Effects of treatment for diabetes mellitus on T concentrations

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Effects of treatment for diabetes mellitus on testosterone concentrations: A systematic review (2022)
Jolijn Van Cauwenberghe, Christophe De Block, Dirk Vanderschueren, Leen Antonio


Abstract

Background


Low testosterone levels are frequently present in men with obesity and insulin resistance. Currently, available treatment options (testosterone replacement therapy or lifestyle changes) hold possible risks or are insufficient. Since low testosterone levels are closely related to obesity and type 2 diabetes, treatment modalities for these conditions could result in an improvement in testosterone levels.


Objectives

To summarize the available evidence on the effects of traditional and recent treatment modalities for diabetes mellitus on testosterone levels and androgen-deficiency-related signs and symptoms.


Materials and methods

PubMed was searched from the year 2000 till the present using MESH terms: “hypogonadism,” “testosterone,” “testosterone deficiency,” “functional hypogonadism,” and the different classes of medications. Studies with observational and experimental designs on humans that evaluated the effect of antidiabetic medications on gonadotropins and testosterone were eligible for inclusion.


Results

Currently, available data show no or only limited improvement in testosterone levels with the classic antidiabetic drugs. Studies with GLP1-receptor analogs show beneficial effects on both body weight and testosterone levels in men with low testosterone levels and obesity with or without type 2 diabetes. However, data are limited to small and heterogeneous study groups and only a few studies report data about the impact on androgen-deficiency-related signs and symptoms.


Discussion and conclusion

With the recent advances in the knowledge of the pathophysiological pathways in obesity, there is enormous progress in the development of medications for obesity and type 2 diabetes. Newer incretin-based agents have great potential for the treatment of functional hypogonadism due to obesity since they show promising weight-reducing results. However, before the use of GLP1-receptor analogs can be suggested to treat functional hypogonadism, further studies are needed.




1 INTRODUCTION


Functional hypogonadism (also referred to as late-onset hypogonadism) is defined as the presence of low normal or low serum testosterone levels in the presence of clinical symptoms or signs of hypogonadism with the absence of intrinsic structural hypothalamic-pituitary-testicular (HPT) axis pathology. The HPT axis is intact while the rise in gonadotropin levels is absent due to functional HPT axis suppression. This entity is mostly observed in men with obesity and associated illnesses (e.g., metabolic syndrome, type 2 diabetes) or with the use of specific medications (e.g., opioids or glucocorticoids).1,2 The prevalence estimates range from 2.1% to 12.3%, depending on the definition, and there is an 8- to 13-fold increased prevalence in men with obesity or comorbidities.1,3 Furthermore, weight gain in the general population clearly leads to a decrease in total and free testosterone and hereby increase in sexual symptoms.4–6 How men with functional hypogonadism should be treated remains a topic of debate. Treatment with testosterone replacement suffers from a lack of convincing data on efficacy and holds possible risks.2 For example, the risk of erythrocytosis is present but appears to be dependent on the formulation of testosterone used.7 The risk of cardiovascular disease, venous thromboembolism, or prostate-related problems seems no higher with the use of testosterone replacement therapy in the treatment of hypogonadal men, but well-conducted studies and definite evidence are currently still lacking.7 Furthermore, treatment with testosterone impairs fertility due to interference with spermatogenesis. Moreover, low testosterone secondary to obesity is potentially reversible.8,9 A recent guideline by the European Academy of Andrology states that lifestyle changes, including physical activity and weight reduction, in overweight and obese men, are therefore recommended.2 This recommendation is supported by a meta-analysis, evaluating 24 studies, where weight loss, achieved by low-calorie diet or bariatric surgery, indeed resulted in a significant increase in plasma total testosterone, calculated free testosterone, sex hormone binding globulin (SHBG), and gonadotropins. The elevation of plasma testosterone was more pronounced in subjects with a higher body mass index (BMI) at entry. Furthermore, a larger decline in BMI was associated with a higher testosterone increase. This is reflected in the effects of the different methods for achieving weight loss: lifestyle interventions lead to a mean weight loss of 9.8 ± 4.5% and a modest increase in plasma testosterone (mean difference 82.8 ng/dl) while bariatric surgery resulted in a higher mean weight loss (32 ± 5.4%) and plasma testosterone rise (mean difference 251.8 ng/dl).8 Nevertheless, both lifestyle interventions and bariatric surgery have their limitations. The achievement and maintenance of body weight loss with lifestyle interventions are often challenged by a lack of compliance, failure in the long term, and high dropout rates.10 On the other hand, bariatric surgery results more frequently in a rapid body weight reduction10 but poses a risk of acute and long-term complications (e.g., surgical complications, osteoporosis, vitamin deficiencies,. . . ). Furthermore, the weight loss induced by standard antiobesity medication is moderate, for example, Orlistat, which showed a mean weight loss of 3.1kg (CI: −3.8 to −2.4 kg).11 Recently, the US Food and Drug Administration did approve high-dose semaglutide (2.4 mg once weekly SC), a glucagon-like-peptide-1 receptor analog (GLP1-RA) for the treatment of obesity, with a mean weight loss ranging from 9.6% to 17.4%.12–15 Due to the link between metabolic disorders (obesity, metabolic syndrome), type 2 diabetes mellitus, and functional hypogonadism, treatment with these and new promising antidiabetic agents could hypothetically provide benefits for men in the treatment of functional hypogonadism. Nevertheless, data on the effects of antihyperglycemic agents on hypogonadism are scarce.

*The aim of this systematic review is to summarize the available evidence on the effects of treatments for diabetes mellitus on testosterone levels and androgen-deficiency-related signs and symptoms.




3 RESULTS

3.1 Medications associated with weight gain or neutral effects on weight

3.1.1 Sulfonylureas
3.1.2 Pioglitazone



3.2 Medications associated with weight loss
3.2.1 Metformin
3.2.2 SGLT2 inhibitors
3.2.3 Incretin mimetics





4 DISCUSSION AND PERSPECTIVE

Since low testosterone levels are closely related to obesity and its comorbidities, such as insulin resistance and type 2 diabetes, treatment modalities for obesity and type 2 diabetes could result in an improvement in testosterone levels. Currently, available data show no or only limited improvement in low testosterone levels with the classic antidiabetic drugs, and studies on the effect on androgen-deficiency-related symptoms are not available. Thus far, there have been very few data on SGLT2i on testosterone levels in men with type 2 diabetes with hypogonadism. On the other hand, studies with GLP1-R analogs show beneficial effects on both body weight and testosterone levels in men with low testosterone levels and obesity with or without type 2 diabetes. Overall, it is expected that the weight-lowering effect is the main contributor to the improvement of low testosterone levels in the treatment with antidiabetic drugs. Nevertheless, the currently available data suggest that the rise in testosterone levels due to treatment with GLP1-RA is higher than what could be expected for the amount of weight loss.21,43 This might be explained by acting on the testicular GLP1-R and/or by the decrease of the antioxidants in the testes, but this hypothesis needs further exploration.40,44 Similarly, one might hypothesize that apart from weight loss, the improvement in glycemic control leads to an improvement in testosterone levels in men treated with antidiabetic medications. Observational data in men with suboptimal T2D (mean HbA1c 7.6%) showed that total testosterone was inversely correlated with HbA1c, meaning that improvement of HbA1c led to an improvement of total testosterone.45 However, recent data suggest that weight loss caused by antidiabetic medications is the main contributor to the improvement of total testosterone and not an improvement in glycemic control.35 Up to now, evidence in functional hypogonadism is limited to small, heterogeneous study groups and trials on a larger number of participants will be necessary. However, acquiring an appropriate study group is difficult due to the nonstandardized definition of functional hypogonadism and the low estimated prevalence or incidence in the general population (incidence rate of 43.1 per 10,000 per year).9 Furthermore, it remains controversial which treatment modality produces the most benefit for men with functional hypogonadism. It is without a doubt that in obese or overweight men, weight reduction should be aspired. Lifestyle changes comprising lowering calorie intake and increasing physical activity remain the first-line treatment, despite the difficulties in obtaining and preserving weight loss through lifestyle changes.2,10 The addition of new treatment modalities for weight reduction should be investigated since they are associated with other health benefits (e.g., glycemic control). In addition, recent data have shown that the presence of obesity predicted the development of low testosterone levels and that this group of men reported more erectile dysfunction, decreased libido, and decreased morning erections, compared to men with normal testosterone levels.9 Apart from other health benefits (e.g., cardiovascular disease, type 2 diabetes,. . . ), the risk of developing functional hypogonadism could provide additional motivation to men at risk in order to change their lifestyle. Furthermore, recent advances with respect to the knowledge of the molecular background of obesity have led to enormous progress in the development of medications for obesity and type 2 diabetes.46 For instance, the recently developed dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist Tirzepatide has shown to induce a weight loss of ≥15% in 15%– 40% of patients with type 2 diabetes after 40 weeks of treatment.47 Other therapeutic options, for example, GLP1/glucagon dual agonists, GIP/GLP1/glucagon tri-agonists, leptin sensitizers, amylin analogs, and amylin/calcitonin dual agonists, are currently under study for the treatment of obesity and/or type 2 diabetes. Whether these new agents have beneficial effects on testosterone levels, and/or symptoms of androgen deficiency are yet to be discovered but the preliminary promising results on weight loss could provide a new approach for the treatment of low testosterone secondary to obesity. In this line of thinking, a recent controlled study with GLP1-R analogs has already shown a beneficial effect on the severity of erectile dysfunction in men with type 2 diabetes with a high cardiovascular risk.48 We would like to encourage future studies on these new agents to add the assessment of symptoms of hypogonadism.
 

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