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Physiology of Male Hormones (2022)
Juan Gómez Rivas, Aritz Eguibar, Jose Quesada, Mario Álvarez-Maestro, and Diego M. Carrion
2.1 Introduction to Male Sex Hormones
The testicle has two primary functions: endocrine (production of hormones) and exocrine (sperm production) 85–90% of the interior volume testicular is made up of seminiferous tubules and their germinal epithelium, the place of sperm production (10–20 million gametes per day), and only 10–15% is occupied by the interstitium, where testosterone is produced (Jockenhövel and Schubert 2007).
2.2 Hypothalamic and Pituitary Hormones
The testicular function is controlled by the so-called axis hypothalamus-pituitary testicular (Fig. 2.1). The hypothalamus gonadotropin-releasing hormone (GnRH) is secreted in the hypothalamus and stimulates hormonal production of the follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior lobe of the pituitary gland (the adenohypophysis) (Hayes et al. 2001)
Numerous neurotransmitters modulate GnRH secretion and rhythm (Fig. 2.1). Alpha-adrenergic impulses stimulate GnRH secretion. Norepinephrine and prostaglandins increase hypothalamic secretion. Beta-adrenergic and dopaminergic impulses have an inhibitory action on the GnRH secretion. Endorphins, testosterone, progesterone, and prolactin, secreted in stressful situations, decrease GnRH secretion. GnRH is released by the hypothalamus in a pulsatile manner, with peaks every 90–120 min. This type of release is essential for the stimulatory effect of gonadotropin secretion. Continued GnRH administration would curb the pituitary discharge. The amplitude and frequency of the GnRH pulses modulate FSH and LH levels secreted by the anterior pituitary and, subsequently, the gonadal function (Hayes et al. 2001; Morales et al. 2004)
Pituitary hormones stimulate testicular functions: exocrine and endocrine. On the other hand, and due to the negative feedback process, hormones produced in the testis exert inhibitory effects on FSH secretion and LH (Table 2.1).
Pituitary LH stimulates testosterone production by Leydig cells located in the testicular interstitium by binding to specific receptors. LH release is a process discontinuous and occurs, mainly, during the night and in a pulsatile way, at intervals of about 90 min. It corresponds to the pulsatile secretion of GnRH. The available levels of this hormone will determine the amount of secretion of testosterone. But in turn, testosterone levels exert a reciprocal effect by inhibiting the LH production in the pituitary gland through two mechanisms (Table 2.2) (Vignozzi et al. 2005; Vermeulen 2003):
A low testosterone concentration allows the hypothalamus to increase GnRH secretion, which stimulates the release of FSH and LH and thereby increases testosterone. In addition, the testicle can metabolize testosterone to estradiol through the favoring enzymes present in the tubules and interstitium (Kaufman and Vermeulen 2005; Morley 2003). Estradiol, in physiological concentrations, also decreases the frequency and amplitude of the pulses of LH (Hayes et al. 2001).
2.3 Androgens
Male sex hormones or androgens induce the development of primary sexual characteristics in the embryo and secondary sexual characteristics in puberty. They are responsible for the general growth and protein synthesis that is reflected in the skeletal and muscular changes characteristic of the man. They are synthesized mainly in the Leydig cells of the testes, to a lesser extent in men’s adrenal cortex, and in women, in minute quantities, in the ovary. Like the rest of the steroid hormones, androgens are synthesized from cholesterol (Fig. 2.2).
The most important androgens are testosterone (Fig. 2.3), androstenedione, and dehydroepiandrosterone (DHEA), a precursor to the rest of the androgens and to estradiol.
The amount of testosterone is higher than the others, so it can be considered the most important testicular hormone. However, most of it is converted in the effector tissues into dihydrotestosterone (DHT), a more active hormone, as it has a greater affinity for the intracellular androgen receptor (AR) (Kelly and Jones 2013).
There is a considerable fraction of the testosterone produced that binds to albumin or sex hormone-binding globulins (SHBG) to be transported by the bloodstream, being its free concentration in serum minimal. In this way, it remains inactive until binding with its specific receptor (Heinlein and Chang 2002). The factors responsible for this transfer and how the cell causes the dissociation of the hormone-globulin complex are unknown. Still, it is believed to depend on the plasma concentration of the hormone (Heinlein and Chang 2002). Once in the cell, the hormone binds to its receptor, located in the cytoplasm and/or in the nucleus, dimerization of the receptor is induced and its consequent activation.
AR, like those of other steroid receptors, is composed of several functional domains (Evans 1988) (Fig. 2.4):
1. The regulatory and binding domain of steroids is located in the C-terminal domain. It has several phosphorylation sites and is involved in the activation of the hormone-receptor complex
2. The DNA-binding domain is found in the middle part and is essential for the activation of transcription. This portion is responsible for controlling which gene will be regulated by the receptor.
3. The hinge region is located between the two previous domains; it contains an important signal area for receptor movement into the nucleus after synthesis in the cytoplasm. It is a variable hydrophilic region in the different receptors.
The interaction of male sex hormones with the AR produces genomic effects, among which is the activation of the Mitogen-activated protein kinase (MAPK) and other transcription factors that induce the growth and proliferation of different cells (Geraldes et al. 2002).
There are also membrane ARs that induce non-genomic effects as they are not blocked by inhibitors of gene transcription (Gerhard and Ganz 1995; Farhat et al. 1996). Among other effects, there is an increase in the concentration of intracellular Ca +2 due to an increase in the formation of Inositol trisphosphate (IP3) (Estrada et al. 2000) or the phosphorylation of the Ras/Raf/extracellular signal-regulated kinase (ERK) 1/2 (Estrada et al. 2003). Through this non-genomic action, testosterone is capable of exerting a regulatory effect on vascular tone as it is capable of regulating the intracellular Ca+2 concentration. Likewise, testosterone can regulate the vasodilator effect of neurotransmitters, such as nitric oxide (NO) and Calcitonin gene-related peptide (CGRP) (Perusquía 2003; Isidoro et al. 2018).
2.4 Male Sex Hormones, Effects
At the sexual level, it plays a fundamental role in the development and maintenance of sexual characteristics and the male sex glands’ development and functioning. As a “sex” hormone, androgens act on the central nervous system, stimulating and maintaining desire and sexual motivation.
It appears that testosterone is necessary for the normal functioning of the mechanism of ejaculation and the maintenance of spontaneous erections. Its positive influence on erectile response is also known. Testosterone stimulates the activity of the enzyme nitric oxide synthetase (NOS), which contributes to maintaining adequate levels of nitric oxide (NO) in the smooth muscle of the corpora cavernosa of the penis. On the other hand, it has been proven that it favors the phosphodiesterase type 5 activity.
*But testosterone and its metabolites are much more than a sex hormone; it performs numerous important physiological actions in the body, resulting essential for the overall health of men. Androgens play an important role in activating function cognitive; increasing lean body mass; maintaining bone mass (hypogonadism is one of the main causes of osteoporosis in men); stimulating erythropoiesis; have a clear effect on lipids: improving the concentration of high-density lipoprotein (HDL) and decreases the concentration from low-density lipids (LDL); promotes cardiovascular health; even current evidence refers to an increase in life expectancy (Table 2.3).
2.5 Male Sex Hormones and Genitalia
The sex chromosomes determine if the primitive gonad is due to differentiate towards the teste or ovary. Until the seventh week of gestation, the primitive gonad is common to both sexes. Subsequently, anatomical and physiological differentiation occurs that will determine the phenotype of a female or male.
Testicular secretions determine the masculine character of the genitalia, both external and internal. Without this type of secretion, genetically the sex would be female, and there would be no phenotypic differentiation toward males. The control of the formation of the male phenotype is due to the action of several hormones (Melmed and Jameson 2018):
1. Anti-Müllerian hormone, secreted by fetal testes, inhibits the development of Müllerian ducts (which would lead to the development of female internal genitalia).
2. Testosterone converts Wolf’s ducts into the epididymis, the vessel's deferens, and the seminal vesicles.
3. DHT is later synthesized from fetal testosterone, induces the formation of the male urethra and prostate, and the fusion of the midline and elongation of the male external genitalia
Androgen deficiency during sexual differentiation, which occurs between weeks 9 and 14, gives rise to phenotypically intersex states, with the absence of masculinization and more or less ambiguous external genitalia. The deficits in later stages can condition abnormal development of the penis (micropenis) and abnormal testicular positioning. It is unknown how testosterone secretion is controlled in the embryo, although it seems that it can be regulated by LH and also receives influences from the placental choriogonadotropin hormone.
2.6 Testosterone at Puberty
In the prepubertal age, the levels of gonadotropins and sex hormones are low. At 6 or 7 years, the adrenarche begins, partly responsible for the growth of prepubertal and early armpit and pubic hair, but male sexual characteristics are not fully developed until puberty. Some of the organs involved in the appearance of puberty are:
1. The hypothalamic-pituitary axis.
2. The testes.
3. The adrenal glands.
4. Other not well-known factors.
2.7 Testosterone in Adulthood
The effects of testosterone on adult men can be of three types:
1. Permanent and irreversible, which do not return even if there is a posterior androgenic deficiency (e.g., the severity of the voice).
2. Reversible, directly dependent on the continued secretion of androgens (e.g., influence on the production of erythropoietin, the maintenance of hemoglobin, as well as sexual function and libido).
3. Mixed (e.g., influence on spermatogenesis, consistency, and testicular size).
Over time, the sustained deficit of androgens gives rise to the manifestations known clinically as androgen deficiency syndrome in the adult male, whose predominant manifestations can be seen in Table 2.5.
2.8 Male Sex Hormones and the Cardiovascular System
2.9 Male Sex Hormones and Muscular/Bone Metabolism
2.10 Testosterone Effects on Skeletal Muscle in Men
2.11 Testosterone Effects on Bone in Men
2.12 Conclusions
Understanding male hormonal physiology and the functions of testosterone, in the sexual aspect and in other systems, will allow us to understand the clinical consequences of any alteration in the hormone levels. For a correct clinical and analytical evaluation of testosterone deficiency, prior knowledge of the male hormonal pathophysiology is needed. These notions will also help to make a correct replacement treatment in patients who require it.
Juan Gómez Rivas, Aritz Eguibar, Jose Quesada, Mario Álvarez-Maestro, and Diego M. Carrion
2.1 Introduction to Male Sex Hormones
The testicle has two primary functions: endocrine (production of hormones) and exocrine (sperm production) 85–90% of the interior volume testicular is made up of seminiferous tubules and their germinal epithelium, the place of sperm production (10–20 million gametes per day), and only 10–15% is occupied by the interstitium, where testosterone is produced (Jockenhövel and Schubert 2007).
2.2 Hypothalamic and Pituitary Hormones
The testicular function is controlled by the so-called axis hypothalamus-pituitary testicular (Fig. 2.1). The hypothalamus gonadotropin-releasing hormone (GnRH) is secreted in the hypothalamus and stimulates hormonal production of the follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior lobe of the pituitary gland (the adenohypophysis) (Hayes et al. 2001)
Numerous neurotransmitters modulate GnRH secretion and rhythm (Fig. 2.1). Alpha-adrenergic impulses stimulate GnRH secretion. Norepinephrine and prostaglandins increase hypothalamic secretion. Beta-adrenergic and dopaminergic impulses have an inhibitory action on the GnRH secretion. Endorphins, testosterone, progesterone, and prolactin, secreted in stressful situations, decrease GnRH secretion. GnRH is released by the hypothalamus in a pulsatile manner, with peaks every 90–120 min. This type of release is essential for the stimulatory effect of gonadotropin secretion. Continued GnRH administration would curb the pituitary discharge. The amplitude and frequency of the GnRH pulses modulate FSH and LH levels secreted by the anterior pituitary and, subsequently, the gonadal function (Hayes et al. 2001; Morales et al. 2004)
Pituitary hormones stimulate testicular functions: exocrine and endocrine. On the other hand, and due to the negative feedback process, hormones produced in the testis exert inhibitory effects on FSH secretion and LH (Table 2.1).
Pituitary LH stimulates testosterone production by Leydig cells located in the testicular interstitium by binding to specific receptors. LH release is a process discontinuous and occurs, mainly, during the night and in a pulsatile way, at intervals of about 90 min. It corresponds to the pulsatile secretion of GnRH. The available levels of this hormone will determine the amount of secretion of testosterone. But in turn, testosterone levels exert a reciprocal effect by inhibiting the LH production in the pituitary gland through two mechanisms (Table 2.2) (Vignozzi et al. 2005; Vermeulen 2003):
A low testosterone concentration allows the hypothalamus to increase GnRH secretion, which stimulates the release of FSH and LH and thereby increases testosterone. In addition, the testicle can metabolize testosterone to estradiol through the favoring enzymes present in the tubules and interstitium (Kaufman and Vermeulen 2005; Morley 2003). Estradiol, in physiological concentrations, also decreases the frequency and amplitude of the pulses of LH (Hayes et al. 2001).
2.3 Androgens
Male sex hormones or androgens induce the development of primary sexual characteristics in the embryo and secondary sexual characteristics in puberty. They are responsible for the general growth and protein synthesis that is reflected in the skeletal and muscular changes characteristic of the man. They are synthesized mainly in the Leydig cells of the testes, to a lesser extent in men’s adrenal cortex, and in women, in minute quantities, in the ovary. Like the rest of the steroid hormones, androgens are synthesized from cholesterol (Fig. 2.2).
The most important androgens are testosterone (Fig. 2.3), androstenedione, and dehydroepiandrosterone (DHEA), a precursor to the rest of the androgens and to estradiol.
The amount of testosterone is higher than the others, so it can be considered the most important testicular hormone. However, most of it is converted in the effector tissues into dihydrotestosterone (DHT), a more active hormone, as it has a greater affinity for the intracellular androgen receptor (AR) (Kelly and Jones 2013).
There is a considerable fraction of the testosterone produced that binds to albumin or sex hormone-binding globulins (SHBG) to be transported by the bloodstream, being its free concentration in serum minimal. In this way, it remains inactive until binding with its specific receptor (Heinlein and Chang 2002). The factors responsible for this transfer and how the cell causes the dissociation of the hormone-globulin complex are unknown. Still, it is believed to depend on the plasma concentration of the hormone (Heinlein and Chang 2002). Once in the cell, the hormone binds to its receptor, located in the cytoplasm and/or in the nucleus, dimerization of the receptor is induced and its consequent activation.
AR, like those of other steroid receptors, is composed of several functional domains (Evans 1988) (Fig. 2.4):
1. The regulatory and binding domain of steroids is located in the C-terminal domain. It has several phosphorylation sites and is involved in the activation of the hormone-receptor complex
2. The DNA-binding domain is found in the middle part and is essential for the activation of transcription. This portion is responsible for controlling which gene will be regulated by the receptor.
3. The hinge region is located between the two previous domains; it contains an important signal area for receptor movement into the nucleus after synthesis in the cytoplasm. It is a variable hydrophilic region in the different receptors.
The interaction of male sex hormones with the AR produces genomic effects, among which is the activation of the Mitogen-activated protein kinase (MAPK) and other transcription factors that induce the growth and proliferation of different cells (Geraldes et al. 2002).
There are also membrane ARs that induce non-genomic effects as they are not blocked by inhibitors of gene transcription (Gerhard and Ganz 1995; Farhat et al. 1996). Among other effects, there is an increase in the concentration of intracellular Ca +2 due to an increase in the formation of Inositol trisphosphate (IP3) (Estrada et al. 2000) or the phosphorylation of the Ras/Raf/extracellular signal-regulated kinase (ERK) 1/2 (Estrada et al. 2003). Through this non-genomic action, testosterone is capable of exerting a regulatory effect on vascular tone as it is capable of regulating the intracellular Ca+2 concentration. Likewise, testosterone can regulate the vasodilator effect of neurotransmitters, such as nitric oxide (NO) and Calcitonin gene-related peptide (CGRP) (Perusquía 2003; Isidoro et al. 2018).
2.4 Male Sex Hormones, Effects
At the sexual level, it plays a fundamental role in the development and maintenance of sexual characteristics and the male sex glands’ development and functioning. As a “sex” hormone, androgens act on the central nervous system, stimulating and maintaining desire and sexual motivation.
It appears that testosterone is necessary for the normal functioning of the mechanism of ejaculation and the maintenance of spontaneous erections. Its positive influence on erectile response is also known. Testosterone stimulates the activity of the enzyme nitric oxide synthetase (NOS), which contributes to maintaining adequate levels of nitric oxide (NO) in the smooth muscle of the corpora cavernosa of the penis. On the other hand, it has been proven that it favors the phosphodiesterase type 5 activity.
*But testosterone and its metabolites are much more than a sex hormone; it performs numerous important physiological actions in the body, resulting essential for the overall health of men. Androgens play an important role in activating function cognitive; increasing lean body mass; maintaining bone mass (hypogonadism is one of the main causes of osteoporosis in men); stimulating erythropoiesis; have a clear effect on lipids: improving the concentration of high-density lipoprotein (HDL) and decreases the concentration from low-density lipids (LDL); promotes cardiovascular health; even current evidence refers to an increase in life expectancy (Table 2.3).
2.5 Male Sex Hormones and Genitalia
The sex chromosomes determine if the primitive gonad is due to differentiate towards the teste or ovary. Until the seventh week of gestation, the primitive gonad is common to both sexes. Subsequently, anatomical and physiological differentiation occurs that will determine the phenotype of a female or male.
Testicular secretions determine the masculine character of the genitalia, both external and internal. Without this type of secretion, genetically the sex would be female, and there would be no phenotypic differentiation toward males. The control of the formation of the male phenotype is due to the action of several hormones (Melmed and Jameson 2018):
1. Anti-Müllerian hormone, secreted by fetal testes, inhibits the development of Müllerian ducts (which would lead to the development of female internal genitalia).
2. Testosterone converts Wolf’s ducts into the epididymis, the vessel's deferens, and the seminal vesicles.
3. DHT is later synthesized from fetal testosterone, induces the formation of the male urethra and prostate, and the fusion of the midline and elongation of the male external genitalia
Androgen deficiency during sexual differentiation, which occurs between weeks 9 and 14, gives rise to phenotypically intersex states, with the absence of masculinization and more or less ambiguous external genitalia. The deficits in later stages can condition abnormal development of the penis (micropenis) and abnormal testicular positioning. It is unknown how testosterone secretion is controlled in the embryo, although it seems that it can be regulated by LH and also receives influences from the placental choriogonadotropin hormone.
2.6 Testosterone at Puberty
In the prepubertal age, the levels of gonadotropins and sex hormones are low. At 6 or 7 years, the adrenarche begins, partly responsible for the growth of prepubertal and early armpit and pubic hair, but male sexual characteristics are not fully developed until puberty. Some of the organs involved in the appearance of puberty are:
1. The hypothalamic-pituitary axis.
2. The testes.
3. The adrenal glands.
4. Other not well-known factors.
2.7 Testosterone in Adulthood
The effects of testosterone on adult men can be of three types:
1. Permanent and irreversible, which do not return even if there is a posterior androgenic deficiency (e.g., the severity of the voice).
2. Reversible, directly dependent on the continued secretion of androgens (e.g., influence on the production of erythropoietin, the maintenance of hemoglobin, as well as sexual function and libido).
3. Mixed (e.g., influence on spermatogenesis, consistency, and testicular size).
Over time, the sustained deficit of androgens gives rise to the manifestations known clinically as androgen deficiency syndrome in the adult male, whose predominant manifestations can be seen in Table 2.5.
2.8 Male Sex Hormones and the Cardiovascular System
2.9 Male Sex Hormones and Muscular/Bone Metabolism
2.10 Testosterone Effects on Skeletal Muscle in Men
2.11 Testosterone Effects on Bone in Men
2.12 Conclusions
Understanding male hormonal physiology and the functions of testosterone, in the sexual aspect and in other systems, will allow us to understand the clinical consequences of any alteration in the hormone levels. For a correct clinical and analytical evaluation of testosterone deficiency, prior knowledge of the male hormonal pathophysiology is needed. These notions will also help to make a correct replacement treatment in patients who require it.
