Clinical Endocrinology (2013) 78, 505–511
ORIGINAL ARTICLE
Relationship between serum thyrotropin concentrations and
metformin therapy in euthyroid patients with type 2 diabetes
Juan J. Dı́ez and Pedro Iglesias
Department of Endocrinology, Hospital Ramón y Cajal, Madrid, Spain
Summary
Aim A thyrotropin(TSH)-lowering effect of metformin therapy
has been recently reported in patients with type 2 diabetes
(T2D) and hypothyroidism. We aimed to evaluate the interplay
between metformin therapy and serum TSH concentrations in a
group of patients with T2D and normal thyroid function.
Patients and methods Eight hundred and twenty-eight euthy-
roid patients with T2D (53% women, mean age 65
9 years, med-
ian duration of diabetes 10 years) were retrospectively evaluated.
There were 250 patients on metformin treatment (30
2%).
Serum concentrations of TSH were measured in all subjects.
Results Patients on metformin treatment exhibited significantly
higher TSH levels [1
63 (1
11–2
24) mU/l] than those found in
patients without metformin [1
40 (1
01–2
24) mU/l, P = 0
009].
We found no significant differences in TSH levels in patients
who were on therapy with other oral antidiabetics, antihyperten-
sive drugs or hypolipidemic agents in relation to subjects not
taking these drugs. Serum TSH was significantly related to gen-
der, body mass index, hyperlipidaemia and the presence of goi-
tre and diabetic macroangiopathy. In multiple regression
analysis with TSH as dependent variable, goitre was negatively
related to TSH values. Metformin therapy was a nonsignificant
variable in this model.
Conclusion In summary, this is the first survey analysing the rela-
tionship between metformin and thyroid function in a large cohort
of patients with diabetes. Our data do not support the presence of
an independent and significant relationship between TSH values
and metformin treatment in euthyroid patients with T2D.
(Received 10 April 2012; returned for revision 2 May 2012; finally
revised 21 May 2012; accepted 6 June 2012)
Introduction
Type 2 diabetes (T2D) and thyroid dysfunction are the most
common disorders of the endocrine system occurring in the
Correspondence: Juan J. Dı́ez, Department of Endocrinology, Hospital
Ramón y Cajal, Carretera de Colmenar km 9, 28034 Madrid, Spain.
Tel.: +34913368065; E-mail: jdiez.hrc@salud.madrid.org
© 2012 Blackwell Publishing Ltd
doi: 10.1111/j.1365-2265.2012.04468.
general population. The association between diabetes and hypo-
thyroidism is known from the sixties.1 In particular, patients
with T2D exhibit a striking high prevalence of thyroid dysfunc-
tion, ranging from 5% to 13%, as reported by recent retrospec-
tive 2,3 and prospective 4,5 studies. Metformin, an oral
hypoglycaemic biguanide, has been used for the treatment for
T2D for many years, and recently, it is considered the first
choice for oral treatment for T2D patients in the absence of
contraindications.6
Metformin is considered a safe drug with few pharmacological
interactions.7 Several retrospective and prospective studies in a
limited number of patients have suggested that therapy with this
agent is associated with a significant reduction in serum thyrot-
ropin (TSH) concentrations, without relevant changes in serum
thyroxine (T4) and triiodothyronine (T3) levels. This finding
has been reported in diabetic patients with primary hypothy-
roidism both under replacement therapy and untreated.8–10 The
prospective study by Cappelli et al.,10 however, did not report
any significant effect of metformin treatment in a group of 54
patients with T2D and intact pituitary–thyroid axis. Further-
more, in a recent study,11 we have reported that newly diag-
nosed hypothyroidism in patients with T2D was significantly
and directly related not only with thyroid autoimmunity, but
also with metformin therapy. These findings suggest an indepen-
dent association of metformin treatment with newly diagnosed
hypothyroidism in patients with diabetes.
To our knowledge, there are no surveys analysing the relation-
ship between metformin and thyroid function in large cohorts
of diabetic patients with normal thyroid function. Therefore, the
aim of the present study has been to evaluate serum TSH levels
in euthyroid patients with T2D, and their relationship with met-
formin and other antidiabetic treatments in a cross-sectional
design.
Patients and methods
Study design
We designed a cross-sectional study including all euthyroid
patients found in a screening programme for thyroid dysfunc-
tion performed during 2004–2010 in our diabetic clinic.11,12 All
patients were ambulatory and in good health, and had been
diagnosed with T2D according to American Diabetes Association
505
506 J. J. Dı́ez and P. Iglesias
criteria.13 None of them had a recent acute illness or an acute
complication of a chronic disease. Patients taking drugs known
to affect thyroid function were excluded. The study protocol was
approved by the local ethical committee, and all patients gave
informed consent before blood sampling.
We registered demographic and anthropometric data, goitre
(assessed by physical examination), duration of diabetes,
hypertension, hyperlipidaemia, presence or absence of diabetic
complications (diabetic retinopathy, nephropathy, ischaemic
heart disease, cerebrovascular disease, peripheral artery dis-
ease), treatment for diabetes (diet, oral agents and insulin)
and analytical data (glucose, cholesterol, triglyceride and hae-
moglobin A1c). Serum concentrations of TSH were measured
in all patients without previous thyroid dysfunction. Thyroid
autoimmune status was evaluated by means of the measure-
ment of serum levels of thyroid peroxidase autoantibodies
(TPOAb) and thyroglobulin autoantibodies (TGAb). Thyroid
autoimmunity was considered negative when both autoanti-
bodies were negative and positive when any of them were
positive.
Patients
From a total population of 1112 patients included in our
screening programme, we excluded 179 patients who exhibited
previously known thyroid dysfunction. In the remaining group
of 933 patients, there were 828 subjects with normal serum TSH
concentration and 105 with newly diagnosed thyroid dysfunc-
tion (68 of them with elevated TSH and 37 with low TSH
levels). For the purpose of this study, we selected and retrospec-
tively evaluated 828 patients with normal serum TSH concentra-
tions.
Additionally, we also studied the relationship between TSH
and metformin in the group of 933 patients with T2D and no
previously known thyroid dysfunction, that is, including the
group of 105 patients found to have elevated or low TSH levels
in our screening programme. We performed this additional
analysis to evaluate the effects of metformin without the restric-
tion to patients with normal TSH.
Hormone assay
Fasting samples of venous blood were obtained from an antecu-
bital vein between 08:00 and 09:00 for the estimation of hor-
monal and general analytical data. Serum TSH concentrations
were determined by using commercially available immunoche-
miluminescent assay (Immulite; Diagnostic Products Corpora-
tion, Los Angeles, CA, USA). The sensitivity of the assay was
0
004 mU/l. The mean intra- and interassay coefficients of varia-
tion were less than 10%. Normal values for TSH were 0
4–
5
0 mU/l. TPOAb and TGAb were measured using a chemilumi-
nescent immunoassay system (Immulite Thyroid Autoantibody;
Siemens Medical Solutions Diagnostic Ltd., Llanberis, Gwynedd,
UK). Positivity for TPOAb and TGAb was considered when the
titre of these autoantibodies was at least 100 U/ml and at least
340 U/ml, respectively.
Statistical analysis
For quantitative variables, results are expressed as mean ± SD
for normally distributed data and as median (interquartile
range) for nonparametric data. Adjustment to normal distribu-
tion was tested by the Kolmogorov test. Categorical variables are
described as percentages (%). For comparisons of means
between two groups of subjects, the Student’s t-test was used for
normally distributed data and the Mann–Whitney U-test was
employed for nonparametric data. For comparison of means
among more than two groups, we used repeated measures analy-
sis of variance or the Kruskal–Wallis analysis of variance by
ranks, as necessary. Multiple regression analysis and multivariate
logistic regression analysis were used to study the relationship
between quantitative and qualitative variables. For ratio compar-
isons, the chi-square test or Fisher’s exact test was used. Differ-
ences were considered significant when P < 0
05.
Results
Main characteristics of the studied patients
In the study population of euthyroid patients with diabetes,
there were 440 women (53
1%) and 388 men (46
9%) aged
(mean ± SD) 65
9 ± 12
3 years. 297 patients (35
9%) were obese
[body mass index (BMI)  30 kg/m2]. Median duration of dia-
betes was 10 (5–16) years and the percentages of patients with
diabetic microangiopathy, macroangiopathy, hypertension and
hyperlipidaemia were, respectively, 38
2%, 26
4%, 67
8% and
59
7%. Diet was used as the only therapy for diabetes in 127
(15
3%) patients. 246 patients (29
7%) were treated with oral
agents and 455 (55
0%) with insulin (with or without oral an-
tidiabetics). There were 250 patients on metformin therapy, 50
of them in monotherapy, 109 in combination with other oral
agents and 91 in combination with insulin. Mean fasting blood
levels of glucose and haemoglobin A1c were 9
3 ± 3
4 mM and
7
8 ± 1
6%, respectively.
Comparison of data from patients with (n = 250) and without
(n = 578) metformin therapy is shown in Table 1. Patients on
metformin therapy were younger, had a shorter duration of dia-
betes, higher values of BMI and serum triglyceride, and had
higher percentage of females and hyperlipidaemia. On the con-
trary, patients taking metformin were less prone to have micro-
angiopathy, macroangiopathy and hypertension. No differences
were found between both groups in the percentages of goitre or
thyroid autoimmunity, or in the levels of glucose, haemoglobin
A1c and cholesterol.
Thyrotropin values according to diabetes-related
characteristics
Median (IQR) serum TSH concentration in our euthyroid dia-
betic sample was 1
44 (1
03–2
12) mU/l. These values were
slightly higher in female [1
54 (1
05–2
18) mU/l] than in male
patients [1
40 (1
01–2
08) mU/l, N.S.]. We found significantly
elevated TSH levels in patients with obesity in relation to
© 2012 Blackwell Publishing Ltd
Clinical Endocrinology (2013), 78, 505–511
 Thyrotropin and metformin 507

Table 1. Clinical and analytical features of studied diabetic patients with and without metformin therapy

Patients without metformin therapy Patients on metformin therapy

n Value n Value

Clinical data
Sex (females) 578 291 (50
3) 250 149 (59
7)*
Age (years) 578 67
5 ± 12
0 250 62
1 ± 12
2***
Age  65 years 578 386 (66
8) 250 121 (48
4)***
Weight (kg) 570 73
8 ± 13
9 248 78
4 ± 15
5***
Body mass index (kg/m2) 548 29
0 ± 5
0 236 30
9 ± 5
7***
Obesity 548 181 (33
6) 236 113 (47
9)***
Duration of diabetes (years) 557 11 (5–18) 247 9 (5–14)*
Goitre 550 29 (5
3) 250 20 (8
0)
Microangiopathy 532 229 (43
0) 243 67 (27
6)***
Retinopathy 503 57 (11
3) 230 9 (3
9)***
Nephropathy 526 79 (15
0) 240 18 (7
5)**
Macroangiopathy 543 179 (33
0) 250 30 (12
0)***
Coronary heart disease 543 114 (21
0) 250 18 (7
2)***
Cerebrovascular disease 543 27 (5
0) 250 6 (2
4)
Peripheral vascular disease 543 83 (15
3) 250 11 (4
4)***
Hypertension 560 389 (69
5) 250 155 (62
0)*
Hyperlipidaemia 559 309 (55
3) 250 174 (69
6)***
Analytical data
Glucose (mM) 577 9
2 ± 3
2 250 9
6 ± 3
7
Haemoglobin A1c (%) 537 7
8 ± 1
6 247 7
9 ± 1
6
Cholesterol (mM) 576 5
1 ± 1
2 250 5
0 ± 1
1
Triglyceride (mM) 575 1
3 (0
9–1
8) 250 1
4 (1
0–2
0)**
Thyroid autoimmunity 432 19 (4
4) 132 1 (0
8)

*P < 0
05.
**P < 0
01.
***P < 0
001.
Data are the number of patients (percentage), mean ± SD for normally distributed data and median (interquartile range) for nonparametric data.
The total number of patients used to calculate the values of means, medians and percentages in each group is indicated by n.

normal weight subjects, as well as in diabetic patients with hy-
perlipidaemia in relation to patients without this diagnosis. TSH
levels were significantly lower in patients with palpable goitre
and with macroangiopathy (Fig. 1). We found no relationship
between TSH values and the presence of microangiopathy and
hypertension.
Although we found a significant relationship between TSH
and obesity and between TSH and goitre (Fig. 1), goitre and
obesity were nonrelated variables in our patients. In fact, the
prevalence of goitre among patients with obesity (18 out of 289,
6
2%) was very similar to that found in nonobese patients (29
out of 467, 6
2%). BMI was 30
3 ± 5
7 kg/m2 in subjects with
goitre and 29
6 ± 5
3 kg/m2 in subjects without goitre.
Serum TSH concentration was not different in patients classi-
fied according to their antidiabetic treatment modality, that is,
diet [1
48 (1
09–2
10) mU/l], oral antidiabetics [1
49 (1
03–
2
14) mU/l] and insulin therapy [1
41 (1
01–2
12) mU/l].
Patients taking metformin exhibited significantly higher TSH
levels [1
63 (1
11–2
24) mU/l] than those found in patients
without metformin treatment [1
40 (1
01–2
24) mU/l,
P = 0
009]. Nevertheless, we found no significant differences in
TSH levels in patients who were on therapy with sulphonylureas,
meglitinides or thiazolidinediones in relation to subjects not tak-
ing these drugs. No relationship was found between TSH and
treatment with antihypertensive drugs (calcium antagonist, renin
–angiotensin system inhibitors, beta blockers and diuretics) or
hypolipidaemic agents (statins and fibrates) (data not shown).
When including in our analysis the group of 105 patients with
thyroid dysfunction found in the screening programme (69 with
elevated TSH and 37 with low TSH), we again found that
patients taking metformin showed TSH concentration [1
71
(1
13–2
49) mU/l, n = 283] higher than that found in patients
not taking this drug [1
40 (0
98–2
19) mU/l, n = 650,
P < 0
001]. TSH was not related with other drugs in the analysis
performed without restriction to the patients with euthyroid.
Metformin and other variables according to TSH values
Patients with TSH levels in the upper tertile (1
90–5
00 mU/l)
exhibited a BMI value (30
3 ± 6
0 kg/m2) significantly higher
than that found in subjects with TSH levels in the middle or in
the lower tertile. Patients in the upper TSH tertile were also
characterized by a lower percentage of goitre and macroangiopa-
thy, and also by higher serum triglyceride levels (Table 2).

© 2012 Blackwell Publishing Ltd

Clinical Endocrinology (2013), 78, 505–511
508 J. J. Dı́ez and P. Iglesias

5 5 5
P = 0·005 P = 0·005
4 4 4

3 3 3

2 2 2

1 1 1

0 0 0
Female Male No Yes No Yes
(440) (388) (487) (297) (751) (49)
Serum thyrotropin concentration (mU/l)

Gender Obesity Goitre

5 5 5
P = 0·026
4 4 4

3 3 3

2 2 2

1 1 1

0 0 0
No Yes No Yes No Yes
(479) (296) (584) (209) (266) (544)
Microangiopathy Macroangiopathy Hypertension

5 5 5
P = 0·046 P = 0·009
4 4 4

3 3 3

2 2 2

1 1 1

0 0 0
No Yes Diet Oral agents Insulin No Yes
(362) (483) (127) (246) (455) (578) (250)
Hyperlipidaemia Diabetic treatment Metformin

Fig. 1 Box plot diagrams showing serum thyrotropin concentrations in patients with diabetes classified according to gender, obesity, goitre,
microangiopathy, macroangiopathy, hypertension, hyperlipidaemia, group of diabetic treatment and use of metformin. Numbers in abscissa scale
indicate the number of studied subjects in each group. The bottom and top of the box indicate the lower (Q1) and upper (Q3) quartiles, respectively;
median is the band near the middle of the box. The bottom and top ‘whiskers’ are the smallest and largest nonoutliers observations, respectively.
Circles represent outliers (>1
5-fold interquartilic range, IQR=Q3–Q1).

The percentage of patients on metformin therapy was also sig-
nificantly different in patients classified according to tertiles of
TSH levels, being higher in the upper tertile (34
5%) in relation
to the middle (31
0) or the lower tertile (25
0%). We did not
find significant differences in the proportion of other medical
therapies in patients classified according to TSH tertiles. In the
analysis without restriction to euthyroid patients, the propor-
tions of patients with metformin in the upper (35
0%) and mid-
dle (32
2%) tertiles of TSH levels were significantly higher than
that found in the lower tertile (23
8%, P = 0
007).
Values in patients negative for thyroid autoantibodies
Thyroid autoantibodies levels were available in 564 patients.
Results were positive in 20 and negative in 544 patients. In the
group of 544 patients negative for thyroid autoantibodies, TSH
values were significantly higher in those taking metformin [1
64
(1
11–2
19) mU/l] than in those not taking this drug [1
37 (1
01
–2
19) mU/l, P = 0
029].
Regression analysis
A significant correlation was found between TSH and BMI
(ρ = 0
087, P = 0
014) and between TSH and serum triglyceride
levels (ρ = 0
133, P < 0
001) in univariate regression analysis.
These significant correlations persisted when analysing only
patients with negative autoimmunity (n = 544; ρ = 0
116,
P = 0
008 for BMI and ρ = 0
161, P < 0
001, for triglyceride
levels). We performed a multiple regression analysis with TSH
as dependent variable including all the variables found to be
related with TSH levels in Fig. 1, as possible confounders. This
analysis showed that goitre was negatively related to TSH values

© 2012 Blackwell Publishing Ltd

Clinical Endocrinology (2013), 78, 505–511
 Thyrotropin and metformin 509

Table 2. Main clinical and analytical features of patients with diabetes classified according to tertiles of serum TSH concentration

Lower tertile Middle tertile Upper tertile

(0
40–1
19 mU/l) (1
20–1
89 mU/l) (1
90–5
00) P

Clinical data
Sex (female) 138 (50
0) 142 (51
3) 160 (58
2) 0
117
Age (years) 60
5 ± 11
5 65
9 ± 12
7 65
2 ± 12
7 0
459
BMI (kg/m2) 28
8 ± 4
8 29
6 ± 4
9 30
3 ± 6
0 0
004
Duration of diabetes 11 (5–17) 10 (5–17) 10 (5–15) 0
334
Goitre 25 (9
5) 12 (4
5) 12 (4
4) 0
022
Microangiopathy 111 (42
4) 97 (37
0) 99 (37
1) 0
353
Macroangiopathy 84 (32
1) 65 (24
7) 60 (22
4) 0
031
Hypertension 185 (68
8) 176 (65
2) 183 (67
5) 0
666
Hyperlipidaemia 145 (54
1) 166 (61
5) 172 (63
5) 0
066
Analytical data
Glucose (mM) 9
4 ± 3
4 9
3 ± 3
3 9
4 ± 3
4 0
443
Haemoglobin A1c (%) 7
84 ± 1
50 7
75 ± 1
59 7
85 ± 1
70 0
724
Cholesterol (mM) 5
2 ± 1
0 5
2 ± 1
3 5
0 ± 1
1 0
197
Triglyceride (mM) 1
2 (0
9–1
7) 1
3 (0
9–1
8) 1
4 (1
0–2
1) 0
005
Thyroid autoimmunity 9 (4
7) 3 (1
6) 8 (4
4) 0
180
Treatment
Diet 37 (13
4) 52 (18
8) 38 (13
8)
Oral agents 79 (28
6) 78 (28
2) 89 (32
4)
Insulin 160 (58
0) 147 (53
1) 148 (53
8) 0
297
Metformin 69 (25
0) 86 (31
0) 95 (34
5) 0
047
RAS blockers 137 (49
6) 142 (51
3) 130 (47
3) 0
641
Statins 85 (30
8) 102 (36
8) 98 (35
6) 0
287

BMI, body mass index; RAS, renin–angiotensin system.

Data are the mean ± SD for normally distributed data, the median (interquartile range) for nonparametric data and the number (percentage) for
qualitative variables. Significant values (P < 0·05) are highlighted in bold.

(Table 3). Metformin, BMI, macroangiopathy and hyperlipida-
emia were nonsignificant variables in this model. When studying
the subgroup of patients with negativity for thyroid autoanti-
bodies (n = 544), we found that goitre persisted as the only
significant variable in the model. This multiple regression analy-
sis including the group of 105 patients with elevated or low
TSH showed that metformin was a nonsignificant variable in
the model and goitre was near the statistical significance
(P = 0
059).
In a logistic regression analysis model with metformin therapy
as dependent variable, we found that TSH levels and metformin
therapy were significantly related (OR for the highest vs the low-
est tertile of TSH levels, 1
583, 95% CI, 1
095–2
289, P = 0
015).
However, when including BMI, macroangiopathy and hyperlip-
idaemia as independent variables in the model, serum TSH con-
centration was a nonsignificant variable. Similar results were
found when analysing our patients without restriction to euthy-
roid subjects.
Discussion
Results of the present study show that serum TSH concentration
in a sample of euthyroid patients with T2D is related not only
with metformin therapy, but also with some other clinical vari-
ables (Fig. 1), including goitre. Several studies have reported that
TSH levels are increased in obese subjects,14,15 and our metfor-
min group had significantly more obese subjects than the group
of patients not taking this drug. Contrary to the findings of
Cappelli et al. 16 who recently found a significant relationship
between thyroid nodules and morbid obesity, we could not find
any significant relationship between the presence of goitre and
obesity, although our results are limited by the absence of ultr-
asonographic information. Interestingly, there were no relation-
ship between TSH values and any of the analysed
pharmacological therapies, that is, insulin, oral antidiabetics,
antihypertensive and lipid-lowering drugs.
Obesity, goitre and other clinical variables might interact with
the interplay between TSH and metformin therapy as confound-
ing factors. In fact, our multiple regression analysis showed that
the relationship between metformin and TSH values lost its sig-
nificance, being goitre the only significant variable in the model.
In our multivariate logistic regression analysis, the significant
relationship between TSH and metformin was lost when intro-
ducing in the model some confounding variables, such as BMI,
macroangiopathy and hyperlipidaemia. Similar results were
found when analysing patients without restriction to euthyroid
subjects, that is, including patients found to have elevated or
low TSH concentrations.
Although our patients with and without metformin therapy
were not matched for confounding variables, these findings sug-
gest that TSH and metformin are not independently related.
Our results also suggest that thyroid autoimmunity do not

© 2012 Blackwell Publishing Ltd

Clinical Endocrinology (2013), 78, 505–511
510 J. J. Dı́ez and P. Iglesias
Table 3. Multiple regression analysis for TSH as dependent variable in the whole group of euthyroid patients with diabetes and in the subgroup of
patients with negative results for thyroid autoantibodies
All patients
Independent variable B 95% CI
Metformin 0
087 0
052 0
226
BMI 0
009 0
004 0
167
Macroangiopathy 0
107 0
253 0
151
Hyperlipidaemia 0
0124 0
005 0
060
Goitre 0
325 0
580 0
069
Significant values (P < 0·05) are highlighted in bold.
modify this lack of significant relationship between metformin
and TSH.
We could not find any significant relationship between met-
formin therapy and thyroid autoantibodies. This lack of rela-
tionship might be accounted for by the rather low prevalence of
thyroid autoimmunity in our population (3
5%). In agreement
with this finding, our previous study 17 showed an overall preva-
lence of thyroid autoimmunity in diabetic patients without thy-
roid dysfunction slightly higher (5
6%), and no differences
between patients with and without metformin. Another possible
influencing factor is the fact that we could not measure thyroid
autoantibodies in all our patients.
Vigersky et al. 8 fortuitously observed a reversible metformin-
induced suppression of TSH, without changes in free T4 or free
T3, in a patient with hypothyroidism on levothyroxine treat-
ment. This finding was also substantiated in another three
patients with chronic hypothyroidism that started metformin
therapy for diabetes. In a prospective study in 8 obese, diabetic
women with primary hypothyroidism on levothyroxine replace-
ment therapy, the administration of metformin, 1700 mg daily
for 3 months, was accompanied by a significant reduction in
TSH levels from a mean of 3
11 mU/l to 1
18 mU/l,9 which
reverted after withdrawal of the drug. No significant changes in
free T4 or free T3 levels were observed in this study. Interest-
ingly, in this study, patients showed a significant decrease in
body weight that might account for, at least in part, the decline
in TSH levels. Another prospective long-term study in patients
with T2D showed that metformin therapy was accompanied by
a significant reduction in TSH levels in 29 patients with treated
hypothyroidism and in 18 patients with untreated hypothyroid-
ism.10 These authors did not find significant changes in body
mass index or in free T4 levels in their patients. Furthermore, in
this prospective study, the authors did not find any effect of
metformin therapy in a group of 54 euthyroid patients with dia-
betes treated during 1 year.10
The association of metformin therapy with the presence of
newly diagnosed thyroid dysfunction has been specifically
assessed in previous studies. We reported that the presence of
not previously known hypothyroidism was significantly related
not only with thyroid autoimmunity, but also with the presence
of metformin treatment (OR 2
51, 95% confidence interval 1
28
Patients with negative thyroid autoantibodies
P B 95% CI P
0
221 0
084 0
099 0
268 0
368
0
167 0
014 0
002 0
030 0
083
0
151 0
075 0
249 0
100 0
401
0
060 0
115 0
040 0
270 0
146
0
013 0
331 0
646 0
016 0
039
–4
92).11 On the contrary, the presence of thyroid hyperfunction
in patients with T2D was significantly related with age and goi-
tre, but not with metformin therapy.12
It is interesting that the TSH-reducing effect of metformin has
been reported only in diabetic subjects with hypothyroidism, but
not in patients with euthyroidism. In fact, our findings in euthy-
roid patients with diabetes are in line with those of Oleandri
et al. 18 In a prospective, randomized study, these authors
assessed the effects of 3-month treatment with metformin on
anthropometric, metabolic and hormonal variables, including
TSH and thyroid hormones, in a group of 28 patients with
abdominal obesity. Their results showed that metformin did not
modify the effect of diet on serum TSH concentrations in
patients with obesity. The effects of metformin treatment on the
thyroid hormone profile have been evaluated in a recent pro-
spective study including 24 euthyroid women with polycystic
ovary syndrome.19 Serum levels of TSH before starting metfor-
min therapy did not significantly change after a 4-month course
of metformin. Similarly, there were no significant changes in
serum-free T4 in this group of women with euthyroidism.19 Fur-
thermore, no TSH-lowering effect could be demonstrated in the
group of patients with T2D and integrity of the pituitary–thy-
roid axis studied by Cappelli et al.,10 as mentioned above.
Mechanism of action of metformin is complex and multifacto-
rial.20,21 This drug may change the affinity and/or number of thy-
roid hormone receptors, may increase the central dopaminergic
tone or may act directly on TSH regulation, thus enhancing the
effect of thyroid hormones in the pituitary.8,22 Metformin may
also enhance gastrointestinal absorption of levothyroxine or may
produce subtle changes in thyroid hormone protein-binding or
affect thyroid hormone metabolism. All these mechanisms would
act in diabetic hypothyroid subjects; however, our results and
those of other authors in euthyroid subjects with diabetes 10 or
with polycystic ovary syndrome 19 do not support that similar
mechanisms are operative in subjects with integrity of the pitui-
tary–thyroidal axis. It is also possible that the TSH-lowering effect
of metformin is developed slowly as suggested the data from
Cappelli et al. 10 who found that metformin did not exert any
acute change in TSH in 11 patients with treated hypothyroidism.
We are unaware of studies analysing the relationship between
serum TSH and metformin therapy in large series of diabetic
© 2012 Blackwell Publishing Ltd
Clinical Endocrinology (2013), 78, 505–511

patients with euthyroidism. The relative small number of
patients in our sample is the main limitation of this study. The
cross-sectional design of the study prevents drawing firm con-
clusions as to the effect played by metformin on the serum levels
of TSH. Our studied sample is skewed between the metformin
and nonmetformin group, particularly with respect to obesity, a
factor with known relationship with TSH. We could not mea-
sure serum T4 levels in our euthyroid subjects and thyroid au-
toantibodies were not available in the whole sample. Neither
were we able to assess the effects of the duration of metformin
treatment on TSH values in our patients. The lack of informa-
tion of switching from a therapeutic regimen to another could
represent another factor of confusion.
In summary, we found significant relationships between TSH
levels and metformin therapy, obesity, macroangiopathy and hy-
perlipidaemia. However, in multivariate analysis, only the pres-
ence of goitre remained as a significant variable. These results
agree with the findings of some studies showing that metformin
effect on TSH is not observed in patients with normal thyroid
function. Further prospective studies in large samples of euthy-
roid patients with diabetes are needed to clarify the effect of dif-
ferent doses and duration of treatment with metformin on
thyroid economy.
Declaration of Interest
The authors have no conflict of interest in relation to this
article.
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