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Neuroendocrine Regulation of Male Sexual Behavior

Elaine M. Hull, Juan M. Dominguez

10.1002/cphy.c180018

Source: Volume 9, Issue 4, October 2019

Published online: September 2019

Full Article on Wiley Online Library



Abstract

The major brain areas that control males' sexual motivation and performance include the amygdala, the bed nucleus of the stria terminalis (BNST), the medial preoptic area (MPOA), and paraventricular nucleus (PVN) of the hypothalamus, as well as the mesolimbic dopamine (DA) system. The MPOA, PVN, and brain stem and spinal nuclei control the genital reflexes. Sensory and motor aspects are integrated and elicited by the amygdala, BNST, MPOA, PVN, and the mesolimbic and nigrostriatal DA tracts, which are integral for other social behaviors, as well. Developmental hormonal effects organize the network to elicit specific behaviors, which are activated by those hormones in adolescence and adulthood. Steroid hormones primarily work through slow genomic mechanisms that increase enzymes, receptors, or structural proteins, although they may also activate membrane receptors for rapid effects. © 2019 American Physiological Society. Compr Physiol 9:1383‐1410, 2019.

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Figure 1. Figure 1. Schematic diagram of the excitatory (+) and inhibitory (−) innervations of the penis for the regulation of tumescence (T) and detumescence (D). Note that the motor branch of the pudendal nerve is not depicted, nor are the striated muscles to which the pudendal nerve projects. Also, the penis is shown as a single structure, although recent evidence suggests that the innervations of the penile body and glans are not identical. The depicted innervation may better represent that of the body than that of the glans. Reused, with permission, from DeGroat WC and Steers WD, Harwood Academic Publishers. 1988 65.
Figure 2. Figure 2. Some basic structural similarities in penile anatomy illustrated from the human (A: a, lateral view; b, inferior view with penile body lifted; c, cross section) and rat (B: a, lateral view including all muscles; b, lateral view with muscles removed; c, “exploded” view). In both species, the penile crura, attached to the ischium, are covered by the ischiocavernosus muscles and are continuous with the body of the penis, composed primarily of the paired corpora cavernosa. The penile bulb, wrapped by the bulbospongiosus (bulbocavernosus) muscles, gives rise to the corpus spongiosum, which terminates in the glans penis. The rat muscle identified as the external anal sphincter is also known as the levator ani or the dorsal bulbospongiosus. Figures of human penis: Reused, with permission, from Wilson DB and Wilson WJ, Oxford University Press. 1978 322. Figures of rat penis: Reused, with permission, from Hart BL and Melese‐d'Hospital P, Pergamon Press. 1983 110.
Figure 3. Figure 3. (A) Relaxation of penile smooth muscle: cGMP mechanisms. Nitric oxide (NO) produced by nitric oxide synthase Type I (NOS I) in NANC nerves and nitric oxide synthase Type III (NOS III) in endothelial cells activates guanylyl cyclase (GC) in smooth muscles cells. This results in the production of cGMP from GTP. cGMP is metabolized by phosphodiesterase type 5 (PDE5). cGMP causes the activation of PKG. PKG causes an increased uptake of calcium into intracellular stores and a reduction of calcium entry into the cell through calcium channels. PKG also opens potassium channels, leading to hyperpolarization, which also closes the calcium channels. The resulting decrease in intracellular calcium concentration from these mechanisms leads to relaxation of the smooth muscle. (B) Relaxation of penile smooth muscle: cAMP mechanisms. Peptides, such as vasoactive intestinal polypeptide (VIP) and calcitonin gene‐related peptide (CGRP), and prostaglandins, such as PGE1, bind to specific receptors on the smooth muscle cell membrane. These are linked to G protein that activates adenylyl cyclase (AC) in smooth muscles cells. This results in the production of cAMP from ATP. cAMP causes the activation of protein kinase A (PKA). PKA causes an increased uptake of calcium into intracellular stores by inhibiting an inhibitor of calcium uptake, phospholambin. PKA also opens potassium channels, leading to hyperpolarization, which closes the calcium channels. The resulting decrease in intracellular calcium concentration from these mechanisms leads to relaxation of the smooth muscle. Reused, with permission, from Rosen RC and McKenna KE. 2002 254.
Figure 4. Figure 4. The amygdala, an almond‐shaped structure located in each temporal lobe, seen in a schematic drawing of a coronal section of the rat brain. Two general amygdaloid regions, the basolateral and corticomedial nuclei (left), have been studied extensively. Destruction of the corticomedial nuclei, but not the basolateral nuclei, severely affects male copulatory behavior in rodents. The specific nuclei of the basolateral and corticomedial amygdala are depicted (right). Reused, with permission, from Nelson RJ. 2011 210.
Figure 5. Figure 5. Schematic diagram of the principal limbic nuclei and connections in hamster brain that transmit chemosensory and hormonal cues to control male sexual behavior. Shading indicates areas with abundant steroid receptor‐containing neurons. ac, anterior commissure; ACo, anterior cortical amygdaloid nucleus; AOB, accessory olfactory bulb; BL, basolateral amygdaloid nucleus; BNST, bed nucleus of the stria terminalis; BNSTpi, posterointermediate subdivision of BNST; BNSTpm, posteromedial subdivision of BNST; Ce, central amygdaloid nucleus; fx, fornix; lot, lateral olfactory tract; Me, medial amygdaloid nucleus; MeA, anterior subdivision; MeP, posterior subdivision; MOB, main olfactory bulb; MPN, medial preoptic nucleus; MPOAl, lateral subdivision of the medial preoptic area; oc, optic chiasm; OM, olfactory mucosa; ot, optic tract; PLCo, posterolateral cortical amygdaloid nucleus; PMCo, posteromedial cortical amygdaloid nucleus; st, stria terminalis; vaf, ventral amygdalofugal pathway; VNO, vomeronasal organ. Reused, with permission, from Wood RI. 1997 325.
Figure 6. Figure 6. The medial preoptic area (MPOA) receives direct and indirect inputs from brain areas that are important for the assimilation of sexually relevant information. Olfactory stimulation is received by the olfactory bulbs (OB), the OB project to the medial amygdala (MeA), which relays information to the bed nucleus of stria terminalis (BST) and the MPOA (depicted in blue). Additionally, the MPOA and MeA receive somatosensory input via the central tegmental field (CTF) (depicted in green). In turn, the MPOA projects to the ventral tegmental area (VTA) and the brain stem (BS) (depicted in red). The VTA then projects to the nucleus accumbens (NAc) and other structures relevant to reward and motivation (depicted in light green). For a complete description of MPOA afferents and efferents, see Refs. 284,286. The figure above and the placement of structures in the figure are not anatomically accurate. Adapted, with permission, from Hull EM and Dominguez JM. 2006 124.
Figure 7. Figure 7. A schematic representation of oxytocinergic neurons originating in the paraventricular nucleus of the hypothalamus (PVN) and projecting to extrahypothalamic brain areas and the spinal cord involved in sexual activity. Activation of these neurons by dopamine, excitatory amino acids, oxytocin itself, and hexarelin analog peptides facilitates penile erection and sexual activity. The direct or indirect activation of these neurons and the facilitative effects on erection and sexual activity induced by the above substances can be reduced or abolished by the stimulation of opioid and GABAergic receptors. These oxytocinergic neurons are activated by the activation of nitric oxide synthase (NOS) present in their cell bodies. Endogenous NO produced a result of stimulation of dopamine, excitatory amino acid, or oxytocin receptors, or exogenous NO, derived from NO donors delivered to the PVN, activates oxytocinergic neurons by a yet‐unidentified mechanism. This causes the release of oxytocin in brain areas distant from the PVN, as well as the spinal cord, inducing penile erection. Similar mechanisms operate during noncontact erections and copulation. Reused, with permission, from Argiolas A and Melis MR. 2004 10.
Figure 8. Figure 8. Summary figure showing the MPOA‐PAG‐nPGi‐spinal cord circuit. MPOA projections to the periaqueductal gray (PAG) terminate preferentially among PAG neurons projecting to the nucleus paragigantocellularis (nPGi). Descending projections from the nPGi terminate within the dorsomedial and dorsolateral motor pools of the ventral horn of the lumbosacral spinal cord. Motoneurons from these pools innervate the bulbocavernosus and ischiocavernosus muscles, which are essential for penile erection and ejaculation. Reused, with permission, from Murphy AZ and Hoffman GE. 2001 206.


Figure 1. Schematic diagram of the excitatory (+) and inhibitory (−) innervations of the penis for the regulation of tumescence (T) and detumescence (D). Note that the motor branch of the pudendal nerve is not depicted, nor are the striated muscles to which the pudendal nerve projects. Also, the penis is shown as a single structure, although recent evidence suggests that the innervations of the penile body and glans are not identical. The depicted innervation may better represent that of the body than that of the glans. Reused, with permission, from DeGroat WC and Steers WD, Harwood Academic Publishers. 1988 65.


Figure 2. Some basic structural similarities in penile anatomy illustrated from the human (A: a, lateral view; b, inferior view with penile body lifted; c, cross section) and rat (B: a, lateral view including all muscles; b, lateral view with muscles removed; c, “exploded” view). In both species, the penile crura, attached to the ischium, are covered by the ischiocavernosus muscles and are continuous with the body of the penis, composed primarily of the paired corpora cavernosa. The penile bulb, wrapped by the bulbospongiosus (bulbocavernosus) muscles, gives rise to the corpus spongiosum, which terminates in the glans penis. The rat muscle identified as the external anal sphincter is also known as the levator ani or the dorsal bulbospongiosus. Figures of human penis: Reused, with permission, from Wilson DB and Wilson WJ, Oxford University Press. 1978 322. Figures of rat penis: Reused, with permission, from Hart BL and Melese‐d'Hospital P, Pergamon Press. 1983 110.


Figure 3. (A) Relaxation of penile smooth muscle: cGMP mechanisms. Nitric oxide (NO) produced by nitric oxide synthase Type I (NOS I) in NANC nerves and nitric oxide synthase Type III (NOS III) in endothelial cells activates guanylyl cyclase (GC) in smooth muscles cells. This results in the production of cGMP from GTP. cGMP is metabolized by phosphodiesterase type 5 (PDE5). cGMP causes the activation of PKG. PKG causes an increased uptake of calcium into intracellular stores and a reduction of calcium entry into the cell through calcium channels. PKG also opens potassium channels, leading to hyperpolarization, which also closes the calcium channels. The resulting decrease in intracellular calcium concentration from these mechanisms leads to relaxation of the smooth muscle. (B) Relaxation of penile smooth muscle: cAMP mechanisms. Peptides, such as vasoactive intestinal polypeptide (VIP) and calcitonin gene‐related peptide (CGRP), and prostaglandins, such as PGE1, bind to specific receptors on the smooth muscle cell membrane. These are linked to G protein that activates adenylyl cyclase (AC) in smooth muscles cells. This results in the production of cAMP from ATP. cAMP causes the activation of protein kinase A (PKA). PKA causes an increased uptake of calcium into intracellular stores by inhibiting an inhibitor of calcium uptake, phospholambin. PKA also opens potassium channels, leading to hyperpolarization, which closes the calcium channels. The resulting decrease in intracellular calcium concentration from these mechanisms leads to relaxation of the smooth muscle. Reused, with permission, from Rosen RC and McKenna KE. 2002 254.


Figure 4. The amygdala, an almond‐shaped structure located in each temporal lobe, seen in a schematic drawing of a coronal section of the rat brain. Two general amygdaloid regions, the basolateral and corticomedial nuclei (left), have been studied extensively. Destruction of the corticomedial nuclei, but not the basolateral nuclei, severely affects male copulatory behavior in rodents. The specific nuclei of the basolateral and corticomedial amygdala are depicted (right). Reused, with permission, from Nelson RJ. 2011 210.


Figure 5. Schematic diagram of the principal limbic nuclei and connections in hamster brain that transmit chemosensory and hormonal cues to control male sexual behavior. Shading indicates areas with abundant steroid receptor‐containing neurons. ac, anterior commissure; ACo, anterior cortical amygdaloid nucleus; AOB, accessory olfactory bulb; BL, basolateral amygdaloid nucleus; BNST, bed nucleus of the stria terminalis; BNSTpi, posterointermediate subdivision of BNST; BNSTpm, posteromedial subdivision of BNST; Ce, central amygdaloid nucleus; fx, fornix; lot, lateral olfactory tract; Me, medial amygdaloid nucleus; MeA, anterior subdivision; MeP, posterior subdivision; MOB, main olfactory bulb; MPN, medial preoptic nucleus; MPOAl, lateral subdivision of the medial preoptic area; oc, optic chiasm; OM, olfactory mucosa; ot, optic tract; PLCo, posterolateral cortical amygdaloid nucleus; PMCo, posteromedial cortical amygdaloid nucleus; st, stria terminalis; vaf, ventral amygdalofugal pathway; VNO, vomeronasal organ. Reused, with permission, from Wood RI. 1997 325.


Figure 6. The medial preoptic area (MPOA) receives direct and indirect inputs from brain areas that are important for the assimilation of sexually relevant information. Olfactory stimulation is received by the olfactory bulbs (OB), the OB project to the medial amygdala (MeA), which relays information to the bed nucleus of stria terminalis (BST) and the MPOA (depicted in blue). Additionally, the MPOA and MeA receive somatosensory input via the central tegmental field (CTF) (depicted in green). In turn, the MPOA projects to the ventral tegmental area (VTA) and the brain stem (BS) (depicted in red). The VTA then projects to the nucleus accumbens (NAc) and other structures relevant to reward and motivation (depicted in light green). For a complete description of MPOA afferents and efferents, see Refs. 284,286. The figure above and the placement of structures in the figure are not anatomically accurate. Adapted, with permission, from Hull EM and Dominguez JM. 2006 124.


Figure 7. A schematic representation of oxytocinergic neurons originating in the paraventricular nucleus of the hypothalamus (PVN) and projecting to extrahypothalamic brain areas and the spinal cord involved in sexual activity. Activation of these neurons by dopamine, excitatory amino acids, oxytocin itself, and hexarelin analog peptides facilitates penile erection and sexual activity. The direct or indirect activation of these neurons and the facilitative effects on erection and sexual activity induced by the above substances can be reduced or abolished by the stimulation of opioid and GABAergic receptors. These oxytocinergic neurons are activated by the activation of nitric oxide synthase (NOS) present in their cell bodies. Endogenous NO produced a result of stimulation of dopamine, excitatory amino acid, or oxytocin receptors, or exogenous NO, derived from NO donors delivered to the PVN, activates oxytocinergic neurons by a yet‐unidentified mechanism. This causes the release of oxytocin in brain areas distant from the PVN, as well as the spinal cord, inducing penile erection. Similar mechanisms operate during noncontact erections and copulation. Reused, with permission, from Argiolas A and Melis MR. 2004 10.


Figure 8. Summary figure showing the MPOA‐PAG‐nPGi‐spinal cord circuit. MPOA projections to the periaqueductal gray (PAG) terminate preferentially among PAG neurons projecting to the nucleus paragigantocellularis (nPGi). Descending projections from the nPGi terminate within the dorsomedial and dorsolateral motor pools of the ventral horn of the lumbosacral spinal cord. Motoneurons from these pools innervate the bulbocavernosus and ischiocavernosus muscles, which are essential for penile erection and ejaculation. Reused, with permission, from Murphy AZ and Hoffman GE. 2001 206.
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Teaching Material

E. M. Hull, J. M. Dominguez. Neuroendocrine Regulation of Male Sexual Behavior.Compr Physiol 9: 2019, 1383-1410.

Didactic Synopsis

Major Teaching Points:

  • Steroid hormones during early development control the differentiation of the genitals and the brain areas that are important for later sexual behavior.
  • Those same hormones in adulthood elicit sexual attraction and components of sexual behavior, including engorgement of the genitals with blood and, in males, mounting the female, insertion of the erect penis, and ejaculation of semen.
  • In most rodents, but not primates, the organizational and activational effects of testosterone are mediated primarily by conversion of testosterone to an estrogen, a process called aromatization.
  • The most critical central integrative area for male sexual behavior is the medial preoptic area (MPOA), which receives olfactory input from the main and accessory olfactory bulbs, and is processed by the medial amygdala and bed nucleus of the stria terminalis. Sensory input from the genitals is relayed via the spinal cord and subparafascicular nucleus of the thalamus to the MPOA.
  • The neurotransmitter dopamine is released in the MPOA as soon as the male detects the presence of a female and increases during copulation. Its release is triggered by the production of the gaseous neurotransmitter nitric oxide. A large peak in the excitatory neurotransmitter glutamate in the MPOA appears to trigger ejaculation. Dopamine is also released in the mesolimbic tract, which energizes sexual motivation.
  • Output from the MPOA goes to the paraventricular nucleus of the hypothalamus (PVN) and midbrain and brainstem nuclei, which in turn programs the motor output.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1 Schematic diagram of the excitatory (+) and inhibitory (-) innervations of the penis for the regulation of tumescence (T) and detumescence (D). Note that the motor branch of the pudendal nerve is not depicted, nor are the striated muscles to which the pudendal nerve projects. Also, the penis is shown as a single structure, although recent evidence suggests that the innervations of the penile body and glans are not identical. The depicted innervation may better represent that of the body than that of the glans. Reused, with permission, from DeGroat WC and Steers WD, Harwood Academic Publishers. 1988 (65).

Figure 2 Some basic structural similarities in penile anatomy illustrated from the human (A: a, lateral view; b, inferior view with penile body lifted; c, cross section) and rat (B: a, lateral view including all muscles; b, lateral view with muscles removed; c, “exploded” view). In both species, the penile crura, attached to the ischium, are covered by the ischiocavernosus muscles and are continuous with the body of the penis, composed primarily of the paired corpora cavernosa. The penile bulb, wrapped by the bulbospongiosus (bulbocavernosus) muscles, gives rise to the corpus spongiosum, which terminates in the glans penis. The rat muscle identified as the external anal sphincter is also known as the levator ani or the dorsal bulbospongiosus. Figures of human penis: Reused, with permission, from Wilson DB and Wilson WJ, Oxford University Press. 1978 (322). Figures of rat penis: Reused, with permission, from Hart BL and Melese-d’Hospital P, Pergamon Press. 1983 (110).

Figure 3 (A) Relaxation of penile smooth muscle: cGMP mechanisms. Nitric oxide (NO) produced by nitric oxide synthase Type I (NOS I) in NANC nerves and nitric oxide synthase Type III (NOS III) in endothelial cells activates guanylyl cyclase (GC) in smooth muscles cells. This results in the production of cGMP from GTP. cGMP is metabolized by phosphodiesterase type 5 (PDE5). cGMP causes the activation of protein kinase G (PKG). PKG causes an increased uptake of calcium into intracellular stores and a reduction of calcium entry into the cell through calcium channels. PKG also opens potassium channels, leading to hyperpolarization, which also closes the calcium channels. The resulting decrease in intracellular calcium concentration from these mechanisms leads to relaxation of the smooth muscle. (B) Relaxation of penile smooth muscle: cAMP mechanisms. Peptides, such as vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP), and prostaglandins, such as PGE1, bind to specific receptors on the smooth muscle cell membrane. These are linked to G protein that activates adenylyl cyclase (AC) in smooth muscles cells. This results in the production of cAMP from ATP. cAMP causes the activation of protein kinase A (PKA). PKA causes an increased uptake of calcium into intracellular stores by inhibiting an inhibitor of calcium uptake, phospholambin. PKA also opens potassium channels, leading to hyperpolarization, which closes the calcium channels. The resulting decrease in intracellular calcium concentration from these mechanisms leads to relaxation of the smooth muscle. Reused, with permission, from Rosen RC and McKenna KE. 2002 (254).

Figure 4 The amygdala, an almond-shaped structure located in each temporal lobe, seen in a schematic drawing of a coronal section of the rat brain. Two general amygdaloid regions, the basolateral and corticomedial nuclei (left), have been studied extensively. Destruction of the corticomedial nuclei, but not the basolateral nuclei, severely affects male copulatory behavior in rodents. The specific nuclei of the basolateral and corticomedial amygdala are depicted (right). Reused, with permission, from Nelson RJ. 2011 (210).

Figure 5 Schematic diagram of the principal limbic nuclei and connections in hamster brain that transmit chemosensory and hormonal cues to control male sexual behavior. Shading indicates areas with abundant steroid receptor-containing neurons. ac, anterior commissure; ACo, anterior cortical amygdaloid nucleus; AOB, accessory olfactory bulb; BL, basolateral amygdaloid nucleus; BNST, bed nucleus of the stria terminalis; BNSTpi, posterointermediate subdivision of BNST; BNSTpm, posteromedial subdivision of BNST; Ce, central amygdaloid nucleus; fx, fornix; lot, lateral olfactory tract; Me, medial amygdaloid nucleus; MeA, anterior subdivision; MeP, posterior subdivision; MOB, main olfactory bulb; MPN, medial preoptic nucleus; MPOAl, lateral subdivision of the medial preoptic area; oc, optic chiasm; OM, olfactory mucosa; ot, optic tract; PLCo, posterolateral cortical amygdaloid nucleus; PMCo, posteromedial cortical amygdaloid nucleus; st, stria terminalis; vaf, ventral amygdalofugal pathway; VNO, vomeronasal organ. Reused, with permission, from Wood RI. 1997 (325).

Figure 6 The medial preoptic area (MPOA) receives direct and indirect inputs from brain areas that are important for the assimilation of sexually relevant information. Olfactory stimulation is received by the olfactory bulbs (OB), the OB project to the medial amygdala (MeA), which relays information to the bed nucleus of stria terminalis (BST) and the MPOA (depicted in blue). Additionally, the MPOA and MeA receive somatosensory input via the central tegmental field (CTF) (depicted in green). In turn, the MPOA projects to the ventral tegmental area (VTA) and the brain stem (BS) (depicted in red). The VTA then projects to the nucleus accumbens (NAc) and other structures relevant to reward and motivation (depicted in light green). For a complete description of MPOA afferents and efferents, see Simerly and Swanson (1986, 1988). The figure above and the placement of structures in the figure are not anatomically accurate. Adapted, with permission, from Hull EM and Dominguez JM. 2006 (124).

Figure 7 A schematic representation of oxytocinergic neurons originating in the paraventricular nucleus of the hypothalamus (PVN) and projecting to extrahypothalamic brain areas and the spinal cord involved in sexual activity. Activation of these neurons by dopamine, excitatory amino acids, oxytocin itself, and hexarelin analog peptides facilitates penile erection and sexual activity. The direct or indirect activation of these neurons and the facilitative effects on erection and sexual activity induced by the above substances can be reduced or abolished by the stimulation of opioid and GABAergic receptors. These oxytocinergic neurons are activated by the activation of nitric oxide synthase (NOS) present in their cell bodies. Endogenous NO, produced a result of stimulation of dopamine, excitatory amino acid, or oxytocin receptors, or exogenous NO, derived from NO donors delivered to the PVN, activates oxytocinergic neurons by a yet-unidentified mechanism. This causes the release of oxytocin in brain areas distant from the PVN, as well as the spinal cord, inducing penile erection. Similar mechanisms operate during noncontact erections and copulation. Reused, with permission, from Argiolas A and Melis MR. 2004 (10).

Figure 8 Summary figure showing the MPOA-PAG-nPGi-spinal cord circuit. MPOA projections to the periaqueductal gray (PAG) terminate preferentially among PAG neurons projecting to the nucleus paragigantocellularis (nPGi). Descending projections from the nPGi terminate within the dorsomedial and dorsolateral motor pools of the ventral horn of the lumbosacral spinal cord. Motoneurons from these pools innervate the bulbocavernosus and ischiocavernosus muscles, which are essential for penile erection and ejaculation. Reused, with permission, from Murphy AZ and Hoffman GE. 2001 (206).

 


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Article Title: Neuroendocrine Regulation of Male Sexual Behavior
 

How to Cite

Elaine M. Hull, Juan M. Dominguez. Neuroendocrine Regulation of Male Sexual Behavior. Compr Physiol 2019, 9: 1383-1410. doi: 10.1002/cphy.c180018