The Efficacy of Testosterone Ointment on Insulin Resistance in Men with Metabolic Syndrome

Low levels of testosterone are related with metabolic syndrome and type 2 diabetes mellitus. Testosterone levels are considered to be negatively correlated with insulin resistance and HbA1c levels. There are also reports that testosterone replacement therapy reduces insulin resistance or improves glycemic control. Transdermal administration of testosterone ointment (Glowmin) is a method of drug administration that keeps blood concentrations stable and constant. In this study, testosterone ointment (Glowmin) was administrated as a testosterone supplement to male metabolic syndrome with low free testosterone levels. This study included 5 male metabolic syndrome with low free testosterone levels (mean age, 50.6 ± 8.8 years; mean BMI, 29.5 ± 3.1 kg/m2; mean waist circumference, 97 ± 7 cm; free testosterone levels, <8.5 pg/ml; values indicate means ± SD). Glowmin was administrated to the submandibular area at a dose of 0.3 g twice a day for 6 months. Three months after administration, a significant decrease was observed in fasting immunoreactive insulin levels, homeostasis model assessment for insulin resistance, total cholesterol and LDL-C. Six-months after administration, each of these parameter estimates remained steady. In conclusion, transdermal administration of testosterone ointment (Glowmin) gradually reduced insulin resistance in male metabolic syndrome with low free testosterone levels.

Testosterone levels are considered to be negatively correlated with insulin resistance and HbA1c levels [11][12][13]. There are also reports that testosterone replacement therapy reduces insulin resistance or improves glycemic control [13][14][15][16][17]. One report has shown that, in a hypogonadal man with type 2 diabetes mellitus, testosterone replacement therapy reduced insulin resistance and improved glycemic control [13]. At present, testosterone replacement therapy is administered mainly by Enarmon-Depot injection and has an immediate and reliable effect. However, the therapy induces extremely large fluctuations in blood testosterone concentrations; consequently, subjective symptoms may vary and adverse events such as plethora may occur. Because no self-injection kit has been approved, frequent visits to an outpatient clinic for injections are also a problem.
Meanwhile, transdermal administration of testosterone ointment (Glowmin, Daitou Pharma, Japan) is a method of drug administration that keeps blood concentrations stable and constant. However, there are only a few reports that assess whether this mode of administration has an immediate and reliable effect.
In this study, testosterone ointment (Glowmin) was administrated as a testosterone supplement to men with metabolic syndrome who had low FT levels. The effect on insulin resistance was then assessed.

Subjects and Methods
This study included 5 men with metabolic syndrome who had low FT levels (mean age, 50.6 ± 8.8 years; mean body mass index [BMI], 29.5 ± 3.1; mean waist circumference [WC], 97 ± 7 cm; values indicate means ± standard deviation [SD]). This sample included 3 men receiving oral antihypertensive agents and 2 men receiving oral antihyperlipidemic agents. A low FT level was defined as less than 8.5 pg/ml, which is the level recommended by the diagnostic algorithm for late-onset hypogonadism (LOH) syndrome [18]. Metabolic syndrome was defined as a case meeting the Japanese diagnostic criteria [19]. Specifically, men with metabolic syndrome included those with a WC ≥ 85 cm and who met at least 2 of the following 3 criteria: 1) hypertriglyceridemia (≥ 150 mg/dl) and/or low levels of high-density lipoprotein (HDL) cholesterolemia (<40 mg/dl); 2) systolic blood pressure ± 130 mmHg and/or diastolic blood pressure ≥ 85 mmHg; and 3) fasting plasma glucose (FPG) level ≥ 110 mg/dl. All subjects provided informed consent, and Glowmin was administrated to the submandibular area at a dose of 0.3 g twice a day for 6 months. The following parameters were measured before administration of Glowmin and 1, 3, and 6 months after administration, and their fluctuations were analyzed: BMI, WC, FPG, fasting immunoreactive insulin (F-IRI), HbA1c, homeostasis model assessment for insulin resistance (HOMA-R), total cholesterol (TCHO), triglycerides (TG), HDL-cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C, calculated by the Friedewald equation), and FT. HOMA-R was calculated from FPG and F-IRI as follows: HOMA-R ± FPG [mg/dl] × F-IRI [µIU/ml]/405. Free testosterone level was measured by free testosterone RIA kit (Sceti Medicallabo, Sakura city, Chiba, Japan).
The results were expressed as means ± SD. Paired t-tests were performed to compare parameters before and after the administration of Glowmin. A p-value of less than 0.05 was considered to indicate statistical significance.
This study was conducted with the approval of the Ethics Committee of Toho University Omori Medical Center (No. 25-104).

Discussion
Low testosterone level is thought to impair insulin sensitivity and increase body fat percentage, and is associated with truncal obesity, dyslipidemia, hypertension, and cerebrovascular diseases [20]. An epidemiological study has shown that the prevalence of testosterone deficiency is as high as 40% in men with type 2 diabetes mellitus [4]. Furthermore, it has been reported that individuals with metabolic syndrome have lower levels of endogenous total testosterone and FT than those without metabolic syndrome [21]. In addition, low testosterone level is a predictive factor for the development of insulin resistance, metabolic syndrome, and type 2 diabetes mellitus [22].
In 2006, Kapoor et al. [1] reported that testosterone replacement therapy reduced insulin resistance in hypogonadal men with type 2 diabetes mellitus [13]. After testosterone ester was intramuscularly injected at a dose of 200 mg once every 2 weeks for 3 months, insulin resistance (-1.73, HOMA-R) and HbA1c levels (-0.37%) reduced. In addition, improvements in WC, leptin, and TCHO were also observed. Even with transdermal supplementation of testosterone (2% testosterone gel), insulin resistance reduced by 15% after 6 months and 16% after 12 months in hypogonadal men with type 2 diabetes mellitus or metabolic syndrome [17].
In this study, testosterone ointment (Glowmin) was administrated to men with metabolic syndrome who had low FT levels to supplement testosterone, and the effects on glucose and lipid metabolism were assessed. The improvement of insulin resistance and serum lipid level was maintained even 6 months after administration. The FT levels significantly increased 1 month after administration, and the metabolic parameters were assumed to have improved gradually. In this study, Glowmin was administrated to the submandibular area at a dose of 0.3 g twice a day. Studies on the effects of Glowmin on metabolic parameters and the incidence of adverse events might need to be conducted with administration to the abdomen at a dose of 0.6 g per day, and improved administration methods would facilitate long-term use. The mechanism that testosterone improves HOMA-R and LDL-C without changing BMI, glycemia and HbA1c levels is uncertain at present. We speculate that the decrease of visceral fat will became deeply involved. In this study, the improvement of BMI and waist circumference were not demonstrated. However, if we have more longer period of observation, waist circumference may be reduced, because waist circumference has tendency to be decreased compared with values before treatment.

Conclusion
Transdermal administration of testosterone ointment (Glowmin) gradually reduced insulin resistance in men with metabolic syndrome who had low FT levels.