women with active arterial thromboembolic disease such as stroke or myocardial infarction, or a history of it [4]. The cream label carries the older, longer boxed warning covering endometrial cancer, cardiovascular disorders, breast cancer and probable dementia [4].

Does quitting smoking change how estradiol is handled?

In 12 people smoking 20 or more cigarettes a day, abrupt cessation lowered caffeine clearance, a CYP1A2 marker, by 36.1%, with an apparent half-life of the decline of 38.6 hours (95% CI 27.4 to 54.4) [14]. That study measured enzyme activity, not estradiol levels.