Next Article in Journal
Atmospheric Pollutants Affect Physical Performance: A Natural Experiment in Horse Racing Studied by Principal Component Analysis
Previous Article in Journal
Comparison of the Modified TyG Indices and Other Parameters to Predict Non-Alcoholic Fatty Liver Disease in Youth
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biology
Volume 11
Issue 5
10.3390/biology11050686
biology-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Neurons for Ejaculation and Factors Affecting Ejaculation

by
Kiran Kumar Soni
*,†,
Han-Seong Jeong
† and
Sujeong Jang
*
Department of Physiology, Chonnam National University Medical School, Hwasun 58128, Korea
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biology 2022, 11(5), 686; https://doi.org/10.3390/biology11050686
Submission received: 25 March 2022 / Revised: 27 April 2022 / Accepted: 28 April 2022 / Published: 29 April 2022
(This article belongs to the Section Developmental and Reproductive Biology)
Browse Figures
Review Reports Versions Notes

Abstract

:

Simple Summary

Sexual dysfunctions are rarely discussed in our current society. Males experience different sexual dysfunctions, including erectile, infertility, and ejaculatory dysfunctions. In this review only the ejaculatory dysfunction will be discussed. Ejaculation is defined as the ejection of contents collectively from the vas deferens, seminal vesicle, prostate and Cowper’s glands. It is completely controlled by a population of neurons present in the lumbar spinal cord. The presence of lesion in these neurons ceases the ejaculatory behavior in males. This population of neurons was first identified in rats; however, recently it was confirmed that these neurons are present in human males as well. The issues are known as ejaculatory dysfunction. The following are the different types of ejaculatory dysfunctions: early ejaculation, ejaculation into the urinary bladder, late ejaculation and no ejaculation.

Abstract

Ejaculation is a reflex and the last stage of intercourse in male mammals. It consists of two coordinated phases, emission and expulsion. The emission phase consists of secretions from the vas deferens, seminal vesicle, prostate, and Cowper’s gland. Once these contents reach the posterior urethra, movement of the contents becomes inevitable, followed by the expulsion phase. The urogenital organs are synchronized during this complete event. The L3–L4 (lumbar) segment, the spinal cord region responsible for ejaculation, nerve cell bodies, also called lumbar spinothalamic (LSt) cells, which are denoted as spinal ejaculation generators or lumbar spinothalamic cells [Lst]. Lst cells activation causes ejaculation. These Lst cells coordinate with [autonomic] parasympathetic and sympathetic assistance in ejaculation. The presence of a spinal ejaculatory generator has recently been confirmed in humans. Different types of ejaculatory dysfunction in humans include premature ejaculation (PE), retrograde ejaculation (RE), delayed ejaculation (DE), and anejaculation (AE). The most common form of ejaculatory dysfunction studied is premature ejaculation. The least common forms of ejaculation studied are delayed ejaculation and anejaculation. Despite the confirmation of Lst in humans, there is insufficient research on animals mimicking human ejaculatory dysfunction.

1. Introduction

Ejaculation is a spinal reflex. It is the forceful ejection of seminal fluid by the males at the end of coitus [1,2]. During ejaculation, the prostatic urethra has pressure of more than 5 m water pressure [3,4]. Specifically, the parasympathetic nervous system maintains the heart rate at relaxed levels; however, the sympathetic nervous system increases the rate of heart rate through the secretion of epinephrine. At the time of ejaculation, the heart rate may increase by 100% in males owing to sympathetic effects [5,6,7]. In rats, ejaculation is associated with reward [8]. It should not be confused with climax or orgasm, which provides pleasurable feelings. Orgasm and ejaculation can be considered a single incident, however, both are different biological processes [9]. Orgasm can be absent in some men with ejection of seminal contents during ejaculation [10], whereas in some men, ejaculation is absent, and they experience intense orgasm [11,12].
Ejaculation delivers sperm to the female genital tract for offspring generation. The distal epididymis, vas deferens, seminal vesicle, prostate, prostatic urethra, and bladder neck are the male reproductive organs involved in ejaculation [2,13]. The duration and degree of ejaculation vary remarkably among men and individuals in different situations [14]. In rats, ejaculation is distinguished by a prolonged, intense force (750–2000 ms), and much slower dismount [15]. This review aims to explain the neural regulation of ejaculation, its abnormalities, and its etiology. Moreover, this review discusses ejaculation physiology and abnormalities in animals and their correlation with humans, as well as ways to improve studies that allow mimicking this pathology in humans.

2. Neurophysiology of Ejaculation

Ejaculation remains in the control of the parasympathetic (sacral) and sympathetic (thoracic) autonomic nervous systems and spinal centers [16]. It remains intact in animals with complete spinal cord transection, which provides evidence that ejaculation is controlled at the spinal level, despite the loss in connection from supraspinal regions [17]. The integration between spinal centers and the autonomic nervous system is organized by interneurons that shape the spinal ejaculation generator [SEG] [18]. Based on a detailed study of the spinal gray matter and its cellular composition under a microscope, the gray matter of the spinal cord was found to be split into 10 laminae [I–X] [19]. The parasympathetic nucleus (sacral) innervates the prostate and seminal vesicles located in the S2–S4 segments of lamina VII [16]. The sympathetic nucleus (thoracic) innervates the smooth involuntary muscles of the seminal tract and bladder neck located in the T12-L2 segments of lamina VII [20,21]. Motor neurons that govern the pelvic-perineal striated muscles remain in the Onuf’s nucleus of the ventral horn of the segments [22]. The spinal ejaculation generator or lumbar spinothalamic cells are located in lamina X and the medial part of lamina VII of the gray matter in the lumbar L3–L4 spinal cord of rats [23,24]. They are called lumbar spinothalamic cells as they have connections in the lumbar spinal cord and thalamus [22]. Recently, it was confirmed that the spinal ejaculation generator in male humans is in the L3–L5 segment [16].
The marker for neural activation is an increased level of Fos. The activation of these lumbar spinothalamic cells is triggered by stimuli associated with ejaculation; however, mounts or intromissions do not trigger Fos expression in lumbar spinothalamic cells (Figure 1). Activation of lumbar spinothalamic cells or spinal ejaculation generators causes ejaculation [25]. Injury to these neurons acutely compromises ejaculation; hence, these neurons, besides carrying ejaculation-specific sensory information to the brain, also trigger ejaculation [25]. These lumbar spinothalamic cells transport sexual information that is sensory cues prior ejaculation to the thalamus [26] and consolidate the details of the neural interconnection between the somatic/autonomic centers in lumbar spinothalamic cells and the spinal cord [27,28,29]. Interneurons of the spinal ejaculatory generator contain galanin [30], cholecystokinin [31,32], encephalin [33], and gastrin-releasing peptide [34,35,36]; they also co-express androgen receptors [37] and the substance P receptor (neurokinin-1 receptor) [23].

2.1. Neurons for Ejaculation in Non-Mammalians: Corazonin

In non-mammalians, mostly arthropods, there is an 11 amino acid neuropeptides known as Corazonin neurons [38]. Corazonin neurons are specifically located in abdominal ganglion [39]. It is equivalent to the Gonadotrophin Releasing Hormone that is essential for regulation of growth, ethanol-related behavioral states, stress responses and ejaculation. Activation of corazonin neurons induce ejaculation by interacting with Neuropeptide F (npf) that is rewarding to Drosophila males. However, stimulation of corazonin neurons was enough for a rise in npf level, which is similar to a post-copulation state where copulation is without an actual female [40,41]. Stimulation of corazonin neurons to induce ejaculation is possible by “fictive mating”, that is by opto- and thermogenetic [41,42].
Ejaculation consists of two phases: emission and expulsion [13,16,43,44].

2.2. Emission

The beginning of this phase involves the shutdown of the bladder neck to check for retrograde ejaculation [45]. It is followed by a mixture of seminal vesicle, prostatic, vas deferens, and Cowper’s gland secretions into the prostatic urethra [46]. The initiation of the emission phase of ejaculation is not under individual will or controlled cerebrally and can be evoked through visual erotic stimulation or physical stimulation [47,48]. The organs involved in this phase obtain deep autonomic innervations formed by the sympathetic and parasympathetic nerves from the pelvic plexus [48]. The basic neurotransmitter required in the stimulation of the sympathetic nervous system is norepinephrine, and this is balanced by acetylcholine, the parasympathetic neurotransmitter. Sympathetic nerves at levels T10–L2 that leave the spinal cord commence peristaltic contraction of the prostate smooth muscle, seminal vesicles, vas deferens, and epididymis [49]. Once the semen reaches the posterior urethra, ejection of the semen and its content becomes unavoidable [48].

2.3. Expulsion [Anterograde Ejaculation]

Expulsion follows emission, where semen is pushed out as the consequence of the rhythmic contractions of the striated muscles of the pelvis and the ischiocavernosus, bulbospongiosus, and perineal muscles [43]. Electromyographic [EMG] studies of the bulbocavernosus or bulbospongiosus have reported evidence of ejaculation or expulsion in animals following electrical or mechanical stimulation of genital structures or of the dorsal nerve of the penis [32,50], which is controlled by lumbar spinothalamic cells. This induces ejaculation by consolidating the sensory information conveyed by the dorsal nerve of the penis, which is the sensory branch of the pudendal nerve [34]. The pudendal nerve, which begins at the S2–S4 level of the sacral spinal cord, causes rhythmic involuntary contractions (Figure 2) [49]. The ejaculation response in men is generally approximately 10–15 contractions [51]. The intra-seminal vesicle pressure during expulsion in rats is approximately 61.4 mmHg [52]. Men cannot undergo a series of ejaculations rapidly; men enter a refractory period immediately after ejaculation; it is a regaining time in which no ejaculation is possible. The refractory period time varies among individuals, ranging from a few minutes to hours [53].

3. Ejaculatory Dysfunction

Ejaculatory dysfunction can be classified into four types: premature ejaculation, retrograde ejaculation, delayed ejaculation, and anejaculation [54]. Here, delayed ejaculation and anejaculation have been discussed together because the most severe form of delayed ejaculation is anejaculation. Almost all factors for anejaculation are extreme conditions of delayed ejaculation (Figure 3) [20,55,56]. Premature ejaculation and retrograde ejaculation have been widely studied [57]. Unfortunately, delayed ejaculation and anejaculation are the minimally studied ejaculatory dysfunctions [58,59].

4. Premature Ejaculation

Premature ejaculation [PE] is the most common type of ejaculation dysfunction in men, with a prevalence of up to 75% [48,60]. Premature ejaculation [PE] is a male sexual dysfunction identified by ejaculation that always or nearly always occurs prior to or within 1 min of vaginal penetration [61]. Female partners of men with premature ejaculation [PE] were reported to have worse relationships compared to men without premature ejaculation [PE] [62].
Some attempts have been made in rats to create a premature ejaculation model for detailed study. Based on the number of ejaculations in a 30 min period, a premature and delayed ejaculatory animal model has been proposed [63]. A pharmacological model for premature ejaculation has been developed by administering selective 5-HT1A receptor agonists, including flesinoxan, FG-5893, and 8- OH-DPAT [63,64,65]. These drugs reduce ejaculation time, intromission, and mount frequency; however, the actual mechanism of action of these drugs is not clear.
Waldinger suggested four subtypes of PE: [1] lifelong, [2] acquired, [3] natural variable, and [4] premature-like ejaculatory dysfunction [66]. Lifelong PE, which affects men who have never attained ejaculatory control, but have no erectile or desire difficulties; acquired PE, which affects elderly men and is associated with erectile difficulties; natural variable PE is a normal variation in sexual functioning in which a man will have normal and PE at different periods of time; premature-like ejaculatory dysfunction describes men who present with ejaculatory functioning within the normal range, but their PE occurs due to misunderstandings or partner factors [67].
ETIOPATHOGENESIS OF PREMATURE EJACULATION: Psychological and biological factors have conventionally been responsible for this [68].

4.1. Psychological

Factors include anxiety, depression, guilt, stress, history of sexual suppression, lack of poor body image, sexual abuse, problems in understanding among partners, and early sexual experience [43,48,69,70,71,72]. Anxiety is considered the primary cause of rapid ejaculation. The sympathetic nervous system increases anxiety levels and is responsible for rapid ejaculation, whereas low anxiety delays ejaculation [48]. Depression is significantly correlated with decreased orgasm in patients suffering from myasthenia gravis [73]. Cortisol is a hormone associated with mental stress related to high alertness in stressful situations. A recent study showed a relationship between cortisol, stress, and premature ejaculation [74].

4.2. Biological

Factors include endocrine, genetic, urological, and others [48,69].
The thyroid gland is also an endocrine factor considered in sexual disorders. It has been reported that most animals [75] and patients with thyroid hormone disorders experience sexual dysfunction, such as PE, which can be changed by normalizing thyroid hormone levels [76]. Premature ejaculation is observed in patients with thyroid disorders. However, it decreased from 50% to 15% after 2–4 months of treatment [76]. The hyperthyroid rat ejaculation time was shorter than that of the control and returned to normal after treatment [75]. Excessive thyroid hormone levels cause premature ejaculation, as these are clinically related. A high level of thyroid hormones should be regarded as a reversible and novel causative risk factor for premature ejaculation [77,78].
Thyroid hormone levels and ejaculatory time duration have shown an inverse relationship in different reports. Hyperthyroidism is associated with shorter ejaculatory time or PE, whereas hypothyroidism is strongly accompanied by longer ejaculatory time or delayed ejaculation [76,79]. Previous patient data showed the widespread presence of PE in patients with hyperthyroidism, which was approximately 42.4%. In the aforementioned study, it was observed that thyroid-stimulating hormone [TSH] levels altered ejaculation latency, independent of age and testosterone level. Furthermore, the findings showed that hikes in TSH levels also caused increases in intravaginal ejaculatory delay time [IELT] levels [79]. A study involving 94 healthy men and 107 men with PE concluded that free T4 levels were notably higher in the PE group than in healthy controls [80]. In another case–control study involving 39 control men and 63 men with PE, TSH levels were notably lower in men with PE, however, no significant changes were found in their free T3 or free T4 levels [81]. Based on this evidence, it has been suggested that the connection between hyperthyroidism and PE may be secondary to higher sympathetic activity [76].
Testosterone is considered the principal hormone involved in male gonad formation and ejaculation control. However, there are some contradictory data regarding the correlation between testosterone levels and PE [69]. In a study between men with and without PE, there were no notable differences in the levels of gonadal hormones (luteinizing hormone and free and total testosterone) [82]. In contrast, young patients with PE have been reported to have higher total and free serum testosterone levels. It has been proposed that testosterone plays an excitatory role in ejaculatory control [83]. Another study showed that follicle-stimulating hormones and free testosterone in the serum were elevated in patients who had earlier PE compared with control men [84]. Based on a comprehensive review, there are contradictory results regarding the correlation between PE and testosterone. Therefore, more and larger studies are needed to better understand the relationship between PE and testosterone.
Diabetes mellitus (DM) is another common disease. Diabetes mellitus [DM] is a disorder in which there is a markedly higher level of blood glucose due to insufficient insulin, β-cell dysfunction, insulin resistance, or both [85]. Many animal experiments and human records have shown ejaculatory disorders in diabetes subjects. Due to the differences between normal ejaculation, PE, and anejaculation, it is difficult to explain ejaculatory dysfunction in animals. Many factors affect ejaculation in animals, such as animal type, models formed by different techniques, lab experimental plans, and the number of animals used. Some results show variations in the results of DM model animal experiments. Some experiments showed that there was no change in sexual performance in the control and DM animal models [86,87]. A long ejaculation time or delayed ejaculation has been shown in some animal models [88,89,90]. No ejaculation or anejaculation has been observed in some animal models [91,92]. Some animal models have shown reduced PE ejaculation times [93,94]. These findings suggest that there are various types of ejaculatory dysfunction in animal models. Early insulin replacement has been shown to control seminal emission, suggesting that insulin can play a role in preventing ejaculatory dysfunction. Long-term exposure to glucose may cause permanent ejaculatory dysfunction, which shows that once the dysfunction or the issue begins, late insulin therapy cannot recover normal ejaculation function [95]. Animal studies have shown that hyperglycemia is effective in amending the contractility of the epididymis, vas deferens, seminal vesicles, prostate, bladder neck, and urethra by modulating neurotransmitter release [96,97]. The pathology of ejaculatory dysfunction caused by diabetes can be understood by some experiments that show the effects of experimental diabetes on the emission of semen. Chronically, streptozotocin-diabetic animals showed decreased reaction to stimulation of the sympathetic supply of the vas deferens, which may be due to degenerative changes in the autonomic nervous system [96,98,99]. Moreover, reactive oxygen species (ROS) may be the reason for the reduced sympathetic neurotransmission and unusual function of diabetic vas deferens in streptozotocin-induced diabetic animals [99,100]. Changes in serotonin receptors 5-HT also impair serotonergic transmission to the rat brain in animals with long-term hyperglycemia [101,102]. PE is associated with reduced serotonin neurotransmission [103]. However, the mechanisms by which diabetes causes ejaculatory dysfunction remain unclear. Ejaculatory dysfunction occurs in 40% of men with diabetes [104]. PE was higher in men with diabetes than in those without [78.8% vs. 47.5%, p = 0.001], which indicates the prevalence of PE in individuals with diabetes [105]. ED [erectile dysfunction] is the primary cause of PE in type 2 DM. With this in mind, one study showed that ED was reported in 95% of patients with type 2 diabetes. Furthermore the study also reported that males with a diabetes history of ≥10 years have a 2.7 fold greater likelihood of PE than those with a history of <5 years [106].
Obesity and metabolic syndrome are characterized by a lack of outdoor activities and aging [107,108]. Patients with metabolic syndrome showed a higher prevalence of PE and higher waist circumference, (35.2%) and (51%), respectively, than the control groups (7.6%) and (24%) [109,110]. The mechanism underlying the relationship between metabolic syndrome and PE is not yet fully understood. Some reports have shown that the cause may be depression, since it is known that depression can cause PE and metabolic syndrome [111,112].
Vitamin D is a steroid hormone produced in the skin. It is produced by exposure to sunlight [113]. Administration of 2.5 mg of vitamin D3 completely prevented male rat ejaculation [114]. Vitamin D causes anxiety, which may be a probable cause of PE in vitamin D deficiency patients [115,116]. Vitamin D supplementation after 6 months showed improvement in anxiety symptoms [117].
Genetic factor studies indicate that 5-HT1a receptor gene polymorphisms, the 5-HT transporter gene-linked polymorphic region (5-HTTLPR), and 5-HT2c receptor gene polymorphisms may be involved in the progression of PE [118,119]. Lifelong PE has been genetically determined in some men [120].
Urological factors are part of the urological organs involved in ejaculation (Figure 2). It can be understood that inflammation or disease in these organs may be a cause of ejaculatory dysfunction. Patients with chronic prostatitis may experience PE [121]. The exact pathology connecting prostatitis and PE has not yet been elucidated. However, some researchers have proposed that inflammation of the prostate may lead to changes in the regulation and sensation of the ejaculation reflex via a neurophysiologic pathway [122].
Other factors include low seminal plasma magnesium levels and significantly decreased levels of magnesium in the seminal plasma in PE patients [123]. Lower seminal plasma magnesium levels can cause an increase in thromboxane A2 levels, which in turn causes an increase in endothelial intracellular calcium and a decrease in nitric oxide levels. A decline in nitric oxide levels can cause contraction of the penile muscle, leading to PE [124,125].
Varicocele engorges the testicular veins in men. It is also considered one of the causes of male infertility [126]. Additionally, it is associated with PE in patients [127,128]. The exact mechanism of varicocele and PE is difficult to explain; however, it is speculated that varicocele causes intrapelvic congestion, which causes prostatitis or prostate inflammation. Further protection may lead to changes in the regulation and sensation of the reflex of ejaculation via a neurophysiological pathway [122,129].

5. Retrograde Ejaculation

We have already previously described that ejaculation is a reflex. Retrograde ejaculation causes ejaculatory dysfunction, wherein partial or complete passage of semen enters the urinary bladder rather than passing out through the urethra, which occurs due to complete contraction inhibition of the bladder neck [2]. This effect is due to nerve pathology in the sympathetic nervous system or due to biological injury [130,131]. Approximately 0.3% to 2% of infertility in men is due to RE [132]. It occurs when little or no semen is ejaculated, however, the sensation of orgasm and contraction can be felt at the base of the penis in the ischeo- and bulbo-cavernosus muscles. Patients complain of dry ejaculation if no semen is ejaculated, followed by ‘‘white urine’’ when emptying the urinary bladder. Detection of sperm in the urine is a confirmed diagnostic test for RE [130].
ETIOPATHOGENESIS OF RETROGRADE EJACULATION: These factors are classified as pharmacological,neurogenic and other causes of retrograde ejaculation [133].

5.1. Pharmacologic Factors

RE can be induced in one individual undergoing treatment for lower urinary tract symptoms using an alpha-receptor antagonist. Other drugs used for the treatment of hypertension, antidepressants, and antipsychotics have similar effects. Since it is understood that the sympathetic nerves control the contraction of the bladder neck, any drug that obstructs the shutdown of the bladder neck can lead to partial contraction of the bladder neck and cause RE [14,133,134].

5.2. Neurogenic Factors

Include nerve injury or damage. Spinal cord injury is considered a major neurological factor for RE [133]. In patients with spinal cord injury [SCI], sexual function is one of the top priorities for a good quality of life [135,136]. Other neurogenic factors include multiple sclerosis, myelodysplasia, and the most common type of uncontrolled diabetes that causes neuropathy [137]. Diabetic RE patients have lower intraureteral pressure than healthy individuals with diabetes who have somatic innervation of the outer ureteral sphincter [138]. RE is more regularly linked to the composition of the internal urethral sphincter at the time of prostatectomy or after retroperitoneal lymph node dissection [RPLND] [133].

5.3. Other Factors

BPH (benign prostatic hyperplasia) is the enlargement of prostate gland in elderly male population causing lower urinary tract symptoms (LUTS). There are many evidences showing BPH surgery, one of the causative factor for retrograde ejaculation [139].

6. Delayed Ejaculation and Anejaculation

These are unusual forms of male ejaculatory dysfunction, indicated by a noticeable delay in ejaculation or an inability to achieve ejaculation [55,140]. These are the least commonly studied forms of male ejaculatory dysfunction, with an approximate prevalence of 1–4% in males [141]. Difficulties in defining DE are associated with the fact that orgasm and ejaculations generally occur simultaneously, despite being two different phenomena [140]. An animal model for DE/AE has been developed, as previously described in the PE section [63]. An important clinical feature seen in DE is that men are incapable of ejecting semen during intercourse with a partner, despite reaching orgasm and ejaculating during solo masturbation [141].
ETIOPATHOGENESIS OF DELAYED EJACULATION AND ANEJACULATION:
These factors are psychological and biological.

6.1. Psychological Factors Include Religious Factors, Insufficient Arousal, Masturbation, and Homosexuality

Insufficient arousal: Actual subjective arousal is absent in males, whereas sufficient erection is present; however, orgasm is absent. This type of insufficient arousal causes DE/AE [142]. Drugs that treat erectile dysfunction also cause insufficient arousal and absence of orgasm [140].
Masturbation: This is also a cause of DE/AE. Men who masturbate to achieve sexual satisfaction have individual durations, pressures, speeds, and strengths required to produce an orgasm, and these can differ from those required with a partner. As a result, they consider it impossible or difficult to attain orgasm with their partners [143].
Homosexuality: Men in homosexual situations are said to have a highly elevated prevalence of DE compared to heterosexual men, however this finding is not so precise due to very little work done on it [144,145].

6.2. Biological Factors Include Age, Race, Genetic, Congenital, Endocrine, Neurogenic, Infection/Inflammation, and Pharmacological Factors

Age: This may be linked to a decrease in the sensitivity of the penis, which is due to loss of penile receptors and sensory axons [146,147].
Congenital: The female reproductive organs, such as the oviduct and uterus, are formed by the Müllerian duct during the gestational period. The Wolffian duct gives rise to the kidneys and male reproductive organs [148]. Any inborn deformity of the Wolffian duct or partial remnant of the Müllerian ducts may cause DE/AE [149].
Genetic: Patients taking serotonergic antidepressants have been reported to have sexual dysfunction. There is higher risk of DE/AE in patients who take selective serotonin reuptake inhibitors (SSRI) [150]. Genomic methods can be used to identify genes and possible genetic risk factors for SSRI-induced DE [151].
Neurogenic: Men with multiple sclerosis report DE/AE [152]. In addition, the potential to ejaculate is compromised by SCI. The ejaculation rate was higher in patients with lower motor neuron lesions (15%) than in those with upper motor neuron lesions (5%). The feeling of orgasm or pleasure may be absent or completely lost in patients who are able to successfully ejaculate, which can also cause DE [47]. Retroperitoneal lymph node dissection (RPLND) and bladder neck surgery are also causes of DE [153].
Urinary tract infection, pelvic inflammation, and chronic prostatitis are also causes of DE/AE [154].
Endocrine: A reverse connection has been revealed between thyroid hormone levels and ejaculatory duration. Hypothyroidism is robustly linked to a longer ejaculatory duration in DE/AE [79]. Older men with reduced total testosterone and free testosterone levels showed a higher incidence of DE [83].
Pharmacological: Antidepressant drugs composed of serotonin also cause DE/AE. A seven-fold risk of DE/AE can be observed in selective serotonin reuptake inhibitor (SSRI) users [150].
Prostate cancer: It is the third most common type of cancer diagnosed [155]. Radiation therapy and prostatectomy is the method of treatment for prostate cancer. More than 89% patients reported lack of ejaculation after radiation therapy [156]. Anejaculation is anticipated following prostatectomy because prostate and seminal vesicles are removed [157].

7. Future Directions and Limitations

Male ejaculation and ejaculatory dysfunction remains mostly unexplored topic in the field of scientific study. Spinal ejaculatory generator (SEG) or lumbar spinothalamic neurons offer a highly compliant tool for studying different types of ejaculatory dysfunction. Ejaculation in lab animals can be studied in three different ways.
First is manually allowing the opposite gender animals to mate. Ejaculation in males shows activation of Lst neurons, which can be traced by increased Fos level immediately after ejaculation [25]. Fos level can be examined by immunohistochemistry. Second is mechanical or electrical stimulation of genital structures or dorsal penile nerve, respectively. Stimulation causes contraction of bulbocavernosus or bulbospongiosus muscles. This can be traced by electromyographic study [32,50]. Third is optogenetics, where light is used to stimulate the nerve cells [158]. Optogenetics stimulating ejaculation neurons are also suggested in non-mammalians species [41,42].
Previous attempts explained the use of male rats to create premature and delayed ejaculation models by number of ejaculations in a 30 min period, usage of drugs in pharmacological models of premature and delayed ejaculation [63,64,65]. There is a lack of sufficient findings with these animal models in relation to spinal ejaculatory generator. Pharmacological and biological factors affecting retrograde ejaculation are summarized in this review. Spinal cord injury can be considered as one of the ideal models in animal research because spinal cord injury (SCI) is a devastating neurological disorder, which affects around 250,000 to 500,000 individuals each year [159]. Only 9% of men with SCI can ejaculate by masturbation [160], whereas penile vibratory stimulation or electroejaculation is required by a large population of men with SCI [161,162]. Spinal cord injury model in rats have been used to collect partial ejaculation recovery after infusion of dopamine agonist [163]. However, it is not clear whether it is anterograde ejaculation or retrograde ejaculation.
Limitations of this studies are Fos tracing in spinal cord is a terminal experiment, so we will not be able to get further findings for a second attempt. Frequent stimulation of dorsal penile nerve may not respond to stimulus because after ejaculation, the animal has refractory period during which the response of stimulus cannot be seen [25]. Another limitation is within the animal model, diabetes causes premature ejaculation and also retrograde ejaculation in humans, therefore it may be difficult in finding among animals if they show premature or retrograde ejaculation. Similar is the case with SCI model, where animals can show retrograde or anejaculation in laboratory findings.

8. Conclusions

The identification of a potential spinal ejaculation generator is an important breakthrough in the field of sexual function. Several studies have been conducted to understand the regulation of ejaculation after the identification of a spinal ejaculation generator in rats [23]. Furthermore, recent findings have confirmed the presence of a spinal ejaculation generator in humans [16]. Ejaculation is a complicated process that includes different anatomical and neural compositions as well as large-scale neurochemical and hormonal regulation. As evidenced in this review, sexual problems are one of the major issues in relationships between men and women in our society. It has not been addressed properly, which may be due to the lack of interconnection between human ejaculatory dysfunction and the spinal ejaculatory generator. A detailed study on the different ejaculatory dysfunction types should be conducted in animal models, with the spinal ejaculation generator or lumbar spinothalamic cells at the center of the experiment. The spinal ejaculation generator or lumbar spinothalamic cells present in the L3–L4 region and their activation and inhibition at different time intervals may be the best mechanisms to study in animal models. Ejaculation in animal models can also be predicted by contraction of the bulbocavernosus muscle. Thus, knowledge about spinal ejaculation generators might be useful in the production of different animal models for the different types of ejaculatory dysfunctions discussed in this review.

Author Contributions

Each author has substantially contributed to the study conception, design and first draft of this manuscript. K.K.S., H.-S.J. and S.J. critical reading, commenting. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by grants from the National Research Foundation of Korea (grant numbers NRF-2021R1I1A3060435, and NRF-2020R1F1A1076616); a grant from the Chonnam National University Hospital Biomedical Research Institute (BCRI22051); Chonnam National University (Grant number: 2022-0036) and a grant from the Jeollanam-do Science and Technology R&D Project (Development of Stem Cell-Derived New Drug), funded by the Jeollanam-do, Korea.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest related to this article.

References

  1. Clement, P.; Giuliano, F. Physiology and pharmacology of ejaculation. Basic Clin. Pharmacol. Toxicol. 2016, 119 (Suppl. 3), 18–25. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Revenig, L.; Leung, A.; Hsiao, W. Ejaculatory physiology and pathophysiology: Assessment and treatment in male infertility. Transl. Androl. Urol. 2014, 3, 41–49. [Google Scholar] [CrossRef] [PubMed]
  3. Everaert, K.; de Waard, W.I.; Van Hoof, T.; Kiekens, C.; Mulliez, T.; D’Herde, C. Neuroanatomy and neurophysiology related to sexual dysfunction in male neurogenic patients with lesions to the spinal cord or peripheral nerves. Spinal Cord 2010, 48, 182–191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Shafik, A. Response of the urethral and intracorporeal pressures to cavernosus muscle stimulation: Role of the muscles in erection and ejaculation. Urology 1995, 46, 85–88. [Google Scholar] [CrossRef]
  5. Nemec, E.D.; Mansfield, L.; Kennedy, J.W. Heart rate and blood pressure responses during sexual activity in normal males. Am. Heart J. 1976, 92, 274–277. [Google Scholar] [CrossRef]
  6. Kruger, T.; Exton, M.S.; Pawlak, C.; von zur Muhlen, A.; Hartmann, U.; Schedlowski, M. Neuroendocrine and cardiovascular response to sexual arousal and orgasm in men. Psychoneuroendocrinology 1998, 23, 401–411. [Google Scholar] [CrossRef]
  7. Rowland, D.L. Genital and heart rate response to erotic stimulation in men with and without premature ejaculation. Int. J. Impot. Res. 2010, 22, 318–324. [Google Scholar] [CrossRef] [Green Version]
  8. Coolen, L.M.; Allard, J.; Truitt, W.A.; McKenna, K.E. Central regulation of ejaculation. Physiol. Behav. 2004, 83, 203–215. [Google Scholar] [CrossRef]
  9. Wibowo, E.; Wassersug, R.J. Multiple orgasms in men-what we know so far. Sex Med. Rev. 2016, 4, 136–148. [Google Scholar] [CrossRef]
  10. Arafa, M.M.; Zohdy, W.A.; Shamloul, R. Prostatic massage: A simple method of semen retrieval in men with spinal cord injury. Int. J. Androl. 2007, 30, 170–173. [Google Scholar] [CrossRef]
  11. Sipski, M.; Alexander, C.J.; Gomez-Marin, O. Effects of level and degree of spinal cord injury on male orgasm. Spinal Cord 2006, 44, 798–804. [Google Scholar] [CrossRef] [PubMed]
  12. Lu, S.; Cui, Y.; Li, X.; Zhang, H.; Hu, J.; Liu, J.; Chen, Z.J. Sperm retrieval in anejaculatory diabetic men who failed in drug treatment and penile vibratory stimulation during blood sugar under control. Andrologia 2014, 46, 370–373. [Google Scholar] [CrossRef] [PubMed]
  13. Alwaal, A.; Breyer, B.N.; Lue, T.F. Normal male sexual function: Emphasis on orgasm and ejaculation. Fertil. Steril. 2015, 104, 1051–1060. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Barazani, Y.; Stahl, P.J.; Nagler, H.M.; Stember, D.S. Management of ejaculatory disorders in infertile men. Asian J. Androl. 2012, 14, 525–529. [Google Scholar] [CrossRef] [Green Version]
  15. Beyer, C.; Contreras, J.L.; Morali, G.; Larsson, K. Effects of castration and sex steroid treatment on the motor copulatory pattern of the rat. Physiol. Behav. 1981, 27, 727–730. [Google Scholar] [CrossRef]
  16. Chehensse, C.; Facchinetti, P.; Bahrami, S.; Andrey, P.; Soler, J.M.; Chretien, F.; Bernabe, J.; Clement, P.; Denys, P.; Giuliano, F. Human spinal ejaculation generator. Ann. Neurol. 2017, 81, 35–45. [Google Scholar] [CrossRef]
  17. Pescatori, E.S.; Calabro, A.; Artibani, W.; Pagano, F.; Triban, C.; Italiano, G. Electrical stimulation of the dorsal nerve of the penis evokes reflex tonic erections of the penile body and reflex ejaculatory responses in the spinal rat. J. Urol. 1993, 149, 627–632. [Google Scholar] [CrossRef]
  18. Veening, J.G.; Coolen, L.M. Neural mechanisms of sexual behavior in the male rat: Emphasis on ejaculation-related circuits. Pharmacol. Biochem. Behav. 2014, 121, 170–183. [Google Scholar] [CrossRef]
  19. Sengul, G.; Puchalski, R.B.; Watson, C. Cytoarchitecture of the spinal cord of the postnatal (P4) mouse. Anat. Rec. 2012, 295, 837–845. [Google Scholar] [CrossRef]
  20. Mostafa, T.; Abdel-Hamid, I.A. Ejaculatory dysfunction in men with diabetes mellitus. World J. Diabetes 2021, 12, 954–974. [Google Scholar] [CrossRef]
  21. Morgan, C.; de Groat, W.C.; Nadelhaft, I. The spinal distribution of sympathetic preganglionic and visceral primary afferent neurons that send axons into the hypogastric nerves of the cat. J. Comp. Neurol. 1986, 243, 23–40. [Google Scholar] [CrossRef] [PubMed]
  22. Sakamoto, H. Sexually dimorphic nuclei in the spinal cord control male sexual functions. Front. Neurosci. 2014, 8, 184. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Truitt, W.A.; Coolen, L.M. Identification of a potential ejaculation generator in the spinal cord. Science 2002, 297, 1566–1569. [Google Scholar] [CrossRef] [PubMed]
  24. Oti, T.; Ueda, R.; Kumagai, R.; Nagafuchi, J.; Ito, T.; Sakamoto, T.; Kondo, Y.; Sakamoto, H. Sexual experience induces the expression of gastrin-releasing peptide and oxytocin receptors in the spinal ejaculation generator in rats. Int. J. Mol. Sci. 2021, 22, 10362. [Google Scholar] [CrossRef]
  25. Truitt, W.A.; Shipley, M.T.; Veening, J.G.; Coolen, L.M. Activation of a subset of lumbar spinothalamic neurons after copulatory behavior in male but not female rats. J. Neurosci. 2003, 23, 325–331. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Ju, G.; Melander, T.; Ceccatelli, S.; Hokfelt, T.; Frey, P. Immunohistochemical evidence for a spinothalamic pathway co-containing cholecystokinin- and galanin-like immunoreactivities in the rat. Neuroscience 1987, 20, 439–456. [Google Scholar] [CrossRef]
  27. Xu, C.; Yaici, E.D.; Conrath, M.; Blanchard, P.; Leclerc, P.; Benoit, G.; Verge, D.; Giuliano, F. Galanin and neurokinin-1 receptor immunoreactive [corrected] spinal neurons controlling the prostate and the bulbospongiosus muscle identified by transsynaptic labeling in the rat. Neuroscience 2005, 134, 1325–1341. [Google Scholar] [CrossRef]
  28. Xu, C.; Giuliano, F.; Yaici, E.D.; Conrath, M.; Trassard, O.; Benoit, G.; Verge, D. Identification of lumbar spinal neurons controlling simultaneously the prostate and the bulbospongiosus muscles in the rat. Neuroscience 2006, 138, 561–573. [Google Scholar] [CrossRef]
  29. Sun, X.Q.; Xu, C.; Leclerc, P.; Benoit, G.; Giuliano, F.; Droupy, S. Spinal neurons involved in the control of the seminal vesicles: A transsynaptic labeling study using pseudorabies virus in rats. Neuroscience 2009, 158, 786–797. [Google Scholar] [CrossRef]
  30. Newton, B.W. A sexually dimorphic population of galanin-like neurons in the rat lumbar spinal cord: Functional implications. Neurosci. Lett. 1992, 137, 119–122. [Google Scholar] [CrossRef]
  31. Phan, D.C.; Newton, B.W. Cholecystokinin-8-like immunoreactivity is sexually dimorphic in a midline population of rat lumbar neurons. Neurosci. Lett. 1999, 276, 165–168. [Google Scholar] [CrossRef]
  32. Kozyrev, N.; Coolen, L.M. Activation of galanin and cholecystokinin receptors in the lumbosacral spinal cord is required for ejaculation in male rats. Eur. J. Neurosci. 2017, 45, 846–858. [Google Scholar] [CrossRef] [PubMed]
  33. Nicholas, A.P.; Zhang, X.; Hokfelt, T. An immunohistochemical investigation of the opioid cell column in lamina X of the male rat lumbosacral spinal cord. Neurosci. Lett. 1999, 270, 9–12. [Google Scholar] [CrossRef]
  34. Wiggins, J.W.; Sledd, J.E.; Coolen, L.M. Spinal cord injury causes reduction of galanin and gastrin releasing peptide mRNA expression in the spinal ejaculation generator of male rats. Front. Neurol. 2021, 12, 670536. [Google Scholar] [CrossRef]
  35. Sakamoto, H.; Matsuda, K.; Zuloaga, D.G.; Hongu, H.; Wada, E.; Wada, K.; Jordan, C.L.; Breedlove, S.M.; Kawata, M. Sexually dimorphic gastrin releasing peptide system in the spinal cord controls male reproductive functions. Nat. Neurosci. 2008, 11, 634–636. [Google Scholar] [CrossRef]
  36. Kozyrev, N.; Lehman, M.N.; Coolen, L.M. Activation of gastrin-releasing peptide receptors in the lumbosacral spinal cord is required for ejaculation in male rats. J. Sex Med. 2012, 9, 1303–1318. [Google Scholar] [CrossRef]
  37. Facchinetti, P.; Giuliano, F.; Laurin, M.; Bernabe, J.; Clement, P. Direct brain projections onto the spinal generator of ejaculation in the rat. Neuroscience 2014, 272, 207–216. [Google Scholar] [CrossRef]
  38. Veenstra, J.A. Isolation and structure of corazonin, a cardioactive peptide from the American cockroach. FEBS Lett. 1989, 250, 231–234. [Google Scholar] [CrossRef] [Green Version]
  39. Pan, Y.; Robinett, C.C.; Baker, B.S. Turning males on: Activation of male courtship behavior in Drosophila melanogaster. PLoS ONE 2011, 6, e21144. [Google Scholar] [CrossRef] [Green Version]
  40. Khan, Z.; Tondravi, M.; Oliver, R.; Vonhoff, F.J. Drosophila corazonin neurons as a hub for regulating growth, stress responses, ethanol-related behaviors, copulation persistence and sexually dimorphic reward pathways. J. Dev. Biol. 2021, 9, 26. [Google Scholar] [CrossRef]
  41. Zer-Krispil, S.; Zak, H.; Shao, L.; Ben-Shaanan, S.; Tordjman, L.; Bentzur, A.; Shmueli, A.; Shohat-Ophir, G. Ejaculation induced by the activation of crz neurons is rewarding to Drosophila males. Curr. Biol. 2018, 28, 1445–1452.e1443. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Tayler, T.D.; Pacheco, D.A.; Hergarden, A.C.; Murthy, M.; Anderson, D.J. A neuropeptide circuit that coordinates sperm transfer and copulation duration in Drosophila. Proc. Natl. Acad. Sci. USA 2012, 109, 20697–20702. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Porst, H.; Burri, A. Fortacin spray for the treatment of premature ejaculation. Urologia 2017, 84, 1–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Federighi, G.; Asteriti, S.; Cangiano, L. Lumbar spinal cord neurons putatively involved in ejaculation are sexually dimorphic in early postnatal mice. J. Comp. Neurol. 2020, 528, 624–636. [Google Scholar] [CrossRef]
  45. Master, V.A.; Turek, P.J. Ejaculatory physiology and dysfunction. Urol. Clin. N. Am. 2001, 28, 363–375. [Google Scholar] [CrossRef]
  46. Deeh Defo, P.B.; Asongu, E.; Wankeu, M.N.; Ngadjui, E.; Bonsou Fazin, G.R.; Kemka, F.X.; Carro-Juarez, M.; Kamanyi, A.; Kamtchouing, P.; Watcho, P. Guibourtia tessmannii-induced fictive ejaculation in spinal male rat: Involvement of D1, D2-like receptors. Pharm. Biol. 2017, 55, 1138–1143. [Google Scholar] [CrossRef] [Green Version]
  47. Comarr, A.E. Sexual function among patients with spinal cord injury. Urol. Int. 1970, 25, 134–168. [Google Scholar] [CrossRef]
  48. El-Hamd, M.A.; Saleh, R.; Majzoub, A. Premature ejaculation: An update on definition and pathophysiology. Asian J..Androl. 2019, 21, 425–432. [Google Scholar] [CrossRef]
  49. Bettocchi, C.; Verze, P.; Palumbo, F.; Arcaniolo, D.; Mirone, V. Ejaculatory disorders: Pathophysiology and management. Nat. Clin. Pract. Urol. 2008, 5, 93–103. [Google Scholar] [CrossRef]
  50. Carro-Juarez, M.; Rodriguez-Manzo, G.; de Lourdes Rodriguez Pena, M.; Franco, M.A. Rhythmic motor patterns accompanying ejaculation in spinal cord-transected male rats. Int. J. Impot. Res. 2014, 26, 191–195. [Google Scholar] [CrossRef]
  51. Gerstenberg, T.C.; Levin, R.J.; Wagner, G. Erection and ejaculation in man. Assessment of the electromyographic activity of the bulbocavernosus and ischiocavernosus muscles. Br. J. Urol. 1990, 65, 395–402. [Google Scholar] [CrossRef]
  52. Sung, H.H.; Kim, J.J.; Han, D.H.; Kang, S.J.; Chae, M.R.; Kim, C.Y.; Park, J.K.; Lee, S.W. New methodology for investigating ejaculation dysfunction: Measuring intraluminal seminal vesicle pressure in rats with a telemetric device. J. Sex Med. 2015, 12, 2134–2140. [Google Scholar] [CrossRef]
  53. Puppo, V.; Puppo, G. Comprehensive review of the anatomy and physiology of male ejaculation: Premature ejaculation is not a disease. Clin. Anat. 2016, 29, 111–119. [Google Scholar] [CrossRef]
  54. Masugi-Tokita, M.; Tomita, K.; Kobayashi, K.; Yoshida, T.; Kageyama, S.; Sakamoto, H.; Kawauchi, A. Metabotropic glutamate receptor subtype 7 is essential for ejaculation. Mol. Neurobiol. 2020, 57, 5208–5218. [Google Scholar] [CrossRef]
  55. Abdel-Hamid, I.A.; Ali, O.I. Delayed ejaculation: Pathophysiology, diagnosis, and treatment. World J. Mens Health 2018, 36, 22–40. [Google Scholar] [CrossRef]
  56. Gray, M.; Zillioux, J.; Khourdaji, I.; Smith, R.P. Contemporary management of ejaculatory dysfunction. Transl. Androl. Urol. 2018, 7, 686–702. [Google Scholar] [CrossRef]
  57. Hu, J.; Nagao, K.; Tai, T.; Kobayashi, H.; Nakajima, K. Randomized crossover trial of amoxapine versus vitamin B12 for retrograde ejaculation. Int. Braz. J. Urol. 2017, 43, 496–504. [Google Scholar] [CrossRef]
  58. Jannini, E.A.; Lenzi, A. Ejaculatory disorders: Epidemiology and current approaches to definition, classification and subtyping. World J. Urol. 2005, 23, 68–75. [Google Scholar] [CrossRef]
  59. Wolters, J.P.; Hellstrom, W.J. Current concepts in ejaculatory dysfunction. Rev. Urol. 2006, 8 (Suppl. 4), S18–S25. [Google Scholar]
  60. Lee, S.W.; Lee, J.H.; Sung, H.H.; Park, H.J.; Park, J.K.; Choi, S.K.; Kam, S.C. The prevalence of premature ejaculation and its clinical characteristics in Korean men according to different definitions. Int. J. Impot. Res. 2013, 25, 12–17. [Google Scholar] [CrossRef]
  61. Tiefer, L. Medicine, sexual norms, and the role of the DSM. Virtual Mentor 2014, 16, 923–927. [Google Scholar] [CrossRef] [Green Version]
  62. Althof, S.E.; McMahon, C.G.; Waldinger, M.D.; Serefoglu, E.C.; Shindel, A.W.; Adaikan, P.G.; Becher, E.; Dean, J.; Giuliano, F.; Hellstrom, W.J.; et al. An update of the international society of sexual medicine’s guidelines for the giagnosis and treatment of premature ejaculation (PE). Sex Med. 2014, 2, 60–90. [Google Scholar] [CrossRef] [Green Version]
  63. Waldinger, M.D.; Olivier, B. Animal models of premature and retarded ejaculation. World J. Urol. 2005, 23, 115–118. [Google Scholar] [CrossRef]
  64. Andersson, G.; Larsson, K. Effects of FG 5893, a new compound with 5-HT1A receptor agonistic and 5-HT2 receptor antagonistic properties, on male rat sexual behavior. Eur. J. Pharmacol. 1994, 255, 131–137. [Google Scholar] [CrossRef]
  65. Haensel, S.M.; Slob, A.K. Flesinoxan: A prosexual drug for male rats. Eur. J. Pharmacol. 1997, 330, 1–9. [Google Scholar] [CrossRef]
  66. Waldinger, M.D. Premature ejaculation: Definition and drug treatment. Drugs 2007, 67, 547–568. [Google Scholar] [CrossRef]
  67. Wincze, J.P. Psychosocial aspects of ejaculatory dysfunction and male reproduction. Fertil. Steril. 2015, 104, 1089–1094. [Google Scholar] [CrossRef] [Green Version]
  68. Waldinger, M.D. Recent advances in the classification, neurobiology and treatment of premature ejaculation. Adv. Psychosom. Med. 2008, 29, 50–69. [Google Scholar] [CrossRef]
  69. Coskuner, E.R.; Ozkan, B. Premature ejaculation and endocrine disorders: A literature review. World J. Mens Health 2022, 40, 38–51. [Google Scholar] [CrossRef]
  70. Xia, Y.; Li, J.; Shan, G.; Qian, H.; Wang, T.; Wu, W.; Chen, J.; Liu, L. Relationship between premature ejaculation and depression: A PRISMA-compliant systematic review and meta-analysis. Medicine 2016, 95, e4620. [Google Scholar] [CrossRef]
  71. Mourikis, I.; Antoniou, M.; Matsouka, E.; Vousoura, E.; Tzavara, C.; Ekizoglou, C.; Papadimitriou, G.N.; Vaidakis, N.; Zervas, I.M. Anxiety and depression among Greek men with primary erectile dysfunction and premature ejaculation. Ann. Gen. Psychiatry 2015, 14, 34. [Google Scholar] [CrossRef] [Green Version]
  72. Son, H.; Song, S.H.; Lee, J.Y.; Paick, J.S. Relationship between premature ejaculation and depression in Korean males. J. Sex Med. 2011, 8, 2062–2070. [Google Scholar] [CrossRef]
  73. Wang, J.; Yan, C.; Zhao, Z.; Chen, H.; Shi, Z.; Du, Q.; Zhang, Y.; Qiu, Y.; Lang, Y.; Kong, L.; et al. Sexual dysfunction in patients with myasthenia gravis. J. Neuroimmunol. 2021, 358, 577669. [Google Scholar] [CrossRef]
  74. Fiala, L.; Lenz, J.; Konecna, P.; Zajicova, M.; Cerna, J.; Sajdlova, R. Premature ejaculation and stress. Andrologia 2021, 53, e14093. [Google Scholar] [CrossRef]
  75. Cihan, A.; Murat, N.; Demir, O.; Aslan, G.; Demir, T.; Gidener, S.; Esen, A.A. An experimental approach to the interrelationship between hyperthyroidism and ejaculation latency time in male rats. J. Urol. 2009, 181, 907–912. [Google Scholar] [CrossRef]
  76. Carani, C.; Isidori, A.M.; Granata, A.; Carosa, E.; Maggi, M.; Lenzi, A.; Jannini, E.A. Multicenter study on the prevalence of sexual symptoms in male hypo- and hyperthyroid patients. J. Clin. Endocrinol. Metab. 2005, 90, 6472–6479. [Google Scholar] [CrossRef]
  77. Cihan, A.; Demir, O.; Demir, T.; Aslan, G.; Comlekci, A.; Esen, A. The relationship between premature ejaculation and hyperthyroidism. J. Urol. 2009, 181, 1273–1280. [Google Scholar] [CrossRef]
  78. Cihan, A.; Esen, A.A. Systematic review and meta-analysis for the value of thyroid disorder screening in men with ejaculatory dysfunction. Int. J. Clin. Pract. 2021, 75, e14419. [Google Scholar] [CrossRef]
  79. Corona, G.; Jannini, E.A.; Lotti, F.; Boddi, V.; De Vita, G.; Forti, G.; Lenzi, A.; Mannucci, E.; Maggi, M. Premature and delayed ejaculation: Two ends of a single continuum influenced by hormonal milieu. Int. J. Androl. 2011, 34, 41–48. [Google Scholar] [CrossRef]
  80. Ozturk, M.I.; Koca, O.; Tuken, M.; Keles, M.O.; Ilktac, A.; Karaman, M.I. Hormonal evaluation in premature ejaculation. Urol. Int. 2012, 88, 454–458. [Google Scholar] [CrossRef]
  81. Canat, L.; Erbin, A.; Canat, M.; Dinek, M.; Caskurlu, T. Assessment of hormonal activity in patients with premature ejaculation. Int. Braz. J. Urol. 2017, 43, 311–316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Pirke, K.M.; Kockott, G.; Aldenhoff, J.; Besinger, U.; Feil, W. Pituitary gonadal system function in patients with erectile impotence and premature ejaculation. Arch. Sex Behav. 1979, 8, 41–48. [Google Scholar] [CrossRef]
  83. Corona, G.; Jannini, E.A.; Mannucci, E.; Fisher, A.D.; Lotti, F.; Petrone, L.; Balercia, G.; Bandini, E.; Chiarini, V.; Forti, G.; et al. Different testosterone levels are associated with ejaculatory dysfunction. J. Sex Med. 2008, 5, 1991–1998. [Google Scholar] [CrossRef] [PubMed]
  84. Mohseni, M.G.; Hosseini, S.R.; Alizadeh, F.; Rangzan, N. Serum testosterone and gonadotropins levels in patients with premature ejaculation: A comparison with normal men. Adv. Biomed Res. 2014, 3, 6. [Google Scholar] [CrossRef] [PubMed]
  85. Olokoba, A.B.; Obateru, O.A.; Olokoba, L.B. Type 2 diabetes mellitus: A review of current trends. Oman Med. J. 2012, 27, 269–273. [Google Scholar] [CrossRef] [PubMed]
  86. Clark, J.T. Sexual function in altered physiological states: Comparison of effects of hypertension, diabetes, hyperprolactinemia, and others to “normal” aging in male rats. Neurosci. Biobehav. Rev. 1995, 19, 279–302. [Google Scholar] [CrossRef]
  87. Scarano, W.R.; Messias, A.G.; Oliva, S.U.; Klinefelter, G.R.; Kempinas, W.G. Sexual behaviour, sperm quantity and quality after short-term streptozotocin-induced hyperglycaemia in rats. Int. J. Androl. 2006, 29, 482–488. [Google Scholar] [CrossRef]
  88. De, A.; Singh, M.F.; Singh, V.; Ram, V.; Bisht, S. Treatment effect of l-norvaline on the sexual performance of male rats with streptozotocin induced diabetes. Eur. J. Pharmacol. 2016, 771, 247–254. [Google Scholar] [CrossRef]
  89. Shi, G.J.; Zheng, J.; Wu, J.; Qiao, H.Q.; Chang, Q.; Niu, Y.; Sun, T.; Li, Y.X.; Yu, J.Q. Protective effects of Lycium barbarum polysaccharide on male sexual dysfunction and fertility impairments by activating hypothalamic pituitary gonadal axis in streptozotocin-induced type-1 diabetic male mice. Endocr. J. 2017, 64, 907–922. [Google Scholar] [CrossRef] [Green Version]
  90. Li, Z.M.; Liu, N.; Jiang, Y.P.; Yang, J.M.; Zheng, J.; Sun, M.; Li, Y.X.; Sun, T.; Wu, J.; Yu, J.Q. Vitexin alleviates streptozotocin-induced sexual dysfunction and fertility impairments in male mice via modulating the hypothalamus-pituitary-gonadal axis. Chem. Biol. Interact. 2019, 297, 119–129. [Google Scholar] [CrossRef]
  91. Pontes, D.A.; Fernandes, G.S.; Piffer, R.C.; Gerardin, D.C.; Pereira, O.C.; Kempinas, W.G. Ejaculatory dysfunction in streptozotocin-induced diabetic rats: The role of testosterone. Pharmacol. Rep. 2011, 63, 130–138. [Google Scholar] [CrossRef] [Green Version]
  92. Lert-Amornpat, T.; Maketon, C.; Fungfuang, W. Effect of Kaempferia parviflora on sexual performance in streptozotocin-induced diabetic male rats. Andrologia 2017, 49, e12770. [Google Scholar] [CrossRef] [Green Version]
  93. Ghaheri, M.; Miraghaee, S.; Babaei, A.; Mohammadi, B.; Kahrizi, D.; Saivosh Haghighi, Z.M.; Bahrami, G. Effect of Stevia rebaudiana Bertoni extract on sexual dysfunction in streptozotocin-induced diabetic male rats. Cell Mol. Biol. 2018, 64, 6–10. [Google Scholar] [CrossRef] [PubMed]
  94. Minaz, N.; Razdan, R.; Hammock, B.D.; Mujwar, S.; Goswami, S.K. Impact of diabetes on male sexual function in streptozotocin-induced diabetic rats: Protective role of soluble epoxide hydrolase inhibitor. Biomed. Pharm. 2019, 115, 108897. [Google Scholar] [CrossRef] [PubMed]
  95. Yonezawa, A.; Ebiko, M.; Yoshizumi, M.; Ise, S.N.; Watanabe, C.; Mizoguchi, H.; Iwasaki, M.; Kimura, Y.; Sakurada, S. Effects of insulin replacement on ejaculatory dysfunction in streptozotocin-induced diabetic rats. Int. J. Urol. 2009, 16, 208–211. [Google Scholar] [CrossRef] [PubMed]
  96. Longhurst, P.A.; Brotcke, T.P.; Burrell, C.L.; Belis, J.A. Comparison of the effects of castration and streptozotocin-induced diabetes mellitus on contractile responses of the rat vas deferens. Pharmacology 1989, 38, 253–262. [Google Scholar] [CrossRef]
  97. Kaschube, M.; Moller-Hartmann, H.; Zetler, G. The field-stimulated vas deferens of the streptozotocin-diabetic mouse: Effects of prazosin, alpha, beta-methylene ATP, and variation of stimulation parameters. J. Neural Transm. 1989, 77, 171–180. [Google Scholar] [CrossRef]
  98. Kamata, K.; Kirisawa, H. Changes in electrophysiological properties and noradrenaline response in vas deferens of diabetic rats. Eur. J. Pharmacol. 1998, 350, 237–241. [Google Scholar] [CrossRef]
  99. Gunes, A.; Ceylan, A.; Sarioglu, Y.; Stefek, M.; Bauer, V.; Karasu, C. Antioxidants in diabetes-induced complications study group. Reactive oxygen species mediate abnormal contractile response to sympathetic nerve stimulation and noradrenaline in the vas deferens of chronically diabetic rats: Effects of in vivo treatment with antioxidants. Fundam. Clin. Pharmacol. 2005, 19, 73–79. [Google Scholar] [CrossRef]
  100. Tsounapi, P.; Honda, M.; Dimitriadis, F.; Shimizu, S.; Shiomi, T.; Hikita, K.; Saito, M.; Tomita, S.; Sofikitis, N.; Takenaka, A. Antioxidant treatment ameliorates diabetes-induced dysfunction of the vas deferens in a rat model. Andrologia 2018, 50, e12795. [Google Scholar] [CrossRef]
  101. Sandrini, M.; Vitale, G.; Vergoni, A.V.; Ottani, A.; Bertolini, A. Streptozotocin-induced diabetes provokes changes in serotonin concentration and on 5-HT1A and 5-HT2 receptors in the rat brain. Life Sci. 1997, 60, 1393–1397. [Google Scholar] [CrossRef]
  102. Abraham, P.M.; Anju, T.R.; Jayanarayanan, S.; Paulose, C.S. Serotonergic receptor upregulation in cerebral cortex and down regulation in brainstem of streptozotocin induced diabetic rats: Antagonism by pyridoxine and insulin. Neurosci. Lett. 2010, 483, 23–27. [Google Scholar] [CrossRef] [PubMed]
  103. Martin-Tuite, P.; Shindel, A.W. Management options for premature ejaculation and delayed ejaculation in men. Sex Med. Rev. 2020, 8, 473–485. [Google Scholar] [CrossRef]
  104. Dunsmuir, W.D.; Holmes, S.A. The aetiology and management of erectile, ejaculatory, and fertility problems in men with diabetes mellitus. Diabet. Med. 1996, 13, 700–708. [Google Scholar] [CrossRef]
  105. Majzoub, A.; Arafa, M.; Al-Said, S.; Dabbous, Z.; Aboulsoud, S.; Khalafalla, K.; Elbardisi, H. Premature ejaculation in type II diabetes mellitus patients: Association with glycemic control. Transl. Androl. Urol. 2016, 5, 248–254. [Google Scholar] [CrossRef] [Green Version]
  106. El-Sakka, A.I. Premature ejaculation in non-insulin-dependent diabetic patients. Int. J. Androl. 2003, 26, 329–334. [Google Scholar] [CrossRef]
  107. Hammarsten, J.; Peeker, R. Urological aspects of the metabolic syndrome. Nat. Rev. Urol. 2011, 8, 483–494. [Google Scholar] [CrossRef]
  108. Lee, R.K.; Chung, D.; Chughtai, B.; Te, A.E.; Kaplan, S.A. Central obesity as measured by waist circumference is predictive of severity of lower urinary tract symptoms. BJU Int. 2012, 110, 540–545. [Google Scholar] [CrossRef]
  109. Salama, N.; Eid, A.; Swedan, A.; Hatem, A. Increased prevalence of premature ejaculation in men with metabolic syndrome. Aging Male 2017, 20, 89–95. [Google Scholar] [CrossRef]
  110. Bolat, D.; Kocabas, G.U.; Gunlusoy, B.; Aydogdu, O.; Aydin, M.E. The relationship between acquired premature ejaculation and metabolic syndrome: A prospective, comparative study. Int. J. Impot. Res. 2017, 29, 105–109. [Google Scholar] [CrossRef]
  111. Pan, A.; Keum, N.; Okereke, O.I.; Sun, Q.; Kivimaki, M.; Rubin, R.R.; Hu, F.B. Bidirectional association between depression and metabolic syndrome: A systematic review and meta-analysis of epidemiological studies. Diabetes Care 2012, 35, 1171–1180. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Skilton, M.R.; Moulin, P.; Terra, J.L.; Bonnet, F. Associations between anxiety, depression, and the metabolic syndrome. Biol. Psychiatry 2007, 62, 1251–1257. [Google Scholar] [CrossRef] [PubMed]
  113. Holick, M.F. Resurrection of vitamin D deficiency and rickets. J. Clin. Investig. 2006, 116, 2062–2072. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Mirzahosseini, S.; Karabelyos, C.; Dobozy, O.; Csaba, G. Changes in sexual behavior of adult male and female rats neonatally treated with vitamin D3. Hum. Exp. Toxicol. 1996, 15, 573–576. [Google Scholar] [CrossRef]
  115. Hartmann, U.; Schedlowski, M.; Kruger, T.H. Cognitive and partner-related factors in rapid ejaculation: Differences between dysfunctional and functional men. World J. Urol. 2005, 23, 93–101. [Google Scholar] [CrossRef] [PubMed]
  116. Groves, N.J.; Kesby, J.P.; Eyles, D.W.; McGrath, J.J.; Mackay-Sim, A.; Burne, T.H. Adult vitamin D deficiency leads to behavioural and brain neurochemical alterations in C57BL/6J and BALB/c mice. Behav. Brain Res. 2013, 241, 120–131. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Zhu, C.; Zhang, Y.; Wang, T.; Lin, Y.; Yu, J.; Xia, Q.; Zhu, P.; Zhu, D.M. Vitamin D supplementation improves anxiety but not depression symptoms in patients with vitamin D deficiency. Brain Behav. 2020, 10, e01760. [Google Scholar] [CrossRef]
  118. Yang, D.W.; Sun, J. Correlation of lifelong premature ejaculation with 5-HT system gene polymorphism. Zhonghua Nan Ke Xue 2021, 27, 748–752. [Google Scholar]
  119. Waldinger, M.D. The neurobiological approach to premature ejaculation. J. Urol. 2002, 168, 2359–2367. [Google Scholar] [CrossRef]
  120. Waldinger, M.D.; Rietschel, M.; Nothen, M.M.; Hengeveld, M.W.; Olivier, B. Familial occurrence of primary premature ejaculation. Psychiatr. Genet. 1998, 8, 37–40. [Google Scholar] [CrossRef]
  121. Liang, C.Z.; Hao, Z.Y.; Li, H.J.; Wang, Z.P.; Xing, J.P.; Hu, W.L.; Zhang, T.F.; Ge, W.W.; Zhang, X.S.; Zhou, J.; et al. Prevalence of premature ejaculation and its correlation with chronic prostatitis in Chinese men. Urology 2010, 76, 962–966. [Google Scholar] [CrossRef] [PubMed]
  122. Jannini, E.A.; Simonelli, C.; Lenzi, A. Disorders of ejaculation. J. Endocrinol. Investig. 2002, 25, 1006–1019. [Google Scholar] [CrossRef] [PubMed]
  123. Nikoobakht, M.; Aloosh, M.; Hasani, M. Seminal plasma magnesium and premature ejaculation: A case-control study. Urol. J. 2005, 2, 102–105. [Google Scholar] [CrossRef]
  124. Omu, A.E.; Al-Bader, A.A.; Dashti, H.; Oriowo, M.A. Magnesium in human semen: Possible role in premature ejaculation. Arch. Androl. 2001, 46, 59–66. [Google Scholar] [CrossRef]
  125. Aloosh, M.; Hassani, M.; Nikoobakht, M. Seminal plasma magnesium and premature ejaculation: A case-control study. BJU Int. 2006, 98, 402–404. [Google Scholar] [CrossRef]
  126. Soni, K.K.; Zhang, L.T.; Choi, B.R.; Karna, K.K.; You, J.H.; Shin, Y.S.; Lee, S.W.; Kim, C.Y.; Zhao, C.; Chae, H.J.; et al. Protective effect of MOTILIPERM in varicocele-induced oxidative injury in rat testis by activating phosphorylated inositol requiring kinase 1alpha (p-IRE1alpha) and phosphorylated c-Jun N-terminal kinase (p-JNK) pathways. Pharm. Biol. 2018, 56, 94–103. [Google Scholar] [CrossRef]
  127. Lotti, F.; Corona, G.; Mancini, M.; Biagini, C.; Colpi, G.M.; Innocenti, S.D.; Filimberti, E.; Gacci, M.; Krausz, C.; Sforza, A.; et al. The association between varicocele, premature ejaculation and prostatitis symptoms: Possible mechanisms. J. Sex Med. 2009, 6, 2878–2887. [Google Scholar] [CrossRef] [Green Version]
  128. Ahmed, A.F.; Abdel-Aziz, A.S.; Maarouf, A.M.; Ali, M.; Emara, A.A.; Gomaa, A. Impact of varicocelectomy on premature ejaculation in varicocele patients. Andrologia 2015, 47, 276–281. [Google Scholar] [CrossRef]
  129. Sakamoto, H.; Ogawa, Y. Is varicocele associated with underlying venous abnormalities? varicocele and the prostatic venous plexus. J. Urol. 2008, 180, 1427–1431. [Google Scholar] [CrossRef]
  130. Gupta, S.; Sharma, R.; Agarwal, A.; Parekh, N.; Finelli, R.; Shah, R.; Kandil, H.; Saleh, R.; Arafa, M.; Ko, E.; et al. A comprehensive guide to sperm recovery in infertile men with retrograde ejaculation. World J. Mens Health 2021, 40, 208–216. [Google Scholar] [CrossRef]
  131. Yavetz, H.; Yogev, L.; Hauser, R.; Lessing, J.B.; Paz, G.; Homonnai, Z.T. Retrograde ejaculation. Hum. Reprod. 1994, 9, 381–386. [Google Scholar] [CrossRef] [PubMed]
  132. Jefferys, A.; Siassakos, D.; Wardle, P. The management of retrograde ejaculation: A systematic review and update. Fertil. Steril. 2012, 97, 306–312. [Google Scholar] [CrossRef] [PubMed]
  133. Parnham, A.; Serefoglu, E.C. Retrograde ejaculation, painful ejaculation and hematospermia. Transl. Androl. Urol. 2016, 5, 592–601. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Hisasue, S.; Furuya, R.; Itoh, N.; Kobayashi, K.; Furuya, S.; Tsukamoto, T. Ejaculatory disorder caused by alpha-1 adrenoceptor antagonists is not retrograde ejaculation but a loss of seminal emission. Int. J. Urol. 2006, 13, 1311–1316. [Google Scholar] [CrossRef] [PubMed]
  135. Anderson, K.D. Targeting recovery: Priorities of the spinal cord-injured population. J. Neurotrauma 2004, 21, 1371–1383. [Google Scholar] [CrossRef] [PubMed]
  136. Steadman, C.J.; Vangoor, S.S.; Hubscher, C.H. Telemetric monitoring of penile pressure during mating in rats after chronic spinal cord injury. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2019, 317, R673–R683. [Google Scholar] [CrossRef]
  137. Mehta, A.; Sigman, M. Management of the dry ejaculate: A systematic review of aspermia and retrograde ejaculation. Fertil. Steril. 2015, 104, 1074–1081. [Google Scholar] [CrossRef]
  138. Ibragimov, A.Z.; Aliev, T.A.; Abdullaev, K.I.; Mirza-Zade, V.A. The function of the closure apparatus of the bladder in retrograde ejaculation in diabetics. Urol. Nefrol. 1990, 3, 65–68. [Google Scholar]
  139. Couteau, N.; Duquesne, I.; Frederic, P.; Thiounn, N.; Timsit, M.O.; Mejean, A.; Pinar, U.; Audenet, F. Ejaculations and benign prostatic hyperplasia: An impossible compromise? a comprehensive review. J. Clin. Med. 2021, 10, 5788. [Google Scholar] [CrossRef]
  140. Chen, J. The pathophysiology of delayed ejaculation. Transl. Androl. Urol. 2016, 5, 549–562. [Google Scholar] [CrossRef] [Green Version]
  141. Perelman, M.A. Patient highlights. Delayed ejaculation. J. Sex Med. 2013, 10, 1189–1190. [Google Scholar] [CrossRef]
  142. Rowland, D.L.; Keeney, C.; Slob, A.K. Sexual response in men with inhibited or retarded ejaculation. Int. J. Impot. Res. 2004, 16, 270–274. [Google Scholar] [CrossRef] [PubMed]
  143. Perelman, M.A.; Rowland, D.L. Retarded ejaculation. World J. Urol. 2006, 24, 645–652. [Google Scholar] [CrossRef] [PubMed]
  144. Jern, P.; Santtila, P.; Johansson, A.; Alanko, K.; Salo, B.; Sandnabba, N.K. Is there an association between same-sex sexual experience and ejaculatory dysfunction? J. Sex Marital. Ther. 2010, 36, 303–312. [Google Scholar] [CrossRef] [PubMed]
  145. Bancroft, J.; Carnes, L.; Janssen, E.; Goodrich, D.; Long, J.S. Erectile and ejaculatory problems in gay and heterosexual men. Arch. Sex Behav. 2005, 34, 285–297. [Google Scholar] [CrossRef] [PubMed]
  146. Edwards, A.E.; Husted, J.R. Penile sensitivity, age, and sexual behavior. J. Clin. Psychol. 1976, 32, 697–700. [Google Scholar] [CrossRef]
  147. Rowland, D.L. Penile sensitivity in men: A composite of recent findings. Urology 1998, 52, 1101–1105. [Google Scholar] [CrossRef]
  148. Chiga, M.; Ohmori, T.; Ohba, T.; Katabuchi, H.; Nishinakamura, R. Preformed wolffian duct regulates mullerian duct elongation independently of canonical wnt signaling or lhx1 expression. Int. J. Dev. Biol. 2014, 58, 663–668. [Google Scholar] [CrossRef] [Green Version]
  149. Phillips, E.; Carpenter, C.; Oates, R.D. Ejaculatory dysfunction. Urol. Clin. North Am. 2014, 41, 115–128. [Google Scholar] [CrossRef] [Green Version]
  150. Corona, G.; Ricca, V.; Bandini, E.; Mannucci, E.; Lotti, F.; Boddi, V.; Rastrelli, G.; Sforza, A.; Faravelli, C.; Forti, G.; et al. Selective serotonin reuptake inhibitor-induced sexual dysfunction. J. Sex Med. 2009, 6, 1259–1269. [Google Scholar] [CrossRef]
  151. Bishop, J.R.; Moline, J.; Ellingrod, V.L.; Schultz, S.K.; Clayton, A.H. Serotonin 2A-1438 G/A and G-protein Beta3 subunit C825T polymorphisms in patients with depression and SSRI-associated sexual side-effects. Neuropsychopharmacology 2006, 31, 2281–2288. [Google Scholar] [CrossRef] [PubMed]
  152. Redelman, M.J. Sexual difficulties for persons with multiple sclerosis in New South Wales, Australia. Int. J. Rehabil. Res. 2009, 32, 337–347. [Google Scholar] [CrossRef] [PubMed]
  153. Kamischke, A.; Nieschlag, E. Update on medical treatment of ejaculatory disorders. Int. J. Androl. 2002, 25, 333–344. [Google Scholar] [CrossRef] [PubMed]
  154. Tuncel, A.; Akbulut, Z.; Atan, A.; Basar, M.M. Common symptoms in men with prostatic inflammation. Int. Urol. Nephrol. 2006, 38, 583–586. [Google Scholar] [CrossRef] [PubMed]
  155. Giona, S. The epidemiology of prostate cancer. In Prostate Cancer; Bott, S.R.J., Ng, K.L., Eds.; Exon Publications: Brisbane, QLD, Australia, 2021; pp. 1–15. [Google Scholar]
  156. Green, T.P.; Saavedra-Belaunde, J.; Wang, R. Ejaculatory and orgasmic dysfunction following prostate cancer therapy: Clinical management. Med. Sci. 2019, 7, 109. [Google Scholar] [CrossRef] [Green Version]
  157. Benson, C.R.; Serefoglu, E.C.; Hellstrom, W.J. Sexual dysfunction following radical prostatectomy. J. Androl. 2012, 33, 1143–1154. [Google Scholar] [CrossRef]
  158. Uta, D.; Oti, T.; Sakamoto, T.; Sakamoto, H. In vivo electrophysiology of peptidergic neurons in deep layers of the lumbar spinal cord after optogenetic stimulation of hypothalamic paraventricular oxytocin neurons in rats. Int. J. Mol. Sci. 2021, 22, 3400. [Google Scholar] [CrossRef]
  159. Quadri, S.A.; Farooqui, M.; Ikram, A.; Zafar, A.; Khan, M.A.; Suriya, S.S.; Claus, C.F.; Fiani, B.; Rahman, M.; Ramachandran, A.; et al. Recent update on basic mechanisms of spinal cord injury. Neurosurg. Rev. 2020, 43, 425–441. [Google Scholar] [CrossRef]
  160. Kathiresan, A.S.; Ibrahim, E.; Modh, R.; Aballa, T.C.; Lynne, C.M.; Brackett, N.L. Semen quality in ejaculates produced by masturbation in men with spinal cord injury. Spinal Cord 2012, 50, 891–894. [Google Scholar] [CrossRef] [Green Version]
  161. Brackett, N.L.; Ibrahim, E.; Iremashvili, V.; Aballa, T.C.; Lynne, C.M. Treatment for ejaculatory dysfunction in men with spinal cord injury: An 18-year single center experience. J. Urol. 2010, 183, 2304–2308. [Google Scholar] [CrossRef]
  162. Chehensse, C.; Bahrami, S.; Denys, P.; Clement, P.; Bernabe, J.; Giuliano, F. The spinal control of ejaculation revisited: A systematic review and meta-analysis of anejaculation in spinal cord injured patients. Hum. Reprod. Update 2013, 19, 507–526. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Kozyrev, N.; Staudt, M.D.; Brown, A.; Coolen, L.M. Chronic contusion spinal cord injury impairs ejaculatory reflexes in male rats: Partial recovery by systemic infusions of dopamine D3 receptor agonist 7OHDPAT. J. Neurotrauma 2016, 33, 943–953. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Biology 11 00686 g001 550
Figure 1. Schematic diagram of level of spinal cord and neurons regulating ejaculation. Activated spinal ejaculation generator directs and synchronizes the activity of: (a) parasympathetic output that innervate prostate and seminal vesicles secreting seminal fluid. (b) Sympathetic output that innervate smooth muscle cells of the seminal tract and the bladder neck. Contraction of the seminal tract accumulate spermatozoa that is mixed with the seminal fluid to the prostatic urethra. The neck of bladder remains closed to prevent retrograde ejaculation. (c) Somatic output that innervate the pelvic striated muscles (not shown in this figure). The external urethral sphincter relaxes and rhythmic contractions of the bulbospongiosus and ischiocavernosus muscles are responsible for rhythmic forceful expulsion of sperm at the urethral meatus. (a) and (b) = emission; (c) = expulsion.
Figure 1. Schematic diagram of level of spinal cord and neurons regulating ejaculation. Activated spinal ejaculation generator directs and synchronizes the activity of: (a) parasympathetic output that innervate prostate and seminal vesicles secreting seminal fluid. (b) Sympathetic output that innervate smooth muscle cells of the seminal tract and the bladder neck. Contraction of the seminal tract accumulate spermatozoa that is mixed with the seminal fluid to the prostatic urethra. The neck of bladder remains closed to prevent retrograde ejaculation. (c) Somatic output that innervate the pelvic striated muscles (not shown in this figure). The external urethral sphincter relaxes and rhythmic contractions of the bulbospongiosus and ischiocavernosus muscles are responsible for rhythmic forceful expulsion of sperm at the urethral meatus. (a) and (b) = emission; (c) = expulsion.
Biology 11 00686 g001
Biology 11 00686 g002 550
Figure 2. Schematic diagram of organs involved in ejaculation. Anterograde ejaculation (green arrow) and retrograde ejaculation (black arrow) shown in same figure, retrograde ejaculation is due to the inability of the neck of bladder to close completely during expulsion phase. Some amount of semen can be seen in the urinary bladder.
Figure 2. Schematic diagram of organs involved in ejaculation. Anterograde ejaculation (green arrow) and retrograde ejaculation (black arrow) shown in same figure, retrograde ejaculation is due to the inability of the neck of bladder to close completely during expulsion phase. Some amount of semen can be seen in the urinary bladder.
Biology 11 00686 g002
Biology 11 00686 g003 550
Figure 3. Table showing the normal and abnormal types of ejaculation. Their etiologies are described in brief.
Figure 3. Table showing the normal and abnormal types of ejaculation. Their etiologies are described in brief.
Biology 11 00686 g003
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Soni, K.K.; Jeong, H.-S.; Jang, S. Neurons for Ejaculation and Factors Affecting Ejaculation. Biology 2022, 11, 686. https://doi.org/10.3390/biology11050686

AMA Style

Soni KK, Jeong H-S, Jang S. Neurons for Ejaculation and Factors Affecting Ejaculation. Biology. 2022; 11(5):686. https://doi.org/10.3390/biology11050686

Chicago/Turabian Style

Soni, Kiran Kumar, Han-Seong Jeong, and Sujeong Jang. 2022. "Neurons for Ejaculation and Factors Affecting Ejaculation" Biology 11, no. 5: 686. https://doi.org/10.3390/biology11050686

APA Style

Soni, K. K., Jeong, H. -S., & Jang, S. (2022). Neurons for Ejaculation and Factors Affecting Ejaculation. Biology, 11(5), 686. https://doi.org/10.3390/biology11050686

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop