Effect of pioglitazone on testosterone in eugonadal men with type 2 diabetes mellitus: a randomized...

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This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/j.1365-2265.2012.04510.x © 2012 Blackwell Publishing Ltd

Received : 25-May-2012

Returned for Revision: 19-Jun-2012

Finally Revised : 17-Jul-2012

Accepted : 17-Jul-2012

Article type : R

Effect of pioglitazone on testosterone in eugonadal men with type 2

diabetes mellitus: A randomized double blind placebo-controlled study

Subbiah Sridhar*, Rama Walia

*, Naresh Sachdeva, Anil Bhansali

Dr. Subbiah Sridhar – M.D., D.M.

Dr. Rama Walia – M.D., D.M.

Dr. Naresh Sachdeva – Ph.D.

Dr. Anil Bhansali – M.D., D.M.

* First two authors have equal contribution

Department of Endocrinology, Post Graduate Institute of Medical Education and Research,

Chandigarh, India.

Corresponding Author:

Dr. Anil Bhansali,

Professor and Head,

Department of Endocrinology,

Post Graduate Institute of Medical Education and Research,

Chandigarh, India.

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© 2012 Blackwell Publishing Ltd

Email:[email protected]

Fax: 91-172-2744401, 2745078

Key words: testosterone, pioglitazone, sex hormone binding globulin

Conflict of Interest

No conflict of interest to disclose

Acknowledgement

We appreciate the gesture of Sun Pharmaceutical Industries Ltd, Mumbai, India, for

providing the pioglitazone tablet and placebo for the study.

Abstract

Objectives: Pioglitazone is an insulin sensitizer used for the management of type 2 diabetes

mellitus (T2DM). It has been shown to reduce testosterone level in patients with polycystic

ovarian syndrome. However, its effect on testosterone in men has not been studied.

Research design and methods: A randomized, double blind, placebo-controlled trial with

six months follow-up. Fifty (25 in each group) eugonadal men (well virilized and total

testosterone ≥ 12 nmol/L) with T2DM, aged 30-55 yr, and HbA1c of ≤ 7.5%, were randomly

assigned to receive pioglitazone 30 mg per day or placebo along with existing glimepiride

and metformin therapy.

Results: As compared to placebo, six months of pioglitazone therapy in patients with T2DM

resulted in significant reduction in mean total testosterone level (16.1 to 14.9 vs 17.1 to 17.0

nmol/L; p = 0.031), calculated free testosterone (p = 0.001) and bioavailable testosterone (p =

0.000) despite significant increase in sex hormone binding globulin (p = 0.000). Plasma

androstenedione (∆4) level increased (1.5 to 1.9 ng/ml; p = 0.051) following pioglitazone

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therapy. The decrease in testosterone was independent of change in body weight, body fat,

and HbA1c.

Conclusion: Pioglitazone therapy significantly decreases total, free and bioavailable

testosterone in eugonadal men with T2DM. The effects of these alterations need to be

determined by further long term studies.

Introduction

Pioglitazone is an insulin sensitizer, used for the management of type 2 diabetes

mellitus1 (T2DM). It is an agonist of peroxisome proliferator activated receptors

(PPARs) with greatest specificity for PPAR-gamma (PPAR-ϒ ) 2

. Several clinical studies

demonstrated that pioglitazone not only improves insulin sensitivity but also decreases

androgen levels in women with polycystic ovary syndrome (PCOS) 3, 4.

However, whether the

reduction in the androgen levels in PCOS is secondary to improvement in insulin sensitivity

or due to a direct effect of thiazolidinediones on steroidogenesis, is not known. In-vitro

studies in humanized yeast5 and human adrenal NCI-H295R cell lines

6 demonstrated that

pioglitazone inhibits androgen production by directly inhibiting the steroidogenic enzymes

P450c17 hydoxylase and 3β-hydroxysteroid dehydrogenase (3β HSD).

Low testosterone levels in men are associated with reduced insulin sensitivity7,

increased incidence of vascular disease8, anaemia

9, osteoporosis

10 and pathological

fractures11

. Moreover, a high prevalence of hypogonadism has been reported in men with

T2DM12

and use of pioglitazone may further be detrimental in these subjects. Two human

studies have examined the effects of rosiglitazone on testosterone levels in male subjects,

one in healthy individuals 13

and the other in patients with T2DM and hypogonadism14

.

However, the studies had conflicting results. To date, no human study has examined the

effect of pioglitazone on testosterone levels in eugonadal men. Therefore this study

evaluated the effect of pioglitazone on testosterone in eugonadal men with T2DM.

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Research design and methods

This 24 week, randomized, double-blind, placebo controlled study was conducted

between July 2010 and December 2011. The study was approved by Post Graduate

Institute of Medical Education and Research (PGIMER) ethics committee. All patients

provided written informed consent for participation in the trial. The study was registered in

Clinicaltrial.gov, number NCT01206400.

Eligibility criteria

Eugonadal men (well virilized with total testosterone (TT) level ≥ 12 nmol/ L on two

occasions), age 30-55 years with T2DM for < 5 years, BMI of 20-30 kg/m2

and HbA1c level

of ≤ 7.5%, on glimepiride (1-4 mg) and metformin (1-2 gm) were included. During six weeks

run-in-period, doses of glimepiride and metformin were titrated to achieve the target HbA1c

≤ 7.5%, following that stable dosages of glimepiride and metformin were continued for the

next 6 weeks before randomization. Exclusion criteria included previous use of pioglitazone,

current smoking, serum albumin <3gm/dL, hepatic dysfunction, heart failure, renal failure,

presence of macular edema or any acute illnesses.

Randomization and interventions

One hundred and sixty patients receiving glimepiride and metformin were screened,

and of these 97 were excluded because their TT of <12nmol/L or HbA1c > 7.5%, or BMI of >

30 kg/m2.

After fulfilling the inclusion criteria, patients were randomly allocated to treatment

with pioglitazone (30 mg per day) or placebo, taken once daily along with the existing

glimepiride and metformin therapy. Both patients and physicians were blinded to the

treatment. Compliance with the medication was determined by pill count. All the patients

were educated about the disease and advised to follow diabetic diet and exercise throughout

the study period. If hypoglycaemia occurred, the glimepiride dose was reduced. All other

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concomitant medications were continued throughout the study period without any dose

modifications.

Patients were evaluated using questionnaires to assess the complications of diabetes

and hypogonadal symptoms including Androgen Deficiency in the Aging Male (ADAM) 15

and European Male Aging Study (EMAS) 16, 17

. Erectile dysfunction was assessed based on

5-item version of the international index of erectile dysfunction (IIEF-5) symptom score18

.

Body weight, body mass index (BMI) and waist circumference were measured at each visit.

Additional baseline assessments included measurements of blood pressure, body fat

percentage (Omran HBF-302), fasting and postprandial blood glucose, fasting lipid profile,

liver function test, haemoglobin, packed cell volume, 24 hrs urinary protein and

electrocardiography.

Hormonal Parameters:

Venous blood samples of 4 ml were collected in EDTA vacutainers twice at 20

minutes interval and pooled together between 0800h and 0900h. HbA1c and total testosterone

(TT) were measured at each visit (0, 6, 12, 18 and 24 weeks). Sex hormone binding globulin

(SHBG), androstenedione, cortisol, LH, FSH, estradiol, prolactin, and fasting insulin levels

were determined at 0, 12 and 24 weeks of therapy. Total testosterone, cortisol, LH, FSH,

estradiol, prolactin, fasting insulin was determined by electro-chemiluminiscence

immunoassay (ELECSYS-2010, Roche diagnostics, Germany) and HbA1c levels by high

performance liquid chromatography (HPLC) method (ion exchange chromatography, D-10,

Bio-rad, USA). The reference range for total testosterone was 9.9 to 27.8 nmol/L; (inter-

assay CV, 2.5 to 7.5 %; intra-assay CV, 1.5 to 4.7%) cortisol, 171 - 536 nmol/L (inter-assay

CV, 0.4 to 1.6 %; intra-assay CV, 0.5 to 1.4%), LH, 1.7 to 8.6 mIU/ml; (inter-assay CV, 2.4

to 5.2 %; intra-assay CV, 0.3 to 1.8%) FSH, 1.5 to 12.4 mIU/ml; (inter-assay CV, 2.6 to 5.3

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%; intra-assay CV, 0.4 to 2.0%) estradiol, 7.63 to 42.6 pg/ml; (inter-assay CV, 3.5 to 6.2 %;

intra-assay CV, 2.5 to 5.7%) and prolactin, 4.0 to 15.2 ng/ml; (inter-assay CV, 3.1 to 5.0 %;

intra-assay CV, 2.5 to 4.0%). Plasma samples were frozen at – 200 C for SHBG and

androstenedione and measurements were performed after completion of study. Plasma

SHBG was measured by an enzyme linked immunosorbent assay (ELISA) that applies a

technique of sandwich immunoassay (Bluegene Biotech Co Ltd, Shanghai, China). The assay

sensitivity was 1 nmol/L (normal range 13 – 71 nmol/L; inter-assay CV, 5.1 to 7.5 %; intra-

assay CV, 3.5 to 5.5%). Plasma androstenedione was also measured by an ELISA technique

on the basis of competitive immunoassay (normal range 0.5 – 2.5 ng/ml, Oxford Biomedical

research, Oxford, USA). The cross -reactivity of the assay to measure other steroid hormone

was < 0.01%. Biochemistry studies were performed by automated analyzer.

Free and bioavailable testosterone (FT & BioT) were calculated from TT, SHBG and

albumin using the method of Vermulen et al19

by a computer program (Free and Bioavaliable

Testosterone Calculator, developed at the Hormonology Department, University Hospital of

Ghent, Belgium and available at http://www.issam.ch/freetesto.htm. Patients were clinically

evaluated every six weeks (0, 6,12, 18 and 24 wks); At each visit, anthropometric

measurements, blood pressure, HbA1c, TT, drug compliance and adverse effects were

obtained and recorded.

STATISTICAL ANALYSIS

Data were analyzed using the SPSS 17 software package. Values are expressed as mean ± SD

unless otherwise stated. One sample non parametric Kolmogorov-smirnnov test revealed that

the parameters were normally distributed, with no significance (p = 0.233). Paired‘t’ test was

used to compare the changes in body fat, anthropometric measurements, and hormonal levels

before and after pioglitazone vs. placebo therapy within each treatment group. Independent‘t’

tests was used to compare the differences in the changes of measurements between

http://www.issam.ch/freetesto.htm

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pioglitazone treated and placebo treated groups. Data were considered significant if p <0.05.

The impact of clinical variables on testosterone and SHBG levels was determined by linear

regression and correlation.

RESULTS

Fifty four patients were randomly assigned to receive either pioglitazone or placebo

along with the existing glimepiride and metformin therapy. Three patients were lost to

follow-up and one discontinued medication. After exclusion of these subjects, fifty patients

(25 in each group) were finally evaluated at the end of study. Both the treatment groups were

comparable at baseline for duration of diabetes and hypertension, weight, BMI, waist

circumference (WC), percentage body fat and various hormonal parameters including total

and free serum testosterone (table 1). The mean age of the patient in placebo group was 44.0

± 7.2 as compared to 47.9 ± 5.8 years in pioglitazone group. The mean HbA1c of the study

population was 6.8 ± 0.4%.

Table 2 shows the alterations in clinical and glucose homeostatic parameters from

baseline to final visit comparing both the groups. Following six months of pioglitazone

therapy, there was a significant change in weight, BMI, HbA1c, fasting plasma insulin

and HOMA-IR. However when compared to placebo at six months, these changes were

not significant. Eight patients in pioglitazone group and two in placebo group had

symptomatic minor hypoglycaemia which required reduction of glimepiride dose.

Six months of pioglitazone therapy was associated with a significantly greater

increase in the mean SHBG levels as compared to placebo. However, there was a

significant decrease in total testosterone (TT, 16.1 to 14.9 vs 17.1 to 17.0 nmol/L; p = 0.031,

Figure 2), calculated free testosterone (cFT; p=0.004, Figure 3), and bioavailable

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testosterone (BioT, p = 0.001; table 3). There was no alteration in serum albumin level in

both the treatment groups (p = 0.607).

Total cholesterol, LDL cholesterol and triglyceride levels decreased with

pioglitazone therapy as compared to placebo. Pioglitazone therapy was associated with

significant reduction in the haemoglobin level (14.1 to 13.7 vs 13.5 to 13.5 g/dl; p = 0.029) as

compared to placebo.

The decrease in TT, cFT and BioT did not correlate with HbA1c reduction, change in

weight, or body fat. However, the weight gain (r = -0.428; p = 0.037), waist circumference

increase (r = -0.450; p = 0.027) and body fat change (r = -0.446; p = 0.029) were significantly

and inversely correlated with rise in SHBG levels. The increase in SHBG inversely correlated

with both free testosterone (r = -0.433; p = 0.034) and bioavailable testosterone (r = -0.421; p

= 0.041), but not with TT (r = 0.06; p = 0.78). The rise in androstenedione level negatively

correlated with fall in TT (r = -0.392; p = 0.058). There was a strong positive correlation

between TT and cFT (r = 0.935; p = 0.000), and BioT (r = 0.943; p = 0.000). The drop in

haemoglobin level had positive correlation with reduction in TT level (r = 0.475; p = 0.019).

25 patients (12 in pioglitazone treated group and 13 in placebo groups) in our study

group had Androgen Deficiency in Aging Male (ADAM) symptoms questionnaire scores of 3

or more (indicating hypogonadism) at presentation even in the presence of normal total

testosterone level. There was an improvement in the ADAM score level in both the groups

after six months of therapy, irrespective of the change in TT, FT, BioT and HbA1c level and

was comparable between the groups (p = 0.312). European male aging study - overall sexual

functioning questionnaire (EMAS-OSF) also improved following pioglitazone as well as with

placebo therapy and the difference was similar in both groups (p = 0.598). EMAS – sexual

function distress (EMAS-SFD) was decreased in both groups and the difference was not

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significant (p = 0.152). International index of erectile dysfunction (IIEF-5) score also

improved similarly in both the groups (p =0.295). The improvement in the symptoms score is

probably more a result of overall treatment rather than changes in endocrine profile as they

occurred in both pioglitazone and placebo groups.

Adverse events

Pioglitazone was well tolerated. Adverse events occurred in 20 patients in the

pioglitazone group and 10 patients in the placebo group. The most common adverse effect

noted in our study was weight gain followed by minor hypoglycaemia.

Discussion

The present study shows that pioglitazone therapy decreases total testosterone (TT),

calculated free testosterone (cFT), and bioavailable testosterone (BioT) despite increase in

SHBG levels in eugonadal men with T2DM. The decrease in total testosterone was

independent of increase in SHBG, change in body weight, body fat, and HbA1c.

Studies of thiazolidinediones in women with PCOS, an insulin resistant state, have

resulted in improvement, not only in insulin sensitivity but also decrease in testosterone

levels3, 4

.

In men studies reporting the effects of TZDs on testosterone have reported

variable results. In a small (n = 10), short duration (7 days) study by Vierhapper et al13

, the

use of rosiglitazone (8 mg per day) in healthy subjects resulted in significant decrease in the

production rate of testosterone. On the contrary Kapoor et al14

showed, increase in TT, FT

and SHBG in hypogonadal subjects with uncontrolled T2DM after treatment with

rosiglitazone. However this study had limitations including small number of subjects, lack of

placebo controlled arm and the effect of improvement in glycemic control on serum

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testosterone levels following rosiglitazone therapy was not taken into account. As both these

studies were with rosiglitazone and had conflicting results, and currently rosiglitazone is not

available, therefore the present study was planned with pioglitazone.

In the present study, after six months of pioglitazone therapy there was a significant

decrease in TT despite increase in SHBG. It was accompanied with reduction in cFT, BioT

and rise in androstenedione. The alterations in androgen levels were maximally observed

between 3-6 months of therapy and these were independent of the change in body weight,

body fat, and HbA1c suggesting the direct effect of pioglitazone on testosterone biosynthesis.

This is further substantiated by increase in plasma androstenedione (∆4) levels indicating the

blockade at the level of 17β-hydroxysteroid dehydrogenase III (17β-HSD III), thereby

decreasing the conversion of androstenedione to testosterone.

Another intriguing observation in the present study is increase in SHBG inspite of

increase in body weight. The weight gain is usually associated with reduction in SHBG levels

as a result of increase in insulin resistance. However with the use of pioglitazone, there is an

improvement in insulin sensitivity even with weight gain, because of differentiation of pre-

adipocytes into insulin sensitive smaller adipocytes22

and increased adiponectin level, thereby

resulting in increase in SHBG levels. Improvement in hepatic insulin sensitivity following

pioglitazone therapy is another mechanism for increase in SHBG levels. There was no

increase in plasma gonadotropins level even with decrease in TT and FT, possibly because

of modest reduction in testosterone and it was within the reference range.

High prevalence of hypogonadism (30%) has been reported in men with T2DM12

. The

reduction in testosterone has been attributed to visceral adiposity in these subjects. The

reasons for hypogonadism include inhibition of hypothalamo-pituitary-testicular axis by

elevated estradiol because of increased aromatase activity in visceral adipose tissue20

, and by

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pro-inflammmatory cytokines21

. Pioglitazone therapy has been shown to reduce visceral

obesity therefore it should result in increase in TT level. However, in the present study the

decrease in TT seems to be the direct effect of pioglitazone on testosterone biosynthetic

pathway.

The adverse effects of pioglitazone include oedema23

, weight gain, anaemia24, 25

,

osteoporosis10

and fracture11

. The anaemia has been attributed to fluid retention and

haemodilution owing to expansion of plasma volume23

. A recent study24, 25

showed that the

reduction in haemoglobin correlated with decrease in plasma free testosterone level in women

with PCOS receiving pioglitazone therapy. The correlation between decrease in haemoglobin

and TT in the present study requires further elucidation.

The other side effect associated with the use of pioglitazone therapy is osteoporosis

and atypical fractures particularly in post- menopausal women 26, 27

. Diversion of

mesenchymal stem cell (MSC) to differentiate into adipocytes, rather than to osteoblast11

is

incriminated to be the cause for osteoporosis. This may be the direct effect of

thiazolidinedione or decreased testosterone and / or estradiol levels, which also regulate the

MSC differentiation to osteoblast. It is difficult to conclude the contribution of decrease in

testosterone and estradiol to osteoporosis in men from the present study.

None of the patients in this study had deterioration in ADAM, EMAS and IIEF-5

score despite decrease in serum TT, cFT and BioT levels. This can be explained by the fact

that although androgen levels decreased, however, these were still within the reference range.

The strength of the present study include randomized double-blind placebo controlled

trial, well controlled glycemia with duration of diabetes less than five years. The limitation of

the study include small number of patients, study duration of six months, free testosterone

was calculated (cFT) rather than measured by equilibrium dialysis – mass spectrometry. This

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study was also not sufficiently powered to examine the changes in androgen deficiency

symptoms scores and bone mineral density (BMD).

Conclusion

In eugonadal men with T2DM pioglitazone significantly decreased total, free

and bioavailable testosterone. No clinical consequences of this decrease were detected in

this study but this needs to be further assessed in larger studies.

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Table 1 – Baseline clinical and hormonal characteristics of the patients

Parameters

Pioglitazone (N=25)

Placebo (N=25)

p value

Age (yr)

Duration of diabetes (yr)

Weight (Kg)

BMI (kg/m2)

Waist circumference (cm)

Body fat (%)

HbA1c (%)

Fasting plasma insulin

(µU/ml)

Fasting C-peptide (ng/ml)

LH (mIU/L)

FSH (mIU/L)

SHBG (nmol/L)

Total testosterone (nmol/L)

Free testosterone (nmol/L)

Bioavailable testosterone

(nmol/L)

Androstenedione (ng/ml)

Estradiol (pmol/L)

Prolactin (µg/L)

47.9 ± 5.8

2.2 ± 1.7

70.4 ± 11.4

25.3 ± 2.7

93.5 ± 7.3

28.8 ± 3.1

6.8 ± 0.4

10.7 ± 6.5

3.1 ± 1.1

5.2 ± 2.8

6.2 ± 2.8

25.1 ± 6.4

16.1 ± 2.3

0.36 ± 0.07

9.5 ± 1.9

1.5 ± 0.7

169.2 ± 45.1

7.2 ± 3.3

44.0 ± 7.2

2.9 ± 2.1

69.6 ± 7.8

25.1 ± 3.2

91.8 ± 8.5

28.8 ± 4.4

6.8 ± 0.4

12.5 ± 6.8

3.0 ± 1.2

5.1 ± 2.5

5.2 ± 1.9

25.5 ± 5.2

17.1 ± 3.2

0.38 ± 0.09

10.3 ± 2.2

1.7 ± 0.5

163.3 ± 34.4

7.3 ± 2.6

0.047*

0.401

0.780

0.748

0.468

0.968

0.922

0.330

0.832

0.892

0.152

0.832

0.204

0.467

0.195

0.192

0.662

0.992

Data are means ± SD. *statistically significant.

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Table 2 – Alterations in the clinical and glucose homeostasis parameters in the studied

patients

Parameters

Pioglitazone

Placebo

p

value

0 months

6 months

p value

0 months

6 months

p value

Weight (kg)

BMI (kg/m2)

Waist

circumference

(cm)

Body fat (%)

Haemoglobin

(g/dl)

HbA1c (%)

FPI(µU/ml)

Fasting C-

peptide

(ng/ml)

HOMA-IR

70.4± 11.4

25.3 ± 2.7

93.5 ± 7.3

28.8 ± 3.1

14.1 ± 1.1

6.8 ± 0.4

10.7 ± 6.5

3.1 ± 1.1

2.6 ± 1.6

72.3 ± 11.5

26.0 ± 2.9

94.2 ± 8.7

29.6 ± 4.0

13.7 ± 1.1

6.4 ± 0.5

7.4 ± 4.7

3.1 ± 0.8

1.9 ± 1.4

0.015*

0.038*

0.393

0.178

0.002*

<0.001*

<0.001*

0.509

0.002*

69.6 ± 7.8

25.1 ± 3.2

91.8 ± 8.5

28.8 ± 4.4

13.5 ± 0.8

6.8 ± 0.4

12.5 ± 6.8

3.0 ± 1.2

3.2 ± 1.8

69.9 ± 8.0

25.3 ± 3.5

92.4 ± 8.4

28.7 ± 4.5

13.5 ± 0.7

6.4 ± 0.4

10.0 ± 5.9

3.0 ± 0.9

2.8 ± 1.6

0.520

0.238

0.162

0.739

0.785

<0.001*

0.002*

0.919

0.04*

0.058

0.227

0.804

0.164

0.029*

0.528

0.518

0.560

0.801

Data are means ± SD. *statistically significant

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Table 3 Alteration in hormonal parameters in the study subjects

Parameters

Pioglitazone

Placebo

p value

0 months

6 months

p value

0 months

6 months

pvalue

LH (mIU/L)

FSH (mIU/L)

Albumin (g/dL)

SHBG (nmol/L)

Total testosterone

(nmol/L)

Free testosterone

(nmol/L)

Bioavailable

testosterone

(nmol/L)

Androstenedione

(ng/ml)

Estradiol

(pmol/L)

Prolactin (µg/L)

5.2 ± 2.8

6.2 ± 2.8

4.8 ± 0.3

25.1 ± 6.4

16.1 ± 2.3

0.36 ± 0.07

9.5 ± 1.9

1.5 ± 0.7

169.2±45.1

7.2 ± 3.26

5.3 ± 1.7

6.0 ± 2.3

4.6 ± 0.3

31.2 ± 5.6

14.9 ± 3.3

0.30 ± 0.08

7.8 ± 2.2

1.9 ± 0.4

144.2 ± 58.3

7.0 ± 2.3

0.813

0.744

0.168

<0.001*

0.026*

<0.001*

<0.001*

0.025*

0.052

0.656

5.1 ± 2.5

5.2 ± 1.9

5.0 ± 0.2

25.5 ± 5.2

17.1 ± 3.2

0.38 ± 0.09

10.3 ± 2.2

1.7 ± 0.5

163.3±34.4

7.3 ± 2.6

5.6 ± 1.8

5.5 ± 2.0

4.9 ± 0.2

25.2 ± 5.6

17.0 ± 3.3

0.38 ± 0.08

10.2 ± 2.3

1.7 ± 0.4

152.7 ±30.8

8.1 ± 2.6

0.217

0.084

0.134

0.679

0.779

0.866

0.646

1.000

0.157

0.098

0.563

0.431

0.607

<0.001*

0.031*

0.004*

0.001*

0.051

0.536

0.105

Data are means ± SD. *statistically significant

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Figure 1 Change in SHBG level from baseline to 6 months between two

groups with error bars showing one standard deviation

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Figure 2: Change in total testosterone level from baseline to 6 months

between two groups with error bars showing one standard deviation

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Figure 3: Change in free testosterone level from baseline to 6 months

between two groups with error bars showing one standard deviation

Date post:	30-Sep-2016
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Effect of pioglitazone on testosterone in eugonadal men with type 2 diabetes mellitus: a randomized...

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