Best Practice & Research Clinical Endocrinology & Metabolism

Vol. 21, No. 3, pp. 445–461, 2007

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

The neurophysiology of sexual arousal

Justine M. Schober * MD, FAAP

a
Pediatric Urologist
Visiting Professorb
a
Hamot Medical Center, 333 State Street, Suite 201, Erie, PA 16507, USA
b
Pfaff Laboratory, Laboratory of Neurobiology and Behavior, The Rockfeller University, New York, NY, USA

Donald Pfaff PhD

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 influences 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 prim-
itive, 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 uni-
versal 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 fields 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 partic-
ular subject and the possibilities of application of these principles.

* Corresponding author. Tel.: þ1 814 455 5900; Fax: þ1 814 456 0667.
E-mail address: schobermd@aol.com (J.M. Schober).
1521-690X/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.
446 J. M. Schober and D. Pfaff

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 objec-
tives. The strength of a learned response depends on both arousal and drive. Gener-
alized 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, electro-
physiological mechanisms, and genetic influences. Sexual arousal as a subcategory is de-
pendent on all of the above. In its specificity, it has additional dependent factors. Sexual
arousal is dependent on neural (sensation, cognition) factors, hormonal factors, genetic
factors, and influences 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 ep-
ithelial tissue of the vulva, genitalia, and vagina contribute to sexual arousal. These gen-
itosensory areas or fields contribute sensory information to the peripheral and central
neural areas by complex integrative mechanisms. Specific changes in genital structures
that occur after tactile stimulation of the epithelium leading to arousal in the female in-
clude increased clitoral length and diameter, labial blood engorgement, and increased
vaginal luminal diameter. In males, similar processes control penile erection. This

Figure 1. Simplified 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.
 The neurophysiology of sexual arousal 447

vasocongestive and neuromuscular process is controlled by facilitatory parasympa-

thetic and inhibitory sympathetic inputs.2 Gross internal anatomical changes, such as
elevation of the uterus and lengthening of the anterior vaginal wall, have been con-
firmed 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,
Halban’s 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 influenced 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 genito-
sensory field of the pudendal nerve.8–10 In this sensory field it has been shown that
mechanical stimulation of the skin or deflection of the fur (in the case of many ver-
tebrates) – 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 fol-
licles, 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
fields; it may sensitize a central state which in turn exerts a centrifugal effect on the
pudendal fibers by way of another nerve; it may also change the blood supply to
the receptors, thus altering their sensitivity. But in order for these influential changes
in sensitivity to take place at the epithelial level, the epithelium must be estrogen-
receptive, as is the vulvar epithelium. Conversely, no significant androgenic influence
on penile sensitivity via the pudendal nerve has been demonstrated.10

GENITAL SENSORY ACTIVATION SITES

Genital sensory activation sites (genital sensory fields) comprise the following:

 clitoris and clitoral sheath;

 anterior vaginal wall (anterior fornix wall of the vagina);
 labial/introital area;
 urethra;
 Halban’s fascia (space between anterior wall of vagina and bladder, analogous to cor-
pus spongiosum);
 G-spot (paraurethral area);
 cervix;
 penis;
 scrotum;
 perineum and thigh;
 anus and rectum;
 prostate.
448 J. M. Schober and D. Pfaff

NEURAL DETERMINANTS

When considering tactile sensory stimuli applied to areas within the genital sensory
fields, there is an increase in responsiveness as a stimulus is moved from the periphery
to the center of the field. There are also summation effects: stimuli covering smaller
areas might evoke only weak reflexes, whereas stimuli over a larger area could evoke
a stronger reflex response. There is also convergence: cutaneous stimulation from
receptive fields of corresponding areas of pressure-sensitive interneurons come to-
gether onto spinal interneurons. An overlap of dermatomes stimulated may strengthen
the stimulus delivered. As sexual arousal increases, genital sensitivity to stimuli in-
creases. There are multiple avenues to arousal through stimulation of different sites
that overlap. Also, there are many other influences 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 tis-
sue, inflammation, 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 Ruffini 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 net-
works of nerves. The Vater–Pacini 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 spe-
cific 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 cor-
puscular 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 reflex
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 compris-
ing 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
 The neurophysiology of sexual arousal 449

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 ac-
cess 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 cholin-
ergic neurons that powerfully influence 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, hypo-
gastric 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 puden-
dal 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.16–20 The genitofe-
moral nerve innervates the thigh and perineum; it is rostral and complementary to
the pudendal field. 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 fibers from these hindbrain sites

Figure 3. Spinal cord module: cutaneous pressure on the genital dermatome leads to pressure on Ruffini
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.
 The neurophysiology of sexual arousal 451

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 fields in the perineum are thought to be carried
out primarily by sensory–motor discharges associated with pudendal nerve afferents
and are estrogen-influenced.8–10 There is some difference in the origins of afferent fibers
among species; as an example, in the female rat, afferent fibers 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
fibers were located in the spinal cord. The hypogastric, pelvic, and vagus nerves contain
sensory fibers that convey information from the pelvic organs. In the rat, afferent fibers 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 fibers differ in their response to reproductive
organ stimulation and convey their differing inputs separately to the T13–L3 and L6–S2
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, filters 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 informa-
tion having high submodality specificity. As the information filters down to Rexed layer
V, receptive fields become larger and submodality signals are merged.26
The autonomic outflow responsible for the command of the genital sexual re-
sponse originates in the spinal cord. The afferent limb of the sexual reflex 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 transmis-
sion of sensory genital information to the brain is partly spared.27
Women with sensory deficits may manifest abnormalities such as spina bifida, 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
452 J. M. Schober and D. Pfaff

multiplicity ensures against failure. In the hindbrain, neurons important for sexual ex-
citation 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 identified 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 mid-
brain, both the central grey and the ventral tegmental area are involved in sexual
arousal. In addition, signals from the central tegmental field of the midbrain (probably
of genitosensory origin) and from the medial amygdala (probably of olfactory–vomer-
onasal 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 per-
formance 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 spine–brainstem–
spine circuit that controls axial musculature required for the vertebral dorsiflexion
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.
 The neurophysiology of sexual arousal 453

In contrast, neurons in the medial preoptic area are more important for the exe-
cution 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 cer-
tain 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 insu-
lar cortices, and cerebellum.37 Stimulation of pudendal sensory fibers leads to activa-
tion 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, pre-
sumably 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 spinal–brain–spinal reflex but a tonic nature that reflects
durable estrogenic influences originating in the hypothalamus (Figure 4).
Axons descend from the VMN of the hypothalamus through a medial periventric-
ular trajectory or through a lateral sweeping trajectory back to the midbrain reticular
formation.40,41 The existence of a sexual spinal reflex does not imply that the brain is
restricted to an on/off switch of the spinal reflex 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 specific structures
in the brain.42–44 The presence of gabaergic and glutamatergic interneurons has been
demonstrated in the medullary reticular formation and the spinal cord. It can be ex-
pected 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 reflexive effects that excite efferent neurotransmit-
ter release involving these ganglia and peripheral organs. Therefore, we now cover
the neurotransmitters present in the postganglionic fibers to the vagina and clitoris.
These have been studied with immunohistochemical methods in humans and other
454 J. M. Schober and D. Pfaff

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 main-
taining 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 me-
tabolites acting in VTA can foster female sexual behaviors. VTA actions on female
sexual arousal are in the basal forebrain. Reported sex-hormone actions on dopa-
mine-sensitive systems are seen there.48–52 Serotonergic receptors in the hypothal-
amus raphe neurons can affect female sex responses such as lordosis behavior in
vertebrate animals.53–56

ENDOCRINE DETERMINANTS

In female lower animals, sexual arousal is slavishly dependent on estrogen and proges-
terone. In human females, it may be possible that sexual arousal is somewhat emanci-
pated from gonadal hormones; however, sociobiologists have found that some
women’s 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 influ-
ence. Objectifying data that substantiate hormonal influences include the role of estro-
gen 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, al-
tering their sensitivity, and by mediating vaginal neuroplasticity. Specific examples of
these hormonal effects on epithelium and nerves include:

 estrogens may act at the periphery to alter sensory input and enlarge the genitosen-
sory field 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 fibers by way of another nerve at the borders of receptive fields58,59;
 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 influential changes in sensitivity to take place at the epithelial level58,59;
 estrogen has an influence 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 identified in neural, vascular and vulvar, and clitoral/
penile, tissue. We recognize estrogen receptors (ERs) a and b, progesterone recep-
tors (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 influence the
expression of certain genes in nerve cells in those specific parts of the brain that con-
trol sexual behavior performance. Inherited genetic states in animals or humans,
including sex differences, demonstrate roles for genetic influences on sexual motiva-
tion and performance capability (Figure 5).
Hormones (estrogens) working through ligand-activated transcription factors (es-
trogen 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.53–56

 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-immunoreac-
tivity-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 reproduc-
tive 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.
456 J. M. Schober and D. Pfaff

 Estrogens provide the structural basis for increased synaptic activity and greater
behavior-facilitating output.66
 Progesterone amplifies the effect of estrogens on mating behavior and on the ovu-
latory luteinizing hormone (LH) surge.66
 By working in the hypothalamus and the anterior pituitary gland, gonadotrophin-
releasing 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 es-
trogenic actions on hypothalamic neurons and on neurons in the primitive ‘limbic’
forebrain. These actions result in changes in gene expression for the progesterone re-
ceptor, 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 mainte-
nance of erectile function; however, their role in erection and arousal, especially in hu-
mans, remains controversial. In the male, testosterone is aromatized to estradiol and
also reduced to dihydrotestosterone (DHT). In animals E þ 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, Kallmann’s syn-
drome, and X-linked Kallman’s 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 struc-
ture, changes in endothelial morphology, reduced trabecular smooth muscle content,
and increased deposition of extracellular matrix. There is growing insight that testos-
terone has profound effects on tissues of the penis involved in the mechanism of erec-
tion, and that testosterone deficiency 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 in-
flow into the penis is improved by giving androgen.67
Androgen deprivation also results in accumulation of fat-containing cells (adipo-
cytes) 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 pro-
tein synthesis in the corpus cavernosum.68
In humans, androgen-deficiency manifestations have been noted in clinical situations
such as inadequate development of the penis (micropenis), and is responsible for the
 The neurophysiology of sexual arousal 457

loss of erectile function in prostate cancer and benign prostatic hyperplasia patients
managed with medical or surgical castration or anti-androgen therapy. Androgen treat-
ment 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 neu-
rons originating in this nucleus and projecting to extra-hypothalamic brain areas con-
trol penile erection. Synthesis of PDE5 is up-regulated, improving blood flow 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 unidentified,
the release of oxytocin from oxytocinergic neurons in extrahypothalamic brain areas.
Paraventricular oxytocinergic neurons and mechanisms are involved in the expres-
sion of penile erection in physiological contexts. These findings show that paraventric-
ular 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 periph-
eral 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 replenish-
ment. 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 en-
hances 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-depen-

dent. Supporting evidence includes the effects hormones have on maintenance of au-
tonomic 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 hor-
mones 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.71–78 Hormones affect the brain, spinal
cord and peripheral sensory mechanisms that regulate acuity of touch, taste and olfac-
tion. They alter sensory input and change peripheral neural activity in support of
arousal.
In both men and women, arousal is influenced by adrenergic, cholinergic, and niter-
gic activation mechanisms that control vascular changes and underlie vaginal lubrica-
tion and penile erection. These systems respond to descending brain and spinal
influences that generate orgasmic response. Disruption of endocrine, neural, or vas-
cular 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
458 J. M. Schober and D. Pfaff

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 transmis-
sion of sensory impulses for arousal. Gonadectomy may change the hormonal environ-
ment 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 stud-
ied. 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 significantly lower arousabil-
ity 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 dissatisfied 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 specific 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 specific
DSDs based on surgical modifications and hormonal supplementation

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