EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Our goal was to determine levels of sex hormones in men with type 1 diabetes mellitus and type 2 diabetes mellitus after autologous mesenchymal stem cell transplant.
Materials and Methods: We examined 10 male patients (32-56 years old) with type 1 diabetes mellitus and type 2 diabetes mellitus, whom we subsequently divided into 2 groups and examined. Group 1 comprised 5 male patients who received autologous mesenchymal stem cell transplant (cells were obtained from patient ’s iliac crest and cultured for 3-4 weeks) by intravenous infusion. Group 2 comprised 5 male patients (control group) who were on hypoglycemic tablet therapy or insulin therapy. The quantity of autologous mesenchymal stem cells infused was 95 × 106 to 97 × 106 cells. We analyzed levels of testosterone, luteinizing hormone, estradiol, and glycated hemoglobin in patients both before and 3 months after the autologous mesenchymal stem cell transplant procedure.
Results: In men with type 1 diabetes mellitus and type 2 diabetes mellitus, autologous mesenchymal stem cell transplant led to an increase in testosterone levels from 5.31 ± 2.12 to 6.33 ± 2.12 ng/mL (P = .82), a decrease in luteinizing hormone from 8.43 ± 1.25 to 5.94 ± 1.57 mIU/mL (P = .04), and a decrease in glycated hemoglobin from 9.45 ± 1.24% to 8.53 ± 1.08% (P = .25) after 3 months. The increase in testosterone in men with autologous mesenchymal stem cell transplant group of 6.33 ± 2.12 ng/mL was significant compared with men in the control group (3.9 ± 1.18 ng/mL; P = .01).
Conclusions: Testosterone level increased and luteinizing hormone level decreased within 3 months after autologous mesenchymal stem cell transplant in men with diabetes mellitus.

Key words : Glycated hemoglobin, Pancreatic islet cell regeneration, Testosterone

Recently, diabetes mellitus (DM) has become a worldwide public healthcare problem. According to the International Diabetes Federation, the global number of patients with DM will reach 642 million people by 2040.¹

Several studies have reported the association of the sex hormones testosterone and estradiol with DM, insulin resistance, and an increased prevalence of testosterone deficiency (also known as hypogonadism) in men with DM.^2-4 Although testosterone replacement therapy has been shown to improve insulin sensitivity, reduce fat mass, and increase muscle mass in men with hypogonadism and DM, treatment with testosterone preparations is associated with various adverse side effects (eg, infertility, liver and kidney damage, immune system dysfunction) and cancer risk.^5,6 The long-term risks of testosterone therapy in men with hypogonadism are unknown.

Over the past 2 decades, new therapeutic strategies for tissue repair such as stem cell therapy have been developed.^7-9 Mesenchymal stem cell therapy is an innovative tool for tissue regeneration and perhaps may solve the problem of hypogonadism, because mesenchymal stem cells have the potential to differentiate into steroidogenic cells.¹⁰ A number of studies in rats have shown the efficiency of treating hypogonadism (ovarian insufficiency) with mesenchymal stem cells, and other studies have reported the effect of autologous mesenchymal stem cell therapy (AMSCT) in the treatment of patients with type 1 DM and type 2 DM.^9,11-13

However, the effect of AMSCT on sex hormones levels in men with DM has not been sufficiently investigated. Thus, AMSCT has been identified as a potentially effective therapeutic approach for the treatment of hypogonadism in men with DM.

Materials and Methods

This prospective cohort study included 10 male patients (32-56 years old) with type 1 DM and type 2 DM, who were divided into 2 groups and subsequently examined. Group 1 comprised 5 male patients who received AMSCT by intravenous infusion. Group 2 comprised 5 male patients (control group) who were on hypoglycemic tablet therapy or insulin therapy. The quantity of autologous mesenchymal stem cells infused was 95 × 10⁶ to 97 × 10⁶ cells. We analyzed levels of testosterone, luteinizing hormone (LH), estradiol, and glycated hemoglobin (HbA1c) in patients before and 3 months after the AMSCT procedure. Thyroid pathology and hyperprolactinemia were excluded in these patients. Autologous mesenchymal stem cells were obtained from bone marrow samples of the iliac crest and were cultured for 3 to 4 weeks. The AMSCT was given as an intravenous infusion at a rate of 50 mL/hour. The infused quantity of autologous mesenchymal stem cells was 95 × 10⁶ to 97 × 10⁶ cells.

This clinical study and its methods were approved by the Local Ethics Committee following Helsinki Declaration guidelines at our institution. All patients provided written informed consent before recruitment.

Statistical analyses

Before the AMSCT procedure, all patients with type 1 DM and type 2 DM had poor glycemic control. Among all the patients, HbA1c level was more than 7%. In our examination, the mean baseline levels of HbA1c in men with type 1 DM and type 2 DM in the AMSCT group and in men with type 1 DM and type 2 DM the control group were 9.45 ± 1.24% and 8.84 ± 2.2%, respectively (Table 1).

In our examination in both groups of patients, we found that the mean baseline levels of testosterone, LH, and estradiol for the men with type 1 DM and type 2 DM in the AMSCT group were, respectively, 5.31 ± 2.12 ng/mL, 8.43 ± 1.25 mIU/mL, and 30.54 ± 10.51 pg/mL, which are in the reference range. The mean baseline levels of testosterone, LH, and estradiol for the men with type 1 DM and type 2 DM in the control group were, respectively, 5.27 ± 1.8 ng/mL, 4.33 ± 1.35 mIU/mL, and 27.4 ± 7.69 pg/mL, which are in the reference range (Table 1). These mean baseline levels of testosterone, LH, and estradiol were not significantly different between the 2 groups of patients (P = .937, P = .484, and P = .699, respectively).

On the day of AMSCT, the patients with type 1 DM and type 2 DM were given hypoglycemic tablet therapy or insulin therapy. Each patient's dose was adjusted according to the blood glucose level performance, which was examined once every 4 hours during the first day of the AMSCT. During the subsequent 3 days, fasting glucose and postprandial glucose levels were well controlled.

We did not observe any complications after the AMSCT procedure. The baseline data and the changes after the AMSCT are presented in Table 1. In patients with type 1 DM and type 2 DM in the AMSCT group, at 3 months after the procedure the mean testosterone level had increased from 5.31 ± 2.12 to 6.33 ± 2.12 ng/mL (P = .82), and the mean LH level had decreased significantly from 8.43 ± 1.25 to 5.94 ± 1.57 mIU/mL(P = .04). Mean levels of estradiol and HbA1c also changed, but not significantly, from 30.54 ± 10.51 to 26.1 ± 7.54 pg/mL (P = .59) and from 9.45 ± 1.24% to 8.53 ± 1.08%, respectively (P = .25) (Table 1).

The corresponding mean levels of testosterone, LH, estradiol, and HbA1c did not change significantly in the control group of men with type 1 DM and type 2 DM, with baseline versus 3-month levels for testosterone of 5.27 ± 1.8 versus 3.69 ± 1.18 ng/mL (P = .179), LH of 4.33 ± 1.35 versus 3.9 ± 1.21 mIU/mL (P = .72), estradiol of 27.4 ± 7.69 versus 26.7 ± 6.66 pg/mL (P = 1.0), and HbA1c of 8.84 ± 2.20% versus 8.64 ± 1.41% (P = .19) (Table 1).

After 3 months, mean levels of testosterone in men with type 1 DM and type 2 DM who had received the AMSCT were significantly higher versus the control group (6.33 ± 2.12 vs 3.69 ± 1.18 ng/mL, respectively; P = .01).

Three months after the AMSCT procedure, men with type 1 DM and type 2 DM showed significantly increased testosterone with decreased LH. Testosterone is a steroid hormone secreted by Leydig cells of the testes under the action of the pituitary LH. Several observational studies have shown increased prevalence of low testosterone in men with DM.^2,3 There are 2 directions for stem cell therapy for male hypogonadism. The first of these is multiple stem cell therapy to restore the androgenic function of the testes, as sourced from bone marrow, adipose tissue, or fetal tissue.¹⁴ Leydig cells derived from bone marrow, adipose tissues, and umbilical cord have shown promise in future therapy to treat primary hypogonadism.¹⁵ The second method of stem cell therapy for male hypogonadism involves isolation and transplant of Leydig stem cells into testicular tissue.^10,15 Some studies in rats have demonstrated the efficiency of treating hypogonadism (ovarian insufficiency) with mesenchymal stem cells through paracrine mechanisms.¹¹

According to the study by Nguyen Thanh and colleagues, testosterone levels increased after adipose-derived mesenchymal stem cell transplant in men with sexual functional deficiency.¹⁶ Arora and colleagues have shown that Leydig stem cells, when autografted subcutaneously in combination with Sertoli cells and myoid cells, can increase testosterone production.¹⁷

Thus, the significant increase in testosterone level that we observed and the trend toward a decrease in LH level in men who underwent the AMSCT procedure may indicate the efficacy of AMSCT for the treatment of secondary hypogonadism in men with DM.

Volume: 22 Issue: 1 January 2024 - Supplement - 1

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