International Journal of Impotence Research (2009) 21, 213–220 & 2009 Nature Publishing Group All rights reserved 0955-9930/09 $32.00 www.nature.com/ijir

ORIGINAL ARTICLE Midodrine for the treatment of organic anejaculation but not : a prospective randomized placebo-controlled double-blind clinical study

MR Safarinejad

Department of , Urology and Nephrology Research Center, Shahid Beheshti University (MC), Tehran, Iran

Anejaculation is a rare cause of and adversely affects the general sense of well-being and perception of sexual life satisfaction. Evidence to support effective and noninvasive treatment for this ejaculatory disorder is lacking. This study aimed to evaluate the efficacy and safety of midodrine (a1-adrenergic receptor agonist) for the treatment of organic anejaculation but not spinal cord injury (SCI). A total of 128 patients were randomly assigned to oral midodrine 7.5–15 mg per day in a stepwise approach (group 1, n ¼ 64), or a similar regimen of placebo (group 2, n ¼ 64). They underwent a complete physical examination, echocardiography, 12-lead electrocardiogram, transrectal ultrasonography, complete blood count and blood chemistry. Hormonal assays included serum levels of luteinizing hormone, follicle-stimulating hormone, prolactin and testosterone. To rule out other , patients also completed the International Index of Erectile Function questionnaire. Psychiatric disorders were excluded by appropriate tests. Outcome measure was reversal of the anejaculation. None of the patients in the placebo group achieved antegrade or retrograde . At the end of study, antegrade, retrograde and antegra- de þ retrograde ejaculation occurred in 18 (29.5%), 8 (13.1%) and 9 (14.8%) patients in midodrine group, respectively (all P ¼ 0.01). The most and least favorable responses were among patients with and bilateral sympathectomy, respectively. Midodrine improved ejaculation function in a dose-dependent manner. Four participants (6.3%) in midodrine group discontinued this study for reasons of adverse events. In patients with organic anejaculation but without SCI midodrine can reverse anejaculation in more than 50% of patients. Further studies are needed, however, for the evaluation of different treatment regimens in anejaculation therapy. International Journal of Impotence Research (2009) 21, 213–220; doi:10.1038/ijir.2009.19; published online 28 May 2009

Keywords: anejaculation; midodrine; drug treatment; a-agonists

Introduction lamic tract and to the thalamus and sensory cortex. The efferent signals run through the anterolateral Anejaculation is defined as complete absence of column of the sympathetic ganglia at T12–L3. From antegrade or retrograde ejaculation. It is a rare here, sympathetic efferent fibers traverse to the disorder in men (1–4% of sexually active men)1 pelvic plexus through the hypogastric . that can cause male factor infertility and consider- Stimuli from pelvic plexus, cause sequential con- able distress. Anejaculation can be classified as traction of the , , seminal lifelong or acquired subtypes based on the develop- vesicle and , with closure of the bladder mental history. Ejaculation is a reflex comprising neck (emission). After expulsion of ejaculate into afferent and efferent pathways. Afferent stimuli pass the posterior , pudendal , which origi- through the penile dorsal nerve into the spinotha- nates from sacral spinal cord (S2–S4) causes rhythmic contractions of the bulbospongiosus and bulbocavernosus muscles, and true ejaculation is then initiated.2 Emission is a sympathetically Correspondence: Dr MR Safarinejad, Department of mediated process, but true ejaculation is somatically Urology, Urology and Nephrology Research Center, Shahid Beheshti University (MC), P.O. Box 19395-1849, Tehran, mediated event. Failures in the emission lead to Iran. anejaculation. E-mail: [email protected] The etiologies of the anejaculation can be categor- Received 2 February 2009; revised 28 April 2009; accepted ized into three major groups: organic, psychogenic 30 April 2009; published online 28 May 2009 and drug related.3 Any psychological or medical Midodrine for treating of organic anejaculation MR Safarinejad 214 disease, surgical procedure or drug, which affects 47.7±9.4 years (range, 35–55 years). This study was the afferent or efferent nerve supply to the seminal approved by the Human Ethics Committee and was vesicle, vas, bladder neck, posterior urethra or conducted according to the Declaration of Helsinki. pelvic floor, can result in anejaculation. Psycholo- All were diagnosed as having non-SCI-related gical factors underlying this condition are poorly organic anejaculation. The absence of spermatozoa understood. Major psychological etiologies regard- and fructose in centrifuged post-coital specimens of ing the genesis of anejaculation are as follows: strict voided urine confirms the diagnosis. After provid- religious beliefs, lack of sexual or emotional attrac- ing informed consent, recruited subjects were tion to a female partner, low levels of sexual arousal, invited for a test visit. Each subject was adminis- idiosyncratic fear of pregnancy or sexually trans- tered a 2.5-mg oral dose of midodrine and blood missible disease and preference for pressure (BP) was measured every 30 min for 4 h. over partnered sexual intercourse.1,3 Every subject with exaggerated BP responses to Among organic etiologies, are spinal cord injury midodrine (BP4140 mm Hg) was excluded. Aneja- (SCI), obstruction, melli- culation was defined as the complete absence of an tus, transverse myelitis and multiple sclerosis. antegrade or retrograde ejaculation. All of them have Many treatments for anejaculation have been had a period of failed pharmacologic therapy proposed, including psychotherapy, medical ther- including, (96, 77.4%), (78, apy, rectal probe electroejaculation (EE) and penile 62.9%), pseudoephedrine (86, 69.3%), phenylpro- vibratory stimulation (PVS).4 Pharmacologic therapy panolamine hydrochloride (58, 46.8%) and neostig- in non-spinal cord injured patients has been almost mine (29, 23.4%). exclusively with a-agonistic drugs (imipramine, ephedrine, pseudoephedrine and milodrin).5 In contrast, parasympathomimetic drugs (physostig- Inclusion–exclusion criteria mine and neostigmine) almost always have been Only patients with a known cause for their used in SCI-related anejaculation. Although medical anejaculation state other than SCI were included. treatment may not always produce normal ejacula- Exclusion criteria included the presence of any tion, it may convert a patient with lack of emission psychiatric or mental disorders and anxiety; no into one with partial antegrade ejaculation (AE) or discernible cause of anejaculation, serious relation- retrograde ejaculation (RE). ship problems; history of alcoholism or other More recently, the a1-adrenegic agonist midodrine substance abuse; use of any drug that might affect has been proposed to treat RE and anejaculation. sexual function; concurrent other sexual dysfunc- Midodrine, 2-amino-N-(2-(2,5-dimethoxy-phenyl)-2- tion such as ; and possibility hydroxyethyl), is an a1-adrenergic receptor agonist of drug-associated side-effects that could lead prodrug of desglymidodrine.6 Midodrine is a well- to dangerous events in the patients. Patients absorbed (93%) drug and compared with ephedrine with a history of arterial (systolic and other sympathomimetic agents, causes less- pressure 4160 mm Hg, diastolic pressure490 mm Hg), frequent and less-severe a-adrenergic effects.7 Mido- ischemic heart disease, or cerebrovascular disease, drine is widely used in the treatment of various and participants taking any medications likely to hypotensive disorders.8 In a recent study, 185 spinal affect blood vessel compliance were excluded from cord injured patients who failed to respond to PSV the study. were treated with midodrine 30–120 min before a new stimulation.9 Antegrade or retrograde ejacula- tion occurred in 64.6% of the patients. In another Evaluations study, ejaculation potential of 62 spinal cord injured They were asked about their medical and sexual men was assessed with various measures. Of histories, and underwent a complete physical patients who did not respond to PVS, 22% were examination, echocardiography, 12-lead electrocar- salvaged by midodrine combined with PVS.10 diogram, 24-h ambulatory BP monitoring, transrec- To the best of our knowledge, there is no tal ultrasonography, complete blood count and published placebo-controlled study on the effect of blood chemistry. Hormonal assays included serum midodrine in patients with organic anejaculation levels of luteinizing hormone, follicle-stimulating but without SCI. hormone, prolactin and testosterone. To rule out other past and concurrent sexual dysfunction, patients completed the International Index of Erec- Materials and methods tile Function questionnaire at the screening visit.11 The diagnosis of organic anejaculation was based on Study participants the presence of physical causes for the condition, From March 2006 through April 2008, one hundred inability to ejaculate during penetrative sexual and forty-four non-spinal cord injured patients with intercourse and on the absence of nocturnal emis- organic anejaculation were admitted consecutively sions. Retrograde ejaculation was ruled out by the for screening. The mean age of the patients was absence of in urine analysis. To be able to

International Journal of Impotence Research Midodrine for treating of organic anejaculation MR Safarinejad 215 exclude any psychiatric disorder all patients com- discontinued. Antegrade ejaculation was defined as pleted the Dissociative Experiences Scale,12 the more than 20 million spermatozoa per ml in the Hamilton Rating Scale for Depression,13 the Hamil- antegrade specimen. Retrograde ejaculation was ton Rating Scale for Anxiety14 and the Liebowitz defined as the presence of spermatozoa in post- Social Anxiety Scale.15 Of 144 screened patients, urine sample. Outcome measure was rever- 128 met inclusion–exclusion criteria and consented sal of the anejaculation. to proceed with the study protocol.

Safety assessment Treatment protocol Adverse events were monitored with questionnaires The study was conducted under the supervision of a and physical examinations throughout the study. dietician. Patients were requested to have a diet At each follow-up visit patients were questioned with moderate salt restriction, avoidance of caffeine, about the presence of any symptoms they experi- licorice and methylxanthine-containing beverages enced. Treatment-emergent adverse events were and foods, and sympathomimetic substances coded by preferred term (Medical Dictionary for throughout the study period. Patients had discon- Regulatory Activities, MedDRA) as well as by tinued all prescribed medications at least 12 weeks severity and relation to study drug. Changes from before the study. The study length was 14 weeks and baseline in laboratory values, vital signs and ECG included a 2-week placebo lead-in phase and a results were assessed. 4-week dose titration period, followed by 8 weeks at a stable dose. Allocation of participants to treatment or placebo groups was performed by a study coordinator, on the Statistical analysis ± basis of a computer-generated random sequence Data are presented as means s.d. The primary using an interactive voice response system. The statistical analysis was by intention-to-treat with coordinator was responsible for the day-to-day inclusion of all the patients who had had any management of the trial and keeping the allocation assessments after baseline. The last observation information in the sealed envelope. After 2 weeks of carried forward was used for subjects who did not placebo lead-in phase, patients were randomized complete the full study protocol. With a ¼ 0.05, initially to receive midodrine 2.5 mg 3 times daily b ¼ 0.20 and D ¼ 30% a minimum of 52 subjects per (group 1, n ¼ 64) or similar regimen of placebo group should complete the trial. The efficacy end (group 2, n ¼ 64). During this 4-week dose titration points were analyzed by an ANCOVA (analysis of period, patients randomly assigned to midodrine covariance) model with the terms of treatment, and 7.5 mg per day had their dose increased by 2.5 mg investigator. The incidence of adverse events was per week, as at the end of this period all of the compared between the midodrine and the placebo remained subjects in group 1 were receiving mido- groups by using Fisher’s exact test, and the dose– drine 5 mg 3 times daily. All patients were evaluated effect relation was evaluated by using the Cochran– every day, which included assessment of symptom Armitage test. Analyses were performed using SPSS status, general medical condition, and documenta- version 10.0 software (SPSS, Chicago, IL, USA) with tion of BP and heart rate in the supine position and two-sided a ¼ 0.05 considered significant. after 3 min in the upright position. After each dose escalation, participants underwent 24-hour ambula- tory BP monitoring. Thereafter, subjects in mido- Results drine group received a stable dose of midodrine 5 mg 3 times daily up to 8 weeks. Patients who could The causes of anejaculation were shown in Table 1. not tolerate a dose of at least 7.5 mg per day of The baseline clinical and demographic characteris- midodrine were discontinued. Patients and investi- tics of the patients that randomized into the study gator were blinded throughout the study to the order are summarized in Table 1. One hundred and eleven of treatment assignment. (87%) participants randomized to the study com- pleted the 8-week stable dose medication period. Reasons for termination before study completion in Efficacy measures each group are shown in Figure 1. The hormonal Participants were followed up every week during 8- concentrations of all patients were within normal week stable dose period. On the visit day of each limits. The results of ejaculation type are shown in follow-up point, subjects underwent repeat 24-h Table 2. None of the patients in placebo group ambulatory BP monitoring. In dose escalation and achieved antegrade or retrograde ejaculation. At the stable dose periods, patients with a systolic blood end of 8-week stable dose period, antegrade, pressure (SBP) greater than 140 mm Hg or a diastolic retrograde and antegrade þ retrograde ejaculation blood pressure (DBP) greater than 90 mm Hg were occurred in 18 (29.5%), 8 (13.1%) and 9 (14.8%)

International Journal of Impotence Research Midodrine for treating of organic anejaculation MR Safarinejad 216 Table 1 Demographic and clinical characteristics of participants

Variables Midodrine group (n ¼ 64) Placebo group (n ¼ 64) P-value

Mean age (years) 46.9±8.8 47.2±9.8 NS Mean duration of the anejaculation (mo) 48.6±7.4 47.8±9.2 NS Duration of marriage (year) 16.4±6.4 16.7±6.6 NS

Etiology of anejaculation no., (%) Diabetes mellitus 14 (21.9) 13 (20.3) NS Multiple sclerosis 8 (12.5) 9 (14.1) NS Parkinson’s disease 8 (12.5) 8 (12.5) NS Bladder neck surgery 7 (10.9) 8 (12.5) NS Colorectal surgery 7 (10.9) 6 (9.4) NS Transverse myelitis 6 (9.4) 5 (7.8) NS Retroperitoneal lymph node dissection 6 (9.4) 7 (10.9) NS Aortoiliac surgery 5 (7.8) 5 (7.8) NS Bilateral Sympathectomy 3 (4.7) 3 (4.7) NS

Abbreviation: NS, not significant.

Assessed for eligibility (n=144)

Excluded (n=16): Not meeting inclusion–exclusion criteria: 13 Withdraw consent to participate: 3 Placebo responders: 0

Randomized (n=128)

Midodrine group (n=64) Placebo group (n=64)

61 (95.3%) completed at least 61 (95.3%) completed at least one efficacy assessment and one efficacy assessment and analyzed analyzed

54 (84.4%) completed 8-week 57 (89.1%) completed 8-week stable dose period stable dose period Excluded: 10 Excluded: 7 Lack of efficacy: 3 Lack of efficacy: 4 Withdrawal of consent: 1 Withdrawal of consent: 2 Lost to follow-up: 2 Lost to follow-up: 1 Adverse events: 4 Adverse events: 0

Figure 1 Flow chart of recruited patients.

Table 2 Ejaculation type at the end of study no. (%)

Group No ejaculation P-value AE P-value RE P-value AE þ RE P-value

Midodrine 26 (42.6) 0.001 18 (29.5) 0.01 8 (13.1) 0.02 9 (14.8) 0.02 Placebo 61 (100) — 0 — 0 — 0 —

Abbreviations: AE, antegrade ejaculation; RE, retrograde ejaculation. All P-values are versus placebo.

International Journal of Impotence Research Midodrine for treating of organic anejaculation MR Safarinejad 217 patients in midodrine group, respectively (all dual variations among the groups (as shown in P ¼ 0.01). At this time, of participants in midodrine Figure 2) suggest that midodrine could benefit 15– group, 26 (42.6%) had anejaculation yet (P ¼ 0.001). 65% of the patients. Midodrine improved ejacula- Significant differences could be detected between tion function in a dose-dependent manner (Table 4). the response rates to midodrine between the Of patients taking 7.5 mg and 15 mg midodrine, 14.8 different diagnoses (Table 3). The most and least and 57.4% had anejaculation reversal success, favorable responses were among patients with respectively (P ¼ 0.001) (Figure 3). multiple sclerosis and bilateral sympathectomy, Mean (±s.d.) values for sperm variables in men with respectively (Figure 2). At the end of study, of AE were as follows: motility, 62.6±11.4%; progressive patients with multiple sclerosis and bilateral sym- motility, 58.6±11.4%; density, 39.2±12.4 Â 106/ml; pathectomy, 14.3 and 66.7%, had anejaculation, and total sperm count, 75.4±11.4 Â 106/ml; and abnormal 57.1 and 0%, developed AE, respectively. Indivi- sperm morphology, 27.4±8.2%.

Table 3 Ejaculation type and etiology of anejaculation at the end of study n (%)

Etiology of anejaculation No ejaculation P-value AE P-value RE P-value AE þ RE P-value

Diabetes mellitus 7 (53.8) 0.01 3 (23.1) 0.01 1 (7.7) 0.04 2 (15.4) 0.02 Multiple sclerosis 1 (14.3) 0.0001 4 (57.1) 0.001 1 (14.3) 0.02 1 (14.3) 0.02 Parkinson’s disease 2 (28.6) 0.001 2 (28.6) 0.01 2 (28.6) 0.01 1 (14.3) 0.02 Bladder neck surgery 2 (28.6) 0.001 3 (42.9) 0.001 2 (28.6) 0.01 0 — Colorectal surgery 4 (57.1) 0.01 1 (14.3) 0.02 1 (14.3) 0.02 1 (14.3) 0.02 Transverse myelitis 4 (66.7) 0.02 1 (16.7) 0.02 1 (16.7) 0.02 0 — Retroperitoneal lymph node dissection 2 (33.3) 0.001 2 (33.3) 0.01 0 — 2 (33.3) 0.01 Aortoiliac surgery 2 (40) 0.001 2 (40) 0.01 0 — 1 (20) 0.01 Bilateral Sympathectomy 2 (66.7) 0.02 0 — 0 — 1 (33.3) 0.01 Total 26 (42.6) 0.001 18 (29.5) 0.01 8 (13.1) 0.02 9 (14.8) 0.02

Abbreviations: AE, antegrade ejaculation; RE, retrograde ejaculation. P-values were derived from statistical analysis by Student’s t-test. P-values refer to comparison of treatment and placebo.

80 No ejaculation AE 70 RE d d AE+RE 60 b c c

50 b bc

% 40 bcc c 30 bcc b c c c 20 dd d a dd d ddd

10 e

0 y y tis omy sease Myeli RPLND

Diabetes mellitusMultiple sclerosis Aortoiliac surgeral sympathect Parkinsons di Colorectal surgery Bladder neck surger Bilater Figure 2 Different types of ejaculation among studied groups at the end of trial. AE, antegrade ejaculation; RE, retrograde ejaculation; RPLND, retroperitoneal lymph node dissection. All P-values are versus placebo. a P-value ¼ 0.0001, b P-value ¼ 0.001, c P-value ¼ 0.01, d P-value ¼ 0.02, e P-value ¼ 0.04.

International Journal of Impotence Research Midodrine for treating of organic anejaculation MR Safarinejad 218 Table 4 Ejaculation type (%) and midodrine doses

Midodrine dose (mg per day) No ejaculation P-value AE P-value RE P-value AE þ RE P-value

7.5 52 (85.2) 0.01 4 (6.6) 0.03 3 (4.9) 0.06 2 (3.3) 0.08 10 46 (75.4) 0.01 6 (9.8) 0.03 5 (8.2) 0.03 4 (6.6) 0.03 12.5 33 (54.1) 0.001 10 (16.4) 0.02 9 (14.8) 0.02 9 (14.8) 0.02 15 26 (42.6) 0.001 18 (29.5) 0.01 8 (13.1) 0.01 9 (14.8) 0.01

Abbreviations: AE, antegrade ejaculation; RE, retrograde ejaculation. All P-values are versus placebo.

Figure 3 Types of ejaculation with different doses of midodrine (mg per day). AE, antegrade ejaculation; RE, retrograde ejaculation. All P-values are versus placebo. a P-value ¼ 0.001, b P-value ¼ 0.01, c P-value ¼ 0.02, d P-value ¼ 0.04, e P-value40.05.

Adverse events Discussion No remarkable treatment-emergent adverse events of midodrine treatment were recorded. Four partici- This is the first study on midodrine use in men with pants (6.3%) in midodrine group discontinued this organic but non-SCI injury-related anejaculation. study by reason of adverse events (developing The primary outcome of this study indicates that hypertension). Treatment with midodrine increased midodrine, reversed anejaculation in significant mean 24-h ambulatory systolic and diastolic blood numbers of patients. Our relatively high success pressures (Figure 4). Mean 24-h ambulatory BP at rate (58% of men achieved antegrade and/or retro- baseline was 124/67±8/6 mm Hg. During medical grade ejaculation) is probably because of appropriate treatment with midodrine 15 mg per day, the mean patients selection. In this study, underlying diag- 24-h ambulatory BP was 134/72±7/6 mm Hg, repre- nosis had influence on the success rates of medical senting a mean 24-h ambulatory BP increase of treatment. There was a trend toward better outcomes 10.5 mm Hg (8.1% mean SBP increase, 7.5% mean in patients with multiple sclerosis and Parkinson’s DBP increase). The difference in mean 24-h ambu- disease. In an earlier study, 185 spinal cord injured latory BP between treatment doses was significant patients with anejaculation who failed to respond to for systolic and diastolic blood pressures (P ¼ 0.03) PVS were treated with midodrine 30–120 min before (Figure 4). Mean heart rate at baseline was 67±4 per a new stimulation. Antegrade or retrograde ejacula- min. This increased by 20.9% with midodrine 15 mg tion was achieved in 64.6% of men.9 Similarly, in per day (P ¼ 0.02) (Figure 5). another study in 62 men with SCI lesions, ejacula-

International Journal of Impotence Research Midodrine for treating of organic anejaculation MR Safarinejad 219

Figure 4 Blood pressure changes with different doses of midodrine (mg per day). Error bars represent percentages. All P-values are versus baseline. a P-value40.05, b P-value ¼ 0.04, c P-value ¼ 0.04, d P-value ¼ 0.03.

Figure 5 Mean heart rates with different doses of midodrine. All P-values are versus baseline. a P-value40.05, b P-value ¼ 0.04, c P-value ¼ 0.03, d P-value ¼ 0.02. tion potential was assessed with various sources of when PVS was negative, another 22% were salvaged stimulation, beginning with natural stimulation, by midodrine combined with PVS.10 The causes for followed, if the test was negative, by PVS followed, anejaculation include psychogenic disorders, con- if the test was again negative, by PVS combined with genital disorders (obstructions of the efferent ducts oral midodrine. Midodrine was administered at or congenital absence of the vas deferens), SCI and doses ranging from 5 mg to 25 mg using a stepwise various organic diseases (for example, diabetes approach. Of patients with a negative result with mellitus, Parkinson’s disease, multiple sclerosis natural stimulation, 56% were salvaged by PVS, and and transverse myelitis).3,4

International Journal of Impotence Research Midodrine for treating of organic anejaculation MR Safarinejad 220 Treatment modalities include psychotherapy, Conflict of interest rectal probe EE, PVS and drug therapy. In a nice review article, Kamischke et al.5 concluded that, in The author declares no conflict of interest. anejaculation, medical treatment shows low overall success rates compared with electrovibration stimu- lation and EE. However, EE mostly is used in case of Acknowledgments infertility. In addition, adverse events, such as rectal injury and autonomic dysreflexia, are likely after 16 I thank Shiva Safarinejad for critical reading of the EE. For reversal of anejaculation in daily life, paper. I thank Nayyer Shafiei for her professional medical treatment is preferred. Drug therapy and technical assistance during the study. for patients who suffer from organic anejaculation but not SCI, has been exclusively with a-agonistic drugs (imipramine, ephedrine and pseudo- ephedrine).5 Among the different a-agonistic References medical treatments, milodrin is better than imipra- 1 Jannini EA, Simonelli C, Lenzi A. Sexological approach to mine (P ¼ 0.008), pseudoephedrine (P ¼ 0.02) and ejaculatory dysfunction. Int J Androl 2002; 25: 317–323. ephedrine (P ¼ 0.044), in terms of the reversal of 2 Ralph DJ, Wylie KR. Ejaculatory disorders and sexual anejaculation.5 function. BJU Int 2005; 95: 1181–1186. Side effects of a-agonists for the treatment of 3 McMahon CG, Abdo C, Incrocci L, Perelman M, Rowland D, Waldinger M et al. Disorders of orgasm and ejaculation in anejaculation include various degrees of dizziness, men. J Sex Med 2004; 1: 58–65. sleep disturbances, weakness, restlessness, dry 4 Qiu Y, Wang SM, Yang DT, Wang LG. Percutaneous vasal 17 mouth, nausea and sweating. Regardless of the sperm aspiration and intrauterine insemination for infertile mechanism of action, midodrine as a potential males with anejaculation. Fertil Steril 2003; 79: 618–620. therapy for anejaculation has several advantages. It 5 Kamischke A, Nieschlag E. Update on medical treatment of ejaculatory disorders. Int J Androl 2002; 25: 333–344. does not cross the blood–brain barrier and therefore 6 McClellan KJ, Wiseman LR, Wilde MI. Midodrine. A review does not have any side effects such as anxiety, of-its therapeutic use in the management of orthostatic agitation and insomnia common with other hypotension. Drugs Aging 1998; I2: 76–86. a-agonists.18 Daily treatment strategy was used in 7 Mukand J, Karlin L, Barrs K, Lublin P. Midodrine for the management of orthostatic hypotension in patients with this study rather than on-demand treatment. For spinal cord injury: a case report. Arch Phys Med Rehabil reversal of the anejaculation, a-agonists are more 2001; 82: 694–696. effective over a few days rather than as a single dose 8 Lamarre-Cliche M, Souich P, Champlain J, Larochelle P. before intercourse.19 Treatment of an ejaculation Pharmacokinetic and pharmacodynamic effects of midodrine should be etiology specific and address the issue of on blood pressure, the , and plasma natriuretic peptides: a prospective, randomized, single-blind, infertility in men desiring pregnancy. In the avail- two-period, crossover, placebo-controlled study. Clin Ther able literature, we could not find similar studies for 2008; 30: 1629–1638. comparison. Most reports with a-agonists are anec- 9 Soler JM, Previnaire JG, Plante P, Denys P, Chartier-Kastler E. dotal case reports/series. Although midodrine treat- Midodrine improves ejaculation in spinal cord injured men. J Urol 2007; 178: 2082–2086. ment may not always produce AE, it can convert a 10 Courtois FJ, Charvier KF, Leriche A, Ve´zina JG, Coˆte´ M, substantial numbers of patients with lack of emis- Be´langer M. Blood pressure changes during sexual stimula- sion into one with RE. It can result in small amounts tion, ejaculation and midodrine treatment in men with spinal of viable sperm sufficient for use in some forms of cord injury. BJU Int 2008; 101: 331–337. artificial reproductive techniques in infertile cou- 11 Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The International Index of Erectile Function (IIEF): ples. The advantages of oral therapy with midodrine a multidimensional scale for assessment of erectile dysfunc- include broad patient acceptance, ease of adminis- tion. Urology 1997; 49: 822–830. tration and relative efficacy. The disadvantage 12 Bernstein-Carlson E, Putnam FW. An update on the Dissso- includes concomitant vasoconstrictive effect. ciative Experiences Scale. Dissociation 1993; 6: 16–27. 13 Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56–61. 14 Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959; 32: 50–55. Conclusion 15 Heimberg RG, Horner KJ, Juster HR, Schneier FR, Liebowitz MR. Psychometric properties of the Liebowitz Social Anxiety The results of this study are encouraging. In patients Scale. Psychol Med 1999; 29: 199–212. with organic anejaculation, but not in those 16 Schatte EC, Orejuela FJ, Lipshultz LI, Kim ED, Lamb DJ. Treatment of infertility due to anejaculation in the male with with SCI, the administration of midodrine electroejaculation and intracytoplasmic sperm injection. induces antegrade and/or retrograde ejaculation J Urol 2000; 163: 1717–1720. in more than 50% of patient. Further studies are 17 Kamischke A, Nieschlag E. Treatment of retrograde ejaculation needed to confirm the efficacy of this treatment. The and anejaculation. Hum Reprod Update 1999; 5: 448–474. 18 Kaufmann H, Saadia D, Voustianiouk A. Midodrine in current standard practice mandates for a more neurally mediated syncope: a double-blind, randomized, elaborate management of patients with anejacula- crossover study. Ann Neurol 2002; 52: 342–345. tion. 19 Vale J. Ejaculatory dysfunction. BJU Int 1999; 83: 557–563.

International Journal of Impotence Research