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,
From Business Unit Primary Care, Men's
Healthcare, Scientific Affairs, Bayer Schering Pharma AG, Berlin, Germany;
Gulf Medical University, Ajman, United Arab
Emirates; and the Department of Endocrinology,
Vrije University Medical Center, Amsterdam, the Netherlands. *
Dr Heufelder is in private practice in Munich,
Germany.
| Correspondence to: Dr Louis Gooren, Department of Endocrinology, VU University Medical Center, De Boelelaan 1117, 10881 HV Amsterdam, the Netherlands (e-mail: louisjgooren{at}gmail.com). |
| Received for publication October 20, 2008; accepted for publication June 1, 2009. |
Men with the metabolic syndrome (MetS) and type 2 diabetes (T2D) often have
low testosterone levels. Elevating low testosterone levels may improve
features of the MetS and glycemic control. In a single blind, 52-week
randomized clinical trial, the effects of supervised diet and exercise
(D&E) with or without transdermal testosterone administration on
components of the MetS in hypogonadal men with the MetS and newly diagnosed
T2D were assessed. A total of 32 hypogonadal men (total testosterone <12.0
nmol/L) with newly diagnosed T2D and with the MetS as defined by the Adult
Treatment Panel III and the International Diabetes Federation received
supervised D&E, but 16 received it in combination with testosterone gel
(50 mg) once daily (n = 16). No glucose-lowering agents were administered
prior to or during the study period. Outcome measures were components of the
MetS as defined by the Adult Treatment Panel III and the International
Diabetes Federation. Serum testosterone, glycosylated hemoglobin
(HbA1c), fasting plasma glucose, high-density lipoprotein
cholesterol, triglyceride concentrations, and the waist circumference improved
in both treatment groups after 52 weeks of treatment. Addition of testosterone
significantly further improved these measures compared with D&E alone. All
D&E plus testosterone patients reached the HbA1c goal of less
than 7.0%; 87.5% of them reached an HbA1c of less than 6.5%. Based
on Adult Treatment Panel III guidelines, 81.3% of the patients randomized to
D&E plus testosterone no longer matched the criteria of the MetS, whereas
31.3% of the D&E alone participants did. Additionally, testosterone
treatment improved insulin sensitivity, adiponectin, and high-sensitivity
C-reactive protein. Addition of testosterone to supervised D&E results in
greater therapeutic improvements of glycemic control and reverses the MetS
after 52 weeks of treatment in hypogonadal patients with the MetS and newly
diagnosed T2D.
Key words: Male hypogonadism, insulin resistance, HbA1c, lipids, blood pressure
Individuals with T2D often show disturbances consistent with the metabolic syndrome (MetS; Haffner, 2006). On the other hand, individuals with the MetS have increased risk of developing T2D (Hanley et al, 2005). Several definitions of the MetS have been presented in the literature, of which the definitions from the Adult Treatment Panel III (ATP III; Grundy et al, 2004) and the International Diabetes Federation (IDF; Alberti et al, 2005) are the most commonly used. The syndrome includes atherogenic dyslipedemia, abdominal adiposity, and elevated blood pressure in the presence of T2D or an elevated fasting plasma glucose concentration (Kalyani and Dobs, 2007). Most of these symptoms are also often encountered in hypogonadal men (Muller et al, 2005; Traish et al, 2009), and low levels of endogenous sex hormones predict the MetS (Kalyani and Dobs, 2007). Treatment with exogenous testosterone has been shown to improve these metabolic derangements (Kapoor et al, 2006). In another recently published study, testosterone replacement therapy appeared to have beneficial effects on circulating high-sensitive C-reactive protein (hsCRP) levels in individuals with T2D, which some have considered as a key factor in the development of insulin resistance and the MetS (Haffner, 2006).
The goal of the current study was to assess the effects of 52-week treatment with supervised diet and exercise alone or in combination with transdermal testosterone administration on glycemic control and the various components of the MetS in hypogonadal men with the MetS and newly diagnosed T2D.
Materials and Methods
Subjects and Intervention
A total of 32 hypogonadal males with the MetS and newly diagnosed T2D
(fasting plasma glucose >7.0 at baseline and/or >11.1 after a 2-hour,
75-g oral glucose tolerance test, and an elevated level of HbA1c)
were randomized to either supervised diet and exercise (D&E) alone or in
combination with testosterone gel (50 mg once daily; Testogel; Bayer Schering
Pharma AG, Berlin, Germany). The procedure of randomization followed
recommendations as described in Kenjo et al
(2000). The gel was provided
by the personnel of the Business Unit Primary Care, Men's Healthcare,
Scientific Affairs, Bayer Schering Pharma AG, Berlin, Germany; hospital
pharmacy not involved in the study. The study design was single blind; that
is, study personnel were not aware of the treatment arm to which participants
were randomized, and participants were instructed by the prescribing physician
not to disclose their treatment to study personnel. Testosterone deficiency
was defined as a morning plasma testosterone concentration lower than 12
nmol/L on 2 occasions (normal >14.0 nmol/L). For safety reasons, only
participants with a serum prostate-specific antigen (PSA) concentration lower
than 4.0 µg/L and with a normal digital rectal examination of the prostate
were included. The MetS was defined according to the definition of the IDF
(Alberti et al, 2005).
Participants had not been treated previously with any oral antihyperglycemic
agent or insulin. Participants received supervised D&E recommendations by
certified dieticians and physiotherapists. They were frequently (at least
twice a week) contacted by telephone, text messaging, and e-mail to encourage
adherence to treatment. In short, participants were instructed to have 3 meals
per day that were low glycemic load, low in saturated fats, and rich in
omega-3 fatty acids, and to attempt to eat approximately 25% fewer calories
per meal compared with their pretreatment diet. At each visit, the advised
dietary changes were reviewed. Additionally, participants were offered a
controlled and supervised physical activity program: participants walked 3
times per week for 30 minutes and were told to do 15 minutes of
muscle-building exercises with weights or elastic strings 3 times per week.
Probably, as a result of frequent interactions between staff and participants,
compliance with diet and exercise was 100%, and none of the participants
dropped out of the study. Finally, in both treatment groups, participants were
contacted by telephone twice a week for additional follow-up and advice by a
research nurse. All participants completed the study without adverse effects
and without protocol violations, and no oral or injectable treatment of the
diabetes was allowed or used.
Measures
Participants visited the clinic every 13 weeks for assessment; laboratory
tests were done at pretreatment and at 13 and 52 weeks of treatment.
Bioavailable and free testosterone levels were calculated using the method
available at the International Society for the Study of the Aging Male Web
site
(www.issam.ch/freetesto.htm).
Waist circumference was measured and recorded to the nearest 0.5 cm.
Insulin and C-peptide measurements were conducted under standard fasting conditions (after an overnight fasting for at least 12 hours, and no food or fluid intake prior to sampling). The homeostatic model assessment (HOMA) was calculated using a single sample according to Levy et al (1998). Safety parameters, including digital rectal examination of the prostate and measurement of serum PSA, were performed at all visits. All participants gave their written informed consent. The study was approved by the local ethics review board and conducted according to the principles of the declaration of Helsinki.
Statistical Analysis
All data were presented as mean ± SE, unless stated otherwise.
Between treatment groups, pretreatment parameters were analyzed using an
unpaired Student's t test. Chi-square tests were used to test
dichotomous variables. Between-treatment group comparisons of differences from
pretreatment were made with an analysis of covariance model including terms
for treatment group, pretreatment value, and pretreatment x treatment
group interaction. Thus, the model adjusted for any potential influence of
differences in pretreatment value on the response to treatment. Pearson's
univariate correlation coefficients were used to describe between-parameter
correlations. Statistical analysis was performed with SPSS 16.0 for Mac OS X
(SPSS, Chicago, Illinois). P values below .05 were considered
statistically significant.
Results
Baseline characteristics are shown in Table 1. Besides a small, statistically significant difference in baseline hsCRP concentration, no significant differences prior to treatment were present between the 2 treatment groups.
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Effects on Sex Hormones
In the D&E and D&E plus testosterone treatment groups, mean
± SE serum testosterone concentrations significantly increased from
10.4 ± 0.2 nmol/L to 11.2 ± 0.2 nmol/L and from 10.5 ±
0.2 nmol/L to 15.4 ± 0.2 nmol/L, respectively, after 52 weeks of
treatment (between-group difference ± SE, 4.1 ± 0.2 nmol/L;
P < .001; Figure
1). Bioavailable testosterone increased from 4.3 ± 0.1
nmol/L to 5.5 ± 0.1 nmol/L and from 4.5 ± 0.1 nmol/L to 8.1
± 0.1 nmol/L in the D&E and D&E plus testosterone groups,
respectively (between-group difference ± SE, 2.5 ± 0.1 nmol/L;
P < .001; Figure
1). Serum sex hormone–binding globulin (SHBG) concentrations
decreased from 39.7 ± 2.2 nmol/L to 30.8 ± 1.3 nmol/L in the
D&E group and from 37.9 ± 2.0 nmol/L to 28.7 ± 0.7 nmol/L in
the D&E plus testosterone group. However, no significant between-group
differences in serum SHBG concentration were observed after 52 weeks of
treatment (P = .142). Compared with D&E alone, D&E plus
testosterone administration did not increase circulating PSA levels
(between-group difference ± SE, –0.08 ± 0.1 µg/L;
P = .435).
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Effects on Components of the MetS and Insulin Sensitivity
All components of the MetS improved after 52 weeks of treatment with either
supervised D&E alone or in combination with testosterone gel
(Table 2;
Figure 2). Waist circumferences
declined in both groups but more so in the D&E plus testosterone group. A
total of 62.5% of the patients treated with D&E plus testosterone no
longer matched the criteria of the MetS according to the IDF definition,
whereas 12.5% of the D&E alone patients did (P = .003). When
diagnosed with the less-stringent ATP III definition, 81.3% D&E plus
testosterone patients and 31.3% D&E alone patients had recovered from the
MetS after 52 weeks of treatment (P = .004). Changes in serum
testosterone concentrations correlated significantly with changes in the
individual components of the MetS, and these correlations are shown in
Table 3.
|
Discussion
In the present study, we investigated the effects of 52-week transdermal testosterone administration in addition to supervised D&E in hypogonadal men with the MetS and newly diagnosed T2D. A low serum testosterone concentration predicts or is associated with the MetS (Svartberg et al, 2004; Traish et al, 2009) and T2D (Chubb et al, 2008). In addition to the evidence from epidemiologic studies, there appears to be a positive correlation between serum testosterone levels and insulin sensitivity in men across the full spectrum of glucose tolerance (Pitteloud et al, 2005), and this relationship is at least partially direct and not fully dependent on (changes in) elements of the MetS (Yialamas et al, 2007). However, intervention studies are needed to test whether normalization of testosterone levels in hypogonadal men improves insulin resistance and other features of the MetS.
In our study, supervised D&E alone led to significant improvements in testosterone concentrations, glycemic control, and components of the MetS. The addition of a relatively low-dose testosterone preparation (ie, 50 mg of transdermal testosterone gel per day), raising serum testosterone concentrations to the lower range of normal, led to a significant, additional, improvement of glycemic control, insulin sensitivity, and reversal of the MetS in most participants. Results of this study indicate that diet control, exercise, and testosterone supplementation may be beneficial in the management of men with T2D.
The main weakness of our study is the absence of an actively treated placebo group; however, this was not possible because of the design of the study and medication used. Despite this shortcoming in study design, our study was randomized, and the investigators were blinded; only the patients were aware of the treatment group to which they were randomized. Also, supervised D&E by certified staff was offered to both treatment groups.
Clinical studies that evaluate the effect of normalization of serum testosterone concentrations on glucose homeostasis are few (Lee et al, 2005; Basu et al, 2007). These studies employed different experimental designs, and their results showed limited beneficial effects of testosterone administration (Kapoor et al, 2006). In addition, androgen-deprivation therapy in males with prostatic cancer may be associated with an increased risk for T2D, which may be caused by negative effects on insulin sensitivity (Smith et al, 2006).
In our study, insulin sensitivity, measured by HOMA, improved in both groups and with a significantly greater degree when testosterone was added to supervised D&E. Fasting insulin concentrations, a good representative of insulin sensitivity, did show a significant correlation with changes in circulating androgen levels, an observation in support of Pitteloud et al (2005), who showed a direct relationship between insulin sensitivity and circulating testosterone concentrations using the hyper-insulinemic euglycemic clamp technique, the gold standard for the assessment of whole-body insulin sensitivity.
Other than insulin sensitivity, 52 weeks of testosterone treatment also significantly improved circulation levels of adiponectin and hsCRP, key serum markers of insulin sensitivity and hepatic steatosis, respectively. Reports from the 1960s and 1970s already reported the beneficial effects of testosterone administration on hepatic fat content in patients with hepatosteatosis (Resnick and Iber, 1972). The changes in both adiponectin and hsCRP were significantly correlated with the therapy-induced changes in bioavailable testosterone. Our findings are not in line with a previous placebo-controlled, randomized study in hypogonadal T2D patients. In these studies, adiponectin levels decreased after 3 to 6 months of treatment with mixed testosterone esters (Lanfranco et al, 2004). As in our study, a negative correlation was found between hsCRP levels and bioavailable testosterone. The opposing findings in the circulating adiopnectin concentrations could be a result of the different routes of testosterone administration used. After intramuscular testosterone injections, circulating testosterone levels are known to peak above the physiologic range, whereas transdermal testosterone gel produces testosterone levels within the reference range for young adults (Gooren and Bunck, 2004). We found a decline in serum levels of hsCRP upon D&E plus testosterone, a finding not reported by Kapoor et al (2007) but replicated in a recent study (Haider et al, 2009).
In summary, our study shows the beneficial effects of supervised D&E treatment on glycemic control, components of the MetS, and insulin sensitivity in hypogonadal patients with the MetS and newly diagnosed T2D. These effects were even greater when transdermal testosterone gel was added to the supervised D&E, which resulted in more than 80% of the patients showing conversion from the MetS, reaching all of the currently set targets for glycemic control. However, more intervention studies investigating the effects of testosterone replacement therapy on pancreatic beta-cell function in hypogonadal men with T2D are needed to fully understand the relationship between circulating sex hormones and carbohydrate metabolism. Finally, serum PSA concentrations did not differ between the 2 treatment groups, indicating that short-term testosterone administration appears to be acceptably safe.
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