|Year : 2015 | Volume
| Issue : 1 | Page : 29-35
Diabetes mellitus link with hypogonadism in male patients with type 2 diabetes mellitus aged 40-50 years
Nagla F Almihy MD 1, Eman A Eissa2, Eman R Amer2, Mohamed El-Assal3
1 Department of Internal Medicine, Benha Teaching Hospital, Benha, Egypt
2 Department of Clinical Pathology, Benha Teaching Hospital, Benha, Egypt
3 Department of Internal Medicine, Benha University, Benha, Egypt
|Date of Submission||12-May-2015|
|Date of Acceptance||19-May-2015|
|Date of Web Publication||26-Nov-2015|
Nagla F Almihy
Department of Internal Medicine, Benha Teaching Hospital, Qaliubiya-Kafr Shukr-Gamal Abdel Nasser Street, Beside the Benzion-home of Dr Farouk Ahmed Almihy, Benha
Source of Support: None, Conflict of Interest: None
Testosterone levels are frequently low in men with type 2 diabetes mellitus (DM), and the majority of these men have symptoms of hypogonadism. Obesity is associated with low testosterone levels in diabetic men. The aim of our work was to study the link between type 2 DM in men aged 40-50 years and the increased incidence of hypogonadism.
Patients and methods
Our study included two groups of patients: group A, which included 40 male diabetic patients (type 2) aged 40-50 years, and group B, which included 40 healthy age-matched control individuals. All patients and controls were subjected to a medical questionnaire and examination of BMI, waist-hip ratio (WHR), and laboratory investigations for evaluation of total testosterone, free testosterone, sex hormone binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, and glycosylated Hb (HbA1c).
The patient group showed a significant decrease in serum total testosterone (3.83 ± 2.18 ng/ml), free testosterone (4.15 ± 2.08 pg/ml), and SHBG (27.48 ± 10.07 nmol/l) in comparison with the control group (6.14 ± 1.37 ng/ml, 13.82 ± 5.14 pg/ml, and 62.85 ± 9.17 nmol/l, respectively), a highly significant decrease in LH and FSH (2.35 ± 1.98 mIU/ml and 4.79 ± 2.72 IU/ml, respectively, vs. 4.56 ± 1.22 mIU/ml and 6.88 ± 1.69 IU/ml in the control group), and significant increase in prolactin and HbA1c (19.014 ± 8.65 ng/ml and 6.85 ± 2.12%, respectively, vs. 6.51 ± 2.2 and 4.3 ± 1.16 in the control group). In addition, there was a significant increase in BMI (35.2 ± 3.56 kg/m 2 ) and WHR (1.02 ± 0.12) in comparison with the control group (22.22 ± 1.76 kg/m 2 and 0.8 ± 0.04, respectively). Total testosterone concentration showed a positive nonsignificant correlation with SHBG (r = 0.076) but significant positive correlation with FSH and LH (r = 0.672 and 0.696, respectively) and significant negative correlation with serum HbA1c, BMI, and WHR (r = −0.324, −0.442, and −0.306, respectively) and highly significant negative correlation with prolactin (r = −0.783) in male patients with type 2 DM. Free testosterone showed a nonsignificant negative correlation with SHBG (r = −0.0229) and significant negative correlation with HbA1c, BMI, and WHR (r = −0.311, −0.373, and −0.374, respectively) but a highly significant negative correlation with prolactin (r = −0.740) and a highly significant positive correlation with FSH and LH (r = 0.798 and 0.762) in male patients with type 2 DM.
This study demonstrates that significant number of men with type 2 DM aged between 40 and 50 years have testosterone insufficiency and symptoms of hypogonadism.
Keywords: Diabetus mellitus, hypogonadism, in male aged 40 to 50 years
|How to cite this article:|
Almihy NF, Eissa EA, Amer ER, El-Assal M. Diabetes mellitus link with hypogonadism in male patients with type 2 diabetes mellitus aged 40-50 years. Benha Med J 2015;32:29-35
|How to cite this URL:|
Almihy NF, Eissa EA, Amer ER, El-Assal M. Diabetes mellitus link with hypogonadism in male patients with type 2 diabetes mellitus aged 40-50 years. Benha Med J [serial online] 2015 [cited 2017 Sep 19];32:29-35. Available from: http://www.bmfj.eg.net/text.asp?2015/32/1/29/170556
| Introduction|| |
Cross-sectional studies have found that between 20 and 64% of men with diabetes have hypogonadism, with higher prevalence rates found in the elderly. Hypogonadism can be a risk factor for the development of diabetes and metabolic syndrome through various mechanisms including changes in body composition, androgen receptor polymorphisms, glucose transport, and reduced antioxidant effect. Conversely, diabetes and the metabolic syndrome can be risk factors for hypogonadism through some similar but mostly distinct mechanisms, such as increased body weight; decreased sex hormone binding globulin (SHBG) levels, suppression of gonadotrophin release or Leydig cell testosterone production, cytokine-mediated inhibition of testicular steroid production, and increased aromatase activity contributing to relative estrogen excess  .
Type 2 diabetes mellitus (DM)-associated hypogonadism might exacerbate sexual dysfunction by reducing libido and mood and further compromising penile vascular reactivity and lipid metabolism. Hence, testing circulating testosterone is strongly recommended in type 2 DM patients with erectile dysfunction  .
Type 2 DM affects one-third of men aged 65 years and above, and the prevalence is expected to increase 69% over the next two decades. Observational studies consistently show that men with diabetes have lower total testosterone levels compared with nondiabetic controls  . At least 25% of men with type 2 DM have evidence of secondary hypogonadism, and an additional 4% have primary hypogonadism. Given the strong correlation between diabetes and testosterone deficiency, the Endocrine Society recommends the routine measurement of testosterone in patients with type 2 DM. The relationship between testosterone and type 2 DM is complex and likely mediated by obesity  . Still, several studies suggest that men with low testosterone are at a greater risk of developing type 2 DM, and low testosterone may even predict the onset of diabetes  .
Testosterone replacement therapy reduces insulin resistance and improves glycemic control in hypogonadal men with type 2 diabetes. Improvements in glycemic control, insulin resistance, cholesterol, and visceral adiposity together represent an overall reduction in cardiovascular risk  .
| Patients and methods|| |
Forty adult male diabetic patients with type 2 DM, aged between 40 and 50 years (mean = 44.6 ± 3.7), who were undergoing follow-up in the diabetic outpatient clinic in Benha Teaching Hospital and Benha University Hospital were selected for the study. Twenty-one patients were under oral hypoglycemic therapy, 11 patients were under insulin therapy, and eight patients were under both oral hypoglycemic and insulin therapy.
Diabetic patients receiving hormonal replacement therapy as well as those with cardiac disease, liver diseases, infection, or other chronic diseases were excluded.
All patients gave written informed consent according to hospital research ethics. Assessments were always made between 8 and 10 a.m.; patients were screened initially with a questionnaire detailing their medical history and concomitant medications.
Height and weight were measured and BMI was calculated. Waist and hip circumferences were measured and waist-hip ratio (WHR) was calculated (the waist at the navel and hips at the tip of the hip bone).
Patients were asked to complete an Androgen Deficiency in the Aging Male (ADAM) questionnaire. This is a 10-item screening questionnaire used to evaluate androgen deficiency in aging men. Positive response was defined as decrease in libido or strength of erection, or a positive answer to any three nonspecific questions that include fatigability, decrease in muscle strength, and mood changes. This questionnaire has 88% sensitivity and 60% specificity and should be used only in the presence of a low testosterone level.
Forty healthy normal volunteers ranging from 40 to 50 years (mean = 44.39 ± 3.53 years) were chosen as the control group. All individuals gave their informed written consent for the study.
Fasting venous samples were taken during the patient visit to the diabetic clinic to measure serum total testosterone, free testosterone, SHBG, prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and HbA1c.
Hormonal assay for patients and controls
Serum level of testosterone, free testosterone and sex hormone B protein  , (using kits provided by DRG International Inc., Germany), prolactin  , (using kits provided by Omega Diagnostic, United Kingdom), FSH and LH  , (using kits provided by Immunospec Corporation, USA), were evaluated.
A volume of 5 ml of blood was collected from each patient and control and allowed to clot at room temperature. Serum was separated and stored at −20°C until analysis.
The principle of the analysis
The procedure followed the basic principle of enzyme immunoassay in which a competition occurs between an unlabeled antigen and an enzyme-labeled antigen bound to the antibody sites. The amount of enzyme-labeled antigen bound to the antibody binding sites is irreversibly proportional to the concentration of the unlabeled analyte present. The unbound antibody is inversely proportional to the concentration of the unlabeled analyte present. Unbound materials are removed by decanting and washing the wells. The absorbance measured is inversely proportional to the concentration of hormone present in the serum. A set of hormone standards is used to plot a standard curve of absorbance versus hormone from which the hormone concentration in the samples can be calculated.
Determination of glycohemoglobin was performed by mixing a sample of hemolyzed whole blood with cation exchange resin. The nonglycosylated HG binds to the resin, leaving HG A1 free to be removed by means of rising separation on the supernatant. Absorbance was read at 415 nm  .
Data were expressed as mean ± SD. Student's t-test was used to assess the difference between the studied parameters in the two groups. Correlation coefficient (r) was used to evaluate the relation between the studied parameters in the same group. Probability (P) was considered significant if less than 0.05 and highly significant if less than 0.001  .
| Results|| |
Forty male patients having type 2 DM were studied. The clinical data of these patients are summarized in [Table 1]. Forty-five percent of patients had positive symptoms of hypogonadism (18 patients), 52.5% were under oral hypoglycemic drugs (21 patients), 27.5% were under insulin therapy (11 patients), and 20% were under both oral hypoglycemic drugs and insulin therapy (eight patients).
Comparative studies were carried out between diabetic patients and controls as regards total testosterone, free testosterone, SHBG, FSH, LH, glycosylated hemoglobin (HbA1c), prolactin hormone, BMI, and WHR. A significant decrease was seen in serum total testosterone (3.83 ± 2.18 ng/ml), free testosterone (4.15 ± 2.08 pg/ml), and SHBG (27.48 ± 10.07 nmol/l) in comparison with controls (6.14 ± 1.37 ng/ml, 13.82 ± 5.14 pg/ml, and 62.85 ± 9.17 nmol/l, respectively) (P < 0.05 or P < 0.01) and a highly significant decrease in LH (2.35 ± 1.98 mIU/ml) and FSH (4.79 ± 2.72 IU/ml) (P < 0.001); a significant increase was found in prolactin (19.014 ± 8.65 ng/ml) and HbA1c (6.85 ± 2.122%) in comparison with controls (6.51 ± 2.2 ng/ml and 4.3 ± 1.16%, respectively) (P < 0.05 and P < 0.01, respectively), and a significant increase in BMI (35.2 ± 3.56 kg/m 2 ) and WHR (1.02 ± 0.12) (control values were 22.22 ± 1.76 kg/m 2 and 0.8 ± 0.04, respectively; P < 0.05) ([Table 2]).
|Table 2 Comparison of serum total testosterone, serum free testosterone, serum sex hormone binding globulin, serum follicle-stimulating hormone, serum luteinizing hormone, serum prolactin, serum HbA1c, BMI, and waist– hip ratio in male patients with type 2 diabetes mellitus and the control group|
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Total testosterone concentration showed a positive nonsignificant correlation with SHBG (r = 0.076, P > 0.05) but significant positive correlation with FSH (r = 0.672, P < 0.01) and LH (r = 0.696, P < 0.01) and a significant negative correlation with serum HbA1c (r = −0.324), BMI (r = −0.442, P < 0.05), and WHR (r = −0.306, P < 0.05) and a highly significant negative correlation with prolactin (r = −0.783, P < 0.001) in male patients with type 2 DM ([Table 3]).
|Table 3 Correlation between serum total testosterone and waist– hip ratio, BMI, serum HbA1c, serum luteinizing hormone, serum follicle-stimulating hormone, serum sex hormone binding globulin, and serum prolactin|
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Free testosterone showed a nonsignificant negative correlation with SHBG (r = −0.0229, P > 0.05) and a significant negative correlation with HbA1c (r = −0.311, P<0.05), BMI (r = −0.373, P < 0.05), and WHR (r = −0.374, P < 0.05); however, a highly significant negative correlation was seen with prolactin (r = −0.740, P < 0.001) and a highly significant positive correlation with FSH (r = 0.798, P < 0.001) and LH (r = 0.762, P < 0.001) in male patients with type 2 DM ([Table 4]).
|Table 4 Correlation between serum free testosterone and waist– hip ratio, BMI, serum HbA1c, serum luteinizing hormone, serum follicle-stimulating hormone, serum sex hormone binding globulin, and serum prolactin|
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SHBG was negatively and significantly correlated with WHR (r = −0.255, P < 0.05) and BMI (r = −0.538, P < 0.05), as seen in [Table 5].
|Table 5 Correlation between serum sex hormone binding globulin and waist– hip ratio and BMI|
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| Discussion|| |
In the present study we found a high prevalence (45%) of symptomatic hypogonadism in type 2 diabetic men aged 40-50 years. Dheeraj et al.  also showed a high prevalence of symptomatic hypogonadism (42%) in type 2 DM patients in the same age group (40-49 years). Dhindsa et al.  showed that about 33% of type 2 DM men have low serum testosterone levels but these studies did not correlate this value with symptoms. In line with these two studies , we have demonstrated that low testosterone levels cannot be explained only by the lower levels of SHBG associated with insulin resistance. In our study we found significant decrease in total testosterone and free testosterone in comparison with the control group. Testosterone is present in three major fractions: free (2-3%), albumin-bound (20-40%), and SHBG-bound (60-80%). Non-SHBG-bound testosterone is called bioavailable testosterone because both the free and albumin-bound fractions comprise the biologically active component that is readily available to the tissues, whereas SHBG-bound testosterone is tightly bound and thus considered inactive. A recent study has demonstrated that free testosterone levels, which are independent of SHBG, are low in one-third of diabetic men  .
Our data show that obesity and visceral adiposity, as assessed by both BMI and WHR, were significantly negatively correlated with levels of total and free testosterone ([Table 3] and [Table 4]) and that SHBG was significantly negatively correlated with WHR and BMI ([Table 5]).
Visceral obesity is an important cause of insulin resistance. Studies have shown that free testosterone levels are low in obese men and inversely correlate with the degree of obesity  . There is increased deposition of abdominal adipose tissue in hypogonadal subjects, which in turn leads to a further decrease in testosterone concentrations, through conversion to estradiol by aromatase. This leads to further abdominal fat deposition and a greater degree of testosterone deficiency  . Testosterone levels are further lowered as a result of leptin resistance at the hypothalamic pituitary and testicular levels, causing reduced LH release and testosterone secretion  . Interventional studies have shown a beneficial effect of testosterone replacement therapy on insulin resistance. A study on healthy men with low total testosterone levels reported an improvement in insulin sensitivity with testosterone or dihydrotestosterone treatment  . Testosterone treatment has also been shown to reduce insulin resistance in obese men  , in men with heart failure  , and in type 2 diabetic subjects  . Two studies in type 2 diabetic men have shown an improvement in glycemic control  with testosterone replacement therapy, although in a small study of 10 men Corrales et al.  reported a neutral effect using intramuscular testosterone treatment. It is known that a reduction in the degree of obesity results in an elevation of testosterone levels.
The question thus arises as to why diabetic men have lower testosterone levels. In our study we found a highly significant decrease in FSH and LH in patients compared with the control group; free testosterone and total testosterone showed a highly significant positive correlation with FSH and LH.
In our study there was significant increase in serum prolactin in comparison with the control group and prolactin was highly negatively correlated with total and free testosterone. In other studies, prolactin levels were not different between hypogonadal and nonhypogonadal groups  . The levels were comparable to those in normal subjects. Gonadotropin concentrations were not elevated in the hypogonadal patients and thus the primary defect in these patients would appear to be either in the pituitary gland or in the hypothalamus. In fact, the LH and FSH levels were significantly lower in the hypogonadal group than in the eugonadal group  , which is in agreement with our study. This may suggest that the cause of hypogonadism in these patients could be decreased gonadotropin secretion. To rule out the possibility that the cause of hypogonadotropic hypogonadism was a pituitary lesion, the researchers carried out MRI in 10 randomly selected hypogonadal patients. None of the MRIs showed pituitary or hypothalamic abnormalities. Further resolution of this defect was not possible because GnRH was no longer available for testing. Thus, we could not define whether the defect originates in the pituitary or in the hypothalamus  . However, other studies on type 2 diabetic patients with erectile dysfunction had conducted some tests with GnRH  . These tests had revealed a normal LH and FSH increase, suggesting a hypothalamic rather than a pituitary defect.
The existence of a hypothalamic defect resulting in hypogonadotropic hypogonadism in type 2 diabetes is of interest in view of its association with insulin resistance. Neuron-specific insulin receptor knockout (NIRKO) mice with a specific knockout of the insulin receptor in neurons exhibit hypogonadotropic hypogonadism  . Plasma LH levels were decreased by 60-90% in NIRKO mice compared with controls. When these mice were injected with lupron, a GnRH receptor agonist, they displayed a normal to two-fold increase in LH levels compared with control mice. These mice also had increased adipose tissue and insulin resistance. Metabolic syndrome, insulin resistance, and visceral obesity have all been associated with low SHBG and low total T levels in men  .
Tsai et al.  found that, in nondiabetic men, calculated free testosterone and BT (non-SHBG-binding testosterone) correlate inversely with regional and overall body fat as well as with measures of insulin resistance.
In the study by Dhindsa et al.  , total testosterone correlated inversely with BMI. In a multiple linear regression model using testosterone, BMI, and SHBG, both BMI and SHBG were independent predictors of testosterone. Thus, it seems that, in diabetic patients, BMI has an effect on testosterone independently of SHBG concentrations.
It is believed that the low total testosterone in obesity is caused by low SHBG concentrations. However, free testosterone levels have also been found to be low in massively obese men, and the defect appears to be at the hypothalamic or pituitary level. This is in agreement with our study, which showed that total testosterone negatively and significantly correlated with BMI (r = −0.442, P < 0.05).
Zumoff et al.  found that both free testosterone and non-SHBG-bound testosterone correlated inversely with BMI. This is in agreement with our study, which showed that free testosterone negatively correlated with BMI (r = −0.373, P < 0.05).
Other studies also found that total and free testosterone decreased significantly with increased BMI, waist circumference (P < 0.05), and body fat percentage  .
In the study by Vermeulen et al.  35 obese men had significantly lower free testosterone levels compared with 54 lean men. The free testosterone levels correlated inversely with BMI. They also compared LH pulsatility over 12 h in eight obese and eight lean men and found that the mean integrated LH levels over 12 h were significantly lower in obese men. Free testosterone levels correlated positively with the sum of LH pulse amplitudes in each individual.
Our study also showed that free testosterone highly significantly correlated with LH (r = 0.762, P < 0.001).
It is remarkable that 57.9% of massively obese (BMI >40) patients in the study by Dhindsa et al.  were hypogonadal. They found that LH levels correlated significantly and positively with free testosterone concentrations. Thus, data from the literature on humans and NIRKO mice and from the our study and that by Dhindsa et al.  seem to suggest that obesity/insulin resistance is associated with hypogonadism and that hypogonadism appears to be hypogonadotropic in nature. Obesity is associated with increased plasma levels of proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6, C-reactive protein, and adhesion molecules  . In this regard, it is interesting to note that tumor necrosis factor-α and interleukin-1β have been shown to reduce hypothalamic GnRH and LH secretion in animals and in vitro  . In the study by Dhindsa et al.  , both free testosterone and non-SHBG-bound testosterone negatively and significantly correlated with BMI, which is in agreement with our study, which showed free testosterone negatively and significantly correlated with BMI (r = −0.373, P < 0.05).
Furthermore, a large number (31.3%) of lean subjects in the study by Dhindsa et al.  were hypogonadal. Thus, although obesity may explain a part of the high prevalence of hypogonadism, it is likely that other factors associated with type 2 diabetes also contribute significantly.
Testosterone status is becoming increasingly recognized as essential in the assessment and treatment of men with erectile dysfunction. It has been established that men with erectile dysfunction who do not respond to sildenafil frequently have hypogonadal levels of testosterone  , and testosterone replacement therapy converts 60% of sildenafil nonresponders into responders  . Furthermore, there is recent evidence that testosterone replacement therapy improves insulin resistance, glycemic control, cholesterol levels, and waist circumference in diabetic men with low testosterone levels  .
Although testosterone replacement therapy was introduced into clinical practice to improve sexual function in hypogonadal men, there is increasing interest in the use of testosterone replacement therapy to address the array of adverse metabolic issues associated with testosterone deficiency. Given the physiologic importance of testosterone to insulin sensitivity, inflammation, vasodilatation, and endothelial function, restoring optimal testosterone levels has many potential benefits in men with hypogonadism  .
| Conclusion|| |
This study demonstrates that a significant number of men with type 2 DM between 40 and 50 years of age have testosterone insufficiency and symptoms of hypogonadism.
Also diagnosis of hypogonadism is difficult in that the symptoms are nonspecific, especially in diabetic men, and this explains the importance of free testosterone measurement to diagnose hypogonadism in these patients. Further studies are required to establish the benefit of testosterone replacement therapy on the quality of life and the diabetic state in men with type 2 DM aged between 40 and 50 years.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]