Role of the brain in the control of erection.

In contrast to the spinal control of erection, relatively little is known about the brain control. In the present review, we have outlined the role of brain structures involved in penile erection and provided a synopsis on the brain circuit of erection. Findings from both animal and human studies are discussed. Evidence suggests that the most important structures are the frontal lobe, cingulate gyrus, amygdala, thalamus and hypothalamus. Within the brain circuit of erection, the thalamus serves as a gate-controller in which all relevant information is evaluated and further processed to higher and lower centres.

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title: Neural pathways and central sites involved in penile erection: neuroanatomy and clinical implications
abstract: Penile erection occurs in response to tactile, visual, and imaginative stimuli in humans. In animals olfactory and auditory cues are particularly important. The participation of multiple sites with the brain and spinal cord, and coordination of somatic and autonomic pathways make sexual behavior in general, and erection in particular, vulnerable to neurologic injury and disease. Sites within the brain and spinal cord act in concert to process, coordinate, then distribute the neural inputs necessary for sexual behavior including erection. Activation of neurons in some of these regions either pharmacologically or by electrical stimulation has been associated with penile tumescence. This review will provide a geographic framework for understanding the neuroanatomical basis of penile erection based primarily on animal data. Following discussion of the anatomical substrates, a clinical correlation is then provided to confirm and reinforce these experimental observations.

title: Central neural regulation of penile erection
abstract: Penile erection is caused by a change of the activity of efferent autonomic pathways to the erectile tissues and of somatic pathways to the perineal striated muscles. The spinal cord contains the cell bodies of autonomic and somatic motoneurons that innervate the peripheral targets. The sympathetic outflow is mainly antierectile, the sacral parasympathetic outflow is proerectile, and the pudendal outflow, through contraction of the perineal striated muscles, enhances an erection already present. The shift from flaccidity to erection suggests relations among these neuronal populations in response to a variety of informations. Spinal neurons controlling erection are activated by information from peripheral and supraspinal origin. Both peripheral and supraspinal information is capable of eliciting erection, or modulating or inhibiting an erection already present. One can hypothesize a spinal network consisting of primary afferents from the genitals, spinal interneurons and sympathetic, parasympathetic and somatic nuclei. This system is capable of integrating information from the periphery and eliciting reflexive erections. The same spinal network, eventually including different populations of spinal interneurons, would be the recipient of supraspinal information. Premotor neurons that project directly onto spinal sympathetic, parasympathetic or somatic motoneurons, are present in the medulla, pons and diencephalon. Several of these premotor neurons may in turn be activated by sensory information from the genitals. Aminergic and peptidergic descending pathways in the vicinity of spinal neurons, exert complex effects on the spinal network that control penile erection. This is caused by the potential interaction of a great variety of receptors and receptor subtypes present in the spinal cord. Brainstem and hypothalamic nuclei (among the latter, the paraventricular nucleus and the medial preoptic area) may not necessarily reach spinal neurons directly. However they are prone to regulate penile erection in more integrated and coordinated responses of the body, such as those occurring during sexual behavior. Finally, the central and spinal role of regulatory peptides (oxytocin, melanocortins, endorphins) has only recently been elucidated.

title: Some proposals regarding the organization of the central nervous system control of penile erection
abstract: Recent research on the central nervous control of penile erection is discussed. A framework for this control is based upon principles put forward by Frank Beach regarding the neuroendocrine regulation of male copulatory behavior. The current discussion is focused primarily on a subset, penile erection. The spinal cord contains all the necessary components for the production of penile erection. This requires a multisegmental coordination among penile vasodilator and vasoconstrictor autonomic neurons, pudendal motoneurons responsible for penile rigidity and autonomic neurons which control extra-penile blood flow. Genital sensory stimulation can activate this spinal network. The spinal cord is also under excitatory and inhibitory control from supraspinal sites. Penile erection can be driven by supraspinal input alone and supraspinal control can inhibit the erectile effects of genital stimulation.An important aspect of the CNS control of penile erection is that there are extensive interconnections between most of the brain sites identified to date. Most of the pathways are characterized by reciprocal connections. A large number of the CNS sites also receive genital sensory information. Thus, descending control may itself be modulated by ascending sensory pathways which relay information from the genitalia. This raises the possibility that penile erection may involve a positive feedback system. Receptors for gonadal hormones have been identified throughout the neuraxis. However, strong evidence for the control of male sexual function by gonadal hormones has been identified only for forebrain sites. The functional role of brainstem and spinal gonadal hormone receptors has not yet been clarified.

title: Tolerability and safety of apomorphine SL (Ixense (TM) ).
abstract: Apomorphine SL (Ixense (TM) ) (apo SL) is a dopamine receptor agonist that can enhance sexual function in patients with erectile dysfunction (ED). For a patient, the ability to achieve a physiological erection, tolerability, efficacy and the speed of onset of the therapy are of considerable importance when considering ED treatment. Recent studies have focused on determining the patient's tolerability to apo SL as a therapy for ED. In addition, the cardiovascular profile of those patients that would be likely to receive apo SL in the clinic has been assessed. These studies have shown that apo SL is safe and effective in the treatment of ED and offers a new therapeutic option for the first-line treatment of patients with different concomitant diseases including cardiovascular disease and diabetes. The most frequently reported adverse events were nausea and dizziness, but no major adverse events have been noted in any of the clinical trials.

title: Pharmacological management of erectile dysfunction
abstract: Erectile dysfunction (ED) is a common medical condition that affects the sexual life of millions of men worldwide. Many drugs are now available for treating ED; oral pharmacotherapy represents the first‐line option for most patients with ED. Sildenafil, an inhibitor of the enzyme phosphodiesterase type 5, is currently the most widely prescribed oral agent and has a very satisfactory efficacy‐safety profile in all patient categories. Apomorphine SL is a dopamine D1‐ and D2‐receptor agonist which has recently been approved for marketing in Europe. It is best selected for treating patients with mild to moderate ED. Vardenafil and tadalafil are new phosphodiesterase type 5 inhibitors which are expected to be approved this year. Both of them have significant positive efficacy‐safety profiles. Patients who do not respond to oral pharmacotherapy or who cannot use it are good candidates for intracavernosal and intraurethral therapy. Alprostadil is the most widely used drug, both for injection therapy and for the intraurethral route. The efficacy of second‐line treatment is high but the attrition rate remains significant.

title: Central Mechanisms Regulating Penile Erection in Conscious Rats: The Dopaminergic Systems Related to the Proerectile Effect of Apomorphine
abstract: Apomorphine has been used as a pharmacological probe of dopaminergic receptors in a variety of central nervous system disorders. The utility of apomorphine as an agent for the treatment of erectile dysfunction has also been demonstrated clinically. Apomorphine is a nonselective dopaminergic receptor agonist with potent binding affinity (Ki) of 101, 32, 26, 2.6, and 10 nM for D1, D2, D3, D4, and D5, respectively. When administered either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.), apomorphine fully evoked penile erections in conscious rats with maximum effect at 0.1 μmol/kg s.c. and 3 nmol/rat i.c.v., respectively. Apomorphine was less efficacious when injected intrathecally (i.t.) to L4-L6 spinal levels (50% at 30–100 nmol/rat i.t.). Penile erection facilitated by apomorphine was blocked by haloperidol and clozapine (i.p. and i.c.v.) but not by domperidone (a peripherally acting dopaminergic receptor antagonist). In this model using conscious rats, penile erection was significantly induced by quinpirole (D2-D3-D4 receptor agonist), but not by R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF38393) and R(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzapine (SKF81297) (D1 receptor agonists), or a D2 receptor agonist R-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine (PNU-95666E). The role of D4 receptors in penile erection was demonstrated using selective D4 receptor agonists [(4-phenylpiperazinyl)-methyl]benzamide (PD168077) and 5-fluoro-2-{[4-(2-pyridinyl)-1-piperazinyl]methyl}-1H-indole (CP226269), whether administered systemically (s.c.) or locally in the brain (i.c.v.). The ability of apomorphine to activate D3 receptors in relation to its proerectile activity remains to be elucidated by use of selective subtype agonists. These results suggest that the proerectile action of apomorphine in rats is mediated at supraspinal levels and that this effect is not mimicked by a D2 receptor agonist but associated with activation of D4 receptors.

title: New oral agents for erectile dysfunction: what is changing in our practice?
abstract: Erectile dysfunction (ED) is a highly prevalent disorder affecting an estimated 152 million men worldwide and is associated with a variety of behavioral risk factors, such as cigarette smoking and excessive alcohol consumption, as well as numerous age-related medical conditions, notably type-2 diabetes mellitus and cardiovascular disease. A rational step-wise approach which includes comprehensive medical and sexual history, a focused physical examination and essential laboratory tests such as fasting glucose, lipid profile and testosterone assay is to be preferred. Current diagnostic work-up does not recommend any of the specialized tests which were previously considered mandatory-i. e. penile pharmacotesting, Duplex ultrasound and nocturnal penile tumescence. Hormonal replacement therapy is appropriate only in the hypogonadal male with ED. Prior to direct intervention, the physician should consider altering modifiable risk factors or causes, although frequently insufficient to reverse ED completely. When indicated, oral therapy with new molecules (phosphodiesterase inhibitors or apomorphine) is the first-line treatment for the majority of patients because of potential benefits and lack of invasiveness.

title: LOCALIZATION FOR PENILE ERECTION IN MEDIAL FRONTAL LOBE.
abstract: In extending a previous study the medial part of the frontal lobe of squirrel monkey was explored with respect to positive loci for penile erection. Strongly positive loci were found in precallosal...

title: Penile erection evoked from forebrain structures in Macaca mulatta.
abstract: ELECTRICALLY evoked penile erection has been systematically studied in the squirrel monkey1-5but comparable data have not been reported for other primates. This report describes the phenomenon inMacaca mulattaand presents quantitative measures of the density and distribution of points eliciting the response from the forebrain of this species. In addition, an attempt was made to relate penile erection to other effects evoked from the same points, including autonomic changes and behaviors indicative of the reinforcement value of the stimulation.  The methods used in this study have been peviously described.6Briefly, data were gathered from 5,880 loci distributed along 205 electrode tracks in 15, 8 to 10 lb maleM mulatta. Roving monopolar electrodes were used in conjunction with a head-mounted stereotactic electrode guidance platform made of acrylic cement.7This platform allowed the insertion of individual electrodes in unanesthetized animals, exploration of a column

title: A new potential of blood oxygenation level dependent (BOLD) functional MRI for evaluating cerebral centers of penile erection
abstract: It is well known that penile erection is dependent on commands from the central nervous system. However, there has been little research on the central control of penile erection. The aim of this study was to evaluate, for the first time, the cerebral centers of penile erection using BOLD-functional MRI. Functional magnetic resonance imaging (fMRI) on a 1.5T MR scanner was performed in 12 sexually potent male volunteers (mean age: 23) and two hypogonadal impotent patients. In this study, blood oxygenation level dependent (BOLD) technique was utilized to create fMRI reflecting local brain activities. Real-time visual stimulation was performed with an alternatively combined erotic and non-erotic film to identify and quantify the activated brain regions associated with sexual response. Subjective sexual arousal and penile erection responses were assessed using 5-point scales ranging from 1 (no change) to 5 (maximal increase). In normal volunteers, the mean scores on subjective sexual arousal and penile erection by sexual stimulation with erotic film were 3.0 and 3.3 respectively, whereas there were no changes by non-erotic stimulation. During the visual stimulation the occipital cortex was activated by either an erotic or non-erotic film, the erotic film gave 150–200% stronger activation. However, more than seven of the 12 healthy subjects were significantly activated in the areas of inferior frontal lobe, cingulate gyrus, insula gyrus, corpus callosum, thalamus, caudate nucleus, globus pallidus, and inferior temporal lobe by erotic stimulation. In the hypogonadal patients, brain activation in response to the erotic film decreased compared to normal volunteers, however, it was restored by testosterone supplementation. These results are the first demonstration to show the functional neuroanatomy of the brain associated with sexual arousal by visual sexual stimulation using BOLD-based fMRI. Further studies are needed to verify that fMRI provides an important new tool in evaluating the cerebral center of the penile erection.

title: Brain activation and sexual arousal in healthy, heterosexual males.
abstract: Despite the brain's central role in sexual function, little is known about relationships between brain activation and sexual response. In this study, we employed functional MRI (fMRI) to examine relationships between brain activation and sexual arousal in a group of young, healthy, heterosexual males. Each subject was exposed to two sequences of video material consisting of explicitly erotic (E), relaxing (R) and sports (S) segments in an unpredictable order. Data on penile turgidity was collected using a custom-built pneumatic pressure cuff. Both traditional block analyses using contrasts between sexually arousing and non-arousing video clips and a regression using penile turgidity as the covariate of interest were performed. In both types of analyses, contrast images were computed for each subject and these images were subsequently used in a random effects analysis. Strong activations specifically associated with penile turgidity were observed in the right subinsular region including the claustrum, left caudate and putamen, right middle occipital/ middle temporal gyri, bilateral cingulate gyrus and right sensorimotor and pre-motor regions. Smaller, but significant activation was observed in the right hypothalamus. Few significant activations were found in the block analyses. Implications of the findings are discussed. Our study demonstrates the feasibility of examining brain activation/sexual response relationships in an fMRI environment and reveals a number of brain structures whose activation is time-locked to sexual arousal.

title: Lesions in Medial Preoptic Area and Bed Nucleus of Stria Terminalis: Differential Effects on Copulatory Behavior and Noncontact Erection in Male Rats
abstract: The goal of these studies was to assess the regulatory roles of the medial preoptic area (MPOA) and the bed nucleus of the stria terminalis (BST) in sexual arousal, inferred from noncontact erection (NCE) evoked in male rats by remote cues from estrous females. NCE and copulatory behavior were recorded before and after quinolinic acid or radiofrequency (RF) lesions were made in the MPOA (Experiments 1–3) or RF lesions were made in the BST (Experiment 4). All males with MPOA lesions, particularly in the rostral region, displayed severe deficits in copulation but little or no decrement in NCE. In contrast, BST lesions caused relatively moderate deficits in copulation, but they severely impaired NCE. Animals with larger BST lesions, including rostral and caudal medial regions, had more deficits in both copulatory behavior and NCE than did males with smaller lesions confined to the rostral medial BST. These results suggest that (1) the MPOA is critical for copulatory behavior but not for NCE, (2) males that stop copulating after MPOA lesions are still sexually aroused by estrous females, and (3) the BST plays an important role in mediating NCE.

title: Androgen Implants in Medial Amygdala Briefly Maintain Noncontact Erection in Castrated Male Rats
abstract: Castration of male rats causes a rapid loss of their normal erectile response to inaccessible estrous females. Previous studies had demonstrated that these noncontact erections (NCEs), a putative sign of sexual arousal, could be restored by systemic treatment with testosterone (T) or dihydrotestosterone (DHT), but not estradiol (E). We examined whether androgen delivered to the medial amygdala (MeA) of castrated rats would maintain NCE. In Experiment 1, males received bilateral cannulae filled with T, DHT, or E directed at the MeA. Control males had the same hormone-filled cannulae implanted subcutaneously and blank cannulae in the MeA, or they received T in the anterior forebrain. During the 2 weeks after surgery, males were tested twice for NCE and copulation. About half the males with androgens in the MeA had NCEs 1 week after castration, but few responded a week later. Closer proximity of androgen implants to the posterodorsal MeA (MeApd) predicted shorter NCE latencies. No males with subcutaneous androgen had NCEs in either test, and few anterior forebrain-implanted males did. Some males receiving E in MeA or subcutaneously had NCE in each test. In copulation tests, the type of steroid treatment did not affect the incidence of ejaculation or most measures of copulation, and the proximity of cannulae to MeApd predicted only the time from ejaculation to the occurrence of NCE during the postejaculatory interval. Experiment 2 showed that NCEs displayed by males with androgen in MeA occurred in response to estrous females, not spontaneously. The results suggest that androgens, perhaps augmented by estrogen, act in the posterodorsal MeA to facilitate NCE and its associated arousal.

title: Thalamocortical mechanisms in odor-guided behavior. II. Effects of lesions of the mediodorsal thalamic nucleus and frontal cortex on odor preferences and sexual behavior in the hamster.
abstract: The role of the thalamocortical "olfactory" pathway in odor preferences and sexual behavior was examined in the hamster, a species which depends crucially upon olfaction for mating. Before and after ablation of primary or secondary olfactory structures, male hamsters were tested for threshold, interest, and preference for the odor of an estrus female hamster and other odors. Sexual competency was also observed in daily mating sessions. Disruption of the primary olfactory pathway resulted in an absence of interest in odors and mating. Lesions of the mediodorsal thalamic nucleus or frontal neocortex of the rhinal sulcus did not result in anosmia, but did eliminate or alter odor preferences and resulted in inappropriate, inefficient, precopulatory and copulatory behavior. It appears that substructures in the thalamofrontal pathway playa role in discriminative or cognitive aspects of processing adaptively significant stimuli.

title: Brain Lesions Affect Penile Reflexes
abstract: Electrolytic lesions of several potential brain afferents to the spinal nucleus of the bulbocavernosus (SNB) affect the display of penile reflexes. Ablation of the median and pontine raphe areas significantly potentiates the expression of cups and flips. Animals with a bilateral lesion of the paraventricular nucleus of the hypothalamus have a shorter latency to the first erection but otherwise display normal reflex behavior. Although bilateral destruction of the lateral vestibular nucleus (LVN) completely eliminated penile reflex activity, it also caused significant motor impairment thus clouding conclusions concerning the normal role of the LVN in penile reflex behavior. These and other results support the hypothesis that these brain regions which project to the SNB region normally modulate spinal reflex behavior of the rat penis.

title: Opposing roles of the nucleus accumbens and anterior lateral hypothalamic area in the control of sexual behaviour in the male rat
abstract: Opposing roles have been implicated for the nucleus accumbens (NAc) and anterior portion of the lateral hypothalamic area (aLHA) in the regulation of sexual behaviour in male rats based on in vivo neurochemical correlates. The present study provides functional evidence supporting this hypothesis by examining the effects of lesions to these structures on copulation, noncontact erection and receptive female preference. Sexually naïve male Long‐Evans rats received either bilateral 1.0‐µL injections of NMDA (10 µg/µL/side) or vehicle (shams) into either the aLHA or the NAc. During repeated tests of copulation most of the sham‐lesioned males, but few of the aLHA‐lesioned and NAc‐lesioned males, copulated to ejaculation. Most of the NAc‐lesioned males also failed to intromit, whereas the majority of the aLHA‐lesioned males intromitted repeatedly. During exposure to an inaccessible receptive female behind a wire‐mesh screen, aLHA‐lesioned males displayed facilitation of noncontact erections, whereas NAc‐lesioned males displayed impaired noncontact erections. Conversely, during simultaneous exposure to inaccessible receptive and nonreceptive females in different compartments, all males spent more time in the proximity of the receptive female. These findings indicate that the aLHA plays an inhibitory role in the regulation of sexual arousal and an excitatory role in the regulation of ejaculation. Conversely, the NAc plays an excitatory role in the regulation in sexual arousal.

title: Erectile response to hypothalamic stimulation in rats: role of peripheral nerves.
abstract: The role of peripheral parasympathetic and sympathetic pathways was explored in erectile responses elicited by hypothalamic medial preoptic area (MPOA) stimulation in adult male anesthetized rats. Under control conditions, MPOA stimulation reliably elicited erectile responses evidenced by an increase of the intracavernous pressure-to-blood pressure ratio. The erectile response was abolished by 1) acute bilateral section of cavernous or pelvic nerves or cauda equina and 2) chronic lesions of pelvic nerves or cauda equina. Acute section of the hypogastric nerve did not significantly decrease the erectile response. The erectile response was significantly depressed after acute or chronic sections of the paravertebral sympathetic chain at the L4-L5 level or chemical sympathectomy with 6-hydroxydopamine. The decrease due to acute sympathetic chain lesion was reversed by bilateral ligation of the external iliac arteries. Accordingly MPOA stimulation elicits erectile responses via 1) activation of the parasympathetic outflow conveyed by the pelvic and cavernous nerves and 2) activation of neural fibers conveyed by the sympathetic pathways. We propose that sympathetic fibers running in the paravertebral sympathetic chain are responsible for vasoconstriction of nonpenile areas to divert blood to the penis, allowing the dramatic increase of penile arterial inflow required for erection.

title: Stereotactic treatment of Gilles de la Tourette syndrome by high frequency stimulation of thalamus
abstract: Conservative laparoscopic surgery is currently the cornerstone in the treatment of tubal pregnancy in women who desire future fertility. Treatment with systemic methotrexate might, however, offer better fertility prospects by avoiding surgical trauma to the tube. We did a randomised clinical trial comparing systemic multi-dose intramuscular methotrexate with laparoscopic salpingostomy in tubal pregnancy. This trial was done in six Dutch hospitals between January, 1994, and September, 1996. 100 haemodynamically stable patients with a laparoscopically confirmed unruptured tubal pregnancy, without active bleeding and without fetal cardiac activity on transvaginal sonography, were included. There were no large differences in primary treatment success (relative risk 1·2 [95% CI 0·93–1·4]) or in tubal preservation (0·98 [0·87–1·1]) between the two treatments. Tubal patency, assessed in 81 patients, was slightly, but not significantly lower after systemic methotrexate (0·93 [ 0 · 6 4 – 1 · 4 ] ) . 18 months after the trial ended, we assessed fertility outcome in patients who desired pregnancy. All patients were contacted by telephone and were interviewed about when they had tried to conceive and on the occurrence of spontaneous pregnancies. Follow-up ended with the occurrence of an intrauterine pregnancy, or at the last date of contact. Time to pregnancy through in-vitro fertilisation and embryo transfer was censored at the date of ovum pickup minus 2 weeks. Data on follow-up was obtained for 90 women. Of these, 74 had tried to conceive—34 after systemic methotrexate and 40 after laparoscopic salpingostomy. In the systemic methotrexate group, 12 women had a spontaneous intrauterine pregnancy, two had an intrauterine pregnancy following in-vitro fertilisation and embryo transfer, whereas three had a spontaneous ectopic pregnancy. In the laparoscopic salpingostomy group, 16 women had a spontaneous intrauterine prenancy, two had an intrauterine pregnancy following in-vitro fertilisation and embryo transfer, and four had a spontaneous ectopic pregnancy. Cox’s proportional hazards estimates of the relative risks were 0·89 (0·42–1·9) for spontaneous intrauterine pregnancy and 0·77 (0·17–3·4) for spontaneous repeat ectopic pregnancy. Kaplan-Meier curves of the cumulative intrauterine pregnancy rates are shown in the figure. These cumulative spontaneous intrauterine pregnancy rates at 18 months were 36% in the systemic methotrexate group and 43% in the laparoscopic salpingostomy group. There is no large positive effect on future fertility with systemic methotrexate, although a more moderate (but worthwhile) benefit remains plausible. Effectiveness and neuroanatomy of Tourette’s syndrome: an FDG-PET study. I. Regional changes in cerebral glucose metabolism differentiating patients and controls. Neuropschopharmacology 1993; 9 (4): 2 7 7 – 9 1 . 5 Cummings JL, Frankel M. Gilles de la Tourette Syndrome and the neurological basis of obsessions and compulsions. Biol Psychiatry 1985; 20: 1 1 1 7 – 2 6 .

title: Chronic bilateral thalamic stimulation: a new therapeutic approach in intractable Tourette syndrome. Report of three cases.
abstract: Based on the results of thalamotomies described by Hassler in 1970, the authors performed bilateral thalamic high-frequency stimulation (HFS) in three patients with intractable Tourette syndrome (TS). In this report they describe the long-term effects. Three male patients (42, 28, and 45 years of age) had manifested motor and vocal tics since early childhood. The diagnosis of TS was made according to the criteria of the Tourette Syndrome Classification Study Group. Any drug or alternative treatment had been either ineffective or only temporarily effective in all three patients. There was no serious comorbidity. The target for stimulation was chosen at the level of the centromedian nucleus, substantia periventricularis, and nucleus ventrooralis internus. After 2 weeks of test stimulation, the pulse generators were implanted. After a follow-up period of 5 years in the patient in Case 1, 1 year in the patient in Case 2, and 8 months in the patient in Case 3, all major motor and vocal tics had disappeared and no serious complications had occurred. When stimulation was applied at the voltage necessary to achieve an optimal result on the tics, a slight sedative effect was noted in all three patients. In the patients in Cases 1 and 3 there were stimulation-induced changes in sexual behavior. Chronic thalamic HFS may be an effective and safe treatment for medically intractable TS in adult patients. Unwanted stimulation-induced side effects may occur.

title: Psychosurgery on sex offenders and sexual “deviants” in West Germany
abstract: About 70 men have undergone a stereotaxic hypothalamotomy in West Germany for sexual behaviors. In most cases the nucleus ventromedialis (Cajal) has been unilaterally destroyed. The question of whether this kind of psychosurgery should be legally controlled is being discussed by both scientists and the public in West Germany. The justification for this psychosurgery is taken from a theoretical basis which is at least questionable and which stems from a biologically truncated and therefore limited perspective on human sexuality. An inspection of the published reports shows that the indication for surgery was based on questionable scientific and clinical grounds and practically excludes psychotherapeutic and sociotherapeutic aspects. In the authors' opinion stereotaxic hypothalamotomy can in no way be regarded as an unquestioned, applicable method of therapy. We consider it essential that this surgery be suspended at least as long as the possible therapeutic effectiveness and the possible adverse side effects remain unclear.

title: Penile reflexes and copulatory behavior in male rats following lesions in the bed nucleus of the stria terminalis
abstract: Male rats with large lesions in the bed nucleus of the stria terminalis (BNST) had more intromissions preceding ejaculation (if they ejaculated at all), longer intervals between intromissions, and longer postejaculatory refractory periods than control animals. In tests for penile reflexes, BNST males were similar to control males in every respect. The copulatory deficits in BNST males are probably not mediated by a change in penile reflex potential.

title: Sexual Dysfunction in Parkinson's Disease
abstract: Sexual dysfunction is common in Parkinson's disease (PD). We investigated the premorbid and present sexual functioning of 75 people with PD (32 women and 43 men). Women reported difficulties with arousal (87.5%), with reaching orgasm (75.0%), with low sexual desire (46.9%), and wih sexual dissatisfaction (37.5%). Men reported erectile dysfunction (68.4%), sexual dissatisfaction (65.1%), premature ejaculation (40.6%), and difficulties reaching orgasm (39.5%). Premorbid sexual dysfunction may contribute to cessation of sexual activity during the course of the disease (among 23.3% men and 21.9% women). Associated illnesses, use of medications, and advanced stage of PD contributed to sexual dysfunction.

title: Neural control of erection
abstract: Activation of sacral parasympathetic pathways elicits penile erection through the release of vasorelaxant neurotransmitters that increase blood flow to the penis and relax the penile erectile tissue. Sympathetic pathways are antierectile. The pudendal pathway, responsible for the contraction of the perineal striated muscles, enhances an already present erection. All pathways originate in the spinal cord, but at various levels and areas. The convergence of information from peripheral and supra-spinal origins onto spinal neurones is very likely activating more specifically the spinal pro-erectile network. Peripheral information is the afferent limb of reflexive erections, impinges onto spinal interneurones and is able to activate or regulate the activity of sympathetic, parasympathetic and somatic nuclei. Supra-spinal information impinges onto either the same or a different spinal network. Premotor neurones located in supra-spinal structures, that project directly onto spinal sympathetic, parasympathetic or pudendal motoneurones, are present in the medulla, pons and diencephalon. Several of these premotor neurones may in turn be activated by sensory information from the genitals. Descending pathways release a variety of aminergic and peptidergic neurotransmitters in the vicinity of spinal neurones, thereby exerting complex effects on the spinal pro-erectile network. Brainstem and hypothalamic nuclei (among the latter, the paraventricular nucleus and the medial preoptic area) may not reach directly the spinal pro-erectile network. They are prone to regulate penile erection in more integrated and coordinated responses of the body, as those occurring during sexual behaviour. The pro-erectile central and spinal effects of neuropeptides such as oxytocin, melanocortins and endorphins have only recently been analyzed. Such compounds may represent therapeutic strategies to treat erectile dysfunction through a central site of action.

title: Sexual behavior during L-dopa treatment for Parkinsonism.
abstract: Nineteen patients who were receiving L-dopa for parkinsonism were interviewed to assess the effect of L-dopa treatment on sexual behavior. Seven patients (37 percent) reported an activation of sexual behavior at some point during the therapy. Interview data suggested that such a report may actually result from at least three possible effects of L-dopa.

title: Sexual function and affect in parkinsonian men treated with L-dopa.
abstract: Using psychiatric interviews, sexual and affect rating scales, hormonal studies, and neurologic assessment, the authors assessed the effect of L-dopa treatment on men with Parkinson's disease. Patients demonstrated variable affect changes. Approximately one-half of the patients reported an increased sexual interest that was not related to improvement in locomotor function. Hormonal factors appeared to be involved. The findings suggest that male parkinsonian patients who possess an intact hypothalamic-pituitary-gonadal axis experience increased sexual function related to L-dopa treatment.

title: Psychiatric and sexual disorders induced by apomorphine in Parkinson's disease.
abstract: A similar pattern of psychosexual disorders has been observed after long-term treatment with levodopa therapy in four male parkinsonian patients treated with apomorphine for severe on-off motor fluctuations. An acute episode in each case had led them to the hospital in the context of a psychiatric emergency (after punishable sexual acts in two cases). In each case, this episode had been preceded by an increase of self-administered apomorphine, whereas other antiparkinsonian drugs remained unchanged. Questioning had revealed psychosexual disturbances as early as the onset of apomorphine treatment, which tended to progressively worsen with the number of apomorphine daily doses. A decrease in the dosage of apomorphine had been followed by the improvement of the psychiatric condition without worsening of the motor status. Recurrence of psychiatric disorders with similar features had been observed when two patients again increased the number of apomorphine daily injections. The absence of somatic manifestations when apomorphine treatment was withdrawn or reduced, with persistence of psychosexual disturbances, could suggest a psychological dependence from the drug.

title: Apomorphine‐induced penile erections in Parkinson's disease
abstract: Penile erections were regularly induced by intermittent subcutaneous injections of apomorphine in five patients with Parkinson's disease (PD) complicated by motor fluctuations. Four of the patients reported erectile dysfunction before beginning apomorphine and two of these report a significant improvement in their sexual function resulting from apomorphine use. Animal studies suggest central D2‐type dopamine receptor stimulation and oxytocin release from the paraventricular nucleus of the hypothalamus mediate the effect. Erections reported with other dopamine agonists and levodopa are probably mediated by the same mechanism. Apomorphineinduced erections in PD are probably more common than previously thought. The benefit of apomorphine on sexual function in some patients suggests a possible role in the treatment of impotence in PD.

title: Hypersexuality with antiparkinsonian therapy.
abstract: Thirteen parkinsonian patients drawn from two large parkinsonism clinics experienced hypersexuality as a consequence of anti-parkinsonian therapy. The cases include only those whose sexual behavior on treatment became a concern to the patient's family or a social agency. The majority of patients were men and had a relatively early onset of parkinsonian symptomatology. There was no relation between functional improvement and increased sexuality. Most patients showed some element of dose dependency between antiparkinsonian drugs and the hypersexual behavior. Prior sexual profile included from no sexual outlet to hypersexuality. Neither the prior history of psychiatric illness nor brain damage predisposed to such response on treatment, and in most patients, it was not a part of hypomania or a more diffuse psychiatric disturbance. We propose that hypersexuality on antiparkinsonian drugs is consequent to inhibition of prolactin secretion.

title: Thalamus and penile erection
abstract: Penile erection is a complex neurovascular event. The neuronal system involved is often divided into a spinal (generator) and supraspinal (controller) network. Little is known about the supraspinal control. The recent finding of changes in penile erection following deep brain stimulation of the thalamus in two patients has raised the question as to what extent the thalamus is involved in erectile function. The thalamus has generally been regarded as a group of relay nuclei that served as a ‘gate’ for sexual information from the spinal cord towards higher centres. Recent evidence, however, suggests a more integrated regulatory function. Our review of the literature from 1960 until 2003 revealed 13 reports describing original data (preclinical and clinical). Various thalamic regions, varying from the midline thalamus to the posterior thalamus, have been reported to be activated during erection. The majority of the reports, however, showed that mainly the mediodorsal (MD) nucleus and the centromedian–parafascicular nucleus (Cm–Pf complex) are involved in penile erection. MD is the second largest nuclear aggregation located within the medial part of the thalamus. Anatomically, the MD is closely related to the Cm–Pf complex. The Cm–Pf complex is one of the most important relay stations in which the anterolateral spinothalamic pathway is further processed. This pathway is thought to transmit peripheral sexual sensations. On the whole, the present data on the role of the thalamus in erection are far from complete and future experiments are required to delineate its involvement.

title: Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, "prefrontal" and "limbic" functions.
abstract: The central theme of the "segregated circuits" hypothesis is that structural convergence and functional integration occurs within, rather than between, each of the identified circuits. Admittedly, the anatomical evidence upon which this scheme is based remains incomplete. The hypothesis continues to be predicated largely on comparisons of anterograde and retrograde labeling studies carried out in different sets of animals. Only in the case of the "motor" circuit has evidence for the continuity of the loop been demonstrated directly in individual subjects; for the other circuits, such continuity is inferred from comparisons of data on different components of each circuit obtained in separate experiments. Because of the marked compression of pathways leading from cortex through basal ganglia to thalamus, comparisons of projection topography across experimental subjects may be hazardous. Definitive tests of the hypothesis of maintained segregation await additional double- and multiple-label tract-tracing experiments wherein the continuity of one circuit, or the segregation of adjacent circuits, can be examined directly in individual subjects. It is worthy of note, however, that the few studies to date that have employed this methodology have generated results consistent with the segregated circuits hypothesis. Moreover, single cell recordings in behaving animals have shown striking preservation of functional specificity at the level of individual neurons throughout the "motor" and "oculomotor" circuits. It is difficult to imagine how such functional specificity could be maintained in the absence of strict topographic specificity within the sequential projections that comprise these two circuits. This is not to say, however, that we expect the internal structure of functional channels (e.g., the "arm" channel within the "motor" circuit) to have cable-like, point-to-point topography. When the grain of analysis is sufficiently fine, anatomical studies have shown repeatedly that the terminal fields of internuclear projections (e.g., to striatum, pallidum, nigra, thalamus, etc.) often appear patchy and highly divergent, suggesting that neighboring groups of projection cells tend to influence interdigitating clusters of postsynaptic neurons. While more intricate and complex than simple point-to-point topography, however, this type arrangement should also be capable of maintaining functional specificity. As discussed briefly above, it is not yet clear to what extent the inputs to the "motor" circuit from the different precentral motor fields (e.g., MC, SMA, APA) are integrated in their passage through the circuit. It now appears that at the level of the putamen such inputs remain segregated.(ABSTRACT TRUNCATED AT 400

title: Apomorphine‐induced penile erections in Parkinson's disease
abstract: Penile erections were regularly induced by intermittent subcutaneous injections of apomorphine in five patients with Parkinson's disease (PD) complicated by motor fluctuations. Four of the patients reported erectile dysfunction before beginning apomorphine and two of these report a significant improvement in their sexual function resulting from apomorphine use. Animal studies suggest central D2‐type dopamine receptor stimulation and oxytocin release from the paraventricular nucleus of the hypothalamus mediate the effect. Erections reported with other dopamine agonists and levodopa are probably mediated by the same mechanism. Apomorphineinduced erections in PD are probably more common than previously thought. The benefit of apomorphine on sexual function in some patients suggests a possible role in the treatment of impotence in PD.

title: Recovery of erectile function by the oral administration of apomorphine.
abstract: Apomorphine has been reported to be effective in causing erections in animals and man when administered parenterally. The side effects, notably nausea, have seriously limited its clinical usefulness. We formulated apomorphine for controlled sublingual absorption and herein report on four preliminary studies evaluating efficacy and side effects in men with no documentable organic cause of erectile dysfunction.



Patients complaining of erectile dysfunction underwent a careful evaluation. Those with measurable organic dysfunction or known organic factors were excluded. Men with primarily psychogenic impotence were tested with one of four protocols of an apomorphine preparation (preliminary sublingual liquid, preliminary 5 mg tablet, aqueous nasal spray, and new 3 and 4 mg controlled absorption tablets). The erectile response of these men to the drug with visual erotic or sexually neutral stimulation was studied with the Rigiscan.



Seven of 10 evaluable patients responded to the sublingual liquid preparation but the majority experienced significant nausea. The preliminary 5 mg tablet and aqueous forms did not produce useful responses free of side effects. The newly formulated controlled absorption 3 and 4 mg tablets were tested in 12 men. Eight of 12 (67%) developed erections in response to apomorphine. Erectile activity was seen during sexually neutral visual stimulation to a significantly greater extent than with placebo. Home trial use was found to be successful and sustained by 7 of 11 (64%) patients.



We have shown that apomorphine will act as an erectogenic agent when absorbed through the oral mucosa. In a carefully selected group of impotent patients with no documentable organic causes of erectile dysfunction, but with proven erectile potential, 67% will experience significantly durable erections with a dose of 3 or 4 mg of apomorphine when formulated for controlled absorption. The results in these small groups appear to justify larger clinical studies of this proprietary formulation.

title: A new era in the treatment of erectile dysfunction.
abstract: The recent introduction of sildenafil has revolutionized the treatment of erectile dysfunction (ED). The availability of sildenafil, the first effective oral agent for ED, has also expanded the field of sexual healthcare to include general and primary care practitioners and other nonurology specialists. A new process-of-care algorithm has been developed to facilitate the evaluation and treatment of ED in these nonurology settings. Sildenafil has been demonstrated to be safe and effective in randomized, double-blind, placebo-controlled trials involving >3,000 men ages 19-87 years. Sildenafil is effective across a broad range of etiologies including diabetes. For patients in whom first-line treatment with sildenafil fails or ceases to be effective, second-line interventions with intracavernosal self-injection therapy or transurethral alprostadil may be indicated. In addition to sildenafil, other oral agents such as oral phentolamine and sublingual apomorphine are now in clinical trials. Drugs under development include second-generation phosphodiesterase type 5 (PDE5) inhibitors, endothelin antagonists, and agents that offer specific molecular targeting. Clinical studies are also being planned to examine the efficacy of combination oral drug regimens for ED.

title: Efficacy and safety of fixed-dose and dose-optimization regimens of sublingual apomorphine versus placebo in men with erectile dysfunction. The Apomorphine Study Group.
abstract: A sublingual (SL) formulation of apomorphine has been developed and found effective in penile erectile dysfunction (ED). This study assessed the efficacy and safety of several doses of apomorphine SL in a dose-optimization schedule compared with placebo.



In this 8-week, multicenter, double-blind clinical trial, 569 patients were randomized to four groups: a dose-optimization group in which patients began with 2 mg, increased or decreased the dosage as needed for 4 weeks, and thereafter maintained an optimal dose for 4 weeks; two fixed-dose groups of either 5 or 6 mg; and a placebo group. Efficacy was assessed by patient and partner responses to home-use questionnaires about sexual function and activity and by responses to the International Index of Erectile Function and the Brief Sexual Function Inventory.



In all apomorphine SL groups, a significantly higher percentage of patients compared with the placebo group achieved and maintained an erection firm enough for intercourse (48% to 53% versus 35% for placebo, P < or =0.001) and a significantly higher percentage of attempts resulted in intercourse (45% to 51% versus 33%, P < or =0.001). The responses to the questionnaires completed by the patients and partners were similar. Apomorphine SL was well tolerated; nausea, the most common side effect, was dose related and diminished substantially during the second 4-week period at all doses. The dose-optimization schedule resulted in fewer adverse events without impacting efficacy.



Apomorphine SL is an effective and safe treatment for ED, with 2 and 4 mg providing the most acceptable therapeutic index.

title: Double–Blind, Crossover Comparison of 3 mg Apomorphine SL with Placebo and with 4 mg Apomorphine SL in Male Erectile Dysfunction
abstract: To establish the efficacy and safety of a fixed, 3–mg dose of apomorphine SL compared with placebo, and to compare 3 mg with 4 mg apomorphine SL in patients with erectile dysfunction.  This randomized, double–blind, crossover study included 296 heterosexual men with ED of various etiologies and severities. Two crossover groups were evaluated separately: 3 mg apomorphine SL vs. placebo (n = 194), and 3 vs. 4 mg apomorphine SL (n = 102). The primary efficacy variable was the percentage of attempts resulting in erections firm enough for intercourse; additional variables included the percentage of attempts resulting in intercourse and time to erection. Partner assessments were also analyzed.  3 mg apomorphine SL was significantly more effective than placebo (p<0.001) for the percentage of attempts resulting in erections firm enough for intercourse and resulting in intercourse, as assessed by both patients and partners. Median time to erection was 18.8 min. The 3–mg dose was not significantly different from 4 mg in the evaluation of efficacy variables, but the incidence of adverse events was higher with 4 mg. Nausea was the most common event, reported by 3.3% of patients on 3 mg vs. 14.1% on 4 mg; in the placebo comparison, nausea was reported by 7.0% of patients taking 3 mg apomorphine SL vs. 1.1% of those taking placebo.  3 mg apomorphine SL was significantly more effective than placebo and comparable to 4 mg, while offering an improved risk–benefit ratio.