Best Practice & Research Clinical Endocrinology & Metabolism Vol. 21, No. 3, pp.

445461, 2007
doi:10.1016/j.beem.2007.04.006 available online at http://www.sciencedirect.com

8 The neurophysiology of sexual arousal

Justine M. Schober *
Pediatric Urologist Visiting Professorb
a b a

MD, FAAP

Hamot Medical Center, 333 State Street, Suite 201, Erie, PA 16507, USA Pfaff Laboratory, Laboratory of Neurobiology and Behavior, The Rockfeller University, New York, NY, USA
PhD

Donald Pfaff

Professor and Head of Laboratory Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY, USA

Our understanding of the process and initiation of sexual arousal is being enhanced by both animal and human studies, inclusive of basic science principles and research on clinical outcomes. Sexual arousal is dependent on neural (sensory and cognitive) factors, hormonal factors, genetic factors and, in the human case, the complex inuences of culture and context. Sexual arousal activates the cognitive and physiologic processes that can eventually lead to sexual behavior. Sexual arousal comprises a particular subset of central nervous system arousal functions which depend on primitive, fundamental arousal mechanisms that cause generalized brain activity, but are manifest in a sociosexual context. The neurophysiology of sexual arousal is seen as a bidirectional system universal to all vertebrates. The following review includes known neural and genomic mechanisms of a hormone-dependent circuit for simple sex behavior. New information about hormone effects on causal steps related to sex hormones nuclear receptor isoforms expressed by hypothalamic neurons continues to enrich our understanding of this neurophysiology. Key words: sexual arousal; nervous system neurotransmitters; hormones; estrogen; sensory; spinal cord.

A comprehensive overview of the research base that contributes to our present knowledge of the subject of sexual arousal draws from many elds of study. Integration with interdisciplinary approaches brought about by social and cultural changes and by changing research initiatives have broadened the scope of knowledge about this particular subject and the possibilities of application of these principles.

* Corresponding author. Tel.: 1 814 455 5900; Fax: 1 814 456 0667. E-mail address: schobermd@aol.com (J.M. Schober). 1521-690X/$ - see front matter 2007 Elsevier Ltd. All rights reserved.

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Sexual arousal is one aspect of a more global set of generalized central nervous system (CNS) arousal functions which are responsible for the actions and reactions of all living things. When considering vertebrates man and animal alike arousal is the force which makes the animal or human active and responsive such that they will perform instinctive behaviors or learned behaviors directed toward goal objectives. The strength of a learned response depends on both arousal and drive. Generalized arousal is higher in an animal or human being that is more alert to sensory stimuli of all sorts, more motorically active, and more reactive emotionally (Figure 1).1 Generalized arousal is the behavioral state produced by arousal pathways, electrophysiological mechanisms, and genetic inuences. Sexual arousal as a subcategory is dependent on all of the above. In its specicity, it has additional dependent factors. Sexual arousal is dependent on neural (sensation, cognition) factors, hormonal factors, genetic factors, and inuences of culture and context (human). Without sexual arousal, there is no activation of the cognitive and physiologic processes that lead to sexual behaviour.1 GENITAL EPITHELIAL TISSUES Initiation of genital tactile stimulation is regarded as a precursor to sexual arousal. Actions of cutaneous receptors of nerves and the other biochemical properties of epithelial tissue of the vulva, genitalia, and vagina contribute to sexual arousal. These genitosensory areas or elds contribute sensory information to the peripheral and central neural areas by complex integrative mechanisms. Specic changes in genital structures that occur after tactile stimulation of the epithelium leading to arousal in the female include increased clitoral length and diameter, labial blood engorgement, and increased vaginal luminal diameter. In males, similar processes control penile erection. This

Figure 1. Simplied schematic of the major ascending systems supporting central nervous system (CNS) arousal in animal and human brains. Adapted from Pfaff (2006, Brain Arousal and Information Theory: Neural and Genetic Mechanisms Cambridge, Mass: Harvard University Press) with permission.

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vasocongestive and neuromuscular process is controlled by facilitatory parasympathetic and inhibitory sympathetic inputs.2 Gross internal anatomical changes, such as elevation of the uterus and lengthening of the anterior vaginal wall, have been conrmed using magnetic resonance technique.3 Other anatomical investigations that have expanded knowledge about erectile tissue in the female genital tract refer to the clitoral body, vestibular bulbs of the clitoral crura, periurethral region, and vaginal subepithelial vascular reactive tissue.4,5 The anterior vaginal wall, labial/introital urethra, Halbans fascia and G-spot have been described as places for sexual arousal activation.6 Until recently, little attention has been paid to the changes that take place in the vulvar epithelium during female sexual arousal. The potential arousing properties of the skin from the female external genitalia raises several questions about the origin of these properties. Do they simply arise from its neural connectivity? Or are they also the consequence of some properties of the epithelium itself?7 It is well known that the condition of the vulvar epithelium is highly inuenced by estrogen status. On the basis of behavioral responses in animals, it has been proposed that hormones may act at the periphery to alter sensory input and enlarge the genitosensory eld of the pudendal nerve.810 In this sensory eld it has been shown that mechanical stimulation of the skin or deection of the fur (in the case of many vertebrates) as little as a single hair elicited a rapidly adapting response. The response to clitoral sheath brushing was characterized by spikes which were lower in amplitude and had a faster rise time than the units that responded to stimulation of the long fur. Estrogen may change the mechanical properties of the tissue surrounding the hair follicles, thereby changing the movement detection by the sensory nerve endings; it may increase the number or sensitivity of nerve endings, at least at the borders of receptive elds; it may sensitize a central state which in turn exerts a centrifugal effect on the pudendal bers by way of another nerve; it may also change the blood supply to the receptors, thus altering their sensitivity. But in order for these inuential changes in sensitivity to take place at the epithelial level, the epithelium must be estrogenreceptive, as is the vulvar epithelium. Conversely, no signicant androgenic inuence on penile sensitivity via the pudendal nerve has been demonstrated.10

GENITAL SENSORY ACTIVATION SITES Genital sensory activation sites (genital sensory elds) comprise the following:             clitoris and clitoral sheath; anterior vaginal wall (anterior fornix wall of the vagina); labial/introital area; urethra; Halbans fascia (space between anterior wall of vagina and bladder, analogous to corpus spongiosum); G-spot (paraurethral area); cervix; penis; scrotum; perineum and thigh; anus and rectum; prostate.

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NEURAL DETERMINANTS When considering tactile sensory stimuli applied to areas within the genital sensory elds, there is an increase in responsiveness as a stimulus is moved from the periphery to the center of the eld. There are also summation effects: stimuli covering smaller areas might evoke only weak reexes, whereas stimuli over a larger area could evoke a stronger reex response. There is also convergence: cutaneous stimulation from receptive elds of corresponding areas of pressure-sensitive interneurons come together onto spinal interneurons. An overlap of dermatomes stimulated may strengthen the stimulus delivered. As sexual arousal increases, genital sensitivity to stimuli increases. There are multiple avenues to arousal through stimulation of different sites that overlap. Also, there are many other inuences on this genital epithelial tissue that change sexual sensation and make a direct sensory role likely. They include changes in skin temperature, hormonal environment, mechanical compliance of the tissue, inammation, neurotransmitters, and neuropeptides.11 PERIPHERAL NERVE ENDINGS If any single chain of events has a central role, it is that pressure on the crucial skin areas deforms a special class of cutaneous skin receptors called Rufni endings, thereby activating pressure units. The clitoris possesses the most dense nerve supply of any region of the skin, with numerous mucocutaneous end-organs and closely set networks of nerves. The VaterPacini corpuscle is present in the base of the clitoris. The organized mucocutaneous ending is present over the entire inner surface of the labia majora and labia minora, with a concentration toward the clitoris.12 In specic sites of acute erogenous sensation found in mucocutaneous regions of the body, the rete ridges of the epithelium are well formed and nerve tissue rises higher in the dermis, creating a dermal-nerve network with a mucocutaneous end-organ of special consideration. The most numerous nerve terminals are free nerve endings (FNEs) present in almost every dermal papilla and also the deeper dermis. There are also corpuscular receptors in a ratio to FNEs of 1:10. The same ratio describes the large to small axons. Genital end bulbs present on the glans are most numerous in the corona and near the frenulum of the penis.13 Corpuscular receptors of the glans consist of axon terminals that resemble a tangled skein of FNEs at an ultrastructural level. In labia minora pudenda, sensory nerve endings consist of FNEs and arborizations, spray-like endings, clew-like nerve endings (highly predominant) and Pacinian corpuscles.14 Once neural stimulation is presented to the distal nerve terminal the sexual reex is begun. Sexual arousal depends on a circuit or feedback loop. In the lordosis behavior circuit typical of female laboratory animals, a long circuit has been described comprising ascending sensory information to supraspinal nerve cell groups and descending neuronal facilitation from supraspinal nerve cell groups (Figure 2).15 ASCENDING SENSORY INFORMATION Four sensory systems feed ascending arousal pathways in a straightforward fashion. Somatosensory information ascending in the ventrolateral columns of the spinal cord and impacting the hindbrain reticular formation via the trigeminal system make obvious contributions, especially when they signal pain. Auditory stimuli and vestibular stimuli have the opportunity to turn on medullary and reticular neurons via cranial

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Figure 2. Hindbrain module showing the medullary reticular formation (MRF) and the lateral vestibular nucleus (LVN) receiving somatosensory input from the spinal cord ascending through the anterolateral columns; axons from the MRF and the LVN descend through the anterolateral columns to facilitate lordosis. Adapted from Pfaff (1999, In Drive: Neurobiological and Molecular Mechanisms of Sexual Motivation. Cambridge: MIT Press) with permission.

nerve inputs. Gustatory stimuli, having arrived at the nucleus of the tractus solitarius, can then be indirectly registered as arousing through reticular neurons. Two other sensory systems operate through very different routes. Visual stimuli can impact recently evolved thalamocortical arousal subsequent to visual signaling to the lateral geniculate nucleus. In contrast, olfactory information gains immediate access to ancient, primitive arousal mechanisms in the basal forebrain, including those in the amygdala and in the basal nucleus of Meynert. The latter features large cholinergic neurons that powerfully inuence the state of activation of the cerebral cortex. SENSORY SYSTEMS Four systems feed ascending arousal pathways in a straightforward fashion:  vestibular stimuli;  somatosensory;

450 J. M. Schober and D. Pfaff

 auditory;  taste, olfactory and visual.

ASCENDING SENSORY NERVES INVOLVED IN SEXUAL AROUSAL The peripheral nerves involved in sexual arousal include four (pudendal, pelvic, hypogastric and genitofemoral) that send impulses via the spinal cord and one (vagus) that bypasses the spinal cord as it ascends to the supraspinal nerve-cell groups. The pudendal nerve is sensory innervation to the clitoral sheath/foreskin and perineum, giving rise to the dorsal nerve of the clitoris/penis, and the cavernous nerve innervates the female urethral sphincter (Figure 3).15 The pelvic nerve innervates the vaginal wall, rectal wall, and cervix. The hypogastric nerve innervates the cervix and uterus, and in men the prostate.1620 The genitofemoral nerve innervates the thigh and perineum; it is rostral and complementary to the pudendal eld. The vagus nerve innervates the upper vagina and cervix, a novel pathway that bypasses the spinal cord and projects directly to the medulla oblongata.21 ASCENDING SPINAL PATHWAYS Anterolateral columns of the spinal cord target the medullary reticular formation (MRF) and the lateral vestibular nucleus (LVN). Some bers from these hindbrain sites

Figure 3. Spinal cord module: cutaneous pressure on the genital dermatome leads to pressure on Rufni endings in the skin, and action potentials enter the spinal cord and excite second-order neurons. Adapted from Pfaff (1999, In Drive: Neurobiological and Molecular Mechanisms of Sexual Motivation. Cambridge: MIT Press) with permission.

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course to the midbrain central gray. From the central gray, signals are relayed to cells in and immediately surrounding the ventromedial nucleus (VMN) of the hypothalamus.1 NERVES TO SPINAL CORD Sensation from the external genitalia is generally conveyed within the sacral afferent parasympathetic system. Receptive elds in the perineum are thought to be carried out primarily by sensorymotor discharges associated with pudendal nerve afferents and are estrogen-inuenced.810 There is some difference in the origins of afferent bers among species; as an example, in the female rat, afferent bers of the pudendal nerve originate in the L6 and S1 dorsal root ganglia.22 In the female cat; however, afferent axons entered the spinal cord primarily at the S1 and S2 segments.23 Labeled pudendal afferent bers were located in the spinal cord. The hypogastric, pelvic, and vagus nerves contain sensory bers that convey information from the pelvic organs. In the rat, afferent bers in hypogastric and pelvic nerves supply the uterus and vagina. The former is responsive mainly to intense uterine stimulation, the latter to gentle and intense vaginal stimuli.24 Hypogastric and pelvic nerve afferent bers differ in their response to reproductive organ stimulation and convey their differing inputs separately to the T13L3 and L6S2 segmental regions. Although there are differences in primary afferent inputs, there is coordination of reproductive and pelvic function by intersegmental interactions within the spinal cord itself.22,25,26 SPINAL CORD The spinal cord (Figure 4) in its role in sexual arousal has several functions. It receives the major portion of somatosensory input, lters the input in each spinal cord segment, receives the descending facilitatory signals, and generates the motor neuronal output.1 Inputs to the dorsal horn, from both primary afferent (dorsal root) axons and from axons descending from the brain, often respect cytoarchitectural boundaries, as do a considerable number of the dendritic trees of dorsal-horn neurons. These cytoarchitectural boundaries within the dorsal horn of the cord are called Rexed layers. While Rexed layer I (the substantia gelatinosa) deals largely with mechanisms of painful sensations, neurons in Rexed layer II carry high-resolution cutaneous information having high submodality specicity. As the information lters down to Rexed layer V, receptive elds become larger and submodality signals are merged.26 The autonomic outow responsible for the command of the genital sexual response originates in the spinal cord. The afferent limb of the sexual reex is mainly conveyed by the pudendal, hypogastric, and pelvic nerves. Genital sensation still remains in some women with complete spinal cord injury, suggesting that the transmission of sensory genital information to the brain is partly spared.27 Women with sensory decits may manifest abnormalities such as spina bida, multiple sclerosis and metastatic spinal cord lesions. The vagus nerves provide a spinal-cord bypass pathway for vaginal/cervical sensibility in rats and also in women with complete spinal cord injury above the level of entry into spinal cord of the known genitospinal nerves.28,29 SUPRASPINAL NERVE CELL GROUPS All ascending arousal systems begin in the cord and/or brainstem, and converge in the thalamus or in the basal forebrain.1 They overlap and cooperate. Their very

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multiplicity ensures against failure. In the hindbrain, neurons important for sexual excitation have been found in the ventral medullary reticular formation.30,31 In contrast, another group of neurons in the paragigantocellular reticular nucleus in the ventral medulla has been identied and found to mediate descending inhibition. Correlative neuroanatomical studies indicate that the inhibition is mediated via a direct projection to pelvic efferent neurons and interneurons.32,33 Moving up the brainstem to the midbrain, both the central grey and the ventral tegmental area are involved in sexual arousal. In addition, signals from the central tegmental eld of the midbrain (probably of genitosensory origin) and from the medial amygdala (probably of olfactoryvomeronasal origin) interact to promote cellular activity in the medial preoptic area (MPOA). The MPOA is involved in both arousal mechanisms and, most prominently, in the performance of male sexual behavior.34 Neurons in the basomedial hypothalamus are more important for female sexual behavior than for males. For example, nerve cells in and immediately surrounding the ventromedial nucleus (VMN) of the hypothalamus are absolutely essential for female-typical lordosis behavior in animals.11 Heightened electrical activity in these medial hypothalamic neurons activates a phylogenetically ancient spinebrainstem spine circuit that controls axial musculature required for the vertebral dorsiexion of lordosis.

Figure 4. The bilaterally symmetric, estrogen-dependent neural circuit that produces lordosis behavior. It is drawn on one side only for clarity. Adapted from Pfaff (2006, Brain Arousal and Information Theory: Neural and Genetic Mechanisms Cambridge, Mass: Harvard University Press) with permission.

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In contrast, neurons in the medial preoptic area are more important for the execution of male sexual behavior. In animals, olfactory and pheromonal inputs via the basal forebrain to the preoptic area certainly help to activate courtship behaviors by the male which eventually will lead to mounting, intromission and ejaculation. Data are starting to accumulate about activation of the human brain associated with sexual arousal. For example, considering the basal forebrain, olfactory stimuli and certain pheromones affect arousal levels associated with sex and fear by activation of the human amygdala during sexual excitation.35 Likewise, in the basal forebrain, Robert Heath at Tulane Medical School was able to cause feelings of orgasm in a female patient by electrical stimulation of the septum. Human brain functional magnetic resonance imaging (fMRI) studies have recently been reported. The group of Gert Holstege, at the medical school of the University of Groningen, reported activation in the ventral tegmental area of the midbrain during ejaculation in males.36 During another study, in which subjects were instructed to imagine their romantic partners with whom they were infatuated, Helen Fisher at Rutgers University found activation throughout the caudate nucleus in a pattern that suggested massive, generalized arousal of extrapyramidal motor systems. Brain regions that showed activation during female orgasms included hypothalamic paraventricular nucleus, medial amygdala, anterior cingulate, frontal, parietal, and insular cortices, and cerebellum.37 Stimulation of pudendal sensory bers leads to activation of pudendal motoneurons and subsequent contraction of the striated perineal muscles in men and women. Intravaginal electrical stimulation, induced inhibition of bladder contractions and urethral closure has been noted in women and in cats, presumably to promote urinary continence during intercourse.38,39 DESCENDING PATHWAYS Anterolateral columns of the spinal cord constitute the descending pathway for sexual arousal. This is not simply a spinalbrainspinal reex but a tonic nature that reects durable estrogenic inuences originating in the hypothalamus (Figure 4). Axons descend from the VMN of the hypothalamus through a medial periventricular trajectory or through a lateral sweeping trajectory back to the midbrain reticular formation.40,41 The existence of a sexual spinal reex does not imply that the brain is restricted to an on/off switch of the spinal reex leading to female sexual genital arousal. Thus, the generation of a genital sexual response also involves ascending and descending pathways between the spinal autonomic nuclei and specic structures in the brain.4244 The presence of gabaergic and glutamatergic interneurons has been demonstrated in the medullary reticular formation and the spinal cord. It can be expected that these neurons contribute to the regulation of the intraspinal integration of information from the periphery and regulate the volume of information transmitted to supraspinal structures. NEUROTRANSMITTERS Although the interactions among the effects of sensory afferents are complex, likely possibilities include spinal cord reexive effects that excite efferent neurotransmitter release involving these ganglia and peripheral organs. Therefore, we now cover the neurotransmitters present in the postganglionic bers to the vagina and clitoris. These have been studied with immunohistochemical methods in humans and other

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mammalian species. Five major neurochemically distinct systems all work together to increase arousal. The transmitters include norepinephrine, dopamine, serotonin, acetylcholine, and histamine.45 Sensory inputs from the genitalia are possibly gated by norepinephrine at the level of the medial preoptic area. Afferent information from the genitalia carried by the dorsal clitoral/penile nerve and the availability of norepinephrine at the level of the medial preoptic area probably help in maintaining an adequate level of sexual arousal.46 Dopaminergic (DA) terminations in the basal forebrain foster sexual arousal. DA release in the preoptic area fuels sexual arousal and pursuit of females by males in vertebrates.47 Progesterone metabolites acting in VTA can foster female sexual behaviors. VTA actions on female sexual arousal are in the basal forebrain. Reported sex-hormone actions on dopamine-sensitive systems are seen there.4852 Serotonergic receptors in the hypothalamus raphe neurons can affect female sex responses such as lordosis behavior in vertebrate animals.5356 ENDOCRINE DETERMINANTS In female lower animals, sexual arousal is slavishly dependent on estrogen and progesterone. In human females, it may be possible that sexual arousal is somewhat emancipated from gonadal hormones; however, sociobiologists have found that some womens promiscuous sex happens near the time of ovulation.57 This may suggest that even human female sexual arousal is not fully independent of an endocrine inuence. Objectifying data that substantiate hormonal inuences include the role of estrogen in sensitizing tissues and nerves. Estrogen may change mechanical properties of tissue by changing movement detection, increasing the number of nerve endings, increasing the sensitivity of nerve endings, changing blood supply to the receptors, altering their sensitivity, and by mediating vaginal neuroplasticity. Specic examples of these hormonal effects on epithelium and nerves include:  estrogens may act at the periphery to alter sensory input and enlarge the genitosensory eld of the pudendal nerve58,59;  estrogens may change the mechanical properties of the tissue surrounding the hair follicles, thereby changing the movement detection by the sensory nerve endings58,59;  estrogens may increase the number or sensitivity of nerve endings58,59;  estrogens may sensitize a central state which in turn exerts a centrifugal effect on the pudendal bers by way of another nerve at the borders of receptive elds58,59;  estrogens may change the blood supply to the receptor, thus altering their sensitivity;  the epithelium must be estrogen-receptive (as is the vulvar epithelium) in order for these inuential changes in sensitivity to take place at the epithelial level58,59;  estrogen has an inuence on the maintenance of the pudendal nerve: nerve fascicles with evidence of degeneration or regeneration near injured areas appear to be spared with estrogen treatment, particularly in ventral regions60;  vaginal function as well as autonomic nerve density is regulated by estrogen61;  sex steroid receptors have been identied in neural, vascular and vulvar, and clitoral/ penile, tissue. We recognize estrogen receptors (ERs) a and b, progesterone receptors (PRs), and androgen receptors (ARs). The same receptor may have various location-dependent functions.

The neurophysiology of sexual arousal 455

GENETIC DETERMINANTS Steroid sex hormones such as estrogens, progestins and testosterone inuence the expression of certain genes in nerve cells in those specic parts of the brain that control sexual behavior performance. Inherited genetic states in animals or humans, including sex differences, demonstrate roles for genetic inuences on sexual motivation and performance capability (Figure 5). Hormones (estrogens) working through ligand-activated transcription factors (estrogen receptors expressed as ERa or ERb, likely gene duplication products) have been found to induce the expression of another transcription factor gene (PR) in the brain. The action of the PR is necessary in brain neurons for sexual behavior in animals.62,63 A large percentage of dorsal raphe cells express the gene for the sex hormone receptor ERb.5356  Mice in which the gene encoding the a form of the estrogen receptor (ERa) has been knocked out show that ERa is crucial for lordosis behavior.64  Comparing ERa, ERb and double knockouts reveals that different patterns of sexual behaviors in mice require different patterns of ER activity.64  After E2 treatment, both sexes had greatly enhanced numbers of PR-immunoreactivity-containing neurons.65  In females, maximal PR induction required the presence of at least one functional copy of ERa.65  Estrogen leads to increased gene expression for the progesterone receptor.66  Estrogen treatment induces transcription and increases excitability and reproductive behavior.66

Figure 5. A list of known genes associated with lordosis behavior, transcription levels of which are increased by estrogen. GnRH, gonadotrophin-releasing hormone. Adapted from Pfaff (2006, Brain Arousal and Information Theory: Neural and Genetic Mechanisms Cambridge, Mass: Harvard University Press) with permission.

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 Estrogens provide the structural basis for increased synaptic activity and greater behavior-facilitating output.66  Progesterone amplies the effect of estrogens on mating behavior and on the ovulatory luteinizing hormone (LH) surge.66  By working in the hypothalamus and the anterior pituitary gland, gonadotrophinreleasing hormone (GnRH) synchronizes reproductive behavior with the ovulatory surge of LH. A causal connection can be charted from one individual gene to human social behavior, but only via six causal links.66  Neural and genetic mechanisms for motivation may lead to biological understanding of functions that apply to the most primitive aspects of human mental functioning.66 SEXUAL MECHANISMS MORE IMPORTANT IN FEMALES The physiologic underpinnings of libido in its primitive biologic aspects depend on estrogenic actions on hypothalamic neurons and on neurons in the primitive limbic forebrain. These actions result in changes in gene expression for the progesterone receptor, enkephalins, oxytocin and its receptor and other neuropeptides that we have hypothesized help prepare females for more noxious aspects of courtship and mating behaviors (exposure to predation, painful stimuli from the male, etc). SEXUAL MECHANISMS MORE IMPORTANT IN MALES Androgens are deemed critical for penile tissue development, growth, and maintenance of erectile function; however, their role in erection and arousal, especially in humans, remains controversial. In the male, testosterone is aromatized to estradiol and also reduced to dihydrotestosterone (DHT). In animals E DHT can do the job to facilitate sexual behavior. In men, it is clear that loss of testosterone is associated with reduced libido; examples are Lupron therapy for sex offenders, Kallmanns syndrome, and X-linked Kallmans due to failure of migration of GnRH cells from the olfactory placode during brain development. Androgen deprivation causes penile tissue atrophy, changes in dorsal nerve structure, changes in endothelial morphology, reduced trabecular smooth muscle content, and increased deposition of extracellular matrix. There is growing insight that testosterone has profound effects on tissues of the penis involved in the mechanism of erection, and that testosterone deciency impairs the anatomical and physiological substrate of erectile capacity, reversible upon androgen replacement. The synthesis of phosphodiesterase type 5 (PDE5) is up-regulated by androgens, and the arterial inow into the penis is improved by giving androgen.67 Androgen deprivation also results in accumulation of fat-containing cells (adipocytes) in the penis in the subtunical region of the corpus cavernosum. It also diminishes protein expression and enzymatic activity of endothelial nitric oxide synthase (eNOS), neural nitric oxide synthetase (nNOS), and PDE5. After androgen-dependent loss of erectile response, restoration by androgen administration has been demonstrated. This restoration cannot be accomplished by administration of PDE5 inhibitors alone. Androgens also regulate trabecular smooth muscle growth and connective tissue protein synthesis in the corpus cavernosum.68 In humans, androgen-deciency manifestations have been noted in clinical situations such as inadequate development of the penis (micropenis), and is responsible for the

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loss of erectile function in prostate cancer and benign prostatic hyperplasia patients managed with medical or surgical castration or anti-androgen therapy. Androgen treatment has been shown to improve sexual function in hypogonadal patients treated with androgen supplementation; improve nocturnal penile tumescence in hypogonadal patients treated with androgens; improve erectile function in patients who did not respond to PDE5 inhibitor therapy initially; and improve the well-being, mood, energy, and sexual function in aging men.68 The physiologic underpinnings of libido in its biologic aspects depend on androgenic actions on the paraventricular nucleus of the hypothalamus as an integration centre between the central and peripheral autonomic nervous systems. Oxytocinergic neurons originating in this nucleus and projecting to extra-hypothalamic brain areas control penile erection. Synthesis of PDE5 is up-regulated, improving blood ow into the penis. The activation of paraventricular oxytocinergic neurons by dopamine, oxytocin, excitatory amino acids and hexarelin analogue peptides is mediated by the activation of nitric oxide (NO) synthase. NO in turn activates, by a mechanism as yet unidentied, the release of oxytocin from oxytocinergic neurons in extrahypothalamic brain areas. Paraventricular oxytocinergic neurons and mechanisms are involved in the expression of penile erection in physiological contexts. These ndings show that paraventricular oxytocinergic neurons projecting to extrahypothalamic brain areas and to the spinal cord and the paraventricular nucleus play an important role in the control of erectile function and male sexual behavior in mammals.69 Experimental castration results in impaired erectile response to central and peripheral stimulation and decrease in penile tissue concentration of NOS-containing nerves. Testosterone replacement reverses these abnormalities. In the rat penis, apoptosis is induced by castration, and new DNA synthesis is induced by testosterone replenishment. Human data are not as clear as animal data. Castration results in loss of libido and in erectile dysfunction. However, these effects are not universal. Testosterone enhances libido, frequency of sexual acts, and sleep-related erections. Its effects on erotic erections are not clear.70 SUMMARY Both genomics and the neurophysiology of sexual arousal may be hormone-dependent. Supporting evidence includes the effects hormones have on maintenance of autonomic physiology. Sex hormones are accumulated and retained by neurons of autonomic ganglia as well as by cells in the heart and blood vessels. The role of sex hormones leading to sexual arousal, erections and ejaculation is obvious. Sex hormones alter cardiovascular responses to activation of medullary neurons in the arousal crescent, and address oxytocin neurons in the PVN of the hypothalamus which project back to the spinal cord and support erection.7178 Hormones affect the brain, spinal cord and peripheral sensory mechanisms that regulate acuity of touch, taste and olfaction. They alter sensory input and change peripheral neural activity in support of arousal. In both men and women, arousal is inuenced by adrenergic, cholinergic, and nitergic activation mechanisms that control vascular changes and underlie vaginal lubrication and penile erection. These systems respond to descending brain and spinal inuences that generate orgasmic response. Disruption of endocrine, neural, or vascular response caused by aging, disease, surgery, or medication has the potential to lead to lack of arousal and sexual impairment. In humans, arousal is additionally

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impacted by psychological and relationship factors that play an important role in a healthy sexual response and may enhance or impair arousal and thus sexual function. Intersex states or disorders of sexual differentiation (DSDs), by their alterations in gene products and sex steroids, may produce alterations in the base potential for arousal properties. Alterations of tissue during genitoplasty surgery may also alter or impair neural pathways and change epithelium contacts that are crucial to transmission of sensory impulses for arousal. Gonadectomy may change the hormonal environment impacting many neurophysiological processes vital to the production of arousal. A review of the literature reveals that arousability in DSD has not been very well studied. Zuker et al present a self-report study using the Sexual Arousability Inventory Short Form (SAI-SF) of women with congenital adrenal hyperplasia (CAH). Compared to unaffected sisters and cousins, these women reported signicantly lower arousability on SAI. Noted also are higher reported levels of arousal in those women who had the simple virilizing form of CAH and in those assigned female at birth, and higher arousability in those with satisfaction with genital surgery and genital function.79

Practice points  recognize the potential for arousal disorder and sexual dysfunction in patients who have had gonadectomy  recognize the potential for arousal disorder and sexual dysfunction in patients who have had genitoplasty surgery  recognize the potential for arousal disorder and sexual dysfunction in patients who have atypical genitalia  recognize the potential for arousal disorder and sexual dysfunction in patients who are dissatised with the appearance of their genitals  estrogen therapy may be necessary for patients with DSD (assigned female) to achieve satisfactory arousability and sexual function

Research agenda  determine the impact of each specic DSD on sexual arousal capabilities  if sexual arousal problems are manifest in DSD, determine underlying factors that impact arousal  if sexual arousal disorder is found, determine treatment strategies for specic DSDs based on surgical modications and hormonal supplementation

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