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The Effect and Safety of Lisinopril in Non-hypertensive Men With Infertility From Low Sperm Count

Information source: University Of Nigeria Teaching Hospital
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Oligospermia

Intervention: Lisinopril (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: University Of Nigeria Teaching Hospital

Official(s) and/or principal investigator(s):
Anthony U Mbah, MD, FMCP, Principal Investigator, Affiliation: University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu


This study was conceived in order to explain what the investigators previously observed suggesting that lisinopril, a drug normally used to treat patients with high blood pressure and heart failure, may be effective in treating infertile men with low sperm count. The investigators hypothesized, therefore, that the drug will not only improve sperm quantity and quality but also increase the fertility in such patients. The investigators first of all reviewed the results of previously published investigations and found out that there was only a few previous studies done in humans. with this class of drugs. Besides, the methods used in conducting most of those studies have been so faulted that the results cannot be trusted to be showing the true picture. The investigators looked at the various faults pointed out with respect to the their design and conduct and took care of them while designing the investigators own study. This was an attempt to provide more credible answers to the question of whether lisinopril, and possibly other drugs of similar mode of action, can be useful in rectifying the problem of infertility caused by low sperm count and , if so, whether it will be safe to use it in people who do not have high blood pressure or heart failure. In order to achieve this the investigators studied 33 patients with sperm of low cell concentration, low percentage of motile cells and high percentage of abnormal cells from no known cause. The patients were randomly allocated to receive either lisinopril 2. 5mg daily (17 patients) or daily placebo (16 patients)and their sperm characteristics were examined at intervals, starting from the beginning of the study until when it ended 282 weeks later. The patients were also monitored for adverse events throughout the period. The data form all the patients that took part in the random allocation of treatments at the beginning of the study were included in the analysis that followed, irrespective of whether they completed the study or not.

Clinical Details

Official title: A 5-year Prospective, Placebo-controlled, Crossover Evaluation of the Efficacy and Tolerability of Low-dose Lisinopril in Normotensives With Idiopathic Oligospermic Infertility

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome:

Changes From Baseline in the Seminal Fluid Characteristics Throughout the Study

Total Sperm Cell Count Per Milliliter of Seminal Fluid.

Proportion of Sperm Cells With Normal Motility (%)

Proportion of Sperm Cells With Abnormal Morphology (%)

Ejaculate Volume

Total Sperm Cell Count

Proportion of Sperm Cells With Normal Motility (%)

Proportion of Sperm Cells With Abnormal Morphology (%)

Secondary outcome: Adverse Events Monitoring

Detailed description: Introduction. Infertility constitutes the cause for about 16. 6% of patients seeking consultations at the primary healthcare level. Male factor infertility accounts for about 50% of all infertility problems. Of this percentage seminal fluid abnormality of unknown cause is common, occurring in up to 60% of males with unexplained, this type of infertility. Although some subjects with seminal fluid defects have fathered children those with infertility have long posed a major therapeutic challenge. The rationale for using the various hormonal and non-hormonal drugs currently available is, at best, empirical as most of the efficacy trials conducted yielded conflicting results. Although assisted fertilization techniques have now increased the number of therapeutic options available to couples with infertility problems there is still a very serious limitation in the access to the new technology, especially in low-income countries. Besides, there are additional concerns regarding the possible untoward effects. These lingering problems underscore the need for continuing to search for other effective treatment options that will not only be cheaper and more accessible but also less complicated and non-invasive. The current study was occasioned by our previous, independent observations (albeit fortuitous) of normalization of seminal fluid parameters as well as spouse pregnancies in two men with long-standing, idiopathic azoospermia. The common factor between the two men was treatment with low-dose (2. 5mg per day) Lisinopril, an angiotensin converting enzyme inhibitor or ACEI prescribed for the concomitant hypertension. A review of the available literature on the efficacy studies of various types of angiotensin converting enzyme inhibitors on sperm count and quality revealed a near-consistent finding of improvement in animal studies. However, methodological flaws have rendered the results in the very scanty human studies extremely difficult to interpret. The current study design was intentionally rigorous; efforts having been consciously made to control for most known confounding factors as far as was possible. Methods. The study was conducted at the University of Nigeria Teaching Hospital, Enugu. A prior approval of the detailed study protocol was obtained from the Ethics Committee of the same hospital. Each of the patients gave informed consent before enrollment into the study. The investigation was a longitudinal, randomized, double-blind and placebo-controlled clinical trial with a crossover design. The subjects for this investigation were selected from a volunteer pool of male patients attending the fertility clinic of University of Nigeria Teaching Hospital, Enugu. At the time of enrollment each subject was given explicit information about the study with respect to the intention, the expectations from him, the procedure, the planned duration of the investigation, and the potential adverse reactions that could occur from the intended medication. The recruitment of patients took place from March 1998 to September 2001 while the actual study lasted for five years, from January 2002 to December 2006. In strict compliance with the protocol requirement all the participants entered the study within 7 days of starting the onset and they were being followed up concurrently. Throughout the period of the clinical trial the patients mandated to continue their different "background" fertility medications in the same doses as they were being prescribed by their attending fertility physicians. The rationale for this was to avoid the unethical situation whereby a group taking placebo would be denied medication. Conceited efforts were made to exclude subjects with any background medication that had a documented interaction with lisinopril. The apparent superfluity of combining a crossover design (which provides for a within-subjects control) with a separate (between-subjects) control was deliberate. That was done in an effort to control, in one swoop, for two potentially confounding factors; viz., the possible effect on the study out-come of the concurrent background medications, and the possible event of a random, seasonal variation in human seminal fluid characteristics. Throughout the whole period of the study the investigators kept in close touch with the patients by phone calls in order to continually motivate them, remind them of scheduled appointment dates, monitor compliance and detect any possible incidence of adverse drug effect. Assessment of compliance to the medications: Compliance to the medications was monitored by a combination of oral interviews and physical inspection of medication containers for pill counting. These were done at every scheduled visit, through sporadic phone calls and by unscheduled home visits. The level of compliance of each patient was expressed in percent (%) and calculated as the actual number of doses taken/the expected number of doses multiplied by 100 for the period under consideration. Adverse events monitoring: The patients were encouraged to report every event promptly by phone to one of the authors (NOG), no matter however minor and not minding whether related to lisinopril or not. Entries were promptly made and then one of the physicians in the team was detailed to make proper assessment of every reported case and make recommendations with respect to further management and/or the need or otherwise for withdrawal of the patient from the trial. Medical interventions, where needed, were given without any cost to the patients. In addition, the serum potassium concentrations and blood pressures (supine and erect) were measured in every patient at each of the scheduled visits in furtherance of the adverse events monitoring. Clinical measurements: Blood pressure measurements were done with mercury sphygmomanometers fitted with adult-size cuffs (Accoson, England) while korotcoffs I and V were used for systolic and diastolic blood pressures respectively. This was because these had given more concordant results among the team members than the traditional I and IV Korotcoffs. The mean arterial blood pressure (MAP) of each patient was calculated using the conventional formula; MAP = [(2 x diastolic) + systolic] divided by 3. Laboratory measurements: Seminal fluid for analysis was each time collected by self-masturbation in a room close to the laboratory and submitted promptly to the analysts. The collected semen specimens were incubated at 37 degrees Centigrade and allowed to stand for 1 hour in order to thaw. The pipette method was used for the ejaculate volume while microscopic methods were used for the total sperm cell count, the percentage of sperm cell motility and the percentage of abnormal sperm cell morphology in accordance with the World Health Organization (WHO) guidelines. Serum potassium levels were estimated using the flame photo-metric method as described by Davidson and Henry. The latter was a safeguard against hyperkalemia, a well documented, severe side effect of ACEI therapy. Statistical analysis: The statistical analysis was done with the Statistical Package for the Social Sciences

version 16 (SPSS - 16) software. All the data analyses were performed on the basis of the

intention-to-treat in which last observations after the baseline were carried forward to end point. Prior to the analysis all the parameter data were examined for distributional patterns using the Shapiro-Wilk Normality test. All the seminal fluid data as well as the serum potassium values were found to be skewed and so were normalized with logarithmic transformations. Two-group comparisons were performed using the unpaired Student's t-tests while proportions were compared using the Fisher's Exact tests. The data from longitudinally measured out-come parameters were analyzed using two-way repeated measures (mixed model) analysis of variance (mixed model ANOVA). Bonferroni's post-hoc multiple comparison tests were run wherever a statistically significant difference was found (at p < 0. 05) in either the within-subjects means, the between-subjects means or the interaction. The post-hoc tests were done in order to explore further the patterns of within-subjects parameter changes with the duration of treatment in both groups. The unwanted events reported during treatment with lisinopril and during placebo treatment were compared for statistical significance with the Koch's adaptation of Wilcoxon-Mann-Whitney- rank-sum test.


Minimum age: 24 Years. Maximum age: 34 Years. Gender(s): Male.


The subjects for this investigation were selected from a volunteer pool of male patients attending the fertility clinic of University of Nigeria Teaching Hospital, Enugu. The criteria for their selection were: Inclusion criteria:

- regular attendance and on treatment for low sperm count or oligospermia in the

fertility clinic for at least 2 years

- total sperm count at selection from 5 million/ml to 10 million/ml,

- white blood cell (WBC) count less than 1 million per ml of the ejaculate

- evidence of undergone comprehensive investigations to exclude secondary causes of low

sperm count, (e) evidence of comprehensive investigations to exclude female factor infertility in the spouse

- an assurance of a personal commitment to continue participating in the study until

the end-point was reached and (g) normal blood pressure. Exclusion criteria:

- Patients who did not give their consent to participate

- did not meet the diagnostic criteria for oligospermia at the time of recruitment

- failed to fulfill any of the above inclusion criteria, even if the diagnostic

criteria are fulfilled.

Locations and Contacts

University of Nigeria Teaching Hospital, Ituku-Ozalla,, Enugu 01129, Nigeria
Additional Information

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