http://content.nejm.org/cgi/content/full/333/15/964
Impaired Action of Thyroid Hormone Associated with Smoking
in Women with Hypothyroidism
Beat Müller, M.D., Henryk Zulewski, M.D., Peter Huber,
Ph.D., John G. Ratcliffe, M.D., and Jean-Jacques Staub,
M.D.
ABSTRACT
Background The effect of smoking on thyroid
function is controversial, and its effect on thyroid hormone action
is unknown. We investigated the effects of
cigarette smoking in women with various
grades of hypothyroidism and in normal women.
Methods We studied 138 normal women and 135 women with
primary hypothyroidism, of whom 84 had subclinical hypothyroidism
and 51 overt hypothyroidism. Sixty of the women with hypothyroidism
were reevaluated during thyroxine therapy. The women were
categorized as smokers or nonsmokers according to
their responses to a questionnaire. Thyroid function was evaluated
by measurements of serum thyrotropin, free thyroxine, and
triiodothyronine. Peripheral thyroid hormone action was assessed by
a clinical score and measurements of ankle-reflex time and serum
lipids and creatine kinase.
Results Among the women with subclinical hypothyroidism,
the smokers had a higher mean (±SD) serum
thyrotropin concentration (21.3±16.6 vs. 12.7±7.2 mU
per liter, P = 0.004) and a higher ratio of serum triiodothyronine
to serum free thyroxine (by 30 percent, P = 0.003) than the
nonsmokers. Their serum concentrations of total
cholesterol and low-density lipoprotein (LDL) cholesterol were
higher (by 16 percent, P = 0.013; and 28 percent, P = 0.003,
respectively). Among the women with overt hypothyroidism, the serum
concentrations of thyrotropin, free thyroxine, and triiodothyronine
were similar in the smokers and nonsmokers. As
compared with the nonsmokers, the smokers had a
clinical score indicating a greater degree of hypothyroidism
(P<0.001), higher serum concentrations of total and LDL
cholesterol (by 25 percent, P<0.001; and 24 percent, P = 0.002,
respectively), longer ankle-reflex time (by 25 percent,
P<0.001), and higher serum concentrations of creatine kinase (by
236 percent, P<0.001). There were dose–response relations
between smoking and serum concentrations of total and LDL
cholesterol, serum creatine kinase concentrations, and ankle-reflex
time in the women with overt hypothyroidism, and between smoking
and serum concentrations of total and LDL cholesterol in the women
with subclinical hypothyroidism.
Conclusions Smoking increases the metabolic
effects of hypothyroidism in a dose-dependent way. This may be
explained by alteration of both thyroid function and hormone
action.
Thyroid dysfunction and cigarette
smoking are both common in the general population, with
prevalences of about 10 percent and 30 percent, respectively. The
influence of cigarette smoking on thyroid
function is controversial. Both decreased and increased thyroid
function and a goitrogenic effect have been described in
smokers in some studies, but in others smoking has had no
effect on thyroid function or thyroid size. These studies presumed
a direct effect of constituents of cigarette
smoke on the thyroid gland, since some components of
tobacco smoke (e.g.,
nicotine, thiocyanate, hydroxypyridine
metabolites, and benzpyrenes) have been reported to interfere with
thyroid function.Whether smoking has any effect on the peripheral
actions of thyroid hormone is not known. We studied the effect of
cigarette smoking on serum thyrotropin and thyroid hormone
concentrations and on thyroid hormone action in large groups of
women with various grades of hypothyroidism before and during
thyroxine therapy and in normal women.
Methods
Study Subjects
We used a standardized protocol to select the 273 study subjects
from a larger group of 322 women studied prospectively in the
endocrine outpatient clinic of the University Hospital of Basel,
Switzerland. From this larger group we excluded 46 women (5 of them
smokers and 41 nonsmokers) with mild subclinical
hypothyroidism (basal serum thyrotropin concentration, <6 mU per
liter), 2 receiving medications affecting thyroid function, and 1
with subacute thyroiditis. Only women were studied to exclude
variations due to sex. All the hypothyroid women were ambulatory
and in good general health. All the control subjects were normal
women — mainly staff members, their relatives, or friends.
After an overnight fast, all the women underwent full medical
assessment and laboratory examinations (hematology and
blood-chemistry tests and urinalysis) to rule out nonthyroidal
illnesses.
We studied the following groups: 138 normal women, with a mean
(±SD) age of 47±13 years, all of whom had serum
concentrations of thyrotropin (both at base line and after
receiving thyrotropin-releasing hormone), free thyroxine, and
triiodothyronine within normal reference ranges; 84 women, with a
mean age of 52±13, who had subclinical hypothyroidism,
defined as a basal serum thyrotropin concentration higher than 6.0
mU per liter with normal serum concentrations of free thyroxine and
triiodothyronine; and
51 women, with a mean age of 57±12, who had overt
hypothyroidism, defined as a basal serum thyrotropin concentration
higher than 20 mU per liter and low serum free thyroxine
concentrations (<0.6 ng per deciliter [<8 pmol per liter]).
Among the 135 women with hypothyroidism, 62 had chronic autoimmune
thyroiditis; 61 had Graves' hyperthyroidism treated with surgery or
131I; and 12 had undergone thyroidectomy for simple goiter (11
women) or an autonomously functioning thyroid adenoma (1 woman). We
also studied 60 of the 135 women with hypothyroidism (26 with
subclinical and 34 with overt hypothyroidism) when they were
euthyroid after treatment with thyroxine for at least three months,
as confirmed by a normal serum thyrotropin response to
thyrotropin-releasing hormone on two separate occasions.
For each woman, a standardized questionnaire — including
questions about smoking habits, alcohol intake, menopausal
status, and treatment with estrogen or other medications —
was completed by a physician. The physicians did not know the
results of the biochemical studies, which were available only after
the clinical examination. Smoking habits were categorized
in the following way: nonsmokers (women who had never
smoked or had smoked previously but stopped before entering the
study), one-pack-per-day smokers (those who smoked up to
one pack of 20 cigarettes per day),
two-packs-per-day smokers (up to two packs per day), and
smokers of more than two packs per day. All the women
reexamined later maintained their base-line smoking
habits. The overall frequency of smokers among the 273
women was 23 percent, which is almost identical to the 22 percent
frequency in the female population of Switzerland. Thus, the
smoking habits of our cohort are representative of the
smoking habits of women in Switzerland. The study was
approved by the Ethics Committee for Human Studies of the
University Hospital of Basel, and informed consent was given by
each woman.
Serum Hormone Concentrations and Tests of Peripheral Action
of Thyroid Hormone
Serum thyrotropin concentrations (reference range, 0.1 to 4.0 mU
per liter) were measured in most women by immunoradiometric assay
(TSH-RIA-gnost, Behring, Frankfurt, Germany); before its
introduction we used a radioimmunoassay (correlation with the
immunoradiometric assay: r = 0.93, P<0.001, n = 94), as
previously described.
Serum concentrations of triiodothyronine (reference range, 58 to
195 ng per deciliter [0.9 to 3.0 nmol per liter]) and free
thyroxine (reference range, 0.6 to 2.1 ng per deciliter [8 to 27
pmol per liter]) were determined by radioimmunoassay (Clinical
Assays, Baxter, Cambridge, Mass.). An oral thyrotropin-releasing
hormone test was performed to verify the euthyroid status of the
normal women and the thyroxine-treated women with hypothyroidism.
In this test, we determined serum thyrotropin and triiodothyronine
concentrations before and three hours after the oral administration
of 40 mg of thyrotropin-releasing hormone (reference ranges, 7.5 to
37.3 mU per liter and 23 to 97 ng per deciliter [0.4 to 1.5 nmol
per liter], respectively).The increase in serum triiodothyronine
after the administration of thyrotropin-releasing hormone, which we
call the thyroid reserve, is a good marker of impending thyroid
failure.To estimate the proportion of active thyroid hormone
(triiodothyronine) relative to its precursor (thyroxine), we
divided the serum concentrations of triiodothyronine by those of
free thyroxine.
We scored the degree of clinical hypothyroidism using the index of
Billewicz et al. This
index is based on the quantitative scoring of 14 symptoms and signs
of hypothyroidism (euthyroidism is indicated by a score of -30
points or less; clinical hypothyroidism, +25 points or more; and
borderline hypothyroidism, -29 to +24 points). Serum total
cholesterol and triglycerides were measured enzymatically, and
serum low-density lipoprotein (LDL) and high-density lipoprotein
(HDL) cholesterol by ultracentrifugation (Airfuge, Beckman,
Fullerton, Calif.), as described previously. Ankle-reflex time was
measured by photomotography with an achillometer (Polymed,
Glattbrugg, Switzerland; reference range, 290 to 410 msec); six
tracings (three on each ankle) were recorded for each woman. The
ankle-reflex time was the mean of the six readings. Serum creatine
kinase was measured enzymatically by AutoAnalyzer (reference range,
40 to 160 U per liter).
Statistical Analysis
Analysis of frequencies was performed with the use of contingency
tables (chi-square). A two-way analysis of variance, including the
factors smoking (yes or no) and severity of hypothyroidism, was
performed for the peripheral tests of thyroid hormone action to
evaluate the interaction between smoking and
hypothyroidism. In addition, two group comparisons corrected for
multiple testing (a one-way analysis of variance and a
multiple-range test for least-square difference) between
smokers and nonsmokers within the various groups
were performed. Ordinal scaled data (the clinical scores) were
verified by Wilcoxon's rank-sum test. Finally, we categorized the
number of packs of cigarettes smoked per
day and computed the linear contrast for the measurements of
peripheral thyroid hormone action to verify a dose–response
relation within the groups. All
statistical tests were two-tailed.
Results
The effects of cigarette smoking on serum
thyrotropin and thyroid hormone concentrations and on the tests of
peripheral thyroid hormone action are summarized in Table
1 and Table
2 and in Figure
1. The smokers and nonsmokers within the
groups were well matched with respect to age, body-mass index,
menopausal status, estrogen therapy, and incidence of treated
Graves' hyperthyroidism. In all groups, more smokers than
nonsmokers drank alcohol daily; the difference was
statistically significant in the women with subclinical
hypothyroidism.
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