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

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: