madman
Super Moderator
Abstract
Several hormones contribute to ensuring penile erection, a neurovascular phenomenon in which nitric oxide plays a major role. Erectile dysfunction (ED), which is defined as the persistent inability to obtain or maintain penile erection sufficient for satisfactory sexual performance, may be due to arteriogenic, neurogenic, iatrogenic, but also endocrinological causes. The hypothalamus-pituitary axis plays a central role in the endocrine system and represents a fundamental link between the brain and peripheral glands, including gonads. Therefore, the hormonal production of the hypothalamic-pituitary axis can control various aspects of sexual function and its dysregulation can compromise erectile function. In addition, excess and deficiency of pituitary hormones or metabolic alterations that are associated with some pituitary diseases (e.g., Cushing’s disease and acromegaly, hypopituitarism) can determine the development of ED with different mechanisms. Thus, the present review aimed to explore the relationship between hypothalamic and pituitary diseases based on the most recent clinical and experimental evidence.
1. Physiology of Penile Erection and Pathophysiology of Erectile Dysfunction
Penile erection is a vascular phenomenon involving neurogenic, psychogenic, and hormonal mechanisms. Sexual stimulation triggers the release of nitric oxide (NO) by nonadrenergic, noncholinergic (NANC) nerves in penile tissue. NO binds to soluble guanylyl cyclase to increase production of 30,50 -cyclic guanosine monophosphate (cGMP), which activates protein kinase G (PKG) to form a complex cGMP/PKG, inducing relaxation of smooth muscle in the corpora cavernosa and, consequently, dilatation of the cavernous arteries that lead to penile erection [1].
All this, however, occurs thanks to the permissive role of androgens (mainly represented by testosterone, T) that regulate sexual behavior and male reproductive function in numerous ways. First of all, they influence the development of the male reproductive tract in early life and affect sexual behavior and libido in adulthood [2]: sexual complaints are the most specific symptoms of T deficiency (hypogonadism) in adults [3] and can be reversed via T therapy [4]. T upregulates the activity of the enzyme NO synthase (NOS) by endothelial cells (eNOS) and NANC nerves (nNOS) and downregulates the activity of RhoA-ROCK (Ras homolog gene family member A-Rho-associated, coiled-coil containing protein kinase), which is involved in the sensitization to calcium of penile smooth muscle cells, leading in both cases to vasodilation of the penile arteries [3].
When one of the mechanisms described above is compromised, erectile dysfunction (ED), defined as the persistent inability to obtain or maintain penile erection sufficient for a satisfactory sexual performance [5], occurs. ED has a multifactorial etiology with vascular (due to arterial insufficiency or venous incompetency), neurogenic, endocrinological, or iatrogenic causes, but in most cases, it is determined by impaired penile blood flow due to atherosclerosis. As known, many cardiovascular risk factors are associated with ED, and there is a strong association between ED and the development of cardiovascular disease (CVD) [6]. The damage of endothelial cells, caused by numerous conditions such as hypertension, smoking, and diabetes, results in a reduction of NO released in the corpora cavernosa. In addition, low NOS activity is linked to ED, and it has been observed in conditions such as hypercholesterolemia, diabetes, and advanced age [7] as well as in hypogonadism [2], which is associated with increased cardiovascular mortality [8]. In this regard, several studies have documented an age-dependent reduction in circulating T levels in men (a condition named “Late-onset hypogonadism”—LOH) associated with sexual dysfunction and metabolic syndrome [9] and a recent meta-analysis confirmed that low T levels are a marker of cardiovascular risk in aging males [10]. In addition, chronic conditions such as liver cirrhosis, obesity, and hyperinsulinism may increase levels of sex hormone-binding globulin (SHBG), which binds circulating T and limits its biological effects [3]. Despite this, the beneficial effects of T therapy on cardiovascular risk are still debated [11], while those on erectile function in patients with hypogonadism are widely recognized [4].
Apart from the known effects of T, little is known about the clinical effects of hypothalamic-pituitary diseases on erectile function, but much evidence suggests that the maintenance of good gonadal and sexual function depends on the proper functioning of a complex hormonal system that intersects both peripherally and centrally. The objective of the present review, therefore, was to examine the most recent experimental and clinical data to provide a holistic view of the endocrine system involving the hypothalamus and pituitary gland as regulatory centers of sexual and erectile function.
2. Gonadal Axis (Luteinizing Hormone and Follicle-Stimulating Hormone)
2.1. Prolactin
2.2. Growth Hormone
2.2.1. Acromegaly
2.2.2. Growth Hormone Deficiency
2.3. Adrenocorticotropic Hormone
2.3.1. Cushing’s Disease
2.3.2. Adrenal Insufficiency
2.4. Thyroid-Stimulating Hormone
2.5. Vasopressin and Oxytocin
3. Conclusions
Although evidence suggests an important role for hypothalamic-pituitary hormones in the control of erectile function, the actual incidence of ED in pituitary disorders is poorly understood. Since ED presents an important effect on the quality of life, as well as representing an early sign of endothelial dysfunction, it should always be investigated, preferably using validated questionnaires (e.g., IIEF-15 and SIEDY), and treated. In addition to the use of drugs with proven benefit on erectile function such as phosphodiesterase-5 inhibitors, the correction of all cardiovascular risk factors and the restoration of normal pituitary function appear essential in these patients.
Several hormones contribute to ensuring penile erection, a neurovascular phenomenon in which nitric oxide plays a major role. Erectile dysfunction (ED), which is defined as the persistent inability to obtain or maintain penile erection sufficient for satisfactory sexual performance, may be due to arteriogenic, neurogenic, iatrogenic, but also endocrinological causes. The hypothalamus-pituitary axis plays a central role in the endocrine system and represents a fundamental link between the brain and peripheral glands, including gonads. Therefore, the hormonal production of the hypothalamic-pituitary axis can control various aspects of sexual function and its dysregulation can compromise erectile function. In addition, excess and deficiency of pituitary hormones or metabolic alterations that are associated with some pituitary diseases (e.g., Cushing’s disease and acromegaly, hypopituitarism) can determine the development of ED with different mechanisms. Thus, the present review aimed to explore the relationship between hypothalamic and pituitary diseases based on the most recent clinical and experimental evidence.
1. Physiology of Penile Erection and Pathophysiology of Erectile Dysfunction
Penile erection is a vascular phenomenon involving neurogenic, psychogenic, and hormonal mechanisms. Sexual stimulation triggers the release of nitric oxide (NO) by nonadrenergic, noncholinergic (NANC) nerves in penile tissue. NO binds to soluble guanylyl cyclase to increase production of 30,50 -cyclic guanosine monophosphate (cGMP), which activates protein kinase G (PKG) to form a complex cGMP/PKG, inducing relaxation of smooth muscle in the corpora cavernosa and, consequently, dilatation of the cavernous arteries that lead to penile erection [1].
All this, however, occurs thanks to the permissive role of androgens (mainly represented by testosterone, T) that regulate sexual behavior and male reproductive function in numerous ways. First of all, they influence the development of the male reproductive tract in early life and affect sexual behavior and libido in adulthood [2]: sexual complaints are the most specific symptoms of T deficiency (hypogonadism) in adults [3] and can be reversed via T therapy [4]. T upregulates the activity of the enzyme NO synthase (NOS) by endothelial cells (eNOS) and NANC nerves (nNOS) and downregulates the activity of RhoA-ROCK (Ras homolog gene family member A-Rho-associated, coiled-coil containing protein kinase), which is involved in the sensitization to calcium of penile smooth muscle cells, leading in both cases to vasodilation of the penile arteries [3].
When one of the mechanisms described above is compromised, erectile dysfunction (ED), defined as the persistent inability to obtain or maintain penile erection sufficient for a satisfactory sexual performance [5], occurs. ED has a multifactorial etiology with vascular (due to arterial insufficiency or venous incompetency), neurogenic, endocrinological, or iatrogenic causes, but in most cases, it is determined by impaired penile blood flow due to atherosclerosis. As known, many cardiovascular risk factors are associated with ED, and there is a strong association between ED and the development of cardiovascular disease (CVD) [6]. The damage of endothelial cells, caused by numerous conditions such as hypertension, smoking, and diabetes, results in a reduction of NO released in the corpora cavernosa. In addition, low NOS activity is linked to ED, and it has been observed in conditions such as hypercholesterolemia, diabetes, and advanced age [7] as well as in hypogonadism [2], which is associated with increased cardiovascular mortality [8]. In this regard, several studies have documented an age-dependent reduction in circulating T levels in men (a condition named “Late-onset hypogonadism”—LOH) associated with sexual dysfunction and metabolic syndrome [9] and a recent meta-analysis confirmed that low T levels are a marker of cardiovascular risk in aging males [10]. In addition, chronic conditions such as liver cirrhosis, obesity, and hyperinsulinism may increase levels of sex hormone-binding globulin (SHBG), which binds circulating T and limits its biological effects [3]. Despite this, the beneficial effects of T therapy on cardiovascular risk are still debated [11], while those on erectile function in patients with hypogonadism are widely recognized [4].
Apart from the known effects of T, little is known about the clinical effects of hypothalamic-pituitary diseases on erectile function, but much evidence suggests that the maintenance of good gonadal and sexual function depends on the proper functioning of a complex hormonal system that intersects both peripherally and centrally. The objective of the present review, therefore, was to examine the most recent experimental and clinical data to provide a holistic view of the endocrine system involving the hypothalamus and pituitary gland as regulatory centers of sexual and erectile function.
2. Gonadal Axis (Luteinizing Hormone and Follicle-Stimulating Hormone)
2.1. Prolactin
2.2. Growth Hormone
2.2.1. Acromegaly
2.2.2. Growth Hormone Deficiency
2.3. Adrenocorticotropic Hormone
2.3.1. Cushing’s Disease
2.3.2. Adrenal Insufficiency
2.4. Thyroid-Stimulating Hormone
2.5. Vasopressin and Oxytocin
3. Conclusions
Although evidence suggests an important role for hypothalamic-pituitary hormones in the control of erectile function, the actual incidence of ED in pituitary disorders is poorly understood. Since ED presents an important effect on the quality of life, as well as representing an early sign of endothelial dysfunction, it should always be investigated, preferably using validated questionnaires (e.g., IIEF-15 and SIEDY), and treated. In addition to the use of drugs with proven benefit on erectile function such as phosphodiesterase-5 inhibitors, the correction of all cardiovascular risk factors and the restoration of normal pituitary function appear essential in these patients.
