Contraceptive Efficacy Studies Research Articles

An integrated assessment of patient compliance with a weekly contraceptive patch (ORTHO EVRA™/EVRA™).

Objective: To assess patient compliance with a transdermal contraceptive and to compare rates of perfect compliance with a standard oral contraceptive. Design: Two multicenter open-label contraceptive efficacy studies conducted primarily in North America (Studies 002/004) were included in this compliance analysis. Healthy women 18-45 years of age were to be exposed for 6 or 13 cycles to the transdermal contraceptive (n = 1672) in Study 002 or randomized to the transdermal contraceptive (n = 812) or Triphasil® (n = 605) in Study 004. In both studies the transdermal contraceptive regimen was 3 consecutive 7-day patches (21 days) followed by 1 patch-free week per cycle. Thus patches were removed and replaced on the same day of the week. Triphasil® was administered according to the US physician package insert. Materials/Methods: Perfect compliance was defined as 21 consecutive days of drug-taking followed by a 7-day drug-free period; also for transdermal contraceptive users no patch could be worn for more than 7 days. Perfect compliance rates both overall and by age group (18-19 20-24 25-29 30-34 35-39 and >/= 40 years) were summarized. Transdermal contraceptive data from both studies were pooled for analysis; data from Study 004 were presented by treatment group. In Study 004 for purposes of statistical analyses a t test was used to compare the 2 treatment groups with regard to the overall proportion of each subjects’ cycles in which there was perfect compliance (the subject was the experimental unit). Results: In the pooled analysis the percentage of cycles with perfect compliance was 89.7% with the transdermal contraceptive; compliance rates were consistent across age. In Study 004 the percentage of cycles with perfect compliance was 88.7% with the transdermal contraceptive and 79.2% with Triphasil® (p < 0.001). Perfect compliance rates were similar across all age groups with the transdermal contraceptive but were reduced in younger subjects in the Triphasil® group. Conclusions: Compliance with the new ORTHO EVRA™ weekly dosing regimen is superior to compliance with Triphasil®. Compliance with ORTHO EVRA™ is unaffected by age whereas compliance with Triphasil® is lower in younger compared with older subjects. (authors)

Contraceptive efficacy and safety studies of a novel microemulsion-based lipophilic vaginal spermicide

Objective: To investigate the in vivo contraceptive potency and safety of a novel microemulsion-based lipophilic vaginal spermicide. Design: In vitro and in vivo spermicidal activity and safety of a submicron-particle-size, lipophilic gel–microemulsion (GM-4). Setting: Center for Advanced Preclinical Sciences at the Parker Hughes Institute. Patient(s): Nine male volunteer sperm donors. Intervention(s): Motile human sperm in semen and medium were exposed to eight GM-4 components or GM-4 formulation. Forty-eight ovulated NZW rabbits in subgroups of 16 with or without intravaginal administration of GM-4 or nonoxynol-9 gel (N-9; Gynol II) were artificially inseminated and allowed to complete pregnancy. Eleven rabbits were exposed to daily intravaginal application of GM-4 with and without N-9 for 10 consecutive days. Ten of 20 B 6C 3F 1 mice were given repetitive intravaginal application of GM-4 for 5 days/week over 13 consecutive weeks. Main Outcome Measure(s): The motility of human sperm treated with GM-4 components and GM-4. Term pregnancy in rabbits and histopathological grading of rabbit vaginal tissue for irritation. Evaluation of mice for survival, growth, hematologic parameters, blood-chemistry profiles, absolute and relative organ weights, and histopathology. Result(s): The individual components of GM-4 lacked spermicidal activity in human semen, whereas the GM-4 formulation containing all the eight pharmacological excipients exhibited potent spermicidal activity with rapid kinetics. GM-4 showed remarkable contraceptive activity in the rigorous rabbit model. None of the 16 (0%) rabbits given GM-4 intravaginally before artificial insemination became pregnant. By contrast, 15 of 16 (93.7%) control rabbits and 5 of 16 (31.2%) Gynol II-treated rabbits became pregnant and delivered newborns. Thus, GM-4 was a significantly more effective contraceptive than a commercially available N-9 gel [100% vs. 68.7% protection; P< 0.05, Fisher’s exact test]. Unlike the rabbits treated with N-9, none of the rabbits that were given GM-4 intravaginally for 10 consecutive days developed epithelial ulceration, edema, leukocyte influx, or vascular congestion characteristic of inflammation. Furthermore, repeated intravaginal application of GM-4 for up to 13 weeks in mice had no adverse effects on survival, growth, metabolism, or organ function. Conclusion: We conclude that the novel spermicidal GM-4 formulation is safe and significantly more effective than N-9 in preventing conception.

Efficacy and acceptability of testosterone implants, alone or in combination with a 5α-reductase inhibitor, for male hormonal contraception

Testosterone (T) treatment suppresses serum gonadotropins and reduces sperm output sufficiently for contraceptive efficacy in ∼70% of Caucasian men. In the remaining 30% of men, an increase in 5α-reductase activity may maintain testicular androgen activity, thus accounting for the failure of sperm suppression. The form of T therapy is a major consideration in the safety and acceptability of T-based contraception. As compared to T ester injections, T implants provide a more physiological serum T profile and fewer side effects, but have not yet been used in contraceptive efficacy studies. We have used T implants (800–1200 mg every 3 months) in 29 normal men for 3–16 months. T implants produced long-term suppression of sperm densities below 1 million/mL in ∼70% of men without significant androgenic side effects. No pregnancies occurred in 214 months of exposure. In 16 men failing to suppress within 3 months of T 800 mg, no evidence of enhanced spermatogenic suppression was seen with the co-administration of the type 2 5α-reductase inhibitor, finasteride, for 3 months when compared to placebo. We conclude that: 1) T implants provide adequate spermatogenic suppression in ∼70% of Caucasian men, a rate comparable to intramuscular T injections but with minimal side effects; and, 2) the inclusion of a type 2 5α-reductase inhibitor does not enhance spermatogenic suppression.

Oligozoospermia Induced by Exogenous Testosterone is Associated With Normal Functioning Residual Spermatozoa

Objective: To determine the functional capacity of residual spermatozoa in semen samples from normal men with T enanthate-induced oligozoospermia. Design: Prospective clinical study. Setting: Academic research center. Patient(s): Twelve healthy men were studied while participating in a multicenter T enanthate contraceptive efficacy study. Data were analyzed from only eight subjects, whose sperm concentrations were between 1.3 and 10 × 10 6 /mL at the suppression phase. Intervention(s): Testosterone enanthate (200 mg) was administered IM weekly during the suppression and treatment (efficacy) phases (total 15 months). Main Outcome Measure(s): Sperm function tests (stimulated acrosome reaction, sperm hyperactivation [HA], and zona-free hamster oocyte penetration tests) were performed during the pretreatment, suppression (usually after 6 to 10 weeks of treatment, when sperm concentration was anticipated to decrease to 6 /mL), and recovery phases. Studies were not done during the contraceptive efficacy phase because only one of the subjects was not azoospermic. Result(s): Mean sperm concentration was reduced but sperm motility, motility characteristics, and morphology were not affected by T enanthate treatment. The residual spermatozoa in the ejaculate could acrosome react, exhibited normal HA, and maintained the capacity to penetrate and fuse with the oocyte. Conclusion(s): Suppression of spermatogenesis to moderate oligozoospermia ( 6 /mL) with exogenous T enanthate administration was not associated with impaired sperm function of the residual spermatozoa. The study did not exclude the possibility that disorders of sperm function might occur when spermatogenesis is suppressed further to very severe oligozoospermia ( 6 /mL), commonly observed in hormonal male contraceptive clinical trials.

Sperm output of healthy men in Australia: magnitude of bias due to self- selected volunteers

Controversial claims, based on a meta-analysis aggregating 61 heterogeneous observational studies, have been made that human sperm output has decreased by 50% over the last six decades and that this trend may be due to global pollution. If true, such effects should be evident in all areas of the globe; however, longitudinal studies within single centres in Europe and America have produced conflicting results and there are no reports from the southern hemisphere. We therefore reviewed semen analyses obtained from 1980-1995 from 689 healthy men volunteering for screening either as potential sperm donors for a donor insemination programme (n = 509) or to participate in five male contraception research studies (studies no. 1-5, n = 180). All were recruited through the Andrology Unit of the Royal Prince Alfred Hospital, Sydney, by the same doctors using standard methods of recruiting, screening and laboratory examination throughout the period 1980-1995. Recruitment was by advertising without regard to marital or fertility status except in two contraceptive efficacy studies (no. 1 and no. 3) where participants had to be in a stable relationship requiring contraception. Analysing the first semen sample individually or when grouped by year of ejaculation, there was no significant difference in sperm concentration over time or between years or according to year of birth. During the second half of this period, 180 consecutive volunteers were recruited by the same doctors and staff for five male contraception studies. The median sperm concentration for studies no. 1 (103 x 10(6) ml) and no. 2 (142 x 10(6) ml) were significantly (P < 0.05) higher than for studies no. 3-5 (84, 67 and 63 x 10(6) ml, respectively) and for potential sperm donors (median 69 x 10(6) ml). The inconsistency of these estimates illustrates the magnitude of bias (up to 100%) in sperm output that may occur in recruiting groups of self-referred volunteers within a single centre. This highlights the invalidity of extrapolating similar findings on sperm output of self-selected volunteers to the general male community or in using such study groups to characterize sperm output in supposedly 'normal' men.

Oligozoospermia induced by exogenous testosterone is associated with normal functioning residual spermatozoa

To determine the functional capacity of residual spermatozoa in semen samples from normal men with T enanthate-induced oligozoospermia. Prospective clinical study. Academic research center. Twelve healthy men were studied while participating in a multicenter T enanthate contraceptive efficacy study. Data were analyzed from only eight subjects, whose sperm concentrations were between 1.3 and 10 x 10(6)/mL at the suppression phase. Testosterone enanthate (200 mg) was administered IM weekly during the suppression and treatment (efficacy) phases (total 15 months). Sperm function tests (stimulated acrosome reaction, sperm hyperactivation [HA], and zona-free hamster oocyte penetration tests) were performed during the pretreatment, suppression (usually after 6 to 10 weeks of treatment, when sperm concentration was anticipated to decrease to < 10 x 10(6)/mL), and recovery phases. Studies were not done during the contraceptive efficacy phase because only one of the subjects was not azoospermic. Mean sperm concentration was reduced but sperm motility, motility characteristics, and morphology were not affected by T enanthate treatment. The residual spermatozoa in the ejaculate could acrosome react, exhibited normal HA, and maintained the capacity to penetrate and fuse with the oocyte. Suppression of spermatogenesis to moderate oligozoospermia (< 10 x 10(6)/mL) with exogenous T enanthate administration was not associated with impaired sperm function of the residual spermatozoa. The study did not exclude the possibility that disorders of sperm function might occur when spermatogenesis is suppressed further to very severe oligozoospermia (< 1 x 10(6)/mL), commonly observed in hormonal male contraceptive clinical trials.

Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men

To determine contraceptive efficacy of hormonally induced sperm suppression to severe oligozoospermia or azoospermia. Prospective, noncomparative contraceptive efficacy study. Multicenter study in 15 centers in nine countries. Three hundred ninety-nine normal, healthy, fertile men requesting a male contraceptive method. Weekly IM injection of 200 mg T enanthate. Incidence of pregnancies in efficacy when couples relied on T injections alone for contraception. Four pregnancies occurred during 49.5 person-years involving men with oligozoospermia (0.1 to 3 x 10(6)/mL) and none during 230.4 person-years in azoospermic men: pregnancy rates 8.1 (95 percent confidence interval [CI] 2.2 to 20.7) and 0.0 (95 percent CI, 0.0 to 1.6) per 100 person-years, respectively, or 1.4 (95 percent CI, 0.4 to 3.7) per 100 person-years for oligozoospermia and azoospermia (O to 3 x 10(6)/mL) combined. Pregnancy rates were related to sperm concentration. Inadequate suppression of spermatogenesis occurred in eight men and escape from suppression occurred in four. Discontinuations were due to personal reasons (50 men, cumulative annual life-table rate 12.2 percent [95 percent CI, 9.1 percent to 16.1 percent]) and dislike of the injection schedule (21 men, 5.1 percent [95 percent CI, 3.2 percent to 7.9 percent]). Thirty-five men discontinued for medical reasons (9.4 percent [95 percent CI, 6.7 percent to 13.2 percent]), with no serious treatment-related side effects. After stopping injections, sperm output recovered; additionally, fertility was demonstrated in 33 couples. Suppression of spermatogenesis to azoospermia or severe oligozoospermia (< or = 3 x 10(6)/mL) induced by weekly T enanthate injections results in sustained, reversible contraception with good efficacy and minimal short-term side effects. New hormonal regimens with more convenient delivery and improved spermatogenic suppression would provide practical male contraception.

Effects of testosterone enanthate in normal men: experience from a multicenter contraceptive efficacy study

To evaluate the secondary impact of a prototype androgen contraceptive regimen on physical, metabolic and behavioral variables. Prospective, open, noncomparative contraceptive efficacy study. International multicenter study comprising 10 centers in seven countries. Two hundred seventy-one healthy men, age 31.8 +/- 5.4 years (mean +/- SD), range 21 to 45 years. Weekly IM injections of 200 mg T enanthate. Adverse effects and discontinuations; biochemical and hematologic changes and interpopulation differences. Chinese subjects were shorter and lighter and their baseline hemoglobin, plasma lipid, and liver enzyme levels were lower than in non-Chinese subjects. The most common side effects were painful injections, acne, fatigue, and weight gain. Gynecomastia and prostate problems were detected in 24 and 9 men, respectively, though no men stopped injections for such reasons. Testosterone enanthate increased body weight, hemoglobin, and urea but decreased testicular volume and creatinine. Plasma triglyceride, cholesterol, and low-density lipoprotein cholesterol were unchanged; high-density lipoprotein cholesterol decreased by 14% to 18% in non-Chinese but was unchanged in Chinese men. Liver transaminases were increased by 36% to 51% in Chinese but were unchanged in non-Chinese subjects. These T enanthate-induced effects were reversible within 6 months of stopping injections and were not related to the duration of T exposure. Testosterone enanthate administration in a contraceptive trial produced significant but reversible effects on skin, muscle, liver, lipid metabolism, and hemopoietic functions that varied between population groups. These effects reflect the relatively high peak levels and fluctuations of plasma T produced by the weekly T enanthate regimen rather than an inherent feature of hormonal male contraception. The results highlight the need for long-acting preparations of T with more stable delivery kinetics.

Hormonal male contraception: progress and prospects for the 21st century.

During the second half of the 20th century, progress in developing novel, practical contraceptive methods for men has lagged significantly behind developments for women. Despite the lack of reliable, reversible methods, men throughout the world continue to be strongly involved in family planning but a greater involvement will require more attractive and reliable contraceptive options for men. The closest to fruition are hormonal methods the features of which are reviewed. Landmark WHO contraceptive efficacy studies have established that hormonally-induced azoospermia provides highly effective and reversible contraception for at least 12 months with minimal short-term side effects. Even among the small subgroup of men who remain oligozoospermic during hormonal suppression, good contraceptive efficacy is achieved. The present goals are to develop improved second generation hormonal regimens which provide more uniform azoospermia to obviate the need for monitoring of sperm output and to develop long-acting depot testosterone formulations used alone or with additional gonadotrophin suppressive agents such as progestins or GnRH antagonists. Significant obstacles to progress are the flight of industry from contraceptive R&D dur to the financial deterrent posed by the product liability crisis as well as the low priority accorded male reproductive health. Together those will determine whether the range of contraceptive options available to our children in the 21st century will improve, or whether the historically recent unbalanced increase in reliance on women for family planning will continue.