HYPOGONADOTROPHIC HYPOGONADISM IN DIABETES AND OBESITY:A LITERATURE REVIEW

ABSTARCT:

Obesity, diabetes mellitus and hypogonadotropic hypogonadism in men are interlinked with each other in a complicated manner in respect of etiology, pathogenesis and therapeutics. Significant number of patients with type 2 diabetes mellitus have hypogonadotropic hypogonadism with subnormal free testosterone concentrations along with inappropriately low luteinizing hormone and follicle stimulating hormone levels. Secondary hypogonadism is related to obesity, high C-reactive protein levels, insulin resistance and type 2 diabetes mellitus but not with duration of diabetes or glycosylated hemoglobin concentrations. Treatment of hypogonadism in obese and diabetic men have shown increase in insulin sensitivity and decrease in waist circumference, along with beneficial impacts on restoration of normal sexual function and overall well-being. Further trials of a longer duration are definitely required to establish the advantages and risks of testosterone replacement therapy in patients with type 2 diabetes and low testosterone concentrations.

1. Introduction

1.1 Background:

An estimated population of 285 million worldwide with type 2 diabetes mellitus shows increasingly endemic situation with 7 million people developing diabetes every year. This number is expected to reach at 438 million by the year 2030. In a representative US men population older than 50years of age, type 2 diabetes mellitus is ranked third amongst top ten most prevalent diagnosed diseases (Issa et al., 2006). In the year 2000, the worldwide prevalence of diabetes for all age groups was estimated to be 2.8% with a possible projection of 4.4% in 2030. Estimation was done on the basis of factors including population growth, ageing and increased prevalence of obesity and sedentary life style (Wild et al., 2004). Similar data statistics have been reported in European populations (von Eckardstein, Schulte and Assmann, 2000),(Gatling et al., 2001).

Since the early 1980s, cross‐sectional studies have demonstrated a relationship between low testosterone levels and type 2 diabetes mellitus (Daubresse et al., 1978);(Shahwan et al., 1978);(Andò, Rubens and Rottiers, 1984);(Phillips, 1984);(Small et al., 1987);(Semple, Gray and Beastall, 1988);(Barrett-Connor, 1992);(Barrett-Connor, Khaw and Yen, 1990a);(Andersson et al., 1994);(Tibblin et al., 1996);(Defay et al., 1998);(Chearskul et al., 2000) ;(Zietz et al., 2000);(Jang et al., 2001);(Abou-Seif and Youssef, 2001);(Abate et al., 2002);(Corona and Maggi, 2010);(Corrales et al., 2004);(Dhindsa et al., 2004a);(Johan Svartberg et al., 2004); (Achemlal et al., 2005); (Pitteloud et al., 2005a);(Rhoden et al., 2005);(Chen, Wittert and Andrews, 2006) ;(Crawford et al., 2007);(Kapoor et al., 2006);(Selvin et al., 2007);(Ibáñez et al., 2008); (Hamdan and Al-Matubsi, 2009);(Corona et al., 2010). In a previous meta‐analysis (Ding et al., 2006) on the basis of available cross‐sectional studies stated that total testosterone was significantly lower in men with type 2 diabetes mellitus. Possible role of low sex hormone‐binding globulin (SHBG) levels , which is very common in type 2 diabetes mellitus, induced by insulin resistance was suggested by (Simon et al., 1997) in this regard. Furthermore, some demonstrated not only a decreased total testosterone levels but also reduction in both bioavailable and free testosterone in patients with type 2 diabetes mellitus (Barrett-Connor, Khaw and Yen, 1990a);(Dhindsa et al., 2004a);(Kapoor et al., 2006);(Corona et al., 2010). Several international societies on the basis of available data recognize type 2 diabetes mellitus as risk factor for hypogonadism (Wang, 2009); (Buvat et al., 2010).

(Saboor Aftab, Kumar and Barber, 2013) explained very close association of Obesity, (SH) secondary hypogonadotropic hypogonadism and T2DM (Type 2 Diabetes mellitus). They suggested male obesity associated secondary hypogonadism (MOSH) be considered as separate entity and distinct subtype of secondary hypogonadism, though its exact pathogenesis is unknown.

(Dandona and Dhindsa, 2011a); (Mammi et al., 2012); (Hofstra et al., 2008) worked on prevalence of hypogonadotropic hypogonadism in obese people. Secondary hypogonadism can be caused by many diseases but obesity itself is an established cause of male hypogonadism (Saboor Aftab, Kumar and Barber, 2013); (Mammi et al., 2012); (P G Cohen, 1999).

Clinical features include sexual dysfunction characterized by poor libido and erectile disorder, feeling of decreased wellbeing, fatigue, mood disorder, lack of concentration, sarcopenia, increased fat mass, dyslipidemia along with osteopenia and osteoporosis (Saboor Aftab, Kumar and Barber, 2013). Pathogenesis, clinical correlation and management of obesity associated secondary hypogonadism is not understood completely.

There is a marked difference in the levels of total testosterone concentrations in diabetics and non-diabetics described by (Buvat et al., 2010) .They found 64% of diabetics had total testosterone levels below 300ng/dl as compared to 38% of non-diabetic men.

Type 2 diabetic men with low testosterone levels also show high prevalence of symptoms which are associated with hypogonadism. This was described by (D. Kapoor et al., 2007a) in a cross sectional study showing high prevalence of low libido (64%) , erectile dysfunction (74%) , and fatigue (63%) in hypogonadal men with type 2 diabetes. These reports show low total testosterone levels in older diabetics than in non-diabetics of the same age group.

1.2 Rationale for study:

In 2001 (Mokdad et al., 2003) described hypogonadism, type 2 diabetes and obesity as overlapping in nature in American population. He estimated 21.4 million men as obese, 6.9 million as type 2 diabetics and 5 million as hypogonadal.

Populations of American men with obesity, type II diabetes, and hypogonadism display a high degree of overlap. *21.4 million men were considered obese in 2001.[5]†6.9 million men had type II diabetes in 2001.(Mokdad et al., 2003) ‡5 million men are thought to be hypogonadal.

Different researches and literature reviews are there to elaborate the link of hypogonadism with type 2 diabetes mellitus, aging, obesity and other disorders.

Many epidemiological studies show that low baseline testosterone increases odds of development of type 2 diabetes mellitus approximately two times (Oh et al., no date); (Haffner et al., 1996); (Laaksonen et al., 2004a).

(Saboor Aftab, Kumar and Barber, 2013) stated that there is a well-established relation between obesity and hypogonadism (testosterone deficiency). There is complex relationship between body composition, obesity, androgen levels, vascular disease and type 2 diabetes mellitus.

(Mogri et al., 2013) and (Chandel et al., 2008) described a link between type 2 diabetes mellitus and hypogonadism in younger men aged 18-35.

(Ding et al., 2009) described the possible role of low SHBG concentrations in this association. Lower SHBG concentrations occurring due to SHBG polymorphism are strongly predictive of type 2 diabetes mellitus. While (Perry et al., 2010) described genetic evidence that raised SHBG reduces the risk of type 2 Diabetes mellitus.

One of the aims of this research is to review all these possible associations of hypogonadism, diabetes and obesity.

1.3 Aim and objectives of Literature Review:

The overall aim of this literature review is to advance an understanding of the association between hypogonadism, diabetes mellitus and obesity. The following objectives have been identified to be important in achieving the aforementioned aim:

• Explore the prevalence of hypogonadotropic hypogonadism in diabetics.

• Critically assess the data supporting an association between hypogonadotropic hypogonadism with diabetes mellitus.

• Identify the relationship of hypogonadism with obesity.

• Review the overlapping nature of hypogonadism, obesity and type 2 diabetes mellitus.

• Explore the impacts of correction of hypogonadism on type 2 diabetes mellitus and obesity.

2. METHODS

2.1 Search Methodology:

An up to date literature review of different randomized control trials, reviews, multicenter studies related to association of hypogonadotropic hypogonadism with that of obesity and type 2 diabetes mellitus was conducted. Database for searching of online available publications included Google scholar, PubMed, Cochran review, Wiley online library, ResearchGate, Web of Science, different search engines and the University of Warwick Libraries. Primary focus was on research papers available in English using keywords like “hypogonadotropic hypogonadism in diabetes and obesity”, “hypogonadism in obesity”, “secondary hypogonadism”, “obesity associated hypogonadism “and “hypogonadism in type2 diabetes mellitus”.

This review was conducted in line with the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement (Moher et al., 2010).

2.2 Eligibility criteria

The titles and abstracts were reviewed to identify potentially relevant studies. Full-text manuscripts were reviewed if they met all the following inclusion criteria:

1. Original studies (retrospective/prospective/cross sectional) on patients of secondary hypogonadism with diabetes mellitus and obesity.

2. Studies reporting hypogonadotropic hypogonadism as significant entity in type 2 diabetes mellitus.

3. Studies comparing secondary hypogonadism in diabetic and normal population.

4. Studies were eligible for inclusion in the systematic review if they reported the relationship of hypogonadotropic hypogonadism with important interlinking factors as metabolic syndrome, waist circumference, insulin resistance and impacts of testosterone replacement therapy on them.

2.3 Exclusion criteria

Studies including patient without biochemically confirmed secondary hypogonadism in diabetes mellitus were excluded.

Unpublished data or taken from extracts was not used in this systemic review.

2.4 Data extraction

The patients in the studies were classified into three groups having: hypogonadotropic hypogonadism with type 2 diabetes mellitus, hypogonadotropic hypogonadism with obesity, and hypogonadotropic hypogonadism in diabetes mellitus and obesity both.

A predesigned data extraction form was used to collect data from the eligible studies. All variables were listed for which data was sought and information was extracted from each study including:

1. First author’s last name, publication year, country, study design, number of participants.

2. Age range and gender of study participants.

3. Endocrine tests performed for secondary hypogonadism in association with type 2 diabetes mellitus and obesity.

4. Outcome measures including prevalence of secondary hypogonadism in patients with type 2 diabetes mellitus and obesity.

2.5 Risk of Bias in included studies:

NIH quality assessment tool for observational cohort and cross-sectional studies was used to assess risk of bias in the included studies. This quality assessment tool is neither a scale nor a checklist to simply tally up to arrive at a summary judgment of quality (Higgins et al., 2011).

It is an evaluation which helps focusing on the key concepts for evaluating the internal validity of a study. The critical assessments are made separately and are divided into fourteen set of questions, as enumerated below (Higgins et al., 2011)

1. Research question: was the research question or objective in this paper clearly stated?

2. Study population: Was the study population clearly specified and defined?

3. Was the participation rate of eligible persons at least 50%?

4. Recruitment and eligibility criteria: Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study pre-specified and applied uniformly to all participants?

5. Sample size justification: Was a sample size justification, power description, or variance and effect estimates provided?

6. Exposure assessment prior to outcome measurement: For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured?

7. Sufficient timeframe: Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed?

8. Different levels of the exposure of interest: For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)?

9. Exposure measures and assessment: Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants?

10. Repeated exposure assessment: Was the exposure assessed more than once over time?

11. Outcome measures: Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants?

12. Blinding of outcome assessors: Were the outcome assessors blinded to the exposure status of participants?

13. Follow up rate: Was loss to follow-up after baseline 20% or less?

14. Statistical analyses: Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)?

Critical appraisal was done considering the risk of potential for selection bias, information bias, measurement bias and confounding. Each of the included study was judged according to the answers to the above fourteen questions. To help determine whether there is a causal relationship between hypogonadotropic hypogonadism in diabetes and obesity the study design was looked into detail for factors including the temporal relation between exposure outcomes, accuracy of measurement of exposure and outcome definitions and whether the time frame was sufficient to see an effect. By focusing on the concepts underlying the questions in the quality assessment tool, the author looked into potential risks of bias resulting from flaws in the study design or execution.

3. Hypogonadism and Obesity

3.1 What is Hypogonadism:

Impaired testicular function is called Hypogonadism. It can be primary testicular disorder called hypergonadotropic hypogonadism or secondary to hypothalamic pituitary dysfunction known as hypogonadotropic hypogonadism (HH). In Hypogonadotropic hypogonadism secretion of gonadotropic releasing hormone (GnRH) is absent or inadequate. HH can be congenital or acquired. Acquired Hypogonadotropic Hypogonadism can occur due to many reasons including drugs, pituitary lesions, hyperprolactinemia, excessive exercise, alcohol, and systemic diseases (Fraietta, Zylberstejn and Esteves, 2013). Hypogonadism is manifested by low testosterone levels.

3.2 Secondary Hypogonadism:

Male hypogonadotropic hypogonadism is characterized by signs and symptoms of hypogonadism along with low levels of serum testosterone due to abnormal function of hypothalamic pituitary axis. Large community based samples suggested a cut-off value of <12.1 nmol/l of total serum testosterone and free testosterone levels of <243 pmol/l for identification of hypogonadism in men (Bhasin et al., 2011a) . In a large community based study on men aged 40-79 years, (Wu et al., 2010a) described threshold for total testosterone as <8 nmol/l for reduced frequency of sexual thoughts, for erectile disorder <8.5 nmol/l , reduced frequency of morning erections at <11 nmol/l and diminished vigor at < 13nmol/l . (Wu et al., 2010a) described strongest indicators of hypogonadism in this age group as decreased sexual thoughts, less and weak morning erections, erectile disorder, free testosterone < 220 pmol/l, and either a total testosterone < 8 nmol/l or serum testosterone between 8-11 nmol/l. Samples which were collected at the morning time depicted high values of testosterone and best reproducibility.

Factors of pulsatile, diurnal and circannual rhythms were found in laboratory estimation methods for plasma testosterone measurement (Wu et al., 2010b); (Bhasin et al., 2011a).

Central defects of the hypothalamus or pituitary cause secondary testicular failure. Male secondary hypogonadism is characterized by low or normal serum FSH and LH along with low testosterone. Pineal tumors, pituitary adenomas, Kalman syndrome, hemochromatosis, and obesity are frequently associated with male secondary hypogonadism (Hofstra et al., 2008) ; (Guay et al., 2003) ; (Pitteloud et al., 2005a)

3.3 Relationship of hypogonadism and obesity:

(Camacho et al., 2013) observed weight changes and life style effects on hypothalamic pituitary testicular function in middle aged and older men in a longitudinal study. It was conducted by recruiting 2736 men aged 40-79 years from eight different centers across Europe with the follow up assessment 4.4+-0.3 years.

Analysis of paired testosterone results of available 2395 samples indicated a curvilinear relationship of testosterone to weight change. Weight loss showed proportionate increase and weight gain showed proportionate decrease in testosterone levels.

It was shown that body weight influences function of hypothalamic pituitary axis in ageing men and weight loss is associated with rise in testosterone, free testosterone and SHBG (sex hormone binding globulin) levels while weight gain causes hypogonadism with low testosterone, free testosterone and SHBG levels.

Some important points regarding hypogonadism and obesity are discussed below:

a: Association of male obesity with lower testosterone levels:

(Hofstra et al., 2008) described association of male obesity with lower plasma testosterone levels.

b: Low testosterone level and insulin sensitivity:

• (D. Kapoor et al., 2007a); (Dhindsa et al., 2016a) explained independent association of plasma testosterone levels and insulin sensitivity in males.

c: risk of developing hypogonadism in men with both obesity and type 2DM:

• (Dhindsa et al., 2004b); (Tomar et al., 2006) elaborated high risk of developing secondary hypogonadism in people with obesity and type 2 diabetes mellitus.

Some previous studies have also described relationship of hypogonadism with upper abdominal adiposity, metabolic syndrome and insulin resistance.

(Haffner et al., 1996) in a detailed discussion highlighted epidemiological and clinical correlation of sex hormone levels with obesity, diabetes mellitus type 2, insulin resistance and fat distribution in the body.

Similar findings regarding levels of sex hormones with metabolic syndrome were revealed by (Laaksonen et al., 2004b) in a population based study.

3.4 Prevalence:

(D. Kapoor et al., 2007a) described obesity as one the most frequently associated factor of low free testosterone levels (in hypogonadal range) and biomedical picture of secondary hypogonadism. He further described linear association of BMI with secondary hypogonadism and found low testosterone levels in diabetic obese men. (Dhindsa et al., 2004b); (Mulligan et al., 2006) described an inverse relationship between BMI and testosterone levels regardless of diabetes.

(Hofstra et al., 2008) in a study on 160 obese men showed that 40% of those having BMI more than 40 had a free testosterone less than 225pmol/l.

In another study on 1849 men, (Dhindsa et al., 2004b) determined subnormal free testosterone levels in 40% of obese men having BMI above 30 with normal glucose tolerance test, while this percentage was 50% in obese men with diabetes aged above 45 years.

3.5 Clinical diagnosis of Obesity associated Hypogonadism:

(Saboor Aftab, Kumar and Barber, 2013) described clinical diagnosis of Obesity associated hypogonadotropic hypogonadism in the presence of following defining features:

• Male with BMI 30 or above.

• Any sign and symptom of hypogonadism such as poor or deteriorating sexual, physical or mental performance, impaired sexual characteristics, breast pain or true gynecomastia, unexplained anemia, sleep disturbances, low bone mineral density, dysglycemia or flushing episodes.

• Low or subnormal Follicles stimulating hormone, Luteinizing Hormone in absence of another obvious cause of hypopituitarism.

• Morning total testosterone levels below the limit of healthy young males in the presence of normal Sex hormone binding globulin levels (SHBG).

• Free testosterone levels below the lower limit of healthy young males in the presence of abnormal sex hormone binding globulin levels (SHBG).

• While other probable causes of hypogonadism have been ruled out systematically.

Male hypogonadism is associated with comorbidities such as sexual health, adverse effect on bone health, psychological functioning, body composition and metabolic health. Presumption of similar improvement in health can be predicted from the treatment with testosterone replacement therapy in patients with obesity associated hypogonadotropic hypogonadism (T. H. Jones et al., 2011) ; (Kalinchenko et al., 2010); (Jungwirth et al., 2012); (Bhasin et al., 2011b).

3.6 Pathogenesis:

3.6.1 Male Hypothalamic-Pituitary-Testicular axis:

Testosterone levels in men are regulated by intact hypothalamic-pituitary-testicular axis. The hypothalamus releases a tripeptide called gonadotropin-releasing hormone (GnRh). This gonadotropin-releasing hormone causes release of two important hormones named as follicle-stimulating hormone (FSH) and Luteinizing hormone (LH) from the anterior pituitary gland. This FSH stimulates spermatogenesis in testicular Sertoli cells while LH affects testicular interstitial Leydig cells to release testosterone.

This system works as a negative feedback mechanism where adequate circulating testosterone levels inhibit this hypothalamic- pituitary axis. If serum levels of FSH and LH are inappropriately low or subnormal then it leads towards less production of testosterone and this condition is called Secondary Hypogonadism (Seftel, 2006).

3.6.2 Role of Aromatase activity:

Aromatase activity within the obesity is directly associated with male obesity. (Dandona and Dhindsa, 2011a) described that it is increased in obese people and causes increased peripheral conversion of testosterone into estradiol and results in subsequent increase in estradiol levels. Negative feedback mechanism initiated by estradiol results in decreased LH secretion from the pituitary and reduced testosterone levels as it suppresses the HPT axis and leads towards SH (Pitteloud et al., 2005a).

In severe obesity, increased serum estradiol and decreased serum testosterone are present. Inhibitory effect of estradiol on HPT axis is there but with no compensatory increase in gonadotropin secretion which further progresses towards secondary hypogonadism.

According to (Isidori et al., 1999) and (Mammi et al., 2012) hypogonadism increases fat mass and further aggravates hypogonadal crisis, hence is a worsening factor for obesity while low testosterone reduces muscle mass and increases visceral fat volume. Testosterone exerts differential effect on fat turnover rates in visceral adipose tissue and subcutaneous tissue, this fact can explain occurrence of central adiposity with reduced endogenous androgen production. Androgen is mandatory for muscle tissue sustenance and prevents it from atrophy (Saad and Gooren, 2011).

3.6.3 Hypogonadal Obesity Cycle:

In male hypogonadism there is more tendency of abdominal fat deposition. Aromatase activity keeps on increasing with increased deposition of adipose tissue, causing even greater conversation of testosterone to estradiol and often termed as testosterone-estradiol shunt. It behaves in a cyclic pattern by further decreasing testosterone levels, increasing preferential abdominal fat deposition, and is termed as “Hypogonadal-Obesity cycle” elaborated by (P.G. Cohen, 1999) .This cycle is interrupted by aromatase inhibitors by reducing serum estradiol levels, curtailing negative feedback effect of estradiol on hypothalamic-pituitary-axis ,thus restoring the suppressed levels of LH, FSH and testosterone. It also reverses the preferential abdominal fat deposits.

3.6.4 Relationship of Obesity with Testosterone levels:

(Isidori et al., 1999) ; (Blouin, Boivin and Tchernof, 2008); (Zumoff, Miller and Strain, 2003); (Dandona and Dhindsa, 2011a) discussed complex relationship between testosterone, estradiol and obesity. Mild to moderate obesity causes increase in estradiol levels but cease to show further rise in severe obesity while free testosterone levels keep on decreasing with increasing severity of obesity.

3.6.5 Relationship of Leptin levels on Obesity associated SH:

Proper reproduction in men and women require normal physiological levels of Leptin. Its increased level is associated with obesity (Isidori et al., 2005). Increased leptin levels exert direct negative impact on Lh/hCG stimulated testicular androgen production. It also causes decreased Leydig cell response to gonadotropin stimulation (Mammi et al., 2012); (Dhindsa et al., 2004b); (Isidori et al., 2005); (Ganesh et al., 2009). High levels of leptin may have important role in obesity associated hypogonadotropic hypogonadism.

3.6.6 Impact of weight loss on Testosterone levels in Obese men:

(Luconi et al., 2013) in a longitudinal study of patients undergoing bariatric surgery observed median weight loss of 24.6% and 27.0% at 6 and 12 months post-surgery. This weight loss was associated with increased total testosterone levels versus baseline at both time points (14.80 and 13.90 vs. 8.75 nmol/L, respectively; p<0.001. These results were significantly higher than that of expected outcome obtained on the basis of cross-sectional survey by (Luconi et al., 2013).

3.6.7 Impact of Age and Weight gain on Testosterone levels:

(Camacho et al., 2013) in a large community-based study indicated that decrease in testosterone levels is not due to age but is related to concomitant increase in body weight. He further stated that testosterone levels show significant change in response to weight loss or gain.

• During large community-based study, men showed a mean annualized decrease in total and free testosterone values of 0.1 nmol/L and 3.83 pmol/L per year.

• Participants who lost ≥10% of their baseline body weight over the study period showed increase in average testosterone values of 2.9 nmol/L.

• This change was significantly different from that seen in participants whose body weight remained within 10% of the baseline (-0.4 nmol/L; p<0.01.

• In terms of weight gain and its impact on testosterone levels, participants who gained ≥10% of their baseline body weight over the study period depicted a decrease in testosterone levels. This reduction was significantly more than those whose body weight remained ‘stable’ (-2.4 nmol/L vs. -0.4 nmol/L; p<0.01)

The study indicated that even loss of ≥5% of baseline body weight resulted in a significant increase in testosterone levels, and additional increase in testosterone levels was observed with further weight loss.

Weight gain resulted in progressive decreases in testosterone (Figure 1)

4. HYPOGONADISM AND Diabetes Mellitus

4.1 Background:

Many studies in the past clearly established relationship of type 2 diabetes mellitus and hypogonadotropic hypogonadism. At least 25 percent of men with type 2 diabetes mellitus have below normal free testosterone levels in association with inappropriately low LH and FSH concentrations (Dandona and Dhindsa, 2011b). (Barrett-Connor, Khaw and Yen, 1990b) in Rancho Bernardo Study tried to highlight the relationship of hypogonadism with type 2 diabetes mellitus and showed hypogonadism was more common finding in diabetic men as compared to non-diabetics. He evaluated 985 men between age 40-70 years and described 21% men as hypogonadal with diabetes as compared to 13% hypogonadal without diabetes.110 men with diabetes were having lower total testosterone levels and lower SHBG (Sex hormone binding globulin) as compared to non-diabetic men. (Table:1)

This subnormal testosterone concentration is related to obesity, mild anemia and very high C-reactive protein values but not with glycosylated hemoglobin or duration of diabetes. Hypogonadotropic hypogonadism is not associated with hyperglycemia in individuals.

4.2 Contrasting Testosterone Concentrations in Type 1 and Type 2 Diabetes

(Dhindsa et al., 2004b) stated frequent occurrence of hypogonadotropic hypogonadism in patients with T2DM. (Tomar et al., 2006) in an attempt to evaluate relationship of hypogonadotropic hypogonadism in both types of diabetes depicted as very rare in type 1 diabetes mellitus, so it is not a function of hyperglycemia or diabetes per se.

(Tomar et al., 2006) stated that T1DM is associated with increased SHBG ; normal TT, LH, and FSH concentrations; and normal FT and calculated FT concentrations in >90% of patients. On the other hand, T2DM participants have frequent hypogonadotropic hypogonadism and low SHBG levels. A higher BMI has a significant effect on calculated FT and FT in both patients with type 1 as well as with T2DM. Hence suggested that even type 1 diabetics may develop hypogonadism at higher levels of BMI.

Fifty patients with type 1 diabetes mellitus (T1DM) (age range 23–58 years) and 50 age-matched patients with T2DM (age range 28–51 years) were inducted in their study.

Mean TT, FT, and bioT concentrations in T1DM were found in the middle of the normal range (table 2). No participant was found having subnormal TT. Three patients had above normal TT, while two patients had subnormal FT and bioT concentrations.

The mean TT concentration in patients with T2DM was significantly lower than that in T1DM (table 2). The prevalence of low TT concentrations was 24 of 50 (48%), while low measured and/or calculated FT was 13 of 50 (26%). LH and FSH concentrations in 12 of 13 hypogonadal patients were in the normal range and were thus inappropriately low. One patient had increased LH and FSH concentrations and thus had primary hypogonadism.

Mean SHBG concentration in T1DM was at the upper end of the reference range. The level of SHBG was higher than normal in 16 patients. The mean SHBG in T2DM participants was significantly lower than that in type 1 diabetic subjects (table 1).

In T1DM, plasma TT concentrations were negatively related to BMI. In T2DM, BMI was also negatively related to FT, calculated FT, bioT, and TT (Fig 2). BMI was also found inversely related to SHBG.

4.3 Prevalence:

Current available literature estimates the prevalence of hypogonadotropic hypogonadism in males with Type 2 Diabetes mellitus as 29% (range 25-40%). This is even higher up to 50% if obesity is also there with Type 2 Diabetes mellitus (Dhindsa et al., 2004b); (Grossmann et al., 2008). While (Chandel et al., 2008) described prevalence of secondary hypogonadism in young men aged 18-35 years with Type 2 Diabetes mellitus as 33%.

4.4 Pathogenesis:

There are many possible mechanisms explaining relationship of type 2 diabetes mellitus and male secondary hypogonadism (Isidori et al., 1999) ; (Mammi et al., 2012) . Strong co-existing nature of male SH, obesity and type 2 DM raises a possibility that obesity related factors like enhanced aromatase activity mediates association between secondary hypogonadism and type2 diabetes mellitus. (Dhindsa et al., 2004b); (Grossmann et al., 2008) elaborated greater risk of secondary hypogonadism in the simultaneous presence of both obesity and type2 diabetes mellitus. It implies possibility of involvement of other factors in pathogenesis than obesity alone. Male secondary hypogonadism is rare in type 1 diabetes mellitus but it needs to be investigated further (Tomar et al., 2006).

Insulin resistance and lipases are obesity related pathogenic mechanisms and might play a role in development of male secondary hypogonadism in type 2 diabetes mellitus according to (Isidori et al., 2005); and (Yeap et al., 2009). Low testosterone levels in men reduces muscle mass, increases visceral fat mass, causes insulin resistance and enhances activity of lipoprotein lipase ( LPL) (Isidori et al., 1999);(Yeap et al., 2009). Lipoprotein lipase is induced by hypogonadism at the level of adipose tissue hence promotes triglycerides storage. Hypogonadism by inhibiting hormone sensitive lipase checks beta-oxidation and increases fat mass (Li et al., 2010). This leads towards enhanced aromatase activity and increased formation of estradiol (Dandona and Dhindsa, 2011a).

In increased insulin resistant state, there occurs a compensatory hyperinsulinemia along with suppression of hepatic SHBG formation and inhibition of hypothalamic-pituitary-axis (Dandona and Dhindsa, 2011a) ;(Li et al., 2010). In hypothalamic neurons there is impaired insulin signaling which might have a role in development of secondary hypogonadism.

The hypothesis stating 60-90% decrease in serum LH levels in the presence of normal or above normal LH in response to Gonadotropin release hormone stimulation was based on data collected from neuron-specific insulin receptor knockout male mice (Brüning et al., 2000).

A study in 240 type 2 diabetic men with and without secondary hypogonadism suggested a direct relationship between free estradiol and free testosterone irrespective of the age or BMI.

Another hypothesis, supported by European Male Ageing Study about testosterone and estradiol, states that reduced availability of testosterone as an aromatization substrate in adipose tissue might be an important determinant of estradiol levels (Tajar et al., 2010).

Another mechanism which might explain relationship of type 2 diabetes and hypogonadotropic hypogonadism is based on the fact that inflammatory mediators, such as tumor necrosis factor alpha (TNF-alpha) and interleukin beta, suppress hypothalamus gonadotropin release hormone and luteinizing hormones in vitro (Watanobe and Hayakawa, 2003) ; (Russell et al., 2008).

4.4.1 Role of C- Reactive proteins:

C-reactive proteins are found in higher concentrations in type 2 diabetic men with hypogonadism in comparison of type 2 diabetic men with normal testosterone levels and are important in development of hypogonadotropic hypogonadism in type 2 diabetes mellitus. This observation is based on a hypothesis which states that inflammatory mediators like C-reactive proteins might not only play an important role in suppression of hypogonadal axis but also worsen insulin resistance by interfering with insulin signal transduction (Watanobe and Hayakawa, 2003); (Dandona and Dhindsa, 2011a) ; (Russell et al., 2008).

These mediators are also found in higher levels in obesity and provide a possible link between obesity, type 2 diabetes mellitus and hypogonadotropic hypogonadism in men (Dandona and Dhindsa, 2011a); (D. Kapoor et al., 2007b); and (Ghanim et al., 2007).

4.4.2 Role of SHBG:

It is found that lower SHBG levels predict development of type 2 diabetes mellitus and higher SHBG levels protect from type 2 diabetes mellitus but its actual mechanism in the pathogenesis of male secondary hypogonadism and type 2 diabetes mellitus is still not clear (Ding et al., 2009). Sex hormone binding globulin is produced in liver. It has high binding affinity for testosterone and helps in androgen delivery to the peripheral tissues (D. Kapoor et al., 2007b). Sex hormone bunding globulin levels have inverse relationship with that of BMI and degree of insulin resistance (Dhindsa et al., 2004b);(Perry et al., 2010). Obesity induced insulin resistance which results in compensatory hyperinsulinemia causes suppression of hepatic production of sex hormone binding globulin (SHBG). This observation might establish a link between obesity and SHBG. Reduction in SHBG levels can result in decreased delivery of testosterone to the peripheral tissue explaining one possible mechanism of hypogonadism development. Reduced SHBG might also leads towards increased availability of free testosterone as a substrate for aromatase activity to convert estradiol.

Association of hypogonadism with the development of adverse metabolic features including insulin resistance and type 2 diabetes mellitus has substantial evidence (Laaksonen et al., 2004b) ;(Salam, Kshetrimayum and Keisam, 2012).

A study on 702 middle aged men with metabolic syndrome or diabetes at baseline observed for 11 years, indicated many fold higher risk of developing metabolic syndrome and dysglycaemia in men with lower baseline levels of testosterone (Salam, Kshetrimayum and Keisam, 2012).

4.4.3 Hypogonadism or Type 2 Diabetes mellitus, which comes first?

(Dhindsa et al., 2004b) described that newly diagnosed people with type 2 diabetes mellitus and young men with type 2 have high prevalence of hypogonadotropic hypogonadism, indicating probable role of hypogonadotropic hypogonadism preceding Diabetes. Testosterone concentration at baseline almost doubles the prospect of development of type 2 diabetes mellitus. Total testosterone is more important indicator to predict the impact as compared to that of free testosterone (Dhindsa et al., 2004b); (Laaksonen et al., 2004a).

5. Hypogonadotropic Hypogonadism, Obesity and T2DM: Important studies:

5.1 Insulin Resistance and Inflammation in HH and their reduction after TRT in men withT2DM

(Dhindsa et al., 2016b) conducted a randomized, parallel, placebo-controlled, double-blind, prospective, single-center trial and elaborated relationship of testosterone in type 2 diabetes mellitus with hypogonadotropic hypogonadism. In his study he explained that testosterone treatment in men with type 2 diabetes and hypogonadotropic hypogonadism increases insulin sensitivity, increases lean mass, and decreases subcutaneous fat.

5.1.1 Study Design and Technique:

At the research center of the Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo (Buffalo, NY) this trial was conducted. Total 94 men with type 2 diabetes mellitus participated in this study; 50 being eugonadal, and 44 having hypogonadotropic hypogonadism. Glucose infusion rate (GIR) during hyperinsulinemia-euglycemic clamp technique was used to calculate insulin sensitivity. DEXA and MRI scans were used to calculate lean body mass and fat mass. To assess insulin signaling genes subcutaneous fat samples were used. Men with hypogonadotropic hypogonadism were randomized to receive intramuscular testosterone (250 mg) or placebo (1 mL saline) every 2 weeks for 24 weeks.

5.1.2 Results:

Men with hypogonadotropic hypogonadism found to have higher subcutaneous and visceral fat mass than eugonadal men. Glucose infusion rate was 36% lower in men with hypogonadotropic hypogonadism. Glucose infusion rate was increased by 32% after 24 weeks of testosterone therapy but remained unchanged after placebo (P = 0.03 for comparison). Decrease in subcutaneous fat mass (−3.3 kg) and increase in lean mass (3.4 kg) after testosterone treatment (P < 0.01) compared with placebo was also observed. There was found no impact on visceral and hepatic fat. Men with hypogonadotropic hypogonadism exhibited significantly lower expression of insulin signaling genes (IR-β, IRS-1, AKT-2, and GLUT4) in adipose tissue which was found to be upregulated after treatment with testosterone. Significant fall in circulating concentrations of free fatty acids, C-reactive protein, interleukin-1β, tumor necrosis factor-α (TNF alpha) , and leptin was also noted with the testosterone treatment (P < 0.05 for all).

5.2 Impact of TRT in T2DM with HH: BLAST Study

(Hackett et al., 2014) conducted a double-blind placebo-controlled study in male type 2 diabetes population with hypogonadism to assess metabolic changes with long acting testosterone undecanoate.

In a double‐blinded placebo‐controlled study, 211 patients with type 2 diabetes mellitus were inducted to observe changes in glycosylated hemoglobin (HbA1c) and testosterone level at which response is achieved. They were administered with long acting testosterone undecanoate 1,000 mg for 30 weeks followed by 52 weeks of open‐label use.

A significant reduction in HbA1c at 6 and 18 weeks was noted. Most marked decrease in poorly controlled patients with baseline HbA1c more than 7.5 was observed after a further 52 weeks of open‐label drug administration. It provided evidence of direct relationship of testosterone levels and HBA1c values. The reduction was 0.41% within 6 weeks, and a further 0.46% after 52 weeks of open‐label drug use. A significant reduction in waist circumference, weight, and body mass index was also noted in men without depression. These results were related to achievement of adequate testosterone levels.

5.3. Testosterone levels and Mortality in Hypogonadal men Type 2 DM:

Men with type 2 diabetes are known to have a high prevalence of testosterone deficiency. No long-term data are available about relationship of testosterone deficiency and mortality or effects of testosterone replacement therapy (TRT) in men with type 2 diabetes mellitus. (Muraleedharan et al., 2013) reported a 6-year follow-up study on hypogonadal type 2 diabetics. He stated that low testosterone levels predict an increase in all-cause mortality during long-term follow-up and testosterone replacement may improve survival in hypogonadal men with type 2 diabetes.

5.3.1. Research design and methods:

A total of 581 men with type 2 diabetes who had testosterone levels obtained between 2002 and 2005 were followed up for a mean period of 5.8±1.3 S.D. years. Mortality rates were compared between total testosterone >10.4 nmol/l (300 ng/dl; n=343) and testosterone ≤10.4 nmol/l (n=238). The effect of TRT (as per normal clinical practice: 85.9% testosterone gel and 14.1% intramuscular testosterone undecanoate) was assessed retrospectively within the low testosterone group.

5.3.2 Results: Mortality was increased in the low testosterone group (17.2%) compared with the normal testosterone group (9%; P=0.003) when controlled for covariates. In the Cox regression model, multivariate-adjusted hazard ratio (HR) for decreased survival was 2.02 (P=0.009, 95% CI 1.2–3.4). TRT (mean duration 41.6±20.7 months; n=64) was associated with a reduced mortality of 8.4% compared with 19.2% (P=0.002) in the untreated group (n=174). The multivariate-adjusted HR for decreased survival in the untreated group was 2.3 (95% CI 1.3–3.9, P=0.004).

5.4. Subnormal Plasma Testosterone in Men with Newly Diagnosed T2DM:

(Heufelder et al., 2009) in a 52-week long study established a link between hypogonadism and type 2 diabetes mellitus. Males having metabolic syndrome (MetS) and type 2 diabetes (T2DM) often show low testosterone levels. Improving low testosterone levels may help improvement of features of metabolic syndrome and glycemic control.

A single blinded, 52 weeks (RCT) randomized clinical trial was conducted by (Heufelder et al., 2009). The study was conducted to understand the effects of supervised diet and exercise intervention alone or in conjunction with transdermal testosterone administration, on features of Metabolic Syndrome in hypogonadal men with metabolic syndrome or newly diagnosed type 2 diabetes mellitus.

A total of 32 men with hypogonadal character having total testosterone <12.0 nmol/L with newly diagnosed cases of type 2 diabetes mellitus or with the metabolic syndrome, defined according to the Adult Treatment Panel III and the International Diabetes Federation, were administered supervised diet and exercise intervention. 16 participants received it along with testosterone gel (50 mg) once a day (n = 16). No hypoglycemic agents were given prior or during the study duration. The components of the metabolic syndrome according to the definition by Adult Treatment Panel III and the International Diabetes Federation were the outcome measures. Serum testosterone levels, glycosylated hemoglobin values (HbA1c), fasting blood sugar levels, high-density lipoprotein cholesterol levels, triglyceride values, and the waist circumference were observed to be improved in both treatment groups after 52 weeks of treatment. Intervention with the testosterone addition further improved these components in a significant way as compared with the diet and exercise alone. All diet and exercise plus testosterone patients attained the HbA1c goal of less than 7.0%; and 87.5% of them achieved an HbA1c of less than 6.5%. Those 81.3% of the patients based on Adult Treatment Panel III guidelines, were randomized to diet and exercise plus testosterone, no longer matched the component criteria of the metabolic syndrome while 31.3% of the Diet and Exercise alone participants still matched the criteria. Furthermore, treatment with testosterone showed improvement in insulin sensitivity, adiponectin, and high‐sensitivity C‐reactive protein values. Additional testosterone intervention to the supervised diet and exercise alone patients resulted in significant therapeutic improvements of glycemic control and reversed the metabolic syndrome after 52 weeks of treatment in hypogonadal patients with metabolic syndrome and newly diagnosed type 2 diabetes mellitus.

5.4.1 Study Design and Intervention:

A total of 32 hypogonadal men with metabolic syndrome and newly diagnosed with type 2 diabetes mellitus (fasting blood glucose >7.0 as baseline and/or >11.1 after a 2‐hours 75‐g oral (GTT) glucose tolerance test were included in the study. A high level of HbA1c was randomized to either supervised diet and exercise alone or in conjunction with testosterone gel 50 mg once a day. It was single blinded study, where conducting personnel did not know about the treatment arm to which participants of the study were randomized. Participants were also instructed not to disclose their treatment to study conductors. A morning plasma testosterone concentration lower than 12 nmol/L at least on 2 occasions (normal >14.0 nmol/L) was defined as testosterone deficiency. For standard safety precaution, participants with prostate‐specific antigen (PSA) concentration less than 4.0 μg/L were included in the study. A normal digital rectal examination of the prostate was also included as inclusion criteria. The metabolic syndrome was defined according to Adult Treatment Panel III and the International Diabetes Federation (Alberti et al., 2005) . Participants had never been treated previously with any of the oral hypoglycemic drugs or insulin.

Results

5.4.2 Impact on Sex Hormones:

In diet and exercise alone and diet and exercise plus testosterone treatment groups, mean ± SE serum testosterone concentrations increased in significant manner 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:3). Bioavailable testosterone levels 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 both groups respectively (between‐group difference ± SE, 2.5 ± 0.1 nmol/L; P < .001( Figure 3). 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. Compared with diet and exercise alone, D&E plus testosterone administration did not increase circulating PSA levels (between‐group difference ± SE, −0.08 ± 0.1 μg/L; P = .435).

5.4.3 Impacts on Glycemic Control:

Glycemic control showed improvement in both treatment groups after 52 weeks of treatment (figure3). HbA1c decreased by 0.5% ± 0.1% to 7.1% ± 0.1% in the D&E group and by 1.3% ± 0.1% to 6.3% ± 0.1% in the D&E plus testosterone group (between‐group difference ± SE, −0.8% ± 0.1%; P < .001). Fasting plasma glucose reduced to 6.6 ± 0.2 mmol/L in the diet and exercise group and to 6.1 ± 0.1 mmol/L in the diet and exercise plus testosterone group; however, this difference did not reach statistical significance (P = .062; table 5). All of the patients treated with combined diet and exercise plus testosterone reached the HbA1c target levels of less than 7.0%, and 87.5% attained less than 6.5%, while only 40.4% of the diet and exercise alone participants reached less than 7.0%, and none attained less than 6.5% (P < .001 for both comparisons). Correlations between the change in testosterone levels and glycemic control are shown in table 5.

5.4.4 Impact on features of the metabolic syndrome and Insulin Sensitivity:

All components of the MetS improved after 52 weeks of treatment with either supervised diet and exercise alone or in combination with testosterone gel (Table 5; Figure 4). Waist circumferences declined in both groups but more so in the diet and exercise plus testosterone group. A total of 62.5% of the patients treated with diet and exercise plus testosterone no longer matched the criteria of the metabolic syndrome, whereas 12.5% of the D&E alone patients did (P = .003). Changes in serum testosterone levels correlated in a significant manner with changes in the individual features of the metabolic syndrome and these are shown in table 4.

In both treatment groups, the pretreatment increasingly fasting serum insulin concentrations, often used as a measure of insulin resistance, reduced significantly after 52 weeks of treatment, whereas no correlation was observed with homeostatic model assessment for insulin resistance (HOMA‐IR). Supervised diet and exercise alone reduced insulin levels from 116.9 ± 6.1 pmol/L to 60.2 ± 2.5 pmol/L (P < .001). The addition of testosterone to supervised diet and exercise alone resulted in an additional decrease to 40.2 ± 2.1 pmol/L (between‐group difference ± SE, −19.2 ± 2.8; P < .001; table 4). Insulin sensitivity, assessed by HOMA‐IR, improved in both groups, in addition of testosterone resulting in a greater reduction in HOMA‐IR (between‐group difference ± SE, −0.9 ± 0.1; P < .001; Table 5). No significant relation between changes in total testosterone concentrations or bioavailable testosterone values and HOMA‐IR was noted in the current study; however, a significant relationship was observed with changes in insulin levels and changes in total testosterone and in bioavailable testosterone (r = −0.401; P = .023, and r = −0.480; P = .005, respectively; Table 5). Moreover, hsCRP concentrations decreased and adiponectin levels increased in both groups (between‐group difference ± SE, −0.5 ± 0.1; P < .001; and 1.0 ± 0.3; P = .005; D&E and D&E plus testosterone groups, respectively table 4).

5.5 Clinical and Biochemical Assessment of Hypogonadism in Men with T2DM:

(Dheeraj Kapoor et al., 2007) conducted a study to assess the prevalence of clinical hypogonadism, its symptoms, and measures of biochemically available testosterone deficiency in men with type 2 diabetes mellitus.

5.5.1. Study Design and Technique:

A cross-sectional study including 355 men with type 2 diabetic mellitus aged greater than 30 years, was conducted to measure total and bioavailable testosterone, sex hormone–binding globulin, body mass index, and waist circumference along with free testosterone calculations. In the study, presence of clinical symptoms of hypogonadism was defined as overt hypogonadism, low testosterone levels as (total testosterone <8 nmol/l and bioavailable testosterone was taken as <2.5 nmol/l). Presence of clinical symptoms and total testosterone level of 8–12 nmol/l or bioavailable testosterone of 2.5–4 nmol/l was taken as borderline hypogonadism.

5.5.2 Observations:

A decreased blood testosterone concentration was common in diabetic men, and significant number of these men showed symptoms of hypogonadism. Overt hypogonadism was observed in 17% of men with total testosterone levels <8 nmol/l and 14% with bioavailable testosterone concentrations <2.5 nmol/l. Borderline hypogonadism was noted in 25% of participants with total testosterone concentrations 8 to 12 nmol/l and bioavailable testosterone between 2.5 and 4 nmol/l. 42% of the men had free testosterone values <0.255 nmol/l. Waist circumference and body mass index was found to have negative correlation with testosterone levels in men, while the association being stronger for waist circumference as compared to body mass index.( fig 5, fig 6)

(Dheeraj Kapoor et al., 2007) observed almost one third of the hypogonadal men with type 2 diabetes mellitus had primary or secondary hypogonadism. The remaining of the hypogonadal group presented low testosterone levels with normal gonadotrophin concentrations. These men can have primary or secondary hypogonadism (Dhindsa et al., 2004c). Men with low serum testosterone values and normal or low gonadotrophins concentrations were thought to have hypogonadotropic hypogonadism, or a combination of both primary as well as secondary hypogonadism with aging (Nieschlag et al., 2004).

Another important observation made in this study was about inverse relationship of serum testosterone levels with waist circumference and BMI. An explicit explanation for this occurrence can be given by hypogonadal obesity cycle (Kapoor et al., 2005) .This cycle was firstly explained by (P G Cohen, 1999).

In this study (Dheeraj Kapoor et al., 2007) showed significant association of glycemic control with BMI and waist circumference in line of findings described by (J Svartberg et al., 2004) . Similar findings were noted by (Iso et al., 1991) in Japanese men stating relationship of obesity in terms of waist-to-hip ration with that of HBA1C in type 2 diabetics.

6 DISCUSSION

Review of existing literature highlights important relationship of hypogonadotropic hypogonadism with type 2 diabetes and obesity and uncovers many significant details about this correlation. An important factor of Insulin resistance was also observed about hypogonadotropic hypogonadism in patients with type 2 diabetes being directly related to the significant increase in insulin resistance as indicated in decreased GIR by 36% (Dhindsa et al., 2016b). Along with a marked decrease in the expression of IR-β, IRS-1, AKT-2, and GLUT4, the major genes mediating insulin signaling responsible for glucose transport was noted. The lower insulin sensitivity of men with hypogonadotropic hypogonadism is probably due to increased adiposity as difference in GIR between the two groups was insignificant after correction for adiposity (especially visceral fat) (Dhindsa et al., 2016b).This explains relationship of adipose tissue (obesity) in body with that of hypogonadotropic hypogonadism in type 2 diabetes mellitus and the possible role of insulin sensitivity too.

Previous available studies investigated the impact of testosterone therapy on insulin sensitivity by calculating HOMA-IR (Gianatti et al., 2014); (T Hugh Jones et al., 2011) but with inconsistent results (Grossmann et al., 2015) .It was noted that (Dhindsa et al., 2016b) study was the first to describe the insulin-sensitizing effect of testosterone therapy in hypogonadal men with type 2 diabetes by using hyper insulinemic-euglycemic clamp technique. Their findings were consistent with studies in obese men without diabetes mellitus (Mårin et al., 1993);(Sattler et al., 2014) .This finding was contrary to the studies in non-obese men which do not show a change in insulin sensitivity after testosterone replacement (Frederiksen et al., 2012); (Rita Basu et al., 2007); (Tripathy et al., 1998). So probably, testosterone-induced increase in insulin sensitivity was in obese and insulin-resistant men only.

(Dhindsa et al., 2016a) study was found deficient in recording of HbA1c values in spite of a marked reduction in insulin resistance, but it observed a significant reduction in fasting glucose concentrations after testosterone therapy. This drawback of (Dhindsa et al., 2016a) study can be explained by short duration of study, limiting HBA1C value monitoring and relatively low baseline HbA1c concentrations (mean 7.0 ± 1.1% [53 ± 12 mmol/ml]) amongst the participants.

The high dropouts rate was also observed in some studies, up to around (36%) in the placebo arm in comparison with testosterone arm being (9%)(Dhindsa et al., 2016b). It can also be explained by short duration of the study which hindered following study protocol in entirety. But the overall dropout rate in (Dhindsa et al., 2016b) study was (23%) which was less than the rate accounted in the study design as (25%), the comparable dropout was observed in other similar studies (T Hugh Jones et al., 2011)

(Hackett et al., 2014) provided evidence that low testosterone level (hypogonadism) is related to type 2 diabetes mellitus and obesity by observing significant improvement in HbA1c and waist circumference in men with type 2 diabetes having testosterone replacement therapy. This improvement in HBA1c and waist circumference was related to achievement of adequate serum testosterone levels but was not observed in men with depression (Hackett et al., 2014).

The possible link and the impact of testosterone administration and supervised diet and exercise in hypogonadal men, with metabolic syndrome and newly diagnosed type 2 diabetes mellitus, was also explored in this review (Heufelder et al., 2009). It is already established by (Alberti et al., 2005), (Traish, Saad and Guay, 2008); (Paul Chubb et al., 2008) that a reduced serum testosterone concentration predicts a relationship with the Metabolic Syndrome. Many epidemiologic studies and (Pitteloud et al., 2005b) suggested a positive relationship between serum testosterone levels and insulin sensitivity in men across the full spectrum of glucose tolerance. (Yialamas et al., 2007) elaborated this relationship as partially direct and is not fully dependent on (changes in) components of the metabolic syndrome.

(Heufelder et al., 2009) noted that supervised diet and exercise alone can not only improve testosterone concentrations, glycemic control, but also features of the metabolic syndrome, thus suggested important link between hypogonadism, weight and diabetes mellitus. Addition of relatively low‐dose testosterone with the diet and exercise can bring significant additional improvement in glycemic control, insulin sensitivity, and can cause even reversal of the features of metabolic syndrome (Heufelder et al., 2009). This observation is important in a way as it depicts that diet control, exercise, and testosterone supplementation may be beneficial in the management of men with type 2 diabetes mellitus (Heufelder et al., 2009). Main shortcoming of the (Heufelder et al., 2009) study was absence of actively treated placebo group.

As only few clinical studies (Lee et al., 2005); (R. Basu et al., 2007) evaluating the effect of normalization of serum testosterone levels on glucose homeostasis are available, (Heufelder et al., 2009) measured insulin sensitivity by HOMA showing significant improvement with testosterone. Fasting insulin levels which are good indicator of insulin sensitivity, showed important correlation with the changes in circulating androgen levels and hence supported (Pitteloud et al., 2005b) who described direct relationship between insulin sensitivity and circulating testosterone concentrations using the hyper‐insulinemic euglycemic clamp technique.

It was noted that 52 weeks of testosterone treatment significantly improved adiponectin level and CRP which are key serum markers of insulin sensitivity and hepatosteatosis (Heufelder et al., 2009). Impact of diet, exercise and testosterone on reduction of C-reactive protein levels was not reported by (D Kapoor et al., 2007) but was replicated in a study conducted by (Haider et al., 2009).

High prevalence of symptomatic hypogonadism in men with type 2 diabetes mellitus correlates with testosterone concentrations and symptoms of testosterone deficiency (D. Kapoor et al., 2007a). This factor was not discussed in previous studies (Dhindsa et al., 2004c) which showed about one-third of type 2 diabetic men having low plasma testosterone levels. Findings of (Dheeraj Kapoor et al., 2007) were in line with the study of (Dhindsa et al., 2004c) stating that low testosterone levels cannot be explained only on the basis of lower levels of SHBG in association with insulin resistance. (Dheeraj Kapoor et al., 2007) noted a high percentage of diabetic men with low levels of bioavailable and free testosterone. Another point of this study was about the negative correlation of body mass index, visceral obesity and obesity with low testosterone concentrations.

On the bases of normal values and international recommendations, (Dheeraj Kapoor et al., 2007) reported 17% of the diabetic men having overt hypogonadism with total testosterone concentrations <8 nmol/l, and a further 25% having symptoms of hypogonadism had testosterone between 8 and 12 nmol/l. The factor of low sex hormone binding globulin levels with insulin resistance might have probable role in lower total testosterone levels in this population strata. But the occurrence of similar hypogonadism using bioavailable testosterone and the wide range of SHBG levels (5.14–129 nmol/l) suggests the otherwise case needing assessment of individual patients separately on independent basis.

Ageing has impact on decline in testosterone levels in men . (Nieschlag et al., 2004) in a longitudinal Baltimore Ageing Study showed that 8, 12, 19, and 28% of men aged above >40, 50, 60, and 70 years, respectively, had total serum testosterone levels less than the normal range (<11.3 nmol/l) (Harman, 2001). This study demonstrated a higher prevalence of hypogonadism across all age-groups (42, 44, 39, and 56% in the age-groups 40–49, 50–59, 60–69, and 70–79 years, respectively) using the Baltimore study criteria. The mean total and bioavailable testosterone concentrations in type 2 diabetic men of (Dheeraj Kapoor et al., 2007) study, were lower in all age-groups as compared to data reported by (Leifke et al., 2000) in non-obese healthy males and by (Muller et al., 2003) in independently living males. The similar findings of total and free testosterone concentrations in type 2 diabetic men were noted by (Dhindsa et al., 2004c).

6.1 Limitations and Strengths:

The possibility of publication bias related to non-inclusion of all the eligible studies could not be excluded even though a comprehensive literature search was performed. Considerable heterogeneity amongst the studies made it difficult to generalize the data. Consequently, a meta-analysis was not attempted.

In spite of the above limitations, this systematic review has important strengths including an in-depth and comprehensive literature search, a focused review question, predefined inclusion criteria and use of standard quality assessment tool.

7 CONCLUSION

Obesity and type 2 diabetes mellitus, but not the type 1 diabetes, are closely related to hypogonadotropic hypogonadism in men. There is a complicated interlink between obesity, glycemia, metabolism and HPT function in men. Insulin resistance probably contributes to the pathogenesis of hypogonadotropic hypogonadism along with increase in BMI and known association of hypogonadism with obesity. Hyperglycemia with insulin resistance further worsens the pro-inflammatory state and hypogonadism. It is clear that pathological defect in the secretion of testosterone is at the hypothalamic level. The stance is strengthened with the presence of inappropriately low concentrations of LH and FSH while response of these hormones to GnRH being normal. The mechanism underlying this defect is not entirely understood but insulin resistance and the associated inflammatory mediators may contribute to this defect. This relationship between obesity, T2DM and hypogonadotropic hypogonadism is not unidirectional in nature. Future studies should focus on clear elaboration and understanding of these complex interlinking mechanisms. Treatment with testosterone has shown positive impact on the hypogonadotropic state and adiposity and all-cause mortality but further studies are definitely required in this regard.

7.1 FUTURE DIRECTIONS

Hypogonadism might be one of the mechanisms contributing to increased total and regional adiposity, increased body mass index, decreased insulin sensitivity and reduced sexual function in type 2 diabetics and obese men. It could also contribute to the increased prevalence of the metabolic syndrome. It is therefore extremely important to define not only the relationship of obesity, T2DM and hypogonadotropic hypogonadism but also its underlying pathogenic mechanisms. The potential beneficial effects of testosterone replacement therapy have been established on adiposity, hyperglycemia, components of metabolic syndrome and overall mortality. Further prospective trials are required to establish the long-term impacts of prolonged testosterone therapy in this regard. The results of such trials will have a paramount significance on understanding the effect and treatment of hypogonadotropic hypogonadism, obesity and T2DM.

7.2 ETHICAL CONSIDERATIONS:

As no confidential patient data was accessed or analyzed so no known ethical constraints seem to be attached with this literature review.

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