Abstract:Despite varying findings, TST has been used for a long time to treat hypogonadal males with type 2 diabetes mellitus (T2DM). The function of TST was evaluated in this meta-analysis in hypogonadal males with type 2 diabetes. Relevant randomised controlled trials and observational studies were identified by searching PubMed, Embase, and Google Scholar. The effects of TST were evaluated using pooled mean differences (MDs) and relative risks with 95% confidence intervals (CIs).Our meta-analysis includes 3,002 hypogonadal, type 2 diabetics from 13 randomised controlled trials and 2 observational studies. Total testosterone levels increase significantly with testosterone replacement, and TST significantly improves glycemic management compared to placebo by lowering homeostatic model assessment of insulin resistance (WMD = -1.47 [-3.14, 0.19]; p=0.08; I2=56.3%), fasting glucose (WMD = -0.30 [-0.75, 0.15]; p=0.19; I2= 84.4%), fasting insulin (WMD = -2.95 [-8. Overall, TST resulted in a greater increase in free testosterone levels compared to placebo (WMD = 81.21 [23.87, 138.54] p=0.07; I2= 70%) when comparing patients' individual measurements.We conclude that TST can help hypogonadal Type 2 Diabetes patients with better glycemic control and hormone levels, as well as lower total cholesterol, triglyceride, and LDL cholesterol while raising HDL cholesterol. Therefore, in addition to the usual care for diabetes, we advise TST for these individuals.Introduction:An abnormality in one or more of the testicular hormone concentrations along the hypothalamic-pituitary-testicular axis is the cause of the clinical syndrome known as hypogonadism. In men, hypogonadism is diagnosed when low levels of testosterone (both total and free) are found in the blood. [1] The annual incidence rate of hypogonadism is 12.3 per 1000 people, affecting between 5.1% and 12.3% of men between the ages of 30 and 79. When free testosterone levels fall below 225 pmol/l (65 pg/ml), a pathology is present and treatment is necessary. [2] Due to the devastating effects it can have on a patient's ability to perform basic bodily functions and their overall quality of life, hypogonadism is a global health problem. Recent studies have found strong evidence connecting hypogonadism and type 2 diabetes mellitus (T2DM). This is because low T levels cause an increase in fat storage, insulin resistance, and poor glycemic control, and a higher risk of obesity increases the likelihood of TD. [3] The use of testosterone in routine clinical care for type 2 diabetes is being questioned by a growing (and sometimes conflicting) body of research. Numerous studies have shown that testosterone treatment lowers the risk factors for cardiovascular disease and diabetes in men with type 2 diabetes, including systolic and diastolic blood pressure, lipid profiles, insulin sensitivity, inflammation, and levels of fasting plasma glucose (FPG) and glycated haemoglobin (HbA1c). It has also been suggested that men with hypogonadism who undergo long-term testosterone therapy have a lower chance of developing type 2 diabetes and a higher quality of life, as measured by the Aging Male Symptoms (AMS) questionnaire. [5] There were, however, studies that found the opposite. Hypogonadal patients with type 2 diabetes have been shown in multiple studies to benefit greatly from testosterone replacement therapy (TRT), as measured by decreases in fasting serum glucose (FSG), fasting serum insulin (FSI), and haemoglobin A1C (HBA1C). [6] These indicators did not significantly decrease in TRT groups, according to other data. Total cholesterol, triglyceride, and serum low-density lipoprotein (LDL) levels have all been shown to be reduced in studies where TRT was used, while high-density lipoprotein (HDL) levels were found to be increased. [7,8] But no other studies found evidence of a statistically significant improvement in lipid metabolism.Only a small number of randomised control trials and observational studies have looked at the role of TRT in male hypogonadism caused by TDM, and the results have been inconsistent. To better understand the role of TRT in hypogonadal males with type 2 diabetes, we conducted a systematic review and meta-analysis. As far as we can tell, this meta-analysis provides the most recent look at how testosterone therapy stacks up against no treatment or placebo.Methods and MaterialsThis meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). [9]Search strategyMethods From the study's inception on September 5, 2022, to the present day, PubMed (Medline) and Cochrane were combed extensively. Searches on ClinicalTrials.gov, Google Scholar, and Medrxiv uncovered the grey literature and preprints. An indexing strategy was developed using both keywords and Medical Subject Headings (MESH terms). ['Testosterone' OR 'TST' OR Testosterone undecanoate] were among these. AND [[Diabetes Mellitus OR [Hypogonadism]]. Table S1 provides details on the search parameters and parameters. In conducting this search, we did not apply any filters or limitations. In the case of non-English text, Google Translate was used to produce an English version. The studies were located through manual searches of review articles. Two reviewers independently and anonymously evaluated the titles, abstracts, and full texts (MK and SK). The relevant studies were imported into Endnote X9 to avoid repetition (Clarivate Analytics, US).Criteria for EligibilityCriteria for inclusionThe studies were chosen based on their language, study design, patient population, intervention, comparison, outcomes of interest, and definition.Publications were limited to those written in English, and studies had to be either randomised clinical trials or observational studies that met certain criteria for inclusion before the meta-analysis could be performed.Hypogonadism patients are those who have type 2 diabetes and have been diagnosed with the condition.Patients who participated in the study's exposure group included those who had received testosterone therapy.The non-TST group served as a control and received either the gold standard of care or a placebo in this analysis.Implications on glucose homeostasis and hormonal levels after treatment constitute the Primary Outcomes.Measurements of cholesterol, body mass index, waist size, fat percentage, and systolic and diastolic blood pressure were recorded as secondary outcomes.Criteria for exclusionThe following significant exclusion criteria were established to ensure the quality of this meta-analysis:• There are no agreed-upon criteria for making a diagnosis of late-onset hypogonadism or type 2 diabetes, determining the appropriate population to study, dosage, or administration method for testosterone, or evaluating outcomes.There are no control or placebo groups• Duplicate publications • Inadequate data for estimating a mean difference (MD) with a 95% confidence intervalIn addition, the 25-item CONSORT checklists, which stress describing how trials were conceived, analysed, and interpreted, were used to assess all included RCTs (Table S2). The 25 reported items were used to evaluate the quality of the included RCTs. The strength of a randomised controlled trial (RCT) correlates with the number of outcomes that were reported. All 25 criteria should be present in high-quality research.Data ExtractionData ExtractionTwo researchers (HN and RI) independently read and evaluated each article to determine whether or not it should be included in the review. Questions were answered and doubts dispelled. We collected the following data from each trial: first author's name, publication year, country, ethnicity, testosterone cut-off point, diabetes duration, testosterone regimen, medications on comparators, mean age, Hba1c percentage, and total serum testosterone level. Table 1 summarises these facts. Parameters such as HOMA-IR, fasting plasma glucose, fasting serum insulin, haemoglobin A1c, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, body fat percentage, body mass index, systolic blood pressure, diastolic blood pressure, erectile function, and the ageing male score are listed in Table 2.Study quality assessmentPublished RCT quality was evaluated using a modified version of the Cochrane Collaboration risk of bias tool [10], while observational study quality was measured using the New Castle Ottawa scale. [11] Statistical analysis The aforementioned meta-analysis was conducted using the statistics software Review Manager 5.4 (Cochrane Collaboration). For a simple yes/no outcome, we found the relative risk (RR) and 95% CI. The average and standard deviation were used to illustrate continuous results. In this meta-analysis, we show the combined effect of relative risks (RRs) and weighted mean differences (WMDs) calculated with the generic-inverse variance and continuous outcome functions using a random-effects model. Results were considered to be statistically significant when the p-value was less than 0.05. In order to assess the possibility of publication bias, funnel plots were constructed for primary outcomes.Using I2 statistics, we were able to quantify the degree of disagreement between studies. Low heterogeneity was represented by an I2 value of 25%, moderate heterogeneity by a value between 25% and 50%, and high heterogeneity by a value of 50% or more. A sensitivity analysis on outcomes with a high degree of heterogeneity was performed to investigate the impact of individual studies on the overall pooled estimate.ResultsStudy selectionThe initial literature search yielded a total of 659 articles. Out of the initial 30 publications, only 15 met the inclusion criteria for this meta-analysis; 2 were observational [12,24] and 13 were randomised trials [5,8,13-23]. The distinguishing characteristics of the selected studies are outlined in (Supplementary table S2 and S3)Baseline characteristics Three thousand and two people met the criteria for hypogonadism across the 15 studies; 1484 received testosterone and 1518 received a placebo. Six studies [8,12,14,18,20,24] required the presence of at least three sexual symptoms and a total testosterone level of 12 nmol/L to diagnose hypogonadism, while the remaining studies [5,13,15,16,17,19,21,22] required the presence of a total testosterone level of 15 nmol/L or a free testosterone level of 225 pmol/L to make the diagnosis. The cutoff for hypogonadism in another study [13] was set at TT13 nmol/L. The primary testosterone regimens used in the included studies varied widely. Only one study () used oral testosterone, three (15,17,21) injected testosterone gel subcutaneously, and eleven (5,8,12-14,16,18-20,22,23,24) injected testosterone intramuscularly. Testosterone was administered in a wide variety of doses and at different intervals in these studies. Only two of the RCTs [17,19] lacked a control group entirely, while the other eleven [5,8,13-16,18,20-23] were double-blind placebo-controlled studies. Table 1 and Table 2 provide information about the participants' demographics, medical histories, hormone levels, and glycemic indices as appropriate for the study.Quality assessment and publication biasAccording to the New Castle-Ottawa scale, an instrument for assessing the quality of studies, there is a low risk of bias in observational studies (Supplementary Table 4). The Cochrane method for evaluating randomised controlled trials yielded results of moderate to high quality (Supplementary Table 5). Publication bias did not affect the findings, as demonstrated by the funnel plots (Supplementary Figure S1).Primary outcomes:The effects of testosterone on glucometabolism were assessed by measuring HOMA-IR, haemoglobin A1c, fasting serum glucose (FSG), and fasting serum insulin (FSI). Data from 9 of the 15 studies reporting on HOMA-IR ([5,8,13,14,16,17,21,22,24]) showed that testosterone therapy was superior to placebo at lowering HOMA-IR levels (WMD = -1.47 [-3.14, 0.19]; p = 0.08; I2 = 56.3%). Patients in the testosterone group showed a greater decrease in FSG after treatment compared to those in the placebo group (WMD = -0.30 [-0.75, 0.15]; p=0.19; I2= 84.4%). FSG was measured in 14 [5,8,12-19,21-24] of the 15 studies. WMD = -2.95 [-8.64,2.74]; p = 0.31; I2 = 49.3%]; 8 [8,13,15-18,22,24] of 15 studies found that patients treated with testosterone had greater reductions in FSI levels. Among the 15 studies, 13 reported HbA1c values, and pooled analysis showed that testosterone treatment was associated with a greater improvement in post-treatment HbA1c levels (WMD = -0.29 [-0.57, -0.02] p=0.04; I2= 89.8%). (Figure 3)Total testosterone, free testosterone, serum hormone binding protein (SHBG), and prostate specific antigen (PSA) were taken into account to determine testosterone's impact on hormone levels. The pooled analysis of 9 studies that measured total testosterone levels [5,12,13,18,19,21-24] found that testosterone therapy is associated with a significant increase in total testosterone levels (WMD = 4.51 [2.40, 6.61] p0.0001; I2= 96.3%). The in-study heterogeneity was unaffected by excluding individual studies from the pooled analysis.Combining data from three studies [13,14,21] found that patients on testosterone therapy experienced a greater increase in free testosterone levels compared to those on placebo (WMD = 81.21 [23.87, 138.54] p=0.07; I2= 70%). After pooling data from 5 studies [13,17,21,22,23], researchers found that SHBG level decreased more with testosterone therapy (WMD = -1.28 [-5.51, 2.96] p=0.55; I2 = 0%). There was no statistically significant difference in PSA levels between the two groups after therapy (WMD = -0.02 [-0.13, 0.08] p=0.65; I2 = 0%) across seven studies [8,13,14,15,17,21,23].Secondary outcomes: (Table 3)Treatment with testosterone has been shown in a pooled analysis of secondary outcomes to improve HDL cholesterol and IIEF, as well as reduce total cholesterol, LDL cholesterol, triglyceride, body fat, waist circumference, body mass index, systolic blood pressure, diastolic blood pressure, arterial mean stiffness, and mortality.Discussion:Recent studies have found that hypogonadism occurs in a high percentage of men with Type-2 diabetes. Despite growing knowledge of the correlation between T2D and hypogonadism, no universally accepted guidelines exist for dealing with the condition. The purpose of this meta-analysis was to develop clear, evidence-based recommendations for the treatment of hypogonadism in men with Type 2 diabetes mellitus who are taking testosterone replacement therapy. Evidence linking type 2 diabetes and low blood testosterone due to an amplified insulin signalling pathway has been established by multiple studies showing a significant incidence (30-80%) of hypogonadism in males with diabetes mellitus. [25] Hypogonadism is more common in males with diabetes than in non-diabetic men across the globe, including in the West, Asia, and Africa. The effects of testosterone replacement therapy in hypogonadal males with type 2 diabetes were compared to those in a control group in a systematic review and meta-analysis involving 15 studies and 3002 patients (T2DM). All men with Type 2 diabetes and all men with a body mass index (BMI) greater than 30 or a waist circumference greater than 104 cm were recommended for screening for hypogonadism by the American Academy of Clinical Endocrinologists in 2016. The 2018 Endocrine Society guidelines continue to discourage testosterone monitoring despite the high prevalence of hypogonadism in conditions like type 2 diabetes. [26] Screening for hypogonadism was advocated for in 2016 by the American Academy of Clinical Endocrinologists in all men with Type 2 diabetes and in all men with a body mass index (BMI) of 30 or higher, or a waist circumference of 104 centimetres or more. In spite of the high prevalence of hypogonadism in conditions such as type 2 diabetes, the Endocrine Society's 2018 guidelines still discourage testing for the hormone. [26] In men with hypogonadism, testosterone replacement therapy (TRT) has been shown to have a positive effect on a wide range of outcomes, including sexual desire and function, bone mineral density, muscle mass, body composition, mood, erythropoiesis, cognition, quality of life, and cardiovascular disease, but the indications for testosterone supplementation are still up for debate. Potential side effects of testosterone replacement therapy have been categorised by the guidelines into two groups: those with a strong association to testosterone therapy, such as acne and oily skin, an increase in hematocrit, decreased fertility, locally active prostatic carcinoma, and the development of metastatic prostatic carcinoma, and those with a weak association, such as gynecomastia, worsening sleep apnea, and the progression of breast cancer. [27] Our results confirm the findings of previous studies [5,8,12-19,21-24] showing that TRT can significantly enhance glucose control by decreasing Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), fasting serum glucose (FSG), fasting insulin (FSI), and glycated haemoglobin (HBA1C). Recent research has established a correlation between baseline HOMA-IR and body mass index, waist circumference, and C-peptide. Insulin sensitivity, as measured by changes in HOMA-IR, HOMA-%, and blood C-peptide and proinsulin levels, was also enhanced by testosterone supplementation, demonstrating the presence of metabolic syndrome. [28] Testosterone replacement therapy for hypogonadal males with diabetes has been linked to improvements in both body mass index and glucose control. The testosterone treatment group showed statistically significant improvements in body mass index, fasting glucose, A1C, blood pressure, lipid profiles, and liver enzymes, according to a study. [29] Twelve months of testosterone treatment (adjusted to mid-normal concentrations for healthy men) decreased insulin resistance modestly, HOMA-IR 0.6, p = 0.03, but had no effect on body weight or waist circumference in a large testosterone trial involving 788 men over the age of 65 (72% were obese and 37% had diabetes at baseline). [29] Testosterone therapy has been linked to long-term weight loss, a marked decrease in cardiometabolic risk factors, and in some cases, the complete reversal of diabetes, according to a number of case studies. Treatment with testosterone undecanoate depot injections was initiated for a 57-year-old man with benign prostatic hyperplasia, erectile dysfunction, apathy, and subpar physical fitness (intramuscular injections at 3-month intervals following a 6-week gap). Patients on testosterone therapy saw improvements in fasting blood glucose (to 6.0 mmol/L after 3 months, to below 5.7 mmol/L after 12 months, and then permanently below this value), insulin resistance (HOMA-IR: 3.9 at month 24), and serum lipid levels (LDL/HDL ratio: 3 and triglycerides: 2.5 mmol/L). [30] To fully understand the connection between circulating sex hormones and glucose metabolism, more interventional studies are required.In our meta-analysis, we looked at a lipid panel consisting of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglyceride levels. Thirteen studies found that testosterone recipients had lower total cholesterol levels compared to placebo recipients. On the other hand, 14 studies showed that while HDL cholesterol increased, triglyceride levels decreased. However, there was less of a difference in LDL cholesterol levels between the two groups. Similarly, Si Hyun Kim et al2021 .'s meta-analysis found that TRT significantly lowered total cholesterol compared to placebo. There was also a reduction in triglycerides, though it was not statistically significant. HDL levels unexpectedly dropped after TRT compared to the placebo group. TRT's role in HDL was unclear due to a lack of evidence and conflicting results. It has been shown that high doses of TRT lower levels of HDL and lipoprotein A. TRT's effect on blood lipid and lipoprotein levels is controversial, however. [31] The 14 studies that made up our meta-analysis all showed a reduction in diastolic blood pressure (DBP) and a modest rise in systolic blood pressure (SBP). The effects of testosterone on lipid profiles in the blood are ambiguous. In men with and without type 2 diabetes, low testosterone has been linked to elevated levels of LDL and triglycerides and decreased HDL. In patients with high endogenous testosterone profiles, several cross-sectional studies found no association between elevated serum lipid levels or even elevated LDL. TRT has been shown to significantly reduce LDL-C and total cholesterol in men with eugonadism and hypogonadism in numerous systematic reviews and meta-analyses. [32] Measurements of the patient's waist and body mass index (BMI) can be used for screening for cardiometabolic risk. Testosterone supplementation is gaining popularity as an anti-obesity medication due to its ability to decrease visceral adipose tissue and increase muscle mass in males with hypogonadism. Thirteen additional studies, which contradict the aforementioned randomised controlled trials, have found that testosterone therapy results in a greater reduction in body mass index. [32]A significant correlation between total serum testosterone and AMS and IIEF scores was found in three studies. Treatment with testosterone significantly reduced AMS scores while increasing IIEF. Slight enhancements in sexual functioning, as measured by the AMS scale, the IIEF erectile dysfunction domain, and the IIEF-5 scale, have been associated with low testosterone in older men (testosterone threshold, 10.4 nmol/L [300 ng/dL]). Physical function, depressive symptoms, energy, vitality, and cognitive abilities do not significantly improve, however, according to the literature. Since the AMS scale was the only source of data on life satisfaction, we can assume that the slight improvement in quality of life was attributable to a rise in sexual satisfaction. [33] Different levels of testosterone were analysed including total, free, SHBG, and PSA. Both total and free testosterone levels increased significantly, while SHBG dropped significantly. However, PSA levels were not related to this therapy. The impact of TRT on PSA has been the subject of multiple meta-analyses. Despite this, the primary focus of the papers reviewed was not on PSA and testosterone but on TRT and the risk of prostate cancer. Risk factors for cardiovascular disease (CVD) such as obesity, hypertension, dyslipidemia, and diabetes are often co-occurring with androgen insufficiency. Androgens have a direct effect on PSA, and the protein's level has been suggested as a possible indicator of androgen deficiency in a number of studies. According to the research conducted by Do Kyung Kim et al., TRT significantly increased PSA levels compared to placebo. [34]Numerous benefits can be gained from our meta-analysis. If we add two more studies to our meta-analysis, we'll have about twice as large of a sample to work with. (2) A sensitivity analysis was run to determine the impact of various studies on the final tally. (3) Multiple plots and tests, such as the funnel plot, Egger's test, and Begg's test, were used to evaluate estimates of publication biases, and all of them concluded that the estimates were not statistically significant. Our meta-analysis also included an additional observational study, and we checked it for publication bias using the New Castle-Ottawa Scale. (4) We integrated mortality, total testosterone, free testosterone, SHBG, and PSA to account for new information in the literature that is rarely mentioned in individual studies.While we did collect a substantial amount of statistical data, it is important to note the caveats of our study. 1) Most studies had different follow-up times, with some indicating longer times. Because of the significance of homeostasis in the body, longitudinal follow-up studies are preferred when evaluating hormonal diseases like hypogonadism. Testosterone was used in a wide variety of doses and administration routes across a large number of studies spanning many weeks. This clinical heterogeneity may be attributable to (2) differences in study designs, interventions, and patient factors (including body mass index, age, sample size, ethnicity, and trial characteristics). (3) There have been few randomised controlled trials investigating the association between body fat, AMS and IIEF scores, free testosterone, and mortality rates. (4) All included RCTs displayed signs of selective reporting bias, except for Groti 2020. More research was needed to ascertain how testosterone therapy affected libido. (5) Also, most studies did not include information on doses for control groups, which may have added uncertainty.Conclusion Our results demonstrate that hypogonadal T2DM patients who underwent long-term testosterone replacement therapy experienced a sustained remission of their diabetes. 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Legends to figuresFigure 1: Prisma flow chartFigure 2: Effects on Glucometabolism; A= HOMA-IR (Homeostatic model assessment for insulin resistance), B= FSG (Fasting serum glucose), C= FSI (Fasting serum insulin), D= HbA1C (Glycated hemoglobin), WMD= weighted mean difference, CI= confidence intervalFigure 3: Effects on Hormonal levels; A= TT (Total testosterone), B= FT (Free testosterone), C = SBHG (sex hormone binding globulin), D= PSA (Prostate specific antigen).
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