TREATMENT
OF RETROGRADE
EJACULATION
WITH BROMPHENIRAMINE VINCENT
A. ANDALORO,
ARTHUR DUBE,
JR., M.D.
M.D.
From the Departments of Urology and Medicine, State University Hospital, Upstate Medical Center, Syracuse, New York
ABSTRACT - The retrograde ejaculation experienced by a juvenile diabetic man was successfully treated with brompheniramine, a drug having antihistaminic and anticholinergic properties. A possible mechanism of action is suggested.
Retrograde ejaculation can occur when the internal sphincter of the bladder neck fails to close during orgasm. This abnormal state commonly is a result of mechanical disruption during transurethral resection of bladder neck or prostate. It also may be seen after interruption of the sympathetic nervous innervation of these structures following extensive retroperitoneal surgery. Transmission of nerve impulses to the bladder neck can be effectively blocked by guanethidine which interferes with the function of postganglionic sympathetic fibers and can result in retrograde ejaculation. That retrograde ejaculation could be caused by diabetes mellitus was first described in 1963 by Greene, Kelalis, and Weeks.’ It is believed by most investigators that retrograde ejaculation is only one manifestation of the symptom complex caused by autonomic neuropathy in the diabetic patient. The sterility which results from retrograde ejaculation has been difficult to treat. Since the problem appears to result from incompetency of bladder neck closure during orgasm, the use of sympathomimetic drugs has been suggested. Unfortunately, no beneficial effect was found by Greene and Kelalis2 using a variety of sympathomimetic drugs. Until now, the only reported successful treatment for those men with retrograde ejaculation who desire to father a child has’ been the artificial insemination technique described by Hotchkiss, Pinto, and Kleegman.3 In
520
this procedure sperm are recovered from the patient’s bladder via catheterization after intercourse, and the semen is used to inseminate the female partner artificially. Several successful pregnancies have resulted from the use of this technique. 2,4 We wish to describe the successful treatment of retrograde ejaculation with brompheniramine maleate (Dimetane), a drug having antihistaminic and anticholinergic properties. Case Report A twenty-five-year-old married white man has known juvenile diabetes mellitus which is under good control with 55 units of lente insulin daily. Diabetic retinal disease has required laser therapy in the past. He was seen in urologic consultation in September, 1973, because of retrograde ejaculation which had been present since 1971. Prior to that time, his ejaculations had always been antegrade. The patient requested consultation because of infertility. Since a careful history and physical examination failed to reveal any urologic basis for the problem with ejaculation, the possibility of obtaining his semen for artificial insemination by Hotchkiss’ technique was suggested, but he did not wish to pursue this approach. Thereafter, he began taking medication for nasal congestion. This contained a decongestant,
UROLOGY
I
APRIL 1975 / VOLUME
V, NUMBER4
phenylpropanolamine, and two antihistamine drugs, chlorpheniramine and methapyrilene (Allerest). He noted that around the same time, he began having normal antegrade ejaculations following masturbation, and it was his impression that antegrade ejaculation occurred only on those days he took the nasal decongestant. In June, 1974, he began taking brompheniramine 8 mg., twice daily as prescribed by his physician for hay fever. Coincidentally, he noted the return of normal antegrade ejaculation. When he would discontinue the medication, the antegrade ejaculation would disappear within one day of ingestion of his last pill. He also noticed that if he took a brompheniramine tablet in the morning and none in the evening and then engaged in sexual activity in the late evening, his ejaculation would be retrograde. The patient was seen again in August, 1974. The details of the foregoing history were discussed and their possible significance was explained to him. A clinical trial was outlined in which the patient would carefully record both the times he took medication and indulged in sexual activity and which type, either masturbation or intercourse using a condom. Also recorded was the presence or absence of semen occurring with ejaculation. Records were meticulously kept for five weeks. The only medication taken during this time was insulin and brompheniramine. During the month of August, the patient took no brompheniramine and experienced no antegrade ejaculation of semen associated with sexual activity culminating in orgasm, which was occurring about two to three times weekly. On August 25, he began taking brompheniramine, 8 mg. at 7 A.M. and 6 P.M. daily. On the first night on two occasions, several drops of semen were ejaculated. The amount of semen increased as the clinical trial proceeded over the following twentyfour days. Masturbation or sexual intercourse using a condom was performed eleven times and antegrade ejaculation occurred nine times. On September 19, the brompheniramine was discontinued. By the evening of September 20, no semen was ejaculated in an antegrade fashion, although orgasm did occur during sexual intercourse. During the following eleven days, sexual activity resulted in orgasm on four occasions, none with antegrade ejaculation. (“All went normally except at climax, there was no semen present at all.“) On September 30, the brompheniramine was again begun and antegrade ejaculations returned by the next evening.
UROLOGY
/
APRIL 1975
I
VOLUME V, NUMBER4
Comment The smooth muscle of bladder detrusor, bladder neck, and posterior urethra are innervated by the autonomic nervous system. Various drugs and pathologic processes involving the nerves to this region are known to cause disturbances of micturition or sexual functions. During voiding, the detrusor contracts under the influence of parasympathetic fibers. Simultaneously, the smooth muscle around the bladder neck and urethra relaxes, allowing the bladder to empty. This muscle acts as the internal urinary sphincter, and its tone is under the influence of sympathetic innervation. During normal antegrade ejaculation, the internal sphincter must close to prevent semen from being propelled into the bladder. Any condition which can interfere with sympathetic nerve transmission to the lower urinary tract can produce retrograde ejaculation. The most common cause is iatrogenic and is a result of mechanical disruption of the internal sphincter during surgery. Functionally, similar end results may be produced b y 1umbar sympathectomy, abdominal-perineal bowel resection, and retroperitoneal lymph node dissection.5 The ability to obtain an erection and experience orgasm may be preserved, but semen ejaculation is retrograde. Various antiadrenergic blocking agents of alpha-receptors of the sympathetic nervous system also have retrograde ejaculation as a side effect. Diabetes mellitus has long been known to cause autonomic nervous dysfunction usually of the sympathetic system. Kleeman’ studied the physiologic structure of the internal urinary sphincter. Using dogs, he observed the bladder neck region from inside the bladder using a panendoscope placed through the dome. Various drugs were administered intravenously including alpha-sympathetic stimulating and blocking agents and the parasympathomimetic drug, bethanechol. Epinephrine tightly closed the bladder neck. The cholinergic agent consistently opened the bladder neck, and this effect could be reversed by epinephrine. Many drugs such as brompheniramine and chlorpheniramine, which are classified as antihistaminic agents, exhibit various degrees of anticholinergic side effects. ’ It is possible to postulate that the smooth muscle of the internal sphincter has dual innervation, both sympathetic and parasympathetic. Except during voiding, sympathetic action is dominant and the bladder neck remains closed
521
preventing incontinence. When micturition occurs, there is outflow of parasympathetic stimulation and suppression of the sympathetic fibers, causing opening of the bladder neck and detrusor contraction. During normal ejaculation, sympathetic influence maintains closure of the bladder neck and the semen proceeds antegrade. In some diabetic men there is disease of the sympathetic nervous system which could diminish the sympathetic input to the smooth muscle of the bladder neck and result in dominance of the parasympathetic influence on this tissue. There would be failure of bladder neck closure during ejaculation and thus retrograde ejaculation. This relative imbalance might account for the success of an agent such as brompheniramine having anticholinergic properties in allowing for bladder neck closure during ejaculation. The use of a drug with anticholinergic effects appeared to reverse retrograde ejaculation in a male diabetic. Further clinical trial is needed to learn if this drug will be effective in other diabetics as well as in those patients who have retro-
522
grade ejaculation as a result of retroperitoneal surgery and surgery on the bladder neck itself. 750 East Adams Street Syracuse, New York 13210 (DR. ANDALORO) References 1. GREENE, L. F., KELALIS, P., and WEEKS, R.: Retrograde ejaculation of semen due to diabetic neuropathy, Fertil. Steril. 14: 617 (1963). 2. GREENE, L. F., and KELALIS, P.: Retrograde ejaculation of semen due to diabetic neuropathy, J. Urol. 98: 693 (1967). 3. HOTCHKISS,R. S., PINTO, A. B., and KLEEGMAN, S.: Artificial insemination with semen recovered from the bladder, Fertil. Steril. 6: 37 (1955). 4. BOURNE, R. B., KRETZ?,CHMAR,W. A., and ESSER, J. H.: Successful artificial insemination in a diabetic with retrograde ejaculation, ibid. 22: 275 (1971). 5. LESTER, E., and BRENDLER, H.: Loss of ejaculation following bilateral retroperitoneal lymphadenectomy, J. Urol. 98: 375 (1967). 6. KLEEMAN, F. J.: The physiology of the internal urinary sphincter, ibid. 104: 549 (1970). 7. GOODMAN,L. S., and GILMAN,A. : The Pharmacological Basis of Therapeutics, 4th ed., New York, The Macmillan Company, 1970, p. 640.
UROLOGY /
APRIL 1975 / VOLUME V, NUMBER4
OF RETROGRADE
EJACULATION
WITH BROMPHENIRAMINE VINCENT
A. ANDALORO,
ARTHUR DUBE,
JR., M.D.
M.D.
From the Departments of Urology and Medicine, State University Hospital, Upstate Medical Center, Syracuse, New York
ABSTRACT - The retrograde ejaculation experienced by a juvenile diabetic man was successfully treated with brompheniramine, a drug having antihistaminic and anticholinergic properties. A possible mechanism of action is suggested.
Retrograde ejaculation can occur when the internal sphincter of the bladder neck fails to close during orgasm. This abnormal state commonly is a result of mechanical disruption during transurethral resection of bladder neck or prostate. It also may be seen after interruption of the sympathetic nervous innervation of these structures following extensive retroperitoneal surgery. Transmission of nerve impulses to the bladder neck can be effectively blocked by guanethidine which interferes with the function of postganglionic sympathetic fibers and can result in retrograde ejaculation. That retrograde ejaculation could be caused by diabetes mellitus was first described in 1963 by Greene, Kelalis, and Weeks.’ It is believed by most investigators that retrograde ejaculation is only one manifestation of the symptom complex caused by autonomic neuropathy in the diabetic patient. The sterility which results from retrograde ejaculation has been difficult to treat. Since the problem appears to result from incompetency of bladder neck closure during orgasm, the use of sympathomimetic drugs has been suggested. Unfortunately, no beneficial effect was found by Greene and Kelalis2 using a variety of sympathomimetic drugs. Until now, the only reported successful treatment for those men with retrograde ejaculation who desire to father a child has’ been the artificial insemination technique described by Hotchkiss, Pinto, and Kleegman.3 In
520
this procedure sperm are recovered from the patient’s bladder via catheterization after intercourse, and the semen is used to inseminate the female partner artificially. Several successful pregnancies have resulted from the use of this technique. 2,4 We wish to describe the successful treatment of retrograde ejaculation with brompheniramine maleate (Dimetane), a drug having antihistaminic and anticholinergic properties. Case Report A twenty-five-year-old married white man has known juvenile diabetes mellitus which is under good control with 55 units of lente insulin daily. Diabetic retinal disease has required laser therapy in the past. He was seen in urologic consultation in September, 1973, because of retrograde ejaculation which had been present since 1971. Prior to that time, his ejaculations had always been antegrade. The patient requested consultation because of infertility. Since a careful history and physical examination failed to reveal any urologic basis for the problem with ejaculation, the possibility of obtaining his semen for artificial insemination by Hotchkiss’ technique was suggested, but he did not wish to pursue this approach. Thereafter, he began taking medication for nasal congestion. This contained a decongestant,
UROLOGY
I
APRIL 1975 / VOLUME
V, NUMBER4
phenylpropanolamine, and two antihistamine drugs, chlorpheniramine and methapyrilene (Allerest). He noted that around the same time, he began having normal antegrade ejaculations following masturbation, and it was his impression that antegrade ejaculation occurred only on those days he took the nasal decongestant. In June, 1974, he began taking brompheniramine 8 mg., twice daily as prescribed by his physician for hay fever. Coincidentally, he noted the return of normal antegrade ejaculation. When he would discontinue the medication, the antegrade ejaculation would disappear within one day of ingestion of his last pill. He also noticed that if he took a brompheniramine tablet in the morning and none in the evening and then engaged in sexual activity in the late evening, his ejaculation would be retrograde. The patient was seen again in August, 1974. The details of the foregoing history were discussed and their possible significance was explained to him. A clinical trial was outlined in which the patient would carefully record both the times he took medication and indulged in sexual activity and which type, either masturbation or intercourse using a condom. Also recorded was the presence or absence of semen occurring with ejaculation. Records were meticulously kept for five weeks. The only medication taken during this time was insulin and brompheniramine. During the month of August, the patient took no brompheniramine and experienced no antegrade ejaculation of semen associated with sexual activity culminating in orgasm, which was occurring about two to three times weekly. On August 25, he began taking brompheniramine, 8 mg. at 7 A.M. and 6 P.M. daily. On the first night on two occasions, several drops of semen were ejaculated. The amount of semen increased as the clinical trial proceeded over the following twentyfour days. Masturbation or sexual intercourse using a condom was performed eleven times and antegrade ejaculation occurred nine times. On September 19, the brompheniramine was discontinued. By the evening of September 20, no semen was ejaculated in an antegrade fashion, although orgasm did occur during sexual intercourse. During the following eleven days, sexual activity resulted in orgasm on four occasions, none with antegrade ejaculation. (“All went normally except at climax, there was no semen present at all.“) On September 30, the brompheniramine was again begun and antegrade ejaculations returned by the next evening.
UROLOGY
/
APRIL 1975
I
VOLUME V, NUMBER4
Comment The smooth muscle of bladder detrusor, bladder neck, and posterior urethra are innervated by the autonomic nervous system. Various drugs and pathologic processes involving the nerves to this region are known to cause disturbances of micturition or sexual functions. During voiding, the detrusor contracts under the influence of parasympathetic fibers. Simultaneously, the smooth muscle around the bladder neck and urethra relaxes, allowing the bladder to empty. This muscle acts as the internal urinary sphincter, and its tone is under the influence of sympathetic innervation. During normal antegrade ejaculation, the internal sphincter must close to prevent semen from being propelled into the bladder. Any condition which can interfere with sympathetic nerve transmission to the lower urinary tract can produce retrograde ejaculation. The most common cause is iatrogenic and is a result of mechanical disruption of the internal sphincter during surgery. Functionally, similar end results may be produced b y 1umbar sympathectomy, abdominal-perineal bowel resection, and retroperitoneal lymph node dissection.5 The ability to obtain an erection and experience orgasm may be preserved, but semen ejaculation is retrograde. Various antiadrenergic blocking agents of alpha-receptors of the sympathetic nervous system also have retrograde ejaculation as a side effect. Diabetes mellitus has long been known to cause autonomic nervous dysfunction usually of the sympathetic system. Kleeman’ studied the physiologic structure of the internal urinary sphincter. Using dogs, he observed the bladder neck region from inside the bladder using a panendoscope placed through the dome. Various drugs were administered intravenously including alpha-sympathetic stimulating and blocking agents and the parasympathomimetic drug, bethanechol. Epinephrine tightly closed the bladder neck. The cholinergic agent consistently opened the bladder neck, and this effect could be reversed by epinephrine. Many drugs such as brompheniramine and chlorpheniramine, which are classified as antihistaminic agents, exhibit various degrees of anticholinergic side effects. ’ It is possible to postulate that the smooth muscle of the internal sphincter has dual innervation, both sympathetic and parasympathetic. Except during voiding, sympathetic action is dominant and the bladder neck remains closed
521
preventing incontinence. When micturition occurs, there is outflow of parasympathetic stimulation and suppression of the sympathetic fibers, causing opening of the bladder neck and detrusor contraction. During normal ejaculation, sympathetic influence maintains closure of the bladder neck and the semen proceeds antegrade. In some diabetic men there is disease of the sympathetic nervous system which could diminish the sympathetic input to the smooth muscle of the bladder neck and result in dominance of the parasympathetic influence on this tissue. There would be failure of bladder neck closure during ejaculation and thus retrograde ejaculation. This relative imbalance might account for the success of an agent such as brompheniramine having anticholinergic properties in allowing for bladder neck closure during ejaculation. The use of a drug with anticholinergic effects appeared to reverse retrograde ejaculation in a male diabetic. Further clinical trial is needed to learn if this drug will be effective in other diabetics as well as in those patients who have retro-
522
grade ejaculation as a result of retroperitoneal surgery and surgery on the bladder neck itself. 750 East Adams Street Syracuse, New York 13210 (DR. ANDALORO) References 1. GREENE, L. F., KELALIS, P., and WEEKS, R.: Retrograde ejaculation of semen due to diabetic neuropathy, Fertil. Steril. 14: 617 (1963). 2. GREENE, L. F., and KELALIS, P.: Retrograde ejaculation of semen due to diabetic neuropathy, J. Urol. 98: 693 (1967). 3. HOTCHKISS,R. S., PINTO, A. B., and KLEEGMAN, S.: Artificial insemination with semen recovered from the bladder, Fertil. Steril. 6: 37 (1955). 4. BOURNE, R. B., KRETZ?,CHMAR,W. A., and ESSER, J. H.: Successful artificial insemination in a diabetic with retrograde ejaculation, ibid. 22: 275 (1971). 5. LESTER, E., and BRENDLER, H.: Loss of ejaculation following bilateral retroperitoneal lymphadenectomy, J. Urol. 98: 375 (1967). 6. KLEEMAN, F. J.: The physiology of the internal urinary sphincter, ibid. 104: 549 (1970). 7. GOODMAN,L. S., and GILMAN,A. : The Pharmacological Basis of Therapeutics, 4th ed., New York, The Macmillan Company, 1970, p. 640.
UROLOGY /
APRIL 1975 / VOLUME V, NUMBER4
