In 1999, over 1.2 million new cases of invasive
cancer were diagnosed in the United States. More than half of these
cases occurred in men. Over 80% of men afflicted with cancer consider
future reproductive and sexual function to be a principal concern.
The surgical, chemotherapeutic, and radiation therapies used to treat
cancer can adversely influence erectile and sexual function.
Significant basic and clinical research performed in the past decade
have led to a better understanding of the mechanism of erection at
the organ, cellular, and molecular level. New directed developments
in clinical research have led to effective local and systemic
treatments for erectile dysfunction.
The pathophysiology of erectile dysfunction in cancer patients is
often multifactorial, involving both psychogenic and physiologic
mechanisms. In order to effectively treat erectile dysfunction in
cancer patients, providers must understand the mechanism of erection
and be familiar with the effects of a variety of treatment regimens.
Such knowledge will enable clinicians to help the majority of
patients resume a satisfying sexual relationship after treatment of
This article will provide an overview of the pathophysiology of
erectile dysfunction, as well as outline useful treatment regimens.
Effects of specific cancer treatments on male sexual function will be
addressed as they relate to the pathophysiology of erectile dysfunction.
The erectile bodies of the penis are the paired corpora cavernosa
located on the dorsal aspect of the penile shaft (Figure
1). Each corpus is covered by the relatively inelastic bilaminar
tunica albuginea. The corpora are loosely separated in the midline by
fibrous septa that permit cross-flow of blood between the two corpora.
The arterial blood supply to the cavernosal sinusoids is provided by
cavernosal arteries that run through the center of each corpus. The
cavernosal artery is a branch of the penile artery, which, in turn,
is a branch of the internal pudendal artery. The cavernosal artery
branches into a series of smaller helicine arterioles that provide
arterial inflow to the caver-nosal sinusoids. Venous drainage of the
sinusoids ultimately leads to small emissary veins that run under the
tunica albuginea, draining to superficial veins on the exterior of
the penile shaft.
Cavernosal smooth muscle cells surround the cavernosal sinusoids,
which are lined by endothelial cells. When the penis is in a flaccid
state (Figure 2), the cavernosal
smooth muscle cells are contracted, which keeps the sinusoids collapsed.
The erectile cascade begins with a neural impulse triggered by local
penile stimulation or activation from the central nervous system
(CNS) during erotic sensation or stimulation. This impulse travels
down spinal nerve routes S2-S4 to the penile nerves. The cavernosal
branches of the penile nerves follow the anterolateral aspect of the
prostate gland and enter each corpus.
When the nerve impulse reaches the corpora, it initiates the release
of nonadrenergic, noncholinergic neurotransmitters. The principal
neurotransmitter in the cavernosal smooth muscle is nitric oxide,
which initiates and potentiates cavernosal smooth muscle relaxation.
Once the cavernosal smooth muscle has relaxed, blood flow through the
helicine arterioles increases, filling the cavernosal sinusoids (Figure
2). The expanding cavernosal sinusoids increase penile tumescence.
As the sinusoids fill with blood, the penile emissary veins become
compressed against the tunica albuginea, thereby decreasing venous
outflow. At a critical point, vascular inflow exceeds outflow and the
penis becomes rigid. Detumescence occurs after ejaculation when
cavernosal smooth muscle contraction is restored, decreasing
sinusoidal inflow and increasing venous outflow.
The greatest advance in understanding the erectile cascade was the
discovery of the molecular mechanism that initiates an erection. This
discovery led to the development of directed pharmacotherapy to
restore erections in men with erectile dysfunction. Multiple pathways
ultimately lead to the release of intracellular calcium (Ca++) and
cavernosal smooth muscle relaxation.
The principal metabolic pathway that causes cavernosal smooth muscle
relaxation is mediated by the release of nitric oxide and the
stimulation of the guanylate cyclase system (Figure
3). Guanylate cyclase converts guanosine triphosphate (GTP) to
cyclic guanosine 3¢,5¢-monophosphate
(cGMP) inside the cavernosal smooth muscle cell, and cGMP initiates
the release of intracellular Ca++. Type 5 phosphodiesterase converts
cGMP back to GTP and triggers the return of Ca++ into the cell,
thereby causing smooth muscle contraction and detumescence.
Alternate pathways that can initiate intracavernosal smooth muscle
Ca++ release include the adenylate cyclase system and separate
inducible potassium (K+) channels. In addition to nitric oxide,
vasoactive intestinal peptide and prostaglandin E1 act as
nonadrenergic, noncholinergic neurotransmitters to initiate the
Cavernosal smooth muscle contraction is enhanced by chronic
alpha-adrenergic tone that maintains the penis in its flaccid state.
Pharmacologic alterations in adrenergic tone may enhance or inhibit
the erectile mechanism.
Erectile dysfunction is not a solitary entity, but rather, is a
symptom of many different disease states. It is important to
understand this concept when evaluating the multifactorial nature of
erectile dysfunction in cancer patients, as well as when utilizing
different regimens to effectively treat erectile dysfunction in a
variety of patients. Several pathophysiologic mechanisms may be in
effect in patients with cancer and in those who have received
anticancer therapy. Breaking down the mechanism of erectile function
into its component parts will facilitate an understanding of the
pathophysiology of erectile dysfunction in cancer patients.
The neurologic mechanism involved in attaining or maintaining an
erection can be adversely affected by cancer or its treatments.
Central nervous system disease can alter the initiation of erection
by inhibiting the erotic or erectogenic centers. Spinal cord
impingement by tumor or peripheral nerve or nerve root involvement
can prevent the transmission of a neural impulse to initiate the
erectogenic cascade. Extirpative surgery, such as radical
prostatectomy or abdominal perineal resection, can damage the
cavernosal nerves as they transverse the surface of the prostate.
In cases in which the neural mechanism has been injured, the local
mechanism for erection is intact, but the signal never reaches the
corpora cavernosa. Pharmacotherapeutic agents that rely on an intact
neural mechanism (ie, sildenafil [Viagra] or apomorphine [Britaject])
will be far less effective in patients whose pelvic nerves have been
injured. Locally acting agents (ie, intracavernosal injections or
transurethral therapy) can be highly effective in such cases and may
be used in lower doses because of the hypersensitivity that develops
in cases of nerve injury.
Erection is principally a vascular event. Disease processes that
adversely affect penile blood flow are the most common causes of
erectile dysfunction. Arteriogenic erectile dysfunction is usually a
small-vessel disease (atherosclerosis), but a large pelvic tumor can
also inhibit penile blood flow. Diabetes mellitus can contribute to
erectile dysfunction by accelerating small-vessel disease; local
diabetic neuropathy may also play a role.
Anticancer therapy can cause vasculogenic erectile dysfunction by
limiting penile blood flow and damaging the pudendal or penile
arteries. The cavernosal arteries are less than 1 mL in diameter and
can be easily injured by pelvic or perineal surgery. Arteriosclerosis
is also accelerated by radiation therapy. Small-vessel disease and
cavernosal smooth muscle injury can be caused by pelvic or perineal
ionizing radiation. Erectile dysfunction occurs in over 90% of
patients receiving pelvic irradiation.
Veno-occlusive dysfunction is a term to describe failure of the
passive venous outflow obstructive mechanism. In patients with this
condition, arterial inflow is adequate, but the sinusoids fail to
1. Costabile RA, Spevak M: Cancer and male factor infertility.
Oncology 12(4):557-562, 1998.
2. Functional anatomy and mechanism of penile erection, in Lue T,
Tanagho E, Melure R (eds): Contemporary Management of Impotence and
Infertility, p 30. Baltimore, Maryland, Williams & Williams, 1988.
3. Kirby RS: Impotence: Diagnosis and management of male erectile
dysfunction. Br Med J 308:957-961, 1994.
4. Lue T: Physiology of penile erection and pathophysiology of
erectile dysfunction and priapism, in Walsh P, Retik A, Vaughan ED,
et al (eds): Campbells Urology, p 1157. Philadelphia, WB
5. Benson G, Boileau M: The penis: Sexual function and dysfunction,
in Gillenwater, Grayhack T, et al (eds): Adult and Pediatric Urology,
p 1951. St. Louis, Missouri, Mosby, 1996.
6. Siegel T, Spevak M, Moul J, et al: Erectile dysfunction in
prostate cancer patients (abstract). J Urol 161(4; suppl):179, 1999.
7. Johnson AR III, Jarow JP: Is routine endocrine testing of impotent
men necessary? J Urol 147(6):1542-1543, 1992.
8. Vigersky RA, Chapman RM, Berenberg J, et al: Testicular
dysfunction in untreated Hodgkins disease. Am J Med 73:482, 1982.
9. Chlebowski RT, Heber D: Hypogonadism in male patients with
metastatic cancer prior to chemotherapy. Cancer Res 42:2495, 1982.
10. Mehta MK, Garde SV, Sheth AR: Occurrence of FSH, inhibin and
other hypothalamic-pituitary-intestinal hormones in normal fertility,
subfertility, and tumors of human testes. Int J Fertil Menopausal
Stud 40:39-46, 1995.
11. Costabile RA, Spevak M, Fishman IJ, et al: Efficacy and safety of
transurethral alprostadil in patients with erectile dysfunction
following radical prostatectomy. J Urol 160:1325-1328, 1998.
12. Walsh PC, Donker PJ: Impotence following radical prostatectomy:
Insight into etiology and prevention. J Urol 128(3):492-497, 1982.
13. Catalona WJ, Carvalhal G, Mager D, et al: Potency, continence,
and complication rates in 1,870 consecutive radical retropubic
prostatectomies. J Urol 162:433-438, 1999.
14. Litwin MS: Health-related quality of life in men with erectile
dysfunction. J Urol 160(2):445-448, 1998.
15. Willke RJ, Yen W, Parkerson GR Jr, et al: Quality-of-life effects
of alprostadil therapy for erectile dysfunction: Results of a trial
in Europe and South Africa. Int J Imp Res 10(4):239-246, 1998.
16. Williams G, Abbou CC, Amar ET, et al: The effect of transurethral
alprostadil on the quality of life of men with erectile dysfunction,
and their partners: MUSE Study Group. Br J Urol 82(6):847-854, 1998.
17. Rosen RC, Riley A, Wagner G, et al: The International Index of
Erectile Function (IIEF): A multidimensional scale for assessment of
erectile dysfunction. Urology 49:822-830, 1997.
18. Morales A, Condra M, Owen JA, et al: Is yohimbine effective in
the treatment of organic impotence? Results of a controlled trial. J
Urol 137:1168-1172, 1987.
19. Costabile RA, Spevak M: Oral trazodone is not effective therapy
for erectile dysfunction: A double-blind, placebo-controlled trial. J
Urol 161:1819-1822, 1999.
20. Goldstein I, Lue TF, Padma-Nathan H, et al: Oral sildenafil in
the treatment of erectile dysfunction: Sildenafil Study Group. N Engl
J Med 338:1397-1404, 1998.
21. Virag R: Intracavernous injection of papaverine for erectile
failure (letter). Lancet 2:938, 1982.
22. Livet O, and the Alprostadil Study Group: Efficacy and safety of
intracavernosal alprostadil in men with erectile dysfunction. N Engl
J Med 334:873, 1998.
23. Sexton WJ, Benedict JF, Jarow JP: Comparison of long-term
outcomes of penile prostheses and intracavernosal injection therapy.
J Urol 150(3):811-815, 1998.
24. Padma-Nathan H: Treatment of men with erectile dysfunction with
transurethral alprostadil. N Engl J Med 336:1-7, 1997.
25. Godschalk M, Chen J, Katz P, et al: Treatment of erectile failure
with prostaglandin E1: A double-blind, placebo-controlled, dose
response study. J Urol 151(6):1530, 1994.