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The Leslie and Susan Gonda (Goldschmied) Diabetes and Genetic Research Center, Department of Diabetes, Endocrinology & Metabolism, City of Hope National Medical Center, Duarte, California 91010; and Department of Medicine, Harbor-UCLA Medical Center, Torrance, California 90502
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Abstract |
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 Top Abstract I. IntroductionII. Physiology of Male...III. Disorders of Male...IV. Diagnostic Assessment of...V. TreatmentVI. Summary and Future...References |
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I. Introduction
II. Physiology of Male Sexual Function
A. Penile structure, vasculature, and innervation
B. Normal penile and testicular size in adult males
C. Local control of penile erection
D. Normal control of male sexual response
E. Penodynamic changes during the male sexual cycle
F. Nocturnal penile tumescence (NPT)
G. Male sexual function and aging
III. Disorders of Male Sexual Function
A. Disorders of desire
B. Erectile dysfunction
C. Disorders of ejaculation
D. Disorders of orgasm
E. Failure of detumescence
IV. Diagnostic Assessment of Sexual Dysfunction in the Male
A. History
B. Physical examination
C. Selective investigations for male sexual dysfunction
V. Treatment
A. Hypoactive or deficient sexual desire
B. Partial or complete erectile dysfunction
C. Disorders of ejaculation
D. Absence of orgasm
E. Failure of detumescence (priapism)
F. Effect of sexual dysfunction and its treatment on quality of life in
VI. Summary and Future Directions
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I. Introduction |
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TopAbstractI. IntroductionII. Physiology of Male...III. Disorders of Male...IV. Diagnostic Assessment of...V. TreatmentVI. Summary and Future...References |
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Significant advances in the understanding of the physiology and pathophysiology of male sexual function, and in methods of its investigation and treatment, have been attained during the past three decades. In the field of physiology, the nature and elements of the normal sexual response have been delineated, and functional activities of all penile structures have been clarified and integrated. The exact role of the various components of the neural system has also become more fully understood. In the field of pathophysiology, estimations of the relative contribution of psychogenic and organic factors to genesis of the various forms of male sexual dysfunction have approached the reality; and many risk factors for development of organic dysfunction have been identified. In the field of physical and laboratory evaluation, many new psychometric, hormonal, vascular, and neurological investigative procedures have been attempted. As a result, sound techniques for accurate prediction of functional and structural changes are now emerging.
This review describes many of these recent advances in the understanding of male sexual function and its disorders. Currently available methods of investigation are outlined and clinical algorithms for their use are presented. Recently developed strategies in psychological, medical, and surgical treatments are also summarized and related to the relevant pathophysiology. It is hoped that information provided in this review will help scientists and healthcare policy makers to develop appropriate and timely strategies to meet current and future demands to prevent and/or alleviate male sexual dysfunction. It is also hoped that material provided in this review will help the reproductive endocrinologist to widen the scope of his or her professional activity from the limited focus on gonadal function to the wider consideration of all inseparable and integrated aspects of human sexual and reproductive capacities.
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II. Physiology of Male Sexual Function |
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TopAbstractI. IntroductionII. Physiology of Male...III. Disorders of Male...IV. Diagnostic Assessment of...V. TreatmentVI. Summary and Future...References |
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) (2). Histologically, the tissue of the
corpora cavernosa consists of bundles of smooth muscle fibers
intertwined in a collagenous extracellular matrix. Interspersed within
this parenchyma is a complex network of endothelial cell-lined sinuses,
or lacunae, helicine arteries, and nerve terminals.
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The autonomic innervation of the penis is both parasympathetic and
sympathetic (Fig. 2). The major efferent
parasympathetic pathway originates in the intermediolateral aspect of
the sacral cord (S2–S4)
traveling in the pelvic nerve (Nervi Erigentes) to supply a
vasodilating innervation to the corporeal bodies. After the
parasympathetic nerve fibers exit the spinal cord, they run
through the retroperitoneal space in the lateral aspect of the
rectum and bladder, and then pass inferiorly and laterally toward the
prostate and urogenital diaphragm. The cavernous nerve enters the
corporeal body alongside the cavernous artery at the crura of the
corpora as preganglionic nerve fibers. The most likely neurotransmitter
at the synaptic end of these fibers is acetylcholine. The
postganglionic nerve fiber segments terminate either on the vascular
smooth muscle of the corporeal arterioles or the nonvascular smooth
muscle of trabecular tissue surrounding the corporeal lacunae (see Ref.
3 for review). The sacral parasympathetic neurons are chiefly
responsible for the erectile function and are influenced by a
cortical-sacral efferent pathway. The penile erection can be initiated
with a single episode of pelvic nerve electrical stimulation.
Maintenance of erection for an extended period of time without
significant changes in corporeal body blood gases can be achieved with
repetitive stimulation for 40–50 sec, with a minimum latency period of
50 sec between each stimulus (3). The sympathetic innervation of
the penis mediates the detumescence after the orgasmic relief, and in
the absence of sexual arousal it maintains the penis in the flaccid
state.
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Reports on penile volume are limited and have relied either upon the measurement of penile circumference manually (5) or penile cross-section by ultrasound techniques (4, 6, 7). The increase in central obesity may contribute to occasionally reported decrease in penile length with age. There is a loss of tensile strength of the tunica as men grow older, but no loss of the tunica albuginea itself.
Normally, the testis increases in size from 1–3 cm3 during the neonatal period of life to 15–30 cm3 in adulthood. The germ cells and seminiferous tubules represent 90% of the testicular volume while Leydig cells contribute to less than 1%. A normal size adult testis has dimensions of 4.1–5.2 cm in length and 2.5–3.3 cm in width (8). Based on the available data, Wessells and colleagues (4) considered adult men with penile length of greater than 4 cm in the unstretched flaccid state or greater than 7.5 cm in the stretched flaccid state or the erect state to have a normal penile length. No parallel suggestions were made for penile girth or volume.
C. Local control of penile erection
Acetylcholine appears to be the neurotransmitter of the
preganglionic parasympathetic neurons. The neurotransmitters for the
short postganglionic neurons have not been fully defined. Acetylcholine
does not appear to influence the contractility of the corporeal smooth
muscle fibers directly, but does so through activation of cholinergic
receptors on the endothelial cells (Fig. 3). Nitric oxide (NO) has been identified
in the corporeal tissue (9) and is believed to be the
endothelial-derived relaxation factor(s). NO is synthesized from its
precursor, L-arginine, by the enzyme nitric oxide synthase
(NOS). Both constitutive and inducible NOS isoforms are produced in the
cavernosal tissues (10, 11). Constitutive NOS is produced by the
endothelial cells and the nerve terminals, whereas the inducible NOS
appears to be produced by the corporeal smooth muscle cells only.
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Other noncholinergic parasympathetic neurotransmitters capable of promoting smooth muscle relaxation, and hence the erectile response, include vasoactive intestinal polypeptide (VIP), bradykinin, peptide histidine methionine, pituitary adenylate cyclase-activating polypeptide, helospectin, galanin, calcitonin gene-related peptide (CGRP), and prostaglandin E-1 (18, 19, 20, 21). Before the identification of NO in the penile tissue, VIP was thought to be the chief neuromediator of the erectile function; however, VIP was found to colocalize with NOS in penile neurons of rats and humans (22). Its relaxation effect on the corporeal smooth muscle fibers appears to be mediated by the NO-cGMP pathway (23) similar to bradykinin’s ability to stimulate the endothelial NOS pathway to generate NO (24). However, the exact mechanisms by which other neuropeptides participate in regulation of the erectile function remain to be determined.
Norepinephrine is responsible for regulation of corpus cavernosum
smooth muscle tone via the interaction with 
-1 and -2 adrenergic
receptors (25). Other neurotransmitters capable of promoting smooth
muscle contraction, and hence detumescence, include endothelin-1,
substance-P, PGF-2, thromboxane A-2, angiotensin II, and calcium
(18, 20, 26, 27, 28, 29, 30). Some of these agents exert their effect through
modulation of the presynaptic -2 adrenergic receptors. A role for
sympathetic innervation of the penis in mediation of psychologically
provoked erection has been suggested, but the validity of such a belief
was disputed based upon the observation of a full retainment of
erectile capacity in men who undergo bilateral complete sympathectomy
(31, 32). However, the recent in vitro studies demonstrating
the relaxation effect of the ß-2 adrenergic receptor agonist
isoproterenol on noradrenaline-precontracted human penile smooth muscle
cells (33) suggest that, at least in some situations, ß-adrenergic
innervation could participate in the mediation of human erection.
-1 Adrenergic receptors are the preponderant subtype in corporeal
smooth muscles (34) and the deep dorsal penile vein (35), whereas -2
receptors dominate in the cavernosal arteries (34). However, no
quantitative differences in the prevalence of the two subtypes have
been found in the circumflex veins of either potent or impotent men.
Crowe and colleagues (36) found the greatest density of nerves
supplying the deep dorsal vein and the vasa vasorum to be (in
decreasing order) neuropeptide-Y (NPY), VIP, and
dopamine-ß-hydroxylase-containing nerves. These investigators
proposed that NPY, by its prolonged vasoconstricting effect, may aid in
penile erection, and the vasodilating effect of VIP may be involved in
facilitating the drainage of penile blood during detumescence. A recent
series of in vitro experiments by Segarra and colleagues
(37) using ring segments of human penile dorsal vein has provided
additional evidence for an active role of the deep dorsal vein in the
total penile vascular resistance through the release of NO from both
neural and endothelial elements.
The presence of a critical balance of smooth muscle to connective
tissue has been suggested for the successful veno-occlusion and the
manifestation of erectile response to occur. A potential role for
transforming growth factor ß-1 (TGF-ß1) and PGE-1 in maintaining
this critical balance of smooth muscle/connective tissue and a role for
intracorporeal oxygen tension in regulation of synthesis of these
regulatory factors have also been suggested (38). Thus, neuronal
dysregulation or poor intrinsic compliance of the corporeal smooth
muscle cells could be a significant factor in the pathogenesis of
erectile dysfunction (Fig. 4) (39).
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D. Normal control of male sexual response
Sexual stimulation of the human male results in a series of
psychological, neuronal, vascular, and local genital changes. At least
three different classifications for these changes have been described.
Kolodny et al. (40) described a psychosexual response cycle
that consists of four phases: excitement, plateau, orgasm, and
resolution. Table 1 describes neural
pathways, end-organ changes, penile hemodynamic changes, and genital
responses that occur during each phase of this cycle.
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A third classification focuses on the functional activities during the sexual cycle (43). It adds an initial phase of desire or libido to encompass the sex-seeking behavior, pools together excitement and plateau into a single phase of erection, and splits the orgasmic phase into the physical function of ejaculation and the psychological sensation of orgasmic pleasure. Thus, the normal male sexual response cycle can be functionally divided into five interrelated events that occur in a defined sequence: libido, erection, ejaculation, orgasm, and detumescence. Since the functional classification of the male sexual cycle is the most physically quantifiable one, it will constitute the basis for the following discussion.
1. Libido or sexual desire. Libido is defined as the biological need for sexual activity (the sex drive) and frequently is expressed as sex-seeking behavior. Its intensity is variable between individuals as well as within an individual over a given time. Little is known about the physiological basis of libido. However, previous and recent sexual activity, psychosocial background, brain and spinal cord dopaminergic receptor activation, and gonadal hormones are among the factors that are believed to participate in regulation of male sexual desire.
Several lines of evidence in animal and human males support a role for
central dopaminergic neurotransmission in mediating sexual behavior and
erection (see Ref. 44 for review). Further, testosterone promotion of
copulation appears to be mediated by an increase in dopamine release in
the medial preoptic area, possibly via up-regulation of NO synthesis
(45). A role for dopaminergic activation in stimulation of sexual
behavior in the human is supported by the following observations:
administration of the dopamine agonists apomorphine, bromocriptine, and
pergolide mesylate frequently elicits spontaneous penile erection; use
of the dopamine precursor levodopa is associated with increased libido
(46), return of spontaneous erection (47), or onset of nocturnal
emissions (48) in 20–30% of patients with Parkinson’s disease who
are treated with this agent; and use of pharmacological agents with
antidopaminergic effects is associated with decreased libido and
erectile dysfunction in up to 50% of cases. However, caution must be
exerted in interpreting some of these data for the following reasons:
lack of consistency in the results of many investigations;
pharmacological agents used may stimulate or inhibit other central
neuromediator systems, including adrenergic, cholinergic, serotonergic,
histaminic, and peptidergic systems; and many neuroleptics increase PRL
secretion, which can decrease libido through inhibition of the
hypothalamic-pituitary- gonadal axis or inhibition of
5-reductase activity (49).
Evidence for a role of androgens in regulation of sexual behavior in the human male has been reviewed by Mooradian and colleagues (50). Higher serum testosterone appears to be associated with greater sexual activity in healthy older (51) but not younger (52) men. Further, higher testosterone levels may also shorten the latency of erection stimulated by the exposure to erotic material (53), and testosterone replacement in hypogonadal males restores sexual interest (54), shortens latency, and increases frequency and magnitude of nocturnal penile tumescence (NPT) (55). Conversely, withdrawal of androgen therapy in hypogonadal males leads to a decline of libido in 3–4 weeks (56), and unreplaced hypogonadal men have impairment in spontaneity of erection (56, 57). Despite these androgen deficiency-related abnormalities, hypogonadism does not appear to compromise the ability to achieve erection in response to viewing of erotic films (55, 58).
2. Erection. Erection is the ultimate response to multiple psychogenic and sensory stimuli from imaginative, visual, auditory, olfactory, gustatory, tactile, and genital reflexogenic sources, which effect several neurological and vascular cascades that lead to penile tumescence and rigidity sufficient for vaginal penetration. Further, erection is associated with significant psychological and physical changes, including heightened sexual arousal, full testicular assent and swelling, dilatation of the urethral bulb, an increase in glans and coronal size, cutaneous flush over the epigastrium, chest, and buttocks, nipple erection, tachycardia and elevation in blood pressure, hyperventilation, and generalized myotonia (40, 59). The local penile changes are effected by a vasodilating parasympathetic discharge subsequent to the central nervous system (CNS) inputs or as a result of reflex action in response to local afferent stimulation of the sacral parasympathetic nuclei.
New data implicating gonadal androgens in modulation of penile erection through local regulation of NO secretion and/or action need to be emphasized. Experiments that have shown castrated rats to have reduced penile tissue NOS content and androgen replacement to restore NOS production and action (60) have cast doubt on the older dogma that androgens act only centrally to modulate sexual libido. Data in which androgens were shown to influence the frequency of nonerotic or "reflex" erection support a role for peripheral androgen actions in the human (61). Moreover, a recent study in rats by Lugg and colleagues (62) implicates dihydrotestosterone and not testosterone as the local modulating androgen of the NO-cGMP pathway. However, the fact that androgens can enhance NPT, but not erection in response to erotic stimuli (61), may suggest the presence of both androgen-sensitive and androgen-insensitive central pathways for erectile control.
3. Ejaculation. The ejaculation phase is controlled by sympathetic innervation of the genital organs and occurs as a result of a spinal cord reflex arc. There is a considerable voluntary inhibitory control over this phase of the sexual response, which consists of two sequential processes. The first process is called emission and is associated with deposition of seminal fluid into the posterior urethra. Simultaneous contractions of the ampulla of the vas deferens, the seminal vesicles, and the smooth muscles of the prostate (43, 63) mediate emission. The second process is the true ejaculation and results in expulsion of the seminal fluid from the posterior urethra through the penile meatus.
Evidence reviewed by Segraves (44) suggests that serotonergic neurotransmission has an inhibitory effect on male sexual function and ejaculation. The inhibitory action of serotonin neurotransmission on ejaculation is likely to be mediated by the serotonergic tracts in the medial forebrain bundle.
4. Orgasm. Both physiological and psychogenic elements contribute to genesis of the orgasmic phase (43, 64). Afferent stimuli that transmit via the pudendal nerve induce the following physiological events: smooth muscle contraction of the accessory sex organs; buildup and release of pressure in the posterior urethra; sensation of the ejaculatory inevitability; contraction of the urethral bulb and perineum; rhythmic contractions of the pelvic floor muscles; semen emission and ejaculation; and finally, the reversal of the generalized physiological changes and sexual tension. Sensory cortical neurons perceive these events as pleasurable. Factors that influence the subjective sensation of orgasmic pleasure include the degree of sexual excitement, recency of sexual activity, and the psychosexual makeup of the individual. It is possible for orgasm to occur without being preceded by the previous two phases of erection and ejaculation. Conversely, contractions of pelvic musculature and ejaculation could occur in the absence of orgasmic sensations.
5. Detumescence. During this phase the penis returns to the
flaccid state. Vasoconstriction of the arterioles and reversal of
events within the contractile corporeal units divert the blood away
from the cavernous sinuses and allow an increase in the venous drainage
of their contents. Initially, the rate of blood outflow increases by
about 10-fold, followed by a progressively decreasing rate until it
reaches the pretumescence level (63) and a period of inhibition to
resumption of erectile and ejaculatory functions. The length of this
refractory phase is dependent upon many variables including age,
physical state, and psychological environment (43, 63, 64). However,
the traditional view that assumes male orgasm is instantly followed by
detumescence and refractoriness has recently been challenged by
reported observations in which some men were multiorgasmic, and the
phenomenon of repeated orgasms without intervening detumescence and
refractoriness was actively learned by some males (65). Local penile
-adrenergic receptor activation is the most important neuromediator
effecting detumescence. Interference with this function through the
-1 receptor blockade may lead to the development of priapism (66).
E. Penodynamic changes during the male sexual cycle
The evidence reviewed above suggests that a fall of resistance
within the corporeal vascular bed and the subsequent increase in
arterial inflow are the major vascular events leading to erection of
the penis (Figs. 4
and 5) (39, 63, 67). A
dramatic increase in penile arterial blood flow to about 25 to 60 times
that of the flaccid state occurs during the rapid period of tumescence
(63). Pulse Doppler analysis studies with intracavernous vasoactive
drug injections have established that a peak cavernosal artery systolic
flow greater than 25 ml/sec is required for erection to occur (68, 69, 70, 71).
At full rigidity, an increase in penile length of 7.5 cm usually
requires the entrapment of 80–115 ml of blood. As the penile volume
increases to near maximum (from <10 ml in the flaccid state to 
60
ml in the erect state), the arterial influx declines and plateaus at a
level that is sufficient to keep the penis in the rigid (full erection)
state. Dynamic infusion cavernosometry and cavernosography (DICC)
studies have shown that a fluid flow rate between 5 and 40 ml/min is
required to maintain a normal penis in the erect state (72, 73).
Further, at these minimum flow rates of full erection, the cavernosal
artery occlusion pressure (CAOP) equilibrates with the intracavernous
pressure.
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F. Nocturnal penile tumescence (NPT)
NPT refers to spontaneous penile erections that occur during the
rapid eye movement (REM) stage of sleep. The phenomenon occurs four to
five times per night at 90-min intervals, and each episode lasts 30–45
min. Total NPT time ranges between 90 and 180 min per night and
accounts for 20–25% of the total sleep time (67, 74, 75, 76). Ninety
percent of REM sleep episodes are associated with penile tumescence,
with maximum changes in circumference and about 70% of full rigidity.
The number of erectile and maximum tumescence episodes decreases with
age, from 6.8 and 4 per night at age 13 yr, to 3.5 and 1.7 per night at
age 70 yr, respectively. As a result, total tumescence time decreases
by about 25% between these two ages. Most dreams associated with NPT
are not associated with erotic content. Erections on waking usually
represent NPT associated with the last episode of REM sleep and are not
related to bladder fullness (see Ref. 75 for review).
Serum androgen concentrations may have a role in regulation of NPT (54, 55, 58, 77). In addition, studies during waking and sleep in normal
males and in men with erectile insufficiency suggest that -2
antagonists enhance central arousability of the kind that is androgen
dependent. These studies also suggest that more than one
norepinephrine-mediated system is involved in this process, with
possible contrasting and counteracting effects (77, 78).
A small number of studies have reported on the effect of
pharmacological agents on NPT. Antidepressants and antihypertensives
are the most investigated classes of drugs for their effect on NPT.
Trazodone, an antidepressant with complex pharmacological effects
including serotonin reuptake inhibition, prolongs NPT while it
decreases REM sleep duration (79). In contrast, amitriptyline (a
tricyclic antidepressant) and mianserin (a tetracyclic -2 receptor
blocker) decrease both the amplitude and duration of NPT (80). Varying
effects on NPT have been seen with different members of the ß-blocker
family (81, 82, 83).
G. Male sexual function and aging
Males reach peak sexual capacity in the late teens. With
advancement of age, a gradual decrease in sexual responsiveness occurs
(84), characterized by a prolongation of the time required to achieve
full erection and decrease in the effectiveness of psychic and tactile
stimuli. The plateau phase is also prolonged, and the maintenance of
erection requires continuing direct genital stimulation. Orgasm and the
feeling of ejaculatory inevitability frequently become less intense.
Penile detumescence occurs more rapidly and the refractory period is
more prolonged. The ejaculatory volume also decreases with age. Recent
studies in rats have shown that advanced age is associated with a
decrease in the number of NOS-containing penile nerve fibers, erectile
response to apomorphine stimulation, and maximum intracavernous
pressure. It is not clear at present whether some of these changes are
related to the age-associated decline in serum testosterone
concentrations.
The effects of age on male reproductive physiology have recently been
reviewed (85). Aging is associated with decreased total serum and
bioavailable testosterone concentrations, decreased testosterone to
estradiol ratio, increased sex hormone-binding-globulin (SHBG) leading
to increased plasma protein binding of circulating testosterone and
decreased testosterone clearance, decreased LH pulse frequency, and
diminished accumulation of 5-reduced steroids in reproductive
tissues. Some of these changes are related to the increased incidence
of idiopathic hypogonadotropic hypogonadism (86) and/or a decline in
serum levels of GH, insulin-like growth factor-1 (IGF-1), and
dehydroepiandrosterone sulfate (DHEA-S) (85). Normally, IGF-I enhances
the Leydig cell response to LH, and DHEA-S provides a precursor for
testosterone production.
Recent studies, such as the Massachusetts Male Aging Study, showed that
between the ages of 40 and 70 yr, serum levels of both free- and
albumin-bound testosterone decrease annually by about 1% (87). Several
studies have confirmed the role of obesity in the decline of androgen
levels in aging men (88). Both age- and obesity-related reduction in
gonadal hormones are caused by a parallel decline in the functional
capacity of the hypothalamic-pituitary axis (88). A decrease in number
of testicular Leydig cells (82) and in their secretory capacity for
testosterone in response to hCG injections (89) in aging men has also
been shown. Recent studies have implicated leptin (the obese
ob gene product) in the development of some of these
abnormalities. Decreased testosterone production with age could be due
to a decrease in dehydroepiandrosterone (DHEA) and DHEA-S formation
(90) as a result of a differential decrease in the side chain cleavage
(17,20-lyase activity) rather than in the 17-hydroxylation of the
cytochrome P450C17 enzyme system. This decrease
in 17,20-lyase activity restricts the metabolic conversion of 17--
hydroxy progesterone to DHEA and its steroid derivatives, including
testosterone (91).
Korenman and colleagues (92) have suggested that 90% of older men with reduced testosterone concentration have evidence of hypothalamic-pituitary dysfunction as reflected by a low-normal serum LH and reduced LH response to GnRH stimulation. A few other studies have also shown the absence of correlation between erectile dysfunction and testosterone concentration (93). However, since long-standing hypogonadal men usually complain of loss of sexual interest and activity, decrease in seminal emission volumes, loss of nocturnal and morning erections, and loss of energy and sense of well-being, and, since testosterone replacement is associated with improved self-reported libido, sexual potency, and both subjective (56, 57) and objective measures of nocturnal erections (94), severe testosterone deficiency is likely to be the primary cause of sexual dysfunction in many cases of combined hypogonadism and erectile dysfunction.
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III. Disorders of Male Sexual Function |
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The National Institutes of Health (NIH) Consensus Development Conference (96) advocated that "erectile dysfunction" be used instead of "impotence" to describe disorders of male sexual function and defined the new terminology as the "inability to achieve an erect penis as part of the overall multifaceted process of male sexual function." However, use of the term "erectile dysfunction" to refer to all aspects of male sexual dysfunction would be inappropriate.
Major advances have been made in the last few years toward
understanding the nature of various forms of male sexual dysfunction
and the possible underlying organic and psychological factors. Table 2 lists the clinical manifestations and
the most common etiological categories for sexual dysfunction in the
male. Identification of the sexual response component central to the
dysfunction can significantly reduce the number of investigations
required to characterize the underlying etiology(s) (97). However, the
exact contribution of each etiological category to the genesis of a
given dysfunction may be difficult to establish, but the knowledge of
its presence is essential to treatment planning.
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Psychogenic conditions leading to a desire deficiency state in men (previously termed desire inhibition) include psychiatric illnesses such as depression or psychosis, preoccupation with life crisis or grief, maternal transference to sexual partners, gender identity conflicts, and aging-related psychological issues (57, 97, 101). Another form of secondary desire disorder caused by psychological factors is termed "excitement inhibition" and is seen in patients who have sexual drive but cannot maintain excitement. It is commonly seen in patients with performance anxiety due to the fear of sexual failure and the vigilant preoccupation with erection during lovemaking (57, 101). Traumatic employment or marriage-related issues may contribute to diminished self-image and heightened anxiety leading to male sexual dysfunction. A substantial number of patients with affective disorder, chronic depression, and obsessional personality may also develop a desire disorder. A high frequency of sexual dysfunction was also reported in males with schizophrenia (102).
Patients with a primary CNS disease such as partial epilepsy (103), Parkinsonism (104), poststroke (95), and adreno-leukodystrophy (105) may have diminished sexual arousal. The pathogenesis of desire insufficiency in these disorders appears to be multifactorial in origin and includes disease-related hormone abnormalities, physical restrictions, and reduced general well-being.
A critical level of blood androgens is required for the maintenance of normal sexual desire, NPT, and nonerotic penile erections in most men. A certain concentration of androgens is required for initiation and maintenance of spermatogenesis and for maximum stimulation of growth and function of the prostate and seminal vesicles (43, 67). The amount of androgens required for these latter effects is greater than that needed for maintenance of libido.
Not all studies that have examined the relationship between serum testosterone and sexual desire in aging men have reported a robust relationship. Therefore, total or free-testosterone levels may not be an adequate measure of sexual drive, at least in some populations.
A number of pharmacological agents or drugs of addiction could potentially induce libido dysfunction, including antihypertensives (chlorthalidone, guanadrel, guanethidine, methyldopa, reserpine, and spironolactone), psychiatric medications (fluoxetine, barbiturates, clomipramine, and fluphenazine), and others (danazol, digoxin, ethinyl-estradiol, ketoconazole, methadone, niacin, alcohol, diazepam, and marijuana) (99, 100, 106, 107, 108).
Several mechanisms of action exist for drugs commonly associated with male sexual dysfunction. Drugs that create HSD can have sedating effects and/or produce a central neurogenic blockade. Testosterone deficiency and antagonism may also lead to HSD. Medications that produce an elevation in PRL or induce parasympatholysis can manifest erectile dysfunction. Absence of emission and/or retrograde ejaculation can be found in men using antihypertensives, monoamine oxidase (MAO) inhibitors, or antipsychotics due to sympatholysis. Lastly, delayed ejaculation and/or orgasmic dysfunction may occur with selective serotonin reuptake inhibitors (SSRI) usage due to serotonergic agonist effects.
Another group of desire disorders with psychological bases is known as compulsive sexual behaviors (CSBs) (109, 110). CSBs constitute a wide range of complex sexual behaviors that have strikingly repetitive, compelling, or driven qualities. They usually manifest as one or more of several aberrant sexual behaviors, including obsessive-compulsive sexuality (e.g., excessive masturbation and promiscuity), excessive sex-seeking in association with affective disorders (e.g., major depression or mood disorders), addictive sexuality (e.g., attachment to another person, object, or sensation for sexual gratification to the exclusion of everything else), and sexual impulsivity (failure to resist an impulse or temptation for sexual behavior that is harmful to self or others such as exhibitionism, rape, or child molestation). Detailed discussion of these disorders is beyond the scope of this review and can be found elsewhere (109, 110).
B. Erectile dysfunction
This is best defined as persistent failure to generate sufficient
penile body pressure to achieve vaginal penetration and/or the
inability to maintain this degree of penile rigidity until ejaculation
(63). Although the exact prevalence of erectile dysfunction in the
United States male population is not known, estimates have ranged from
12% of males above age 18 in the report of Furlow (111) to 25–30% of
men between ages 60 and 70 in the surveys of Kinsey and colleagues
(59), Schiavi and colleagues (112), and Diokno and colleagues
(113), and to 52% in the Massachusetts Male Aging Study (93).
The current literature on the relationship between sexual dysfunction and psychiatric disorders in men is not extensive, and much of the older literature is limited by methodological flaws. However, several new studies have established some association between sexual dysfunction and psychological disorders. In the Massachusetts Male Aging Study, male erectile dysfunction was found to be associated with depressive symptoms (odds ratio 1.82) (114). Similar results were reported by at least one other study in which depressed patients with erectile dysfunction had lower libido and were more likely to discontinue treatment for their erectile problem than other patients without depression (115). Further, in the cross-sectional Massachusetts Male Aging Study the incidence of moderate to complete erectile dysfunction was estimated to be nearly 90%, 60%, and 25% in men with severe, moderate, and minimal depression, respectively (114). In addition, older studies have estimated that approximately one-third of all patients with untreated depression have reported sexual dysfunction (116). The association between male erectile dysfunction and panic disorder (117) and perfectionism (118) has also been reported.
Many commonly prescribed pharmacological agents can adversely influence sexual function of the male (107, 108). Antihypertensives, anticholinergics, psychotropics, and many other agents are common causes for erectile dysfunction. The percentage of men with complete erectile dysfunction in the Massachusetts Male Aging Study who were taking hypoglycemic agents (26%), antihypertensive drugs (14%), vasodilators (36%), and cardiac drugs (28%) was significantly higher than the 9.6% observed for the sample as a whole (93). The cause of erectile dysfunction in many of these patients may not be related to the intake of the pharmacological agent but to the underlying disease. Another possibility in the case of antihypertensives is the reduction of blood pressure in the face of penile arterial atherosclerosis (119).
Mechanisms by which medications can induce erectile dysfunction may include central and/or peripheral neurological blockade or stimulation of PRL secretion. Hyperprolactinemia may reduce testosterone concentration and action through a variety of mechanisms including disruption of the anatomic integrity of the hypothalamic-pituitary axis, decreased GnRH expression (120), interference with GnRH action on the pituitary (121), inhibition of gonadotropin secretion (122), and reduction of testosterone conversion to the more active metabolite dihydrotestosterone (123). Hypogonadism has recently been shown to be associated with decreased NO formation and action in the penis, thus reducing erectile capacity (124, 125). Priapism as a mechanism for erectile dysfunction may be invoked by the intake of phenothiazines (e.g., thioridazine and chlorpromazine) (107) or the newer antidepressant trazodone (107, 108). At present, it is not clear whether drugs of addiction such as alcohol, methadone, and heroin reduce sexual potency by influencing the secretion and metabolism of androgens or by the associated deterioration in the general physical and psychological status of the addict (43, 107).
There is convincing evidence that smoking is a major risk factor for the development of erectile dysfunction (93, 126). Recent statistical studies have shown that the relative risk of developing arterial atherosclerosis in the penis, and subsequent erectile dysfunction, is 1.31 for each 10 pack-years smoked (127), and that 86% of smokers have an abnormal penile vascular evaluation (128). Long-term smoking has also caused ultrastructural damage to the corporeal tissue in impotent men (129). Acute vasospasm of penile arteries in response to cigarette smoking, possibly subsequent to excessive release of catecholamines, has also been reported (130). Nicotine and conitine were shown to inhibit steroidogenesis in mouse Leydig cells (131), and long-term passive smoking in the rat has been shown to cause an age-independent moderate hypertension as well as considerable decrease in penile NOS activity and neuronal NOS content (132). Thus, smoking impairs erection through a variety of mechanisms, including enhancing atherogenesis, reduction in testosterone production, inappropriate adrenergic stimulation, and inhibition of local vasodilator(s) release.
The organic causes of erectile dysfunction can be grouped into systemic diseases and endocrine, neurological, vascular, or local penile disorders (43). A variety of advanced states of systemic diseases are associated with sexual dysfunctions (97), including chronic liver disease (133), renal failure (134), chronic obstructive pulmonary disease (135), sleep apnea (136, 137), cancer (138, 139), and postorgan transplantation (140). Hepatic cirrhosis and renal failure adversely affect androgen production and/or metabolism.
In addition to deficiency of androgen secretion and/or action that has already been addressed in the preceding section, diabetes mellitus has increasingly been recognized as a major cause for erectile dysfunction (141, 142). Surveys by various investigators suggest that erectile dysfunction occurs in about 50% of diabetic males (97), which is twice the incidence in nondiabetic normal males (111). Moreover, the frequency of erectile dysfunction in diabetics increases with age, from about 25% at age 35 to greater than 70% after age 60, and among diabetic patients with autonomic neuropathy.
Vascular insufficiency is probably the most common cause of organic male sexual dysfunction (67, 143, 144, 145, 146, 147). Atherosclerosis of the large pelvic arteries (common iliac, hypogastric, or pudendal) can lead to inadequate perfusion of the penis. In some instances of unilateral disease, erection is achievable while the patient is in the supine position but is lost upon initiation of active pelvic movements. Shunting of blood from the penis to the hip muscles constitutes the pathogenic mechanism for this "steal" phenomenon (144). Other examples of large vessel disease are Leriche syndrome (143) and penile Raynaud’s phenomenon (147). In the former condition, impedance of penile blood supply occurs as a result of obstruction of the distal aorta and presents with claudication of lower back, buttocks, and thighs, whereas the latter condition is due to a vasospastic disorder superimposed on borderline penile arterial flow. Alternatively, obliteration of the small vessels of the cavernous tissue is frequently implicated in the diminution of erectile rigidity in aged men and in men with diabetes (67, 141, 148, 149).
Erectile dysfunction secondary to excessive venous leakage is being reported with significant frequency in clinical studies (72, 73, 150). However, studies in animal models and the low success rate of venous ligation surgery in humans (28–73% of patients recover their erectile function after surgery) suggest that the primary defect is likely to be related to an abnormal function (incomplete relaxation) of trabecular smooth muscle cells of the corpora cavernosa rather than due to a pathological process inflecting the penile veins themselves (151).
Erectile dysfunction can accompany a variety of acute and chronic central and peripheral nervous system diseases (67, 74, 152, 153, 154). Spinal cord injuries deserve a special comment. Loss of erectile or ejaculatory functions in these conditions depends upon the level and extent of the damage. Upper motor neuron lesions diminish the erectile response to psychogenic stimuli but leave the reflexogenic erections intact. The degree of diminution in psychogenic erections is directly related to the extent of the lesion. In contrast, lower motor neuron lesions abolish the reflexogenic response without altering the psychogenic erections except when the lesion is complete. When the latter occurs, psychogenic erections diminish in about 75% of patients (153, 155).
Penile diseases, such as congenital malformation (156), Peyronie’s disease (157), priapism (158, 159, 160, 161), phimosis (162), and, rarely, cold abscess (163), may interfere with erectile function. Sporadic reports of congenital anomalies, such as absent communication between the corpora cavernosa (isolated cavernous bodies), corporeal venoocclusive dysfunction, and/or hypoplastic cavernous arteries leading to primary erectile dysfunction, have also been reported (156, 164). Lack of circumcision in older men was reported to be associated with a higher incidence of sexual dysfunction (165).
Genitourinary trauma that results in rupture of the corpora cavernosa or the encapsulating connective tissue sheaths, formation of traumatic occlusion of multiple arteries, posttraumatic aneurysmal dilatation with arteriovenous fistulae, resection of the cavernosal nerves during pelvic surgery, penile schwannoma, or pelvic irradiation can all be causes for erectile dysfunction (158, 159, 160, 161, 162). Radiation exposure has been shown to decrease the number of NOS-containing nerves in the rat penis (166), and regeneration of penile NOS-containing nerves was shown to coincide with the recovery of erectile function in animals with unilateral cavernous nerve injury (167). Such observations suggest that NO pathway abnormalities are involved in the pathogenesis of erectile dysfunction after unilateral cavernosal nerve injury or pelvic radiation in man (10).
C. Disorders of ejaculation
There exists a spectrum of disorders of ejaculation ranging from
mild premature to severely retarded or absent ejaculation. Normally, by
age 17 or 18 yr, 75% of men are able to control their ejaculation
(168). Premature ejaculation is the most common male sexual dysfunction
(169). Several surveys among different populations estimate its
prevalence at 29%, with a range between 1% and 75% depending on the
population and criteria used to define the condition (see Refs.
169, 170, 171 for review). The DSM-VI (98) defines the diagnostic criteria
for premature ejaculation as follows: 1) persistent or recurrent
ejaculation with minimum sexual stimulation that occurs before, upon,
or shortly after penetration and before the person wishes it; 2) marked
distress or interpersonal difficulty; and 3) the condition does not
arise as a direct effect of substance abuse, i.e., opiate
withdrawal. Premature ejaculation and sexual desire disorders were the
frequent reported problems in young adult males with adverse familial
relationship to attachment figures (172). Premature ejaculation was
also found to be associated with anxiety in a recent survey of 789 men
in England (173). Table 2 delineates other common causes of disorders
of ejaculation.
Several classifications for premature ejaculation have been reported. In one, premature ejaculation was classified into primary and secondary disorders (170). Primary premature ejaculation describes persons who, since the beginning of sexual experience, have never been able to control the ejaculatory function, whereas secondary premature ejaculation describes individuals who develop the condition after years of satisfactory sexual activity.
Painful ejaculation has been reported as a side effect of tricyclic antidepressants in at least two patients (174). Psychogenic postejaculatory pain syndrome (PEPS) is a rare sexual disorder of male dyspareunia that was first described in 1979 (175) as a persistent and recurrent pain in the genital organs during ejaculation or immediately afterward. Detailed descriptions of clinical features, pathogenesis, and treatment of this syndrome have recently been reviewed by Kaplan (176).
Ejaculatory pain in the testicular region may result from epididymal congestion after vasectomy (177) or from duct obstruction and/or infection (178), testicular torsion, mass lesion, or prostatitis (179). In some cases, specific etiological factors other than psychological stress cannot be identified (180).
D. Disorders of orgasm
Male orgasmic disorder is defined as a persistent or recurrent
delay in, or absence of, orgasm after a normal sexual excitement phase
during sexual activity (98, 181). The disorder is relatively rare,
occurring in 3–10% of patients presenting with sexual dysfunction
(181). Table 2 delineates the most common causes of orgasmic
dysfunction.
E. Failure of detumescence
Priapism is a prolonged (>4 h duration) and extremely painful
erection unaccompanied by sexual desire and is often preceded by usual
sexual stimuli. The condition is self- perpetuating and is
characterized by diminished perfusion of the corporeal bodies. When
chronically present, corporeal fibrosis and erectile dysfunction occur.
At least two classifications of priapism have been described (158). The
first is etiologically based and classifies the condition into primary
(idiopathic) and secondary priapism. The latter condition could be
precipitated by causes listed in Table 2. Of particular note,
drug-induced priapism lasting for more than 48 h frequently leads
to the development of corporeal fibrosis (182), and cocaine-induced
priapism can be refractory to treatment (183). The second
classification is pathophysiologically based and depends on measurement
of penile blood gases and pressures. It classifies priapism into
low-blood flow (ischemic) and high-blood flow (nonischemic) conditions.
In the majority of ischemic priapism cases, erection probably starts
with a normal or high-blood flow state (particularly in cases induced
with intrapenile drug injection) and ischemia ensues when a large
number of emissary veins become occluded. Recent studies in rabbits
(184) showed that acidosis impairs trabecular smooth muscle
contractility, probably secondary to the interference of
[H+] with the intra- and extracellular
mechanisms that regulate homeostasis of [Ca2+].
Since acidosis is an early complication of ischemic priapism, it was
thought that the reduced contractility of trabecular smooth muscle is a
significant factor in the perpetuation of the ischemic state (184). A
variant of high-flow priapism that is caused by perineal or penile
trauma occurs as a result of arterial-lacunar fistula. In this
condition, blood bypasses the helicine artery and passes directly into
the lacunar spaces. Characteristically, there is no pain or tenderness
in this form of priapism, and the penis is incompletely but constantly
rigid with a focal area of high-flow turbulence on color-flow Doppler
ultrasound examination and high-oxygen tension (160). Sexual
stimulation may cause a further increase in penile rigidity.
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IV. Diagnostic Assessment of Sexual Dysfunction in the Male |
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TopAbstractI. IntroductionII. Physiology of Male...III. Disorders of Male...IV. Diagnostic Assessment of...V. TreatmentVI. Summary and Future...References |
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A. History
Medical, psychological, and sexual histories are extremely helpful
in providing clues to the underlying cause of the dysfunction and they
reduce the need for an expensive investigation to rule out all possible
etiologies.
1. Medical history. Historical events related to the presence of chronic disease (e.g., diabetes, hepatic failure, renal failure, cardiac failure, advanced pulmonary disease, tabes dorsalis, multiple sclerosis, cerebrovascular accident), use of pharmacological agents (e.g., antihypertensives, antihistamines, antipsychotics, anticholinergics), endocrine disorders (gonadal failure, pituitary tumors, thyroid disease, adrenal disease), prior surgeries (prostatectomy, proctectomy, vascular surgery), and trauma (temporal lobe and spinal cord lesions, blunt pelvic trauma) should all be carefully evaluated. Further, vascular risk factors such as family history of cardiovascular disease, hypercholesterolemia, hypertension, diabetes, cigarette smoking, and pelvic radiation therapy should be inquired about, and, if present, vascular etiology should be highly suspected. Potentially irreversible pathology should be anticipated in patients with evidence for other microvascular disease (peripheral neuropathy, retinopathy, and nephropathy). Patients with neurological disease should be questioned about the temporal relationship between the development of the sexual dysfunction and that of the neurological disorder. Patients suspected for hypogonadism should specifically be assessed for family history of the disease, deviation of adolescence from normality, recent changes in secondary sexual characteristics, symptoms of pituitary dysfunction, history of orchitis, testicular trauma, infertility, or exposure to radiation or cytotoxic agents. Patients should also be assessed for symptoms of thyroid and adrenal diseases.
2. Psychological history. Psychological factors associated with male sexual dysfunction have recently been classified into three categories (95, 188): predisposing factors, precipitating factors, and maintaining factors. Restrictive upbringing, disturbed family relationships, traumatic early sexual experiences, inadequate sexual information, and insecurity in the psychosexual role are among the frequently encountered predisposing factors. Unreasonable expectations, random failure, discord in the relationship, dysfunction in the partner, infidelity, reaction to organic disease, or depression or anxiety are some of the factors that could precipitate the onset of sexual dysfunction. Performance anxiety, guilt, poor communication, loss of attraction between partners, and impaired self-image are among the factors that lead to maintenance of the sexual dysfunction. Affective disorders or character pathology can lead to both precipitation and maintenance of sexual problems. Evidence for the presence of any of these psychological or situational conditions should be carefully assessed. Moreover, it should not be forgotten that the existence of an organic disease does not preclude the possibility of a coexisting psychogenic factor. Such omission could lead to diagnostic difficulties as well as to therapeutic failures.
3. Sexual history. One of the first goals of the differential diagnosis during history taking is to ascertain the nature of the sexual dysfunction. The patient should be asked to describe his problem, the time and manner of onset, its course, its current status, and any associated medical or psychological problems.
Decreased libido should alert the clinician to three probable causes:
endocrinopathy, affective disorder, or relationship discord. A history
of frequent strong erections under any circumstances (during foreplay,
fantasy, or masturbation, with another partner or upon awakening)
indicates that the endocrine, vascular, and neurological systems are
probably intact and that the erectile dysfunction is predominantly
psychogenic. Conversely, historical data indicating the presence of
decreased erectile turgidity in noncoital activities are highly
suggestive of an organic etiology. Moreover, a report of firm sustained
erections during foreplay that are lost after intromission or upon
initiation of pelvic movements might suggest either a psychogenic
etiology or a vascular problem (pelvic steal syndrome). A history of
delayed or retrograde ejaculation is suggestive of a neuropathy or an
adverse drug effect. Premature ejaculation, on the other hand, is more
compatible with a psychogenic dysfunction. Finally, it must be
remembered that absence of orgasmic sensations in patients with normal
erectile and ejaculatory functions is almost always due to psychogenic
etiology, whereas failure of detumescence is usually organic in nature,
which should direct the investigations toward ruling out local penile,
neurological, and hematological etiologies. Table 3 lists other historical events most
useful in differentiating predominantly psychogenic from predominantly
organic erectile dysfunctions.
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Patients suspected of hypogonadism should be assessed for evidence of muscle development, size and structure of the penis (normal adult penis is >6 cm in length in the unstretched flaccid state, 3 cm or more in width, has normal urethral opening, and no evidence of hypospadias) and size and consistency of the testes and the prostate. Patients with moderate hypogonadism including some with Klinefelter’s syndrome and many patients with gonadotropin deficiency usually exhibit a decrease in testicular volume from a normal size of 15–30 cm3 to a size of 6–12 cm3 (2.9–3.7 cm length, 1.8–2.3 cm width) (189). Patients with severe hypogonadism and many with Klinefelter’s syndrome usually have infantile size testis of 2–4 cm3 (2.0–2.5 cm length, 1.2–1.5 cm width) (8).
A careful vascular assessment should include the palpation of ankle, femoral, and dorsal penile arteries. Penile systolic blood pressure should be determined with a 3-cm blood pressure cuff placed around the base of the penis and a Doppler stethoscope positioned over each cavernosal artery (67, 99, 143, 185, 186). The penile systolic occlusion pressure is then obtained and compared with that of a brachial artery, and a penile brachial index (PBI) is derived (190, 191, 192, 193). Values greater than 0.7 are considered normal (192, 193). Studies by Chiu and colleagues (193) suggested that PBI is highly diagnostic in patients with evidence for peripheral vascular disease but no other risk factors such as diabetes or current intake of medications with potential adverse effects on the erectile function. The PBI is less predictive in patients with peripheral vascular disease and diabetes, and least predictive in those without peripheral vascular disease, diabetes, or current drug intake. Repeating the measurements after 3–5 min of gluteal muscle exercise (186) may enhance sensitivity of the test. Reduction in PBI by more than 0.15 is suggestive of redistribution of the blood supply and its shunting away from the arterial penile bed to the gluteal region. Such a phenomenon is characteristic of patients with steal syndrome (144). Further, the significance of a low PBI may go beyond aiding the diagnosis of vasculogenic erectile dysfunction. This is suggested by a prospective study in 130 impotent patients that were followed for 24–36 months in which a low PBI (0.65 or less) was shown to predict occurrence of a future major vascular event (myocardial infarction or cerebrovascular accident) (194). Physical signs of muscular atrophy, pallor, and/or loss of hair growth of the lower extremities are also consistent with vascular pathology.
Neurologically, the patient should be evaluated for the presence of motor deficits, changes in deep tendon reflexes, loss of sphincter tone, or decrease in light touch or pinprick sensations, particularly in the genital area. Penile temperature sensation testing could also be performed with the use of alcohol swabs (3). In addition, the bulbocavernosus reflex should be elicited by squeezing the glans penis and assessing the evoked contractions of external anal sphincter or bulbocavernosus muscles (186, 195). This reflex response is clinically detectable in 70% of normal males (186). The more sensitive penile vibration perception threshold testing (3, 152, 185, 186, 196, 197) may be performed to confirm results of the bulbocavernosus reflex. Testing of penile vibration perception threshold is performed by sequentially placing a tuning fork on the glans and bilaterally on midshaft of the penis. Vibration amplitude is then increased until the patient perceives the stimulus. The vibration perception threshold testing is the most predictive sensation testing procedure, but others can also help in evaluating a loss of somatic innervation. The penis should also be examined for evidence of masses or plaque formation, angulation, unprovoked persistent erection, or tight unretractable foreskin.
C. Selective investigations for male sexual dysfunction
A detailed patient history is important in the evaluation of male
sexual dysfunction as it can help suggest the underlying etiology and
narrow the scope of the required investigation for selecting an
appropriate modality of treatment. A thorough physical examination and
brief office-based investigation with assessment of PBI and real-time
penile tumescence may also be sufficient to corroborate the nature of
the problem and to suggest an etiological basis in most male patients
with sexual dysfunction. Once detailed history and physical examination
are completed, focus of the medical investigation can then be shifted
toward confirming the underlying pathophysiological abnormalities and
devising a treatment plan.
Patients with desire disorder, premature ejaculation, and/or
postejaculatory pain require a careful assessment of drug use, possible
underlying hypogonadism, or presence of psychological or psychiatric
conditions (Table 2). Patients with HSD and absent or retarded emission
or anorgasmia may need to be evaluated for the presence of CNS disease.
