We treated two patients affected by retrograde ejaculation (RE) with the pure α1-adrenergic agonist methoxamine; the drug was self-administered intramuscularly by the patients 30 min prior to intercourse or masturbation. A previous trial with oral imipramine had been ineffective in both patients. Sperm count increased substantially, particularly in the first patient who had insulin-dependent diabetes and was seeking fertility. In this patient, total ejaculated sperm increased from 22 millions to 488 and 419.5 millions on two different occasions, with good motility; two clinical pregnancies were obtained in the partner of this patient after 3 and 4 months of treatment, respectively. The second patient did not desire fertility. In both patients, no side effects were seen except for slight piloerection; blood pressure values increased slightly, and heart rate was unchanged. We conclude that self-administered methoxamine can be a useful, noninvasive and inexpensive treatment of RE, when oral agents are ineffective.
Retrograde ejaculation (RE) is an infrequent but treatable cause of infertility.1 It is different from anejaculation, because in RE semen is emitted in the posterior urethra, whence a substantial proportion is propulsed into the bladder.
Its causes can be classified into two broad categories: neurogenic and anatomic. Neurogenic RE includes autonomic dysfunction (diabetes mellitus, multiple sclerosis) and surgical disruption of the peripheral autonomic sympathetic fibers (eg after radical prostatectomy, retroperitoneal lymph node dissection for testis cancer, or pelvic dissection during colon surgery).2 Anatomic causes are unusual at present, and may be secondary to surgery of the bladder neck or transurethral resection of the prostate; they are not amenable to pharmacologic manipulation. In many cases, RE has no discernible cause (idiopathic).
Among treatments reported in the literature, pharmacological intervention aims to correct the problem by helping to coapt the bladder neck, thus inducing antegrade ejaculation; this has been attempted with antihistamines (brompheniramine), tricyclic antidepressants (imipramine), and other drugs, including anticholinergic and adrenergic agents.3 The second approach involves collecting the retrograde ejaculate and using it for assisted reproduction techniques. For example, prefilling of the bladder with a suitable medium (or alkalinization with bicarbonate), followed by masturbation and immediate recovery of the emptied bladder content, has been used for successful artificial insemination;4 electroejaculation induced by a rectal probe5 has had limited success. More complex reproductive technologies, such as in vitro fertilization (IVF), and gamete intrafallopian transfer (GIFT)6 or intracytoplasmic sperm injection (ICSI)7 have also been used successfully, although their cost and impact on the couple may make them an unsatisfactory first-line treatment.8
We report here two cases of RE, treated with the pure α1-adrenergic agonist methoxamine (Figure 1).
Patients and methods
The first patient was a taxi-cab driver, aged 28 y, who had been affected by insulin-dependent diabetes mellitus for 14 y and infertility for 4 y, due to partial RE (95% of ejaculated sperm went into the bladder). Reproductive hormone levels (LH, FSH, testosterone, prolactin) were well within normal limits, and testes were 22 ml bilaterally. Examination of the partner, who was 25 y old and healthy, did not disclose any significant abnormality.
The second patient was a 23-y-old clerical worker, affected by ‘primary’ idiopathic RE (he had never had any ejaculate), possibly due to a localized neurological impairment as there was absence of sweating after local painful stimulation of the skin. The patient was not seeking treatment for infertility. Hormonal levels were again normal; however, testes were slightly atrophic (12 and 15 ml).
In both cases, diagnosis of RE and post-treatment measurements were performed by asking the patient to void the bladder after an attempt to collect seminal fluid by masturbation. Any ejaculated seminal fluid was then examined according to the WHO manual for the examination of seminal fluid, and the voided urine was centrifuged at 800 g for 10′; the pellet was then resuspended in 10 ml of isotonic medium, and sperm cells were counted in the suspension. The ratio of total ejaculated vs urinary sperm cells was used to estimate the percentage of RE.
We performed, in both patients, two trial administrations of methoxamine (Vasoxine, Wellcome, UK) 5 mg i.m. 30 min before masturbation and semen analysis, which was performed on the semen sample and on immediately voided urine. Methoxamine is an α1-adrenergic agonist, used in higher doses for the treatment of hypotension and shock.
The first patient was also instructed to self-administer the drug 30 min prior to each periovulatory intercourse; also the couple was given general advice regarding optimum timing and technique of intercourse, and ovulation was monitored with basal temperature recording. The study protocol had been approved by the Ethical Committee of the University of Sassari.
In the first patient, recumbent blood pressure increased from 95/75 to 120/80 and from 100/80 to 120/85 mmHg in the two occasions, while heart rate remained constant. The fraction of ejaculated sperm increased from 5 to 57 and 49%, and the total ejaculated sperm increased from 22 millions to 488 and 419.5 millions, with comparable motility in the ejaculated sperm: the motility index, that is, the percentage of progressively motile sperm, was 60 vs 61 and 58%. Seminal fluid volume increased from 0.2 to 3.0 and 3.2 ml; pH was unchanged at 7.8. After 3 months of self-administered treatment, the patient's wife had a sonographically confirmed pregnancy, which terminated with a spontaneous abortion at 10 weeks of gestation. A second 4-month course of treatment induced another pregnancy, carried to term with delivery of a normal male infant.
In the second patient, who had no ejaculate without treatment, i.m. methoxamine allowed to collect a 0.2 and 0.1 ml quantity of ejaculate in the two tests, thus permitting a full semen analysis to be performed; sperm concentration was 7.9 and 10.2 million sperm per ml, with a total of 790 000 and 2.04 million sperm per ejaculate. However, most sperms were still being emitted in the bladder (fraction of ejaculated sperm: from 0% without treatment to 15 and 7% after treatment). Motility was unchanged (progressive motility percentage: 45 vs 53 and 37%). The pH ranged from 7.7 to 8.0. Blood pressure was slightly increased in the two occasions (105/75 to 120/80 and 115/85 to 125/80 mmHg), with no change in the heart rate.
The only reported adverse effect after methoxamine administration was piloerection in both patients. Subjective penile rigidity was reported to be unchanged by the two patients.
Many patients with RE are treated today with IVF, GIFT or ICSI after sperm cell retrieval from alkalinized urine (or preinstilled culture medium); although these method are effective, they are expensive and time-consuming, and require preparation of the partner. Other existing medical therapies, while simpler to assume and not expensive (as per os (p.o.) imipramine), may require daily treatment for prolonged periods.
Studies in experimental animals have shown that circulating adrenal medullary amines play a fundamental role in ejaculation, and that sympathetic denervation causes RE in the dog.9 Indeed, a new oral antihypotensive agent, amezinium, has been successfully employed to treat RE.10 Other medical treatments like imipramine (which inhibits reuptake of adrenergic amines) may also act via an increased adrenergic stimulation, in addition to the known anticholinergic effect of the drug. In the published literature, when pregnancy was desired imipramine was the chosen treatment in approximately 80% of the patients, with approximately 1/3 of them achieving their objective.3
In our two patients, a previous therapeutic trial with imipramine (25 mg p.o. 2 h prior to masturbation) had not been effective, with a comparable (very low) ejaculated volume in the first, and persistence of complete RE in the second. The treatment had been given for 4 months, during which patient 1 reported anejaculation on almost all occasions.
In our limited experience, methoxamine at the dose we used has been a safe agent, devoid of significant side effects. Although the reversal of RE was not complete in either patient (particularly in the second case), in our first patient it permitted two pregnancies to occur after 3 and 4 months of treatment, as compared to 4 y of infertility, and 4 months of ineffective treatment with oral imipramine.
Methoxamine has a long half-life, compared to other adrenergic agents, and can be administered i.m. However, methoxamine can increase afterload without any compensatory inotropic effect, and may thus precipitate an important reduction of cardiac output in patients with left ventricular dysfunction or aortic insufficiency, in whom it would be clearly contraindicated. Although α1-adrenergic agonists can induce peripheral vasoconstriction and thus might impair erection, no subjective decrease of penile rigidity was reported by our patients; however, moderate diffuse piloerection was noted in both cases, which was well tolerated. In our first patient, intramuscular (i.m.) therapy with methoxamine was a safe and effective way to treat the infertility due to RE, probably acting through an increased tone of the bladder neck.
These results confirm that medical treatment should the modality of first choice in male infertility due to RE;3 we suggest that if oral medications, such as imipramine or ephedrine, are not effective, a trial with self-administered i.m. methoxamine may be warranted.
We sincerely thank Robert Oates, MD, from Boston University Medical School, Boston MA (USA), for his very helpful comments and assistance in reviewing the manuscript. This work has been made possible by a grant awarded from Fondazione Banco di Sardegna, Sassari, Italy, to one of us (PA Tomasi).
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Disruption of Prepulse Inhibition after Stimulation of Central but not Peripheral α-1 Adrenergic Receptors