Diabetes mellitus (DM) comprises a group of

Assessment of Hypogonadism with Reference to Clinical Features and Serum Testosterone Levels in Asian-Indian Male Type 2 Diabetics Ibraheem Khan*, Chandra Kant**, Anil Samaria Abstract Objective: To assess the prevalence of hypogonadism in Asian-Indian males with type 2 diabetes (T2DM) with reference to clinical feature and total serum testosterone levels. Material and methods: In the cross-sectional study of 50 diabetics of 30-76 years age group preferably without chronic illness, total testosterone, body mass index (BMI) and waist circumference (WC) were measured. Overt hypogonadism was defined as the presence of clinical symptoms of hypogonadism and low testosterone level (total testosterone <8 nmol/l). Borderline hypogonadism was defined as the presence of symptoms and total testosterone of 8-12 nmol/l. Results: A low serum testosterone level was common in diabetic men and a significant proportion of these men had symptoms of hypogonadism. Overt hypogonadism was seen in 30% of men with total testosterone levels <8 nmol/l and borderline hypogonadism was found in 28% of men with total testosterone levels 8-12 nmol/l. Total serum testosterone levels significantly and negatively correlated with both BMI (r = 0.334, p < 0.05) and WC (r = 0.443, p < 0.001), with the association being stronger for WC. HbA 1C also significantly and negatively correlated with serum testosterone levels (r = 0.503, p < 0.001). Conclusions: Testosterone levels are frequently low in men with T2DM and the majority of these men have symptoms of hypogonadism, even in the younger age group (early-onset hypogonadism). Obesity and BMI are also associated with low testosterone levels in Asian-Indian diabetic men. Keywords: Type 2 diabetes, serum testosterone, overt hypogonadism, obesity Diabetes mellitus (DM) comprises a group of common metabolic disorders that share the phenotype of hyperglycemia, factors may include reduced insulin secretion, decreased glucose utilization and increase glucose production depending upon the etiology of DM. Metabolic dysregulation associated with DM causes secondary pathophysiologic changes in multiple organ systems. DM, with its attendant acute and long-term complications and the myriad of disorders associated with it, is a major health hazard. 1 India has an estimated population of 44 million diabetic subjects, which is chiefly contributed by the urban population. 2 Type 2 diabetes (T2DM) in Indians differs from that in Europeans in several aspects: The onset is *Postgraduate **Professor Associate Professor Dept. of Medicine, Jawaharlal Nehru Medical College, Ajmer Address for correspondence Dr Ibraheem Khan Samraya, Weir, Bharatpur, Rajasthan - 321 408 E-mail: imedicine2008@gmail.com at a younger age, 3 obesity is less common 4 and genetic factors appear to be stronger. 5 Insulin resistance (IR) is an common feature of T2DM. 6 It is now increasingly being recognized that low testosterone level in men is associated with reduced insulin sensitivity and T2DM. 7 An inverse relationship has been seen between testosterone levels and insulin concentrations in healthy men. 8 Testosterone was inversely related to the degree of hyperglycemia. 9 IR and risk of diabetes development was more in patient with low testosterone levels. 10 Low testosterone was also associated with diabetic dyslipidemia. 9 A recent study has demonstrated that free testosterone levels, which are independent of sex hormone-binding globulin (SHBG), are low in onethird of diabetics. 11 Hypogonadism is defined as the presence of clinical symptoms and low testosterone levels (total testosterone <8 nmol/l). Although there is no uniform definition of classical hypogonadism, various guidelines for the diagnosis of hypogonadism are available, for example from Bhasin and colleagues. 12 Recently published recommendations that patients with total testosterone <8 nmol/l should be treated with testosterone therapy, 92 Indian Journal of Clinical Practice, Vol. 23, No. 2, July 2012

those with testosterone 8-12 nmol/l and hypogonadal symptoms should be given a trial of testosterone therapy, and those with total testosterone >12 nmol/ l are not hypogonadal and should not be treated. 13 Overt hypogonadism is the presence of clinical symptoms of hypogonadism and low testosterone levels (total testosterone <8 nmol/l). Borderline hypogonadism is the presence of symptoms along with total testosterone 8-12 nmol/l. The major symptoms of hypogonadism are reduced libido, reduced duration of erection, fatigue, reduced physical strength and mood changes. Questionnaires have been developed to assess hypogonadism. Androgen deficiency in the aging male (ADAM) questionnaire is one of them. It lacks specificity (66%) but it has reasonable sensitivity (88%) in the presence of low testosterone levels. This is a 10-item screening questionnaire used to evaluate ADAM. 14 Normal testosterone production rates by the Leydig cells vary considerably between healthy young individuals and range from 3 to 10 mg/day. 15 It is thought that most testosterone in the blood, about 65%, is strongly bound to SHBG; about 35% is relatively loosely to albumin and only 1-2% is free. Free and albumin-bound testosterone is called bioavailable testosterone because both fractions comprise the biologically active component that is readily available to the tissues, whereas SHBG-bound testosterone is tightly bound and thus considered inactive. Testosterone concentrations vary considerably between individuals. The normal range of total testosterone in young adult men being 12-35 nmol/l and bioavailable testosterone is 2.5-4.2 nmol/l. 16 Testosterone concentrations also follow a diurnal rhythm with highest levels in morning and falling by as much as 35% in the afternoon and evening. 17 A confounding factor is that SHBG rises with age, and thus free testosterone decreases more rapidly than total testosterone in older men. Thus, it is important to measure bioavailable or free testosterone in men with diabetes. Erectile dysfunction (ED) is best defined as persistent failure to generate sufficient penile body pressure to achieve vaginal penetration and/or the inability to maintain this degree of penile rigidity until ejaculation. 18 Symptomatically, ED is common in diabetic men, 19 although the etiology may be vascular disease, autonomic neuropathy, hypogonadism or a combination of these. 20 Erection is a complex process mediated by combination of neurotransmission and vascular smooth muscle responses due to increase arterial inflow and signaling by endothelial cavernosal sinusoids and underlying smooth muscle cells. Cholinergic parasympathetic pathways, nonadrenergic, noncholinergic pathways and endothelial cells, all release nitric oxide (NO) that triggers a molecular cascade result in the relaxation of smooth muscle cell and occluding venous return through venous compression of the subtunical venules resulting in an erection. Parasympathetic outflow is impaired in diabetics and causes reduction in NO resulting in smooth cell apoptosis and decrease in sinusoidal compliance leading to ED. 21 Loss of Libido Libido is defined as the biological need for sexual activity (the sex drive) and frequently is expressed as sex-seeking behavior. Evidence for a role of androgens in regulation of sexual behavior in the human male has been reviewed by Mooradian and colleagues. 22 In a study, withdrawal of androgen therapy in hypogonadal males led to a decline of libido in 3-4 weeks, and untreated hypogonadal men have impairment in spontaneity of erection. 23 According to Kapoor et al 63% diabetic men had loss of libido. Testosterone levels inversely correlate with waist circumference (WC) and body mass index (BMI). A plausible explanation for this is the hypogonadal - obesity cycle, which was first described by Cohen. 24 Essentially, visceral adipocytes have a high activity of the enzyme aromatase, which converts testosterone to estrogen. Testosterone inhibits the enzyme lipoprotein lipase, which takes up free fatty acids into adipocytes. 25 Lower testosterone levels result in increased triglyceride levels in adipocytes, which promote further adipocyte proliferation and hence higher aromatase activity. Testosterone levels are further lowered as a result of leptin resistance at the hypothalamic-pituitary and testicular levels, causing reduced luteinizing hormone (LH) release and testosterone secretion. 26 It is known that a reduction in the degree of obesity results in an elevation of testosterone levels. Dhindsa and colleagues conducted some tests with gonadotropin-releasing hormone (GnRH) in T2DM patients with ED and demonstrated a normal LH, and follicle-stimulating hormone (FSH) rise, suggesting a hypothalamic rather than a pituitary defect. 11 The existence of a hypothalamic defect resulting in hypogonadotropic hypogonadism in T2DM is of Indian Journal of Clinical Practice, Vol. 23, No. 2, July 2012 93

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. 27 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 2-fold increase in LH levels compared with control mice. These mice also had increased adipose tissue and IR. Metabolic syndrome, IR and visceral obesity have all been associated with low total testosterone levels in men. 28 Data from literature in humans and NIRKO mice and from the study by Dhindsa and colleagues, seem to suggest that obesity/ir is associated with hypogonadism and that the hypogonadism appears to be hypogonadotropic in nature. Obesity is associated with increased plasma levels of proinflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin (IL)-6, C-reactive protein and adhesion molecules. 29,30 In this regard, it is interesting to note that TNF-a and IL-1b have been shown to reduce hypothalamic GnRH and LH secretion in animals and in vitro. 31 So, it may be worthwhile to know the status of testosterone level in diabetic patients. Testosterone level is affected by factors like obesity, BMI and age of patient. 19 Bioavailable testosterone appears to represent reliable index of biologically readily available testosterone, but is not well-suited for clinical routine, being too time-consuming and expensive. Hypogonadism was defined in many studies 13,19 by total testosterone levels, so total testosterone levels can be used for the study. Very few studies have been done so far on this topic so an assessment of clinical hypogonadism in 50 patients of T2DM was done. AIM AND OBJECTIVES To estimate serum testosterone levels in T2DM. To correlate the serum testosterone levels with clinical hypogonadism in T2DM. MATERIAL AND METHODS The study was conducted at Jawaharlal Nehru Medical College and Associated Group of Hospitals, Ajmer, Rajasthan to evaluate clinical and biochemical hypogonadism in men with T2DM ( 5 years duration) attending medical OPD and various medical wards. Inclusion Criteria Male patients with T2DM in 30-76 years age group. Patients with T2DM 5 years. Normal value was taken as control for that age group. Exclusion Criteria Patients taking drugs which are known to interfere e.g., glucocorticoids, hormone replacement therapy, ketoconazole, opiods, alcohol, methadone, heroin and marijuana. Patients with features associated with congenital GnRH deficiency (midline facial defects, synkinesis or a family history of GnRH deficiency or anosmia). History of tumor, exposure to radiation, history of head trauma, spinal cord injuries, history of pelvic trauma and surgery. Any disease other than diabetes known to cause autonomic dysfunction. Any other chronic disease such as human immunodeficiency virus (HIV), end-stage renal disease, cirrhosis of liver and psychiatric disease. Special Investigations Total testosterone was measured by electrochemilumiscence immunoassay by ECLIA kit. In patient with diabetes, blood sample was collected always between 8 a.m. and 10 a.m. Serum sample was obtained by centrifugation. Sample remained stable for one week at 2-8 C, for six month at 20 C, though it was not needed to freeze the serum sample for storage. Examination of the Patients History Total 50 patients were taken. A detailed history of present illness was recorded including duration of the onset of symptoms (Table 1). Complete ADAM questionnaire, past history and family history for hypertension, and DM and history of medications was asked. Personal history like early morning erection, smoking, alcohol consumption, decrease in libido, lack of energy, decrease in strength and/or endurance, loss of height, decreased enjoyment of life, feeling of sadness and/or grumpy, decrease strength of erection, recent deterioration in ability to play sports and a recent deterioration in work performance were noted. Positive response was based on decreases in loss of libido, strength of erections or any three nonspecific 94 Indian Journal of Clinical Practice, Vol. 23, No. 2, July 2012

questions that include fatigability, mood changes and loss of height. Clinical Examination A detailed clinical examination was done. General examination including height, weight, WC (defined as the point midway between the iliac crest and the costal margin) and blood pressure (BP). Systemic examination included cardiovascular, respiratory, gastrointestinal and neurological examination (Table 1). Clinically ED (organic or psychogenic) was assessed by Stamp test Testicular sensation test Interruption of urination. OBSERVATION and RESULTS Statistical Analysis Values were expressed as a percentage of each group or as mean ± SE (standard error) unless otherwise stated. The impact of clinical variables on testosterone levels was determined by correlation. Comparisons between groups were made using X 2 test. The unpaired t test was used to compare testosterone levels in men with ED and without ED (Table 2). Student test was also used to compare testosterone in others variables like glycosylated hemoglobin (HbA 1C ), BMI, WC, smokers and nonsmokers, hypertension. Results were considered statistically significant at p < 0.05. Prevalence of low testosterone levels: Thirty percent (15 men) had testosterone level <8 nmol/l and 28% (14 men) had testosterone between 8 and 12 nmol/l. Prevalence of low testosterone levels was not uncommon in all age groups but it was maximum (80%) in old age >69 years and 43% in young adults (<40 years). Percentage of diabetic men with low testosterone per decade is shown in Figure 1. Prevalence of symptoms and low testosterone levels (hypogonadism): Prevalence of overt hypogonadism in diabetic patients with positive ADAM score was 30% (15 men) and borderline hypogonadism was 28% (14 men) based on symptoms as suggested by ADAM questionnaire and low serum testosterone levels. Incidence of positive symptoms in men with low testosterone by decade of age is shown in Figure 2. ED and loss of libido were the common symptoms, 46% and 52%, respectively, in these patients with low testosterone levels (<12 nmol/l), while the incidence of these symptoms were 60% and 64%, respectively in the diabetic study group. Only 16% patient had other symptoms. Association of body composition and testosterone levels in diabetic Asian-Indian adults: Total serum testosterone levels significantly and negatively correlated with both BMI (r = 0.334, p < 0.05) and WC (r = 0.443, p < 0.001). Patients having BMI >23 kg/m 2, 37% diabetic men had low testosterone <8 nmol/l and adding the value 8-12 nmol/l, it was increased to 78% (p < 0.01). In patients with WC, Table 1. The Baseline Characteristics of Subjects Parameter Sample range Average SD Age (years) 35-76 54.3 ±12.9 Serum testosterone (nmol/l) 3.51-27.10 12.14 ±6.04 HbA 1C (%) 5.6-12.4 8.27 ±1.52 Body mass index (kg/m 2 ) 18.75-33.89 23.54 ±3.71 Waist circumference (cm) 75-105 87.2 ±6.88 Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) 110-160 136.32 ±14.51 70-100 83.88 ±6.70 Duration (years) 5-17 7.48 ±3.52 Smoking Others (occupation and residence) SD = Standard deviation Table 2. Comparisons of Testosterone Levels in Men with and without Variables by Unpaired t Test Variable Mean SD` t P Serum testosterone levels With ED 9.48 4.24 4.13 <0.001 Without ED 16.10 6.26 With HbA 1C 9 13.75 6.24 4.42 <0.001 With HbA 1C >9 8.75 3.97 With WC <85 cm 15.02 6.47 3.80 <0.001 With WC >85 cm 9.26 3.91 With BMI <23 kg/m 2 14.30 5.99 2.38 <0.05 With BMI >23 kg/m 2 10.30 5.54 In hypertensive 13.49 6.16 1.07 >0.05 In nonhypertensive 11.51 5.97 In smokers 12.01 6.42 0.122 >0.05 In nonsmokers 12.23 5.89 ED = Erectile dysfunction; WC = Waist circumference; BMI = Body mass index. Indian Journal of Clinical Practice, Vol. 23, No. 2, July 2012 95

Percentage of men with low testosterone 90 80 70 60 50 40 30 20 10 0 <40 40-49 50-59 60-69 >69 Age in years Testosterone <8 nmol/l Testosterone <12 nmol/l Figure 1. Percentage of diabetic men with low testosterone and borderline testosterone levels as per decade. Percentage of men with low testosterone 90 80 70 60 50 40 30 20 10 0 <40 40-49 50-59 60-69 >69 Age in years Figure 2. Incidence of positive symptoms in men with low testosterone by decade of age. >85 the serum testosterone levels were 12 nmol/l in 80% cases (p < 0.001) (Table 3). Correlation between HbA 1C and low testosterone: HbA 1C significantly and negatively correlated with serum testosterone levels (r = 0.503, p < 0.001). Eighty-six percent patients with HbA 1C >9% had low testosterone levels, while 44% diabetics with HbA 1C <9% had serum testosterone <12 nmol/l showing statistical significance (p < 0.001). Hypertension, smoking duration, socioeconomic factor and serum testosterone: Statistical correlation and significance between hypogonadism and diabetes Table 3. Association of Low Testosterone Level with Clinical Variable Parameter (n) BMI >23 kg/m 2 (27) duration, smoking and history of hypertension could not be established (p > 0.05). DISCUSSION <8 nmol/l (15) 8-12 nmol/l (14) >12 nmol/l (21) 10 11 6 <0.01 WC >85 cm (25) 9 11 5 <0.001 HbA 1C >9% (16) 8 6 2 <0.01 Hypertension (16) 3 4 9 >0.05 Smoking (20) 7 4 9 >0.05 Erectile dysfunction (23) 11 12 <0.001 Loss of libido (26) 12 14 <0.001 Other symptoms (8) 5 3 Age <40 (7) 2 1 4 40-49 (10) 4 2 4 50-59 (14) 3 5 6 60-69 (14) 3 5 6 >69 (5) 3 1 1 Hypogonadism, a clinical condition comprising both symptoms and biochemical evidence of testosterone deficiency is associated with T2DM. The purpose of this study was to determine the prevalence of clinical hypogonadism based on both symptoms and biochemical available measure of testosterone deficiency in men of T2DM in Indian perspectives. In present study, we observed that there is a high prevalence of symptomatic hypogonadism in men with T2DM. Previous studies 11 have shown that about one-third of men with T2DM have low serum testosterone levels. In our study, we found that a high proportion of diabetic men had low levels of serum testosterone. There is no widely accepted consensus as to what constitutes the levels of testosterone below which treatment is to be considered. But on the basis of normal ranges and international recommendations overt hypogonadism <8 nmol/l and borderline hypogonadism 8-12 nmol/l serum testosterone level was considered. In the present study, 30% subjects with T2DM had symptoms and P 96 Indian Journal of Clinical Practice, Vol. 23, No. 2, July 2012

associated serum testosterone level <8 nmol/l, which was called as overt hypogonadism. Further 28% of diabetic men had symptoms of hypogonadism with testosterone level in the range of borderline hypogonadism i.e. 8-12 nmol/l. These findings support the study done by Kapoor and colleagues. 19 Aging is associated with decline in testosterone levels even in healthy men according to Nieschlag, Behre and colleagues. 32 In the Baltimore Longitudinal Study on aging, 8, 12, 19 and 28% of men aged >40, 50, 60 and 70 years, respectively had serum total testosterone levels below the normal range of <11.3 nmol/l in that study. 33 Using the criteria in that study, we found a higher prevalence of hypogonadism across all age group 43% in <40, 60% in 40-49, 57% in 50-59, 57% in 60-69 and 80% in >69 years. Kapoor et al 19 also found similar results in all diabetic age groups (42, 44, 39 and 56% in the age-groups 40-49, 50-59, 60-69 and 70-79 years, respectively). Although hypogonadism increases with age, it is also common in younger diabetic age groups. Dhindra and colleagues 11 have shown low testosterone level in T2DM. Frequency of symptoms in all defined groups of their study was studied. It is important to note that the ADAM questionnaire lacks specificity and this questionnaire is useful only in the presence of a biochemical evidence of low level of serum testosterone. Asian-Indians are known to have a lower BMI than Europeans. For any given BMI, Asian-Indians have a greater waist-to-hip ratio than Europeans. To clarify the issue, Ramachandran and colleagues performed a case-control study in 82 subjects with T2DM and 82 sex- and age-matched nondiabetic controls from the Chennai Urban Rural Epidemiology Study. 34 Visceral, subcutaneous and total abdominal fat were measured by computed tomography (CT), while dual-energy X-ray absorptiometry (DEXA) was used to measure central abdominal and total body fat.diabetic subjects had significantly higher visceral and central abdominal fat compared to controls. Both measurements correlated well with each other as well as with the WC. Therefore, WC is a valid measure of visceral adiposity in this population. To clarify the anthropometric variables in Asian-Indian adults, 19,025 adults over 20 years of age were given an oral glucose tolerance test using World Health Organization (WHO) criteria. 35 The calculations were done to stratify subjects with diabetes against subjects without diabetes using multiple logistic analyses. The upper limit of the stratum in which the risk became clinically significant was considered the cut-off for normal values. The normal cut-off for BMI was 23 kg/m 2 in both sexes. The cut-off for WC was 85 cm for men and 80 cm for women. The present study showed that there is strong negative correlation between WC and hypogonadism in cases of diabetes (r = 0.443, p < 0.001) and between BMI and hypogonadism in these cases (r = 0.334, p < 0.05). The study supports the results of previous study done by Kapoor and colleagues according to which there was strong correlation between body composition and total testosterone levels. We observed that serum testosterone decreased more in uncontrolled diabetic men showing correlation and statistical significance (r = 0.503, p < 0.001). In this study, we did not find any association between the duration of diabetes, socioeconomic status and history of smoking with hypogonadism. The previous study did not show any clear cut relation with these findings. Further studies with a large number of subjects may determine the clear cut association. Testosterone therapy has important role in treatment of ED and also in management of IR. Men with ED who fail to respond to phosphodiesterase inhibitors have been shown to have low testosterone levels. 36 Testosterone replacement therapy in two studies was found to convert sildenafil nonresponders to responders. 37 Interventional studies have shown a beneficial effect of testosterone replacement therapy on IR. A study in healthy men with low total testosterone reported an improvement in insulin sensitivity with testosterone or dihydrotestosterone treatment. 38 Testosterone treatment has also been shown to reduce IR in obese men, men with heart failure and T2DM subjects. Studies on T2DM men have shown an improvement in glycemic control with testosterone replacement therapy. 39 Conclusion Testosterone levels are frequently low in men with T2DM and the majority of these men have symptoms of hypogonadism, even in the younger age group (early-onset hypogonadism). Obesity and BMI are also associated with low testosterone levels in Asian-Indian diabetic men. Control of diabetes and associated risk factor should be the goal of therapy. More studies are required to establish the benefit of testosterone replacement therapy on quality-of-life and the diabetic state in Indian men. Indian Journal of Clinical Practice, Vol. 23, No. 2, July 2012 97

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