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Abnormalities in sex hormones and sexual dysfunction in males with diabetes mellitus: A mechanistic insight (2022)
Nida Andlib, Mohd Sajad, Rajesh Kumar, Sonu Chand Thakur
ABSTRACT
Diabetes is a considerate metabolic disorder that can lead to a series of complications, involving the malfunctioning of the reproductive system of males. It has been observed that there is a gradual rise in male diabetic patients and almost half of the diabetic males have low semen quality and decrease reproductive function. In diabetic conditions, prolonged hyperglycemia leads to oxidative stress, diabetic neuropathy, and insulin resistance. Insulin resistance and its deficiency can impair the hypothalamus, pituitary gland, gonads, and perigonads. This causes a decrease in the secretion of gonadal steroids such as GnRH (gonadotropin-releasing hormone), FSH (follicle-stimulating hormone), LH (luteinizing hormone), and Testosterone. Moreover, it also causes damage to the testicles, spermatogenic and stromal cells, seminiferous tubules, and various structural injuries to male reproductive organs. During spermatogenesis, glucose metabolism plays an important role, because the fundamental activities of cells and their specific features, such as motility and mature sperm fertilization activity, are maintained by glucose metabolism. All these activities can influence the fertility and reproductive health of males. But the glucose metabolism is primarily disrupted in diabetic conditions. Until now, there has been no medicine focusing on the reproductive health of diabetic people. In this chapter, we review the consequences of diabetes on the reproductive system of males and all the pathways involved in the dysfunction of the reproductive system. This will help interpret the effects of DM on male reproductive health.
1. Introduction
Diabetes mellitus (DM) is an incurable disorder with varied morbific potential and causes damage to various organs. According to an IDF report, there are 463 million adults suffered from DM worldwide, which is supposed to rise to 578 million by 2030. Hyperglycemia is the most common symptom of diabetes, which is caused either by an autoimmune disease of pancreatic cells, that leads to a drop in insulin secretion in type 1 diabetes (T1DM) or by complete resistance or poor insulin secretion in type 2 diabetes (T2DM). In the past few decades, awareness and knowledge are very limited about diabetes and its effects on reproductive health. The main target of medicinal treatment was to eliminate the cause of disease to restore normal health. However, it is very essential to observe the consequences of DM on reproductive function. It causes impairment in both the male and female reproductive systems (Baccetti et al., 2002; Seethalakshmi et al., 1987; Sajad and Thakur,), leads to a reduction in the fertility ratio, and reproductive casualties rise (Greene, 1993; Lucas et al., 1989; Meller et al., 1981; Mills et al., 1988). Endothelial dysfunction, vascular dysfunction, and resulting oxidative stress are often caused by diabetes (Brownlee, 2001, 2005; Abdul-Ghani et al., 2006), and it is not unusual if it directly or indirectly affects several activities of the reproductive system (Dinulovic and Radonjic, 1990; Glenn et al., 2003; Hassan et al., 1993; Jackson, 2004, Mallidis et al., 2011; Sajad et al.). It is shown that almost half of DM men have poor semen quality and dysfunctional reproductive systems. In diabetic men, reproductive activity is affected at several steps because of endocrine control of spermatogenesis itself, or by impairing penile erection and ejaculation (Sexton and Jarrow, 1997, Baccetti et al., 2002; Ballester et al., 2004; Daubresse et al., 1978; Dinulovic and Radonjic, 1990; Garcia-Diez et al., 1991; Handelsman et al., 1985). It is affected by various mechanisms like neuropathy, a rise in oxidative stress, and endocrinopathies. There is a substantial body of literature on these reports, but their findings have been contradictory, as the described malfunctions are unlikely to cause significant impairment in reproductive function alone (Sexton and Jarrow, 1997). However, diabetes mellitus is a known source of sexual dysfunction in men, which may result in subfertility.
2. Effect of DM on males
Sexual dysfunction caused by DM has been broadly studied in males. There are various data showing clinical and experimental studies on diabetic males. There are four stages in which DM affects the male reproductive system, which involves structural changes in reproductive organs, erectile dysfunction, malfunctioning in ejaculation, and changes in semen quality. According to various reports, erectile dysfunction (ED) is caused in 59 % of men affected by DM. Many diabetic patients who are impotent (DMED) have nerve stiffening in the penis or pearled neuropathy. Due to DM, testosterone level also decreases which affects vascular endothelial function. ED is caused by hyperglycemia as it causes an increase in the quantity of ROS (reactive oxygen species) and AGEs (advanced glycation end products), eNOS (endothelial nitric oxide synthase) metabolism is inhibited and reduction in synthesis of endothelial and nitric oxide (NO) discharge (Fig. 1)
2.1. Pre-testicular effect of DM
The hypothalamus-pituitary-gonadal (HPG) axis is disrupted in DM which leads to alteration in the expression of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone in men.
2.2. Testicular effect of DM
2.2.1. Metabolism of energy in the testis
2.2.2. Testicular oxidative stress
2.2.3. Steroidogenesis
2.2.4. Spermatogenesis
2.2.5. Testicular histology and germ cell apoptosis
2.3. Post-testicular effect of DM
2.3.1. Erectile dysfunction (ED)
2.3.2. Ejaculatory disorders
2.3.3. Libido
3. Effect of DM on glucose metabolism in sperm
3.1. Insulin resistance effect on DM males
4. Effect of DM on the endocrine system (Role of hypothalamus pituitary-testicular axis)
5. Effect of neuropathy and infectious on DM males
6. Effect of DM on spermatogenesis and sperm
7. Possible damaging pathways
7.1. Role of mitochondria and ROS
7.2. Germ cell apoptosis
7.3. Germ cell autophagy
8. Biomarkers of diabetes-associated infertility in males
8.1. Reproductive hormones
8.2. Steroidogenic acute regulatory protein (StAR)
8.3. Hydroxysteroid dehydrogenase
8.4. AGE (advanced glycation end products)
8.5. Protein expression of lactate dehydrogenase (LDH) and monocarboxylate transporter-4 (MCT4)
8.6. Antioxidant enzymes
8.6. Antioxidant enzymes
8.8. Neurotrophic factor (NGF)
9. Medicinal plants
10. Conclusions
Till now the effect of DM on reproductive health is highly ignored. Many studies have shown that DM has a negative impact on male fertility, particularly the quality of sperm, semen constituents, sperm motility, and sperm DNA damage. It’s possible that this may not only result in subfertility or infertility but will also pass to the offspring and cause in subfertility or infertility in them. Reproductive dysfunction is caused by several DM-related factors, including oxidative stress, disruption of the HPG axis, and apoptosis. All these elements lead to aberrant hormone production and affect the morphology of the testis and epididymis. They also result in a decrease in the amount and quality of Leydig, Sertoli, and germ cells, which further causes sperm to have aberrant morphology, count, and motility. This condition has also been linked to several biomarkers, including AGE, StAR, VEGF, etc. Numerous medicinal herbs have been shown to play a significant role in preventing and reducing the impact of DM on the male reproductive system. However, further research is needed to fully understand the effect of phytochemicals in preventing the pathophysiology of diabetes on male fertility. To clearly understand the impact of DM on the male reproductive system, future studies must put detailed emphasis on the molecular level.
Nida Andlib, Mohd Sajad, Rajesh Kumar, Sonu Chand Thakur
ABSTRACT
Diabetes is a considerate metabolic disorder that can lead to a series of complications, involving the malfunctioning of the reproductive system of males. It has been observed that there is a gradual rise in male diabetic patients and almost half of the diabetic males have low semen quality and decrease reproductive function. In diabetic conditions, prolonged hyperglycemia leads to oxidative stress, diabetic neuropathy, and insulin resistance. Insulin resistance and its deficiency can impair the hypothalamus, pituitary gland, gonads, and perigonads. This causes a decrease in the secretion of gonadal steroids such as GnRH (gonadotropin-releasing hormone), FSH (follicle-stimulating hormone), LH (luteinizing hormone), and Testosterone. Moreover, it also causes damage to the testicles, spermatogenic and stromal cells, seminiferous tubules, and various structural injuries to male reproductive organs. During spermatogenesis, glucose metabolism plays an important role, because the fundamental activities of cells and their specific features, such as motility and mature sperm fertilization activity, are maintained by glucose metabolism. All these activities can influence the fertility and reproductive health of males. But the glucose metabolism is primarily disrupted in diabetic conditions. Until now, there has been no medicine focusing on the reproductive health of diabetic people. In this chapter, we review the consequences of diabetes on the reproductive system of males and all the pathways involved in the dysfunction of the reproductive system. This will help interpret the effects of DM on male reproductive health.
1. Introduction
Diabetes mellitus (DM) is an incurable disorder with varied morbific potential and causes damage to various organs. According to an IDF report, there are 463 million adults suffered from DM worldwide, which is supposed to rise to 578 million by 2030. Hyperglycemia is the most common symptom of diabetes, which is caused either by an autoimmune disease of pancreatic cells, that leads to a drop in insulin secretion in type 1 diabetes (T1DM) or by complete resistance or poor insulin secretion in type 2 diabetes (T2DM). In the past few decades, awareness and knowledge are very limited about diabetes and its effects on reproductive health. The main target of medicinal treatment was to eliminate the cause of disease to restore normal health. However, it is very essential to observe the consequences of DM on reproductive function. It causes impairment in both the male and female reproductive systems (Baccetti et al., 2002; Seethalakshmi et al., 1987; Sajad and Thakur,), leads to a reduction in the fertility ratio, and reproductive casualties rise (Greene, 1993; Lucas et al., 1989; Meller et al., 1981; Mills et al., 1988). Endothelial dysfunction, vascular dysfunction, and resulting oxidative stress are often caused by diabetes (Brownlee, 2001, 2005; Abdul-Ghani et al., 2006), and it is not unusual if it directly or indirectly affects several activities of the reproductive system (Dinulovic and Radonjic, 1990; Glenn et al., 2003; Hassan et al., 1993; Jackson, 2004, Mallidis et al., 2011; Sajad et al.). It is shown that almost half of DM men have poor semen quality and dysfunctional reproductive systems. In diabetic men, reproductive activity is affected at several steps because of endocrine control of spermatogenesis itself, or by impairing penile erection and ejaculation (Sexton and Jarrow, 1997, Baccetti et al., 2002; Ballester et al., 2004; Daubresse et al., 1978; Dinulovic and Radonjic, 1990; Garcia-Diez et al., 1991; Handelsman et al., 1985). It is affected by various mechanisms like neuropathy, a rise in oxidative stress, and endocrinopathies. There is a substantial body of literature on these reports, but their findings have been contradictory, as the described malfunctions are unlikely to cause significant impairment in reproductive function alone (Sexton and Jarrow, 1997). However, diabetes mellitus is a known source of sexual dysfunction in men, which may result in subfertility.
2. Effect of DM on males
Sexual dysfunction caused by DM has been broadly studied in males. There are various data showing clinical and experimental studies on diabetic males. There are four stages in which DM affects the male reproductive system, which involves structural changes in reproductive organs, erectile dysfunction, malfunctioning in ejaculation, and changes in semen quality. According to various reports, erectile dysfunction (ED) is caused in 59 % of men affected by DM. Many diabetic patients who are impotent (DMED) have nerve stiffening in the penis or pearled neuropathy. Due to DM, testosterone level also decreases which affects vascular endothelial function. ED is caused by hyperglycemia as it causes an increase in the quantity of ROS (reactive oxygen species) and AGEs (advanced glycation end products), eNOS (endothelial nitric oxide synthase) metabolism is inhibited and reduction in synthesis of endothelial and nitric oxide (NO) discharge (Fig. 1)
2.1. Pre-testicular effect of DM
The hypothalamus-pituitary-gonadal (HPG) axis is disrupted in DM which leads to alteration in the expression of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone in men.
2.2. Testicular effect of DM
2.2.1. Metabolism of energy in the testis
2.2.2. Testicular oxidative stress
2.2.3. Steroidogenesis
2.2.4. Spermatogenesis
2.2.5. Testicular histology and germ cell apoptosis
2.3. Post-testicular effect of DM
2.3.1. Erectile dysfunction (ED)
2.3.2. Ejaculatory disorders
2.3.3. Libido
3. Effect of DM on glucose metabolism in sperm
3.1. Insulin resistance effect on DM males
4. Effect of DM on the endocrine system (Role of hypothalamus pituitary-testicular axis)
5. Effect of neuropathy and infectious on DM males
6. Effect of DM on spermatogenesis and sperm
7. Possible damaging pathways
7.1. Role of mitochondria and ROS
7.2. Germ cell apoptosis
7.3. Germ cell autophagy
8. Biomarkers of diabetes-associated infertility in males
8.1. Reproductive hormones
8.2. Steroidogenic acute regulatory protein (StAR)
8.3. Hydroxysteroid dehydrogenase
8.4. AGE (advanced glycation end products)
8.5. Protein expression of lactate dehydrogenase (LDH) and monocarboxylate transporter-4 (MCT4)
8.6. Antioxidant enzymes
8.6. Antioxidant enzymes
8.8. Neurotrophic factor (NGF)
9. Medicinal plants
10. Conclusions
Till now the effect of DM on reproductive health is highly ignored. Many studies have shown that DM has a negative impact on male fertility, particularly the quality of sperm, semen constituents, sperm motility, and sperm DNA damage. It’s possible that this may not only result in subfertility or infertility but will also pass to the offspring and cause in subfertility or infertility in them. Reproductive dysfunction is caused by several DM-related factors, including oxidative stress, disruption of the HPG axis, and apoptosis. All these elements lead to aberrant hormone production and affect the morphology of the testis and epididymis. They also result in a decrease in the amount and quality of Leydig, Sertoli, and germ cells, which further causes sperm to have aberrant morphology, count, and motility. This condition has also been linked to several biomarkers, including AGE, StAR, VEGF, etc. Numerous medicinal herbs have been shown to play a significant role in preventing and reducing the impact of DM on the male reproductive system. However, further research is needed to fully understand the effect of phytochemicals in preventing the pathophysiology of diabetes on male fertility. To clearly understand the impact of DM on the male reproductive system, future studies must put detailed emphasis on the molecular level.
