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The Possible Role of the Catecholamines of the Corpora in Penile Erection
0022-534 7/79/1214-0419$02. 00/0 Vol. 121, April
THE JOURNAL OF UROLOGY
Copyright© 1979 by The Williams & Wilkins Co.
Printed in U.S.A.
THE POSSIBLE ROLE OF THE CATECHOLAMINES OF THE CORPORA IN PENILE ERECTION ARNOLD MELMAN*
AND
DAVID HENRY
From the Departments of Urology, Pharmacology and Medicine, Indianapolis Veterans Administration Hospital, Indiana University Medical Center, Lilly Laboratory for Clinical Research, Indianapolis, Indiana
ABSTRACT
The etiolog-y- of impotence, which affects 50 per cent of the men with diabetes, is unknown. The neurotransmitter (norepinephrine) released. from adrenergic neurons is thought to be the most direct regulator of vascular smooth muscle. We have measured the norepinephrine content of the erectile tissue of diabetic men. Our results indicate the presence of a dual neural regulator mechanism of the corpora that controls erection. Impotence is a symptom in nearly 50 per cent of the estimated 1.5 million male subjects in the United States who have diabetes mellitus. 1 Eighty-eight per cent of these people with diabetes and erectile impotence also have a polyneuropathy. 2 In addition, dysfunction of the autonomic nervous system has been a long-recognized concomitant of diabetes mellitus. 3 The precise mechanism of human penile erection in health and its dysfunction in disease remain undefined. In the broadest terms erection can be conceived mechanistically as autonomic neuronal stimulation of the vascular tissue of the penis with resultant vasodilatation and filling of the intratrabecular spaces of the corpora cavernosa with blood. Classical teaching holds that erection is predominantly a parasympathetic function. This theory has been extant since 1863, when Eckhardt electrically stimulated the pelvic nerves of dogs and, thereby, caused an erection presumably by increasing penile vascular flow. 4 The nerves that he stimulated, designated the nervi erigentes, are preganglionic parasympathetic neurons arising from the second, third and fourth sacral segments. In 1947 Root and Bard demonstrated that the adrenergic nerves also are a factor in penile erection.' In their experiments surgical ablation of the lower sacral spinal cord (L4 to 83) did not cause cessation of erection in male cats. However, when the thoracic sympathetic chain was excised the animals were no longer capable of erection. Additional support for adrenergic stimulation was reported by Whitelaw and Smithwick, who performed surgical sympathectomies in patients with severe hypertension.'; Disturbance of erectile function was demonstrated in 57 per cent of the patients undergoing sympathetic ablation of T2 through T12 and in 63 per cent of the patients undergoing the operation in Ll through L3. Impotence is an important problem in men with diabetes and, because the role of the sympathetic (adrenergic) neurons in penile erection is undefined, we have measured the norepinephrine content of the erectile tissue of diabetic patients undergoing penile surgery. N orepinephrine has been shown to be the chemical neurotransmitter of the peripheral sympathetic nervous system. 7 The substance is concentrated, stored and released from vesicles contained in the terminal axons of sympathetic neurons." The axons form an autonomic ground plexus surrounding blood vessels and smooth muscle cells. '1 The norepinephrine concentration in tissue reflects the density of sympathetic innervation of that tissue. 7
METHODS
The spongy erectile tissue of the penile corpora was obtained from 28 patients during placement of a penile prosthesis or total penectomy. Eleven patients had diabetes. Two other g-rnups included men with impotence resulting from a radical operation or perineal trauma and spinal cord injury. Two patients could achieve erections but with severe chordee as a result of Peyronie's disease. Tissue from these 2 patients and 2 potent patients undergoing penectomy served as controls. After removal the tissue was frozen immediately and later analyzed for norepinephrine concentration by a radioenzymatic technique. 10 No clinical evidence of aortofemoral occlusive disease as the cause of impotence was present in any of the patients.
Accepted for publication July 26, 1978. Read at annual meeting of American Urological Association, D. C . May 21-25. 1978. address: Department of Beth Israel Medicai Center 10 :Nathan D. Perlman Place. Nev.: l~evv York 10003. 1
41~
RESULTS
Tissue obtained from within the corpora macroscopically was indistinguishable between the experimental groups. There was no difference between the blood loss from the open corpora of the group at the time of operation. Quantitative measurements of the norepinephrine content of the erectile tissue were summarized (table and fig. 1). There is a significant diminution of norepinephrine concentration in those patients with insulin-dependent diabetes. Those patients form the basis for the incidence oflow concentrations ofnorepinephrine in patients without erections (fig. 1). The norepinephrine concentration in all diabetic patients who required insulin was 71.4 ± 25.3 pg./mg. wet weight tissue. Within this group, however, 1 patient with a norepinephrine concentration of 121 pg./mg. tissue had severe chordee from Peyronie's disease but was able to have erections. The mean concentration in the remaining 4 patients was 59.0 ± 28.4 pg./mg. wet weight. These results are significantly different from the normal mean of 580.6 pg./mg. weight of tissue in normal men (p <0.05). There was no difference between patients with normal erections and those with diabetes controlled by diet and/or oral antihypoglycemic agents, the patients with spinal cord injury, or those men who had undergone a radical pelvic operation or had suffered perineal injury. DISCUSSION
The specific neurovascular mechanism of tumescence is not known. However, that an increase in corpora cavernosa volume results in erection was demonstrated Newman and associates in cadavers and normal volunteers." These invesshowed that erection occurred when 20 to 50 ml. into the corpora. This Shirai and associates,
420
MELMAN AND HENRY
Concentration (pg./mg. wet weight) ofnorepinephrine in human penile erectile tissue
Group
Normal
Diabetes InsulinDependent
Mean ± Standard error No. subjects
563.8 182.3 4
71.4 25.3 5*
Diabetes Diet/ Oral Medication
Spinal Cord Injury
Radical Cystectomy Prostatectomy/ Perineal Injury
594.7 100.0 6t
680.6 166.5 5
427.3 88.1 8
* Significant difference from control group (p <0.05). t Differences from insulin-dependent patients with diabetes (p <0.001). 1200 ~ - - - - - - - - - - - - - - - - - - - ~
1100 -
•
-
1000 -
-:.r, " '.; "
900 -
800 -
el
"
700 -
cJ;
:,.
al
::
600 -
""
500 -
p:; ;c al
z
• • • I • • •
-
•
-
• •
;;: al
p:; 0
•
I
400 -
z
300 -
200 -
100 -
0
I
I• •
NO ERECTIONS
•
• •
-
REFLEX ERECTIONS
NORMAL ERECTIONS
esis suggests a functional role for the histologically evident endothelial pads within the penile arteries. These pads are thought to offer resistance to arterial flow, thus multiplying the effect of arterial vasoconstriction and resulting in a shift of arterial flow through alternative pathways. This concept attempts to account for corporeal filling and detumescence with the selective vasoconstriction of the appropriate feeding vessel (fig. 2). Experimental data to confirm this theory are lacking. Another hypothesis suggests a role for the erectile tissue of the corpora themselves. This tissue is composed of smooth muscle trabeculae that could be seen as offering resistance to flow within the corporeal spaces. Contraction of these trabeculae will expand the potential intravascular volume of the spaces that are known to function as arteriovenous shunts, thus decreasing vascular resistance to the afferent helicine arterioles and allowing tumescence. Adrenergic neurons function as the effector control mechanism of vascular smooth muscle. 16 It was anticipated that quantitative analysis of the norepinephrine concentration of the corpora in patients with impaired and normal tumescence would clarify the role of adrenergic transmission in controlling erection. The results demonstrated that a high concentration of norepinephrine is present in the blood vessels or intrinsic smooth muscle of the corporeal tissue. Our findings suggest that only patients with insulin-dependent diabetes have diThe factors associated with insulin-requiring diabetes mellitus result in impotence associated with low corporeal norepinephrine concentration are unknown but may be related to the duration or severity of the disease. However, previous studies have not shown a relationship between either the duration or the severity of diabetes when impotence alone was evaluated. 17 Other patients in our study, equally impotent, had norepinephrine concentrations similar to those in normal men (fig. 1). This result demonstrates a dual or bimodal distribution of norepinephrine concentration in the corporeal tissue (p <0.0001), suggesting the presence of at least 2 interdependent neurotransmitter regulator mechanisms that control erection. Damage to either mechanism (as in insulindependent diabetic patients) or both (as in patients having trauma or a radical operation) would result in erectile impotence. The parasympathetic neurons that release acetylcholine could be altered as a result of disease or injury. The modification of release of norepinephrine from nerves by acetylcholine has been demonstrated by Vanhoutte. 18 His finding suggests that a modulating relationship may exist between the acetyl-
Fm. 1. Concentration of norepinephrine in erectile tissue of men undergoing penile operation. Each circle represents 1 patient. used a nnm technetium-labeled autologous red blood cell technique to determine penile volume. In their patients an average increase of32 ml. volume occurred within the penis during erection. 12 The mechanism that produces the increased intracorporeal volume of blood is unknown. There may be increased delivery of blood into the corporeal spaces as a result of arteriolar vasodilatation without alteration of venous outflow, which could result in an expanded intracorporeal blood volume. Conversely, a concomitant decrease in venous outflow resulting from constriction of the deep veins draining the corpora would cause secondary engorgement of the trabecular spaces. 13 The continued rigidity of the turgid phallus, when it is compressed by pressure greater than partial pressure, sugFm. 2. Adaptation of Conti's theory of erection. 14 A, detumesgests that arteriolar and venular constriction is present during cence. In this state helicine arteries entering corpora are constricted, erection. whereas arteries surrounding corpora are dilated. There is minimal Conti, 14 expanding on the earlier theories of Kiss, 15 has blood flow within intratrabecular spaces (speckled area). B, tumessuggested that tumescence occurs when there is a shunting of cence. Peripheral artery is constricted with additional intravascular obstruction theoretically created by Von Ebner pads. This forces blood away from the extracorporeal spaces directly through blood into helicine arteries and intratrabecular spaces of corpora, the helicine arteries to the spaces of the corpora. This hypoth- which results in erection.
CATECHOLAMINES AND PENILE ERECTION
choline-releasing neurons and the sympathetic nerves. An alternative explanation is that a substance other than norepinephrine or acetylcholine is important in controlling penile erection. Other substances known to affect norepinephrine release, a receptor activity or re-uptake ofnorepinephrine by the neuron include the prostaglandins, rn histamine and 5hydroxytryptamine, 20 dopamine, 21 adenosine, 22 angiotensin and the enkephalins. 23 The physiologic role of these substances is unknown. The results of our study suggest that the impotence of insulin-dependent diabetes is associated with drastic impairments of at least one component of a regulator of vascular smooth muscle, norepinephrine. The future measurement of the other chemical modifiers of neuronal control will be needed to define fully the erectile mechanism. REFERENCES
1. Tokuhata, G. K., Miller, W., Digon, E. and Hartman, T.: Diabetes mellitus: an underestimated public health problem. J. Chron. Dis., 28: 23, 1975. 2. Rundles, R. W.: Diabetic neuropa:thy: general review with report of 125 cases. Medicine, 24: 111, 1945. 3. Ellenberg, M.: Impotence in diabetes: the neurologic factor. Ann. Intern. Med., 75: 213, 1971. 4. Eckhardt, C.: Untersuchungen iiber die Ereketion des Penis beim Runde. Beitr. Anat. Physiol., 3: 123, 1863. 5. Root, W. S. and Bard, P.: The mediation of feline erection through sympathetic pathways with some remarks on sexual behavior after deafferentation of the genitalia. Amer. J. Physiol., 151: 80, 1947. 6. Whitelaw, G. P. and Smithwick, R.H.: Some secondary effects of sympathectomy with particular reference to disturbance of sexual function. New Engl. J. Med., 245: 121, 1951. 7. Euler, U. S. V.: Physiology of catecholamines. In: Neurochemistry, 2nd ed. Edited by K. A. C. Elliot, I. H. Page and J. H. Quastel. Springfield, Illinois; Charles C Thomas Publishers, pp. 578-589, 1962. 8. Westfall, T. C.: Local regulation of adrenergic neurotransmission. Physiol. Revs., 57: 659, 1977. 9. Falck, B.: Observation on the possibilities of the cellular localization ofmonoamines by a fluorescence method. Acta Physiol. Scand., suppl. 197, 56: 1, 1962. 10. Henry, D. P., Starman, B. J., Johnson, D. G. and Williams, R. H.: A sensitive radioenzymatic assay for norepinephrine in tissues and plasma. Life Sci., 16: 375, 1975. 11. Newman, H. F., Northup, J. D. and Devlin, J.: Mechanism of human penile erection. Invest. Urol., 1: 350, 1964. 12. Shirai, M., Nakamura, M., Ishii, N., Mitsukawa, S. and Sawai, Y.: Determination of intrapenial blood volume using 99mTclabeled autologous red blood cells. Tohoku J. Exp. Med., 120: 377, 1976. 13. Deysach, L. J.: The comparative morphology of erectile tissue of the penis with especial emphasis on probable mechanism of erection. Amer. J. Anat., 64: 111, 1939. 14. Conti, G.: L'erection du penis humain et ses bases morphologicovasculaires. ActaAnat., 14: 217, 1952. 15. Kiss, F.: Anatomisch-histologische Untersuchungen iiber die Erektion. Z. Anat. Entwickl.-Gesch., 61: 455, 1921. 16. Marshall, J. M.: Modulation of smooth muscle activity by catecholamines. Fed. Proc., 36: 2450, 1977. 17. Rubin, A. and Babbott, D.: Impotence and diabetes mellitus. J.A.M.A., 168: 498, 1958. 18. Vanhoutte, P. M.: Cholinergic inhibition of adrenergic transmission. Fed. Proc., 36: 2444, 1977. 19. Hedqvist, P.: Studies on the effect of prostaglandins E, and E 2
20. 21.
22. 23.
421
on the sympathetic neuromuscular transmission in some animal tissues. Acta Physiol. Scand., suppl., 345: 1, 1970. McGrath, M.A.: Histamine and 5-hydroxytryptamine inhibition of transmitter release mediated by H 2 and 5-HT receptors. Fed. Proc., 37: 195, 1978. Enero, M. A. and Langer, S. Z.: Inhibition by dopamine of 3Hnoradrenaline release elicited by nerve stimulation in the isolated cat's nicitating membrane. Naunyn-Schmiedebergs Arch. Pharmacol., 289: 179, 1975. Su, C., Bevan, J. A. and Burnstock, G.: [3 H]-adenosine triphosphate release during stimulation of enteric nerves. Science, 173: 336, 1971. Zimmerman, B. G., Gomer, S. K. and Liao, J. C.: Action of angiotensin on vascular adrenergic nerve endings: facilitation ofnorepinephrine release. Fed. Proc., 31: 1344, 1972. EDITORIAL COMMENT
It is good to see application of the neurohistologic technique to the study of diabetic impotence. Such has been done for the ureter and the bladder to elucidate the intrinsic innervation and neurotransmitter function. The authors point out and the reader should take heed that the demonstration of sympathetic nerve damage neither proves nor disproves the presence or absence of parasympathetic nerve damage. It will require further study to determine whether the damage of diabetic neuropathy is specific to the adrenergic system. There is no reason to believe that it will be; there is reason to suspect that the parasympathetic nerves may be similarly damaged. This report strongly suggests that diabetic impotence is accompanied by nerve damage. However, there is no reason to believe that the critical lesion, the causative damage, is localized to the penis and the penile vessels themselves. In fact, there is every reason to believe that other nerves in the body are damaged in diabetic neuropathy, in the bladder, the blood vessels and elsewhere. The reported work is helpful in providing evidence of the nerve damage and assigning a mechanism for the neuropathies that diabetes cause, and for providing evidence that the more severe forms or the insulin-dependent forms of the disease tend to develop this neuropathy more readily. The work may provide a diagnostic technique to differentiate psychogenic impotence in diabetes from that caused by diabetes neuropathy, although I personally believe that psychologic diagnosis should not be diagnoses by exclusion but diagnoses made positively from psychologic facts. Not all diabetics need be impotent because of the diabetes. Diabetes mellitus and psychogenic impotence are common conditions and there is bound to be some overlap, so that we can expect to find a subgroup of patients who have diabetes but whose impotence is psychogenic. Ifl interpret the data properly only the insulin-resistant diabetics had measurements that fall more than 2 standard deviations away from the normal. Those patients with post-prostatectomy and spinal cord injury do not have the loss of catecholamines from the peripheral nerves, which any reaction to degeneration or denervation sensitivity phenomena would predict. Hence the suggestion is that impotence is caused by nerve damage at a more central level. The authors might comment on this. Saul Boyarsky Division of Urology Washington University School of Medicine St. Louis, Missouri
REPLY BY AUTHORS As Doctor Boyarsky suggests several alternative explanations are possible for our findings. These include injury to cholinergic and purinergic neurons or other nerves releasing other transmitters either peripherally and/or at the level of the spinal cord.
THE JOURNAL OF UROLOGY
Copyright© 1979 by The Williams & Wilkins Co.
Printed in U.S.A.
THE POSSIBLE ROLE OF THE CATECHOLAMINES OF THE CORPORA IN PENILE ERECTION ARNOLD MELMAN*
AND
DAVID HENRY
From the Departments of Urology, Pharmacology and Medicine, Indianapolis Veterans Administration Hospital, Indiana University Medical Center, Lilly Laboratory for Clinical Research, Indianapolis, Indiana
ABSTRACT
The etiolog-y- of impotence, which affects 50 per cent of the men with diabetes, is unknown. The neurotransmitter (norepinephrine) released. from adrenergic neurons is thought to be the most direct regulator of vascular smooth muscle. We have measured the norepinephrine content of the erectile tissue of diabetic men. Our results indicate the presence of a dual neural regulator mechanism of the corpora that controls erection. Impotence is a symptom in nearly 50 per cent of the estimated 1.5 million male subjects in the United States who have diabetes mellitus. 1 Eighty-eight per cent of these people with diabetes and erectile impotence also have a polyneuropathy. 2 In addition, dysfunction of the autonomic nervous system has been a long-recognized concomitant of diabetes mellitus. 3 The precise mechanism of human penile erection in health and its dysfunction in disease remain undefined. In the broadest terms erection can be conceived mechanistically as autonomic neuronal stimulation of the vascular tissue of the penis with resultant vasodilatation and filling of the intratrabecular spaces of the corpora cavernosa with blood. Classical teaching holds that erection is predominantly a parasympathetic function. This theory has been extant since 1863, when Eckhardt electrically stimulated the pelvic nerves of dogs and, thereby, caused an erection presumably by increasing penile vascular flow. 4 The nerves that he stimulated, designated the nervi erigentes, are preganglionic parasympathetic neurons arising from the second, third and fourth sacral segments. In 1947 Root and Bard demonstrated that the adrenergic nerves also are a factor in penile erection.' In their experiments surgical ablation of the lower sacral spinal cord (L4 to 83) did not cause cessation of erection in male cats. However, when the thoracic sympathetic chain was excised the animals were no longer capable of erection. Additional support for adrenergic stimulation was reported by Whitelaw and Smithwick, who performed surgical sympathectomies in patients with severe hypertension.'; Disturbance of erectile function was demonstrated in 57 per cent of the patients undergoing sympathetic ablation of T2 through T12 and in 63 per cent of the patients undergoing the operation in Ll through L3. Impotence is an important problem in men with diabetes and, because the role of the sympathetic (adrenergic) neurons in penile erection is undefined, we have measured the norepinephrine content of the erectile tissue of diabetic patients undergoing penile surgery. N orepinephrine has been shown to be the chemical neurotransmitter of the peripheral sympathetic nervous system. 7 The substance is concentrated, stored and released from vesicles contained in the terminal axons of sympathetic neurons." The axons form an autonomic ground plexus surrounding blood vessels and smooth muscle cells. '1 The norepinephrine concentration in tissue reflects the density of sympathetic innervation of that tissue. 7
METHODS
The spongy erectile tissue of the penile corpora was obtained from 28 patients during placement of a penile prosthesis or total penectomy. Eleven patients had diabetes. Two other g-rnups included men with impotence resulting from a radical operation or perineal trauma and spinal cord injury. Two patients could achieve erections but with severe chordee as a result of Peyronie's disease. Tissue from these 2 patients and 2 potent patients undergoing penectomy served as controls. After removal the tissue was frozen immediately and later analyzed for norepinephrine concentration by a radioenzymatic technique. 10 No clinical evidence of aortofemoral occlusive disease as the cause of impotence was present in any of the patients.
Accepted for publication July 26, 1978. Read at annual meeting of American Urological Association, D. C . May 21-25. 1978. address: Department of Beth Israel Medicai Center 10 :Nathan D. Perlman Place. Nev.: l~evv York 10003. 1
41~
RESULTS
Tissue obtained from within the corpora macroscopically was indistinguishable between the experimental groups. There was no difference between the blood loss from the open corpora of the group at the time of operation. Quantitative measurements of the norepinephrine content of the erectile tissue were summarized (table and fig. 1). There is a significant diminution of norepinephrine concentration in those patients with insulin-dependent diabetes. Those patients form the basis for the incidence oflow concentrations ofnorepinephrine in patients without erections (fig. 1). The norepinephrine concentration in all diabetic patients who required insulin was 71.4 ± 25.3 pg./mg. wet weight tissue. Within this group, however, 1 patient with a norepinephrine concentration of 121 pg./mg. tissue had severe chordee from Peyronie's disease but was able to have erections. The mean concentration in the remaining 4 patients was 59.0 ± 28.4 pg./mg. wet weight. These results are significantly different from the normal mean of 580.6 pg./mg. weight of tissue in normal men (p <0.05). There was no difference between patients with normal erections and those with diabetes controlled by diet and/or oral antihypoglycemic agents, the patients with spinal cord injury, or those men who had undergone a radical pelvic operation or had suffered perineal injury. DISCUSSION
The specific neurovascular mechanism of tumescence is not known. However, that an increase in corpora cavernosa volume results in erection was demonstrated Newman and associates in cadavers and normal volunteers." These invesshowed that erection occurred when 20 to 50 ml. into the corpora. This Shirai and associates,
420
MELMAN AND HENRY
Concentration (pg./mg. wet weight) ofnorepinephrine in human penile erectile tissue
Group
Normal
Diabetes InsulinDependent
Mean ± Standard error No. subjects
563.8 182.3 4
71.4 25.3 5*
Diabetes Diet/ Oral Medication
Spinal Cord Injury
Radical Cystectomy Prostatectomy/ Perineal Injury
594.7 100.0 6t
680.6 166.5 5
427.3 88.1 8
* Significant difference from control group (p <0.05). t Differences from insulin-dependent patients with diabetes (p <0.001). 1200 ~ - - - - - - - - - - - - - - - - - - - ~
1100 -
•
-
1000 -
-:.r, " '.; "
900 -
800 -
el
"
700 -
cJ;
:,.
al
::
600 -
""
500 -
p:; ;c al
z
• • • I • • •
-
•
-
• •
;;: al
p:; 0
•
I
400 -
z
300 -
200 -
100 -
0
I
I• •
NO ERECTIONS
•
• •
-
REFLEX ERECTIONS
NORMAL ERECTIONS
esis suggests a functional role for the histologically evident endothelial pads within the penile arteries. These pads are thought to offer resistance to arterial flow, thus multiplying the effect of arterial vasoconstriction and resulting in a shift of arterial flow through alternative pathways. This concept attempts to account for corporeal filling and detumescence with the selective vasoconstriction of the appropriate feeding vessel (fig. 2). Experimental data to confirm this theory are lacking. Another hypothesis suggests a role for the erectile tissue of the corpora themselves. This tissue is composed of smooth muscle trabeculae that could be seen as offering resistance to flow within the corporeal spaces. Contraction of these trabeculae will expand the potential intravascular volume of the spaces that are known to function as arteriovenous shunts, thus decreasing vascular resistance to the afferent helicine arterioles and allowing tumescence. Adrenergic neurons function as the effector control mechanism of vascular smooth muscle. 16 It was anticipated that quantitative analysis of the norepinephrine concentration of the corpora in patients with impaired and normal tumescence would clarify the role of adrenergic transmission in controlling erection. The results demonstrated that a high concentration of norepinephrine is present in the blood vessels or intrinsic smooth muscle of the corporeal tissue. Our findings suggest that only patients with insulin-dependent diabetes have diThe factors associated with insulin-requiring diabetes mellitus result in impotence associated with low corporeal norepinephrine concentration are unknown but may be related to the duration or severity of the disease. However, previous studies have not shown a relationship between either the duration or the severity of diabetes when impotence alone was evaluated. 17 Other patients in our study, equally impotent, had norepinephrine concentrations similar to those in normal men (fig. 1). This result demonstrates a dual or bimodal distribution of norepinephrine concentration in the corporeal tissue (p <0.0001), suggesting the presence of at least 2 interdependent neurotransmitter regulator mechanisms that control erection. Damage to either mechanism (as in insulindependent diabetic patients) or both (as in patients having trauma or a radical operation) would result in erectile impotence. The parasympathetic neurons that release acetylcholine could be altered as a result of disease or injury. The modification of release of norepinephrine from nerves by acetylcholine has been demonstrated by Vanhoutte. 18 His finding suggests that a modulating relationship may exist between the acetyl-
Fm. 1. Concentration of norepinephrine in erectile tissue of men undergoing penile operation. Each circle represents 1 patient. used a nnm technetium-labeled autologous red blood cell technique to determine penile volume. In their patients an average increase of32 ml. volume occurred within the penis during erection. 12 The mechanism that produces the increased intracorporeal volume of blood is unknown. There may be increased delivery of blood into the corporeal spaces as a result of arteriolar vasodilatation without alteration of venous outflow, which could result in an expanded intracorporeal blood volume. Conversely, a concomitant decrease in venous outflow resulting from constriction of the deep veins draining the corpora would cause secondary engorgement of the trabecular spaces. 13 The continued rigidity of the turgid phallus, when it is compressed by pressure greater than partial pressure, sugFm. 2. Adaptation of Conti's theory of erection. 14 A, detumesgests that arteriolar and venular constriction is present during cence. In this state helicine arteries entering corpora are constricted, erection. whereas arteries surrounding corpora are dilated. There is minimal Conti, 14 expanding on the earlier theories of Kiss, 15 has blood flow within intratrabecular spaces (speckled area). B, tumessuggested that tumescence occurs when there is a shunting of cence. Peripheral artery is constricted with additional intravascular obstruction theoretically created by Von Ebner pads. This forces blood away from the extracorporeal spaces directly through blood into helicine arteries and intratrabecular spaces of corpora, the helicine arteries to the spaces of the corpora. This hypoth- which results in erection.
CATECHOLAMINES AND PENILE ERECTION
choline-releasing neurons and the sympathetic nerves. An alternative explanation is that a substance other than norepinephrine or acetylcholine is important in controlling penile erection. Other substances known to affect norepinephrine release, a receptor activity or re-uptake ofnorepinephrine by the neuron include the prostaglandins, rn histamine and 5hydroxytryptamine, 20 dopamine, 21 adenosine, 22 angiotensin and the enkephalins. 23 The physiologic role of these substances is unknown. The results of our study suggest that the impotence of insulin-dependent diabetes is associated with drastic impairments of at least one component of a regulator of vascular smooth muscle, norepinephrine. The future measurement of the other chemical modifiers of neuronal control will be needed to define fully the erectile mechanism. REFERENCES
1. Tokuhata, G. K., Miller, W., Digon, E. and Hartman, T.: Diabetes mellitus: an underestimated public health problem. J. Chron. Dis., 28: 23, 1975. 2. Rundles, R. W.: Diabetic neuropa:thy: general review with report of 125 cases. Medicine, 24: 111, 1945. 3. Ellenberg, M.: Impotence in diabetes: the neurologic factor. Ann. Intern. Med., 75: 213, 1971. 4. Eckhardt, C.: Untersuchungen iiber die Ereketion des Penis beim Runde. Beitr. Anat. Physiol., 3: 123, 1863. 5. Root, W. S. and Bard, P.: The mediation of feline erection through sympathetic pathways with some remarks on sexual behavior after deafferentation of the genitalia. Amer. J. Physiol., 151: 80, 1947. 6. Whitelaw, G. P. and Smithwick, R.H.: Some secondary effects of sympathectomy with particular reference to disturbance of sexual function. New Engl. J. Med., 245: 121, 1951. 7. Euler, U. S. V.: Physiology of catecholamines. In: Neurochemistry, 2nd ed. Edited by K. A. C. Elliot, I. H. Page and J. H. Quastel. Springfield, Illinois; Charles C Thomas Publishers, pp. 578-589, 1962. 8. Westfall, T. C.: Local regulation of adrenergic neurotransmission. Physiol. Revs., 57: 659, 1977. 9. Falck, B.: Observation on the possibilities of the cellular localization ofmonoamines by a fluorescence method. Acta Physiol. Scand., suppl. 197, 56: 1, 1962. 10. Henry, D. P., Starman, B. J., Johnson, D. G. and Williams, R. H.: A sensitive radioenzymatic assay for norepinephrine in tissues and plasma. Life Sci., 16: 375, 1975. 11. Newman, H. F., Northup, J. D. and Devlin, J.: Mechanism of human penile erection. Invest. Urol., 1: 350, 1964. 12. Shirai, M., Nakamura, M., Ishii, N., Mitsukawa, S. and Sawai, Y.: Determination of intrapenial blood volume using 99mTclabeled autologous red blood cells. Tohoku J. Exp. Med., 120: 377, 1976. 13. Deysach, L. J.: The comparative morphology of erectile tissue of the penis with especial emphasis on probable mechanism of erection. Amer. J. Anat., 64: 111, 1939. 14. Conti, G.: L'erection du penis humain et ses bases morphologicovasculaires. ActaAnat., 14: 217, 1952. 15. Kiss, F.: Anatomisch-histologische Untersuchungen iiber die Erektion. Z. Anat. Entwickl.-Gesch., 61: 455, 1921. 16. Marshall, J. M.: Modulation of smooth muscle activity by catecholamines. Fed. Proc., 36: 2450, 1977. 17. Rubin, A. and Babbott, D.: Impotence and diabetes mellitus. J.A.M.A., 168: 498, 1958. 18. Vanhoutte, P. M.: Cholinergic inhibition of adrenergic transmission. Fed. Proc., 36: 2444, 1977. 19. Hedqvist, P.: Studies on the effect of prostaglandins E, and E 2
20. 21.
22. 23.
421
on the sympathetic neuromuscular transmission in some animal tissues. Acta Physiol. Scand., suppl., 345: 1, 1970. McGrath, M.A.: Histamine and 5-hydroxytryptamine inhibition of transmitter release mediated by H 2 and 5-HT receptors. Fed. Proc., 37: 195, 1978. Enero, M. A. and Langer, S. Z.: Inhibition by dopamine of 3Hnoradrenaline release elicited by nerve stimulation in the isolated cat's nicitating membrane. Naunyn-Schmiedebergs Arch. Pharmacol., 289: 179, 1975. Su, C., Bevan, J. A. and Burnstock, G.: [3 H]-adenosine triphosphate release during stimulation of enteric nerves. Science, 173: 336, 1971. Zimmerman, B. G., Gomer, S. K. and Liao, J. C.: Action of angiotensin on vascular adrenergic nerve endings: facilitation ofnorepinephrine release. Fed. Proc., 31: 1344, 1972. EDITORIAL COMMENT
It is good to see application of the neurohistologic technique to the study of diabetic impotence. Such has been done for the ureter and the bladder to elucidate the intrinsic innervation and neurotransmitter function. The authors point out and the reader should take heed that the demonstration of sympathetic nerve damage neither proves nor disproves the presence or absence of parasympathetic nerve damage. It will require further study to determine whether the damage of diabetic neuropathy is specific to the adrenergic system. There is no reason to believe that it will be; there is reason to suspect that the parasympathetic nerves may be similarly damaged. This report strongly suggests that diabetic impotence is accompanied by nerve damage. However, there is no reason to believe that the critical lesion, the causative damage, is localized to the penis and the penile vessels themselves. In fact, there is every reason to believe that other nerves in the body are damaged in diabetic neuropathy, in the bladder, the blood vessels and elsewhere. The reported work is helpful in providing evidence of the nerve damage and assigning a mechanism for the neuropathies that diabetes cause, and for providing evidence that the more severe forms or the insulin-dependent forms of the disease tend to develop this neuropathy more readily. The work may provide a diagnostic technique to differentiate psychogenic impotence in diabetes from that caused by diabetes neuropathy, although I personally believe that psychologic diagnosis should not be diagnoses by exclusion but diagnoses made positively from psychologic facts. Not all diabetics need be impotent because of the diabetes. Diabetes mellitus and psychogenic impotence are common conditions and there is bound to be some overlap, so that we can expect to find a subgroup of patients who have diabetes but whose impotence is psychogenic. Ifl interpret the data properly only the insulin-resistant diabetics had measurements that fall more than 2 standard deviations away from the normal. Those patients with post-prostatectomy and spinal cord injury do not have the loss of catecholamines from the peripheral nerves, which any reaction to degeneration or denervation sensitivity phenomena would predict. Hence the suggestion is that impotence is caused by nerve damage at a more central level. The authors might comment on this. Saul Boyarsky Division of Urology Washington University School of Medicine St. Louis, Missouri
REPLY BY AUTHORS As Doctor Boyarsky suggests several alternative explanations are possible for our findings. These include injury to cholinergic and purinergic neurons or other nerves releasing other transmitters either peripherally and/or at the level of the spinal cord.