The Effect and Safety of Lisinopril in Non-hypertensive Men With Infertility From Low Sperm Count
Condition: Oligospermia
MeSH terms: Infertility; Oligospermia
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

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.
    

Intervention name(s): Lisinopril
Intervention type(s): Drug
Intervention description(s): The two groups of patients, A and B, were randomly allocated treatments in a double-blind fashion. Group A was started on the coded drug "DY1" while group B was started on the coded drug "DZ2". Both "DY1" and "DZ2" were very identical in appearance. At week 96 the drugs were swopped between the groups such that group A changed to drug "DZ2" while group B changed to drug "DY1". There was no intervening washout period. The codes were concealed until after the data analysis.
Other intervention name(s): (Zestril®, AstraZeneca Pharmaceuticals,Washington NC, USA)
Intervention MeSH terms: Lisinopril
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Oligospermia; Male infertility; Lisinopril