I routinely utilize Sphenopalatine Ganglion Blocks or SPG Blocks to treat patients with chronic pain issues. These include TMJ disorders, headaches, migraines, myofascial pain and dysfunction, anxiety, panic attacks and other problems associated with Autonomic Sympathetic Overload. While there are numerous methods of delivering SPG Blocks my preferred method is a cotton-tipped continual feed nasal catheter. The results are similar or better compared to other delivery methods but self administration gives patients control of their issues with dangerous medication and associated side effects. The cost of self-administration after initial training is approximately$1.00 per block. They can be administered in the comfort of home without trips to doctors offices or emergency departments. This makes their use exceptionally easy and the rapid onset can often begin in minutes.
A surprising side effect of Sphenopalatine Ganglion Blocks is the frequent increase in sexual desire in female patients receiving these blocks. This may be due to reduced pain and anxiety but it may actually be a key for women who are troubled by low sexual desire or responsiveness. This specific side effect and the ability to self-administer SPG Blocks the blocks at home makes it an ideal treatment for sexual difficulties relating to reduced desire or inability to achieve sexual satisfaction.
The Sphenopalatine Ganglion is the largest Parasympathetic Ganglion of the head and also carries sympathetic fibers of the superior cervical chain. It is located on the maxillary division of the trigeminal nerve in the pterygopalatine fossa. Sphenopalatine Ganglion Blocks are also know as Nasal Ganglion Blocks, Pterygopalatine Ganglion Blocks, Nasal Ganglion Blocks and Meckel’s Ganglion Block. These blocks were features in the 1986 book “Miracles on Park Avenue”
The blocks appear to reset the autonomic nervous system turning off Sympathetic Overload (dominance) and allowing Parasympathetic response to dominate.
I like to compare this autonomic reset to correcting computer problems by hitting CONTROL-ALT-DELETE buttons. Chronic pain issues can be likened to input- output errors (I/O errors) on a computer.
The Sympathetic response is a survival of the individual response also called the “FIGHT OR FLIGHT REFLEX” It gets our bodies prepared to defend ourselves or to flee.
The Parasympathetic response is on of safety and satiety. It is called the “FEED AND BREED” or “EAT AND DIGEST REFLEX” and is a reflex that is important to the survival of the species.
I believe the sexual effects in men and women are significantly different. Female sexual response begins with an AROUSAL PHASE that is mediated by Parasympathetic activity ie the “FEED AND BREED REFLEX”
Orgasm is primarily a Sympathetic process in women. I do not think this is normally a FIGHT OR FLIGHT REFLEX but a different type of sympathetic reflex. It is a strong Sympathetic response that follows a strong Parasympathetic response and is proceded and followed by primarily parasympathetic responses.
I believe high stress and sympathetically maintained pain is a major cause of female sexual issues. Turning off this sympathetic overload by resetting the autonomic nervous system allows women a healthier normal sexual response. I often hear from women patients that they are sexually aroused during or after the block and had one patient who experience an orgasm while transnasal catheters were in place delivering lidocaine by capillary action.
I reference this work for more information about Autonomic responses in female sexuality.
in Female Sexual Arousal
It is openly available for download on the internet so I reprinting it at the end of this post for your convenience: This will link to pdf of the paper. http://citeseerx.ist.psu.edu/viewdoc/download;jsessionid=F042258337EC489C74CC4799BC7D97E5?doi=10.1.1.658.2614&rep=rep1&type=pdf
Male Sexual Response is very different than female response. The following link is excellent on male response. The full paper is open access and is reproduced at the end of this post.
I believe that while women initially respond sexually due to primarily due to Parasympathetic Activity that men initiate sexual responses initially from increased Sympathetic Activity. Something akin to “FIGHT OR FLIGHT REFLEX” as males strive to “WIN” the fight for the female. This is seen in dominant male activity in many species mating rituals.
This makes sense when we consider what a parasympathetic response is. I explain to patients that the parasympathetic response is what we feel when we play with puppies or kittens or babies. We leave our sympathetic system and become very different individuals and this response is almost universal.
I propose that Self-Administered SPG Blocks be considered a treatment of choice for female patients suffering reduced desire for sexual activities or who have trouble achieving orgasm or are aorgasmic. Side effects like reduced depression, anxiety and blood pressure are all positive.
These blocks reduce sympathetic activity and increase parasympathetic activity. This is cuddling behavior, relationship behavior and communication behavior. Common complaint are that men do not spend enough time getting women in the mood. The sexual act is often “Wham, Bam, thank you mam” rather than the warm cuddling, holding, stroking behavior that women crave.-
Young mothers who work and take care of families often lose all interest in sex as the rigors of everyday living leaving them in a sympathetic overload and saving what little parasympathetic activity for “motherly behaviors” a sort of natural birth control. Self-Administration of Sphenopalatine Ganglion Blocks after the children are in bed can reduce sympathetic overload that modern society causes and allow patients to decrease or eliminate pain and anxiety, stroll out of sympathetic overload and enjoy wallowing in their parasympathetic system. This is a very empathetic state and a state susceptible to sexual arousal.
system (SNS) is associated with physiological sexual arousal in females. The anatomy and
pharmacology of the SNS in the female genital region is complex and not fully understood.
Within these limitations, several animal and human models of SNS activity and sexual arousal
have been studied. Some evidence suggests that biological markers of SNS activity are elevated
after sexual arousal. It has also been observed that pharmacological and physiological
manipulations that increase SNS activity potentiate physiological sexual arousal. These findings
are in conflict with basic physiological research demonstrating that sympathetic input results in
vasoconstriction within genital tissues. With incomplete knowledge of autonomic physiology
and pharmacology, resolving the discrepancy among findings represents a methodological
challenge. The results of recent investigations are discussed in the context of theoretical
perspectives emphasizing the interaction of the parasympathetic and sympathetic nervous
systems in sexual arousal.
Anatomy of the Sympathetic Nervous System in the Female Genitalia
The autonomic nervous system provides most of the innervation to the internal genital
organs and is essential to the sexual response. It has generally been presumed that
parasympathetic activity is responsible for achieving sexual arousal through localized
vasocongestion, resulting in genital swelling and lubrication, while orgasm is mediated through a
sympathetic response. However, the interaction of these two systems is complex, and remains
poorly understood. Innervation of the genitalia in human females runs primarily through a
common network of converging autonomic and sensory fibers known as the pelvic plexus. In
some non-human mammals it has been observed that sympathetic and parasympathetic fibers
may dually innervate a few post-synaptic neurons in the pelvic plexus. In addition, sympathetic
and parasympathetic neurons in the pelvic plexus may sometimes communicate laterally (Dail,
1996). However, the degree to which different nerve types in the plexus might interact with one
another remains speculative. The significance of such interactions is likewise unknown.
Anatomical studies have indicated that the sympathetic nervous system’s (SNS)
contribution to the pelvic plexus originates from multiple sources. The superior hypogastric
plexus gives rise to two sympathetic nerves that run bilaterally into the left and right pelvic
plexuses (Donker, 1986; Maas, DeRuiter, Kenter, & Trimbos, 1999). Other inputs stem directly
from sympathetic chain ganglia along the thoracolumbar spinal cord (Donker). In addition to
these routes, genital tissues may receive innervation from so-called “short” adrenergic fibers that
arise from localized ganglia. Ownman, Rosengren, and Sjoberg (1967) found that such ganglia
were particularly abundant in the human vagina. Interestingly, estrogen and other sex steroids
may significantly influence sympathetic innervation in the pelvic organs (e.g., Zoubina & Smith,
Rosengren, & Sjoberg, 1967), it is generally accepted that norepinephrine is the dominant
neurotransmitter of the SNS. Adrenergic nerve fibers from the pelvic plexus have been found to
target both vascular and non-vascular smooth muscle in most if not all female genital organs.
The study of adrenoceptors in the genital tract is therefore extremely important to the
understanding of the role of the SNS in physiological sexual arousal. However, this approach is
not comprehensive. Studies of adrenoceptors alone cannot address the effects of nonadrenergicnoncholinergic
(NANC) neurotransmitters, such as neuropeptide Y and galanin, which are often
co-localized within sympathetic nerve fibers. The functional significance of these neuropeptides
is only beginning to be understood (for review, see Argiolas, 1999).
Attempts have been made to characterize the distribution of adrenoceptors in genital
tissue. Anatomical studies have suggested that mammalian vaginal, cervical, uterine and clitoral
tissues contain both alpha1 and alpha2 adrenoceptors. Beta adrenoceptors are also present in
some genital tissues, particularly the uterus, although they have received considerably less
attention in studies of sexual function. In humans, both alpha1 and alpha2 adrenoceptors appear
to regulate smooth muscle tone in vaginal and clitoral tissue (Min et al., 2001; Traish et al.,
1999). Traditionally, it has been thought that alpha1 adrenoceptors are located postsynaptically
and regulate smooth muscle contractility, while alpha2 adrenoceptors are located presynaptically
and serve an autoregulatory function to inhibit release of norepinephrine and other
neurotransmitters (e.g., Iversen, Iversen, & Saper, 2000). However, it is known that the alpha2
receptor subtype is found both pre- and postsynaptically. A recent study indicates that activation
of postsynaptic alpha2 adrenoceptors in male corpus cavernosum induces smooth muscle
contraction (Gupta et al., 1998). Therefore, alpha2 adrenoceptors appear to serve opposite ends,
depending on their location within the synapse. This somewhat paradoxical conclusion must be
approached with caution. Understanding how adrenergic mechanisms influence female sexual
arousal is limited by current knowledge of the distribution of adrenergic receptors on the nerves
serving the genitalia.
Animal Models of Sympathetic Nervous System Activity and Sexual Arousal
Pharmacological Manipulation of Sexual Behavior
Using pharmacological treatments, a number of studies have demonstrated the influence
of adrenergic transmission in the regulation of sexual behavior in females. Most studies of this
nature have used ovariectomized animals treated with standardized doses of estradiol and
progesterone. This strategy serves two purposes: first, to elicit sexually receptive behavior from
a sexually unreceptive baseline, and second, to control for the potential influence of unequal sex
hormone levels on adrenergic transmission. Animal models of female sexual behavior may
assess several different measures of sexual responding: receptivity (lordosis quotient), which is
the ratio of the number of spinal reflexes in response to male attempts to mate; proceptivity,
which is measured as the number of ear wiggles per minute; and rejection behaviors which are
measured as the number of kicking, boxing, running away, and squealing behaviors in response
to a male’s attempt to mate. Application of these behaviors to human sexual behavior is
obviously limited. Although there is no human equivalent of lordosis, it is considered an analog
of sexual arousal in other mammals.
Yanase (1977) found that epinephrine, but not norepinephrine, stimulated lordosis
behavior in estradiol-treated, ovariectomized rats. However, other findings have supported the
role of norepinephrine in stimulating lordosis. Vincent and Feder (1988) found that injection of
either an alpha1 or alpha2 adrenergic agonist induced lordosis behavior in a small proportion of
guinea pigs, but when used in combination, induced lordosis in 76% of the animals.
Studies examining the effects of adrenergic and anti-adrenergic agents are complicated
by the fact that some of the drugs used do not act exclusively on adrenergic systems. For
example, yohimbine acts as both an alpha2 adrenoceptor antagonist and a serotonin receptor
antagonist (Broadley, 1996, p. 216). In such a case, the study design must incorporate a method
to rule out the effects of different neurotransmitter systems on the phenomenon of interest. Nock
and Feder (1979) observed that the dopamine beta-hydroxylase inhibitor U-14,624 abolished
lordosis behavior in female guinea pigs. U-14,624 was believed to increase dopamine and
serotonin availability while decreasing norepinephrine levels. After both dopamine and
serotonin blockade failed to reverse the effects of U-14,624, the authors determined that only
concurrent administration of the alpha2 adrenergic agonist clonidine was able to restore lordosis
behavior in animals treated with U-14,624. Thus, the inhibitory effects of U-14,624 on lordosis
were concluded to be associated primarily with decreased availability of norepinephrine, rather
than increased dopamine or serotonin levels.
Although central mechanisms have usually been implicated in the adrenergic control of
lordosis, a peripheral mechanism cannot be ruled out. The facilitatory effect of norepinephrine
on lordosis responses may indicate the involvement of the SNS. If so, one would expect drugs
that decrease SNS activity might also decrease sexual arousal. To examine this possibility,
Meston and colleagues (Meston, Moe, & Gorzalka, 1996) conducted a series of studies which
examined the influence of various drugs that inhibit SNS activity on sexual responding in the
female rat. The first study examined the influence of clonidine, an antihypertensive medication,
on sexual responding. Clonidine acts centrally and peripherally as an alpha2 adrenergic agonist,
presumably with the effect of decreasing norepinephrine release. In the second and third studies,
the effects of drugs guanethidine and naphazoline on sexual responding were examined.
Naphazoline also acts as an alpha2 adrenergic agonist, and guanethidine works by a distinct
mechanism to directly block the release of norepinephrine from sympathetic nerves. These two
drugs were chosen because they are believed to exert effects similar to those of clonidine but
they do not cross the blood brain barrier, hence their action is strictly at peripheral sites. Each
study involved 15 ovariectomized female rats treated with estrogen and progesterone to induce
heat, and used a repeated measures design in which the animals received either saline or
moderate or high doses of the drug.
Clonidine, guanethidine, and naphazoline all significantly suppressed lordosis responses
at both moderate and high doses. Clonidine and guanethidine significantly decreased proceptive
behavior at both moderate and high doses, and naphazoline significantly decreased proceptivity
at moderate doses. Clonidine significantly increased the number of rejection behaviors at both
moderate and high doses; guanethidine and naphazoline also increased rejection behaviors but
the results did not reach statistical significance. The fact that rejection behaviors were increased,
not decreased, with these drugs is important in that it suggests that the suppression of sexual
responding is not likely attributable to the potential sedative effects of these drugs given that
rejection behaviors are active behavioral responses. Because guanethidine and naphazoline act to
selectively inhibit peripheral sympathetic outflow without influencing adrenergic mechanisms at
a central level, the results of this study suggest that inhibition of the SNS may inhibit sexual
behavior in the female rat.
Effects of Direct Stimulation of Nerves and Tissues
In vivo studies of direct nerve stimulation can differentiate genital responses to
parasympathetic and sympathetic outflow. Studies of this type have used electrical stimulation
of dissected nerves in order to determine specific effects on target tissues. In rats, electrical
stimulation of both the pelvic (parasympathetic) and hypogastric (sympathetic) nerves induced
contractions of uterine and cervical smooth muscle, which were further enhanced by
pretreatment with estrogen (Sato et al., 1989; Sato et al., 1996). Pelvic nerve stimulation
increased uterine blood flow, while hypogastric nerve stimulation decreased blood flow. The
decrease in uterine blood flow following hypogastric stimulation was eliminated with
phenoxybenzamine, an alpha-adrenergic antagonist (Sato et al., 1996). Similarly, in guinea pigs,
stimulation of the hypogastric nerve induced uterine contractions and increased uterine
sensitivity to oxytocin; these effects could be blocked with the alpha-adrenergic antagonist
phentolamine (Marshall and Russe, 1970). Stimulation of the pelvic plexus, which comprises
both pelvic and hypogastric nerves, increased clitoral and vaginal blood flow in rats (Vachon et
al., 2000). However, another study found that direct stimulation of the sympathetic chain
countered the increase in vaginal blood flow resulting from pelvic nerve stimulation (Giuliano et
al., 2001).
A different strategy used to examine adrenergic influences on genital tissue function
involves electrical stimulation of smooth muscle tissue dissected from genital organs.
Subsequent treatment with anti-adrenergics and other agents can be used to detect moderating
influences of neurotransmitters on tissue responses. In a study of rabbit myometrium and cervical
tissue, contractile responses to electrical field stimulation was attenuated by both guanethidine,
an anti-adrenergic agent, and atropine, an anti-cholinergic agent, but not by propalanol, a
selective beta-adrenergic antagonist (Bulat, Kannan, & Garfield, 1989). Rabbit vaginal tissue
contractile responses to electrical stimulation were attenuated by several alpha1 and alpha2
adrenergic antagonists (Kim et al., 2002).
The above studies suggest that stimulation of the sympathetic nerves supplying the
genitalia results in contractions of both non-vascular and vascular smooth muscle, which may in
turn limit blood flow to the uterus, vagina, and other tissues. Given that sexual arousal involves
a vasocongestive response, the contention that arousal is mediated through activity of the SNS is
apparently contradictory. To date, this discrepancy has been addressed infrequently in the
literature. It has been suggested, however, that the vasoconstrictive effects of norepinephrine are
superseded by the effects of other neurotransmitters that act as local vasodilators in the presence
of sexual stimulation. If this is the case, then other peripheral effects of SNS activation, such as
increased heart rate and blood pressure, may facilitate the vasocongestive response (Kim et al.,
Human Models of SNS Activity and Sexual Arousal
Neuroendocrine Markers of Sympathetic Activity and Sexual Arousal
Indirect evidence for a facilitatory influence of SNS activation on female sexual arousal
is provided by biochemical and physiological research which indicates that diffuse SNS
discharge occurs during the later stages of sexual arousal (Jovanovic, 1971) with marked
increases in heart rate and blood pressure occurring during orgasm (Fox & Fox, 1969).
Significant increases in urinary (Levi, 1969) and plasma (Exton et al., 2000) norepinephrine
concentrations have been found in women after viewing a sexually arousing film. Increases in
plasma norepinephrine, a sensitive index of SNS activity, have also been shown to accompany
increases in sexual arousal during intercourse, and to decline rapidly following orgasm
(Wiedeking, Ziegler, & Lake, 1979). Ende and associates (1988) measured urinary
vanillylmandelic acid (VMA) 1 hour before, within an hour after intercourse, and in a 23-hour
pooled sample after intercourse in eleven females. Vanillylmandelic acid is the ultimate
metabolic product of epinephrine and norepinephrine in the urine and, thus, one of the most
accurate methods of studying total sympathetic activity. The authors found a significant increase
in VMA 1 hour prior to intercourse and 1 hour post-intercourse in comparison to pre-intercourse
baseline levels. The pooled 23-hour sample showed levels of VMA higher than pre- but not
post-intercourse levels. These findings provide objective evidence for considerable involvement
of the SNS during, and in anticipation of, intercourse.
Spinal Cord Injury Studies
The sexual impairments brought about by spinal cord injury (SCI) provide a novel model
of sexual dysfunction with which to investigate the SNS contribution to sexual arousal. The
origin of much of the sympathetic innervation to the genitalia can be localized to a discrete
region of the thoracolumbar spinal cord. By observing sexual responses in women who have
lesions to these areas, the effects of sympathetic disruption can be inferred to some degree.
Research in this area has focused on specific arousal phase responses, notably vaginal
vasocongestion, among women with varying types and degrees of SCIs. These studies have
typically distinguished between “psychogenic” arousal, modeled by genital responses to erotic
audiovisual stimuli, and “reflex” responses to tactile stimulation of the genitals.
Berard (1989) studied 15 women with complete and incomplete SCIs at the cervical,
thoracic, and lumbar levels. According to their medical records, both reflex and psychogenic
vaginal lubrication were absent among women with SCIs between T10 and T12, a region from
which genital sympathetic nerves originate. In addition, these women reported an absence of
sensations associated with sexual arousal. Only reflex lubrication was preserved in women with
injuries above T10, whereas psychogenic lubrication was preserved in women with injuries
below T12. The absence of vaginal lubrication and subjective sensation in women with injuries
to the lower thoracic spinal cord suggests involvement of the sympathetic nervous system in
these responses.
Using vaginal photoplethysmography, Sipski, Alexander, and Rosen (1997) studied
vaginal pulse amplitude (VPA) responses to erotic stimulation in women with SCIs affecting
sensation to the T11-L2 dermatomes. It was reasoned that women with damage to sensory
neurons at these levels would also have impaired SNS outflow from those regions, given the
close proximity of the sympathetic and somatosensory neurons within the spinal cord. The
authors compared women with SCI who had preserved some degree of pinprick sensation in the
T11-L2 dermatomes to women who had lost all sensation in these areas. Each woman was
examined under two conditions: audiovisual erotic stimulation alone, and audiovisual erotic
stimulation with manual clitoral stimulation. Both groups showed increases in subjective sexual
arousal under the two conditions. Whereas women with some preserved dermatomal sensation
showed increased VPA responses to audiovisual stimuli, women with absent sensation showed
no vaginal response. When manual stimulation was added to the audiovisual stimulation, the
groups showed similar increases in VPA responses. However, heart rate and respiration rate
were significantly greater among women with preserved sensation during the combined
stimulation condition.
A second study by Sipski and associates (Sipski, Alexander, & Rosen, 2001) used a
similar methodology to compare VPA responses of a control group of 21 able-bodied women to
those of 68 SCI women under conditions of audiovisual stimulation alone and audiovisual plus
manual stimulation. Consistent with previous findings, women with impaired sensation at the
T11-L2 dermatomes showed decreased physiological sexual arousal compared to able-bodied
women. Further, the degree of sensory impairment resulting from injury to the T11-L2 region
was predictive of the intensity of the vasocongestive response, with less impaired women
responding more like able-bodied women. When compared to women with injuries at different
levels of the spinal cord, this pattern was unique to women with injuries between T11 and L2.
Effects of Physiologically-induced SNS Activation on Sexual Arousal
The above studies suggest an active role of the SNS during sexual arousal in women.
Whether or not activation or inhibition of the SNS influences subsequent sexual arousal is a
related but different question. Hoon, Wincze, and Hoon (1977) were the first to report that
vaginal blood volume (VBV) responses were increased when women viewed an anxiety-evoking
film prior to an erotic film versus a neutral travel film prior to an erotic film. Palace and
Gorzalka (1990) replicated these findings in both sexually functional and dysfunctional women.
To the extent that anxiety-evoking films increase SNS arousal, these findings support a
facilitatory role of SNS activation on sexual arousal in women. However, it should be noted that
heart rate, an indirect indicator of SNS activity, was either not measured or failed to increase
significantly with exposure to the anxiety films. Hence, assumptions about SNS activation in
these studies are highly speculative. Wolpe (1978) offered an alternative explanation for these
findings. He described the finding as an “anxiety relief” phenomenon by which the anxiety films
were so aversive that, by contrast, the erotic films were so much more appealing that they
consequently facilitated sexual responding strictly via cognitive processes.
Meston and colleagues examined the effects of SNS activation on sexual arousal using
intense, acute exercise as a means of eliciting SNS activity. Exercise was chosen based on
numerous pharmacological and physiological studies which indicate that moderate to high
intensities of exercise are accompanied by significant SNS activity (for review, see DiCarlo &
Bishop, 1999). In the first of this series of studies (Meston & Gorzalka, 1995), 35 sexually
functional women between the ages of 18 and 34 participated in two counterbalanced sessions
during which they viewed a neutral film followed immediately by an erotic film. In one of the
sessions, subjects engaged in 20 minutes of intense stationary cycling before viewing the films.
Prior to engaging in the two experimental sessions, the women were given a submaximal bicycle
ergometer fitness test in order to estimate their maximum volume of oxygen uptake (VO2 max),
an indicator of cardiovascular fitness. This allowed the workload and cycle speed to be set so
that all participants exercised at a constant 70% of their VO2 max. By having women exercise at
relative workloads, differences in physiological responses resulting from variations in fitness
levels are minimized (Grossman & Moretti, 1986). Sexual arousal was measured subjectively
using a self-report questionnaire adapted from Heiman & Rowland (1983), and physiologically
using a vaginal photoplethysmograph (Sintchak & Geer, 1975). Both vaginal pulse amplitude
(VPA) and VBV were used as indices of sexual arousal. Heart rate was used as an indirect
indicator of SNS activation.
The results indicated a significant increase in both VPA and VBV responses to the erotic
films with exercise. Heart rate was significantly increased with exercise (70 bpm vs. 90 bpm);
there were no significant changes in heart rate between the neutral and erotic films. There were
no significant differences in self-report measures of sexual arousal, positive affect, or negative
affect with exercise, and correlations between subjective and physiological indices were not
Meston and Gorzalka (1996b) used the same methodology to examine the indirect effects
of SNS activation in women with sexual difficulties. Twelve participants were sexually
functional, 12 reported low sexual desire, and 12 were anorgasmic. There were no significant
differences in VPA or VBV responses between the subject groups during the No-exercise
condition. With exercise, however, there were significant increases in VPA and VBV among
sexually functional women, a significant increase in VPA and VBV responses among women
with low sexual desire, and a significant decrease in VPA and a non significant decrease in VBV
with exercise among anorgasmic subjects. Heart rate was significantly increased with exercise
among all subject groups. There were no significant effects of exercise on subjective ratings of
sexual arousal, positive affect, negative affect, or anxiety among either of the subject groups, and
no significant differences between groups on these measures.
A follow-up study conducted by Meston and Gorzalka (1995) examined whether the
exercise-induced increases in VPA and VBV responses may have been the result of other
potential “non sexual” consequences of exercise or, alternatively, to the passage of time postexercise
given that the presentation of the erotic films consistently followed that of the neutral
films. Ten sexually functional women between the ages of 19-34 participated in a repeatedmeasures
design study in which they engaged in two counterbalanced sessions where they
viewed either a neutral film followed by an erotic film, or two consecutive neutral films (Meston
& Gorzalka, 1995). In both sessions subjects engaged in 20 minutes of stationary cycling at 70%
of their VO2 max. Vaginal pulse amplitude and VBV were significantly increased with the
presentation of an erotic film, but showed no change with the presentation of a second neutral
film. The results of this experiment suggest that exercise per se does not simply increase VBV
and VPA responses but, rather, exercise in the presence of an erotic stimulus enhances genital
engorgement.
In the exercise studies noted above, approximately 15 minutes had passed from the
cessation of exercise to the onset of the erotic stimulus. Although research indicates that SNS
influences remain significantly elevated for approximately 30-40 minutes following intense
exercise, at 15 minutes post-exercise heart rate had declined considerably from levels during and
immediately following exercise. This leads one to question whether exercise would have an even
greater facilitatory influence on physiological sexual responses if measured immediately
following exercise, and whether the level of SNS activation is in some way related to the level of
physiological sexual arousal. Thirty-six sexually functional women, between the ages of 18-45
participated in a study designed identically to the original exercise study with the following
exception: Sexual arousal was measured at either 5 minutes, 15 minutes, or 30 minutes postexercise
in an effort to examine the approximate influences of high, moderate, and low levels of
SNS activation on sexual responding (Meston & Gorzalka, 1996a). Vaginal pulse amplitude
responses were significantly decreased at 5 minutes, significantly increased at 15 minutes (a
replication of the original study), and marginally increased at 30 minutes post-exercise. Vaginal
blood volume findings showed a similar pattern to the VPA results but did not reach statistical
significance. Heart rate was significantly increased with exercise in each of the conditions (97,
87, 80 bpm at 5, 15, and 30 minutes post exercise, respectively), and there were no significant
effects of exercise on subjective ratings of sexual arousal, positive or negative affect. One
interpretation of these findings is that there may be an optimal level of SNS activation for
physiological sexual arousal below and beyond which SNS activation may have less of a
facilitatory influence or even an inhibitory influence on physiological sexual arousal.
Interpretation of the above studies which used exercise to increase SNS activity is
confounded by the potential role of hormones. In addition to creating SNS dominance, exercise
at the intensity used in the above studies has been shown to influence the secretion of hormones
such as estrogen, testosterone, cortisol, and prolactin (e.g., Keizer, Kuipers, de Haan, Beckers, &
Habets, 1987). To date, research has not adequately addressed whether short term changes in
these hormones influence sexual arousal in women.
Brotto and Gorzalka (2002) examined sexual responses in pre- and postmenopausal
women using laboratory-induced hyperventilation as a means of increasing SNS activity. The
authors did not measure heart rate or any other indicator of SNS activity but cited research that
this technique induces sympathetic dominance for approximately 7 minutes (Achenback-Ng, et
al., 1994). Twenty-five young pre-menopausal women, 25 post-menopausal women, and 25 premenopausal
women age-matched to the menopausal group participated in two counterbalanced
sessions in which VPA and subjective sexual arousal was measured either during baseline or
following the hyperventilation procedure. The authors found that SNS activation increased VPA
responses compared to baseline only among the young pre-menopausal women. Using the same
hyperventilation procedure to induce SNS activity, Brotto (unpublished manuscript) found that
SNS activation significantly increased VPA responses among sexually healthy women but
significantly decreased VPA responses among women with sexual arousal difficulties that were
psychological in nature. Women with sexual arousal difficulties that were physical in nature
showed a marginal, but non-significant increase in VPA with heightened SNS activity. In both
studies, SNS activation using a hyperventilation technique had no significant impact on
subjective sexual arousal.
Effects of Adrenergic Agonists on Sexual Arousal
Meston and Heiman (1998) examined the effects of ephedrine, an alpha- and betaadrenergic
agonist, on VPA responses. Twenty sexually functional women participated in two
counterbalanced conditions in which they received either placebo or ephedrine (50 mg) using a
double-blind protocol. Ephedrine significantly increased VPA responses to an erotic, but not
neutral, film, and had no significant effect on subjective ratings of sexual arousal or on measures
of positive or negative affect. The finding that when subjects viewed a nonsexual, travel film,
there were no significant differences in VPA responses between the ephedrine and placebo
conditions parallels the findings that exercise significantly increased VPA responses to erotic but
not neutral stimuli. As was the case noted with exercise, this suggests that ephedrine did not
simply facilitate physiological responses through a general increase in peripheral resistance but,
rather, acted in some way which selectively prepared the body for genital response. While
ephedrine substantially increases peripheral sympathetic outflow, interpretation of this study
findings is limited by the fact that ephedrine also has centrally acting properties which
potentially could account for the results.
In a recent follow-up study, Meston (2003) examined whether ephedrine would be
effective in reversing antidepressant-induced sexual dysfunction. Given that treatment for SSRIinduced
sexual side effects using centrally acting serotonergic agents may diminish the
antidepressant’s therapeutic effectiveness (e.g., Gitlin, 1994), it was hypothesized that targeting
peripheral rather than central mechanisms may be a more viable treatment approach.
Presumably, this would circumvent the reversal of antidepressant’s therapeutic effects on
depression that are presumably centrally mediated. Nineteen sexually dysfunctional women
receiving either fluoxetine, sertraline, or paroxetine participated in an eight-week, double-blind,
placebo-controlled, cross-over study of the effects of ephedrine (50 mg) on self-report measures
of sexual desire, arousal, orgasm, and sexual satisfaction. While there were significant
improvements relative to baseline in sexual desire and orgasm intensity/pleasure on 50mg
ephedrine one hour prior to sexual activity, significant improvements in these measures, as well
as in sexual arousal and orgasmic ability were also noted with placebo. Whether or not the
women in this study experienced an increase in genital vasocongestion was not assessed thus
assertions regarding the indirect impact of SNS activation on physiological sexual arousal can
not be made. As was the case in the laboratory study noted above, ephedrine did not substantially
impact the women’s psychological experience of sexual arousal.
Two studies were conducted which examined the effects of moderate doses of clonidine,
a selective alpha2 adrenergic agonist, on subjective and plethysmograph indices of sexual arousal
(Meston, Gorzalka, & Wright, 1997). In the first study, 15 sexually functional women, ages 18-
42, participated in two sessions in which they viewed a neutral film followed immediately by an
erotic film. In one session the women received a placebo and in one session they received .2 mg
clonidine one hour prior to viewing the films. The study was conducted using a double-blind,
placebo-controlled, repeated-measures protocol. The second study followed the identical
procedure with the exception of the following: In both sessions, subjects engaged in 20 min of
intense stationary cycling one hour following either placebo or clonidine administration but prior
to viewing the films.
In the first study, 9/15 and 7/15 subjects showed a decrease in VPA and VBV,
respectively, with clonidine but the results did not reach statistical significance. In the second
study which involved heightened SNS activation there was a significant decrease in both VPA
and VBV with clonidine administration during the erotic films. Heart rate was significantly
decreased with clonidine during the second (heightened SNS) study only. Subjective ratings of
sexual arousal were marginally decreased in the first study and significantly decreased in the
second (heightened SNS) study. Because clonidine has both central and peripheral properties, it
is unclear at which level clonidine acted to influence sexual responding. Centrally, clonidine may
have suppressed sexual responses indirectly via changes in neurohypophyseal hormone release,
or directly by activating central sites responsible for the inhibition of sexual reflexes (Riley,
1995). Peripherally, clonidine may have suppressed sexual arousal by decreasing norepinephrine
release from sympathetic nerve terminals. Support for this latter notion is provided by the finding
that clonidine inhibited sexual responding only when subjects were in a state of heightened SNS
activity. The fact that clonidine has been reported to significantly inhibit SNS, but not hormonal,
responses to exercise (Engelman et al., 1989) is consistent with the suggestion that clonidine
acted to inhibit sexual responding via suppressed SNS activity. However, given that the role of
the alpha2 adrenoceptor in female sexual function has not been clearly elucidated, the
presumption that clonidine inhibits SNS outflow to the genitalia is tentative.
Effects of Adrenergic Antagonists on Sexual Arousal
Several studies have examined adrenergic blocking drugs on sexual arousal in women.
Rosen and associates (1999) found a facilitatory effect of the nonselective alpha adrenergic
antagonist phentolamine mesylate (40 mg administered orally) on VPA and subjective sexual
arousal responses in six post-menopausal women with Female Sexual Arousal Disorder. A
facilitatory influence of phentolamine mesylate on VPA responses was also noted in a larger
sample of postmenopausal women with Female Sexual Arousal Disorder receiving hormone
replacement therapy (HRT) (Rubio-Aurioles et al., 2002). The study was conducted using a
double-blind, placebo-controlled, randomized, four-way crossover design in which
postmenopausal women either on (n = 19) or not on (n = 22) HRT received placebo (vaginal
solution or oral tablet), 5 mg and 40 mg phentolamine vaginal solution, and 40 mg phentolamine
oral tablets. Physiological sexual responses were significantly greater than placebo with 40 mg
phentolamine vaginal solution among the HRT but not among the non HRT women. Subjective
sexual arousal was increased with 40 mg phentolamine oral tablet and to a lesser degree with 40
mg phentolamine vaginal solution only among the women receiving HRT. Because
phentolamine crosses the blood-brain barrier, it is not known whether these effects are
attributable to a central or peripheral mechanism, or both.
Meston and Worcel (2002) examined the effects of the alpha2 adrenoceptor antagonist
yohimbine, either alone or in combination with the nitric oxide-precursor L-arginine on
subjective and physiological responses to erotic stimuli in postmenopausal women with Female
Sexual Arousal Disorder (FSAD). Twenty-four women participated in three treatment sessions
in which subjective and VPA sexual responses to erotic stimuli were measured following
administration of either L-arginine glutamate (6 g) plus yohimbine HCl (6 mg), yohimbine alone
(6mg), or placebo, using a randomized, double-blind, three-way cross-over design. Sexual
responses were measured at approximately 30, 60, and 90 min post-drug administration. The
combined oral administration of L-arginine glutamate and yohimbine increased VPA responses
at 60 min post drug administration compared with placebo. VPA responses at 30 and 90 min
post drug administration were increased compared to placebo, but did not reach significance.
Yohimbine alone had no significant impact on VPA responses at any of the time periods. There
were no significant increases in subjective measures of sexual arousal in any of the experimental
conditions. These findings are limited by the fact that the study design was unable to control for
potential central nervous system effects of yohimbine.
The traditional model of the female sexual response holds that the arousal phase is
mediated by parasympathetic activity, with sympathetic impulses predominating at orgasm.
However, several lines of evidence suggest that increased sympathetic nervous system activity is
a prominent feature of sexual arousal. Lacking sufficient knowledge about the function and
distribution of sympathetic nerves, as well as ethical and accurate means of directly manipulating
SNS outflow, investigators have been limited to conclusions drawn from indirect observations of
SNS activation and inhibition in humans. Studies of women before and after exposure to
sexually arousing stimuli have shown that concentrations of norepinephrine and its metabolites
are elevated immediately following sexual arousal. Research conducted on women with spinal
cord injuries suggests that damage to the spinal cord at the level of sympathetic innervation
significantly impairs the sexual response. Physical exercise at intensities that are thought to
increase SNS outflow has been shown to enhance sexual arousal responses in women. Based on
putative pharmacological manipulations of SNS outflow, several studies suggest that sexual
arousal may be enhanced or inhibited by adrenergic potentiation or blockade, respectively.
These findings are supported by observations in animal models suggesting that adrenergic
agonists increase, and adrenergic antagonists decrease, sexual behavior. However, these findings
do not positively establish SNS activation as a mediator of sexual arousal. At least one wellcontrolled
pharmacological study has demonstrated that adrenergic blockade, an analog of SNS
inhibition, enhances sexual arousal responses in some women.
Indirect examinations of the effects of SNS stimulation have substantial limitations.
Although experimental manipulations designed to increase sympathetic activity are informed by
previous physiological research, their effectiveness cannot be verified directly. Further, the
impact of these manipulations is generally not limited to the SNS, making it difficult to rule out
effects due to hormonal or other nervous system changes. By using a more reductive animal
model, several recent studies have been able to examine the effects of sympathetic and
adrenergic stimulation on genital tissue with greater specificity. Using techniques to directly
stimulate autonomic nerve branches in the pelvic region, these studies have supported the
conclusion that sympathetic impulses cause genital vascular and non-vascular smooth muscle to
contract, limiting blood flow and preventing a full vasocongestive response. However, it is not
known to what degree the effects of experimentally induced nerve impulses in isolation resemble
physiological processes in natural behavior.
In summary, studies of the role of the SNS in sexual arousal have reached seemingly
contradictory conclusions. Although putative markers of increased SNS activity have been
associated with enhanced sexual arousal, this is not in accord with physiological research
suggesting that sympathetic outflow limits genital responses necessary for physiological sexual
arousal. It is possible that indirect approaches to studying the SNS in sexual arousal are not
measuring the effects of sympathetic activity, but rather the effects of some other physiological
process. For example, pharmacological studies have not typically controlled for the central
nervous system effects of the agents used, and exercise studies have not assessed the contribution
of hormonal changes that accompany physical activity. On the other hand, it is possible that
sympathetic activity may have a facilitatory effect on sexual arousal in the context of other
processes. The localized effects of SNS activation on genital blood flow may be overridden by
opposing activity of the parasympathetic nervous system, while the systemic effects of SNS
activity, such as increased blood pressure, may facilitate genital engorgement (Kim et al., 2002).
If this is the case, discrepancies among study findings may be attributable to the fact that some
experiments, particularly in animal models, manipulate sympathetic outflow in relative isolation.
However, these explanations are hypothetical, as the interaction of the parasympathetic and
sympathetic systems during sexual arousal remains largely unknown. Better knowledge of the
autonomic innervation to the genitalia and autonomic pharmacology is needed to facilitate the
understanding of the processes involved in female sexual arousal.
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The male genital system consists of external and internal reproductive and sexual organs such as the penis, prostate, epididymis, and testes. Figure 1 shows the gross anatomy of the ejaculatory structures. Table 1 provides a summary of the functional anatomy of these organs (2–5).
PHYSIOLOGY OF ERECTION
The penile erection results from complex neurovascular mechanisms. Several central and peripheral neurological factors in addition to molecular, vascular, psychological and endocrino-logical factors are involved, and the balance between these factors is what eventually determines the functionality of the penis. In this section, we summarize some of those mechanisms.
Cerebral Control
Cerebrally controlled penile erections are induced through erotic visual stimuli or thoughts. The main cerebral structures involved in erection are contained within the medial preoptic area (MPOA) and paraventricular nucleus (PVN) in the hypothalamus (6). Dopamine is the most important brain neurotransmitter for erection, likely through its stimulation of oxytocin release (7). Another important neurotransmitter is norepinephrine, which is demonstrated through the erectogenic effect of the α-2 agonist (Yohimbine) (8). Several other brain neurotransmitters are involved in the erection process to varying degrees such as nitric oxide (NO), α-melanocyte stimulating hormone (α-MSH), and opioid peptides (9).
Autonomic Control
Parasympathetic stimulation is the main mediator for penile tumescence, although central suppression of the sympathetic nervous system also plays a role. Parasympathetic supply to the penis is derived from the sacral segments S2-S4 (10). However, patients with sacral spinal cord injury still maintain erections through psychogenic stimulation, although of less rigidity than normal. These psychogenic erections do not occur in patients with lesions above T9 (11), suggesting that the main mechanism for these erections is central suppression of sympathetic stimulation (12). Patients with lesions above T9 still may maintain reflexogenic erections. This implies that the main mechanism for reflexogenic tumescence is the preservation of the sacral reflex arc, which mediates erection through tactile penile stimulation (13, 14).
Molecular Mechanisms
The penis at baseline is in a flaccid state maintained by the contraction of corporal smooth muscles and constriction of cavernous and helicine arteries leading to moderate state of hypoxia with partial pressure of oxygen of 30–40 mm Hg (15). During sexual arousal, NO is released from cavernous nerve terminals through the action of neuronal NO synthase (16). The NO activates guanylate cyclase, which in turn converts guanosine triphosphate to cyclic guanosine monophosphate (15, 17), leading eventually to smooth muscle relaxation and vasodilation (18). Although the initiation of tumescence is through neuronal NO synthase, the maintenance of erection is through endothelial NO synthase (19). The eventual smooth muscle relaxation and vasodilation results in blood flowing into the paired corpora and filling of the sinusoids, with increased intracorporal pressure (to >100 mm Hg during full erection) and compression of the subtunical venules, markedly reducing the venous outflow (13).
PHYSIOLOGY OF ORGASM
There is no standard definition of orgasm. Each specialty such as endocrinology or psychology examines this activity from each one’s perspective, making it difficult to reach a consensus on the definition. Orgasm is generally associated with ejaculation, although the two processes are physiologically different (20). Certain physiological features are associated with orgasm, including hyperventilation up to 40 breaths/min, tachycardia, and high blood pressure (21). In fact, faster heart rate was found to be an indicator of “real” male orgasm during intravaginal intercourse, differentiating it from “fake” orgasm (22). Orgasm is also associated with powerful and highly pleasurable pelvic muscle contractions (especially ischiocavernosus and bulbocavernosus) (23), along with rectal sphincter contractions and facial grimacing (21). There is also an associated release and elevation in PRL and oxytocin levels after orgasm; however, the significance of this elevation is not entirely clear (24).
Studies using positron emission tomography, which measures changes in regional cerebral blood flow, have identified areas of activation in the brain during orgasm. Primary intense activation areas are noted to be in the mesodiencephalic transition zones, which includes the midline, the zona incerta, ventroposterior and intralaminar thalamic nuclei, the lateral segmental central field, the suprafascicular nucleus, and the ventral tegmental area. Strong increases were seen in the cerebellum. Decreases were noted at the entorhinal cortex and the amygdale (25).
Quality and intensity of orgasms are variable. For instance, short fast buildup of sexual stimulation toward orgasm is associated with less intense orgasms than slow buildup. Early orgasms are less satisfying than later orgasms in life as the person learns to accept the pleasure associated with orgasms. Lower levels of androgen are associated with weaker orgasms, such as in hypogonadism or in older age (20). It has been suggested that pelvic muscle exercises, particularly the bulbocavernosus and ischiocavernosus muscles, through contracting those muscles 60 times, 3 times daily for 6 weeks will enhance the pleasure associated with orgasm (20). However, the effort and time associated with such exercises prevent their utilization. The orgasm induced through deep prostatic massage is thought to be different from the orgasm associated direct penile stimulation. Although penile stimulation orgasms are associated with 4–8 pelvic muscle contractions, prostatic massage orgasms are associated with 12 contractions. Prostatic massage orgasms are thought to be more intense and diffuse than penile stimulation orgasms, but they require time and practice and are not liked by many men (20, 26, 27).
Following orgasm in men is a temporary period of inhibition of erection or ejaculation called the refractory period. This is a poorly understood phenomenon, with some investigators suggesting a central rather than spinal mechanism causing it (28). Elevated levels of PRL and serotonin after orgasm have been suggested as a potential cause; however, there is much debate about their exact role (29). More research is still needed in the area of male orgasm (20).
PHYSIOLOGY OF EJACULATION
Ejaculation is a physiological process heavily controlled by the autonomic nervous system. It consists of two main phases: emission and expulsion. The main organs involved in ejaculation are the distal epididymis, the vas deferens, the seminal vesicle, the prostate, the prostatic urethra, and the bladder neck (30).
The first step in the emission phase is the closure of bladder neck to prevent retrograde spillage of the seminal fluid into the bladder. This is followed by the ejection of prostatic secretions (10% of the final semen volume) containing acid phosphatase, citric acid, and zinc, mixed with spermatozoa from the vas deferens (10% of the volume) into the prostatic urethra. Subsequently, the fructose-containing seminal vesicle fluid alkalinizes the final ejaculatory fluid. The seminal vesicle fluid constitutes 75%–80% of the final seminal fluid. Cowper’s glands and periurethral glands produce a minority of the seminal fluid (1, 31). The organs involved in the ejaculation process receive dense autonomic nerve supply, both sympathetic and parasympathetic, from the pelvic plexus. The pelvic plexus is located retroperitoneally on either side of the rectum, lateral and posterior to the seminal vesicle (32). It receives neuronal input from the hypogastric and pelvic nerves in addition to the caudal paravertebral sympathetic chain (33). The sympathetic neurons play the predominant role in the ejaculation process. Their nerve terminals secrete primarily norepinephrine, although other neurotransmitters such as acetylcholine and nonadrenergic/noncholinergic also play important roles (34). The role of the hypogastric plexus in emission is best demonstrated clinically by the loss of emission after non-nerve sparing para-aortic lymph node dissection for testicular cancer (35), and induction of emission in paraplegic men through electrical stimulation of superior hypogastric plexus (35). Input from genital stimulation is integrated at the neural sacral spinal level to produce emission (36). The emission phase of ejaculation is also under a considerable cerebral control, and can be induced through physical or visual erotic stimulation (37).
Expulsion follows emission as the process of ejaculation climaxes, and refers to the ejection of semen through the urethral meatus. The semen is propelled through the rhythmic contractions of the pelvic striated muscles in addition to the bulbospongiosus and ischiocavernosus muscles (23). To achieve antegrade semen expulsion, the bladder neck remains closed, whereas the external urethral sphincter is open. The external sphincter and the pelvic musculature are under somatic control; however, there is no evidence that voluntary control plays a role in the expulsion process (30). The exact trigger for expulsion is unknown. It has been suggested that a spinal center is triggered during emission of seminal fluid into the prostatic urethra (38). However, there is mounting evidence through clinical and experimental studies to suggest that this is not the case. For instance, men can still have rhythmic contractions during orgasm despite “dry ejaculation,” for example, due to prostatectomy (23, 39, 40). This, in addition to the identification of spinal generator for ejaculation (SGE) in rats, led to the postulation that the process of expulsion is a continuum of the process initiated through emission, after reaching a certain spinal activation threshold (30, 41).
NEURONAL CONTROL OF EJACULATION
Ejaculation is heavily controlled by the nervous system. Figure 2 summarizes the reflex circuit necessary to elicit ejaculation.
The main sensory input from the penis comes from the dorsal nerve of the penis, which transmits sensation from the glans, prepuce, and penile shaft. It transmits signals to the upper and lower segments of the sacral spinal cord (42). The glans contains encapsulated nerve endings, termed Krause-Finger corpuscles, whereas the remaining penile shaft contains free nerve endings. Stimulation of these corpuscles potentiated by stimulation from other genital areas, such the perineum, testes, and penile shaft, play an important role in the ejaculation process (43). A secondary afferent route is through the hypogastric nerve, which runs through the paravertebral sympathetic chain to enter the spinal cord through the thoracolumbar dorsal roots (44). The sensory afferents terminate in the medial dorsal horn and the dorsal gray commissure of the spinal cord (45).
The efferent peripheral nervous system constitutes of sympathetic, parasympathetic, and motor nervous components (46). The soma of the preganglionic sympathetic cell bodies involved in ejaculation are located in the intermedio-lateral cell column and in the central autonomic region of the thoracolumbar segments (T12-L1) (47). The preganglionic sympathetic fibers emerge from the ventral roots of the spinal cord and travel through the paravertebral sympathetic chain to relay either directly through the splanchnic nerve, or through relaying first in the celiac superior mesenteric ganglia and then through the intermesenteric nerve, to the inferior mesenteric ganglia (48). The hypogastric nerve then emanates from the inferior mesenteric ganglia to join the parasympathetic pelvic nerve to form the pelvic plexus, which then sends fibers to the ejaculation structures (49). The preganglionic parasympathetic cell bodies are located in the sacral parasympathetic nucleus. The sacral parasympathetic nucleus neurons travel then in the pelvic nerve to the post-ganglionic parasympathetic cells located in the pelvic plexus. The motor neurons involved in ejaculation are located in Onuf’s nucleus in the sacral spinal cord, which projects fibers through the motor component of the pudendal nerve to reach the pelvic musculature, including the bulbospongiosus, ischiocavernosus, and external urethral sphincter (50).
Spinal network
The thoracolumbar sympathetic, sacral parasympathetic (mainly sacral parasympathetic nucleus), and somatic sacral Onuf’s nucleus ejaculatory spinal nuclei play an important role in the integration of peripheral and cerebral input and coordinating output to the pelviperineal structures involved in ejaculation (46). An additional spinal center is the SGE located in laminae X and VII of L3-L4 spinal segments (51). The SGE contains spinal interneurons called lumbar spinothalamic cells, which project fibers to the parvocellular subparafascicular nucleus of the thalamus in addition to preganglionic sympathetic and parasympathetic neurons innervating the pelvis (41). The SGE stimulation elicits a complete ejaculatory response resulting in collection of motile spermatozoa in anesthetized rats (52). Further research on the SGE spinal center is still needed, and it is unclear whether it contains other cells than lumbar spinothalamic cells.
Brain network
Sensory and motor areas in the brain play an important role in the ejaculation, which requires a highly coordinated and integrated central process. The study by Holstege et al. (25) using positron emission tomography showed that certain areas in the brain are activated in the orgasm and ejaculation process. Furthermore, specific areas in the brain have been involved in the ejaculation process, as demonstrated in animal immunohistochemical studies examining Fos protein pattern of expression (53–56), and confirmed using a serotonin 1A subtype receptor agonist proejaculatory pharmacologic agent in rats (57). These are discrete areas within the posteromedial bed nucleus of stria terminalis, the parvicellular part of the subparafascicular thalamus, the posterodorsal preoptic nucleus, and the posterodorsal medial amygdaloid nucleus. There are reciprocal connections that link those areas to the MPOA of the hypothalamus, a brain area with a well-established role in controlling sexual behavior as demonstrated by anatomical and functional studies (54, 55, 58). Electrical or chemical stimulation of the MPOA elicited ejaculation (59–62), whereas an MPOA lesion was shown to abolish both phases of ejaculation (63). No direct connections of MPOA to the spinal centers for ejaculation were found on neuroanatomical studies; however, there are projections of MPOA to other regions in the brain involved in ejaculation, such as PVN, the periaqueductal gray, and the paragigantocellular nucleus (nPGi) (64–66).
The PVN projects to pudendal motor neurons located in the L5-L6 spinal segment in addition to autonomic preganglionic neurons in the lumbosacral spinal cord in rats (45, 67, 68). It also projects to nPGI in the brainstem (69). Bilateral lesions of the PVN with N-methyl-D-aspartate (NMDA) results in a one-third reduction of the seminal ejaculate material weight (70). The parvicellular part of the subparafascicular thalamus was found to send projections to bed nucleus of stria terminalis, medial amygdala (MeA), and MPOA (71, 72) and receives input from lumbar spinothalamic cells (51). The precise role of these regions is still unclear but they are likely involved in relaying genital signals to MPOA (53, 55). The brainstem regions (nPGI and periaqueductal gray) have recently received increasing attention. The nPGI nucleus likely plays an inhibitory role in ejaculation as evidenced through the urethrogenital reflex experimental model, a rat model for the expulsion phase of ejaculation (73, 74). Using the same model, the periaqueductal gray was found to be important for the ejaculation process, likely by acting as a relay between MPOA and nPGI (75). Midbrain structures have a significant role in ejaculation; however, much is still unknown about their exact role and further research is needed. Figure 3 summarizes the putative brain structures involved in ejaculation.
Putative brain structures involved in ejaculation. BNSTpm = posteromedial bed nucleus of stria terminalis; MeApd = posterodorsal medial amygdaloid nucleus; MPOA = medial preoptic area; PAG = periaqueductal gray; nPGi = paragigantocellular nucleus; PNpd …
NEUROCHEMICAL REGULATION OF EJACULATION
Many neurotransmitters are involved in the ejaculation process. Defining the exact role of these neurotransmitters is difficult given the variety of sexual parameters affected, the different sites of action within the spinal and the supraspinal pathways, and the presence of multiple receptor types. Some of the molecules that received special attention for their role in ejaculation are mentioned later.
Dopaminergic Control
Dopamine is known to be important for normal male sexual response (76, 77). Two families of dopamine receptors exist, D1-like (D1 and D5 receptors) and D2-like (D2, D3, and D4 receptors) (46). In rats, D2-like receptors are known to stimulate ejaculation (78, 79), and trigger ejaculation even in anesthetized rats (80, 81). Systemic injection of the D3 receptor agonist 7-OH-DPAT has been shown to trigger ejaculation in rats without affecting arousal (82, 83). It also triggers ejaculation in anesthetized rats when injected directly into the cerebral ventricles or MPOA with the effect being specifically reversed by the D3, not the D2 antagonist (84, 85). The D3 receptor blockage has been shown to inhibit the expulsion phase of ejaculation and lengthen ejaculation latency in rats (86).
Serotonergic Control
Evidence suggests that serotonin (5HT) inhibits ejaculation (87). Selective serotonin reuptake inhibitors increase 5HT tone resulting in impairment of ejaculation, which led to their clinical use in premature ejaculation. This inhibitory effect is likely to occur in the brain (88), as 5HT effect on ejaculation in the spine is likely stimulatory (89). The amphetamine derivative p-chloroamphetamine leads to a sudden release of 5HT in synaptic clefts triggering ejaculation in anesthetized rats with complete spinal cord lesion (89). Intrathecal serotonin or selective serotonin reuptake inhibitor injection leads to enhancement of the expulsion phase of ejaculation (88). There are 14 receptor subtypes for 5HT, with 1A, 1B, and 2C being the ones involved in ejaculation (90). It is difficult to designate one influence for each receptor subtype, as each receptor could either activate or inhibit ejaculation depending on its location within the central nervous system (46).
The role of NO in ejaculation has received special attention after the introduction of type-5 phosphodiesterase (PDE5) inhibitors and using them for premature ejaculation. Nitric oxide has an inhibitory role on the ejaculation process (1). Centrally, intrathecal sildenafil results in elevation of NO and cyclic guanosine monophosphate levels in MPOA causing a decreased peripheral sympathetic tone and inhibition of ejaculation (91). N-Nitro-l-arginine methyl-ester injection, an NO synthase inhibitor, was shown to increase the number of seminal emissions and reduce latency to first seminal emission in rats (92). Peripherally, nitronergic innervation and NO synthase were found in the seminal vesicle, vas deferens, prostate, and urethra (93–97). Therefore, drugs such as PDE5 inhibitors or NO donors are associated with reduced seminal vesicle contraction and inhibit seminal emission (92). The administration of NO inhibitors, such as l-nitroarginine-methylester, diminishes human seminal vesicle contraction (98), inhibits vasal contraction in guinea pigs (99), and decreases latency to ejaculation in rats (100). Furthermore, reduced latency to emission was found in knockout mice for the gene encoding endothelial NO synthase compared with their wild-type counterparts (101).
HORMONAL REGULATION OF EJACULATION
Although male sexual function is heavily regulated by the hormonal system, there are few clinical studies performed to evaluate hormonal regulation of ejaculation, and the knowledge about hormonal effect on ejaculation is still lacking. We discuss some of the studies examining the effect of different hormones on ejaculation.
Oxytocin is an oligopeptide synthesized in the supraoptic and PVN of the hypothalamus and released from the posterior pituitary gland. Oxytocin serum level increases after male ejaculation to levels ranging from 20%–360% of normal levels before reaching baseline at 10 minutes after ejaculation (102). Pharmacologic oxytocin administration in humans and animals results in increased ejaculated spermatozoa (103), confirming that oxytocin has a role in male genital tract motility. It was specifically found to augment powerful epididymal contractions and sperm motility (104), an important effect blunted by pretreatment with the oxytocin antagonist (des Gly–NH2d(CH2)5–[d-Tyr2,Thr4] ornithine vasotocin) (105). Peripheral oxytocin receptors were found to be highly expressed in the epididymis and tunica albuginea (in smooth muscles more than epithelial cells), and to a lesser extent in the vas deferens and seminal vesicle (104). Oxytocin has a synergistic action on the epididymis with endothelin-1, where they augment epididymal contraction and propel spermatozoa forward (102, 106). Injection of oxytocin into the cerebral ventricles in male rats facilitated ejaculation by shortening the ejaculation latency and postejaculatory refractory periods (107), whereas these effects were curbed using the oxytocin receptor antagonist (d(CH2)5–Tyr(Me)–[Orn8]vasotocin) injected into the cerebral ventricles (108). Despite these encouraging findings and some anecdotal evidence suggesting that intranasal oxytocin can facilitate orgasm in an anorgasmic male (109), a double-blind placebo-controlled clinical study (110) failed to demonstrate an effect of intranasal oxytocin on sexual behavior.
Prolactin
Hyperprolactinemia has a marked inhibitory effect on male sexual desire (111). A modest increase in serum PRL levels (15–20 ng/mL) has been detected in men after orgasm, and could be contributing to the after-orgasm refractory period (112). Some investigators have hypothesized that a low PRL level is a cause of premature ejaculation, where PRL levels were similarly low in those men with lifelong or acquired premature ejaculation (113). Further research is needed on this issue.
Thyroid Hormones
The relationship between thyroid hormonal abnormalities and ejaculatory dysfunction has been well documented (114–116). In rats, l-thyroxin administration has been shown to increase bulbospongiosus contractile activity and seminal vesicle contraction frequency (117). Clinically, the prevalence of suppressed TSH, which is a marker of hyperthyroidism, was found to be twofold higher in patients with premature ejaculation than in patients who reported normal ejaculatory timing (118). In the first prospective multicenter study (114) on the topic, half of hyperthyroidism patients had premature ejaculation, whereas only 15% reported this symptom after cure of their thyroid dysfunction. Another single-center prospective study by Cihan et al. (116) demonstrated a prevalence of 72% of premature ejaculation in hyperthyroidism, which was reduced after treatment. It also identified a positive correlation of TSH with intravaginal ejaculation latency time. Öztürk et al. (119) found similar results. However, Waldinger et al. (120) found no correlation between TSH and intravaginal ejaculation latency time in a cohort of Dutch men with lifelong premature ejaculation. A meta-analysis by Corona et al. (102) demonstrated a threefold increase of hyperthyroidism in patients with premature ejaculation compared with controls, a finding that was more pronounced in patients with acquired rather than lifelong premature ejaculation. They also showed an increase in intravaginal ejaculation latency time by 84.6 ± 34.2 seconds (P=.001) upon treatment of hyperthyroidism. These findings suggest that thyroid hormones do not only affect the ankle reflex, but also the ejaculatory reflex, and screening patients with ejaculatory dysfunction for thyroid hormone abnormalities is warranted (102).
Cortisol (F) levels in several animal studies were found to be elevated during arousal and ejaculation (121–123). In horses and donkeys, F was elevated 30 minutes after ejaculation, with unknown significance of this finding (124, 125). In addition, F levels were sharply elevated after electroejaculation in several anesthetized animal studies (126, 127). In humans, however, there was no change in F levels whether during sexual stimulation or orgasm (128–131). Although hypercortisolism in men was associated with reduced libido, no effect was identified on orgasm or ejaculation (132). Replacement of F in Addison disease was associated with improvement in overall sexual function including orgasm (133). Data in humans are still too preliminary to draw final conclusions, and further research is needed.
Estrogens
Estradiol plays an important role in the regulation of the emission phase of ejaculation through the regulation of epididymal contractility, luminal fluid reabsorption, and sperm concentration (134, 135). This role in the epididymis is the reason for recommending Tamoxifen as a first-line treatment for idiopathic oligospermia by the World Health Organization (136). Finkelstein et al. (137) showed that E2 deficiency, along with androgen deficiency, contributes to decreased libido and erectile function.
Androgens
Testosterone, through its central and peripheral androgen receptors, has a well-known role on male sexual function, particularly on libido (138). Low T levels are associated with delayed ejaculation, whereas high levels were associated with premature ejaculation (102). This is likely because the emission phase of the ejaculation relies on the NO-PDE5 system, which is influenced by T (138, 139). Testosterone facilitates the control of the ejaculatory reflex through its androgen receptors in the MPOA and other areas in the central nervous system (140). Furthermore, pelvic floor muscles involved in ejaculation are androgen dependent (141). There are likely multiple mechanisms involved in T action and further research is needed to identify specific targets for treatment in the ejaculatory reflex. Table 2 summarizes the neurochemical and hormonal regulation of ejaculation.
Neurochemical and hormonal regulation of ejaculation.
In conclusion, ejaculation is a complex process involving several anatomical structures and under extensive neurochemical and hormonal regulation. Orgasm, although associated with ejaculation, is a distinct physiological process, different from ejaculation. Many aspects of these physiological processes are still unknown and further research is needed to identify treatments for ejaculatory dysfunction.
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[Eur Urol. 2007] Activation by p-chloroamphetamine of the spinal ejaculatory pattern generator in anaesthetized male rats.
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[Am J Physiol Regul Integr Comp Physiol. 2001] The roles of nitric oxide in sexual function of male rats.
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[Int J Impot Res. 2003] Coitus-induced orgasm stimulates prolactin secretion in healthy subjects.
[Psychoneuroendocrinology. 2001] Hypoprolactinemia: a new clinical syndrome in patients with sexual dysfunction.
[J Sex Med. 2009] Multicenter study on the prevalence of sexual symptoms in male hypo- and hyperthyroid patients.
[J Clin Endocrinol Metab. 2005] The relationship between premature ejaculation and hyperthyroidism.
[J Urol. 2009] Investigation of the neural target level of hyperthyroidism in premature ejaculation in a rat model of pharmacologically induced ejaculation.
[J Sex Med. 2011] SIEDY scale 3, a new instrument to detect psychological component in subjects with erectile dysfunction.
[J Sex Med. 2012] Hormonal evaluation in premature ejaculation.
[Urol Int. 2012] Thyroid-stimulating hormone assessments in a Dutch cohort of 620 men with lifelong premature ejaculation without erectile dysfunction.
[J Sex Med. 2005] Review The hormonal control of ejaculation.
[Nat Rev Urol. 2012] Effects of sexual stimulation, with and without ejaculation, on serum concentrations of LH, FSH, testosterone, cortisol and prolactin in stallions.
[J Anim Sci. 1989] Hormonal and behavioral correlates of emotional states in sexually trained boars.
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